key: cord- -gcdn yc authors: nevez, gilles; guillaud-saumur, thibaud; cros, pierrick; papon, nicolas; vallet, sophie; quinio, dorothée; minoui-tran, adissa; pilorgé, léa; de parscau, loïc; sizun, jacques; ochoa, theresa j; bustamante, beatriz; ponce, carolina; vargas, sergio l; le gal, solène title: pneumocystis primary infection in infancy: additional french data and review of the literature date: - - journal: med mycol doi: . /mmy/myz sha: doc_id: cord_uid: gcdn yc data on features of pneumocystis primary infection in infancy are still fragmented. to study pneumocystis primary infection, infants who were monitored for acute pulmonary disease or fever over a -month period were retrospectively investigated. p. jirovecii detection on archival nasopharyngeal aspirates was performed using a qpcr assay. factors associated with p. jirovecii were assessed using univariate and multivariate analyses. p. jirovecii genotypes in infants and a control group of adults contemporaneously diagnosed with pneumocystis pneumonia were identified using unilocus, bilocus, and multilocus sequence typing (mlst). p. jirovecii was detected in infants ( . %). the univariate analysis pointed out four factors: viral infection (p = . , or [ic ], . [ . – . ]), lower respiratory tract infection (p = . , or [ic ], . [ . – . ]), absence of hospital discharge after birth (p = . , or (ic ), . ( . – . ]), and the – -day group (p < . , or [ic ], . [ . – ]). the multivariate analysis confirmed these two latter factors (p = . , or [ic ], . [ . – . ]; p = . , or [ic ], . [ . – . ]). thus, p. jirovecii acquisition mostly takes place in the community. a comparison of these data with those of previously published studies showed that median and interquartile range of positive-infant ages were close to those observed in chile, denmark, and peru, highlighting similar characteristics. common unilocus or bilocus genotypes were identified in infants and adults, whereas no mlst genotypes were shared. therefore, a common reservoir made up of infected infants and adults is still hypothetical. finally, primary infection is a worldwide phenomenon occurring at the same time in childhood regardless of geographical location, rather than an incidental event. pneumocystis pneumonia (pcp) contemporary to pneumocystis primary infection has been well recognized as an important cause of morbidity and mortality in premature infants or weakened children since at least the s. since the s, pcp has also occurred in immunosuppressed infants and children mostly with human immunodeficiency virus (hiv) infection and specifically in developing countries. in contrast, seroepidemiological surveys conducted in the s have suggested that first contacts with the fungus occurred in % of nonimmunosuppressed infants before two years of age. , until the beginning of the s, there were no microbiological data or clinical profiles related to primary infection in nonimmunosuppressed infants which was thought to be essentially asymptomatic. [ ] [ ] [ ] in fact, studies by vargas and colleagues and nevez and colleagues showed that primary infection in nonimmunosuppressed infants can be symptomatic, associated or not with viral or bacterial infections. , later, larsen and colleagues reported that primary infection occurred contemporary to a self-limiting upper respiratory tract infection (urti) in infants. available data on p. jirovecii genomic characteristics in infants developing primary infection are limited, whereas p. jirovecii genotypes have mostly been identified in pcp adult patients. totet and colleagues have shown that genotypes of p. jirovecii organisms involved in primary infection in non-immunosuppressed infants and in pcp adults were similar, suggesting that both populations were part of a common reservoir. , conversely, beard and colleagues suggested that circulation and transmission of the fungus in the two populations occurred independently. nonetheless, due to method discrepancies these results are still subject of debate. be that as it may, clinical profiles, microbiological and p. jirovecii genomic characteristics related to primary infection are still poorly understood. in this context, the objectives of the present study were i) to detect p. jirovecii in a cohort of infants at risk for primary infection, ii) to correlate its presence with infants' characteristics, iii) to identify p. jirovecii genotypes through unilocus, bilocus and multilocus sequence typing (mlst) approach in this infant population, and to compare them to those found in pcp adults; both populations being monitored in the same geographical area. one hundred and ninety-two nonimmunosuppressed infants (sex ratio m/f / , median age days [limits, - days]) were retrospectively enrolled. the infants were initially admitted to the brest university hospital, france, between april , and july , . they were submitted to nasopharyngeal aspi-rates (npas) ( infants, npas) for viral diagnosis within the framework of investigation of pulmonary symptoms or fever. nucleic acids from the npas were extracted using nuclisens r easymag r (bio-mérieux) and stored at − • c for further examination or control. p. jirovecii detection was retrospectively performed in npas using a real-time quantitative polymerase chain reaction (qpcr) assay targeting mitochondrial large subunit ribosomal rna (mtlsurrna) as described elsewhere on real time pcr system (applied biosystems, foster city, ca, usa). , primary infection was defined as detection of p. jirovecii in a npa sample from an infant, an infant who was a priori immunenaive to p. jirovecii. twenty-one adults with pcp (sex ratio m/f / , median age years [limits, - years]) were retrospectively enrolled. they were also monitored at brest university hospital and were submitted to bronchoalveolar lavage (bal) procedure for pcp diagnosis. twenty-one bal specimens were examined contemporaneously with infant npa examination between january , , and october , . p. jirovecii was detected using microscopic examination (indirect immunofluorescence assay, bio-rad, marnes-la-coquette, france) and the aforementioned qpcr assay as described elsewhere. , this population represented a control population for pneumocystis genotyping. to avoid contamination, each step of the pcr assays was performed in different areas of the laboratory with different sets of micropipettes. mix reagents were prepared in a laminar flow cabinet. to monitor for possible contamination, negative controls were included in each experiment and pcr round. extracted dnas of positive npas from infants and bal samples from adults were examined for pneumocystis genotyping based on unilocus, bilocus, and multilocus sequence typing (mlst) methods. three loci, mtlsurrna, cytochrome b (cyb) and superoxide dismutase (sod) genes were analyzed, as we previously described. first, a single-round pcr was performed for each locus, as described elsewhere. [ ] [ ] [ ] [ ] a nested pcr was performed for sod locus, as previously described on samples that failed to give amplification with a single-round pcr. the discriminatory power was determined using hunter index (h). , discriminatory power was considered good when h > . . prevention of cross contamination during pcr and sequencing assays of genotyping was done as described above. moreover, these assays were performed in a different laboratory than the one where p. jirovecii infection diagnosis was initially performed, the two laboratories being located at different hospital sites. ( ). c p. jirovecii was detected in only out of infants who had been hospitalized since birth whereas it was mostly detected in infants who were discharged after birth ( out of the infants); indeed, some newborns and infants were hospitalized after birth and discharge of their mothers; d infants who presented fever in absence of overt respiratory symptoms, e p. jirovecii was detected in a context of co-infections with viruses and/or bacteria in infants whereas it was detected alone in infant and adult sociodemographic and clinical data were collected using brest university hospital online software "portail d'informatisation du processus de soin" (ips). statistical analyses were performed using prism software (version . , graphpad software, san diego, ca, usa) and xl-stat software (version . . , addinsoft, brooklyn, ny, usa). qualitative variables were compared using fisher exact test or χ test when appropriate. quantitative variables were compared using mann-whitney test. a two-sided p-value <. was considered significant. logistic regression was used for univariate and multivariate analyses. the study was noninterventional, which did not require inform consents and ethical approval according to french laws and regulations (csp art l e . ). p. jirovecii was detected in out of infants, . % ( out of npas, . %). results of p. jirovecii detection and infants' characteristics are shown in table . the first approach of qualitative data analysis using χ or fisher exact test pointed out the following characteristics: infant age (p < . ), underlying diseases (p = . ), hospital discharge or not after birth (p < . ). indeed, some newborns and infants were hospitalized after birth and discharge of their mothers. univariate and multivariate analyses through a logistic regression are shown in table . the univariate analysis pointed out the following factors positively associated with p. jirovecii detection: distribution of age groups, specifically the - -day group (third quartile) ( tables and . taking the results of p. jirovecii typing in infants and adults together, the hunter indexes of the unilocus approach based on each mtlsu, cyb, and sod genes were ≤ . each. the hunter index of the bilocus genotyping method and of mlst was . and . , respectively. in the infant population, considering the mtlsu, cyb, and sod alleles previously described elsewhere, three mtlsu alleles were identified; mtlsu being the most frequent ( infants). , , five cyb alleles were identified; cyb being the most frequent ( infants). two sod alleles were identified, sod being the most frequent allele (seven infants). the bilocus typing system, based on analysis of mtlsu locus combined with cyb locus, enabled us to identify seven mtlsu-cyb genotypes in infants; mtllsu -cyb being the most frequent (three infants). using the mlst, seven genotypes were identified in six infants. in the adult population, four mtlsu alleles were identified; mtlsu being the most frequent (seven adults). in addition, six cyb alleles were identified; cyb being the most frequent ( adults). three sod alleles were identified; sod being the most frequent ( adults). the bilocus typing locus permitted to iden-tify mtlsu-cyb genotypes, mtlsu -cyb , and mtlsu -cyb being the most frequent (three adults respectively). twelve mlst genotypes were also identified. three of them were found in two adults each, the nine others were found in one adult each. among the four mtlsu alleles, mtlsu was identified only in the adults, whereas the three others were both identified in infants and adults. among the seven cyb alleles, cyb was identified only in the infants, whereas cyb and cyb were identified only in the adults. the two major cyb alleles, cyb and cyb , were shared by the two populations. among the three sod alleles, sod was only identified in adults, whereas the two others, sod and sod , were shared by the two populations. five bilocus genotypes were common in both populations, whereas two other genotypes were found only in infants and nine other genotypes were exclusively found in adults. a total of mlst genotypes were identified, but none were shared by the two patient populations. we detected p. jirovecii in out of infants ( . %), while in our former study it was detected in out of infants ( . %). these results, obtained years apart in two similar infant populations from two french regions km apart, do not differ significantly (p = . , χ ). p. jirovecii presence and its detection in an infant by definition a child less than years old, was considered to be related to first contacts with the fungus and consequently to be contemporary with primary infection. this definition of primary infection could be discussed because putative p. jirovecii reinfection could not be strictly ruled out in some cases. it is noteworthy that p. jirovecii was mainly detected in young infants and in only four infants over year old. thus, the concept of reinfection with p. jirovecii remains the alleles were identified considering changes at nucleotide positions described elsewhere by beard et al. , esteves et al. , and maitte et al. . cyb, cytochrome b gene; mtlsu, mitochondrial large subunit ribosomal rna gene; sod, superoxide dismutase gene. a the infants underwent nasopharyngeal aspirates two times, only one sample was considered for statistical analysis. b ". . . ", typing failure. c allele mix, presence of several different alleles that were not identified. speculative. the infants enrolled in the study may have presented with pulmonary colonization or pcp. nonetheless, the hypothesis of pcp development was improbable since they recovered without specific treatment. infection due to viruses as an associated factor to the presence of p. jirovecii was expected since infants enrolled in the present study mostly presented with bronchiolitis, a pulmonary syndrome specifically related to viruses. moreover, we have previously described and reported this microbial association. in the present study, p. jirovecii was detected in the apparent absence of other pathogens in infants, suggesting that the fungus may play a role in pulmonary syndrome pathogenesis. nonetheless, all positive infants recovered, despite the absence of specific treatment for the fungus. we can hypothesize that the presence of p. jirovecii followed by clinical improvement could be explained by the "immune-naive" status of infants on the one hand, and the role of symptomatic treatment and physiotherapy in the absence of overt immunosuppression on the other hand. contrary to larsen and colleagues' study in which p. jirovecii detection was specifically associated with urti, in our study lower respiratory tract infections (lrti) appear as an associated factor. this result is consistent with the fact that p. jirovecii infection effectively takes place deep within the lungs and specifically in alveoli in close contact with type i pneumocytes. pneumocystis primary infection contemporary to first contacts with the fungus may present as a mild lrti. the alleles were identified considering changes at nucleotide positions described elsewhere by beard et al. , esteves et al. , and maitte et al. . multilocus genotypes are named following the pattern [x-y] (two-loci genotypes) or [x-y-z] (three-loci genotypes) where x = mtlsu allele number, y = cyb allele number and z = sod allele number. cyb, cytochrome b gene; mlst, multilocus sequence typing; mtlsu, mitochondrial large subunit ribosomal rna gene; n/a, not applicable; sod, superoxide dismutase gene. not typed: typing failure due to amplification and/or sequencing and/or sequence analysis issues. undetermined mix: detection of several undetermined alleles or multilocus genotypes in the same sample. a allele mix, presence of several different alleles that were not identified. we did not identify prematurity as a factor associated with p. jirovecii. nonetheless, p. jirovecii was detected in out of preterm infants ( . %), whereas rojas et al. in seville, spain, have recently detected the fungus in of preterm infants ( . %). these discrepant results, . % versus . % (p = . ), are probably due to the difference in sampling methods and difference in hospital locations, brest, brittany, france versus seville, andalusia, spain, geographical differences in p. jirovecii epidemiology in europe having previously been reported in patients with chronic pulmonary diseases. , be that as it may, our results combined with those of rojas and colleagues obtained from french and spanish populations, respectively, show that p. jirovecii is still involved in non-immunosuppressed preterm infants in europe, as it was described in the s. , these important findings have already been published separately as a correspondence and should arouse the interest of pediatricians. congenital diseases appear as an associated factor (table ) . to the best of our knowledge none of them are associated with overt immunosuppression. nonetheless, this association pro-vides additional arguments to the well-recognized links between p. jirovecii and infant frailty. hyaline membrane disease or bronchopulmonary dysplasia is a factor negatively associated with p. jirovecii detection. this negative association remains unclear, but it may be explained by the fact that we did not identify prematurity as an associated factor, whereas it is assumed that there is a relationship between prematurity and hyaline membrane disease or bronchopulmonary dysplasia. the univariate analysis pointed out the absence of hospital discharge after birth as a factor negatively associated with p. jirovecii detection. this result was confirmed by multivariate analysis. thus, p. jirovecii is mostly acquired in the community by infants who have left the hospital after birth. in contrast, p. jirovecii was only found in two out of the infants who had not left the hospital after birth. these results were expected since the infants who stayed at the hospital after birth were younger than those who were discharged (median age, days; interquartile range [iqr], . - vs. median age, days; iqr, - ). nonetheless, p. jirovecii acquisition can happen within the hospital premises, the potential human sources such as health care workers, patients or mothers remaining undetermined in this case. to sum up, our results support the possibility of both community and nosocomial acquisitions of the fungus also in the context of primary infection in infants as previously shown for pcp in immunosuppressed adults. , the multivariate analysis also identified the - -day group as a factor associated with p. jirovecii detection. the median age of positive infants was months and days (iqr, - days), whereas it was months (iqr, . - . months), months (iqr, - days), months ( - months) in chile, denmark, and peru, respectively (ochoa tj, bustamante b, garcia c al., manuscript in preparation). , in our study reported years ago, the median age of positive infants was months (iqr, - months) ( figure ). , comparing the results of the aforementioned studies must be done cautiously, nonetheless the values of median and iqr ages of positive infants are close. these common characteristics suggest that first contacts with p. jirovecii, and consequently primary infection in infants, is a common process occurring at the same time in life, regardless the geographical location, rather than an incidental event. the analysis of p. jirovecii detection results in infants in chile, denmark, peru, and france, pointed out significant differences of prevalence (p < . ) with a higher prevalence in south america than in europe (figure ) (ochoa tj, bustamante b, garcia c al., manuscript in preparation). , beyond differences in methods, these results may be related to the genuine geographical specificity of pneumocystis epidemiology. this hypothesis was previously assumed to explain the difference of pneumocystis colonization prevalence in patients with chronic pulmonary diseases. , considering maitte and colleagues' proposal for p. jirovecii genotyping and our skill in this area, we chose to analyze the mtlsu, cyb and sod loci. , the discriminatory power of the typing system increased from the unilocus approach through the bilocus approach to the mlst method. these results were expected, considering recommendations of mlst for microorganism typing methods published elsewhere. the apparent diversity of p. jirovecii grew according to the increase in discriminatory power of the typing method used. consequently, the unilocus and bilocus approaches showed that genotypes were common in infants and adults, whereas no mlst genotype was shared. these apparently contradictory results due to technological constraints make it impossible to conclude whether the acquisition/transmission cycle of p. jirovecii in primary infected infants and pcp adults are independent or not. our results of mlst suggested a putative correlation between specific genotypes and clinical presentation, that is, primary infection in infants versus pcp in adults. the hypothesis can be ruled out, since only one mlst genotype (mtlsu -cyb -sod ) identified in our infant population was also identified by maitte and colleagues among adults developing pcp and monitored in another french university hospital centre. it is noteworthy that the genotypes in the two positive infants who had not left the hospital after birth (e , e ) were different than those in infants who were discharged after foot notes. the analysis pointed out significant differences of prevalence (p < . , κ test) with a higher prevalence in south america than in europe. birth (table ). this observation is consistent with a different source of p. jirovecii in this two-infant population. however, genotyping results should not be too conclusive considering the low numbers of patients for whom mlst was successful ( pcp adults and six infants) (tables and ). the study presents some limitations such as the retrospective approach, the enrolment of only symptomatic infants, the examination of npas from infants and bal specimens in adults. nonetheless, our investigation of a infant population in brittany, france, combined with the results of a meta-analysis of available data from another french region, and from chile, denmark, and peru, shows that, despite putative geographical specificities, pneumocystis primary infection in nonimmunosuppressed infants appears to be a common event occurring worldwide. pneumocystis carinii-etiologic agent of interstitial plasma cell pneumonia of premature and young infants pneumocystis pneumonia, th edn parasitologic and serologic observations of infection with pneumocystis in humans pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children seroepidemiological study of pneumocystis jirovecii infection in healthy infants in chile using recombinant fragments of the p. jirovecii major surface glycoprotein pneumocystis carinii detection using nested-pcr in nasopharyngeal aspirates of immunocompetent infants with bronchiolitis search for primary infection by pneumocystis carinii in a cohort of normal, healthy infants primary pneumocystis infection in infants hospitalized with acute respiratory tract infection pneumocystis jirovecii multilocus gene sequencing: findings and implications genotypes at the internal transcribed spacers of the nuclear rrna operon of pneumocystis jiroveci in nonimmunosuppressed infants without severe pneumonia pneumocystis jiroveci genotypes and primary infection genetic differences in pneumocystis isolates recovered from immunocompetent infants and from adults with aids: epidemiological implications real time quantitative pcr assay for pneumocystis jirovecii detection a misleading false-negative result of pneumocystis real-time pcr assay due to a rare punctual mutation: a french multicenter study outbreak of pneumocystis jirovecii infection among heart transplant recipients: molecular investigation and management of an interhuman transmission population structure of pneumocystis jirovecii isolated from immunodeficiency virus-positive patients multilocus sequence typing of pneumocystis jirovecii from clinical samples: how many and which loci should be used? an improved single-round pcr leads to rapid and highly sensitive detection of pneumocystis spp genetic diversity of pneumocystis jirovecii in colonized cuban infants and toddlers reproducibility and indices of discriminatory power of microbial typing methods consensus guidelines for appropriate use and evaluation of microbial epidemiologic typing systems genetic variation in pneumocystis carinii isolates from different geographic regions: implications for transmission early acquisition of pneumocystis jirovecii colonization and potential association with respiratory distress syndrome in preterm newborn infants colonization by pneumocystis jirovecii and its role in disease pneumocystis jirovecii and cystic fibrosis in brittany pneumocystis is still involved in nonimmunosuppressed preterm infants in europe current concepts on respiratory distress syndrome in the newborn (hyaline membrane disease) nosocomial pneumocystis jirovecii infections systematic review of outbreaks of pneumocystis jirovecii pneumonia: evidence that p. jirovecii is a transmissible organism and the implications for healthcare infection control molecular biology and epidemiology of pneumocystis jirovecii in infants the authors would like to thank v abiven, p bargain, c cam, e guillotel, c le guen, k quinaou, c roger, and d roué for their contribution and doctor hans henrik larsen for providing additional data on pneumocystis primary infection in denmark.the results were reported in part at asm microbe meeting, new orleans, la, usa, june - , . this study was supported by the european commission (eranet-lac) within the framework of the project "recognition of the primary infection by pneumocystis in infants: a silent threat to public health" (capri-pc hid- ). the authors report no conflicts of interest. the authors alone are responsible for the content and the writing of the paper. key: cord- -no pmw authors: pineda, roberta; prince, danielle; reynolds, jenny; grabill, molly; smith, joan title: preterm infant feeding performance at term equivalent age differs from that of full-term infants date: - - journal: j perinatol doi: . /s - - - sha: doc_id: cord_uid: no pmw objective: to identify differences in feeding skill performance among preterm infants at term equivalent age compared with full-term infants. study design: ninety-two infants ( preterm infants born ≤ weeks gestation at term equivalent age and full-term infants within days of birth) had a standardized oral feeding assessment. result: preterm infants at term equivalent age had lower neonatal eating outcome assessment scores ( . ± . compared with . ± . ; p < . ) and were more likely to have poor arousal (p = . ), poor tongue positioning (p = . ), suck–swallow–breathe discoordination (p < . ), inadequate sucking bursts (p = . ), tonal abnormalities (p < . ), discoordination of the jaw and tongue during sucking (p < . ), lack of positive engagement with the feeder and/or discomfort (p < . ), signs of aspiration (p < . ), difficulty regulating breathing (p < . ), and have an inability to maintain an appropriate state (p < . ), and complete the feeding (< . ). conclusion: a broad range of feeding-related difficulties appear to remain evident in preterm infants at term equivalent age. an estimated % of premature infants will experience difficulty with oral feeding during neonatal intensive care unit (nicu) hospitalization [ ] [ ] [ ] . feeding difficulties can result from central nervous system immaturity [ ] [ ] [ ] , medical complications [ ] , and/or cerebral injury [ , ] . immaturity can result in inadequate readiness cues, poor state regulation, and poor oral motor reflexes that support feeding [ ] , but most infants will progress to full oral feedings prior to or close to term equivalent age ( - weeks postmenstrual age (pma)) [ , ] . while many preterm infants are able to achieve full oral feedings prior to nicu discharge, many continue to have feeding challenges at term equivalent age [ ] . in the nicu, the introduction of oral feeding occurs when the infant demonstrates signs of oral feeding readiness, which typically occurs around weeks pma [ ] . during this time of early oral feedings, preterm infant feedings are frequently characterized by an inability to maintain an appropriate state for feeding, discoordination of sucking, and inadequate organization of the suck-swallow-breathe pattern [ , , , , ] . feeding may also be further complicated by physiological instability of the infant, with bradycardic and desaturation events, which have been associated with an increased risk of aspiration during feeding [ , ] . these early feeding challenges can result in an extended stay in the nicu [ ] [ ] [ ] [ ] . oral feeding in preterm infants improves as they approach term equivalent age [ ] . specifically, behavioral responses needed for successful oral feeding, coordination of the sucking pattern, and protection of the airway during swallow improve in a linear fashion with maturity [ ] . studies have demonstrated differences in suck-swallow-breathe coordination [ ] , oral tone [ ] , and sucking efficiency among preterm infants and full-term infants [ , ] . capilouto and colleagues were able to demonstrate differences in preterm and full-term infants' feeding using a technology that quantifies nutritive sucking. they observed that preterm infants have higher suck frequency, with shorter suck duration, and less sucking smoothness [ ] . however, no studies that we are aware of have defined differences in oral feeding performance, along with differences in specific types of feeding-related behaviors, among full-term infants compared with preterm infants at term equivalent age using standardized feeding assessments of a typical oral feeding in the nicu. understanding if differences exist, and what aspects of feeding differ, can improve our understanding of feeding challenges that continue to exist among preterm infants at term and enable targeted interventions to optimize outcome. this study was approved by the human research protection office at washington university in st. louis, and the infant's mother provided written informed consent. one hundred and one infants were prospectively enrolled ( preterm infants and full-term infants) and had feeding assessed using the neonatal eating outcome assessment [ ] . feeding performance, as well as different types of feeding behaviors represented on the standardized feeding assessment were compared between the preterm and full-term groups. fifty preterm infants born ≤ weeks estimated gestational age (ega) were prospectively enrolled prior to oral feeding initiation from january to june as part of an overarching study investigating feeding progression across pma. infants were excluded if they had a congenital anomaly or were born > weeks ega. all congenital anomalies were excluded including conditions such as trisomy , vacterl sequence, cardiac anomalies, and cleft lip and palate. infants were recruited from the -bed level iv nicu at st. louis children's hospital in st. louis, missouri. at term equivalent age (between and weeks pma), after the infant had achieved full oral feeding and nicu discharge was being planned, an oral feeding was video recorded and scored with the neonatal eating outcome assessment. full oral feeding was defined on the infant having full oral intake of their nutritional volume for at least h. for the assessment, each feeder was instructed to feed the infant as they normally would. at the study site, infants were fed by their parents when they were present, and the mode of feeding (breast or bottle) was at their discretion. when parents were unavailable, infants were most often fed by a member of the nursing staff, an occupational therapist, or speech-language pathologist by bottle. fifty-one consecutive admissions of full-term infants born > weeks ega were enrolled within the first h of life from may to august . infants were excluded if they had a congenital anomaly, cerebral injury, intensive care stay, if they were born < weeks ega, or had parents who were non-english speakers. infants were recruited from the -bed labor and delivery floor at barnes-jewish hospital in st. louis, missouri. an oral feeding assessment was performed within days of birth, prior to discharge from the hospital. parents were instructed to feed their infant as they normally would, and the feeding was video recorded and scored with the neonatal eating outcome assessment. the mode of feeding (breast or bottle) was at the parent's discretion. the following information was collected from the medical record: maternal age, maternal marital status, insurance type (public or private), infant sex, and infant race (african-american or non-african-american). infant medical factors collected included the presence of cerebral injury [defined as presence of cystic periventricular leukomalacia or grade iii-iv intraventricular hemorrhage (ivh) from mri or cranial ultrasound], necrotizing enterocolitis (nec; all stages), and chronic lung disease (requiring supplemental oxygen at weeks pma or requiring at least days on > % oxygen). the number of days on supplemental oxygen, continuous positive airway pressure, mechanical ventilation, and total parenteral nutrition were also documented. finally, the ega at birth (based on dates or ballard exam, when dates could not be determined with accuracy) and length of stay in the hospital after birth were documented. the neonatal eating outcome assessment is a standardized tool used to assess feeding skills in infants prior to and at term equivalent age and includes scored feeding items [ ] . the neonatal eating outcome assessment has good to excellent inter-rater reliability and has concurrent validity with relationships to the neonatal oral motor assessment scale [ , ] . the neonatal eating outcome assessment has three scored sections, (prefeeding behaviors, oral feeding, and observations at the end of feeding). there are six items related to oral motor skills assessed prior to initiation of oral feeding, nine items assessed during oral feeding, and three items related to observations made at the end of the feeding. each item receives a letter score, derived from specific standardized criteria outlined in the manual. scores for each item adjust based on expected performance for each pma, with the letter score being converted to either , , or points. a score of on an item reflects a feeding challenge (abnormal) for that pma, a score of reflects a questionable performance (emerging, immature response, or feeding challenge), and a score of reflects a normal performance. each item score is then summed for a total raw score. raw scores can range from to , with higher scores indicating better oral feeding performance. raw scores can then be categorized as normal ( - ), questionable ( - ), or feeding challenged ( - ), based on established ranges. in addition to investigating total feeding assessment scores, various aspects of oral feeding were captured from specific items on the neonatal eating outcome assessment including: i- arousal, i- rooting and grasp, i- initiation of sucking, i- tongue, i- nonnutritive sucking, ii- suck-swallow-breathe coordination, ii- sucking burst length, ii- suction, ii- oral tone, ii- quality of sucking movements, ii- behavioral response to feeding, ii- fluid loss, ii- swallow, iii- feeding completion, and iii- state maintenance. because of the variety of potential feeding behavior manifestations, the items from the assessment were recoded and grouped to ensure optimal exploration of infant feeding capabilities during statistical analysis. see table for information on how each feeding construct was recoded to define poor arousal, poor rooting and grasp, lack of sucking initiation, poor tongue positioning, suck-swallow-breathe discoordination, inadequate sucking bursts, inadequate suction, tonal abnormalities, discoordination of the jaw and tongue during sucking, lack of positive engagement and/or discomfort during feeding, moderate to severe fluid loss, signs of aspiration, difficulty regulating breathing, inability to finish feeding, and inability to maintain an appropriate state for feeding. each video recorded feeding was assessed by a single evaluator, who had been trained by the author of the assessment and underwent testing to ensure reliability. videotapes were not blinded as it was apparent which infants were in the nicu and which were on the labor and delivery floor. statistical analyses were conducted using ibm's statistical package for the social sciences version . ibm corp., armonk, n.y., usa. independent samples t-tests were used to determine differences in neonatal eating outcome assessment scores among the preterm and full-term infants. chi-squared analyses and fisher's exact tests were used to determine differences between the preterm and full-term infants on each of recoded feeding behaviors from the neonatal eating outcome assessment. significance was defined as p < . . one hundred and one infants ( preterm and full-term) were enrolled. one full-term infant was later excluded due to an identified congenital anomaly. due to the lack of feeding readiness at the time of assessment, feeding assessments were not obtained on infants ( preterm and full-term infants), leaving infants ( preterm infants and full-term infants) for analysis. the mean pma when the feeding assessment was administered did not differ significantly between preterm and full-term infants ( . ± . in the preterm group, compared with . ± . in the fullterm group; p = . ). there were more infants who were bottle-fed in the preterm group ( ; %) compared with the full-term group ( ; %); p < . . table identifies infant medical and maternal characteristics for each group. differences in feeding performance among preterm and full-term infants table displays the differences in feeding performance between preterm infants at term equivalent age and full-term infants. preterm infants had significantly lower scores on the neonatal eating outcome assessment [ . ± . (which is considered "questionable"), compared with . ± . (which is considered normal) among full-term infants; (p < . )]. more full-term infants (n = ; %) received "normal" scores, compared with preterm infants (n = ; %; p < . ). fewer full-term infants (n = ; %) had a "feeding challenge," compared with preterm infants (n = ; %; p < . ). there were also fewer "questionable" feeders in the full-term group (n = ; %), compared with preterm group (n = ; %; p < . ). refer to table for differences in each feeding construct among preterm and full-term infants. we reran the analyses excluding infants < weeks pma at the time of testing, and the findings remained largely unchanged. we reran the analyses excluding infants with cerebral injury and nec, and the findings remained largely unchanged. oral tone normal oral facial tone that is adequate for feeding (score of c) ii- respiratory control during feeding difficulty regulating breathing quiet and rhythmic breathing during feeding (score of d) respiratory rate increases ten or more breaths per minute; increased work of breathing. retractions may be present. (scores of a, b, or c) observations at end of feeding inability to finish feeding infant completed feeding (score of d or e) did not complete feeding due to discomfort, fatigue, or physiological instability (scores of a, b, or c) inability to maintain an appropriate state for feeding infant maintained state or > min (score of d or e) infant maintained state or < min (scores of a, b, c) items were recoded for the purposes of data analysis in order to dichotomize normal and abnormal skill performance on each item on the neonatal eating outcome assessment. each construct is bolded. the key findings of this study are that preterm infants at term equivalent age continue to experience difficulty with oral feeding performance. their feeding behaviors differ from their full-term counterparts, with poor arousal, poor tongue positioning, suck-swallow-breathe discoordination, inadequate sucking bursts, tonal abnormalities, discoordination of the jaw and tongue during sucking, lack of positive engagement or discomfort, signs of aspiration, difficulty regulating breathing, and inability to maintain an appropriate state and complete the feeding. by identifying specific alterations in the feeding performance of preterm infants, targeted interventions can be developed, implemented, and tested. our findings of lower scores on standardized feeding assessments in preterm infants at term equivalent age are consistent with other reports. eleven ( %) preterm infants were identified to have a "feeding challenge," and ( %) had "questionable" feeding performance. other reports of feeding problems in preterm infants at term equivalent age report a prevalence between % and % [ ] [ ] [ ] . these high rates of feeding alterations are not observed among infants born full-term [ , ] . it is well-understood that arousal increases across pma [ , ] , yet it is not well-understood when and if preterm infants demonstrate the same level of arousal as their fullterm counterparts by the time they reach term equivalent age. observations of lower arousal during periods of immaturity have led to a model of care in the nicu that allows the infant to demonstrate readiness cues to indicate they are ready for oral feeding, with arousal being one of the precursors [ , ] . although infants that are born preterm frequently struggle to maintain an appropriate level of arousal to facilitate safe and efficient early oral feeding [ ] , this is thought to improve in a linear fashion as they approach term equivalent age [ ] . the current study documented significantly higher rates of poor arousal as well as inability to maintain the appropriate state for oral feeding in the preterm group, compared with the full-term group. prior work has found that more time spent in a quiet alert state increases oral feeding efficiency [ ] , and bold values are those that reached significance (p < . ), indicating a difference in the preterm and full term groups. *p value is from investigations of differences in maternal and infant factors across the preterm and full-term groups using independent sample ttests for continuous variables and chi-squared analyses for categorical variables. the quiet alert state is the most optimal state for infant engagement and safety during feeding [ ] . lower arousal in the preterm group can decrease successful oral feeding. these factors could have impacted our results, as many of preterm infant feedings were stopped due to low arousal and physiologic instability. preterm infants in our study were more likely to demonstrate suck-swallow-breathe discoordination, compared with their full-term counterparts. suck-swallowbreathe discoordination can often appear as repetitive sequences of sucking and swallowing without adequate pauses for respiration [ ] . the feeder can assist the infant by providing imposed breaks for respiration through external pacing methods [ ] . coordination of the suck-swallow-breathe pattern has been shown to improve with maturation [ , , , ] . there were no significant differences in pma at the time of assessment among the preterm and full-term infants, yet differences in the coordination of the suck-swallow-breathe pattern were evident. these findings are consistent with previous studies that have identified that lower ega at birth and greater medical complexity can contribute to suck-swallow-breathe coordination difficulties in infants born preterm [ , , ] . our findings also support previous research that has identified that suck-swallow-breathe discoordination in preterm infants can be seen at term equivalent age [ ] . tonal abnormalities in preterm infants at term equivalent age were also observed in the current study. when oral tone variables that were different across groups (p < . ) are bolded. *p value is from investigating differences in preterm infants and full-term infants using independent samples t-tests for continuous variables and chi-square analyses and fisher's exact test for categorical variables. of the preterm infant is insufficient, the infant may not be able to generate adequate pressure and suction needed to extract milk from the nipple; conversely if oral tone is too high, too much compression of the nipple may limit the efficiency at which milk is expressed and lead to diminished endurance and stamina [ , ] . our findings are consistent with a previous study that identified low oral motor tone in preterm infants [ ] . the tonal alterations observed in preterm infants could have been a contributing factor to observing a flat position of the tongue in the mouth with limited tongue cupping during feeding, as maintaining positioning of the tongue relies on adequate tone [ ] . although others have identified a decrease in compressive forces of the tongue during nutritive sucking among preterm infants [ , ] , we were not able to isolate this difference in the current study. however, these other studies used technologies that allowed precision in quantification, whereas the current study relied on a standardized assessment of feeding through observation. poor arousal, tone abnormalities, and suck-swallowbreathe discoordination in preterm infants could have contributed to observed discoordination of the jaw and tongue during sucking, moderate to severe fluid loss, difficulty regulating breathing, signs of aspiration, and lack of positive engagement and/or discomfort during oral feeding. our study supports other research that has demonstrated that preterm infants have a higher risk of aspiration and physiologic instability during feeding [ , ] . our findings are also consistent with other work that has demonstrated fewer sucks per burst and discoordination of the jaw and tongue during sucking [ ] . the period prior to and at term equivalent age is a rapid period of brain development [ ] , where experiences drive functional connections and relationships between brain regions [ ] . while our study did not assess previous early feeding experiences, it is possible that early negative experiences may be related to the high prevalence of limited engagement in oral feeding and active avoidance. these negative experiences have been shown to lead to higher rates of aversive feeding behaviors and other oral feeding alterations that are prevalent in this population later in infancy and early childhood [ , ] . definitions of oral feeding success vary, but largely relate to intake of an appropriate volume without physiological instability [ ] . however, the current study elucidates the significant feeding challenges that continue to exist among preterm infants at term equivalent age, even when feeding success can be claimed. while oral feeding is often the last milestone needed in order for preterm infants to be discharged from the nicu [ ] , careful attention must be paid to the feeding process during the delicate neonatal period. neonatal therapists (largely occupational therapists and speech-language pathologists) can provide assessment and intervention to optimize the early feeding process and drive positive feeding experiences into childhood [ , ] . while successful oral feeding may be the goal, a focus on quality and positive feeding experiences, especially in the midst of feeding impairment, are important and can be guided by these early therapies. this study had its limitations. this study was limited by significant variability in the medical courses of the preterm cohort, along with the timing that the feeding assessment occurred (between and weeks pma for the preterm group and within days of life for the full-term group). preterm infants were assessed as close to nicu discharge as possible, but this was as early as weeks pma in some infants. the preterm group was evaluated during a period of rapid change in feeding skills, which could have introduced variability in performance. while there were no significant differences in the pma at the time of testing among the preterm and full-term group, it is unclear if the findings would have been different if the preterm group was assessed at a different time period. likewise, the time period in the hospital after full-term delivery is a period of transition, and feeding performance may or may not have evolved in the days or weeks following the assessment in the full-term group. there were more infants who were breastfed during the assessment in the full-term cohort, and it remains unclear if overall feeding performance could have been better or worse based on whether the infant was breast or bottle-fed. feeding assessment was limited to one time frame, and this feeding assessment may or may not have been representative of the infant's general feeding performance. the feeding assessment also could have been impacted by other factors including the feeder, other activities that occurred during the day, hunger, or environmental factors. this study also relied on multiple comparisons, which increases the risk of a type i error. the sample was derived from studies aimed at exploring early feeding performance, but the current study did not undergo prior power analysis. despite these limitations, this is the first study, that we know of, to analyze the multiple components of feeding skill performance in preterm infants at term equivalent age compared with fullterm infants. the findings aid our understanding of early differences in feeding performance and set the stage for further inquiry. feeding is a complex task that requires the integration and organization of many skills. our findings support that although oral feeding may be achieved, preterm infants continue to experience feeding performance alterations at term equivalent age. isolating these differences can lead to individualized, targeted interventions to optimize early feeding experiences and improve outcomes. disclosure the neonatal eating outcomes assessment copyright is currently owned by the office of technology management at washington university in st. louis. this tool can be accessed by the public through licensing. while currently available "at cost," there could be potential profit to washington university in st. louis in the future. author contributions rp was involved with concept/design, developing methodology and supervising the investigation, providing oversight, achieving funding, writing the initial draft of the manuscript, as well as editing and approving the final version of the manuscript submitted. dp was involved with data acquisition and management, conducting analyses, writing the initial draft of the manuscript, and editing and approving the final draft for submission. jr was involved with oversight regarding intellectual content as well as reviewing, editing, and approving the final version of the manuscript submitted. mg was involved with data acquisition and management, formal analyses, as well as reviewing, editing, and approving the final version of the manuscript submitted. js was involved with conducting the investigation, oversight of methodology, as well as reviewing, editing, and approving the final version of the manuscript submitted. conflict of interest rp is the author of the neonatal eating outcome assessment. the other authors declare that they have no conflict of interest. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. development of infant oral feeding skills: what do we know? early nicu discharge of very low birth weight infants: a critical review and analysis development of oral feeding skills in the preterm infant development of suck and swallow mechanisms in infants development of suck and swallow relationship between feeding difficulties, medical complexity, and gestational age feeding problems in children with neonatal arterial ischemic stroke dorsal brain stem syndrome: mr imaging location of brain stem tegmental lesions in neonates with oral motor dysfunction oral feeding and the late preterm infant multiple factors related to bottle-feeding performance in preterm infants impact of prematurity and co-morbidities on feeding milestones in neonates: a retrospective study state of the science: feeding readiness in the preterm infant feeding immaturity in preterm neonates: risk factors for oropharyngeal aspiration and timing of maturation the development of sucking patterns in preterm, small-for-gestational age infants comparison of tongue muscle characteristics of preterm and full term infants during nutritive and nonnutritive sucking physiologic sequelae of prematurity: the nurse practitioner's role. part v. feeding difficulties and growth failure (pathophysiology, cause, and data collection) bradycardia and desaturation spells in premature infants: impact of a protocol for the duration of 'spell-free' observation on interprovider variability and readmission rates prediction of feeding performance in preterm infants development of coordination of sucking, swallowing and breathing: ultrasound study of term and preterm infants feeding patterns of fullterm and preterm infants at forty weeks postconceptional age a comparison of the nutritive sucking performance of full term and preterm neonates at hospital discharge: a prospective study neonatal eating outcome assessment: tool development and inter-rater reliability neonatal eating outcome assessment manual and scoresheet inter-rater reliability and concurrent validity of the neonatal eating outcome assessment persistent early feeding difficulties and subsequent growth and developmental outcomes identification of neonates at risk of developing feeding problems in infancy the prevalence of feeding problems in children formerly treated in a neonatal intensive care unit patterns of altered neurobehavior in preterm infants witin the neonatal intensive care unit neurobehavior of preterm infants from to weeks postmenstrual age changing feeding documentation to reflect infant-driven feeding practice the relationship between behavioral states and oral feeding efficiency in preterm infants supporting oral feeding in fragile infants: an evidence-based method for quality bottle-feedings of preterm, ill, and fragile infants the development of sucking patterns and physiologic correlates in very-low-birthweight infants longitudinal changes in suck-swallow-breathe, oxygen saturation, and heart rate patterns in term breastfeeding infants breastfeeding progression in preterm infants is influenced by factors in infants, mothers and clinical practice: the results of a national cohort study with high breastfeeding initiation rates the effect of oral support on sucking efficiency in preterm infants sucking and swallowing in infants and diagnostic tools oral and respiratory control for preterm feeding the brain before birth: ssing fmri to explore the secrets of fetal neurodevelopment identification and management of the transitional suck pattern in premature infants oral feeding success: a concept analysis occupational therapy, physical therapy and speech-language pathology in the neonatal intensive care unit: patterns of therapy usage in a level iv nicu care of the neonatal intensive care unit graduate after discharge acknowledgements this work was supported by nih (r hd /hd/nichd) awarded by the boston rehabilitation outcomes center and by the eunice kennedy shriver national institute of child health and human development (u hd ) to the intellectual and developmental disabilities research center at washington university. we would like to sincerely thank all the families and infants who participated in this research. key: cord- -m kxc x authors: croop, sarah e. w.; thoyre, suzanne m.; aliaga, sofia; mccaffrey, martin j.; peter-wohl, sigal title: the golden hour: a quality improvement initiative for extremely premature infants in the neonatal intensive care unit date: - - journal: j perinatol doi: . /s - - - sha: doc_id: cord_uid: m kxc x background: following delivery, extremely premature infants are vulnerable to rapid development of hypothermia and hypoglycemia. to reduce local rates of these morbidities, a multidisciplinary team developed a protocol standardizing evidence-based care practices during the first hour after birth. methods: using quality improvement methodology, the golden hour protocol was implemented for all inborn infants < weeks’ gestation. data were collected ( – ) over three phases; pre-protocol (n = ), phase i (n = ), and phase ii (n = ). results: there were no significant differences in infant characteristics. improvements in hypothermia ( % vs % vs %; p = . ), hypoglycemia ( % vs % vs %; p = . ), and minutes to completion of stabilization [median (q ,q ) ( , ) vs ( , ) vs ( , ); p = . ] were observed. conclusions: implementation of an evidence-based, golden hour protocol is an effective intervention for reducing hypothermia and hypoglycemia in extremely premature infants. prematurity is the leading cause of neonatal death and contributes to~ % of childhood disabilities in the united states [ , ] . the highest risks of morbidity and mortality are seen with the most premature infants [ ] . extremely premature (< weeks' gestation), extremely low birth weight (< g) (ep-elbw) infants' mortality rates are - % [ ] . survivors face substantial risk of morbidities including intraventricular hemorrhage (ivh), chronic lung disease (cld), and retinopathy of prematurity (rop) [ ] . these morbidities are predictors of long-term neurodevelopmental, sensorial, and psychiatric disabilities, which affect quality of life and can negatively impact the family [ , [ ] [ ] [ ] . following birth, ep-elbw infants are susceptible to rapid development of hypothermia, hypoglycemia, hypotension, and respiratory failure [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . resuscitation in the delivery room (dr) and stabilization during admission to the neonatal intensive care unit (nicu) involves a series of interdependent tasks and procedures. these interventions must be performed quickly, proficiently, and systematically to minimize the short-term sequelae of prematurity, which contribute to the risk of long-term morbidity and mortality [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the hour immediately following the birth of an ep-elbw infant is referred to as the "golden hour" (gh) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this term denotes the period of time in which medical care to prevent irreversible damage is most effective and represents the inverse relationship between elapsing minutes and likelihood of survival. due to the complexity of the care required at birth, protocols that bundle evidence-based practices and standardize their application to the first few minutes after birth have been used to improve the quality and consistency of care for ep-elbw infants during the gh [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in , vermont oxford network database reports for the nicu at the university of north carolina (unc) children's hospital revealed admission temperatures for ep-elbw infants fell below the unit's goal range ( . - . °c), and the network's reported ranges for similar type nicus. in our unit, % of infants < weeks' gestation and % of infants - weeks' gestation were euthermic compared to and % of similar type nicus in vermont oxford network. a propensity for early hypoglycemia (glucose < mg/ dl) was also noted. at baseline, % of ep-elbw infants were hypoglycemic on admission. in addition, retrospective chart review demonstrated the time from birth to obtaining intravascular (iv) access, subsequent administration of iv fluids and antibiotics, and overall time to completion of admission stabilization was prolonged, increasing the risk for hypothermia and hypoglycemia. in a review of the literature, nine quality improvement (qi) studies were identified presenting outcomes following implementation of a gh protocol in the nicu [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . admission temperature was reported as a short-term outcome measure and improvements in temperatures to goal range were described in eight of the studies [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . one study provided statistical analysis of improvement in admission serum glucose concentration to > mg/dl following protocol implementation [ ] . another described "stable" glucoses throughout the qi project [ ] . the only other study that discussed glycemic control reported an increase in the rate of hypoglycemia which was attributed to increased physiologic stress [ ] . although long-term outcomes were not consistently evaluated in the studies, several authors described improvements in the incidence of ivh, rop, cld, late-onset sepsis, and/or length of stay in their units [ , , , , ] . our goal was to design and implement a systematic, evidencebased approach to the care of ep-elbw infants during the gh. the primary aims were to increase the percentage of temperatures within euthermic range, reduce the incidence of hypoglycemia, and decrease the time to completion of admission stabilization to less than min after birth. a retrospective-prospective study design was used for comparison of data from a preprotocol cohort with postprotocol cohorts. retrospective data were collected january, through march, from electronic medical records. prospective data collection began with project implementation in april, and continued through february, for phase i and march, through march, for phase ii ( table ). the effectiveness of interventions was evaluated using plan-do-study-act (pdsa) cycles in accordance with institutional use of lean six sigma qi methodology [ , ] . this single-center, qi study was conducted in the -bed level iv nicu at unc children's hospital, in chapel hill, nc. the nicu is part of a large academic medical center and serves as a regional referral center for the state. nearly two-thirds of the - infants admitted to the unit each year are inborn. the study population included all inborn infants < weeks' gestation who survived resuscitation in the dr and were admitted to the nicu. exclusion criteria were major congenital anomalies resulting in death within the first h after birth and/or parental decision to provide palliative care on admission. a multidisciplinary team of nicu providers including neonatologists, neonatal nurse practitioners, neonatal fellows, nurses, and respiratory therapists designed the evidence-based bundles included in the protocol. representatives from each of these groups of key stakeholders were chosen to lead the proposed culture change. prior to implementation, presentations demonstrating baseline variation in practices were given to increase awareness of the need for improvement. disciplinary-specific education sessions were provided with each phase. to promote sustainability, gh care was incorporated into the nurses' yearly competencies and new fellows' bootcamp. updates were provided throughout the project to maintain stakeholder engagement. to minimize heat loss, the dr temperature was increased ( - °f) prior to delivery and the radiant warmer was prepared in collaboration with the obstetrical team. in the nicu, the isolette and all supplies were warmed. radiant heat, plastic wrap, and stocking-knit caps were used at delivery in the baseline cohort. with project implementation, a warming mattress was added and the technique for wrapping the infant in plastic was modified to improve integrity during resuscitation. one corner of the plastic was folded over the infant's head and secured with a stocking-knit cap, as plastic head-coverings have been shown to be more effective at preventing heat loss than use of stocking-knit caps alone [ ] . in phase ii, the to achieve early initiation of glucose infusion, peripheral iv access was established in the dr with a maximum of two attempts at placement. on admission to the nicu, a % dextrose infusion was administered peripherally while central umbilical access was being established. following radiographic confirmation of placement, the peripheral infusion was discontinued, and central infusions were initiated using % dextrose, . % amino acid solution via the umbilical venous catheter and . % isotonic amino acid solution via the umbilical arterial catheter. a nicu-specific system for ordering umbilical line placement films was developed in collaboration with the radiology department to reduce time to confirmation of central placement. establishing vascular access was also vital to treating potential sepsis. when indicated, antibiotics were started on admission to the nicu. all lab work including the blood culture was collected as soon as blood return was obtained during central umbilical line placement. once the blood culture was collected, antibiotics could be administered peripherally before central line placement had been completed or confirmed. collaboration with the pediatric pharmacy department improved timing of delivery of antibiotics to the bedside. a respiratory management plan for dr resuscitation was implemented, based on gestational age and risk factors for respiratory compromise (fig. ). this plan was used throughout the project in complement with the neonatal resuscitation program (nrp) guidelines. following publication of the th edition nrp guidelines, cardiorespiratory monitoring in the dr was implemented and initiation of supplemental oxygen was reduced from . to . (table ) [ ] . administration of intramuscular vitamin a and intravenous caffeine was routine for the first two study cohorts. however, there were some inconsistencies with the timing of initiation. in an effort to improve outcomes, the initiation of these medications was standardized (table ) [ , ] . during phase ii, both medications were added to the admission order set in the emr and ordered within the first hour after birth for all ep-elbw infants. many of the interventions implemented with phase ii of the project were focused on improving teamwork and communication. a detailed process flowchart was developed to guide the team through the gh (fig. ) . at baseline, respiratory therapy presence at ep-elbw deliveries was inconsistent. for implementation of phase ii, a respiratory therapist was assigned to attend every gh delivery. an additional, experienced nurse, and an additional, experienced provider were also added to the team. previously, one provider assumed responsibility for establishing the airway and leading the team. with implementation of phase ii, two providers, physician or neonatal nurse practitioner, attended the delivery and divided these roles. the leader was responsible for supervising the resuscitation and stabilization of the infant from birth to completion of the gh as well as communicating with the obstetrical team and the family. the second provider focused on establishing an airway in the dr and inserting umbilical lines in the nicu. at this time, each team member was also assigned specific tasks and positions around the radiant warmer in the dr to improve team dynamics and communication [ ] . just-in-time training simulations were employed to solidify these interventions. when delivery of an infant < weeks' gestation was imminent, the team members assigned to attend reviewed their roles, responsibilities, and positions around the radiant warmer and performed a quick, just-in-time simulation. consistent exposure to each team member's role created a shared mental model of what needed to be accomplished and who was responsible for each task throughout the gh. consequently, the team was able to assume and divide additional responsibilities on the rare occasion one role was unfulfilled. initially, a basic handout reminded providers of the goals of the gh and served as the data collection tool. subsequently, a detailed process flowchart with corresponding questions for data collection replaced the initial handout (fig. ) . all information gathered from the data collection tools was confirmed in the medical record prior to analysis. each phase of the project corresponded to changes in the bundles of interventions (table ) . changes in interventions were determined using pdsa cycles, taking into consideration trends in outcomes, stakeholder feedback, and availability of new products and evidence-based practices. evaluation of short-term outcomes and other process fig. golden hour algorithm initial airway management was based on the infant's gestational age and assessment of risk factors for respiratory failure. choices included intubation with surfactant administration (in/in), intubation for surfactant administration with immediate extubation to cpap (in/out), or cpap without surfactant administration. aa amino acid, cbc w/diff complete blood count with differential, cpap continuous positive airway pressure, cr cardiorespiratory, d %w dextrose % in water; ett endotracheal tube, fio fraction of inspired oxygen, huc hospital unit coordinator; nccc newborn critical care center, nnp neonatal nurse practitioner, ob obstetrician, pal peripheral arterial line, peep positive end expiratory pressure, pip positive inspiratory pressure, piv peripheral intravenous line, poc point-of-care, rn registered nurse, rt respiratory therapist, stat immediately, uac/uvc umbilical arterial and venous catheters measures including time to achieving various gh goals provided benchmarks for determining the effectiveness of interventions. to ensure internal validity, implementation fidelity was evaluated based on the consistency of adherence to protocol interventions. primary, short-term outcome measures were those obtained during admission stabilization. axillary temperatures were measured on admission to the nicu (goal range . - . °c ). serum glucose concentration was obtained during central line placement and measured using point-of-care testing (goal ≥ mg/dl). completion of admission stabilization included dr resuscitation, initiation of iv fluids and antibiotics (when indicated), establishing central access, closing the top of the isolette, initiating humidity, and providing decreased environmental stimulation to approximate the intrauterine environment. process measures that directly contributed to thermoregulation, glycemic control, and time to completion of gh stabilization were tracked. these measures included the percentage of time plastic wrap or thermoregulation suit, warming mattresses, and peripheral iv insertion were utilized in the dr and minutes from birth to admission temperature, initiation of iv fluids, initiation of antibiotics, central line confirmation, and closure of the isolette. long-term outcomes including severe ivh (grade iii or iv hemorrhages), severe cld defined as the need for supplemental oxygen ≥ % or positive pressure at weeks' post menstrual age (pma) or discharge [ ] , rop requiring treatment, pma on the day of discharge home, and mortality served as balancing measures to ensure changes in interventions were not having unintended, negative impacts. statistical process control charts were created in qi macros for excel. outcomes were compared with chi-square or fisher's exact test for categorical data and one-way anova or kruskal-wallis for continuous data using stata statistical software. median values with interquartile ranges are presented due to non-normal distribution of data. statistical significance was set at p values of ≤ . . the study included inborn infants < weeks' gestation. three infants were excluded due to severe congenital anomalies resulting in death shortly after admission. data were collected over three phases; pre-protocol (n = ), phase i (n = ), and phase ii (n = ) ( table ). there were no significant differences in infant characteristics (table ) . adherence to the intended interventions were as follows: the use of plastic wrap or thermoregulation suit was % and % in phases i and ii respectively and the use of warming mattresses was % in both phases. the number of attempts for iv insertion in the dr was limited (max of two) and overall, an iv was placed in the dr for % of infants in phase i and % in phase ii. significant improvements were observed in all three primary outcome measures including the incidence of temperatures outside goal range ( % vs % vs %; p = . ), the incidence of hypoglycemia ( % vs % vs %; p = . ), and median time in minutes to gh stabilization ( vs vs min; p = . ) ( table ). evaluation of long-term morbidity and mortality as balancing measures to stabilize our metrics did not reveal any unintended negative effects (table ) . statistical process control charts were used to analyze process performance. changes in the center line and control limits were based on process shifts that occurred with continuous evaluation and implementation of interventions throughout the project. at baseline, both processes were stable. a few instances of a single measure above the upper control limit or below the lower control limit were noted on both control charts. these special cause variations were related to deviation from or noncompliance with the process. new control limits were calculated for both charts when clinically relevant special cause variation was identified ( fig. a, b) . the limits were recalculated for admission temperature two months after project implementation resulting in a new center line with a euthermic temperature . °c (fig. a) . the limits were recalculated for time to completion during phase ii resulting in a new center line at min (fig. b) . both processes remained stable around the new center line. implementation of an evidence-based gh protocol was effective at significantly improving euglycemia, euthermia, and time to completion of admission stabilization for ep-elbw infants in our nicu. following project implementation, admission temperatures in our unit for infants < weeks' gestation consistently fell within the vermont oxford network's reported ranges for similar type nicus. although we did not consistently meet our goal of completion within the first min after birth, we made significant improvements in time from baseline. our gh protocol was implemented in a more premature population of infants than those of the studies in our review. only one of the review studies focused on a population of infants < weeks' gestation, while inclusion criteria for the remaining studies ranged from < to < weeks' gestation [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, despite a more vulnerable population, the improvements in admission glucoses and temperatures demonstrated in our study were consistent with the results reported by the studies in our review. initially, we noted a slight increase in time which we contributed to the learning curve associated with project implementation. the significant decrease in time to gh stabilization during phase ii was associated with efforts to improve team dynamics and implementation of simulation training. a potential confounder was the increase in the resuscitation and survival of periviable infants ( - weeks' gestation) during the course of our interventions, a phenomenon which was not isolated to our unit [ , ] . we noted that the percent of periviable infants remained stable across the first two cohorts and nearly doubled in the third cohort ( %, %, and % respectively). the inverse relationship between gestational age and survival without morbidities is well-recognized and confers a higher degree of vulnerability to those infants delivered at the "cusp of viability" [ , ] . periviable infants are more susceptible to hypothermia and hypoglycemia and less resilient from the ensuing morbidities [ ] . despite an increasing percentage of more immature infants, the rates of hypothermia and hypoglycemia improved without significant differences in balancing measures. this finding remained when balancing measures were evaluated separately for and week infants. we speculate that implementation of the interventions in our gh protocol may offer a protective effect which may be even more beneficial at lower gestational ages. one limitation to the study was the transfer of stable infants to lower-level facilities. there was a loss of % of the data for cld and % of the data related to rop for survivors transferred prior to weeks' pma. sample size was also a limiting factor. the sample size for phase i of the project was approximately % that of the baseline and phase ii cohorts. although no power analysis was performed, it is likely that the sample size of this study was not adequate to assess for differences in long-term outcomes which were used as balancing measures. the -year span of this project and the retrospective/ prospective cohort design introduce the risk of historical threat to the long-term outcomes which served as balancing measures. although we saw no significant differences in the rates of mortality, ivh, cld, or rop we recognize that these disease processes are multifactorial in etiology. changes in practice over time and other confounding variables, not related to the interventions of the gh might contribute to variations in outcomes and in some instances, provide an alternative explanation of the study findings. other nicus may not have been exposed to the same changes in practice or confounding factors thus limiting the generalizability of the study. the study was a single-center qi project and the generalizability of the protocol is also limited as a result of potential differences in resources, staffing, and physical space. however, transferability is comparatively high as the evidencebased practice bundles that make up the protocol can be modified and adapted to fit the needs of any nicu providing care to ep-elbw infants. gh protocols prioritize maintaining the stability of the most vulnerable population of infants in the nicu through the first, tenuous minutes after birth. these protocols promote efficient care delivery and provide a structure for effective teamwork and communication across multidisciplinary groups. the findings of our study and their consistency with the findings of previous studies support implementation of gh protocols in the nicu to decrease admission hypothermia and hypoglycemia in ep-elbw infants. our findings also fill a gap in the literature related to the care of the periviable infant, suggesting gh protocols may be even more beneficial in this subpopulation. health resources and services administration, maternal and child health bureau prediction of neurodevelopmental and sensory outcome at years in norwegian children born extremely premature mental health in children born extremely preterm without severe neurodevelopmental disabilities preterm birth: causes, consequences, and prevention the first golden minutes of the extremely-low-gestational-age neonate: a gentle approach the golden hour the neonatal golden hourintervention to improve quality of care of the extremely low birth weight infant fluid, electrolytes, and nutrition: minutes matter nascar pit-stop model improves delivery room and admission efficiency and outcomes for infants < weeks' gestation sixty golden minutes outcomes of a neonatal golden hour implementation project the golden hour: improving the stabilization of the very low birth-weight infant first golden hour of life: a quality improvement initiative the golden hour: care of the lbw infant during the first hour of life one unit's experience implementation and evaluation of "golden hour" practices in infants younger than weeks' gestation golden hour protocol for preterm infants golden hour" quality improvement intervention and shortterm outcome among preterm infants is evidence-based practice routine in the golden hour? iatrogenic hyperthermia and hypothermia in the neonate thermoregulation in very low-birthweight infants during the golden hour: results and implications temperature management in the delivery room hypothermia in very low birth weight infants: distribution, risk factors and outcomes the neonatal research network. admission temperature of low birth weight infants: predictors and associated morbidities qi training and education: lean six sigma. institute for healthcare quality improvement. unc school of medicine website the applicability of lean and six sigma techniques to clinical and translational research heat loss prevention in very preterm infants in delivery rooms: a prospective, randomized, controlled trial of polyethylene caps textbook of neonatal resuscitation vitamin a supplementation to prevent mortality and short-and long-term morbidity in very low birth weight infants caffeine therapy for apnea of prematurity nichd/nhlbi/ord workshop summary: bronchopulmonary dysplasia policy change for infants born at the "cusp of viability": a canadian nicu experience survival among infants born at or weeks' gestation following active prenatal and postnatal care neonatal outcomes of extremely preterm infants from the nichd neonatal research network initial resuscitation and stabilization of the periviable neonate: the golden-hour approach conflict of interest the authors declare that they have no conflict of interest.ehtical approval in accordance with ethics and human subject permissions, this study was submitted to the institutional review board of unc, chapel hill and deemed exempt.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -hya ch authors: nan title: abstracts der . jahrestagung der gesellschaft für neonatologie und pädiatrische intensivmedizin date: - - journal: monatsschr kinderheilkd doi: . /s - - -y sha: doc_id: cord_uid: hya ch nan von der körperhöhe der mutter beeinflusst wird. dieses hat dann auch folgen für das ursachenspektrum von schwangerschafts-und geburtsrisiken bei hypotophen, eutrophen und hypertrophen neugeborenen. maternal prepregnancy weight and neonatal outcome: does adiposity really matter? ziel. es werden die bedeutung ausgewählter mütterlicher merkmale (alter, körpergewicht, körperhöhe, bmi, gewichtszunahme während der schwangerschaft, gestationsdiabetes, rauchverhalten, parität, alleinstehend/nicht alleinstehend) für das auftreten einer neonatalen makrosomie bei reifgeborenen analysiert. methode. die daten von . neugeborenen der jahre - aus der deutschen perinatalerhebung von bundesländern werden analysiert. die maternalen daten von kinder > . geburtsgewichtsperzentile (n= . ) wurden mit den von eutrophen termingeborenen (n= . ) verglichen. die statistische auswertung erfolgte deskriptiv sowie mittels χ -test. die risikokalkulation erfolgte mittels univariater und multivariablen logistischer regression mit dem programmpaket "spss" im rechenzentrum der universität rostock. ergebnisse. risikofaktoren für ein hypertrophes neugeborenes sind ( ) ein maternales gewicht > kg (or , % ci , - , ) und mütterliche adipositas (bmi> ). (or , ). ( ) ein schwangerschaftsdiabetes (or , ), ( ) eine überstarke gewichtszunahme > kg während der schwangerschaft (or , ). ( ) mehrgebärende haben häufiger hypertrophe neugeborene (or , ). Überraschender weise stellen das mütterliche alter und alleinstehende mütter keine wesentlichen unabhängigen risikofaktoren dar. schlussfolgerung. es konnten für eine mitteleuropäische population risikofaktoren definiert werden, die für die primär-und sekundärprävention von fetalen makrosomien ansatzpunkte geben können. background. hypoxic-ischemic encephalopathy (hie) still is a major cause of neonatal mortality and morbidity. the amplitude-integrated electroencephalogram (aeeg) is reliable for prediction of outcome in asphyxiated neonates. near-infrared spectroscopy (nirs) offers the possibility to continuously monitor cerebral oxygen saturation. only few data have been published on the combined use of nirs and aeeg in neonates cooled for hie. the aim of this study was to investigate the correlation between continuous aeeg and nirs during the first days of life in hie. methods. aeeg: brain function was measured continuously immediately after the hypoxic event, during hypothermia, until the end of rewarming using a olympic (natus©). aeeg tracings were analysed for background patterns, appearance of sleep-wake cycling and the presence of seizure activity. furthermore, a combined aeeg-score was calculated for the timeperiod before, during and after hypothermia. nirs: patients were monitored using nirs (invos system by covidien©) for the mentioned time period. changes in regional cerebral oxygen saturation (rcso ) were measured. fractional tissue oxygen extraction (ftoe) was calculated for the entire duration of the measurement in order to investigate the balance between oxygen delivery and oxygen supply. results. a significant correlation coefficient (corrc) was found between swz and rcso post cooling (corrc: . ) as well as ftoe during (corrc: . ) and post cooling (corrc: . ). furthermore, a significant corrc was found between the total aeeg score and rcso post cooling (corrc: . ) as well as ftoe during (corrc: . ) and post cooling (corrc: . ). conclusion. our data show a significant correlation between continuous aeeg monitoring, which is a valuable and reliable method for prediction of neurodevelopmental outcome in neonates with hie, and nirs measurements. therefore, we suggest that nirs can serve as an additional prognostic tool in hie. n. baik , b. urlesberger , b. schwaberger , g. schmölzer , l. mileder , a. avian , g. pichler universitätsklinik für kinder-und jugendheilkunde, klinische abteilung für neonatologie, graz, Österreich, department of neonatology, royal alexandra hospital, edmonton, canada, edmonton, kanada, medizinische universität graz, medizinische informatik und statistik, graz, Österreich hintergrund. nichtinvasive Überwachung des gehirns mit nahinfrarot-spektroskopie (nirs) während der adaptationsphase nach der geburt ist von wachsendem interesse. die referenzwerte von crso und cftoe gemessen mit invos c wurden daher bereits etabliert. fragestellung. das ziel dieser prospektiven beobachtungsstudie war es die referenzwerte und perzentilen der regionalen zerebralen oxygenierung (ctoi) und der zerebralen sauerstoffgewebsextraktion (cftoe)gemessen mit niro nx -während der ersten minuten nach der geburt bei früh-und neugeborenen mit unauffälliger adaptationsphase zu definieren. material und methoden. ctoi wurde mit niro nx in den ersten minuten nach der kaiserschnittentbindung in früh-und neugeborenen gemessen. der nirs sensor wurde an der stirn rechts frontal angelegt. periphere arterielle sauerstoffsättigung (spo ) und die herzfrequenz (hf) wurden kontinuierlich mittels pulsoxymetrie gemessen. cftoe wurde aus ctoi und spo berechnet. neugeborene, die während der adaptationsphase sauerstoff-und/oder respiratorische unterstützung erhielten, wurden ausgeschlossen. hintergrund. nahinfrarotspektroskopie (nirs) ermöglicht eine kontinuierliche, nichtinvasive messung der zerebralen konzentrationsänderungen von oxygeniertem (Δo hb) und desoxygeniertem hämoglobin (Δhhb) bei neugeborenen. veränderungen des totalen hämoglobins (Δchb=Δo hb+Δhhb) können unter berücksichtigung der hämoglobinkonzentration in den großen gefäßen in veränderungen des zerebralen blutvolumens (Δcbv) umgerechnet werden. unsere studiengruppe zeigte einen signifikanten abfall des cbv bei gesunden reifgeborenen in den ersten lebensminuten. bislang gibt es jedoch keine daten, wie sich das cbv während der postnatalen adaptationsphase von früh-und reifgeborenen mit und ohne atemunterstützung verhält. fragestellung. wie verändert sich das Δcbv in der adaptationsphase von früh-und reifgeborenen mit und ohne atemunterstützung? material und methode. diese sin gle-center-studie wurde als prospektive beobachtungsstudie durchgeführt. inkludiert wurden früh-und reifgeborene mit und ohne notwendigkeit einer atemunterstützung nach schnittentbindung. für die nirs-messungen wurde ein "niro- -nx" (hamamatsu; japan) verwendet. der nirs-sensor wurde rechts frontal mit elastischer binde fixiert. der verlauf des Δcbv wurde für die unmittelbare postnatale adaptationsphase über minuten berechnet. ergebnisse. es wurden insgesamt neugeborene inkludiert, davon waren frühgeborene ( mit und ohne atemunterstützung) mit einem mittleren gestationsalter von ± wochen und reifgeborene ( mit und ohne atemunterstützung) mit einem mittleren gestationsalter von ± wochen. Δcbv bei früh-und reifgeborenen zeigte sich ein signifikanter abfall des cbv in den ersten lebensminuten. bei frühgeborenen ohne atemunterstützung ist das cbv um , (± , ) ml/ g gehirngewebe, bei frühgeborenen mit atemunterstützung um , (± , ) ml/ g gehirngewebe abgefallen. bei reifgeborenen ohne atemunterstützung ist das cbv um , (± , ) ml/ g gehirngewebe, bei reifgeborenen mit atemunterstützung um , (± , ) ml/ g gehirngewebe abgefallen. schlussfolgerung. bei früh-und reifgeborenen findet man unmittelbar postnatal einen abfall des cbv, wobei dieser bei gesunden reifgeborenen ohne atemunterstützung am stärksten ausgeprägt ist. inwieweit diese beobachtung vor allem bei frühgeborenen mit risiko einer zerebralen schädigung von klinischer relevanz ist, muss in zukünftigen studien geklärt werden. introduction. the amplitude-integrated eeg (aeeg) is becoming more important to monitor brain activity in premature infants. studies have shown that early aeegs correlate with later neurodevelopmental outcome. various scoring systems for the assessment of aeegs are being used, which complicates the comparison of published data. the aim of our study was to compare two scoring systems for aeeg and correlate with the neurodevelopmental outcome. methods. preterm infants [gestational age (ga) < weeks of gestation] who had an aeeg within the first days of life and a neurodevelopmental outcome at the age of were retrospectively included into the study. the aeegs had been analyzed with the aeeg sum score [background activity (ba) = percentage of different background patterns based on gestational age related standard values, the occurrence of sleep-wake cycles (swc) and seizure activity] and the burdjalov score [continuity (co), cyclicity (cy), amplitude of lower border (lb) and bandwidth span and amplitude of lower border (b) of the aeegs -regardless of gestational age] and the results had been correlated with the outcome [bayley scales (mdi and pdi) at the age of ]. results. both total scores (p≤ . ) and the different subscores correlated statistically significant (p≤ . ) with each other. both total scores showed significant correlation (burdjalov score p= , and aeeg sum score p≤ . ) with the outcome. the burdjalov score showed increasing values with increasing ga, while the aeeg sum score showed no differences in the various ga. conclusion. both scoring systems allow a simple classification of aeegs. the burdjalov score shows specific differences for the ga, while the aeeg sum score correlates better with the later outcome. universitätsklinik für kinder-und jugendheilkunde, klinische abteilung für neonatologie, graz, Österreich, department of neonatology, royal alexandra hospital, edmonton, canada, edmonton, kanada, medizinische universität graz, medizinische informatik und statistik, graz, Österreich fragestellung. ziel dieser studie war es, einen möglichen zusammenhang zwischen regionaler zerebraler oxygenierung (crso ) und mittlerem arteriellen druck (mad) bei früh-und reifgeborenen während der adaptationsphase zu untersuchen. material und methode. in diese prospektive beobachtungsstudie wurden früh-und reifgeborene eingeschlossen. die zerebrale regionale oxygenierung (crso ) wurde mittels nahinfrarot-spektroskopie (nirs) mit dem invos c während der neonatalen adaptationsphase ( minuten unmittelbar nach der geburt) gemessen. der nirs sensor wurde an der stirn links frontal angelegt. ferner wurde ein pulsoxymeter angelegt, um die arterielle sauerstoffsättigung (spo ) und die herzfrequenz (hf) zu überwachen. in der . lebensminute wurde einmalig der blutdruck am linken oberarm gemessen. die zerebrale sauerstoffgewebsextraktion (cftoe) wurde aus spo und crso berechnet. um den zusammenhang zwischen cftoe und mad zu untersuchen, wurde eine korrelationsanalyse durchgeführt. ergebnisse. es wurden insgesamt früh-(n= ) und reifgeborene (n= ) eingeschlossen. das mittlere gestationsalter betrug , ± , wochen bei frühgeborenen, , ± , wochen bei reifgeborenen, das mittlere geburtsgewicht ± g bei frühgeborenen, ± g bei reifgeborenen. die korrelationsanalyse zeigte keinen statistisch signifikanten zusammenhang zwischen mad und cftoe bei reifgeborenen, im gegensatz dazu gab es aber eine statistisch signifikante negative korrelation bei frühgeborenen zwischen mad und cftoe (p= , ). diskussion. die vorliegende beobachtungsstudie zeigt einen statistisch signifikanten zusammenhang zwischen cftoe und mad bei frühgeborenen, obwohl es keinen zusammenhang bei reifgeborenen gibt. dies könnte darauf hindeuten, dass bei reifgeborenen eine funktionierende gefäßautoregulation bereits während der adaptationsphase existiert, während diese bei frühgeborenen fehlt. schlussfolgerung. mad hat einen einfluss auf zerebrale oxygenierung bei frühgeborenen. die Überwachung des mads bereits während der erstversorgung der frühgeborenen könnte für den klinischen alltag relevant sein, um mit der eventuellen therapie die zerebrale oxygenierung positiv zu beeinflussen. peri-/intraventrikuläre blutung bei frühgeborenen: einfluss der zerebralen oxygenierung während der adaptationsphase tationsphase ( minuten unmittelbar nach der geburt) gemessen. der sensor wurde an der stirn links frontal angelegt. ferner wurde präduktal ein pulsoxymeter angelegt, um die arterielle sauerstoffsättigung (spo ) und die herzfrequenz (hf) zu überwachen. ultraschalluntersuchungen des gehirns wurden am tag , , nach der geburt und vor der entlassung durchgeführt, um peri-/intraventrikuläre blutung zu identifizieren. je nach ultraschalluntersuchungsergebnissen wurden die fg in zwei gruppen eingeteilt: ivh-gruppe und non-ivh-gruppe. um die zwei gruppen vergleichbar zu machen, wurden fg mit ivh zu den fg ohne ivh im bezug auf gestationsalter (± woche) und geburtsgewicht (± g) gepaart. ergebnisse. fg wurden in die studie eingeschlossen: der fg entwickelten ivh. diese wurden mit fg ohne ivh aus der non-ivh-gruppe (n= ) verglichen. es gab keinen unterschied zwischen den zwei gruppen in bezug auf spo und hf. die ivh gruppe zeigte statistisch signifikant niedrigere crso -werte als die non-ivh-gruppe ab der minute bis zum ende der beobachtungsphase. schlussfolgerung. die frühgeborenen der ivh-gruppe zeigten signifikant niedrigere crso -werte während der adaptationsphase, obwohl es keinen unterschied in spo und hf gab. das zusätzliche monitoring der zerebralen regionalen oxygenierung mittels nahinfrarot-spektroskopie während der adaptationsphase könnte hilfreich sein, um die frühgeborenen mit einem höheren risiko für spätere ivh-entwicklung bereits während der adaptationsphase zu erkennen. s. herber-jonat hintergrund. ein schweres neonatales lungenversagen führt zum einsatz von additiven therapien, wie der applikation von surfactant, inhalativem stickstoffmonoxid (ino), hochfrequenz-oszillationsbeatmung (hfov) oder der extrakorporalen membranoxygenierung (ecmo). ziel dieser studie war es anwendung und effektivität dieser additiven therapien zu dokumentieren. patienten und methodik. einschlusskriterien waren gestationsalter > ssw, akutes lungenversagen unter invasiver beatmung mit fio > , und anwendung mindestens einer additiven therapie. Über die erhebungseinheit für seltene pädiatrische erkrankungen in deutschland (esped) wurden n= patienten innerhalb von jahren in die studie aufgenommen. die effektivität der jeweiligen additiven therapie wurde durch den behandelnden arzt beurteilt. vorgabe für einen positiven effekt war eine senkung des oxygenierungsindex um oder anstieg der pao /fio ratio um mmhg. ergebnisse. die häufigste diagnose war der surfactantmangel mit , %, gefolgt von pneumonie/sepsis ( , %), mekoniumsaspirationssyndrom und der kongenitalen zwerchfellhernie. surfactant wurde in , % appliziert mit einer effektivität von , %. , % aller patienten wurden mit ino behandelt, mit einer wirksamkeit von , %. hfov wurde bei , % aller fälle mit einer wirksamkeit von , % angewendet. die ec-mo-therapie kam bei , % der patienten zum einsatz und war in , % erfolgreich. die gesamtsterblichkeit innerhalb der kohorte lag bei , %. signifikante einflussfaktoren auf das Überleben waren: die zugrundeliegende diagnose, die anzahl additiver therapien und der initiale effekt additiver therapien ohne ecmo. patienten starben ohne ecmo-therapie. davon lag in fällen eine ecmo kontraindikation vor. die restlichen patienten, die womöglich von einer ecmo-therapie profitiert hätten wurden nicht in ein ecmo-zentrum überwiesen. schlussfolgerung. die anwendung und effektivität additiver therapien beim lungenversagen des neugeborenen entspricht in deutschland den international vorliegenden daten. jedoch zeigt sich, dass jährlich eine bedeutende anzahl neugeborener mit ecmo-indikation nicht an ein entsprechendes zentrum verlegt wird. hintergrund. beim lungenversagen des neugeborenen haben schonende beatmung und die additiven therapien surfactant und stickstoffmonoxid den bedarf für die extrakorporale membranoxygenierung (ecmo) reduziert. die erworbenen atemstörungen mekoniumaspiration und pneumonie/sepsis sind dadurch beherrschbarer geworden, womit die angeborenen atemstörungen mehr ins visier für die ecmo treten. die folgende analyse soll die frage beantworten wie das diagnoseprofil für ein ecmo zentrum heutzutage aussieht und ob sich dadurch die Überlebenszahlen geändert haben. patienten und methodik. in den jahren - wurden an unserem zentrum neugeborene mit der ecmo behandelt. diese patienten wurden hinsichtlich der ursächlichen diagnose und des Überlebens ausgewertet. für die angeborene zwerchfellhernie wurde konsequent ein standardisierter therapiealgorithmus angewendet. ergebnisse. von ecmo patienten ( , %) haben überlebt und konnten nach hause entlassen werden. damit hat sich die gesamtüberlebensrate im vergleich zu früheren daten und den daten der extracorporeal life support organisation (elso) leicht verbessert. und das obwohl die angeborene zwerchfellhernie (cdh) mit fällen noch deutlicher zur führenden diagnose geworden ist. die Überlebensrate der cdh liegt mit , % sogar minimal über dem durchschnitt und deutlich über den ergebnissen der elso. es zeigt sich die besonderheit unseres zentrums mit der spezialisierung auf die diagnose cdh mit durchschnittlich ecmo fällen bei dieser diagnose pro jahr, wobei ca. ein drittel der prä-und postnatal verlegten cdh-kinder mit ecmo behandelt werden. aus allen anderen diagnosegruppen ergaben sich zusammen durchschnittlich ecmo fälle pro jahr. hierbei erfüllten zwei drittel der seit abgeholten neugeborenen die ecmo-kriterien und ein drittel konnte mittels optimierung der therapie stabilisiert werden konnten. die mekoniumaspiration (mas) ist mit , % der ecmo fälle die zweithäufigste diagnose nach der cdh und hierbei überlebten % der patienten. deutlich schlechtere Überlebensraten zeigten die diagnosen primäre persistierende pulmonale hypertension (pphn) [ , % der patienten] mit nur % und die pneumonie/ sepsis [ , %] mit , %. von kindern mit sonstigen diagnosen überlebten . gerade bei der pphn fällt der mit durchschnittlich lebenstagen relativ späte verlegungszeitpunkt auf. schlussfolgerung. ein optimierter therapiealgorithmus und die hohe spezialisierung mit hohen fallzahlen haben bei der diagnose cdh zu deutlich verbesserten ecmo-Überlebensraten geführt. bei allen anderen diagnosen sind die fallzahlen für ecmo rückläufig und es zeigt sich, dass die therapieabläufe für die pphn verbessert werden sollten. täglich wird ab dem zweiten lebenstag bis zum zehnten lebenstag der pda-score erhoben, wobei definierte klinische parameter beurteilt werden: herzgeräusch, sichtbare präkordiale pulsationen, herzfrequenz > /min (ohne hypovolämie), apnoen oder respiratortherapie, kräftige periphere pulse, hepatomegalie, metabolische azidose, respiratorische verschlechterung. es wird pro positivem merkmal ein punkt im score-system vergeben. bei erreichen eines ductus-scores von ≥ punkten wird eine echokardiographische untersuchung (als goldstandard in der diagnostik des pda) initiiert. ergebnisse. das mittlere gestationsalter der studiengruppe beträgt , ssw (σ , ssw). das mittlere geburtsgewicht liegt bei , g (σ , g). die gruppe setzt sich zusammen aus , % männlichen sowie , % weiblichen neonaten. um die einzelnen parameter des vereinfachten pda-scores zu wichten, wurden mittels kreuztabellen die klinischen bestandteile des scores jeweils einzeln der entwicklung eines echokardiogaphisch bestätigten hrpda gegenübergestellt. durch die ermittlung des angepassten residuums, sowie der exakten signifikanz mittels fisher-test konnten die signifikanten, statistisch stärksten einzelparameter ermittelt werden. ein versuch der zusammenfassung der klinischen merkmale mittels logistischer regressionsanalyse konnte einzelne kernmerkmale, wie metabolische azidose, präkordiale pulsationen, periphere pulse sowie apnoe bzw. respiratortherapie (pulmonale verschlechterung) herauskristallisieren. am dritten und vierten lebenstag korrelieren diese parameter am besten mit der entwicklung eines echokardiographisch bestätigten hrpda. schlussfolgerung. der von uns getestete klinische pda-score ist in der anwendung einfach, nichtinvasiv und schnell durchführbar. in kombination mit der kontinuierlichen erfassung dieses klinischen pda-scores lässt sich die echokardiographie gezielter einsetzen und gegebenenfalls die anzahl der notwendigen echokardiografischen untersuchungen reduzieren. hintergrund. der verschluss des ductus arteriosus bei reifen neugeborenen ist mit der bildung eines stabilen thrombus assoziiert. bei frühgeborenen unter g geburtsgewicht verschließt sich ein offener duktus arteriosus (pda) häufig nicht spontan, so dass bei hämodynamischer relevanz ein medikamentöser oder operativer verschluss notwendig werden kann. es ist bisher unklar, ob die postnatale transfusion von adulten thrombozyten den spontanen oder medikamentös induzierten verschluss des pda beeinflusst. fragestellung. in einer retrospektiven datenbankanalyse wurde untersucht, ob die transfusion adulter spender-thrombozyten innerhalb der ersten lebenstage den verschluss eines hämodynamisch relevanten persistierenden duktus arteriosus (hrpda) bei frühgeborenen mit extrem geringem geburtsgewicht und bereits begonnener indomethacin-therapie begünstigt. material und methoden. frühgeborene mit einem geburtsgewicht unter g und einem gestationsalter von bis zu wochen, die zwischen und geboren wurden, wurden retrospektiv untersucht (n= ; ausgangspopulation). für / ( %) lagen alle erforderlichen daten für eine analyse vor. wir definierten eine thrombozytenzahl unter g/l als thrombozytopenie. die dateneingabe sowie die statistische auswertung wurden mittels excel (microsoft corp., usa) und spss (ibm inc., usa) durchgeführt. ergebnisse. von den kindern entwickelten ( , %) einen hrpda und erhielten eine therapie mit indomethacin. zehn dieser kinder verstarben postnatal ( , %) . es bestand kein zusammenhang zwischen der schwere der thrombozytopenie und dem auftreten eines hrpda. der erfolgreiche medikamentöse verschluss eines hrpda war unabhängig von einer postnatal beobachteten thrombozytopenie ( . % vs. . %, mit/ohne thrombozytopenie, p= , ). die transfusion von adulten thrombozyten hatte keinen einfluss auf die notwendigkeit einer duktusligatur ( , % mit vs. , % ohne transfusionen, p= , ). eine analyse nur der überlebenden kinder erbrachte ein ähnliches ergebnis ( , % mit vs. , % ohne transfusionen; p= , ). wesentlicher prädiktiver faktor für das versagen einer medikamentösen duktus-therapie war das postmenstruelle alter bei geburt (p< , ). diskussion. unsere daten zeigen, dass eine postnatale transfusion von adulten thrombozyten keinen effekt auf den erfolg oder misserfolg einer indomethacin-therapie bei hrpda hat. unsere daten widerlegen außerdem frühere beobachtungen, die einen zusammenhang einer thrombozytopenie mit dem auftreten eines hrpda implizierten. eine limitation dieser retrospektiven analyse ist, dass ein signifikanter unterschied zwischen thrombozytopenen und nicht-thrombozytopenen kindern hinsichtlich wesentlicher klinischer parameter (gestationsalter, geburtsgewicht, hirnblutungsrate und mortalität) bestand, so dass anhand der vorgelegten daten keine abschließenden schlüsse gezogen werden können. background. our "artificial placenta" neonatal lung assist device is a stacked array of microfluidic polydimethylsiloxane (pdms) sous (abb. p . . ; schematic of a sou). blood contacting surfaces within the sous need to be hemocompatible, a method using pda as a 'bioglue' to attach a covalent ath complex, a potent anticoagulant, has been developed to achieve hemocompatibility. objective. to quantify ath binding and bioactivity on pda modified sous. methods. quantification and evaluation of surface bound ath was carried out through blood exposure. two sets of oxygenators (n= total) were incubated in dopamine hydrochloride ( mg/ml in pbs, ph . , hrs) which oxidizes to pda. subsequent ath incubation formed the pdms-pda-ath complex ( . mg/ml in pbs, ph . , hrs). i-labeled ath was used as a tracer. one set of sous (n= ) was then exposed whole blood (hematocrit . ) for days. the heparin component of ath, if active, selectively binds antithrombin (at); therefore, the anticoagulant activity of ath modified sous was evaluated by measuring at uptake from plasma ( hrs, n= ) to pdms-pda-ath. i-labeled at was added to plasma as a tracer. results. initially, . µg/cm of ath was bound to the pdms-pda oxygenators after hours. this level suggests monolayers were formed. subsequent exposure to blood removed % after hours, with . µg/ cm of ath remaining on the surface. this indicates the binding of ath to pdms-pda was relatively stable. abb. p - . shows that pdms-pda-ath sous bound . ng/cm of at from plasma, significantly higher than the precursor pdms-pda, at . ng/cm . this demonstrates that the anticoagulant activity of heparin in ath remains active when attached through pda. conclusions. pda, used as an adhesive agent to attach ath to pdms microfluidic sous, provides high ath surface density, increased stability, and increased anticoagulant activity. introduction. in neonatal intensive care units, respiratory insufficiency among low-birth weight infants has been a major cause of mortality. for preterm infants, central umbilical cannulation has been widely performed for administering antibiotics, electrolytes, and nutrients. these umbilical vessels can become a source of vascular access to connect the preterm infant to an artificial placenta (ap) that provides sufficient gas exchange to overcome respiratory distress. the concept of an ap requires large bore access via umbilical vessels. in utero, umbilical artery (ua) and vein (uv) have wide diameters ( - and - mm, respectively). after birth, these vessels constrict, and need to be re-expanded to maintain high extracor- background. respiratory adaptation comprises the fundamental transition from a hydrospheric to an atmospheric environment at birth, realized by different, highly regulated physiologic changes in the cardiorespiratory system. if these are disturbed or delayed, cardiorespiratory disorders occur, frequently appearing as respiratory distress in the first hours of life. the management of respiratory transitional disorders is focused mainly on respiratory support. in addition to conventional therapies, anthroposophically extended medicine offers the possibility of treatment options based on an integrative approach to man and nature, to illness and healing. the anthroposophic medication pulmo/vivianit comp. proved to be effective in the treatment of pulmonary disorders in children and adults without indication of safety problems. therefore, we hypothesized a possible effect in neonatal respiratory transitional disorder. case report . a newborn girl presented progressive signs of respiratory distress after birth. pregnancy, delivery by elective cesarean section at a gestational age of / weeks and primary adaptation had been normal. after repetitive application of pulmo/vivianit comp. orally signs of respiratory distress disappeared within minutes and the girl could stay with the mother under continuous monitoring, that did not reveal abnormal findings until discharge on day five. case report . twin boys were delivered by cesarean section at / weeks of gestation. only the second twin developed signs of respiratory distress including the need for supplemental oxygen. to support the child's own effort in managing the respiratory transition, pulmo/ vivianit comp. was given orally. within minutes this was followed by a gradual improvement of respiratory symptoms. the sustainable effect was confirmed by normal findings during monitoring and regular examinations until discharge on day seven. discussion. respiratory transitional disorders have a high incidence and there is an urgent need for preventive and therapeutic interventions. based on the anthroposophic knowledge of human, nature and substance, the treatment with pulmo/vivianit comp. supports specifically the transitional changes in the respiratory system at birth. the rapid and sustainable improvement of respiratory symptoms and the overall functional state of the babies in both cases following the application of pulmo/vivianit comp. gives reason to be attributed to this specific treatment. no adverse effects could be observed. the idea of specifically supporting the infants own regulative forces in managing the disorder is confirmed by the fact, that the observable development after application of the medication resembles exactly the natural course of the disease, however in an accelerated mode. conclusion. according to the encouraging results presented here, the treatment of respiratory tranistional disorders with pulmo/vivianit comp. merits further attention in clinical practice and research. introduction. necrotizing enterocolitis, an idiopathic inflammatory bowel necrosis, is a common gastrointestinal emergency in very low birth weight premature neonates. neonatal intestinal macrophages progressively acquire a gestational age-dependent non-inflammatory profile. thus, the higher proinflammatory activity of premature intestinal macrophages might contribute to inflammatory mucosal injury leading to nec. lactoferrin, a mammalian milk glycoprotein, has various effects on the host innate immune defense and showed promising results in clinical studies to prevent late-onset sepsis and nec in premature infants. therefore, the aim of the study was to investigate the effect of human lactoferrin on lps and lta stimulated cord blood monocyte-derived macrophages of term and preterm neonates compared to healthy adults. methods. cord blood and peripheral blood monocytes were differentiated in the presence or absence of lactoferrin and then stimulated with the tlr agonist lta or the tlr agonist lps. the surface expression of tlr /tlr , tlr-signaling, intracellular tnfα production and secretion were evaluated by flow cytometry. results. lactoferrin attenuates in a dose-dependent manner the tnfα production of monocyte-derived macrophages among the age groups. this effect is mediated by a decreased tlr-expression of lactoferrin treated macrophages and resulted in diminished tlr-signaling of p and erk / upon stimulation with lps and lta. conclusion. in summary, human lactoferrin attenuates the proinflammatory response upon tlr /tlr activation of neonatal macrophages. these data show that lactoferrin mediates anti-inflammatory effects by down-regulation of tlr and tlr expression on neonatal macrophages. we thus conclude that these anti-inflammatory properties might be a potential mechanism contributing to the preventive effects of lactoferrin in the premature gut. background. very early life pain exposure and stress induces alterations in the developing brain and leads to altered pain sensitivity. in premature infants with a history of numerous early postnatal adverse events, behavioral responsiveness and hypothalamic-pituitary-adrenal (hpa) axis reactivity may show alterations as well. aims. we compared a multidimensional response to a painful situation (vaccination) in three month old infants. the study involved very preterm, moderate to late preterm infants and full-term infants with varying exposure to pain and stress within the first weeks of life. study design. at the age of three months, we evaluated the infants' reactivity to intramuscular injections for immunization. subjects. the study included very preterm infants, moderate to late preterm infants and full-term infants. outcome measures. we assessed heart rate recovery, bernese pain score and increase of salivary cortisol following vaccination. we also evaluated the flexor withdrawal reflex threshold as well as prechtl's general movements. secondly, we assessed factors potentially influencing pain reactivity such as exposure to pain/stress, gender, use of steroids or opioids and mechanical ventilation. results. very preterm, moderate to late preterm and full-term infants showed different reactivity to pain in all analyzed aspects. very preterm infants showed a lower level of behavioral and physiologic reactivity and exposure to pain/stress predicted lower cortisol increase. conclusion. at three months of age, very preterm infants show an altered level of hpa axis reactivity. efforts aiming at minimizing pain and stress in premature infants should be taken. background. moderately and late preterm infants represent a considerable and increasing proportion of infants cared for in neonatal departments worldwide. preterm infants parents are at risk for postpartal depression (ppd) and traumatization (ptsd) and preterm infants are at risk for developmental impairment. aim. to assess the correlation of parental ppd and ptsd and infants' neurologic abnormalities and illness severity. subjects. we studied mothers and fathers of preterm infants (born at to weeks of gestation) and mothers and fathers of fullterm infants. we assessed parental ppd, ptsd and perceived social support and infants' neurologic development at birth, term and three months corrected age. results. preterm mothers and fathers had significant higher depression scores after birth compared to fullterm parents (p= . and . ). preterm fathers also had higher traumatization scores compared to fullterm fathers (p< . ). probable or possible ppd/ptsd was not correlated to infant's illness severity. no differences in neurologic development were found between preterm and fullterm infants. conclusion. moderate to late preterm infants' parents are at increased risk for ppd irrespective of infants' neurologic development or illness severity. aim. this study evaluated the impact of blood sampling via peripheral arterial catheters on cerebral oxygenation and blood volume as a function of blood sampling velocity. methods. near infrared spectroscopy was applied to very low birth weight infants during peripheral arterial blood sampling. changes in cerebral oxygenated, deoxygenated and total haemoglobin, cerebral blood volume and cerebral oxygenation index were recorded. heart rate and oxygen saturation were measured continuously. to assess the impact of blood sampling velocity, both fast second and slow second sampling procedures were performed in a cross-over study design, in which the order of sampling velocities was randomised for each patient. results. both fast and slow blood sampling procedures resulted in a significant decrease in cerebral oxygenation index (fast, p= . , slow, p= . ), and an increase in mean heart rate (both p= . ) and mean blood pressure (p= . and . ). oxygenated and total haemoglobin and cerebral blood volume only decreased significantly after slow blood sampling (p< . ). conclusion. blood sampling from peripheral arterial catheters leads to significant fluctuations in cerebral oxygenation independent of the sampling velocity. changes are comparable to those reported from umbilical blood sampling. we advise that blood sampling should be restricted as much as possible. l vapotherm l vapotherm l optiflow l optiflow background. there are different organisational models to manage a nicu. we recently introduced "microsystems" and cohorting of patients according to acuity in our level iii unit. one outcome parameter to assess the impact of this change is the noise level as this implementation will create designated areas with more and less intensive care within the nicu. we hypothesize that noise levels will be different in both areas before and after introduction. weekends: compared to weekdays, average noise levels were significantly reduced by at least dba to ± . dba (day) and ± . dba (night). conclusion. measured noise levels are higher than current recommendations for nicus (aap: < dba). noise level seems to be more affected by organisational conditions (e.g. handover, day/night and weekends). overall, ms seems to lower the noise exposition significantly; it does not increase the noise exposition in the acute area but reduces it in the intermediate area. acknowledgement. the project is funded by hahso. background. there are different organisational models to manage a nicu. we recently introduced "microsystems" and cohorting of patients according to acuity in our level iii unit. one outcome parameter to assess the impact of this introduction is the length of rounds. this implementation will create designated areas with more and less intensive care within the nicu. we hypothesize that round length will be shorter after introduction of the new model. introduction. evidence is inconsistent to support checking gastric residual volumes (grv) in predicting feeding intolerance in preterm infants. checking of gastric residual volume remains standard practice in guiding feeding advancement in several neonatal centers. we hypothesizes that this practice delays establishment of full enteral feeding with associated complications. objective. the effect on time to reach full feeds ( ml/k/day) of not checking gastric residual volume in advancing feeds in preterm infants. results. infants were enrolled. there was no difference in time to reach full feeds in both groups. there was no difference in episodes of feeding interruptions, incidence of sepsis, reaching bw, and % of bw between two groups. however, two infants in the control group developed nec. please see table and for results. conclusion. there were no adverse events noted. the time to achieve full enteral feeds was short in both groups. in clinical practice, vlbw babies take longer time to reach full enteral feeds and gastric residuals could be a significant barrier to advancement of feeds. this study serves as a feasibility trial to do multicenter rct to study effect of not checking gastric residual on time to reach full feeds and incidence of nec in vlbw babies. application of fortifier during breastfeeding -a new perspective for the discharged premature infant? background. to meet the nutritional needs of preterm infants and to establish adequate growth, multicomponent fortifiers are added to expressed human milk until term or in growth restriction up to weeks of gestation according to the espghan guidelines. this is in conflict with direct breastfeeding. we established a method of feeding fortifier with finger feeder during breastfeeding and investigated the impact of this new method on weight gain in preterm born infants after discharge. furthermore, acceptance and practicability of fortification with the finger feeder were evaluated. materials und methods. infants born < weeks were included in this observational study. before discharge mothers were trained by lactation consultants to feed fortifier with finger-feeder during breastfeeding. therefore the fortifier was dissolved in ml of warm water. the mixture was drawn up in a syringe attached to a finger-feeder and injected slowly in the mouth corner of the infant during breastfeeding. primary outcome of the study was weight gain; secondary outcomes were acceptance and practicability of this new method. results. in total, infants were analysed and divided into "fortifier acceptors" (n= ) and "non-fortifier acceptors" (n= ). demographic parameters were similar between the two groups. weight gain per day after discharge was higher in the fortifier acceptors (median weight gain: , g/d vs. , g/d, p= , ) without reaching statistical significance. in % of the study population, the acceptance was very high; the other half reported feeding problems and irritation of the infant due to fingerfeeder use. discussion. finger-feeder use for fortifier application in preterm infants enables mothers to exclusively breastfeed their baby. weight gain of premature infants after discharge was higher in the group where mothers used this new method. a after passage through the ngt (a total of runs and measurements using a new ngt for each individual run), concentrations of retinol palmitate were measured. the same measurements were performed with droplets of vitamin a mixed in ml of the same preterm formula feeds over a -minute period. these measurements were then compared to and droplets of vitamin a in ml and ml of preterm formula feeds without prior passage through a ngt ( runs each). all measurements were performed in preterm formula after a run through the ngt and not in a blood sample. retinyl palmitate was extracted from formula and oil samples ( µl each) by adding tetrahydrofuran (thf; , ml), vortexing and centrifugation. hplc buffer ( % acetonitril; % thf; mg butylhydroxytoluol as antioxidant) was added to supernatant of milk samples ( , ml) and oil samples ( µl). analysis was performed using standard hplc method using uv-detection at nm. results. the measurements were as follows: droplets of vitamin a in ml of feeds: ± µm; droplets of vitamin a in ml of feeds: ± µm; droplets of vitamin a in ml of preterm formula without prior passage through ngt: ± µm, and droplets of vitamin a in ml of preterm feeds ± µm. no significant differences were seen between the measurements (p> . ). conclusions. we conclude that vitamin a can be given as an oral solution with preterm formula feeds through a ngt, yielding similar concentrations when compared to oral administration. this finding may be of relevance to the conceptualization of future studies in the field of neonatology and pediatrics using vitamin a preparations. background and aim. studies show that more than two thirds of perinatal death could be attributed to insufficient or ineffective team communication [ ] . therefore, it has been suggested to include simulationbased learning methods to acquire and enhance important skills for high-risk events such as neonatal resuscitation [ ] . high fidelity simulation training is an ideal tool to improve team behavior [ ] . we aim to examine if targeted simulation training improves skills, the postnatal management of extremely preterm infants, teamwork and communication during simulated neonatal scenarios. methods. physicians and nurses from several international hospitals are invited to our simulation centre. during a two-day workshop(ws), participants are exposed to different simulation scenarios. the ws includes delivery room management as well as less invasive surfactant administration. after a theoretical session, the participants are actively involved in simulation scenarios using the premiehal®/newbornhal®. all simulations are video recorded using simstation. the simulation room is fully equipped and resembles a neonatal intensive care unit (nicu). after each simulation, participants receive feedback using structured debriefing and video analysis. all participants have to complete a preand post-ws questionnaire. follow-up-questionnaires after three and months post-ws are sent by e-mail. these questionnaires are used to evaluate the clinical benefit of the training. the pre-ws questionnaire includes demographic data of participants (e.g. home institutional guidelines), current teamwork and communication during emergency situations in their nicu. post-ws questionnaires assess their experience with the ws and their own learning effect. the follow-up questionnaires aim to determine whether the ws impacts the participants' approach of neonatal emergencies, teamwork, and communication or improves patient safety at the participants home nicu. results. this is an ongoing study. by comparing pre-, post-and followup questionnaires we can identify if the participants changed the management in their home hospitals and if these changes are related to a better outcome. furthermore, we can identify what problems and obstacles occur during this process of change. the first analysis showed that our ws led to the introduction of regular simulation team trainings at the participant's hospital, to a change of teamwork and communication (e.g. identification of the team-leader) and to a better cooperation with the department of obstetrics and gynaecology. also, participants wish to introduce special skills(e.g. developmental care handling procedures, less invasive surfactant administration procedure)in their nicus. discussion. we employed a new approach of ongoing education and skills enhancement during the immediately newborn care. global rating scales should be used for the objective measurement of teamwork before and after the ws. on-site visits after the ws for evaluating the benefit of the changes and to help introducing new methods locally would be preferable. intuitive parenting: a dialectic counterpart to the infant's integrative competence diagnostic interview to assess regulatory disorders in infancy and toddlerhood (baby-dips) eltern-belastungs-inventar. deutsche version des parenting stress index (psi) the utility of simulation in medical education: what is the evidence? team training in the neonatal resuscitation program for interns: teamwork and quality of resuscitations münster schlaganfallregister unterscheiden sich anzahl der intubationsversuche und gesamtdauer der intubation zwischen zwei perinatalzentren (pnz) mit unterschiedlichen prämedikationsrichtlinien? material und methoden. an zwei level -pnz (pnz und pnz ) wurden prospektiv in einem zeitraum von monaten früh-und reifgeborene untersucht, die endotracheal intubiert wurden. anhand einer videodokumentation wurden anzahl der intubationsversuche und gesamtdauer vom erstmaligen einführen des tubus in die nase bis erreichen der lage der fixierung evaluiert. ein intubationsversuch begann und endete jeweils mittelwert (quartilen) und an pnz , ( ; ) (p= , ). die gesamtdauer der intubation mit prämedikation war an anzahl der intubationsversuche (nicht signifikant) und gesamtdauer (signifikant) der intubation waren bei pnz geringer als bei pnz . ohne prämedikation (nur an pnz durchgeführt) dauerten elektive intubationen kürzer als mit. dies spiegelt vermutlich die anweisung in pnz wider, dass prämedikation nur bei abwehr/ schmerzreaktion des kindes gegeben werden sollte, so dass wartezeiten zur applikation entstanden. schlussfolgerung. an pnz erhielten % der kinder zwei, % drei und % vier medikamente, an pnz erhielten % kein medikament, % eines acknowledgements. we wish to acknowledge the contribution of medical and nursing staff at neonatal intensive care unit at mcmaster children hospital to conduct the study. abstracts scheint demnach eine größere bedeutung für das belastungserleben zu haben, als das kindliche regulationsverhalten. schlussfolgerung. für das langfristige gelingen der co-regulation zwischen eltern und kind spielt das elterliche selbstvertrauen eine wesentliche rolle (papoušek u. papoušek, ) . so ergibt sich für die nachsorge der frühgeborenen und ihrer familien der anspruch, neben entwicklungsthemen des kindes, auch die psychische anpassung der eltern und insbesondere deren elterliche kompetenzwahrnehmung in den blick zu nehmen. methoden. alle studierenden des reformstudiengangs medizin des . semesters wurden befragt, um freiwillig an der studie teilzunehmen. studierende wurden eingeschlossen und in zwei gruppen randomisiert: simmed-gruppe (n= ) und campus-gruppe (n= ). den gruppen wurde eine typische anamnese eines kleinkindes mit meningokokken-sepsis präsentiert und die studierenden hatten minuten zeit, den virtuellen patienten (simmed bzw. campus) zu untersuchen, diagnostische maßnahmen durchzuführen und entsprechend zu behandeln. zwei wochen später wurde ein -minütiger osce-test (objective structured clinical examination) anhand einer kleinkindpuppe mit den klinischen zeichen einer meningokokkensepsis durchgeführt. im osce war gefordert, eine körperliche untersuchung und diagnostische/therapeutische maßnahmen durchzuführen. anhand einer checkliste mit items wurde geprüft (maximal zu erreichende gesamtpunktzahl , - punkte je item). verglichen wurde die im osce erreichte gesamtpunktzahl und die punktzahl der einzelnen items mittels t-test. die osce-prüfer waren hinsichtlich der gruppenzuordnung geblindet. ergebnisse. die simmed-gruppe erreichte im osce-test signifikant mehr gesamtpunkte (mw , ; sd± , ) als die campus-gruppe (mw , ; sd± , ; p< . ). insbesondere bei den therapeutischen maßnahmen wie volumengabe und kortikosteroidgabe erreichten die studierenden der simmed-gruppe bessere ergebnisse. bei den diagnostischen maßnahmen, wie auskultation, blutdruckmessen, sauerstoffsättigung messen zeigte sich kein signifikanter unterschied zwischen den gruppen. diskussion. die ergebnisse dieser studie zeigen, dass die schulung am simmed-tisch eine geeignete möglichkeit darstellt, das theoretisch erworbene wissen in konkrete handlungen bei einer patienten-simulation umzusetzen (abb. p - ). s. meyer , s. gottschling , e. tutdibi , l. gortner , i. oster universitätsklinikum des saarlandes, klinik für allgemeine pädiatrie und neonatologie, homburg, deutschland, universitätsklinikum des saarlandes, klinik für kinder-und jugendmedizin, zentrum für kinderschmerztherapie und palliativmedizin, homburg, deutschland, unversitätsklinik für kinder und jugendmedizin gebäude , homburg, deutschland, universitätskinderklinik homburg, homburg, deutschland hintergrund. die verwendung von komplementär-und alternativmedizin (cam) findet bei pädiatrischen patienten mit bösartigen erkrankungen nicht selten statt. patienten und methodik. fallbericht. ergebnisse. hier berichten wir über einen -jährigen jungen mit einem metastasierten ependymom, bei welchem es im rahmen einer cam-behandlung zu einer schweren iatrogenen zyanidvergiftung gekommen war. klinisch imponierte ein encephalopathisches krankheitsbild mit agitation und einer schweren initialen bewusstseinsstörung (gcs: ) . die bei aufnahme durchgeführte blutgasanalyse zeige eine schwere metabolische azidose mit ausgeprägter laktaterhöhung. nach intensiver befragung der eltern berichteten diese über die inanspruchnahme von cam-therapien. hierbei wurden über einen zeitraum von rund einer woche tägliche infusionstherapien sowie orale gaben mit soge-nanntem "vitamin b " durchgeführt. nach gabe von natriumthiosulphat kam es zu einer raschen besserung der klinischen symptomatik ohne auftreten von residuen. die toxikologische bestimmung der serumzyanidkonzentration ergab einen hochpathologischen befund. schlussfolgerung. bei kindern, bei denen es zum auftreten eines akuten encephalopatischen krankheitsbildes kommt, sollte differenzialdiagnostisch an eine iatrogene zyanidintoxikation gedacht werden. diese kann im rahmen einer cam-therapie mit amydalin und aprikosenkernen auftreten. hintergrund. ein substratmangel, wie hypoxie oder hypoglykämie, können cerebral zum zellschaden oder gar zelluntergang führen. nach schwerer perinataler asphyxie kommt es bei reifen neugeborenen typischerweise zu einer parenchymschädigung im bereich der basalganglien. weniger bekannt ist aber, dass durch einen mangel an glucose, im gehirn verursachte schädigungsmuster, welches so bei reifen neugeborenen vorkommt. durch bildgebende verfahren ist jedoch ein unterschied der beschädigten cerebralen areale, je nach substratmangel, festzustellen. kasuistik. wie berichten von einem reifen weiblichen neugeborenen der . ssw. die geburt erfolgte mittels vakuumextraktion. postnatal fielen bis auf eine kleine ve-marke keine weiteren auffälligkeiten auf. am dritten lebenstag zeigte sich das kind in der geburtsklinik zunehmend schlapp und trinkfauler bei gleichzeitig bestehender hyperbilirubinämie. aufgrund eines serum-bilirubinwertes von mg/dl wurde das kind zur weiteren therapie auf unsere neonatologische intensivstation überwiesen. bereits im verlauf des transportes kam es zu einem generalisierten tonisch klonischen krampfereignis. der erste gemessene blutzucker bei ankunft lag bei mg/dl. nach glucose-bolus und dauerinfusion, sistierten die klinischen zeichen einer hypoglykämie und die blutzuckerwerte waren im verlauf stets im normbereich. ein erweitertes neugeborenen screening zum ausschluss einer gluconeogenesestörung oder anderer ursachen einer postnatalen hypoglykämie oder stoffwechselstörung war unauffällig. das initiale aeeg zeigte ein anfallsgeschehen. im mrt zeigten sich parietooccipital bilaterale diffusionsrestriktionen und eine verminderte mark-rindendifferenzierung. auch im verlauf konnte bis auf die anamnestisch berichtete malnutrition keine ursache für die hypoglykämie gefunden werden. schlussfolgerung. in der neonatalperiode kann eine protrahierte, nicht erkannte und zu spät therapierte hypoglykämie zu einer irreversiblen okzipitalen parenchymschädigung des kindlichen gehirns führen. warum es ausgerechnet in dieser region bei hypoglykämie in der neonatalperiode zu einem lokalisierten zelluntergang kommt, bleibt unklar. results. neonates with normal mdi or mild disability show significantly lower wms, gms and cs compared to infants with moderate or severe mental disability at year corrected age. the same is true for pdi at year corrected age for wms, gms and cs and years corrected age for wms and cs. conclusion. there is currently not much evidence with regard to the relevance of topography of injury when trying to predict long-term outcome in preterm infants with ivh. the proposed score might serve as a prognostic tool with regard to the severity of brain damage and longterm neurological outcome in preterm infants with ivh. gestational age related reference values in preterm infants < weeks of gestation for the amplitude-integrated eeg using the burdjalov score introduction. the amplitude-integrated eeg (aeeg) is becoming more important to monitor brain activity in premature infants. studies have shown that early aeegs correlate with later neuro-developmental outcome. various scoring systems and missing gestational age related reference values for the aeegs complicate the comparison of published data. the aim of our study was to establish gestational age related reference values for the aeegs using the burdjalov score in preterm infants < weeks of gestation. methods. preterm infants [gestational age (ga) < weeks of gestation] who had an aeeg within the first days of life were retrospectively included into the study. the aeegs had been analyzed using the burdjalov score [continuity (co), cyclicity (cy), amplitude of lower border (lb) and bandwidth span and amplitude of lower border (b)] and correlated with the gestational age. results. the analysis of aeegs showed increasing total burdjalov scores at higher ga. the subscores [continuity (co), cyclicity (cy), amplitude of lower border (lb) and bandwidth span and amplitude of lower border (b)] also increased with increasing ga. conclusion. gestational age related reference values for the burdjalov score were determined in preterm infants < weeks ga. increasing total burdjalov scores correlate with increasing ga. background. hypoxic-ischemic injury (hi) to the developing brain occurs in in live births and remains a major cause of significant morbidity and mortality. a large number of survivors have long-term sequelae including seizures and neurological deficits. however the pathophysiological mechanisms of recovery after hi are not clearly understood and preventive measures or clinical treatments are non-existent or not highly effective in the clinical setting. sildenafil as a specific pde inhibitor leads to increased levels of the second messenger cgmp and has the ability to promote neuroprotection. objective. in this study we investigated the effect of sildenafil treatment on activation of histological recovery and neurogenic response after an ischemic insult to the developing brain. methods. -day-old c bl/ -mice were subjected to sham-operation or underwent ligation of the right common carotid artery followed by hypoxia ( %) for minutes. animals were administered either a single dose of sildenafil ( mg/kg, ip) or received multiple doses on consecutive days starting h after hypoxia. animals treated with vehicle served as controls. furthermore pups received brdu ( mg/kg, daily) from p to p and were either perfusion-fixed at p for immunohistochemical analysis or brains were dissected and h after hypoxia and analyzed for cgmp by means of elisa. results. based on cresylviolet staining, single and multiple sildenafil injections revealed no differences in histological injury compared to sham animals. in addition animals treated with sildenafil showed no increase in brdu positive cells in the striatum. nevertheless doublecortin x as a marker for neuronal precursor cells, was enhanced after sildenafil therapy. furthermore cgmp was enhanced after sildenafil therapy. here we report that single or multiple treatment with sildenafil after hi showed no improvement in histological brain injury or promotion of cell proliferation but enhanced neuronal precursors. our results suggest involvement of the cgmp signaling pathway after hi and contribute to a better understanding of neonatal hi. background. hypoxic-ischemic injury (hi) to the developing brain occurs in in live births and remains a major cause of significant morbidity and mortality. a large number of survivors have long-term sequelaes including seizures and neurological deficits. however the pathophysiological mechanisms of recovery after hi are not clearly understood and preventive measures or clinical treatments are nonexistent or not highly effective. sildenafil as a specific phosphodiesterase- (pde ) inhibitor leads to increased levels of the second messenger cgmp and has the ability to promote neuroprotection. objective. in this study we investigated the effect of sildenafil treatment on activation of intracellular signaling pathways, especially the involvement of the pi /akt and gsk- β pathway after an ischemic insult to the developing brain. methods. -days-old c bl/ -mice were subjected either to shamoperation or underwent ligation of the right common carotid artery followed by hypoxia ( %) for minutes. animals were administered sildenafil ( mg/kg, ip) or vehicle hrs after hypoxia and brains were dissected or h after sildenafil injection. pde expression was analyzed using pcr and pkg-i, p-akt, p-gsk- β and β-catenin were quantified using western blot analysis. results. here we show that the expression of pde in injured animals is decreased at and h. animals treated with sildenafil, who underwent hi showed no further difference compared to controls. furthermore pgsk- β is increased after hi at h. sildenafil enhanced p-akt in treated animals whereas there was no detectable difference in pkg-i and β-catenin levels. conclusions. although pkg-i and β-catenin were not upregulated at h, our data suggest that sildenafil activates the pi /akt signaling pathway through pde inhibition. einleitung. rm sind die häufigsten herztumore im kindesalter und meist mit einer tuberösen sklerose assoziiert. in der regel zeigen sie ein gutartiges verhalten mit einer spontanen regredienz nach der geburt. sie können jedoch auch zu intrakardialen stenosen und/oder arrhythmien führen, die einer spezifischen therapie bedürfen. everolimus wird seit einigen jahren erfolgreich in der behandlung cerebraler tumoren bei kindern mit tuberöser sklerose eingesetzt. kasuistik. bei einem männlichen feten waren multiple kardiale rm festgestellt worden, die während der schwangerschaft ein deutliches wachstum zeigten. der größte tumor füllte das cavum des linken ventrikels nahezu vollständig aus. eine tuberöse sklerose wurde genetisch gesichert (mutation im tsc -gen). nach ausführlicher aufklärung und beratung der eltern erfolgte die geburt spontan beim gestationsalter von + ssw (gg g, gl cm, na-ph , ) in einem perinatalzentrum. die postnatale anpassung verlief regelrecht (apgar / / ). nach anlage eines nabelvenenkatheters und beginn einer dauerinfusion mit alprostadil wurde das neugeborene im alter von stunden in unsere klinik verlegt. klinisch war das kind stabil. auskultatorisch war ein / -systolikum nachweisbar. obwohl dopplersonographisch nur eine milde flussbeschleunigung von , m/s im linksventrikulären ausflusstrakt (lvot) messbar war, wurde aufgrund des morphologischen befundes mit dem potential einer vollständigen obstruktion des lvot u.a. die indikation zur chirurgischen resektion diskutiert. mit dem einverständnis der eltern wurde stattdessen am . lebenstag ein therapieversuch mit everolimus begonnen. die erhaltungsdosis für den angestrebten serum-talspiegel von - ng/ml lag bei mg/m /d. zusätzlich wurden prophylaktisch trimethoprim-sulfamethoxazol und nystatin gegeben. unter der behandlung kam es zu einer raschen und deutlichen größenregredienz der tumore. die infusion mit alprostadil erfolgte bis zum . lebenstag; der ductus arteriosus verschloss sich spontan. die behandlung mit everolimus konnte nach tagen beendet werden. klinisch wurden keine nebenwirkungen beobachtet. laborchemisch war eine leichte hypertriglyceridämie nachweisbar. in der durchflusszytometrie zeigte sich eine lymphopenie mit verminderter anzahl von b-zellen sowie cd -und cd -positiven t-zellen. bei entlassung am . lebenstag war der knabe in sehr gutem allgemeinzustand. ein herzgeräusch war nicht mehr nachweisbar. bei den nachuntersuchungen über einen zeitraum von wochen konnte ein erneutes tumorwachstum ausgeschlossen werden. schlussfolgerung. die behandlung mit everolimus führte bei unserem patienten zu einer regredienz eines riesigen rm im linken ventrikel, die erheblich schneller verlief als sie im rahmen des spontanen verlaufs zu erwarten gewesen wäre. ein komplizierter herzchirurgischer eingriff konnte vermieden werden. die dokumentierten immunologischen nebenwirkungen sollten sich im verlauf zurückbilden. möglicherweise ist die behandlung mit everolimus auch für patienten mit therapiepflichtigen kardialen rm geeignet. eine seltene differentialdiagnose der pulmonalen hypertonie: diffuse kapilläre pulmonale hämangiomatose key: cord- - pkhgn authors: o'riordan, declan; porcelli, peter j. title: neonatal care and data date: journal: pediatric informatics doi: . / - - - - _ sha: doc_id: cord_uid: pkhgn neonatology encompasses the care of all infants: from term newborns to extremely premature infants, from healthy infants to those suffering from severe infections or genetic disorders. while the management of infants can vary greatly, there are essential core data and knowledge that is needed to care for them. to characterize baseline information about pregnancy, labor, and delivery • needed by neonatal practitioners during birth and transition from obstetrical to pediatric care to outline medical concerns of premature infants, the levels and environments • of neonatal care and the information needs in the transition from neonatal to primary care to describe information challenges in neonatal care • neonatology encompasses the care of all infants: from term newborns to extremely premature infants, from healthy infants to those suffering from severe infections or genetic disorders. while the management of infants can vary greatly, there are essential core data and knowledge that is needed to care for them. in neonatal care, the medical history covers two patients: the mother and the infant. thorough knowledge of the maternal history (medical, obstetrical, medication, and social) is crucial for evaluating any newborn. the efficient and accurate transfer of this information from the obstetrical to neonatal providers is a great challenge, but can benefit care tremendously. detailed knowledge of the current pregnancy is vital, but may be difficult to obtain, particularly when complications prompt emergency delivery. prenatal obstetrical care is largely delivered in outpatient centers that are associated to labor and delivery wards of delivering hospitals. a major impediment to the development of complete electronic patient records has been the inherent difficulty of integrating timely outpatient data into inpatient records, particularly during nonbusiness hours (nights, weekends, and holidays). gestational age-an infant may be term (between and weeks gestation), preterm (< weeks) or postterm (> weeks), where weeks are counted from the date of the last menstrual period (lmp), sometimes called post-menstrual age (pma). the date of (term) delivery (also called the "estimated date of confinement" or edc) can be calculated from the gestational age, when known or estimated from physical exam. obstetricians may modify the estimated due date based on ultrasound, if the mother's lmp is unknown. the gestational age (in days) of fetuses conceived via assisted reproduction (art) is determined by adding to the number of days since implantation of the fertilized egg. number of expected fetuses-until recently, higher ordered multiple gestations (triplets, quadruplets, etc.) were rare. assisted reproduction has made twins and triplets commonplace. between and , the number of twin live births rose % and the number of triplets and higher order deliveries rose %. higher-order pregnancies are at higher risk for complications and prematurity is commonplace. prenatal studies-prenatal care usually includes a standard battery of prenatal laboratory tests at various points during pregnancy. some tests (screens for maternal hiv, group b streptococcal and drugs of abuse) may prompt treatment protocols for mother and infant. these test results are a vital part of the prenatal and infant record and must be easily available as they can influence care shortly after birth. prenatal laboratory test results include: each of these results has implications for evaluation and treatment of the newborn, such as the administration of hepatitis b immune globulin in addition to hepatitis b vaccine. a major challenge of neonatal care is collection and processing of maternal data from obstetric records when outpatient offices are closed. in some cases, this may leads to duplication of maternal testing and possible unnecessary treatments of the infant. linkage of information between hospitals and obstetric offices could decrease this problem. in some cases, maternal prenatal lab tests processed at the intended delivery hospital can facilitate data availability at delivery. pregnancy complications-the evolution of a pregnancy greatly impacts neonatal conditions. potential complications include premature labor, fetal growth restriction, pregnancy-induced hypertension, pre-eclampsia, and others. these complications can extend maternal hospitalization, sometimes for weeks, well before delivery. fetal ultrasounds/echocardiograms-prenatal ultrasound provides an opportunity to estimate gestational age and identify problems in the developing fetus. a suspected heart malformation prompts a fetal echocardiogram and cardiology evaluation. an ultrasound-detected heart or other malformation may critically determine the location of delivery, the resuscitation protocol and treatment plan shortly after birth. maternal infections during pregnancy-infections by viruses, bacteria, and fungi may affect the developing fetus and newborn. some infections, particularly viral infections, may cross the placenta and have severe, sometimes fatal effects. other maternal infections, such as urinary tract infections, place the infant at higher risk for bacterial infections after birth. others, such as torch infections, may place the infant at risk for life-long complications. the prenatal course and treatment of maternal infection may help determine the extent of evaluation and need for treatment of the newborn. pregnancy interventions-perinatologists and surgeons are increasingly able to directly intervene in the course of fetal development. some of these interventions have been well accepted (amniotic fluid sampling, fetal transfusions), while others (fetal surgery) are experimental. nevertheless, fetal interventions will likely become more frequent in the future and their incorporation into a maternal-fetal record electronic record should be standard. consulting physicians-pediatric subspecialists (geneticists, nephrologists, cardiologist, neonatologists, and others) may meet with expecting parents prior to delivery and may participate in postnatal care. easy access to information about specialists' involvement and their contact information may help to streamline infant care after delivery. delivery records must document the onset of labor, time of rupture of membranes, presence of maternal fever, type and timing of medications/anesthesia administered to mother and method of delivery (vaginal, caesarean, forceps, or vacuum). obstetricians often note the presence of fetal heart rate decelerations prior to delivery that comprise four varieties: early, late, variable, and prolonged. while documentation may indicate only the presence of "decels," the type, frequency, duration, and severity of fetal heart rate deceleration may indicate placental insufficiency. meconium may be passed in utero and its presence in amniotic fluid place the infant at risk for fetal meconium aspiration and respiratory distress after birth. additionally, infection of the amniotic fluid, chorioamnionitis, may produce malodorous, cloudy amniotic fluid and place the newborn at high risk for bacterial infection. as a part of delivery, the newborn's condition is immediately assessed. many infants are initially cyanotic with rapid improvement as breathing begins. some infants require resuscitation, which may be complex and prolonged, for a variety of reasons, including persistent apnea, prolonged cyanosis, bradycardia, or poor tone. the apgar score is assigned to describe the infant's initial condition and response to resuscitation (table . ). good documentation of resuscitation describes an infant's condition, resuscitation steps instituted and response to resuscitation. because resuscitation may be prolonged and time is often short, thorough documentation may be difficult and may follow resuscitation and stabilization of the infant. while real-time documentation of resuscitation would be ideal, manpower and space for a human scribe are often limited in the delivery or operating room. while many parents learn the gender of the newborn during an antenatal ultrasound, some prefer wait to know until delivery. in most cases, the gender is readily apparent, but in a small percentage of newborns, the gender is not immediately evident in the delivery room and assignment must be deferred. ambiguous genitalia require careful discussions between all members of the treatment team and parents. as such, premature assignment of gender is inappropriate. the birthweight, length, and head circumference determine whether an infant is appropriately sized for the estimated gestational age based on normative values readily available on growth charts. infants who are smaller than expected (< %) are small for gestational age (sga) while infants who are larger than those infants whose weight, head circumference, and length are between the th to th percentiles are appropriate for gestational age (aga). while parents in united states almost exclusively use the english system (pounds, ounces, inches) when referring to the weight and length of the newborn, medical care of newborns, particularly medication dosing, requires these measurements in metric. in many cases, term newborns stay in the mother's room to facilitate bonding and feeding or are admitted to a well baby nursery, with anticipated discharge in - h. routine newborn care is often high-volume and information systems that link obstetrical care to newborn nursery to primary pediatric care may bring benefits in multidisciplinary care and patient satisfaction. in a typical community nursery, primary care practitioners (pediatricians and family practitioners) examine infants and review their records in the morning prior to seeing patients in the outpatient setting. challenges include: identifying subtle signs of illness-early signs of illness in the newborn may be subtle. some, such as difficulty in establishing feedings after delivery or heart murmurs may not manifest until after discharge, yet can be life-threatening if not detected early. high patient volume-newborn nurseries vary greatly in size. larger nurseries may employ hospitalists in addition to private pediatricians and family physicians to examine newborns prior to discharge. a challenge to planning newborn nursery information systems is the collection of examination data for documentation and conveyance to primary care practices efficiently, particularly when patient loads are high. critical laboratory values-efficient and coordinated notification of abnormal laboratory test results, such as direct antibody tests (dat), complete blood counts (cbcs), electrolytes, blood glucoses, and blood gas determinations may alert nursery physicians to potentials for problems that may delay discharge or require further workup or referral to a neonatal intensive care unit. infants are discharged from the nursery by h of age with office follow-up at week, but some may be eligible to go home with closer follow-up. issues such as resolving jaundice, early discharge from the hospital and first-time breast feeding mothers may require a coordinated follow-up visit sooner than - weeks. continuity of care from the nursery to primary care can be enhanced by phone calls to follow-up physicians, in addition to hospital documentation. the typical summary for term newborns contains: although many hospitals provide low level neonatal intensive care, very ill term infants requiring mechanical ventilation and advance life support must be stabilized and transported to the closest neonatal intensive care unit (nicu) . term nursery planning includes standardized procedures for the management and transfer of such infants, including: medical stabilization protocols for infants (including appropriate equipment • and trained physicians) coordination and transport of infants to known nicus • information transfer and documentation of care • well-designed information systems within a regional network can facilitate the gathering of needed information. transfer documentation for neonatal transport includes: a summary by the clinician of the infant's course and copies of the nursing flow sheets, medication records, laboratory results, and radiographic studies. design of computerized systems, in addition to collecting and making necessary information available, should facilitate its summarization and organization for optimal care. premature births currently account for - . % of all births in the united states. , advances have extended survival of infants as early as weeks gestation, with standard treatments for previously fatal diseases such as respiratory distress syndrome (rds). neonatal nurseries comprise a range of facilities of different sizes and capabilities. the march of dimes reports "toward improving the outcome of pregnancy" (tiop i and tiop ii) described criteria stratifying nurseries according to the complexity of care. , , level i nurseries offer basic resuscitation and care for uncomplicated deliveries. level ii (specialty) nurseries offer care for limited conditions that are expected to resolve quickly and that do not require extensive care. level iii (subspecialty) nurseries offer complex care, including surgical interventions, for critically ill term and preterm infants. further classification, that addresses the need for regionalization of specialized critical care, such as extracorporeal membrane oxygenation (ecmo) and neonatal cardiac surgery, has been proposed. higher level nicus employ high-risk obstetricians, perinatologists, neonatalogists, pediatric subspecialists, and neonatal nurses, dieticians, pharmacists, and respiratory therapists. prematurity is defined as birth occurring at less than completed weeks since the onset of the lmp. the range of gestational ages of premature infants conveys a range of birth weights (that may extend to as low as - g) and risks for both morbidity and mortality. viability indicates the possibility, but not the probability of long term survival. the limit of viability varies but may be estimated to be - weeks. because of their premature systems, these infants are at risk for a number of problems. respiratory insufficiency or failure is a frequent consequence of prematurity and may be multifactorial in nature. premature infants are at risk for respiratory distress syndrome (rds), due to surfactant deficiency and structural lung immaturity. therapies to support infants with immature lungs include endotracheal administration of surfactant and ventilatory support. premature infants with rds are at risk for subsequent chronic lung disease (bronchopulmonary dysplasia). measures of respiratory distress include: vital signs (respiratory rate, heart rate, and oxygen saturation), the physical exam and arterial blood gas results (ph, pao , paco ) and physiologic measures such as mean airway pressure (map) and inspired oxygen (fio ), with the oxygenation index (oi) as a calculated measure whose trends can be tracked over time. oi = (map × fio × )/pao infants with relatively mild respiratory insufficiency may be placed on one of several varieties of continuous positive airway pressure (cpap, a device that blows air into the nose at a controlled pressure): bubble cpap, mask cpap, and prong cpap. cpap pressure must be tracked as it follows potential improvement or worsening of respiratory status. infants who experience failure with cpap require mechanical ventilation. mechanical ventilation of the premature neonate is a complex and controversial topic. two general varieties of mechanical ventilation are available: conventional ventilation and high frequency ventilation. conventional ventilation provides a standard breath (pressure or volume) into the lungs at a given minimum rate per minute, dependent on the ventilator settings. available neonatal systems incorporate these varieties and offer the user the ability to adjust variables (tidal volume, peak pressure, rate, peep, and others). the second major classification of ventilators is the high-frequency ventilator. several types of these ventilators are available. high frequency ventilation provides small gas volumes at rapid rates to decrease the pulmonary trauma. the most common type is high-frequency oscillatory ventilator (hfov or oscillator) which cycles air in and out of the lungs rapidly. the oscillator has relatively few variables to track: mean airway pressure (map), displacement (delta p), frequency, and fio . while the individual level of these variables is very important, the trends of the variables and blood gas results provide a highly useful picture of an infant's respiratory status. two other types of high frequency ventilators are in general use include the jet ventilator, which is similar to the oscillator, but cumulatively provides for oxygenation and removal of waste gases and high frequency flow interrupters (hffi). the jet ventilator is used in combination with a conventional ventilator to provide positive end-expiratory pressure (peep) and intermittent breaths. it is more complex than a conventional ventilator, with different variables: jet peak pressure (jpip), inspiratory time, back up peep (baseline pressure), back up rate ( to several breaths per minute) and back up peak pressure. hffi is similar to jet ventilation but uses slower rates. airway pressure release ventilators (aprv) have also been used on neonates, but on a more limited basis. the tremendous cardiovascular changes occur during the transition from intrauterine to extrauterine life place premature infants are at high risk for two particular cardiovascular problems: patent ductus arteriosus (pda) and hypotension. pda is a persistence of an essential fetal connection (the ductus arteriosus) between the pulmonary artery and aorta that normally closes within - h in term neonates. in premature infants, the pda can worsen respiratory distress and lower systemic blood pressure. various medical and surgical therapies are used to close the duct. hypotension, another complication of prematurity, is a poorly defined entity in extremely preterm infants. at this time, neonatalogists commonly attempt to keep the mean blood pressure at least the gestational age during the first several days after birth. mean blood pressure = dbp + / * (sbp − dbp) the medical management of hypotension includes: (dopamine, dobutamine, epinephrine) are administered on a microgram per kilogram per minute rate (unlike narcotics, which are infused on a microgram per kilogram per hour rate). manual calculation of infusion rates and doses is error-prone. errors can be reduced through the design and mandated use of calculators that can be used in stressful situations. in addition to calculators, the mandated use of standard concentrations for continuous infusion medications by the joint commission, which limits available concentrations of medications, thus reducing pharmacy preparation errors. the large variations in neonatal weights may create fluid overload for premature infants, but this may be offset by the use of computerized "smart" pumps (see chapter ). steroids (in particular hydrocortisone), dosed by weight (mg/kg/day) or by body surface area (bsa) may help stabilize blood pressure (using calculator support): neonatal estimated bsa (m ) = . × wt (kg) + . extremely premature infants are at risk for brain damage due to hypoxic and ischemic insults to the developing brain and nervous system. infants less than weeks gestational age (at birth) are at significant risk for intraventricular hemorrhage (ivh). hemorrhages, detected using cranial ultrasonography, can range from very small to catastrophic, lethal hemorrhagic infarctions, which may create posthemorrhagic hydrocephalus, requiring neurosurgical intervention. periventricular leukomalacia (pvl), resulting from blood flow instability and exposure to infection among extremely premature infants, may be detected by cranial ultrasound and places an infant at significant risk for long term developmental problems. the presence of intraventricular hemorrhages, periventricular leukomalacia, or hydrocephalus is vitally important for future medical and developmental care and this information must be clearly conveyed to future physicians and allied developmental professionals. premature infants are immunologically naïve and vulnerable to a number of serious systemic infections, not only from maternal sources, but also those associated with hospitalization: vascular catheters, ventilator associated pneumonias, and necrotizing enterocolitis. in extremely premature neonates, use of the gut is limited initially, and therefore they must be supported at first with intravenous nutrition (total parenteral nutrition, tpn). as enteral nutrition is increased, the tpn is decreased accordingly. the management of premature infant nutrition is complex, requiring calculation of daily caloric, protein, fat, minerals, vitamins, and fluid needs as well as monitoring of growth and biochemical parameters. computer applications can reduce the time spent in performing these calculations and the errors inherent in detailed information tracking. applications that support tpn formulations have been described in the literature, with demonstrated reductions in both time spent and errors. [ ] [ ] [ ] [ ] in addition, systems have been deployed over several hospitals to extend standardization of tpn formulation. we are entering a new era for growth and nutrition monitoring that individualizes postnatal growth by integrating perinatal, family, and postnatal data. a multitude of peri-and postnatal factors influence infants' postnatal growth to determine what is "best," according to gestational age and pathology. determining adequacy of postnatal growth is more difficult than anticipated. an important distinction should be made between an intrauterine growth curves and a postnatal growth curves. intrauterine growth curves describe the distribution of fetal weights based on gestational age. they can be used to determine whether a newborn is small or large for gestational age. a postnatal growth curve describes the growth in weight, head circumference, and length after birth. superimposing the curves for premature infants reveals a striking deviation of the postnatal curve below the intrauterine curve, indicating a period of growth failure, particularly among those infants born most prematurely. while the intrauterine growth curve may represent ideal postnatal growth, with the current state of neonatal care, intrauterine growth curves cannot be used to assess the adequacy of postnatal growth of premature infants. in evaluating any standardized growth curve for use, several questions must be considered: from which population (ethnicity, gestational ages, socioeconomic status, etc.) • was the reference standard generated? does this population accurately reflect the infants whose growth will be assessed • with the chart in question? for example, standard intrauterine growth curves include only caucasian infant's from to weeks gestation in denver from to . a more recent study using a more diverse population with larger numbers of infants at each gestational age describes birth weight percentages for infants between to weeks (including a small number of infants between to weeks gestation). when was the population (from which the growth curve was derived) studied? • as advances in obstetrics, neonatology, and neonatal nutrition improve the care of premature neonates, recent studies may better reflect current care. for example, one of the earliest postnatal growth curves for premature infants demonstrated that kg infants regained birthweight by days, while a more recent curve reveals birth weight is regained much sooner ( . days). , ongoing care of infants requires accurate and efficient transfer of care plans and results of studies to the primary care pediatrician. the tremendous volume of information and documentation generated during a prolonged neonatal hospitalization is compounded by the fragmented nature of nicu care. an extremely premature infant may have many attending neonatologists, consultants, and trainees prior to discharge from the hospital. a major benefit of an effective information system in the nicu is the ability to locate and organize crucial information for follow-up of neonatal problems. states vary in the number of diseases included in the newborn screening panel and the number of newborn screens administered to each infant. the first sample is usually sent shortly after birth (after the first feeding) and the second sample between day and . samples are sent to state laboratories and results return in - weeks. accurate and timely collection and tracking of metabolic screens is vitally important and failure may result in preventable or treatable disease with devastating complications. regional registries, in conjunction with dedicated support personnel, can facilitate sharing of information and completion of follow-up with primary care physicians and specialists. newborn hearing screens are performed prior to infant hospital discharge. nicu infants are at particular risk for hearing loss (up to % in one series of infants born between to g. ) information about the necessity and timing of additional hearing tests for all infants should be transparent to parents and follow-up physicians. premature infants currently are covered by the same immunization schedule as term infants. a week gestational age premature infant receives month immunizations at a post-menstrual age of weeks. it is not uncommon for very premature infants to be hospitalized for months, with multiple immunizations given in the hospital. palivizumab, a monoclonal antibody against respiratory syncytial virus (rsv), is recommended to prevent rsv infection in many premature infants or those with chronic lung or congenital heart disease. eligible infants should be given as monthly injections during the rsv season, for up to the first years of life. communication of administered immunization, dates, and adverse reactions, must be communicated to the primary care physician to avoid lapses and unnecessary duplication of immunization doses. retinopathy of prematurity (rop) refers to the disordered growth of blood vessels supplying the developing retina. very premature infants are at greatest risk for rop and its sequelae because of the underdevelopment of retinal vessels. regular eye exams by a pediatric ophthalmologist are necessary to monitor the growth of retinal blood vessels and for the development and progression of rop. frequency of ophthalmologic examinations is scheduled according to disease progression, the risk of complications (permanent blindness) and the need for intervention (retinal ablative surgery) to lessen the risk for retinal detachment. , neonatal follow-up tracking systems for premature infants should include the ability to track scheduling, completion, and reports of ophthalmology exams to the primary care physician and to parents to ensure appropriate future care. although many infants assume the shared surname of parents, particularly if they are married, a significant portion of infants will not retain the surname initially assigned by the birth hospital. changes in parental marital and legal status, as well as adoption, may result in infant name changes. these issues (and potential for errors) are increased with multiple gestations and infants with the same name in the same nursery, and when the infant is discharged to follow-up with the primary care physician. nicus and neonatal identification systems must be able to disambiguate infants, even when names are changed, in the nicu and after discharge. the institute of medicine report stating that tens of thousands of patients die yearly in the us from medical errors. infants in the nicu are particularly vulnerable to errors and their impacts. pediatric medications dosing is based on patient weight. the small weights of premature infants, with rapid weight and body surface area changes and variable physiologies place sick neonates at high risk for medication errors. in the nicu, preterm neonates may receive multiple medications, which increase the likelihood of errors and drug interactions. the task of prescribing in the nicu is made even more difficult by the lack of accepted dosing guidelines for medications and the high rate of "off label" medication use due to overall paucity of studies specifically looking at medication use in neonates. nicu medication errors commonly occur at the ordering stage. extremely premature (low weight) infants are at risk for decimal place errors in dosing, that can be exacerbated with poor handwriting. in addition, many neonatal drugs are dispensed in vials from which very small amounts of drug must be withdrawn, which enable order of magnitude errors in ordering and administration. medication ordering error frequencies appear to be inversely proportional to body weight, with % of errors occurred at the prescribing and % of errors at administration. the two most common types of errors were incorrect dose and dosing interval, with increased rates of dosing errors occurring when new housestaff rotated through the nicu. additional risks for errors are incurred with complex calculations, such as discussed previously for continuous infusion ("drips") and total parenteral nutrition. in addition to calculators, standard concentrations for continuous infusions, with smart-pump technology and improved medication labeling have been associated with marked decreases in continuous infusion errors. quality improvement in medication delivery demands consideration of the entire delivery process rather than independent events. failure mode and effects analysis (fmea), a quality improvement technique developed in industry to improve safety, has identified general lack of awareness of medication safety, problems with administration and ordering of medications to be the most significant issues in nicu medication delivery. integration of information technology into ordering, dispensing, and administration of medications in inpatient environments is examined in chapter . code cards detail specific emergency medications and their doses according to weight in both milligrams and milliliters to be given during resuscitations. during neonatal resuscitation, drug doses are ordered, drawn from stock vials and administered emergently, and errors may easily occur. a preterm infant's weight may change markedly over a short period of time, and therefore, code cards must be updated frequently. one benefit of computer-generated code cards (that can be created using commercially available software, such as a spreadsheet) is automated updating, especially if the dosing is linked to the current weight (from an electronic record), or as part of the regular care routine. though medicine has been late to incorporate computers into daily routines, use of computers in neonatology is growing. linkage with obstetrical information systems can streamline entry of information into the neonate's record. growth may be more easily monitored. crucial information for follow-up physicians can be easily tracked and synthesized into discharge summaries. patient safety can be enhanced by decreasing errors in medication and tpn orders. as obstetricians, neonatologists, nurses, and pharmacists increasingly incorporate computer systems, a major challenge will be to synthesize these systems into a cohesive outpatient and inpatient network. maternal-perinatal morbidity and mortality associated with adolescent pregnancy in latin america: cross-sectional study teenage mother's predictions of their support levels before and actual support levels after having a child is adolescent pregnancy associated with adverse perinatal outcome? pregnancy in patients of advanced maternal age diabetes mellitus in pregnancy risk factors for early-onset group b streptococcal disease in neonates: a population-based case-control study obstetrics -normal and problem pregnancies first-and second-trimester ultrasound assessment of gestational age epidemiology and biology of multiple gestations committee on infectious diseases the apgar score has survived the test of time a practical approach to intersex in the newborn period signs and symptoms of neonatal illness a pilot project to design, implement and evaluate an electronic integrated care pathway epidemiology of preterm birth and its clinical subtypes year position statement: principles and guidelines for early hearing detection and intervention programs eye manifestations of intrauterine infections and their impact on childhood blindness trends in preterm birth and perinatal mortality among singletons: united states toward improving the outcome of pregnancy: recommendations for the regional development of matrnal and perinatal health services. white plains, ny: march of dimes national foundation toward improving the outcome of pregnancy: the s and beyond. white plains, ny: march of dimes birth defects foundation neurodevelopmental outcome of the late preterm infant management and outcomes of very low birth weight high-frequency ventilation is/is not the optimal physiological approach to ventilate ards patients invasive and noninvasive neonatal mechanical ventilation the sy-fi study: a randomized prospective trial of synchronized intermittent mandatory ventilation versus a high-frequency flow interrupter in infants less than g other approaches to open-lung ventilation: airway pressure release ventilation evolution of strategies for management of the patent arterial duct cardiovascular support in the preterm: treatments in search of indications decreasing errors in pediatric continuous intravenous infusions joint commision on accreditation of healthcare organizations. requirement b of joint commission national patient safety goals implementation expectations periventricular hemorrhagic infarction: risk factors and neonatal outcome incidence of healthcare-associated infections in high-risk neonates: results from the german surveillance system for very-low-birthweight infants development and evaluation of vie-pnn, a knowledgebased system for calculating the parenteral nutrition of newborn infants of lobsters, electronic medical records and neonatal total parenteral nutrition using information technology to reduce pediatric medication errors preventing provider errors: online total parenteral nutrition calculator parenteral nutrition in neonatology-to standardize or individualize longitudinal growth of hospitalized very low birth weight infants intrauterine growth in length and head circumference as estimated from live births at gestational ages from to weeks equations describing percentiles for birthweight, head circumference, and length of preterm infants a grid for recording the weight of premature infants newborn screening expands: recommendations for pediatricians and medical homes-implications for the system outcomes of extremely low birth weight infants primary care follow-up of the neonatal intensive care unit graduate retinopathy of prematurity requires diligent follow-up care to err is human: building a safer health system potential tenfold drug overdoses on a neonatal unit medication errors and incidents in pediatric inpatients use of nasal continuous positive airway pressure during neonatal transfer standard drug concentrations and smart-pump technology reduce continuous-medication-infusion errors in pediatric patients identification of priorities for medication safety in neonatal intensive care key: cord- - p b tyf authors: hartert, tina v.; carroll, kecia; gebretsadik, tebeb; woodward, kimberly; minton, patricia title: the tennessee children's respiratory initiative: objectives, design and recruitment results of a prospective cohort study investigating infant viral respiratory illness and the development of asthma and allergic diseases date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: p b tyf background and objective: the ‘attack rate’ of asthma following viral lower respiratory tract infections (lrti) is about – fold higher than that of the general population; however, the majority of children who develop viral lrti during infancy do not develop asthma, and asthma incidence has been observed to continuously decrease with age. thus, we do not understand how viral lrti either predispose or serve as a marker of children to develop asthma. the tennessee children's respiratory initiative has been established as a longitudinal prospective investigation of infants and their biological mothers. the primary goals are to investigate both the acute and the long‐term health consequences of varying severity and aetiology of clinically significant viral respiratory tract infections on early childhood outcomes. methods: over four respiratory viral seasons, – , term, non‐low birth weight previously healthy infants and their biological mothers were enrolled during an infant's acute viral respiratory illness. longitudinal follow up to age years is ongoing. results: this report describes the study objectives, design and recruitment results of the over families enrolled in this longitudinal investigation. the tennessee children's respiratory initiative is additionally unique because it is designed in parallel with a large retrospective birth cohort of over mother–infant dyads with similar objectives to investigate the role of respiratory viral infection severity and aetiology in the development of asthma. conclusions: future reports from this cohort will help to clarify the complex relationship between infant respiratory viral infection severity, aetiology, atopic predisposition and the subsequent development of early childhood asthma and atopic diseases. the tennessee children's respiratory initiative (tcri) has been established as a longitudinal prospective investigation of term, non-low birth weight otherwise healthy infants and their biological mothers. the primary goals of the study are: (i) to investigate both the acute and the long-term health consequences of varying severity and aetiology of clinically significant viral respiratory tract infections on the outcomes of allergic rhinitis (ar) and early childhood asthma; and (ii) to identify the potentially modifiable factors that define children who are at greatest risk of developing asthma following infant respiratory viral infection. this study is unique, in that it was designed in parallel with our tennessee asthma bronchiolitis study (tabs), which is a retrospective birth cohort study of over infants and their biological mothers similarly designed to elucidate the factors predisposing to childhood asthma and allergic this report describes the study objectives, design and recruitment results of the tennessee children's respiratory initiative, designed to investigate the role of respiratory viral infection severity and etiology in asthma development. future reports will address the complex relationship between infant respiratory viral infection and asthma and atopic diseases. diseases, but lacking biospecimens. thus, we designed the prospective tcri to establish a base for the evaluation of both the risks and benefits of documented significant infant viral respiratory infection of varying severity and aetiology and other environmental exposures on childhood atopy outcomes and to establish a biospecimen repository for analyses including biomarker testing and genotyping. the prospective cohort has the longitudinal design properties that may overcome potential limitations intrinsic to retrospective studies, such as our tabs cohort. [ ] [ ] [ ] [ ] [ ] it is our eventual goal that the findings from these investigations, in conjunction with other investigations that have helped to elucidate genetic and environmental factors associated with asthma development, will help in the identification of primary and secondary prevention strategies for asthma. this report describes the study objectives, design and recruitment results of this study cohort. the tcri is a prospective cohort of mother-infant dyads enrolled in a longitudinal investigation of the relationship of infant viral respiratory infection severity and aetiology and the interaction of other risk factors on the development of childhood asthma and allergic diseases. the study was approved by the vanderbilt institutional review board, and parents provided written informed consent for both their and their child's study participation. term, non-low birth weight, otherwise healthy infants were enrolled along with their biological mothers, at a single academic institution, vanderbilt children's hospital, at the time of an acute visit (hospitalization, emergency department or unscheduled outpatient visit) for presumed viral bronchiolitis or upper respiratory tract infection (uri) during respiratory viral seasons september through may - . inclusion and exclusion criteria are outlined in table . because of the grant funding start date, the first study season did not begin until november . recruitment was solely hospital-and clinic-based, and was performed days/week during the first years of cohort accrual, and days per week for the two subsequent years. screening and recruitment were done by experienced congenital or acquired chronic heart or lung disease, prior requirement for mechanical ventilation for cardiac or pulmonary disease, immunodeficiency, neurologic disease with possible aspiration, significant gastroesophageal reflux disease felt to contribute to pulmonary disease, tracheomalacia ever received one or more doses of rsv-ivig or palivizumab prior study inclusion fever and neutropenia children whose parents or guardians were not able to understand the consent process, or a language barrier † research nurses using computerized medical charts to screen infants with presumed respiratory viral illness. the components and time line of the subject visits are outlined in table mothers underwent prick skin testing to eight common aeroallergens and a blood specimen was obtained by venepuncture for serum immunoglobulin e (ige) and dna. a structured abstraction form was used to obtain information from the medical record regarding the index enrolment visit: current infant weight, confirmation of birth weight, room air pulse oximetry, requirement for supplemental oxygen, medication administration, prior wheezing episodes and detailed information on the current illness and hospital course. following discharge from the hospital or outpatient setting, the final discharge diagnosis and results of culture data were obtained through chart review. there are three phases of cohort follow up. first, mothers and children undergo an in-person wellchild follow-up visit during the child's second year of life conducted in the vanderbilt clinical research center, or during a home visit. second, families are re-contacted every - months by phone and/or mailings for purposes of cohort retention, and to provide reminders about the remaining study components. third, mothers, or the current guardians, undergo a phone interview during the fourth and sixth years of life to identify children with asthma, transient wheezing, ar and eczema. the -year in-person well-child visit is conducted in the vanderbilt clinical research center, or during a home visit offered to those unable to return to the study institution. during the visit, the isaac questionnaire is administered, blood samples are obtained from children and mothers (if not previously collected) and a buccal swab is collected for dna if blood cannot be obtained. a structured telephone questionnaire is administered to the mother/parent when their child is and again at years. trained interviewers employed in the vanderbilt survey research shared resource use a web-based computer system to conduct structured telephone interviews, which capture detailed information on asthma and atopy diagnoses and symptoms, extensive environmental exposure history, physical activity, and comorbidities. asthma, ar and atopic dermatitis outcomes are determined using the isaac questionnaire. for children with report of asthma and/or asthma symptoms in the previous months, the asthma therapy assessment questionnaire is administered, and information on asthma medications, and asthma-related health-care visits are sought. , biospecimen collection and laboratory analyses table outlines the details of cohort biospecimen collection, repository and testing, which includes infant nasopharyngeal, urine, blood and nasal epithelial cell sample collection, and maternal prick skin testing and blood samples. the discharge diagnosis and supporting clinical parameters of the infant acute respiratory illness visit were reviewed to confirm whether each child had lower respiratory tract infections (lrti) or uri (n = ) or another diagnosis (n = ). lrti and uri were defined using both the physician discharge diagnosis, as well as post-discharge chart review, and those cases that were not clearly identified as either lrti or uri were reviewed by a panel of paediatricians who determined whether the illness represented an lrti, uri, croup or other, which included those that could not be categorized with the available clinical information. acute respiratory illness severity was determined using the ordinal bronchiolitis score that incorporates admission information on respiratory rate, flaring or retractions, room air oxygen saturation and wheezing, into a score ranging from to ( being most severe). , highly sensitive and specific qrt-pcr assays for many common respiratory viruses, including hmpv, hcov, rsv, influenza a and b, parainfluenzaviruses - and rhinovirus. real-time rt-pcr is performed using the cepheid smart cycler ii. all specimens are first tested for gapdh to confirm integrity of rna and monitor for potential pcr inhibitors. negative and positive controls are included with each run, including rna runoff transcripts to generate a quantitation curve. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] if rapid antigen and/or culture for rsv or influenza were performed at the discretion of the admitting physicians during the index visit, these results are also captured and entered in the database. the cells are collected using mid turbinate peds nylon flocked swabs (microrheologics, brescia, italy), and placed into collection and digestion media, followed by processing and plating onto collagen iv coated tissue culture and grown at °c in a % co incubator. to develop techniques for isolation, short-term culture, and in vivo modelling of epithelial and stromal cells, a xenograph model has been developed. following short-term growth in culture, cells are transferred to denuded rat tracheas and implanted subcutaneously in nude mice. follow-up well-child visit mother and child dna is collected from both the mother and child during the blood collection, or using a buccal swab if blood can not be obtained. dna is extracted by the vanderbilt center for human genetics research core laboratory and stored following extraction for future studies. enrolment infant urine is collected from hospitalized infants during the acute infant illness at study enrolment, and from a convenience sample of outpatient subjects. urinary measurements including, leukotrienes c /d /e (ltc /d /e ), and urinary metabolite of the isoprostane, -f t-isop ( -iso-pgf a) will be measured by a gas chromatographic, and other biomarkers and the remainder of the urinary biospecimens will be maintained in the repository. , ige, immunoglobulin e; lrti, lower respiratory tract infections; uri, upper respiratory tract infection. the family history of atopy was obtained using a family tree. maternal atopy will be categorized as evidence of atopy by skin testing or specific ige, and/or clinical symptoms of an atopic disease as assessed by the isaac questionnaire. atopic status of the child will be determined by laboratory evidence of specific ige during the second year of life, and by clinical evidence based on the above definitions. the diagnosis of asthma will be determined at age years based on responses to the isaac questionnaire. [ ] [ ] [ ] the following criteria will define asthma during the sixth year of life: (i) -month prevalence of symptoms of asthma (current wheeze) or the presence of exercise-induced wheeze or dry cough at night not due to a cold or chest infection; and (ii) physician diagnosis as determined by the isaac questionnaire using either parental reported physician diagnosis of asthma or chronic use/ prescription of asthma-specific medications. probable asthma will be defined as physician diagnosis only and analysed separately. transient early wheezing will be defined as wheezing episodes present in the first years of life, but not meeting the definition for childhood asthma at age and years. allergic rhinitis will be determined through the isaac core questions on ar. , children will be considered to have definite ar if each of three conditions is present between age and years: (i) a history of nasal congestion, runny nose, itchy watery eyes, sinus pain or pressure or headaches, sneezing, blocked nose, loss of sense of smell; (ii) substantial variability in symptoms over time or seasonality; and (iii) diagnosed as having allergic rhinitis by a physician or on medications for ar. probable allergic rhinitis will be defined as meeting two of the three criteria, or only criteria . atopic dermatitis will be determined through the isaac core questions on atopic dermatitis, which are based on a list of major and minor criteria widely applied in clinical studies. , , as eczema is probably more readily confirmed by objective tests than either asthma or rhinitis, patients will be considered to have definite atopic dermatitis if between age and years they report ever having an itchy rash that comes and goes for at least months, and being diagnosed with eczema by a physician. , probable atopic dermatitis will be defined as one of the two above criteria. in order to standardize and monitor the quality of data collection and processing, all study personnel received training and were certified for all the study procedures. information is recorded on paper case report forms, data are entered and then checked by a second reviewer. logical data checks are programmed and additionally performed by our systems analyst, investigators and again by our biostatisticians. for laboratory analyses, blind qualitycontrol samples are included in each biospecimen run. telephone interviewers complete classroom training, orientation to the study population, computer modules, role play interviewing and training on study-specific protocols, and are formally evaluated at the end of training. a verbatim-recording of the interviewer and participant responses, and % participant re-contact allows quality-control staff to verify responses. the outcome variables of interest are the incidence of asthma and allergic rhinitis. the primary exposure variables of interest are the severity and aetiology of the infant viral illness and maternal and familial atopic status and other environmental exposures. cumulative asthma incidence over time, taking into account loss to follow up, will be used for illustrating incidence data. incidence of asthma and allergic diseases among the enrolled infant population with viral respiratory illness will be calculated by dividing the number of incident asthma cases by the person time of follow up. a kaplan-meier plot of cumulative incidence over time, taking into account loss to follow up, will be used for illustrating incidence data. incidence rates will be calculated by dividing the patient population into quartiles/quintiles of bronchiolitis severity scores. the adjusted risk of asthma and allergic rhinitis with bronchiolitis severity will be evaluated using the cox proportional hazard regression model. to assess the relationship between biomarker concentrations and increased risk of infant bronchiolitis, and early childhood asthma outcomes, we will conduct a nested case-control study. geometric means of urinary biomarker concentrations for those who develop and do not develop asthma will be calculated separately and compared using the paired t-test. the association between these biomarkers and the risk of asthma and allergic rhinitis will be assessed using odds ratios and their corresponding % confidence intervals from adjusted logistic regression models. the potential confounders that will be considered in multivariable analyses will include demographic and exposure characteristics. subject recruitment for the tcri study occurred over years, and was completed in may . overall, visits were screened, representing unique infants, and of these infants met study eligibility requirements. from the eligible infants, infants and their biological mothers were enrolled (fig. ) . among the subjects who were available during the recruitment periods, the major reasons for non-response were refusal ( %), insufficient time/ unwilling to stay for the visit (outpatients) ( %), conflict with or already enrolled in another study ( %), and other ( %) (includes language barrier, mother/ guardian not present, previously enrolled and other miscellaneous). in . % of the cohort, the nasal/ throat swab was obtained, and in % of the hospitalized infants one spot urine sample was obtained at hospital admission. weekly enrolment into the cohort is depicted in figure . the tcri is a large and comprehensive prospective epidemiologic study of mothers and their biologic children enrolled during infancy with a clinically significant lrti or uri who are being followed through early childhood. this study will provide important information about the role of infant respiratory viral infection severity, aetiology, biomarkers and predictors important in the development of early childhood asthma and allergic rhinitis. the tcri is additionally unique because it is designed in parallel with a large retrospective birth cohort of over mother-infant dyads with similar objectives to investigate the role of respiratory viral infection severity and aetiology in the development of asthma. as evidence suggests that the development of asthma may result in part from respiratory viral infection during infancy, which has a predilection for infecting, destroying and/or in some way biologically altering lower airway epithelium, this study will help to delineate whether the severity of that infection and other early-life events impact the risk of asthma and allergic disease development in later childhood. despite a high attack rate of developing asthma following viral bronchiolitis, the majority of children who have infant bronchiolitis do not develop childhood asthma. thus while viral respiratory infections may alter lung physiology and target the inflammatory response to the lower airway, this may only occur during a vulnerable time period during development of the immune system or lung, or in the presence of other risk factors. this developmental component may further reflect important gene-environment interactions that regulate both short-and long-term airway physiological alterations that manifest themselves clinically as childhood asthma. efforts to determine and define the role of these factors, including disease severity, maternal atopy and other environmental exposures, such as second-hand smoke, to asthma pathogenesis are the focus and goal of the tcri. several limitations of this study should be noted. first, the study sample was not randomly selected from the general population, but instead was recruited from a single hospital and clinic-based setting, the vanderbilt children's hospital. while vanderbilt hospitalizations represent greater than % of davidson county/nashville infant hospitalizations, it represents a smaller proportion of emergency department visits ( %), and likely even fewer paediatric acute care visits. the relatively low participation rate among eligible subjects is multifactorial and the result of the long-term nature of the study, the lack of study personnel to enrol all eligible subjects, as well as lower willingness among outpatients to extend their visit in order to participate in the study. while this impacts the demographics and exposures of the study population, and thus generalizibility of our study results, it should not impact the findings of the role of infant viral infection on the outcomes of interest. next, while airway hyperreactivity is not assessed in making the diagnosis of childhood asthma, the identification of incident asthma cases will take into consideration the positive response to a validated written questionnaire that has been compared with bronchial provocation testing. , while such an ascertainment strategy might result in the underdiagnosis of asthma, it is unlikely to result in false positive diagnoses during the sixth year of life. finally, as with many studies, where all eligible participants were approached for participation, difficulty was encountered in follow up of those currently age-eligible for follow up. strategies to address this include study personnel doing a significant number of follow-up visits at the subject's home, and shipping follow-up materials and requests to paediatricians of subjects who have moved from the region. future reports from this cohort will help to clarify the complex relationship between infant respiratory viral infection severity, aetiology, atopic predisposition, and the development of early childhood asthma and other atopic diseases. ultimately, this study, along with the companion tabs cohort, has the potential to provide new approaches to identify infants at high risk of developing early childhood asthma and allergic diseases, as well as provide important information that may contribute to the development of prevention strategies. increasing burden and risk factors for bronchiolitis-related medical visits in infants enrolled in a state health care insurance plan the underrecognized burden of influenza in young children evidence of a causal role of winter virus infection during infancy on early childhood asthma the severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma international study of asthma and allergies in childhood (isaac) written questionnaire: validation of the asthma component among brazilian children validation of a rhinitis symptom questionnaire (isaac core questions) in a population of swiss school children visiting the school health services. scarpol-team. swiss study on childhood allergy and respiratory symptom with respect to air pollution and climate. international study of asthma and allergies in childhood international study of asthma and allergies in childhood (isaac): rationale and methods collection of dietary-supplement data and implications for analysis a data-based approach to diet questionnaire design and testing nutrition quest, assessment tools for health researchers asthma control test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists development of the asthma control test: a survey for assessing asthma control human metapneumovirus plays an etiologic role in acute asthma hospitalization in adults high-throughput, sensitive, and accurate multiplex pcr-microsphere flow cytometry system for large-scale comprehensive detection of respiratory viruses human metapneumovirus infection in children hospitalized for wheezing a prospective study comparing human metapneumovirus with other respiratory viruses in adults with hematologic malignancies and respiratory tract infections association of human metapneumovirus with acute otitis media the role of human metapneumovirus in upper respiratory tract infections in children: a -year experience comparison of the mchip to viral culture, reverse transcription-pcr, and the quickvue influenza a+b test for rapid diagnosis of influenza a diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants in vitro assays for the diagnosis of ige-mediated disorders clinical laboratory assessment of ige-dependent hypersensitivity elevations of local leukotriene c levels during viral upper respiratory tract infections quantification of the major urinary metabolite of -f t-isoprostane ( -iso-pgf alpha) by a stable isotope dilution mass spectrometric assay prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis dexamethasone and salbutamol in the treatment of acute wheezing in infants asthma and wheezing in the first six years of life. the group health medical associates diagnostic features of atopic dermatitis evaluation and relevance of atopic basic and minor features in patients with atopic dermatitis and in the general population we would like to thank the many families, paediatricians and their office staff, who have participated in this study, as without them, this work would not have been possible. key: cord- -bb z j authors: nan title: abstracts der gnpi und dgpi: . jahrestagung der gesellschaft für neonatologie und pädiatrische intensivmedizin gemeinsam mit der . jahrestagung der deutschen gesellschaft für pädiatrische infektiologie, .– . mai , leipzig date: - - journal: monatsschr kinderheilkd doi: . /s - - -x sha: doc_id: cord_uid: bb z j nan fragestellung: die einnahme von medikamenten während der schwangerschaft sowie die medikamentöse exposition von kleinen frühgeborenen kann sich nachteilig auf die organogenese auswirken. für zahlreiche medikamente ist ein potenzieller einfluss auf die organogenese jedoch unzureichend untersucht. ursächlich hierfür war bislang ein mangel an geeigneten tiermodellen und innovativen technologien zur durchführung hochskalierter substanzscreening-untersuchungen. - % aller schwangeren nehmen im ersten trimenon medikamente ein, oft noch in unkenntnis der schwangerschaft. der prozentuale anteil medikamentös induzierter nierenfehlentwicklungen ist unbekannt. auf der anderen seite ist z. b. für die nierenhypo-bzw. -dysplasie als häufigster ursache der chronischen niereninsuffizienz im kindesalter die Ätiologie bislang weitgehend ungeklärt. im aktuellen projekt wurde der einfluss zugelassener medikamente auf die nierenentwicklung in der zebrafischlarve untersucht. der zebrafischembryo stellt u. a. aufgrund seiner geringen größe, seiner transparenz sowie der hohen genetischen und funktionellen Übereinstimmung mit säugetieren ein zunehmend favorisiertes modellsystem für embryologische in vivountersuchungen dar. methoden: ein automatisiertes high content screening erfolgte in transgenen wilms tumour b:green fluorescent protein (tg(wt b:gfp)) zebrafischlarven mit nierenspezifischer fluoreszenz. h alte larven (n = ) wurden über h mit substanzen der prestwick chemical libraryÒexponiert. nach der exposition wurden die larven mittels d-druck generierter orientierungstools in mikrotiterplatten dorsal ausgerichtet und einer automatisierten mikroskopie unterzogen. software tools wurden entwickelt, um im folgenden die quantifizierung der renalen phänotypen zu ermöglichen. ergebnisse: circa % der getesteten substanzen induzierten abnorme renale phänotypen mit glomerulären und/oder tubulären veränderungen. bekannte human-nephrotoxische substanzen riefen auch in der zebrafisch larve veränderungen am pronephros hervor. die quantifizierung der veränderungen ermöglichte im folgenden ein clustering der substanzen nach jeweiligem entwicklungsnephrotoxischem effekt. beispielhaft führten nicht-steroidale antiphlogistika zu schweren malformationen am pronephros. auch antiinfektiva, antiseptika und glukokortikoide beeinflussten die nierenentwicklung negativ. die genaue wirkung dieser substanzgruppen auf die nierenentwicklung wird gegenwärtig in sekundärassays näher charakterisiert. schlussfolgerung: die aktuelle studie zeigt, dass die zebrafischlarve unter zuhilfenahme innovativer mikroskopischer technologien ein gutes tier-im rahmen der europäischen albino studie wird die neuroprotektive wirkung von allopurinol bei neugeborenen mit schwerer perinataler aspyhxie zusätzlich zur hypothermiebehandlung geprüft. dabei muss allopurinol innerhalb von - min nach geburt verabreicht werden, um seine volle wirkung erzielen zu können. gemäß § der deklaration von helsinki (fortaleza ) kann in notfallsituationen die informierte einwilligung unter best. bedingungen erst nach studieneinschluss eingeholt werden (deferred consent, dc). fragestellung: ziel dieser arbeit war, ein meinungsbild zum dc im kontext der albino studie von werdenden bzw. nicht betroffenen eltern und von eltern nach geburt eines asphyktischen kindes zu erheben. material und methoden: ein fragebogen mit fragen wurde an schwangere und deren partner bei vorsorgeuntersuchungen (gruppe a ), eltern gesunder neugeborener auf der wochenbettstation (gruppe a ) und eltern, die in den jahren - ein asphyktisches kind (≥ . ssw, naph < , oder apgar " ≤ ) geboren hatten (gruppe b) verteilt. die auswertung erfolgte deskriptiv. ergebnisse: fragebögen wurden ausgewertet ( × a , × a , × b). die rücklaufrate betrug % (a = %, a = %, b = %). frauen und männer (durchschnittsalter jahre) antworteten. die mehrheit gab an, dass sie den entscheidungen ihrer Ärzte ( %) und kinderärzte ( %) vertrauen. % holen sich generell eine zweite meinung. % wollten vor behandlung ihres kindes informationen über art und sinn der therapie und % wünschten dies auch, wenn die zeitliche verzögerung den therapieerfolg beeinflussen könnte. gleichzeitig stimmten % zu, dass in notfallsituationen eine therapie sofort beginnen müsse und keine zeit für aufklärung verschwendet werden solle. % sahen durch einen dc ihr vertrauen zu ihren kinderärzten erschüttert und % dachten, dass sie in einer solchen notfallsituation richtig entscheiden würden und wünschten daher eine kurze mündliche information. betroffene eltern gaben signifikant häufiger an, dass sie froh wären nicht um erlaubnis gefragt worden zu sein, da sie sich hilflos und unfähig zu entscheiden gefühlt hätten und ohnehin dem rat der Ärzte gefolgt wären (b % vs. a &a %, p = , ). diskussion und schlussfolgerung: diese umfrage zeigt, dass eltern grundsätzlich ihren Ärzten vertrauen. darüber hinaus wollen eltern informiert und in entscheidungen einbezogen werden -auch in notfallsituationen. die mehrzahl der eltern würde einen dc akzeptieren, einzelne lehnten ihn jedoch strikt ab. eine kurze information und erbitten einer mündlichen zustimmung könnte in der beschriebenen notfallstudie die zufriedenheit der eltern verbessern. , % (ci % , ) in wo . die cox-regressionsanalyse identifizierte geburtsgewicht und -modus sowie verweildauer des kindes als potenzielle einflussfaktoren für die besiedlung mit o. g. erregern. bei fg mit einem gg > g lag die wahrscheinlichkeit signifikant höher, sich erstmalig mit kns ( , -fach; p = , ), enterobacter sp. ( , -fach; p = , ) und klebsiella sp. ( , - fach; p = , ) zu besiedeln im vergleich zu leichteren fg. eine entbindung per sectio steigerte das risiko für eine besiedlung mit klebsiella sp. um den faktor (p = , ). schlussfolgerung: während der postnatalen betreuung von fg war eine rasche ansteigende bakterielle besiedlung nachweisbar, mit dominaz von bedeutsamen erregern mit potenziell pathogenen eigenschaften. risikofaktoren für die besiedlung stellten ein gg von > g, die entbindung per sectio sowie die zunehmende verweildauer dar. die "stumme" kolonisation mit diesen erregern ist wohl physiologisch, wie die pathogenität (potenziell infektiös) einzustufen ist, bleibt bisher offen. hierfür sind weiterführende spezifische analysen (virulenzfaktoren zur einschätzung eines möglichen infektionsrisikos) sinnvoll. background: individualized postnatal growth trajectories (gtc) for preterm infants incorporate postnatal weight loss, and adjusted median intrauterine growth rate merged with who growth standards at term age (www.growthcalculator.org). they provide daily reference weights from birth to weeks of postmenstrual age (pma) objective: the study aims to: ) compare observed deviations of weight (∆w) from the gtc trajectory between cohorts and ) analyze relationships between ∆w and short-term outcomes. design/methods: international multicohort study, including infants with a gestational age (ga) from to weeks with weekly or daily weight data from eight local cohorts (austria, germany, sweden, australia, canada, usa) and the german neonatal network (birth weight (bw), weeks pma, discharge) during to . for each infant, the gtc trajectory was calculated based on ga, bw, and sex. the difference between the gtc trajectory and ) individual weights at various single time points (∆w), and ) deviations integrated over the nicu stay (∆w-auc) were determined. the relationship of ∆w with head circumference (hc), length (l), lean mass, fat mass, and blood pressure (bp) at discharge, adjusting for major nicu morbidities were analyzed. the relationship of ∆w-auc with outcomes was assessed for -week periods from birth to ergebnisse: ausgangssituation: level i-neonatologie mit ~ frühgeborene (fg) < g geburtsgewicht/jahr. milchküche mit m fläche (je ein produktions-, lager-, abstell-, büro-, aufenthalts-und ausgussraum) und , vk pflege (ausschließlicher einsatz in der milchverarbeitung), vorhandenes haccp(hazard analysis and critical control points)-konzept. investitionen: gefrierlagerschrank, pasteurisiergerät, flaschenversiegelungsgerät und transportboxen. laufende kosten: mikrobielle untersuchungen, versiegelungsdeckel, duplexetiketten. milchverarbeitung: single-donor-prinzip, poolen der h-milchmenge einer spenderin, daraus gewinnung eines aliquots für eine kulturelle untersuchung, ggf. holderpasteurisierung der sm. insgesamt wurden monatlich , l spendermilch ausgegeben (im beobachtungszeitraum l gesamt). spenderkollektiv: mütter der eigenen abteilung mit mehr als ausreichender laktation ( %) unabhängig vom cmv-serostatus nach anamnese und serologie (kosten €/spenderin). / ( %) der potenziellen spenderinnen konnten rekrutiert werden, ausschlussgründe waren u. a. sekundär nicht ausreichende milchproduktion (n = ), medikamenteneinnahme (n = ), ablehnung der spende (n = ) und nikotinabusus (n = ). ausgegebene menge pro spenderin war im median (range) , ( - ) l, für , ( - ) empfänger/spenderin. aufgrund mangelnden bedarfs wurde die milch von spenderinnen nicht ausgegeben. empfängerkollektiv: profil: fg < g gg bis zum gewicht von g oder nach abdominellen operationen ohne eigene muttermilch. / ( %) von diesen fg/ng wurde im median (range) bis zum lebensalter von ) tagen , l ( , - , l) sm ausgegeben. gründe für ernährung mit formula waren zu dem zeitpunkt nicht vorhandene sm (n = ) und ablehnung von sm (n = ). schlussfolgerung: je nach vorhandener infrastruktur ist auch mit verhältnismäßig geringem strukturellem aufwand eine versorgung mit frauenmilch zu leisten, die bedarfsplanung und ständige vorhaltung von sm ist jedoch schwierig. nicht einberechnet sind in dieser aufstellung u. a. zusätzliche personalkosten, planungszeit und auch der investitionsbedarf kann stark schwanken. insgesamt können diese daten jedoch zur orientierung bei der neueinrichtung von frauenmilchbanken dienen. zum zeitpunkt der entlassung beurteilt (tod, ivh, rop, bpd, pvl). der einfluss der einzelnen interventionen in abhängigkeit vom jeweiligen zustand auf das neonatale outcome wurde mittels logistischer regressionsanalyse analysiert. ergebnisse: die analyse der angewandten erstmaßnahmen ergab in abhängigkeit vom ausgangszustand des frühgeborenen im hinblick auf das outcome signifikante unterschiede. die verwendung von cpap nach min und min (im vergleich mit bmv oder intubation) war unabhängig vom zustand des kindes zur . minute immer mit einem verbesserten outcome verbunden (bmv vs. cpap: tod or , [ %-ki ; , ], ivh , [ , ; , ] , bpd , [ , ; , ] , pvl , [ ; , ]), ein effekt der unabhängig vom gg oder ga nachweisbar war. der einfluss der sauerstoffgabe in der . bzw. . minute auf das outcome variierte in abhängigkeit vom jeweiligen zustand. jedoch hatte eine sauerstoffgabe in der . minute einen negativen einfluss auf verschiedene outcomeparameter. die frühzeitige surfactantgabe erwies sich bei einer subgruppe von frühgeborenen (sapgar < , gg < g, ga < . ssw) als vorteilhaft. schlussfolgerung: während in den aktuellen empfehlungen zur erstversorgung frühgeborener ein relativ standardisiertes vorgehen empfohlen wird, scheint eine variation der maßnahmen in abhängigkeit vom jeweiligen zustand des kindes vorteile bezüglich des neonatologischen outcomes zu bringen. insbesondere unterstützen die vorliegenden daten die empfehlung, die erstversorgung dieser kinder mit cpap zu beginnen und eine beatmung in der ersten lebensminute zu vermeiden. künftige studien zur erstversorgung sollten immer auch den aktuellen zustand des kindes miterfassen. die test-apgar studie wurde finanziell unterstützt durch die else kröner-fresenius stiftung. discharge using a sequential multinomial logistic regression. level of significance was p < . . results: in this study, infants from cohorts ( < weeks) and , infants from the german neonatal network ( < weeks) were included. at weeks, preterm infants showed a significantly different ∆w for ga and cohort (. fig. | gnpi-v ) . for infants < weeks at birth, ∆w was large and cohort-specific variations significant (. fig. | gnpi-v ) . at discharge, hc, l, fat mass, and lean mass were significantly related. bp before discharge tended to be higher with high deviation from ∆w. ∆w-auc before discharge was the strongest predictor of outcomes. converging towards the gtc trajectory until discharge seemed to improve outcomes while diverging was related to unfavorable outcomes. conclusion(s): this is the first study to analyze growth of preterm infants by comparing them to individual gtc. the results show that outcomes were independently related to growth pattern. hintergrund: die erfassung des postnatalen hirnwachstums bei frühgeborenen ist ein wichtiger parameter, um die neurologische entwicklung abzuschätzen. bisher wird auf kopfgröße (cranial volume -crv) und hirnvolumen (brain volume bv) aus der messung des kopfumfanges rückgeschlossen. diese zweidimensionale messung korreliert nur schlecht mit dem tatsächlichen craniellen volumen resp. dem hirnvolumen. mittels dreidimensionaler laserscanner kann das cranielle volumen schnell, zuverlässig und unbelastend gemessen werden [ ] . groups started at different gestational ages and %fm, fm trended towards a similar average mean of % for all groups. also, dynamics to reach this %fm was comparable amongst all groups (. fig. | gnpi-v . for example, at weeks postmenstrual age infants born at < wks had a fm of %, and at weeks leveled out to %. also, for other gestational ages, infants achieved a fm of to % by wks. from weeks onwards, maximum %fm remained constant at approximately to % for all infants. median %fm trajectories for all preterm infants had their best fit with term infants when data points were shifted by . , . , and . wks for groups a, b, and c, respectively (. fig. this study confirms that preterm infants experience increased %fm at an earlier postmenstrual age than term infants. however, dynamics of fm accretion is comparable amongst all groups of infants thought having different gestational ages at birth. it could, therefore, be hypothesized that postnatal changes in fm accretion is a physiological process induced by the transition to the extrauterine environment (thermomanagement, nutritional sources, etc.). further research is needed to explore mechanisms underlying such postnatal adaptation. mit dieser studie sollten durch erstellung von perzentilenkurven für das cranielle volumen (crv) grundlagen geschaffen werden, damit das postnatale hirnwachstum frühgeborener besser erfasst werden kann. ein weiteres ziel war es, die zunahme des crv bei frühgeborenen mit zunehmendem postnatalem alter zu evaluieren. methoden: in den jahren - wurde bei allen kindern, die in der universitätskinderklinik dresden geboren wurden, das crv innerhalb der ersten lebenswoche gemessen. dafür wurde ein d-laserscanner (star-scanner, orthomerica, orlando, fl, usa) verwendet [ ] . als referenzpopulation für die erstellung der perzentilen wurden gesunde, eutrophe einlinge ausgewählt, die keiner behandlung auf der neonatologischen intensivstation bedurften, die keinerlei schädel-oder hirnauffälligkeiten aufwiesen und die mit einem postmenstruellen alter (pma) zwischen und wochen gemessen wurden. die perzentilenkurven für das crv wurden nach pma, geburtsgewicht (bw) und kopfumfang (ku) generiert. diese wurden dann verwendet, um das postnatale wachstum des design/methods: a longitudinal observational study was conducted for infants (gestational age [ga] < weeks). the body composition was measured with air-displacement plethysmography using the peapod during the nicu stay and also at , and months follow-ups. infants with respiratory support (cpap > cm h o or high-flow nasal cannula > l/min) were excluded. body composition indicators including % body fat (%bf), fat mass (fm), fat-free mass (ffm), fat mass/length (fmi), fatfree mass/length (ffmi) were graphed against postmenstrual age (pma). at months, the infants received a bayley iii assessment. for descriptive statistics, the infants were stratified in two gestational age groups: < weeks and to weeks. percentiles were calculated using gamlss package in r statistics. further, the infants were subdivided into three quantiles according to the neurodevelopment. results: this study includes infants, infants received a bayley assessment at months (. fig. | gnpi-v ) . in total, body composition measurements were performed. at weeks, the younger preterm infants had higher %bf compared to those born with to weeks. at weeks pma, %bf leveled out in both groups at to % and remained stable at this value until weeks pma. preterm infants with ga < weeks had slightly shorter body length and lower neurodevelopmental scores. infants with higher measurements for fat mass had higher bayley score. for %bf, and fat mass the average curve for infants with lower language score (< percentile) was considerably lower (. fig. | gnpi-v ) . also, fatmass and percent free-mass were significantly correlated with language score (p < . ). conclusion(s): body composition during a nicu stay is related to neurodevelopment at months. this is an important finding to support optimizing nutrition at nicu. hintergrund: die ernährung frühgeborener (fg) sollte idealerweise wachstum und entwicklung wie in utero ermöglichen. eine postnatale wachstumsrestriktion ist bei fg mit schlechterer neurokognitiver entwicklung assoziiert. auch bei fg < ssw kann nach raschem enteralen nahrungsaufbau eine perzentilenparallele gewichtszunahme erreicht werden, jedoch entspricht ihre körperzusammensetzung dann am errechneten termin nicht der reifgeborener, sondern zeigt eine erhöhte fett-geschaffen. diese ermöglichen ein besseres postnatales monitoring des kopfwachstums bei frühgeborenen und somit eine beurteilung des hirnwachstums im verlauf der neonatologischen betreuung. body composition (fat mass and fat-free mass) of preterm infants less than weeks and neurodevelopment at months n. rochow *, , e. tsang , a. ali , g. fusch , s. el helou , c. fusch , mcmaster university, pediatrics, hamilton, canada; paracelsus medical university, pediatrics, nuremberg, germany background: weight measurements alone are insufficient indicators of individual body composition (i. e. fat mass and fat-free mass). also, there is growing evidence that nutrition and resulting body composition at discharge are related to the neurodevelopment outcome. air displacement plethysmography (pea pod) was used to create a database of body composition measurements for preterm and term infants. objective: to calculate percentiles for body composition measurements and to compare the body composition with the neurodevelopmental outcome at months. in diesem vortrag wird der frage nachgegangen, warum bindung, familie und entwicklung zusammengehören und was das mit dem personal neonatologischer stationen zu tun hat. der gemeinsame bundesausschuss legt mit seinem beschluss augenmerk auf eine hochqualifizierte medizinische versorgung frühgeborener und kranker neugeborener. doch auch aspekte der psychosozialen begleitung und nachsorge als voraussetzung für die betreuung, sind festgeschrieben. psychologische unterstützug, bonding, anleitung auf station, elternkurse und sozial-medizinische nachsorge gehören in einigen kliniken bereits seit jahren zum alltag. entwicklungsfördernde pflege, nidcap als betreuungskonzepte sind wissenschaftlich gut untersucht und in ihrer bedeutung anerkannt. zwangsläufig verändert sich das berufliche selbstverständnis von pflegenden und Ärzten. ohne zusätzliche ausbilung und entsprechende schulungen zu diesen speziellen themen wird eine tatsächliche familienbegleitung nicht möglich sein. es stellt sich die frage nach der finanzierbarkeit und warum es in einigen kliniken gelingt! hintergrund: circa - % aller neugeborenen benötigen unterstützung bei der postnatalen erstversorgung. von diesen kindern reagieren zwei drittel auf taktile stimulation oder pharyngeales absaugen, wohingegen das verbliebene drittel noch im kreißsaal ventiliert wird. in den leitlinien zur neugeborenenreanimation wird daher auch vorgeschrieben, neugeborene mit insuffizienter atmung innerhalb der ersten minute zu stimulieren, um ihren atemantrieb anzuregen. allerdings sind die verschiedenen methoden der taktilen stimulation, sowie der ort und die häufigkeit von stimulationen bisher noch nicht wissenschaftlich untersucht und die effektivität von stimulationen ist ungenügend beschrieben. ziel: beschreibung von häufigkeit, zeitpunkt und effektivität von stimulationen während der neonatalen transition. material und methoden: neugeborene wurden direkt nach der geburt gefilmt und die videoaufnahmen retrospektiv bezüglich häufigkeit, ort masse und erniedrigte fettfreie körpermasse. prädisponiert diese ernährung frühgeborene deshalb zu adipositas oder metabolischem syndrom? fragestellung: ziel war, die wachstumsdaten bis zum alter von jahren von zwei fg-kohorten mit langsamerem und bzw. rascherem enteralen nahrungsaufbau zu erheben und auf hinweise für einen einfluss des neonatalen ernährungsregimes zu untersuchen. material und methoden: fg (< , ssw oder gg< g) der jahrgänge / - / (gruppe : enterale nahrungssteigerung - ml/ kg/d) und des jahrgangs - / (gruppe : enterale nahrungssteigerung - ml/kg/d) wurden eingeschlossen. daten zur ernährung wurden der patientenakte entnommen und die im rahmen der kindervorsorgeuntersuchungen u -u erhobenen anthropometrischen parameter per fragenbogen erfragt. die daten sind als median und interquartilbereich dargestellt und wurden mittels wilkoxon-test ausgewertet. ergebnisse: von ursprünglich fg nahmen ( %) an der untersuchung teil, ( %) kinder waren vor erreichen der u verstorben. bei der kumulativen einweißzufuhr tag - fand sich kein unterschied zwischen den beiden gruppen, ebensowenig bei der u im alter von jahren hinsichtlich sds für kopfumfang und gewicht. der niedrigste gewichts-sds fand sich in beiden kohorten zum zeitpunkt der u . schlussfolgerung: sehr unreife fg, die eine neonatale gewichtsentwicklung in der nähe intrauteriner wachstumskurven aufwiesen, waren im alter von jahren nicht adipös. der schnellere nahrungsaufbau war nicht mit einem veränderten wachstum bis zum alter von jahren assoziiert. noch langfristigere auswirkungen der intensiven ernährungsstrategie müssen noch geprüft werden. abb. | gnpi-v ausgewählte maternale und kindliche outcome parameter von einlingsschwangerschaften in sniip die eingeschlossen wurden, wiesen normale il- -werte auf, während ( , %) neugeborene il- -werte zeigten, die höher waren als der definierte grenzwert von ng/ l. nach statistischer korrektur nach gestationsalter zeigte sich keine korrelation mehr zwischen erhöhter il- -therapie und lungenreifeinduktion oder pathologischer ctg-Überwachung. bei der analyse verschiedener binärer eigenschaften bei den reifen neugeborenen waren die folgenden faktoren signifikant mit erhöhten il- -werten verbunden: mütterliche leukozyten > /mm (p-wert < , ), verfärbtes fruchtwasser (p-wert , ), apgar bei min < (p-wert , ), neonatalen neutrophilen > × /l (p-wert , ), neonatalen unreifen neutrophilen > % (p-wert , ) und i/ t-quotient > , (p-wert , ). schlussfolgerungen: bei einem relevanten anteil von neugeborenen ohne klinischer manifestation einer infektion findet man bei der untersuchung von nabelschnurblut erhöhte il- -werte. die bei diesen kindern bestehende signifikante erhöhung mütterlicher leukozyten sowie aktivierung fetaler immunabwehrzellen ist am ehesten auf ein firs zurückzuführen. eine signifikant erhöhte anzahl von neugeborene mit erhöhten il- -werten (bzw. firs) unter den frühgeborenen bestärkt den verdacht, dass eine intrauterine inflammation vorzeitige wehen triggern kann. [ ] und über % in japan [ ] . ein bmi < , kg/ m vor der schwangerschaft ist mit niedrigem geburtsgewicht und zu früher geburt assoziiert [ , ] koffeincitrat. zwei behandlungsgruppen erhielten × täglich inhalativ einen pde -hemmer in einer tierstudienbasierten dosierung ( µg/kg, "ipde ") und einer niedrigeren dosierung basierend auf humanen daten von erwachsenen ( µg/kg, "ipde "). als kontrolle dienten unbehandelte, beatmete tiere ("control") sowie feten gleichen gestationsalters gemessen. hierfür wurden mittels einer aktiven testlunge für frühgeborenen (gina®, dr. schaller medizintechnik, dresden, deutschland) lunge und atmung von drei säuglingen mit jeweils unterschiedlichem gewicht und compliance der lunge simuliert. ergebnisse: ein frühgeborenes mit g und einer compliance von , ml/mbar muss für ein atemzugvolumen von ml/kg pro atemzug am rpap® eine atemarbeit von , (± , ) mj, am t-stück resuscitator , (± , ) mj und am benveniste ventil , (± , ) mj aufbringen (p = , ). ein frühgeborenes mit g und einer compliance von , ml/mbar muss für ml/kg pro atemzug am rpap® eine atemarbeit von , (± , ) mj, am t-stück resuscitator , (± , ) mj und am benveniste ventil , (± , ) mj aufbringen (p < , ). ein säugling mit g und einer compliance von , ml/mbar muss für background: we report on the latest progress made in the development of a lung assist device in the artificial placenta configuration. the lad is designed to be solely powered by the neonatal heart and to be connected between the umbilical artery and the vein to provide partial support. it allows newborns to continue breathing while a partial fetal circulation via umbilical artery, lad circuit, and umbilical vein is established. the lad has been further miniaturized with high gas exchange and hemocompatibility. objective: to test the perfusion and blood gas exchange performance of the new lad in a newborn piglet model. design/methods: the lad (filling volume is ~ . ml) consisting of stacked microfluidic blood oxygenators connected via carotid artery (ca) and jugular vein (jv) was tested in one-day-old heparinized piglets weighing . to . kg (. fig. | gnpi-v ). blood flow in the lad was measured with an ultrasonic transducer. catheters were placed into the right heart"s atrium (ra) via jv, femoral artery (fa), femoral vein and abdominal vein. venous access was used for fluids, nutrition, and drugs. blood gas analysis was done from the lad inlet and outlet, from ra via jv, and fa. heart rate (hr) and blood pressure (bp) were measured in the lad circuit and at fa, o saturation by pulse oximetry. the piglet was anesthetized with pentobarbital and pancuronium and ventilated via tracheostomy. a series of hypoventilation cycles were applied over h. the spo target before activating the lad was to %. the lad was tested with oxygen and in room air. the lad provided clinically significant gas exchange. the lad with units achieves blood flow rates through the lad comparable with one-third of the cardiac output and will be able to provide to % of the oxygen requirements of a preterm infant ( . - . kg). further steps in the development of the lad include the establishment of hemocompatibility using heparin coating and of large bore vascular access via umbilical vessels. fig. | gnpi-v ) . the highest differences were observed between the subgroups "ctl, low protein" and "intvn, high protein". statistical significance was achieved for language scores (p < . ). language score was correlated with variation of protein intake and gross-motor score related to fat-free mass index(kg/m ) (. fig. abstracts inflammatorisch polarisierte pbmΦ weisen eine stärkere hif -α expression als cbmΦ auf. dagegen zeigen infizierte, anti-inflammatorisch polarisierte cbmΦ eine bis zu -fach stärkere hif -α expression als pbmΦ (p < , ). weder infektion noch polarisierung führten zur aktivierung von nfkappab p . schlussfolgerung: der stat -pathway, jedoch nicht nfkappa-b p ist in der hoch-regulation der hif -α expression in pbmΦ involviert. e.coli infektionen aktivieren die hif -α expression unabhängig von tlr /nf-kappab p und stat in cbmΦ. in der lunge könnte nach infektion eine il- gabe cbmΦ so polarisieren, dass eine höhere hif -α expression erzielt wird. diese hif -αhigh cbmΦ könnte zu einer differenzierteren alveolarisierung beitragen. einleitung: hif- alpha (hif -α) ist ein wichtiger sensor für die sauerstoffkonzentration im gewebe und verknüpft metabolische und gewebsdifferenzierende prozesse, welche sich in makrophagen neugeborener und erwachsener grundlegend unterscheiden. bei neugeborenen mit e.coli infektion (early onset infection) fand sich hif -α auf transkriptionsebene signifikant verstärkt. die bedeutung von hif -α wurde in tiermodellen der brochopulmonären dysplasie (bpd) untersucht: werden neugeborene ratten einem infektionsreiz (lps) und hyperoxie ausgesetzt, so wird die lungen-alveolisierung gestört. dies kann durch verminderung der hif -α autoproteolyse verhindert werden. in makrophagen (mΦ) führt hif -α expression zur aktivierung mit pro-inflammatorischen reaktionen wie regulatorische t-zell suppression und th aktivierung. mΦ lassen sich durch ifn-γ in inflammatorische und durch il- in anti-inflammatorische subpopulationen polarisieren. die hif -α expression in den geweben kann über ifn-ɤ/stat und tlr /nfkappab p hochreguliert werden. hypothese: hif -α ist bei nicht polarisierten mΦ aus nabelschnurblut (cbmΦ) im vergleich zu mΦ erwachsener (pbmΦ) stärker exprimiert. eine infektion mit e. coli erhöht die hif -α expression in cbmΦ stärker als in pbmΦ. inflammatorische und anti-inflammatorische polarisation verstärkt die expressionsunterschiede. methoden: polarisierung von pbmΦ und cbmΦ durch m-csf, ifn-ɤ und il- wie vorbeschrieben. immunotypisierung und protein-nachweis durch (intrazelluläre) facs färbung. in-vitro infektionsmodell. ergebnisse: im vergleich zeigen nicht-polarisierte cbmΦ eine signifikant stärkere hif -α expression als pbmΦ. dagegen wird hif -α in inflammatorisch polarisierten pbmΦ deutlich höher exprimiert als in cbmΦ. bei anti-inflammatorischer polarisierung gibt es keine gruppenunterschiede. e.coli infektion führt bei pbmΦ zu höherer stat aktivierung als bei cbmΦ, wobei ifn-ɤ polarisierung die stat -aktivierung in beiden gruppen nicht verändert. e.coli infektion führt bei nicht-polarisierten cbmΦ zu stärkerer hif -α expression als bei pbmΦ. auch infizierte, outcomes were collected using a detailed questionnaire. all bacteria detected in blood or pleural fluid by culture or pcr were considered. results: a total of hospitalised children with ppe/pe (median age of . years, iqr . - . ) were included. of these, . % had received ph-abt: . % as monotherapy and . % as combination therapy. antibiotics used for monotherapy were cephalosporins ( . %), aminopenicillins ( . %), macrolides ( . %), aminopenicillin/beta-lactamase inhibitor combinations ( . %) and penicillins ( . %). for children with/ without ph-abt, median hospital length of stay (los) was (iqr - ) versus (iqr - ) days (p < . ), median duration from onset of symptoms until hospital discharge was (iqr - ) vs. (iqr - ) days (p = . ), rate of intensive care unit admission was . % vs. . % (p = . ) and occurrence of complications was . % vs. . % (p = . ). bacterial detection was achieved in ( . % of ) patients. in samples tested by culture (n = ), the detection rate in children with/without ph-abt was . % of versus . % of children (p < . ), whereas in samples tested by pcr (n = ), the detection rate was . % of vs. . % of children (p = . ). conclusions: ph-abt of children with ppe/pe was associated with shorter los (by a median of days) and a lower rate of intensive care treatment and complications. ph-abt reduced the sensitivity of bacterial culture but not of pcr, suggesting that pcr should be test of choice for bacterial detection in such patients. only one fifth of children with ph-abt received an oral aminopenicillin, despite existing recommendations for the treatment of paediatric community-acquired pneumonia in germany. nahezubringen (und adressieren meist die erwachsenenmedizin). dabei werden aber wichtige faktoren unzureichend berücksichtigt: bestehende leitlinien sind meist komplex und daher für den ambulanten praxisalltag weniger geeignet, und: die Ärzteschaft orientiert sich nicht nur an "bester evidenz", sondern auch an lokalen "verordnungskulturen". daraus entstand die idee, beides in einem neuen ansatz aufzugreifen. wurde von niedergelassenen kinder-und jugendärztinnen und -ärzten das projekt "antibiotische therapie in bielefeld" (antib) begründet. eine erste maßnahme war die erstellung von kurzgefassten empfehlungen zur antibiotischen therapie häufiger infektionen. dabei sollte kein leitlinienersetzender "standard", sondern innerhalb der fachgruppe vor ort eine einheitliche behandlung unter standardbedingungen angeregt werden. die empfehlungen wurden in einem strukturierten prozess erstellt, mit den schnittstellen zur notfallversorgung (klinik) konsentiert und formal in der fachgruppe beschlossen. sie sind seit januar in kraft und wurden seither sehr gut angenommen. erfolgte bereits eine Überarbeitung, weitere aktualisierungen sind turnusmäßig geplant. das konzept der erstellung solcher lokalen empfehlungen wurde inzwischen von ambulanten pädiatrischen fachgruppen in anderen städten übernommen und dabei lokal angepasst. zusammen mit der kvwl wurde ein "antibiotika-sonderreport" erarbeitet, der ab u. a. der pädiatrischen fachgruppe in westfalen-lippe eine individuelle rückmeldung mit "benchmarking" ihrer antibiotikaverordnungen bietet. darüber hinaus war antib an der gründung eines sektorübergreifenden abs-netzwerks bielefeld -ostwestfalen-lippe beteiligt. antib wird auch wissenschaftlich evaluiert, etwa durch die erfassung der antibiotikaverordnungsdaten vor und nach einführung des projektes. die entsprechenden ergebnisse werden im laufe des jahres vorliegen. das lokale konzept, mit einerseits "bottom up"-strukturen zur besseren verankerung von abs in den jeweiligen pädiatrischen fachgruppen, und andererseits sektorübergreifendem und interdisziplinärem ansatz, erscheint im ambulanten abs-bereich als innovativ und erfolgversprechend und sollten auch überregional berücksichtigung finden. background: due to continuous, violent conflicts in northern africa and in the middle east, more than one million refugees sought shelter to germany in and . accompanied and unaccompanied minors constitute a particularly vulnerable group as they can be exceedingly exposed to the physical and emotional burdens of their flight. hardly any data are available regarding types of illnesses of refugee minors accommodated in germany. migrants under the age of are expected to predominantly present with diseases of the well-known paediatric spectrum but important infectious diseases less common in the general german population, such as measles, tuberculosis, hepatitis b, malaria or the rare louse-borne relapsing fever, mustn't be missed. methods: about irreversibly anonymized in-and out-patient files from two sites in munich (refudocs registered association, bayernkaserne and dr. von hauner children's hospital) from the years and were statistically analysed in the context of a descriptive, retrospective, cross-sectional study. additional records including about out-patient files are still to be analysed at the moment. for data capture, evaluation and statistics microsoft excel and stata® were used. results: date analysed so far show that the spectrum of health problems of refugee minors does not significantly differ from that of the corresponding general population living in germany. among underage asylum seekers diagnoses such as common cold, respiratory infections or gastroenteritis account for the biggest part of the reported diseases. of note, the initial analysis revealed frequent cases of parasitic diseases such as scabies or pediculosis ( cases in patient contacts, prevalence in europe: , - / residents). furthermore, diagnoses such as tuberculosis ( cases in patient contacts) or posttraumatic stress disorder ( cases in patient contacts) were also frequently reported. discussion: the up to now presented results of our study are similar to data previously described in the adult asylum seeker populations. factors such as country of origin or type of accommodation seem to favour the occurrence of diseases like tuberculosis or scabies. once completed, the final analysis of this extensive data collection could help to improve the medical care for accompanied and unaccompanied refugee minors in the future. regulatorische t-zellen sind im blut frühgeborener kinder erhöht enac and na,k-atpase activity and gene expression. inhibition of hepatocyte growth factor (hgf) signaling downregulated the effect of msc-cm on enac activity, although hgf itself did not enhance enac activity. thus, we analyzed phosphoinositide -kinase (pi -k) signaling which is activated by hgf receptor and known to stimulate enac activity. inhibitory studies of pi -k downstream targets showed a significant reduction of msc-cm mediated enac activity. the results demonstrate that msc-cm increases na + transport in fdle cells, possibly attributable to pi -k signaling, and improves branching morphogenesis. therefore, msc-cm can stimulate lung structural and functional maturation in vitro and might represent a future therapeutic option for preterm infants. in der vorliegenden analyse wurde einerseits der "erfüllungsgrad" in einzelnen pnz ermittelt und andererseits evaluiert, wie sich darunter die versorgung weiterer patientengruppen und die noch freie pflegerische personalkapazität (ppk) für akut zu versorgende fg darstellt. methodik: aus einem regionalen verbund von vier großen pnz mit zusammen ca. . geburten pro jahr wurde der anteil der : / : -versorgten, patientenzahl pro pflegekraft (pat/p) und ppk nach zentrum, schicht und wochentag über einen zeitraum von fünf monaten hinsichtlich erfüllungsgrad der gba-rl bzw. der empfehlungen der deutschen gesellschaft für perinatale medizin (dgpm) ausgewertet. zusätzlich wurden geburtshilflich anstehende fg erfasst und mit der vorhandenen freien ppk abgeglichen. ergebnisse: die gba-rl konnte in % der schichten (n = ) erfüllt werden. lediglich ein zentrum konnte die vorgabe ( % schichterfüllungsquote) erreichen. hierbei nahm der erfüllungsgrad von früh-über spät-zu nachtdienst kontinuierlich ab (p < , ). analog verhielt sich die zahl der eingesetzten pflegekräfte sowie die freie ppk, während pat/p zunahm (p jeweils < , ). an zwei zentren mit annähernd gleicher gba-erfüllungsquote (p = , ) zeigte sich ein deutlicher unterschied bzgl. der pat/p (p < , ). im gegensatz zur gruppe der : -versorgten (p = , ) lag der anteil der : -versorgten fg in den zentren bei nichterfüllung der vorgaben signifikant höher als bei erfüllung (p < , ). von den anstehenden fg hätten lediglich , % unter einhaltung der personalvorgaben versorgt werden können. schlussfolgerungen: drei der vier pnz konnten die gba-rl nicht erfüllen. insbesondere in den nachtschichten war die ppk unzureichend. die diktion zur : -versorgung stellte den wesentlichen faktor dar, der zu nicht-erfüllung der vorgaben und zahlenmäßig schlechterer versorgung der übrigen intensivpatienten führte. der erfüllungsgrad bzgl. der dgpm-empfehlungen lag hierbei nochmals deutlich niedriger, was ebenfalls auf eine schlechtere personelle betreuung dieser patientengruppe hinweist. freie ppk war selten vorhanden, was eine versorgung selbst eines geringen anteils der anstehenden fg unter einhaltung der gba-personalvorgaben ausschließt. statistisch kann erstmals an einem großen kollektiv gezeigt werden, dass aufgrund der aktuellen gba-vorgaben selbst an einem der größten verbund-pnz die deutlich angespannte personalsituation es nicht zulässt, entsprechende richtlinienvorgaben bei gleichzeitiger versorgung anderer patientengruppen zu erfüllen. realisierbarkeit, praktikabilität, nutzen und aussagekraft der gba-rl müssen daher klar hinterfragt, wissenschaftlich exakt evaluiert und weiter analysiert werden. hintergrund: trotz der seit über jahren andauernden anwendung der extrakorporalen membranoxygenierung (ecmo)-therapie in der neonatologie ist das optimale koagulationsmanagement nach wie vor umstritten und variiert stark unter den verschiedenen ecmo-zentren weltweit. heutzutage liegt die komplikationsrate in folge der koagulationsdysregulation noch immer auf einem hohen niveau ( - %). unfraktioniertes heparin (unfh) ist das meist verwendete systemische antikoagulans während der ecmo-therapie. im pädiatrischen ecmo-zentrum der universitätsmedizin mannheim erfolgt aktuell die ufnh-titration nach regelmäßigen bestimmungen der act-und aptt-werte. fragestellung: eine lediglich auf aptt-und act-messungen basierende heparin-steuerung unter ecmo-therapie könnte zu einer suboptimalen antikoagulationstherapie des patienten führen. die zusätzliche bestimmung des anti-faktor xa-spiegels und die verwendung der thromboelastometrie könnte eine präzisere aussage über die koagulation unter ecmo-therapie bei neugeborenen liefern und damit die entwicklung eines neuen antikoagulationsprotokolls ermöglichen, welches das blutungssowie thrombose-risiko und die damit verbundene ecmo-assoziierte morbidität und mortalität reduzieren könnte. material und methoden: im rahmen dieser beobachtungsstudie wurden zwischen märz und januar neugeborenen mit angeborener zwerchfellhernie, die nach geburt eine ecmo-therapie benötigten, eingeschlossen. die steuerung der antikoagulationstherapie während der ecmo-therapie wurde weiterhin gemäß dem bisherigen antikoagulationsprotokoll durchgeführt. zusätzlich erfolgten täglich die messung des anti-faktor xa-spiegels sowie eine thromboelastometrie. klinische parameter wie dauer der ecmo-therapie, ufnh-dosierung, sowie thrombotische-und blutungskomplikationen und die notwendigkeit von blutprodukttransfusionen wurden mit den gerinnungsparametern korreliert. ergebnisse: bei neugeborenen mit angeborener zwerchfellhernie unter ecmo-therapie zeigte der anti-faktor xa-spiegel eine gute korrelation mit der unfh-dosis. die act-, aptt-werte und der mittels thromboelastometrie gemessene heparin effekt (ctintem-ctheptem) zeigten eine schlechte korrelation mit der unfh-dosierung. schlussfolgerung: der anti-faktor xa-spiegel zeigt eine bessere korrelation mit der ufnh-dosis als das bisher für die heparin-steuerung benutzte antikoagulationsprotokoll, so dass in dieser patientengruppe unter ecmo-therapie der anti-faktor xa-spiegel ein präziserer parameter für die ufnh-steuerung zu sein scheint. die thromboelastometrie stellt zu diesem ziel keinen mehrwert dar. , care was given to two infants < g, infants < g. overall mortality was . %, and . % for infants < g. most frequent diagnoses were infections ( . %) and prematurity ( . %). there was also a significant number of very severe diagnoses (e. g. neonatal tetanus, tracheo-esophageal fistula, necrotizing fasciitis, gastroschisis). discussion and conclusion: nicu in jimma is treating patients that are comparable to middle european level- -centres in respect to disease severity. conditions are not yet comparable to western standards, thus explaining the high mortality. our common aim for the future will be to establish improved protocols for standard care (e. g. regarding hygiene, feeding, monitoring) to achieve better outcomes. results: over the study period, patients with gs were admitted to our neonatal intensive care unit. seven patients underwent staged repair after initial placement of a spring loaded silo. the mean gestational age was + weeks ( + - + ) with a mean birth weight of g ( g- g). all patients were delivered by cesarean section. in three cases, immediate caesarian section was necessary. in one patient with concommitant cloacal exstrophy, the spring loaded silo was placed in the operating room under general anesthesia. in all other cases, bedside-placement with analgesia and sedation provided by the neonatologists was performed. definite repair after gradual reduction of the viscera was performed on day of life (dol) - (mean . days), after complete bedside reduction. ampicillin/gentamycin were administered until definite repair. in patients, operative reconstruction of the abdominal wall was performed in the operating room. in one case, secondary bedside sutureless closure was possible yielding excellent cosmetic outcome. full enteral feedings were achieved on dol - (mean . d) and patients were released on dol - (mean . d). longer hospital stay was associated with co-morbidity in three patients (cloacal exstrophy, cystic fibrosis, nec). conclusion: bedside primary closure of gastroschisis with the spring loaded silo is safe and feasible without need for general anesthesia, even in special situations such prematurity. this simple procedure can be performed at any time of day, including after vaginal delivery or immediate caesarian section. sutureless secondary closure is possible, yielding excellent cosmetic results. pediatric surgery at the university of munich. two ethiopian general surgeons are currently trained as pediatric surgeons. the aim of jimmachild is to establish a paediatric surgery at the ju. the evaluation of jimmachild after year identified the very limited possibilities of postoperative care at the neonatal intensive care unit (nicu) as a major risk factor for poor outcome or death. in order to improve the problem of postoperative care, the idea of a follow-up project by jimmachild was developed specifically for the field of neonatology. the project is intended to provide further education and training in neonatal care for experienced paediatric residents or specialists. this training is based on the european syllabus for neonatology training. after finalizing the training participants are involved in implementing standards of postoperative neonatal care to the jimma university nicu. during our visits in jimma it became clear that an inventory of the actual situation is necessary to enable such a project. assisted by dr. tesfaye workineh chimissa the local partner in jimma we are currently clarifying and sorting responsibilities, develop training plans and evaluate the local conditions. the aim of this collaboration is to improve neonatal care through a specific sustainable training and education program of pediatric colleagues in jimma, in line with jimmachild and thus improve postoperative outcome in the neonatal population in jimma. the four metabolites with the most pronounced differential trans-rv gradients (step up in pah) are involved in lipid metabolism/lipotoxicity; they include a dicarboxylic acid (octadecanedioate) and an acylcarnitine (stearoylcarnitine), accumulation of which indicate a major block in β-fatty acid oxidation in the hypertensive rv. these novel pah-metabolites represent emerging biomarkers and promising targets for future pah therapy. lipid metabolism, epigenetic mirna dysregulation, and revival of a fetal gene program, in the suhx rat model of pah/rvh/rv failure and in human endstage pah/rvh/rv failure. however, rna expression profiling in human non-failing (compensated) rvh has not been performed, and thus rvh-specific regulatory networks are largely unknown. methods: we studied intraoperative rv tissue from infants with tof/ ps and rvh (age - months) and non-rvh age-matched control infants with ventricular septal defects (vsd; - months). rna was extracted and sequenced, capturing mrna, lncrna, and circrna (≥ gb of cleaned data, mio. pairs of bp pe reads). the reads were aligned to the grch .p human genome reference using star, followed by differential expression analysis (edaseq/deseq/starchip). results: using go-elite we performed over-representation analysis of the differentially expressed genes in kegg pathways, cellular biomarkers, and go-terms. we found differentially expressed genes (rvh vs. no-rvh), significantly overrepresented in pathways related to mapk signaling, extracellular matrix (ecm)-receptor interaction, focal adhesion and adherens junctions. additional ipa analysis revealed perturbations in inhibition of matrix metalloproteases, iron homeostasis signaling, tight junction signaling, cardiomyocyte differentiation via bmp receptors, and apelin cardiac fibroblast signaling pathways. to the best of our knowledge, this is the first unbiased, comprehensive rna-seq study of mrna expression patterns in human rv hypertrophy (here: tetralogy of fallot). multiple genes and pathways identified overlap with the mrna signature we had previously identified in rat and human adult rv failure. our results advance our current understanding of rv hypertrophy and progressive rv failure, and highlight future therapeutic targets. the upcoming analysis of lncrna and circrna expression will allow us to investigate further the related complex transcriptional regulation and rna biology specific for human rv hypertrophy in tetralogy of fallot (in the absence of rv failure). self-organizing three-dimensional ( d) structures that can be grown from stem cells or defined tissue-specific progenitor cells. they supposedly recapitulate structural organization and functionality of the organ, and can be used to model developmental and disease processes, although actual organ-like functionality has yet to be determined. aim: we aim to establish fetal lung organoids (los) as an in vitro model to study fetal lung maturation and to compare these los with fetal lungs in vivo. methods: los were derived from alveolar and endothelial cells isolated from fetal rat lung tissue. the crude cell mix obtained after enzymatic digestion of fetal lungs was used to isolate cd + endothelial cells utilizing magnetic beads, which represented . ± . % (mean ± sd; n = ) of total lung cells. an extracellular matrix gradient (matrigel), air-liquid-interface (ali), and a defined media composition were used to cultivate the los. introduction: high flow nasal therapy (hfnt) is being increasingly adopted for use in the paediatric patient population. it also provides the potential for concurrent delivery of nebulised medications and initial reports in the literature support the feasibility of this approach ( , ) . recently, accommodation of concurrent aerosol delivery has been facilitated through the release of the bespoke fisher & paykel airvo nebuliser adapter for use with vibrating mesh type nebulisers. vibrating mesh nebulisers do not introduce additional gas flow or pressure to the circuit, and so must not be considered in the prescription of applied gas flow rate to the patient. the objective of this bench study was to characterise the level of drug deposition delivered by an aerogen vibrating mesh nebuliser across clinically relevant hfnt gas flow rates in models of both a month old and a year old paediatric patient. methods: ml of mg/ml salbutamol was nebulised using an aerogen solo nebuliser (aerogen, ireland). the nebuliser performance characteristics were as follows; average droplet size (volumetric mean diameter) . µm and an aerosol output rate of . ml/min (measured using the malvern spraytec). a sophia anatomical infant nose-throat (saint) model based on a scan of a month old child was connected to a breathing simulator (asl , ingmar, us), fig. | lu-p ) . we sought to define the role of carbonic anhydrases (cas) in macrophage activation in experimental ph. we hypothesized that ca inhibitors (cais) might modulate pulmonary inflammation and ameliorate ph. methods: we used the rat sugen-hypoxia rat model of ph. animals were treated with acetazolamide (actz) in the drinking water for weeks. we assessed hemodynamics and cardiac hypertrophy (fulton"s index, fi). lung tissue, alveolar macrophages and serum were collected for rt-qpcr and elisa. bone marrow-derived macrophages (bmdms) were activated with lps+ ifng or il- +il- and treated with different cais (actz and ethoxyzolamide). results: alveolar macrophages from ph animals and activated bmdms showed elevated expression of ca isoform ii and iv. actz or ethoxyzolamide suppressed macrophage activation and cytokines production in bmdms. in vivo, actz improved hemodynamics and fi compared to untreated ph animals. expression of tnfα, il- , and mcp- in lungs and alveolar macrophages and serum il- were significantly lower in treated animals. we found increased markers of proliferation and vascular smooth muscle (vsmc) de-differentiation in pas from ph animals, and reversal by both interventions. conditioned media of alveolar macrophages from animals with ph was sufficient to induce vsmv de-differentiation as seen in ph. abstracts similar to the adult range. hierarchical clustering analyses suggested that apoc-ii and c-iii mainly reside on high-density lipoprotein (hdl) particles in children but on very-low-density lipoprotein (vldl) particles in adults. high-density lipoprotein cholesterol (hdl-c) concentrations were similar to those seen in adults but the pattern of hdl-associated apolipoproteins was different (lower apoa-i but higher a-ii, a-iv and m). comparing children born term and preterm, apoa-i, a-iv, c-ii, and c-iii were significantly higher in the latter group. conclusion: our study defines apolipoprotein profiles in preschoolers and reports potential effects of prematurity. further large-scale studies are required to provide evidence whether this apolipoprotein signature of prematurity, including high apoc-ii and c-iii levels, might translate into adverse cardiometabolic outcome in later life. background: despite the routine use of antenatal steroids, exogenous surfactant and differentiated non-invasive ventilation methods, some preterm and term infants still require invasive ventilation. in turn, mechanical ventilation can induce ventilator induced lung injury leading to lifelong pulmonary sequelae. high-frequency oscillatiory ventilation (hfov) with tidal volumes below dead space and high frequency is widely used either as primary or rescue therapy in severe neonatal respiratory failure and may be lung-protective. nevertheless, the underlying gas exchange mechanisms during hfov are not fully understood to date. methods: in this study, gas transport and exchange mechanisms along the airway tree of a preterm infant have been investigated using a highly resolved patient specific computational lung model. lung modelling was based on in-vivo data, derived from magnetic resonance imaging (mri) and infant lung function testing (ilft) from a child with bpd. in order to compare the suitability of different respirator settings, gas flow and oxygen delivery have been computed for two high frequency (hf) ventilation settings and one conventional frequency (cf) setting. in this in-silico bpd-lung model, both hf-settings deliver more oxygen to the lung tissue at lower pressures amplitudes compared to conventional ventilation ( . ml o /s in hf-setting two vs. . ml o /s in the cf-setting). further, the regional lung tissue aeration is more homogeneous for the hfov settings reducing the risk for overdistension in regions with low regional compliance. in our computational lung model derived from individual infant lung data hfov is superior in terms of oxygen supply, homogeneity of lung tissue aeration and pressure reduction compared to a conventional ventilation strategy. with this knowledge we are now able to study different ventilator settings in silico for a specific clinical patient. the awareness of gas transport phenomena during hfov in preterm infants advances general knowledge on protective ventilation strategies in neonatal care and can support decisions on various modes of ventilatory therapy at high frequencies. background: in germany, every year an estimated . babies are born preterm with . infants born before weeks of gestation. progress in perinatal medicine has increased their survival rates, but up to % of survivors remain at high risk for life-long motor, cognitive and behavioral impairment. thus, there is a great need to identify neonates at risk for neurological impairment. in adults, alpha b crystallin, an endogenous immunomodulatory neuroprotectant, in neurons and astrocytes is upregulated after cerebral ischemia. alpha b crystallin expression increases rapidly with maximum levels at the -h time point and a gradual decrease over the next days (arac et al., ) . objective: here, we investigated whether the presence of alpha b crystallin in plasma can function as a reliable detection tool for the diagnosis of acute brain damage in neonates, since alpha b crystallin increase in plasma correlates with white matter damage. material and methods: blood samples from preterm infants (born at less than weeks' gestation) and term infants were collected within the first hour and on the third day of life using plasma samples. alpha b crystallin concentration was analyzed via elisa. all infants underwent a detailed clinical evaluation including cranial ultrasound, fundus examination and neurodevelopmental follow-up for the preterm cohort. results: only one out of term infants showed an increase in plasma abc. in contrast, we detected elevated alpha b crystallin levels in out of premature infants. out of these "alpha b crystallin-positive" infants, brain injury was confirmed in neonates on cranial ultrasound, and in one on neurodevelopmental follow-up. none of these children had increased alpha b crystallin levels on day three. discussion: this study found that elevated alpha b crystallin levels at birth indicate a high risk for acute brain injury and could serve as a very early biomarker. prior to changes in cranial ultrasound. it might also serve as a biomarker for brain damage not visible on ultrasound. vorbereitet: einem patienten zweck einer impfung ( , %) und herdenschutz ( %) erklären; informationsquellen zu impfungen für medizinisches personal finden ( , %); eine impfung am patienten durchführen ( , %). "mäßig bis unzureichend" vorbereitet fühlten sich ms in folgenden bereichen: eine vorstellung zu kosten und kostenerstattung einer impfung haben ( , %); fragen des patienten zu potentiellen risiken von adjuvantien beantworten ( , %); impfungen mit inadäquaten durchimpfungsraten in deutschland kennen ( , %); einem patienten den nutzen von adjuvantien erklären ( , %); mit impfverweigerern kommunizieren ( , %); zu reiseimpfungen beraten ( , %). die kenntnisse wurden insgesamt als "adäquat" mit einem item-mittelwert ("mw") von , bis , (je nach universität) angegeben. kommunikative kompetenzen (mw: , - , ), allgemeine kenntnisse (mw: , - , ) und praktische fertigkeiten (mw: , - , ) wurden ebenfalls als "adäquat" eingeschätzt. ms erachteten eine verbesserung der impfausbildung als wichtig, insbesondere wurden hier die bereiche wirksamkeit ( %) und nebenwirkungen ( %) von impfstoffen angegeben. schlussfolgerungen: insgesamt fühlten sich % der ms "adäquat", jedoch mehr als ein drittel "unzureichend" oder "mäßig" auf impfungen im späteren beruf vorbereitet. an allen vier universitäten schätzten ms ihre kommunikativen kompetenzen etwas schlechter ein als ihre allgemeinen und praktischen kenntnisse. Ärzte sollten in der lage sein, zweifel von patienten anzusprechen und die bedeutung von impfungen zu kommunizieren. dies ist insbesondere in zeiten notwendig, in denen sowohl informationen als auch fehlinformation im internet leicht zugänglich und nicht einfach zu differenzieren sind. kompetenzen zu impfungen könnten im medizinstudium noch besser, einheitlicher und strukturierter vermittelt werden. background: non-immunological hydrops fetalis (nihf) is still a challenging diagnosis. the differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. therefore we developed a genetic panel for early diagnosis of nihf. this is important for management and intervention of the underlying disease. this female premature was delivered via emergency cesarean at + weeks of gestational age due to rapidly developing nihf to a healthy mother with no consanguinity in family history. in former prenatal screenings there was the suspicion of a congenital cardiac defect but no signs of increased nuchal translucency, polyhydramnios or short femur, otherwise typical for noonan syndrome. case report: the patient was born with nihf, hypovolemic shock, severe anemia (hemoglobin , g/dl), severe thrombocytopenia ( /nl) and disseminated intravascular coagulation. at immediate drainage of both pleural and the peritoneal cavities, bloody effusions were observed. after stabilization with fluid and catecholamine rescue, the patient was transferred to our nicu. physical examination revealed muscular hypotonia and a distinct short and webbed neck. one sided brain infarction and bilateral intraventricular hemorrhage grade ii were detected on ultrasound. echocardiography confirmed a double-outlet right ventricle in combination with an atrial septum defect with left-right shunt. due to persistent low platelet count, platelet transfusions were done weekly until to date. during the first few weeks the infant was mechanically ventilated and had bilateral chest tube drainage for chylothoraces. we excludedbacterial or viral infection, coagulation disorders andalloimmune and familiar thrombocytopenia. genetic testing with the genetic panel especially developed gegenübergestellt werden, um eine aussage bzgl. der anwendbarkeit in der pädiatrie zu erhalten. angeborene störungen der immunfunktion (primäre immundefekte, pid) prädisponieren zu progredient-destruktiven pulmonalen komplikationen auf der basis einer infektiösen (bspw. bei antikörpermangel) und autoimmunologischen genese (bspw. lymphozyteninfiltration). die initiale und therapiebegleitende diagnostik umfasst neben dem klinischen verlauf immunzelluläre und mikrobiologische bronchioläre lavageuntersuchungen und feinstrukturelle bildgebende verfahren. da pid allerdings auf der basis von dna-reparaturstörungen/chromosomenbrüchigkeitssyndromen entstehen können (bspw. rad , nbs, at), ist eine kritische indikationsstellung vor jeglicher röntgen-oder ct-untersuchungen unerlässtlich; unsere lokale erfahrung zeigt hierbei die validität von modernen laboruntersuchungen (gamma-h ax assay) zur vorherigen risikostratifizierung. therapeutisch berichten wir über möglichkeiten der intensivierten substitution von immunglobulinen, der inhalativen antimikrobiellen anwendung von colistin/tobramycin und der moderierung autoimmunologischer komplikationen unter mycophenolatmofetil (mmf) und nach anti-cd b-zell-depletion (rituximab), sowie über die theoretische perspektive einer seketorischen iga-inhalationstherapie. wochen, diffusen intrapulmonalen infiltraten in allen lungenabschnitten sowie einer generalisierten lymphadenopathie zur weiteren infektiologischen, immunologischen und onkologischen abklärung übernommen. ein erregernachweis -abgesehen von adenoviren im nasopharnygealsekret -war bis zu diesem zeitpunkt nicht gelungen. bei weiterer respiratorischer verschlechterung und nach ausschluss von neoplasie und hämaphagozytose zeigten sich im thorax-ct eine hiliäre lymphadenopathie, bronchiektasen und diffuse interstitielle lungenstrukturveränderungen. in der folgenden bronchoalveolären lavage ließen sich säurefeste stäbchen nachweisen, die molekularpathologisch als m.tuberculosis complex und kulturell als. m. tuberculosis spezifiziert wurden. ein bereits bei aufnahme angefertigter tuberkulin-hauttest war negativ, ebenso ein interferon-γ-release assay (quantiferon). im verlauf entwickelte der junge eine rechtsseitige hemiparese, die mrt-morphologisch mit einer zns-vaskulitis ursächlich vereinbar war. eine liquorpunktion zeigte eine leichte schrankenstörung ohne zellzahlerhöhung, ohne mikroskopischen nachweis säurefester stäbchen, bei allerdings positiver m. tuberculosis complex pcr. eine kombinationstherapie mit isoniazid, ethambutol, rifampicin, pyrazinamid und amikacin sowie methylprednisolon und pyridoxal wurde begonnen. darunter entfieberte der patient innerhalb von h und stabilisierte sich deutlich. auch die neurologische symptomatik bildete sich langsam zurück. nach wenigen tagen kam es jedoch zu einem erneuten fieberanstieg. im vollblut wurde eine fehlende ifnγ-produktion nach stimulation mit il- festgestellt. die therapie wurde daher um die substitution mit interferon-γ erweitert, was zu erneuter entfieberung führte. anti-il- oder anti-ifnγ-autoantikörper konnten nicht nachgewiesen werden. eine sequenzierung von il rb und il rb wurde eingeleitet. als infektionsquelle konnte retrospektiv ein an offener lungentuberkulose erkrankter onkel identifiziert werden. schlussfolgerung: tuberkulose sollte bei unklaren systemerkrankungen auch bei anamnestisch fehlenden risikofaktoren differentialdiagnostisch erwogen werden. bei einer disseminierten verlaufsform sollte ein immundefekt ausgeschlossen werden. tuberkulin-hauttest und interferonγ-release assays können trotz infektion falsch negativ sein. bei verdacht auf tuberkulose muss ein direkter erregernachweis angestrebt werden. ( )). die patientin verstarb im multiorganversagen bevor die therapie begonnen werden konnte. schlussfolgerung: auch ohne angeborene oder medikamentöse immunsuppression kann eine immunparalyse bei schwerer erkrankung -in diesem fall einem postoperativen toxic-shock-syndrom -eine prädisposition für invasive pilzinfektionen inklusive mucormykosen sein. eine experimentelle immunaktivierende therapie sollte bei progredientem verlauf frühzeitig diskutiert werden. introduction: haemolytic uremic syndrome (hus) is characterized by a trilogy of symptoms: haemolytic anemia, thrombocytopenia, and acute renal injury. hus has been classified in two groups, typical hus or atypical hus, depending on the microbiologic findings. the typical syndrome is caused by escherichia coli in % of the cases (usually o : h ) and the treatment is based on hemodynamic and renal support. the atypical hus is caused by a deregulation in complement activation (for diagnosis the complement mutation has to be found). another differential diagno- the retrospective single center study enrolled all pts who underwent allo-hsct between and . primary endpoint was the incidence of proven, probable and possible ifds (eortc/msg). all pts were to receive antifungal prophylaxis with fluconazole. management of persistent fever consisted of blood cultures, pulmonary ct imaging, galactomannan (gm) screening in the case of infiltrates, and modification of antibacterial empiric therapy. empirical or targeted antifungal therapy was at the discretion of the attending physician. results: a total of first ( ), second ( ) or third ( ) procedures were performed in pts (median age: y, r, . - ) for leukemia/lymphoma ( ) and non-malignant disorders ( ) from a matched sibling ( ), a matched unrelated ( ) or a mismatched ( ) donor. the median times to engraftment and to discharge were (r, - ) and (r, - ) days, respectively. prophylaxis was administered to hsct procedures ( %; fluconazole, , mold-active agents, ). at least one ct scan was performed in , and at least one gm assay was in procedures. there were cases of proven (candidemia, ; aspergillosis, ) or probable (aspergillosis, ) ifds, accounting for an incidence rate of . % post-transplant. twenty-nine pts ( . %) fulfilled criteria of a possible pulmonary mold infection. overall mortality at last follow-up (january ) was . %; in instances, death was attributable to ifd ( . %). conclusions: morbidity and mortality from ifds at our institution were consistent with data reported from other centers worldwide. utilization of health care resources for prevention, diagnosis and management of ifds were considerable. introduction: peripheral blood samples of newborns are precious and only minimal blood drawing should be performed for research interests. therefore, it is important to establish methods designed to work with low volumes of whole blood. concerning the stimulation of blood samples in the research field of neonatal sepsis, mainly purified cell wall components such as lipopolysaccharides (lps) or killed bacteria are used. however, the use of living bacteria would simulate a closer in vivo situation by inducing a more physiological immune response compared to killed bacteria or bacterial products. thus far, data on immune responses after stimulation with whole living bacteria in peripheral blood of infants are scarce. the aim of this study is to assess the lowest possible blood volume for ex vivo stimulation of whole blood with bacterial antigens and to assess optimal agents and media simulating an in vitro infection with escherichia coli such as pure lps, heat-killed e. coli (hkec) and living e. coli (lec) developing a methodological approach for further research on neonatal sepsis. methodological approach: blood volume kinetic as well as dose kinetic experiments with lps, hkec and lec were performed in peripheral blood of healthy adults (n = ) and in cord blood of term infants (n = ). the amounts of tnfα, il- ß, il- , il- and il- in the supernatants were analyzed with elisa. additionally, different serum-free and serum-containing media were assessed for the use in an in vitro assay. preliminary results: stimulation experiments with lps, hkec and lec showed reliable cytokine results using µl of whole blood. notably, the use of different types of cell culture media for lps stimulation resulted in highly different values of tnfα, il- ß, il- , il- and il- . in hkec experiments, only differences in tnfα levels could be shown between the media whereas the values of il- ß, il- , il- and il- were similar among all media used. the experiments on lec bacteria showed an increase of tnfα levels with rising concentrations of bacteria. the highest values of tnfα were measured using of living bacteria for the stimulation process. interestingly, using a concentration of lec resulted in diminished tnfα levels in serum-containing medium and low as well as highly variable tnfα values in serum-free aim v medium. discussion: the use of µl of whole blood for cytokine measurements after stimulation with bacterial products or whole bacteria seems to be sufficient. comparing hkec and lec, stimulation with up to whole living bacteria induce a higher tnfα cytokine response compared to similar amounts of killed bacteria. to ensure the most accurate simulation of a bacterial e. coli infection in vitro, the use of living bacteria should rückgang am . postoperativen tag kann allerdings auf eine infektion hindeuten. in der späten postoperativen phase sollte ein anhaltender crp-anstieg über tage zusammen mit der klinisch-infektiologischen beurteilung des patienten weitere diagnostik veranlassen. therefore be preferred. avoiding bacterial overgrowth after lec stimulation, the type and amount of culture medium used must be taken into consideration. hintergrund: neugeborene besitzen im vergleich zu erwachsenen eine erhöhte anfälligkeit gegenüber infektionen, was unter anderem auf eine veränderte funktion der neutrophilen granulozyten zurückzuführen ist. als teil der neutrophilen abwehr ist die bildung von reaktiven sauerstoffspezies, auch als oxidativer burst bekannt, bereits untersucht. kürzlich konnte gezeigt werden, dass neutrophile granulozyten keine homogene gruppe darstellen, sondern sich in proinflammatorische (cd dim cd l + ), reife (cd + cd l + ) und suppressive (cd + cd l -) neutrophile einteilen lassen. untersuchungen des oxidativen burstes dieser neutrophilen-subpopulationen bei neugeborenen fehlen bisher. fragestellung: ist eine abweichende produktion von sauerstoffspezies innerhalb der neutrophilen-subpopulationen teil der unreifen immunabwehr von neugeborenen im vergleich zu jungen erwachsenen? material und methoden: die bildung von reaktiven sauerstoffspezies mittels phagoburst tm -kit (glycotype, heidelberg) wurde aus nabelschnurblut von gesunden neugeborenen (mittelwert ± standartabweichung: + ± + ssw, gewicht: , g ± , g, männlich , sectio ) durchflusszytometrisch untersucht. als kontrolle dienten gesunde erwachsene (alter: , a ± , a, männlich ). die bestimmung des prozentualen anteils von zellen sowie der radikalmenge pro zelle als mean fluorescence intensity (mfi) erfolgte bei formyl-methionyl-leucyl-phenylalanin (fmlp), e. coli und phorbol- -myristat- -acetat (pma) stimulierten sowie unstimulierten zellen. on clinical examination, he was found to be hyperpyrexic and tachypnoeic with sternal recessions and decreased air entry on his right side. laboratory investigations showed a raised c-reactive protein level of mg/l (normal value < · mg/l) and a leucocytosis ( · × per l) without eosinophilia. chest x-ray showed a large, ill-defined, radiolucent, cavernous lesion in the right upper lobe with a radiopaque mass in its lower part (. fig. | bkb-fp ). our initial differential diagnosis included a possible bacterial infection that had subsequently developed into an abscess, mycobacterium tuberculosis infection, or cystic echinococcosis. the patient was started on antibiotics-piperacillin and tazobactam initially, with linezolid added to cover any presumed infection with community-associated methicillin-resistant staphylococcus aureus (mrsa). a contrast-enhanced, chest ct scan (coronal reconstruction) showed a large cystic mass with a thick, contrast-enhancing wall in the right upper lobe (. fig. | bkb-fp ) . a corresponding lung window ct scan reconstruction showed marked consolidation of the adjacent lung parenchyma, with curvilinear septa within the lesion-the so-called water-lily sign (figure). these findings were highly suggestive of a ruptured echinococcus granulosus hydatid cyst in the right upper lobe of the lung. microbiological examination of bronchial alveolar lavage samples grew haemophilus influenzae but no mrsa. linezolid was therefore stopped. additionally, no evidence of mycobacterial infection was found. however, week after admission, the initially negative serology for echinococcosis became strongly positive and the patient developed eosinophilia. additional investigations found a solitary hydatid cyst in the patient's liver. he was therefore diagnosed with cystic echinococcosis with both pulmonary and hepatic manifestations. as the imaging and the seroconversion provided good evidence of recent cyst rupture, the risk of further spillage of the contents of a cyst was considered high, so the patient was started on anthelmintic therapy-oral albendazone-prior to surgical resection. the patient finally went home well on albendazole. acute rupture of pulmonary e granulosus cysts with or without superimposed bacterial infection can mimic other pulmonary infections. in the context of recent and continued migration of people from areas where the disease is endemic, it is important to consider this rare clinical entity in children and adults. of note, serology is frequently negative even in the presence of large, non-ruptured hydatic cysts and the optimal time to start albendazole treatment remains uncertain. background: congential sodium diarrhea is a rare cause of severe metabolic acidosis and hyponatremia. case: prenatal ultrasound demonstrated dilated bowel loops and a prominent polyhydramnios suggesting intestinal atresia. the -kg-newborn was delivered via cesarian section at / weeks due to pathological umbilical cord doppler ultra-sound and pathological cardiotocogram. postnatally, the preterm adapted poorly (apgar at / / min of life: / / ) and was therefore intubated. high respiratory support had to be applied to ensure adequate oxygenation (maximum peak inspiratory pressure , peep , fio ). additionally, the baby presented with massive abdominal distension. circulatory support via fluid application, combined with extensive catecholamine support was needed. dehydration was suspected despite high fluid substitution which had to be increased up to more than ml/kg/day. metabolic acidosis became worse at day three of life (ph . , co . kpa, be- mmol/l). full parenteral nutrition was installed. gastric fluid levels were widely inconsistent varying between to ml every h and abdominal surgery did not show any intestinal obstruction. on day three of life, sodium levels below mmol/l were detected and only sodium substitution higher than mmol/kg helped to normalize blood sodium levels. evaluation of differential diagnoses suggested gastrointestinal losses. analysis of electrolytes in body fluids revealed high sodium levels in stool secretions (> mmol/l). consequently, congenital sodium diarrhea was suspected. sequence analysis in genomic leukocyte-derived dna samples detected a de-novo gu-cy c p.thr ile mutation, confirming the clinical diagnosis. conclusion: if low sodium levels cannot be explained by increased intravascular water content, sodium loss has to be suspected. these losses may be caused by decreased levels of aldosterone or cortisone, by vomiting, diarrhea or impaired skin barrier. if there is a prenatal history of polyhydramnios and massive bowel dilatation combined with postnatal impressive loss of water and sodium, sodium diarrhea is one-rare-differential diagnosis. in this case, massive fluid and sodium needs have to be considered. introduction: lethal anomalies and genetic syndromes account for more than one third of neonatal intensive care unit deaths among term neonates. to date, around phenotypes of single gene disorders and traits are known. therefore, a clinical diagnosis is possible in only a minority of unexpected neonatal deaths. this is underlined by the fact, that "intrauterine growth retardation/restriction" yields , "microcephaly" matches on omim®-both frequent findings in impaired neonates. whole exome sequencing (wes) or whole genome sequencing (wgs) are, consequently, important diagnostic tools to unravel underlying causes of disease in critically ill neonates. case report: we report a term neonate, born to a -year-old primigravida after induction of labor due to intrauterine growth retardation and polyhydramnios. prenatally, fisting, jerky fetal movements and organ ultrasound without pathological findings were reported. clinical features of the newborn included a birthweight of g (< rd percentile), microcephaly, tented mouth, low set ears, short neck, fisting, elongated fingers and toes with syndactyly / , contractures, jaw lock, facial fasciculations, horizontal nystagmus and rigid eye sockets/orbital fibrosis. evident laboratory abnormalities were anemia, neutropenia and elevated urinary excretion of -methylglutaconic-acid. on mri, thymus volume was reduced and myelination severely delayed. in the setting of abnormal brain development, permanent unconsciousness, status epilepticus and consequently severe encephalopathy without respiratory drive the decision was made for therapy-limitation and death occurred on day eight of life. trio-wes revealed the diagnosis of a homozygous clpb-mutation (c. c > t) causing autosomal-recessive -methylglutaconic aciduria ( -mga) type vii. discussion: this case illustrates a severe form of -mga caused by a homozygous nonsense mutation in the clpb gene and describes a phenotypic extension as rigid eye rockets/orbital fibrosis and reduced thymus volume have not been described as features of this relatively new disease. visualizing the prenatal pathologies with fisting and potentially intrauterine seizures on the one hand, and the clinical presentation at birth with contractures, absence of respiratory efforts and movements other than seizures on the other hand, it seems likely that a degenerative process already started during fetal development. background: "blueberry-muffin-baby" describes the presence of dermal erythropoiesis clinically appearing in a variable manner of focal isolated up to generalized papules orhemorrhagic purpuric eruptions. most commonly associated diseases are connatal infections like torch (toxoplasmosis, other, rubella, cytomegalovirus, herpes) or parvovirus, but also malignancy and hematologic disorders. langerhans cell histiocytosis (lch) is a rare disease with a wide spectrum of clinical presentation, from localized to disseminated manifestations. the diagnostic method of choice is biopsy, showing a proliferation of langerhans cells. the therapy varies depending on the organs involved, but in severecases chemotherapy is indicated. case presentation: a male late preterm was born as the first child of healthy parents. during the uneventful pregnancyorgan screening was without pathologic findings. cesarean section performed because of pathologic ctg. the baby presented without spontaneous breathing turning into an apgar score of / / . moreover the whole skin was covered with disseminated red-blueish cutaneous and subcutaneous papules, hemorrhagic crusts and petechia mimicry a blueberry muffin phenotype. the lesions also included the oral mucosa. in addition the boy presented with a distinctive hepatosplenomegaly anddeveloped a pronounced hyperbilirubinemia. laboratory findings suggested first a congenital cmv (weak positive pcr in urine) which could be ruled out next to the other important connatal infections. in the peripheral blood count there were no anemia, no signs of leukemic blasts but a severe and lasting thrombocytopenia. the skin biopsy was performed and lead to the post mortem diagnosis of disseminated lch with severe skin involvement. on the fifth day of life the patient was showing signs of multiple organ failure and died despite maximal intensive care on the sixthday of life. litz). das kind zeigte bereits unmittelbar postnatal die typischen hauterscheinungen mit periungualen erosionen v. a. der finger sowie stehenden blasen mit gelblich-serösem inhalt. schon in den ersten lebenstagen kam es zu einer raschen zunahme der blasenbildung v. a. im windelbereich und an den extremitäten. das kind wurde aus der geburtsklinik in unser verbrennungszentrum verlegt, wo die hautläsionen nach verbrennungsstandard versorgt wurden (supratheldeckung, fettgazeverband). nach histopathologischer analyse eines hautbiopsats wurde die diagnose einer epidermolysis bullosa junctionalis gestellt. die exom-analyse bei der patientin ergab zwei klinisch relevante compound-heterozygote varianten im lamb -gen. varianten in diesem gen sind mit einer schweren generalisierten form (typ herlitz) der hauterkrankung assoziiert. die mütterlich vererbte variante ist bislang noch nicht beschrieben. trotz intensiver interdisziplinärer bemühungen schritt die erkrankung rasch fort. das kind wurde septisch und reanimations-sowie intubationspflichtig. die eltern wurden über die infauste prognose dieser schweren verlaufsform aufgeklärt und sie akzeptierten ein palliatives vorgehen. zwar konnte das kind wieder extubiert werden, jedoch waren zuletzt weit mehr als % der hautfläche blasig verändert oder erodiert und das kind war kaum noch in der lage, selbständig nahrung aufzunehmen. schließlich wurde die patientin in ein kinderpalliativzentrum verlegt, wo sie im alter von wochen verstarb. bei der epidermolysis bullosa junctionalis kommt es bereits nach minimaler mechanischer beanspruchung der haut zu einer abhebung der epidermis auf ebene der basallamina, wobei meistens eine genetische veränderung des lamb -gens vorliegt. die schwerste verlaufsform (typ herlitz) folgt einem autosomal-rezessivem erbgang und führt bereits intrauterin zu blasenbildung und hauterosionen, die nach geburt rasch fortschreiten, wobei auch die schleimhäute betroffen sind. zudem bildet sich granulationsgewebe, das in den atemwegen zu einer obstruktion führen kann. weitere komplikationen sind anämie, gedeihstörung sowie z. t. schwere infektionen, sodass von einer infausten prognose auszugehen ist und die kinder meist innerhalb von ca. jahren versterben. bisher ist nur ein einziger fall bekannt, bei dem in einem experimentellen heilversuch die haut eines patienten mit epidermolysis bullosa regeneriert werden konnte, nachdem durch retrovirale transduktion das betroffene gen in hautstammzellen ersetzt wurde. diese methode scheint derzeit die einzige zukünftige behandlungsoption zu sein und birgt damit hoffnung für betroffene familien. l. schnürch, v. sittig*, d. vlajnic, s. buderus gfo kliniken bonn, st. marien-hospital, pädiatrie, bonn, deutschland ein / jahre alter junge wird mit akutem abdomen und verdacht auf eine stenosierende crohn-erkrankung als verlegung aus einer benachbarten kinderklinik vorgestellt. die krankheitsgeschichte des sonst gesunden jungen ist kurz: vor vier tagen aufnahme dort mit gastroenteritis bei erbrechen, bauchschmerzen. letzter normaler stuhlgang vor fünf tagen. nach rapider verschlechterung mit fieber, leukozytensturz, oligurie und sonographisch stenosierendem, am ehesten entzündlichem prozess im rechten abdomen, einleitung einer antibiotischen therapie (ceftriaxon, metronidazol) und kontaktaufnahme mit unserer kindergastroenterologie. bei aufnahme ist der junge in reduziertem allgemeinzustand, ansprechbar, aber schläfrig, blass, tachykard, peripher auffallend warm mit ausladendem, prall elastischem sowie diffus druckschmerzhaftem abdomen ohne resistenz. peristaltik lässt sich im linken unteren quadranten spärlich auskultieren. bei erfüllung der sirs-kriterien und drohendem warmen schock großzügige volumentherapie, erweiterung der antibiose um ampicillin/sulbactam, tobramycin und anlage von magensonde und blasenkatheter. sonographisch zeigt sich das bild eines dünndarmileus mit aszites. die darmschlingen sind aton, flüssigkeitsgefüllt und dilatiert; eine stenose lässt sich nicht identifizieren. die appendix ist nicht darstellbar; hinweise für einen volvulus gibt es nicht. die hinzugezogenen kinderchirurgen sehen keine indikation für eine notfallmäßige laparoskopie. nach stabilisierung des jungen auf der kinderintensivstation wird bei unverändertem abdominellen befund am folgetag eine kontrollsonographie durchgeführt. dort nun zeichen einer mechanischen obstruktion, so dass die indikation zur laparoskopie gestellt wird. intraoperativ massiv dilatierte, gefüllte darmschlingen und darstellung einer cm langen reizlosen, narbig wirkenden stenosierung im terminalen ileum. via laparotomie erfolgt die resektion des stenotischen segments mit endzu-end-anastomose und simultaner appendektomie unter erhalt der bauhin'schen klappe. histologisch entzündungsfreies resektat mit nachweis von serosaadhäsionen und lumenobstruktion, texturstörung der muscularis propria und reduktion der cajal-zellen. der postoperative verlauf gestaltet sich komplikationslos; nach zehn tagen wird der junge in gutem allgemeinzustand entlassen. im stuhl nachweis von clostridium difficile und toxin. zusammenfassend muss angenommen werden, dass bei diesem kritisch kranken jungen eine angeborene ileumstenose ursächlich für den erkrankungsverlauf war. ungewöhnlich ist, dass eine dünndarmobstruktion so lange symptomlos bleibt; am ehesten ist es im rahmen einer infektion zu einer dekompensation mit massiver prästenotischer dilatation, bakterieller translokation und sepsis gekommen. die angeborene dünndarmstenose muss als differentialdiagnose eines ileus nicht nur im säuglings-, sondern auch im kindesalter beachtet werden. twin anemia-polycythemia sequence (taps) is a severe and acute complication in multiple pregnancies, which is associated with high morbidity and mortality. taps affects more than % of monochorionic twin pregnancies through placental vascular connections that lead to hypovolaemia and anaemia in the donor and hypervolemia and polycythaemia in the recipient. thus, the donor could benefit from receiving placental blood during neonatal transition. performing delayed cord clamping (dcc) exclusively for the donor presents a serious challenge for obstetricians. recently we described the modified extrauterine placental transfusion (ept) approach as an alternative procedure for dcc, which allows both lung aeration and cord blood transfusion during neonatal transition. in the modified ept procedure preterm born infants are delivered by caesarean section with the placenta still attached to the infant via an intact umbilical cord. then, placental transfusion is performed up to several minutes by holding the placenta approximately - cm above the infant's heart level, while simultaneously, respiratory support by mask continuous positive airway pressure (cpap) support is initiated. in taps the modified ept provides an early disconnection of recipient's placental blood circulation and a selective placental transfusion for the donor. here we describe neonatal resuscitation of male twins with taps, born at / weeks' gestation by caesarean section with a donor's birth weight of g (perc. ) and a recipient's birth weight of g (perc. ), respectively. cpap support was initiated after transfer of both twins together with placenta to the resuscitation unit and placental blood was simultaneously transfused selectively to the donor by performing modified ept for min while the recipient's cord was immediately clamped. both infants had similar apgar scores ( / / and / / , respectively), and received less invasive surfactant application (lisa) without intubation. first haemoglobin was . g/dl for the donor and . g/dl for recipient. we conclude that a selective modified ept is feasible in neonatal resuscitation of preterm twins. it represents in our view the only strategy available for supply in taps to prevent severe anaemia associated morbidities and might improve neonatal outcome. medizin und werden von pflegerischen und ärztlichen mitarbeiterinnen und mitarbeitern auf freiwilliger basis erstellt. nach einer vollumfänglichen literaturrecherche zur bisherigen anwendung dieser methode in großbritannien und deutschland, entwickelten wir ein eigenes vorgehen zur praktischen umsetzung des konzeptes auf der neonatologischen intensivstation der uniklinik köln. zum jetzigen zeitpunkt existiert unter anderem bereits ein "eine minute wissen" kurzfortbildung zum thema stillen und laktation, entwicklungsfördernde pflege, beatmungsmodi. aktuell haben wir in unserem interdisziplinären team sechs kurzfortbildungen entworfen und wechseln diese in einem festgelegten intervall aus. neben der evaluation unseres projektes ist es ein weiteres ziel von uns, die interdisziplinäre gestaltung der kurzfortbildungen weiter auszubauen. neben den ärztlichen kollegen, die bereits involviert sind, werden wir unter anderem mitarbeiterinnen und mitarbeiter des psychosozialen dienstes und auch physiotherapeutinnen und physiotherapeuten kontaktieren, um so das themenspektrum weiter ausbauen zu können. darüber hinaus ist, neben der implementierung in die bereiche der weiteren pädiatrischen intensivstationen der uniklinik köln, auch eine datenbank mit verschiedenen "eine minute wissen kurzfortbildungen" geplant. die umsetzung des g-ba beschlusses hat level und level kliniken vor großen herausforderungen bezüglich der umsetzung und finanzierung gestellt. derzeit geht es darum diesen beschluss inhaltlich auszugestalten und neue konzepte für die veränderten teams zu entwickeln. zum einen mussten die teams deutlich größer werden und sind -für neonatologische stationen überdurchschnittlich -mit vielen jungen kollegen aufgefüllt worden, zum anderen nimmt die arbeit im rahmen unserer patientenversorgung mit den eltern und den angehörigen einen immer größer werdenden anteil ein. wie schwierig und belastend das für alle beteiligten seien kann, merken wir jeden tag. diese neuen voraussetzungen führten zu umstrukturierungen im team und es entwickelten sich grundlegend neue aufgabenfelder. . entwicklung einer wöchentlichen pflegegeleiteten familienvisite, koordiniert mit dem austausch im team sowie der unterstützung der verschiedenen berufsgruppen wie psychologen, babylotsen, klinikspfarrerin, physiotherapeuten und ethikberatung. die erfahrungen in der familienvisite haben uns gezeigt, dass bei der klinischen visite viele wichtige dinge aus dem sozialen sowie familiären umfeld nicht ausreichend besprochen werden. seitdem wir die medizinischen belange von der psychosozialen visite getrennt haben und alle berufsgruppen sich auf augenhöhe einbringen können, rutscht die ganze familie in den mittelpunkt, erleichtert uns so die elternarbeit und trägt zur unterstützung aller beteiligten bei. . für den einarbeitungsprozess neuer mitarbeiter bringt die eigenverantwortliche prozessbegleitung in der familienvisite einen positiven effekt, den wir für die teamentwicklung und stabilisierung in der patientenversorgung sowie einarbeitung brauchen. targeted pharmacotherapies for defective abc transporters development of new therapeutic strategy for transporter-related diseases -phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps -phenylbutyrate modulates ubiquitination of hepatocanalicular mrp and reduces serum total bilirubin concentration bilirubin-induced er stress contributes to the inflammatory response and apoptosis in neuronal cells protective effects of -phenylbutyrate derivatives on the neuronal cell death and endoplasmic reticulum stress freie themen ft-fp deutschland literatur . wong et al ( ) what happens after kasai for biliary atresia? a european multicenter survey successful outcome and biliary drainage in an infant with concurrent alpha- -antitrypsin deficiency and biliary atresia. case rep surg does time taken to achieve jaundice-clearance influence survival of the native liver in post-kasai biliary atresia? bereits innerhalb der ersten lebensstunde manifestierte sich ein zerebraler krampfanfall mit blickdeviation und tonuserhöhung der extremitäten. das eeg bestätigte den verdacht mit nachweis von epilepsietypischen potentialen links temporal. mehrfache und teils prolongierte anfällen machten eine antikonvulsive dauertherapie (pb, lev) erforderlich. eine metabolische oder infektiöse ursache bzw. eine koagulopathie wurde nicht gefunden, die zns. die sonographie war unauffällig. das cmrt wies neben grenzzoneninfarkten der linken hemisphäre auch infarzierungen rechts occipital und im bereich der basalganglien links auf. der weitere klinische verlauf (tag - ) mit blasenhochstand, klaffendem anus und fehlenden muskeleigenreflexen (lebenstag ) ließ eine zusätzliche spinale beteiligung erwarten, die sich kernspintomographisch als Ödem mit schrankenstörung im zentralen conus medullaris und eine hydrosyringomyelie des thorakalen myelons bestätigte. verlauf: eine neurogene blasenentleerungsstörung manifestierte sich ab der . lebenswoche das kind war unter der antikonvulsiven dauertherapie mit pb/lev anfallsfrei. schlussfolgerung: vorliegende risikofaktoren in zusammenhang mit neugeborenenanfällen ab dem ersten lebenstag legen die verdachtsdiagnose eines perinatalen arteriellen strokes nahe erstdiagnose einer mütterlichen myasthenia gravis auf der wochenstation -und das neugeborene? -transiente neonatale myasthenia gravis j tienten mit primärer ciliärer dyskinesie (pcd, kartagener-syndrom) auf die pcd ist eine seltene, angeborene erkrankung der atemwege, bei der die bewegung der zilien gestört ist [ ]. in deutschland leben rund pcd-patienten persistierende pulmonale hypertension des neugeborenen (pphn)/persistierende fetale zirkulation (pfc). checkliste neonatologie current and future treatments for persistent pulmonary hypertension in the newborn diagnosis and management of children with primary ciliary dyskinesia klinikum st. georg ggmbh, klinik für diagnostische und interventionelle radiologie klinikum st. georg ggmbh, klinik für kinder-und jugendmedizin, leipzig, deutschland primäre pulmonale hypertension (pphn) ist das andauern der alveolaren pulmonalen konstriktion nach der geburt stationäre aufnahme in der . lebensstunde mit respiratorischen auffälligkeiten mit verdacht auf das vorliegen einer konnatalen infektion bei positivem b-streptokokken-status in der schwangerschaft. wir sahen ein eutrophes männliches neugeborenes in reduziertem allgemeinzustand mit tachydyspnoe, knorksen und einziehungen, kolorit blass-rosig blutgase und elektrolyte ausgeglichen. initial cpap-atemhilfe, bei klinischer verschlechterung maschinelle beatmung ( tage) mit % sauerstoff ( tage) sowie ino röntgenologisch situs inversus und atelektase im linken oberlappen. trachea ohne einengung mit regelrecht liegendem tubus. unauffälliges achsenskelett in einer ebene. echokardiographie: situs inversus totalis, asd ii mit bidirektionalem shunt, zeichen einer pphn, ductus bereits verschlossen, gute biventrikuläre funktion, kein erguss. abdomensonographie: situs inversus mit sonst normaler anlage der organe. schädelsonographie: unauffälliger befund. if-mikroskopie von respiratorischen epithelzellen: uneinheitliche färbung der äußeren dyneinarme häufigste ursachen einer pphn sind . primäre und sekundäre adaptationsstörungen (perinatale asphyxie oder hypoxie, idiopathisches atemnotsyndrom, sepsis), . mediahypertrophie bei sonst normaler entwicklung des pulmonalen gefäßbettes, . hypoplasie des pulmonalen gefäßbettes bei fehlbildungen (zwerchfellhernie, hydrops fetalis). im hier vorliegenden fall war das röntgenbild wegweisend. der situs inversus tritt bei etwa einem von bis . menschen und bei der hälfte der pa-rean-fp unklare schwere hyponatriämie beim neugeborenen georg ggmbh, selbstständige abteilung für neonatologie -perinatalzentrum level (p < , ) unterschieden sich die gruppen a und b besonders hinsichtlich der mortalität (or , ; , - , ) und bpd ° - (or , ; , - , ). obwohl die daten der gruppe c in fast allen parametern besser waren als bei b, fanden sich zwischen diesen beiden gruppen to date, the function of human clpb is insufficiently understood. our case reinforces the hypothesis, that it might play a role in the development of the central nervous system by functioning as a chaperone, especially required for mitochondrial function in glycinergic cells. this case elucidates, that rapid wes/wgs in neonates is needed to estimate prognosis, reduce suffering and enable earlier decision making for caregivers and parents. it also-as in this case-allows for preimplantation or prenatal genetic testing in a successive pregnancy. conclusion: a patient presenting with "blueberry-muffin"-phenotype should lead to most common diagnostics to rule out connatal infections. nevertheless differential diagnosis for further diseases like leukemia, neuroblastoma and lch should also be considered early. especially in critically ill patientsspecialists should be involved early and biopsy of unknown skin lesions should be performed. neonatale cholestase -seltene gemeinsame manifestation von gallengangsatresie und alpha -antitrypsinmangel bei einer neonatalen hyponatriämie denkt man differentialdiagnostisch zunächst an eine verminderte zufuhr, zum beispiel im rahmen einer nahrungsverweigerung [ ] . sekundär müssen das adrenogenitale syndrom (ags) oder eine nebennierenrindeninsuffizienz ausgeschlossen werden. auch im rahmen einer sepsis oder asphyxie kann die hyponatriämie auftreten [ ] . key: cord- -a d a w authors: puig, carme; sunyer, jordi; garcia‐algar, oscar; muñoz, laura; pacifici, roberta; pichini, simona; vall, oriol title: incidence and risk factors of lower respiratory tract illnesses during infancy in a mediterranean birth cohort date: - - journal: acta paediatr doi: . /j. - . . .x sha: doc_id: cord_uid: a d a w aim: to investigate the incidence rate, viral respiratory agents and determinants of lower respiratory tract illnesses (lrtis) in infants younger than year. methods: a total of infants were recruited at birth for the asthma multicenter infant cohort study in barcelona (spain). cases of lrtis were ascertained through an active register including a home visit and viral test in nasal lavage specimens during the first year of life. cotinine in cord blood, household aeroallergens, indoor no( ) and maternal and neonatal ige were measured. other maternal and infants' characteristics were obtained from structured questionnaires. results: the incidence rate of at least one lrti was . infants per persons‐years. the most frequently isolated viral agent was respiratory syncytial virus ( . %). the risk of lrtis was higher in infants with a maternal history of asthma and in those with siblings (or = . ; % ci: . – . and or = . ; % ci: . – . , respectively). the risk of lrtis was lower in infants who were breast fed for more than weeks (or = . ; % ci: . – . ) and in those from a low socioeconomic class (or = . ; % ci: . – . ). conclusion: viral lrtis are frequent in infants younger than year of age and there is an inter‐relationship between maternal asthma, siblings, breast feeding and socioeconomic status. acute illnesses of the respiratory tract are the most common diseases during childhood and most of them involve the upper respiratory tract. however, the incidence of lower respiratory tract illnesses (lrtis) could be considerable, as well. in developed countries, a lrti occurs in - % of infants and children under years of age ( ) ( ) ( ) . moreover, lrtis not only constitute a burden on health care costs ( ), but are also a possible risk factor for developing asthma and allergy during early childhood ( ) and may lead to chronic obstructive pulmonary disease in late adulthood ( ) . recent studies reporting incidence and risk factors for lr-tis in early infancy are based on hospitalized infants ( ), on infants with a predisposition to allergy ( , ) , on a particular type of lrti (with or without wheezing) ( ) or on a causal agent (such as respiratory syncytial virus [rsv]) ( ) . the aim of the present study was to determine the incidence rate of lrtis during infancy, identify viral respiratory abbreviations amics, asthma multicenter infant cohort study; der p , dermatophagoides pteronyssinus ; ets: environmental tobacco smoke; fel d , felus domesticus ; lrti, lower respiratory tract illness; no , nitrogen dioxide; no-lrti, no lower respiratory tract illness; npa, nasopharyngeal aspirate; rsv, respiratory syncytial virus; ses, socioeconomic status. agents and ascertain the association of lrtis with different risk factors in a mediterranean population. the barcelona birth cohort consisted of infants from the asthma multicenter infant cohort study (amics). the amics study was designed to investigate the effects of several pre-and postnatal environmental exposures on the inception of atopy and asthma, and included four cohorts in different european countries. mothers and their infants were recruited during the prenatal visit to the hospital del mar, barcelona, spain. participants were invited to join the study if they anticipated living in the city during the study period and had a telephone. the clinical research ethics committee (ceic-imas) approved the study protocol and mothers signed a written informed consent form. data collection on lrti was conducted between january and october , when infants were recruited prenatally and followed up until they reached year of age. data on the presence of lrti were obtained from two sources. diagnoses established by study paediatricians on enrolment, the mother was instructed to contact the local -h coordinating centre if her infant developed relevant symptoms lasting at least two consecutive days (runny nose, fever, dry cough, wet cough and difficulty breathing). within h, a home visit was arranged and infant visited by a study paediatrician. the event was classified as no lrti (no-lrti) or lrti. lrti was further stratified according to the clinical features previously described ( ) into laryngotracheobronchitis, bronchitis, bronchiolitis and pneumonia. a fifth diagnosis of non-specific lrti was made when the infant could not be classified within the other four diagnoses (these infants often only had wheezing). a new lrti was recorded if the infant was symptom free for at least days between two episodes. a nasopharyngeal aspirate (npa) sample was obtained only in infants with a lrti diagnosed by the study paediatrician, instilling ml of normal saline into the nasopharynx and aspirating with a sterile syringe. the npa sample was preserved at • c in a sterile container for transport to the laboratory and was analysed within - h. during the follow-up, the mother was called every month by a nurse, who inquired whether the infant had been diagnosed with a lrti during the previous month by the family paediatrician without the -h coordinating centre being informed. the occurrence of a lrti was defined as a positive answer to the question, 'has a doctor told you that your son/daughter has laryngotracheobronchitis, bronchitis, bronchiolitis, pneumonia or wheezing, since we spoke with you last?' a negative answer was registered as no-lrti. npa samples were analysed at a local virology research laboratory (hospital vall d'hebron, barcelona) and were classified as positive when a respiratory virus was identified by at least one of the following procedures: • rapid detection for rsv and coronavirus with direct fluorescent monoclonal antibodies (bartels immunodiagnostics supplies, inc., bellevue, wa, usa). • virus culture in human epidermal carcinoma (hep- line) and madin-darby canine kidney (mdck) cells and indirect fluorescent antibody identification with a pool of monoclonal respiratory viral antibodies for rsv, adenovirus, influenza virus types a and b, and parainfluenza types , and (bartels immunodiagnostics supplies, inc.). • conventional tissue culture in hep- , mdck and the llc-mk line of rhesus monkey kidney cells for examination of the characteristic cytophatic effect. at the first prenatal care visit to the hospital, usually during the third trimester of pregnancy, a detailed questionnaire including information on smoking habits, sociodemographic characteristics and parental history of asthma was completed. social class was defined by paternal occupation using the uk registrar general's classification, which groups people with similar levels of occupational skill. upon delivery, general information (gestational age, gender, weight, length and head circumference at birth) was recorded from medical files. one year after birth, a total of ( . %) mothers were contacted for a structured telephonic interview to record the approximate frequency of respiratory symptoms such as wheezing, cough and noisy breathing in the preceding months caused by airway secretions, as well as information on the duration of breast feeding (regardless of whether other foods were given), number of siblings, day care attendance and parental smoking. specific ige to dermatophagoides pteronyssinus (der p ) were determined in maternal blood samples ( . %) obtained in the third trimester of pregnancy by the pharmacia cap system rast-feia (pharmacia, freiburg, germany) and total ige levels in umbilical cord blood ( . %) were determined by pharmacia cap system low-range feia (pharmacia). maternal atopy was defined by detectable serum levels (> . ui/ml) of specific ige to der p and elevated cord blood total ige levels were defined at concentrations of > . ui/ml. umbilical cord serum ( . %) was analysed to determine cotinine concentration by radioimmunoassay as a biomarker of exposure to tobacco smoke during pregnancy. a cut-off of ng/ml was used for cord serum cotinine to distinguish exposed from non-exposed mothers ( ) . dust samples and passive no filter badges (toyo roshi no filter badges, tokyo, japan) were collected months after birth ( %). concentrations of household dust mite (der p ) and cat (felus domesticus [fel d ]) allergens were determined using an enzyme-linked immunoabsorbent assay according to standard procedures described elsewhere ( ) and grouped in categories with potential relevance for sensitization to der p and fel d (> μg/g and > μg/g of dust, respectively) as reported in the international literature ( ) . indoor no concentration was measured by colorimetric reaction and spectrophotometric analysis described previously ( ) . the incidence rate was estimated by incidence density and calculated as i/pt, where i is the number of infants with at least one lrti during the observation period, and pt is the amount of population time observed in the population during this period. chi-square tests were used to assess differences between infants with no-lrtis and lrtis in maternal, neonatal and postnatal characteristics. statistical significance was set at p < . . multivariate logistic regression was used to evaluate associations between predictor variables and lrtis. variables were chosen for the multivariable model if they entered at a level of p ≤ . ; odds ratios (or) with % confidence intervals ( % ci) were estimated. all analyses were performed using the stata . statistical package (statacorp, college station, tx, usa). more than half of the newborns ( . %) were male. the mean maternal age was years (se: . ). the maternal ethnic distribution ( . % spanish vs. . % non-spanish) reflected the demographics of the population attending the hospital del mar. socioeconomic status (ses) measured by paternal profession was broadly distributed as follows: . % of fathers were in professional, managerial or technical occupations (classes i and ii); . % were in skilled nonmanual occupations (class iii, nm); . % were in skilled manual (class iii, m) occupations and . % were in partly skilled or unskilled occupations (classes iv and v). a total of infants had at least one lrti during the first year of life (fig. ). of these, infants ( . %) had one lrti and ( . %) had two or more other episodes of lrti. the study paediatrician directly identified at least one lrti in infants ( . %), and the monthly calls by the nurse identified retrospectively at least one lrti in infants ( . %). the incidence rate of at least one lrti was of . infants per persons-years during the follow- up. the most frequent clinical diagnosis was bronchitis (table ) . out of the infants with an npa sample, one virus was detected in infants ( . %) and two viruses were detected in the same npa sample in infants ( . %). the most commonly detected virus was rsv in infants ( . %). adenovirus was detected in seven ( . %), enterovirus in six ( . %), influenza a in six ( . %) and cytomegalovirus in five ( . %). other viruses identified in these infants were coronavirus in three ( . %), parainfluenza in three ( . %) and influenza b in two ( . %). the viral isolation rate in the npa samples was %. the viruses recovered from different respiratory syndromes are shown in table s (in supplementary material online). pneumonia and bronchiolitis had a viral isolation rate of approximately %, rsv being the most commonly isolated virus. laryngotracheobronchitis was caused mainly by the parainfluenza virus. non-specific lrtis were mainly caused by other viruses. when examining the results of the structured telephonic interviews, no significant differences were found in the prevalence of respiratory symptoms reported by the mothers among infants with lrtis and without lrtis irrespective of the health professional making the diagnosis. there were no differences between the two groups (lrti and no-lrti) with respect to the maternal age or maternal birth country (see table s in supplementary material online). lrtis were less frequent in social classes iv and v, comprising skilled and unskilled occupations. a maternal history of asthma was more frequent in infants with lrti. the prevalence of mothers who smoked during pregnancy was very high not only in the no-lrti group ( %) but also in the lrti group ( . %). indeed, more than % of the total number of infants had cotinine levels in cord blood above ng/ml, suggesting exposure to tobacco smoke during fetal life. der p and fel d levels higher than the threshold for sensitization to allergens (> μg/g and > μg/g of dust, respectively) were less frequent among the lrti group. no differences between groups were detected in indoor no levels. infants who were breast fed for more than weeks showed a lower frequency of lrti. the presence of one or more siblings was more frequent in the lrti group; also, more children in this group attended day care centres compared to the no-lrti group; however, in this cohort, the difference did not reach statistical significance. in the multivariate model (see table s in supplementary material online), the risk of lrtis was . times higher in infants with a maternal history of asthma (or = . ; % ci: . - . ) and was . times higher ( % ci . - . ) in infants with siblings. the risk of lrtis was lower among infants who were breast fed for more than weeks (or = . ; % ci: . - . ) and among those in social classes iv-v (or = . ; % ci . - . ). we present the first study in a mediterranean area of infant outpatients with a prospective record of lrtis, which includes an ad hoc register and laboratory diagnosis, and a wide record of possible risk factors. maternal asthma as a risk factor for the development of lrti in infants was found to be significant, as was the number of siblings. breast-fed infants and those from a low social class had a lower risk of lrtis. lrtis and viral agents in our study, . % infants had at least one lrti during the first year of life while the incidence of lrtis reported in other community-based longitudinal studies ranges from to . % ( ) ( ) ( ) . the higher percentage observed in this study may be the result of using both active follow-up of direct diagnosis and self-reporting. the viral isolation rate in the npa specimens ( %) was higher than those reported in other community-based studies ( - . %) ( , , ) , probably due to immediate specimen collection. however, the rate was lower than those in hospital-based studies ( - . %.) ( ) , probably because we had antigen tests only for rsv and coronaviruses and no pcr was available. when both antigen tests and pcr are used, the proportion of virus-positive cases is almost %. viral agents in the present cohort were identified in almost % of bronchiolitis and pneumonia episodes while only . % of bronchitis episodes were positive. virus-negative illnesses could be caused by other viruses not isolated in this study (i.e. the recently discovered metapneumovirus ( ) or rhinoviruses ( ) detected by the newer pcr techniques). since both antigen tests for all respiratory viruses and pcr have been introduced, the proportion of virus identified has notably increased. at the follow-up of our cohort, new data about wheezing illnesses and its risk factors, as rsv, or other virus infections or environmental tobacco smoke exposure will be included. the association between viral isolates and clinical diagnosis in this study was not statistically significant but the distribution was similar to that in other publications ( , , ( ) ( ) ( ) ( ) . our finding that a maternal history of asthma was associated with lrtis in infants is in agreement with data from other birth cohort ( ) . over-reporting of asthmatic mothers is not a likely explanation, because the association in the current study was evaluated with medical diagnosis and not symptoms. similar to other studies ( ) we found that the presence of siblings was a significant risk factor for lrtis due to increased exposure to viral agents. however, unlike other authors ( ), we found no significant differences between infants with lrtis and no-lrtis with respect to the frequency of day care attendance. this may be due to the low attendance at day care before the first year of age in our population (nearly % vs. more than % in the abovementioned study). of note, nor household dust mite (der p ) or cat (fel d ) allergens higher than the threshold for sensitization were found to be associated with lrtis. in contrast, it can be hypothesized that high der p and fel d levels were less frequent among the lrti group due to more frequent cleaning in the houses of these infants, whose families were those with higher ses. breast feeding for more than weeks was significantly associated with protection against lrtis in our study, which is in agreement with other birth cohort studies ( ) suggesting that specific nutritional, immunoregulatory and immunomodulatory factors in maternal milk may promote maturation of infant immune competence ( ) . our finding that the prevalence of lrti was lower in infants with low ses than in those with high ses was unexpected. these results could be explained if families with low ses were less likely to call us and therefore would have diminished the frequency due to misclassification. however, the surveillance project designed a monthly call to reduce this effect. studies describing the inverse relationship between ses and lrtis provide limited information because only differences in mortality or hospitalization rates were examined ( ) . recently, it has been suggested that the relationship between ses and physical health may not be constant across ages. in a cross-sectional interview about acute respiratory conditions in infants and children aged - , a reverse ses gradient was found in early years (low seslow frequency of respiratory illnesses), whereas an expected ses gradient appeared during adolescence (low ses -high frequency of respiratory illnesses) ( ) . interestingly, in our study cohort, no association between exposure to tobacco smoke and lrtis was demonstrated, just the fact that nearly all infants were prenatally and postnatally exposed. indeed, cord serum cotinine concentrations were higher than those in other european birth cohorts ( , ) and the percentage of self-reported postnatal parental smoke was extremely high. in conclusion, our study highlights important risk factors such as maternal asthma, the number of siblings and ses for the development of lrtis in infants from a mediterranean area. acute lower respiratory tract infections in nonhospitalized children the tucson children's respiratory study: ii. lower respiratory tract illness in the first year of life prospective population-based study of viral lower respiratory tract infections in children under years of age (the pride study) economic impact of communityacquired and nosocomial lower respiratory tract infections in young children in germany asthma and immunoglobulin e antibodies after respiratory syncitial virus bronchiolitis: a prospective cohort study with matched controls do lower respiratory tract infections in early childhood cause chronic obstructive pulmonary disease? persistence of rhinovirus and enterovirus rna after acute respiratory illness in children rhinovirus illnesses during infancy predict subsequent childhood wheezing role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: a birth cohort study a parental history of asthma is a risk factor for wheezing and nonwheezing respiratory illnesses in infants younger than months of age prevalence of respiratory syncytial virus infection in italian infants hospitalized for acute lower respiratory tract infections and association between respiratory syncytial virus infection risk factors and disease severity cord serum cotinine as a biomarker of foetal exposure to cigarette smoke at the end of pregnancy domestic aeroallergen levels in barcelona and menorca (spain) the relevance of allergen exposure to the development of asthma in childhood a badge-type personal sampler for measurements of personal exposure to no and no in ambient air surveillance of respiratory viral infections among pediatric outpatients in northern taiwan viral etiology of lower respiratory tract infections in hospitalized children in mexico a newly discovered human pneumovirus isolated from young children with respiratory tract disease frequency of detection of picornaviruses and seven other respiratory pathogens in infants association of rhinovirus infection with increased disease severity in acute bronchiolitis nasal swabs versus nasopharyngeal aspirate for isolation of respiratory viruses respiratory picornaviruses and respiratory syncytial virus as causative agents of acute expiratory wheezing in children vial respiratory disease in children: classification, etiology, epidemiology and risk factors respiratory infections in infants: interaction of parental allergy, child care and siblings (the piama study) day care attendance in the first year of life and illnesses of the upper and lower respiratory tract in children with a familial history of atopy breast feeding and respiratory morbidity in infancy: a birth cohort study the role of breast-feeding in the development of allergies and asthma effects of socioeconomic status on presentation with acute lower respiratory tract disease in children in salvador, northeast brazil socioeconomic status and health: do gradients differ within childhood and adolescence? fetal exposure to tobacco smoke is common the asthma multicenter infants cohort study received the following funding: fis / , fis / , fis / , fis / , istituto superiore di sanitá, cirirt- sgr , colt foundation. the following supplementary material is available for this article: please note: blackwell publishing is not responsible for the content or functionality of any supplementary materials supplied by the authors. any queries (other than missing material) should be directed to the corresponding author for the article. key: cord- - kbq v w authors: heath, joan a.; zerr, danielle m. title: infections acquired in the nursery: epidemiology and control date: - - journal: infectious diseases of the fetus and newborn infant doi: . /b - - - / - sha: doc_id: cord_uid: kbq v w nan neonates, especially premature neonates, requiring intensive care support constitute a highly vulnerable population at extreme risk for nosocomial or health care-associated infections. it has been estimated that as many as % to % of infants who survive or more hours in a high-risk nursery or neonatal intensive care unit (nicu) acquire a nosocomial infection."* although nosocomial infections have long been recognized in nicus, only recently have data on rates been documented in the literature. as technology and treatments have advanced to significantly diminish mortality and morbidity among critically ill neonates, especially infants of very low birth weight (less than g), this vulnerability has only increased, as a result of both more profound immune system immaturity and more frequent use of invasive interventions that bypass skin and mucous membrane barriers. ' nosocomial infections in neonates carry high attendant morbidity and mortality and health care costs. prevention and control of these infections, although highly desirable, present a formidable challenge to health care professionals. because control over birth weight-the most significant predictor of nosocomial infection risk-is limited, proper nicu customs, environment, and procedures (e.g., hand hygiene, antimicrobial usage, catheter-related practices, skin and cord care, visitation policies, unit design, and staffing) can reduce the risk for infection in the nicu. understanding the epidemiology of nosocomial infections in neonates and methods for their prevention and control is critical to minimizing poor outcomes. this chapter describes the epidemiology, etiology, and clinical characteristics of neonatal nosocomial infections as well as the methods required for effective infection prevention and control. it is well recognized that the immune system of the newborn infant, especially the premature infant, is functionally inferior to that of older infants, children, and adults (see chapter ). the lineages of the cells that will develop into the immune system are present at the beginning of the second trimester. the major components of the neonatal immune system, including t cells, neutrophils, monocytes, and the complement pathways, are functionally impaired, however, when compared with those in older infants and adults. for example, neonatal neutrophils show decreased chemotaxis, diminished adherence to the endothelium, and impaired phagocyto~is~~~; neonatal complement levels and opsonic capacity also are reduced, particularly in the premature ne nate. '~ in addition, neonatal t cell lymphokine production, cytotoxicity, delayed-type hypersensitivity, and help for b cell differentiation all are inferior when measured against those in adults! antigenic naivete may account for many of these differences; however, inherent immaturity also appears to account for certain inequities. for example, neonatal t cells are delayed in their ability to generate antigen-specific memory function after hsv infection, even in comparison with naive adult t cells. ' passively acquired maternal immunoglobulin g (igg) is the sole source of neonatal igg. soon after birth, maternal igg levels begin to fall; weeks later, production of immunoglobulins by the neonate commences. neonatal igg levels reach about % of adult levels by year of age. unfortunately, because much of the maternal igg is not transferred to the infant until the last to weeks' gestation, premature infants start with significantly lower levels of serum igg than in their term counterparts, which persist throughout most of the first months of life. other issues specific to the premature neonate also affect the functional immune system. for instance, the immature gastrointestinal tract (lack of acidity worsened by use of histamine h blockers and continuous feedings) and easily damaged skin constitute open potential portals of entry for pathogens or commensals. in addition, like other intensive care unit populations, the nicu population frequently experiences extrinsic breeches of the immune system through use of intravascular catheters as well as other invasive equipment and procedures used to care for critically ill patients. it is generally accepted that colonization with "normal flora" prevents, to some degree, colonization by pathogenic organisms. the neonate begins life essentially sterile. in the healthy term neonate, colonization occurs within the first few days of life. the organisms involved by site are a-hemolytic streptococci in the upper respiratory tract, staphylococcus epidermidis and other coagulase-negative staphylococci (cons) on the skin, and gram-negative bacilli and anaerobes in the gastrointestinal tract. this process of colonization with normal flora is disrupted in infants cared for in an nicu in part because of exposure to the nicu environment, the hands of health care workers (hcws), antimicrobial agents, and invasive procedures. as a result, the microflora of infants in the nicu can be markedly different from that of healthy term infantses multiple antimicrobial agent-resistant cons, klebsiella, enterobacter, and citrobacter species colonize the skin and the respiratory and gastrointestinal tracts of a high proportion of nicu neonates by the second week of hospitali~ation.'~-'~ in addition, neonates in the nicu become colonized not only with candida albicans but also with non-albicans candida species and malasse~ia.'~-' ' because colonization of the neonate with pathogenic organisms is a prelude to invasive infection from the same pathogens? measures to prevent such colonization need to be considered. first, as a result of abnormal colonization, infants in the nicu themselves serve as an important reservoir of potential pathogens. second, contamination of the hands of hcws during routine patient care has been well documented.'* thus, careful attention to hand hygiene before and after contact with patients and their environment, as well as decontamination of potential fomites, are crucial measures in preventing spread of colonization and infection. nosocomial infections in healthy term infants are uncommon unless other conditions require that they be cared for in the nicu for several days to weeks. on the other hand, these other conditions are frequent in neonates of very low birth weight (less than g), who require prolonged nicu care. understanding the epidemiology of nosocomial infections in nicus can be challenging, because reported rates vary dramatically by institution. this variation probably results from use of nonstandard definitions of nosocomial infection and from differences in patient populations, such as mean gestational age, birth weight, and severity of underlying illness, which significantly affect the incidence of nosocomial infection." the national nosocomial infections surveillance (nnis) system is a national surveillance system of the centers for disease control and prevention (cdc) that uses standardized surveillance protocols and the involvement of multiple medical centers to provide benchmark data for the epidemiology of nosocomial nicu infections. using standardized definitions, "is reported in that , nosocomial infections occurred between and in , neonates in nicus.~' in this study, rates of intravascular catheterassociated bloodstream infection, the most frequent nosocomial infection, ranged from fewer than infections per umbilical or central catheter days in infants with a birth weight greater than g to almost infections per catheter days in the lowest-birth-weight group (less than another national, multicenter surveillance study, the pediatric prevention network's (ppn) point prevalence survey, was undertaken in to determine the point prevalence of nosocomial infections in nicus and to define risk factors associated with development of these infections." this study included infants from nicus. of the infants, ( . %) had an active nosocomial infection on the day of the survey. bacteremia accounted for % of infections; lower respiratory tract infections, ear-nose-throat infections, and urinary tract infections accounted for %, %, and %, respectively (table - ) . in contrast with the nicu setting, the frequency of nosocomial infection in well-baby nurseries has been estimated to be between . % and . %? - in general, non-lifethreatening infections such as conjunctivitis account for a majority of infections in the well-baby population. the remainder of this chapter focuses almost entirely on nosocomial infections in and control measures for the nicu setting. g). / ( . ) / ( ) / ( ) for purposes of surveillance and tracking, all infections occurring in hospitalized newborns could be considered nosocomial. infections that are manifested in the first few days of life, however, usually are caused by pathogens transmitted vertically from the maternal genital tract. unfortunately, no precise time point perfectly distinguishes maternally acquired neonatal infections from those transmitted within the nicu. nnis has attempted to address this issue by stratifying infections according to whether they are likely to be maternally acquired. in % of neonates who had an infection thought to be maternally acquired, onset occurred within hours of birth. use of a cutoff period of hours or less to designate maternally acquired infections allowed . % of bacteremias and . % of pneumonias to be considered as originating from a maternal source. maternally acquired bloodstream infections were more likely to be caused by group b streptococci, other streptococci, and escherichia coli, whereas those not maternally acquired usually were caused by coagulase-negative staphylococci. in general, nonmaternal routes of transmission of microorganisms to neonates are divided into three categories: contact (from either direct or indirect contact from an infected person or a contaminated source), droplet (from large respiratory droplets that fall out of the air at a maximum distance of feet), and airborne (from droplet nuclei, which can remain suspended in air for long periods and as a result travel longer distances). specific microorganisms can be spread by more than one mechanism; in most instances, however, a single mode of spread predominates. the cdc has developed a system of precautions for the control of nosocomial infections that is based on these modes of transmi~sion.~~ contact transmission of bacteria, viruses, and fungi on the hands of hcws is arguably the most important yet seemingly preventable means of transmission of nosocomial infection. spread of infection by this means can occur either by transmission of the hcw's own colonizing or infecting pathogens or, more often, by transmission of pathogens from one patient to another. that the hands of hcws become contaminated even in touching intact skin of patients has been well demonstrated.'* poor compliance with hand hygiene is another means by which the hands of hcws can spread organisms from one patient to another. furthermore, hands of hcws have been implicated in multiple outbreaks with a variety of different organisms; through experimental studies, a causal link between hand hygiene and nosocomial infection has been established. contact transmission by means of fomites also can occur and has been described as a potential mechanism of spread of pathogens in multiple nicu outbreaks. as described later in this chapter, implicated items have included linens, medical devices, soap dispensers, and breast pumps, to name a few. these observations highlight the need for careful attention to disinfecting items shared between infants. spread through large respiratory droplets is an important mode of transmission for pertussis and infections due to neisseria meningitidis, group a streptococci, and certain respiratory viruses, whereas airborne transmission by means of droplet nuclei is relevant for measles, varicella, and pulmonary tuberculosis. for large droplet or droplet nuclei transmission, usually an ill adult, either an hcw or a parent, is the source of infection in an nicu setting. in general, these organisms are rare sources of outbreaks. infusates, medications, and feeding powders or solutions can be intrinsically or extrinsically contaminated and have been reported as the source of outbreaks due to a variety of different pathogens. it is important when possible to mix infusates in a controlled environment (usually the pharmacy), to avoid multiuse sources of medication, and to use bottled or sterilized feeding solutions when breast milk is not available. of course, nosocomial infection also can arise from endogenous sources within the neonate. the "abnormal flora" of the neonate residing in the nicu, however, is determined at least in part by the nicu environment and hcws' hands. with use of molecular techniques, even organisms typically considered to originate solely from normal flora (e.g., cons) have been shown to have clonal spread in the hospital setting, suggesting transmission by means of the hands of hcws.~~,~' as discussed earlier, infants in nicus have intrinsic factors predisposing them to infection, such as an immature immune system and compromised skin or mucous membrane barriers. in addition, multiple extrinsic factors play important roles in the development of infection, such as presence of indwelling catheters, performance of invasive procedures, and administration of certain medications, such as steroids and antimicrobial agents. birth weight is one of the strongest predictors of risk for nosocomial infection. for instance, "is data demonstrate that compared with larger infants, low-birth-weight infants are at higher risk of developing bloodstream infections and ventilator-associated pneumonia, even after correction for central intravascular catheter and ventilator use." similarly, in the ppn's point prevalence survey, infants weighing g or less at birth were . ( % confidence interval [ci] . % to . %; p < . ) times more likely to have an infection than those weighing more than g. ' the relationship between birth weight and nosocomial infection is complicated by multiple other factors that accompany low birth weight and also increase risk for nosocomial infection. low birth weight, however, has been shown to be an independent predictor for nosocomial infection, after adjustment for use of vascular catheters, parented alimentation, and mechanical ~entilation.~~ it is likely that birth weight also is a surrogate marker for other unmeasured factors, such as immune system immaturity. central venous catheters (cvcs) increase the risk for development of nosocomial bloodstream infections. in a study by chien and colleagues , infants admitted to nicus in canada, nosocomial bloodstream infections were found to occur at a rate of . to . infections per catheter days, depending on the type of catheter, versus . infections per noncatheter days. other studies have demonstrated that the association between cvcs and bloodstream infection is independent of birth weight. ' mechanisms for cvc-related nosocomial bloodstream infections probably involve colonization of the catheter by means of the catheter hub, colonization of the skin at the insertion site? or hematogenous spread of pathogens from distant sites of infection or colonization. bloodstream infections also can result from contaminated intravenous fluids, which have the potential for intrinsic or, especially with use of multiuse vials, extrinsic contamination. factors related to the management of cvcs influence the risk of infection. disconnection of the cvc and the frequency of blood sampling through the catheter increase the frequency of catheter-related infection^.^^ by contrast, administration of a solution with heparin and exit-site antisepsis decreased infection. lower frequency of cvc tubing changes (every hours versus every hours) was associated with increased catheter contamination, suggesting a potential for increased risk of infecti n. ~ cvc management techniques, including use of antiseptic-impregnated dressings, antimicrobialcoated catheters, and avoidance of scheduled replacement of cvcs, are discussed in the most recent cdc recommendations, summarized in "guidelines for the prevention of intravascular catheter-related infection," published in and prepared by the hospital infection control practice advisory c~m m i t t e e .~~ it has been suggested that use of peripherally inserted central catheters (piccs) may be associated with a lower rate of infection than for other cvcs. studies based in nicus have yielded conflicting results. in a study by chien and colleagues?' the relative risk of bloodstream infection, after adjustment for differences in infant characteristics and admission illness severity, was . per catheter days for umbilical venous catheters, . for piccs, and . for broviac catheters, compared with no catheter ( p < . ). another study also documented similar rates of infection for broviac catheters and for piccs.~~ by contrast, a higher rate of infection with broviac catheters than with piccs was suggested by brodie and co-w~rkers.~~ further study of different cvcs in nicu infants is needed to delineate infection risks for individual catheter types. parented alimentation and intralipids have been shown to increase risk of bloodstream infection in premature infants even after adjustment for other covariables such as birth weight and cvc use. etiologic agents often associated are cons, candida species, and malassezia species. the pathogenesis of this association remains unclear. potential hypotheses are many. intralipids, for example, could have a direct effect on the immune system, perhaps through inhibition of interleukin- . alternatively, as with any intravenous fluids, parented alimentation has the potential for intrinsic and extrinsic contamination, and intralipids especially may serve as a growth medium for certain bacteria and fungi. finally, total parented alimentation and intralipids delay the normal development of gastrointestinal mucosa because of lack of enteral feeding, encouraging translocation of pathogens across the gastrointestinal mucosa. it is well accepted that mechanical ventilation is an important risk factor for nosocomial lower respiratory tract infection. a large multicenter study of neonates found that mechanical ventilation was a risk factor for bloodstream infection as well, even after adjustment for a number of covariables such as birth weight, parented nutrition, and umbilical catheterization:' clinically obvious respiratory infection appeared to precede some but not all cases of bloodstream infection associated with mechanical ventilation. the study authors suggested that the increased risk of mechanical ventilation could be attributed to colonization of humidified air, as well as to physical trauma from the endotracheal tube and its suctioning. a number of medications critical to the survival of infants in the nicu increase risk of infection. broad-spectrum antimicrobial agents, especially with prolonged use, are important in the development of colonization with pathogenic micro-organism~.~ the widespread use of broad-spectrum antimicrobial agents has been associated with increased colonization with resistant organisms in many settings, including nicus." in addition to colonization, antimicrobial agents also have been shown to increase risk of infection with resistant bacteria ' and with fungal pathogens!' other medications also appear to play a role in nosocomial infection. for instance, infants who receive corticosteroids after delivery are at approximately . to . times higher risk for nosocomial bacteremia in the subsequent to weeks than that observed for infants who do not receive this in addition, colonization and infection with bacterial and fungal pathogens have been shown to increase with the use of h, blocker^.'^"' measures of illness severity have been developed, in part, in an effort to account for variations in birth weight-adjusted mortality scores between nicus. the score for neonatal acute physiology (snap) was developed and validated by richardson and ass ciates, ~ and the clinical risk index for babies (crib) was developed by the international neonatal network.% these scores are highly predictive of neonatal mortality even within narrow birth weight strata and are predictive of nosocomial infection. thus, in investigating potential risk factors for nosocomial infection, it is important to consider adjusting for illness severity using such measures, in addition to adjusting for other potential confounders. other risk factors related to infection include poor hand hygiene and environmental issues, such as understaffing and overcrowding. b these and related issues are discussed later in this chapter under "prevention and control." nosocomial infections can affect any body site or organ system and manifest in a multitude of different ways. "is and ppn data demonstrated that bloodstream infections are the most common manifestation of nosocomial infection and account for % to % of infections (table - ; see also table - ). ,'' respiratory infections and eye, ear, nose, or throat infections are second and third in frequency, whereas gastrointestinal infections, urinary tract infections, surgical site infections, meningitis, cellulitis, omphalitis, septic arthritis, and osteomyelitis are reported less frequently."*" bloodstream infections are the most common and one of the most potentially serious nosocomial infections that occur in nicu patients. factors discussed earlier, including birth weight, intravascular catheters, mechanical ventilation, use of parented alimentation, and steroids, all have been shown to be associated with an increased risk of bloodstream infection. the most common pathogen associated with nosocomial bloodstream infections is cons (see table - ). staphylococcus aureus, enterococcus, candida species, e. coli, enterobacter species, klebsiella pneurnoniae, and pseudomonas aeruginosa also play important roles and are associated with higher morbidity and mortality rates than those associated with cons?^,^" in one study, the frequency of fulminant sepsis (fatal within hours) was estimated to be % ( % ci % to %) when the bloodstream infection was caused by pseudomonas species, whereas it was only % ( % ci % to %) when infection was caused by cons.^" the difficulty of assigning an etiologic role to cons on the basis of one blood culture that could be contaminated probably accounts for some distortion of the incidence and mortality data related to this organism, and this problem is discussed in detail in chapter . pneumonia accounts for % to % of nicu nosocomial infections" and has been associated with prolonged hospital stay and increased mortality. organisms most commonly associated with nosocomial pneumonia include cons, s. aureus, and i? aeruginosa (see table - ). mechanical ventilation and birth weight are important risk factors for nosocomial respiratory infection^.^^ diagnosis of nosocomial respiratory infections requires correlation of microbiologic results with clinical findings and can be challenging in lowbirth-weight infants because of the mostly nonspecific associated signs of illness and often misleading results of radiologic ~tudies.~' eye, ear, nose, and throat infections account for approximately % to % of infections, depending on birth weight." common etiologic organisms include cons and s. aureus, although gram-negative organisms, such as e. coli, e! aeruginosa, and k. pneumoniae, also can be isolated from these sites (see table - ). conjunctivitis appears to be the most common of these infections, accounting for % to %, depending on birth weight?' risk factors for neonatal conjunctivitis identified in a study from nigeria included vaginal delivery, asphyxia, and prolonged rupture of membranes. in the nnis review, gastrointestinal infections were estimated to account for % to % of nosocomial infections, depending on birth weight. necrotizing enterocolitis (nec) was the most common presentation.'" nec carries high morbidity and mortality rates. a review of nec epidemics estimated that surgery was required for a mean of % (range, % to %) of infants, and death occurred in a mean of % (range, % to y ) .~~ in controlled studies, identified risk factors for nec have included young chronologic age, low gestational age, low birth weight, and young age at first feeding. implication of specific pathogens is complex, requiring careful selection of an appropriate control population and attention to how and where specimens are collected. pathogens associated with nec outbreaks have included pseudornonas species, salmonella species, e. coli, k. pneumoniae, enterobacter cloacae, s. epidermidis, clostridium species, coronavirus, and r~t a v i r u s .~~'~~ the importance of infection control methods such as strict attention to hand hygiene and cohorting patients in the nicu is suggested by the observation that their implementation has been followed by resolution of the outbreak. a detailed discussion of the cause of nosocomial sepsis and meningitis is found in the chapter on bacterial sepsis (chapter ) and chapters describing specific etiologic agents. s. aureus is a colonizing agent in neonates and has been a cause of nosocomial infection and outbreaks in well-baby nurseries and nicus. methicillin-resistant s. aureus (mrsa) has become a serious nosocomial pathogen, and outbreaks have been reported in many areas of hospitals, including n~rseries.~~-~' in addition to the usual manifestations of neonatal nosocomial infection (conjunctivitis, bloodstream infections, and pneumonia), nosocomial s. aureus infections can manifest as skin infection^?^ bone and joint infections,@' parotitis:' staphylococcal scalded skin syndr me, ~*~~ toxic shock syndrome? and disseminated sepsis. the role of the hands of hcws in transmitting and spreading pathogenic organisms among infants was demonstrated with s. aureus in the ~."*~~ currently, in a majority of instances, s. aureus transmission is thought to occur by direct contact. thus, it is not surprising that understaffing and overcrowding have been associated with s. aureus outbreaks in n i c u s .~~.~ the potential for airborne transmission, however, has been suggested by the occurrence of "cloud babies? described by eichenwald and colleagues in . "cloud" hcws also have been described; in such cases, the point source of an outbreak was determined to be a colonized hcw with a viral respiratory infe~tion.~~'~' in one of these studies, dispersion of s. aureus from the implicated hcw was found to be much higher after experimental infection with rhinovirus. more recently, molecular techniques not only have defined outbreaks but also have demonstrated that transmission to infants probably occurs from colonized hcws, * and sometimes from colonized parents. nasal mupirocin ointment has been used to control outbreaks of both methidin-susceptible s. aureus and mrsa. , the pharynx, rather than the anterior nares, however, may be a more common site of colonization in neonates and infants," and eradication of the causative organisms with nasal mupirocin may be more difficult in this site. since the early s, cons has been the most common cause of nosocomial infection in the nicu. ' this finding suggests that a portion of cons infections may be preventable by strict adherence to infection control practices. the fact that a hand hygiene campaign was associated with increased hand hygiene compliance and a lower rate of cons-positive cultures supports this ~ontention.'~ enterococcus has been shown to account for % of total nosocomial infections in neonates, % to % of bloodstream infections, % to % of cases of pneumonia, % of urinary tract infections, and % of surgical site sepsis and meningitis are common manifestations of enterococcal infection during nicu outbreak^'^,^^; however, polymicrobial bacteremia and nec frequently accompany enterococcal sepsis. identified risk factors for enterococcal sepsis, after adjustment for birth weight, include use of a nonumbilical cvc, prolonged presence of a cvc, and bowel resection?' because enterococcus colonizes the gastrointestinal tract and can survive for long periods of time on inanimate surfaces, the patient's environment may become contaminated and, along with the infant, serve as a reservoir for ongoing spread of the organism. the emergence of vancomycin-resistant enterococci (vre) is a concern in all hospital settings, and vre have been the cause of at least one outbreak in the nicu setting ' in the neonate, resistant strains appear to cause clinical syndromes indistinguishable from those due to susceptible enteroco~ci.'~ the conditions promoting vre infection, such as severe underlying disease and use of broad-spectrum antimicrobial agents, especially vancomycin, can be difficult to alter in many nicu settings. guidelines for the prevention and control of vre infection have been published; these focus on infection control tools such as rapid identification of a vrecolonized or vre-infected patient, cohorting, isolation, and barrier precautions. historically, before the recognized importance of hand hygiene and the availability of antimicrobial agents, group a streptococci (gas) were a major cause of puerperal sepsis and fatal neonatal sepsis. although less common now, gas continue to be a cause of well-baby and nicu outbreak^.'^-'^ gas-associated clinical manifestations include severe sepsis and soft tissue infections. one report described a high frequency of "indolent omphalitis"; in this outbreak, the umbilical stump appeared to be an important site of gas colonization and an ongoing reservoir of the organism." routine cord care included daily alcohol application. after multiple attempts, the outbreak finally was interrupted after a -day interval during which bacitracin ointment was applied to the umbilical stump in all infants, and affected infants received intramuscular penicillin. molecular techniques have enhanced the ability to define outbreaks, and use of these techniques has suggested that transmission can occur between mother and infant, between hcw and infant, and between infantsprobably indirectly on the hands of hcws.",~~ in one recurring outbreak, inadequate laundry practices appeared to be a contributing factor. nnis data have shown that group b streptococci (gbs) infections account for less than % of non-maternally acquired nosocomial bloodstream and pneumonia infections." a number of studies from the s and s demonstrated nosocomial colonization of infants born to gbs-negative ~o m e n .~~-~o these studies suggested a rate of transmission to babies born to seronegative mothers as high as % to / . ~,~' a recent case-control study evaluating risk factors for lateonset gbs infection demonstrated that premature birth was a strong predictor?' in that study, % of the infants with late-onset gbs infection were born at less than weeks of gestation (compared with % of controls), and only % of the mothers of these infants were colonized with gbs, suggesting possible nosocomial transmission of gbs during the nicu stay. the hands of hcws are assumed to account for the transmission of most cases of nosocomial gbs infection. breast milk also has been implicated as a potential mode of acquisition, however. in one report, gbs probably was transmitted from breast milk to one set of premature triplets between days and of life. two maternal vaginal swabs taken before delivery did not grow gbs, but repeated cultures of the mother's breast milk yielded a pure growth of gbs (greater than ' colony-forming units [ cfu] /ml) despite no evidence of mastitis. in this report, antimicrobial therapy administered to the mother appeared to eradicate the organism. the enterobacteriaciae family has long been recognized as an important cause of nosocomial infection. neonatal infection can be manifested as sepsis, pneumonia, urinary tract infections, and soft tissue infections; morbidity and mortality rates frequently are enterobacter species, k. pneumoniae, e. coli, and serratia marcescens are the members of the family enterobacteriaciae most commonly encountered in the nicu. enterobacter species have been estimated to account for % of bloodstream infections, % of cases of pneumonia, and % of surgical site infections in the nicu setting (see table - ). outbreaks due to enterobacter species in nicus have been associated with thermometer^?^ a multidose vial of d e x t r o~e~~ intravenous fluids,% and powdered formula? as well as with understaffing, overcrowding, and poor hand hygiene practice^.'^ in one outbreak in which contaminated saline was linked to the initial cases, subsequent ongoing transmission was documented, presumably by means of the hands of hcws and the environment." in that study, early gestational age, low birth weight, exposure to personnel with contaminated hands, and e. cloacae colonization of the stool were associated with e. cloacae bacteremia, whereas use of cvcs and mechanical ventilation was not. k. pneumoniae has been estimated to account for a similar proportion of infections in the nicu setting to that identified for enterobacter species. investigations in outbreaks involving klebsiella species have implicated contaminated breast milk, oo infusion therapy practices,"' intravenous dextrose,io cockroaches, di~infectant,"~ incubator humidifier^,'^' thermometers, oxygen saturation probes,io and ultrasonography coupling ge .io in a surveillance study of nicu infants in brazil, % became colonized with kleb~iella.'~ in this study, colonization was associated with use of a cephalosporin and aminoglycoside combination therapy, as well as with longer duration of the nicu stay. e. coli has been estimated to cause % of bloodstream, % of gastrointestinal, and % of surgical site infections. e. coli also has been responsible for outbreaks of pyelonephritis,io ga~troenteritis,'~'*"o and nec. s. marcescens is an opportunistic pathogen that survives in relatively harsh environments. disease due to s. marcescens often is manifested as meningitis, bacteremia, and pneumonia.'" s. marcescens infections have a high potential for morbidity and mortality." ,' s. marcescens outbreaks have been associated with, but not limited to, contaminated soap, multiuse bottles of theophylline," formula,"' enteral feeding additives,l breast pumps,' ",'i and transducers from internal monitors.ii although point source environmental contamination is important in serratia outbreaks, in many of these outbreaks and in reports in which no point source was identified,"' patient-to-patient spread of the organism by means of the hands of hcws appeared to be an important mechanism of spread.i extended-spectrum p-lactamases (esbls) are plasmidmediated resistance factors produced by members of the enterobacteriaceae family. esbls inactivate third-generation cephalosporins and aztreonam. they most commonly occur in k. pneumoniae and e. coli but have increasingly been found in other gram-negative bacilli. colonization with esblproducing organisms has been associated with administration of certain antimicrobials and longer duration of hospitalization, whereas infection has been associated with prior colonization and use of cvcs.i that the esbl-containing plasmids can be transmitted to other enterobacteriaceae organisms has been demonstrated in nicu outbreaks in which the implicated plasmid spread from klebsiella species to e. coli, e. cloacae, and citrobacter fieundii.' s'zl the gastrointestinal tract in neonates and the hands of hcws serve as reservoirs for members of the enterobacteriaceae family. thus, in general, measures aimed at controlling spread of organisms in this family have focused on attention on hand hygiene, cohorting of patient and staff, and observation of isolation precautions.' " i? aeruginosa, an opportunistic pathogen that persists in relatively harsh environments, frequently has been associated with nosocomial infections and outbreaks in the nicu setting. nosocomial i! aeruginosa infections vary in their clinical presentation, but the most common manifestations are respiratory, ear, nose, or throat and bloodstream infections.*' from the ppn data it has been estimated that j? aeruginosa species account for . % of total pathogens, % of bloodstream infections, and % of respiratory infections. l ? aeruginosa infections, particularly bloodstream infections, have been associated with a very high mortality rate.' feeding intolerance, prolonged parented alimentation, and long-term intravenous antimicrobial therapy have been identified as risk factors for pseudomonas infe~ti n.l~~ outbreaks due to i! aeruginosa have been linked with contaminated hand lotion,' respiratory therapy solution, ' a water bath used to thaw fkesh-frozen plasma,' a blood gas analy~er,'~' and bathing sources. in one case, neonatal pseudomonas sepsis and meningitis were shown by pulsed-field gel electrophoresis to be associated with shower tubing from a tub used by the infant's mother during labor.i ' of importance, hcws and their contaminated hands also have been linked with pseudomonas infections in the nicu setting. in a study of a new york outbreak, recovery of pseudomonas from the hands of hcws was associated with older age and history of use of artificial nails. ' this and other studies suggest that the risk of transmission of pseudomonas to patients is higher among hcws with onychmycosis or those who wear long artificial or long natural nail^.'^^,'^^ as a result of these and other findings, the cdc revised its hand hygiene recommendations to include a recommendation against the presence of hcws with artificial fingernails in intensive care units.' bordetella pertussis is a rare cause of nosocomial infection in neonates. when b. pertussis infection occurs, parents and hcws typically are the source. a parent was the source of an outbreak involving three neonates and one nurse in a special care nursery in a~stralia.'~' in in knoxville, tennessee, an outbreak involving six neonates probably was due to transmission of infection by an hcw."' as a result of the tennessee outbreak, infants received erythromycin prophylaxis. subsequently, an increase in infantile hypertrophic pyloric stenosis was noted by local pediatric surgeons. results of a cdc investigation suggested a causal role of erythromycin in the cases of hypertrophic pyloric steno~is.'~~~~" erythromycin remains the recommended agent of choice for prophylaxis after pertussis exposure, but parents should be informed of the risk and signs of hypertrophic pyloric stenosis, and cases associated with erythromycin use should be reported to medwat~h.'~~ newborn infants are particularly prone to infection and disease following exposure to mycobacteriurn tuberculosis. a cluster of multidrug-resistant m. tuberculosis infections was noted in three infants born during a -week period in one new york h spita .l~~ investigation implicated an hcw who visited the nursery several times during that period. pulmonary and extrapulmonary disease occurred in three infants to months after exposure, highlighting the vulnerability of the newborn p~pulation.'~~ tuberculosis screening of hcws, ultraviolet lighting, and a high number of air exchanges appear to be effective methods in preventing nosocomial tuberculosis infe~ti n.i~' the cdc's "guidelines for preventing the transmission of mycobacteriurn tuberculosis in health-care settings" emphasizes ( ) use of engineering controls and personal protective equipment, ( ) risk assessments for the development of institutional tuberculosis control plans, ( ) early identification and management of individuals with tuberculosis infection and disease, ( ) tuberculosis screening programs for hcws, ( ) hcw education and training, and ( ) evaluation of tuberculosis control prograrns.l * candida species are an increasingly important cause of nosocomial infection in nicu patients and have been estimated to account for . % of bloodstream infections and % of urinary tract infection^.^^^"^ prospective studies have estimated colonization rates with candida to be % to % in low-birth-weight neonate^,'^"^^-'^' and colonization has been associated with subsequent invasive disease. ' the mortality rate can be high in invasive candidiasis. in one study of patients with fungemia due to candida species, a case-fatality rate of % was r e~ r t e d . i~~ risk factors for fungal infections in neonates are similar to risk factors for bacterial infections; low birth weight and gestational age are important predictors. in addition, a prospective, multicenter study of infants found that use of a third-generation cephalosporin, presence of a cvc, intravenously administered lipids, and hz blocker therapy were associated with candida colonization after adjusting for length of stay, birth weight of g or less, and gestational age less than weeksl candida parapsilosis appears to be the most frequent species associated with nosocomial candida infection in nicu infants. both cross-contamination and maternal reservoirs are sources of nosocomial candida albicans infection, as demonstrated in studies using molecular typing method^.'^-'^^ malassezia species, lipophilic yeasts, frequently colonize nicu patients. in one french study, of preterm neonates ( %) became colonized with malassezia fit+r. malassezia pachydermatis, a zoonotic organism present on the skin and in the ear canals of healthy dogs and cats, also has been associated with nosocomial outbreaks in the nicu setting. , in one report, the outbreak appeared to be linked to colonization of hcws' pet dogs.i ' pichia anornala, or hansenula anornala, a yeast found in soil and pigeon droppings, and on plants and fruits, also can colonize the human throat and gastrointestinal tract. in general, it is an unusual cause of nosocomial infection in neonates, but it was the cause of two reported outbreaks in this ~e t t i n g . '~~, '~~ in both reports, carriage on the hands of hcws appeared to be a factor. invasive mold infections are a rare cause of nosocomial infection in neonates, but when they occur, they are associated with high mortality rate. aspergillus infections may manifest as pulmonary, central nervous system, gastrointestinal, or disseminated disease. a cutaneous presentation, with or without subsequent dissemination, appears to be the most common presentation for hospitalized premature infants without underlying immune defi~iency.'~'.'~~ often, skin maceration is the presumed portal of entry. in a series of four patients who died of disseminated aspergillus infection that started cutaneously, a contaminated device used to collect urine from the male infants was impli~ated.'~' similarly, contaminated wooden tongue depressors, used as splints for intravenous and arterial cannulation sites, were associated with cutaneous infection due to rhizopus microsporus in four premature infants.' in addition to preterm birth, use of broad-spectrum antimicrobial agents, steroid therapy, and hyperglycemia are thought to be risk factors for mold infection. even zoophilic dermatophytes have been described as a source of nosocomial infection in neonates. in one report, five neonatal cases in one unit were traced to an infected nurse and her cat. prolonged therapy for both the nurse and her cat was necessary to clear their infections. although many pathogens can cause nosocomial gastroenteritis, rotavirus is responsible for % or more of viral infections in high-risk nurseries, including the nicu." in one longitudinal study, rotavirus infection developed during hospitalization in of neonates ( ? ).'~~ in this study, rotavirus was manifested as frequent and watery stools in term infants and as abdominal distention and bloody, mucoid stools in the preterm neonates. a high titer of virus is excreted in stool of infected persons, and the organism is viable on hands and in the environment for relatively prolonged periods of time.' " attention to hand hygiene and disinfection of potential fomites are crucial in preventing spread of infection. this concept is illustrated by the results of one study in which rotavirus infection was associated with ungloved nasogastric tube feeding. respiratory viruses including influenza a virus, parainfl uenza virus, coronavirus, respiratory syncytial virus, and aden )virus have been reported to cause nosocomial infections in qicu patient^.'^^-'^' associated clinical findings include rhino rrhea, tachypnea, retractions, nasal flaring, rales, and wheezir g, but illness also can be manifested as apnea, sepsis-like i lness, and gastrointestinal symptoms. ', * identified risk f ictors for acquisition vary from study to study but have includl id low birth weight, low gestational age, twin pregnancy, mech anical ventilation, and high crib s~o r e . '~~-'~* contact and d :oplet transmission are the most common modes of sprcad of infection, again highlighting the importance of scrul (dous hand hygiene in delivery of patient care for this popul, tion. numerous nursery and nicu outbreaks of enterovii a infection have been r e p~r t e d . '~~"~ in the neonate with e iteroviral infection, clinical manifestations can range fron mild gastroenteritis to a severe and fulminant sepsis-like sync home or meningitis/encephalitis. the latter presentation c m be associated with a high mortality rate.lw in index cas :s, the patient may have acquired disease vertically, with subst quent horizontal spread leading to outbreak^'^^'^^; with othe r viral pathogens, virus can be shed into the stool for prolnged periods, enabling patient-to-patient transmission by the hands of hcws when hand hygiene procedures are impr iperly performed. congenitally acquired cytomegalovirus (cmv) infecti )n is a cause of morbidity and occasionally death, whereas postnatally acquired cmv infection follows a benign col rse in virtually all healthy term infants. postnatal cmv infi ction, however, can cause considerable morbidity and death i n premature infants. hepatitis, neutropenia, thrombocyto penia, sepsis-like syndrome, pneumonitis, and developmi nt of chronic lung disease each have been associated with postnatal acquisition of cmv in premature infant^.'^^''^^ w th the routine use of cmv-seronegative blood products in these neonates, a majority of postnatal cmv infections ap ear to be acquired through breast milk.' it has been estinated that transmission by this mode occurs in approximate y % of breast-fed infants of mothers with cmv detec ed in breast milk. ' in one study, approximately % of these infants had clinical features of infection, and % pre iented with a sepsis-like syndrome. nosocomial person-to-] ierson transmission has been d o~u m e n t e d , '~'~'~~ but the exl ent to which this occurs is contr~versial.'~~ at present, no p :oven, highly effective method is available for removing cml ' from breast milk without destroying its beneficial compc nents. some data, however, suggest that freezing the breas: milk before use may decrease the cmv titer, thereby liniting subsequent transmission."* in a majority of cases, neonatal herpes simplex virus hsv) infection is acquired vertically from the mother. nursery transmission of hsv infection is rare but has been describe( . [ ] [ ] [ ] in each of these cases, hsv- was involved. in one infa it, the source of virus was thought to be a patient's father, wl had active herpes labiali~.'~~ subsequent spread of virus from this first infant to a second infant was thought to have occurred by means of the hands of an hcw. in another report, the source of hsv for the index case, an infant who died of respiratory distress in whom evidence of hsv infection was found at postmortem examination of the brain, was un- the hands of hcws were implicated in the spread of hsv to three subsequent cases, however. in another report, direct spread from an hcw was thought to be responsible for transmission of hsv to three infants over a period of approximately years.' studies of adults with herpes labialis suggest a high frequency of recovery of virus from the mouth and the hands ( % and %, re~pectively).'~~ in this same study, hsv was shown to survive for to hours on skin, cloth, and plastic. implementing contact precautions for infants with hsv and instructing hcws with active herpes labialis regarding control measures, such as covering the lesion, not touching the lesion, and using strict hand hygiene, are reasonable means to prevent nosocomial transmission of hsv. if there are concerns that an hcw would be unable to comply with control measures or if the hcw has a herpetic whitlow, such persons should be restricted from patient contact. nosocomial transmission of varicella in the nicu setting, although unusual, has been de~cribed.'~~ large-scale outbreaks in nurseries and nicus are rare, most probably because of the high rate of varicella-zoster virus (vzv) immunity in hcws and pregnant women. premature infants born at less than weeks of gestation are unlikely to have received protective levels of vzv igg from their mothers, so their potential risk is significant if an exposure occurs. transmission is most likely to occur from an adult with early, unrecognized symptoms of varicella. in such instances, the potential risk for vzv-seronegative exposed infants and hcws is substantial, especially if the patient in the index case is an hcw.'" for this reason, it is recommended that hcws be screened for prior varicella infection by history, with subsequent immunization as indicated. hepatitis a is a rare cause of nosocomial infection in nicus, but a number of outbreaks in this setting have been r e p~r t e d . '~' . '~~ in most instances, disease in neonates is clinically silent. neonatal cases often are detected only through recognition of the symptomatic secondary adult cases. in one report, disease was acquired by patients in the index cases through blood transfusion from a donor with acute hepatitis of note, the virus subsequently spread to another infants, nurses, and other hcws. overall, hepatitis a affected % of the patients and % of the nurses. lapses in infection control practices and the prolonged shedding of the virus in infants stool probably contributed to the rapid spread and high attack rate documented in the outbreak. outbreaks such as this one are unlikely because of current blood product practices to eliminate transmissible agents from donor blood. an effective infection control program that focuses on reducing risk on a prospective basis can decrease the incidence of nosocomial infection^.'^"^^ the principal function of such a program is to protect the infant and the hcw from risk of hospital-acquired infection in a manner that is cost-effective. activities crucial to achieving and maintaining this goal include collection and management of critical data relating to surveillance for nosocomial infection, and direct intervention to interrupt the transmission of infectious diseases. reducing the incidence of nosocomial infection for neonates must begin with surveillance for these events. surveillance has been defined as "a comprehensive method of measuring outcomes and related processes of care, analyzing the data, and providing information to members of the health care team to assist in improving those outcomes."' essential elements of a surveillance program include the following: defining the population and data elements as concisely collecting relevant data using systematic methods consolidating and tabulating data to facilitate evaluation analyzing and interpreting data reporting data to those who can bring about changeia surveillance systems necessarily vary, depending on the population; accordingly, a written plan, based on sound epidemiologic principles,ls should be in place to track rates of infection over time. because new risks can emerge, such as new interventional technology or drugs, changing patient demographics, and new pathogens and resistance patterns, the plan should be reviewed and updated the joint commission on accreditation of healthcare organizations (jcaho) recommends that hospitals have a written infection control plan that includes a description of prioritized risks; a statement of the goals of the infection control program; a description of the hospital's strategies to minimize, reduce, or eliminate the prioritized risks; and a description of how the strategies will be evaluated. the jcaho further recommends that hospitals identify risks for transmission and acquisition of infectious agents (table - system provides high-risk nursery-specific data collection methods as well as denominator data and allows external benchmarking of infection rates for this populati~n.'~~,'~' the nnis system defines a nosocomial infection as a localized or systemic process that results from adverse reaction to the presence of an infectious agent(s) or its toxin(s) and that was not present or incubating at the time of admission to the hospital. nnis also recognizes as special situations, and defines as nosocomial, some infections in neonates that result from passage through the birth canal but do not become clinically apparent until several or more days after birth. it does not, however, consider infections that are known or proved to have been acquired transplacentally to be noso-~omial.'~' distinction between maternal and hospital sources of infection is important, although difficult at times, because control measures designed to prevent acquisition from hospital sources will be ineffective in preventing perinatal acquisition of pathogen^.'^' surveillance for infections in healthy newborns also is challenging because of the typically short length of stay. infections can develop after discharge, and these are more difficult for infection control practitioners (icps) to capture. methods for postdischarge surveillance have been developed, but because most neonatal infections that occur following discharge are noninva~ive,'~~ such surveillance has not been widely implemented, because of concerns about the cost-effectiveness of these labor-intensive processes. the ultimate goal of surveillance is to achieve outcome objectives (e.g., decreases in infection rates, morbidity, mortality, or cost).is baseline infection rates for an inpatient unit must be established so that the endemic rate of infection can be understood and addressed. in the nicu, concurrent surveillance (initiated while the infant is in the hospital) should be conducted by persons trained to collect and interpret clinical information. typically, such persons are icps working closely with hcws and using various data sources (table - ) . using nnis or other accepted definitions, the icp should collect data regarding cases of nosocomial infection in the nicu population as well as population-specific denominator data. denominators must be carefully chosen to represent the population at risk. attempts to stratify risk should take into account both underlying infant-specific risks and those resulting from therapeutic or diagnostic interventions.' risk stratification techniques that attempt to control for distribution of risk have included severity of illness score, intensity of care required, and birth weight. because the risk for developing nosocomial infection is greater for lower-birthweight infants:' the nnis system breaks down data collection and analysis into birth weight categories (tables - and - ).' ' the use of invasive devices, however, also is an important factor to consider. the appropriate denominator for an infection related to the use of a medical device, such as a cvc-related primary bloodstream infection, according to nnis, would be total device days for the population during the surveillance period. the formula generally used for calculating nosocomial infection rates is (x/y)k, where x equals the number of events (infections) over a specific time period, y equals the population at risk for development of the outcome, and k is a constant and a multiple of . rates can be expressed as a percentage (k = loo), although device-related infections usually are expressed as events per device days (k = ). a value should be selected for k that results in a rate greater than because use of invasive devices is such a significant risk factor both for bloodstream infection and ventilatorassociated pneumonia, assessing nicu practices with device use may be warranted. "is provides a benchmark for nicu device utilization broken down into birth weight categories. an nicu device utilization ratio can be calculated using the following formula: in those units with device utilization ratios above the nnis th percentile, investigation into the practices surrounding use of invasive devices may be ~a r r a n t e d . '~~ calculating monthly and annual rates to employ as benchmarks can assist in identification of a potential problem in device-related procedures. surveillance data must be arranged and presented in a way that facilitates interpretation, comparison both directed internally and with comparable external benchmarks, and dissemination within the organization. quality improvement tools (e.g., control and run charts) can be useful for these purposes. statistical tools should be used to determine the significance of findings, although statistical significance should always be balanced with the evaluation of clinical ~ignificance."~ external benchmarking through interhospital comparison is a valuable tool for improving quality of are'^,'^^ but should be performed only when surveillance methodologies (e.g., case definitions, case finding, data collection methods, intensity of ~urveillance)'~~ can reasonably be assumed to be consistent between facilities. few overall infection rates in nicus are available, but a small study done in children's hospitals performing nicu nosocomial infection surveillance reported a median nosocomial infection rate of . infections per patient days (range, . to . ). ' nnis does not provide a benchmark for overall infection rates within nicus. instead, nnis provides birth weight-stratified device-associated infection rates for umbilical and central intravascular line-associated bloodstream infections. the most recent rates for catheterrelated bloodstream infections ( to nicus reporting) and ventilator-associated pneumonias ( to nicus reporting) are summarized in table e~ . l~~ once arranged and interpreted, nosocomial infection data must be shared with personnel who can effect change and implement infection control interventions. written reports summarizing the data and appropriate control charts should be provided to the facility's infection control committee, unit leaders, and members of the hospital administration on an ongoing basis. the interval between reports is determined by the needs of the institution. in addition to formal written reports, face-to-face reports are appropriate in the event of identification of a serious problem or an outbreak. icps can serve as consultants to assist nicu or neonatology service leaders in addressing infection rate increases or outbreak management. surveillance activities typically identify endemic nosocomial infections (i.e., those infections that represent the usual level of disease within the nursery or nlcu).' although the rate can fluctuate over time, in the absence of interventions that successfully reduce risk of infection, the difference rarely is statistically significant. establishing an nicu's endemic infection rate and expected variation around that rate allows the icp to rapidly identify unusual increases in rates that may indicate on outbreak (epidemic) of a particular infection. using baseline surveillance data along with aggregate data from sources such as the "is system allows the icp to develop meaningful threshold rates for initiating outbreak investigation.is alternatively, hcws can be the first to sense an increase in infections, which then can be confirmed or refuted by surveillance data? even a single case of infection due to an unusual and potentially dangerous pathogen (e.g., salmonella) can constitute the index case for a subsequent outbreak and thus merits rapid and comprehensive investigation. outbreaks may need to be reported to health authorities, depending on local and state requirements as well as the organism involved. numerous studies have described nursery and nicu epidemics caused by a variety of pathogens (table - ) , and most such epidemics have required the coordinated efforts of icps, nicu leadership, staff, and hospital administration outbreak investigation and intervention should be approached systematically, applying sound epidemiologic principles. in general, the process should include the follo~ing'~~~~''": for resolution. , , , , i j i, ,zo - confirming that an outbreak exists, by comparing the outbreak infection rate with baseline data (or with rates reported in the literature if baseline data are not available), and communicating concerns to stakeholders within the institution (and to those in other agencies if notification of health authorities is necessary) assembling the appropriate personnel to assist in developing a case definition and in planning immediate measures to prevent new cases performing active surveillance using the case definition to search for additional infections and collecting critical data and specimens characterizing cases of infection by person, place, and time, including plotting of an epidemic curve (to facilitate identification of shared risk factors among involved patients, such as invasive devices, proximity to other infected patients or temporal association with infection in such patients, common underlying diagnoses, shared medical or nursing staff, surgery, and medications, including antimicrobial agents) formulating a working hypothesis and testing this hypothesis (if the severity of the problem warrants this level of study, and provided that the institution has and can commit the necessary resources), with use of analytic approaches, including case-control and cohort studies, as appropriate to determine the likely cause of the outbreak instituting and evaluating control measures, which can be implemented anywhere in the foregoing process (more directed measures become possible as more is learned about the outbreak, and efficacy of control measures can be judged on whether the outbreak resolves, as indicated by return of number of cases to endemic levels or by cessation of occurrence of infections) reporting findings to appropriate personnel, including unit staff, hospital administration, and public health authorities (if involved in management of the outbreak), in comprehensive written reports, including summaries of how the outbreak was first recognized, study and analysis methods used, interventions implemented to resolve the epidemic, results, and a discussion of any other important outcomes or surveillance and control measures identified interventions used to control and limit outbreaks usually have consisted of isolation and cohorting of infected or colonized infants to prevent transmission of organisms. transmission-based precautions, a system developed by the cdc, can be used to determine the most effective barrier precautions to use with affected patients. cohorting, or placing infants infected or colonized with the outbreak organism together in geographically segregated areas and assigning dedicated staff and equipment to their care, also has been used successfully to halt outbreaks in nurseries and nicus. in extreme cases, closure of an nicu to admissions has been necessary to bring an outbreak under ~o n t r o l .~~~'~~, '~~ every attempt should be made to identify the source of a nursery outbreak, although this is not always possible. sources implicated in nicu outbreaks have included medications, equipment, and enteral feeding solutions; person-to-person transmission and environmental reservoirs also have been efforts to identify the source may include culturing of specimens from hcws, equipment, and the environment, although careful consideration should be given to the potential benefits before initiating these measures. culture of samples from the environment and equipment, in view of the vast number of objects that could be contaminated, usually is not helpful in identifying the source of an outbreak unless specific case characteristics or microbiologic data strongly suggest the location. culture of specimens obtained from hcws when person-to-person transmission is suspected may be more likely to identify the source of an outbreak, but it must be remembered that an hcw whose culture specimen yields the outbreak organism may have been transiently colonized while working with an affected infant, rather than constituting the source of the infection. management of culture-positive hcws (possible furlough, treatment, and return to work criteria) should be planned in advance of widespread culture surveillance and should involve supervisors of affected employees and occupational health services.'" reported. , , , , , the most widely accepted guideline for preventing the transmission of infections in hospitals was developed by the cdc. most recently revised in , the system contains two tiers of precautions. the first and most important, standard precautions, was designed for the management of all hospitalized patients regardless of their diagnosis or presumed infection status. the second, transmission-based precautions, is intended for patients documented or suspected to be infected or colonized with highly transmissible or epidemiologically important pathogens for which additional precautions to interrupt transmission are needed. standard precautions are designed to reduce the risk of transmission of microorganisms from both recognized and unrecognized sources and are to be followed for the care of all patients, including neonates. they apply to blood; all body fluids, secretions, and excretions except sweat; nonintact skin; and mucous membranes. components of standard precautions include hand hygiene and wearing gloves, gowns, and masks and other forms of eye protection. hand hygiene plays a key role for caregivers in the reduction of nosocomial infection for patient^'^.^'^ and in prevention of nosocomial or health cart+associated infections. hand hygiene should be performed before and after all patient contacts; before donning sterile gloves to perform an invasive procedure; after contact with blood, body fluids or excretions, mucous membranes, nonintact skin, and wound dressings; in moving from a contaminated body site to a clean body site during patient care (ie., from changing a diaper to performing mouth care); after contact with inanimate objects in the immediate vicinity of the patient; after removing gloves; and before eating and after using the re~troom.'~~ when hands are visibly soiled or contaminated with proteinaceous materials, blood, or body fluids, and after using the restroom, hands should be washed with antimicrobial soap and water. soaps containing % to % chlorhexidine gluconate or . % t r i~l o s a n '~~ are recommended for hand washing in n~rseries.'~~ when hands are not visibly soiled, alcohol-based hand rubs, foams, or gels are an important tool for hand hygiene. compared with washing with soap and water, use of the alcohol-based products is at least as effective against a variety of pathogens and requires less time, and these agents are less damaging to skin. the cdc "guideline for hand hygiene in the health care setting" calls for use of alcohol hand rubs, foams, or gels as the primary method to clean hands, except when hands are visibly soiled.i l programs that have been successful in improving hand hygiene and decreasing nosocomial infection have used multidisciplinary teams to develop interventions focusing on use of the alcohol rubs in the settin of institutional commitment and support for the initiativetj ~ hcws should wash hands and forearms to the elbows on arrival in the nursery. a -minute scrub has been suggested?l but consensus on optimal duration of initial hand hygiene is lacking. at a minimum, the initial wash should be long enough to ensure thorough washing and rinsing of all parts of the hands and forearms. routine hand washing throughout care delivery should consist of wetting the hands, applying product, rubbing all surfaces of the hands and fingers vigorously for at least seconds, rinsing, and patting dry with disposable t we s.l~~ wearing hand jewelry has been associated with increased microbial load on hands. whether this results in increased transmission of pathogens is not known. many experts, however, recommend that hand and wrist jewelry not be worn in the in addition, the cdc guideline states that staff who have direct contact with infants in nicus should not wear artificial fingernails or nail extenders."' only natural nails kept less than y.. inch long should be allowed. clean, nonsterile gloves are to be worn whenever contact with blood, body fluids, secretions, excretions, and contaminated items is anticipated. the hcw should change gloves when moving from dirty to clean tasks performed on the same patient, such as after changing a diaper and before suctioning a patient, and whenever they become soiled. because hands can become contaminated during removal of gloves, and because gloves may have tiny, unnoticeable defects, wearing gloves is not a substitute for hand hygiene. hand hygiene must be performed immediately after glove removal. personnel in nurseries including the nicu historically have worn cover gowns for all routine patient contact. the practice has not been found to reduce infection or colonization in neonates and is u n n e c e~s a r y ? '~~~~~ instead, cdc guidelines recommend nonsterile, fluid-resistant gowns to be worn as barrier protection when soiling of clothing is anticipated and in performing procedures likely to result in splashing or spraying of body substance^.^^ possible examples of such procedures in the nicu are placing an arterial line and irrigating a wound. the perinatal guidelines of the american academy of pediatrics and the american college of obstetricians and gynecologists recommend that a longsleeved gown be worn over clothing when a neonate is held outside the bassinette by nursery personnel.'" nonsterile masks, face shields, goggles, and other eye protectors are worn in various combinations to provide barrier protection and should be used during procedures and patient care activities that are likely to generate splashes or sprays of body substances and fl~ids.'~ standard precautions also require that reusable patient care equipment be cleaned and appropriately reprocessed between patients; that soiled linen be handled carefully to prevent contamination of skin, clothing, or the environment; that sharps (i.e., needles, scalpels) be handled carefully to prevent exposure to blood-borne pathogens; and that mouthpieces and other resuscitation devices be used, rather than mouth-to-mouth methods of re~uscitation.'~ in addition to standard precautions, which must be used for every patient, the cdc recommends transmission-based precautions when the patient is known or suspected to be infected or colonized with epidemiologically important or highly transmissible organisms. always used in addition to standard precautions, transmission-based precautions comprise three categories: contact precautions, droplet precautions, and airborne precautions. contact precautions involve the use of barriers to prevent transmission of organisms by direct or indirect contact with the patient or contaminated objects in the patient's immediate e n~i r o n m e n t .~~ sources of indirect contact transmission in nurseries can include patient care equipment such as monitor leads, thermometers, isolettes, breast pumps,le toys, and instruments and contaminated hands. the patient requiring contact precautions should be placed in a private room whenever possible but, after consultation with an infection control practitioner, can be cohorted with a patient infected with the same microorganism but no other infection. many nurseries, however, have few if any isolation rooms. the american academy of pediatrics states that infected neonates requiring contact precautions can be safely cared for without an isolation room if staffing is adequate to allow appropriate hand hygiene, a -to -footwide space can be provided between care stations, adequate hand hygiene facilities are available, and staff members are well trained regarding infection transmission modes.'" hcws should wear clean, nonsterile gloves when entering the room or space of a patient requiring contact precautions and should wear a cover gown when their clothing will have contact with the infant, environmental surfaces, or items in the infant's area. a cover gown also should be worn when the infant has excretions or secretions that are not well contained, such as diarrhea or wound drainage, which may escape the diaper or dressing. infant care equipment should be dedicated to the patient if possible so that it is not shared with thers. ~ examples of conditions in the neonate that require contact precautions include neonatal mucocutaneous herpes simplex virus infection, respiratory syncytial virus infection, varicella (also see airborne precautions), infection or colonization with a resistant organism such as mrsa or a multiple drug-resistant gram-negative bacillus, and congenital rubella syndrome. droplet precautions are intended to reduce the risk of transmission of infectious agents in large-particle droplets from an infected person. such transmission usually occurs when the infected person generates droplets during coughmg, sneezing, or talking, or during procedures such as suctioning. these relatively large droplets travel only short distances and do not remain suspended in the air, but can be deposited on the conjunctiva, nasal mucosa, andfor mouth of persons working within feet of the infected patient. patients requiring droplet precautions should be placed in private rooms (see earlier discussion of isolation rooms in nurseries in the paragraph on contact precautions), and staff should wear masks when working within feet of the patient. examples of conditions in the neonate that necessitate droplet precautions are pertussis and invasive n. meningitidis infection. airborne precautions are designed to reduce the risk of airborne transmission of infectious agents. because of their small size, airborne droplet nuclei and dust particles containing infectious agents or spores can be widely spread on air currents or through ventilation systems and inhaled by or deposited on susceptible hosts. special air-handling systems and ventilation are required to prevent transmission. patients requiring airborne precautions should be placed in private rooms in negative air-pressure ventilation with to air changes per hour. air should be externally exhausted or subjected to high-efficiency particulate air (hepa) filtration if it is recirculated. examples of conditions in the neonate for which airborne precautions are required are varicella-zoster virus infections and measles. susceptible hcws should not enter the rooms of patients with these viral infections. if assignment cannot be avoided, susceptible staff members should wear masks to deliver care. if immunity has been documented, staff members need not wear masks. airborne precautions also are required for active pulmonary tuberculosis, and although neonates are rarely contagious, the cdc recommends isolating patients while they are being e~aluated.~'~ a more important consideration is the need to isolate the family of a suspected tuberculosis patient until an evaluation for pulmonary tuberculosis has been completed, because the source of infection frequently is a member of the child's before the s, well-baby nurseries and many nicus were constructed as large, brightly lit open wards with rows of incubators surrounded by equipment. sinks could be provided in such rooms only around the periphery, limiting access to hand hygiene facilities for staff and families. in these nicus, parents' time with their infant was severely restricted, and the units were designed for the convenience and function of the hcw. more recently, perinatal care professionals have come to understand that neonates (and especially preterm infants) can benefit from a quiet, soothing atmosphere and protection from unnecessary light, noise, handling, uncomfortable positioning, and sleep disruptions? if infants are kept in a central nursery rather than roomingin with mothers, at least square feet of floor space should family. ,z be provided per neonate, and bassinets should be at least feet apart. teams designing units delivering higher levels of perinatal care, including nicus, should plan individual bed areas large enough for families to stay at the bedside for extended periods of time without interfering with the staffs ability to care for the child. if individual rooms cannot be provided, at least square feet of floor space should be allowed for each neonate in an nicu, incubators or overhead warmers should be separated by at least to feet, and aisles should be at least feet a scrub sink with foot, knee, or touchless (electronic sensor) controls should be provided at the entrance to every nursery and should be large and deep enough to control splashing. sinks in patient care areas should be provided at a minimum ratio of sink for at least every to stations in the well-baby nursery and sink for every or stations in higher-level nurseries, including the nicu.'i every bed position should be within feet of a hand-washing sink and accessible for children and persons in wheelchairs. for nicus composed of individual rooms, a hand-washing sink should be located in each room near the door to facilitate hand hygiene on entering and leaving the room. environmental surfaces should be designed so that they are easy to clean and do not harbor microorganisms. sink taps and drains, for instance, have been implicated in outbreaks of infection. z installing sinks with seamless construction may minimize this risk by decreasing areas where water can pool and microorganisms proliferate. faucet aerators have been implicated in outbreaks of infection and should be avoided in the intensive care unit. although carpeting can reduce noise levels in a busy nicu, the cdc "guidelines for environmental infection control in health-care facilities" recommend against use of carpeting in areas where spills are likely, including intensive care units. the guidelines further recommend against upholstered furniture in nicus.~~' if, for reasons of noise reduction and developmentally appropriate care, porous surfaces such as carpeting and cloth upholstery are selected for the nicu, cleaning must be performed carefully. carpet should be vacuumed regularly with equipment fitted with hepa filters, and upholstered furniture should be removed from inpatient areas to be cleaned. attention also should be paid to air-handling systems. according to the perinatal guidelines, minimal standards for inpatient perinatal care areas include six air changes per hour, and a minimum of two changes should consist entirely of outside air. air delivered to the nicu should be filtered with at least % efficiency. in addition, nurseries should include at least one isolation room capable of providing negative pressure vented to the outside, observation windows with blinds for privacy, and the capability for remote m~n i t o r i n g .~~~'~~~ floors and other horizontal surfaces should be cleaned daily by trained personnel using environmental protection agency (epa)-registered hospital disinfectantddetergents. these products (including phenolics and other chemical surface disinfectants) must be prepared in accordance with manufacturers' recommendations and used carefully to avoid exposing neonates to these products. phenolics should not be used on surfaces that come in direct contact with neo-nates' skin. high-touch areas, such as counter tops, work surfaces, doorknobs, and light switches, may need to be cleaned more frequently because they can be heavily contaminated during the process of delivering care. hard, nonporous surfaces should be "wet dusted" rather than dry dusted, to avoid dispersing particulates into the air, and then disinfected using standard hospital disinfectant^.'^^ sinks should be scrubbed daily with a disinfectant detergent. walls, windows, and curtains should be cleaned regularly to prevent dust accumulation, but daily cleaning is not necessary unless they are visibly soiled. bassinets and incubators should be cleaned and disinfected between infants, but care must be taken to rinse cleaning products from surfaces with water before use. care units should not be cleaned with phenolics or other chemical germicides during an infant's stay. instead, infants who remain in the nursery for long periods of time should periodically be moved to freshly cleaned and disinfected units. ' patient care equipment must be cleaned, disinfected, and, when appropriate, sterilized between patients. sterilization (required for devices that enter the vascular system, tissue, or sterile body cavities) and higher levels of disinfection (required for equipment that comes in contact with mucous membranes or that has prolonged or intimate contact with the newborn's skin) must be performed under controlled conditions in the central processing department of the hospital. examples of patient care equipment that require these levels of processing are endotracheal tubes, resuscitation bags, and face masks. , , low-level disinfection is required for less critical equipment, such as stethoscopes or blood pressure cuffs, and usually can be performed at point of use (e.g., the bedside), although this type of equipment should be dedicated to individual patients whenever possible. requirements for linen handling and management for neonates do not vary appreciably from those for other hospitalized patients. although soiled linen can contain large numbers of organisms capable of causing infections, transmission to patients appears to be rare. studies suggesting linen as a source of infection often have failed to confirm it as the source of infection. at least one report, however, has implicated linen in the transmission of group a streptoco~ci.~~ investigation of this outbreak revealed that clothing worn by the neonates was being washed in the local hospital "mini laundry," rather than being processed under the usual laundry contract. investigation of the dryers revealed extensive contamination with the outbreak organism. this case illustrates the importance of having standard hospital laundry protocols and ensuring that appropriate water and dryer temperatures are maintained. when such protocols are followed, the mechanical actions of washing and rinsing, combined with hot water and/or the addition of chemicals such as chlorine bleach, and a final commercial dryer and/or ironing step significantly reduce bacterial few hospitals in the united states use cloth diapers, but regardless of type used, soiled diapers should be carefully bagged in plastic and removed from the unit every hours. hcws caring for neonates have the potential both to transmit infections to infants and to acquire infections from vaccine should be considered for all hcws, including those born before , who have no proof of immunity (receipt of doses of live vaccine on or after first birthday, physician-diagnosed measles, or serologic evidence of immunity). hcws believed t o be susceptible can be vaccinated; adults born before can be considered immune. hcws, both male and female, who lack documentation of receipt of vaccine on or after first birthday or serologic evidence of immunity should be vaccinated; adults born before can be considered immune, except women of childbearing age. hcws without a reliable history of varicella or serologic evidence of varicella immunity should be vaccinated. patients. educating hcws about infection control principles is crucial to preventing such transmission. hospitals should provide education about infection control policies, procedures, and guidelines to staff in all job categories during new employee orientation and on a regular basis throughout employment. the content of this education should include hand hygiene, principles of infection control, the importance of individual responsibility for infection control, and the importance of collaborating with the infection control department in monitoring and investigating potentially harmful infectious exposures and outbreaks. transmission of infectious organisms between patients and hcws has been well documented. several studies have indicated that a high proportion of hcws acquire rsv ( % to %) when working with infected children, and these workers appear to be important in the spread of the illness within hospital^.^^'.^^^ although % of the infected hcws in one of these rsv studies were asymptomatic, staff should be aware of the importance of self-screening for communicable disease. they should be encouraged to report personal infectious illnesses to supervisors, who in turn should report them to occupational health services and infection control. in general, hcws with respiratory, cutaneous, mucocutaneous, or gastrointestinal infections should not deliver direct patient care to neonates. i in addition, seronegative staff members exposed to illnesses, such as varicella and measles, should not work during the contagious portion of the incubation period. staff members with hsv infection rarely have been implicated in transmission of the virus to infants and thus do not need to be routinely excluded from direct patient care. those with herpes labialis or cold sores should be instructed to cover the lesions and not to touch their lesions, and to comply with hand hygiene policies. persons with genital lesions also are unlikely t o transmit hsv so long as hand hygiene policies are followed. however, hcws who are unlikely or unable to comply with the infection control measures and those with herpetic whitlow should not deliver direct patient care to neonates until lesions have healed. acquisition of cmv often is a concern of pregnant hcws because of the potential effect on the fetus. approximately % of newborn infants in most nurseries and a higher percentage of older children (up to % of children to years of age in child-care centers) excrete cmv without clinical manifestation^.'^^ the risk of acquiring cmv infection has not been shown to be higher for hcws than for the general for this reason, pregnant caregivers need not be excluded from the care of neonates suspected to be shedding cmv. they should be advised of the importance of standard precautions. hcws in well-baby nurseries and nicus should be as free from transmissible infectious diseases as possible? and ensuring that they are immune to vaccine-preventable diseases is an essential part of a personnel health program. the cdc recommends several immunizations for health care personnel (table - ) . staffing levels in a patient care setting also can affect patient outcomes. a number of studies suggest that as patient-tonurse ratios in intensive care units increase, so do nosocomial infections and mortality rate^.^^,'^^,'^ although optimal staffing ratios have not been established for nicus and will vary according to characteristics of individual units, one study demonstrated that the incidence of clustered s. aureus infections was times higher after periods when the infantto-nurse ratio exceeded : . decreased compliance with hand hygiene during a period of understaffing frequently is cited as contributing to nosocomial infection rate increases." further study is necessary to determine best practice surrounding staffing levels in nicus. the first nicus in the late s grouped infants together in large, brightly lit rooms with incubators placed in rows. parents were allowed very little time with their babies and even less physical contact. in the decades since, it has been recognized that "the parent is the most important caregiver and constant influence in an infant's life" and that hcws working in nicus should encourage parents to become involved in the nonmedical aspects of their child's care. principles of family-centered care also include liberal nicu visitation for relatives, siblings, and family friends and the involvement of parents in the development of nursery policies and programs that promote parenting skills. care must be taken, however, to minimize risk of infection for the neonate. mothers can transmit infections to neonates both during delivery and post partum, although separation of mother and newborn rarely is indicated. in the absence of certain specific infections, mothers, including those with postpartum fever not attributed to a specific infection, should be allowed to handle their infants if the following conditions are met: they feel well enough. they wash their hands well under supervision. a clean gown is worn. contact of the neonate with contaminated dressings, a mother with a transmissible illness not requiring separation from her infant should be carefully educated about the mode of transmission and precautions necessary to protect her infant. personal protective equipment, such as cover gowns, gloves, and masks, and hand hygiene facilities should be readily available to her, and she should perform hand hygiene and don a long-sleeved cover gown before handling her infant. if wounds or abscesses are present, drainage should be contained within a dressing. if drainage cannot be completely contained, separation from the infant may be necessary. care should be taken to prevent the infant from coming in contact with soiled linens, clothing, dressings, or other potentially contaminated items. the mother with active genital hsv lesions need not be separated from her infant if the foregoing precautions are taken. those with herpes labialis should not kiss or nuzzle their infants until lesions have cleared; lesions should be covered and a surgical mask may be worn until the lesions are crusted and dry, and careful hand hygiene should be stressed. mothers with viral respiratory infections should be made aware that many of these illnesses are transmitted by contact with infected secretions as well as by droplet spread, that soiled tissues should be disposed of carefully, and that hand hygiene is critical to transmission prevention. masks can be worn to reduce the risk of droplet t r a n s m i s s i~n .~~~'~~~ as previously mentioned, although very few infections require separation of mother and infant, women with untreated active pulmonary tuberculosis should be separated from their infants until they no longer are contagious. mothers with group a streptococcal infections, especially when involving draining wounds, also should be isolated from their infants until they no longer are contagious. less certain is the necessity of separating mothers with peripartum varicella (onset of infection within days before or days after delivery) from their uninfected infants. the perinatal guidelines recommend that such infants remain with their mothers after receiving varicella-zoster immune globulin (vzig) but caution that infant and mother must be carefully managed in airborne and contact precautions to prevent transmission within the nursery. some experts recommend separating these mothers from their infants until all lesions are dried and crusted. numerous studies support the value of human milk for infants (see chapter ). besides providing optimal nutritional content for infants, it has been shown to be associated with a lower incidence of infections and sepsis in the first year of linen, clothing, or pads is avoided. although contraindications to breast-feeding are few, mothers who have active untreated tuberculosis, human immunodeficiency virus (hiv) infection, breast abscesses (as opposed to simple mastitis that is being treated with antimicrobial therapy), or hsv lesions around the nipples should not breast-feed. mothers who are hepatitis b surface antigen positive may breast-feed, because ingestion of an infected mother's milk has not been shown to increase the risk of transmission to her child, but the infant must receive hepatitis b virus immune globulin (hbig) and vaccine immediately after birth. because systemic disease may develop in preterm infants with low concentrations of transplacentally acquired antibodies to cmv following ingestion of milk of cmv-seropositive mothers, decisions regarding breast-feeding should consider the benefits of human milk versus the risk of cmv transmission. freezing breast milk has been shown to decrease viral titers but does not eliminate cmv; pasteurization of human milk can inactivate cmv. either method may be considered in attempts to decrease risk of transmission for breast-feeding nicu neonates. neonates in the nicu frequently are incapable of breastfeeding because of maternal separation, unstable respiratory status, and immaturity of the sucking reflex. for these reasons, mothers of such infants must use a breast pump to couect milk for administration through a feeding tube. pumping, collection, and storage of breast milk create opportunities for contamination of the milk, and for cross-infection if equipment is shared between mothers. several studies have demonstrated contamination of breast pumps, contamination of expressed milk that had been frozen and thawed, and higher levels of stool colonization with aerobic bacteria in infants fed precollected breast milk. , * consensus is lacking on the safe level of microbiologic contamination of breast milk, and most expressed breast milk contains normal skin flora. although breast milk containing greater than cfu/ml of gram-negative bacteria has been reported to cause feeding intolerance and to be associated with suspected sepsis, routine bacterial culturing of expressed breast milk is not recommended. v instead, efforts to ensure safety of expressed milk should focus on optimal collection, storage, and administration techniques. cleaning and disinfection of breast pumps should be included in educational material provided to nursing mothers (table - ). in addition, mothers should be instructed to perform hand hygiene and cleanse nipples with cotton and plain water before expressing milk in sterile containers. expressed breast milk can be refrigerated for up to hours and can be safely frozen (- " c f °c [- " f f . " f]) for up to months. it can be thawed quickly under warm running water (avoiding contamination with tap water) or gradually in a refrigerator. exposure to high temperatures, as may be experienced in a microwave, can destroy valuable components of the milk. thawed breast milk can be stored in the refrigerator for up to hours before it must be discarded. to avoid proliferation of microorganisms, milk administered through a feeding tube by continuous infusion should hang no longer than to hours before replacement of the milk, container, and for mothers who choose not to breast-feed, commercial infant formula is available. most hospitals now use sterile, ready-to-feed formulas provided by the manufacturer in bottles, with sterile nipples to attach just before use. nipples each mother is supplied with a personal pumping kit. nursing staff instruct mothers in techniques of milk expression and appropriate procedures for cleaning breast pump parts: wipe all horizontal surfaces at the pumping station with hospital disinfectant before and after pumping. wash hands with soapy water before and after pumping. wash all parts of the breast pump kit that have been in contact with milk in hot water and dish detergent or in a dishwasher. expressed milk is collected in sterile, single-use plastic (polycarbonate or polypropylene) containers. breast milk containers are labeled with infant's name and the date and time of collection. administration containers (bottle or syringe) are similarly labeled when breast milk is transferred from collection containers. all hcws wear gloves when handling and administering breast milk. two persons check t h e labeled administration container against the infant's hospital identification band before administering breast milk (may be two hcws or one hcw and a family member). hcw. health care worker. from infection control policy, children's hospital and regional medical center, seattle, are best attached at the bedside just before feeding, and the unit should be used immediately and discarded within hours after the bottle is ~ncapped.'~' specialty and less commonly used formulas may not be available as a ready-to-feed product, and breast milk supplements do not come in liquid form. after a recent report of a case of fatal enterobacter sakazakii meningitis in a neonate fed contaminated powdered infant formula: concerns have risen about the safety of these products. although powdered formulas are not sterile, preparation and storage practices can decrease the possibility of proliferation of microorganisms after preparation. the cdc, the food and drug administration, and the american dietetic association offered updated recommendations on the safe preparation and administration of commercial formula after the recall of the product linked to the e. sakazakii case. these recommendations instruct the care provider as follows: use alternatives (ready-to-feed or concentrated formulas) to powdered infant formula whenever possible. prepare formula using aseptic technique in a designated formula preparation room. refrigerate prepared formula so that a temperature of " to " c is reached by hours after preparation, and discard any reconstituted formula stored longer than hours. limit ambient-temperature hang time of continuously infused formula to no longer than hours. use hygienic handling techniques at feeding time, and avoid open delivery systems. have written guidelines for managing a manufacturer's recall of contaminated formula. the fda also recommended that boiling water be used to prepare powdered formulas, but concerns about this recommendation include potential damage to formula components from the high temperature of the water, a lack of evidence that using this method would lull potential pathogens in the formula, and risk of injury to persons preparing the f rmula. ~' the concept of co-bedding, or the bunlung of twin infants (or other multiples) in a single isolette or crib, is being explored in nicus for the potential benefits offered to the babies. co-bedding as a component of developmentally supportive care is based on the premise that extrauterine adaptation of twin neonates is enhanced by continued physical contact with the other twin. potential benefits need further study but may include increased bonding, decreased need for temperature support, and easier transition to home. it is certainly possible, however, for one of a set of multiples to be infected while the others are not, and for parents to be implicated as vectors in infection transmission. it also is possible for invasive devices and intravascular catheters to be dislodged by close contact with an active sibling. therefore, exclusion criteria for co-bedding infants should include clinical findings suggesting infection that could be transmitted to a sibling (e.g., draining wound) and the need for drains and central venous or arterial line^.*^^-'^^ the principles of family-centered care encourage liberal visitation policies, both in the well-baby nursery (or roomingin scenario) and in the nicu. parents, including fathers, should be allowed unlimited visitation to their newborns, and siblings also should be allowed liberal visitation. expanding the number of visitors to neonates may, however, increase the risk of disease exposure if education and screening for symptoms of infection are not implemented. written policies should be in place to guide sibling visits, and parents should be encouraged to share the responsibility of protecting their newborn from contagious illnesses. the perinatal guidelines regarding persons who visit newborns are listed in table - . adult visitors to neonates, including parents, have been implicated in outbreaks of infections including p aeruginosa infection, pertussis, and salmonella i n f e c t i~n . '~'~~~~~~~~ ac cordingly, the principles for sibling visitation should be applied to adult visitors as well. they should be screened for symptoms of contagious illness, instructed to perform hand hygiene before entering the nicu and before and after touching the neonate, and should interact only with the family member they came to the hospital to visit. families of neonates who have lengthy nicu stays may come to know each other well and serve as sources of emotional support to one another. nevertheless, they should be educated about the potential of transmitting microorganisms and infections between families if standard precautions and physical separation are not maintained, even though they may be sharing an inpatient space. sibling visits should be encouraged for healthy and ill newborns. parents should be interviewed at a site outside the nursery to establish that the siblings are not ill before allowing them to visit. children with fever or other symptoms of an acute illness such as upper respiratory infection or gastroenteritis, or those recently visiting children should visit only their sibling. children should be prepared in advance for their visit. visitors should be adequately observed and monitored by hospital staff. children should carefully wash their hands before patient contact. throughout t h e visit, siblings should be supervised by parents or another responsible adult. exposed to a known communicable disease such as chickenpox, should not be allowed to visit. bathing the newborn is standard practice in nurseries, but very little standardization in frequency or cleansing product exists. if not performed carefully, bathing actually can be detrimental to the infant, resulting in hypothermia, increased crying with resulting increases in oxygen consumption, respiratory distress, and instability of vital signs. although the initial bath or cleansing should be delayed until the neonate's temperature has been stable for several hours, removing blood and drying the skin immediately after delivery may remove potentially infectious microorganisms such as hepatitis b virus, hsv, and hiv, minimizing risk to the neonate from maternal infection. when the newborn requires an intramuscular injection in the delivery room, infection sites should be cleansed with alcohol to prevent transmission of organisms that may be present in maternal blood and body for routine bathing in the first few weeks of life, plain warm water should be used. this is especially important for preterm infants, as well as full-term infants with barrier compromise such as abrasions or dermatitis. if a soap is necessary for heavily soiled areas, a mild ph-neutral product without additives should be used, and duration of soaping should be restricted to less than minutes no more than three times per week. few randomized studies comparing cord care regimens and infection rates have been performed, and consensus has not been reached on best practice regarding care of the umbilical cord stump. a review published in described care regimens used for more than decades, including combinations of triple dye, chlorhexidine, % alcohol, bacitracin, hexachlorophene, povidone-iodine, and "dry care" (soap and water cleansing of soiled periumbilical skin) and found variable impact on colonization of the stump. the study authors suggested that dry cord care alone may be insufficient and that chlorhexidine seemed to be a favorable antiseptic choice for cord care because of its activity against gram-positive and gram-negative bacteria. they went on to stress, however, that large, well-designed studies were required before firm conclusions could be drawn. the current perinatal guidelines do not recommend a specific regimen but warn that use of alcohol alone is not an effective method of preventing umbilical cord colonization and ~mphalitis.'~~ the perinatal guidelines further recommend that diapers be folded away from and below the stump and that emollients not be applied to the although blindness resulting from neonatal conjunctivitis is rare in the united states, with a reported incidence of . % or less, the rate among the million infants born annually throughout the world is as high as %. chlamydia trachornatis has been the most common etiologic agent in the united states, but other organisms such as neisseria gonorrhoeae, s. aureus, and e. coli also can cause ophthalmia neonatorum. use of % silver nitrate drops, at one time the agent of choice, is no longer recommended because of concerns about associated chemical irritation. agents thought to be equally efficacious and now recommended include % tetracycline and . % erythromycin ophthalmic ointments, administered from sterile single-use tubes or vials. ~ povidone-iodine ( . %) ophthalmic solution also can be used and in one study was shown to be more effective than silver nitrate or erythromycin in the prevention of ophthalmia neonatorum. bacterial resistance has not been seen with this agent, it causes less toxicity than either silver nitrate or erythromycin, and it is less expensivea definite consideration in developing countries. whatever the agent selected, it should reach all parts of the conjunctival sac, and the eyes should not be irrigated after application. ophthalmic agents will not necessarily prevent ocular or disseminated gonorrhea in infants born to mothers with active infection at time of delivery. these infants should be given parenteral antimicrobial therapy as well as ocular p r o p h y l a~i s . '~~,~~~ some experts also advise giving infants born to mothers with untreated genital chlamydia infections a course of oral erythromycin beginning on the second or third day of life. primary bloodstream infections (defined by the cdc nnis system as being due to a pathogen cultured from one or more blood specimens not related to an infection at another site) account for a large proportion of infections in nicu infants:' and most are related to the use of an intravascular catheter. peripheral intravenous catheters (pivs) are the most frequently used devices for the neonate for intravenous therapy of short duration. when longer access is necessary, nontunneled cvcs such as umbilical catheters and piccs most commonly are the most recent data available conduct surveillance in nlcus to determine catheter-related bloodstream infection rates, monitor trends, and identify infection control lapses. investigate events leading to unexpected life-threatening or fatal outcomes. select the catheter, insertion technique, and insertion site with the lowest risk for complications for the anticipated type and duration of intravenous therapy. use a cvc with the minimal number of ports essential f o r management of t h e patient. designate one port for hyperalimentation if a multilumen catheter is used. educate hcws who insert and maintain catheters, and assess their knowledge and competence periodically. use aseptic technique and maximal sterile barriers during insertion of cvcs (cap, mask, sterile gown, sterile gloves, and a large sterile barrier). do not routinely replace cvcs, piccs, or pulmonary artery catheters to prevent catheter-related infections. do not remove on the basis of fever alone. in pediatric patients, leave peripheral venous catheters in place until intravenous therapy is completed unless a complication (e.g., phlebitis, infiltration) occurs. remove intravascular catheters promptly when no longer essential. observe proper hand hygiene procedures either by washing with antiseptic-containing soap and water or use of waterless alcohol-based products before and after working with intravascular lines. disinfect skin with an appropriate antiseptic before catheter insertion and during dressing changes. a % chlorhexidine-based preparation is preferred. do not use topical antibiotic ointment or creams on insertion sites, except when using dialysis catheters. use either sterile gauze or sterile, transparent, semipermeable dressing to cover t h e catheter site. replace gauze dressings on short-term cvc sites every days and transparent dressings at least weekly, except in pediatric patients, in whom the risk of dislodging the catheter outweighs the benefit of changing the dressing. change if damp, loosened, or visibly soiled. replace dressings on tunneled or implanted cvc sites no more than once per week until the insertion site has healed. chlorhexidine sponge dressings are contraindicated in neonates younger than days or those born at a gestational age of less than weeks. clean injection ports with % alcohol or an iodophor before accessing the system. use disposable transducer assemblies with peripheral arterial catheters and pressure monitoring devices. keep all components of such systems sterile, and do not administer dextrose-containing solutions or parenteral nutrition fluids through them. from nnis (august ) revealed that the mean umbilical catheter-and cvc-associated bloodstream infection rates for nicus ranged from . per catheter days for infants whose birth weight was less than g to . per catheter days in infants whose birth weight was g or more.' the cdc recommends implementing strategies to reduce the incidence of such infections that strike a balance between patient safety and cost-effectiveness. few large studies of risks related to intravascular devices have been performed in nicu patients. as a result, intravascular device recommendations for neonates are based on those developed for adults and older pediatric patients (table - ) . several differences in their management should be considered. although the cdc recommends, in certain circumstances, using antimicrobialor antiseptic-impregnated cvcs in adults whose catheters are expected to remain in place more than days, these catheters are not available in sizes small enough for neonates. of more importance, studies to evaluate their safety in neonates, especially premature neonates of very low birth weight, have not been performed. in addition, although the cdc recommends changing the insertion site of pivs at least every to hours in adults, data suggest that leaving pivs in place in pediatric patients does not increase the risk of complications. the cdc guidelines recommend that pivs be left in place in children until therapy is completed, unless complications occur. careful skin antisepsis before insertion of an intravascular catheter is critical to prevention of intravascular devicerelated bacteremia, although care in the selection of a product for use on neonatal skin is required. chlorhexidine preparations are recommended by the cdc because these products have been found to be superior to povidone-iodine in reducing the risk for peripheral catheter colonization in neonates. residues left on the skin by chlorhexidine prolong its half-life, providing improved protection for catheters in neonates that must be left in place for longer periods of timef ' umbilical veins and arteries are available for cvc insertion only in neonates and are typically used for several days; thereafter, the cvc is replaced with another, nontunneled cvc or picc if continued central venous access is required. the umbilicus provides a site that can be cannulated easily, allowing for collection of blood specimens and hernodynamic measurements, but after birth, the umbilicus quickly becomes heavily colonized with skin flora and other microorganisms. colonization and catheter-related bloodstream infection rates for umbilical vein and umbilical artery catheters are similar. colonization rates for umbilical artery catheters are estimated to be % to %; the estimated rate for umbilical artery catheter-related bloodstream infection is %? colonization rates are from % to % for umbilical vein catheters; rates for umbilical vein catheter-related bloodstream infections are % to ? .~~ a summary of the cdc recommendations for management of umbilical catheters is presented in table - . as mentioned earlier, nnis data indicate that nosocomial pneumonia is the second most common infection type in cleanse umbilical insertion site with an antiseptic before catheter insertion. avoid tincture of iodine; povidone-iodine can be used. add low doses of heparin to fluid infused through umbilical artery catheters. remove and do not replace umbilical catheters if signs of catheter-related bloodstream infection, vascular insufficiency, or remove umbilical catheters as soon as possible when no longer needed or if any sign of vascular insufficiency to the lower umbilical artery catheters should not be left in place for longer than days. umbilical venous catheters should be removed as soon as possible when no longer needed but can be used for up to nicu patients. risk factors for ventilator-associated pneumonia can be grouped as host-related (prematurity, low birth weight, sedation or use of paralytic agents), devicerelated (endotracheal intubation, mechanical ventilation, orogastric or nasogastric tube placement) and factors that increase bacterial colonization of the stomach or nasopharynx (broad-spectrum antimicrobial agents, antacids, or h, b l o c k e r~) . ~,~"~~~ ventilator-associated pneumonia generally refers to bacterial pneumonia that develops in patients who are receiving mechanical ventilation. aspiration and direct inoculation of bacteria are the primary routes of entry into the lower respiratory tract; the source of these organisms may be the patient's endogenous flora or transmission from other patients, staff members, or the e n~i r o n m e n t .~~'~~~ few studies have been performed to assess the effectiveness of prevention strategies in pediatric patients. strategies to prevent ventilator-associated pneumonia in the nicu patient are therefore based primarily on studies performed in adults (table - ) . hand hygiene remains critical to the prevention of ventilator-associated pneumonia, and hcws should consistently apply the principles of standard precautions to the care of the ventilated patient, wearing gloves to handle respiratory secretions or objects contaminated by them, and changing gloves and performing hand hygiene between contacts with a contaminated body site and the respiratory tract or a respiratory tract device. because mechanical ventilation is a significant risk factor for the development of nosocomial infection or ventilatorassociated pneumonia, weaning from ventilation and removing endotracheal tubes as soon as indication for their use ceases are key infection control strategies. as an alternative to endotracheal intubation, noninvasive nasal continuous positive airway pressure (cpap) ventilation avoids some of the common risk factors for ventilator-associated pneumonia and has been used successfully for neonate^?^^"^^ respiratory care equipment that comes in contact with mucous membranes of ventilated patients or that is part of the ventilator circuit should be single use (discarded after one-time use with a single patient) or be subjected to sterilization or high-level disinfection between patients. wet heat pasteurization (processing at oc for minutes) or chemical disinfectants can be used to achieve high-level disinfection of reusable respiratory equipment. ventilator circuits should be changed no more frequently than every hours, and evidence suggests that extending the length of time between changes to days does not increase the risk of ventilator-associated pneumonia.z s circuits should be monitored for accumulation of condensate and drained periodically, with care taken to avoid allowing the condensate, a potential reservoir for pathogens, to drain toward the sterile fluids should be used for nebulization, and sterile water should be used to rinse reusable semicritical equipment and devices such as in-line medication nebulizers. basic infection control measures, such as hand hygiene and wearing gloves during suctioning and respiratory manipulation, also can reduce the risk of nosocomial pneumonia. both open, single-use and closed, multiuse suction systems are available. if an open system is used, a sterile single-use catheter should be used each time the patient is suctioned. closed systems, which do not need to be changed daily and can be used for up to have the advantage of lower costs and decreased environmental cross-contamination but have not been shown to decrease the incidence of nosocomial pneumonia when compared with open systems. v although not well studied in pediatric patients, aspiration of oropharyngeal secretions is believed to contribute to development of ventilator-associated pneumonia in adults. placing the mechanically ventilated patient in a semirecumbent position or elevating the head of the bed in an attempt to minimize aspiration is recommended unless medically contraindicated. also, placement of enteral feeding tubes should be verified before their to prevent regurgitation and potential aspiration of stomach contents by the sedated patient, overdistention of the stomach should be avoided by regular monitoring of the patient's intestinal motility, serial measurement of residual gastric volume or abdominal girth, reducing the use of narcotics and anticholinergic agents, and adjusting the rate and volume of enteral fee ding^.^^^,^^^ oral decontamination, with the intent of decreasing oropharyngeal colonization, has been studied in adults and seems to lower the incidence of ventilatorassociated pneumonia (although not duration of ventilation or mortality but further work is needed to determine whether this is an effective strategy in neonates. in addition, medications such as sucralfate, as opposed to histamine h, receptor antagonists and antacids, which raise gastric ph and can potentially result in increased bacterial colonization of the stomach, have been used to prevent development of stress ulcers and have been associated with lower incidence of ventilator-associated pneumonia in adults. two studies suggest, however, that this approach is of no benefit in pediatric patients, but the authors stress that additional studies with larger sample sizes are needed to confirm these nosocomial infections in a neonatal intensive care unit: incidence and risk factors. am infect control bektas s, goetze b, speer cp. decreased adherence, chemotaxis and phagocytic activities of neutrophils from preterm neonates surgery, sepsis, and nonspecific immune function in neonates. pediatr surg - , . stiehm er. the physiologic immunodeficiency of immaturity diminished interferongamma and lymphocyte proliferation in neonatal and postpartum primary herpes simplex virus infection importance of the environment and the faecal flora of infants, nursing staff and parents as sources of gram-negative bacteria colonizing newborns in three neonatal wards use of human milk in the intensive care nursery decreases the incidence of nosocomial sepsis colonization and infection associated with malassezia and candida species in a neonatal unit. hosp infect - requirements for infrastructure and essential activities of infection control and epidemiology in hospitals: a consensus panel report. society for health care epidemiology of america guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee effectiveness of a hospitalwide programme to improve compliance with hand hygiene skin hygiene and infection prevention: more of the same or different approaches? molecular epidemiology of staphylococcus epidermidis in a neonatal intensive care unit over a three-year period nosocomial staphylococcus epidermidis septicaemia among very low birth weight neonates in an intensive care unit a randomized trial of -versus -hour intravenous tubing set changes in newborns receiving lipid therapy. infect control hosp epidemiol - occurrence of nosocomial bloodstream infections in six neonatal intensive care units effect of lipid emulsion on il- production by mononuclear cells of newborn infants and adults risk factors for nosocomial sepsis in newborn intensive and intermediate care units extended-spectrum plasmid-mediated beta-lactamases neonatal suppurative parotitis: a study of five cases molecular epidemiology of staphylococcal scalded skin syndrome in premature infants a double outbreak of exfoliative toxinproducing strains of staphylococcus aureus in a maternity unit acquisition of staphylococci by newborns. direct versus indirect transmission transmission of staphylococci between newborns. importance of the hands to personnel the role of understaffing and overcrowding in recurrent outbreaks of staphylococcal infection in a neonatal special-care unit the"c oud baby": an example of bacterial-viral interaction a cloud adult: the staphylococcus aureus-virus interaction revisited nosocomial transmission of methicillin-resistant staphylococcus aureus from a mother to her preterm quadruplet infants control of a methicillin-resistant staphylococcus aureus outbreak in a neonatal intensive care unit by unselective use of nasal mupirocin ointment preferential pharyngeal colonization of methicillin resistant staphylococcus airreus in infants nasal mupirocin treatment of pharynx-colonized methicillin resistant staphylococcus aureus: preliminary study with carrier infants a ten year, multicentre study of coagulase negative staphylococcal infections in australasian neonatal units coagulasenegative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome effect of an evidence-based hand washing policy on hand washing rates and false-positive coagulase negative staphylococcus blood and cerebrospinal fluid culture rates in a level nicu streptococcus faecium outbreak in a neonatal intensive care unit neonatal enterococcal bacteremia: an increasingly frequent event with potentially untreatable pathogens outbreak of vancomycin-resistant enterococcusfuecium in a neonatal intensive care unit centers for disease control and prevention. recommendations for preventing the spread of vancomycin resistance: recommendations of the hospital infection control practices advisory committee (hicpac) group a streptococcal infections in newborn nurseries an outbreak of m serotype group a streptococcus in a neonatal intensive care unit mother-to-infant vertical transmission and cross-colonization of streptococcus pyogenes confirmed by dna restriction fragment length polymorphism analysis clinical laboratory and epidemiological investigations of a streptococcus pyogenes cluster epidemic in a newborn nursery infection and hospital laundry nosocomial transmission of group b streptococci in a newborn nursery nosocomial transmission of group b streptococci epidemiology of the group b streptococcus: maternal and nosocomial sources for infant acquisitions nosocomial transmission of group b streptococci unusual occurrence of an epidemic of type ib/c group b streptococcal sepsis in a neonatal intensive care unit a d a m k. prematurity is the major risk factor for late-onset group b streptococcus disease neonatal group b streptococcal disease associated with infected breast milk analysis of three outbreaks due to klebsielh species in a neonatal intensive care unit enterobacter cloacae outbreak in the nicu related to disinfected thermometers enterobacter cloacae and pseudomom ueruginosa polymicrobial bloodstream infections traced to extrinsic contamination of a dextrose multidose vial enterobacter sakazakii infections associated with the use of powdered infant formula-tennessee outbreak of enterobacter cloacae related to understaffing, overcrowding, and poor hygiene practices outbreak investigation of nosocomial enterobacter cloacae bacteraemia in a neonatal intensive care unit contaminated breast milk: a source of klebsiella bacteremia in a newborn intensive care unit klebsiella pneumoniae bloodstream infections in neonates in a hospital in the kingdom of saudi arabia identification of an iv-dextrose solution as the source of an outbreak of klebsielh pneumoniae sepsis in a newborn nursery invasive disease due to extended spectrum beta-lactamase-producing klebsiella pneumoniae in a neonatal unit: the possible role of cockroaches disinfectant contaminated with klebsiella oxytoca as a source of sepsis in babies neonatal intensive care unit outbreak caused by a strain of klebsielh oxytoca resistant to aztreonam due to overproduction of chromosomal beta-lactamase nosocomial outbreak of klebsiella pneumoniae producing shv- extended-spectrum betalactamase, originating from a contaminated ultrasonography coupling gel epidemic outbreaks of acute pyelonephritis caused by nosocomial spread of p fimbriated eschm'chia coli in children enteropathogenic escherichia coli (epec) and enterotoxigenic (etec) related diarrhoeal disease in a neonatal unit an outbreak of gastroenteritis due to escherichia coli h in a neonatal department molecular epidemiology of an outbreak of serratia marcescens in a neonatal intensive care unit nosocomial outbreak of serratia marcescens in a neonatal intensive care unit serratia marcescens infections in neonatal departments: description of an outbreak and review of the literature serratia marcescens outbreak associated with extrinsic contamination of / chlorxylenol soap investigation of a nosocomial outbreak due to serratia marcescens in a maternity hospital an outbreak of serratia marcescens transmitted by contaminated breast pumps in a special care baby unit a bacteriological examination of breast pumps use of pulsed-field gel electrophoresis to investigate an outbreak of serratia marcescens infection in a neonatal intensive care unit molecular epidemiology of an shv- extended-spectrum beta-lactamase in enterobacteriaceae isolated from infants in a neonatal intensive care unit. c l i infect dis a hospital outbreak of extendedspectrum beta-lactamase-producing klebsielh pneumoniae investigated by rapd typing and analysis of the genetics and mechanisms of resistance outbreak of nosocomial sepsis and pneumonia in a newborn intensive care unit by multiresistant extended-spectrum beta-lactamase-producing klebsiella pneumoniae: high impact on mortality pseudomonas aeruginosa infection in very low birth weight infants: a case-control study pseudomonas aeruginosa outbreak in a neonatal intensive care unit: a possible link to contaminated hand lotion nosocomial pseudomonm pickem'i colonization associated with a contaminated respiratory therapy solution in a special care nursery neonatal infections with pseudomonas aeruginosa associated with a water-bath used to thaw fresh frozen plasma pseudomonas aeruginosa outbreak associated with a contaminated blood-gas analyser in a neonatal intensive care unit sepsis in a newborn due to pseudomonas aeruginosa from a contaminated tub bath endemic pseudomonas aeruginosa infection in a neonatal intensive care unit a prolonged outbreak of pseudomonas aeruginosa in a neonatal intensive care unit: did staff fingernails play a role in disease transmission? guideline for hand hygiene in healthcare settings. recommendations of the health care infection control practices advisory committee and the hicpacishenapiciidsa hand hygiene task force. society for health care epidemiology of association for professionals in infection control/infectious diseases society of america pertussis: adults as a source in health care settings centers for disease control and prevention. hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycin infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study red book: report of the committee on infectious diseases a continuing outbreak of multidrug-resistant tuberculosis, with transmission in a hospital nursery nursery exposure of newborns to a nurse with pulmonary tuberculosis guidelines for preventing the transmission of mycobacterium tuberculosis in health-care facilities prevalence of candida species in hospitalacquired urinary tract infections in a neonatal intensive care unit association of fungal colonization and invasive disease in very low birth weight infants candida tropicalis in a neonatal intensive care unit: epidemiologic and molecular analysis of an outbreak of infection with an uncommon neonatal pathogen low rate of candida parapsilosisrelated colonization and infection in hospitalized preterm infants: a one-year prospective study when to suspect fungal infection in neonates: a clinical comparison of candida albicans and candida parapsilosis fungemia with coagulase-negative staphylococcal bacteremia evidence of nosocomial spread of candida nlbicans causing bloodstream infection in a neonatal intensive care unit vertical and horizontal transmission of unique candida species to premature newborns outbreak of candida afbicans fungaemia in a neonatal intensive care unit malassezia pachydermatis fungaemia in a neonatal intensive care unit an epidemic of malassezia pachydermatis in an intensive care nursery associated with colonization of health care workers' pet dogs pichia anomah outbreak in a nursery: exogenous source? outbreak of pichia anomah infection in the pediatric service of a tertiary-care center in northern india invasive pulmonary aspergillosis in a critically ill neonate: case report and review of invasive aspergillosis during the first months of life outbreak of systemic aspergillosis in a neonatal intensive care unit nosocomial infection with rhizopus microsporus in preterm infants: association with wooden tongue depressors nosocomial ringworm in a neonatal intensive care unit: a nurse and her cat clinical manifestations of rotavirus infection in the neonatal intensive care unit interruption of rotavirus spread through chemical disinfection an outbreak of diarrhea in a neonatal medium care unit caused by a novel strain of rotavirus: investigation using both epidemiologic and microbiological methods adenovirus type conjunctivitis outbreak in a neonatal intensive care unit neonatal nosocomial respiratory infection with coronavirus: a prospective study in a neonatal intensive care unit an outbreak of influenza a in a neonatal intensive care unit outbreak of parainfluenza virus type in an intermediate care neonatal nursery outbreaks of influenza a virus infection in neonatal intensive care units clinical and epidemiological aspects of an enterovirus outbreak in a neonatal unit severe neonatal echovirus infection during a nursery outbreak an outbreak due to echovirus type in a neonatal unit in france in : usefulness of pcr diagnosis cytomegalovirus infection in a neonatal intensive care unit. subsequent morbidity and mortality of seropositive infants transmission of cytomegalovirus to preterm infants through breast milk cytomegalovirus infection and bronchopulmonary dysplasia in premature infants cytomegalovirus infection of extremely low-birth weight infants via breast mdk epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding molecular epidemiology and significance of a cluster of cases of cmv infection occurring on a special care baby unit transmission of cytomegalovirus among infants in hospital documented by restriction-endonuclease-digestion analyses nosocomial cytomegalovirus infections within two hospitals caring for infants and children prevention of postnatal cytomegalovirus infection in preterm infants transmission of herpes-simplexvirus type in a nursery for the newborn. identification of viral isolates by dna ''fingerprinting an outbreak of herpes simplex virus type in an intensive care nursery two outbreaks of herpes simplex virus type nosocomial infection among newborns shedding and survival of herpes simplex virus from 'fever blisters varicella exposure in a neonatal medical centre: successful prophylaxis with oral acyclovir varicella exposure in a neonatal intensive care unit: case report and control measures nosocomial hepatitis a. a multinursery outbreak in wisconsin vertical transmission of hepatitis a resulting in an outbreak in a neonatal intensive care unit hepatitis a outbreak in a neonatal intensive care unit: risk factors for transmission and evidence of prolonged viral excretion among preterm infants the efficacy of infection surveillance and control programs in preventing nosocomial infections in us hospitals prevention of nosocomial infections in the neonatal intensive care unit recommended practices for surveillance. association for professionals in infection control and epidemiology, inc. surveillance initiative working group af'ic text for infection control and epidemiology hospital epidemiology and infection control pre-publication edition. oak brook terrace, ill national nosocomial infections surveillance system (nnis): description of surveillance methods cdc definitions for nosocomial infections epidemiology of neonatal infections: experience during and after hospitalization. pediatr infect dis j . centers for disease control and prevention, division of health care quality promotion. national nosocomial infections surveillance the newborn nursery improving hospital-acquired infection rates: the cdc experience hospital-acquired infections in the united states. the importance of interhospital comparisons nosocomial infection rates in us children's hospitals' neonatal and pediatric intensive care units af'ic text for infection control and epidemiology outbreak investigation in a neonatal intensive care unit outbreak of necrotizing enterocolitis associated with enterobacter sakamkii in powdered milk formula outbreak of acinetobacter spp. bloodstream infections in a nursery associated with contaminated aerosols and air conditioners nosocomial neonatal outbreak of serratia marcescen+analysis of pathogens by pulsed field gel electrophoresis and polymerase chain reaction an outbreak of epidemic keratoconjunctivitis in a pediatric unit due to adenovirus type a five year outbreak of methicillin-susceptible staphylococcus aureus phage type , in a regional neonatal unit outbreak of invasive disease caused by methicillin-resistant staphylococcus aureus in neonates and prevalence in the neonatal intensive care unit infection due to extended-spectrum beta-lactamase-producing salmonella enterica subsp. enterica serotype infantis in a neonatal unit an outbreak of necrotizing enterocolitis associated with a novel clostridiurn species in a neonatal intensive care unit flavobacterium) rneningosepticum outbreak associated with colonization of water taps in a neonatal intensive care unit a nursery outbreak of staphylococcus aureus pyoderma originating from a nurse with paronychia parainfluenza w e viral outbreak in a neonatal nursery an organizational climate intervention associated with increased handwashing and decreased nosocomial infections improving adherence to hand hygiene practice: a multidisciplinary approach american academy of pediatrics and american college of obstetricians and gynecologists. inpatient perinatal care services the effect of rings on microbial load of health care workers' hands impact of ring wearing on hand contamination and comparison of hand hygiene agents in a hospital gowning does not affect colonization or infection rates in a neonatal intensive care unit gowning on a postpartum ward fails to decrease colonization in the newborn infant guidelines for perinatal care infection control for hospitalized children guideline for preventing the transmission of mycobacterium tuberculosis in health care fac tuberculosis among adult visitors of children with suspected tuberculosis and employees at a children's hospital single-room infant care: future trends in special care nursery planning and design the principles for family-centered neonatal care recommended standards for newborn icu design: report of the fifth consensus conference on newborn icu design. consensus committee to establish recommended standards for newborn icu design reservoirs of pseudomonas in an intensive care unit for newborn infants: mechanisms of control multi-resistant pseudomonas aeruginosa outbreak associated with contaminated tap water in a neurosurgery intensive care unit aerators as a reservoir of acinetobacter junii: an outbreak of bacteraemia in paediatric oncology patients guidelines for environmental infection control in health-care facilities. recommendations of cdc and the health care lnfection control practices advisory committee (hicpac) newborn nursery and neonatal intensive care unit association for professionals in infection control and epidemiology apic guideline for selection and use of disinfectants central services, linens, and laundry the inanimate environment guidelines for environmental infection control in health-care facilities. chicago, ill, american society for health care engineering and the american hospital association nosocomial respiratory syncytial virus infections neonatal respiratory syncytial virus infection control of nosocomial respiratory syncytial viral infections herpes simplex red book risk of cytomegalovirus infection in nurses and congenital infection in their offspring cytomegalovirus infection among employees of a children's hospital. no evidence for increased risk associated with patient care the role of understaffing in central venous catheter-associated bloodstream infections american academy of pediatrics and american college of obstetricians and gynecologists. perinatal infections fetal and neonatal varicella-zoster infections breast-feeding reduces incidence of hospital admissions for infection in infants human milk report of the committee on infectious diseases american academy of pediatrics and american college of obstetricians and gynecologists. care of the neonate bacterial contaminants of collected and frozen human milk used in an intensive care nursery preventing contamination of breast pump kit attachments in the nicu infant formula safety. pediatrics - co-bedding twins: a developmentally supportive care strategy co-bedding of twins in the neonatal intensive care unit parents as a vector for nosocomial infection in the neonatal intensive care unit a parent as a vector of salmonella brandenburg nosocomial infection in a neonatal intensive care unit role of antimicrobial applications to the umbilical cord in neonates to prevent bacterial - , . colonization and infection: review of the evidence a controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum ocular applications of povidoneiodine peripheral intravenous catheter complications in critically ill children: a prospective study guidelines for prevention of nosocomial pneumonia risk factors for nosocomial infections in critically ill newborns: a -year prospective cohort study nosocomial pneumonia hospital-acquired pneumonia: perspectives for the health care epidemiologist the prevention of ventilator-associated pneumonia non-invasive mandatory ventilation in extremely low birth weight and very low birth weight newborns with failed respiration ventilator-associated pneumonia with circuit changes every days versus every week cost analysis and clinical impact of weekly ventilator circuit changes in patients in intensive care unit weekly versus daily changes of inline suction catheters: impact on rates of ventilator-associated pneumonia and associated costs incidence of colonization, nosocomial pneumonia, and mortality in critically ill patients using a trach care closed-suction system versus an open-suction system: prospective, randomized study prevention of ventilatorassociated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study oropharyngeal decontamination decreases incidence of ventilator-associated pneumonia. a randomized, placebo-controlled, double-blind clinical trial stress ulcer prophylaxis in critically ill patients. resolving discordant meta-analyses occurrence of ventilator-associated pneumonia in mechanically ventilated pediatric intensive care patients during stress ulcer prophylaxis with sucralfate, ranitidine, and omeprazole ventilator-associated pneumonia and upper airway colonisation with gram negative bacilli: the role of stress ulcer prophylaxis in children rr- ):l- key: cord- -igzs rdm authors: dornelles, cristina t.l.; piva, jefferson p.; marostica, paulo j.c. title: nutritional status, breastfeeding, and evolution of infants with acute viral bronchiolitis date: - - journal: j health popul nutr doi: nan sha: doc_id: cord_uid: igzs rdm acute viral bronchiolitis is a common respiratory infectious disease of infancy. a prospective study was carried out with infants aged up to six months to evaluate their nutritional and breastfeeding status as possible risk factors for unfavourable evolution of previously-healthy infants from a care hospital. immunofluorescence test for virus and anthropometric assessment were performed. outcomes were length of oxygen-use, length of hospital stay, and type of hospital unit needed. seventy-three percent of the infants were well-nourished, % undernourished, . % at a nutritional risk, . % overweight, and . % obese. eighty-one percent of the undernourished and nutritionally at-risk infants and % of the well-nourished, overweight, and obese infants did not receive exclusive breastfeeding. the median length of hospital stay was four days and of oxygen-use was hours. the nutritional status did not affect the clinical course of previously-healthy infants with acute viral brochiolitis. the duration of exclusive breastfeeding, but not type of breastfeeding, was inversely related to the length of oxygen-use and the length of hospital stay. shorter exclusive breastfeeding was observed in infants who were assigned to a paediatric ward or to an intensive care unit. in conclusion, longer duration of breastfeeding was associated with better clinical outcomes. acute viral bronchiolitis is a common infectious disease of the lower small airways that affects mostly infants aged less than one year ( ). approximately . cases of acute viral bronchiolitis occur per infants annually, and % of these are hospitalized ( ) . the disease is characterized by a diffuse bronchiolar inflammation induced by viruses (respiratory syncytial virus-responsible for - % of cases, parainfluenza, influenza, rhinovirus, adenovirus, human metapneumovirus, coronavirus, enterovirus, and others) ( ) ( ) ( ) . malnutrition and infection are among the most frequent causes of morbidity and mortality in infancy, especially in developing countries, where the frequency, duration, and severity of the infection are related to the nutritional status of children ( , ) . breastfeeding provides protection against infections in newborns and infants, and it is associated with low levels of morbidity and mortality in developing countries ( ) ( ) ( ) . this effect can substantially decrease when the child is fed other than maternal milk, including even water or tea. the reason for this is that the child who is not exclusively breastfed receives less protection factors that exist in mother's milk, besides receiving food or water that are frequently contaminated ( ) ( ) ( ) . the present study is original in evaluating such an association in the evolution of acute viral bronchiolitis. its importance is the impact of the nutritional and breastfeeding status on this infection which has not yet been completely studied. this understanding would lead to the accomplishment of other studies focused on the prevention of malnutrition and breastfeeding interruption in infants with acute viral bronchiolitis. the objective of the present study was to evaluate the risk factors-especially the nutritional status and type of breastfeeding-in the evolution of bronquiolite viral aguda in previously-healthy infants aged up to six months. a prospective transversal study was carried out with previously-healthy infants aged - month(s), with a clinical diagnosis of acute viral bronchiolitis and first episode of wheezing, who were admitted to the emergency ward or to intensive care paediatric units, in a tertiary public hospital-hospital de clínicas de porto alegre (hcpa)-in the state of rio grande do sul, in southern brazil. the ethics and research committee of this institution approved the study, which was carried out during april -april . infants were selected when they arrived at the hospital and were diagnosed by the on-duty emergency paediatrician as having acute viral bronchiolitis based on the symptoms, such as respiratory distress, tachypnea, wheezing, or crackles in pulmonary auscultation, and coughing with a history of upper airway infection with signs and symptoms no longer than seven days. prematurely-born (< weeks) or low-birthweight (< , g) infants, those with congenital malformations, inborn errors of metabolism, heart, neurological or liver disease, other chronic or intercurrent respiratory diseases, immunodepression, hiv-positive mother, and diseases that could influence the nutritional status (pathologic gastroesophageal reflux, acute gastroenteritis, diarrhoea, or others) were excluded. although malnutrition could be considered a chronic disease, it was not listed as a criterion for exclusion since, as we will present later on, this was one of the study factors. nasal aspirate from the nasopharynx was collected to detect virus by the indirect immunofluorescence test as part of the paediatric emergency routine care of hcpa. the viruses tested were respiratory syncytial virus, parainfluenza, influenza, and adenovirus. the paediatricians were not blind to any data, and the researchers did not influence the management of patients. if the infant met the inclusion criteria and the parents signed the consent term, a form was filled in with clinical evaluation and with data from the patient records. data on type of breastfeeding, duration of exclusive breastfeeding, exposure to a smoking mother or passive smoking, i.e. smoking people living in the same home, and socioeconomic situation of the infant's family were collected through a structured interview at admission with parents. immediately after the infants were weighed and measured by a clinical dietitian and three trained nutrition students, a research nutritionist checked the assessments. weight of the infant was measured without clothes on, using a urano ® electronic scale that stands a maximum weight of kg and g precision. the measurement of length was done from the top of the head to the heels with the child lying on a wood slab with a fixed piece on one side and a moveable one on the other (top of head on the fixed part). data were processed using the epi info™ software (version . ) (atlanta, georgia) that uses the standards from the national center for health statistics (nchs) as a reference and calculates mean deviations, percentiles, and z-scores for the ratio lengthfor-age, weight-for-length, and weight-for-age ( ) . for classifying the nutritional status of infants, we compared measurements of length-for-age and weight-for-length with the nchs standard reference. undernourishment was defined based on the z-score for length-for-age and weight-for-length below - . (< rd percentile). for obesity, we used the weight-for-length ratio above + . (> th percentile) according to the criteria recommended by the world health organization (who) ( , ) . for classification of nutritional risk, we considered the z-score levels to be ≤- . (< th percentile) for weight-for-length, and for overweight a z-score of ≥+ . (> th percentile) for weight-for-length, as recommended by the american society for parenteral and enteral nutrition ( ) . the use of the th percentile was also adopted for weight-for-age in the classification of the nutritional risk ( ) . the infants who presented a z-score on the limit between - . and + . for weight-for-length were considered well-nourished. in the classification of nutritional status, where more than one of the anthropometrical ratios was used (length-for-age, weight-for-age, weight-for-length) and a discrepancy existed between the levels used, the lowest one was considered. in the classification of types of breastfeeding, the categories defined by who were adopted ( ): exclusive breastfeeding was considered when the infant received only maternal milk, either directly from the breast or extracted and no other liquid or solid, with the exception of drops or syrups of vitamins, minerals, and/or medicine. predominant breastfeeding referred to when the infant received together with maternal milk water or water-based drinks, such as fruit juices and tea. the classification of breastfeeding was given when the infant received maternal milk, directly from the breast or extracted, independently of receiving other foods or liquids, including non-human milk. artificial feeding was considered when the infant was no longer breastfed but received cow's milk-in natural or powdered-and formula feeding for the first semester along with other liquids and solids. all the infants were monitored until discharge to obtain data with regard to the length of oxygenuse and hospital stay. clinical data were confirmed by a cross-check with the electronic records after discharge from the hospital. infants who stayed in the hospital for more than days were excluded. at the hcpa, the usual criteria for withdrawal of oxygen is the absence of respiratory distress and haemoglobin saturation of > % in room air. this decision, and that of discharging the patients, was taken by the paediatrician-in-charge. the clinical evolution of infants with acute viral bronchiolitis was also evaluated according to the more complex hospital unit needed. for such classification, paediatric emergency care was considered as of least complexity where the infants were usually admitted for observation and the intensive care unit as the most complex one. the paediatric ward, in this context, was considered intermediate complexity between the other two. to calculate the sample size, a preliminary analysis was used considering an α= . and a β= . , with a prevalence of % of grouped malnutrition and nutritional risk. considering relevant, a difference of two days of length of hospital stay with standard deviation (sd) of . days, the need of infants was estimated. in the association between the quantitative variables in relation to the length of hospital stay and oxygen-use, the spearman's correlation coefficient was used because the dependent variables presented an asymmetric distribution. to compare the types of breastfeeding and the nutritional classification in relation to the length of hospital stay and oxygen-use, the mann-whitney test was used. for the variables with more than two categories, a kruskal-wallis test was used, and the dunn test was run as a complement. later, a multiple linear regression test was applied. in the association between the categorical variables and the hospital unit needed or saturation interval, pearson's chi-square test was applied and, as a complement, the adjusted standardized residual was used for checking local associations. to compare the quantitative variables in relation to the hospital unit used, either anova or the kruskal-wallis test was used, complemented by the tukey test in the presence of the significant statistical difference and simple and multiple poisson regression with over dispersion. the p value of . was considered significant, and the analyses were carried out using the spss software (version . ) (spss inc., chicago, il). for this study, infants who met the inclusion criteria were enrolled. there were no refusals to participate. of the infants, were excluded because the length of their stay in the hospital was more than days, which left infants at the time of conclusion. the evaluation of all the infants did not show significantly different results compared to those of the remaining when comparing the nutritional status and types of breastfeeding with the outcomes considered. data from these infants are presented below. table describes the general characteristics of the infants with acute viral bronchiolitis before hospital admission. of the cases presented, . % of the hospitalized infants evaluated were aged three months or less. only . % of the infants attended daycare centres. . % of the children had the exposure to a smoking mother and . % to passive smoking-both the factors previously associated with a greater risk for hospitalization due to acute viral bronchiolitis. the data relating to the socioeconomic situation of the infants' family showed that % of mothers and . % of fathers had not completed elementary school. the median monthly family income was € which corresponds to . minimum national salaries. initial saturation at admission was > % in . % of the infants. results of viral identification tests from nasopharynx secretion showed that . % were respiratory syncytial virus, % parainfluenza , . % influenza a, . % adenovirus; . % were negative; and samples could not be collected from . % for op-erational difficulties, like unavailability of reagents during weekends or scarcity of nasal secretions. table shows the classification categories of the nutritional status and breastfeeding. the nutritional status was compared in relation to exclusive breast-feeding. eighty-one percent of the undernourished and nutritionally at-risk infants and % of the well-nourished, overweight, and obese infants did not receive exclusive breastfeeding (p= . ). the other comparisons were not significant. the clinical evolution of the infants with acute viral bronchiolitis was evaluated according to the more complex hospital unit needed, length of hospital stay, and oxygen-use. ninety-three ( . %) infants needed to be hospitalized in a paediatric ward, but only four ( . %) were sent to an intensive care unit. the median duration of hospital stay was four days, the initial saturation was %, and the length of oxygen-use was hours. there were no deaths among the infants followed. sixty-seven percent of the infants in whom the presence of infecting virus was identified needed to be hospitalized in the paediatric ward or intensive care unit compared to % of the others who had no infecting virus (p= . ). infants admitted to paediatric emergency care had been on exclusive breastfeeding for a median of days compared to days in the paediatric ward and days in the intensive care unit (χ = . ; p= . ). even when the hospital unit was needed and the presence of virus, age, and nutritional status were analyzed together under a multiple linear regression, the presence of virus and the duration of exclusive breastfeeding continued to present as the only significant correlations. the chance of hospitalization increased by % when the virus was identified (relative risk= . ; confidence interval . - . ). table shows the association between the anthropometric variables studied and the length of hospital stay and oxygen-use. an inverse association was observed among age, weight-for-length and weightfor-age ratios, duration of exclusive breastfeeding, and hours on oxygen-use. a negative correlation between age and length of hospital stay was also observed. statistically significant correlations were not found between the outcomes evaluated and gestational age, weight, and length at birth, initial saturation, number of rooms and people living in them, family income, and z-score for length-forage. the same analysis, taking into consideration only the infants in whom any virus or respiratory syncytial virus was identified, was significant in the same correlations presented here. a multiple linear regression was elaborated to evaluate the variables in this study that had significance in the prediction of the length of oxygen-use and of hospital stay. the linear regression model for the variable-length of oxygen-use-was statistically significant by means of multiple regression variance analysis (f , = . ; p= . ). as shown in table , the significant predictor values are shown to be duration of exclusive breastfeeding and identification of the virus in the infants studied. using beta-coefficients of linear regression, it can be interpreted that infants with an identified virus had increased the length of oxygen-use by an average of approximately hours. since the duration of exclusive breastfeeding variable was measured in days, for each additional day of exclusive breastfeeding, the infants had an average reduction of . hours in the length of oxygen-use. so, for each month of exclusive breastfeeding, the infants studied presented a reduction of approximately hours in this variable. likewise, the linear regression model for the variable-length of hospital stay-was statistically significant by means of multiple regression variance analysis (f , = . ; statistically significant differences were not observed in relation to the length of hospital stay when comparing sex, initial saturation, classification of nutritional status, classification of lengthfor-age, weight-for-age, and weight-for-length, type of breastfeeding, level of parental education, whether mother was a smoker, and if any of the people living in the home smoked. the infants with positive virus stayed for an average of . (± ) days in the hospital, while others stayed for . (± . ) days (p= . ). in the present study, the nutritional status and type of breastfeeding did not affect the clinical course of previously-healthy infants with acute viral bronchiolitis. on the other hand, the duration of exclusive breastfeeding was inversely related to the length of oxygen-use and the length of hospital stay. also, infants who needed a less complex care at paediatric emergency had been on exclusive breastfeeding for a longer period than infants assigned to different units. the study was carried out during the one-year period at a public university hospital evaluating a representative number of infants. the decision to restrict the inclusion of patients to the first six months of life was made because, during this agerange, the diagnosis of acute viral bronchiolitis in infants that present initial acute wheezing is the most probable and not asthma or reactive airway disease. furthermore, it is during this age that exclusive breastfeeding is recommended, which makes it possible to compare it with other types of feedings that are considered to be less adequate ( , , ) . the exclusion of infants with more than days of hospitalization represented less than % of the sample. the reason these infants were excluded was the possibility of other undetected associated co-morbidity factors since acute viral bronchiolitis is a viral infection that usually has an activity period of - week(s) ( , ) . fifty-eight percent of the infants were males, possibly because of smaller airways present in boys. these results are similar to those reported by others ( ) ( ) ( ) . the role of infections is very important in the evolution and survival of the malnourished child. the effects of malnourishment and infection, even in the mild and moderate stages, are not additive but multiplicative ( ) . we did not evaluate the impact of infection on the nutritional status since the study was transversal, but we proposed to check the impact of nutritional status on the clinical evolution of acute viral bronchiolitis. in different studies, a strong association was evident for the protection of exclusive or predominant breastfeeding against respiratory morbidity as opposed to the introduction of formula milk ( , , ( ) ( ) ( ) . in agreement with this, in the present study, the longer duration of exclusive breastfeeding was associated with the shorter length of hospital stay and oxygen-use. breastfeeding for less than one month increased the incidence of respiratory syncytial virus-associated infection. it is reasonable to speculate that human milk may confer several effects on the development of the respiratory tract and its subsequent ability to fight infections and illnesses. the specific nutritional immunoregulatory and immunomodulatory factors in maternal milk may promote maturation of the infant's immune competence ( , ) . the optimal duration of exclusive breastfeeding recommended by who is six months ( , ( ) ( ) ( ) . given this recommendation, it is important to stress the role of exclusive breastfeeding in the prevention of childhood illnesses and infection in infants. in brazil, the most recent poll showed that % of women initiated breastfeeding, and only % exclusively breastfed during - months of life, and the mean duration of exclusive breastfeeding was only one month ( ) . in relation to the length of oxygen-use and the length of hospital stay, the duration of exclusive breastfeeding and the presence of virus were determinants in the clinical evolution. as for the treatment-location, % of the infants identified as having the virus were hospitalized in the paediatric ward or in the intensive care unit, compared to % of the others who had no infecting virus. although this difference could be secondary to a greater availability of beds for infants with an identified virus in the endemic months, these infants also presented other criteria of severity mentioned above. these findings suggest that infants with respiratory syncytial virus and those with shorter duration of exclusive breastfeeding present more severe clinical outcomes ( ) . in the present study, a prevalence of undernourishment of %, . %, and . % according to the ratios of length-for-age, weight-for-age, and weightfor-length respectively was found, which are sat-isfactory rates according to the recommendations of who and lower when compared with findings of other studies ( , , ) . no statistically significant associations were found among the anthropometric rates (length-for-age, weight-for-age, and weight-for-length), nutritional status, or among the types of breastfeeding, with the length of oxygen-use, and the length of hospital stay. however, only ( . %) infants were undernourished, and were at a nutritional risk. it is possible that, with a sample with a greater number of malnourished infants, some difference in the outcomes could be demonstrable. this study was limited because it evaluated the infants in a hospital setting, i.e. it included only the more severe cases. the study design used could not exclude that a larger proportion of infants from the same population of origin on exclusive breastfeeding had milder cases of bronquiolite viral aguda or even did not get sick, representing a protective effect of the mother's milk, that would not be detected. another limitation was that the paediatricians were not blind either to the age or to viral diagnosis. this fact could explain, at least in part, the prolonged care taken with infants who were respiratory syncytial virus-positive as this is a known factor of worse prognosis in acute viral bronchiolitis. social factors may have been involved at the length of hospital stay in some infants. in conclusion, the shorter duration of exclusive breastfeeding was a risk factor for the unfavourable clinical evolution of acute viral bronchiolitis in previously-healthy infants from a tertiary-care hospital. shorter exclusive breastfeeding was observed in infants who were assigned to the paediatric ward or to an intensive care unit. these findings emphasize the importance of promoting exclusive breastfeeding up to six months of life, not only because of prevention of infectious diseases but also because of the lesser aggressive course of bronchiolitis in breastfed children. acute lower respiratory tract infections in nonhospitalized infants new approaches to respiratory infections in infants. bronchiolitis and croup comparison of the seroprevalence of human metapneumovirus and human respiratory syncytial virus immune responses during recovery from protein-energy malnutrition atencion integrada a las enfermidades prevalente e la infância (aiepi) em las américas effect of breastfeeding on infant and child mortality due to infectious diseases in less developed countries: a pooled analysis. who collaborative study team on the role of breastfeeding on the prevention of infant mortality ecological study of effect of breast feeding on infant mortality in latin america breast feeding and respiratory morbidity in infancy: a birth cohort study effects of exclusive breastfeeding for four versus six months on maternal nutritional status and infant motor development: results of two randomized trials in honduras breast feeding in clinical practice us department of health, education, and welfare, . p. (vital and health statistics: series report of a who expert committee. geneva: world health organization an evaluation of infant growth: the use and interpretation of anthropometry in infants american society for parenteral and enteral nutrition. definition of terms used in aspen. guidelines and standards evaluation of the use of the th percentile of weight for age as a cut point for detection of infants under nutritional risk world health organization. indicators for assessing breastfeeding practices. geneva: world health organization the optimal duration of exclusive breastfeeding: a systematic rewiew respiratory syncytial virus bronchiolitis supportive care and therapies designed to overcome airway obstruction treatment of respiratory syncytial virus: antiviral therapies physiologic growth and development of the lungs during the first year of life risk factors associated with hospitalization for bronchiolitis in the post-neonatal period clinical and transcutaneous oxygen saturation characteristics in hospitalized infants with acute viral bronchiolitis potentiating effects of malnutrition on child mortality: epidemiologic evidence and policy implications evidence for protection by breast-feeding against infant deaths from infectious diseases in brazil breast-feeding, morbidity and mortality breastfeeding and the risk of hospitalization for respiratory disease in infancy. a meta-analysis guiding principles for complementary feeding of the breastfed child word heath organization. global strategy for infant and young child feeding. geneva: world health organization growth of exclusively breastfed infants in the first months of life respiratory syncytial virus ações de saúde materno infantil a nível local segundo as metas da cúpula mundial em favor da infância evolution of nutritional status in hospitalized infants the authors thank the pediatric emergency care, nutrition and dietary department of hcpa for their help and the fundo de incentivo a pesquisa e grupo de pós-graduação e pesquisa for their financial support. key: cord- -e zp gux authors: meissner, h. cody title: bronchiolitis date: - - journal: principles and practice of pediatric infectious diseases doi: . /b - - - - . - sha: doc_id: cord_uid: e zp gux nan all references are available online at www.expertconsult.com bronchiolitis, a disease primarily of the first years of life charac terized by signs and symptoms of obstructive airway disease, is caused most commonly by viruses. approximately % to % of infants in the first months of life are hospitalized with bron chiolitis, accounting for approximately , hospitalizations and to deaths annually in the united states. data from the centers for disease control and prevention (cdc) indicate that the number of yearly hospital admissions attributable to bronchiolitis increased more than twofold between and . increasing survival rates for premature infants as well as infants with compromised cardiac, pulmonary, and immune status increase the number of children at risk for severe bronchiolitis. many viruses can cause bronchiolitis, although respiratory syn cytial virus (rsv), human metapneumovirus, and parainfluenza virus type are the most common etiologic agents. [ ] [ ] [ ] [ ] [ ] [ ] [ ] other viruses are implicated less frequently (table ) . [ ] [ ] [ ] during the winter months, rsv is identified as the etiologic agent by cell culture or antigen detection assays in up to % of children hos pitalized with bronchiolitis or pneumonia. epidemics of bronchi olitis in early spring and fall often are caused by parainfluenza virus type . [ ] [ ] [ ] [ ] the yearly cycles of these respiratory viruses are depicted in figure . other viral causes of bronchiolitis include rhinoviruses and coronaviruses. bordetella pertussis, mycoplasma pneumoniae, measles, influenza, and adenovirus have been associated with a severe form of bron chiolitis, bronchiolitis obliterans. [ ] [ ] [ ] [ ] this uncommon obstructive pulmonary disease is characterized histologically by the progres sion of acute airway inflammation to necrosis of the cells lining the lumen with severe obliterative fibrosis in the final stages. the pathogenesis of bronchiolitis obliterans probably differs from that of simple viral bronchiolitis. bronchiolitis may be defined as an episode of obstructive lower airway disease precipitated by a viral infection in infants younger than months of age. the peak incidence of severe disease occurs between and months of age. , , rates of hospitalization are higher in boys and among infants living in industrialized urban settings rather than in rural settings. hospitalization rates are about times higher among infants and children in highrisk groups than among nonhighrisk infants. highrisk groups include premature infants (< weeks' gestation), infants born with hemodynamically significant congenital heart disease, as well as infants with chronic lung disease of prematurity (previously called bronchopulmonary dysplasia). [ ] [ ] [ ] [ ] [ ] [ ] although mortality has been reduced in recent years, morbidity among highrisk patients can be high, with average hospital length of stay and intensity of care several times that of previously healthy infants. , occurrence of the respiratory virus season is predictable, even though the severity of the season, the date of onset, the peak of activity, and the end of the season cannot be predicted with preci sion. there can be variation in timing of community outbreaks of disease due to rsv from year to year in the same community and among neighboring communities, even in the same season. in the u.s., communities in the south tend to experience the earliest limited numbers of cases of bronchiolitis occur during summer and early fall, and they are likely to be caused by viruses other than rsv, such as rhinovirus and parainfluenza viruses. these cases are generally milder than rsvrelated cases. in tropical coun tries, the annual epidemic of rsv coincides with the rainy season or "winter," although sporadic cases can occur throughout the year. rsv can be divided into a and b strains, each with numerous subtypes or genotypes. type a strains may be associated more commonly with epidemics, severe disease, and a higher hospitali zation rate than type b strains, although not all studies are consist ent with regard to differences in severity. [ ] [ ] [ ] [ ] both strains may circulate during the same season, and infants may be reinfected within the same year. a progressive increase in hospitalization rates for bronchiolitis in the u.s. has occurred since the late s. , this increase may be related to a greater ability to identify hypoxic infants through the use of pulse oximetry. alternatively, the increase in hospitaliza tion may reflect increased use of daycare centers or changes in criteria for admission. household crowding is an important risk factor for severe viral lower respiratory tract illness due to rsv as well as other respiratory viruses. , generally it is recognized that as the number of household members increases, the risk of expo sure to infectious respiratory secretions also increases. childcare attendance has been correlated with an increased risk of bronchi olitis in some studies. unlike other respiratory virus infections, exposure to passive household tobacco smoke has not been asso ciated with an increased risk of rsv hospitalization on a consist ent basis. in contrast to the welldocumented beneficial effect of breastfeeding against some viral illnesses, existing data are con flicting regarding the specific protective effect of breastfeeding against rsv infection. [ ] [ ] [ ] [ ] [ ] parental history of bronchiolitis or week no. onset of rsv activity and the midwest tends to experience the latest onset. the duration of the season for the west and the northeast is typically between that in the south and the midwest. nevertheless, these variations occur within the overall pattern of rsv outbreaks, usually beginning in november or december, peaking in january or february, and ending by the end of march or april. all references are available online at www.expertconsult.com asthma is associated with a higher risk for the development of lower respiratory illness in offspring. , young chronologic age at the beginning of the rsv season is a consistent risk factor for rsv hospitalization. several reasons may account for this increase in risk. most severe rsv disease occurs in the first months of life so that birth shortly before or early after the onset of the rsv season will result in a longer period of exposure to rsv earlier in life. second, maternal antibody concen trations to rsv show seasonal variation and infants born early in the rsv season are more likely to be born to mothers with low serum antibody concentrations to the f (fusion) protein of rsv. , low concentrations of rsv antibody correlate with susceptibility to severe rsv disease in infants. acute bronchiolitis generally implies disease of infectious etiology, usually due to viruses with specific tropism for bronchiolar epi thelium. because most healthy infants recover from bronchiolitis without incident, information regarding the pathologic changes caused by infection is inferred from animal studies and from biopsy or autopsy materials in severe cases. viral infection causes profound alterations in the epithelial cell and mucosal surfaces of the human respiratory tract. the characteristic histopathology in bronchiolitis is a lymphocytic infiltration of the bronchiolar walls and edema of the surrounding tissue. disease progression is asso ciated with proliferation and necrosis of the bronchiolar epithe lium. the sloughed necrotic epithelium and the increased mucus production lead to obstruction of the lumen of the infant's small airways. air movement is restricted during inspiration and expira tion but is more restricted during expiration when the lumen is further compromised by positive expiratory pressure, resulting in expiratory wheezing. the obstruction results in air trapping and the characteristic appearance of hyperinflation on chest radio graphs. as this air is absorbed, the radiographic pattern evolves to show atelectasis. [ ] [ ] [ ] [ ] [ ] [ ] the presence of high serum concentrations of immunoglobulin igg antibodies to rsv (whether transplacentally acquired or administered intramuscularly) ameliorates rsv illness. - severe obstructive illness may be related to stimulation of virusspecific igemediated hypersensitivity responses or altered cellmediated immune responses. - bronchiolitis represents the late stage of a respiratory disease that progresses over several days. upper respiratory tract symptoms consisting of nasal discharge and mild cough begin about to days after onset of infection. approximately % to % of rsv infected infants have progression of disease to involve the lower respiratory tract. spread to the lower airway occurs either by aspi ration of rsvinfected epithelial cells or by celltocell spread of the virus. lowerairway involvement is marked by a sudden increase in the work of breathing, cough, tachypnea, wheezing, crackles, use of accessory muscles, and nasal flaring. , the respi ratory rate often exceeds to breaths/minute in young infants, and expiration is prolonged. intercostal and subcostal retractions with wheezing are evident. initially, wheezing occurs during the expiratory phase only and is only audible through a stethoscope. as wheezing progresses, it can be heard without a stethoscope. the chest becomes hyperexpanded and hyperresonant, respirations more labored, and retractions more severe. hypoxemia out of proportion to clinical distress is typical of rsv infection. mild hypoxemia occurs even in otherwise wellappearing infants, the socalled happy wheezers. respiratory failure can be due to hypox emia (an early and sometimes sudden occurrence) or progressive hypercapnia due to fatigue. the small airways of young infants can become so narrowed that wheezing is inaudible. in this setting disease severity is recognized by the absence of audible air exchange, flaring of the alae nasae, expiratory grunting, severe subcostal, supraclavicular, and intercostal retractions, and hypox emia. progressive illness often is accompanied by a rapid fall in oxygen saturation after minimal manipulation. a child with these findings usually requires intubation and ventilatory support. apnea can be an early manifestation of rsv infection, at times resulting in respiratory failure. rsvrelated apnea is mediated by the central nervous system, occurring in young, often prematurely born infants. because the severity of bronchiolitis often waxes and wanes prior to consistent improvement, assessment of respira tory status can vary markedly over a short period. the ability of the young infant to breast or bottlefeed without distress over time often provides a practical guide to disease severity and man agement. an infant who has substantial difficulty feeding as a result of respiratory distress has moderate or severe illness and usually requires hospitalization. otherwise healthy infants younger than months of age, infants born prematurely (less than weeks' gestation), and infants with chronic lung disease of prematurity (previously called broncho pulmonary dysplasia) or infants born with congenital heart disease have the highest morbidity and mortality rates due to bronchiolitis. , infants born with congenital heart disease at greatest risk of hospitalization due to bronchiolitis include those with moderate to severe pulmonary hypertension and infants with cyanotic heart disease. rsvinfected infants and children with the following hemodynamically insignificant heart disease are gener ally not considered to be at increased risk of hospitalization: secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarcta tion of the aorta, and patent ductus arteriosus, as well as infants with lesions adequately corrected by surgery (unless they continue to require medication for management of congestive heart failure). , severe respiratory distress with bronchiolitis can be the presenting manifestation of previously unrecognized con genital heart disease. once hospitalized, the rsvinfected infant may have a highly variable course of illness. [ ] [ ] [ ] [ ] [ ] among otherwise healthy infants, intensive care unit admission because of respiratory deterioration is uncommon. a decision to admit to the intensive care unit is based on the possible need for intubation because of progressive hypercapnia, increasing hypoxemia despite supplemental oxygen, or apnea. the typical course for a previously healthy infant older than months is one of improvement over to days, as evi denced by decreases in respiratory rate, retractions, duration of expiration, and oxygen requirement. the median duration of symptoms in infants with firsttime bronchiolitis who came to medical attention at an emergency department in wisconsin was days and onequarter of the infants remained symptomatic after weeks. pulmonary function abnormalities and evidence of mild desaturation (oxygen saturations in the range of % to %) can persist for several weeks. the differential diagnosis of bronchiolitis includes airway hypersensitivity to environmental irritants, anatomic abnormality of the airway, cardiac disease with pulmonary edema, cystic fibrosis, foreignbody aspiration, and gastroesophageal reflux. the diagnosis of bronchiolitis is based on clinical criteria with supporting radiographic findings. typical chest radiographic find ings are hyperinflation, with flattening of the diaphragms and hyperlucency of the lungs, and patchy atelectasis, especially involving the right upper lobe (figures and ) . , atel ectasis is due to airway narrowing or mucous plugging and is associated with volume loss; it may be confused with lobar con solidation or aspiration pneumonia, both of which are generally volumeexpanding lesions. bacterial pneumonia infrequently occurs as a complication of bronchiolitis but should be suspected in the infant with fever persisting for more than to days and lack of response to supportive management. establishing a specific etiologic diagnosis is helpful in predict ing the clinical course, in cohorting in the hospital, and may become increasingly useful as more antiviral agents effective against respiratory viruses become available. although viral culture of respiratory secretions has been the "gold standard" for reverse transcription-polymerase chain reaction-enzyme hybridi zation assay (hexaplex) is available to test a single nasopharyngeal sample for rsv, influenza a and b viruses, parainfluenza virus, and adenoviruses. antigen detection tests are useful in diagnosing certain viral infections, but, as with all tests, the positive predictive value decreases as disease incidence goes down. specificity of antigen detection assays are lowest during the off season and at the onset and end of the respiratory virus season. most infants with bronchiolitis can be managed at home with supportive care, but hypoxia or inability to feed adequately neces sitate hospitalization. once hospitalized, most infants respond to administration of supplemental oxygen and replacement of fluid deficits. the value of mist inhalation by vaporizer or tent is not proven; its use can provoke reflex bronchoconstriction. the spe cific treatment strategies used differ widely across children's medical centers. fewer than % of previously healthy infants hospitalized for bronchiolitis require intubation and mechanical ventilation because of respiratory failure or apnea; the percentage is higher for prematurely born infants and infants with chronic lung disease or congenital heart malformations. the therapeutic role of bronchodilator agents in bronchiolitis is controversial. , bronchodilator therapy is not recommended for routine management of first time wheezing associated with rsv bronchiolitis. occasionally, a single administration of an aero solized bronchodilator elicits a response, but this improvement is not seen in most infants with bronchiolitis and is not generally reproducible with subsequent doses. [ ] [ ] [ ] [ ] [ ] [ ] [ ] modest improvement in clinical scores and in tests of pulmonary function have been reported with use of inhaled racemic epinephrine [ ] [ ] [ ] and βadrenergic agents, principally salbutamol and albuterol. [ ] [ ] [ ] however, clinical improvement following repeated doses of epine phrine is not sustained and favorable response to βadrenergic agents, as measured by clinical score and oxygenation, is inconsistent. - flores and horwitz performed a metaanalysis of eight studies with similar designs. overall, their analysis sup ported a beneficial effect in certain infants, but identifying those infants could not be consistently accomplished at the time of initial presentation. on balance, an initial trial of bronchodilator therapy for the hospitalized infant with bronchiolitis is reasona ble, although brief episodes of hypoxia can be precipitated by adrenergic agents. bronchodilator therapy should only be contin ued if consistent improvement in respiratory distress or oxygen saturation is observed. racemic epinephrine should not be con tinued beyond one or two doses. although corticosteroids reduce the inflammatory changes observed with bronchiolitis, they may increase viral replication and prolong shedding. most studies examining the role of corti costeroids alone in the treatment of bronchiolitis have not demonstrated a consistent clinical benefit. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] although one metaanalysis of previously published reports of corticosteroid use in bronchiolitis concluded that there may be slight improvements in duration of symptoms, length of hospital stay, and clinical scores, these benefits appear to be limited. the routine use of corticosteroids in bronchiolitis is not recommended. however, a national collaborative, blinded, placebocontrolled trial con ducted in canada demonstrated that the combination of neb ulized epinephrine and oral dexamethasone treatment for children with bronchiolits evaluated in emergency departments reduced the subsequent rate of hospitalization by % compared with placebo or either treatment alone (p= . ) and was less costly. , diagnosis of rsv infection, it often is too slow a method to be clinically useful. enzyme immunoassays and direct fluorescent antibody (dfa) techniques for the identification of rsv, influenza virus, parainfluenza viruses, and adenoviruses permit rapid and accurate diagnoses. [ ] [ ] [ ] [ ] [ ] nasal wash is the preferred method of specimen collection. the dfa test permits evaluation of adequacy of the specimen's number of epithelial cells for antigen detection. a respiratory screening of nasal secretions using pooled mono clonal antibodies to the common agents of bronchiolitis, followed by specific identification for a positive reaction, is a cost and timesaving procedure compared with standard tissue culture iso lation. amplification of virus using the shell vial method, fol lowed by use of specific monoclonal agents, and amplification of viral genome by the polymerase chain reaction offer the promise of improved sensitivity for rapid detection but are not as widely available nor as rapid as enzyme immunoassay and fluorescent antibody techniques. , a multitest system for quantitative in infancy increases the likelihood of childhood asthma. numer ous studies have defined a higher risk of recurrent wheezing throughout childhood after bronchiolitis in infancy, and abnor malities of smallairway function have been identified in school aged children with a history of bronchiolitis in infancy. however, each of these findings may simply be a reflection of hereditary tendencies that are expressed both at the time of bronchiolitis and upon allergen exposure in later childhood. [ ] [ ] [ ] [ ] [ ] moreover, by adolescence, the rate of recurrent wheezing in subjects who had bronchiolitis in infancy appears to fall to the rate observed in subjects without a history of bronchiolitis. thus, it is uncertain whether bronchiolitis is causally associated with longterm respi ratory morbidity. strategies that reduce contact of vulnerable infants with individu als with respiratory tract infections, minimizing passive exposure to cigarette smoke, and limiting nosocomial transmission of caus ative agents offer immediate opportunities to reduce bronchiolitis morbidity. monthly administration of monoclonal antif anti body (palivizumab) throughout the rsv season reduces the inci dence of hospitalization due to rsv infection in infants with bronchopulmonary dysplasia, congenital heart disease, and pre maturity by about % (see chapter , respiratory syncytial virus). the high cost and modest effect of palivizumab limit its use for passive immunoprophylaxis to the most medically fragile infants. no vaccine to prevent infection with rsv or parainfluenza viruses, the most common causes of bronchiolitis, is licensed or near licensure. trivalent influenza vaccine is recommended for all infants older than months of age during the influenza season. because this is not approved for use in infants younger than months, routine influenza vaccination is important for family members and caregivers of these young patients. potential rsv vaccine candidates currently being evaluated include inactivated preparations of the purified fusion protein of rsv, dna vaccines coding for the major immunogenic proteins of the virus, and rep licating mutants of the virus that replicate in the upper respiratory tract but are inactivated at the higher temperatures of the lung. ribavirin is a nucleoside analogue with in vitro activity against rsv, adenovirus, influenza a and b viruses, and parainfluenza viruses. early trials indicated that ribavirin therapy was associated with modest improvement in clinical scores, oxygenation, and duration of mechanical ventilation for infants with severe bron chiolitis due to rsv infection. these studies were challenged on the basis that control groups received water aerosols, which may produce bronchospasm in individuals with hyperreactive airways. clinical trials with ribavirin have not demonstrated a consistent decrease in need for mechanical ventilation, decrease in length of stay in the intensive care unit, or reduction in days of hospitaliza tion. conflicting results from efficacy trials, concern about poten tial toxic effects among exposed healthcare professionals, aerosol route of administration, and high cost have all resulted in limited use of ribavirin. [ ] [ ] [ ] guidelines for the use of ribavirin in rsv disease are presented in chapter , respiratory syncytial virus. potential options for the treatment of bronchiolitis, if caused by influenza a or b viruses, are discussed in chapter , influ enza viruses. [ ] [ ] [ ] [ ] [ ] immune globulins and other therapies antibody preparations containing high titers of neutralizing anti body against rsv as well as a preparation of monoclonal antibod ies directed against one of the two major rsv surface glycoproteins (fusion glycoprotein) reduce the risk of hospitalization due to rsv infection. , used therapeutically, they result in more rapid clear ing of virus from the respiratory tract but do not alter the course of illness and should not be used for the treatment of rsv infection. [ ] [ ] [ ] [ ] [ ] although vitamin a levels have been demon strated to be low in infants with rsv bronchiolitis, a therapeutic benefit of vitamin a therapy has not been demonstrated. [ ] [ ] [ ] most otherwise healthy infants recover completely from acute bronchiolitis, although subtle pulmonary abnormalities can persist for weeks. diagnosis and management of bronchiolitis the burden of rsv infection in young children bronchiolitis associated hospitalizations among us children, - the epidemiology of acute respiratory tract infection in young children: comparison of findings from developing countries epidemiologic patterns of acute lower respiratory disease of children in a pediatric group practice a newly discovered human pneumovirus isolated from young children with respiratory tract disease incidence and etiology of pneumonia, croup and bronchiolitis in preschool children belonging to a prepaid medical care group over a fouryear period epidemiology of respiratory syncytial virus infection in washington, dc. i: importance of the virus in different respiratory tract disease syndromes and temporal distribution of infection differential detection of rhinovirus and enterovirus rna sequences associated with classical immunofluorescence assay detection of respiratory virus antigens in nasopharyngeal swabs from infants with bronchiolitis etiologic and clinical evaluation of acute lower respiratory tract infections in young argentinean children: an overview reducing the impact of viral respiratory infections in children parainfluenza viruses seasonal trends in human parainfluenza viral infections: united states studies on the role of viruses, bacteria and m. pneumoniae as causes of lower respiratory tract infections in children pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis review bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type infection in young children an outbreak of adenovirus type infection in children in montreal persistent adenoviral infection and chronic airway obstruction in children the etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice risk of primary infection and reinfection with respiratory syncytial virus national surveillance for respiratory syncytial virus, united states, - rehospitalization for respiratory syncytial virus among premature infants fatal respiratory syncytial virus infection in severe combined immunodeficiency syndrome selected populations at increased risk from rsv infections respiratory syncytial virus infection in children with bronchopulmonary dysplasia preterm twins and triplets: a highrisk group for severe respiratory syncytial virus infection annual variation in rsv season and decisions regarding immunoprophylaxis with palivizumab bronchiolitis associated mortality and estimates of rsv associated deaths among united states children - substantial variability in community rsv season timing distribution and clinical impact of human respiratory syncytial virus genotypes in hospitalized children over two winter seasons multicenter study of strains of respiratory syncytial virus occurrence of groups a and b of respiratory syncytial virus over years: associated epidemiologic and clinical characteristics in hospitalized and ambulatory children correlation between rsv genotype and severity of illness the unresolved issue of risk factors for hospitalization of infants with rsv infection born after - weeks gestation environmental and demographic risk factors for rsv lower respiratory tract disease daycare center attendance and hospitalization for lower respiratory tract illness longterm prospective study in children after respiratory syncytial virus infection relationship between urinary cotinine level and diagnosis in children admitted to hospital risk factors for respiratory syncytial virusassociated lower respiratory illnesses in the first year of life parental childhood respiratory illness and respiratory illness in their infants. group health medical associates airway response to a bronchodilator in healthy parents of infants with bronchiolitis respiratory syncytial virus related apnea in infants central apneas in infants with bronchiolitis admitted to the paediatric intensive care unit revised indications for the use of palivizumab and rsv immune globulin intravenous for the prevention of rsv infections revised indications for the use of palivizumab and rsv immune globulin intravenous for the prevention of rsv infections rsv immune globulin for prophylaxis against rsv disease in infants and children with congenital heart disease palivizumab prophylaxis reduces hospitalization due to rsv in young children with hemodynamically significant congenital heart disease prediction of the duration of hospitalization in patients with respiratory syncytial virus infection: use of clinical parameters duration of hospitalization in previously well infants with respiratory syncytial virus infection the effect of practice variation on resource utilization in infants hospitalized for viral lower respiratory illness predicting deterioration in previously healthy infants hospitalized with rsv infection clinical and physiological manifestations of bronchiolitis and pneumonia: outcome of respiratory syncytial virus radiologic appearance of viral disease of the lower respiratory tract in infants and children duration of illness in infants with bronchiolitis evaluated in the emergency department roentgenographic features of common pediatric viral respiratory tract infections respiratory syncytial virus: a comparison of diagnostic modalities efficiency of immunofluorescence for rapid detection of common respiratory viruses application of directigen flua for the detection of influenza a virus in human and nonhuman specimens simulfluor respiratory screen for rapid detection of multiple respiratory viruses in clinical specimens by immunofluorescence staining rapid diagnosis of respiratory viral infections by using a shell vial assay and monoclonal antibody pool use of pcrenzyme immunoassay for identification of influenza a virus matrix rna in clinical samples negative for cultivable virus detection of respiratory syncytial virus a and b parainfluenzavirus sequences in respiratory tracts of infants by a single pcr with primers targeted to the lpolymerase gene and differential hybridization rapid simultaneous diagnosis of infections with respiratory syncytial viruses a and b, influenza viruses a and b, and human parainfluenza viruses types , , and by multiplex quantitative reverse transcription polymerase chain reactionenzyme hybridation assay (hexaplex) bronchodilators for bronchiolitis decreased neutrophil betaadrenergic receptors in the neonate influence of the pattern of structural growth of lung on susceptibility to specific infectious diseases in infants and children effect of salbutamol on histamineinduced bronchoconstriction in healthy infants lung function and bronchial challenges in infants the effect of age on bronchodilator responsiveness effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis a randomized trial comparing the efficacy of epinephrine to salbutamol in acute bronchiolitis inhaled nebulized adrenaline improves lung function in infants with acute bronchiolitis assessment of bronchodilator responsiveness in infants with bronchiolitis: a comparison of the tidal and the raised volume rapid thoracoabdominal compression technique recent advances in the treatment of bronchiolitis and laryngitis bronchodilator responsiveness in infants with bronchiolitis bronchodilators for treatment of mild bronchiolitis: a factorial randomised trial oral versus nebulized albuterol in the management of bronchiolitis in egypt the use of albuterol in hospitalized infants with bronchiolitis a multicenter, randomized, double blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis efficacy of beta agonists in bronchiolitis: a reappraisal and meta analysis dexamethasone in salbutamoltreated inpatients with acute bronchiolitis: a randomized, controlled trial the effect of high dose inhaled corticosteroid on wheeze in infant after rsv infection: randomized double blind placebo controlled trial a multicenter randomized controlled trial of dexamethasone for bronchiolitis corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis longterm effects of prednisolone in the acute phase of bronchiolitis caused by respiratory syncytial virus early nebulized budesonide in the treatment of bronchiolitis and the prevention of postbronchiolitic wheezing efficacy of corticosteroids in acute bronchiolitis: shortterm and longterm followup efficacy of oral dexamethasone in outpatients with acute bronchiolitis oral prednisolone in the acute management of children age to months with viral respiratory infectioninduced lower airway disease: a randomized, placebocontrolled trial systemic corticosteroids in infant bronchiolitis: a metaanalysis epinephrine and dexamethasone in children with bronchiolitis costeffectiveness of epinephrine and dexamethasone in children with bronchiolitis committee on infectious diseases. reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections aerosolized ribavirin treatment of infants with respiratory syncytial viral infection: a randomized doubleblind study ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants prevention and control of influenza with vaccines neuraminidase inhibitors for treatment of influenza a and b infections use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza infection: randomized controlled trials for prevention and treatment clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, doubleblind, placebocontrolled european study zanamivir for treatment of symptomatic influenza a and b infection in children five to twelve years of age: a randomized controlled trial intravenous immunoglobulin treatment of respiratory syncytial virus infections in infants and young children controlled trial to evaluate protection of high risk infants against rsv by using standard intravenous immune globulin respiratory syncytial virus (rsv) immunoglobulin therapy for rsv lower respiratory tract infection in infants and young children at high risk for severe rsv infection respiratory syncytial virus immune globulin treatment of rsv lower respiratory tract infection in previously healthy children reduction of respiratory syncytial virus (rsv) in tracheal aspirates in intubated infants by the use of humanized monoclonal antibody to rsv f protein a randomized controlled trial of vitamin a in children with severe measles serum vitamin a levels in respiratory syncytial virus infection vitamin a and respiratory syncytial virus infection the relationship of childhood respiratory illness to adult obstructive airway disease pulmonary function changes in children after respiratory syncytial virus infection in infancy the relationship of rsvspecific immunoglobulin e antibody responses in infancy, recurrent wheezing, and pulmonary function at age - years asthma and wheezing in the first six years of life respiratory syncytial virus in early life and risk of wheeze and allergy by age years evaluation of combined live, attenuated rsv and parainfluenza virus vaccines in infants and young children key: cord- -p d t v authors: nan title: neocore conference abstracts date: - - journal: indian j pediatr doi: . /s - - -y sha: doc_id: cord_uid: p d t v nan neonatal conference on research and expert talks (neocore) is an annual conference jointly organized by departments of neonatology of sri ramachandra institute of higher education and research (sriher), chennai; christian medical college (cmc), vellore; and jawaharlal institute of postgraduate medical education and research (jipmer), puducherry. there had been three successful conferences conducted in turns since , with good response every time. the fourth annual conference 'neocore ' was conducted by sriher from march - , at chennai. the main objective of the conference is to encourage high-quality research in neonatology in india. the conference serves as a platform to present research works in neonatology to eminent faculty for critical appraisal. there was a total of abstracts for podium presentations, submitted by delegates from leading institutions across the country. gold medal and cash awards were given to the best five papers, that were selected based on the combined score from the evaluations based on a pre-defined scoring system of the blinded manuscript prior to the conference and podium presentation during the conference. in addition, there were expert talks by pioneer neonatologists from all over india. this included the 'dr r shanmugasundaram oration' on "traversing the journey from evidence to clinical practice" delivered by renowned neonatologist, professor siddharth ramji from maulana azad medical college, new delhi. there were expert talks and one debate. the audience were neonatology residents doing dm, dnb or fellowship, as well as practicing neonatologists. in view of travel restrictions due to covid- , two sessions were conducted using an online platform and they were attended online by many neonatologists across the country, in addition to the delegates of the conference. two pre-conference workshops were also conducted. one was 'research methodology and biostatistics -basic and advanced' with professor sourabh dutta, pgimer, chandigarh as the lead instructor. the second was an innovative workshop on 'next-gen learning', first of its kind in a medical conference, in which the delegates were taught advanced functions of basic softwares such as microsoft word, powerpoint and excel, research related softwares such as zotero and spss, online teaching platforms such as kahoot and moodle and search strategy for evidence. the lead instructors for the latter workshop were professor prakash, sriher, chennai, and dr nishad plakkal, jipmer, puducherry. over the years, we envisage neocore to serve as a desired platform for researchers in neonatology to look forward for presenting their high-quality research and to have expert talks based on the expert's own research. it gives us immense pleasure to announce the grand success of neocore under the patronage of professor vishnu bhat and professor binu ninan. we take this opportunity to invite you to participate in the fifth annual conference 'neocore ' to be held in cmc, vellore. it is a great honour and privilege to publish the abstracts of research papers presented in neocore in 'indian journal of pediatrics' and we extend our sincere thanks to the ijp publishers. papers awarded gold medal . comparison of the effect of non-nutritive sucking and cold compression on pain during heel stick procedure among preterm neonates-a randomized controlled trial soumi pal , sivam thanigainathan , vetriselvi p college of nursing, department of neonatology, jawaharlal institute of postgraduate medical education and research, puducherry corresponding author: sivam thanigainathan email: thanigaipaeds@yahoo.com importance: effective pharmacological and non-pharmacological methods are available to control pain. non-nutritive sucking is one of the non-pharmacological methods used widely in reducing pain but this method requires extra manpower in addition to the person doing the procedure. objective: to compare the effect of non-nutritive sucking (nns) and cold compression (cc) in reducing pain during heel prick in preterm neonates. design, setting and participants: this was an unblinded parallel randomized controlled trial, done in tertiary care neonatal unit. the authors recruited preterm infants ( in each group) ≥ wk gestational age, admitted in nicu. methods: after getting written consent from the parents, babies were assigned to either of two groups. for group babies (nns), mothers were instructed to wash their hands and to start non-nutritive sucking before min of the heel prick using her little finger. for group babies (cc), the cold compression was given to the baby using x cm size ice cubes covered by thin cling wrap sheet and was kept for s over the lateral aspect of the sole. physiological parameters and pain score using nips pain scale were measured before, during, after one minute, after two minutes and after min of the heel prick for both groups. results: group and group had equal distribution of gender, birth weight and gestational age. there was no difference in the severity of pain perception during and one minute after the prick (p . and . respectively) between two groups. but, mild to moderate pain persisted till min after the heel prick for group babies than group babies ( . % vs. . % respectively, p . ). after min of prick, no baby was in pain. conclusions and relevance: more babies perceived pain for more than two minutes after heel prick in cold compression group than in nns group. hence, non-nutritive sucking was more effective in reducing the pain due to heel prick than cold compression. objective: to compare the incidence and severity of nasal injury at the removal of cpap in the two groups (hudson prong and ram cannula). patients and methods: neonates with gestational age between - wk and birth weight ≥ g and with respiratory distress needing nasal cpap were enrolled. enrolled infants were randomly allocated to either cpap with hudson prongs or with ram cannula using computer generated random numbers. appropriately sized prongs were used in both the groups. cannula id was used for creating zero leak at nostril in the ram group. all enrolled infants were monitored and assessed for nasal injury using a standard nasal injury score every hourly. relevant infant data was collected prospectively from admission till discharge. results: two hundred twenty nine infants were enrolled. of these, infants were randomized to ram cannula and infants to hudson prongs. both groups were comparable for all the baseline characteristics. any nasal injury at cpap removal was significantly lower in the ram cannula group [n= ( . %) vs. n= ( . %), p= . ]. moderate nasal injury was present in ( . %) infants in the hudson prongs group. none of the study infants had severe nasal injury. any nasal injury at discharge was lower in ram group [n= ( %) vs. n= ( . %) p= . ]. need for mechanical ventilation in the first h was similar between the two groups [ram cannula . % vs. hudson prongs . % p= . ]. nasal interface was changed in infants in hudson prongs and in infant in the ram group. the median duration of cpap was higher in the ram group, p= . . conclusions: for preterm infants supported with nasal cpap, any nasal injury was significantly lower in infants with ram cannula compared to hudson prongs. objective: to study the effect of prophylactic % oral dextrose gel on prevention of neonatal hypoglycemia in infants of diabetic mothers (idm) compared to the standard of care (early, prolonged and frequent breastfeeding with strict thermoregulation). this was an open label, parallel design, randomized controlled trial, done in a tertiary care neonatal unit. infants of diabetic mothers born in authors' unit with > wk and > kg and not requiring admission were enrolled in this study. total babies were randomized to either the study group or the standard of care group. after randomization, mg/kg of % oral dextrose gel was applied to the buccal mucosa of infants in the study group. the standard of care including breastfeeding within - min of birth, prolonged as well as frequent breastfeeding, and strict thermoregulation were followed in both the groups. blood sugars were checked as per unit protocol till h of life. infants with symptomatic, severe or recurrent hypoglycemia were admitted to nicu and the same treatment protocol was followed for both the groups. results: incidence of hypoglycemia in study group and control group were % and % respectively (p . ). there was no difference in neonatal admission due to hypoglycemia, incidence of recurrent and severe hypoglycemia between two groups. incidence of hyperglycemia was more in the study group (p . ) conclusions: prophylactic use of oral % dextrose gel is not superior to standard of care in reducing the incidence of hypoglycemia in idm infants. *** background: among term and late preterm infants, hypoxic ischemic encephalopathy (hie) contributes to % of all neonatal deaths in india. objectives: the primary objective was to study the incidence of survival to discharge among late preterm and term infants with moderate or severe hie. secondary objectives were to explore variation in hie across participating sites and to identify the predictors of survival. methods: it was a retrospective cohort from innc database. survival to discharge was estimated for the whole cohort and individual centers. a multivariable logistic regression model was constructed to identify the predictors of survival. p < . was considered significant. results: of term ( - wk) and late preterm ( - wk) infants with moderate or severe hie from - , % survived to discharge. % of these infants received therapeutic hypothermia (th). phase change material based devices were most commonly used for th. after adjusting for confounders, severe hie (aor . ; % ci . - . ) and pphn (aor . ; % ci . - . ) were independently associated with decreased odds of survival to discharge. objective: family-centered care (fcc) in the neonatal intensive care unit (nicu) facilitates mother-infant bonding with potential benefit for the parents and infants. in this quality improvement initiative (qi), authors planned to effectively implement fcc (defined as proportion of eligible infants receiving fcc on a daily basis) from a baseline of % to % among stable infants admitted in level- nicu over a period of mo through parental education and parental capacity building. methods: this qi is based on a model for improvement and done in three phases; baseline ( mo), intervention (three months) and post-intervention period ( mo) from august to january . neonates admitted in level- nicu were eligible for fcc if they had at least one female family member willing to allocate h a day for neonatal care. neonates with major malformations, hemodynamic instability and those requiring respiratory support were excluded. in pdsa cycle- authors created educational videos for parents in tamil language familiarizing them with nicu, preparing them for entry to nicu and how they could contribute to their infant's care. this was reinforced with one-to-one training by the bed-side nurse on general care, feeding and kangaroo care. in pdsa cycle- , authors identified fcc champions among mothers and facilitated peer teaching and motivation. the primary outcome was the proportion of eligible neonates receiving fcc. results: the proportion of eligible mother-infant dyads involved in fcc increased from a mean of % in baseline phase to % during intervention phase and further to % in post intervention period. the authors did not observe an increase in culture positive sepsis ( per nicu admissions at baseline) or any inadvertent event during the study period. feed interruptions may result in extra uterine growth retardation-a known risk factor for poor neurodevelopmental outcome, especially in vlbw babies. in view of this, a team was assembled and a qi project was initiated with the primary objective being reduction in unnecessary feed interruptions objectives: the primary objective was reduction in unnecessary feed interruptions as part of a quality improvement initiative. the secondary objective was to develop and maintain a written feeding policy to ensure sustained compliance. methods: this project was undertaken in a level iii nicu, catering exclusively to outborn neonates. a qi team was assembled and after a fishbone analysis of problems were identified, a written feeding policy was developed. after three pdsa cycles and looking at run charts for feedback, feed interruption rates were recorded post intervention. results: post intervention, the total feed interruptions reduced from a baseline to . the total rate expressed as a percentage of interruption hours and feed hours reduced from a baseline % to %. conclusions: the implementation of the qi initiative significantly decreased the feed interruption rates from % to %. *** . assessment of age of achievement of full oral feeding and its associated factors among very preterm neonates -a prospective observational study saswati bhowmick , p. vetriselvi , sindhu sivanandan department of nursing and neonatology, jipmer, puducherry corresponding author: sindhu sivanandan email:drsindhusivanandan@gmail.com importance: competency at oral feeding is a must for hospital discharge among preterm neonates admitted to nicu. they are at risk of various morbidities during hospital stay that influences achieving feeding milestones. objectives: this study aimed to assess the progression of feeding milestones and factors influencing the age of achievement of full oral feeding in very preterm neonates ( - wk of birth ga) admitted to nicu. methods: this prospective observational study included very preterm neonates admitted in nicu during august and september . the authors used a convenient sampling technique that enrolled neonates tolerating any volume of milk for three consecutive days. they excluded neonates with major congenital malformations, craniofacial anomalies, surgical conditions of gastrointestinal tract and death during hospitalization. the authors collected data on demographics, morbidities and feeding milestones during hospital stay after obtaining informed parental consent. the feeding milestones assessed were, age at first enteral feeding, full enteral feeding, first oral feeding, and full oral feeding. results: fifty six neonates belonged to - wk ga category and to - wk ga category. the pma of initiation and achievement of full oral feeding were (mean ± sd) . ± . and . ± . wk respectively. infants belonging to the - wk ga category required gavage feeding for a longer duration compared to those belonging to the - wk ga category ( . ± . vs. . ± . d). however, both the ga categories achieved full oral feeds at similar pma ( . ± . wk compared to . ± . wk). conclusions: in this study, the age of achievement of full oral feeding among very preterm neonates was wk. although the duration of gavage feeding was greater among - wk category, this group also achieved full oral feeding at wk pma despite being at higher risk of morbidities. *** . a quality improvement project to improve functioning of donor human milk bank sylvia jabakani, divya p, krishma k, vijaya calevanane, bethou adhisivam, sindhu sivanandan department of neonatology, jipmer, puducherry corresponding author: sindhu sivanandan email: drsindhusivanandan@gmail.com background: mother's milk is the ideal food for a neonate. when mother's milk is unavailable for any reason, pasteurized donor human milk is the next best option. objective: this quality improvement project evaluated the effect of a multipronged intervention for improving voluntary donation in a public human milk bank (hmb) in south india. methods: between january and june , the hmb received an average of l of donor milk per month ( . l/d). the aim was to increase voluntary milk donation by % from baseline over a period of mo using qi methods. two pdsa cycles were done during the intervention period ( mo). in cycle- , multiple micro teams were formed in all the postnatal wards to promote exclusive breastfeeding, troubleshoot breastfeeding issues and to form a liaison with the core qi team. a whatsapp group was used for networking among the teams. a separate milk expression area was created in the postnatal ward. in cycle- authors focused on counselling postnatal mothers for milk donation and addressed supply chain issues like sterile pumping accessories. the qi efforts were sustained in the post intervention phase ( mo) by monthly staff appraisal and feedback. results: the average daily donation to hmb increased from . l/d in the baseline phase to . and . l per day in the intervention and postintervention phases. the volume of pasteurized donor milk disbursed from hmb increased from . ( . ) l/mo to . ( . ) l/mo; p= . after qi. the number of mothers donating milk per month did not change significantly during the study period. background: postnatal growth failure (pgf) is a major morbidity of vlbw infants, which can have long term effects. objective: the primary objective was to reduce the pgf rate of vlbw infants by %. methods: this was a quality improvement project in a tertiary care nicu. the authors included all inborn vlbw infants not having major congenital anomaly or genetic and metabolic disorders. baseline phase was november and december of and intervention phase was between january and july. interventions included introduction of new feeding protocol, feedback for the stakeholders in person or via messages, education of mothers for breastfeeding and kangaroo mother care, peer group teaching by mothers and providing tags for adequately growing babies. progress was plotted in run charts. spss and ms excel were used for the analysis. results: study sample included infants ( . % males) in baseline phase and infants ( . % males) in the intervention phase and infants in sustenance phase ( . % males). the mean gestation was . , . and wk during the baseline, intervention and sustenance phase respectively. pgf decreased from . %to % and sustained at %. time to first feed decreased by h and mean age at reaching ml/kg/d of feeds decreased by d and time to regain birth weight decreased by d. incidence of mortality, nec, anemia requiring transfusion, pda and metabolic bone disease did not change significantly during the study. conclusions: pgf can be reduced by systematic feeding protocol and by quality improvement methods. *** background: among term and late preterm infants, hypoxic ischemic encephalopathy (hie) contributes to % of all neonatal deaths in india. therapeutic hypothermia is the standard of care in term infants with hie but has been shown to provide up to % neuroprotection in moderate to severe hie. additional neuroprotection may be achieved by using concomitant pharmacological neuroprotective agents. the neuroprotective role for the magnesium sulfate therapy given to at-risk mothers for preterm birth for the preterm fetus is well established now. objectives: primary objective: to compare the composite outcome of neonatal mortality or abnormal neurodevelopmental outcome ( y of age) among term infants with hie treated with magnesium sulfate and therapeutic hypothermia (group a) and therapeutic hypothermia alone (group b). secondary objectives were to compare the neonatal mortality, neurodevelopmental disability at y of age, hospital course and adverse effects of magnesium sulfate. methods/design: parallel group randomized controlled trial. results: the baseline characteristics were comparable between the intervention and comparator group. a total of infants died or had abnormal neurodevelopmental outcomes at y of age in the magnesium and therapeutic hypothermia group as compared to infants in the therapeutic hypothermia alone group. however the difference was not statistically significant (p value . ; relative risk . ; % confidence interval . - . ). conclusions: the combination of magnesium sulfate and therapeutic hypothermia did not improve the composite outcome of neonatal mortality and neurodevelopmental outcome at mo of age. the dose of mg/kg/dose once every h for d did not result in the adverse effects like hypotension or respiratory depression requiring assisted ventilation, however, it caused hypermagnesemia in the intervention group. *** . d speckle tracking echocardiography derived deformation imaging in very preterm neonates-a prospective exploratory study sreedhara ms, prakash a, umamaheswari b, ashok c department of neonatology, sri ramachandra institute of higher education and research, chennai corresponding author: prakash a email: draprakash @gmail.com background: deformation imaging by d speckle tracking echocardiography is a promising tool for cardiac assessment of preterm neonates. objectives: to assess the . feasibility and reproducibility of deformation imaging . normal pattern of global longitudinal strain (gls) . usefulness of gls in predicting the need for pda treatment and development of bpd. methods: very preterm neonates were recruited prospectively. echocardiography was performed by a single investigator at - , - & - d of life and at wk pma or before discharge using philips cx machine. strain quantification in apical -chamber loops was done using q lab tm software. reproducibility was evaluated by repeating the analysis on % of images by the primary investigator and a cardiologist. . ( . ), . ( . ), . ( . ) respectively at predefined time points. repeated measures of anova did not show any change in gls over time. icc for intra-observer and inter-observer agreement for gls-lv and gls-rv were . , . , . and . respectively. gls-lv at - d predicted pda treatment (p= . ) and gls-rv at - d (p= . ) and at - d ( . ) predicted bpd by multivariate analysis. conclusions: deformation imaging is feasible in very preterm neonates with good reproducibility. lv-gls and rv-gls within h predict pda treatment and bpd respectively. *** . non-invasive bilirubin sensor for continuous monitoring and automatic control of phototherapy for infant jaundice treatment akshaya j , k ragadeepthi , vijitha venugopal , prakash amboiram , angeline kirubha sp biomedical engineering, srm institute of science and technology, chennai; department of neonatology, sri ramachandra institute of higher education and research, chennai corresponding author: angeline kirubha sp email: angeline.sp@ktr.srmuniv.ac.in abstract: measurement of bilirubin content in neonates at an early stage is important to prevent any serious illness such as jaundice. jaundice meter that can determine bilirubin count is widely used as a diagnosis procedure and the treatment procedure includes phototherapy, which uses blue light to break down the bilirubin by isomerization. both the diagnosing and treatment procedures are manual methods which require external assessment. in order to make both the procedures automatic, the non-invasive bilirubin sensor has been designed which is compact for continuous monitoring of bilirubin values. based on bilirubin value measured by sensor, light intensity of phototherapy setup can be altered using machine learning and iot technology. the non-invasive bilirubin sensor follows spectro-photometry principle. a machine learning algorithm is developed in order to provide high speed optimization and control of the overall application. various aspects like the bilirubin count, severity of fever, saturation of skin pigment, etc. will be used as a predetermine input for the ml algorithm, based on which, the measures for various treating parameters will be controlled. the microprocessor will offer the system to run as a standalone application and aids to update the results to a cloudbased server-client (iot) system for the hospital to maintain and organize patient records. *** . cerebroplacental ratio percentile -a predictor of adverse pregnancy outcome sunantha perumal, chitra andrew division of fetal medicine, department of obstetrics & gynecology, sri ramachandra institute of higher education and research, chennai corresponding author: chitra andrew email: chitraandrew@gmail.com aim: to evaluate the predictive efficacy of cerebroplacental ratio (cpr) percentile in third trimester to identify fetuses at risk of adverse pregnancy outcome and to compare with the conventional parameters estimated fetal weight, umbilical artery pulsatility index and cerebroplacental ratio (cutoff < ). methods: this was a retrospective cohort study done between september and september , at fetal medicine unit, sri ramachandra medical centre. following approval from the ethics committee, women with a single non-anomalous fetus, delivered within wk of fetal doppler study in the third trimester were included in the study. the parameters efw (< th centile), ua-pi (> th centile) and cpr (< th centile) were calculated. perinatal outcomes assessed were intrapartum ctg abnormalities, operative delivery for fetal distress, preterm delivery, low birth-weight (bw) centiles, and a composite neonatal outcome. statistical indices calculation and results analysis was done using spss software version . results: cpr (< th centile) had a sensitivity of %. when all parameters were normal, pregnancies had adverse outcomes. cpr percentile values were abnormal in of them ( %). combination of cpr and efw had high specificity of . % and positive predictive value of . %. conclusions: comparatively, cpr percentile is a better predictor of adverse outcome and can be affected earlier in fetal hypoxia, than other parameters. the addition of cpr percentile to efw improves the positive predictive value of the test which can be used to optimize the perinatal outcome without increasing unnecessary interventions. *** . effect of hydrocolloid dressing on nasal injury among preterm neonates on nasal continuous positive airway pressure (ncpap): a randomized controlled trial takhelmayum bideshwori , nishad plakkal , p vetriselvi college of nursing, jipmer; department of neonatology, paediatric c.o.n, jipmer corresponding author: nishad plakkal email: plakkal@gmail.com importance: nasal continuous positive airway pressure (ncpap) is widely used in management of respiratory distress. preterms are at high risk for nasal injury during ncpap. objectives: to assess the effect of hydrocolloid dressing, when compared to petrolatum jelly (vaseline®) application, on nasal injury among preterm neonates on ncpap and to identify the association of nasal injury with their clinical characteristics. design, setting and participants: this randomized controlled trial was conducted at nicu, jipmer. seventy-eight preterm neonates with gestational age - wk receiving ncpap > h were consecutively enrolled and randomly allocated to treatment (hydrocolloid, n= ) or control group (vaseline, n= ). methods: in group , hydrocolloid dressing was cut to a length of - cm with two holes applied around the nostril before ncpap was connected. in group , vaseline was smeared around the nostril before ncpap was connected. assessment was done at baseline and once daily, until wk of age or when ncpap was discontinued, whichever was earlier. the dressing in group was changed daily; petrolatum was applied during assessment as per standard practice. the skin, nasal septum and nostrils were examined, and findings were recorded, along with a clinical photograph. results: fourteen preterm neonates (hydrocolloid= and control= ) developed nasal injury. the difference was not statistically significant [in group , normal= ( . %) and mild= ( . %); in group , normal= ( . %), mild= ( . %) and moderate= ( . %)]. no infant in the study had severe injury. an association between the level of nasal injury and duration of ncpap (p < . ) in the hydrocolloid group was noted. conclusions: although not statistically significant, there was a reduction in each level of nasal injury and overall incidence with the use of hydrocolloid dressing. objectives: to determine the effect of time to reach full feeds ( ml/ kg/d) on mortality and morbidity among preterm neonates and factors influencing the time to reach full feeds. methods: this prospective observational study was conducted in a level iii nicu, department of neonatology, iog from july to january , and included preterms - wk. results: out of the preterms, babies were started exclusive enteral feeding on day reaching full feeds within h with . % survival, mortality being significantly less (p < . ). the incidence of culture positive sepsis was less in babies reaching full feeds within h ( . %) with a significant less usage of antibiotics [median duration of ( , ) d] vs. babies taking > d [ . %culture positive sepsis, ( . , ) d of iv abx.]. the incidence of pda ( . %), ivh ( . %), rop ( . %), bpd ( %), nec ( %) & inotropic requirement ( . %) was significant less in the babies reaching full feeds earlier whereas the same being %, %, %, %, % & % respectively for babies reaching full feeds > d; the duration of nicu stay & ventilation being significantly shorter in babies reaching full feeds earlier. doppler abnormality, sga < rd centile, steroid coverage and hie had no influence on time to reach full feeds. conclusions: early attainment of full enteral feeds reduces the mortality, culture positive sepsis, nec, pda, ivh, rop, bpd, inotropic requirement, duration of ventilation, iv antibiotics and hospitalization. *** . what are the factors associated with necrotizing enterocolitis in a developing country? a multicenter collaborative study gokuldas punnadan koroth , nivedita mondal , sreekumaran nair , nishad plakkal department of neonatology and medical biometrics and informatics, jipmer, puducherry corresponding author: nishad plakkal email: plakkal@gmail.com background: necrotizing enterocolitis (nec) is a serious morbidity of preterm infants. objective: the primary objective was to identify the incidence of nec in infants < wk or with very low birth weight (bw < g). design/methods: setting: the indian neonatal collaborative (innc) is a network of neonatal units in india. design: retrospective cohort; infants born at < wk or bw < g in - were included. analysis: after descriptive statistics, multivariate logistic regression model was constructed to identify potential predictors. stata was used for analysis. results: two thousand six hundred thirty two infants from centers were included ( . % males). the mean gestation was . wk (iqr - wk) and mean birth weight was g. seventy six infants developed nec (incidence . %). among infants with nec, mean gestational age was . wk and mean bw was g. mortality was . % in infants with nec, compared to . % in infants without nec. among sites, the incidence of nec varied from % to . %. after adjusting for potential confounders in the regression model, antenatal doppler abnormalities (aor . ; % ci . - . ) and neonatal sepsis (aor . ; % ci . - . ) were independently associated with increased odds of nec, and higher bw was associated with lower odds (aor . ; % ci . - . ). conclusions: the incidence of nec in this cohort of infants was . %. nec increased with sepsis, antenatal doppler abnormalities and lower birth weight. large inter-center variation in nec was noted. *** outcomes such as cognitive, language, gross and fine motor development, behavioral and emotional regulation. programs that are culturally appropriate, independent of literacy, easily understood and implemented are lacking in our population. objectives: to develop an educational-behavioral program on early intervention for parents of preterm infants admitted in the neonatal icu. also to evaluate the effectiveness of this program in reducing maternal stress, anxiety and improving parent-infant bonding. study design: prospective phase lag interventional cohort trial methodology: this is a preliminary report. mothers of preterm infants (≤ wk and birth weight < g) with working knowledge of english or tamil were recruited. a wk pictorial educational behavioral program was developed entitled "parent administered neuro-developmental activities (nicu-panda)". mothers attended sessions of min each in addition to standard care. pre and post tests were done at recruitment and after wk using the state-trait anxiety inventory (stai), parental stress scale (pss-nicu) and postpartum bonding questionnaire (pbq). results: twenty-three mothers completed the intervention program. there was a significant reduction in the mean anxiety (p < . ), stress (p < . ) and improved postpartum bonding (p < . ) between the pre and post-test scores using stai, pss-nicu and pbq respectively. the post-test scores were not associated with any maternal or infant demographic variables except length of hospital stay. conclusions: the parent-mediated early intervention program which was developed was found effective in reducing anxiety, stress and improving postpartum bonding for the mothers of preterm infants in nicu. *** . effect of early sodium supplementation in preterm neonates between and weeks of gestational age on postnatal weight gain: a double blinded randomized controlled trial anvesh amiti, prakash a, umamaheswari b, usha devi r, abdhul gani department of neonatology, sri ramachandra institute of higher education and research, chennai corresponding author: prakash a email: draprakash @gmail.com objectives: to compare velocity of weight gain (g/kg/d) at wk pma in neonates born between + and + wk of ga with early sodium supplementation vs. placebo. methods: this double blinded rct was conducted in a level iii tertiary nicu and included neonates + to + wk ga who had reached minimum of ml/kg/d feeds and between and dol and with serum sodium < mmol/l. neonates with major malformations incompatible with life, gastrointestinal anomalies, npo and renal insufficiency were excluded. intervention group received enteral meq/kg/d of % sodium chloride equally distributed in all feeds and control group received . % saline of similar volume. weekly growth velocities of weight, length and hc were taken. results: interim analysis was done for this study. total neonates were eligible for the study; parents were not given consent, neonates did not reach feed volume ml/kg/d, neonates had sodium > and hence were excluded. so, the authors enrolled neonates for the study. out of them, currently the study is ongoing on neonates. finally, total neonates ( -intervention, -study group) were included for analysis. there was no statistical difference in baseline variables except for mode of delivery. median weight gain velocity (g/kg/d) was higher in intervention group . (iqr: . - . ) compared to control group . (iqr: . - . ) and it was statistically significant (p value- . ). no difference was found in other secondary outcomes like weekly length and hc velocities, duration of ventilation, bpd, rop, ivh, and days to reach birth weight. conclusions: early sodium supplementation improves short term weight gain at wk of pma. larger studies are required to see long term outcomes and adverse effects. *** background: most neonatal intensive care units (nicus) use fortified human milk but specifics of timing, composition, and advancement of feeds vary. as per the evidence available, early fortification of human milk improves postnatal growth, improves protein, calorie and mineral intake without any significant issues of nec and feed intolerance. however, data regarding long term growth and neurodevelopment remains inconclusive. objectives: to study the efficacy of early vs. delayed human milk fortification in very low birth infants and its effect on anthropometry and morbidities. methods: very low birth weight preterm babies (n = ) were prospectively randomized to early fortification (ef) (beginning at a feeding volume of ml/kg/d) or delayed fortification (at a feeding volume of ml/kg/d). the authors employed a standardized feeding protocol and parenteral nutrition guidelines for the nutritional management of all study infants. results: the median duration of tpn was equivalent in the groups ( vs. . d; p= . ). no significant difference was observed in the total number of episodes of feeding intolerance and necrotizing enterocolitis. median ofc gain velocity (cm/wk) was significantly higher in ef group introduction: surfactant is essential to normal lung function in babies. policy of early rescue should be standard i.e., within h of birth. it is commonly seen that there is a delay in administering surfactant. objective: the authors aimed to identify the reason of delayed dosing and clinical implications of the same by an observational study. materials and methods: all babies who received surfactant over a year were included in the study. babies with congenital anomalies were excluded. quantitative data was expressed in percentage and central tendency was expressed in median. mann whitney test was done for evaluation of difference in outcome. p less than . was considered significant. results: total neonates received surfactant; % received delayed surfactant. median gestational age for early group was wk and late group was wk respectively. primary respiratory support was cpap in . % babies, intubation in . % babies and oxyhood in . % babies who eventually received surfactant. mann whitney test was done to find the difference in duration of respiratory support, which was found to be statistically significant (p= . ). main cause of delayed surfactant in inborns was due to persistent / progressing distress on cpap ( . % of inborn babies who received late) and in outborns due to delay in transport from referral hospital ( . %) and no cpap ( . %) as initial respiratory support. conclusions: clinicians must be aware of early use of cpap and early transport to facilitate early surfactant. one must also be aware on use of surfactant in view of persistent or worsening distress and not just fio requirement to give surfactant. objective: to analyze the perinatal outcome of antenatally detected fetal intra-abdominal cysts. methods: this was a retrospective study of fetuses with intra-abdominal cysts on antenatal scans done between january and december at sri ramachandra medical centre. data was collected from the ultrasound database. maternal, fetal, and neonatal characteristics were retrieved from the electronic patient records and through telephonic enquiry. results: a total of fetuses were diagnosed with intraabdominal cysts antenatally; mostly in third trimester. of these, there was one ongoing pregnancy, two lost to follow up, three pregnancy losses and live births. isolated cysts were seen in ( %) fetuses and five ( %) had associated abnormalities. cyst regression was observed in utero in two ( %) and postnatally in cases. postnatal diagnosis was not made in ten cases. there were more girls than boys ( girls and boys) in this study. ovarian cysts were diagnosed in % of cases with persistent cysts. most pregnancies ( %) were managed conservatively and % underwent surgical management. conclusions: isolated cysts have good outcome. those with associated abnormalities are likely to have poor prognosis. cysts are common in girls and are usually ovarian cysts, which can regress in utero or postnatally. gastrointestinal tract abnormalities are mostly observed in boys and are likely to have good outcome following surgical management in the immediate postnatal period. antenatal detection of intra-abdominal cystic lesion helps to offer appropriate antenatal and postnatal follow up and management. *** received nephrotoxic drugs (p < . ). duration of hospital stay (days) in aki group was . ( . ) compared to non aki group, . ( . ), p= . . on logistic regression, use of nephrotoxic drug was found to be the single most risk factor with or . ( % ci: . - . ). conclusions: male sex, sepsis and nephrotoxic medications are independent risk factors for aki. use of nephrotoxic medication is the single most important risk factor for aki. *** . knowledge, attitude and practices in breastfeeding among health care professionals in a tertiary care centre ajinkya wazurkar, nalini, neelam sundara raghupathy department of pediatrics, avmch puducherry, vinayaka mission's research foundation university, salem corresponding author: nalini email: nallu_ @yahoo.co.in importance: mothers should be instructed about baby's hunger cues, proper positioning and attachment, feeding frequency and counselling regarding problems faced during breastfeeding. health care professionals can play an important role in this aspect. objective: to assess knowledge attitude and practices of health care professionals in breastfeeding through a pre-validated questionnaire in avmch, puducherry. methods: pre validated open ended questionnaire was given to all the participants comprising faculty, postgraduates, staff nurses, interns, final year mbbs and nursing students. results: out of participants, mean knowledge score was highest among faculties which was . % (range . to . %) and mean practice score was . % ( . to %) and lowest among bsc final year nursing students where mean knowledge score was . % ( . to %) and mean practice score was . % ( . to . %). there was a statistical difference (p value < . ) between combined knowledge and practice scores of interns, final year mbbs and nursing students. participants were having lack of knowledge especially about contraindication of breastfeeding among nursing final year students ( . % score), staff nurses ( . %) and mbbs students ( . %). attitude had been assessed by likert scale, where faculty and postgraduates were having good attitude regarding all questions asked, whereas among other participants some lack of attitude was observed. conclusions: in this study, gaps in knowledge and practices among health care workers was identified. in professional students it is evident that there should be improvement in knowledge through proper teaching and they should be taught skills for practices, for example, proper positioning and attachment for breastfeeding. counselling efforts were lacking. *** . effect of antenatal corticosteroids (acs) in neonatal mortality and morbidity in preterm - weeks small for gestational age (sga) infants when compared to non-sga infants: a retrospective single centre cohort study p ajai kumar, mangalabharathi sundaram, prakash vinayagam department of neonatology, institute of obstetrics and gynecology, madras medical college, chennai corresponding author: mangalabharathi sundaram email: drmangalabharathi@gmail.com introduction: maternal antenatal corticosteroid (acs) administration in preterm labor reduces the incidence of neonatal respiratory distress syndrome (rds) and neonatal mortality. acs usage is the most effective intervention for these risks associated with preterm birth but current recommendations for acs use do not differentiate between sga and non-sga fetuses. objectives: to analyze neonatal outcomes in sga and non-sga preterm infants with acs usage. methods: a retrospective database analysis was performed for preterm infants ( - completed wk) born in july -september . clinical details, weight for gestational age, mortality and major adverse events were noted. analysis was done with chi square, fischer's and t-test. results: one hundred ninety six preterm infants were included in the study. there were non-sga infants and sga infants, with acs usage of and respectively. there was no difference in mortality between sga and non-sga with acs usage (or . , %ci . to . p= . ) there were no significant differences in incidence of rds (or . , %ci . to . ), nec, pda, rop and ivh. conclusions: usage of acs in sga fetuses at risk of preterm delivery does not lead to worse perinatal outcome. *** validation of winrop for prediction of severe retinopathy of prematurity among preterm less than weeks-a diagnostic study . follow-up rates in a three-year longitudinal study of neurodevelopmental outcomes of a preterm cohort in south india acute kidney injury in neonates in level nicu-a matched case control study methods: children (n= ) born ≤ wk ga or between - wk with significant risk factors, enrolled in a child development unit formed the sampling frame. families were contacted over the phone for enrollment and follow-up. field and research assistants conducted developmental screening and assessments respectively at -, -and -mo. appointments were rescheduled as needed and reasons for missing appointments were documented. home visits were made for families who consented to participate but were unable to visit the clinic. results: among the children enrolled at -mo ca, ( %) and ( %) children completed participation at -and -mo respectively. follow-up rate at the clinic was % and % respectively. the reasons for home-visits and loss to follow-up differed at different timepoints. families with twins/ triplets requested home visits at enrollment. subsequent pregnancy of the mother and child going to school/presence of a younger sibling at home were reasons for the inability to visit the clinic at -and -mo respectively. timely scheduling, multiple reminders and rescheduling facilitated follow-up clinical and investigation data were extracted from medical records. risk factors were analyzed using multivariate logistic regression. results: total cases and controls were enrolled for the study. incidence of aki was . %. among aki patients, ( . %) were males. mean birth weight (sd) in kilograms of aki group was . ( . ) and . ( . ) among non-aki group. the incidence of aki was higher in those who received nephrotoxic drugs background: poor postnatal weight is a risk factor for rop. winrop (weight, igf , neonatal rop) algorithm is an online tool which predicts the risk for severe rop (type ) based on gestational age, birthweight and weekly weight gain. objective: to validate the diagnostic accuracy of the winrop (https:// winrop.com/) in predicting type i rop. methods: diagnostic study design was conducted among babies < wk gestation born between jan and dec with weekly weight and final rop status available. based on weekly weight, algorithm signaled an alarm to indicate high risk for type rop. from rop requiring treatment, sensitivity, specificity, ppv and npv were calculated. results: a total of babies were included with a mean gestational age of ± . wk and mean birth weight of ± g. sixty three ( %) developed type rop and ( %) developed type rop. the median time from birth to alarm was wk (iqr - wk) and alarm to treatment was . d (iqr . - . ). overall sensitivity of winrop for type rop was %, specificity %, ppv %, npv . %, lhr (+) was . . among less than wk, sensitivity was % and npv . %. conclusions: winrop is a useful non-invasive tool for screening, particularly in babies less than wk in early identification of type rop. *** . follow-up rates in a three-year longitudinal study of neurodevelopmental outcomes of a preterm cohort in south india lakshmi venkatesh , adhirai garibaldi , roopa nagarajan , binu ninan , udayakumar narasimhan , prakash boominathan key: cord- -er ug w authors: maayan-metzger, ayala; itzchak, amir; mazkereth, ram; kuint, jacob title: necrotizing enterocolitis in full-term infants: case–control study and review of the literature date: - - journal: j perinatol doi: . /sj.jp. sha: doc_id: cord_uid: er ug w objective: to examine the increasing number of full-term infants at our hospital exhibiting necrotizing enterocolitis (nec) in order to characterize these cases and to discover common risk factors. methods: medical charts were reviewed for all full-term infants (gestational age > weeks) that were born in our institution during a -year period (from january , to december , ) and that developed definite nec. data regarding the rate of cesarean section (cs) in our institution over the study period and five years prior to the study was also recorded. results: during the years of the study, full-term infants were found to have nec. the incidence of nec in full-term infants increased from . to . per live births in the -year period. mean birth weight was g. all the nec infants except one were delivered by cs, and all of them were fed either with a mixture of breast milk and formula or entirely by formula. seven of the infants ( %) had no major known risk factors predisposing them for nec. mean age of disease onset was very early ( . days) in most of the infants ( infants), and the colon was the main nec site. the short-term outcome was favorable in all but one case, which required explorative laparotomy for intestinal perforation. the number of infants born by cs has been steadily increasing, and was almost three times greater during the study period in comparison to the preceding years. conclusions: the etiology of nec in the full-term population seems to differ from the etiology for the preterm group in its intestinal location and in the timing of its onset. the increase in the rate of cs over the years might be related to the concurrent increase in nec, and this relationship should be further investigated. the most important risk factor for necrotizing enterocolitis (nec) is prematurity. nonetheless, the incidence of nec among the population of very low birth weight (vlbw) infants at our hospital has been decreasing over the years, as has the incidence of mortality and morbidity from this disease. over the past years, however, our hospital has experienced an increase in the incidence of full-term babies exhibiting nec. nec in full-term infants is well documented, accounting for about % of babies with nec; it usually involves babies with known risk factors, such as intrauterine growth retardation (iugr), birth asphyxia, congenital heart disease, gastroschisis, polycythemia, hypoglycemia, sepsis, exchange transfusion, umbilical lines, milk allergy, premature rupture of membranes with and without chorioamnionitis and gestational diabetes. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the purpose of the current study was to characterize this group of full-term infants with nec, to discover whether there are any common known risk factors, and to review the relevant literature. medical charts were reviewed for all full-term infants (gestational age > weeks) that were born in our institution from january , to december , and that developed definite nec. for the purpose of this study, only the files of those babies exhibiting bell stage ii and beyond were reviewed. for those babies, all relevant maternal and infant details were recorded, including details of maternal illnesses and drugs during and prior to the pregnancy, mode of delivery, birth weight, sex, apgar scores, type of feeding prior to disease onset, bilirubin and hematocrit level, blood glucose levels, drugs or procedures administered prior to disease onset, other documented diseases, age at onset of first symptoms, abdominal x-ray interpretations, blood count and culture results, duration of clinical and radiological disease, and early and late complications as evidenced by rehospitalizations in our pediatric department. no significant changes were made in terms of feeding patterns, percent of breast feeding in our nursery ( to %), timing of feeding initiation after birth ( to hours) and type of formula given. no infection outbreaks or change in colonization were recorded during the study time period. there were no changes in obstetrical policies, such as epidural anesthesia or type of medications used (analgetics, antibiotics or other drugs) except for an overall gradual increase in the rate of cs. the incidence of infants who are small for gestational age remained the same in our institution, about %, over the study period. the work-up on each of the infants in the study included complete blood count and blood culture, stool cultures for bacteria (salmonella, shigella, enteropathogenic escherichia coli, yersinia and campylobacter) and viruses (enteroviruses and rota virus), blood electrolytes, and renal and liver function tests. serial abdominal x-rays were taken until complete resolution of clinical and radiological findings. feeding was resumed days after normalization of abdominal x-rays. each infant received intravenous cefotaxim and amikacin for a total of days until cultures came back negative. table shows that over the last years, the incidence of nec among full-term infants at our institution has increased, from . per live births (full-term infants only) in to . per live births in . this increase has been conspicuous mainly over the last years, as shown in the table. the incidence of cs increased from % in to % in (in comparison to to % in the previous years). during the years of the study, full-term infants were found to have nec. in this same period, the rate of nec among vlbw infants born at our hospital decreased from . % in to % in . maternal diseases observed in this group of infants included gestational diabetes, hypothyroidism and turner's syndrome. all but one of the infants with nec were born by cs, six due to nonreassuring fetal heart rate monitoring without apparent birth asphyxia (with one exception). the other seven infants were born by elective cs due to breech presentation, twin pregnancy or previous cs. as shown in table , seven infants had known predisposing risk factors for nec, such as growth retardation, polycythemia, congenital hypothyroidism, birth asphyxia, congenital heart malformation, and one infant with an as yet undiagnosed syndrome. the other seven infants either exhibited no obvious predisposing risk factors or had some common mild conditions, such as hyperbilirubinemia, early asymptomatic hypoglycemia and transient tachypnea. none of these infants was entirely breast-fed. the age of nec onset in most of these babies was only a few days, except for two infants (n & ), with congenital heart disease and undiagnosed syndrome, respectively. nine babies had colon involvement, and in five babies, the radiologist was unable to unconditionally detect the exact location of the nec. one baby was operated on for early perforation. all blood cultures were negative; in one case the urine culture was positive, and in one case clostridium toxin was detected in the stool. all infants were discharged to their homes in good condition. during a -month follow-up period, two infants were re-admitted for obstructive ileus due to late-onset intestinal strictures that required explorative laparotomy with end-to-end anastomosis. the incidence of nec among full-term infants at our hospital has increased markedly over the last years, while the incidence of nec in vlbw infants has gradually decreased. the findings of the current study show that only half of these full-term infants with nec exhibited known predisposing risk factors, including congenital heart disease, undiagnosed syndrome, birth asphyxia, intrauterine growth retardation and congenital hypothyroidism. most of these infants had colon involvement, making this location typical among this group as compared to the preterm group, where the most common site is the jejunum and ileum. the early age at which the first clinical signs became obvious for most of the group is also unique as compared to reports for the preterm group, in whom the mean age of onset is days of age. the incidence of nec in infants with birth weight over g has previously been reported as . per live births, and about to % of all nec cases are term infants. , , , over the last years, a five-fold increase in the number of full-term infants with nec was detected in our population, reaching an incidence of . per live births in , equivalent to % of all nec cases in our institution that year. the clinical presentation of the infants at our hospital was similar to that described for preterm infants, , including abdominal distension, vomiting, bloody stools and septic appearance. we experienced no mortality among our group of patients, whereas the literature describes and % mortality for full-term and preterm babies, respectively. nec appears to occur earlier in full-term infants. in a casecontrol study of full-term infants, wiswell found the median onset of nec to be only days ( developed nec on the first day of life). ruangtrakool studied full-term infants; among them, nec developed . days after birth, in comparison to . days after birth in preterm controls. kabeer also found that nec appeared earlier in a group of full-term infants: at . days versus . days (in preterm infants). in the current study, the group mean age of nec onset was . days among a group of babies; however, for two other babies, one with congenital heart disease and the other with an as yet undiagnosed syndrome, nec appeared much later, suggesting another pathogenesis. the early age of onset may suggest a prenatal ischemic insult in six infants in the study group born by cs due to non-reassuring fetal monitoring, although without postnatal clinical signs of birth asphyxia (except one case). another seven infants were born by elective cs. the possible relationship between increasing rates of cs and early nec in full-term infants may be explained by the fact that sicker infants are saved by cs and by improved neonatal resuscitation. however, the low rate of birth asphyxia in the study group as well as the high rate of elective cs do not support such a hypothesis. so far, cs on its own has not been considered a risk factor for nec by most authors, although uauy et al. did mention cs as a significant risk factor in their group of vlbw infants with nec. recently, minkoff and chervenak discussed a possible mechanism by means of which the anesthesia involved in elective cs causes a possible transient drop of blood pressure, perhaps thus compromising placental blood supply and fetal circulation. in addition, the maternal supine position prior to and during the operation may further reduce fetal circulation and thus interfere with intestinal blood supply. the increasing incidence of cs in our institution may play some role in the higher incidence of nec observed in this study. about % of all elective cs in our institution are under epidural anesthesia capable of compromising splanchnic blood supply to the fetus. this hypothesis should be further investigated by means of fetal doppler blood flow measurements. in the literature, proposed risk factors for nec in term infants include cyanotic heart disease, perinatal asphyxia, hypoglycemia, polycythemia, respiratory distress syndrome, protracted diarrhea, pre-eclampsia, cocaine abuse during pregnancy, cows' milk allergy and anti-c rhesus incompatibility. , , , one case-control study of infants weighing over g at birth who developed nec found a higher frequency of premature rupture of membranes, chorioamnionitis, apgar score less than for the first and fifth minute, respiratory distress syndrome, congenital heart disease, hypoglycemia and exchange transfusion, but no greater frequency of pre-eclampsia, maternal diabetes, maternal drug abuse, meconium-stained amniotic fluid or polycythemia. in that study, only three patients were healthy prior to development of nec. other studies have also confirmed the hypothesis that the occurrence of nec in a full-term infant is usually associated with a predisposing event. out of full-term infants with nec, bolissety found only two that had no prior illness known to be associated with the development of nec. beeby reported eight full-term infants with nec, all with a predisposing event. similarly, wiswell found an unremarkable course prior to the development of nec in only three of full-term infants with nec. our study shows only a % rate of infants with known risk factors for nec. the other seven infants had no known risk factors for nec, but still exhibited some minor medical conditions, such as asymptomatic hypoglycemia, mild tachypnea, hyperbilirubinemia requiring phototherapy, and delivery by cs with or without mild abnormal fetal heart monitoring and with no apparent birth asphyxia. several studies identified a connection between congenital heart disease and nec in term infants. the frequency of this connection ranged from . % to % of term infants with nec: polin f out of , thilo f out of , andrews f out of and bolissety f out of . to the best of our knowledge, only two cases of hypothyroidism and nec have been described so far. the first was the case of a day-old full-term infant with a history of hyperbilirubinemia requiring phototherapy. positive clinical signs included persistent open posterior fontanelle. no thyroid tissue was identified by ultrasound. the infant was treated with intravenous thyroxin. the second patient developed nec at the age of weeks, days after nissen funduplication for severe gastro-esophageal reflux. prior history included hypoxic-ischemic encephalopathy with seizures within the first hours, treated with anticonvulsants. thyroxin was commenced at age days. investigation confirmed thyroid dysmorphogenesis. both infants were diagnosed by the newborn screening test, as was the case presented in our study. a pathogenic relationship between hypothyroidism and nec has been suggested. thyroid hormone deficiency causes decreased gut motility due to peripheral neuropathy of the intestine. in the presence of feeding, this may allow for intestinal bacterial overgrowth, increased gas production and abdominal distension. a second factor relating the hypothyroid state with nec is the hemodynamic effect of thyroid hormone deficiency. in the fetal and perinatal periods, the thyroid hormone is required for normal increase in cardiac output in response to catecholamines. an unsatisfactory increase in cardiac output in response to stress may lead to decreased mesenteric blood flow and bowel ischemia. nec in term infants has also been associated with the repair of gastroschisis and myelomeningocele and lipomyelomeningocele. the pathogenesis is unknown, but several factors appear to play either a primary or a secondary role, including infectious agents and toxins, enteral alimentation, exposure to anesthetic agents and mesenteric ischemia with tissue hypoxia. the development of nec most probably involves multiple factors in the setting of a stressed intestinal system with immature protective mechanisms. about % of nec infants in the study group were receiving all of their meals by mouth prior to the development of nec. it is hypothesized that ( ) incompletely digested formula can provide a substrate for bacterial proliferation and ( ) feeding increases intestinal oxygen demand during nutrient absorption, thus increasing the risk of intestinal tissue hypoxia that can cause mucosal injury and bacterial invasion. most neonatologists increase feeding volumes gradually in preterm infants, although this is usually not the case for full-term infants. human milk appears to be beneficial in preventing nec, most probably by enhancing growth of lactobacilli and by immunologic mechanisms. , the infants in the study group were distinguished by a lack of sufficient breast milk. for many years, mesenteric ischemia was postulated to be the common denominator in nec. cardiovascular stresses such as hypotension, hypothermia, hypoxia, feeding, anemia and umbilical vessel catheterization are all associated with the development of nec. the immature intestines may have reduced ability to regulate blood flow and oxygenation. bacterial colonization of the intestinal tract is a prerequisite for initiation of nec. the occurrence of nec in epidemics suggests that an infectious agent may play a role in the pathogenesis of nec. numerous bacteria and viruses have been isolated in epidemics, including pseudomonas aeruginosa, e. coli, klebsiela pneumonia, clostridium perfringes, butyricum and difficile, enteroviruses, coxsackie b virus, corona virus and rotavirus. nonetheless, most of these isolated organisms are part of the normal intestinal flora. supplementation with bifidobacterium infantis and lactobacillus acidophilus reduced the incidence of nec, probably by preventing the overgrowth of more pathogenic enterobacteria. , , this etiology could not explain the high incidence of nec in the study infants described here. locally produced cytokines may have a detrimental effect during the evolvement of nec. other mechanisms are in place for downward regulation of this proinflammatory activation. a relative deficiency in protective responses may account for the propensity of intestinal injury in premature infants. the concentration of interleukin and (il- , il- ) and tumor-necrosis-factor-alpha (alpha-tnf) is elevated locally. nitric-oxide (no) production by enterocytes is increased and results in enterocyte apoptosis through peroxy-nitrite formation. conversely, no deficiency may also predispose the intestine to nec. moreover, deficiencies in both magnesium and copper can damage the gut's antioxidative defense and produce a pro-nec intestinal cytokine profile. the phospholipid inflammatory mediator, platelet-activating factor, has also been implicated in the pathogenesis of nec. erythropoietin is a trophic hormone that protects against intestinal cell death and was found to have a protective role, as did epidermal growth factor and hepatocyte growth factor. in conclusion, only half of our full-term infants exhibited any major known risk factors that predisposed them to nec. the early onset of nec both with and without any major risk factors might suggest a common mechanism related to a perinatal ischemic insult. such an insult may compromise the intestinal blood supply without our ability at present to detect any sign of it prior to feeding initiation. the increasing rate of cs in our institution, together with the fact that all the study infants except one were born by cs, either elective or urgent, might suggest that cs plays a role in the pathogenesis of nec. the etiology of the increasing number of full-term infants with nec in our institution and the possible role of cs in its pathogenesis deserve further investigation. neonatal-perinatal medicine nelson textbook of pediatrics a regional study of underlying congenital diseases in term neonates with necrotizing enterocolitis necrotizing enterocolitis in term infants necrotizing enterocolitis in fullterm or near-term infants: risk factors necrotizing enterocolitis in the first hours of life necrotizing enterocolitis in term neonates the development of necrotizing enterocolitis following repair of gastroschisis: a surprisingly high incidence neonatal necrotizing enterocolitis. therapeutic decisions based upon clinical staging necrotizing enterocolitis in the full term neonate new concepts in necrotizing enterocolitis necrotizing enterocolitis in full-term infants, a case-control study necrotizing enterocolitis: a comparison between full-term and pre-term neonates neonatal necrotizing enterocolitis. a year review at a country hospital necrotizing enterocokitis in very low birth weight infants: biodemographic and clinical correlates. national institute of child health and human development neonatal research network elective primary cesarean delivery gastro-intestinal complications following neonatal cardiac catheterization risk factors for necrotizing enterocolitis: the influence of gestational age necrotizing enterocolitis and hypothyroidism in a newborn infant: treatment with intravenous l-thyroxin key: cord- - z uyn p authors: hammer, j.; newth, c. j. l. title: infant lung function testing in the intensive care unit date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: z uyn p as a result of the previous shortage of tools to assess objectively the overall physiological status of the respiratory system in infants and young children, it has been difficult to measure the degree of physiological disorder or the response to therapy in respiratory diseases such as bpd, the pediatric version of ards, bronchiolitis, pneumonia, asthma and croup in this patient population. the newborn — four-year old child is particularly difficult to study because of their lack of cooperation and size. the recent progress in computer technology made pulmonary function testing available for this age range and opened up new possibilities for monitoring changes in disease processes affecting the respiratory system. this may improve medical management of infants and children with lung and heart diseases in particular. in , shannon [ ] proposed in this journal that the minimum physiological information needed for the intelligent use of mechanical ventilation (particularly if lower airway and/or pulmonary parenchymal disease was apparent) required the measurement of at least variables: i) arterial partial pressure of carbon dioxide; ii) arterial oxygen saturation; iii) the mechanical time constant of the lung and iv) frc. in many circumstances, arterial co( ) is approximated by alveolar (end-tidal) co( ) and the arterial oxygen saturation is obtained from pulse oximetry accurately if perfusion is adequate. the mechanical time constant and frc are easily measured by the techniques described above and together provide important information concerning appropriate ventilator settings for a given disease. the described techniques bring new insights and awareness, but also new responsibilities in the management of infants and children with respiratory compromise. not all of these techniques need to be applied to all infants in the icu. not all the assumptions upon which some of the techniques we have described are based will prove true. any such methods which do not withstand solid scientific testing must be quickly discarded and replaced with better and (hopefully) easier methods. until recently, there has been limited ability to assess objectively the deviations from normal in lung function in infants and children, either within or without the intensive care unit (icu). however, the application of the rapid data acquisition and processing abilities of the personal computer and miniaturization of equipment has led to major changes in this field, particularly for the newborn- -year-old child age range. the modifications of old and development of new pulmonary function tests have allowed those involved in the care of such patients novel measurements and new perspectives in both the assessment and management of respiratory failure. this review will focus on techniques which are used to measure thoracoabdominal asynchrony, tidal breathing flow-volume loops, small airway function (forced expiratory maneuvers), respiratory mechanics and lung volumes in critically ill infants and children. the major goals of these techniques in an intensive care setting are to: i) understand the underlying pathophysiology, ii) aid with diagnosis, iii) provide assessment of therapeutic response, and iv) provide a guide to changes in a patient's condition which will allow timely interventions to support the patient. ideally, such devices should also provide a measure of the disease and a prediction of outcome, in addition to being inexpensive and noninvasive. however, at this point in the evolution of intensive care, our most useful monitors, diagnosticians and medical prognosticators are almost certainly highly trained and "disease-smart" physicians, nurses and respiratory therapists at the bedside. some applications of pulmonary function testing generally require that the infants are heavily sedated, and under neuromuscular blockade when mechanically assisted with ventilation. the latter situation also requires (usually) that there be no leak around the ett in order to obtain good quality studies. this can be achieved in most cases with either a cuffed ett or with an uncuffed tube with pharyngeal packing. cuffed ett are not recommended for use in children under the age of years [ ] , but in a recent prospective study involving infants and children, using cuffed ett one-half size smaller than the calculated uncuffed ett for age, we had no greater incidence of complications either short-term (post-extubation stridor) or long-term (tracheal stenosis) [ ] . we now use cuffed ett routinely in our pediatric icu in infants and young children with pulmonary disease. it is not the intent of this report to justify as "useful" or "essential" any of the techniques which are subsequently mentioned. at one end of the spectrum, demonstration of a significant reduction of mortality and morbidity associated with a change in practice provides a dra-matic justification for the use of a diagnostic or monitoring tool. unfortunately, unlike therapeutic interventions, it is rarely possible to provide evidence of such changes with routine monitoring devices in intensive care. in addition, little has been published on the efficacy or cost effectiveness of the various procedures. at the other end of the spectrum, one can argue that any intervention which provides more understanding of disease processes can be justified, providing there is little or no deleterious effect on the patient. intermittent arterial blood gas analysis is regarded as the standard diagnostic tool for respiratory failure and is fundamental for accurate assessment of pulmonary gas exchange and ventilator management [ ] . however, technologic advances have made non-invasive devices available for continous monitoring of oxygen ( ) and carbon dioxide (co ). these include end-tidal co , transcutaneous co and , and pulse oximetry. if the caregiver is aware of their limitations, they allow quick feedback on rapidly changing conditions and are helpful in the continuous supervision of respiratory therapy. non-invasive blood gas monitoring has the potential to reduce significantly the frequency of abg sampling. detailed descriptions of their operation and limitations are beyond the scope of this paper, but are available in recent reviews [ , . thoracoabdominal asynchrony (taa) and paradoxical breathing are often observed in infants and children with various forms of respiratory diseases including upper airway obstruction (uao), parenchymal processes (such as hyaline membrane disease, pneumonia and pulmonary edema), obstructive lower airways disease (asthma, bronchiolitis, bpd) and neuromuscular diseases. this phenomenon has generally been descriptive and was referred to as chest wall retractions in clinical scoring systems. however, phase angle analysis of the lissajous figure allows us to easily detect, quantify and monitor taa in a non-invasive manner [ ] . in this technique, rib cage (rc) and abdominal (abd) movements are recorded by use of an uncalibrated respiratory inductance plethysmograph, the bands of which are placed at the levels of the nipples and upper abdomen. the analog output of the rc and abd movements is acquired by a computerized data acquisition system that is programmed to calculate continuously phase angles utilizing the method of agostoni and mognoni [ ] . phase angle ( ) is thus calculated according to the equation: m sin = -s where m is the length of the midpoint of the rc excursion and s is the length depicting the abd excursion (fig. ). in addition, rc and abd movements can be continuously displayed as an x-y plot giving optical information about changes in loop shape and loop direction. except during rem sleep, the rc and abd expand and decrease in synchrony in normal full-term infants and children, producing a closed or very narrow loop with a positive slope on the x-y plot (mean = o, range = to o). however, during taa the loop opens and becomes progressively wider as taa increases. paradoxical breathing also creates a closed or very narrow loop, but with a negative slope. important information can further be obtained from the loop direction. this indicates which compartment (rc or abd) precedes the other. counterclockwise loops indicate that the abd compartment (diaphragm) leads the rc as usually observed in normal quiet breathing and most forms of respiratory distress in children. clockwise loops signify the opposite which is typically associated with diaphragmatic paralysis [ ] . continuous phase angle measurement is a promising non-invasive technique for the objective assessment of taa in a variety of respiratory diseases. phase angles are elevated in uao and decrease after (z-agonist therapy (fig. ) , but demand further research and a better understanding of their predictive value for respiratory failure [ ]. we have recently validated phase angle measurements by showing that they correlate with the level of the imposed respiratory load, but do not detect respiratory muscle fatigue, in uao [ ]. however, it has been demonstrated that phase angle measurements correlate with transcutaneous co in infants with severe laryngotracheobronchitis and provide a useful, additional way to . phase angle measurements also correlated with improvement after bronchodilator therapy in children with obstructive airway disease such as asthma and bpd [ ] . the use of phase angle analysis to monitor taa in infants and children with neuromuscular disease (e.g. infant botulism, guillain-barr syndrome, myopathies, neuropathies, spinal cord injuries) needs to be further clarified, but offers a promising tool to monitor sprinting or weaning processes from mechanical ventilation. diaphragmatic paralysis can be easily detected at the bedside by the characteristic generation of clockwise loops, even when this may not be obvious clinically as in the case of unilateral paralysis (e.g. post cardiothoracic surgery) [ ] . a problem often encountered with this technique is that at various times phase angle loops are not based on clear sinusoidal rc and abd movements and produce numerous types of non-sinusoidal patterns [ ] . we have recently suggested that a sine-wave independent mathematical approach in loop analysis improves the accuracy of phase shift calculations under such circumstances [ , . other methods used in the assessment of respiration involve techniques measuring the "work of breathing". the classic method for "work of breathing" has been thoroughly studied in adults by collett and co-workers [ ] . however, modified approaches have been used in infants. the "work of breathing" can be measured relatively non-invasively by use of an oesophageal balloon to record pleural pressure changes and subsequent calculation of the pressure-time index. this index is an estimate of the energy cost of the "work of breathing" because consumption by muscle is proportional to the integral of muscle tension (or pressure) with respect to time. klein and reynolds demonstrated that when the unintegrated pleural pressure signal was used in the index, they were able to show a response to therapy with continuous inflating pressure in sleep-related uao [ ] . since breathing slows and inspiratory pressure is greater with uao, the "raw" pressure-time index underestimates the true integrated pressure-time index. nonetheless, this seems a simple and effective objective measurement for upper airway obstruction. a further variation was suggested by wolfson et al. [ ] in their study on helium breathing in infants with bpd. these techniques await further validation. tidal breathing flow-volume loops tidal breathing flow-volume or pressure-volume loops are increasingly used in continuous or intermittent monitoring of mechanical ventilation in both neonatal and pediatric icus. they can be measured on special "standalone" equipment, or are increasingly incorporated into modern ventilators. these allow the measurement of tidal volume (vt), tidal flows and pressures generated during mechanical and spontaneous breaths. thus, impacts of alteration in ventilator settings or lung physiology on these parameters can be readily detected [ , ] . spontaneous tidal volume breaths and ventilator breaths can be compared (especially along the expiratory flow limb where flow-limitation may be readily seen) which enables an estimate of the ventilatory reserve provided by mechanical ventilation (fig. ). the generation of inadver- unless it is certain that flow is limited (effort independent) at a particular lung volume, changes in flow rates after a therapeutic maneuver (e.g. bronchodilator) may still be attributed to factors other than a simple response to therapy. we have recently shown that the fd technique is capable of producing forced expiratory flows at flow limitation in intubated animals and infants with normal and obstructed airways [ , ] . for the test procedure, the lungs are inflated by squeezing a breathing bag filled from a continuous compressed o~ supply to + cmh inflation pressure, defined as total lung capacity (tlc). inflation pressures are held static for at least s, after which a sliding valve is activated to expose the airways to a -l capacity, constant negative pressure source of - cmh deflation pressure. the lungs are deflated until expiratory flow ceases at residual volume (rv) or for at least s. vc and mef at various subdivisions are measured by an interposed pneumotachograph. throughout the procedure the individual is usually under neuromuscular blockade and/or heavy sedation. normal values for vc and mef at the various subdivisions still need to be defined, but in our laboratory lie in the range of - ml.kg - for vc and - ml.kg -t s - for mef and - ml.kg-t.s -~ for meft . since it has become standard of care to use inhaled bronchodilators on intubated and ventilated patients in a variety of diseases, their effectiveness with respect to bronchodilatation can easily be documented by the fd technique [ , ] . obstructive airway and restrictive lung diseases produce very characteristic patterns (fig. ) which are helpful in assessing the underlying pathophysiology (e.g. rsv infection causing bronchiolitis, ards or pneumonia). serial vc and mef assessments are helpful in a variety of lung diseases like bpd and ards requiring long term mechanical ventilation and document the resolution or progression of the disease process [ , ]. compliance and resistance reflect the mechanical properties of the lungs and require the measurement of flow, volume and pressure. compliance (c) is defined as the change in volume per unit change in pressure: it must be emphasized that compliance is a function not only of the elastic properties of the respiratory system, but also of its volume. in other words, the value obtained is different at various lung volumes, dependent on the shape of the pressure-volume curve, which in turn depends on the amount of lung disease and therapeutic maneuvers such as peep or surfactant administration. sudden changes in compliance often reflect the opening and closing of individual lung units rather than changes in lung tissue and surface tension characteristics and represents the resistive properties of the airways, lung tissue and chest wall. several methods have been designed to measure compliance and resistance in ventilated infants which has led to a confusing nomenclature for the practitioner. compliance is referred to as either dynamic compliance (cdyn) when it is measured when ventilation is in motion, or as static (passive) compliance (crs) when respiratory muscles are inactive during the test procedure. the same applies to the resistance of the respiratory system, which is referred to as either dynamic (re) or total respiratory system resistance (rrs). cdyn can be simply calculated by dividing vt by the total change in pressure necessary to deliver that volume. these numbers can be easily extracted from mechanical ventilation. however, it is understood that cdyn is related to both elastic and flow resistive characteristics according to the equation of motion of the single compartment model of the respiratory system: p = vx+r f c where p = transpulmonary pressure, vx = tidal volume and f = tidal flow. thus, cdyn changes with alteration of mechanical ventilation settings including respiratory frequency, inspiratory and end-expiratory pressure [ ] . the classic technique of determining cdyn is based on the measurement of oesophageal pressure as a quantification of pleural pressure [ ] . this allows differentiation of cdyn into its components of lung compliance (cl) and chest wall compliance (ccw). however, ccw is usually very high in infants and its contribution to total respiratory compliance (cxox) can often be neglected [ , ], since cl and ccw are related as follows: this technique is invasive by virtue of the need of an oesophageal catheter and the accuracy of such measurements in intubated infants and children is controversial [ , . newer methods measure static compliance (crs) and resistance (rrs) and are based on relaxation of both inspiratory and expiratory muscles during brief airway occlusions during exhalation. the most widely used methods are the passive deflation and the multiple occlusion techniques [ ] [ ] [ ] . muscle relaxation is achieved either by invoking the hering-breuer inflation reflex or by use of neuromuscular blockade. we favor the use of shortterm neuromuscular blockade together with sedation for a mechanically ventilated patient in the controlled setting of an icu because it guarantees complete muscle relaxation during the whole expiratory phase. in the following we will concentrate on the discussion of the passive deflation technique (single breath occlusion) and refer the reader to recent literature for the other methods [ ] . the passive deflation technique involves measuring pressure during occlusion of the airway at endinspiration and fitting a straight line to the fv-curve obtained during the subsequent passive exhalation [ , ] . if there is no muscle activity during exhalation, the expiratory time constant (trs) or emptying time of the respiratory system will be entirely dependent on the mechanical properties of the lungs and can be described as follows: thus, both crs and rrs can be obtained from a single breath. the determination of trs gives some idea of how rapidly the lung empties following a mechanical breath. a single time constant is defined as the time required to exhale % of the tidal volume. three time constants are needed to exhale ~ of the delivered tidal volume. this permits the determination of respiratory rates allowing complete exhalation or the detection of rate settings which lead to inadvertent peep. the passive deflation technique relies on the assumption that the respiratory system can be regarded as a single compartment model. this is valid in most healthy infants especially over the tidal volume range. however, in the presence of lung disease, the respiratory system will not always behave like a single compartment model and a single time constant will not adequately describe all the respiratory mechanics [ , ]. we have noted multiple time constants in infants with restrictive lung diseases such as acute ards or pulmonary edema, or with severe obstructive airway disease [ ] . in all these circumstances crs and rrs are best measured over the longest linear fit of the passive expiratory fv-curve. however, calculation of time constants at different intercepts may give additional information and better describe the respiratory mechanics over the whole expiration phase [ . pattern recognition adds valuable information to the interpretation of results obtained by measuring respiratory mechanics. while obstructive lung disease is characterized by a concave slope of the passive expiratory fv-loop, restrictive lung disease often results in convex loop patterns. it is important to note that in the case of intubated patients, crs and rrs measurements include the physical properties of the ett. unfortunately, there is still a great lack of normal values for crs and rrs in intubated infants and children with normal lungs. according to our studies, such normal data lie in the range of . - . ml'cmh:o - kg - for crs and . - .sml'cmh -l"s (up to . with ett < . mm i.d.) for rrs [ ] . pfenninger and aebi [ ] have recently used the passive deflation technique for rrs and crs to compare the response to inhaled and intravenous salbutamol in ventilator-dependent infants with chronic lung disease, and concluded there was no difference. such careful objective physiological measurements should influence how weaning such infants from the ventilator is approached. although the most fundamental interest in lung volume measurements in infancy and childhood relates to the assessment of normal and abnormal lung growth [ , ], the determination of lung volumes is an important part of the respiratory management of infants and children [ ] . lung volume measurements can help in diagnosing respiratory disorders, in evaluating responses to therapy, and in finding suitable ventilator settings with respect to rate and ventilating pressures [ - ]. lung volume is also an important variable when lung mechanics are measured [ ] because specific compliance and specific resistance are normalized by lung volume, i.e. the functional residual capacity (frc). currently, frc and v t are the only lung volumes that can be accurately, repeatedly, and reliably measured in infants and small children. hence, they are the only lung volumes that can be routinely determined for clinical reasons either in the icu or in the out-patient clinic. other lung volumes such as tlc, vc and rv can also be measured, but the techniques are employed mainly for research, and require an endotracheal tube. frc can be measured by three techniques: plethysmographic (infant body box), helium (he) dilution (a closed-circuit method), and nitrogen (n ) washout (in its modern form, an open-circuit method). except in the smallest of infants, sedation is required for each technique. sulphahexafluoride has recently been used in a promising washin-washout technique [ , ] , and has now been validated [ ] . the body plethysmograph technique is labor-intensive, as is the calibration of the infant body box. edberg and colleagues [ ] [ ] [ ] have recently applied modern computing techniques to the infant body box and obtained useful data in the neonatal icu setting. however, their lung volume data was measured using the nitrogen (n ) washout method. for most workers, the use of plethysmographic methods is impractical in the icu environment, particularly for mechanically ventilated patients. the recent advent of a commercially available computerized infant box (j~tger) may modify this opinion. the closed-circuit he dilution method has been adapted to measure frc on ventilated patients by heldt et al. [ ] . the patient is connected via the ett and a sliding valve to both a bag (which is situated inside a transparent plexiglas box) and to the ventilator. in normal pre-test position the patient is ventilated directly by the ventilator through the valve. the bag, which contains a known amount of gas with known he concentration (and thus a known amount of helium) is sealed and is not connected to the patient. at end-exhalation the valve is switched so that the patient is directly connected only to the he-containing bag while the ventilator ventilates the box surrounding the bag and compresses the bag accordingly. the patient is thus ventilated by the bag which is externally compressed by the ventilator cycle. after several breaths, equilibration of he concentration between the lungs and the bag is achieved and frc can be calculated in the same way as in non-ventilated subjects. helium dilution can be used in patients on very high inspired oxygen concentrations (fio = . ). however, most thermal conductivity based he analyzers are inaccurate when o concentrations are high. moreover, calibration depends on the oz/he mixture ratio and should be repeated each time. leak-free connections in intubated infants are more difficult to achieve in this age group, where cuffed tubes are rarely used. if the leak is minimal, it may be eliminated by gentle tracheal pressure during the recording period. although a method for correcting leaks during frci~e measurements has been described by fox et al. [ ] and is currently incorporated into some automated systems. this has not been fully evaluated nor validated and may result in significant errors. the technique is based on washing out the n from the lungs by giving the subject % o to breathe. if the amount of n washed out is measured and the initial alveolar n concentration is known, then the lung volume from which point the washout started can be derived. in this open circuit method, the patient is switched to breathing % and from this point the volume of n exhaled is determined by integration with respect to time of the instantaneous n concentration flowing in the exhalation circuit multiplied by the instantaneous flow. in , gerhardt and co-workers [ ] devised a new open washout system to which a constant background o flow was delivered. the patient inhaled from and exhaled to that circuit with background flow. although the instantaneous flow rate of the washout circuit changes continuously as the subject breathes, the average flow leaving the system over time remains unchanged because the volume of gas subtracted during inspiration is added back to the system during exhalation (this is true as long as the temperature and humidity of the inhaled and exhaled gas are equal -a condition which is easy to meet by using a humidifier). because the method ignored the instantaneous change in flow and used only the average constant flow for calculation, it was essential that sampling of n for concentration measurements would "see" a continuous decrease of n concentration as the washout proceeds, without the effect of the respiratory phase. this was achieved by incorporating a mixing chamber in the exhalation circuit before the sampling port from which mixed expired gas was sampled for n analysis. the technique developed by gerhardt et al. for spontaneously breathing infants [ ] is not immediately applicable to ventilated children mainly because the gas flow during calibration does not equal the flow during the test. in order to overcome this difficulty, sivan and co-workers [ ] used the respiratory mass spectrometer already "in-line" for measuring the instantaneous n concentration, to record the minute ventilation by the argon dilution technique [ ] . at frc the patient is switched to a second ventilator delivering ~ (washout ventilator) and washout starts. this n washout technique (which unlike the he dilution method is limited to patients at fio < . ) allows accurate determination of frc during mechanical ventilation and correlates well with those values produced using the douglas bag technique [ ] . in patients with restrictive lung disease, including a group with ards [ ], frc measured at clinically chosen levels of peep ( - cmh ) was ~ below predicted frc for nonintubated normal children and ~ below that of ventilated children with normal lungs at physiological levels of peep ( - cmh ). the use of progressively greater levels of peep produced increases in frc towards predicted normal values [ ] . however, this suggests that in ards at least, normalization of frc would require sufficient peep to contribute to barotrauma or to compromise cardiac output and systemic oxygen transport. in spontaneously breathing infants and children, frc is the same whether determined by he dilution or n washout methods [ ] , and is in the range of - ml kg- (mean = . ml" kg- ). the only published data on ventilated infants and children with normal lungs demonstrated frcs up to ~ more than the nor-mal values for spontaneously breathing (i.e. not ventilated) children on peeps of - cm h [ ] . as a result of the previous shortage of tools to assess objectively the overall physiological status of the respiratory system in infants and young children, it has been difficult to measure the degree of physiological disorder or the response to therapy in respiratory diseases such as bpd, the pediatric version of ards, bronchiolitis, pneumonia, asthma and croup in this patient population. the newborn -four-year old child is particularly difficult to study because of their lack of cooperation and size. the recent progress in computer technology made pulmonary function testing available for this age range and opened up new possibilities for monitoring changes in disease processes affecting the respiratory system. this may improve medical management of infants and children with lung and heart diseases in particular. in , shannon [ ] proposed in this journal that the minimum physiological information needed for the intelligent use of mechanical ventilation (particularly if lower airway and/or pulmonary parenchymal disease was apparent) required the measurement of at least variables: i) arterial partial pressure of carbon dioxide; ii) arterial oxygen saturation; iii) the mechanical time constant of the lung and iv) frc. in many circumstances, arterial co is approximated by alveolar (end-tidal) co and the arterial oxygen saturation is obtained from pulse oximetry accurately if perfusion is adequate. the mechanical time constant and frc are easily measured by the techniques described above and together provide important information concerning appropriate ventilator settings for a given disease. the described techniques bring new insights and awareness, but also new responsibilities in the management of infants and children with respiratory compromise. not all of these techniques need to be applied to all infants in the icu. not all the assumptions upon which some of the techniques we have described are based will prove true. any such methods which do not withstand solid scientific testing must be quickly discarded and replaced with better and (hopefully) easier methods. ed) textbook of pediatric intensive care. williams & wilkins recognition and management of respiratory failure noninvasive assessment of blood gases effect of positive end-expiratory pressure on respiratory compliance in children with acute respiratory failure functional residual capacity and ventilation homogeneity in mechanically ventilated small neonates measurement of functional residual capacity by sulfur hexafluoride in small-volume lungs during spontaneous breathing and mechanical ventilation immediate effects on lung function of instilled human surfactant in mechanically ventilated newborn infants with irds lung volume, gas mixing, and mechanics of breathing in mechanically ventilated very low birth weight infants with idiopathic respiratory distress syndrom ekstr m-jodal b, hjalmarson o ( ) a plethysmographic method for assessment of lung function in mechanically ventilated very low birth weight infants a simplified method to determine functional residual capacity during mechanical ventilation effects of endotracheal tube leaks on functional residual capacity determination in intubated neonates a simple method for measuring functional residual capacity by n washout in small animals and newborn infants functional residual capacity in normal neonates and children up to years of age determined by a n washout method functional residual capacity in ventilated infants and children the measurement of metabolic gas exchange and minute volume by mass spectrometry alone comparison of helium dilution and nitrogen washout measurements of functional residual capacity in infants and very young children measurement of functional residual capacity by sulfur hexafluoride in small-volume lungs during spontaneous breathing and mechanical ventilation key: cord- - yk o authors: wang, yan; zhu, wei; luo, bi-ru title: continuous feeding versus intermittent bolus feeding for premature infants with low birth weight: a meta-analysis of randomized controlled trials date: - - journal: eur j clin nutr doi: . /s - - -x sha: doc_id: cord_uid: yk o background/objectives: clinical risks and advantages of both continuous feeding and intermittent feeding for preterm infants have been presented in previous studies. to determine the most appropriate feeding method for low-birth-weight infants, a meta-analysis was conducted. subjects/methods: articles related to this topic were searched in pubmed, embase, and cochrane library electronic database from the onset to may . heterogeneity analysis was performed with chi-square and i( ) test. pooled analysis was based on fixed effects model, if heterogeneity between the eligible studies was negligible (i( ) < %, p > . ). in contrast, a random effects model was carried out. the quality of including studies were evaluated by cochrane assessment tool. results: a total of articles identified. altogether, eight articles including infants were included in final analysis based on eligibility criteria. in continuous feeding infants, time to achieving full feeds was longer (weight mean difference . ( % ci . – . , p = . ) days) compared with intermittent feeding infants. pooled analysis indicated there were no significant difference in other variables such as feeding intolerance, duration of hospitalization, days to regain birth weight, days to first successful oral feeding, duration of parenteral feeding, weight growth, length increment, head circumference growth, proven necrotizing enterocolitis, and probable necrotizing enterocolitis. in subgroup analysis for birth weight (< g and > g), we did not identify significant difference in time to full feeds, time to regain birth weight, and duration of hospitalization. conclusions: intermittent feeding may be more beneficial for low-birth weight infants, however, well-designed studies and evidenced-based clinical practice are required to determine the most appropriate feeding method for premature infants with low birth weight. enteral nutrition is the preferred nutrition method for infants in neonatal intensive units [ ] . nasogastric or orogastric tubes are used before infants can be fed orally. only from approximately weeks age or g body weight, infants are able to coordinate sucking, swallowing, and breathing and the danger of aspiration, allowing drinking milk without danger [ ] . generally, tube feeding consists of continuous feeding and intermittent bolus feeding. continuous feeding is defined as delivering enteral nutrition with constant speed for h via nutritional pump [ , ] . intermittent bolus feeding is defined as delivering enteral nutrition multiple times [ ] , generally giving - min every - h by gravity or electric pump. previous studies have found that both continuous feeding and intermittent bolus feeding have benefits and risks for preterm infants. on the one hand, continuous feeding can maintain the gastrointestinal hormonal such as gastrin and insulin at a high level [ ] , leading to the increase of absorption and reduction of energy expenditure [ ] . on the other hand, continuous infusion of milk into the infant's gastrointestinal tract may lead to disorders of gastrointestinal hormones and long-term growth inhibition. a study on animal models suggested that continuous feeding, comparing with intermittent bolus feeding, reduces glucagon like peptide- , which may contribute to organ dysfunction [ ] . in addition, the incidence of prolonged apnea and apnea related hypoxia diseases such as retinopathy [ ] in continuous feeding is significantly higher than that in intermittent feeding [ ] . regarding to intermittent bolus feeding, it was thought to more physiologic [ ] , making infants have cyclical surges of gastrin, gastric inhibitory peptide, and insulin, therefore, promoting the gastrointestinal tract development [ ] . moreover, intermittent feeding allows more parental involvement in feeding [ ] and splanchnic perfusion [ ] . moreover, intermittent feeding promotes protein synthesis and improves the whole body's protein balance [ , ] , which play an important role in regulating nutritional disorders in infants. however, for premature infants, intermittent milk feeding may lead to feeding intolerance because it is easy for infants to exceed the absorbed capacity of their gastrointestinal tract with bolus milk infusion. intermittent feeding also has been reported to be associated with metabolic instability [ ] and impaired pulmonary functions [ ] in preterm infants. to compare the effect of continuous versus intermittent enteral feeding on low-birth weight infants, some studies were carried out [ , , , [ ] [ ] [ ] . however, these studies did not reach an agreement. in , premji and chessell [ ] conducted a meta-analysis of seven randomized and quasi-randomized studies and found that it was inadequate for determining a preferred feeding method because of some limitations, such as small sample size and the inclusion of quasi-randomized studies. therefore, now it is time for an update as larger, well designed studies reported on the effect of continuous feeding and intermittent feeding in preterm infants have appeared after [ , , , ] . the objective of this meta-analysis was to determine the clinical risks and benefits of each method and help clinicians choose appropriate feeding strategy. to identify the studies on the effects of continuous feeding versus intermittent bolus feeding on premature infant with low birth weight, we used mesh terms, keywords, and truncation symbol in the search strategy. ( ) the participants were preterm infants (gestational age < weeks) with low birth weight (birth weight < g). ( ) the type of studies was randomized control trial published in english. quasi-experimental trial, cohort study, review, and commentary were excluded. ( ) the interventions were continuous feeding (nasogastric tube or orogastric tube, breast milk or formula milk) and intermittent feeding (nasogastric tube or orogastric tube, breast milk or formula milk). broadly, continuous feeding can be considered as by using electric infusion pump. intermittent feeding can be given by gravity or electric infusion pump and had a break in their feedings. the total feeding amounts should be same in the study group and control group. the outcomes were measured at the same time point. ( ) the outcomes were feeding intolerance, days to attain full enteral feeds, days to regain birth weight, days to first successful oral feeding, time to discharge (days), duration of supplement parenteral nutrition, somatic growth indexes including weight growth, length growth and head circumference, and necrotizing enterocolitis (nec) including suspected and confirmed (bell's stage ii or greater). feeding intolerance was defined as gastrointestinal complications such as residual gastric volume, diarrhea, vomiting, and hematochezia during enteral nutrition. we identified studies related to the topic by reading the titles and abstracts. then, we reassessed the potentially eligible studies by reading the full text, and excluded irrelevant articles according to eligibility criteria. all assessment was conducted independently by two reviewers (yw and wz). if there were disagreement for the exclusion and inclusion, the issue was discussed until consensus was reached by the reviewers. data extraction was conducted by yw and wz independently. the following data were extracted: study design, publication year, location, demographic characteristics of subjects (especially gestational age and birth weight of infants), intervention methods, outcomes, and potential risk of bias. for quantitative data, the mean values and standard deviations (sd) were extracted. we used the equation from cochrane handbook to merge mean value and sd of two groups if need it. median and interquartile range were converted to mean value and sd using an online calculator (http://www.comp.hkbu.edu.hk/~xwan/median mean. html). for qualitative data, the number of cases of each study were extracted. the qualities of the included studies were evaluated by cochrane assessment tool. all studies were evaluated according to follow criteria: [ ] random assigned, [ ] allocation concealment, [ ] blinding (participants, personnel, and outcome assessment), [ ] incomplete outcome data, [ ] selective reporting, and [ ] other bias by two independent investigators. each criterion must be classified as "low risk", "unclear", or "high risk". we used rev man software version . to conducted the meta-analysis. meta-analysis for dichotomous data was evaluated with risk ratio (rr) with % confidence interval (ci), and continuous variables were analyzed by weight mean difference (md) with % ci. statistical heterogeneity was assessed by χ analysis and i test. fixed effects model was used when there was no obvious heterogeneity (i > %, p < . ). in contrast, a random effects model was carried out. we planned to conduct subgroup analysis for birth weight and gestational age of outcome. publication bias was evaluated by funnel plots. the descriptions of included and excluded studies were presented in fig. . through a comprehensive search in pubmed, embase, and cochrane library, a total of studies were identified, and one of additional records was identified through other sources. in total, articles were removed as they were duplication of the same report. after screening the titles and abstracts, we excluded records as they were irrelevant to the topic of this study and five records as their full texts were not available. fourteen studies were excluded and eight studies were included after rereading the full text for the following reasons: articles were reviews or systematic review [ , [ ] [ ] [ ] ; the study design were not randomized control trails [ , , ] ; the subjects were not low-birth-weight infants [ ] [ ] [ ] ; the primary outcome were not matched [ , [ ] [ ] [ ] . altogether, a total of eight studies including infants were included in this research. table summarized the main features of the eight studies. one article was the conference abstract, which we included because it described the methods and results detailly [ ] . the eight articles were published between and . four studies conducted randomized-controlled trail and compared multiple study groups [ , , , ] . four studies did not describe the detailed intervention methods about the duration of continuous feeding [ , , , ] and one study did not describe the duration of intermittent feeding [ ] . the detailed risk of bias for each study was displayed in fig. a , and the summary of the risk of bias was presented in fig. b . we analyzed the effects of the feeding methods on infants from the aspects of feeding performance, somatic growth, utilization of medical resources, feeding tolerance, and ga gestational age, bw birth weight, con continuous feeding, bol intermittent bolus feeding, nec necrotizing enterocolitis, rct randomized-controlled trial complication of feeding methods. in this study, feeding performance mainly included five outcomes: days to full enteral feeds, days to regain birth weight, days to first successful oral feeding, duration of hospitalization, and duration of supplement parenteral nutrition. the weight mean difference of days to full enteral feeds was . ( % ci . - . , p = . ) days in all infants ( table ) . no significant weight mean difference in other four variables were found between continuous feeding group and intermittent bolus feeding group of all infants. in somatic growth, we did not detect the significant difference in weight growth, length increment, and head circumference growth. as well, no significant were detected in utilization of medical resources (duration of hospitalization), feeding intolerance, and complication (proven or probable nec). we conducted subgroup analysis for birth weight of outcomes. a total of four studies were included [ , , , ] . all infants were divided into groups of < g and > g. however, in subgroup analysis and pooled analysis, we did not find significant difference in days to full enteral feeds, regain birth weight, and duration of hospitalization. the weight mean difference of days to full enteral feeds were . ( % ci − . , . , p = . ) days in groups of < g, . ( % ci − . , . , p = . ) days in groups of > g (fig. ) . the weight mean difference of regain birth weight were − . ( % ci − . , . , p = . ) days in groups of < g, − . ( % ci − . , . , p = . ) days in group of > g (fig. ) . the weight mean difference of duration of hospitalization were − . ( % ci − . , . , p = . ) days in groups of < g, . ( % ci − . , . , p = . ) days in group of > g (fig. ). the results of this meta-analysis showed that continuous feeding needs more days to achieve full feeds compared with intermittent feeding in low-birth-weight infants. for reducing nursing time and medical costs, we thought that intermittent feeding may have more benefit for low-birth weight infants according to current evidence synthesized from randomized-controlled trials, although it was at low level. in this meta-analysis, we found that continuous group need more days to achieve full feeds compared with intermittent group for all infants, which was consistent with some studies [ , [ ] [ ] [ ] . however, our results were different from dsilna's [ ] findings, which displayed that continuous feeding infants achieve full feeds faster than intermittent feeding infants (ahr = . , % ci . - . ), especially in infants with birth weight ≤ g (ahr = . , % ci . - . ). a retrospective study conducted by rojahn [ ] also showed that continuous group had fewer days to attain full feeds. one reason for this difference may be that the characteristics of subject such as birth weight and gestational age were different. dsilna [ ] focused on infants with birth weight < g and nec necrotizing enterocolitis ** p < . fig. pooled weight mean difference in time to achieve full feeds between the continuous feeding group and intermittent feeding group gestational age between and weeks. other studies mainly focused on larger birth weight infants [ , ] . moreover, the feeding protocol including milk composition, starting time of enteral nutrition, and the daily increase of milk volume was different. we did not find significant difference of time to achieve full feeds in subgroup analysis for birth weight. the reason may be that only four studies included in subgroup analysis and the sample size was too small. the finding in our study suggested that intermittent bolus feeding was more preferable for infants in terms of decreasing time to attain full enteral feeds. however, further research is needed on which feeding methods are more beneficial for infants of different gestational age and birth weight. in this study, we did not find significant difference in feeding intolerance, time to regain birth weight, time to attain first successful oral feeding, duration of hospitalization, duration of parenteral feeding, etc. (table ) in pooled analysis. in subgroup analysis, we also did not detect significant difference in time to attain full feeds, time to regain birth weight, and duration of hospitalization. the reason may be that the sample size was insufficient. in addition, the interference from other treatments for premature infants such as invasive or noninvasive ventilator support and prolonged parenteral nutrition may contribute to these results. another reason for these results is that many preterm infants had severe disease, which may affect their nutritional status. pooled analysis is known to have some limitations, resulting from the combination of studies with different feeding protocol, different definitions of outcomes, and different study population. the inconsistence of the feeding protocols of included studies is an example of this issue. in this study, four studies did not state the strategy of continuous feeding strategy or intermittent feeding [ , , , ] . most studies started enteral feeding on the second to fourth day after birth [ , [ ] [ ] [ ] . only two studies started enteral nutrition within h postnatal age [ , ] . a recent review [ ] proposed a reasonable strategy to optimize enteral feeding practice, in which the first feeding time should be started between and h of life, to avoid gastrointestinal atrophy and dysfunction. the pooled weight mean difference in time to regain birth weight between the continuous feeding group and intermittent feeding group continuous feeding versus intermittent bolus feeding for premature infants with low birth weight: a. . . studies included in this meta-analysis were mostly breastfed (from their own mother) or formula-fed. only one study used human milk feeding only, adding frozen pasteurized human milk from the local milk bank when the milk production of the mother was inadequate [ ] . a detailed review [ ] presented the large number of benefits of human milk for premature infants, and advocated donor human milk can be used alternatively when human milk was inadequate. in addition, the lack of uniformity of definition of the outcome index is another issue. for example, the full enteral feeds had different definitions in different studies. schanler [ ] and macdonald [ ] defined full feeds as achieving ml/kg/day, and dsilna [ ] defined full feeds as attaining - ml/kg/day. dollberg [ ] and roverkamp-abels [ ] defined full feeds as achieving ml/kg/day and ml/kg/day, respectively. akintorin [ ] defined full feeds as the ability to tolerate enteral feedings of kcal/kg/day for at least h. furthermore, the measure time points were different in each study. in some studies [ , ] , researchers measured gastric residual every or h to maintain consistency with feeding intervals, and another part of studies [ , ] measured gastric residual every - h, which in line with the physiological characteristics of gastrointestinal activity in infants. birth weight, height, head circumference, and other somatic growth indicators measured daily [ ] or weekly [ ] . only randomized-controlled trials included in this metaanalysis. as we all known, randomized-controlled trials were of the highest quality evidence according to grade guideline [ ] . our synthesis results are more indicative the efficacy of continuous feeding and intermittent feeding on infants compared with previous systematic review [ ] . in addition, we selected several outcomes to evaluate the impact of the two feeding strategies on infants from five aspects, including feeding performance, somatic growth, utilization of medical resources, feeding tolerance, and complications. our study had several limitations. first, gestational age was an additional significant variable. nevertheless, we were unable to examine the effect of sex because there was none randomized-controlled trial reported outcomes by sex. second, the type of gastric tube was another significant variable that we cannot detect its effect as only a limited number of studies reported outcomes by the type of gastric tube. third, our study was short of evaluation of other aspects such as pulmonary function [ ] , splanchnic perfusion [ ] , and laboratory outcomes because a limited number of studies reported these outcomes. this study found that continuous feeding group need more days to achieving full feed compared with intermittent feeding groups. clinical professions can take intermittent bolus feeding as the preferred feeding method to reduce nursing time and medical costs. further research should have clear definition of each outcome index, stratify the birth weight, gestational age, and illness of infants', and then to determine if either feeding strategy is more beneficial for preterm infants. in addition, multicenter large sample studies, especially randomized-controlled trials, are also essential for this topic. author contributions wz contributed in study design, search, screening potentially eligible studies, and data extraction in this work. yw contributed in conception, screening potentially eligible studies, data extraction, data analysis, figures, and drafting the paper. bl contributed to drafting and editing the paper. all authors approved the final paper for submission. feeding of preterm infants and fortification of breast milk continuous intragastric milk feeds in infants of low birth weight intermittent versus continuous feeding in critically ill adults feeding and the development of enteroinsular hormone secretion in the preterm infant: effects of continuous gastric infusions of human milk compared with intermittent boluses cardiorespiratory events with bolus versus continuous enteral feeding in healthy preterm infants enteral feeding in very-lowbirth-weight infants: a comparison of two nasogastric methods feeding critically ill patients the right 'whey': thinking outside of the box. a personal view a higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity gut hormones and "minimal enteral feeding intermittent bolus or semicontinuous feeding for preterm infants? impact of continuous vs bolus feeding on splanchnic perfusion in very low birth weight infants: a randomized trial intermittent bolus feeding has a greater stimulatory effect on protein synthesis in skeletal muscle than continuous feeding in neonatal pigs latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids intraday glucose fluctuation is common in preterm infants receiving intermittent tube feeding a prospective randomized trial of feeding methods in very low birth weight infants survey-methods of feeding low-birth-weight infants feeding tolerance in preterm infants: randomized trial of bolus and continuous feeding continuous feeding promotes gastrointestinal tolerance and growth in very low birth weight infants continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than grams comparison of continuous versus intermittent bolus feeding in preterm infants ≤ weeks and ≤ g a comparison of bolus versus continuous feeding methods in mechanically ventilated children continuous versus bolus intragastric tube feeding for preterm and low birth weight infants with gastro-oesophageal reflux disease continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than grams enteral nutrition for preterm infants: by bolus or continuous? an update nasojejunal feedings in low-birthweight infants lipids in plasma of enterally-fed very low-birthweight neonates gastric residual volumes in critically ill paediatric patients: a comparison of feeding regimens early enteral feeding of infants with lower respiratory infections effect of intermittent versus continuous enteral feeding on energy expenditure in premature infants effect of enteral gavage feeding rate on pulmonary functions of very low birth weight infants behavioral stress is affected by the mode of tube feeding in very low birth weight infants continuous gastric drip versus intravenous fluids in low birthweight infants feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method randomised trial of continuous nasogastric, bolus nasogastric, and transpyloric feeding in infants of birth weight under g a prospective randomized trial comparing continuous versus intermittent feeding methods in very low birth weight neonates enteral feeding in infants < g starting within h post-partum practice of enteral nutrition in very low birth weight and extremely low birth weight infants grade guidelines: . rating the quality of evidence conflict of interest the authors declare that they have no conflict of interest.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -d o z d authors: chang, anne b; grimwood, keith; white, andrew v; maclennan, carolyn; sloots, theo p; sive, alan; mccallum, gabrielle b; mackay, ian m; morris, peter s title: randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in indigenous australian infants: rationale and protocol date: - - journal: trials doi: . / - - - sha: doc_id: cord_uid: d o z d background: acute lower respiratory infections are the commonest cause of morbidity and potentially preventable mortality in indigenous infants. infancy is also a critical time for post-natal lung growth and development. severe or repeated lower airway injury in very young children likely increases the likelihood of chronic pulmonary disorders later in life. globally, bronchiolitis is the most common form of acute lower respiratory infections during infancy. compared with non-indigenous australian infants, indigenous infants have greater bacterial density in their upper airways and more severe bronchiolitis episodes. our study tests the hypothesis that the anti-microbial and anti-inflammatory properties of azithromycin, improve the clinical outcomes of indigenous australian infants hospitalised with bronchiolitis. methods: we are conducting a dual centre, randomised, double-blind, placebo-controlled, parallel group trial in northern australia. indigenous infants (aged ≤ -months, expected number = ) admitted to one of two regional hospitals (darwin, northern territory and townsville, queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin ( mg/kg/dose) or placebo administered once weekly for three doses. clinical data are recorded twice daily and nasopharyngeal swab are collected at enrolment and at the time of discharge from hospital. primary outcomes are 'length of oxygen requirement' and 'duration of stay,' the latter based upon being judged as 'ready for respiratory discharge'. the main secondary outcome is readmission for a respiratory illness within -months of leaving hospital. descriptive virological and bacteriological (including development of antibiotic resistance) data from nasopharyngeal samples will also be reported. discussion: two published studies, both involving different patient populations and settings, as well as different macrolide antibiotics and treatment duration, have produced conflicting results. our randomised, placebo-controlled trial of azithromycin in indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in australian indigenous infants who are at high risk of developing chronic respiratory illness. if azithromycin is efficacious in reducing the morbidly of indigenous infants hospitalised with bronchiolitis, the intervention would lead to improved short term (and possibly long term) health benefits. trial registration: australia and new zealand clinical trials register (anzctr): actrn we are conducting a dual centre, randomised, double-blind, placebo-controlled, parallel group trial in northern australia. indigenous infants (aged ≤ -months, expected number = ) admitted to one of two regional hospitals (darwin, northern territory and townsville, queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin ( mg/kg/dose) or placebo administered once weekly for three doses. clinical data are recorded twice daily and nasopharyngeal swab are collected at enrolment and at the time of discharge from hospital. primary outcomes are 'length of oxygen requirement' and 'duration of stay,' the latter based upon being judged as 'ready for respiratory discharge'. the main secondary outcome is readmission for a respiratory illness within -months of leaving hospital. descriptive virological and bacteriological (including development of antibiotic resistance) data from nasopharyngeal samples will also be reported. discussion: two published studies, both involving different patient populations and settings, as well as different macrolide antibiotics and treatment duration, have produced conflicting results. our randomised, placebocontrolled trial of azithromycin in indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in australian indigenous infants who are at high risk of developing chronic respiratory illness. if azithromycin is efficacious in reducing the morbidly of indigenous infants hospitalised with bronchiolitis, the intervention would lead to improved short term (and possibly long term) health benefits. trial registration: australia and new zealand clinical trials register (anzctr): actrn background worldwide, bronchiolitis is the most common acute lower respiratory tract infection (alri) in infants [ ] [ ] [ ] . in the northern territory (nt, australia), alris are the most frequent reason for hospitalisation of young children (aged < -years). alris are also the commonest cause of preventable deaths in indigenous infants ( times that of non-indigenous) [ ] . of alris, bronchiolitis (with or without pneumonia) is the most frequent reason for hospital admission in nt indigenous infants aged under -months [ ] . despite this heavy burden of bronchiolitis in indigenous infants, currently no prospective studies have been published. our retrospective review of infants hospitalised with bronchiolitis at the royal darwin hospital (darwin, northern territory) found that . % of indigenous infants were readmitted within six-months of discharge from hospital [ ] . as most were retrieved from remote communities, the impact of the illness, its costs and social dislocation were likely to have been substantial. recurrent alris are independently associated with the development of bronchiectasis [ ] and reduced pulmonary function later in life [ ] . low birth weight and pre-existing small lungs are important determinants of future lung function, but there is increasing evidence that events in early life are at least equally important determinants of adult pulmonary dysfunction [ ] [ ] [ ] . the first few years of life are the most critical period [ ] . thus events such as severe alris during this critical period are likely to have long term effects. australia-wide, hospitalisation rates of respiratory disorders among indigenous australians are second only to those for renal dialysis [ ] . furthermore, we have previously documented that the severity of the hospitalised alri episode, as determined by oxygen requirement and duration of hospitalisation, was an independent risk factor for subsequent bronchiectasis [ ] . in the northern territory (nt), bronchiectasis affects one in every indigenous children, far exceeding that of cystic fibrosis (cf) in non-indigenous australian children ( in ) [ , ] . thus, any intervention that reduces bronchiolitis severity and/or risk of readmission for respiratory illness in indigenous infants may have both short term and potential long term benefits in our setting. bronchiolitis is characterised by extensive inflammation of the airways accompanied by increased mucous production and necrosis of airway epithelial cells. in paediatrics, bronchiolitis is a clinical diagnosis characterised by tachypnoea, wheeze and/or crepitations in infants following a preceding upper respiratory illness [ ] . it is primarily caused by infection of the respiratory epithelial cells by a variety of viruses, especially respiratory syncytial virus (rsv). other viruses (adenovirus, influenza, parainfluenza, human metapneumovirus, rhinovirus) are also implicated and increasingly new viruses are being detected in association with this illness [ ] . in addition, mycoplasma pneumoniae and chlamydia species are recognised increasingly as important contributors to the development of chronic lung disease and altered lung maturation [ ] [ ] [ ] [ ] . new treatable bacteria such as simkania negevensis (a chlamydia-like microbe) has been found in canadian inuit infants with bronchiolitis [ ] . there are no published data on the nature or diversity of respiratory pathogens associated with bronchiolitis in indigenous australians infants. typically anti-microbials are not recommended in the routine management of bronchiolitis [ , ] . while there are two rcts on macrolides for bronchiolitis, the single available rct on a non-macrolide anti-microbial was a negative study [ ] . however in our setting, there are several reasons why anti-microbials may reduce the morbidity of hospitalised indigenous infants with bronchiolitis. colonisation of nasopharynx with bacteria is a known risk factor for childhood pneumonia [ ] . indigenous infants not only have colonised nasopharynx very early in life (as early as aged -weeks), but the colonisation is also dense with common respiratory bacterial pathogens, notably streptococcus pneumoniae, haemophilus infleunzae and moraxella catarrhalis [ ] . repeated micro-aspiration of nasopharyngeal secretions heavily laden with pathogenic bacteria during alri may overwhelm already compromised pulmonary defences, increasing the risk of a secondary pneumonia or other lower airway infection. indeed, indigenous infants are more likely to receive antibiotics for an episode of pneumonia diagnosed during an admission for bronchiolitis than non-indigenous infants nursed in the same paediatric unit [ ] . macrolides are a class of antibiotics containing a macrocyclic lactone ring with excellent tissue penetration and antimicrobial activity against a broad range of gram positive and gram negative bacteria, including intracellular pathogens such as chlamydia. those with a -or -membered lactone ring also have several non-antimicrobial properties that have been studied extensively in-vitro and in experimental models and, to a lesser extent, in humans [ ] . one of these effects is modulation of the immune response. the immune modulating properties of macrolides make them attractive candidates for treating inflammatory airways diseases. the two published [ , ] placebo-controlled rcts on macrolides for rsv-bronchiolitis reported contradictory results. in a small turkish study of hospitalised infants with moderate to severe bronchiolitis, -weeks of daily clarithromycin significantly reduced severity of illness (oxygen use, hospital stay) and risk of hospital readmission for respiratory illness during the next months [ ] . however in another larger study involving infants from the netherlands, -days of azithromycin was not efficacious in infants hospitalised with bronchiolitis [ ] . the difference in outcomes seen in the two trials may be related to the dose or length of treatment, chance, or heterogeneity of the study populations. infants in turkey are more likely to have concomitant bacterial infection compared to an affluent european group and moreover in turkey, post-infectious childhood bronchiectasis remains an important health problem [ ] . the populations also differed in age. the european study included infants up to -months of age, whereas the turkish study involved only infants aged < -months [ , ] . clearly, a well designed rct on the efficacy of macrolides to reduce the burden of bronchiolitis in a population at high risk of acute and chronic respiratory disease would be beneficial. our primary research question is: amongst hospitalised indigenous infants with bronchiolitis, does azithromycin (compared to placebo) improve clinical outcomes (length of stay in hospital and duration of oxygen supplementation)? our primary hypothesis is that: the anti-microbial and anti-inflammatory properties of the macrolide, azithromycin, will improve the clinical outcomes of indigenous infants hospitalised with bronchiolitis. our secondary aims are: . to determine the effect of azithromycin on readmissions into hospital within months of treatment; . to assess the short-term impact of azithromycin on macrolide resistance patterns of respiratory bacterial pathogens in the nasopharynx; and . to describe the point prevalence and diversity of respiratory viruses, mycoplasma pneumoniae and chlamydia species using sensitive molecular diagnostic techniques. we are conducting a parallel group, double-blind placebo rct (with concealed allocation) to assess the impact of additional treatment with azithromycin in indigenous infants admitted to two regional hospitals (darwin, northern territory and townsville, queensland) with bronchiolitis. our study plan is summarised in figure . the inclusion criteria are: baseline data, nps- . indigenous infants (aged ≤ -months) admitted to one of our hospitals (darwin and townsville) with a clinical diagnosis of bronchiolitis. in the absence of an international standardised diagnosis of bronchiolitis, [ , ] the accepted australian clinical diagnosis is used (tachypnoea (respiratory rate ≥ /min in infants aged < -months, ≥ /min if - months, and > /min if - months), with wheeze or crackles); [ , ] and . recruited and consented within -hours of presentation to the hospital for the illness. exclusion criteria: admission into intensive care, macrolide therapy contraindicated (e.g. liver dysfunction, hypersensitivity), presence of diarrhoea (stools of increased watery consistency and more than two stools above usual stooling frequency), received macrolides (in last -days), or clinical and radiological features consistent with a primary diagnosis of pneumonia, [ ] at time of randomisation. at each site, the site-specific study nurse visits the wards twice daily to screen all newly admitted infants. a standardised collection form is used to collect clinical data (see below) and hospital outcomes associated with the bronchiolitis episode. all infants are managed according to a standardised protocol. this has been used at the royal darwin hospital since . the protocol outlines when supplementary oxygen is prescribed (sp < %) and reduced, and when nasogastric feeds or intravenous fluids are used. enrolled infants may receive additional therapies (other than macrolides) at the discretion of the attending paediatrician. if eligibility is fulfilled and after informed consent has been obtained, the infant is randomised to receive either a single, oral liquid dose of azithromycin syrup ( mg per kg) or an equivalent volume of placebo. medication is given within -hours of hospitalisation. infants randomised to the intervention arm of the study will receive additional treatment doses of azithromycin syrup ( mg per kg) on day- and day- . those randomised to the control arm receive an equivalent volume of the placebo syrup. the later doses will be either supervised by study nurses or administered by families with phone support on the day the medication is due. final clinical follow up will occur in the local health clinic on day- (or closest available date from day to ). the randomisation sequence was computer generated and used permutated blocks ( or participants per block). the allocation sequence is concealed at all times throughout the study. the computer generation and allocation were performed by a statistician, external to the study team. upon enrolment, an infant is assigned to the next number on the appropriate stratified list. each unique number is assigned to one of the eight treatment alphabets (see below). treatment groups are stratified by age (≤ or > months), site (darwin or townsville) and requirement (yes or no) for oxygen at point of randomisation. the importance of excluding older children and stratifying at the month age group is well described [ , ] . a placebo medication ensures that all children, carers, researchers, hospital staff, and clinic staff are blinded to treatment group until analyses of the data. the placebo medication has been specifically manufactured by the institute of drug technology (idt) australia limited (melbourne, vic) which has a similar taste and colour to azithromycin. the azithromycin medications were repackaged by idt. thus both the azithromycin and placebo are in identical opaque bottles and sealed with an aluminium foil. for both, equal volumes of water are added using a syringe and needle by punching the seal. eight alphabets (n, o, p, q, r, s, t, u) were used for the bottles of azithromycin and placebo medications ( alphabets each). we used multiple alphabets rather than sequential numbers on the bottles to allow storage of extra bottles of trial medications in clinics for the day- and day- doses. this was necessary in the context of our study setting (children mainly from remote indigenous communities), to enhance availability and administration of trial medications once the child has been discharged from the hospital. all data are recorded on standardised forms. demographic information (age, gender, region, birth details, smoke exposure, breast feeding, household size, etc) and medical history are obtained from the primary caregiver and the medical charts. the primary and secondary outcome measures (see below) are monitored twice daily until the hospital admission's end-point is reached (ready for respiratory discharge, defined as > -hours without supplemental oxygen and infant is feeding well). clinical assessment data include oxygen requirement and level, physiological measurements for clinical severity score (respiratory rate, accessory muscle use, degree of wheeze), [ ] other physiological measurement (temperature, heart rate), requirement and duration of other therapies required (intravenous fluids, nutritional support, antibiotics), ear examination findings (signs of suppuration) and subsequent pneumonia (diagnosed by the independent treating 'blinded' paediatrician). in addition, the results of routine investigations (full blood count and chest radiographic findings) are recorded. on day- , the presence of cough, wheeze and auscultatory abnormality on clinical review are documented. adverse effects (vomiting, diarrhoea, rash) are also documented. a single nasopharyngeal swab (nps) specimen for respiratory virus and other potentially important respiratory pathogen (m. pneumoniae, chlamydia spp) testing is collected from each subject at enrolment. in addition, nps is repeated before hospital discharge for bacterial culture and antibiotic susceptibility testing, as per our laboratory research protocol (see below) [ , ] . culturing, identifying and serotyping common respiratory bacteria from nps is an established technique in our laboratory at menzies in darwin [ ] . swabs are stored in smggb at - °c before being batch processed for typical respiratory bacterial pathogens, notably h influenzae and non-typeable h influenzae, m. catarrhalis and s. pneumoniae. batches of swabs are thawed and μl aliquots cultured overnight on selective media at °c in % co . growth of s. pneumoniae, h. influenzae and m. catarrhalis is recorded and confirmed. four isolates each of s. pneumoniae and h. influenzae and two isolates of m. catarrhalis per positive swab are tested for anti-microbial resistance and stored [ , ] . s. pneumoniae isolates are serotyped using the quellung method (antisera from statens serum institute, denmark). in addition to routine susceptibility testing using the calibrated dichotomous susceptibility (cds) disc diffusion method, azithromycin minimum inhibitory concentration (mic) will be determined using etest (ab biodisk, sweden) if the azithromycin disc annulus is less than mm. for s. pneumoniae, the penicillin mic is determined for penicillin non-susceptible isolates (oxacillin and/or penicillin disc annulus < mm) and for h. influenzae, the ampicillin mic is determined for isolates if the ampicillin disc annulus is less than mm. interpretive criteria (csli breakpoints) used for s. pneumoniae are penicillin non-susceptible mic > . μg/ml, azithromycin resistant mic ≥ μg/ml, and for h. influenzae, ampicillin resistant mic ≥ μg/ml, azithromycin resistant mic > μg/ml. beta-lactamase activity will be determined for h. influenzae and m. catarrhalis isolates. our previous methods will be utilised [ , , ] . nps are frozen at - °c. upon thawing nucleic acids will be extracted from . ml of each nps specimen using the high pure viral nucleic acid kit (roche diagnostics, australia), according to the manufacturer's instructions. mono-specific pcr and reverse transcriptase pcr (rt-pcr) method will be used to detect mycoplasma pneumoniae, coronaviruses, bocavirus and human metapneumovirus (hmpv), whereas multiplex pcr and rt-pcr was used to detect adenovirus, parainfluenza ( , ), influenza (a and b) , and respiratory syncytial virus (rsv). all these methods have been previously validated in our viral laboratory at the royal children's hospital, brisbane. participation is complete when day- outcomes have been obtained. other exit points are: intolerance to the trial medications requiring withdrawal from study (as deemed by the treating paediatrician who is not directly connected to the study team). (i) length of stay (los) for respiratory illness in hospital-defined as time from admission to time 'ready for discharge' for respiratory care. 'ready for discharge' means normoxic (sp consistently > % in air for > hrs) and feeding adequately; and (ii) duration of supplemental oxygen required. 'ready for discharge' for respiratory care differs from length of hospitalisation as discharge from hospital may be delayed because of social or transport factors especially in children from remote communities. the major secondary outcome is readmission for respiratory illness (within -months of discharge from hospital). minor outcomes during hospitalisation: clinical severity score, [ ] additional use of antibiotics, and episodes of suppurative otitis media and development of pneumonia. the day- outcomes are: presence of cough, wheeze, abnormal auscultatory chest signs and suppurative otitis media. we will also analyse all clinical outcomes in the following pre-determined sub-groups: (i) age ≤ -months; and (ii) presence of bacterial respiratory pathogens that are resistant to macrolide antibiotics. (i) identification of respiratory viruses and bacterial pathogens and (ii) antibiotic resistance to penicillin and macrolides. we plan to enrol indigenous infants. in our retrospective study, [ ] the mean los in indigenous infants with bronchiolitis at rdh was (sd ) hours. the mean duration of supplemental oxygen requirement in indigenous infants with bronchiolitis was (sd ) hours. for a mean difference of -hours in los between groups (power = %, α = %) the required sample size is per group. the numbers to detect a -hour difference in supplemental oxygen requirement is per group. these are large effect sizes but more conservative estimates than seen in the turkish study [ ] . in that study, [ ] the difference between groups was -hrs for los and -hours for supplemental oxygen requirement. assuming similar effects, a sample size of at least in each sub-age group is also sufficient for an a-priori subgroup analysis based on age (power of % and -tailed α of %). if the effects are smaller, we will have an % power to detect a difference of hours in los in all infants and an % power to detect a difference of -hours in los in the ≤ -months age group. we do not believe that smaller benefits than this would be sufficient to change clinical practice. for the most important secondary outcome (readmission rate for a respiratory illness within -months of discharge), the power of our study to detect a reduction from % to % is % ( % significance). this is a large effect but consistent with the reduction described in the turkish study ( % reduction) [ ] . at % power we will be able to detect a reduction in readmission rates from % to %. for our other secondary outcomes, accurate sample size estimations are not possible given the lack of any relevant data. data will be reported and presented in accordance with the updated consort criteria [ ] . children will be analysed according to allocation status (regardless of subsequent management). an interim analysis is planned and the data safety and monitoring committee will determine if the study should be ceased should superiority of azithromycin be identified after % of sample size is achieved. the primary outcomes (los and duration of supplemental oxygen requirement) will be compared between infants receiving placebo or azithromycin using unpaired student's t-tests or mann-whitney tests (depending on normality of distribution). although we expect randomisation to equally distribute potential confounding factors between each of the groups, we will examine the distribution of known confounders between groups (eg. birth weight, smoke exposure status in-utero and postnatal, breast feeding, etc). should baseline data differ between groups, regression will be used to check that the primary outcomes are not affected by this chance finding. an a-priori sub-analysis will compare infants aged ≤ months with those aged > -months. when examining the efficacy of azithromycin at reducing readmission rate for respiratory illness (secondary aim- ), the odds ratio (or) between groups will be calculated. the or will also be used to compare additional antibiotic use between groups. the number needed to treat (nnt) (for benefit), % ci will be described if any significant differences are found. if significant, nnt for harm will be calculated for adverse events. for secondary aim- (short-term impact of azithromycin on macrolide-resistance of pathogens in nps cultures): the proportions of children with penicillinnon-susceptible s. pneumoniae and macrolide-resistant h. influenzae spp and m. catarrhalis before and after trial medications will be compared using ors and % ci. descriptive data will be utilised for secondary aim- (point prevalence of respiratory viruses and other respiratory pathogens). the acute lower respiratory tract infections are the commonest cause of hospitalisation and potentially preventable deaths in indigenous infants [ ] . bronchiolitis in indigenous infants is more severe than bronchiolitis in non-indigenous infants [ ] . there are higher readmission rates and an increased risk of ongoing respiratory morbidity (including chronic suppurative lung disease) in indigenous infants [ , ] . this may be due to an increased likelihood of recurrent infections and virusbacteria interactions from an early age (as early as aged -wks) along with heavy bacterial colonisation of the nasopharynx [ ] . despite bronchiolitis being the most common cause of alris in infants resulting in hospitalisation, there are no published prospective studies of this illness in australian indigenous infants. two small clinical trials have studied macrolides in bronchiolitis, but with contradictory results. our population setting is more closely related to the turkish study [ ] where a beneficial effect for macrolides was shown. this is in contrast to the negative findings of the dutch study [ ] in an affluent urban setting. our proposed double-blind rct will determine if azithromycin is an effective additional treatment in indigenous infants hospitalised with bronchiolitis. it will also determine whether in the ensuing months it will prevent hospital readmissions from respiratory illnesses, which potentially reduces the likelihood of chronic lung dysfunction [ ] in this high-risk population. azithromycin was chosen over other macrolides because of its prompt and potent anti-inflammatory effects as well as its - hours half-life in children, which permits once weekly dosing [ ] . the possible anti-viral effects is also attractive [ ] . an important safety component of the current study is to monitor for antibiotic resistance in potential respiratory bacterial pathogens colonising the nasopharynx. for the first time in this population, we will determine the nature and diversity of respiratory viruses, mycoplasma, chlamydia and chlamydia-like species in association with cases of bronchiolitis requiring hospital admission. the range of organisms includes newly discovered viruses, [ ] and treatable bacteria that may contribute to chronic lung dysfunction. m. pneumoniae and chlamydia species are increasingly recognised as important contributors to development of chronic lung disease and altered lung maturation [ ] [ ] [ ] [ ] . our study addresses a large clinical research gap for an important and common cause of hospitalisation in indigenous infants. if the intervention is successful, it would lead to improved short term (and possibly long term) health benefits. conclusive results would produce changes to evidencebased standard treatment guidelines in our region and those produced for similar populations nationally and internationally. finally, the intervention would also offer the possibility of preventing (or reducing) the high rates of long-term respiratory dysfunction seen in australian indigenous children and adults. risk factors for bronchiectasis in indigenous children include recurrent hospitalisation for alris and severity of previous arlis (measured by duration of stay and requirement for oxygen supplementation during hospitalisation) [ ] . in the context of the high burden of bronchiectasis in our setting, we considered that the most important outcomes are los, requirement for oxygen supplementation during hospitalisation and readmission within a -month period. length of hospitalisation is a common outcome measure in studies on bronchiolitis. however in our setting, hospitalised children often come from remote comunities and may have multiple co-morbidities [ ] that influences their discharge. thus we used los defined in accordance with 'ready for respiratory discharge'. our study only addresses infants hospitalised for bronchiolitis. the impact of variable presentation particularly that related to the potential influence of azithromycin's acute immune modulation effect is a limitation of our study. however our study design minimises the impact of variable presentation by: (a) standardising our inclusion criteria, (b) limiting enrolment to within hours of hospitalisation; (c) adopting a strategy (double blind, placebo controlled, allocation concealed methodology) that would theoretically distribute any effect equally between groups. additionally in the event that differences in baseline data between groups are found, we will use statistical methods (multivariate analysis) to adjust as required. in summary, given the very high burden of bronchiolitis in indigenous infants (the age when lung growth is most critical post-natally), and the association between alri and future lung dysfunction, our rct on azithromycin in indigenous australian infants hospitalised with bronchiolitis has the potential to have both short term gains and a long-term benefit for reducing morbidity of respiratory illness. subcommittee on diagnosis and management of bronchiolitis: diagnosis and management of bronchiolitis predicting respiratory syncytial virus hospitalisation in australian children bronchiolitis: assessment and evidence-based management from infancy to young adulthood: health status in the northern territory . department of health andcommunity services hospitalisation of indigenous children in the northern territory for lower respiratory illness in the first year of life risks of severity and readmission of indigenous and non-indigenous children hospitalised for bronchiolitis a hospital-based case-control study of bronchiectasis in indigenous children in central australia lifecourse predictors of adult respiratory function: results from the newcastle thousand families study lung parenchyma at maturity is influenced by postnatal growth but not by moderate preterm birth in sheep postnatal growth rate, but not mild preterm birth, influences airway structure in adult sheep challenged with house dust mite the mammalian respiratory system and critical windows of exposure for children's health. environ health perspect australian health ministers' advisory council : aboriginal and torres strait islander health performance framework report. ahmac, canberra non-cf bronchiectasis-clinical and hrct evaluation bronchiectasis: so much yet to learn and to do frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections prenatal inflammation and lung development contribution of inflammation to lung injury and development intermittent azithromycin treatment for respiratory symptoms in patients with chronic chlamydia pneumoniae infection rate of chlamydia trachomatis and chlamydia pneumoniae in paediatric respiratory infections high rate of simkania negevensis among canadian inuit infants hospitalized with lower respiratory tract infections bacteraemia and antibiotic use in respiratory syncytial virus infections antibiotics for bronchiolitis in children. cochrane database syst rev streptococcus pneumoniae colonisation: the key to pneumococcal disease bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in australian aboriginal infants mechanisms of action and clinical application of macrolides as immunomodulatory medications clarithromycin in the treatment of rsv bronchiolitis: a double-blind, randomised, placebo-controlled trial azithromycin does not improve disease course in hospitalized infants with respiratory syncytial virus (rsv) lower respiratory tract disease: a randomized equivalence trial non-cystic-fibrosis bronchiectasis in children: a persisting problem in developing countries diagnosis and testing in bronchiolitis: a systematic review acute viral bronchiolitis: to treat or not to treat-that is the question the management of acute bronchiolitis. thoracic society of australia and new zealand respiratory syncytial virus infection and immunoprophylaxis for selected high-risk children in central australia zinc and vitamin-a supplementation in indigenous children hospitalised with episodes of lower respiratory tract infection: a randomised controlled trial how should we study responses to treatment in children with bronchiolitis? respiratory bacterial pathogens in the nasopharynx and lower airways of australian indigenous children with bronchiectasis streptococcus pneumoniae and noncapsular haemophilus influenzae nasal carriage and hand contamination in children: a comparison of two populations at risk of otitis media random colony selection versus colony morphology for detection of multiple pneumococcal serotypes in nasopharyngeal swabs the impact of viral respiratory infection on the severity and recovery from an asthma exacerbation newly identified respiratory viruses in children with asthma exacerbation not requiring admission into hospital consort statement: updated guidelines for reporting parallel group randomised trials respiratory morbidity in central australian aboriginal children with alveolar lobar abnormalities once-weekly azithromycin in cystic fibrosis with chronic pseudomonas aeruginosa infection azithromycin induces anti-viral responses in bronchial epithelial cells evidence of human coronavirus hku and human bocavirus in australian children randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in indigenous australian infants: rationale and protocol we thank the research staff (lesley versteegh, clare wilson, nerida jacobsen, susan pizzutto and amber revell) for facilitating the study, joseph mcdonnell for generating the randomisation sequences and jana lai for assistance with labelling the bottles. we are also grateful to members of the indigenous reference group of the child health division at menzies for supporting this study and for over-seeing the cultural aspects. we also thank drs ka o'grady, alan isles, alan ruben and william frischman for voluntarily providing their time in their participation in the study's data safety monitoring committee. we are also very appreciative to the channel children's foundation and the financial markets foundation for children for funding the preliminary study that provided us with essential pilot data for our successful nhmrc grant submission. funding study is funded by a -year australian national health and medical research council (nhmrc) project grant ( ). abc is supported by a nhmrc fellowship ( ). authors' contributions ac conceived the study, and participated in its design and coordination and drafted the manuscript. pm, kg, ts, aw, as, cm participated in its design, analysis plan and submission to the nhmrc. gm participated in initiating and running the project and im in the viral analysis plan. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- -ua h jg authors: dersch-mills, deonne title: assessment considerations in pediatric patients date: - - journal: patient assessment in clinical pharmacy doi: . / - - - - _ sha: doc_id: cord_uid: ua h jg pharmacy assessment of pediatric patients is similar in many ways to that of adults; however there are many specific nuances that need to be considered in addition to the typical aspects included in an adult assessment. there is a lack of pediatric-specific medication research and a much higher rate of “off label” medication use, so children are at higher risk of medication errors and related harm. pharmacokinetic differences and other age-related differences result in highly variable responses to medications throughout childhood. pharmacists need to be aware of this variability and use every patient encounter as an opportunity for assessment of many aspects of medication including dose, formulation, administration, and indication. infants and children also have physiological differences that need to be considered especially when assessing efficacy, toxicity, and the patient’s overall response to medications through physical exam or use of laboratory values. lastly, a lack of appropriate medication formulations for children creates a requirement for pharmacists to specifically assess the formulations, measurement, and administration of pediatric medications. this chapter provides an approach to pediatric assessment, highlights common sources of error, and provides strategies for managing pediatric medications. pediatric pharmacy technically includes the care of any patient under the age of years, although practically patients over the age of can usually be cared for following similar dosing/monitoring as in adults. in canada in , children under years comprised ~ % of the canadian population (statistics canada, population by sex and age group ), and accounted for . % of hospital discharges (~ % not including births in hospital) [ ] . approximately % of canadian children receive one or more medications each year; this is up to % in infants < year old [ , ] . while medication use is not uncommon, polypharmacy is much less common than in adult patients. around % of us children received at least one medication in the previous week, but less than % had used two or more medications in the previous week [ , ] . the most common medications filled for children in community pharmacies in included antibiotics (amoxicillin, azithromycin, and cefprozil most commonly), asthma medications (salbutamol, fluticasone, montelukast), and medications for attention deficit hyperactivity disorder (adhd) (methylphenidate primarily) [ ] . before moving forward, it is important for pharmacists to understand age-related terminology for children. gestational age (ga) is the duration of time a newborn has been in utero (full term is considered ~ weeks) while post-natal age (pna), also known as chronological age (ca), is the duration of time since birth (e.g., weeks old). corrected gestational age (cga) or post-menstrual age (pma) are terms used most commonly in infants born prematurely, and refer to their gestational age plus post-natal age. for instance, a baby born at weeks ga, with a pna/ca of days would have a cga/pma of weeks and days (commonly abbreviated as + weeks). a neonate (or newborn) is an infant < days pna/ca, or for premature infants, less than weeks cga/pma. the term "infant" typically refers to a range of pna/ca from days to year. the term "toddler" typically refers to age - years, and "school-age" refers to age from to years. "adolescent" typically refers to age - years, though the true onset of adolescence is determined by the onset of puberty. these distinctions are important due to developmental changes that occur in pharmacokinetics (see more below). there is a distinct lack of research on medication use in children, which adds its own challenges to the practice of pharmacy in children. up to % of medication use in hospitalized children and % of medication use in ambulatory children are considered "off-label," that is, not included in the product labeling/monograph and thus not supported by the manufacturer [ ] . only % of medications on the market are approved for children, and this number is even less for infants [ ] . this results in a lack of detailed pharmacokinetic, dosing, adverse effect, and efficacy data for appropriate medication management in children. as well, due to the lack of studied indications in children, there is little impetus for manufacturers to make formulations appropriate for children and so formulation issues related to availability, palatability, excipients, or measurability are commonplace. due to the abovementioned factors, children are at higher risk of medication errors and have a higher risk of harm from medication errors, so the pharmacist plays an important role in caring for infants and children who use medications [ ] . approximately % of pediatric emergency department visits are medication-related, of which / are deemed preventable (examples include adverse drug reactions, sub-therapeutic doses, or non-adherence due to a variety of factors) [ ] . there are an estimated . adverse drug reactions per inpatient admissions in pediatrics, of which % would be considered preventable [ ] . statistics like this highlight the importance of a complete pharmacist assessment for children using medications. in many ways, assessment of a pediatric patient is not different than assessment of an adult patient. pharmacists should gather information on medical history, medication history, medical conditions, and any other relevant information, and then ensure that all medications are indicated, dosed appropriately, effective, safe, and adhered to. however, each of these steps contains nuances for infants and children. there may be additional steps within each component of the assessment, and there is a significantly smaller evidence base to support decisions and judgment calls made within each step of the assessment. one of the major nuances between pediatric and adult assessments is the need to consider pharmacokinetic ontogeny, or pharmacokinetic differences based on the age of the child. while it is not surprising that there are pharmacokinetic differences between children and adults, there are also important differences between premature newborns, term newborns, infants, toddlers, schoolage children, and adolescents. table . provides a summary of major pharmacokinetic considerations in infants and children. this variability in pharmacokinetics makes dosing medications in children especially challenging as there is no "standard" dose of a medication. medication doses may vary based on cga, pna, as well as body weight or surface area. most notable is the need to use neonatal (not pediatric) dosing in newborns as the first few months of life are characterized by rapidly changing organ function (renal and hepatic most importantly) as well as changes in drugs' volume of distribution. typically, newborns are characterized by reduced renal and hepatic clearance at birth (especially with premature birth), which develops rapidly in the first month of life and reaches adult values at months to year of age. childhood is typically characterized by excellent renal and hepatic clearance, even exceeding that of adults in some cases. normal clearance values approach that of adults around adolescence. this is an oversimplification, given that different aspects of renal and hepatic clearance develop at different rates. full reviews of pharmacokinetic differences in children can be found in kearns et al. [ ] and bartelink et al. [ ] . by selecting age-appropriate doses, the pharmacokinetic differences that occur throughout childhood are taken into account. all pharmacists should ensure that medication doses in children are age and/or weight appropriate by consulting neonatal and/or pediatric dosing references with each and every prescription. in pediatric practice, the gathering of patient history is often not done with the patient themselves. until children are mature enough to provide this information themselves (note that this age varies depending on the child), parents and other caregivers are relied upon to provide an accurate history of the patient's illness(s) and medication(s). this provides an extra challenge to history gathering as the most appropriate person may not be available to provide this history, depending on the circumstances of the child's illness. changing custody or living arrangements may impact a caregiver's ability to provide a history, or one parent may be "in charge" of the medical care of the child and another caregiver might happen to be the one present at the time of pharmacists' information gathering. additionally, information related to symptoms of illness will not be provided first-hand, but rely on observations made by the caregiver. this introduces a source of potential inaccuracy or missing information that is not as commonly encountered when patients provide their own history. while medical histories of children tend to be shorter than that of adults, this is not always the case and many pediatric patients may have long medical histories before they reach school age. gathering this information is not different than gathering it for adult patients using a combination of patient (caregiver) history corroborated by medical records. an important difference to note is that in infants (especially those in the first months of life), maternal pregnancy and delivery history is relevant and should be gathered wherever possible as well. maternal conditions during pregnancy and the circumstances of delivery may be very relevant to an infant's medical care. for instance, a mother using methadone for a substance abuse condition may result in her infant developing signs and symptoms of withdrawal several days after discharge home. likewise, whether or not a mother received intrapartum prophylactic antibiotics is directly related to the infant's risk of group b streptococcus infection in the newborn period. very few medications are contraindicated in breastfeeding, but knowing if an infant is receiving even small amounts of medications via breastmilk may be relevant if concerns arise regarding a potential drug interactions or adverse effect. as with medical history, medication histories are often shorter in duration and length in children as compared to adults. again, there are exceptions to this in children with complex medical needs. all relevant details collected for adult medical histories should be collected for pediatric patients, with some additional factors to consider. many pediatric medications do not come from the manufacturer in appropriate formulations for administration to children, and thus asking about the formulation is an important step in pediatric medication history. extemporaneously compounded liquids are especially risky for creating confusion, as often caregivers know the volume they provide to the child but not the concentrations. if there are multiple concentrations available due to variability in the "recipe" followed by the pharmacy during compounding, this can lead to dose errors and subsequent sequelae (see box . for an example). if there are any questions regarding the strength of a formulation or volume given, call the pharmacy that provided the previous fill and clarify what was provided. medications in tablet form (except many sustained or controlled release formulations) may be crushed or dissolved for ease of administration and the appropriateness of this practice should be assessed by the pharmacist depending on the size of the tablet, ease of splitting, and the possibility of alternate dosing intervals (e.g., a daily dose of asa mg can be delivered as a half tablet [ mg] every other day instead of a quarter tablet [ mg] every day). some medications may be given in a "dissolve-adose" manner, whereby a tablet is crushed and suspended in a small amount of liquid, then the dose is measured from the resulting suspension. certainly, accurate dosing in this situation relies on appropriate suspension of the tablet, and this should be considered when doing an assessment of the patient's dose/response. there is no commercially available clonidine oral liquid on the market, so it is commonly compounded by pharmacies for use in infants and children who cannot swallow tablets or who require very small doses. a -kg child named colin is discharged from a hospital with a prescription for clonidine micrograms po q h. his parents fill the prescription at the outpatient even with commercially available appropriate formulations, administration of pediatric medications can be especially challenging. literature shows that measurement errors are common in caregivers of children and so observing the caregivers measure (and administer if appropriate) the medications may provide insight into dosing appropriateness [ ] . considerations regarding the measurement device should also be made. household teaspoons are not appropriate for measuring medications, and even some medication syringes do not have appropriate markings for accurate measurement of small doses. ensuring an appropriate measuring device is an important part of a pharmacist's assessment of dosing accuracy ( fig. . ) . likewise, how a caregiver gives the medication to the child may be relevant. medications mixed in a small amount of food/milk immediately prior to administration is appropriate, but if it is mixed in a large amount that the child does not consume all of, the dose taken will not be correct. medications given on an "empty stomach" or to be avoided with dairy products are not likely to be given according to these restrictions in new-born infants who typically feed every - hours. in these cases, the medication may be given with feeds (formula or breastmilk) for ease of administration, but a slightly higher dose may need to be used empirically, or the dose may be titrated up based on monitoring parameters (e.g., levothyroxine based on tsh). if this occurs, the administration conditions should be kept consistent for the individual patient, even if "manufacturer recommendations" suggest otherwise. parents and caregivers may ask if it is appropriate to mix all of a child's medications together in one syringe/cup prior to administration. this practice should ideally be discouraged as it may contribute to inaccurate measurement, potential incompatibilities, and will present challenges with re-dosing or estimating the portion of dosages consumed if only part of the "mixture" is taken/ spit-up. other things to consider in the medication history of infants and children include medication storage, timing, and palatability. depending on the frequency of administration of a medication and the child's schedule (school, activities), mediation may not always be stored in an ideal manner. medications may have to go to the soccer field or to the day home, for instance, and storage conditions may be affected during transitions. the timing of medications may be impacted by adults' schedules or bedtimes. for instance, if a medication is meant to be given every hours around the clock, it may have to be given four pharmacy within the hospital on their way home. the outpatient pharmacy provides them with ml of micrograms/ml compounded clonidine suspension with instructions to take ml four times a day. colin's parents go to their neighborhood pharmacy for the next refill. that pharmacy only has a recipe for clonidine micrograms/ml oral liquid and so fills the prescription with that suspension (with instructions to give . ml four times a day). at home colin's parents are used to giving ml four times daily and so continue to do so. in a couple of days, colin is acting lethargic and weak. his parents take him to the nearest emergency department and while they are reviewing the medications with the team, the pharmacist there discovers the error -a times overdose of clonidine. times daily (qid) instead to accommodate bedtimes. lastly, an assessment of the palatability of the medication formulation and the caregiver's report of how often the child takes/receives their full dose should be completed. these types of issues will be further explored in the section on adherence assessment. like in the adult setting, "is this therapy indicated?" is an important question to be assessed by the pharmacist. due to the relative lack of studies in pediatric patients, often medications that do not have an official indication in pediatrics are used (pediatric use is not included in the product monograph). because of the lack of appropriate information in the product labeling, alternative data sources need to be accessed to assess the use of the medication in an infant or child. pediatric medication information sources should be available and reviewed to aid in this part of the assessment, but primary literature may also have to be consulted more often than in adults. assessing whether or not an agent is "firstline" or "ideal" for a child includes special considerations that may not be as necessary in adult patients. an agent may be selected not because it has the best data to support it, but because it is the only agent with pediatric dosing information, or because it is the only one with a formulation appropriate for the age group (or it has the best tasting formulation). a medication may be selected because it has a less frequent administration schedule, accommodating a child's school or activity schedule, or to limit the number of dosage times due to unpleasantness of administration (e.g., bad taste or painful injection). in this sense, assessment of whether or not a medication is the most appropriate choice for the patient is increasingly challenging. because of differences in pathophysiology or pharmacodynamics in pediatric patients as compared to adults, an "appropriate" or "ideal" medication choice in adults may be quite different in pediatrics. likely pathogens in bacterial infec-tions differ between age groups, the causes of thrombosis or hypertension are very different in children as compared to adults, and systemic steroids can have very different safety profiles depending on the age of the child. for this reason, complete assessment of whether or not a medication is "indicated" for a child requires much more in depth look into references than for a typical adult patient. pediatric or neonatal guidelines, reviews, studies, and other literature need to be consulted for this component of the assessment. one cannot rely on what is appropriate in adult patients to be appropriate in newborns, infants, or children. as alluded to above, comprehensive dose assessment in pediatric patients requires several more steps than in adult patients. first, the pharmacist needs to determine how the medication dose is characterized: by gestational age (in newborns), post-natal age, by body weight, by body surface area, or some combination of the above. once that is determined, the pharmacist must gather the needed information to categorize the patient into the appropriate dosing range using a pediatric dosing reference. a common error is to use pediatric doses for neonates; therefore, the age of infants needs to be confirmed. in addition to selection of the appropriate dosing category, the pharmacist must also ensure that the appropriate dose for the indication in question is considered. doses for medications can vary significantly for different indications. for example, the asa dose for antiplatelet effects is - mg/kg/day, where anti-inflammatory doses range from to mg/kg/day. the next step is another common source of error: calculations. doses should never be estimated and calculations should never be done in the pharmacist's head. a calculator is an essential tool for pediatric pharmacists. pediatric doses are typically listed in mg/kg/day divided qxh, or can be listed as mg/kg/dose given qxh. this is a common source of error and must be carefully checked by the pharmacist. while it is common to see pediatric doses that are higher than adult doses on a mg/kg basis because of the pharmacokinetic differences noted above, it is important to note that adult maximum daily doses (total mg) should typically still be observed in pediatric patients. box . provides an example. many medications that children use are on a short-term basis only (e.g., antibiotics); however, with medications that are used on an ongoing basis, pharmacists need to ensure that doses are checked with each fill. children, and especially infants, grow quickly and medications dosed on a mg/kg basis may need adjustment for growth. each fill is an opportunity for the pharmacist to assess the need to continue a medication, its apparent effectiveness and the presence of any adverse effects as part of the decision as to whether or not to increase the dose (or discontinue it altogether, if appropriate). lastly, the pharmacist needs to identify an appropriate formulation; the one that allows the dose to be measured accurately, is (reasonably) palatable, and has suitable stability. as mentioned above, this may be a significant challenge on its own. as an additional challenge, newborns < weeks cga should ideally not use medica-tions containing preservatives (e.g., benzyl alcohol, propylene glycol) and children should ideally not use medications containing alcohol. this is due to adverse effects reported with these additives (gasping syndrome, metabolic acidosis, hypoglycemia) [ , ] . however, if an alternative, preservative-free and/or alcohol-free product is not available, the benefit of the medication should outweigh the risks from a small dose of alcohol or preservative. in pediatrics, often patients are non-verbal or are not at a developmental stage where they can describe their symptoms and so a caregiver's external assessment of the patients' symptoms must be relied upon. there is a greater focus on observation of signs and symptoms when determining a patients need or response to medications. while these observations have some degree of objectivity, many assessments done in this way may include some subjectivity. for this reason, other objective measures may be relied upon more frequently in younger children than in older children or adults. for instance, the objective presence of a fever and results of key lab values (e.g. normalization of white blood cell count) can supplement a parent's subjective report of a child feeling better and acting more "like himself" in an assessment of an infection's response to antibiotics. pain scoring tools that include a measurement of heart rate, blood pressure, as well as an observation of the infants' behavior can add an objective component to a parent's assessment of their child's pain. there are a variety of pediatricspecific assessment tools for a variety of medical conditions and pharmacists should seek those out when needed. table . includes some examples of condition-specific assessment tools for infants and children. it should be noted that dismissing a parent's assessment of their child due to its subjectivity is not advised. caregivers know typical behavior in their children and slight changes in behavior (e.g., poor feeding, decreased energy, altered sleep) can be important signs of rex is a -year-old boy being treated for a pneumonia using amoxicillin. he weighs kg. his prescription states: mg kg day m g po tid days / / = × while mg/kg is much higher than most adults would receive, this is an appropriate dose for pneumonia in children. however, the adult maximum daily dose of amoxicillin for pneumonia is mg, so rex's dose should be adjusted to mg po tid even though this will only be mg/kg/day. illness or adverse medication effects in children. having said that, if subjective observations contradict objective measures, one should proceed with caution. when assessing a child's illness, there are some red flags that should illicit immediate referral to medical care. table . depicts a list of the red flag symptoms that prompts referral in pediatric patients. physical assessment in pediatrics can be limited by both the pharmacists' knowledge of the nuances of pediatric physical exam and by the patient's tolerability of the exam itself. it is beyond the scope of this chapter to describe the differences in physical exam between children and adults, but vital sign assessment can be a simple addition to a pharmacists' assessment in many cases, and the major differences between children and adults are summarized in table . . as in adults, lab values are an important part of assessing both the efficacy and toxicities of medications in children. table . outlines some of the most commonly used laboratory values and how they differ between children and adults. monitoring renal function is especially important for pharmacists, both for assessing the need for dose adjustment in renal dysfunction, but also for monitoring for nephrotoxicity of medications. because normal ranges of serum creatinine in children are relatively wide, serum creatinine values can double, reflecting potential acute kidney injury, but remain in the "normal" range. it is important therefore for pharmacists to follow trends in serum creatinine rather than just absolute values. in cases where the pharmacist needs to estimate renal function, the formula used in children differs from that used in adults. the most accurate and commonly used formula is called the "bedside schwartz" formula. equation . outlines this important formula. estimation of gfr in infants and especially in newborns is challenging as renal function continues to develop rapidly after birth, with most infants reaching full renal function around months of age. again, following trends in serum creatinine (expecting a downward trend in the first - weeks of life) is the most effective method of assessing renal function. other factors such as urine output and hydration should also be considered in the overall assessment of renal function. renal dysfunction in children is fortunately uncommon, and all children with renal dysfunction should be followed by a pediatric nephrology team. "bedside schwarz" formula for estimating glomerular filtration rate (gfr) in children > year of age [ ] : rash with fever fever in infant < months old very fast or very slow heart rate (see table . for age-based normals) elevated respiratory rate at rest (see table . for age-based normals) central nervous system change in/loss of consciousness lack of response to pain decreased tone/floppiness seizure-like activity cardiovascular very fast or very slow heart rate (see table . very fast respiratory rate (see table . for age-based normal values) labored or noisy breathing irregular or absent respiration dermatological skin color changes -dusky/blue very dry lips or mouth genitourinary severely reduced/lack of urine output newborn - - "exercise" in infants is best represented by feeding, thus poor feeding/sweating while feeding may be a sign of cardiac compromise. congenital heart defects are a common cause of cardiac compromise in infants -echocardiography is required to assess heart structure. it is important to assess a child's heart rate at rest and not when they are crying/upset because infectious diseases are commonplace in children, interpretation of bacterial cultures is worth mentioning. sputum cultures are challenging as contamination with saliva is common. it is therefore necessary to note the presence of endothelial cells and/or nasopharyngeal flora in these cultures as they may indicate a lack of appropriate specimen. urinary samples, likewise, can be difficult to obtain appropriately without catheterization and thus have a higher likelihood of contamination by skin flora. lastly, there is a higher rate of false- platelets same as adults newborns may have slightly lower platelets counts, with a lower limit of × /l electrolytes same as adults newborns may have slightly lower sodium (some sodium wasting due to renal immaturity) and higher k (normal state of potassium retention) values than infants and children serum phosphate also tends to be higher in infants and children due to high needs during bone growth and high energy needs creatinine newborns - μmol/l infants - μmol/l children - μmol/l adolescents - μmol/l note that creatinine in the first few days of life often reflects maternal renal function, and a downward trend is expected in the first weeks of life negative blood cultures. blood cultures in children are typically limited to two bottles (adults typically use four bottles), and use smaller volumes of blood, resulting in a higher risk of false-negative results. the reduced number of bottles also makes distinguishing between pathogenic growth and contamination more difficult. in adults, growth of skin flora in one out of four blood culture bottles is typically associated with contamination; however in children growth of the same pathogen in one out of two bottles is less convincing as contamination. for these reasons, it is not uncommon to empirically treat a child for an infection despite negative cultures, purely based on signs and symptoms of infection. this represents a particular challenge for pharmacists attempting to tailor antibiotic therapy to infectious pathogens. antibiotic therapy may have to be assessed based on "typical" pathogens rather than actual. when considering "typical" pathogens, these vary by age and so pharmacists need to consider this when assessing the appropriateness of antibiotic therapy. another major factor in the "likely" bacteria pathogens is immunization status, and pharmacists should be familiar with vaccination history in patients presenting with infectious diseases. for instance, unimmunized children are at much higher risk of infection with hemophilus influenza type b (hib), which can be a significant pathogen in both meningitis and pneumonia. table . outlines common pathogens in common infections throughout infancy and childhood, assuming vaccination in accordance with local immunization programs. an assessment of adherence in children should include not only overt nonadherence (e.g., the child dislikes the taste and spits it out, or the parent forgets to give it on the weekends) but also "covert" nonadherence (e.g., parents make measurement errors, or product is used beyond its stability date). asking to see the caregiver show the dose given as measured, and an examination of the medication bottles can assist with this. questions regarding the appropriate storage of medication are also important (e.g., using coolers for refrigerated medications on long trips). the variability of dosages required for children often make the use of solid dosage forms impractical. if the tablet is appropriate to split, and if a child's dose can be rounded to accommodate a half (or even quarter) tablet, this may be the most practical approach. however, in younger children and for smaller doses, the use of oral liquids may be the only solution. oral liquids should be mea-sured in appropriately sized devices. often, especially in infants, doses may be so small that accurate measurement becomes challenging. doses less than ml are ideally measured in ml (or even . ml) oral syringes in order to maximize accuracy. typically, manufacturer guidance dictates that doses < % of the syringe size cannot be accurately measured (e.g., no less than . ml in a ml syringe or . ml in a . ml syringe). occasionally, unique solutions to measurability issues need to be explored. very small doses of some injectable products (e.g., enoxaparin doses < mg) may be most easily measured using an insulin syringe (e.g., unit = . ml = mg enoxaparin). very small doses of oral medications only available in capsules may require (very careful) preparation of powder papers which involves weighing of powders from capsules and packaging in specially folded papers. whatever the situation, pharmacists must ensure that parents and caregivers using medications in children have an accurate method of measurement available as well as a practical approach to giving the medication. if a medication must be delivered to the child as an unpalatable oral liquid there are some approaches to helping mask the taste of the medication. in infants, most medications can be mixed with a small amount of formula or breastmilk to improve palatability. it is important to instruct parents or caregivers not to mix medications in a full volume of feed (i.e., a full bottle) as the complete dose may not be delivered if the full amount of feed is not taken. older children may find eating frozen treats prior to taking the medication may numb the tongue enough and reduce the bad taste. similarly, allowing the child to choose a food or drink to wash the medication taste away may be helpful. concentrated, sugary beverages or foods (honey, chocolate syrup) or other strongly flavored foods (cheeses) may help mask or remove the taste from the child's mouth. administering oral medications to children can be a significant challenge in itself. after measurement with an appropriate device, oral liquids can be given to infants mixed with a small amount of milk/formula through a bottle nipple, or for older children they can be mixed in a small amount of palatable food or liquid before administration. alternatively, oral liquids can simply be expelled into the cheek (where there are no tastebuds) followed with a drink of palatable liquid. iron liquid can stain teeth, and so rinsing the mouth is important (can also use a straw if the mediation has been diluted in a liquid). note that these precau-tions are unnecessary in infants without teeth, and most important in those with their permanent teeth. the ability to swallow oral solid dosage forms makes oral medication administration easier, and this can usually occur around age or years. if children struggle with pill swallowing, they can practice with candies with increasing sizes (e.g., start with sprinkles, slowly increasing the size of the candies up to the target tablet size. usually small jelly beans are sufficiently sized for most medications). children can place the medication/candy on the back of their tongue, tilt their head back, and have a large drink of liquid to facilitate this. in rare cases, infants and small children can swallow small oral dosage forms with appropriate instruction from qualified professionals. an example is levothyroxine, where crushed tablets and suspensions may not provide the necessary accuracy and part-tablets are the preferred dosage form. medications to be administered via feeding tubes (e.g., nasogastric tubes, gastrojejunal tubes) can be administered without palatability concerns; however the intestinal location of the medication administration should be considered in the context of the intestinal administration site (e.g., ensure the medication can be absorbed if administered into the jejunum), and the tubes should be flushed with water afterward to ensure complete delivery of the dose. as a final comment on adherence assessment, it is important to consider adolescents specifically. increasing independence with medication use and administration is often given to adolescents as they move toward adulthood, which requires a change in the pharmacist's approach. where previously assessment was conducted primarily with the caregivers on behalf of the child, the pharmacist should begin to include the adolescents in these conversations in an attempt to build their health literacy and knowledge of their conditions/medications. also of note, adolescents often become more self-conscious of their medical conditions and associated medication use, and strategies to increase the discreteness of ensure caregivers have a practical approach to measurement and administration of the required doses assess for palatability issues observe measurement and/or administration of medications by caregivers help transition adolescents to adulthood and independent medication use their medication use may be appreciated and improve adherence. for example, selection of a dry powder inhaler instead of a metered-dose inhaler with spacer device, or choosing a once or twice-a-day administered agent instead of one that has to be used at school. considerations such as these should come into a pharmacist's assessment as their pediatric patients move toward adulthood. assessing medication use in children has many similarities to that in adults, and should be approached in a similarly systematic way, bearing slight nuances in mind. table . summarizes the approach to pediatric assessment, highlights common sources of errors, and provides some tips for minimizing these errors. • assessment of dose requires additional steps in children as compared to adults -categorization by age/weight, calculation of appropriate dose, and determination of accurate measurement processes are a few major steps that need to be included. • infants and children have variable pharmacokinetic and pharmacodynamic parameters, and thus dosages vary widely. the use of pediatric/neonatal references is essential for appropriate dosing and indication assessment by pharmacists. • finding appropriate formulations for children is a challenge for pharmacists. careful assessment of doses/concentrations, measurability, and method of administration need to be included in the overall medication assessment for infants and children. • interpretation of diagnostic tests and vital signs varies in children and a basic understanding of these differences is important for pharmacists assessing children medication therapy. canadian institute for health information the institute the expert panel on therapeutic products for infants, children, and youth, council of canadian academies prescription medicine use by one million canadian children prescription drug dispensing profiles for one million children: a population-based analysis medication use among children < years of age in the united states: results from the slone survey koda-kimble and young's applied therapeutics medication errors in children: a descriptive summary of medication error reports submitted to the united states pharmacopeia medicationrelated emergency department visits in pediatrics: a prospective observational study frequency and preventability of adverse drug reactions in paediatric patients developmental pharmacology -drug disposition, action, and therapy in infants and children guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations liquid medication errors and dosing tools: a randomized controlled experiment toxic additives in medication for preterm infants safety of "inert" additives or excipients in paediatric medicines the premature infant pain profile: evaluation years after development the flacc: a behavioral scale for scoring postoperative pain in young children the faces pain scale -revised: toward a common metric in pediatric pain measurement state behavioral scale (sbs) a sedation assessment instrument for infants and young children supported on mechanical ventilation assessing distress in pediatric intensive care environments: the comfort scale the childhood asthma control test: retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma pram score as predictor of pediatric asthma hospitalization red flags in common pediatric symptoms toronto: sickkids; c . pediatric physical assessment uncomplicated pneumonia in healthy canadian children and youth: practice points for management normal ranges of heart rate and respiratory rate in children from birth to years: a systematic review of observational studies fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. [internet] national institute of health physiologic anemia of the newborn infant renal potassium handling in healthy and sick newborn ontogeny of renal sodium transport measurement and estimation of gfr in children and adolescents otitis media urinary tract infections in children the author wishes to express gratitude to jenny wichart and kristen blundell for their thoughtful reviews and comments. key: cord- -hiylqqie authors: namasivayam, abirami; soe, than; palman, jason title: atypical case of covid- in a critically unwell -week old infant date: - - journal: bmj case rep doi: . /bcr- - sha: doc_id: cord_uid: hiylqqie the effect of covid- by sars-cov- on the paediatric population remains an evolving mystery. early reports from china stated that children seem to be unharmed by its dangerous effects, yet more recently there has been evidence of a systemic inflammatory response in a small number of children who are affected. we discuss a -week-old male infant who presented atypically with severe covid- infection. to our knowledge, he is the youngest reported case in the uk to require mechanical ventilation and intensive care treatment as a direct result of covid- following horizontal transmission. this case has generated several learning points with regard to atypical presentations of covid- and identifying a potential cohort of ‘at risk’ infants. we also highlight a number of new challenges that have arisen for paediatricians and anaesthetists providing airway management for infants with sars-cov- . the world has unfortunately entered into a new challenge by facing the global pandemic of covid- . at the time of writing, more than countries have been affected with over million confirmed cases and over deaths. even months from the first reported case there remain vast uncertainties surrounding the virus. there has been extensive evidence which highlights the discriminatory nature of covid- . while the elderly, immunocompromised and black asian and minority ethnic community remain its prime victims; children seem to be largely spared by its effects. why and how children have this tolerance are crucial unanswered questions. between december and february , china reported a total of cases of confirmed covid- . only nine of these cases were infants (aged days to year), none of whom required intensive care, mechanical ventilation or had severe complications. choi et al reviewed the epidemiology and clinical presentation of coronavirus in children as of march , reporting . % ( - years) in china, . % ( months to years) in singapore, . % ( - years) in italy, % ( - years) in republic of korea and . % ( - years) in australia. a larger nationwide study investigating paediatric cases across china reported that % cases had fever, . % cases presented as acute upper respiratory tract infection, . % as mild pneumonia and . % cases were critical; unfortunately, the specific age groups and comorbidities were not reported. the royal college of paediatric child health has recently released evidence of children responding to covid- with a systemic inflammatory response. however, greater awareness and investigation for children with suspected infection is needed. we report the case of a -week-old male infant who presented atypically to the commonly described features and deteriorated rapidly in our district general hospital (dgh). we explore the learning points from this case. a -day-old . kg ex-premature male infant was brought to the paediatric emergency department (ped) with reduced feeding and lethargy; he was + weeks corrected gestation at the time. he was born at + weeks gestation via caesarean section due to maternal type diabetes mellitus and was admitted to the neonatal unit for support of prematurity and respiratory distress. the antenatal history was unremarkable. he was the first child born to parents, both white caucasian. although maternal steroids were given, he required surfactant at hours of age and mechanical ventilation for hours before weaning to continuous positive airway pressure (cpap) for days, and later high flow nasal cannula (hfnc). chest x-ray at day of life is seen in figure . he was off all respiratory support by day of life and quickly established breastfeeding. he was treated with antibiotics for hours with suspected sepsis. he was discharged home at day of life. since being discharged from the neonatal intensive care unit (nicu), he had been breastfeeding and thriving well with no other concerns. his mother brought him to ped because he had not fed well over the last hours and his activity levels were reduced. he had no fever, no increased work of breathing and no cough. on initial assessment, he was alert but quiet. his heart rate was bpm, his respiratory rate was /min, his saturations were % and despite being fully dressed, he was hypothermic with an unrecordable axillary temperature. high flow facial oxygen was given which improved his oxygen saturations to above %. although his respiratory rate was reduced, there were no other clinical signs of respiratory distress-no grunting, no recessions and his chest was clear with good air entry. he was haemodynamically stable with capillary refill time under s. intravenous access was obtained to deliver ceftriaxone and amoxicillin for suspected sepsis; his blood gas at this time showed a partially compensated respiratory acidosis (table ) . during this period he remained alert but was particularly quiet with minimal response to the interventions being performed. shortly after achieving intravenous access, the infant unexpectedly became unresponsive and bradycardic with heart rate reducing to - bpm with minimal respiratory effort. effective bag valve mask (bvm) ventilation was established and an intravenous fluid bolus was given. the heart rate rapidly improved on warming with a bair hugger and warmed intravenous fluids. during rewarming he became increasingly alert and responsive, however, his respiratory effort gradually deteriorated with tachypnoea, grunting, nasal flaring and intercostal recession. chest auscultation remained clear, heart sounds were normal with palpable femoral pulses and no hepatomegaly. the decision for cpap escalated to mechanical ventilation as he then developed frequent apnoeas. his rapid clinical decline within a short time frame and a suspicious chest x-ray raised the likely possibility that this was all attributed to covid- (figure ). as per national and local resuscitation guidelines, minimal staff all wearing full personal protective equipment (ppe), were present during intubation. a size cm endotracheal tube was used; however, ventilation was more difficult than anticipated reflecting a rapidly evolving acute respiratory distress syndrome (ards). to improve ventilation, the infant was mechanically ventilated using a bvm which maintained stable observations. haematological markers revealed thrombocytopenia; platelets × /l while the haemoglobin concentration was g/l, white cell count . × /l, neutrophils . × /l and lymphocytes . × /l. his renal function and electrolytes were normal; his albumin was low at g/l with a raised alanine aminotransferase of iu/l and raised c reactive protein (crp) of mg/l. his clotting studies were normal. table demonstrates his progressive blood gases. his initial chest x-ray showed bilateral consolidation of the lung parenchyma and the subsequent x-ray performed after intubation showed bilateral 'ground-glass infiltration'. the worsening radiological findings correlate to the clinical deterioration of the patient and illustrate evidence of evolving ards. his nose and throat swabs for coronavirus pcr returned after hours as strongly positive for sars-cov- rna. the patient was transferred to a tertiary unit where he required high frequency oscillation ventilation for hours with a trial of inhaled nitric oxide and intermittently kept in prone position. he was conventionally ventilated for a further days before weaning to cpap and later hfnc; he was off respiratory support by day . he was given a -day course of remdesivir along with cefotaxime, clarithromycin and acyclovir and had been on ionotropic support via a peripherally inserted central catheter line. his echocardiogram was structurally normal with normal ventricular function. he unfortunately developed a femoral thrombus for which he remains on dalteparin. he has been discharged from hospital, is developing well and being regularly monitored by the local dgh. at present there are few reports of paediatric patients requiring intensive care support with confirmed covid- . to the best of our knowledge, this is the youngest reported case of sars-cov- following horizontal transmission in the uk. on presentation to ped the patient had no cough or fever symptoms which have been extensively reported as common clinical manifestations of covid- . similarly, the distinguishing biochemical abnormalities associated with covid- positive patients, specifically leucopenia and significantly elevated crp, were not observed in our case. as noted in table , the initial blood gas of the infant demonstrates a mixed acidosis and metabolic alkalosis. a plausible explanation for this could be that the infant had been in respiratory distress prior to presentation. this may also account for his hypothermia, lethargy and subsequent apnoeas; all of which suggest some neurological involvement. this case demonstrates the need for vigilance in considering covid- infection in infants presenting with less discriminatory symptoms such as lethargy or reduced feeding. in adults, comorbidities such as cardiovascular disease, diabetes and hypertension are associated with significant morbidity when infected with covid- . it remains a challenge to identify the most vulnerable groups among children. dong et al report a case series of paediatric patients with confirmed and suspected coronavirus; infants (< year) were noted to be particularly vulnerable. thirteen cases were 'critical'-quickly progressing to ards±shock, encephalopathy, myocardial injury, heart failure, coagulation dysfunction and acute kidney injury-seven of whom were less than year of age. the authors did not report the patient's comorbidities. there is evidence that the respiratory tract of premature babies has an immature mucosal barrier with a reduced mucociliary clearance, increasing their vulnerability to pulmonary infections. although our patient was corrected to weeks at presentation, his prematurity may have contributed to the increased risk of contracting the virus and the cascading response that followed. hong et al hypothesised that the reason for the small number of infants affected by the virus was because of their low risk of unusual presentation of more common disease/injury exposure to the virus. since the infant was discharged from the neonatal unit days before presenting to the emergency department he was within the - day incubation period for covid- . we must therefore consider the possibility of exposure before discharge from the neonatal unit, especially since he had remained at home isolating with his parents following his discharge. however, it is also important to note that there is no substantive evidence for vertical transmission from covid- positive mothers to their baby, and therefore neonatal units are considered a low risk area to covid- . it would have been valuable to have identified sources of potential exposure with contact testing and tracing. it is unfortunate that at the time of presentation, the 'nhs test and trace' service had not been implemented in the uk and therefore the route of transmission and acquisition of covid- remains unsolved. covid- is highly contagious and there is a large concern for healthcare staff involved in airway management for patients with the virus. guidance released by the resuscitation council uk and cook et al is being used to maintain the safety of staff while performing high risk aerosol generating procedures including intubation ; however, the guidance remains quite limited for infants. there are also challenging non-technical factors to consider when providing advanced airway management for an infant with suspected covid- . these factors included designating the most appropriate person to carry out intubation, use of cuffed endotracheal tubes, the number and selection of health professions involved during intubation, and communication barriers with full ppe and designated contained areas for managing the patient. understanding the clinical course of covid- in the paediatric population is continually evolving. although cases of critically unwell infants remain uncommon, this particular group may be more vulnerable. an appreciation for early identification of subtle symptoms, such as reduced feeding, lethargy and hypoxia in the absence of respiratory distress, will enable prompt escalation of care and appropriate stabilisation. although there is no specific guidance on airway management for infants with suspected covid- , it is important to keep up-to-date with local and national guidance to ensure patient and staff safety. further epidemiological reports will hopefully uncover the vast expanse of symptomology of the heterogenic covid- positive paediatric cohort and the optimal management of the virus. contributors an contributed to the concept, write up and literature search of the case as well has being involved in the patient's initial care. ts was the consultant involved in the patient's care. jp reviewed, revised and edited the manuscript. funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. chest x-rays of the patient pre and post intubation . hours apart, showing the transition from bilateral consolidation to bilateral ground glass infiltration due to evolving ards. ards, acute respiratory distress syndrome. ► covid- may present as subtly as lethargy and poor feeding in infants. ► infants may present with hypoxia in the absence of respiratory distress. ► more understanding on the effects of covid- in infants, especially premature infants is required. world health organization. coronavirus disease (covid- ) situation report covid- virus and children: what do we know? novel coronavirus infection in hospitalized infants under year of age in china epidemiology and clinical features of coronavirus disease in children royal college of paediatrics and child health. guidance-paediatric multisystem inflammatory syndrome temporally associated with covid resuscitation council uk statement on covid- in relation to cpr and resuscitation in paediatrics consensus guidelines for managing the airway in patients with covid - clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis hyperinflammatory shock in children during covid- pandemic covid- in children: an epidemiology study from china why are preterm newborns at increased risk of infection? clinical characteristics of novel coronavirus disease (covid- ) in newborns, infants and children the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application incubation period and other epidemiological characteristics of novel coronavirus infections with right truncation: a statistical analysis of publicly available case data clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records coronavirus disease (covid- ) and neonate: what neonatologist need to know patient consent for publication parental/guardian consent obtained.provenance and peer review not commissioned; externally peer reviewed.copyright bmj publishing group. all rights reserved. for permission to reuse any of this content visit https://www.bmj.com/company/products-services/rights-and-licensing/permissions/ bmj case report fellows may re-use this article for personal use and teaching without any further permission.become a fellow of bmj case reports today and you can: ► submit as many cases as you like ► enjoy fast sympathetic peer review and rapid publication of accepted articles ► access all the published articles ► re-use any of the published material for personal use and teaching without further permission if you have any further queries about your subscription, please contact our customer services team on + ( ) or via email at support@bmj.com.visit casereports.bmj.com for more articles like this and to become a fellow key: cord- -qwyddp authors: candy, david c.a.; devane, seán p. title: role of micro-organisms in necrotizing enterocolitis date: - - journal: semin neonatol doi: . /s - ( ) - sha: doc_id: cord_uid: qwyddp the frequency with which necrotizing enterocolitis occurs in outbreaks makes it likely that the illness can have an infective origin. immunological and non-immunological defences of the gastrointestinal are impaired in early life. consequently the gut of the preterm infant is predisposed to bacterial overgrowth. a wide range of pathogenic bacteria and viruses have been isolated from infants with necrotizing enterocolitis or detected histologically. the presence of bacterial metabolites in the breath, intestinal bullae (hydrogen) and urine (d-lactate) during the course of the illness is further confirmatory evidence. the presence of bacteria or bacterial products (such as exo- and endotoxin) in the circulation will lead to ischaemia of the intestine and other organs either directly or via mediators such as cytokines or platelet activating factor. future studies in necrotizing enterocolitis should be directed to understanding and modulating inflammatory mediators in necrotizing enterocolitis and preventing the disease with breast milk and nutritional supplements (glutamine, short chain fatty acids), chemoprophylaxis, and antibodies. witnessing an outbreak of necrotizing enterocolitis first-hand convinced one of us that this illness must have an infectious aetiology. despite strong indirect epidemiological evidence for such an aetiology, the search for a specific microbial cause has been frustrating. many species of micro-organisms have been isolated from infants with necrotizing enterocolitis; some of these are listed in table was responsible for a related disease, 'pig-bel', and the subsequent prevention of this disease by immunization with ~-toxoid, helped to stimulate the search for clostridia in necrotizing enterocolitis. darmbrand, a necrotizing enterocolitis occurring in adults in post-second world war germany was found to have the same aetiology. gram-negative bacterial colonization, mucosal integrity, host resistance, and necrotizing enterocolitis the intestinal flora of low-birth-weight infants differs from that of healthy, full term infants. the establishment of bowel flora in new-born infants receiving intensive care is a protracted process, with a limited number of strains being present initially [ ] , overgrowth of the intestinal tract with klebddla species has been suggested as a risk factor for necrotizing enterocolitis [ ] . there are many factors present in preterm infants which might predispose to bacterial overgrowth of the small intestine, some of which are listed in table . gastric acid production has been described as markedly decreased in the first month of life [ ] . although preterm babies can produce an acid intra-gastric ph, overgrowth of the stomach with bacteria in such babies is a frequent occurrence (b. patel and s. p. devane, unpublished observations) and may predispose to the development of an abnormal intestinal flora. the cleansing effect of normal gastro-intestinal motility is a further defensive mechanism against colonization of the small intestine by bacteria and the damaging effects of the by-products of fermentation of malabsorbed nutrients by bacteria; antro-duodenal motility is immature in preterm infants [ ] . in an analogous situation to pig-bel in which pancreatic insufficiency leads to decreased intraluminal destruction of ] -toxin, pancreatic insufficiency has also been described in low-birth-weight babies who developed necrotizing enterocolitis [ ] . pancreatic insufficiency was measured indirectly by faecal chymotrypsin activities. intestinal mucus provides non-specific protection to the intestine, by binding bacteria and bacterial toxins. this protective mechanism is poorly developed in the new-born mouse [ ] due to defective mucus production; the same may also apply to human infants. adequate intake of glutamine is important for the integrity of the small bowel mucosa and immune function [ ] . glutamine deficiency could occur in preterm babies on parenteral nutrition, or receiving artificial diets. decreased concentrations of short chain fatty acids in the colonic lumen could also decrease integrity of the colonic mucosa [ ] . the delayed establishment of a normal flora in preterm infants receiving intensive care [ ] could lead to deficiency of short chain fatty acids in the colonic lumen. interaction of this and other factors impairing the barrier function of the gastrointestinal mucosa could explain the frequent isolation of enteric micro-organisms from blood cultures of infants with necrotizing enterocolitis. the balance is a fine one, because the by-products of fermentation of malabsorbed nutrients by bacteria can damage the intestinal mucosa. must contribute to the parlous state of these patients and add to the endotoxaemia to which they are exposed. breast milk has been shown to contain specific cellular and antibody activity against a variety of bacterial, viral and food-related antigens. furthermore, it protects against necrotizing enterocolitis [ ] . both cellular and immunological defence mechanisms are immature in infancy. intraepithelial b lymphocytes are decreased [ ] . secretory iga production is virtually non-existent in new-borns [ ] . t lymphocytes are decreased in the intestinal mucosa of new-born animals [ ] . they are important in monitoring the integrity of the mucosa and may destroy cells colonized with an infecting agent. the strongest indirect evidence for a microbial aetiology arises from the epidemiology of the disease [ ] . during a survey lasting one year in the uk, of neonatal centres reported outbreaks. within the six units, of the cases were diagnosed within - days of each other. the clinical features of this group were indistinguishable from sporadic cases. one in three affected neonates have been reported to have a positive blood culture. the organisms isolated are unlikely to be causal and probably translocated from the bowel lumen through a damaged mucosa. nevertheless, such organisms oral vancomycin has been administered to lowbirth-weight infants identified as having a high risk of developing necrotizing enterocolitis prior to the introduction of oral feeds. necrotizing enterocolitis developed in of infants, compared with of low risk infants not given vancomycin. while the trial was not double-blind or randomized, this study [ ] suggests that vancomycin could have a prophylactic role. breath hydrogen concentrations have been studied prospectively in preterm infants as a potential aid to earlier diagnosis [ ] . maximum elevation of breath hydrogen occurred in infants - hours prior to the onset of necrotizing enterocolitis. the presence of elevated breath hydrogen concentrations indicates that bacteria are metabolizing luminal substrates. d-lactate, a product of bacterial metabolism, is found in the urine of infants with necrotizing enterocolitis [ ] . nine of infants with necrotizing enterocolitis had exposure of the thomsen-cryptantigen (t-antigen) with the titre of the antigen correlating with severity. the t-antigen is exposed by cleavage of n-acetylneuramic acid from the red cell surface; neuraminidase is produced by ci. perfringens, ci. butyricum and bacteriodes fragilis. this finding is indirect evidence for the presence of circulating bacterial neuraminidase, and neuraminidase-producing clostridia were isolated from two patients. necrotizing enterocolitis can be induced in neonatal rats colonized with klebsiella sp. and subjected to hypoxia or cold stress which reduce mesenteric blood flow [ ] . breast milk has been shown to be protective. necrotizing enterocolitis has been induced in infant rats by injecting platelet activating factor (paf) into the splanchnic circulation [ ]. platelet activating factor is a phospholipid secreted in response to injection of endotoxin (lipopolysaccharide component of gram negative bacterial cell wall). platelet activating factor may induce intestinal necrosis by release of the vasoconstrictor leukotriene c [ ] . when mesenteric blood flow is re-established the stage is set for reperfusion injury which can be prevented by free-radical scavengers such as superoxide dismutase, catalase or the xanthine oxidase inhibitor, allopurinol [ ] . various authors have cited the presence of inflammatory changes in necrotizing enterocolitis as evidence for an infective aetiology while others have emphasized that the appearances support an ischaemic aetiology. in a systematic review of patients from cleveland, ohio in which histological changes were correlated with clinical findings, ischaemic changes (tissue necrosis with loss of cellular detail but preservation of overall structure) were confirmed in patients of whom had mesenteric artery thromboses [ ] . acute (neutrophils) or chronic (lymphocytes, plasma cells and histiocytes) inflammation was seen in and bacterial toxins are capable of inducing a lesion resembling necrotizing enterocolitis. bacterial toxins previously implicated in necrotizing enterocolitis are listed in table . toxin a, produced by clostridium difficile induced necrosis of intestinal mucosa in vivo and in vitro [ ] the in vitro data indicating that a direct effect on the mucosa was responsible, rather than an effect on mucosal blood supply. the species has been implicated in necrotizing enterocolitis but is ubiquitous in healthy neonates [ ] . clostridium perfringens has been isolated from necrotizing enterocolitis and ] -toxin is involved in the analogous conditions of pig-bel. e. coli producing heat-labile enterotoxin were associated with two clusters of necrotizing enterocolitis [ ] . scheifele's group has suggested that staphylococcus epidermidis, which commonly colonize low-birth-weight infants including those with necrotizing enterocolitis produces a cell-damaging toxin resembling the delta toxin of staphylococcus aureus. the cytotoxin can induce severe mucosal necrosis in rat intestinal loops [ ] . they suggest that hypertoxigenic strains may be responsible for necrotizing enterocolitis. the effects of intestinal infections on mucosal blood supply have not been studied in detail, yet if such effects occur they could explain the link between mucosal infection and ischaemia. the anatomy of the microcirculation of intestinal villi of infant mice has been studied using a histochemical technique that specifically stained erythrocytes [ ] . over - days there was little variation between the same region of the gut with the exception of the distal ileum which was markedly less well perfused with erythrocytes in day old mice than older mice. in the upper intestine, the capillary beds were more complex than in the middle and lower regions. if the anatomy of the villous microcirculation is duplicated in human villi, this may contribute to the vulnerability of the distal small intestine to ischaemia. age-matched infant mice infected with rotavirus developed marked ischaemia and atrophy of the villi between and hours post infection [ ] with preservation of the crypt microcirculation. between and hours post infection, the capillaries of the small intestinal mucosa became engorged, with recovery of villous height. during this phase, the mucosa could have been subjected to a reperfusion injury. a second phase of villous atrophy followed between and hours which was less marked than the initial episode. the villous microcirculation recovered by i hours, and the diarrhoea ceased. these findings could explain how rotavirus infection could initiate necrotizing enterocolitis. perturbations of the enteric microcirculation have also been described in clinical or experimental cholera, salmonellosis, shigellosis, and acute diarrhoea. these data all provide the link between abnormal colonization and ischaemia of the intestinal mucosa. endotoxin is a component of the cell wall of gram negative bacteria which consists of iipopolysaccharide. some systemic effects of endotoxin are listed in table . although only providing circumstantial evidence, there are clearly similarities between the signs of necrotizing enterocolitis and the effects of endotoxaemia. low-birth-weight babies have been shown to experience endotoxaemia when fed [ ] . endotoxaemia has variable effects on intestinal blood flow but can induce ischaemia and increased permeability of the intestinal mucosa which could predispose to absorption of more endotoxin or entry of bacteria from the lumen of the gut. the systemic effects of endotoxin are mediated by the release of proteins called cytokines from monocytes and probably endothelial cells [ ] . in low concentrations, cytokines co-ordinate essential functions such as immune responses, but higher concentrations may have adverse effects. if endotoxaemia is implicated in the pathogenesis of necrotizing enterocolitis then it is likely to be due to the effects of excessive production of cytokines, which in rum trigger the production of substances such as platelet activating factor [ ] . severe shigellosis is an example of a disease of the distal bowel in which endotoxaemia is associated with mucosal and on occasion, full thickness necrosis. it may be complicated by disseminated intravascular coagulation, haemolytic uraemic syndrome and occasionally gangrene and perforation of the large bowel. endotoxaemia induced fibrin degradation products, and deposition of fibrin in glomeruli and in rectal microvasculature have been reported in patients with uncomplicated shigellosis. infusion of either the cytokine tumour necrosis factor or endotoxin in rabbits produced similar pathology including disseminated intravascular coagulation with thrombocytopaenia, damage to glomeruli with leukocyte infiltration, segmental ischaemia, haemorrhage, and necrosis in the liver, bowel, adrenals, pancreas, lung and other tissues. microscopically there were fibrin deposits, polymorphonuclear infiltration and arterial thromboses. similarities between the pathology of shigellosis and endotoxin or tnf infusions prompted measurement of cytokine concentrations in sera and stool extracts from children with shigellosis [ ] . serum interleukin (il- ) and tumour necrosis factor concentrations were significantly elevated during the acute phase of s. dysenteriae infection in children with a complicated course compared to convalescence, and il- concentrations correlated with the presence of complications such as haemolytic uraemic syndrome, microangiopathic haemolytic anaemia, leukemoid reactions, thrombocytopaenia or thrombocytosis and severe colitis associated with persistent diarrhoea. il- has been shown to be a better indicator of disease severity in other septic states although tumour necrosis factor release is essential for the initiation or amplification of il- release. il- and il- are thought likely to be important mediators of the pathological effects of turnour necrosis factor [ ] including endothelial cell damage caused by increasing the adhesiveness of neutrophils and endothelial cells endothelial rearrangement, production of a procoagulant factor by endothelial cells, reduced expression of thrombomodulin, increased production of interleukin , which can in turn activate leukocytes to initiate coagulation and stimulation of endothelial cells, polymorphs, and macrophages to produce platelet activating factor [ ] . future work should be directed to the investigation of the roles of endotoxin, cytokines and their mediators in the pathogenesis of necrotizing enterocolitis. in common with shigellosis, serum tumour necrosis factor concentrations were elevated in necrotizing enterocolitis compared with age-matched control infants [ ] . tumour necrosis factor levels did not correlate with severity or outcome. larger, longitudinal studies are required to investigate the role of inflammatory mediators in necrotizing enterocolitis. treated with vancomycin and aztreonam had lower viable counts of enterobacteriaceae in the stools [ ] . broad spectrum antibiotics with anaerobic cover are part of the treatment regimen for established necrotizing enterocolitis. the documentation of outbreaks of necrotizing enterocolitis suggests that affected infants should be nursed with particular attention to the prevention of cross-infection [ ]. lucas et al. [ ] estimated that necrotizing enterocolitis was - times as common in artificially fed infants ( times more common in infants over weeks gestation) and that infants are developing necrotizing enterocolitis in the uk every year as a result of artificial feeding. they attribute the protective effect to the iga present in breast milk. (see above: protective effect of oral antibiotics.) a report from leeds, uk suggested that the use of vancomycin and aztreonam to treat episodes of sepsis prevented necrotizing enterocolitis compared with vancomycin and gentamicin; infants if endotoxaemia does play a role in the pathogenesis or complications of necrotizing enterocolitis then affected infants may benefit from therapeutic attempts to neutralize endotoxins or their mediators. potential approaches are summarized in table . human polyclonal anti-e, coli j human monoclonal (ha-ia) anti-lipid a mufine monoclonal (e ) anti-lipid a monoclonal anti-turnout necrosis factor antibody monoclonal anti il- antibody soluble tumour necrosis factor receptor il- receptor antagonist (ra) while these potential interventions await clinical trials, there is experimental evidence that platelet activating factor antagonist prevents necrotizing enterocolitis. endotoxin and tumour necrosis factor act synergistically to induce shock, neutropaenia, focal bowel necrosis in young rats; these effects are inhibited by platelet activating factor receptor antagonists [ ] . conventionally, a review such as this should conclude with a complex diagram of 'vicious cycles' summarizing our uncertainty about precise causes. the basic cause of necrotizing enterocolitis remains a mystery, not the least because of occurrence of the disease in infants who 'break the rules' on necrotizing enterocolitis by being full-term or older, previously well, unfed or exclusively breast fed. perhaps a note of greater clarity would be sounded by reproducing a classification of necrotizing enterocolitis (table ) [ ] . any studies on necrotizing enterocolitis should clearly differentiate between these subgroups, which are likely to have different mechanisms with a final common pathway. necrotising enterocolitis of the newborn: is it gasgangrene of the bowel? fulminant necrorising enterocolitis associated with clostridia outbreak of necrotising enterocolitis caused by clostridium butyricum development of gut colonization in preterm neonates quantitative study of the aerobic and anaerobic faecal flora in neonatal necrotising enterocolitis development of the human gastrointestinal tract the ontogeny of fasting small intestinal motor activity in the human infant ontogeny of pancreatic exocrine function microbial flora of the mouse ileum mucous layer and epithelial surface the most important references are denoted by an asterisk nutrition and translocation time of appearance of immunoglobulin-containing cells in the mucosa of the neonatal intestine ontogeny of secretory immunity: levels of secretory iga and natural antibodies in saliva the mouse gut t lymphocyte, a novel type of t cell: nature, origin and traffic in mice in normal and graft-versus-host conditions surveillance of necrotising enterocolitis - necrotizing enterocolitis: intraluminai biochemistry in human neonates and a rabbit model prevention of necrotizing enterocolitis in low birth weight infants by iga-igg feeding prevention of necrotising enterocolitis in neonates at risk by oral administration of monomeric igg oral vancomycin in prevention of necrotising enterocolitis breath hydrogen excretion as a screening test for early diagnosis of necrotizing enterocolitis urinary d-lactate excretion in infants with necrotizing enterocolitis importance of multiple episodes of hypoxia or cold stress on the development of enteroeolitis in an animal model role of platelet activating factor and tumour necrosis factoralpha in neonatal necrotising enterocolitis release of leukotriene c by isolated, perfused rat small intestine in response to platelet-activating factor role of oxygen-derived flee radicals in platelet activating factor induced bowel necrosis pathology of neonatal necrotising enterocolitis: a tenyear experience the effect of toxin a and b of clostridium difficile on rabbit ileum and colon pathogenesis and diagnosis of clostridium difficile enterocolitis. stand ] hrfect dis necrotizing enterocolitis with escherichia colt heat-labile enterotoxin delta-like toxin produced by coagulase-negative staphylococci is associated with neonatal necrotizing enterocolitis a study of the microcirculation in whole villi of neonatal mice using a peroxidase histochemical staining method rotavirusinduced changes in the microcirculation of intestinal villi of neonatal mice in relation to the induction and persistence of diarrhea spontaneous endotoxinemia in premature infants: correlations with oral feeding and bowel dysfunction anti-il- monoclonal antibodies protect against lethal esdzerichia colt infection and lethal tumour necrosis factor-alpha challenge in mice tumor necrosis factor cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet activating factor concentrations of interleukin- and tumour necrosis factor in serum and stools of children with shigella dysenteriae infection enterobacteriaceae and neonatal necrotising enterocolitis breast milk and neonatal necrotising enterocolitis bowel necrosis induced by tumor necrosis factor in rats is mediated by platelet-activating factor necrotizing enterocolitis key: cord- -kmluql h authors: eibl, martha m.; wolf, hermann m.; fürnkranz, heinz; rosenkranz, alfred title: prophylaxis of necrotizing enterocolitis by oral iga-igg: review of a clinical study in low birth weight infants and discussion of the pathogenic role of infection date: journal: j clin immunol doi: . /bf sha: doc_id: cord_uid: kmluql h necrotizing enterocolitis, a severe gastrointestinal disease in the neonatal period, affects primarily premature infants. perinatal complications that predispose the neonate to systemic hypoxia are frequent in infants with necrotizing enterocolitis. ischemia of the intestinal mucosa may facilitate the invasion of enteric microorganisms in stressed low birth weight infants. geographical and temporal clustering of outbreaks of the disease and the termination of epidemics by standard infection control underline the importance of infectious agents in the development of this disease. several studies have established the immunoprotective effect of orally administered antibodies against infection of the gastrointestinal mucosa in children and adults. anecdotal evidence suggested that feeding of human immune globulin might have a positive effect on the incidence of necrotizing enterocolitis in premature infants. this paper reviews a prospective, randomized, controlled trial of the efficacy of an oral immune globulin preparation (published in detail in thenew england journal of medicine, vol. , pp. – , ) and discusses the pathogenic role of infection in necrotizing enterocolitis. necrotizing enterocolitis (nec) is a severe gastrointestinal disease and an important cause of morbidity and mortality among premature, low birth weight infants ( ) . the annual incidence of nec lies between . and . % of all admissions to a neonatal intensive care unit ( ) ( ) ( ) . in a retrospective study reviewing years' experience with patients, institute f immunology, university of vienna, vienna, austria. glanzing children's hospital of the city of vienna, vienna, austria. % of patients developed nec within the first days of life, the most common age of onset of nec being days, with the median at the seventh day of life ( ) . the disease has a considerable mortality which lies between and %, depending on birth weight, maturity, and coexisting medical problems ( ) . clinically, nec presents within a broad spectrum ( , ) . early unspecific signs may be recurrent unexplained apnea, bradycardia, temperature instability, lethargy, poor feeding, and irritability. specific abdominal signs indicative of nec include abdominal distension, diarrhea, gastric retention, emesis, and macroscopic or occult gastrointestinal bleeding. a benign clinical course with minimal gastrointestinal signs and symptoms may lead to complete recovery. however, in case of progression of the disease with unstable vital signs that resemble sepsis, perforation of the intestine, or obstructive pattern on abdominal radiograph, patients require aggressive medical and/or surgical therapy. the disease affects primarily the terminal ileum and ascending colon. pathological examination reveals mucosal edema, intramural hemorrhage, gangrene leading to pseudomembranous mucosal necrosis without inflammatory response, and peritonitis. histologically, the disease is characterized by transmural "bland" necrosis within the gastrointestinal tract and abnormal bacterial intestinal gas formation (i.e., intramural pneumatosis intestinales). as a confirmation of the clinical diagnosis in the absence of histologic examination, a typical abdominal roentgenogram demonstrates abnormal intestinal gas formation such as pneumatosis intestinales, intrahepatic venous gas, or free intraperito-neal gas (due to bowel perforation following distension). important risk factors for nec are prematurity and low birth weight ( , ) . eighty to % of cases of nec occur in infants less than weeks' gestation ( ) . oral alimentation has also been associated with the development of nec. ninety to % of patients have been fed formula, banked human milk, or a combination of these ( , , ) . in addition, perinatal complications such as cesarean section, birth asphyxia, respiratory distress syndrome, umbilical vessel catheters, low -or -min apgar score, patent ductus arteriosus, need for exchange transfusion, and twin birth have been described as risk factors for the development of nec ( , ). as can be seen from the multitude of risk factors for the disease, the pathogenesis of nec is most likely multifactorial. both noninfectious and infectious risk factors ( ) might be important for the development of the disease, as a variety of both bacterial and viral pathogens has been associated with outbreaks of nec (reviewed in refs. and ) . no effective prophylaxis of nec has been described. the use of antibiotics as a prophylaxis of nec has been proposed, but the results of several studies were not conclusive. reports of the possible benefit of prophylactic oral administration of aminoglycoside antibiotics (i.e., kanamycin, gentamicin) ( , ) could not be confirmed in two other studies ( , ) . the pressure of emergence of resistant microorganisms caused by the prophylactic use of antibiotics has been heavily criticized ( ) . other possible adverse effects of the aminoglycoside antibiotics include direct gastrointestinal injury and systemic side effects. this report discusses the importance of infectious factors in the development of nec and reviews the results of a prospective, randomized, controlled trial published in detail in the new england journal of medicine ( ) . there we described the effective prophylaxis of nec by administration of an oral iga-igg preparation in low birth weight infants for whom breast milk from their mothers was not available. geographical and temporal clustering of cases of nec ( , ) , evidence for nosocomial transmission of the disease ( ), and the termination of "epidemics" of nec by strict infection control measures designed to interrupt fecal oral spread of an unidentified agent ( ) strongly support the importance of infectious agents in the pathogenesis of nec. a variety of infectious organisms by their nature is likely to invade susceptible damaged bowel and/or produce large amounts of endotoxin. this probably accounts for the general experience that different infectious agents might play an important role in the development of clinical nec. although clustered cases of nec frequently show positive blood cultures in one institution, no consistent single organism could be associated with outbreaks of the disease. a wide range of bacterial [e.g., klebsiella ( ), salmonella ( ), clostridia ( - ), and nonenteropathogenic strains of escherichia coli ( )] as well as viral [e.g., human enteric coronavirus ( ), rotavirus ( )] pathogens has been associated with nec and was cultured from blood, stool, or peritoneal fluid or identified in samples of resected patient tissue. in stressed low birth weight infants, clinical conditions associated with perinatal systemic hypoxia might result in mucosal ischemia of the intestine due to a reflex redistribution of cardiac output at the expense of sympathetically innervated organs such as the intestine. together with an underdevelopmerit of gastrointestinal immune protection in newborn infants, defects in the integrity of the intestinal mucosa might facilitate the invasion of the damaged intestinal mucosa by enteric microorganisms, resulting in the clinicopathologic features seen in nec. animal experiments support this theory. in an animal model of nec (i.e., neonatal rats) induced hypoxia and cold stress produce a disease similar to neonatal nec when the experimental animals are infected with klebsiella ( ). however, rats whose enteric flora contains an insignificant number of gram-negative organisms do not develop disease when exposed to similar stress. reviews of the gastrointestinal immunologic defense mechanisms of human neonates generally describe a lack of locally produced antibodies (secretory iga, i.e., dimeric iga covalently linked to the secretory piece) in the gastrointestinal tract of full-term as well as premature neonates ( ). in this condition of inadequate local immunoprotection, alternative mechanisms must function to inhibit overgrowth of potentially pathogenic intestinal flora and prevent host invasion. strong evidence has accumulated for the antiinfectious effect of breast feeding ( , ). the intestinal flora of breast- s eibl, wolf, fi rnkranz, and rosenkranz fed and formula-fed infants differs, with a prevalence of apathogenic bacteria in the intestine of breast-fed neonates ( , ). in preterm infants gastrointestinal infection due to enteropathogenic e. coli and salmonella could be prevented by oral administration of colostrum ( ). although potentially pathogenic bacteria were isolated from the feces of some of the infants, they did not cause illness. it appears likely that while the excretion of microorganisms did not change substantially, colonization of the gut could be avoided, suggesting that the protective effect was brought about rather by avoiding colonization than by providing antitoxic immunity. e. coli antibodies have been reported to prevent intestinal disease caused by diarrheagenic e. coli. the surface of enterotoxigenic e. coli contains a heat-labile surface antigen that has pilus-like morphology and is essential for bacterial adherence and colonization of the intestinal mucosa [colonization factor antigen (cfa)]. as demonstrated by electron microscopy, specific anti-cfa antibodies agglutinate the piti and prevent diarrhea normally seen after inoculation of virulent cfa-positive e. coli into the small intestine of baby rabbits ( ). accordingly, antibodies provided by breast feeding may protect infants against clinical gastrointestinal infection. protection against cholera in breast-fed infants is correlated with the breast milk levels of iga antibodies against vibrio cholerae lipopolysaccharide and enterotoxin antigens ( ). breast milk iga inhibits v. cholerae or e. coli enterotoxin-induced diarrhea in the rabbit ileal loop model ( ). secretory iga from human colostrum can also neutralize the cytopathic effect of clostridium difficile toxins a and b both in vitro and in suckling mice ( ). consistent with the important role of gastrointestinal infection in the pathogenesis of the disease, nec has been shown to occur very infrequently in breast-fed infants. furthermore, breast feeding offered complete protection against experimental nec induced by infection with klebsiella in conjunction with hypoxia in neonatal rats, while animals receiving formula feeding developed the disease ( ). iga-igg prepar.ation previous anecdotal evidence by others suggested that feeding of human immunoglobulin (ig) intended for intramuscular use might have a positive effect on the incidence of nec in premature infants ( ). a prospective randomized clinical trial reported in detail in the new england journal of medicine ( ) was carried out in low birth weight infants for whom breast milk from their mothers was not available. the purpose of the study was to investigate whether feeding of an oral iga-igg preparation to low birth weight infants for whom breast milk is not available can effectively prevent nec. the oral iga-igg preparation was prepared from human serum, cohn fraction ii (igabulin, kindly supplied by immuno ag, vienna, austria). nine different lots were used during the study, which contained predominantly monomeric iga ( %) and igg ( %) ( table i) . as determined using standard techniques (hemagglutination inhibition, neutralization, radioimmunoassay, indirect immunofluorescence, bacterial agglutination), the preparation contained high titers of antibodies against a multitude of potential pathogens (bacterial toxins such as pertussis, tetanus, and diphtheria; viruses such as poliovirus, coxsackie virus, rotavirus, and echovirus). in addition, iga and igg antibodies against bacteria that have been associated with outbreaks of nec such as e. coli, klebsiella, salmonella, enterobacter cloacae, and clostridia could be demonstrated (for a detailed characterization of the antibody activity, see ref. ) . during a period of years all infants with a birth weight between and g who were admitted to our hospital were enrolled in the study if breast milk from their mothers was not available and if the parents gave informed consent. a total of infants was enrolled in the study and randomly assigned to one of two groups. starting within the first day of life, infants in the treatment group (n = ) received mg of the oral iga-igg preparation per day in three or more individual doses as a supplement to their feeding. infants in the control group (n = ) received infant formula alone or infant formula plus pasteurized, pooled human milk. the duration of the study was days. two hundred thirty-four infants ( in the iga-igg treatment group and in the control group) were withdrawn during the first week of the study because breast milk from their mothers became available. twenty-one control infants were excluded during weeks to of the study because of violations of the study protocol or because breast milk from their mothers became available. one hundred seventy-nine infants who completed the study ( treated infants and control infants) were evaluated in great detail. iga-igg treatment was accepted by all infants without untoward effects on pulse rate and body temperature; leukocyte, erythrocyte, and platelet counts; white-cell differential count; hematocrit and hemoglobin; serum levels of liver enzymes alt and ast; and serum levels of crp and the complement components c and c . no evidence for the transmission of viral agents or anaphylactic side effects caused by the oral iga-igg could be found. in addition, no increase in the serum levels of iga or igg resulting from resorption of oral immune globulin through the intestinal tract could be observed. for a limited period of the study, serum levels of igm and igg seemed to be lower in the iga-igg-treated infants than in the controls (table ii ) and the percentage of infants with serum iga > mg/dl also appeared to be slightly higher in the control infants ( . % in the third week of the study, as compared to . % in iga-igg-treated infants). this transient increase in serum ig levels might reflect the higher exposure of control infants to environmental antigens through the intestinal tract. as the most significant effect of iga-igg treatment, no case of nec occurred in the treated infants who completed the study. in comparison, cases of nec occurred in the control infants for whom breast milk did not become available during the study (p = . ). the clinical diagnosis of nec was confirmed by typical findings in the abdominal x rays or histopathologic examination of specimens obtained during surgery or of autopsy specimens in the two children who were deceased. among the total number of infants enrolled in the study, two assigned to the control group developed nec, whereas none of the infants assigned to the iga-igg treatment group developed the disease (i.e., cases of nec in controls, as compared to no case of nec in iga-igg-treated infants; p = . ). in addition, iga-igg feeding seemed to have a slight effect on the occurrence of pneumonia in infants who completed the study. not including infants who died with pneumonia (two controls and one treated infant), the total number of days with clinical symptoms of pneumonia compared to the total number of days of observation in the study group was / in four iga-igg-treated infants with pneumonia. in comparison, seven control infants with pneumonia had clinically symptomatic days in days of observation (p < . ). furthermore, iga-igg feeding seemed to have a beneficial effect on thriving in infants with tow birth weight; e.g., the time required to regain birth weight was . +-- . days in iga-igg-treated infants with a birth weight between and g, as compared to . +__ . days in the controls (mean -se; p < . ). the different incidence of nec in the two groups is most likely due to the administration of the oral iga-igg preparation in the treatment group. the distribution of several risk factors for nec was comparable between treated and control infants: low birth weight, incidence of perinatal complications such as low -min apgar score, cesarean section, respiratory distress syndrome, need for oxygen therapy after birth, incidence of twin birth, use of umbilical venous catheters, the infants' ages at the start of enteral feeding, the rate of progression of feedings, the choice and amount of feeding substance (pasteurized, pooled human milk or infant formula), and the use of antibiotics. that the iga-igg feeding prevented nec in our study has been further confirmed by the experience that, after termination of the study, the incidence of nec among all low birth weight infants admitted to our hospital was again comparable to the incidence observed in the control group. several studies have established the immunoprotective effect of orally administered homologous or heterologous antibodies against infection of the gastrointestinal mucosa in children and adults. bovine milk immune globulin has been used successfully to treat infantile diarrhea due to enteropathogenic e. coli, rotavirus, and cryptosporidium ( - ). oral administration of bovine, e. coli-specific ig is an effective prophylaxis against traveler's diarrhea caused by enterotoxigenic e. coil ( ). in our study, examination of fecal ig in iga-iggtreated infants demonstrated that substantial amounts of orally administered iga and igg lacking a secretory component can resist proteolytic degradation in the gastrointestinal tract ( ) . furthermore, the finding of comparable concentrations of fecal iga in the feces of iga-igg-treated and breast-fed infants (data not shown) suggests that we administered "physiologic" amounts of iga-igg as a substitution for the ig normally provided by breast feeding. these data confirm and extend previous reports by others who noted the recovery of undigested and partially digested, functionally active oral igg in the feces ( , ). analogous to the function of antibodies normally provided by breast feeding, the immunoprotective effect of oral ig (iga and/or igg) on the intestinal mucosa can best be explained by the formation of antigen-antibody complexes in the bowel lumen or on the mucosal surface. this hypothesis is supported by the finding of immune complexes formed between orally administered human serum ig and endogenous rotavirus in immunodeficient patients with viral gastroenteritis ( ). binding of functionally intact oral ig (iga and/or igg) to the antigen (e.g., a bacterial or alimentary constituent) may cause intraluminat agglutination of potentially pathogenic microorganisms, thereby interfering with the colonization of the intestinal epithelial surface and neutralizing bacterial virulence factors or preventing toxic effects of an excess of alimentary protein (i.e., formula feeding) on the intestinal mucosa. dr. padilla lugo: you have good comparative groups in terms of risk factors but i worry about how many of these infants really underwent severe perinatal asphyxia with apgar scores of less than at and minutes and underwent severe metabolic acidosis during the first hours of life? dr. eibl: the apgar scores were comparable in both groups. a little less than half the children had low apgar scores during the first minute. we did not monitor acidosis in these patients, but with respect to the clinical experience, the two groups were absolutely comparable. dr. padilla lugo: i am concerned because we are introducing enteric feeding of this preparation and we are not sure how severely acidotic the babies are before this. eibl, wolf, fidrnkranz, and rosenkranz dr. eibl" we had a long discussion as to whether we should introduce enteric feeding at that early stage, but when we did, we did not see any complications. especially in the beginning we were very careful to watch those babies and we had decided that if we saw any side effects we would change the protocol. we did not see any adverse reactions and i think that early feeding is extremely important because, as you know, most patients develop nec very early in life, before the third day in many cases. i am not sure whether we really need to go on for the days and we are now planning to perform studies of feeding oral immune globulin for shorter periods of time. dr. sorensen: i realize your control group and patient group were the same with regard to the factors you mentioned, but if you look at the six patients in the control group who developed nec, was there anything different about them or were they just run-of-the-mill patients? dr. eibl: although we tried very hard to find some predictive characteristics in these patients, we could not. dr. polmar: in the course of this study, did you have the opportunity of systematically looking at the virology and bacteriology of the stools in the treated and untreated groups and is there any modification and colonization in these patients? dr. eibl: in the course of this study we did not look at these parameters. we were uncertain whether this type of treatment would work when we started this study and we decided that we would conduct additional evaluations once we determined that this type of treatment is effective. we have no data on that as yet. dr. wasserman: this study was not blinded. is that correct? dr. eibl" that is correct. dr. wasserman: there was no control treatment, just a control group? dr. eibl" yes. dr. wasserman: many people have the impression that the type of infant feeding in the first week of life can impact on the development of nec, specifically the quantity of each individual feeding or perhaps the rate of the feeding. since your study was not blinded, how were you able to assure that both groups were fed in comparable ways? dr. eibl" we have tried to analyze the quantity of feeding and also the addition of pooled human milk, and we could not find any difference between the two groups, but i agree that blinded studies have to follow. from the data we obtained with respect to the feeding, no difference was found. dr. ballow: did you notice any difference in the two groups in terms of residuals in the stomach, abdominal girth, bloating, number of stools, and so forth? dr. eibl: we looked at these factors very carefully and we did not find any differences. the babies tolerated the feeding. dr. steihrn: did you give just a single dose of iga? dr. eibl dr. eibl: we divided it into at least three doses, and in some of the babies we divided it into six doses. dr. steihm: do you think that the serum iga from which this material is derived gives it any advantage over igg? we all know that secretory iga resists digestion, but does serum iga resist digestion, so that if one were to do a second study, maybe igg could be used rather than an iga/igg preparation? dr. eibl: we believe but we cannot yet prove that iga has an advantage, and i think a great advantage, over igg because it is known that iga eliminates the infectious agents without causing inflammation. i think that this point is extremely important but we have no proof at the moment except that the iga goes through the intestine, at least in part. i think this was a very important point to demonstrate and we looked at a fairly large number of babies on repeated occasions and showed that our preparation goes through the entire intestinal tract, which proves that at least part of it is not digested. dr. golclblum: i was interested to see that you had so much polymeric iga in the preparation that you gave. presumably some of that could be converted into secretory iga in the gastrointestinal tract because the infant does produce a lot of presecretory component as well as (probably) secretory igm. so some of those molecules could be converted and one could look at the fecal samples to see if there were selective survival of the secretory over nonsecretory iga. another selective advantage might be for iga and iga . iga is more susceptible to bacterial proteolysis or specific iga proteolysis, and presumably since your material came from serum, it would be about % iga , whereas human milk would contain an approxi-mately equal mixture of iga and iga . that could also be looked at in the fecal samples. how did you evaluate the iga in the fecal samples? there is a real potential for technical bias there because if you used radial immunodiffusion, for instance, the cleaved molecules would be overread by a large factor. dr. eibl: we used radial immunodiffusion and we have clearly noticed several circles of precipitate in this system. we have also checked the size of the molecules and found that there is a number of cleaved molecules but we could also find intact molecules. dr. kamani: what were the immunoglobulin levels in the two groups of patients? dr. eibl: the immunoglobulin levels in both groups were comparable. if anyttiing, they were minimally lower in the control group than in the treatment group, but there was no significant difference. we did not get any indication of absorption into the cell. dr. heiner: my understanding is that if you include iga in cohn fraction ii, you have to alter the usual isolation procedures, and that opens the door a little bit to including viruses. certainly igg that is pooled would contain antihepatitis virus and that may protect against hepatitis, but what about the possibility of hiv or some other viruses getting into that preparation? i wonder how this is prepared and whether they really looked for the inclusion of viruses. dr. eibl: at the beginning of our study we did not worry because there was a very strong feeling that cohn fraction ii was safe as a starting material. during the middle s some reports of viral transmission did cause worries, and for this reason an additional step of viral inactivation was added to the preparation of the product. that is why we did not treat babies for about a -year period, and in this -year period we saw the same incidence of nec that we had seen before. we started iga/igg treatment again at the beginning of this year with the preparation that has the additional step, which has been very well proven to inactivate both hiv and a number of model viruses. in following the babies from this study we did not observe any indication of viral transmission in any single case. we did not see hiv antibodies and we did not see pathological levels of liver enzymes. necrotizing enterocolitis neonatal necrotizing enterocolitis: a nine-year experience. i. epidemiology and uncommon observations necrotizing enterocolitis necrotizing enterocolitis epidemiology of necrotizing enterocolitis: a case control study acute necrotizing enterocolitis in infancy: a review of cases perinatal events and necrotizing enterocolitis in premature infants necrotizing enterocolitis: controlled study of years' experience in a neonatal intensive care unit neonatal necrotizing enterocolitis how contagious is necrotizing enterocolitis? pathogenesis and prevention of necrotizing enterocolitis: a hypothesis based on personal observation and a review of the literature a prospective controlled trial of oral kanamycin in the prevention of neonatal necrotizing enterocolitis oral gentamicin therapy in the prevention of neonatal necrotizing enterocolitis: a controlled double-blind trial alterations in stool flora resulting from oral kanamycin prophylaxis of necrotizing enterocolitis gentamicin in prophylaxis of neonatal necrotising enterocolitis necrotizing enterocolitis (editorial) prevention of necrotizing enterocolitis in low-birth-weight infants by iga-igg feeding clustering of necrotizing enterocotitis: interrup key: cord- -yz gynn authors: soliman, yasser; alshaikh, belal; alawad, essa; akierman, albert; elsharkawy, adel; yusuf, kamran title: respiratory outcomes of late preterm infants of mothers with early and late onset preeclampsia date: - - journal: j perinatol doi: . /s - - - sha: doc_id: cord_uid: yz gynn objective: to study the effect of early and late onset preeclampsia (eope, lope, respectively) on outcomes of late preterm infants. study design: cohort study of late preterm infants admitted to a tertiary care nicu from january –july . outcomes of late preterm infants of eope mothers were compared with the next late preterm infant of a lope mother and the next two late preterm infants of normotensive non-pe mothers. primary outcome comprised use of continuous positive airway pressure, mechanical ventilation and/or surfactant in the h after birth. results: compared to normotensives (n = ), adjusted odds ratio (aors) of the primary outcome was higher in the eope (n = ) and lope (n = ) groups but reached statistical significance only in the eope group, aors . , % ci . – and . , % ci . – . , respectively. conclusions: compared to late preterm infants of normotensive and lope mothers, infants of mothers with eope have significantly higher respiratory morbidity. late preterm infants, defined as births between + and + weeks gestation, constitute the largest proportion of preterm births, being % in canada [ ] [ ] [ ] . there is significant morbidity associated with late preterm birth with respiratory distress syndrome (rds) and transient tachypnea of the newborn (ttnb) the commonest [ , ] . compared with term infants, late preterm infants are nine times more likely to be placed on continuous positive airway pressure (cpap), five times more likely to be placed on mechanical ventilation and forty two times more likely to need surfactant replacement [ ] . the cost associated with the care of late preterm infants is substantial, corresponding to more than million dollars annually in canada [ ] . initial studies on morbidity in late preterm births compared outcomes to term births without taking into account underlying maternal medical conditions that may lead to preterm birth. this is now being questioned with the realization that in addition to prematurity per se, maternal conditions also contribute to morbidity in late preterm infants [ , ] . one such condition is preeclampsia. preeclampsia is a pregnancy specific disorder characterized by hypertension and proteinuria manifesting at or after twenty weeks of gestation and is a major cause of maternal and neonatal mortality and morbidity worldwide [ ] . although placental dysfunction is a hallmark of preeclampsia, the disorder is heterogeneous [ ] . based on gestational age at onset of disease, preeclampsia is classified as early, occurring before weeks gestation and late occurring at or after weeks of gestation [ , ] . both have similarities and distinct features. placental changes are more marked in early onset preeclampsia while maternal factors such as increased body mass index (bmi) and metabolic syndrome play a greater role in late onset disease [ ] . early onset preeclampsia is also associated with a greater adverse impact on maternal and fetal health [ ] . although early onset disease manifests before weeks gestation, a third of women deliver at or after weeks gestation [ , ] . surprisingly, reports of the effects preeclampsia on outcomes of late preterm infants have not differentiated between early and late onset preeclampsia, despite significant differences between the two. the objective of our study was to investigate the effects of early and late onset preeclampsia on the outcomes of late preterm infants, with the primary objective being respiratory outcomes. the neonatal intensive care unit (nicu) in calgary maintains a prospectively collected electronic database of all infants admitted to the nicu. late preterm infants born between + and + gestation to a mother with early onset preeclampsia between january and july were included in the study. their outcomes were compared with the next late preterm infant born to a mother with late onset preeclampsia and the next two late preterm infants born to normotensive mothers. a prestructured data form was completed for all infants. in case of missing data, the infant's medical record charts were reviewed. the conjoint health research ethics board of the university of calgary approved the study. the primary outcome comprised the use of cpap or mechanical ventilation and/or surfactant use in the first h after birth. we chose this primary outcome for several reasons. amongst all the morbidities faced by late preterm infants, respiratory morbidity is the most common. the two most common diagnosis for respiratory distress in late preterm period, rds and ttnb, can sometimes be difficult to distinguish based on clinical manifestations and chest x-ray [ ] . importantly, similar definition of respiratory morbidity has been used in other large studies [ , ] . secondary outcomes included (i) rds-diagnosed based on signs of respiratory distress, a typical chest x-ray and/or need for surfactant [ ] . (ii) ttnb-diagnosed on a chest x-ray showing good volume with increased vascularity and the presence of a transverse fissure [ ] . (iii) use of supplemental oxygen by nasal cannula. (iv) small for gestational age (sga)-defined as birthweight below the th centile using the fenton growth charts [ ] . preeclampsia definition was based on society of obstetrics and gynecology canada recommendations and was defined as systolic blood pressure≥ mmhg or a diastolic level of (korotkoff ) ≥ mmhg on two or more occasions at least min apart after weeks gestation in a woman with previously normal blood pressure. proteinuria was defined as ≥ . g protein in a h urine sample. when a h urinary sample was not feasible, or ≥ mg/mmol urinary creatinine in a spot urine sample or ≥ + on a urinary dipstick test-strip was used as criteria for proteinuria [ ] . early onset preeclampsia was onset of symptoms at < weeks gestation and late onset preeclampsia onset of symptoms ≥ weeks gestation. histological chorioamnionitis was defined as infiltration of polymorphonuclear leukocytes in the fetal membranes and chorionic plate, and funisitis as the presence of these cells in the umbilical cord blood vessel walls and wharton's jelly [ ] . antenatal steroids were considered a course if more than twelve hours had elapsed after the first dose [ ] . diabetes included both gestational and pregestational forms of the disease. gestational age was based on a first trimester ultrasound and date of embryo transfer in cases of in vitro fertilization. surfactant was administered when oxygen requirements were persistently > %. exclusion criteria included infants born with any congenital malformations or chromosomal anomalies, infants of mothers with chronic hypertension (onset before weeks of gestation), maternal renal, cardiovascular, endocrine or autoimmune disease, substance abuse, and torch infections. women who did not have a first trimester ultrasound were also excluded. as the distribution of the relevant variables was not normal, we chose conservative nonparametric analysis for continuous variables, using the kruskal-wallis test. categorical variables were compared using the χ or fisher's exact test as appropriate. bonferroni correction was used post hoc for multiple comparisons. to identify risk factors for development of the primary outcome, multivariable ordered logistic regression with backward elimination approach was performed. any risk factors that demonstrated associations, whether statistically significant or judged to be clinically significant, with both preeclampsia and the primary outcome but were not intermediate variables, were included in the modeling process as possible confounders [ ] . the least significant variables were then removed until all remaining variables were significant at p value of . . the p value of . was set conservatively as an entry for variables to proceed to the next step in the analysis [ ] . the adjusted odds ratio (or) and their % confidence interval (ci) are reported. a p < . was considered significant. data were analyzed using stata v. (college station, texas, usa). during the study period, there were admissions to the nicu. amongst the women with early onset preeclampsia, four women with chronic hypertension and two with a history of substance abuse were excluded. there were three sets of twins in the group resulting in infants eligible for the study. of the women with late onset preeclampsia, two women with substance abuse and one with chronic hypertension were excluded. there were no twins in the group resulting in infants eligible for the study. one hundred and thirty three normotensive women who delivered late preterm infants between and weeks gestation were included as controls. on chart review, four of these women had a history of substance abuse, two had chronic hypertension and one each had systemic lupus erythematosus and antiphospholipid syndrome. they were excluded from the study. there were six sets of twins in the group resulting in infants eligible for the study (fig. ) . table shows the maternal and neonatal demographic variables between the three groups. there was no difference in the maternal age, diabetes, twins, chorioamnionitis, smoking, number of male infants and apgar scores < at min between the three groups. compared to the normotensive group, the number of primigravida mothers was late onset preeclampsia vs. normotensive c early onset preeclampsia vs. late onset preeclampsia higher in the two preeclamptic groups but the difference did not reach statistical significance. compared with the other two groups, gestational age was significantly lower in the early onset preeclampsia group. birthweight was significantly lower and sga rates significantly higher in the two preeclampsia groups compared with the normotensive group (p < . ). antenatal steroid use, c-section rates, and apgar scores < at min were significantly higher in the early onset preeclampsia group. table a shows the univariate analysis of the primary outcome and its components in the three groups. all infants who received surfactant were also placed on mechanical ventilation. the composite outcome as well as the individual components were significantly higher in the early onset preeclampsia group (p = . for surfactant and < . for the other variables). table b shows the results of multivariable ordered logistic regression as the odds ratio (ors) of the primary outcome in early and late onset preeclampsia with the normotensive group as the reference group. the final model included gestation, mode of delivery, sex, antenatal steroids, and small for gestational age. the odds of the primary outcome-cpap use, mechanical ventilation and/or surfactant use-was greater in the two preeclampsia group with the early onset preeclampsia group having the higher odds. however, the higher odds in the late onset group did not reach statistical significance (or . % ci . - , p = < . for early onset preeclampsia and or . % ci . - . , p = . ). table shows the secondary outcomes between the three groups. compared to the normotensive group, ttnb, nasal cannula oxygen, hypoglycemia, sga infants and use of phototherapy, duration of hospital stay was higher in the two preeclampsia groups. rds was significantly higher in the early onset group. during the study period, there were no deaths in any of the groups. although infants were placed on anti-biotics for suspected sepsis, none of the infants had a positive blood or cerebrospinal fluid culture. our results show that late preterm infants of mothers with preeclampsia have worse respiratory outcomes compared to late preterm infants of normotensive mothers. the outcome is significantly worse in infants of mothers with early onset preeclampsia and persisted after controlling for potential confounders. we also demonstrate that late preterm infants of mothers with preeclampsia also have significantly more non-respiratory morbidity. this is the first study to differentiate between outcomes of late preterm infants of early and late onset preeclampsia. studies on the outcomes of late preterm infants of preeclamptic mothers show divergent results with worse outcomes and no difference when compared to late preterm infants of normotensive mothers [ , [ ] [ ] [ ] . these conflicting results are, we believe, due to investigators not differentiating between late preterm infants of early and late onset preeclampsia. gouyon et al., using a large cohort from france, reported higher risk of severe respiratory morbidity, in late preterm infants of mothers with hypertensive disorder of pregnancy [ ] . as in our study, severe respiratory morbidity was defined as the need for mechanical ventilation and/or cpap. habli et al., in a secondary analysis of [ ] . respiratory morbidity, defined by the need for oxygen, cpap or mechanical ventilation was higher at each gestational age in infants of hypertensive mothers but reached statistical significance only at weeks. lagenveld et al. compared outcomes of late preterm infants of mothers with preeclampsia, gestational hypertension and normotensive pregnancies in a large cohort from the netherlands [ ] . they found higher rates of hypoglycemia and sga in the preeclampsia group, results similar to our study. the odds of rds were lower in the preeclampsia group with no difference in ttnb and need for oxygen. however, the study did not have data on antenatal corticosteroid use, systolic blood pressure was not used in the definition of preeclampsia and % of the cohort was excluded because of missing data. masoura et al. reported increased rates of hypoglycemia and rds and lower apgar scores in late preterm infants of preeclamptic mothers [ ] . in a study from australia, of infants - weeks gestation, ventilator support was required significantly more in infants of mothers with preeclampsia [ ] . as in other studies, no distinction was made between early and late onset preeclampsia. our results demonstrate increased ttnb in late preterm infants of both early and late onset preeclampsia and increased rds in early onset preeclampsia. in addition, the use of surfactant cpap and mechanical ventilation was higher in late preterm infants of mothers with preeclampsia, with higher rates in infants of mothers with early onset preeclampsia. as primary cpap is associated with better respiratory outcomes compared with elective intubation, nine of the fifteen infants placed on mechanical ventilation were initially tried on cpap but had to be intubated because of worsening respiratory status and increasing oxygen requirements [ ] . of these nine patients, six were from the early onset, two from the late onset and one from the normotensive group. increased respiratory morbidity in preterm infants of mothers with preeclampsia can potentially be explained by the antiangiogenic state in preeclampsia. several studies have demonstrated higher levels of antiangiogenic factors, soluble vascular endothelial growth factor receptor- (sflt- ) and soluble endoglin and lower levels of angiogenic factors, vascular endothelial growth factor (vegf), and placental growth factor in preeclampsia [ , [ ] [ ] [ ] [ ] . vegf plays a key role in lung vascular development, which promotes alveolar growth, and also enhances surfactant protein production [ , ] . in animal models, vegf prevents rds and higher levels of sflt and lower levels of vegf are described in more severe rds [ ] [ ] [ ] . importantly, this antiangiogenic state is much more pronounced in early onset preeclampsia with levels of sflt much higher and levels of vegf much lower in early onset preeclampsia as compared with late onset preeclampsia [ , ] . in addition, in early onset preeclampsia the fetus is exposed to the hostile intrauterine antiangiogenic environment for a longer period. these factors may be responsible for the worse respiratory outcomes in late preterm infants of mothers with early onset preelampsia as compared with infants of mothers with late onset preeclamsia and normotensive mothers. a negative correlation between sflt levels and birthweight is reported in preeclampsia, with higher sflt levels associated with lower birthweight [ , ] . in our cohort, the lower birthweight in infants of preeclamptic mothers, more marked in the early onset group, can conceivably be attributed to this negative correlation. the composite outcome of cpap and/or mechanical ventilation use in the normotensive group in our cohort was %, similar to the reports by habli et al. and gouyon where it was . % and %, respectively [ , ] . the rate of cpap and/or mechanical ventilation use was higher in the preeclamptic group in our cohort compared to the study by habli et al. ( vs. %) . however, their cohort included both preeclampsia and gestational hypertension which is a less severe disease associated with less respiratory morbidity, diluting the number of infants needing cpap or mechanical ventilation. antenatal steroid use was % in our normotensive cohort and % ( / ) in the entire cohort. these mothers had received steroids for threatened preterm labor before weeks gestation. although no study has reported on the antenatal steroid use in late preterm infants of early and late onset preeclamptic mothers, suga et al. and gymanfi-bannerman et al. reported rates of . % and . %, respectively, in late preterm infants, not dissimilar to our cohort [ , ] . the increased respiratory morbidity in infants of mothers with early onset preeclampsia in our cohort was despite the increased use of antenatal steroids. in addition to being the first study to report on the outcomes of late preterm infants of mothers with early and late onset preeclampsia as distinct groups, there are other strengths to our study. we had a well-defined cohort from a recent era with little or no missing data and detailed demographic characteristics that affect outcomes, especially respiratory outcomes in late preterm infants. this included antenatal steroid use and chorioamnionitis, data that is missing from most studies. importantly, our gestation was based on first trimester ultrasound or the date of embryo transfer in cases of ivf, largely limiting misclassification of gestation. in addition, health care in canada is universal, negating the effect of socioeconomic status and differing antenatal and postnatal care on outcomes. however, there are limitations of our study. we did not investigate outcomes like intraventricular hemorrhage, bronchopulmonary dysplasia, or retinopathy of prematurity, which some studies have reported. these outcomes are, however, extremely uncommon in late preterm infants and an extremely large cohort would be needed to study them. our population was also from single center making generalization of our results difficult. although not the focus of the study, we did not measure any angiogenic or antiangiogenic factors in our population. in summary we report, worse outcomes in late preterm infants of mothers with preeclampsia, which are considerably worse in infants of mothers with early onset preeclampsia as compared with late onset preeclampsia. there is uncertainty between planned immediate delivery or expectant management in women with preeclampsia between and weeks gestation [ ] . our data can be used to counsel mothers with preeclampsia in the late preterm period and help in identifying mothers who may benefit from delivery at facilities with higher levels of neonatal intensive care. our results, however, need validation in a larger cohort. how often are late preterm births the result of non-evidence based practices: analysis from a retrospective cohort study at two tertiary referral centres in a nationalised healthcare system canadian perinatal health report. public health agency of canada the problem of late-preterm (near-term) births: a workshop summary respiratory morbidity in late preterm births a systematic review of severe morbidity in infants born late preterm clinical issues in the management of late preterm infants the economic burden of prematurity in canada effect of late-preterm birth and maternal medical conditions on newborn morbidity risk neonatal outcome associated with singleton birth at - weeks of gestation preeclampsia part : current understanding of its pathophysiology subclassification of preeclampsia incidence of pre-eclampsia: risk factors and outcomes associated with early-versus late-onset disease maternal morbidity associated with early-onset and late-onset preeclampsia clinical differences between early-and late-onset severe preeclampsia and analysis of predictors for perinatal outcome diagnosis of neonatal transient tachypnea and its differentiation from respiratory distress syndrome using lung ultrasound core concepts: respiratory distress syndrome respiratory distress in the term and near-term infant a systematic review and meta-analysis to revise the fenton growth chart for preterm infants canadian hypertensive disorders of pregnancy working group diagnosis, evaluation, and management of the hypertensive disorders of pregnancy chorioaminionitis and funisitis: their implications for the neonate antenatal steroids: are incomplete courses beneficial risk factors, confounding, and the illusion of statistical control backward, forward and stepwise automated subset selection algorithms: frequency of obtaining authentic and noise variables neonatal outcomes in pregnancies with preeclampsia or gestational hypertension and in normotensive pregnancies that delivered at , , or weeks of gestation neonatal outcome of pregnancies complicated by hypertensive disorders between and weeks of gestation: a year retrospective analysis of a national registry neonatal outcomes of late preterm deliveries with pre-eclampsia predicting the need for ventilatory support in neonates - weeks' gestational age strategies for the prevention of continuous positive airway pressure failure circulating angiogenic factors and their association with birth outcomes in preeclampsia circulating concentrations of sflt (soluble fms-like tyrosine kinase ) in fetal and maternal serum during pre-eclampsia circulating concentrations of soluble endoglin (cd ) in fetal and maternal serum and in amniotic fluid in preeclampsia change in amniotic fluid levels of multiple antiangiogenic proteins before development of preeclampsia and intrauterine growth restriction angiogenesis in lung development, injury and repair: implications for chronic lung disease of prematurity high-dose vascular endothelial growth factor increases surfactant protein gene expressions in preterm rat lung loss of hif- alpha and inhibition of vegf impair fetal lung maturation, whereas treatment with vegf prevents fatal respiratory distress in premature mice the role of vegf and its soluble receptor vegfr- in preterm newborns of preeclamptic mothers with rds circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates the relationship of angiogenic factors to maternal and neonatal manifestations of early-onset and late-onset preeclampsia the course of angiogenic factors in early-vs. late-onset preeclampsia and hellp syndrome maternal, gestational and neonatal characteristics and maternal angiogenic factors in normotensive pregnancies risk factors associated with respiratory disorders in late preterm infants effect of antenatal corticosteroids on respiratory morbidity in singletons after late-preterm birth is early induction or expectant management more beneficial in women with late preterm preeclampsia? acknowledgements the authors are grateful to the alberta children's hospital research institute for providing the funding for the study. conflict of interest the authors declare that they have no conflict of interest.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - jn ns x authors: lawrence, robert m. title: host-resistance factors and immunologic significance of human milk date: - - journal: breastfeeding doi: . /b - - - - . - sha: doc_id: cord_uid: jn ns x nan some of the most dramatic and far-reaching advances in the understanding of the immunologic benefits of human milk have been made using newer techniques to demonstrate the specific contribution of the numerous "bioactive factors" contained in human milk (table - ). the multifunctional capabilities of the individual factors, the interactive coordinated functioning of these factors, and the longitudinal changes in the relative concentrations of them for the duration of lactation make human milk unique. the immunologically active components of breast milk make up an important aspect of the host defenses of the mammary gland in the mother; at the same time, they complement, supplement, and stimulate the ongoing development of the infant' s immune system. [ ] [ ] [ ] the explosion of research on all the immunologic properties and actions of breast milk in the last years makes it impossible to summarize all the important aspects of what we now know about the immunologic benefits of breast milk. the recently developed technologies of genomic studies using microarrays and proteomics promise to continue this rapid expansion of knowledge on the biology of the mammary gland, human milk, and the infant's developing immune system. this chapter emphasizes the important concepts of these immunologic benefits and refers the interested reader to the most recent literature for more extensive information on the many specific components. the immunologic benefits of human milk can be analyzed from a variety of perspectives: . reviewing the published information on the protection of infants from specific infections that compares breastfed and formula-fed infants. developing immune systems and the actions of bioactive factors provided in breast milk. . examining the proposed function of the active components contained in human milk: antimicrobial, antiinflammatory, and immunomodulating. . considering the nature of the different factors: soluble, cellular, and hormone-like. . examining the contribution of breast milk to immune function of mammary glands and infants as an evolutionary process. . determining the site of the postulated action of the specific factors (e.g., in the breast or in the infant) at the mucosal level (respiratory tract or gastrointestinal [gi] tract) or at the systemic level. . classifying the factors relative to their contribution to the constitutive defenses (innate immunity) versus the inducible defenses (adaptive immunity) of the infant' s immune system. . clarifying the mechanism of action of the proposed immunologic benefit (the mucosalassociated lymphoid tissue formation of the chapter bioactive factors at the level of the mucosa and their subsequent action at the breast or in an infant). . considering the contribution of human milk to the development of an infant' s immune system relative to potential long-term immunologic benefits, such as protection against allergy, asthma, autoimmune disease, or inflammatory bowel disease. the protective effect of breast milk against infection was documented as early as in the medical literature by data proving that milk from various species, including humans, was protective for offspring, containing antibodies against a vast number of antigens. veterinarians have long known the urgency of offspring receiving the early milk of the mother. death rates among human newborns not suckled at the breast in the third world are at least five times higher than among those who receive colostrum and mother' s milk. the evidence that a lack of breastfeeding and poor environmental sanitation have a pernicious synergistic effect on infant mortality rate has been presented by habicht after studying women in malaysia. the evidence that breastfeeding protects against infections in the digestive and respiratory tracts has been reported for several decades. however, many of the older studies were criticized for flawed methodology and because they were performed in "developing countries," where the risk for infection due to poor sanitation was expected to be higher. , , various researchers have proposed specific criteria for assessing the methodology of studies reporting on the protective effects of breast milk, clearly identifying measurable outcomes and the definition of breastfeeding, with other methods to limit bias and to control for confounding variables. , , , more recent studies, which have incorporated many of the proposed methodologic criteria, continue to document that breastfeeding protects infants against diarrhea, respiratory infections, and otitis media.* individual papers report protection against urinary tract infections and neonatal sepsis. , , , several papers document the decreased risk for dying in infancy associated * references , , , , , , , , , , , , . with exclusive or predominant breastfeeding in pakistan, peru, ghana, india, nepal, and bangladesh. , , , , a systematic review by the bellagio child survival study group predicted that exclusive breastfeeding for % of all infants through months of age could prevent % of the childhood deaths occurring younger than years of age. a recent review on human breast milk documents the evidence for protection against infectious diseases from breastfeeding for resource-rich and resourcepoor countries. one of the important considerations relative to measuring the immunologic benefits of breast milk is the exclusivity and duration of breastfeeding. the basic concept is identifying a dose-response relationship between the amount of breast milk received by an infant during the period of observation and the immunologic benefit gained with greater exclusivity and duration equaling greater volume of breast milk or "dose." dr. labbok and krasovec have carefully defined breastfeeding in terms of the patterns of breastfeeding relative to the amount of supplementation with formula or other fluids or foods (full/nearly full, medium or equal, low partial, or token) to standardize the use of equatable terms in different studies. box - outlines these definitions of the "amount" of breastfeeding. raisler et al referred to a doseresponse relationship when they studied the effect of "dose" of breast milk on preventing illness in more than infants. "full breastfeeding" was associated with the lowest rates of illness (diarrhea, cough, or wheeze) and even children with "most" or "equal" breastfeeding had evidence of lower odds ratios of ear infections and certain other illnesses. a number of other long-term studies demonstrated greater protection from infection with increased exclusivity of breastfeeding and durations of at least months.* a couple papers demonstrated a "dose" effect relative to decreased occurrence of late onset sepsis in very low-birth-weight infants and premature infants associated with the infants receiving at least ml/kg per day of mother' s milk compared with receiving other nutrition. the current recommendations from the american academy of pediatrics reinforce the importance of the doseresponse relationship between breastfeeding and the benefits of breastfeeding when it recommends exclusive breastfeeding for the first months of life and at least partial breastfeeding after the introduction of solid foods for an additional months or longer. another important consideration relative to exclusive breastfeeding is the potential effect of other foods and fluids in an infant' s diet that could negatively influence immunologic benefits and infection-protective effects at the level of the gi mucosa. the human immune system begins forming and developing in the fetus. newborn infants' immune systems are immature and inadequate at birth. immune systems rapidly adapt in the postnatal period related to the natural maturation of the skin and mucosal barriers and in response to the exposure of infants to inhaled and ingested antigens and microbial agents in the extrauterine environment. infants' immune systems develop throughout at least the first years of life. overall, infants have limited abilities to respond effectively and quickly to infectious challenges, which explains infants' ongoing susceptibility to infections. † box - lists most of the better understood deficiencies in infants' immune systems. an extensive discussion of these developmental immune deficiencies affecting infants is presented by lawrence and pane. the b-lymphocytes and immunoglobulin production are deficient in the amount and specificity of antibodies produced. there is limited isotype switching and slow maturation of the antibody response to specific antigens (polysaccharides). , the systemic cell-mediated immune response, including complement components, and both the "classical" and alternative pathways have limitations for complement activation. , , , numerous immune components are produced in limited amounts in infancy, including complement, interferon-γ, secretory immunoglobulin (ig) a, interleukins (il- , il- , il- ), tumor necrosis factor (tnf)-α, lactoferrin, and lysozyme. , relative to these various immune deficits in infants, one can find various bioactive and immunomodulating factors in breast milk that are potentially capable of complementing and enhancing the development of infants' mucosal and systemic immune systems. , this concept of bioactive and immunomodulating factors in breast milk is an important area of evolving research that has been extensively reviewed in the literature. , , , the most intense focus of this research centers on the effects of human milk on infants' gi tract. , the bioactive factors being studied are as diverse as proteins (lactoferrin, lysozyme, etc.), hormones (erythropoietin, prolactin, insulin, etc.), growth factors (epithelial growth factor, insulin-like growth factor, etc.), neuropeptides (neurotensin, somatostatin, etc.), cytokines (tnf-α, il- , etc.), antiinflammatory agents (enzymes, antioxidants, etc.), and nucleotides (see table - ). in the past, it was adequate to point to the lists of factors (especially immunoglobulins) to "explain" the immunologic benefit of breast milk. today, it is necessary to understand the multifunctional and dynamic action of these individual factors, their specific mechanisms of action on the innate, the adaptive, and the mucosal immune system, and their role in direct infection protection, in the normal development of infants' immune systems, and their contribution against potentially harmful inflammation. from an evolutionary perspective, maternal antibody is transmitted to the fetus by different pathways in different species. , , an association has been recognized between the number of placental membranes and the relative importance of the placenta and the colostrum as sources of antibodies. by this analysis, horses, with six placental membranes, pass little or no antibodies transplacentally and rely totally on colostrum for protection of foals. humans and monkeys, having three placental membranes, receive more of the antibodies via the placenta and less from the colostrum. the transfer of igg in humans is accomplished by active transport mechanism of the immunoglobulin across the placenta. secretory iga (siga) immunoglobulins are found in human milk and provide local protection to the mucous membranes of the gi tract. other investigations have established that the mammary glands and their secretion of milk are important in protecting the infant not only through the colostrum but also through mature milk from birth through the early months of life. although the predominance of iga in human colostrum and milk had long been described, the importance of this phenomenon was not fully appreciated until the discovery that iga is a predominant immunoglobulin present in mucosal secretions of other glands in addition to the breast. mucosal immunity has become the subject of extensive research. , , , it is clear that considerable traffic of cells occurs between mucosal epithelia and secretory or lymphoid tissue sites. the data support the concept of a general system of mucosa-associated lymphoid tissue (malt), which includes the gut, lung, mammary gland, salivary and lacrimal glands, and the genital tract ( figure - ). through the immune response of malt, a reaction to an immunogen at a mucosal site may be an effective means of producing immunity at distant sites. antibodies against specific antigens found in milk have also been found in the saliva, evidence for transfer of protection to two different distant sites simultaneously. evidence suggests that the mammary glands may act as extensions of the gut-associated lymphoid tissue (galt) and possibly the bronchiole-associated lymphoid tissue. the ability of epithelial surfaces exposed to the external environment to defend against infectious agents has been well documented for the gi, genitourinary, and respiratory tracts. siga and secretory igm (sigm) produced through the adaptive response of the mucosal-lymphoid immune system act by blocking colonization with pathogens and limiting the passage of harmful antigens across the mucosal barrier. activated b cells and cytokines pass to the mammary gland where they contribute to the production of siga in breast milk. direct contact between the antigen and the lymphoid cells of the breast is unlikely. peyer patches, tonsils, and other malt structures appear to be well developed at birth. nevertheless, the actual effective production of siga to various antigens presented to infants' mucosal surfaces (respiratory and gi tracts) is still inadequate to protect against infection. a breastfeeding infant, as part of the maternal-infant dyad exposed to the same antigens via their mucosal services, can receive protective siga and sigm in the mother' s breast milk produced by the mother' s malt ( figure - ) . the protective properties of human milk can be divided into cellular factors and humoral factors for facility of discussion, although they are closely related in vivo. a wide variety of soluble and cellular components and hormone-like agents have been identified in human milk and colostrum (see table - ). although the following discussion separates these elements, it is important to emphasize that the constituents of human milk are multifunctional and their functioning in vivo is interactive and probably coordinated and complementary. cells are an important postpartum component of maternal immunologic endowment. more than years ago, cell bodies were described in the colostrum of animals. as with much lactation research, further study of colostral corpuscles was undertaken by the dairy industry for commercial reasons in the early s. this research afforded an opportunity to make major progress in the understanding of cells in milk. initially, it was thought that these cells represented a reaction to infection in the mammary gland and were even described as "pus cells." it has become clear that the cells of milk are normal constituents of colostrums in all species. cells include macrophages, lymphocytes, neutrophils, and epithelial cells, and they total approximately /mm . cell fragments and epithelial cells were examined by electron microscope in fresh samples from women by brooker. he found that the membrane-bound cytoplasmic fragments in the sedimentation pellet outnumbered intact cells. the fragments were mostly from secretory cells that contained numerous cisternae of rough endoplasmic reticulum, lipid droplets, and golgi vesicles containing casein micelles. secretory epithelial cells were found in all samples and, after the second month postpartum, began to outnumber macrophages. ductal epithelial cells were about % of the population of cells for the first week or so and then disappeared. all samples contained squamous epithelial cells originating from galactophores and the skin of the nipple. living leukocytes are normally present in human milk. the overall concentration of these leukocytes is of the same order of magnitude as that seen in peripheral blood, although the predominant cell in milk is the macrophage rather than the neutrophil. macrophages compose about % of the leukocytes, and to /mm are present. lymphocytes make up about % to % of the cells ( to /mm ), which is a much lower concentration than in human blood. the number of cells found in human milk increases with mastitis. both large and small lymphocytes are present. by indirect immunofluorescence with anti-t-cell antibody to identify thymus-derived lymphocytes, it has been shown that % of human colostral lymphocytes are t cells, and in human milk up to % of the lymphocytes are t cells. immunofluorescence procedures to detect surface immunoglobulins characteristic of b lymphocytes identified % as b lymphocytes. the number of leukocytes and the degree of mitogenic stimulation of lymphocytes sharply decline during the first or months of lactation to essentially undetectable levels, according to ogra and ogra ( figure - ). enumeration of the total cell numbers in milk has been difficult, but when various techniques are compared (coulter electronic particle counter, visual cell counting with special stains, filter trapping with fluorescent detection, and automated fluorescent cell counting), stains for deoxyribonucleic acid (dna) were superior to the other techniques. macrophages are large-complex phagocytes that contain lysosomes, mitochondria, pinosomes, ribosomes, and a golgi apparatus. the monocytic phagocytes are lipid laden and were previously called the colostral bodies of donne. they have the same functional and morphologic features as phagocytes from other human tissue sources. these features include ameboid movement, phagocytosis of microorganisms (fungi and bacteria), killing of bacteria, and production of complement components c and c , lysosome, and lactoferrin. other milk macrophage activities include the following : phagocytosis of latex, adherence to glass secretion of lysozyme, complement components c b-mediated erythrocyte adherence igg-mediated erythrocyte adherence and phagocytosis bacterial killing inhibition of lymphocyte mitogenic response release of intracellular iga in tissue culture giant cell formation interaction with lymphocytes data suggest these macrophages also amplify t-cell reactivity by direct cellular cooperation or by antigen processing. the colostral macrophage has been suggested as a potential vehicle for the storage and transport of immunoglobin. a significant increase in iga and igg synthesis by colostral lymphocytes, when incubated with supernatants of cultured macrophages, has been reported. the macrophage may also participate in the biosynthesis and excretion of lactoperoxidase and cellular growth factors that enhance growth of intestinal epithelium and maturation of intestinal brush-border enzymes. the mobility of macrophages is inhibited by the lymphokine migration inhibitor factor, which is produced by antigen-stimulated sensitized lymphocytes. the activities of macrophages have been demonstrated in both fresh colostrum and colostral cell culture, and certain functions are altered compared with their counterpart in human peripheral blood. the highest concentration of cells occurs in the first few days of lactation and reaches more than a million per milliliter of milk. colostrum ( to days postpartum) contains to × leukocytes/ml, and % to % are polymorphonuclear cells (pmns). mature milk (i.e., after days) has fewer cells (see figure - ), approximately /ml with % to % pmns. after weeks, few pmns are present. the functions of the pmns normally include microbial killing, phagocytosis, chemotactic responsiveness, stimulated hexose monophosphate shunt activity, stimulated nitroblue tetrazolium dye reduction, and stimulated oxygen consumption. when milk pmns are compared with those in the serum, their activity is often less than that of serum pmn cells. whether milk pmns actually perform a role in protection of the infant has been studied by many investigators using many techniques. briefly, animal studies have shown that ( ) the mammary gland is susceptible to infection in early lactation, ( ) a dramatic increase in pmns occurs with mammary inflammation, and ( ) in the presence of peripheral neutropenia during chronic mastitis, severe infection of the gland occurs. this implies, according to buescher and pickering, that the primary function of milk pmns is to defend the mammary tissue per se and not to impart immunocompetence to the newborn. this may explain the presence of large numbers of pmns that are relatively hypofunctional early and then disappear over time. evidence shows that neutrophils found in human milk demonstrate signs of activation, including increased expression of cd b (an adherence glycoprotein), decreased expression of l-selectin, spontaneous production of granulocyte-macrophage colony-stimulating factor (gm-csf), and the ability to transform into cd + dendritic cells (dcs). human milk macrophages have the morphology and motility of activated cells. the movement of these cells in a three-dimensional system is greater than that of monocytes, their counterparts in peripheral blood. such activated neutrophils may play a role in phagocytosis at the level of the mucosa of the gi tract, supplementing infants' poor ability to recruit phagocytes to that site. both t and b lymphocytes are present in human milk and colostrum and are part of the immunologic system in human milk. t cells are % of the lymphocytes in breast milk. human milk lymphocytes respond to mitogens by proliferation, with increased macrophage-lymphocyte interaction and the release of soluble mediators, including migration inhibitor factor. cells destined to become lymphopoietic cells are derived from two separate influences, the thymus (t) and the bursa (b) or bursal equivalent tissues. the population of the b cells makes up the smaller part of the total. they synthesize iga antibody. the term b cell is derived from its origination in a different anatomic site from the thymus; in birds, it has been identified as the bursa of fabricius. the b cells can be identified by the presence of surface immunoglobulin markers. the b cells in human milk include cells with iga, igm, and igg surface immunoglobulins. b cells transform into plasma cells and remain sessile in the tissues of the mammary gland. more rapid mitotic activity occurs in the thymus gland than in any other lymphatic organ, yet % of the cells die within the cell substance. the thymus is the location for much of the t-cell differentiation and selection and plays a major role in the development of infants' immune systems. thymosin has been identified as a hormone produced by thymic epithelial cells to expand the peripheral lymphocyte population. after emergence from the thymus gland, t cells acquire new surface antigen markers. the t cells circulate through the lymphatic and vascular systems as long-lived lymphocytes, which are called the "recirculating pool." they then populate restricted regions of lymph nodes, forming thymic-dependent areas. it is interesting to note that exclusively breastfed infants have a significantly larger thymus than formula-fed infants at and months. the significance of the lymphocytes in human milk in affording immunologic benefits to breastfed infants continues to be investigated. it is suggested that lymphocytes can sensitize, induce immunologic tolerance, or incite graft-versus-host reactions. according to head and beer, lymphocytes may be incorporated into sucklings' tissues, achieving short-term adoptive immunization of the neonate. studies of the activities of lymphocytes have been carried out by a number of investigators who collected samples of milk from lactating women at various times postpartum, examined the number of cell types present, and then studied the activities of these cells in vitro. , ogra and ogra collected samples from women and measured the cell content from through days (see figure - ). they then compared the response of t lymphocytes in colostrum and milk with that of the t cells in the peripheral blood. t-cell subpopulations have also been shown by surface epitopes to be similar to those in the peripheral blood. the greatest number of cells appeared on the first day, with the counts ranging from , to , /mm for total cells. by the fifth day, the count had dropped to % of the first day' s count. in addition, the number of erythrocyte rosette-forming cells was determined by using sheep erythrocyterosetting technique. the erythrocyte rosette formation lymphocytes constituted a mean /mm on the first day and ⁄ of that by the fifth day. at days, total cells were , /mm , lymphocytes were , /mm , and erythrocyte rosette formation lymphocytes were /mm . the investigators compared the values with those in the peripheral blood of each mother; the levels remained essentially constant. in a similar study, bhaskaram and reddy sampled milk over time from women and found comparable cell concentrations. they examined the bactericidal activity of the milk leukocytes and found it to be comparable with that of the circulating leukocytes in the blood, irrespective of the stage of lactation or state of nutrition of the mother. ogra and ogra also studied the lymphocyte proliferation responses of colostrum and milk to antigens. their data show response to stimulation from the viral antigens of rubella, cmv, and mumps. analysis of cell-mediated immunity to microbial antigens shows milk lymphocytes are limited in their potential for recognizing or responding to certain infectious agents compared with cells from the peripheral circulation. this is thought to be an intercellular action and not caused by lack of external factors. in contrast, the t cells and b cells have been shown to have unique reactivities not seen in peripheral blood. colostral lymphocytes are derived from mature rather than immature t-cell subsets. the distribution of t-cell subsets in colostrum includes both cd + and cd + cells. the distribution of cd cells in colostrum and human milk is lower than in the serum, and fewer cd cells exist than cd cells. the percentage of cd cells is higher than in the serum of either postpartum donors or normal control subjects. no correlation exists with length of gestation and number of cells (normal blood usually contains twice as many cd + as cd + lymphocytes). parmely et al partially purified and propagated milk lymphocytes in vitro to study their immunologic function. milk lymphocytes responded in a unique manner to stimuli known to activate t lymphocytes from the serum. the authors found milk lymphocytes to be hyporesponsive to nonspecific mitogens and histocompatibility antigens on allogenic cells in their laboratory. they found them unresponsive to candida albicans. significant proliferation of lymphocytes occurred in response to k capsular antigen of escherichia coli. lymphocytes from blood failed to respond to the same antigen. this supports the concept of local mammary tissue immunity at the t-lymphocyte level. more recent experiments in rodents have provided evidence that t lymphocytes that are reactive to transplantation alloantigens can adoptively immunize a suckling newborn. foster nursing experiments performed in rodents have shown that newborn rats exposed to allogenic milk manifested alterations in their reactivity to skin allografts of the foster mother' s strain. in animals, mothers may give their suckling newborn immunoreactive lymphocytes. the influence of maternal milk cells on the development of neonatal immunocompetence has been demonstrated in several different immunologic contexts. congenitally, athymic nude mice nursed by their phenotypically normal mothers or normal foster mothers had increased survival. the mothers contributed their t-cell-helper activity to the suckling newborn. colostral lymphocytes proliferate in response to various mitogens, alloantigens, and conventional antigens. colostral cells survive in the neonatal stomach and in the gut of experimental animals, some remaining viable in the upper gi tract for a week. no evidence, however, indicates that transepithelial migration takes place when neonatal mice are foster-nursed by newly delivered animals whose colostral cells were tagged with h-thymidine. cells in human milk have been studied using the same markers employed with cells in the peripheral blood; % of the lymphocytes are t cells that are equally distributed between cd + and cd + subpopulations, and their t-cell receptors are principally of the α/β type. cd + cells are common leukocyte cells of the helper and suppressorinducer subsets, and cd + cells are leukocytes of the cytotoxic and noncytotoxic subsets. t cells in human milk are presumed activated because they display increased phenotypic markers of activation including hla-dr and cd (il- receptor). the majority of t cells in human milk are cd ro + , consistent with effector and memory t cells. , these cells are effective producers of interferon-γ, which is consistent with their phenotypic features. here again, human milk may supplement the infant with a functioning immune cell to compensate for an identified deficiency in the infant, a paucity of memory t cells. juto studied the effect of human milk on b-cell function. cell-free, defatted, filtered colostrum as well as mature breast milk showed an enhancing effect on b-cell proliferation and generation of antibody secretion. this was not seen with formula. juto suggested that this could represent an important immunologic mechanism. goldblum et al were able to show a b-cell response in human colostrum to e. coli given to the mother orally, which was not accompanied by a systemic response in the mother. this suggests that the breast and breast milk reflect sites of local humoral or cell-mediated immunity, which were initially induced at a distant site such as the gut and transferred via reactive lymphoid cells migrating to the breast. head and beer provided a scheme to describe this mechanism (see figure - ). the diagram depicts the progeny of specifically sensitized lymphocytes that originated in galt, specifically peyer patches, as they migrate to the mammary gland. as they infiltrate the mammary gland and its secretion, they supply the breast with immune cells capable of selected immune responses. ogra and ogra , suggest that the cells may selectively accumulate in the breast during pregnancy. the responses of milk cells and their antibodies are not representative of an individual' s total immunity. most of these immunocompetent cells, initially stimulated in galt, recirculate to the external mucosal surface and populate the lamina propria as antibody-producing plasma cells. a substantial number of these antigen-sensitized cells selectively home-in to the stroma of the mammary glands and initiate local iga antibody synthesis against the antigens initially encountered in the respiratory or intestinal mucosa. more recent work on human-milk-derived b cells demonstrates that breast milk contains activated memory b cells, different than those in the blood. these cells express mucosal adhesion molecules (α β -/+ , α β + , cd + , cd l -) suggesting origin in the mammary gland, but similar to galt-associated b cells. the mucosae-associated epithelial cytokine ccl may contribute to migration of and retention of these cells in the mammary gland. this information supports the concept of the mammary gland as an effector site of the mucosal immune system. the accumulated epidemiologic research support the concept that colostrum and milk provide human infants with immunologic benefits. both t and b lymphocytes found in breast milk are reactive against organisms invading the intestinal tract. however, the proof of specific viral or bacterial protection secondary to the action of immunologically active b cells has not been demonstrated. although it is clear that cells are provided in the colostrum and milk, the effectiveness and impact of these cells on the neonate depend on their ability to survive in the gi tract. it has been demonstrated in several species, including humans, that the ph of the stomach can be as low as . , but the output of hydrochloric acid is minimal for the first few months, as is the peptic activity. immediately after a feeding begins, the ph rises to . and returns to normal in hours. the cells from milk tolerate this. studies in rats have also shown that intact nucleated lymphoid cells are found in the stomach and intestines. these cells, when removed from rat stomachs, are capable of phagocytosis. lymphoid cells in milk have been shown to traverse the mucosal wall. when human milk is stored, however, the cellular components do not tolerate heating to ° c ( . ° f), cooling to − ° c (− . ° f), or lyophilization. although a few cells may be identified in processed milk, they are not viable. cregan et al have reported the presence of mammary stem cells in human breast milk based on the demonstration of the cytokeratin mammary stem cell marker. additionally cells from breast milk were analyzed after culturing which showed both a multipotent stem cell marker, nestin, and the cytokeratin marker. although human milk may serve as a source of mammary stem cells in the future, no evidence of an immunologic role for these cells in developing infants currently exists. all classes of immunoglobulins are found in human milk. the study of immunoglobulins has been enhanced through the techniques of electrophoresis, chromatographics, and radioimmunoassay. more than components have been identified; of these, are associated with proteins in the maternal serum, and the others are found exclusively in milk. the concentrations are highest in the colostrum of all species, and the concentrations change as lactation proceeds. iga, principally siga, is highest in colostrum. although postpartum levels fall throughout the next weeks, substantial levels are maintained throughout the first year, during gradual weaning between and months, and even during partial breastfeeding (when infant receives solid foods) in the second year of life (figures - and - and table - ). specific siga antibodies to e. coli persist through lactation and may even increase (see figure - ). the main immunoglobulin in human serum is igg; iga content is only one fifth the level of igg. in milk, however, the reverse is true. iga is the most important immunoglobulin in milk, not only in concentration but also in biologic activity. siga is likely synthesized in the mammary alveolar cells or by lymphocytes that have migrated from peyer patches in the gi tract or from lymphoid tissue in the respiratory tract via the lymphatics to the breast. cytokines cause isotype switching of local igm + b cells to become iga + b lymphocytes. , , these isotype switched cells travel to the breast where they are transformed into plasma cells producing secretory, dimeric iga. it is through this "enteromammary" pathway that the mother provides increased amounts of siga to the infant against the microorganisms present in the mother' s and infant' s environment. brandtzaeg et al have proposed a model for the transport of iga (polymeric) and igm (pentameric), produced by plasma cells, across the secretory epithelium with the formation of siga and igm through binding with the secretory component attached to the epithelial membrane. this occurs in the membrane of mammary epithelial cells during lactation. , quantitative determinations of immunoglobulins in human milk were made from milk collected at birth to as long as months postpartum by peitersen et al iga is the predominant immunoglobulin in breast milk, constituting % of all the immunoglobulins in colostrum and milk. ogra and ogra [ ] [ ] [ ] studied the serum of postpartum lactating mothers and nonpregnant matched control subjects and noted that the individual and mean concentrations of all ig classes were lower in the postpartum subjects. the levels were statistically significant for igg; they were to mg higher in the nonpregnant women. immunoglobulin levels, particularly iga and igm, are very high in colostrum and drop precipitously in the first to days, but igg does not show this decline. the volume of mammary secretion, however, increases dramatically in this same period; thus the absolute amounts of immunoglobulins remain more nearly constant than it would first appear. local production and concentration of iga and probably igm may take place in the mammary gland at delivery. ige and igd have also been measured in colostrum and milk. using radioimmunoassay techniques, colostrum was found to contain concentrations of . to . iu/ml ige in % of samples and less in the remainder. igd was found in all samples in concentrations of to mg/dl. plasma levels were poorly correlated. the findings suggest possible local mammary production rather than positive transfer. the question of whether ige or igd antibodies in breast milk have similar specificities for antigens as the iga antibodies in milk remains unanswered. keller et al examined the question of local mammary igd production and its possible participation in a mucosal immune system by comparing colostrum and plasma levels of total igd with specific igd antibodies. from their work comparing colostrum/plasma ratios for igg, igd, and albumin and measuring igd against specific antigens, the authors reported evidence for igd participation in the response of the mucosal immune system, with increases in total igd and igd against specific antigens found in colostrum. to address the question of total quantities of immunologic components secreted into human milk per day and available to an infant, butte et al lysozyme, in contrast, rose during the same period in total amount available and amount per kilogram per day. the authors suggest that production and secretion of these immunologic factors by the mammary gland may be linked to the catabolism of the components at an infant' s mucosal tissues. when the concentrations of siga, igg, igm, α antitrypsin, lactoferrin, lysozyme, and globulins c and c were compared in relationship to parity and age of the mother, no consistent trend was observed. when maturity of the pregnancy was considered, however, mean concentrations of all these proteins were higher, except for iga, when the delivery was premature. because several proteins in human milk have physiologic function in infants, davidson and lönnerdal examined the survival of human milk proteins through the gi tract. crossed immunoelectrophoresis showed that three human milk proteins transversed the entire intestine and were present in the feces: lactoferrin, siga, and α -antitrypsin. miranda et al reported on the effect of maternal nutritional status on immunologic substances in human colostrum and milk. maternal malnutrition was characterized as lower weight-to-height ratio, creatine/height index, total serum proteins, and igg and iga. in malnourished mothers, the colostrum contained one third the normal concentration of igg, less than half the normal level of albumin, and lower iga and complement c . lysozyme, complement c , and igm levels were normal. levels improved with development of mature milk and improvement in maternal nutrition. according to one report in , moderate exercise during lactation does not affect the levels of iga, lactoferrin, or lysozyme in breast milk. immunologic components contained in human milk during the second year of lactation become a significant point as more infants are nursed longer. for a longitudinal study of lactation into the second year by goldman et al, women were included who had fully breastfed their infants for months to a year, and were continuing to partially breastfeed. samples were collected by fully emptying the breast by electric pump. table - summarizes the concentrations of the measured factors. no leukocytes were detected. concentrations of total iga and siga, lactoferrin, and lysozyme were similar to those to months postpartum and during gradual weaning. siga antibodies to e. coli were produced in the second year, demonstrating significant immunologic benefit to the infant with continued breastfeeding. iga, igm, and igg were measured in nursing women from the beginning of lactation and simultaneously in the feces of their children by jatsyk et al at the academy of medicine in moscow. they reported iga to be very high in the milk and rapidly increasing in the feces. igg and igm levels, however, were low in both milk and feces. in normal full-term bottle-fed infants, iga appeared in the feces at to weeks of age but at much lower levels than in breastfed infants. koutras reported that in the first weeks of life increased amounts of siga are found in the stools of breastfed infants compared with formula-fed infants. the authors ascribed this phenomenon to the presence of siga in human milk and a stimulation of the local gi production of immunoglobulin. savilahti et al measured serum levels of igg, iga, and igm in infants at , , , , and months of age. by months, the exclusively breastfed infants had igg and igm levels significantly lower than those who had been weaned early (before . months) to formula. six infants were still exclusively breastfed at months, and their iga levels had also lowered to levels found at months with bottle feeders. infection rates were similar. two months after the children were weaned to formula, the igg and igm levels were comparable. iron and zinc levels were the same in all children. siga antibodies have been identified in human milk that recognize a large variety of microorganisms. the siga antibodies that recognize bacteria, viruses, parasites and fungi are listed in table , the list of viruses for which siga antibodies exist in human milk is equally long including enteroviruses (poliovirus, coxsackie, and echovirus), cytomegalovirus (cmv), herpes simplex virus, human immunodeficiency virus (hiv), semliki forest virus, respiratory syncytial virus (rsv), rubella, reovirus type , rotavirus, measles, norovirus, and porcine coronavirus. igg and igm antibodies also exist in human milk against cmv, rsv, and rubella as well as ige antibodies against parvovirus b . noguera-obenza and cleary reviewed the role of breast milk siga in providing protection for infants against various agents specifically causing bacterial enteritis. preservation of human milk at − ° c for up to months does not decrease significantly the levels of iga, igg, igm, c , c , lactoferrin, or lysozyme. , , , the preservation of siga, il- and tnf-α with freezing at ° c or − ° c was recently confirmed by hines et al. a variety of different heat treatments have been applied to milk to protect against bacterial contamination or to protect against infection with specific infectious agents (especially hiv and cmv). heat treatments include low-temperature, short-time ° c for minutes; holder pasteurization . ° c for minutes; high-temperature, short-time ° to ° c for seconds; boiling ° c for greater than minute; sterilization, variable time periods, pretoria pasteurization ° to . ° c for approximately minutes ; flash heating ° c for approximately minutes with a peak temperature at ° c , ; and microwave heating, with milk temperatures of ° to ° c for seconds. boiling or sterilization essentially destroys % of immunologic activity. siga and lysozyme activities drop by % with holder pasteurization and by % at ° c. neither low-temperature, short-time nor high-temperature, short-time reduces the siga or lysozyme content markedly. igg and igm are greatly reduced by holder pasteurization. siga differs antigenically from serum iga. iga can be synthesized in the nonlactating as well as in the lactating breast. it is a compact molecule and resistant to proteolytic enzymes of the intestinal tract and the low ph of the stomach. siga present in human milk is primarily manufactured by plasma cells in the mammary gland, modified in its translocation across the mammary epithelia and only minimally produced by the cellular lymphocytes in milk. levels in milk are to times higher than in serum. levels in cow milk are very low, that is, a tenth of the level in mature human milk ( . mg/dl). later in life, the human intestinal tract's subepithelial plasma cells secrete iga. the intestinal secretion of siga does not occur in the neonatal period but increases between to months of life. discussion continues as to whether any antibodies are absorbed from the intestinal tract, although probably % are absorbed. almost % of ingested iga from milk survives passage through the intestinal tract and is excreted in the feces. all immunoglobulin classes have been identified in the feces. a large body of evidence demonstrates the activity of the immunoglobulins, especially iga, at the mucosal level of the gi and respiratory tracts. these antibodies provide local intestinal protection against microorganisms, which may infect the mucosa or enter the body through the gut or respiratory tract. it is well established that the predominant bacteria found in breastfed infants are bifid bacteria. bifid bacteria are gram-positive, nonmotile, anaerobic bacilli. many observers have shown the striking difference between the flora of the guts of breastfed and bottle-fed infants. györgy demonstrated the presence of a specific factor in colostrum and milk that supported the growth of lactobacillus bifidus. bifidus factor has been characterized as a dialyzable, nitrogen-containing carbohydrate that contains no amino acid. in vitro studies by beerens et al showed the presence of a specific growth factor for bifidobacterium bifidum in human milk, which they called bb. other milks, including cow milk, sheep milk, pig milk, and infant formulas, did not promote the growth of this species but did show some activity supporting b. infantis and b. longum. this growth factor was found to be stable when the milk was frozen, heated, freeze-dried, and stored for months. growth-promoting factors were present for the six strains studied, which varied in their resistance to physical change. because all these factors were active in vitro, they did not require the presence of intestinal enzymes for activation. it has not been possible to show the presence of this growth factor in other mammalian milks; thus it may contribute to the implantation and persistence of b. bifidum in a breastfed infant' s intestine. lactobacillus has been described as one of a number of probiotic bacteria, which provide an immune protective benefit to their host. lactobacillus reportedly stimulates antibody production and improves phagocytosis by blood leukocytes. , the use of probiotic bacteria has reportedly produced benefits in a variety of situations associated with infections. the addition of such bacteria to formula is another example of trying to make formula better by making it more like breast milk. hatakka et al examined the possible effect of adding probiotic bacteria to formula on the occurrence of infection in children attending day care. they reported modest reductions in the number of children with complicated respiratory infections or lower respiratory tract infections as well as the number of children receiving antibiotics for a respiratory infection in the group of children receiving formula supplemented with lactobacillus rhamnosus gg compared with children receiving unsupplemented formula. it was well known in the preantibiotic era that human milk protects human infants throughout lactation against staphylococcal infection. györgy identified the presence of an "antistaphylococcal factor" in experiments with young mice that had been stressed with staphylococci. this factor, with no demonstrable direct antibiotic properties, was termed resistance factor and described as nondialyzable, thermostable, and part of the free fatty acid part of the phosphide fraction, probably c : , but distinct from linoleic acid. human milk contains a nonspecific antimicrobial factor, lysozyme, which is a thermostable, acidstable enzyme. this enzyme is a -amino-acidcontaining glycoprotein that can hydrolyze the - linkage between n-acetylglucosamine and n-acetylmuramic acid in bacterial cell walls. it is found in large concentrations in the stools of breastfed infants and not in stools of formula-fed infants; thus it is thought to influence the flora of the intestinal tract. goldman et al describe an initial fall in lysozyme levels from to mg/ml to mg/ml at to weeks and then an increase during months to mg/ml (see . lysozyme levels show an increase over time during lactation; this finding is more apparent in indian women than in those of the western world. reddy et al studied the levels of lysozyme in well-nourished and poorly nourished women in india and found no difference between them (table - ) . as shown in this study, lysozyme levels increase during lactation. levels in human milk are times the level in cow milk. lysozyme is bacteriostatic against enterobacteriaceae and gram-positive bacteria. it is secreted by neutrophils and some macrophages and is present in many body secretions in the adult. in a study of immunologic components in human milk in the second year of lactation, goldman et al reported that concentrations of lysozyme, lactoferrin, and total and siga were similar to those in uninterrupted lactation and in gradual weaning at to months. siga antibodies to e. coli were also produced during the second year. the authors state that "this supports the idea that the enteromammary lymphocyte traffic pathway, which leads to the development of lymphoid cells in the mammary gland that produce iga antibodies to enteric organisms, operates throughout lactation." when cow milk formula is added to human milk, it reduces the effect of lysozyme; however, powdered human milk fortifier (enfamil) did not inhibit the antiinfective properties. lactoferrin is an iron-binding protein closely related to the serum iron transport protein, transferrin, and is part of the larger transferrin protein family. lactoferrin is found in mucosal secretions (tears, saliva, vaginal fluids, urine, nasal and bronchial secretions, bile, gi fluids) and notably in milk and colostrum. a bacteriostatic effect of lactoferrin is well established for a wide range of microorganisms, including gram-positive and gram-negative aerobes, anaerobes, viruses, parasites, and fungi. the original proposed mechanism of action for its bacteriostatic effect was depriving the microorganism of iron. a second antibacterial action involving direct action with bacterial surfaces; binding negatively charged molecules (lipoteichoic acid) on the surface of gram-positive bacteria neutralizing the surface charge allowing the action of other antibacterial factors like lysozyme or binding lipid a on gram-negative bacteria, releasing the lipid, producing damage to the cell membrane. another antibacterial action is binding bacterial adhesions blocking host cell interaction. lactoferrin can kill candida albicans and c. krusei by changing the permeability of the fungal cell surface. lactoferrin now is considered a multifunctional, immunoregulatory protein. the biologic role of lactoferrin has been reviewed in several studies. , , , they point out that lactoferrin reversibly binds two ferric ions and that its affinity for iron is times greater than that of transferrin, retaining iron down to a ph of . human lactoferrin is strongly basic. lactoferrin is normally unsaturated with iron, and it is usually less than % saturated with iron in human milk. , oral iron therapy for an infant can interfere with the bacteriostatic action of lactoferrin, which depends on its unsaturated state for some portion of its bacteriostatic function. reddy et al showed that giving iron to the mother did not interfere with the saturation of lactoferrin in the milk or thus its potential bacteriostatic effect. protein energy malnutrition, rather than iron supplies, influences lactoferrin synthesis in the mammary gland. malnourished but non-iron-deficient mothers are lactoferrin deficient. the concentration of lactoferrin is high in colostrum- mg/dl-then progressively declines over the next months of lactation, leveling at about mg/dl. breast milk also contains small amounts of transferrin ( to mg/ml). lactoferrin is % to % of the total protein content of human milk. lactoferrin is resistant to proteolysis, especially in its iron-saturated form. intact lactoferrin is detectable in the stool of infants, with higher proportions of lactoferrin measurable in the stool of premature infants. both intact lactoferrin and fragments have been detected in the urine of premature infants, although absorption is less likely in full-term infants. the absorption of iron from breast milk is directly enhanced by lactoferrin. many bacteria require iron for normal growth, and one bacteriostatic effect of lactoferrin has been ascribed to its iron-binding action. in neutrophils, lactoferrin within neutrophilic granules tightly binds iron, but neutrophils with excessive iron are inefficient at destroying bacteria. lactoferrin does not limit the growth of all microorganisms; helicobacter pylori and neisseria, treponema, and shigella species all have receptors for lactoferrin, directly binding iron and allowing adequate growth. some evidence supports various other proposed mechanisms of action for lactoferrin' s antimicrobial effect. lactoferrin has been shown to limit the formation of biofilms by specific organisms, inhibit adhesion to host cells by other organisms and to directly bind to viral particles of herpes simplex virus, hiv, and adenovirus. a proteolytic action of lactoferrin appears to inactivate virulence factors of some organisms. separately, lactoferrin binds directly to glycosaminoglycans (gags) and integrins interrupting the binding of various viruses (herpes simplex virus, hiv, adenovirus, cmv, hepatitis b virus [hbv]) to host cells. pepsin hydrolysate products of lactoferrin (b or h) may exert a direct bactericidal effect by binding to lipopolysaccharide of gram-negative organisms and disrupting bacterial membranes. lactoferrin may cause an increased release of cytokines by cells including antiinflammatory cytokines such as il- . , others have shown that lactoferrin suppresses the release of il- , il- , il- , il- , and tnf-α, all proinflammatory cytokines, which would be more of an immune-modulating effect. other investigators using a recombinant human lactoferrin (talactoferrin) demonstrated evidence of lactoferrin causing increased maturation of dcs and talactoferrin causing the recruitment and activation of neutrophils and macrophages as other examples of how lactoferrin affects the innate immune protection of the growing infant. several other effects have been proposed for lactoferrin, including inhibition of hydroxyl radical formation, decreasing local cell damage; lipopolysaccharide binding, also leading to a diminished inflammatory response; and dna binding, affecting transcription and possibly regulation of the production of cell products. activation of natural killer (nk) cells, modulation of complement activity, and blocking of adhesion of enterotoxigenic e. coli and shigella flexneri are other proposed actions of lactoferrin. a specific region of lactoferrin, near the n terminus of the molecule, is strongly basic and is reported to mediate some of lactoferrin' s antimicrobial activity. "lactoferricins," small peptides containing this basic region, produced by proteolytic cleavage reportedly bind to lipopolysaccharide, leading to disruption of the bacterial cell wall and cytoplasmic membrane. in another area of immune protection, lactoferrin may limit cancer development. the proposed mechanisms of its anticancer effects includes increasing nk cell cytotoxicity, increased production of il- and inhibition of angiogenesis, augmented apoptosis of cancer cells and initiation of cell cycle arrest in growing tumor cells. the multiple roles and proposed mechanisms of action of lactoferrin in breastfed infants continue to be more specifically elucidated. colostral cells in culture have been shown to be stimulated to secrete an interferon-like substance with strong antiviral activity up to national institutes of health units/ml. this property has not yet been identified in the supernatant of colostrum or milk. interferon-γ has been produced by t cells from human milk when stimulated in vitro. the t cells isolated from human milk were the cd ro phenotype and have been identified as a source of interferon. srivastava et al have measured low levels of interferon-γ in not only colostrum but also transitional and mature milk. they postulated that the low level of interferon-γ ( . to pg/ml) might be adequate to protect against infection without hyperactivation of t cells. interferon is produced by nk cells and by t cells, phenotypically thy and thy . it can cause increased expression of major histocompatibility complex molecules, increase macrophage function, inhibit ige and il- production, and produce antitumor and antiviral activity. the exact role of interferon-γ in breast milk has not been delineated. the c and c components of complement, known for their ability to fuse bacteria bound to a specific antibody, are present in colostrum in low concentrations compared with their levels in serum. igg and igm activate complement. c proactivator has been described, and iga and ige have been identified as stimulating the system. activated c has opsonic, anaphylactic, and chemotactic properties and is important for the lysis of bacteria bound to a specific antibody. no functional role for complement in breast milk has been identified. unsaturated vitamin b -binding protein of high molecular weight has been found in very high levels in human milk and in the meconium and stools of breastfed infants compared with its levels in infant formulas and infants who are formula fed. the protein binding renders the vitamin b unavailable for bacterial growth of e. coli and bacteroides. glycans are complex carbohydrate structures attached to various other structures (a lactose moiety, a lipid component, peptides, proteins, or aminoglycans) that are present in large amounts in human milk. they include glycoproteins, glycolipids (gangliosides), glycosaminoglycans, mucins, and oligosaccharides. oligosaccharides are composed of a basic core structure derived from glucose, galactose, or n-acetylglucosamine and are linked to a variety of terminal fucose linkages or sialic acid linkages to create numerous different compounds. oligosaccharides compose the major portion of glycoconjugates in milk and are present in the milk-fat globule membrane and in skim milk. , gangliosides are glycolipids found in the plasma membrane of cells, especially in cells in the gray matter of the brain. more specifically, gangliosides are glycosphingolipids that contain sialic acid, hexoses, or hexose amines as the carbohydrate component and ceramide as the lipid component of the molecule. the predominant gangliosides in human milk are gm , gm , gm , and gd , as reported by newburg. a diverse abundance of these complex carbohydrates are synthesized by the many glycosyltransferases contained in the mammary gland. mucin and lactadherin are two glycoproteins included in this group that have antimicrobial effects. some of these carbohydrate molecules are structurally similar to glycans on the surface of small intestine epithelial cells that act as receptors for microorganisms. one proposed mechanism for the antimicrobial effect of these soluble substances is direct binding with the potential pathogenic organisms. , schroten et al proposed that mucins contained in the human milk fat-globule membrane can block bacterial adhesion throughout the intestine after studying the adhesion of s-fimbriated e. coli to buccal epithelial cells. gangliosides appear to be responsible for blocking the activity of heat-labile enterotoxin from e. coli and the toxin from vibrio cholerae in rat intestinal loop preparations. another toxin from campylobacter jejuni, with similar binding specificity, also seems to be inhibited by gm . , globotriaosylceramide, another glycolipid in human milk, is the natural cell surface receptor for the toxin from shigella dysenteriae and verotoxin released by enterohemorrhagic e. coli. the proposed mechanism of action of these glycolipids is that by binding to the toxin they form a stable complex that prevents the toxin from binding to the appropriate receptors on intestinal cells; however, crane et al proposed from their studies that the oligosaccharide binds to the toxin receptor to block the action of the heatstable enterotoxin of e. coli. human milk gangliosides may be important in protecting infants against toxin-induced diarrhea, but this has not been specifically demonstrated in vivo in controlled trials. , evidence exists that human milk glycans inhibit a broad range of pathogens (table - ) . [ ] [ ] [ ] [ ] [ ] [ ] newberg et al document the constitutive expression of various fucosylated glycans in human milk and secretions and present "typical" concentrations of these active agents in human milk from the literature. their secretion is related to the "secretor" and lewis genes, which control the individual differences in expression of lewis blood group types. chaturvedi et al have recently examined the survival of oligosaccharides from human milk in infants' intestines. they demonstrated that the concentrations of oligosaccharides were higher in the infants' feces than in mothers' milk and higher in feces than urine. the profile of oligosaccharides found in the infants was similar to that found in their mothers' milk. the formula-fed infants had lower concentrations of oligosaccharides and the profiles of the oligosaccharides were different from those found in the breastfed infants. the oligosaccharides remained intact passing through the intestine. a small percentage are absorbed and excreted intact in the urine. the oligosaccharides were available at these sites to block intestinal and urinary pathogens. two other groups of researchers have documented variation of the composition of glycans in human milk over the first months of lactation and variations in the composition of glycans in diverse populations. therefore a diverse repertoire of glycans are present in large amounts in human milk, which persist intact in the intestine and reach the urine, and have demonstrated inhibitory effects on a variety of pathogens. these components constitute a major contribution of human milk to innate immunity at the level of an infant' s gut. ganglioside gm cholera toxin other authors propose that the gangliosides gd and gm may play an immunomodulatory role early in lactation by affecting dcs decreasing the production of interleukins (il- and il- ) and suppressing the expression of various cluster designation (cd) markers and major histocompatability complex class ii on dcs. interleukins (ils) are considered a "subgroup" of cytokines. originally, when cytokines were first hypothesized, it was thought that they were primarily produced by leukocytes and acted on other leukocytes, and therefore they could be called ils. although much of their effect is on lymphocyte activation and differentiation, it is now known that ils act on and are produced by a variety of cells. goldman et al identified il- β, il- , il- , and il- in breast milk (table - ). srivastava et al reported measuring moderate amounts of il- , il- , and il- in the different stages of breast milk. very low amounts of il- β were detected, especially in comparison with the amount of il- receptor antagonist (ra), which presumably could block the activity of the small amount of il- . hawkes et al reported on the amount of cytokines in breast milk over the first weeks of lactation. the proposed "proinflammatory" cytokines, il- β, il- , and tnf-α, were present in only of mothers who donated samples at each point throughout the study. a broad range of concentrations of each of these cytokines was seen during the course of the study. the "antiinflammatory" cytokines, transforming growth factor (tgf) -α and tgf-β , were present in significant amounts in all samples. il- has also been reported in breast milk in % of the mothers tested, with milk (aqueous) levels correlating with plasma il- levels. il- was constitutively produced from % of milk cell samples and il- production was markedly increased by stimulation of the cells with con a. il- has been identified in breast milk by other investigators, especially in the first days of life. , the authors suggest that il- in human milk may augment the newborn' s immune functions before the body can begin full production of cytokines. specifically, this is accomplished by increasing antibody production, especially iga; enhancing phagocytosis; activating t cells; and increasing α -antitrypsin production by mononuclear phagocytes. il- is a chemokine known to improve thymic output in animals and appears related to the proliferation and survival of t cells in all stages of development. ngom et al have described improved thymic function in exclusively breastfed infants associated with higher il- concentrations in the mother' s breast milk. the breast milk of gambian mothers contained variable levels of il- , but the geometric mean levels were higher in the first weeks postpartum in mothers whose infants were born in the "harvest-season" (january to june) compared with those mothers whose infants were born in the "hungry-season." the authors postulate that il- in breast milk enhances t-cell proliferation and survival and overall thymic development in the infant, leading to long-term benefits in protection from infection. il- is a chemokine capable of attracting and activating neutrophils and attracting cd ra + t cells. il- is produced by mammary epithelial cells. srivastava et al also detected messenger ribonucleic acid (mrna) for il- , suggesting that cells in breast milk were capable of producing il- . the exact function of il- in breast milk remains to be elucidated. il- is thought to have antiinflammatory effects, including decreasing the production of interferon-γ, il- , and other proinflammatory cytokines. it has been reported to enhance iga, igg, and igm synthesis. il- has been identified in colostrum, early milk, and mature milk with the highest levels occurring in colostrum and in association with preterm deliveries and complications of pregnancy in the mothers. the levels of il- were correlated with soluble fas ligand in colostrum. il- was detected by immunohistochemical staining in actively secreting epithelial cells in a lactating breast. il- has been shown to be produced by intestinal epithelial cells and activated macrophages. it leads to the production of other chemokines (gm-csf, il- , tnf-α). it induces the expression of fas ligand on lymphocytes. the authors suggested that il- present in colostrum may play a role in stimulating a systemic t h response and causing nk cell and macrophage activation in neonates. the interaction and the direct effect of these ils in breast milk must be clarified. the amount of t cells bearing markers of recent activation is increased in human milk compared with the results in peripheral blood of adults. wirt et al of the many bioactive substances that have been identified in human milk, cytokines are some of the most recently identified and investigated agents, although their existence has long been suspected in attempts to explain certain immunologic and protective effects of breast milk on infants. more than cytokines have been described, and more than of these have been identified in human milk. , cytokines are small proteins or glycoproteins that, through binding to receptors on immune and nonimmune cells, produce a broad range of effects (many still unidentified) through autocrine, paracrine, and endocrine actions. cytokines are produced predominantly by immune cells and function in complex associations with other cytokines to stimulate and control the development and normal functioning of the immune system. the nomenclature and abbreviations used are complicated and confusing. newer systems of classification have been established according to which cells produce them or what their general functions are or based on the relative position of their cysteine residues or their receptor types (ccr, cxcr, cx cr). box - provides a simplified list with abbreviations. little evidence demonstrates specific in vivo activity of the different cytokines. based on general information on the function and interaction of the particular cytokines, as well as consideration of as yet unexplained effects of breast milk, proposed functions of the cytokines include initiation of development of host defense, stimulation of host defenses, prevention of autoimmunity, antiinflammatory effects in the upper respiratory tract and gi tract, and stimulation of the development of the digestive system, especially the mucosal immune system of the alimentary tract and the proximal respiratory tract. the maternal breast may respond to feedback stimulation or suppression by secreted cytokines, influencing the growth, differentiation, and secretory function of the breast. as shown in other situations, cytokines may enhance receptor expression on cells in the respiratory and gi tracts for major histocompatibility complex molecules or immunoglobulins. various cell types in the mucosal immune system may be activated or attracted to specific sites in the gi tract by the action of cytokines. beyond these proposed beneficial effects of cytokines, newer studies are identifying specific leukocyte inhibitory factor lif immunologic and protective roles for different cytokines in developing infants. for example, extensive work has been done on epidermal growth factor (egf) and other growth factors (hb-egf, g-csf, epo, and epo-like growth factors) have been studied relative to their role in preventing necrotizing enterocolitis (nec) and gut homeostasis. a number of potential roles for egf in gut homeostasis have been proposed and studied, including intestinal development, proliferation and adaptive response to damage, repair and regeneration and diminishing inflammatory responses to various stimuli. tgf-β has been studied for its role in initiating and stimulating iga production early on in infancy. the actual measurement of cytokines in breast milk has been complicated by a number of factors, including different assays used (bioassays, enzyme-linked immunosorbent assay [elisa], radioimmunoassay), binding to proteins, their existence in monomeric or polymeric forms, the presence of antagonists, and their varying presence in colostrum, early milk, or mature milk. goldman et al reported on the bioactivity and concentration of cytokines in breast milk from their own work and that of others (see table and at lower levels in mature milk, as well as high levels of soluble tnf-α receptor i (stnf-αri), stnf-αrii, and il- ra. also, they identified that most tnf-α did not exist "free" in breast milk but was associated with tnf receptors. the in vivo significance of these findings remains to be assessed. given the complex interaction and regulation of cytokine production and cytokines' relation to coordinated inflammatory and antiinflammatory responses in tissues, one should assume that the interaction of cytokines in breast milk and the effect of cytokines, cytokine receptors (soluble and expressed on various cell types), and cytokine antagonists on the infant will be equally complex. a new methodology, antibody-based protein arrays has been applied to identify cytokines in human milk. kverka et al analyzed colostrums and milk samples from the first days postpartum using two different arrays capable of detecting and cytokines. three cytokines (egf, il- /cxcl , gro/cxcl - ) were detected in all of the tested samples. nineteen cytokines were present in more than % of the samples. an additional cytokines were identified in human milk for the first time. the concentration of cytokines varied in the different women and varied over time. continued investigation with this and other assays will be essential to understanding the significance and specific effects of these substances in breast milk. nucleotides, nucleosides, nucleic acids, and related metabolic products are essential to many biologic processes. although they are not essential nutrients because they can be synthesized endogenously and recovered from in vivo "salvage" sources, their presence in the diet may carry significant benefits under various conditions (i.e., "conditionally essential"). , , in situations of disease, stress, rapid growth, or limited dietary intake, supplementation of the diet with nucleotides may decrease energy expenditure to synthesize or salvage nucleotides, which optimizes the host response to these adverse situations. nucleotides exist in relatively large amounts in human milk, % to % of the nonprotein nitrogen, suggesting that they have some nutritional significance, although no clinical syndromes have been associated with nucleotide deficiency to date. nucleotides are present in the natural milk of different species in varying amounts and composition. the nucleotide content and composition of bovine milk are particularly less and different from human milk. infant formulas supplemented with nucleotides contain roughly the same amounts of nucleotides as human milk, from to mg/l. , , unsupplemented formulas contain less and different amounts of nucleotides. mammalian cells contain a large variety of nucleotides and related products, which have many metabolic functions, including the following - : . energy metabolism: adenosine triphosphate is a major form of available cellular energy. . nucleic acid precursors: the monomeric units for rna and dna are present. . physiologic mediators: cyclic adenosine monophosphate and cyclic guanosine monophosphate serve as "messengers" for cellular processes; adenosine diphosphate is necessary for platelet aggregation; and adenosine has been shown to affect vasodilatation. . related products function as coenzymes in metabolic pathways: nicotinamide-adenine dinucleotide, flavin adenine dinucleotide, and coenzyme a. rying molecules in synthetic reactions: uridine diphosphate glucose in glycogen synthesis and guanosine diphosphate mannose, guanosine diphosphate-fucose, uridine diphosphate-galactose, and cytidine monophosphate sialic acid in glycoprotein synthesis. . allosteric effectors: the intracellular concentrations of nucleotides influence the progression of certain steps of metabolic pathways. . cellular agonists: extracellular nucleotides influence intracellular signal transduction (e.g., cyclic adenosine monophosphate and inositol-calcium pathway). nucleotide concentrations in cells and tissues are maintained by de novo synthesis and salvage from intermediary metabolism and diet ( figure - ). nucleosides are the predominant product absorbed in the small intestine. nucleosides are probably transported by passive diffusion and a carrier-mediated process; purines and pyrimidines are transported by passive diffusion at high concentrations and by a sodium-dependent active mechanism at low concentrations ( figure - ) . the digestion and absorption of nucleotides, nucleosides, and pyrimidines and purines also involve polymeric and monomeric nucleotides and other adducts (nucleosides in a biologically active moiety). in early reports on the nucleotide and nucleoside content of milk, various methods of measurement were used, and the amounts were described as either the monomeric fraction of nucleotides or the total rna. leach et al, recognizing the complex nature of digestion and absorption of nucleotides and related products, attempted to measure the total potentially available nucleosides (tpans) in human milk using solid-phase extraction, highperformance liquid chromatography analysis, and enzymatic hydrolysis of the various fractions. they analyzed breast milk samples at various stages throughout lactation (colostrum; transitional, early, and late mature milk) from european women and american women. they used an aqueous tpan-fortified solution containing ribonucleosides, ′-mononucleotides, polymeric rna, and nucleoside-containing adducts to estimate the accuracy of their process. the mean ranges of tpan values were similar for european women from different countries and american women, although broad ranges were seen and the composition of individual nucleotides varied. the mean tpan value was lowest in colostrum but did not show a consistent upward or downward trend in transitional, early, or late mature milk. the mean ranges of tpan values were to mmol/l for colostrum, to mmol/l for transitional milk, to mmol/l for early mature milk, and to mmol/l for late mature milk (table - ) . monomeric and polymeric nucleotides were the predominant forms of tpan in pooled samples. cytidine, guanosine, and adenosine were found mainly in these fractions, whereas uridine was found primarily as free nucleotide and adduct ( concluded that their process of estimating tpans, including sequential enzymatic hydrolyses, and measuring the entire nucleotide fraction provides a reasonable estimate of the in vivo process and the nucleotides available to the infant from human milk. proposed effects of dietary nucleotides include effects on the immune system, iron absorption, intestinal flora, plasma lipoproteins, and growth of intestinal and hepatic cells. effects on the immune system, related to nucleotide supplementation to the diet, have mainly been reported from animal studies and include increased mortality rate from graft-versus-host disease, improved delayed-type cutaneous hypersensitivity and alloantigen-induced lymphoproliferation, reversal of malnutrition and starvation-induced immunosuppression, increased resistance to challenge with s. aureus and c. albicans, and enhanced t-cell maturation and function. spleen cells of mice fed a nucleotide-free diet produce lower levels of il- , express lower levels of il- receptors, and have decreased nk cell activity and macrophage activity. , presumably these nucleotide-associated changes are related to t-helper/inducer cells and the initial phases of antigen processing and lymphocyte proliferation. , , in vitro and in vivo experiments have documented that ingested nucleotides increased iron absorption, perhaps affecting xanthine oxidase. although in vitro studies showed that added nucleotides enhanced the growth of bifidobacteria, conflicting results have been obtained on the influence of dietary nucleotides on the fecal flora of infants receiving breast milk or nucleotide-supplemented formula. , clinical studies in infants receiving nucleotide-supplemented formula demonstrated increased high-density lipoprotein cholesterol, lower very-low-density lipoprotein cholesterol, increased long-chain polyunsaturated fatty acids, and changes in red blood cell membrane phospholipid composition. supplementation studies in animals have shown enhanced gi tract growth and maturation, improved intestinal repair after diarrhea, stimulation of hepatic growth, and augmented recovery from hepatectomy. a recent review discusses the effects of dietary nucleotides on the immune system and protection against infection reported in studies in the literature. carver et al †adducts are of the form nucleoside-phosphate-phosphate-x, where x is a biologically relevant moiety (e.g., uridine diphosphate-galactose or nicotinamide-adenine dinucleotide). months, nk cell activity and il- production were higher in the breastfed and nucleotidesupplemented groups compared with those receiving formula without nucleotide supplements. infections occurred infrequently in all groups, but slightly less in the breastfed group. no differences were noted in hematologic profiles and plasma chemistry values, and no toxicity or intolerance was associated with nucleotide supplementation. the sample size was small, marked variability was seen in the il- measurements, and the differences noted at months were less than at months. therefore the authors concluded that dietary nucleotides may contribute to improved immunity in breastfed infants. brunser et al examined the effect of a nucleotide-supplemented formula on the incidence of diarrhea in infants in chile, studied through months of age. although the infants receiving the supplemented formula ( mg/l) experienced less diarrhea, the difference in the duration of diarrhea was small. the numbers were too small to comment on the causative agents of diarrhea, although no apparent protection against any one agent was seen. the beneficial effect of nucleotides against diarrhea was proposed to be secondary to enhanced immune response to intestinal pathogens or improved intestinal integrity or a combination of both. in a larger study of infants younger than months of age, the severity of the diarrhea (duration and number of bowel movements) as well as the incidence of diarrhea was lower in the nucleotide supplemented group. two groups of premature infants fed either nucleotide supplemented ( mg/l) or unsupplemented formula were followed, measuring the concentration of plasma immunoglobulins throughout the first months of life. igg plasma concentrations were not different in the two groups during the study period. igm plasma levels were higher in the nucleotide supplemented group at to days and months of life, while iga plasma levels were significantly higher at months of age in the supplemented group. pickering et al published a -month, controlled, randomized study of infants to examine the effect of added nucleotides at levels comparable to human milk on infants' immune responses to various vaccine antigens; nonrandomized infants received breast milk for at least months and then either human milk or a standard infant formula. another infants were randomized to receive either a standard infant formula or one supplemented with nucleotides. the amount and actual nucleotide content added were based on tpans, as measured by leach et al, equaling mg/l. overall growth and nutrition tolerance were similar in each group. the nucleotide group had significantly higher geometric mean titers of h. influenzae type b antibody and diphtheria antibody than the control group or the breastfed infants. no significant difference was seen between the nucleotide and control groups for the igg response to oral poliovirus vaccine or tetanus. infants who are breastfed for longer than months had significantly higher antibody responses to oral poliovirus vaccine than children breastfed for less than months or either of the two formulafed groups. no significant differences were found between the different groups with respect to total igg, iga, or ige. differences were seen in the number of children who experienced at least one episode of diarrhea: the nucleotide group ( / , %) versus the control group ( of , %, p < . ) and the breastfed group ( of , %) . notably, the breastfed group was heterogeneous relative to the amount of breast milk received and the duration of feeding, whereas the nucleotide group received supplementation for the entire months. questions that remain concerning nucleotides and their proposed beneficial effects in an infant' s diet include the following: • what are the proven mechanisms of action of these proposed benefits? • what form and concentration of nucleotides are necessary to effect these benefits? • is adequate information available to justify using nucleotides in infant formula in higher amounts and different compositions than are currently used? debate and research to answer these and other questions concerning nucleotides will continue. a primary function of each of the body' s different mucosal surfaces is immunologic. each distinct mucosal surface has multiple other physiologic functions including gas exchange (in the lungs), nutrient absorption (in the gut), sensory detection (in the eyes, nose and mouth) and reproduction (in the uterus and vagina). the thin, permeable nature of these barrier mucosal surfaces, their large surface area and the constant exposure to microorganisms, foreign proteins, and chemicals predisposes the mucosal membranes to damage and infection. during the first year(s) of life, when the infant' s immune system is developing and maturing, it is doing so on a systemic and a mucosal basis as well as involving both innate and adaptive immune mechanisms. that development must include the ability to respond to and protect against invasive pathogens at the same time as "tolerate" or "ignore" the multitude on commensal organisms that reside at these surfaces. during this early development, breast milk contains numerous bioactive factors that supplement the immune protection at the mucosal level while limiting inflammation and contribute to the immune modulation and growth stimulation of infants' mucosal and systemic immune defenses. the mucosal immune system involves both innate mechanisms and adaptive immune mechanisms functioning in concert. the development of the mucosal immune system occurs in the prenatal period and continues in the postnatal period. the functional mucosal barrier includes the action of enzymes, chemicals, acidity or ph, mucus, immune globulins and indigenous flora. in as early as weeks of gestational age, researchers have identified changes in the intestinal barrier with the development of enterocytes, goblet cells and enterochromaffin cells along with evidence of development of tight junctions between the epithelial cells. , mucus production, which can block adherence of pathogens to epithelial cells, demonstrates both pre-and postnatal development beginning with evidence of expression of the muc gene as early as weeks' gestational age. this is approximately the same time that paneth cells appear in intestinal crypts. these cells secrete various products, including α-defensin, lysozyme, secretory phospholipase a , and tnf-α, which contribute to protection from pathogens, stem cell protection within the epithelia layer and influence the selection and number of commensal organisms. , secretory immune globulins siga and igm act at the epithelial surface, largely without inflammation, by limiting adherence and transmigration and facilitating phagocytosis of potential pathogens. the well-recognized malt is present in localized areas beneath the mucosal surfaces: tonsils and adenoids in the nasopharynx and peyer patches and isolated lymphoid follicles in the intestine. overlying the isolated lymphoid follicles of the gut are specialized epithelial cells called m-cells. m-cells (membrane, microfold, or multifenestrated cells) come in direct contact with microorganisms and antigens due to a lack of a surface glycocalyx covering. these remarkable cells endocytose, phagocytose and transcytose molecules, and antigens from their luminal surface to their basal surface. antigenpresenting cells and lymphocytes process the trancytosed molecules, presenting them to submucosal aggregates of lymphocytes. the activated lymphocytes that have responded to the specific presented antigens migrate via the lymphatics to the thoracic duct and into the blood. these lymphocytes circulate in the blood, until they return to mucosal tissues, predominantly the same ones they originated from, where they now function as effector lymphocytes in the lamina propria. this process of "directed migration" to specific sites occurs due to the influence of cytokines and adhesion molecules, such as chemokine ccl (mucosal epithelia chemokine) expressed in the colon and salivary glands and ccl (thymus-expressed chemokine) which effects the site-specific migration. the immune response of lymphocytes in the submucosa and the subsequent directed migration to the same and other mucosal sites produces a focused response to a selected repertoire of antigens at those sites. the lactating mammary gland is an essential component of malt. a mother' s mature effective immune response to microorganisms in her and her infant' s environment through this antigenic stimulation of malt in the mother' s gut and respiratory mucosa and the directed migration of cells to the breast results in activated lymphocytes and antibodies in the breast milk providing protection to the infant against those microorganisms. this is a wellrecognized example of how breast milk can provide additional immune protection to the infant. it is also one of the reasons to continue breastfeeding when a mother or the infant have a possible infection. the mucosal immune system undergoes significant postnatal development, in part due to the dramatic exposure of the mucosa to large numbers of microorganisms in early postnatal life. peyer patches are rudimentary, and few immunoglobulinproducing intestinal plasma cells are present until several weeks after birth. after several weeks, germinal centers within the lymphoid follicles develop, and the number of igm-and iga-producing cells in the intestine increase. immunoglobulin-producing intestinal plasma cells (primarily iga-producing cells) in the lamina propria increase in number from to months of age. with normal maturation of the mucosal immune system, large numbers of immunoglobulin-producing cells locate in the intestinal lamina propria. the monomeric iga produced by these plasma cells is transported through epithelial cells to the mucosal lumen. attachment of an epithelial glycoprotein, the membrane secretory component to two iga molecules leads to the formation of a dimeras; the siga molecule is "secreted" at the mucosal surface. igm, in the form of a pentamer, contains a polypeptide j-chain and is transported by the same mechanism. a portion of the secretory component remains attached to the siga and igm, which protects these molecules against proteolysis and contributes to their stability. large amounts of siga and igm are produced, in a similar fashion, by the mammary glands and delivered to the infant via breast milk. the siga and igm remain stable in saliva and feces and provide specific protection by blocking adherence and entry and facilitating inactivation, neutralization, and agglutination of a wide variety of microorganisms. distinct from the action of immunoglobulins, a large number of bioactive factors in breast milk act at the mucosal level to supplement the innate defenses. these include lactoferrin, lysozyme, casein, oligosaccharides, glycoconjugates and lipids. mucin- , lactadherin, and a glycosaminoglycan are antimicrobial components, which are part of the milk-fat globule. free-fatty acids and monoglycerides, digested components of the milk-fat globule, can cause lysis of enveloped viruses, bacteria, fungi, and protozoa. lauric and linoleic acids, which constitute a large percentage of the ffe in human milk, are two such acids produced by lipolysis in the stomach. additional factors contained in breast milk with demonstrated activity at the level of the mucosa include cytokines, hormones and growth factors. il- and ifn-γ act by influencing epithelial barrier integrity. other factors that are considered to contribute to mucosal growth and development are tgf-α, egf, and hormones (insulin and insulinlike growth factor). many other factors contained in breast milk have the potential for activity at the level of the mucosa, including nutrients, vitamins, nucleotides, enzymes, and soluble molecules with receptor-like structures (soluble cd , soluble toll-like receptor ) , , toll-like receptors (tlrs) and the complex interaction between indigenous bacterial flora and the intestine is an important aspect of research into the development of the mucosal immune system. forchielli and walker have reviewed many of these immune mechanisms acting at the mucosal level. tlrs are transmembrane receptors (pattern recognition receptors) that are capable of detecting and discriminating among various groups of potential pathogens and initiate different immune responses to them. tlrs "recognize" pathogenassociated molecular patterns, conserved features in the pattern of molecules expressed by pathogens and commensal organisms. specific tlrs recognize a particular repertoire of patterns: tlr identifies bacterial lipoproteins and peptidoglycan molecules; tlr recognizes double-stranded dna and tlr identifies lipopolysaccharide. ten tlrs are recognized in humans to date; some have identified legends (pathogen-associated molecular patterns from viruses, bacteria, and protozoa) to which they bind. tlrs are present on some epithelial cells, but are predominantly expressed on macrophages and dcs. intestinal epithelial cells are influenced by gut flora and local immune response to express specific tlrs. the recognition of specific antigens by epithelial cell tlrs stimulates different intracellular signal pathways that lead to different t-lymphocyte immune responses. it has been postulated that the ongoing immune stimulation elicited by the microbial flora in the gut "programs" the host to predominately express different t-helper cell responses: t h -like, t h -like and t h -like. this is referred to as "crosstalk" between the indigenous intestinal flora and the body' s immune system. the t h -like response is described as delayed-type hypersensitivity or cellular immunity; characterized by the predominant release of il- , il- and interferon-γ. the t h -like is primarily humoral immunity, antibody production (especially ige) associated with ils: il- , il- , and il- . the t h -like response is related to oral tolerance and antiinflammatory effects in association with the release of il- and tgf- . a theoretical "ideal" for this system is the ability of the host to respond to various stimuli with balanced protection against the microbial invasion without excessive inflammation or damage to the host. an imbalanced (or poorly regulated) response of this system could result in an allergic reaction against food proteins (t h excess) or an autoimmune inflammatory response against self-antigens (t h excess). ongoing research continues to explore these molecular mechanisms, their potential contribution to allergy, autoimmune disease and normal immune function development within a fetus, infant, and young child. the role of breast milk in the development of the systemic and mucosal immune systems takes on new significance when considering these concepts and mechanisms. this is especially true when examining the role of breast milk in adding to the innate and adaptive immune response at the level of the mucosa, the effect breast milk has on the respiratory and intestinal microbiota, the purported antiinflammatory effects of breast milk, and the proposed influence of breast milk on the maturational development of the intestine. vorbach, capecchi, and penninger postulated that the mammary gland evolved from a protective immune gland as part of the innate immune system. they present a list of various protective molecules that are part of both mucosal secretions and human milk. they discuss how specific nutritional factors in human milk have dual functions: nutritional and protective. this highlights the dual role of the breast as a nutritional and immune organ and should stimulate further research into the breast' s role in innate immunity as a component of the mucosal immune system. investigation into the microbial colonization of the intestinal tract has exploded. much of this investigation has been driven by new molecular techniques involving the analysis of ribosomal rna sequences of microbes that might not have been identified by traditional culture techniques. the diversity of the microbiota (all the microbes which colonize the gi tract) can be viewed from different perspectives based on the technical methods used. probiotics have been broadly defined as microorganisms that can exist within a host while affording benefits for the organisms and the host. prebiotics are substances that (through different mechanisms) increase the growth and survival of probiotic bacteria within the host. commonly recognized probiotic bacteria are lactobacillus rhamnosus gg, bifidobacteria infantis, streptococcus thermophilus, bacillus subtilis, saccharomyces boulardii, and bifidobacteria bifidus. many more organisms are considered to be probiotic, some of which are commercially available. prebiotics are predominantly nondigestible oligosaccharides that ferment within the colon changing the ambient ph and producing small-chain fatty acids. breast milk with its significant composition of oligosaccharides functions as a prebiotic source for an infant, facilitating the growth of bifidobacteria and lactobacilli. , ongoing research is exploring the potentially mutually beneficial relationship between the microbes and the host with particular attention to nutrition (the availability of nutrients, energy sources, and synthesis of vitamins as influenced by the microbes), the developing gi tract (including angiogenesis and mucosal barrier repair), , , the maturation of mucosal immunity, , both the innate system and adaptive system, and the bioavailability and metabolism of drugs and chemicals in the gi tract. , specific proposed mechanisms of how probiotic bacteria and prebiotic substances contribute to an infant' s developing immune system include competition with pathogenic bacteria for colonization, strengthening the tight junctions to enhance the mucosal barrier, producing antimicrobial bacteriocidins, stimulating mucus production, stimulating peristalsis, influencing the secretion of siga, stimulating the crosstalk interaction between intestinal cells and colonizing bacteria to affect the mucosal immune development, and increasing the production of certain cytokines (il- and interfer on-γ). , , , the microbial colonization of an infant' s intestinal tract begins at birth, with organisms from the maternal flora being the first colonizers. numerous additional factors directly influence the composition of the intestinal microbiota in early infancy, including gestational age, ingestion of breast milk or formula, initiation of solid foods, mode of delivery, the route of delivery of food, the time of onset of feeding, exposure to other microbes through contact (with family, animals, persons from other environments), antibiotics, and intercurrent or chronic illness. , the predominant flora of breastfed infants are lactobacillus bifidus and bifidobacterium spp., which constitute up to % of the culturable organisms. the remaining minority of bacteria include streptococcus, bacteroides, clostridium, micrococcus, enterococcus, e. coli, and other uncommon organisms in small numbers. , , lactobacillus bifidus metabolizes milk saccharides, producing large amounts of acetic acid, lactic acid, and some formic and succinic acids, which create the low ph of the stool of breastfed infants. l. bifidus also produces short-chain fatty acids in the course of colonization. large numbers of bifidobacteria can lower the ph of the intestine, which limits the growth of some pathogens such as e. coli, bacteroides, and staphylococci. the flora of bifid bacteria is inhibitory to certain pathogenic bacteria. substantial clinical evidence is available to demonstrate protection against intestinal infections from s.aureus, shigella, salmonella, vibrio cholerae, e. coli, rotavirus, campylobacter, and protozoa. two facilitory actions of breast milk are apparent. the first encourages the growth of l. bifidus and thus crowds out the growth of other bacteria. in the second, the number of pathogens is also kept low by the direct action of lysozyme and lactoferrin. when the number of pathogenic bacteria is kept low, immune antibodies can keep the growth of potentially pathogenic bacteria under control and limit the invasion of bacteria through the gut wall into the bloodstream. the intestinal flora of formula-fed infants is made up of predominantly gram-negative bacteria, especially coliform organisms, bacteroides, and including clostridium, enterobacter, and enterococcus. studies have demonstrated that potentially four distinctly different "microhabitats" for microflora within the gi lumen, within the mucus layer, separately within crypt mucus, and directly on the surface of the intestinal epithelium. the significance of the microhabitats and the effect of specific microorganisms has yet to be determined. at weaning, the facultative anaerobes decline in number and obligate anaerobes (bacteroides) become the predominant organisms in the intestine. preterm infants are colonized with different types and numbers of bacteria from full term infants. the environment of neonatal intensive care units (nicus), including incubators, widespread use of antibiotics and parenteral nutrition, and illness influence the microbial colonization. the short-and long-term effects of the different and changing gi microbiota are a concern. , this is particularly true when one considers the contributing factors or causes for sepsis, nec, chronic lung disease, or poor neurologic outcome in nicus. the question of a causal role of intestinal microflora and the development of nec in premature and very-low-birth-weight (vlbw) infants has been proposed. , gewolb et al suggested that a low percentage of bifidobacterium and lactobacillus in the stool of vlbw infants within the first month of life is a risk factor for infection. some studies on the use of probiotics and the occurrence of nec have demonstrated a lower incidence of nec in infants receiving probiotics. , , here again, the use of mothers' breast milk for premature infants and vlbw infants decreases the risk to the infant of sepsis, nec, and infection-related events. , in a controlled prospective study of high-risk, low-birth-weight infants in india using donor human milk, significantly fewer infections and no major infections were found in the group receiving human milk, although the control infants experienced diarrhea, pneumonia, septicemia, and meningitis. the properties of human milk do appear to control or limit infections in infants. hundreds of articles , have been written about the protective effect of breastfeeding, including the recent agency for healthcare research and quality publication on breastfeeding and maternal and infant health outcomes in developed countries from . using evidence-based analyses, the report documents the decreased risk for acute otitis media, gi infections, and lower respiratory tract diseases in breastfed infants in developed countries. breast milk iga has antitoxin activity against enterotoxins of e. coli and v. cholerae that may be significant in preventing infantile diarrhea. antibodies against o antigen of some of the most common serotypes of e. coli were found in high titer in breast milk samples collected from healthy mothers in sweden. the infants who had consumed reasonable amounts of breast milk with high titers of e. coli antibodies had antibodies in their stool. protection against cholera in breastfed children by antibodies in breast milk was studied by glass et al. a prospective study in bangladesh showed cholera antibody levels to vary in the colostrum and milk. the correlation among colonization, disease, and milk antibodies led the authors to conclude that breast milk antibodies against cholera do not protect children from colonization with v. cholerae, but they do protect against disease. salmonella infection was similarly studied by france et al to evaluate the immunologic mechanisms in host colostrum and milk specific for salmonellae. vigorous responses of colostral and milk cells against these organisms and nonspecific opsonizing capacity of the aqueous phase of colostrum and milk were demonstrated. gothefors et al showed that e. coli isolated from stools of breastfed infants differed from strains found in formula-fed infants in two respects. first, e. coli strains were more sensitive to the bactericidal effect of human serum. second, and more often, spontaneously agglutinated bacteria from other sites, such as the prepuce or periurethral area, were less sensitive in breastfed infants. these findings support the theory that breast milk favors proliferation of mutant strains, which have decreased virulence. this mutation of bacterial strains is another way breastfeeding may protect against infection. it has been suggested that "milk immunization" is a dynamic process because a mother' s milk has been found to contain antibody to virtually all her infant' s strains of intestinal bacteria. the mother exposed to the infant' s microorganisms through either the breast or the gut responds immunologically to those microorganisms and thus directly provides protection for her immunologically immature infant. the orderly review of data on the presence of antibodies in human milk has produced a substantial list of affected organisms. in addition to e. coli, antibodies to bacteroides fragilis, clostridium tetani, haemophilus pertussis, diplococcus pneumoniae, corynebacterium diphtheriae, salmonella, shigella, chlamydia trachomatis, v. cholerae, s. aureus, and several strains of streptococcus (table - ) have been identified. noguera-obenza and cleary have summarized the contribution of siga in breast milk in protecting infants from bacterial enteritis. a study in oslo by hanson of an outbreak of severe diarrhea caused by e. coli strain showed that six severely ill children were formula fed. two infants who were breastfed had e. coli strain in their stools but showed few symptoms. their mothers had no detectable antibodies for strain in their milk, which would suggest that other factors in human milk protect the infant from serious illness when no antibodies are in the milk. hanson also reported the results of another study in which after colonization with a specific strain of e. coli, mothers had large numbers of lymphoid cells in their milk with antibodies to that e. coli. the mothers' serum showed no such response. this supports the concept that antigen-triggered lymphoid cells from peyer patches seek out lymphoid-rich tissue, producing iga in the mammary gland. the mother is immunized in the gut at the same time as her milk. it has also been shown that e. coli enteritis can be cured by feeding human milk. schlesinger and covelli studied possible cell-mediated immunity in breastfed infants. they showed that tuberculin-positive nursing mothers had reactive t cells in their colostrum and early milk. furthermore, of infants nursed by tuberculin-positive mothers had tuberculinreactive peripheral blood t cells after weeks. cord blood had no such activity. no clinical or research data suggesting a protective effect of this apparently induced tuberculin reactivity in infants are available. protection against viruses has been the subject of similar studies. breast milk contains antibodies against poliovirus, coxsackievirus, echovirus, enterovirus, influenza virus, reovirus, rsv, rotavirus, and rhinovirus. , it has been confirmed that human milk inhibits the growth of these viruses in tissue culture. nonspecific substances in human milk are active against arbovirus and murine leukemia virus, according to work by fieldsteel. a high degree of antiviral activity against japanese b encephalitis virus as well as the two leukemia viruses has been found in human milk. the factor was found in the fat fraction and was not destroyed by extended heating, which distinguishes it from antibodies. may believes the nonimmunoglobulin macromolecule antiviral activity in human milk is caused by specific fatty acids and monoglycerides (table - ) . it is important to recognize other factors besides immmunoglobulins are contained in breast milk that can play a role in protection of the breastfeeding infant from viral infections. , specimens of human colostrum have been found to contain neutralizing activity against rsv. rsv has become a major threat in infancy and is the most common reason for hospitalization in infancy in some developed countries. it has a high mortality rate. epidemics have occurred in special care nurseries. statistically significant data collected by downham et al showed that, compared with uninfected control subjects who were breastfed ( of ), few breastfed babies ( of ) were among the infants hospitalized for rsv infection. fishaut et al studied the immune response to rsv prospectively in nursing mothers during several months. antiviral igm and igg were rarely found in colostrum or milk. rsv-specific iga, however, was identified in % to % of specimens. two mothers with the disease had specific igg, igm, and iga antibody in serum and nasopharyngeal secretions, but only iga was found in their milk. this confirms that iga antibody to specific respiratory tract pathogens is present in the products of lactation. because rsv appears to replicate only in the respiratory tract, the authors suggest that viral-specific antibody activity in the mammary gland may be derived from the bronchioleassociated lymphoid tissue. in human milk, bile salt-stimulated lipase has been found to be the major factor inactivating protozoans (table - ). the mechanism by which lipase acts is not known, although it may generate fatty acids and monoglycerides, which inactivate enveloped bacteria, viruses, or protozoa. a nonimmunoglobulin, nonlipase, heat-stable factor has been identified in human milk that can inactivate giardia lamblia. human milk protects against many intestinal and respiratory pathogens with minimal evidence of inflammation. goldman et al hypothesize that human milk is poor in initiators and mediators of inflammation but rich in antiinflammatory agents. several major biochemical pathways of inflammation, including the coagulation system, the fibrinolytic system, and complement, are poorly represented in human milk. box - outlines the antiinflammatory properties of various constituents and the paucity of certain proinflammatory mediators in breast milk. the interaction of factors in the milk with one another or with host defenses cannot be entirely predicted by examining each factor separately. when the decreased response of human milk leukocytes to chemoattractant peptides was demonstrated by thorpe et al, the failure of the response of human milk leukocytes was not caused by alterations in maternal peripheral blood leukocytes. this suggests that inhibitors are in the milk and that human milk leukocytes may be modified in the mammary gland to protect through noninflammatory mechanisms. only low numbers of basophils, mast dells, eosinophils, and cytotoxic t-cells are present in breast milk. many other studies have documented the decreased function of milk polymorphonuclear leukocytes and macrophages in both colostrum and mature milk. the antioxidant properties of human colostrum were demonstrated by buescher and mcilheran using aqueous human colostrum on human pmns. the colostrum significantly interfered with pmn oxygen metabolic and enzymatic activities that are important in the mediation of acute inflammation. antioxidants in breast milk can also contribute to the overall antiinflammatory effect of breast milk. demonstrated antioxidants contained in breast milk include an ascorbate-like compound, uric acid, α-tocopherol, β-carotene, and l-histidine, all of which scavenge oxygen radicals. blood levels of α-tocopherol and β-carotene are higher in breastfed than unsupplemented formula-fed infants. catalase, glutathione peroxidase, and lactoferrin are functionally antioxidants. antioxidant activity has been demonstrated in colostrum and at lower levels in mature human milk. additionally, specific cytokines that can exhibit antiinflammatory effects have also been identified in human colostrum and milk: tgf-β and -β , , and il- . a cytokine antagonist, il- ra, and soluble receptors for tnf-α are also found in colostrum and milk. , palkowetz et al have reported that il- ra can decrease the action of il- β. both human colostrum and milk cause a diminished influx of polymorphonuclear cells to a local site of inflammation in two different in vivo models of inflammation in rats. , , the inflammatory response can be protective for the host at the same time as it can produce the symptoms of clinical illness. breast milk contains a large variety of antimicrobial factors that exert their protective effect without causing significant inflammation (e.g., siga, oligosaccharides, lactoferrin, nucleotides). many other cells and factors in breast milk participate in a complex interaction to both protect the infant and limit the potential damaging effects of an uncontrolled inflammatory response. further study into the dynamic interplay of the many factors in breast milk with developing infants' mucosal barriers and immune systems is needed to fully understand the protective immune response and the antiinflammatory benefits of human milk. (see chapter on human milk as prophylaxis in allergy) in discussing the allergic protective properties of human milk, it is difficult to identify specific protective factors that are proved to protect against allergy. it is equally difficult to discuss the proposed mechanisms of protection because the exact mechanism of "oral tolerance" remains theoretic and the relative importance of contributing factors to hypersensitivity must still be adequately defined. some of the important variables concerning tolerance and sensitization are genetic background of the host, nature and dose of the antigen, frequency of exposure, timing (age) at first and subsequent exposures, immunologic status of the host, and route of exposure. during the neonatal period the small intestine has increased permeability to macromolecules. infants have more serum and secretory antibodies against dietary proteins than children or adults. production of iga in the intestinal tract is delayed until weeks to months of age. iga in colostrum and breast milk prevents the absorption of foreign macromolecules when an infant' s immune system is immature. mucin, oligosaccharides, and other factors within breast milk may affect antigen presentation. protein of breast milk is species specific and therefore nonallergic for human infants. no antibody response has been demonstrated to occur with human milk in infants. it has also been shown that macromolecules in breast milk are not absorbed. indirect evidence can be inferred from a demonstration of an infant' s response to cow milk protein. within days of taking cow milk, the infant will begin to develop antibodies. since the advent of prepared formulas, in which the protein has been denatured by heating and drying, the incidence of cow milk allergy has been considered to be %. the most reliable means of diagnosing cow milk allergy is by challenging with isolated cow milk protein. although circulating antibodies and coproantibodies have been identified, these are not reliable techniques for a clinician involved in patient care. the allergic syndromes that have been associated with cow milk allergy include gastroenteropathy, atopic dermatitis, allergic rhinitis, chronic pulmonary disease, asthma, eosinophilia, failure to thrive, and sudden infant death syndrome, or cot death, which has in some cases been attributed to anaphylaxis to cow milk. , gi symptoms have received the greatest attention and include spittingup, colic, diarrhea, blood in the stools, frank vomiting, weight loss, malabsorption, colitis, and failure to thrive. cow milk has been associated with gi protein and blood loss. the diagnosis is best made by elimination of cow milk from diet and, when appropriate, challenge tests. cutaneous testing is of little help. cow milk allergy has been described in breastfed infants, and exclusive breastfeeding alone is not sufficient to protect an infant at high risk to become sensitized to cow milk proteins. the incidence of cow milk allergy in exclusively breastfed infants has been estimated as . % to . % compared with the overall incidence ranging from . % to . % in population-based studies. murray showed the association of nasal secretion eosinophilia with infants freely fed cow milk or solid foods compared with eosinophilia in strictly breastfed infants. in infants receiving cow milk, % had high eosinophilic secretions, and only % of breastfed infants had eosinophils present in nasal secretions. not surprisingly, many different antigenic specificities are recognized when the colostrum or milk of one species is fed to or injected into another species. cow milk is high on the list of food allergens, particularly in children. sensitivity to cow milk is responsible for at least % of all pediatric allergic conditions, according to gerrard. evidence indicates that iga antibodies play an important role in confining food antigens to the gut. food antigens given to bottle-fed infants before they can make their own iga, and when they are deprived of that in human milk and the plasma cells, may be expected to be more readily absorbed. glaser first made the association between the drop in breastfeeding and the rise in allergy. he pioneered the theory of prophylactic management of allergy. allergy in infancy is associated with a familial history of atopic disease and elevated cord blood ige levels. the introduction of "foreign" proteins to an infant' s diet and even to the mother' s diet in the breastfeeding dyad can lead to allergic symptoms in the infant. exclusive breastfeeding does not protect high-risk children from allergic symptoms unless the mother also adheres closely to a restrictive diet that excludes common allergens. , a large body of literature examines whether breastfeeding protects against atopic disease. in , kramer defined standards for methodology and the study of allergy and breastfeeding. the standards clarified the definitions of breastfeeding, measurable outcomes, and the diagnostic criteria for specific allergic syndromes, defined children at high risk for atopic disease, and addressed methods to decrease bias and control for confounding variables. several recent large meta-analyses have been performed assessing the protective effect of breastfeeding against allergic rhinitis, atopic dermatitis, and asthma. , , exclusive breastfeeding during the first months of life protected against allergic rhinitis (summary odds ratio . ; % confidence interval . to . ) with or without a family history of atopy. exclusive breastfeeding for at least months was associated with lower rates of atopic dermatitis in children with a family history of atopy. exclusive breastfeeding in the first months of life was protective against asthma during childhood (odds ratio . ; % confidence interval . to . ). chapter discusses the prophylactic management of the potentially allergic infant. the major elements in human milk related to the infant' s immune system are direct-acting antimicrobial factors, antiinflammatory factors, and immunomodulating bioactive compounds. epidemiologic studies have produced compelling information that suggests that breastfeeding for months or longer can provide some immunologic protection against some childhood-onset diseases. , , in , viirtanen et al reported a prospective long-term study among children in finland that showed a significantly lower incidence of type diabetes in those at-risk children who had been breastfed for months or longer. other epidemiologic studies have demonstrated a decreased incidence of type insulin-dependent diabetes mellitus in breastfed children. , , these clinical observations have been supported in the laboratory by studies of diet control in diabetic mice. the isolation of a bovine albumin peptide as a possible trigger of type insulin-dependent diabetes mellitus makes further study imperative. based on limited data, the recent agency for healthcare research and quality report cautiously concluded that breastfeeding for at least months reduced the risk for type diabetes compared with breastfeeding for less than months. for type diabetes, the same report concluded that breastfeeding in infancy produced a decreased risk compared with not breastfeeding. the review of the national perinatal collaborative study by davis et al showed a protective effect against development of childhood cancer by being breastfed for months or longer for children followed for years. the effect was greater for acute leukemia and lymphoma. the role of infant feeding practices showed a similar effect of breastfeeding as protective in postponing or decreasing the occurrence of inflammatory bowel disease in childhood. , greco et al reported a decreased risk for celiac disease in breastfed infants. the ahrq report concluded that an association exists between breastfeeding for at least months and a decreased risk for developing acute lymphocytic leukemia and acute myelogenous leukemia. maternal renal allografts have a better survival rate in individuals who were breastfed in infancy compared with those who were not breastfed. , the mechanism of these apparent long-term immunologic benefits remains unclear, although theories abound. given the potential for confounding factors and bias in large long-term studies, confirmation of these proposed benefits by additional carefully controlled trials is required. an increasing amount of accumulated epidemiologic literature, utilizing improved methodology and statistics, demonstrates the protective benefits of human milk for infants. a large number of bioactive factors have been identified and measured in breast milk during the period of lactation. additional research is needed to clarify the interactions and the mechanisms of action of the many bioactive factors in human milk and then correlate these immunomodulatory actions with specific protective benefits for the infant. section on breastfeeding: breastfeeding and the use of human milk activity of the alternative pathway of complement in the newborn infant a prospective cohort study on breast-feeding and otitis media in swedish infants exclusive breastfeeding reduces acute respiratory infection and diarrhea deaths among infants in dhaka slums sensitization to common allergens and its association with allergic disorders at age years: a whole population birth cohort study breast feeding and protection against neonatal sepsis in a high risk population breastfeeding and the capital risk of hospitilization for respiratory disease in infancy human chemokines: an update infant feeding patterns and risks of death and hospitalization in the first half of infancy: multicentre cohort study ige and igd in human colostrum and plasma diet and faecal flora in the newborn: nucleotides influence of dietary manipulation on incidence of atopic disease in infants at risk studies of breastfeeding and infections. how good is the evidence? relation between infant feeding and infections during the first six months of life positional otitis media immunologic benefits and hazards of milk in maternal-perinatal relationship influence of breast-feeding on the bifid flora of the newborn intestine bactericidal activity of human milk leukocytes oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus: a hypothesis development and basic mechanisms of human gut immunity mucosal immunity: integration between mother and the breast-fed infant mucosal and glandular distribution of immunoglobulin components: differential localization of free and bound secretory component in secretory epithelial cells ontogeny of the mucosal immune system and iga deficiency the b-cell system of human mucosae and exocrine glands milk derived gm and gd differentially inhibit dendritic cell maturation and effector fuctionalities the epithelial cells and cell fragments in human milk effect of dietary nucleotide supplementation on diarrhoeal disease in infants interleukin- in human milk: a potential modulator of lymphocyte development in the breastfed infant bioactive components of human milk antioxidant properties of human colostrum soluble receptors and cytokine antagonists in human milk polymorphonuclear leukocytes in human colostrum and milk developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. ii. duodenum and liver, gallbladder, and pancreas iron-binding proteins and other factors in milk responsible for resistance to escherichia coli daily ingestion of immunologic components in human milk during the first four months of life breast feeding and maternal-donor renal allografts: possibly the original donor-specific transfusion endotoxin and hypoxiainduced intestinal necrosis in rats: the role of platelet activating factor advances in nutritional modifications of infant formulas dietary nucleotides: cellular immune, intestinal and hepatic system effects dietary nucleotide effects upon immune function in infants the role of nucleotides in human nutrition full breastfeeding duration and associated decrease in respiratory tract infection in us children bioactive components of human milk decreased interleukin- production by neonatal monocytes and t cells: relationship to decreased production and expression of tumor necrosis factor-alpha and its receptors changes in carbohydrate composition in human milk over months of lactation oligosaccharides from human milk block binding and activity of the escherichia coli heat-stable enterotoxin (sta) in t intestinal cells identification of nestin-positive punitive mammary stem cells in human breastmilk regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin breastfeeding reduces risk of respiratory illness in infants role of oligosaccharides and glycoconjugates in intestinal host defense persistence of human milk proteins in the breast-fed infant infant feeding and childhood cancer differences in morbidity between breast-fed and formula-fed infants partition of nitrogen intake and excretion in low-birth-weight infants maternal exposure to endocrine-active substances and breastfeeding breast-feeding protects against respiratory syncytial virus infections the effects of infant feeding on rotavirus-induced gastroenteritis: a prospective study exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media exclusive breast-feeding for at least months protects against otitis media delayed breastfeeding initiation increases risk of neonatal mortality deficient classical complement pathway activity in newborn sera variability of human milk neutral oligosaccharides in a diverse population effect of storage and heat on antimicrobial proteins in human milk intestinal microflora in early infancy: composition and development nonspecific antiviral substances in human milk active against arbovirus and murine leukemia virus bronchomammary axis in the immune response to respiratory syncytial virus the role of gut-associated lymphoid tissues and mucosal defense influence of the heat treatment of human milk on some of its protective constituents breast-feeding and salmonella infection iron in human milk the effect of maternal milk on neonatal morbidity of very low-birth-weight infants expression of functional immunomodulatory and anti-inflammatory factors in human milk impact of the intestinal microbiota on the development of mucosal defense breastfeeding and the onset of atopic dermatitis in childhood: a systematic review and meta-analysis of prospective studies breast-feeding and the risk of bronchial asthma in childhood: a systematic review with meta-analysis of prospective studies sensitization to substances in breast milk: recognition, management and significance stool microflora in extremely low birthweight infants the dietary prophylaxis of allergic disease in infancy protection against cholera in breast-fed children by antibodies in breast milk antibodyforming cells in human colostrum after oral immunisation rapid hightemperature treatment of human milk immunologic system in human milk the immune system of human milk: antimicrobial, antiinflammatory and immunomodulating properties modulation of the gastrointestinal tract of infants by human milk: interfaces and interactions-an evolutionary perspective evolution of immunologic functions of the mammary gland and the postnatal development of immunity spectrum of immunomodulating agents in human milk immunologic components in human milk during the second year of lactation anti-inflammatory properties of human milk cytokines in human milk: properties and potential effects upon the mammary gland and the neonate immunologic factors in human milk during the first year of lactation immunologic protection of the premature newborn by human milk lactoferin structure, function and applications breast feeding and biological properties of faecal e. coli strains antiinflammatory effects of human milk on chemically induced colitis in rats case control study on nutritional risks in celiac disease free secretory components and lactoferrin of human milk inhibit the adhesion of enterotoxigenic escherichia coli possible influence of vitamin b -binding protein in milk on the intestinal flora in breast-fed infants. ii. contents of unsaturated b -binding protein in meconium and faeces from breast-fed and bottle-fed infants a hitherto unrecognized biochemical difference between human milk and cow' s milk mother' s milk and sewage: their interactive effects on infant mortality antiviral activity of purified human breastmilk mucin bioactive factors in human milk protective function of human milk: the milk fat globule immunoglobulins in feces from infants fed human or bovine milk the mammary gland as an immunological organ host defense of the neonate and the intestinal flora the state of health of children in the developing world the role of breastfeeding in prevention of neonatal infection immune system modulation by human milk breastfeeding influences thymic size in late infancy effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial cytokines (il- [beta], il- , tnf-[alpha], tgf-[beta] , and tgf-[beta] ) and prostaglandin e in human milk during the first three months postpartum b cell function in the newborn the immunologic role of viable leukocytic cells in mammary gland/human lactation/milk synthesis host defense benefits of breastfeeding for the infant assays for endogenous components of human milk: comparison of fresh and frozen samples corresponding analytes in serum human colostral cells: phagocytosis and killing of e. coli and c. albicans angiogenins: a new class of microbicidal proteins in in innate immunity postnatal maturation of immune competence during infancy and childhood xenobiotics and breastfeeding protective effect of breast feeding against infection quantitative changes in faecal microflora preceding necrotizing enterocolitis in premature neonates reduced incidence of necrotizing enterocolitis associated with enteral administration of lactobacillus acidophilus and bifidobacterium infantis to neonates in an intensive care unit breast milk macrophages spontaneously produce granulocyte-macrophage colony-stimulating factor and differentiate into dendritic cells in the presence of exogenous interleukin- alone breastfeeding, maternal and infant health outcomes in developed countries viral, nutritional, and bacterial safety of flash-heated and pertoria-pasteurized breast milk to prevent mother-tochild transmission of hiv in resource-poor countries bacterial safety of flash-heated and unheated expressed breastmilk during storage development of cow' s milk allergy in breast-fed infants immunological protection of the neonatal gastrointestinal tract: the importance of breast feeding the effect of pretoria pasteurization on bacterial contamination of hand-expressed human breast milk dietary prophylaxis of allergic disease in children how many child deaths can we prevent this year? human milk stimulates b cell function enhancement of the circulating antibody secreting cell response in human diarrhea by a human lactobaccillus strain a bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus activated neutrophils and neutrophil activators in human milk: increased expression of cd b and decreased expression of l-selectin t cell subsets in human colostrum igd in human colostrum commensal gut bacteria: mechanisms of immune modulation effects of nutritional supplements on anti-infective factors in human milk the enteromammary immune system: an important new concept in breast milk host defense influence of breast feeding on subsequent reactivity to a related renal allograft growth factors and cytokines in milk role of infant feeding practices in development of crohn' s disease in childhood fecal secretory immunoglobulin a in breast milk versus formula feeding in early infancy infant feeding, infection, and public health cytokine profiling human colustrum and milk by protein array toward consistency in breastfeeding definitions innate recognition of bacteria in human milk is mediated by a milk-derived highly expressed pattern recognition receptor, soluble cd kolsto otnaess ab: trace amounts of ganglioside gm in human milk inhibit enterotoxins from vibrio cholerae and escherichia coli efecto de la suplementacion dietetica con nucleotidos sobre la diarrea en el lactante sano human breast milk: current concepts in immunology and infectious diseases total potentially available nucleosides of human milk by stage of lactation soluble forms of toll-like receptor (tlr) capable of modulating tlr signaling are present in human plasma and breast milk cow' s milk protein allergy lactoferrin structure and functions impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability-increasing protein the influence of parity, age and maturity of pregnancy on antimicrobial proteins in human milk alterations of lymphocytes and of antibody content of human milk after processing review: nomenclature and biologic significance of cytokines involved in inflammation and the host immune response oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants lactoferrin in milk nutritional roles of lactoferrin effect of exercise on immunologic factors in breast milk chemokines-chemotactic cytokines that mediate inflammation lower respiratory illness in infants and low socioeconomic status antimicrobial properties and microbial contaminants of breast milk: an update reduced risk of iddm among breast-fed children. the colorado iddm registry an immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system antibodies in milk leukocyte function and the development of opsonic and complement activity in the neonate the antimicrobial activity of human colostral antibody in the newborn enterobacteriaceae and neonatal necrotizing enterocolitis gdalevich m: does breastfeeding protect against allergic rhinitis during childhood? a meta-analysis of prospective studies effect of maternal nutritional status on immunological substances in human colostrum and milk igg subclasses: development of the serum concentrations in "normal" infants and children intestinal microflora of human infants and current trends for its nutritional modulation breastfeeding patterns, time to initiation, and mortality risk among newborns in southern nepal innate defenses of the intestinal epithelial barrier human colostrum has antiinflammatory activity in a rat subcutaneous air pouch model of inflammation infant feeding and respiratory allergy role of epidermal growth factor and other growth factors in the prevention of necrotizing enterocolitis influence of dietary nucleotides on plasma immunoglobulin levels and lymphocyte subsets of preterm infants the value of human milk in the prevention of infection in the high-risk low-birth-weight infant microbes and the developing gastrointestinal tract nutrition in clinical practice antiviral components of human milk human glycoconjugates that inhibit pathogens neonatal protection by an innate immune system of human milk consisting of oligosaccharides and glycans oligosaccharides and glycoconjugates in human milk: their role in host defense neutral glycolipids of human and bovine milk carbohydrates in milks: analysis, quantities and significance human milk glycans protect infant against enteric pathogens improved thymic function in exclusively breastfed infants is associated with higher interleukin concentrations in their mothers breastmilk transforming growth factor activity in human colostrum fw: a meta-analysis of infant diet and insulin-dependent diabetes mellitus: do biases play a role structure and biological actions of lactoferrin breast feeding and respiratory morbidity in infancy: a birth cohort study role of transforming growth factor-β in breast milk for initiation of iga production in newborn infants immunologic aspects of human colostrum and milk. ii. characteristics of lymphocyte reactivity and distribution of e-rosette forming cells at different times after the onset of lactation immunologic aspects of human colostrum and milk. i. distribution characteristics and concentrations of immunoglobulins at different times after the onset of lactation immunologic aspects of human colostrum and milk: interaction with the intestinal immunity of the neonate techniques for the storage of human breastmilk: implications for anti-microbial functions and safety of stored food alterations in intestinal microbial flora and human disease inhibition of enterotoxin from escherichia coli and vibrio cholerae by gangliosides from human milk relation of infant feeding practices, cigarette smoke exposure, and group child care to the onset and duration of otitis media with effusion in the first two years of life production of interleukin- and interleukin- by human mammary gland epithelial cells development of the human infant intestinal microbiota development of the gastrointestinal mucosal barrier. evidence for structural differences in microvillus membranes from newborn and adult rabbits in vitro studies on the t-lymphocyte population of human milk quantitative determination of immunoglobulins, lysozyme, and certain electrolytes in breast milk during the entire period of lactation, during a -hour period, and in milk from the individual mammary gland probiotic bacteria down-regulate the milk-induced inflammatory response in milk-hypersensitive subjects but have an immunostimulatory effect in healthy subjects factors influencing the composition of the intestinal microbiota in early infancy bacterial imprinting of the neonatal immune system: lessons from maternal cells? control of lymphocyte recirculation in man. ii. differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing t cells modulation of the immune system by human milk and infant formula containing nucleotides human milk humoral immunity and infant defense mechanisms breast-feeding and urinary tract infection the milk mononuclear phagocyte tight junctions in epithelial cells of human fetal hindgut, normal colon, and colon adenocarcinoma breast-feeding and diarrheal morbidity do infants need nucleotide supplemented formula for optimal nutrition? effects of microwave radiation on anti-infective factors in human milk breastfeeding and hospitilization for diarrheal and respiratory infection in the united kingdom millenium cohort study breast-feeding and infant illness: a dose-response relationship? innate recognition of intracellular pathogens: detection and activation of the first line of defense antimicrobial factors in human milk current concepts of infections of the fetus and newborn infant lymphocyte subsets in colostrum breast-feeding and maternal smoking in the etiology of crohn' s disease and ulcerative colitis in childhood lactoferrin acts as an alarmin to promote the recruitment and activation of apcs and antigen-specific immune responses interleukin- in human milk cholera-like enterotoxin produced by campylobacter jejuni breastmilkderived antigen-specific cd + t cells: an extralymphoid effector memory cell population in humans maternal antibodies in breast milk protect the child from enterovirus infections muc in human milk blocks transmission of human immunodeficiency virus from dendritic cells to t cells transforming growth factor-beta (tgf-beta) in human milk paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa biological role of lactoferrin prolonged exclusive breast-feeding results in low serum concentrations of immunoglobulin g, a and m a longitudinal analysis of infant morbidity and the extent of breastfeeding in the united states ribonucleotides: conditionally essential nutrients shown to enhance immune function and reduce diarrheal disease in infants randomized trial of donor human milk vs. preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants evidence for transmission of lymphocyte responses to tuberculin by breast-feeding inhibition of adhesion of s-fimbriated escherichia coli to buccal epithelial cells by human milk fat globule membrane components: a novel aspect of the protective function of mucins in the nonimmunoglobulin fraction control of isotype switching by t cells and cytokines continuous culture selection of bifidobacteria and lactobacilli from human faecal samples using fructooligosacchirade as selective substrate functional analysis of neutrophil granulocytes from healthy, infected, and stressed neonates complement system in healthy term newborns: reference values in umbilical cord blood lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells delineation of the functional capacity of human neonatal lymphocytes cytokines in human milk diversity of the human gastrointestinal tract microbiota revisited secretory iga against enterotoxins in breast-milk immunoglobulin secretion by the normal and the infected newborn infant activation and activity of the superoxide-generating system of neutrophils from human infants reciprocal ifn-gamma and tgf-beta responses regulate the occurrence of mucosal inflammation interleukin- in human milk antibodies in milk decreased response of human milk leukocytes to chemoattractant peptides antimicrobial peptides of lactoferrin determination of total potentially available nucleosides in human milk from asian women human milk-derived b cells: a highly activated switched memory cell population primed to secrete antibodies dietary nucleotides, a requirement for helper/inducer t lymphocytes cd : a soluble pattern recognition receptor in milk infant feeding in finnish children less than yr of age with newly diagnosed iddm. childhood diabetes in finland study group early and late effects of breastfeeding: does breast-feeding really matter? evolution of the mammary gland from the innate immune system immune components of colustrum and milk: a historical perspective ig isotype switching in b lymphocytes. the effect of t cellderived interleukins, cytokines, cholera toxin, and antigen on isotype switch frequency of a cloned b cell lymphoma basis and implications of selectively diminished cytokine production in neonatal susceptibility to infection ccl controls immunologlobulin (ig)a plasma cell accumulation in the lactating mammary gland and iga antibody transfer to the neonate does breast milk protect against septicaemia in the newborn? activated and memory t lymphocytes in human milk the development of the complement system after weeks' gestation breast feeding and lower respiratory tract illness in the first year of life. group health medical associates the development of the immune system development of natural killer cytotoxicity during childhood: marked increases in number of natural killer cells with adequate cytotoxic abilities during infancy to early childhood an increase in polymorphonuclear leucocyte chemotaxis accompanied by a change in the membrane fluidity with age during childhood development and differences of intestinal flora in the neonatal period in breastfed and bottle-fed infants scientific rationale and benefits of nucleotide supplementation of infant formula key: cord- -d cj v authors: mcevoy, cindy t.; ballard, philip l.; ward, robert m.; rower, joseph e.; wadhawan, rajan; hudak, mark l.; weitkamp, joern-hendrik; harris, julia; asselin, jeanette; chapin, cheryl; ballard, roberta a. title: dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (sassie) date: - - journal: pediatr res doi: . /s - - -y sha: doc_id: cord_uid: d cj v background: initial trials of lung-targeted budesonide ( . mg/kg) in surfactant to prevent bronchopulmonary dysplasia (bpd) in premature infants have shown benefit; however, the optimal safe dose is unknown. methods: dose-escalation study of budesonide ( . , . , . mg/kg) in calfactatant in extremely low gestational age neonates (elgans) requiring intubation at − days. tracheal aspirate (ta) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. outcomes were compared with matched infants receiving surfactant in the trial of late surfactant (tolsurf). results: twenty-four infants with mean gestational age . weeks and g birth weight requiring mechanical ventilation were enrolled at mean age days. budesonide was detected in the blood of all infants with a half-life of . h. of infants with elevated ta cytokine levels at baseline, treatment was associated with sustained decrease (mean %) at all three dosing levels. there were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. respiratory outcomes did not differ from the historic controls. conclusions: budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated elgans. one-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action. the survival of extremely low gestational age newborns (elgans) has dramatically improved; however, bronchopulmonary dysplasia (bpd) remains the most common morbidity of preterm birth. there are few effective and safe therapies to prevent bpd, which is associated with significant complications in the neonatal intensive care unit (nicu) and increased respiratory exacerbations, altered pulmonary function, and neurodevelopmental abnormalities after discharge. [ ] [ ] [ ] the pathogenesis for bpd is multifactorial, but an important component is inflammation that results from intrauterine events and postnatal hypoxia, hyperoxia, ventilator trauma and/or infection in susceptible infants with immature lungs. [ ] [ ] [ ] one of the most consistent clinical factors associated with the development of bpd is the need for mechanical ventilation, with bpd occurring in > % of elgans who require ventilation at − days of age. systemic postnatal corticosteroids (pcs) are potent antiinflammatory agents and are one of the few therapies shown to decrease the severity of bpd. , unfortunately, the heterogeneous pcs treatment regimens that have been studied have not established the optimal type of corticosteroid, optimal dosage, or the optimal timing of initiation for the safe prevention of bpd. early steroid treatment in conjunction with indomethacin treatment for the patent ductous arteriosus (pda) has been associated with intestinal perforation. , systemic pcs, particularly dexamethasone, started at < days of life has been associated with increased cerebral palsy. , there is interest in the potential to deliver a postnatal steroid topically to the lungs to improve the benefit:risk ratio. a trial of tapering inhaled budesonide started at < h of life in infants < weeks postmenstrual age (pma) on any positive pressure support showed a significant decrease in bpd at weeks pma, but there was increased death in the treated group and no information on systemic levels of budesonide. yeh et al. have conducted two unblinded pilot randomized trials of budesonide ( . mg/kg) mixed in surfactant (survanta) versus surfactant alone administered soon after delivery to infants < g with severe respiratory distress syndrome (rds). both trials demonstrated a significant decrease in the primary outcome of death or bpd at weeks pma (p < . ) without adverse neurodevelopmental effects at years of age. [ ] [ ] [ ] while these surfactant-based trials are encouraging, further investigation is required to assure efficacy and safety and to establish the lowest effective dose. there are preclinical data supporting the use of a much lower dose of budesonide. for example, budesonide is five times more potent than dexamethasone for suppression of chemokines in fetal human lung explants; thus, treatment with . mg/kg budesonide in surfactant would expose the lung to much higher glucocorticoid levels than i.v. . mg/kg dexamethasone, an effective systemic dose for prevention of bpd. the objective of our study was to investigate the optimal dose of budesonide suspended in surfactant and given intratracheally to decrease the short-term respiratory support and pulmonary inflammatory response of intubated elgans at risk for bpd. we hypothesized that a lower dose than the previously administered . mg/kg of budesonide would be equally effective in decreasing short-term respiratory support and the inflammatory response that contributes to bpd in intubated preterm infants. the steroids and surfactant in elgans study (sassie) was a phase i/ii open label dose-escalation trial conducted at four us hospitals (clinicaltrials.gov: nct ). we treated eight intubated elgans at risk for bpd with budesonide in surfactant at each of three dosing levels: . , . , . mg/kg. the first eight enrolled infants received the dose of . mg/kg, the second eight received . mg/kg, and the third group of eight received the dose of . mg/kg. inclusion criteria were infants with a gestational age of / to / weeks who were mechanically ventilated between postnatal days − . infants who had received systemic steroids, or indomethacin, ibuprofen, or acetominophen to treat a pda ≤ h before the enrollment window ended, or had congenital malformations or chromosomal anomalies were excluded. case-matched infants who received calfactant in the trial of late surfactant (tolsurf) served as the control group. controls were matched to for birth weight, gestational age, sex, race, and initial respiratory severity score (rss = mean airway pressure × fraction of inspired oxygen). the trial was conducted under the ind # for the combined use of budesonide with the standard dose of calfactant. the research protocol was approved by the institutional review boards of the participating institutions, and a parent of each infant provided written informed consent. an independent data safety monitoring board (dsmb) approved the protocol and met after each group of eight patients reached days of age to review study progress and adverse events prior to approving progress to the next dosing level. the primary objective of the study was to determine the clinical and anti-inflammatory efficacy by monitoring clinical outcome up to days of age, including rss, and measuring tracheal aspirate cytokine levels. by protocol, dose escalation was to be stopped if the dsmb had safety concerns or after two dose levels that met predefined efficacy criteria. efficacy criteria included both clinical criteria (five of eight infants extubated within h of the first study dose or after ≤ daily treatments or one of several other predefined clinical respiratory outcomes at days of age (see supplement) and evidence of anti-inflammation (≥ % suppression of baseline tracheal aspirate interleukin- (il- ) or monocyte chemoattractant protein (mcp ) at − h after the initial dose of study medication). we chose to start the dose escalation at . mg/kg of budesonide mixed in the standard dose of calfactant because data from our fetal lung explant model had suggested this dose should effectively suppress lung chemokine levels. the subsequent dosing levels of budesonide were . mg/kg and . mg/kg. the research pharmacy at each institution prepared the study medication as described in methods supplement. infants were dosed every h if still requiring ventilation and could receive up to five doses. clinical guidelines for management of ventilation and other patient care practices were developed and approved by investigators. materials and procedures tracheal aspirate (ta) samples were collected for markers of inflammation. dried blood spot (dbs) samples were collected for the measurement of budesonide and untargeted metabolomics to assess time-and dose-dependent changes in cortisol and other biochemicals. ta were collected from the infant's endotracheal tube prior to and h after the first study dose, just before each of the subsequent doses, and h after the fifth dose if the infant remained intubated. dbs samples were collected at min and at , , and h after the initial dose if the infant had a central line, or , , and h after the first dose if obtained by heel stick, and at h after subsequent doses. , human chemokines cxcl- /il- and mcp- /ccl were quantified in ta samples by enzyme-linked immunosorbent assay (elisa) (r&d systems, minneapolis, mn) that have intraassay variability of . % each and interassay variability of . % and . %, respectively. both assays have a sensitivity range of − pg/ml. secretory human iga (siga) was used to normalize cytokine/chemokine data and was measured by elisa (lifespan biosciences, inc., seattle, wa); intraassay variability of . % and interassay variability of . %, with a sensitivity range of . − ng/µl). all samples were assayed in duplicate as twofold dilutions. we used the victor multichannel plate reader (perkin elmer, waltham, ma) for absorbance measurements. nine additional inflammatory mediators (il- , il- p , il- , il- β, il- , il- , tnf-α, inf-γ) were measured from ta samples collected during the . mg/kg dose of budesonide; analysis was by a multiplex assay as previously described. , budesonide concentrations were measured in dbs using a validated liquid chromatography-tandem mass spectrometry (lc-ms/ms) as previously described. the assay was linear between and ng/ml. pharmacokinetic (pk) analysis of blood budesonide was conducted using the noncompartmental analysis module in phoenix winnonlin v . (certara, princeton, nj). an extravascular dosing model was used to represent budesonide administration via intratracheal instillation. the elimination slope was fit to the and h samples, and the linear up-log down calculation method was used. data below the limit of quantitation for the lc-ms/ms assay (i.e. < ng/ml) were set as missing values. global metabolomic analysis using dbs was performed by metabolon inc. using ultrahigh performance liquid chromatography-tandem mass spectroscopy (uplc-ms/ms). the processing, assay and analysis procedures have been described in detail. statistical analysis data are presented as mean ± sd unless otherwise indicated. cytokine and chemokine data were analyzed using mann− whitney test and analysis of variance (anova) as appropriate. dose-dependent differences in systemic budesonide exposure were assessed using anova with tukey post-hoc tests in graphpad prism v . (graphpad software, san diego, ca). anova contrasts and welch's two-sample t test were used to identify biochemicals that differed significantly between the dosing levels of budesonide. analysis by two-way anova identified biochemicals exhibiting significant interaction and main effects for experimental parameters of dose and time point. patients were enrolled between / / and / / . a total of elgans were screened with eligible and consented into the study (fig. ). one infant in the . mg/kg group had consent withdrawn prior to treatment. an additional infant was enrolled at that dosing level to provide eight infants per dosing level. three dosing levels of budesonide in calfactant were administered. enrollment into the study was stopped after completion of the . mg/kg dosing as no patient at any of the three dosing levels had fulfilled the predefined efficacy criteria. the mean gestational age, birth weight, and age at study dosing of enrolled infants at the respective dosing levels are presented in table along with the demographics of the matched tolsurf infants. all of the infants at the first two dosing levels and six of eight at the third dosing level had received surfactant within the first h as per standard of care. all sassie infants remained intubated after the first dose of study drug and received two to five doses. no infant at any of the three dosing levels achieved the primary outcome of meeting both the predefined clinical respiratory criteria and a > % suppression of il- or ccl . there was a significant decrease in rss at h after initial dosing for the . mg/kg group and for the entire cohort (table ) . table shows the respiratory outcomes of sassie and tolsurf infants at days and and weeks of pma. all infants required respiratory support at days. survival without bpd at and weeks was higher in the . mg/kg dosing group than the . or . mg/kg groups; however, the mean birth weight of the . mg/kg group was g compared to and g in the other two groups. overall, of ( . %) in sassie vs. of ( . %) tolsurf infants died and fewer infants in sassie survived without bpd at and weeks ( % vs. and % vs. %). no death or serious adverse events were considered to be related to treatment. budesonide was detected in the circulation of all subjects; however, two (one in the . mg/kg and one in the . mg/kg dose cohorts) had insufficient data to calculate an elimination slope based on and h data. all but two of the samples collected at h after the prior dose were below the limit of quantitation (n = of collected samples). figure a shows the observed concentrations of budesonide in dbs at . , , and h following the first dose for all three dosing cohorts. the half-life of blood budesonide was short ( . h) and similar between all dosing cohorts with mean peak concentrations for the . , . , and . mg/kg dose cohorts of . , . , and . ng/ ml, respectively. when normalized for dose, the . mg/kg and . mg/kg cohorts had similar areas under the h concentrationtime curve (auc ), but both were significantly different from the . mg/kg dose cohort (fig. b, table ). combined, these data suggest that while systemic budesonide is eliminated at the same rate independent of dose, the systemic absorption from the intratracheal dose was not dose-linear in this cohort. we assessed anti-inflammatory effects of budesonide in infant lungs by the assay of ta levels of two chemokines. there was adequate recovery of lung fluid for assay of il- , mcp and siga in ta of of the enrolled infants. the ratio of the mean chemokine value during treatment (from h after the first dose to h after the last dose) was determined, and infants designated as apparent responders if there was > % decrease compared to predosing. the time course for il- in two infants is shown in fig. a ; infant had a sustained decrease in il- beginning h after the first dose with an increase at h after the last dose, whereas infant had no consistent change in il- levels until after days of therapy. infant in this figure represented a responder, while infant was a nonresponder (fig. a) . overall for the infants, there were apparent responders for il- and for mcp- (fig. b) , with a similar mean level of suppression noted for il- ( ± %) vs. mcp ( ± %, ns). we explored possible factors related to the chemokine response to budesonide. of interest, the predose levels of il- and mcp varied widely ( -fold and -fold, respectively) and the levels of the two chemokines were strongly correlated (r = . , p = − ). there was a strong association between predose levels and the decrease during treatment, with higher baseline levels for both il- and mcp (~ -fold, p < . ) for responders compared to nonresponders (fig. c) . there was a weak correlation between blood budesonide level (at h) and the change in ta il- at h (r = . , p = . , n = , fig. ) , indicating that responsiveness was not strongly related to systemic budesonide levels. no significant differences were observed in clinical parameters comparing infants with suppression of il- vs. those without suppression, although more of the responders ( / ) than nonresponders ( / , p = . ) had a decrease in rss with budesonide treatment (table ). neither the number of responders, nor the level of suppression of il- among responders, showed apparent dose-dependency: of with ± % suppression at . mg/kg, of and ± % suppression at . mg/kg, and of and ± % suppression at . mg/kg. corresponding numbers for mcp were / , / , and / with suppression of ± %, ± %, and ± %, respectively. we used a multiplex approach to assay an additional nine inflammatory mediators in ta from infants receiving the . mg/kg dose (table ). consistent decreases during budesonide treatment were observed for all mediators (mean % suppression values ranging from to %) in three of the four infants with suppression of il- . baseline levels were higher for responders than nonresponding infants for each mediator (range . -to . -fold) as observed for il- and mcp ( . -and . -fold) at this budesonide dose. overall, our results provide evidence for a strong antiinflammatory response in the lung for some, but not all, infants that is independent of the budesonide dose between . and . mg/kg and is related to elevated inflammatory status in the lung at baseline. we identified eight infants in the tolsurf cohort who received late surfactant, but not systemic pcs, and who had five ta samples collected over a ± -day period. in this group, comparing mean levels for samples − with sample , there was a consistent suppression of il- and mcp in and infants, respectively, with suppression ranging between and %. for the value for the group. to examine systemic responses to budesonide, we performed untargeted metabolomics on sassie dbs. a total of named biochemicals were detected in dried blood spots from infants over time points ( min− h post infants with declining chemokine levels over time, baseline values (sample ) were near the median treatment initiation). there was a statistically significant, time-dependent decrease in cortisol for infants receiving . and . mg/kg budesonide, with decreased levels occurring at h and mean suppression of % and %, respectively, at h (fig. a) . by contrast, blood cortisol did not change significantly for the group of infants treated with . mg/kg budesonide. to evaluate global systemic metabolic responses, the number of significant (p < . ) changes (decreased or increased) were determined for each time point compared to the -min value (fig. b) . there was a time-dependent increase in number of changes at all three doses, with a similar relatively low level of changes (< ) in the first h, and a dose-dependent response at later time points; at h, the number of metabolite changes were , , and at . , . , and . mg/kg, respectively, representing . %, . %, and . % of the known biochemicals detected. these results indicate that intratracheal budesonide: surfactant treatment, at the doses and frequency used, has an we performed a dose-escalation study of budesonide in calfactant given intratracheally to elgans still requiring mechanical ventilation at − days of age starting at one-tenth the dose used in previous studies. , although most infants had a decrease in rss following treatment, there were no differences between dosing groups in clinical respiratory outcomes at th day. bpd at or weeks pma was less common in infants in the . mg/kg group; however, these infants had a higher mean birth weight than the other two groups. only half of the infants had evidence of increased inflammatory markers in ta at initiation of the study, and these infants had a similar decrease in levels of the two cytokines with treatment at all three dosing levels. there was a dose-dependent increase in both suppression of blood cortisol and in the number of alterations in levels of other blood metabolites indicating systemic absorption and effects of the corticosteroid. these results suggest that intratracheal budesonide reduces lung inflammation only in infants who have elevated inflammatory status, and that this effect occurs at the lowest dose tested ( . mg/kg), which has minimal systemic metabolic effects and can be safely repeated if the infant remains intubated. survival without bpd for sassie infants was lower than for the historical matched tolsurf cohort, which may reflect in part benefit from inhaled nitric oxide in nonwhite infants. the apparent lack of clinical benefit is also in contrast to the two pilot rcts of yeh et al., in which significantly fewer infants in the treated group (single dose of . mg/kg budesonide in survanta) had bpd at weeks pma. , there are several possible explanations for this difference. our study did not have concurrent controls nor was it powered to detect significant differences in clinical outcomes. importantly, in the yeh studies, , infants were enrolled within the first h of receiving fio > . and were mechanically ventilated whereas infants in sassie were only enrolled if they required mechanical ventilation between postnatal days and and were therefore in the highest risk group (> %) for bpd. the lack of apparent clinical response may also reflect differences in the patient populations. the infants in yeh's studies were more mature and larger than the infants in sassie. in sassie, infants treated within h of dosing for a pda were excluded to minimize any potential interactions with study medication and this may have biased results. yeh et al. previously described the pharmacokinetics of budesonide in ten preterm neonates (< g at birth) following intratracheal instillation of . mg/kg budesonide. the observed elimination half-life ( . h) in our study was similar to the yeh study ( . h). the auc reported in yeh's study (auc − = . ng × h/ml) extrapolates to an auc of approximately ng × h/ml. when normalized for dose, this value is similar to the auc observed for the . mg/kg cohort in our study. these kinetics support daily treatment to sustain elevated blood budesonide. concentrations of budesonide in human lung are not known, but in lambs levels in lung tissue decrease to . % of the initial dose at h. the yeh study observed a peak concentration of approximately ng/ml at min after dose. this peak concentration is similar to the c max of . ng/ml at min post dose from a lower dose ( . mg/kg) in our study, suggesting a~ . -fold difference in observed c max between the studies. from the data collected, it is unclear whether the difference in c max is due to a difference in absorption secondary to the surfactant used (survanta in yeh's trial, calfactant in our study), the gestational weight and/or age differences between study populations, the difference between samples collected at and min post dose, and/or methodologic differences. the plasma concentrations of budesonide in infants can be compared to those achieved with antenatal betamethasone for enhancing fetal maturity and postnatal dexamethasone given for prevention of bpd. in this calculation, we convert corticosteroid levels to cortisol equivalents using factors of -fold for betamethasone and dexamethasone and -fold for budesonide based on receptor affinity and dose−response data from cultured human fetal lung. , mean peak concentrations as cortisol equivalents are: µg/ dl for normal -week human fetus, µg/dl in cord blood after intramuscular antenatal betamethasone, µg/dl with . mg/kg postnatal dexamethasone, and µg/dl after . mg/kg intratracheal budesonide. [ ] [ ] [ ] thus, both postnatal dexamethasone and budesonide at current doses transiently expose the infant to plasma concentrations considerably greater than those occurring with physiologic stress in the newborn (e.g., rds~ µg/dl). risks for the infant associated with these higher exposures may depend on both the concentration of corticosteroid and duration of exposure. treatment with budesonide in surfactant primarily targets lung inflammation, although it is possible that local effects are modulated by systemic exposure to budesonide. to assess local effects of budesonide, we measured two chemokines in lung fluid that are chemoattractants for neutrophils (il- ) and lymphocytes (mcp ). both mediators are produced in human fetal lung and are suppressed by glucocorticoids in explant culture. levels of the two chemokines were strongly correlated at both baseline and after treatment, which is consistent with a previous observation for multiple cyto/chemokine levels in ta and indicate that our findings likely reflect the overall inflammatory status in the lung. apparent suppression of il- and mcp was observed in half of the sassie infants and was strongly associated with higher baseline levels, suggesting that inflammation is not a universal feature of lung injury in the first week and that benefit from budesonide (or any glucocorticoid) will only occur in selected infants with elevated inflammatory status. the global blood metabolomic data demonstrated a clear dose−response association with budesonide. at . mg/kg budesonide, there was a small suppression of cortisol, and limited changes in other biochemicals, and both responses increased progressively with higher doses. this pattern contrasts with suppression of ta chemokines where no differences were apparent between doses, and is consistent with elevated levels of budesonide within the lung, compared to systemic levels, with intratracheal delivery. thus, our results suggest that the best benefit:risk ratio of budesonide:surfactant therapy occurs at doses of . / . mg/kg, which are fiveto tenfold lower than used currently in clinical studies. strengths of our study include the study population of intubated elgans who are at high risk for bpd, the doseescalation study design, and measurement of multiple biomarkers for both lung anti-inflammatory and systemic effects of budesonide. previous studies , using surfactant-antibiotic mixtures had demonstrated interactions between these agents; however, we recently reported no apparent adverse effect of budesonide on calfactant activity in vitro nor an effect of calfactant on budesonide action. an important limitation of our chemokine data is the possibility that, in some infants, the lower chemokine levels during budesonide treatment reflected decreasing inflammation independent of glucocorticoid exposure as observed in some of the tolsurf infants. however, the pattern of suppression observed with budesonide, beginning in most infants h after the first dose and sustained during the treatment period, is consistent with suppression in response to budesonide. also, we used siga to normalize chemokine levels to volume of lung fluid in the ta sample; it is possible that siga production in vivo varied during the collection period, which would introduce variability in the chemokine data. a limitation of our pharmacokinetic analysis is the absence of data after the h time point; however, our halflife value was similar to that reported by yeh et al., supporting the accuracy of our pk results. the dose-escalation study design limited the number of infants studied at each dosing level. also, concurrent controls were not included in the study design, for ethical reasons, and the matched historical controls received inhaled no and were not evaluated for other potential confounding factors such as chorioamnionitis. earlier dosing, longer dosing, or the use of noninvasive approaches to surfactant delivery may result in different clinical outcomes. the original study design included a fourth dosing level (which would have been either . mg/kg or . mg/kg contingent on the response to dosing level ), which may have provided more detail regarding clinical and anti-inflammatory response to the combination of the study medications. however, we decided not to continue enrolling the infants in this study after the first three dosage levels failed to show clinical benefit. given that aggressive use of noninvasive mechanical ventilation has not reduced the incidence of bpd, that bpd may develop in elgan babies with little clinical initial evidence of lung disease, and that inflammation associated with bpd worsens over the first weeks after birth, the question of whether serial instillation of budesonide suspended in surfactant reduces bpd remains an unanswered question. future randomized trials in elgans at high risk for bpd should require treatment over the biological period of risk to assess efficacy and safety in a fair way. our results do not support the "late" treatment of intubated elgans with a regimen of budesonide in surfactant at the three dosages we tested, but do provide important insights into blood budesonide concentrations, lung anti-inflammatory effects and potentially global metabolomics effects that are critical to the consideration of treatment with this combination of medications. we were not powered to investigate association of inflammation with near-term pulmonary outcome, but we suggest that measurement of ta inflammatory mediators would be informative in future trials of pcs therapy. in conclusion, assuming that the respiratory benefits of pcs therapy primarily relate to anti-inflammatory effects in the lung, our results suggest that one-tenth the budesonide dose in data are by multiplex assay for the first nine mediators and by elisa for il- and mcp ; suppression occurred in the same infants for each mediator. apparent suppression was assigned for infants with consistently lower values during treatment compared to predosing with a mean value of > %. surfactant used in previous studies is sufficient to reduce inflammation with minimal systemic effects even with repeated treatment. additional trials of this promising lung-targeted approach to preventing bpd are needed using lower doses of budesonide with further study of efficacy, safety, inflammatory markers and endocrine and metabolic responses. bronchopulmonary dysplasia: executive summary of a workshop bronchopulmonary dysplasia: nhlbi workshop on the primary prevention of chronic lung diseases bronchopulmonary dysplasia and perinatal characteristics predict -year respiratory outcomes in newborns born at extremely low gestational age: a prospective cohort study an update on pulmonary and neurodevelopmental outcomes of bronchopulmonary dysplasia late-onset sepsis in very low birth weight neonates: the experience of the nichd neonatal research network antenatal determinants of bronchopulmonary dysplasia and late respiratory disease in preterm infants randomized trial of late surfactant treatment in ventilated preterm infants receiving inhaled nitric oxide late (> days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants prophylactic postnatal corticosteroids: early hydrocortisone systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review adverse effects of early dexamethasone in extremely-low-birthweight infants. national institute of child health and human development neonatal research network early (< days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants long-term effects of postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia: balancing the risks and benefits early inhaled budesonide for the prevention of bronchopulmonary dysplasia a follow-up study of preterm infants given budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study intra-tracheal administration of budesonide/surfactant to prevent bronchopulmonary dysplasia antiinflammatory effects of budesonide in human fetal lung tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure development and validation of an assay for quantifying budesonide in dried blood spots collected from extremely low gestational age neonates blood cytokine profiles associated with distinct patterns of bronchopulmonary dysplasia among extremely low birth weight infants simultaneous measurement of inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xmap technology whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites race effects of inhaled nitric oxide in preterm infants: an individual participant data meta-analysis effects of budesonide and surfactant in preterm fetal sheep a radioreceptor assay for evaluation of the plasma glucocorticoid activity of natural and synthetic steroids in man changes in concentrations of cortisol, dehydroepiandrosterone sulphate and progesterone in fetal and maternal serum during pregnancy pharmacokinetics of dexamethasone in premature neonates glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome pilot trial of late booster doses of surfactant for ventilated premature infants exogenous pulmonary surfactant as a drug delivering agent: influence of antibiotics on surfactant activity influence of pulmonary surfactant on in vitro bactericidal activities of amoxicillin, ceftazidime, and tobramycin. antimicrob., agent chemother the authors thank the parents and all nicu personnel for their support. the authors appreciate the assistance of namasivayam ambalavanan, md at the university of alabama for performance of the multiplex cytokine analyses and the study coordination of : substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: all authors. drafting the article or revising it critically for important intellectual content: all authors. final approval of the version to be published: all authors. the online version of this article (https://doi.org/ . /s - - -y) contains supplementary material, which is available to authorized users. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -qom rokn authors: chen, long; li, jie; wang, nan; shi, yuan title: post-newborn: a new concept of period in early life date: - - journal: frontier and future development of information technology in medicine and education doi: . / - - - - _ sha: doc_id: cord_uid: qom rokn post-newborn infants refer to infants from > days to < days after birth. during this period, infants are still completely dependent on breast milk or/and formula milk for feeding. up to now, the concept of post-newborn has not been mentioned in classic textbooks. with the development of perinatal medicine, mortality rate of diseases in neonates such as premature infants, asphyxia, infectious diseases have decreased significantly, and consequently, issues of the quality of life for these survivors have aroused widespread concerns. the post-newborn infants have some important characteristics differing from both newborn infants and infants after the period: ( ) different fatal diseases and mortality rate; ( ) the diseases inherited from newborn period requiring early and prompt treatments; ( ) some peculiar diseases during this period requiring much attention; ( ) either similar or different immune function; ( ) rapid growth and uneven development of organ systems. establishment of the new concept of post-newborn will further reveal the nature of life, reduce the mortality rate of infants, and improve the quality of life. unit (nicu) could greatly reduce the mortality rate of newborn infant, but not improve the quality of life synchronously in the early s, the world's first nicu was established at new haven hospital of yale university, which became a milestone in the developmental history of modern neonatal medicine. after that, nicu has been established in the world in succession and developed rapidly, and thus, neonatal medicine has entered a booming era. with the establishment of transfer and treatment network for the critically ill neonatal infant in the developed areas, the constant in-depth development of the relevant basic and clinical research, improvement of the treatment techniques, and especially the use of pulmonary surfactant, the mortality rate for the seriously ill newborn infants such as low birth weight newborns, extreme low birth weight newborns, severe respiratory distress syndrome have been decreased significantly. the mortality rate of the newborn in united states in has been dropped by nearly half as compared with that in (from . to . %) [ ] , where as the neonatal mortality rate in china in has been decreased by % as compared with that of (from . to . %) [ ] . however, a few surviving infants suffered from different kinds complications in the post-newborn, such as recurrent respiratory infections, physical retardation, cerebral palsy, bronchopulmonary dysplasia, retinopathy, and congenital heart disease requiring early surgical treatment [ ] [ ] [ ] [ ] [ ] . moreover, the complication and sequelae could change the way of life and learning of the children to some extent, affect their formation of good personality and mentality, lead to various kinds of personal and social problems in adults, add a great deal of disease burden to the countries, families and individuals [ , ] . although most of these children in the postnewborn have obtained some treatment and their prognosis has been improved, the post-newborn is still a very fragile, important and special stage in early life, which lacks a specific concept to define the short but crucial time. the post-newborn is a continuation of neonatal period. in addition to the abovementioned sequelae and complications during the neonatal period, there is no clear distinction between the physiological and pathological condition of early infants. because the symptoms and signs of diseases are more atypical in early infants, pediatricians should hold very cautious attitude. nevertheless, it's lack of a specific term to cluster the infants during this period. so far most of literatures have described the early infant as ''baby'', ''early baby'', or ''small baby''. a clear and specific concept has not been mentioned in the previous classic textbooks. with the development of perinatal medicine, the neonatal mortality rate has been gradually decreased. chinese ministry of health recently announced the infant mortality rate was run down from . % in to . % in , achieving the un millennium development goals [ ] [ ] [ ] ahead of schedule. consequently the issues of quality of life for these infants surviving in the neonatal period have caused widespread concerns. the task of pediatrics is not only to focus on reducing morbidity and mortality rate, but also to guarantee children's health, improve the quality of life. the disease sequelae of the post-newborn might affect the health and well-beings of future life. within this period, the infant have a very strong repair and remodeling capacity. when given appropriate rehabilitation, the infant could obtain unimaginable therapeutic efficacy. at the same time, early prevention of some adult diseases such as hypertension and diabetes should be paid much attention. studies have suggested that these main diseases in adulthood have a close relationship with early infancy, especially nutritional status of the post-newborn [ ] . how to further promote the growth and development and correct the complications and sequelae at the post-neonatal period, make the ill infants reach the level of normal infant development as early as possible, and reduce the incidence of adult-related diseases has become an important issue. it is necessary to carry out professional studies. for this purpose, we give the definition for this period which refers to post-newborn from [ days to \ days. in this period, the infant still completely depend on breast milk and/or formula milk for feeding. up to now, the concept of post-newborn has not been mentioned in classic textbooks. the concept of post-newborn is mainly based on the following reasons: ( ) the supplementary food is usually introduced from the th month after birth. after this period, the gastrointestinal function of infant begins to adapt to the supplementary food and has significant changes. ( ) after days, most of the common neonatal diseases and complications have been cured. ( ) for most infant medications at this period, no reference for dosage has been made yet, which is not consistent with evidence-based medicine: whether the application of various drugs has an effect or not? how the level of such drug's effect is produced? is there any possible side effects or delayed benefits? the emphasis on this period is helpful for promoting the drug research and development in this specific period. after this period, most of the medications have some reference usage, which has greatly enhanced the safety. ( ) in this period, the antibody levels of infants from breast milk are high, while its own immune function is low, and there are few autoimmune diseases. investigation of the immunity and its tolerance in this period is expected to provide new treatment methods for immunological disease/rheumatic diseases in the future. however, due to different kinds of reasons, there is no infant mortality reported within months alone. it is reported that in some asian developing countries, neonatal disease is still the first cause of death, and infectious disease is the major killer after the neonatal period. in western developed countries, the first cause of death is the congenital malformation, and the death age of those infants is not at the neonatal period [ , ] . because of high infant mortality rate and various kinds of complicated diseases, this indicator can not fully reflect the health level of infants. clinical practice experience suggests that most of the deaths occurred in younger infants after the neonatal period, especially within days. in the united states, sudden infant death syndrome is one of the main causes of infant mortality [ ] , the peak age of death appeared in - months after birth, and the infant mortality rate decreased after months [ , ] . . . . the disease inherited from neonatal period requires early and prompt treatment. there might be a distinct defect in terms of the time concept for neonatal period. although during neonatal period, a few of the mother-born diseases have been corrected, such as hemolytic disease of newborns, premature rupture of membranes, gestational diabetes etc. [ ] , it is impossible for the sequelae and complications of neonatal diseases to be fully corrected in this period. how to better diagnose and treat these diseases in post-neonatal period is the issue which the pediatricians have to pay much attention to. these diseases often require the full co-operation of many specialties including screening and correcting for hearing anomalies, treatment of persistent pathological jaundice, rehabilitation for hypoxic ischemic encephalopathy, screening and treatment for retinopathy, therapy for repeated infection of bronchopulmonary dysplasia, congenital heart disease requiring early surgical treatment due to repeated or fatal respiratory infections affecting infant growth and development. . . . in this period, some special diseases need attention, such as late-onset vitamin k deficiency, which is frequently present in infant with exclusive breastfeeding, chronic diarrhea, and malnutrition. it is prone to have fatal intracranial hemorrhage, and the survivors often leave behind the neurological sequelae, seriously harming the health of babies. during this period, the nerve myelin development is obvious. early diagnosis and treatment of cerebral palsy can help reduce neurological sequelae. . . . the immune function has similarities and differences. the common point of post-neonatal infant and other infancy stages is the low immune function. during this period, the non-specific immunity, humoral and cellular immune function are very immature, and levels of siga and igg are low, with low resistance to infection, prone to have various bacterial and viral infections. clinical manifestations of pneumonia in the post-newborn is more insidious than those of children's pneumonia, the post-newborn infants suffering from pneumonia have usually very light and a typical symptoms such as refusing milk or milk feeding decreasing, no weight increasing, weak cry, and some even lack any clinical manifestation but with rapid disease progress. the difference between neonatal and post-neonatal infants is that the neonatal babies have significantly increased resistance because of colostrum feeding. as the time going on, the maternal antibodies decrease obviously, leading to a variety of infectious diseases such as respiratory syncytial virus, eb virus and ev virus. . . . there is a conflict between the rapid development and growth and uneven development of organ systems during the post-newborn period. this period is the stage for extremely strong growth. the weight of infant has been more than doubled that at the birth. the nutritional requirements are relatively high. at the same time, the uneven development of organ systems, especially the digestive system is often difficult to adapt to a large number of food digestion and absorption. it has been suggested that both nutritional deficiencies and overnutrition are able to significantly affect adult metabolic diseases [ , , ] . the fine mapping of the human genome indicated that diseases were genetically related. not only genetic (congenital) disease but also risk of acquired and some so called adulthood-starting diseases (such as diabetes, hypertension) might start to be increased before birth or at the infancy and childhood. moreover, it has made people realize that gene could not be the only factor to decide the human disease. through epigenetic modifications of gene, early nutrition and its regulation could alter genetic pathway, and then prevent or inhibit the occurrence of disease in adulthood. classical genetics indicated that individuals of the same gene should have exactly the same phenotype, but the truth is not the case. one pair of identical twins often has the differences in terms of appearance, personality of many aspects, which might be the result of epigenetic modifications. the epigenetics has made the research that under the situation gene dna sequence has not changed, the gene expression has the inheritable changes. the epigenetics has three important features: ( ) not involving dna changes; ( ) gene functions have changed; ( ) the change of gene function has heritability and reversibility. food, as a source of methyl donor may change the gene expression and thus affect the development of various organ systems, possibly through epigenetic methylation modifications. further reveal the nature of life and improve life quality of children pediatrics is the only vertical division of subject in clinical medicine in accordance with the process of human life (age group). the division of each age group has accordingly promoted the research progress of the stage. especially the establishment of neonatology and its specialties has made remarkable achievements. the infant stage, especially post-newborn is one of the critical periods for individual physique and neurogenesis, with time and spatial differences. not only the normal anatomy and physiology have the characteristics, but also diseases in different system in terms of etiology, clinical phenotype, assessment method, diagnosis and treatment are quite different from those newborns, children and adults. the research on the developmental law of post-neonatal infants will help to find new diagnosis, treatment and prevention methods for the diseases of children and adults. the task of the post-newborn research remains how to better promote physical and neurological growth and development of the infants, which are the most basic features and the most common issues in children's life course. the physical development integrates child nutrition, endocrine and metabolic diseases, genetics and environmental medicine. nutrition is the material basis for physical growth and development, whereas environmental factors are the important aspect affecting development. researches have revealed that developmental abnormalities are related to human abuse of the environmental substances such as melamine and phthalate esters, whose mechanism may be through endocrine and epigenetic modification. it's important to maintain the balance of nutrients, trace elements, minerals and vitamins. the neurological development is the essence of life quality, which includes the prevention and treatment of children's neurological diseases and mental illness, and promotion of neural development level. although neurological rehabilitation medicine has been significantly improved, the number of children with neurological and intellectual disabilities has been not significantly decreased because the mortality for neonatal disease, especially preterm infants, severe asphyxia, severe respiratory distress syndrome has been dropped significantly and many survivors suffer from neurological complications. it is a big challenge for pediatrician to carry out the early identification and intervention for the infants with the intellectual disability and high risk factors, and finally reduce the incidence of children with intellectual disabilities. prevention of infectious disease and immunization is important for infants during post-newborn. infectious diseases once led to the death of large number of infants. along with development of antibiotics and vaccine work, infectious diseases have been obviously under control. however, a few of infectious diseases such as tuberculosis and measles have flared up in recent years. more seriously, at the same time, new resistant strains such as the production ndm- ''super bacteria'' have been emerged constantly. in addition, a number of newly-emerging viruses including h n avian flu virus, ev virus, sars virus have brought forward new challenges. the strengthening of the development for anti-infective drugs, vaccines and vaccination during this period will help decrease the illness of infant, reduce costs for health care, lower the social and family burden, and thus abate infant mortality. the strengthening of the post-newborn research, especially the research on translational medicine [ ] , may help to find new ways and methods for the treatment of diseases in infants, children, and adult caused by nutritional abnormalities. the nutritional abnormalities could cause disease by means of epigenetic modification. dna methylation depends on the dietary intake of methionine and folate which are subject to individual nutrient levels. low dietary intake of methionine in rats could lead to the occurrence of dna demethylation, more prone to liver cancer [ ] . it has been suggested that mammals should have a critical developmental period before and after birth, and nutrition as well as other environmental stimuli have an impact on developmental processes and cause permanent change in terms of metabolism and susceptibility to chronic disease [ ] [ ] [ ] [ ] . a few of population epidemiological and animal model experimental data support this view, but the complex biological mechanism is still unclear. future research in this area is to select possible target goal to improve the nutritional regulation of intestinal development, namely the detailed understanding of the relationships among nutrients, epithelial cells, intestinal flora, enteric nerves and endocrine. it's of great value to find what nutrients and metabolic pathways get involved in regulation of early life and adult dietary regulation of epigenetic mechanisms. more importantly, epigenetic modifications might occur in the critical window period of early life, especially in the post-newborn. the premise of research is to enhance the degree of concerns on post-newborn. first of all, it is to strengthen the promotion of concept of post-newborn. in the s, the textbook set the ''newborn of diabetic mothers'' as the independent chapter for etiological diagnosis, which caused a high degree of perinatal medical attention, hence greatly contributed to the research on this disease. for this reason, it's strongly recommend that post-neonatal should be defined as an independent age group and be regulated. the post-newborn should be write into pediatric articles and textbooks. in addition, the relevant theoretical system should be built in time. at the same time, specialized training courses and academic conferences should be held to study on the basis of post-newborn so that the concept of postnewborn could go deep into the field. deaths: final data for causes of deaths in children younger than years in china research on prevention of bilirubin-induced brain injury and kernicterus: national institute of child health and human development conference executive summary the impact of pediatric vision disorders in adulthood retinopathy of prematurity-epidemics, incidence, prevalence, blindness delayed diagnosis of congenital heart disease worsens preoperative condition and outcome of surgery in neonates quality of life in children with heart disease as perceived by children and parents respiratory symptoms in preterm infants: burden of disease in the first year of life countdown to for maternal, newborn, and child survival: the report on tracking coverage of interventions ministry of health of the people's republic of china ( ) china health statistics yearbook . ministry of health of the people's republic of china the fetal origin of adult diseases evolution of cause of infant and mortality in some countries and regions in the world sudden infant death syndrome sudden infant death syndrome: seasonality and a biphasic model of pathogenesis the changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk attention to mother-born diseases of newborn infant mortality, childhood nutrition, and ischaemic heart disease in england and wales fetal and infant growth and impaired glucose tolerance at age hypomethylation of hepatic nuclear dna in rates fed with a carcinogenic methyldeficient diet programming by early nutrition in man potential mechanisms of metabolic imprinting that lead to chronic disease developmental origins of disease paradigm: a mechanistic and evolutionary perspective developmental origins of the metabolic syndrome prediction, plasticity, and programming key: cord- - slh nbk authors: jacobs, j.w.; peacock, d.b.; corner, b.d.; caul, e.o.; clarke, s.k.r. title: respiratory syncytial and other viruses associated with respiratory disease in infants date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: slh nbk diagnosis by virus isolation and serology was attempted in cases of respiratory-tract infection in infants under one year of age admitted to hospital during two winters. a diagnosis of infection with respiratory syncytial (r.s.) virus was made in %, rhinovirus in · %, adenovirus in · %, parainfluenza in · %, enterovirus in · %, and influenza in · %. r.s.-virus infections were more severe than others and occurred mostly in the first five months of life, with a peak at two months. rhinovirus infections occurred at all ages, and often involved the lower respiratory tract. of the deaths, only (due to r.s. virus) was not associated with a contributory cause. maternal antibody to r.s. virus did not notably affect the incidence or severity of r.s.-virus infections. there have been few intensive studies of respiratoryvirus infections of infants. - to prevent these infections, it is necessary to know which viruses cause the most severe illness and whether maternal antibody plays any part in their prevention. we report here the results of a survey of respiratory-virus infections in infants under one year of age in hospital. all infants under one year of age in southmead hospital and bristol children's hospital who had respiratory infections during a period covering two winters (nov. , , to july , , and sept. , , to april , ) were included. had respiratory infections on admission and developed respiratory infections in hospital. soon after admission (or onset) nose and throat swabs were taken by one of us (j. w. j.) from each infant. the throat swabs were taken with a gagging technique, so that the infants coughed over the swab. at the same time blood was taken from most of the mothers. paired serum samples were obtained from some of the infants with an interval of [ ] [ ] [ ] weeks. one throat swab from each infant was inoculated into bristol hela-cell tissue cultures at the bedside, and was examined thereafter in the university of bristol department of bacteriology. a second throat swab and the nose swab were put together into % milk-saline transport medium and inoculated in the public health laboratory into hela cells and primary monkey-kidney tissue culture within minutes. they were also inoculated (often after storage at &mdash; &deg;c, and if not already yielding a virus) into human embryo kidney and wi- human embryo fibroblast tissue cultures and into suckling mice. the methods used have already been described. , serology sera were tested by complement fixation (c.f.) against respiratory syncytial (r.s.) virus antigen but not against other viruses. the methods of preparing the antigen and conducting the test have already been described. , e this was graded retrospectively according to a scheme developed during the survey. signs in order of severity were: ( ) upper-respiratory-tract infection. ( ) specific treatment (excluding nasal drops but including humidified air, physiotherapy, or antibiotics) or temperature > - c. ( ) chest signs found by radiography, auscultation, or aspiration for less than three days. ( ) chest signs for three days or more unless the patient died. ( ) oxygen therapy for one or more days, or respiration-rate or more per minute, or peripheral cyanosis. ( ) digoxin therapy or heart-rate of or more per minute. ( ) additional treatment (cortisone, intubation, or tracheostomy). ( ) death. the grade was the most severe sign the patient showed, providing that all the less severe signs were also present. for example, an infant showing signs , , , and was said to have a severity grade of . in practice it was rare for an infant not to show an intermediate sign. in cases routine bacteriological examination was undertaken. staphylococcus aureus was isolated from %, and streptococcus pneumoniae from %. several &bgr;-haemolytic streptococci were isolated, but none were group a. haemophilus influen. was isolated from ( %), in of which r.s. virus infection was also diagnosed. twenty of the infants were admitted with respiratory infections twice, and two were admitted three times. from one infant, two different m rhino viruses were isolated-type b at the age of two months and type at the age of ten months. one infant, a premature baby, was admitted seven times over a period of four months (table ). different viruses were isolated. there was no evidence of hypogammaglobulinsemia. the infant's twin sister was in hospital once with a chest infection due to r.s. virus at the same time as her sister's first admission. subsequent infections of the twin were less severe and frequent, and she was not readmitted. fold or greater rise in titre between acute and convalescent specimens, or a change from passive maternal (secondary) type of antibody to an active (primary) type of antibody in a chequerboard c.f. test with a potent antigen. of the fifty-four infants in whom r.s.-virus infection was diagnosed and both isolation and serology attempted, the diagnosis was made in twenty-four by serology alone (nineteen infants showed a fourfold rise and five a change from secondary to primary antibody), six by isolation alone, and in twenty-four by both methods (twenty-two showed a fourfold rise and two a change from secondary to primary antibody). r.s. virus was isolated more frequently from throat swabs inoculated direct into tissue culture at the cotside ( / ) than from swabs put into transport medium and inoculated within ninety minutes ( / isolates). r.s. virus was isolated more frequently from specimens taken three to six days after the onset of the illness ( % of specimens) than from those taken before three days ( % of specimens) or after six days ( % of specimens) from onset. age table i shows virus infections diagnosed in infants of different ages. two-thirds of the specimens came from infants under six months of age. the rate of virus diagnosis was higher under six months of age, with a peak at three months. this was because most infections were caused by r.s. virus, and the peak for this virus was in the age range one to five months. parainfluenza and influenza viruses were found only over four months of age; and rhino viruses, enteroviruses, and adenoviruses were found at all ages. the viruses recognised in the first month of life were r.s. ( ), rhinovirus m, and coxsackie b . of the respiratory infections, ( %) were in boys and ( %) in girls (p< - ). there was no significant difference between the two sexes in the severity of the illness either in all the infants, or in those in whom r.s.-virus infections were diagnosed. rhinoviruses were often associated with lower-respiratory-tract illnesses. an eight-month-old boy was admitted with a ten-day history of wheezing getting worse two days before admission. coarse crepitations in right and left lower lobes. intercostal recession. pneumonia confirmed radiologically. chest signs persisted four days. respiration and heart rates up to and per minute. temperature up to more than - &deg;c. oxygen and cortisone given. discharged after ten days. nose and throat swabs taken on the second day in hospital yielded rhinovirus h. there was no evidence of r.s.-virus infection by either serology or isolation. no bacteria implicated. enteroviruses also were often associated with lowerrespiratory-tract illness. a four-month-old girl was admitted with a three-day history of worsening coryza. inspiratory wheeze and coarse rales. bronchopneumonia confirmed radiologically. no fever. respiration and heart rates up to and per minute, respectively. liver enlarged. cyanosis. chest signs lasted two days. discharged after nine days. echo- virus isolated from swabs taken on the second day in hospital. there was no evidence of infection with r.s. virus by serology or isolation. no bacteria implicated. the grade of severity was calculated for all illnesses in which definite viruses were implicated and in others (table iv). infants with r.s.-virus infection were more severely ill than other infants. illnesses due to rhinoviruses were of moderate severity. the small numbers of parainfluenza, influenza, and enterovirus infections were mild. there was a contributory cause of death in eleven; ten had congenital defects and one had gastroenteritis due to escherichia coli . the remaining infant was first admitted aged four months with severe bronchiolitis. discharged after twenty-five days, but readmitted two days later with bronchopneumonia. coarse rales in upper anterior chest and right axilla. temperature slightly raised. respiration and heart rates up to and per minute, respectively. no viruses or other organisms were implicated during the first admission, but the throat swab taken on the day of second admission yielded r.s. virus. no other organisms implicated. died three days after admission. at necropsy, muco-pus in larynx, trachea, and bronchi. generalised congestion of lungs. normal aeration in only a few small peripheral areas. the microscopical appearance resembled hyaline-membrane disease of newborn. no other abnormalities. in our hands the c.f. test was a more sensitive method than isolation for diagnosis of r.s.-virus infections in the infants where both methods were attempted. r.s.-virus infections were diagnosed by demonstrating a change from passive to active antibodies, for which it is necessary to do a cumbersome chequerboard titration, but most showed straightforward rises in titre when a large amount of antigen was used in the c.f. test. berglund and strahhnann conclude that isolation is better than serology. much will depend on the potency of the c.f. antigen, the number of antigen units used, and the time of taking the convalescent serum ; and the sensitivity of the cell line used for isolation and the timing of inoculation are also important. other respiratory pathogens the diagnosis-rate for all respiratory pathogens of % might have been higher if paired sera had been obtained from all the infants, and if serology for viruses other than r.s. virus had been performed. we did not look for mycoplasma pneumoniae & o a c u t e ; or coronaviruses or cytomegaloviruses, all of which are known to cause respiratory infections, especially cytomegalovirus in the first year of life. there is no convincing evidence that the bacteria we isolated (staph. aureus, str. pneumoniae, and hcemophilus infiuenzae) are a frequent primary cause of respiratory illness in infants. all are common in healthy infants. thiese were found on occasions. in double infections an adenovirus was isolated, but here the second virus (r.s. and influenza) probably caused the illness, the adenovirus being carried in the tonsils. the findngs in one patient (table ) support this. are subclinical. however, when one of these viruses is isolated from a child with a respiratory infection, it is probable that it is the cause of the illness. it is even more probable that illnesses associated with r.s. and parainfluenza viruses are due to these viruses. type of illness we found that rhinoviruses often produced a severe lower-respiratory-tract illness, as did hamparian et al. the finding of lower-respiratory-tract illness in association with echo virus is interesting in view of similar associations described by berkovich and smithwick. of the twelve infants who died with respiratory infections, eleven had a contributory cause of death. it seems, therefore, that respiratory viruses are not frequent killers of otherwise healthy infants in bristol. in newcastle only a quarter of infants who died with respiratory infections had congenital defects. r it seems that viruses, especially r.s. virus, are more important as a cause of severe illness and death among infants in newcastle than among infants in bristol. there may be socioeconomic reasons for this. in this survey, as in others, r.s. virus was the commonest cause of respiratory illness requiring admission at this age ( &deg; ), and the illnesses were more severe than those associated with other viruses (table iv). rhinoviruses were the next most important ( %) and often caused severe illnesses. in this age-group, adenoviruses, influenza, and parainfluenza viruses were relatively unimportant. this is supported by work with respiratory viruses in the bristol public health laboratory over the past nine years (unpublished). we found a heightened susceptibility of males to respiratory infections, previously noted by moss et al. effect of maternal antibody the few parainfluenza virus infections observed in this survey occurred only in infants more than four months of age. over the past nine years in the bristol public health laboratory, among large numbers of parainfluenza viruses isolated, parainfluenza types , , and have only occasionally been isolated from infants under four months of age, and type never. this is not a new observation, and there is evidence that maternal antibody protects against these viruses. our experience with influenza virus is similar, and in this survey there were no influenza virus infections below the age of four months. maternal antibodies probably played their role here also. on the other hand, rhinovirus infections were detected from a very early age, and this is to be expected because mothers would not have antibodies against all rhinovirus types at the time of delivery. indeed maternal antibody may protect against infections with this group of viruses. the position with regard to r.s.-virus infections is less clear-cut. for instance it is widely accepted that the majority of severe infections occur in the first three months of life. in our series the peak of incidence was at two months, and infections have been recorded as early as ten days after birth. there is no multiplicity of antigenic types to account for this early incidence as there is for rhinoviruses. on the other hand, the incidence of antibodies to r.s. virus in the adult population-and by implication exposure to r.s. virus-is very high. one would expect, therefore, the epidemiological features of this infection in infants to resemble influenza more closely than the common cold. the series we investigated may have been a selected group, in that for some reason we saw principally infants of mothers who lacked antibodies to r.s. virus. unfortunately a retrospective survey such as this cannot distinguish between maternal-antibody levels present before birth and those acquired at the time of, or just before, the infant's illness; and it is far more likely that the mother of an infected baby has just had an antigenic stimulus from the same virus. the high levels of antibody we observed in mothers of infected infants are thus meaningless in terms of protection afforded to the population studied. the vaccination studies carried out by some american workers, using killed virus vaccines - have often been quoted in support of the idea that antibody to r.s. virus actually increases the severity of a subsequent infection. however, other types of r.s.-virus vaccines prepared differently may not have the same effect. , ! neither is there any concrete evidence in table vil to support the hypothesis of antibody potentiation, for although at two months of age the geometric mean titre of antibody is higher in the group with r.s.-virus infections, as is the percentage of acute sera with antibody present, this trend is reversed at one month of age. similarly there is no correlation between high antibody titre and mean severity grade. although the numbers are extremely small, there was evidence in table v that in the first month of life infants had less severe r.s. infections than older infants. this could be taken as evidence that maternal antibody may actually have a protective effect. chanock et al. found that the titre of r.s.-neutralising antibody was two times lower in the acute sera of infants with r.s. infections than in those without, and suggests that antibody-antigen complexes in the lung may lead to depletion of antibody in the serum. gardner et al. present persuasive evidence in support of the postulate that the development of immediate hypersensitivity plays a dominant role in the pathogenesis of acute bronchiolitis in r.s. infections. however, they favour the idea of a gell and coombs type-i hypersensitivity response, and to sustain this argument they postulate a previous exposure to r.s.virus antigen. again we find no evidence to support this hypothesis, since, where antibody was detected in the acute-phase sera, it behaved like adult antibody in the c.f. test and was thus, presumably, maternal in origin. we thank the other clinicians for permission to study the infants under their care and dr. m. . roebuck for typing the rhinoviruses. financial support for one of us (j. w. j.) by the medical research council is gratefully acknowledged. requests for reprints should be addressed to j. w. j., department of pathology, royal veterinary college, royal college street, london n.w.i. one of the major problems in clinical organ transplantation is the detection and reversal of rejection episodes. centres differ in their methods of overcoming such episodes, but most administer an increased dose of oral steroids. - actinomycin c, - , antilymphocyte globulin and local graft irradiation , , have been used to the same end. at the start of our clinical renal-transplant programme we decided to use prednisolone given as a single g. intravenous dose over a period of hours for the treatment of acute rejection crises. this decision was made for several reasons. firstly, prednisolone at this dose level is lympholytic and has a short half-life of - minutes, , giving maximum lymphocyte damage with relatively little in the way of chronic side-effects. secondly, we were impressed by the results published by kountz and cohn, who used large doses of intra-arterial steroids, but we felt that this method was potentially dangerous and, perhaps, unnecessary. thirdly, we hoped to avoid the high oral doses of steroids normally used to control rejection and thereby avoid serious complications in the first few months after transplantation. the ability of a high dose of intravenous prednisolone to reverse acute rejection episodes was also investigated using the heterotopic rat-heart-transplant model. we present here the clinical and experimental results of this type of antirejection treatment. sixteen patients were transplanted over a -month period. three patients received kidneys from sibling medical research council working party on acute respiratory virus infections. ibid. , ii acta p&oelig;diat. scand "... we need to concentrate less on the reduction of infant mortality as a goal in itself than on assuring that children who survive are whole and healthy; and that it is fallacious to argue about whether the quality of medical care or the child's environment is the more important factor in relation to infant mortality. these cannot be separated. no matter how good the medical care system is, mortality rates cannot be lowered below a certain point unless certain changes are made in the social environment. the ability of single large ( g.) doses of intravenous prednisolone to reverse rejection episodes has been investigated clinically and experimentally. sixteen renal-transplant recipients have been treated in this way. the oral dose of prednisone was not increased during these episodes and no additional treatment was given. this therapy reversed % of rejection crises without any toxic effects. one patient has died from infection, month after transplantation. using the heterotopic rat-heart-transplant model the ability of intravenous prednisolone, antilymphocyte serum (a.l.s.), intraperitoneal prednisolone, and azathioprine to reverse rejection in recipients immunosuppressed with a single dose of a.l.s. at the time of transplantation were compared. intravenous prednisolone was the only successful agent and prolonged survival by &plusmn; days. key: cord- -t ghng authors: santos, roberto parulan; tristram, debra title: a practical guide to the diagnosis, treatment, and prevention of neonatal infections date: - - journal: pediatric clinics of north america doi: . /j.pcl. . . sha: doc_id: cord_uid: t ghng neonatal infections continue to cause morbidity and mortality in infants. among approximately , infants followed nationally, the incidence rates of early-onset sepsis infection within days of life are . cases per live births. newborn infants are at increased risk for infections because they have relative immunodeficiency. this article provides evidence-based practical approaches to the diagnosis, management, and prevention of neonatal infections. neonatal infections continue to cause morbidity and mortality in infants. among approximately , infants followed nationally, the incidence rates of early-onset sepsis (eos) infection within days of life were . cases per live births. more than two-thirds of the frequently isolated organisms were associated with group b streptococcus (gbs) ( %) and escherichia coli ( %). although % of the term infants were treated in the newborn nursery, % of the infected infants required intensive care management. of those who survived beyond days of life, about % had an episode of late-onset sepsis (los) infection after days of life. the overall mortality rate of infected infants was %. newborn infants are at increased risk for infections because they have relative immunodeficiency. this may be due to decreased passage of maternal antibodies in preterm infants and to immaturity of the immune system in general. , the innate immune functions in infants are impaired with decreased production of inflammatory markers (interleukin and tumor necrosis factor) and with decreased dendritic and neutrophil functions. the adaptive immune system is less than optimal with decreased cytotoxic functions, decreased cell mediated immunity, and delayed or lack of isotype switching. , complement is important in opsonization and bacterial killing. in term infants, complement levels are approximately half compared with adults. taken together, these predispose infants to severe, prolonged, or recurrent infections associated with bacterial, viral, or fungal infections. suspected sepsis, presumed infection, and ruling out sepsis remain the most common diagnoses in the nursery intensive care unit (nicu). the american academy of pediatrics (aap) committee on fetus and newborn has published a clinical report extensively discussing clinically relevant challenges: identifying newborns with signs of sepsis with high likelihood of eos requiring antimicrobial regimen and identifying healthy-appearing newborns with high likelihood of eos requiring antimicrobial regimen. the committee concluded that, although these guidelines are evidencebased, they may be modified by the clinical judgment of the provider. the primary reason is that the clinical presentation of neonatal infection may be subtle and nonspecific, and may overlap with noninfectious causes. , many clinicians empirically start broad spectrum antimicrobial regimen for infants considered at risk for sepsis but antibiotics are occasionally continued despite a negative blood culture. this practice may be detrimental to the infant because it increases the risk of invasive fungal infections, necrotizing enterocolitis (nec), or death, , which increases the pressure for selecting multidrug-resistant organisms and even the risk of los. the purpose of this article is to provide evidence-based practical approaches to the diagnosis, management, and prevention of neonatal infections. the timing of transmission is one of the factors contributing to the cause of neonatal infections. different pathogens may be acquired during pregnancy (prenatal), during delivery (perinatal), or after delivery (postnatal). table shows the different periods of transmission of various neonatal pathogens. the introduction of new molecular-based assays, such as quantitative real-time polymerase chain reaction (pcr), has paved the way for increasing recognition of respiratory viral infections contributing to ruling out sepsis in late-onset infections. table includes respiratory viral infections (coronavirus, enterovirus, human metapneumovirus, influenza, parainfluenza virus, respiratory syncytial virus [rsv], and rhinovirus) as possible causes of postnatal infections in infants. [ ] [ ] [ ] clinical presentations early-onset infections eos is arbitrarily defined as infection within the first days of life. the most common organisms associated with eos include gbs and e coli. , in general, the risk of bacterial infection in a healthy-appearing newborn remains relatively low. the most common clinical findings include hypoglycemia (< mg/dl, %) and hypothermia (< . c, %), followed by hyperglycemia (> mg/dl, %) and apnea ( %). edwards and baker summarized that newborn infants with sepsis manifest similar clinical signs as those with meningitis, including hyperthermia; hypothermia; respiratory distress; anorexia or vomiting; jaundice; and lethargy. hypotension may be more frequently found in infants with sepsis, whereas irritability, convulsions, and bulging or full fontanel is found in those with meningitis. however, they cautioned that absence of any of the aforementioned signs do not exclude central nervous system involvement. furthermore, it was suggested to evaluate infants for various foci of infections such as acute otitis media, conjunctivitis, osteomyelitis, pyogenic arthritis, and skin soft-tissue infections. los is arbitrarily defined as infection after days of life. the most common organisms isolated with los include coagulase-negative staphylococci in more than a third of the cases, which may or may not be associated with a medical device. yeast or candida spp infection is another important pathogen. also, there is increasing recognition of viral respiratory infections as a possible cause in los. the most common clinical findings include hypothermia ( %), hyperglycemia ( %), apnea ( %), and bradycardia ( %). there are several factors that may increase the risk for los. there are significantly more infants with los who have an indwelling central vascular catheter at the time of infection than those infants with eos ( % vs %, p<. ). additionally, there are more infants with los who had a surgical procedure before infection ( % vs %, p<. ). the clinical presentations of infections may overlap with noninfectious causes in newborns. it has been previously demonstrated that relying on symptoms alone may not be sufficient in diagnosing neonatal infections. bacteremia has been reported in infants without clinical signs of sepsis. there are several diagnostic tests and principles that may guide clinicians in evaluating infants with infections. the aap committee on fetus and newborn have published a clinical report on the evaluation of asymptomatic infants (< and ! week gestation) with risk factors for sepsis. evaluation of asymptomatic preterm infants (< -week) with risk factors for sepsis is shown in fig. . similar algorithms for the evaluation of asymptomatic term infants (! week gestation) are available from the aap committee on fetus and newborn. (http://www.ncbi.nlm.nih.gov/pubmed/ ). additional principles in the evaluation of infants with risk factors for sepsis follow: major risk factors for neonatal sepsis include chorioamnionitis, prolonged rupture of membrane or more hours, and colonization of gbs with inadequate intrapartum antimicrobial prophylaxis (iap). chorioamnionitis usually presents as maternal fever greater than c ( . f) and its diagnosis should be discussed with the obstetric providers. maternal fever may be the only abnormal finding in chorioamnionitis. adequate iap means maternal treatment with penicillin, ampicillin, or cefazolin at or earlier than hours before delivery. at least ml of blood may be sufficient for a single blood culture from a peripheral vein. blood culture from umbilical artery catheter or umbilical vein may be a reliable alternative following aseptic techniques screening blood cultures have not been proven of value and are not recommended. complete blood count with differential has poor positive predictive value and it is suggested waiting to hours after birth to avoid falsely normal values at birth. platelet counts remain low days to weeks after sepsis; thus this cannot be used in following response to treatment. the sensitivity of c-reactive protein (crp) improves if done to hours after birth. bacterial sepsis is unlikely if crp remains normal. lumbar puncture may be indicated in infants whom sepsis is highly suspected, those infants with bacteremia, and in infants who fail to respond to antimicrobial therapy. urinary tract infection in newborns is associated with episodes of bacteremia; thus urine culture should not be part of routine sepsis workup. microbiologic evaluation using gastric aspirates, tracheal aspirates, or superficial body sites cultures are of limited value and are not routinely recommended for sepsis. several acute-phase reactants or biomarkers (neutrophil cd [ncd ], procalcitonin [pct], or crp) may be used adjunctively in the evaluation and management of neonatal infection. the diagnostic usefulness of the various surrogate markers depends on the phases of neonatal sepsis: early phase or to hours (ncd ), mid phase or - hours (pct), and late phase or greater than hours (crp). ncd is a high-affinity fc receptor that increases with exposure to bacterial or fungal agents. , the usefulness of ncd is related to its high negative predictive value as well as decreasing concentration on serial determinations on infants undergoing antimicrobial treatment of bacteremia. however, there is a scarcity of medical evidence to recommend ncd for routine evaluation of neonatal infection and this may not be readily available. procalcitonin released from tissues increases with infection at around hours and peaks at hours. it may also increase with noninfectious causes such as in respiratory distress syndrome and a physiologic increase during the first hours of birth. pct may not be readily available and the turnaround time varies in different institutions from minutes to hours. crp increases around hours associated with an inflammatory response with release of interleukin- and peaks at hours. crp has been used in the algorithm-based guideline from the aap committee on fetus and newborn for the evaluation of asymptomatic term and preterm infants with a risk factor for sepsis. it is best used as part of a group of diagnostic tests together with blood culture and white blood cell with differential in the evaluation of neonatal infection. however, there is not enough medical evidence at this time to recommend serial determinations of crp in guiding duration of antimicrobial therapy in infants. , further studies are needed to evaluate the usefulness of sequential determination of crp and biomarkers for an antimicrobial stewardship program (asp) in the nicu setting. in , the infectious disease society of america, in collaboration with the american society for microbiology, affirmed the importance of close collaboration and positive working relationships between clinicians and microbiologists to better serve patients. the most up-to-date edition of the red book provides contact information for expert advice and national collaborative study groups that give guidance on diagnostic assays regarding specific agents causing mother-to-child transmission. it is important to know the various microbiologic resources available locally, which include but are not limited to pcr and matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof). rapid antigen tests for respiratory viruses may lack sensitivity, which is important in the nicu setting in controlling local outbreaks. there are several nucleic acid amplification test platforms currently available that differ in the number of analytes detected. it is important to obtain adequate specimens and to use suitable viral transport media following manufacturer instructions. maldi-tof is a valuable alternative to the conventional microbiologic assays; however, it may not be a readily available resource for diagnostic testing in most institutions. however, if it is available, it has several practical applications that may benefit clinical management even in the nicu settings: earlier and accurate diagnosis of neonatal sepsis due to various bacteria rapid identification of highly virulent gbs that causes meningitis and los in infants identification of maternal-to-child transmissions (chorioamnionitis and neonatal infections) of opportunistic pathogen accurate identification of bloodstream infection associated with fungal infections in the nicu identification and monitoring the spread of nosocomial outbreak (eg, methicillinresistant staphylococcus aureus [mrsa] and candida parapsilosis in the nicu). when appropriate specimens for diagnostic evaluations are collected in clinically stable patients, then empirical antimicrobial therapy should be initiated for neonatal sepsis. it is recommended to discuss complicated cases, such as multidrug resistant organisms and infants not improving while on therapy or those requiring unconventional dosing regimens and antimicrobial agents, with pediatric infectious disease specialists. ampicillin and gentamicin remains the cornerstone of initial antimicrobial regimen for early-onset neonatal infections. the combination of such broad-spectrum antibiotic regimens cover the most common cause (gbs and e coli in more than %) of eos and has synergistic activity (against gbs and listeria monocytogenes). , the dosing regimen for ampicillin may change over time based on the chronologic age of the infant and body weight. for example, an -day-old infant weighing greater than g may need dosing adjustment of ampicillin from mg/kg/d intravenous (iv) divided every hours to mg/kg/d iv divided every hours. once-daily dosing of gentamicin ( mg/kg iv qd) has been used in the term newborn for more than a decade. the pharmacodynamic characteristics of aminoglycosides that allow the use of once-daily dosing include concentration-dependent killing (peak concentration to minimal inhibitory concentration [peak/mic] ratio), , postantibiotic effect with leukocyte enhancement, , and prevention of adaptive resistance. third-generation cephalosporins should be used judiciously. there is significant association between the use of third-generation cephalosporins and invasive candidiasis in preterm infants. cefotaxime has excellent penetration to the cerebrospinal fluid and its therapeutic use should be limited to gram-negative meningitis. routine use of cefotaxime for eos may lead to rapid development of drug-resistant organisms. ceftriaxone is contraindicated in neonates for reasons: ( ) it is highly protein bound and may displace bilirubin progressing to hyperbilirubinemia and ( ) concurrent administration with calcium-containing solutions may produce insoluble precipitates (ceftriaxone-calcium salts) leading to cardiorespiratory complications. the aap periodically updates the dosing regimens and recommended therapy for selected neonatal infections through nelson's pediatric antimicrobial therapy. it provides various antimicrobial regimens (antibiotic, antiviral, and antifungal agents) based on body weight of infants and their chronologic age or gestational and postnatal age. between new editions, a monthly update of short and interesting reports related to pediatric antimicrobial therapy is posted at www.aap.org/en-us/aap-store/nelsons/ pages/whats-new.aspx. suggested durations of antibiotic therapy for eos adapted from nelson's pediatric antimicrobial therapy and the aap committee on fetus and newborn are shown in table . there are several antiviral agents that can be used for the treatment of neonatal viral infections. acyclovir ( mg/kg/d iv divided every hours) is the treatment of choice for term infants with herpes simplex virus (hsv) and varicella-zoster infections. there are several topical agents ( . % ganciclovir ophthalmic gel, . % iododeoxyuridine, or % trifluridine) that may be added to systemic antiviral regimen if there is eye involvement. after parenteral therapy with acyclovir, it is recommended to give hsv suppressive regimen ( mg/m /dose po tid), which improves neurodevelopmental outcomes of infants with central nervous system involvement. there is currently no dosing regimen for valacyclovir in infants younger than months of age. the aap committee on infectious diseases and the committee on fetus and newborn recently published an algorithm-based guideline on the evaluation and treatment of asymptomatic infants born to mothers with active herpes lesions (http:// www.ncbi.nlm.nih.gov/pubmed/ ). oral valganciclovir ( mg/kg/dose po bid) is the drug of choice for infants with symptomatic congenital cytomegalovirus (cmv) disease with or without central nervous system involvement. , the treatment of congenital cmv should be initiated in the first month of life. kimberlin and colleagues concluded from the phase iii randomized double-blind placebo-controlled multinational study that months of valganciclovir regimen for symptomatic congenital cmv disease significantly improves hearing and neurodevelopmental outcomes. there is significant improvement in language and receptive communication at years of age. there was less grade to neutropenia at weeks oral valganciclovir (w %) compared with weeks of iv ganciclovir ( %) reported previously. iv ganciclovir ( mg/kg/dose bid) can be used initially for infants with symptomatic congenital cmv disease if oral valganciclovir is contraindicated due to extreme prematurity or nec. the same dosing regimen is the treatment of choice for perinatally or postnatally acquired cmv disease associated encephalitis, hepatitis, pneumonitis, or persistent thrombocytopenia. oral oseltamivir ( mg/kg/dose bid) remains the treatment of choice for term infants with influenza infections. , oral suspension formulation is available ( mg/ml) and should be offered to young infants with suspected or confirmed influenza infection regardless of severity because they are at higher risk for complications. limited data are available for the weight-based dosing regimen for preterm infants using postmenstrual age (ie, gestational age plus chronologic age): less than weeks postmenstrual age, mg/kg/dose po bid to weeks, . mg/kg/dose po bid greater than weeks, mg/kg/dose po bid. there is currently no dosing regimen for inhalational zanamivir for young infants. suggested durations of antiviral therapy, prophylaxis, and suppressive regimen for congenital and perinatal or postnatally acquired viral infections adapted from nelson's pediatric antimicrobial therapy and the aap committee on infectious diseases and the committee on fetus and newborn are shown in table . fig. shows an extensive cutaneous aspergillosis on a preterm infant who was a poor surgical risk successfully treated with combination antifungal agents. fluconazole prophylaxis ( mg/kg/d twice a week) may be indicated in high-risk infants with birth weight of less than g from institutions with high incidence of candidiasis (ie, above %). fluconazole prophylaxis ( mg/kg once weekly) may be offered to young infants younger than months old on extracorporeal membrane oxygenation. suggested durations of antifungal treatment of candidiasis and aspergillosis adapted from nelson's pediatric antimicrobial therapy are shown in table . surgical interventions may be indicated for the source control of neonatal infections. in a single-center -year retrospective study, nec-associated blood stream infection (bsi) occurred within days of nec diagnosis and was noted in approximately % ( out of infants with one episode of bsi). infants with nec-associated bsi had higher odds (adjusted odds ratio . ; % ci . - . ) of having surgical interventions compared with those without bsi. it is of utmost importance to correspond with pediatric surgery regarding source control of infection if clinically indicated because nec-associated bsi had higher odds of death (adjusted odds ratio . ; % ci . - . ). the following includes disease-specific conditions that may require surgical interventions for adequate source control of infections if the infant is clinically stable. pediatric providers are encouraged to discuss with their surgical colleagues the following surgical treatment options : early debridement of cutaneous lesions with disseminated aspergillosis surgical drainage of peritonitis with bowel rupture wound cleaning and debridement rapidly spreading cellulitis (s aureus), necrotizing fasciitis (group a or b streptococci), tetanus neonatorum surgical drainage of pus in osteomyelitis and suppurative arthritis thoracostomy drainage of empyema surgical drainage of breast abscess may be needed to minimize damage to breast tissue. surgical interventions for primary diseases in infants may also increase the risk for neonatal infections. higher rates of surgical site infection defined as superficial, deep, and organ infections within days of surgical procedures were noted among infants following closure of gastroschisis. it is important to closely monitor infants with surgical site infection because they require significantly longer hospital stay. there are various measures that can be used, depending on the availability of local resources, to prevent neonatal infections. these include but are not limited to gbs prophylaxis, hand hygiene, immunization and immunoprophylaxis, asp, probiotics and prebiotics, and care bundles. iap is the only preventive strategy that substantially reduces the incidence of earlyonset gbs. , the following are indications for iap: previous infant with invasive gbs disease gbs bacteriuria during the current pregnancy positive gbs vaginal-rectal screening (at - week gestation) except for cesarean delivery without labor or ruptured membrane unknown maternal gbs status with delivery at less than weeks, rupture of membrane at or before hours, or fever equal to or greater than . f (! c). adequate iap means receiving penicillin, ampicillin, or cefazolin for at least hours before delivery. cefazolin may be used if with nonserious b-lactam allergy. if there is history of serious b-lactam allergy (anaphylaxis, angioedema, respiratory insufficiency, or urticarial rash) and if gbs isolate is susceptible, clindamycin may be used. otherwise, vancomycin is an alternative. because of high resistance rates, erythromycin is not recommended. the center for disease control and prevention has an extensive online resource on gbs for clinicians, including the algorithm-based guidance on secondary prevention of eos in newborns. the web page also provides an application, prevent group b strep, which includes guidance on various patient scenarios in collaboration with different medical societies, such as the aap and the american college of obstetricians and gynecologists (http://www.cdc.gov/groupbstrep/guidelines/index.html). there is no doubt that hand hygiene remains the cornerstone in decreasing health care-associated infections in different hospital settings, including the nicu. in fact, there are various educational programs, multidisciplinary quality-improvement teams, and guidelines on the proven effectiveness of hand hygiene in decreasing infection; however, this is significantly affected by compliance. , the center for disease control and prevention has a web site (http://www.cdc.gov/handhygiene/) containing resources for hand hygiene in health care settings including an application, iscrub, for monitoring hand hygiene compliance using an iphone or ipod touch. thus, hand hygiene guidelines are effective in reducing infections only if we use it. soap and water is recommended for decontaminating visibly soiled hands by rubbing hands together vigorously for seconds. , alcohol-based gel or foam or an antiseptic soap may be used for routine hand hygiene if not grossly contaminated. , hand hygiene compliance is improved if with available alcohol-based products at the infant's bedside. antimicrobial-impregnated towelettes or wipes are considered alternatives but not substitutes for washing with soap and water or alcohol-based gel or foam. the development of a safe and effective vaccine is arguably one of the greatest medical interventions in the last century. hepatitis b vaccine is the only agent in the united states recommended to be administered at birth. the various brands available in the united states have an efficacy of % to % in preventing hepatitis b virus infection and disease. additional information regarding recommended dosages of hepatitis b vaccines are available in the most recent edition of the red book and in the annual publication from the advisory committee on immunization practices. the first dose in the primary series of the subsequent vaccines (diphtheria and tetanus toxoids and acellular pertussis vaccine [dtap], haemophilus influenza type b, inactivated polio, pneumococcal, or rotavirus vaccine) can be administered at a minimum age of weeks. care givers at home should be advised on the importance of immunizing family members to protect infants who are too young to be vaccinated. this is called cocooning and prevents vaccine-preventable diseases, such as pertussis and influenza, in young infants. educational materials on cocooning for parents and clinicians are available at the aap web site http://www .aap.org/immunization/families/ cocooning.html. in october , the use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (tdap) during every pregnancy was recommended because of increasing cases of pertussis in young infants in the recent years. the mother's protective antibodies against pertussis are short-lived and a dose of tdap in a previous pregnancy may not be protective to the infants of subsequent pregnancies. young preterm infants (< year of age born at < weeks and -day gestation) should receive palivizumab during the rsv season for immunoprophylaxis. five monthly doses of palivizumab at mg/kg given intramuscularly will provide adequate protection for months. other indications during the rsv season include preterm infants (< year of age born at < weeks and -day gestation) with chronic lung disease of prematurity who required greater than % oxygen for at least the first days of life and young infants (< year of age) with certain hemodynamically significant heart disease. clinicians should consult the most current guidelines or policy statement from the aap regarding palivizumab prophylaxis among young children at increased risk for hospitalization for rsv infection. injudicious use of antibiotics can alter the neonates' microflora that increases exposure and pressure that leads to antimicrobial resistance. the nicu milieu and interventions are permissive for the development of antibiotic-resistant organisms. , the aap committee on fetus and newborn have listed asp strategies that may be useful in the nicu setting based on the guideline from the infectious diseases society of america and the society for healthcare epidemiology of america (box ). there is some medical evidence supporting the use of probiotics in the prevention of nec in preterm infants. probiotic is an oral supplement containing sufficient amount of viable microorganisms that alters the host microflora with potential for health benefits. a meta-analysis based on randomized control trials involving approximately infants born before or at weeks gestation and/or weighing less than or equal to g at birth showed that enteral use of probiotic significantly decreased the incidence of severe nec and mortality. there were no severe adverse events or systemic infections directly related to the probiotics used were reported. the aap committee on nutrition, however, cannot recommend the use of all probiotics in young infants until further studies are done to resolve problematic issues. they noted the large heterogeneity of the studies included in the review, the different mixture of probiotics used, and that the combinations of probiotics used in the studies are not available in the united states. further, there remains some gap in knowledge on which probiotic bacteria species to use, the microbial dose, as well as the duration of administration. in , an updated review of the aforementioned meta-analysis of randomized controlled trials continues to support a change in practice of supplementing preterm infants with probiotics. the review provided similar results involving more than infants in whom probiotics significantly reduced severe nec and mortality. however, the previously mentioned gap in knowledge remains, as well as the need for comparative studies. there is scarcity of medical evidence to recommend the addition of prebiotics such as oligosaccharides in infant formula. prebiotics are nondigestible food ingredients that occur naturally or as dietary supplements that enhance growth of probiotic bacteria such as bifidobacterium spp. several studies had reported that the addition of prebiotics in infant formula significantly increased the bifidobacteria counts in their stool without adverse effects noted. however, clinical efficacy as well as cost-benefit analyses regarding the addition of oligosaccharides to infant formulas is lacking. for infants, human milk remains the best source of naturally occurring prebiotics and probiotics, and immunoprotective compounds known to decrease the incidence of respiratory and gastrointestinal infections. , nursery intensive care unit care bundles there are invasive procedures that may increase the infant's risk of health care-associated infections in the nicu setting. these infections include central line-associated bsis (clabsis), pneumonia, skin, and soft tissue infections; and, occasionally, vaccine-preventable diseases and outbreak of respiratory viral infections. care bundles are sets of interventions aimed at reducing health care-associated infections in the nicu. the most common cause of clabsi and los are coagulase-negative staphylococci. several randomized clinical trials on the use of low-dose vancomycin in parenteral solutions in preterm infants did not show significant decrease in the length of stay and mortality. there is an antibiotic-lock therapy done in neonates that significantly decrease clabsi however it was not powered to answer whether vancomycin resistance occurred. both are currently not recommended because of the lack of long-term efficacy evidence as well as concern for development of drug-resistant organisms. infection control intended to decrease clabsi in the nicu should include measures to decrease extraluminal and intravascular catheter-related infections. various techniques and guidelines in the prevention of clabsi in infants adapted from the aap committee on fetus and newborn are shown in box . there are specific practices that may be adapted in the local setting for preventing vaccine-preventable diseases and outbreaks of respiratory viral infections. these include but are not limited to vaccination of health care providers against influenza and pertussis (tdap), visitation guidelines to screen ill or symptomatic visitors, and cohorting in cases of clustering of infections or in outbreak situations. cohorting may only be possible if early screening procedures, such as the use of pcr-based assays, are in place if available in cases of clustering of respiratory viral infections. [ ] [ ] [ ] further, appropriate isolation (eg, contact precautions for mrsa, droplet precautions for influenza, and airborne precautions for measles) should be observed if the infant is clean the umbilical insertion site using an antiseptic such as povidone-iodine before catheter insertion. avoid using topical antibiotic ointment or creams on insertion sites to prevent fungal infections and antimicrobial resistance. use low doses of heparin ( . - . u/ml) to the fluid infused through umbilical arterial catheter. remove umbilical catheters as soon as no longer needed or if signs of vascular insufficiency to the lower extremities (for umbilical artery access) are present; they may be replaced if malfunctioning. umbilical artery catheters should not be left in place for more than days. umbilical venous catheters may be used up to days if managed aseptically. colonized or infected with a pathogen requiring additional protection beyond standard precautions. neonatal infections continue to cause morbidity and mortality in infants. gbs and e coli are the most common agents of eos, whereas coagulase-negative staphylococcus is the predominant cause for los. there is increasing recognition of respiratory viral infections contributing to ruling out sepsis in very young infants whose presentations are similar to bacterial infections. blood culture at birth and white blood cell with or without crp has been used in the algorithm-based guideline for the evaluation of asymptomatic term and preterm infants with risk factors for sepsis. ampicillin and gentamicin remains the cornerstone of initial antimicrobial regimen for neonatal infections. third-generation cephalosporins should be used judiciously. the use of antiviral (acyclovir, ganciclovir, valganciclovir, and oseltamivir) and antifungal (fluconazole, amphotericin b, and voriconazole) treatment and prophylactic regimens may reduce mortality and morbidity to specific viral and fungal disease in infants. there are various strategies, such as gbs prophylaxis, hand hygiene, immunization, and immunoprophylaxis, asp, probiotics, and prebiotics, and nicu care bundles, which may be used in preventing infections in infants. early onset neonatal sepsis: the burden of group b streptococcal and e. coli disease continues neonatal infectious diseases: evaluation of neonatal sepsis the many faces of b cells: from generation of antibodies to immune regulation neonatal innate tlr-mediated responses are distinct from those of adults innate immunity of the newborn: basic mechanisms and clinical correlates the neonatal adaptive immune system committee on fetus and newborn. management of neonates with suspected or proven early-onset bacterial sepsis antibiotic use and misuse in the neonatal intensive care unit the association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants duration of empiric antibiotics for suspected early-onset sepsis in extremely low birth weight infants clinical utility of pcr for common viruses in acute respiratory illness viral respiratory tract infections in the neonatal intensive care unit: the virion-i study unrecognized viral respiratory tract infections in premature infants during their birth hospitalization: a prospective surveillance study in two neonatal intensive care units nosocomial rhinovirus infection in preterm infants principles and practice of pediatric infectious diseases successful medical treatment of cutaneous aspergillosis in a premature infant using liposomal amphotericin b, voriconazole and micafungin seventy-five years of neonatal sepsis at yale: - neonatal sepsis workups in infants >/ grams at birth: a population-based study principles and practice of pediatric infectious diseases culture negative sepsis and systemic inflammatory response syndrome in neonates utility of complete blood count and blood culture screening to diagnose neonatal sepsis in the asymptomatic at risk newborn effective biomarkers for diagnosis of neonatal sepsis a guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: recommendations by the infectious diseases society of america (idsa) and the american society for microbiology (asm)(a) laboratory medicine in neonatal sepsis and inflammation group b streptococcus st- and emerging st- clones by maldi-tof mass spectrometry capnocytophaga species and perinatal infections: case report and review of the literature bloodstream infections by malassezia and candida species in critical care patients first outbreak of pvl-positive nonmultiresistant mrsa in a neonatal icu in australia: comparison of maldi-tof and snp-plus-binary gene typing maldi-tof mass spectrometry and microsatellite markers to evaluate candida parapsilosis transmission in neonatal intensive care units nelson's pediatric antimicrobial therapy introduction to paediatric and perinatal drug therapy the therapeutic monitoring of antimicrobial agents in vitro postantibiotic effect and postantibiotic leukocyte enhancement of tobramycin once-daily versus multiple-daily dosing of aminoglycosides pharmacodynamic factors of antibiotic efficacy gentamicin vs cefotaxime for therapy of neonatal sepsis. relationship to drug resistance intravenous ceftriaxone and calcium in the neonate: assessing the risk for cardiopulmonary adverse events oral acyclovir suppression and neurodevelopment after neonatal herpes committee on infectious diseases, et al. guidance on management of asymptomatic neonates born to women with active genital herpes lesions six months versus six weeks of oral valganciclovir for infants with symptomatic congenital cytomegalovirus (cmv) disease with and without central nervous system (cns) involvement: results of a phase iii, randomized, double-blind, placebo-controlled, multinational study. id week. infectious disease society of america committee on infectious diseases. recommendations for prevention and control of influenza in children concurrent bloodstream infections in infants with necrotizing enterocolitis surgical site infections in infants admitted to the neonatal intensive care unit prevention of perinatal group b streptococcal disease-revised guidelines from cdc group b strep (gbs) strategies for prevention of health careassociated infections in the nicu healthcare infection control practices advisory committee, et al. guideline for hand hygiene in health-care settings: recommendations of the healthcare infection control practices advisory committee and the hic-pac/shea/apic/idsa hand hygiene task force hygiene in healthcare settings how to communicate with vaccine-hesitant parents recommended childhood and adolescent immunization schedule-united states committee on practice and ambulatory medicine, et al. immunizing parents and other close family contacts in the pediatric office setting updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (tdap) in pregnant women-advisory committee on immunization practices (acip) importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (tdap) immunization and protection of young infants updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection neonatal sepsis: the gut connection infectious diseases society of america and the society for healthcare epidemiology of america guidelines for developing an institutional program to enhance antimicrobial stewardship probiotics and prebiotics in pediatrics probiotics for prevention of necrotizing enterocolitis in preterm infants probiotics for prevention of necrotizing enterocolitis in preterm infants transmission-based precautions key: cord- -vmuqbpkk authors: leibowitz, jill; krief, william; barone, stephen; williamson, kristy a.; goenka, pratichi k.; rai, shipra; moriarty, shannon; baodhankar, prachi; rubin, lorry g. title: comparison of clinical and epidemiologic characteristics of young febrile infants with and without sars-cov- infection date: - - journal: j pediatr doi: . /j.jpeds. . . sha: doc_id: cord_uid: vmuqbpkk objective: to determine features that distinguish febrile young infants with sars-cov- infection. study design: retrospective single-center study included febrile infants < days evaluated in the emergency department of cohen children’s medical center of northwell health, new hyde park, new york during march -april of , , and . sociodemographic and clinical features were compared between those seen during the covid- pandemic and previous years, as well as between sars-cov- infected infants and sars-cov- uninfected infants (sars-cov- negative or evaluated during and ). results: in all, febrile infants < days of age were identified; during the -month study period in , in , and in . during , fewer febrile infants had a serious bacterial infection (sbi) or a positive respiratory viral panel (rvp) than in prior years ( % versus %, p = . ; % versus %, p<. , respectively). sars-cov- was the most frequent pathogen detected in ; of infants tested, tested positive. infants with sars-cov- were more likely to identify as hispanic (p=. ), have public insurance or were uninsured (p=. ), exhibited lethargy (p=. ), had feeding difficulties (p=. ), and had lower white blood cell (p=. ), neutrophil (p<. ), and lymphocyte counts (p=. ) than the infants without sars-cov- infection. none of the infants with sars-cov- had concurrent sbi or detection of another virus. overall, disease in infants with sars-cov- was mild. conclusions: during the peak of the pandemic, sars-cov- was the predominant pathogen among febrile infants. socioeconomic, historical, and laboratory features differed significantly between sars-cov- infected and uninfected infants. none of the infants with sars-cov- infection had an identified co-viral or serious bacterial infection. based on data from the centers for disease control and prevention through july , infants < months of age accounted for . % of hospitalized pediatric covid- patients in the us, and children younger than one year of age accounted for % of fatalities associated with sars-cov- in us children, however, the proportion of children younger than - months of age was not specified. , although an early study from wuhan, china reported . % of covid- cases in children less than one year of age to be critical or severe, of these cases, not all were laboratory confirmed sars-cov- infection and other viral etiologies of illness were not excluded. since then, a number of case reports and small series describing infants less than months of age have been published, most reporting mild disease, with many infants coming to medical attention due to fever, lethargy and poor feeding, but without respiratory manifestations as seen in adult patients. , , , , , , the largest case series to date describes infants younger than days of age who tested positive for sars-cov- , of whom were febrile. the objective of this study was to compare the clinical and demographic characteristics and hospital course of febrile infants who presented to cohen children's medical center (ccmc) during march and april of , the time period of peak covid- incidence in our region, to febrile infants treated in ccmc during march and april of previous years. particular emphasis was placed on infants in whom sars-cov- was detected in order to provide relevant clinical data for clinicians evaluating infants with fever during the pandemic. we conducted a single centered, retrospective study of febrile infants evaluated in the york, which was the epicenter of covid- in the us during the study period. the investigation included both infants who were evaluated and discharged from the ccmc ed and those admitted to an inpatient unit. per institutional policy, all febrile infants < days are hospitalized, but for infants - days of age a decision to hospitalize is based on clinical criteria. for infants with an ed revisit or readmission to ccmc within days, only the first visit was included in the study. patients were classified as having sars-cov- when a nasopharyngeal or combined nasopharyngeal/oropharyngeal swab tested positive by one of several nucleic acid amplification (naa) assays for sars-cov- in northwell health laboratories. as of march , all infants admitted to ccmc underwent sars-cov- testing but prior to march , testing for sars-cov- was not universal because of limited testing capacity. during the study period sars-cov- testing of febrile infants who were discharged from the emergency department was not universally applied. cases were ascertained through review of icd- billing codes and discharge diagnosis in the electronic medical record. clinical, laboratory and sociodemographic data were abstracted from the electronic health record and managed with the use of a redcap electronic database. collected data included age, sex, ethnicity, race, primary language, insurance, length of hospital stay, history of sick contacts or known covid- exposure, history of prematurity or underlying medical condition, disposition from the ed (discharged home versus hospital admission), and need for admission to the pediatric intensive care unit (picu). the presence or absence of symptoms such as fever, cough, rhinorrhea, feeding difficulties (defined as decreased oral intake), emesis, diarrhea, irritability, lethargy and rash, and vital signs and ascultatory lung examination were also recorded. laboratory results included sars-cov- naa assays test results, complete blood count (cbc) and white blood cell differential, urinalysis, hepatic assays, cerebrospinal fluid parameters, bacterial cultures (urine, blood, cerebrospinal fluid), respiratory viral panel (rvp); genmark diagnostics, carlsbad, ca), erythrocyte sedimentation rate and c-reactive protein, stool assays (stool culture, rotavirus antigen, multiple pathogen gastrointestinal panel by naa (gi naa) assay, and herpes simplex virus (hsv) testing (naa testing of cerebrospinal fluid, whole blood, surface specimens and vesicles). days of antimicrobial therapy, measured from date of first to last dose, and type and duration of respiratory support (e.g., supplemental oxygen, non-invasive ventilation or mechanical ventilation), measured from date of initiation to discontinuation, were recorded. neutropenia was defined as an absolute neutrophil count (anc) of < cells/µl, lymphopenia was defined as an absolute lymphocyte count (alc) of < j o u r n a l p r e -p r o o f blood, urine, or cerebrospinal fluid that was deemed pathogenic. , febrile infants were classified based on the year of presentation (eg, , , ). febrile infants were also categorized based on their sars-cov- status: ( ) infants who were sars-cov- test positive during march-april were classified as sars-cov- infected; ( ) infants who were treated between march and april but were not tested for sars-cov- sixteen of the sars-cov- infected infants were reported in previous studies. , this study was approved by the northwell health institutional review board. we categorized and analyzed the data according to the patients' sars-cov- status (infected or uninfected) and year of presentation. for purposes of analysis, we combined the and cohorts as a single cohort. we performed descriptive and bivariable analyses using fisher exact test for categorical data, student t test for continuous variables, and the wilcoxon rank-sum test j o u r n a l p r e -p r o o f for ordinal data. all tests of significance were -sided with an α value of . . statistical analysis was performed by using spss (ibm corp, armonk, ny). overall, the age distribution was as follows: ( %) were - days, ( %) were - days, and ( %) were - days; ( %) were male; ( %) were admitted to general inpatient unit, ( %) to the picu, and ( %) were discharged home from the ed. patient demographics are summarized in table i . compared with febrile infants presenting in and , febrile infants in were similar in age and by sex, but were more likely to identify as hispanic (p=. ) ( table ). in , there were significantly fewer infants with a sbi, as sbi was detected in three of ( %) infants in demographic and clinical variables of sars-cov- positive infants were compared with uninfected infants ( seen and and the sars-cov- negative infants seen in ) ( table and table ) . a significantly higher proportion of infants in the covid- group had public insurance or were uninsured and identified as hispanic (p=. and p=. , respectively). the racial distribution of the groups differed significantly with a higher proportion of patients identified as "multiracial/other" and a smaller proportion identified as asian or black in the sars-cov- group (p=. ). infants with covid- were significantly younger (p=. ), had a higher proportion with reported feeding difficulty (p=. ) and had a higher proportion with reported lethargy (p=. ) than the sars-cov- negative group. infants the key findings of our study are that during the peak of the covid- pandemic in new york, sars-cov- was the predominant pathogen identified among febrile infants younger than days of age, and the disease was self-limited in all infants with covid- . none of the infants infected with sars-cov- had an additional pathogen identified. febrile young infants with sars-cov- infection differ from other febrile infants in that they are younger, are more likely to be lethargic or exhibit feeding difficulties, have lower mean wbc, anc, and alc and have a higher likelihood of neutropenia and lymphopenia despite performing sars-cov- testing on only % of the cohort of febrile infants due to limitations on availability of testing during this time, sars-cov- was detected in % of the entire cohort and % of those tested. in contrast, although the entire cohort was tested for other respiratory viruses, a virus was detected in only % of febrile infants, similar to a study that demonstrated a decrease in influenza rates while covid- was prevalent and while local school closures and stay-at-home orders were in place. the majority of febrile infants with covid- had a relatively mild infections, with only of infants requiring supplemental oxygen, one of whom also required high flow nasal cannula, findings similar to those described in other case reports and small case series. , , , , however, severe disease with respiratory failure has been reported in a -weekold infant with covid- who was born after a -week gestation and in previously healthy infants with covid- who developed pneumonia and evidence of myocardial involvement. , , the significantly higher proportion of infants with sars-cov- infection of hispanic ethnicity and with public health insurance compared with sars-cov- uninfected infants may reflect the more pronounced impact of covid- in hispanic persons than those of other ethnicities and in persons from lower socioeconomic groups that has been observed in adults. , the sars-cov- infected infants were younger than the sars-cov- uninfected infants, and were also younger than the subgroup with other respiratory viral infections. this may in part be an artifact of our practice of admitting infants younger than days of age hospital and preferential testing of admitted patients over ambulatory patients. this finding also could reflect the high prevalence of sars-cov- among women presenting in labor during this pandemic with transmission from the infant's mother or another household member. infants with covid- presented with lethargy and feeding difficulty more with sars-cov- infection among infants younger than days of age. , the uncommon occurrence of sbi or a second viral pathogen strongly support the assertion that sars-cov- infection is the cause of the febrile illness in most or all of these infants rather than that detection reflects an asymptomatic infection. there were several limitations to this study. this was a single center study and findings may not be generalizable. additionally, as the initial phase of the covid- pandemic in the united states took place in march and april of , we compared febrile infants seen during this time period with febrile infants evaluated in the ed during corresponding months of and so generalizability to other time periods is not possible. lastly, due to variable testing for sars-cov- at the initial stages of the pandemic, of infants evaluated in the ed because of fever were not tested; therefore we may have underestimated the prevalence of covid- in this patient population during this time period. sars-cov- should be considered as a cause of fever in young infants, particularly when the infant has poor feeding and/or lethargy and when leukopenia, lymphopenia, or neutropenia is present. the infection generally is self-limited and has a relatively rapid clinical resolution. j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f . j o u r n a l p r e -p r o o f . mean wbc x defined as presence of any of the following: abnormal lung exam (crackles, rhonchi or wheeze), hypoxia, parenchymal infiltrate on chest x-ray defined as an anc of < . x / l defined as an alc of < . x / l j o u r n a l p r e -p r o o f clinical features of patients infected with novel coronavirus in wuhan who declares covid- a pandemic novel coronavirus in the united states hospitalization rates and characteristics of children aged < years hospitalized with laboratoryconfirmed covid- -covid-net, states sars-cov- associated deaths among persons aged < years -united states epidemiology of covid- among children in china mmwr morb mortal wkly rep febrile infant: covid- in addition to the usual suspects sars-cov- infection in infants less than days old sars-cov- infection (covid- ) in febrile infants without respiratory distress fever without a source in a young infant due to sars-cov- novel coronavirus infection in febrile infants aged days and younger a case series of the novel coronavirus (sars-cov- ) in febrile infants in new york early experience of covid- in a us children' hospital research electronic data capture (redcap)-a metadata-driven methodology and workflow process for providing translational research informatics support screening for severe combined immunodeficiency in neonates lanzkowsky's manual of pediatric hematology and oncology th ed the changing epidemiology of serious bacterial infections in young infants a clinical prediction rule to identify febrile infants days and younger at low risk for serious bacterial infections comparison of clinical features of covid- vs seasonal influenza a and b in us children infant with sars-cov- infection causing severe lung disease treated with remdesivir a day old female infant infected with covid : presenting with pneumonia, liver injury and heart damage sars-cov- infection in febrile neonates disparities in incidence of covid- among underrepresented racial/ethnic groups in counties identified as hotspots during hospitalization and mortality among black patients and white patients with covid- universal screening for sars-cov- in women admitted for delivery neonates hospitalized with community-acquired sars-cov- in a colorado neonatal intensive care unit clinical features of patients infected with novel coronavirus in wuhan epidemiology, clinical features, and disease severity in patients with coronavirus disease children's hospital in new york city risk of bacterial coinfections in febrile infants days old and younger with documented viral infections key: cord- -c xxo d authors: stuebe, alison title: should infants be separated from mothers with covid- ? first, do no harm date: - - journal: breastfeed med doi: . /bfm. . .ams sha: doc_id: cord_uid: c xxo d nan ( ) separation may not prevent infection. a study published in late march reported that of infants born in wuhan, china, to mothers with covid- tested positive for sars-cov- ; the infants were born by cesarean and managed with strict isolation precautions. even if separation prevents infection during the maternity stay, it does not address exposure after the infant is discharged. especially in the context of social distancing and travel restrictions, few families have the resources to isolate the infant at home, and it is highly plausible that other household members may be infected. hospital isolation may therefore delay, but not prevent, infant infection. ( ) interruption of skin-to-skin care disrupts newborn physiology. infants who are separated from their mothers have higher heart rates and respiratory rates and lower glucose levels than infants who are skin-toskin. this holds true even for infants who are placed in incubators. in a randomized controlled trial for -to -gram newborns, among infants who were skin-to-skin, % of infants experienced instability, based on objective parameters, compared to % of the infants in conventional incubators. in a subsequent study among term infants placed skin-toskin versus alone in a crib, separation increased stress activity by %. as noted by the royal college of obstetricians and gynecologists, ''routine precautionary separation of a mother and a healthy baby should not be undertaken lightly, given the potential detrimental effects on feeding and bonding.'' isolation is a significant stressor for newborn infants; for those infants already infected with sars-cov- , isolation could worsen the disease course. ( ) separation stresses mothers. when mothers held their preterm infants skin-to-skin in the neonatal intensive care unit, their heart rate, salivary cortisol level, and stress scores decreased. separating mothers from their infants, especially in the context of being diagnosed with a pandemic disease, has the potential to cause significant suffering, and the associated physiologic stress could worsen the mother's disease course. of the infant microbiome. antibodies specific to maternal antigen exposure begin to appear in milk within days, protecting the infant from infection. furthermore, human milk contains multiple oligosaccharides and innate immune factors that mitigate the impact of viral infections. ( ) early separation disrupts breastfeeding, and not breastfeeding increases the risk of infant hospitalization for pneumonia. early separation decreases breastfeeding duration compared to keeping mothers and infants together. and when infants are not breastfed, they have . times the risk of being hospitalized for pneumonia compared to infants who are exclusively breastfed for ‡ months. separating mother and baby immediately after birth may make the infant more vulnerable to severe respiratory infections, including covid- , in the first year of life. ( ) separate isolation doubles the burden on the health system. separately isolating mother and infant requires twice the resources: two hospital rooms, two provider teams, and two sets of personal protective equipment (ppe) each time a provider enters or leaves the room. in the context of hospital overcrowding and dangerous shortages of ppe, this is deeply problematic. in the united states, technology and clinical science have long been ''normal,'' whereas skin-to-skin contact and rooming in defy the reductionism of western medicine. in contrast, officials at the who remember the lessons of the human immunodeficiency virus epidemic, where recommendations to substitute formula for breastfeeding had devastating consequences in low-income countries. at the time of writing, we have no evidence to show that early separation improves outcomes. as we navigate the covid- pandemic, i am hopeful that we can center mothers and babies and remember to first do no harm. clinical management of severe acute respiratory infection (sari) when covid- disease is suspected. geneva: world health organization interim considerations for infection prevention and control of coronavirus disease (covid- ) in inpatient obstetric healthcare settings neonatal early-onset infection with sars-cov- in neonates born to mothers with covid- in wuhan, china early skin-toskin contact for mothers and their healthy newborn infants randomized controlled trial of skin-to-skin contact from birth versus conventional incubator for physiological stabilization in -to -gram newborns should neonates sleep alone? royal college of paediatrics and child health, et al. coronavirus (covid- ) infection in pregnancy: information for health care professionals salivary cortisol and mood and pain profiles during skin-to-skin care for an unselected group of mothers and infants in neonatal intensive care kinetics of the antibody response to tetanus-diphtheriaacellular pertussis vaccine in women of childbearing age and postpartum women breastfeeding and the risk of hospitalization for respiratory disease in infancy: a meta-analysis current knowledge and future research on infant feeding in the context of hiv: basic, clinical, behavioral, and programmatic perspectives key: cord- - ep authors: el basha, noussa r.; marzouk, huda; sherif, may m.; el kholy, amani a. title: prematurity, a significant predictor for worse outcome in viral bronchiolitis: a comparative study in infancy date: - - journal: j egypt public health assoc doi: . /s - - - sha: doc_id: cord_uid: ep background: the rate of admissions to hospital with bronchiolitis has increased over the past years. the reasons for this are likely to be multifactorial including improved survival of preterm infants. aim: to assess the severity of viral bronchiolitis in preterm compared to term infants admitted at a tertiary hospital in cairo, egypt, based on the outcome. patients and methods: this prospective study was conducted throughout a -year period from september to october . it included infants, healthy preterm, and healthy term infants admitted with clinical diagnosis of bronchiolitis at a tertiary hospital in cairo, egypt. bronchiolitis severity score (bss) was recorded, and nasopharyngeal swabs were obtained from each patient at the time of presentation. viruses were identified using reverse transcription polymerase chain reaction (rt-pcr). the clinical course and patient’s outcome were recorded. results: this study recorded a significantly more severe bss for preterm compared to term infants. the preterm group had an increased mean length of hospital stay and oxygen therapy and was more likely to need intensive care unit admission and mechanical ventilation (mv) compared to the term group. the mean (± sd) bss for infections with h-mpv, rsv, and para-influenza was more significantly severe in preterm compared to term infants. bacterial co-infection was significantly correlated with severity scoring in both groups. conclusion: prematurity significantly affects the severity of bronchiolitis, and this underscores the importance of early categorization as a high-risk group on their first visit. the physician should be aware that their illness runs a more severe course, even if they have no underlying disorders. bronchiolitis is the most common lower respiratory tract infection in children less than year of age and is usually of viral etiology [ ] . human respiratory syncytial virus (rsv) is the most commonly causing virus and identified in - % of hospitalized infant with bronchiolitis [ ] . bronchiolitis by itself accounts for the greatest number of hospitalization in infancy during the fall and winter season [ ] . bronchiolitis is a self-limiting condition but may be life threating causing significant severe illness [ ] [ ] [ ] , and it is the most common cause of hospital admission for infant beyond the neonatal period with rate varying between and %. furthermore, approximately % of hospitalized infants will need intensive care admission [ ] [ ] [ ] [ ] . the rate of admissions to hospital with bronchiolitis has increased over the past years. the reasons for this are not fully understood and are likely to be multifactorial and include improved survival of preterm infants [ ] . epidemiological evidence revealed that young age (less than - weeks) and premature birth (less than weeks) are associated with high risk of severe bronchiolitis [ , , ] . the aim of the present study was to assess the severity of viral bronchiolitis in healthy preterm compared to healthy term infants in terms of the duration of hospital stay, oxygen saturation and duration of oxygen requirement, and icu and/or mv requirement. this prospective study was conducted throughout a -year period from september to october . it included infants in the first year of life with clinical diagnosis of bronchiolitis, according to american academy of pediatrics [ ] , and all were admitted to inpatient departments at the cairo university specialized pediatric hospital. seventy-four of those infants were healthy preterm (less than weeks) and infants were healthy term. the following specific groups were excluded: neonates, recurrent wheeze, and association of underlying chronic diseases. this study was approved by the cairo university clinical research ethics committee, and informed verbal consents were obtained from parents of the included children. the study design conformed to the revised helsinki declaration of bioethics. all patients were subjected to thorough history taking, including demographic data, and also, full physical examination was performed with emphasis on signs of respiratory tract infection. the respiratory severity score that has been used in this study is the modified tal score. this score ranges from to , with a higher score indicating more severe disease. each score is an aggregate of assigned values ranging from to in categories of respiratory rate, retractions, wheezing, and oxygen saturation in room air [ ] . bronchiolitis severity score (bss) was recorded for each patient at the time of presentation. subsequently, during inpatient management, the following data were recorded: the clinical course was observed during the hospital stay including the need for intensive care unit (icu) admission, need for mechanical ventilation (mv), duration of oxygen therapy, and duration of hospital stay. complete blood count (cbc) and c-reactive protein (crp) were determined at the time of study enrollment for each patient. oropharyngeal (op) and nasopharyngeal (np) swabs were obtained for pcr at the time of presentation and put in viral transport media (vtm). total nucleic acid (tna) was extracted from the np/op swabs by the automated kingfisher flex magnetic particle processor (thermo scientific, waltham, usa) using magmax total nucleic acid isolation kit (cat no. am , applied biosystems, foster city, usa) according to the manufacturer's instructions. all the viral targets were amplified using specific primers and probes produced by the center of disease control and prevention (cdc), atlanta, usa, and following standard protocol for quantitative reverse transcription pcr detection. detection of influenza viruses was conducted in the cairo university hospital laboratory and confirmed by the naval medical research unit no. (namru- ) laboratory. the samples were screened for the presence of influenza a and b using the cdc kit for influenza following cdc protocol [ ] . samples positive for influenza a were further subtyped according to the cdc protocol to the following types: pandemic influenza a(h n ) and seasonal h and h . testing for adenovirus; human parainfluenza viruses , , and (hpiv); respiratory syncytial virus (rsv); and human metapneumovirus (hmpv) was done at namru- laboratory by rt-qpcr using cdc specific primers and probes and following a cdc protocol for the detection of non-influenza viruses. samples were considered positive to the viral target if the amplification curve crossed the threshold line before cycle . all clinical samples had to be positive for the human rnase p gene (rp), with a ct value ≤ , for validation. a positive control for each virus was added to each run to ensure adequate amplification of the target genes. precoded data was entered on the statistical package of social science software program, version (ibm spss statistics for windows, version . . armonk, ny, ibm corp.) to be statistically analyzed. data was presented using mean and standard deviation for quantitative variables and frequency and percentage for qualitative ones. comparison between groups was performed using independent sample t test or mann-whitney for quantitative variables and chi-square and fisher's exact test for qualitative ones. spearman correlation coefficient was used to estimate the association between different quantitative variables. p values less than . were considered statistically significant. the study included infants with a clinical diagnosis of acute bronchiolitis in otherwise healthy infants. seventy-nine of them were term and were preterm infants. the detailed demographic characteristics including risk factors for bronchiolitis of both preterm and term infants are summarized in table . preterm infants were significantly younger than term infants (p value . ). clinical findings at the time of presentation, bss, and outcomes of both groups are shown in table . bss (mean ± sd) was significantly more severe for preterm compared to term infants at time of presentation (p value . ). also, preterm group had an increased mean length of hospital stay, and mean duration of oxygen therapy compared to term group (p value . and . , respectively). preterm infants were significantly more likely to need icu admission (p value . ) and mv (p value . ) than term infants. viral screening results are summarized in table . respiratory viruses were detected in ( . %) preterm patients and in ( %) term patients with acute bronchiolitis. rsv was the most commonly detected virus in both groups, although, more significantly frequent in term infants ( %) than preterm infants ( . %) (p value . ). on the other hand, adenovirus was more significantly frequent in preterm than term infants ( . % and . %; respectively, p value . ). concomitantly with the viral respiratory infection, preterm patients had more frequent concomitant bacterial infections than term despite non-significance (p value . ). on comparing bss of different viral agents in preterm and term infants, the mean (± sd) score for h-mpv, rsv, and para-influenza was more significantly severe in preterm compared to term infants (p value . , . , and . , respectively), as shown in table . on correlating bronchiolitis severity score to screened viruses and outcome in both groups mixed viral infection did not correlate with severity scoring of bronchiolitis in preterm and term groups (p value. . , . , respectively). however, bacterial co-infection was significantly correlated with severity scoring in both groups (p value < . ). also, we found significant correlation between bss and need for admission. also, there was significant correlation between severity and duration of hospital stay and oxygen therapy as are shown in table . we identified a viral etiology in . % of preterm infants and in % of term infants hospitalized with acute bronchiolitis; one or more viral pathogens were detected. rsv was the most frequently isolated respiratory virus in both preterm and term infants with bronchiolitis, and adenovirus was the second most frequently detected virus in the current study. the predominance of rsv is in concordance with the assertion that this virus is the single most frequently identified lower respiratory tract pathogen in hospitalized infants worldwide [ ] [ ] [ ] [ ] . although, rsv significantly affects more term infant in this study, yet it is likely to be associated with more severe disease in preterm infants, this observation is important in planning protocols for bronchiolitis prophylaxis and management in such high-risk preterm infants. similarly, h-mpv and para-influenza infections were more severe in preterm than term infants. so, physicians treating preterm infants with rsv, h-mpv, and para-influenza bronchiolitis should be aware that their illness is more protracted and runs a more severe course than term infants, even if otherwise healthy. the low prevalence of virus detection among preterm compared to term infants with acute bronchiolitis in this study could be attributed to other respiratory viruses which were not included in this study such as coronaviruses, bocaviruses, and rhinoviruses, and may be also explained by the fact that only patients admitted with severe infections were included in our study. although there were no significant differences in the length of stay in picu and the duration of mv among preterm and term, these preterm patients had more frequent need to be managed in picu, more frequent need for mv, and more prolonged oxygen therapy and hospital stay than term ones. these findings were in consistence with the study by howidi et al. [ ] . these differences may be explained by smaller airway and/or suboptimal immune response in preterm infants. in addition, the significant difference in age between the two groups could partly explain the higher severity among preterm group. we found also significant correlation between bronchiolitis severity scoring and need of hospital admission, the same as for the duration of hospital stay and duration of oxygen therapy. this was similar to results reported by ricart et al. [ ] who found that severe bronchiolitis had more mean of hospital stay compared to non-severe and more prolonged duration of oxygen and mv. we documented that preterm infants have a more severe form of illness than term infants where we found that prematurity significantly affects the severity score of bronchiolitis. increased illness severity in infants who had bronchiolitis was discussed in several researches [ , ] . in this study, we found that preterm infants were significantly younger than those born term, similar to that reported by fleming et al. [ ] . mixed viral infection and bacterial co-infection in the present study were more frequently observed in preterm compared to term infants with acute bronchiolitis. however, bacterial co-infection was significantly correlated with severity scoring, while mixed viral infection did not correlate with severity scoring of bronchiolitis, and this was in consistence with what was reported by others [ , , ] . this indicates that infection with multiple viruses in infants is a common situation that does not change the clinical course of bronchiolitis. however, some studies have reported an increased risk for severe bronchiolitis in dual viral infection [ ] [ ] [ ] or even in some specific viral infections such as rsv and h-mpv co-infection [ ] [ ] [ ] . although respiratory viruses seem to be related to increased risk of severe disease, our data suggest that prematurity have more specific weight in predicting bronchiolitis outcome. so, understanding host susceptibility and immune response of preterm infants to these viruses, as well as targeting the prevention of infection with these viruses in preterm infant, may have even broader implications than only focusing on their role in disease morbidity. limiting this study is a possible underestimation of viral etiologies of acute bronchiolitis because testing for rhinoviruses, coronaviruses, and other viruses was not done, and these viruses were previously detected in such patients [ ] [ ] [ ] [ ] . also, the enrolled patients were from a single tertiary institution which is a referral center for many local hospitals, so enrolled cases may be more ill than those at other hospitals. the enrolled patients were inpatients only, while patients with mild respiratory symptoms did not undergo diagnostic testing for viral infections; they were treated in outpatient clinics and this could further direct results towards a more severe population and could influence the scores. prematurity is one of the risk factors that significantly affect the bronchiolitis severity, and this underscores the importance of early categorization of these infants as a high-risk group on their first visit. physicians treating preterm infants with bronchiolitis should be aware that their illness runs a more severe course than term infant, even if they have no underlying disorders. authors would acknowledge all patients included in this study. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors' contributions nreb and hm have conducted, analyzed, and drafted the manuscript of this study. mms and aaek have performed the laboratory workup. all authors read and approved the final manuscript. ethics approval and consent to participate this study was approved by cairo university clinical research ethics committee, and informed verbal consents were obtained from parents of the included children. informed verbal consent has been obtained because most of our patient guardian's are uncomfortable with reading and writing and may be too embarrassed by the written consent process to participate in a research. this informed verbal consent has been approved by cairo university clinical research ethics committee as it covers the basic elements of the consent process that include full disclosure of the nature of the research, adequate comprehension on the part of the potential participant, and the participant's voluntary medical retrieval and needs of infants with bronchiolitis: an analysis by gestational age detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study respiratory syncytial virus coded pediatric hospitalizations the cochrane library and the treatment of bronchiolitis in children: an overview of reviews. evid based child health bronchiolitis among infants under year of age in france: epidemiology and factors associated with mortality bronchiolitis: recent evidence on diagnosis and management the clinical and health economic burden of respiratory syncytial virus disease among children under years of age in a defined geographical area complications in infants hospitalized for bronchiolitis or respiratory syncytial virus pneumonia impact of severe disease caused by respiratory syncytial virus in children living in developed countries viral bronchiolitis for children severity of respiratory syncytial virus bronchiolitis is affected by cigarette smoke exposure and atopy factors associated with disease severity in children with bronchiolitis risk factors for hypoxemia and respiratory failure in respiratory syncytial virus bronchiolitis american academy of pediatrics subcommittee on diagnosis and management of bronchiolitis severity scoring systems: are they internally valid, reliable and predictive of oxygen use in children with acute bronchiolitis? information for molecular diagnosis of influenza virus in humans-update. geneva: who frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections detection of a broad range of human adenoviruses in respiratory tract samples using a sensitive multiplex real time pcr assay adenovirus pneumonia in infants and factors for developing bronchiolitis obliterans: a -year follow-up the burden of respiratory syncytial virus infection in young children the severity of respiratory syncytial virus bronchiolitis in young infants in the united arab emirates clinical risk factors are more relevant than respiratory viruses in predicting bronchiolitis severity acute viral bronchiolitis in south africa: strategies for management and prevention human metapneumovirus infections cause similar symptoms and clinical severity as respiratory syncytial virus infections prevalence and clinical characteristics of human metapneumovirus infections in hospitalized infants in spain respiratory syncytial virus, human bocavirus and rhinovirus bronchiolitis in infants impact of human metapneumovirus and respiratory syncytial virus co-infection in severe bronchiolitis the impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis human metapneumovirus infection in young children hospitalized with respiratory tract disease human metapneumovirus in severe respiratory syncytialvirus bronchiolitis coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus human bocavirus and acute wheezing in children epidemiological, molecular, and clinical features of enterovirus respiratory infections in french children between and emerging respiratory agents: new viruses for old diseases? choice to participate. the study design conformed to the revised helsinki declaration of bioethics. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -vrs je x authors: powers, karen s. title: acute pulmonary infections date: - - journal: pediatric critical care study guide doi: . / - - - - _ sha: doc_id: cord_uid: vrs je x acute lower respiratory infection is a common cause of morbidity in infants and children, and at times, requires intensive care and mechanical ventilation. viral bronchiolitis and bacterial pneumonia account for the majority of lower respiratory tract infections that lead to respiratory insufficiency and pediatric intensive care admission. twenty-seven percent of children who require mechanical ventilation for at least h in pediatric intensive care units are diagnosed with bronchiolitis and % have the diagnosis of pneumonia. the median length of time intubated for an acute pulmonary infection leading to respiratory failure is approximately days. acute lower respiratory infection is a common cause of morbidity in infants and children, and at times, requires intensive care and mechanical ventilation. viral bronchiolitis and bacterial pneumonia account for the majority of lower respiratory tract infections that lead to respiratory insuffi ciency and pediatric intensive care admission. twenty-seven percent of children who require mechanical ventilation for at least h in pediatric intensive care units are diagnosed with bronchiolitis and % have the diagnosis of pneumonia. the median length of time intubated for an acute pulmonary infection leading to respiratory failure is approximately days. viral bronchiolitis remains the leading cause for hospital admission in infancy and the most frequent cause of acute respiratory failure in children admitted to pediatric intensive care units in north america. pneumonia in children younger than years of age has an annual incidence karen s. powers of - cases per , . community acquired pneumonia can also lead to severe respiratory compromise especially in children with pre-existing disease. a detailed understanding of the diverse etiologies and distinct clinical courses of acute pulmonary infections is essential for the pediatric critical care practioner. this chapter will focus on bronchiolitis and pneumonia as the two leading causes of pulmonary infections leading to picu admission. approximately one third of children develop bronchiolitis during the fi rst years of life. of these, only in ( % of all infants in the united states) will require hospitalization. although hospitalization rates have increased over the last three decades, mortality remains low. overall mortality rate is - %, but as high as % in high risk infants. most deaths occur in infants younger than months of age with co-morbidities such as prematurity, congenital heart disease, congenital or acquired lung disease or immunodefi ciency. respiratory syncytial virus (rsv) was fi rst isolated in and still represents the major cause of bronchiolitis. other causative viruses include parainfl uenza, adenovirus, enterovirus, infl uenza and most recently human metapneumovirus and human bocavirus (hbov). in the northern hemisphere, rsv outbreaks occur from october to june. human metapneumovirus (hmpv) recently has been identifi ed as the causative agent in - % of bronchiolitis cases, possibly surpassing parainfl uenza as the second most common etiology. its prevalence is slightly higher in the late winter and spring. parainfl uenza infections peak at months of age, representing approximately - % of cases of bronchiolitis. parainfl uenza (piv- ) is endemic throughout the year, but especially common in the late spring. males are . - times more likely to require hospitalization for bronchiolitis and are likely to have more severe disease. an x-linked genetic trait that results in a reduced tolerance to hypoxia has been postulated and would be consistent with the observation of increased mortality in newborn males with infant respiratory distress syndrome. virtually all children by the age of two will have been infected with rsv, all children by the age of fi ve will have been infected with hmpv, and all children by the age of nine will have been infected with hbov. the remainder of the discussion on bronchiolitis will be divided into rsv and non-rsv bronchiolitis. although etiologic agents may differ, clinical courses are often similar. respiratory syncytial virus (rsv) accounts for - % of bronchiolitis, infecting one-half of all infants within the fi rst year of life and hospitalizing approximately , infants yearly (about % of affected infants). approximately % of these infants require mechanical ventilation. co-infection with either hmpv or rhinovirus occurs in - % of young children. two types of rsv exist -types a and b. type a is more common and is believed to cause more severe disease, although data is not conclusive. both types may exist simultaneously in the community. infants less than year will typically shed the virus for about days. children with immunodefi ciencies may shed the virus for months. the immune response varies with age and contributes to both termination of the disease and its pathologic features. the virus is transmitted from respiratory secretions by close contact with infected persons or by contact with contaminated objects or surfaces. there is a % rsv transmission rate within families and about one-half of hospital workers will acquire rsv. therefore, hand washing and the wearing of gowns and gloves is of primary importance to attenuate transmission. mortality from rsv bronchiolitis continues to decline with better intensive care and the use of preventive therapies. male infants are more likely to require hospitalization and usually manifest more severe disease. about ½ of all infants will be infected with rsv bronchiolitis in their st year of life; % will be hospitalized; % of hospitalized infants will require mechanical ventilation. antibody-mediated immunity rsv introduced onto the nasal or conjunctival mucosal surface causes profuse rhinorrhea within a few days. during the fi rst months of life, passively acquired maternal antibodies are protective. however, as maternal antibody titers gradually decrease, infants become susceptible to severe disease. cell-bound iga may develop to help clear the virus. circulating igg directed against the glycoprotein (g) and fusion (f) proteins (operative in syncytia formation) on the viral surface will develop several days later. infants less than months of age appear to induce a weaker antibody response likely due to the presence of maternal antibodies. virus-specifi c ige in the respiratory tract is associated with disease severity. often, complete and effective immune responses are not induced, thus re-infections are possible even during the same season. epithelial cells and alveolar macrophages are key activators of cellular immunity. although these cells enhance viral clearing, they also contribute to airway infl ammation through the release of cytokines and chemokines. these include interleukin (il)- , tumor necrosis factor-alpha, il- , il- , macrophage-infl ammatory protein (mip)- -alpha and rantes (regulated upon activation, normal t cell expressed and secreted). release of these cytokines and chemokines are believed to be partially responsible for airway infl ammation and hyperreactivity. the effects of these mediators persist beyond the acute infection and contribute to prolonged pulmonary dysfunction. children who require mechanical ventilation have lower peripheral t cell counts compared to hospitalized infants not requiring mechanical ventilation. these infants demonstrate low t cell proliferative responses and interferon (ifn-g ) production. il- is required for the initiation of cellular immunity. the length of time requiring mechanical ventilation has been found to be inversely related to il- production. the role of th /th -like cytokine profi les, expressed as ifn-g /il- ratios, is controversial. in some studies, these ratios decreased after polyclonal stimulation in hospitalized infants with rsv. however, more recent studies have shown normal ratios following polyclonal stimulation. neutrophils are the predominant cell found in the airways of infants with rsv bronchiolitis. elevated levels of il- are found in high concentrations in the nasal secretions of infected children and act as a neutrophil chemoattractant. further evidence of cellular induced injury is seen in post-mortem examination where peribronchial lymphocyte infi ltration with bronchial epithelial necrosis is typically present. infants typically present with tachypnea, rhinorrhea, cough, low-grade fever, irritability, poor feeding and vomiting. respiratory rates greater than breaths per minute are often associated with room air saturations of less than %. infants may also have tachycardia, mild conjunctivitis, otitis media, or pharyngitis. low-grade fever usually persists for - days. in addition, infants may develop a metabolic acidosis from poor caloric and fl uid intake. apnea often is the fi rst presenting symptom of rsv bronchiolitis in small infants. the etiology of apnea remains unknown; however, is likely related to the immaturity of the respiratory control center in the brainstem. the incidence of apnea in infants with bronchiolitis is approximately - %. the heterogeneous nature of rsv induced lung disease can cause atelectasis in some areas and overdistension in others. chest roentgenograms often show hyperinfl ation with fl attening of the diaphragms and patchy or peribronchial infi ltrates. atelectasis, especially of the right upper lobe, is often seen. infants may have high lung volumes with the functional residual capacity often being twice normal. the decrease in dynamic compliance and increase up regulation of the infl ammatory cascade with release of chemokines and cytokines are contributory to the airway infl ammation and hyperreactivity. c hapter • ac ute pu lmonary i n fections in airway resistance leads to marked increase in work of breathing, often worse during expiration from lower airway obstruction. alterations in gas exchange and hypoxemia are secondary to a ventilation-perfusion mismatch. the anatomical differences between young infants and older children contribute to the severity of the disease in the young. due to the highly compliant cartilaginous chest wall and poor thoracic musculature, the infant's chest wall has diffi culty countering the lung's inherent tendency towards collapse. this leads to a greater propensity of small infants towards atelectasis compared with older children. the absence of effective collateral ventilation in infants also contributes to the development of atelectasis and impaired gas exchange. cellular debris in small airways and peribronchial edema increase airways resistance leading to wheezing as the predominant symptom in some infants. despite the potential for severe impairment in lung function, most hospitalized infants improve within - days. typically, by weeks, they have normal respiratory rates, oxygenation, and ventilation. chest radiographs usually normalize by day . however, about % of infants will have a protracted course, with some mild respiratory symptoms persisting for months. viral respiratory infections have been linked to the development of asthma later in childhood. the tucson children's respiratory study group prospectively followed for years, infants who had bronchiolitis and found an increased risk for subsequent wheezing episodes. some infants are at an increased risk for severe rsv disease such as those with chronic lung disease due to prematurity (bronchopulmonary dysplasia), cystic fi brosis, congenital heart disease, and immunodefi ciencies. in children with cystic fi brosis, rsv accounted for % of symptomatic infections, % of hospitalizations for infants less than year, and % of infants requiring mechanical ventilation. in a study of hospitalized infants with congenital heart disease infected with rsv, % required intensive care, % received mechanical ventilation, and . % died. children having undergone hematopoietic stem cell transplants who develop rsv infections have an extremely high mortality of - % despite mechanical ventilation and antiviral therapy. environmental factors such as crowding, passive exposure to tobacco smoke, and lack of breast-feeding are associated with the development of severe disease. compared to national averages, native american and alaskan children younger than year of age have higher rates of infections. there are three subtypes of human parainfl uenza viruses. hpiv- is most frequently isolated from children with bronchiolitis, while piv- and piv- most commonly cause croup. similar to rsv, both cell-mediated hyper-responsiveness to viral antigen and virus-specifi c ige responses are observed in children with parainfl uenza bronchiolitis. upper airway edema with concomitant obstructive symptoms may be present. children that are infected with parainfl uenza have a signifi cant likelihood of developing asthma later in life. the human metapneumoviruses (hmpv) are a group of rna viruses of the paramyxoviridae family identifi ed in humans in . hmpv appears to be the second most common cause of bronchiolitis in children throughout the world. the majority of children are born with maternal hmpv specifi c igg which wanes to around % by - months of age. by age fi ve, essentially % of children have been exposed to hmpv and will have neutralizing antibody to hmpv. there are two subgroups, a and b, with group a having more severe clinical symptoms. clinical presentation of children with this virus is similar to rsv. the pulmonary infl ammation generally peaks on day which includes interstitial edema and infl ammatory cell infi ltrates of the bronchioles and alveoli. these infl ammatory changes can persist for up to days. about half of infected children are - months of age, and infection is primarily in the winter months. human bocavirus (hbov) was recently discovered in . with amino acid sequencing, this new member of the parvoviridae family was found to be closely related to the bovine parvovirus and the canine minute virus, hence the name bocavirus (bo for bovine and ca for canine). detection of the hbov from the respiratory tract in symptomatic children and its absence of detection in non-symptomatic controls strongly suggest the virus to have a role in respiratory infections in children. co-infection is commonly described in up to % of samples. it remains unclear if hbov is a primary pathogen or acts to exacerbate other viral illnesses. the pathogenesis of hbov has not been well described, but with the high occurrence of wheezing and lower respiratory tract symptoms in children infected with the virus, it is speculated that this virus may be a signifi cant contributor to asthma exacerbations. the majority of infected children have rhinorrhea, cough, and wheezing, however, diarrhea has been reported in up to % of these children. in children with high viral loads, hbov has been detected in the serum suggesting the potential for disease beyond the respiratory tract. both infl uenza a, including novel infl uenza strains such as h n , and infl uenza b can cause a clinical picture consistent with bronchiolitis in the small infant. these viruses may cause severe multisystem disease and are discussed in greater detail in the viral pneumonia section. rapid diagnostic assays are available for early detection of many viruses. the older assays are antigen-based and include indirect immunofl uorescence/direct immunofl uorescence (ifa/ dfa), enzyme immunoassay (eia), optical immunoassay (oia), and neuraminidase activity assays. although still widely used because they are inexpensive and technically simple, they have a low specifi city and sensitivity. molecular assays are becoming the new "gold standard" for respiratory virus detection -replacing tissue culture that may take days. the published sensitivities and specifi cities approach % when compared to tissue culture or antigen assay. these assays generally use polymerase chain reaction (pcr) amplifi cation. signifi cant advancements in these assays are being made to simplify the performance of the assay and decrease the required time. the most important cause of false negative test results remains poor specimen handling or inadequate sample collection. other than aiding with cohorting of hospitalized patients, serologic detection of respiratory viruses is rarely clinically useful. regardless of the viral etiology of bronchiolitis, supportive care remains the mainstay of treatment. supplemental humidifi ed oxygen is frequently needed. due to many infants being obligate nasal breathers, frequent nasal suctioning may be benefi cial to maintain an unobstructed upper airway. the affected infant or child is often unable to take adequate fl uids complicated by increased insensible losses from the respiratory tract; hence, intravenous fl uids may be required. infants and children with severe respiratory distress should be kept npo in the event respiratory failure ensues and endotracheal intubation is required. antibiotics are not routinely indicated in previously healthy children infected with rsv. progressive disease, leukocytosis, persistent fever, consolidation on radiograph or systemic toxicity should prompt an evaluation of bacterial co-infection and the use of empiric antibiotics. high risk patients often require close monitoring and care in an intensive care unit. these include infants less than weeks of age or infants with a history of prematurity, congenital heart disease, bronchopulmonary dysplasia, immunodefi ciency or neurologic disease. infants with rsv bronchiolitis typically have a combination of hyperinfl ation, pulmonary infi ltrates, supportive therapy is the mainstay of treatment for bronchiolitis. ribavirin, bronchodilators, and corticosteroids have not shown to be of benefi t. secondary bacterial infections are rare. and atelectasis. therefore, no one mode of ventilation can be recommended for all infants. non-invasive positive pressure (niipp) modes (cpap or bipap) may be attempted in infants where their primary respiratory embarrassment is secondary to atelectasis. however, this may not be suitable if the disease process appears severe or protracted as prolonged use of nipp may make feeding diffi cult, cause breakdown of facial tissue, or be diffi cult to maintain without signifi cant sedation that further compromises ventilation. if an infant requires endotracheal intubation, the mode of mechanical ventilation should be tailored to the predominant lung pathology present (i.e. atelectasis versus hyperinfl ation). children with signifi cant air trapping may need mechanical ventilation similar to a child with asthma, providing low respiratory rates and longer inspiration and exhalation times. the more typical infant will lose functional residual capacity (frc) because of atelectasis and alveolar infi ltrates. therefore, despite having some air trapping, these infants often need peep to be adjusted to recruit alveoli and return frc to normal. in the setting of elevated pulmonary vascular resistance (pvr) which may occur in infants with congenital heart disease or bronchopulmonary dysplasia, lowering pvr by traditional methods such as maintaining oxygenation, deep sedation, muscle relaxation and even nitric oxide may be indicated. ribavirin is the only fda-approved antiviral drug for rsv. ribavirin inhibits viral replication and is active against rsv, infl uenza a and b, adenoviruses, and hepatitis viruses. for lower respiratory tract diseases, ribavirin is typically administered via aerosolization. in , a meta-analysis of studies involving ribavirin was discouraging and was consistent with the common clinical experience that ribavirin did not improve clinical outcomes. therapy targeted at attenuating the virus-induced infl ammatory cascade has also been disappointing. corticosteroid administration was not associated with reduction in clinical scores, the need for hospitalization, or the length of hospitalization. routine use of any corticosteroid given via any route (intravenous, enteral or aerosolized) is not indicated, except in patients with pre-existing chronic lung disease. bronchodilators have not shown a clear benefi t in patients with acute rsv bronchiolitis. in randomized control trials, involving infants, evaluating the effect of salbutamol or albuterol on bronchiolitis, ( %) showed no effect. the remaining three studies demonstrated only a small transient improvement in the acute clinical score. although the routine use of bronchodilator therapy cannot be recommended, it has become acceptable practice to attempt to see if individual infants are beta agonist responsive or not. if no clinical response is seen after a trial of a beta agonist, its use should be discontinued. in the s, fi ve randomized trials involving infants, evaluating the effect of nebulized adrenaline (epinephrine) on bronchiolitis showed clinical improvement, with reductions in oxygen requirement, respiratory rate, wheezing, and decrease in pulmonary vascular resistance. two of these studies showed lower hospital admission rates and earlier discharge. a cochrane systematic review suggested a potential benefi t with epinephrine administration. however, subsequent studies have not supported its routine use. as with albuterol, a clinical trial in selected infants seems reasonable. nebulized hypertonic saline has been used for treating hospitalized, as well as ambulatory, children with viral bronchiolitis with variable success. a recent cochrane meta-analysis of nebulized hypertonic saline has shown an improvement in clinical scores and decrease in hospital duration. several studies have evaluated the benefi t of surfactant and nitric oxide for severe respiratory distress. the results have been inconclusive and do not currently support their routine use. heliox, a mixture of oxygen ( - %) and helium ( - %) with lower viscosity than air has been used successfully in cases of airway obstruction, croup, airway surgery, and asthma to reduce respiratory effort during the period of airway compromise. several studies have shown improved respiratory distress scores in patients on heliox with continuous positive airway pressure obviating the need for intubation and mechanical ventilation. palivizumab is a neutralizing humanized mouse monoclonal antibody directed against the rsv-f glycoprotein. it was licensed by the food and drug administration (fda) in for premature infants and infants with bronchopulmonary dysplasia. the randomized, double blind, placebo controlled impact-rsv trial involving , high risk infants found a signifi cant reduction of % in hospitalizations. with the exception of very rare anaphylaxis, no signifi cant adverse effects have been observed. palivizumab has been approved for use in infants with congenital heart disease. the cardiac synagis study group included , children with congenital heart disease in a randomized, double blind, placebo controlled trial; it found a % relative reduction in rsv associated hospitalizations with no deaths attributable to the palivizumab. since cardiopulmonary bypass can decrease serum drug concentrations by about %, it is recommended that an additional dose be given following surgery, if continued protection is desired. palivizumab should be administered intramuscularly as mg/kg every days for a total of fi ve doses during rsv season, which is generally from november through march, to high risk infants. infants or children that develop an rsv infection should continue to receive prophylaxis following recovery because the naturally acquired antibodies are not fully protective. motavizumab, a new, enhanced potency, humanized rsv monoclonal antibody has demonstrated - times greater neutralizing activity against rsv. in completion of a phase iii trial, motavizumab was found equal to palivizumab for the prevention of rsv hospitalization and superior to palivizumab for reduction of rsv-specifi c outpatient medically attended lower respiratory tract infections (malris). pneumonia describes any infl ammatory condition of the lung in which the alveoli are compromised by aspirated foreign matter, infl ammatory fl uid, or cellular debris. infection is the primary cause of parenchymal injury to the lung. pathogens include viruses, bacteria and fungi. signs and symptoms of pneumonia are non-specifi c and may be occult in the young infant. children often have fever, chills, headache, malaise, restlessness, and irritability. gastrointestinal complaints such as abdominal pain, distention, or emesis may also be present in young children. the symptoms are often preceded by minor upper respiratory tract infections characterized by low-grade fever and rhinorrhea. with more signifi cant involvement of the lower respiratory tract, tachypnea, dyspnea, cough, nasal fl aring, grunting, or retractions may be seen. the older child may demonstrate productive sputum and complain of pleuritic chest pain. on auscultation of the chest, rales and/or decreased breath sounds might be heard over areas of consolidation or pleural effusions. however, due the short path for transmission of breath sounds and the small chest size in infants, breath sounds may not be decreased, even in the presence of effusions. children with pleural irritation might prefer to lie on the affected side with legs fl exed and may complain of radiating pain to the neck and shoulder or into the abdomen. community acquired pneumonia (cap) is a common, and at times, a serious infection in children. the incidence of cap is - cases per , children less than years of age and - cases per , children - years of age. the exact prevalence of the etiologic agents causing pediatric pneumonia is diffi cult to ascertain. it is often diffi cult to differentiate viral from bacterial pneumonia based solely on clinical examination. specifi c pathogens causing cap can be determined in only approximately one-third of children using commonly available cultures, antigen detection, or serologic techniques. blood cultures yield pathogens in only about - % of infants and children with bacterial cap and many children do not undergo viral testing as it is often unnecessary. with these inherent limitations, it is generally thought that viruses account for approximately % of cap in children under the age of years and approximately % of cap in preschool children ages - years. palivizumab should be used as preventive therapy in infants with chronic lung disease and congenital heart disease. cardiopulmonary bypass signifi cantly lowers the serum level of palivizumab, so it should be redosed following surgery if continued protection desired. viral causes decline in the school age and adolescent child and bacterial causes such as streptococcus pneumoniae and mycoplasma become important pathogens ( fig. - ) . overall, bacteria account for - % of community-acquired pneumonias. the likelihood of infection with different bacteria varies by age. in the newborn period, organisms from the maternal genital tract are likely causes and include group b streptococcus , escherichia coli , enteric gram-negative bacilli, listeria , and chlamydia . in older infants, streptococcus pneumoniae becomes a signifi cant cause and remains so until years of age. group a streptococcus and staphylococcus aureus are uncommon causes. moraxella catarralis is a common cause of upper respiratory tract disease, but rarely causes pneumonia. about % of infants with pertussis will have bacterial co-infection. in children older than years of age, streptococcus pneumoniae remains the most common cause. hemophilus infl uenzae type b (hib), and most recently streptococcus pneumoniae , have decreased signifi cantly as causes of cap due to the widespread use of effective vaccines. in the older child and young adolescent, the atypical pneumonias, mycoplasma and chlamydia , become more prevalent and viral causes less common. rare bacterial pneumonias can occur with animal contact and include: francisella tularensis (rabbits); chlamydia psittaci (parrots and birds); coxiella burnetii (sheep); and salmonella choleraesuis (pigs). children with congenital anatomical defects, immunodefi ciencies, and genetic disorders are at increased risk for bacterial, viral and fungal pneumonia. the airways are normally sterile below the sublaryngeal area to the lung parenchyma. there are several protective mechanisms that include anatomic and mechanical factors, local immune defenses, and the systemic immune response. microbes are fi ltered by nasal hairs or are expelled from the airways by the epiglottic refl ex, cough refl ex, and mucociliary apparatus. immunoglobulin a (iga) is the predominant immunoglobulin present in the upper respiratory tract. iga is able to bind two antigens simultaneously, forming large antigen-antibody complexes. in this manner, the microbes are neutralized and removed by ciliary clearance, thus preventing microbial binding to the epithelium. in the lower tract, immunoglobulin g (igg) provides humoral protection by opsonizing microbes for phagocytosis by neutrophils and macrophages, activating the complement cascade, and by neutralizing bacterial it is diffi cult to determine the etiologic agent causing pneumonia, but when microbial agents are identifi ed, bacteria are isolated in - %. etiology of community acquired pneumonia based on age endotoxin. alveolar macrophages produce superoxide anions, hydrogen peroxide, and hydroxyl radicals that serve an important role in the host defense; however, uncontrolled production can lead to lung injury. in addition to oxygen radicals, a number of cytokines are produced by the alveolar macrophages. these include il- , il- , tnf, transforming growth factor-β (tgf-b ), chemotactic factors, platelet derived growth factor, and m-csf. these cytokines play a central role in phagocytic recruitment and activation. infection occurs when one or more of the defense mechanisms is altered or if the inoculum is too large. pathogens typically gain entry through inhalation of aerosolized material or through aspiration of resistant organisms inhabiting the upper airways. less frequently, pneumonia can occur via hematogenous spread. in children with bacterial pneumonia, a signifi cant portion will have a concurrent or preceding viral infection. viral infection may predispose to bacterial superinfection by reducing clearance mechanisms and by weakening the host immune response. pathogens entering the lower airways evoke an exudative consolidation of pulmonary tissues. initially, there is hyperemia of lung parenchyma due to vascular engorgement and capillary leak causing exudation and intra-alveolar fl uid accumulation. fibrin is then deposited and the airways are infi ltrated with neutrophils. consolidation causes a decrease in lung compliance and vital capacity and a total reduction in the surface area available for gas exchange. a physiologic shunt (v/q mismatch) occurs as there is increased blood fl ow through poorly ventilated segments of lung, resulting in hypoxia. compensatory hypoxic vasoconstriction may occur in an attempt to reduce v/q mismatch and hypoxia, especially in localized areas of consolidation. with treatment, resolution of consolidation will occur in - days. the exudate undergoes enzymatic digestion and is either reabsorbed or removed by coughing. if the bacterial infection extends into the pleural cavity, an empyema may result. streptococcus pneumoniae is a gram-positive diplococcus that is frequently found in the upper respiratory tract. there are over capsular serotypes with % of infections caused by serotypes. it is the most common bacterial cause for pneumonia occurring at a peak age of - months. typically, it causes a lobar or segmental consolidation, but it may manifest as patchy infi ltrates in infants. pleural effusions occur in up to % of children that require hospitalization (fig. - ) . pneumatocoele formation is rare. hemolytic uremic syndrome is associated with neuraminidase-producing strains. treatment is typically with a penicillin or cephalosporin. emerging resistance may require initial therapy with vancomycin. in hospitalized patients, parenteral therapy is generally needed for - h after fever resolves, followed by completion of - days of enteral therapy. pneumococcal conjugate vaccines (pcv) have been developed that confer immunity against and serotypes. the -valent pcv (prevnar) was licensed for use in the united states in . a -valent pcv has been recently introduced and will replace the -valent pcv. the pcvs have been highly effective at reducing hospitalizations among children younger than years for pneumococcal pneumonia. pcv is now recommended universally for children younger than months of age and older children at high risk due to underlying diseases. high risk children include those with sickle cell disease and other types of functional asplenia, human immunodefi ciency syndrome, primary immunodefi ciency, children receiving immunosuppressive therapy, and children with chronic pulmonary or cardiac disease. a -valent pcv is available for pneumonia occurs when one or more of the host defense mechanisms are altered. viruses enhance the host susceptibility to bacterial pathogens by affecting clearing mechanisms and by weakening the host immune response. streptococcus pneumoniae is the most common bacterial cause for pneumonia. c hapter • ac ute pu lmonary i n fections high risk children who need expanded serotype coverage. children with sickle cell disease or functional asplenia should continue to receive antibiotic prophylaxis regardless of whether or not they have received pneumococcal vaccines. approximately - % of infants born to chlamydia trachomatis -infected mothers will become infected at one or more anatomical site, including conjunctiva, nasopharynx, rectum, and vagina. about % of infants with nasopharyngeal infections will develop pneumonia. the infants usually present at about - weeks of age with cough and congestion, but an absence of fever. the cough often interferes with the ability to feed. infants generally have tachypnea and rales on examination and chest x-ray frequently shows hyperinfl ation. a peripheral eosinophilia may be present. c . trachomatis is susceptible to macrolides, tetracyclines, quinolones, and sulfonamides. erythromycin for - weeks is the treatment of choice for neonatal pneumonia. mycoplasma pneumoniae and chlamydia pneumoniae play a greater role in causing respiratory tract disease in children then previously thought. an indolent course that develops over - days manifested by low-grade fever, scratchy sore throat, aches, and headaches characterizes both pathogens. after a few days, rales may be heard, particularly in the bases where the infi ltrates tend to occur. these organisms have been associated with the initiation, promotion, and exacerbation of asthma in children. in addition, a pertussis-like illness with acute bronchitis has been described. a recent study has shown that nearly half of the cases of community-acquired pneumonia in children aged - years were associated with m . pneumoniae or c . pneumoniae . classic atypical pneumonias caused by these organisms are usually mild and self-limited. however, a number of studies have suggested that severe pulmonary infection may occur in otherwise healthy children. pleural effusions, pneumatocoeles, lung abscesses, pneumothoraces, bronchiectasis, chronic interstitial fi brosis, and acute respiratory distress syndrome although rare complications, have all been reported. serological testing is the most common means of diagnosis, but this is often retrospective. cultures obtained from swabbing the nasopharynx may take several days to grow. pcr techniques are currently being refi ned and standardized. treatment with antibiotics reduces the rate of recurrent wheezing episodes, decreases morbidity, and shortens the duration of symptoms. the organisms are susceptible to tetracyclines, macrolides, and quinolones. the optimal doses and duration of treatment is unclear; however, some data suggest that prolonged treatment for greater than weeks may be more desirable to decrease symptoms and eradicate the organism from the nasopharynx. chlamydia pneumoniae have an increased prevalence in older children. chest radiograph of year old female with streptococcus pneumoniae pneumonia. note the combination of consolidation and effusion affecting the right lung. (image provided courtesy of fa maffei) staphylococcus aureus is a gram-positive organism that can be found on the skin, nasal mucosa, and other mucus membranes. about - % of children are carriers. it is generally spread by direct contact or by respiratory particles. s . aureus is an unusual cause of lower airway disease in otherwise healthy children. it is more typically isolated from infants and young children with debilitating conditions. primary s . aureus pneumonia presents in the winter or early spring with a short febrile prodrome and a rapid onset of pulmonary symptoms. blood cultures are positive in - % of patients. secondary staphylococcal pneumonia will have a more prolonged prodrome with no seasonal predilection, but is often seen after infl uenza infections. as this secondary pneumonia is usually a result of hematogenous spread, blood cultures are positive in about % of patients. unilateral lobar disease is more typical with primary disease, while diffuse bilateral infi ltrates are more frequent with secondary pneumonia. effusions can be diagnosed in about % of children at presentation, but ultimately will develop in about % of cases. pneumatocoeles occur in up to - % of children. treatment is with nafcillin or oxacillin, but more organisms are becoming resistant and require therapy for serious or invasive disease with vancomycin, linezolid, daptomycin, or quinupristin-dalfopristin. methicillin resistant staphylococcus aureus (mrsa) was once considered to be restricted to hospitals and long-term care facilities. however, community acquired mrsa (ca-mrsa) is now a signifi cant cause of a variety of infections (including pneumonia) in children without prior health care facility exposure. the majority of community acquired mrsa infections involve minor skin and soft tissue infections, but invasive and sometimes fatal infections can occur in otherwise healthy individuals. ca-mrsa and healthcare-associated mrsa (ha-mrsa) can be distinguished by several important features. patients with ca-mrsa by defi nition have not had recent hospitalization (acute or chronic care), prolonged antibiotic use or chronic underlying disease. toxin production also distinguishes ca-mrsa from ha-mrsa. panton valentine leukocidin (pvl) is a toxin which is present in most ca-mrsa isolates, but rarely in ha-mrsa isolates. pvl toxin lyses white blood cells leading to leukopenia and a decreased ability to kill s . aureus . its production has been implicated as a contributor to the development of ca-mrsa necrotizing pneumonia. ca-mrsa isolates, unlike ha-mrsa, lack multi-drug resistance. ca-mrsa is generally more susceptible to clindamycin, trimethoprim-sulfamethoxazole and doxycycline than ha-mrsa, probably because ha-mrsa has developed resistance to survive in the healthcare setting. group a betahemolytic streptococcus (gabhs) is a gram-positive organism responsible for about % of pharyngitis and tonsillitis in children. it is rare as a primary cause of pneumonia. when it does occur, the children generally have high fever and appear toxic. the pneumonia is typically lobar. associated empyemas are common and pneumatocoeles may develop. there are several virulent toxin-producing gabhs m-serotypes that are associated with toxic shock syndrome. pre-existing varicella disease with disruption of skin and soft tissue as the port of entry is reported approximately - % of the time. an associated pneumonia occurs in - % of children with toxic shock syndrome. gabhs are highly susceptible to penicillins and cephalosporins. in cases of toxic shock, clindamycin is often added to inhibit the production of streptococcal pyrogenic exotoxins a (spe-a) and b (spe-b). about - % of infants with perinatally acquired group b streptococcus (gbs) infections will have pneumonia. the infant usually has systemic disease and blood cultures are frequently positive. late-onset gbs is predominantly caused by the type iii serotype. in these infants, the infection is usually manifest as bacteremia without a focus or with meningitis. pneumonia is rare in late-onset disease. gbs is uniformly sensitive to penicillin. while staphylococcus aureus pneumonia is uncommon, effusions ultimately develop in about % of cases and pneumatocoeles occur in - %. pertussis, or "whooping cough" is a highly contagious respiratory tract infection caused by the gram-negative pleomorphic bacillus bordetella pertussis and less commonly bordetella parapertussis . with the development and widespread use of a vaccine in the s, a significant and sustained decrease in incidence has occurred. however, despite immunization rates greater than %, cyclical recurrences of the disease have occurred every - years since the s. this is likely secondary to the waning of immunity in adolescents and young adults. under-immunized or unimmunized infants are the most vulnerable. nearly all deaths reported from pertussis occur in infants younger than months of age. pertussis is often divided into catarrahal (fever, rhinnorhea and initiation of cough), paroxysmal (severe coughing episodes, lymphocytosis, potential for complications) and convalescent stages (slow waning of cough over weeks to months). complications include secondary bacterial or viral pneumonia, apnea, malnutrition, pulmonary hypertension and neurologic involvement including seizures and encephalopathy. infants less than months of age are at highest risk for complications and mortality. characteristic paroxysms of cough with an end inspiratory whoop occur in children. infants may present with a nonspecifi c cough with associated apnea and cyanosis, without a whoop. adolescents may be asymptomatic or have only a mild prolonged cough. an increased white blood count up to , with a lymphocytosis is characteristic early in the course of the disease. the preferred test for laboratory confi rmation is the detection of b. pertussis dna by pcr assay. bacteriologic culture provides a defi nitive diagnosis. if administered during the early stages of the disease (fi rst - days of illness), erythromycin for days may decrease symptoms and reduce the risk of spread. a day course of azithromycin or a - day course of clarithromycin has been found to be as effective with less gastrointestinal symptoms. corticosteroids, bronchodilators, or intravenous immunoglobulins have not demonstrated effi cacy. supportive care with supplemental oxygen, mechanical ventilation, intravenous fl uids, maintenance of adequate caloric intake, and treatment of secondary bacterial infections are the mainstay of therapy. the use of extracorporeal membrane oxygenation in infants with hypoxemia, pulmonary hypertension and right heart failure refractory to conventional mechanical ventilation has resulted in poorer outcomes than expected. vaccination in infancy with booster doses in adolescence is preventative. about - % of pneumonias in children are caused by viruses. there is considerable evidence that viral infections often precede bacterial pneumonias and cause weakening of the host defenses. viral pneumonias with rsv and parainfl uenza are discussed in more detail in the bronchiolitis section. infl uenza is the main viral cause of pneumonia in school-aged children requiring hospitalization. there are three serotypes, a, b, and c which are further divided into subtypes based on the hemagglutinin and neuraminidase genes. hemagglutinin , , and and neuraminidase and typically infect humans. the gene segments for the surface glycoproteins are unstable, so mutations, called antigenic shift, occur regularly. epidemics occur annually during the winter months with a short, - day incubation period. the virus causes destruction of the ciliated respiratory epithelium within day of symptoms. airway edema and infi ltration with infl ammatory cells into the airway mucosa and epithelium follows. slow repair occurs over - weeks. a severe fulminating pneumonia may result in hemorrhagic exudates that contain many polymorphonuclear and mononuclear cells. destruction of the respiratory epithelium often leads to secondary bacterial infections. during the - infl uenza season, infl uenza-related deaths occurred in children; of these, % were less than years of age. forty-fi ve percent of the older children ( - years of age) did not have an underlying medical condition. rare complications of although death from infl uenza pneumonia is uncommon, a signifi cant number of the children that died were previously healthy. infl uenza include acute myositis, rhabdomyolysis, myocarditis, pericarditis, reye syndrome, encephalitis, transverse myelitis, and guillain-barré syndrome. children may present with an abrupt clinical course manifested by high fever, myalgias, headaches, scratchy sore throats, and dry cough. peripheral white blood counts are usually less than , . pulmonary infi ltrates often involve multiple lobes. bacterial co-infection, especially with mrsa, increases morbidity and mortality signifi cantly. rimantidine and amantadine can shorten the course for infl uenza type a disease by limiting viral replication, but only if given within the fi rst h of the disease. prophylactic dosing is - % effective and does not interfere with antibody production from the vaccine. both drugs have central nervous system and gastrointestinal side effects, including an increase in the incidence of seizures. oseltamivir and zanamivir have recently been approved for the treatment of infl uenza infections in children. they inhibit neuraminidase, an enzyme produced by infl uenza a and b. the course of disease in healthy adults can be reduced by - days, if started within h of the onset of symptoms. zanamivir is a dry powder aerosol that must be delivered by a special breath-activated device. bronchospasm in patients with asthma has been reported. aspirin or aspirin-containing products should be avoided due to the risk of reye syndrome. immunoprophylaxis is the most effective strategy for the prevention of infl uenza infection. inactivated vaccines have effi cacy rates from % to %. currently, the inactivated vaccine is recommended for all children older than months of age with high risk conditions including chronic pulmonary or cardiac disease, immunosuppressive disorders, sickle cell disease and other hemoglobinopathies, diseases requiring long-term aspirin therapy, chronic metabolic and renal diseases; healthy children aged - months; and household contacts over the age of months of high risk persons. a live, attenuated infl uenza vaccine was licensed in . it is administered by the intranasal route and is approved for healthy children aged - years. avian infl uenza viruses do not normally infect species other than birds and pigs. however, in , the fi rst human death from avian infl uenza occurred in hong kong in a year old with reye syndrome. subsequently, an epidemic occurred among humans in hong kong with close contact to live, infected poultry. the subtype h n appears to be the most ominous due to its ability to rapidly mutate and infect new species. the overall mortality rate is greater than %. the avian viruses are not believed to be transmissible from person-to-person, but some recent cases are being investigated for this possibility. children uniformly present with fever and cough. symptoms range from typical infl uenza-like symptoms to conjunctivitis to respiratory disease and failure. signifi cant laboratory data include leukopenia and thrombocytopenia. all children who developed pneumonia and progressed to ards died. diagnosis remains diffi cult, as no tests are widely available. of the antiviral drugs available for infl uenza a, the most recent h n strains in southeast asia are resistant to rimantadine and amantadine. therefore, treatment is mainly supportive. a prototype h n vaccine was made available to manufacturers in april , but production is diffi cult because the standard means of producing infl uenza vaccines from specially grown chicken eggs is not feasible. h n kills the embryo before enough viruses can be harvested for vaccine production. in april, , the centers for disease control confi rmed the emergence of a novel infl uenza a (h n ) virus with genes from swine viruses of the eurasian lineage and genes from avian infl uenza viruses. by june, , the fi rst infl uenza pandemic since was declared, affecting over countries and territories. in comparison to illnesses with seasonal infl uenza, the majority of cases occurred in individuals younger than years of age, with nearly half of the cases occurring in children under years of age . the clinical symptoms can be typical for infl uenza; fever, sore throat, cough, and muscle aches with the addition of vomiting and diarrhea in children. a wide range of complications although antiviral medications may attenuate the course of infl uenza when given early, immunoprophylaxis with vaccines is the most effective strategy for the control of infl uenza infections. avian infl uenza has occurred in epidemics among persons with close contact to live, infected poultry. all children with pneumonia that progressed to ards succumbed to the disease. have been reported that include mild-to-moderate (otitis media, sinusitis, myositis, and febrile seizures) to more severe complications such as myocarditis, rhabdomyolysis or encephalitis. severe complications may frequently involve invasive bacterial co-infection (i.e. mrsa) and/or exacerbation of underlying medical conditions in particular asthma. children who present initially with uncomplicated infl uenza may have rapidly progressive hypoxemic respiratory failure and multiorgan system dysfunction that is refractory to all therapies ( fig. - ) . of reported h n deaths, approximately % were in children. the majority of these children had comorbid asthma, neuro-developmental conditions, or obesity. an american academy of pediatrics work group identifi ed children at greatest risk for life-threatening h n infl uenza disease (table - ) . the centers for disease control has recommended prompt empiric antiviral therapy for infants, children, and adolescents of any age presenting with suspected or confi rmed h n infl uenza and any of the following conditions: illness requiring hospitalization ■ progressive, severe, or complicated illness, regardless of previous health ■ presence of signifi cant risk factors (see table ■ - ) the h n strain has been found to be resistant to amantadine and rimantadine, but is usually sensitive to neuraminidase inhibitors, specifi cally oseltamivir or zanamir. in , oseltamivir was emergently approved for treatment in children less than months of age. resistance to oseltamivir has been reported and is thought due to the h y mutation. interestingly, the mutation confers resistance to oseltamivir, but not to zanamivir. peramivir, a neuraminidase inhibitor, an unapproved (investigational) antiviral available in an intravenous formulation received an emergency use authorization permit from the fda for use in children with confi rmed severe refractory h n infl uenza. its use should be restricted to children that are not responding to either oral or inhaled antiviral drugs or if the parenteral route is the only dependable method of drug delivery. a vaccine was manufactured and licensed using the same standards as seasonal infl uenza by late . a single dose was found to provide adequate protection in children older than years of age, younger children requiring two doses separated by at least days. adenoviruses have been implicated in - % of pneumonias in children. adenoviruses are classifi ed into serotypes with types , , a, , and being the most common etiologic agents of lower respiratory disease and causing a severe necrotizing pneumonitis. these serotypes are associated with serious pulmonary sequelae, such as bronchiectasis, bronchiolitis obliterans, unilateral hyperlucent lung, and persistently abnormal pulmonary function tests. adenovirus infections peak between months and years of age. mortality from severe respiratory infections can be high, because the disease often involves multiple organ systems. survivors may have permanent lung injury often in the form of bronchiolitis obliterans. in the immunocompromised host, mortality rates are as high as - %. cidofovir has in vitro activity against adenovirus, but proof of effi cacy is limited. therapy is supportive. severe acute respiratory syndrome is a newly described pulmonary infection caused by a novel sars-associated coronavirus. sars-cov is highly contagious and was coined "the fi rst plague of the twenty-fi rst century". the disease rapidly spreads among household contacts and healthcare personnel. children less than years of age account for only approximately % of those affected, with a mean age of years. no deaths were reported among children in the outbreak. children and adults present with fever, malaise, cough, coryza, chills or rigor, sputum production, headache, myalgia, leukopenia, lymphopenia, thrombocytopenia, mildly elevated activated partial thromboplastin times, and elevated levels of lactate dehydrogenase. radiographs of the chest show non-specifi c infi ltrates. apart from diarrhea, patients have minimal extrapulmonary symptoms. early diagnosis by reverse transcription-polymerase chain reaction (rt-pcr) can be made with % sensitivity on nasopharyngeal aspirates within the fi rst days of the illness. the clinical course follows a triphasic pattern. there is an incubation period of - days with a prodrome of high fever, chills, malaise, headache, and myalgias. diarrhea occurs in up to % of adults. after - days, the disease progresses to involve the lower airways with a dry non-productive cough and dyspnea. in - % of cases, acute respiratory distress syndrome (ards) follows and often patients require mechanical ventilation. deaths occur from respiratory failure. young children run a milder and shorter biphasic clinical course. cough is found in approximately half the children, and crackles are rarely heard despite radiographic evidence of infi ltrates. a regimen of antibiotics, ribavirin, and corticosteroids was proposed based on initial anecdotal success. however, ribavirin has demonstrated minimal activity against sars-cov isolates in vitro . non-randomized studies of corticosteroids have reported favorable outcomes. a pediatric series of children with confi rmed sars treated with ribavirin and corticosteroids showed no adverse effects and all survived. mortality from adenovirus infections remains high because of multiple organ system involvement. sars rarely affects children, and when it does, morbidity is less, with no reported mortalities. . neurological disorders, such as epilepsy, cerebral palsy, developmental delay and neuromuscular disorders . chronic respiratory diseases associated with impaired pulmonary function and/or diffi culty handling lung secretions, moderate and especially severe persistent asthma, technology-dependent children (e.g., those requiring oxygen, tracheostomy, or a ventilator) . primary immunodefi ciencies or conditions that require medications or treatments that result in secondary immunodefi ciencies . congenital heart disease . metabolic (e.g., mitochondrial) or endocrine disorders, especially if cardiopulmonary function is impaired adapted from http://www.aap.org/new/swinefl u.htm hantavirus cardiopulmonary syndrome is a viral zoonotic disease that affects healthy children and adolescents who are exposed to aerosols of rodent excreta. the deer mouse is the main rodent reservoir. most cases occur in the southwestern united states, but cases have been confi rmed in states. hcps presents with a prodrome of fever, chills, myalgia, headache, and gastrointestinal symptoms. respiratory compromise requiring supplemental oxygen generally occurs within h. the disease can progress to respiratory distress and ards. the majority of deaths result from hypoxemia and cardiac dysfunction with marked hypotension and ventricular arrhythmias. in adults, the case fatality rate is approximately %. a recent case series of children aged - years, revealed that % of infected children developed hcps, % died, and % were critically ill and required mechanical ventilation. treatment is supportive as ribavirin has not been proven to reduce mortality. extracorporeal membrane oxygenation was used on two patients, one of which survived. laboratory evaluation reveals thrombocytopenia, leukocytosis, and circulating immunoblasts. an elevated prothrombin time of ³ s is predictive of severe disease. no deaths were reported in children younger than years of age. diagnosis can be made by detection of hantavirus-specifi c immunoglobulin m, hantavirus-specifi c rna by polymerase chain reaction, or hantavirus antigen by immunohistochemistry. respiratory infections in children with primary or acquired immunodefi ciencies requiring intensive care are not uncommon. these infants and children are susceptible to many organisms that are rarely pathogenic in a normal host. primary immunodefciencies include abnormalities or defi ciencies in immunoglobulins and antibodies, t and b cells, phagocytes, natural killer cells, and complement. acquired immunodefi ciencies include asplenia, human immunodefi ciency virus (hiv), corticosteroid therapy, and immunosuppresion used for marrow or solid organ transplants. immunocompromised children can present with attenuated signs and symptoms of respiratory infections. in addition to physical examination and chest roentgenograms, these children often require chest computed tomography to better delineate the extent of disease. bronchoalveolar lavage, needle aspiration, or lung biopsies might be required to make a defi nitive diagnosis. pulmonary specimens should be tested for common bacteria as well as for pneumocystis carinii, acid-fast bacilli, nocardia, legionella, crytococcus, aspergillus, candida, histoplasma, coccidioides, and blastomyces. viruses such as cytomegalovirus, varicella, herpes virus, and measles should be considered. pneumocystis carinii (now known pneumocystis jiroveci ) is an opportunistic pulmonary pathogen in infants and children with human immunodefi ciency virus (hiv) and other primary immunodefi ciencies, malnutrition, hematological malignancies, solid organ and bone marrow transplant recipients, and patients on high dose corticosteroid therapy for infl ammatory and collagen-vascular diseases. it is a unicellular organism that exists as a cyst (the diagnostic form). the organism attaches to the type i alveolar cells resulting in an alveolitis characterized by ventilation-perfusion mismatch and decreased pulmonary compliance. if untreated, pcp carries a mortality rate of - %, and nearly % in the hiv-seropositive child. fortunately, the incidence has markedly decreased with the administration of chemoprophylactic agents to high risk patients. children typically present with fever, tachypnea, non-productive cough, and hypoxia with an absence of rales on auscultation of the chest. initially, they may have an elevated ph and low carbon dioxide levels. lactate dehydrogenase levels are generally elevated. bilateral diffuse alveolar infi ltrates are seen with initial hilar involvement subsequently spreading to the periphery (fig. - ) . diagnosis is made by demonstrating the organism with the methenamine silver nitrate stain on pulmonary tissue, respiratory secretions, or lung fl uid. bronchoalveolar lavage is the most widely used technique to obtain lung fl uid for diagnosis. treatment consists of supportive therapy hantavirus is rare in infants and school-aged children. no deaths have been reported in children less than years of age. with supplemental oxygen; ultimately continuous positive airway pressure or mechanical ventilation may be necessary if respiratory failure occurs. trimethoprim-sulfamethoxazole (tmp-smx) is the recommended initial treatment. in patients that cannot tolerate tmp-smx, then pentamidine isoethionate should be used. corticosteroids in anti-infl ammatory doses as an adjunct to antimicrobial therapy have improved clinical outcomes. concurrent pulmonary infections were found in % of patients, most frequently bacterial or cytomegalovirus pneumonia. determination of the etiologic agent in pneumonia is diffi cult. fortunately, in most community-acquired pneumonias, identifi cation of the specifi c causative organism is not critical. however, in children with a complicated course that fails to respond to standard therapies, defi nitive diagnosis of the etiologic agent is essential. complete blood counts, infl ammatory markers, and chest radiographs do not differentiate the causative agents for pneumonia. blood cultures are rarely positive outside of the neonatal period. rapid antigen tests are available for rsv, parainfl uenza, infl uenza, and adenovirus. nasopharyngeal swabs for viral cultures generally take - days to become positive, and in one study, % of the patients had been discharged prior to the positive results. older children and adolescents might be able to produce sputum for gram stain and culture. an adequate specimen should contain more the leukocytes and fewer than squamous epithelial cells per low-power fi eld. in the intubated patient, sputum can be more easily acquired. however, interpretation of the results of gram stains and cultures is at times diffi cult in differentiating colonizing from pathologic organisms. colonization of the endotracheal tube may occur as early as h, but most frequently between and h. the oropharynx becomes colonized within h, the stomach at - h, and the lower respiratory tract between and h. in addition, a comparison of infectious agents isolated by both tracheal aspirates and bronchoalveolar lavage found only % concordance. bronchoalveolar lavage (bal) can be safely used to obtain secretions from the lower airways for gram stain and culture. it is especially useful in the diagnosis of pneumonia in the immunocompromised child. however, bal performed directly through the bronchoscope carries a risk of contamination. the smallest bronchoscope that can accommodate a protected specimen brush is . mm and requires a . mm endotracheal tube for passage. the smallest fl exible fi beroptic bronchoscope with a suction channel has an external chest radiograph of severe pneumocystis carinii pneumonia in a month old male with combined immunodefi ciency. note the diffuse alveolar involvement and air bronchograms. (image provided courtesy of fa maffei) diameter of . mm and is too small to admit a double-sheathed brush. non-bronchoscopic double-lumen plugged catheters can be inserted blindly through the endotracheal tube to obtain a non-contaminated specimen. the sensitivity and specifi city of these samples are similar to those obtained by a bronchoscopic guided protected specimen. transthoracic needle aspirations are performed in some centers with good results. one study reported a diagnostic success rate in % of patients. the incidence of pneumothorax was approximately %, but none required subsequent placement of a pleural drainage catheter. a lung biopsy is rarely needed to make a defi nitive diagnosis. supportive treatment with oxygen and intravenous fl uids are often standard therapies. as both pneumonia and mechanical ventilation can cause an elevation in anti-diuretic hormone levels, careful fl uid monitoring is essential to avoid overhydration, excessive lung water and hyponatremia. initial antibiotic choices should be empiric and based upon the likely organisms for each age group, because of the diffi culty in identifying the causative agent. the child's respiratory status including respiratory rate, work of breathing, pulse oximetry, and central nervous system response should be closely monitored. non-invasive bi-level positive airway pressure (bipap) has been effective for use in children with mild to moderate respiratory insuffi ciency, defi ned as an a-a gradient > and < or pao /fio ratio < but > mm hg. serial evaluation of mask-face contact areas is essential to avoid skin breakdown. children with moderate or severe respiratory insuffi ciency often require intubation and mechanical ventilation. children with respiratory failure secondary to pneumonia often require increased positive end expiratory pressure (peep), increased inspiratory time, and aggressive pulmonary toilet to recruit alveoli. for patients requiring high levels of peep, adequate sedation is often required to prevent patient/ventilator asynchrony and barotrauma. spontaneous respirations should be encouraged while on mechanical ventilation. rarely, the use of neuromuscular blockade is required to allow mechanical ventilation. prone positioning may improve ventilation/perfusion (v/q) mismatching in dependent lung regions. lung protective strategies allowing permissive hypercapnea with small lung volumes to ventilate and appropriate peep to maintain alveolar recruitment is recommended for children with pneumonia. high frequency oscillatory ventilation can also be utilized to maintain mean airway pressure and alveolar recruitment. airway pressure release ventilation (aprv) provides recruitment of alveoli while allowing spontaneous respirations. in children with severe respiratory distress syndrome, treatment with bovine surfactant may improve oxygenation. extracorporeal life support continues to have a role in children with reversible severe acute hypoxemic respiratory failure refractory to mechanical ventilation. pneumonias can often be complicated by the development of pleural effusions and empyemas. these occur when the fl uid production by the interstitial lung tissue exceeds the maximum pleural lymphatic fl ow. parapneumonic effusions often occur from pneumonia as white blood cells and other debris of infection block the lymphatics resulting in elevation of protein in the pleural space, increase in colloid osmotic pressure, and consequent failure of fl uid reabsorption. on physical exam, the child will have decreased breath sounds over the effusion. in older children, auscultatory percussion changes might be appreciated. plain chest radiographs can reveal most clinically signifi cant effusions. ultrasound and chest computed tomograms are useful in determining the volume and quality of the fl uid and the presence of loculations. simple parapneumonic effusions or transudates can also be differentiated from exudates by using the criteria of light et al. (table - ). a pleural fl uid ph less than . indicates a complicated effusion that is likely exudative and requires drainage whereas a pleural fl uid ph more than . suggests that the effusion may be managed with systemic antibiotics alone. complicated parapneumonic effusions or empyemas occur when the fl uid becomes purulent. during this stage, the effusions undergo a fi brinopurulent stage with many polymorphonuclear leukocytes, bacteria, and cellular debris entering the fl uid. fibrin is deposited over the pleural surfaces and loculations begin to form. the ph and glucose levels fall as the ldh levels rise. if untreated, they often progress to a third organizing stage in which the exudate non-invasive bipap ventilation can be effective for children with moderate respiratory insuffi ciency. develops into an inelastic, fi brotic peel that restricts the lung. simple parapneumonic effusions usually resolve with thoracentesis or tube thoracostomy and antibiotic treatment of the pneumonia. more complicated parapneumonic effusions have been successfully treated with thoracotomy tubes and fi brinolytics. however, although risks for bleeding are reportedly low, this therapy requires close monitoring of chest tube drainage and instillation of expensive medications with intermittent clamping of the chest tube. no single recommendation for the choice of fi brinolytic agent or dosage has been established. also, if tried late in the organizing phase, this is often unsuccessful due to loculations and the high viscosity of the purulent fl uid. surgical debridement either by open procedure or by video-assisted thorascopic surgery (vats) is often needed for organizing, complicated parapneumonic effusions. multiple studies have reported that early vats or thoracotomy for empyema leads to a shorter hospital stay. the treatment modality is best determined by the temporal stage and nature of the effusion. acute pulmonary infections are common diagnoses that require admission to the pediatric intensive care units. understanding the pathophysiology of lower respiratory infections enables the intensivist to tailor therapy to the individual child and pathogen. early establishment of a specifi c etiology and the selection of the correct treatment plan directly impacts clinical outcome. video-assisted thorascopic surgery (vats) for the treatment of empyemas has been associated with shorter hospital stay. which of the following therapies have been proven to be a consistent benefi t for rsv bronchiolitis? a. aminophylline b. bronchodilators c. corticosteroids d. ribavirin e. supportive care . palivizumab is indicated for which of the following children? a. a month old, former week premature infant who just underwent surgical repair of a large ventricular septal defect who received palivizumab weeks ago b. a month old, former week premature infant with mild bronchopulmonary dysplasia who received palivizumab weeks ago c. a month old, former week premature infant with peripheral pulmonic stenosis who has never received palivizumab d. a month old full term infant with a urea cycle defect who has never received palivizumab e. an month old, former week premature infant with bronchopulmonary dysplasia who received his fi fth dose of palivizumab a month ago pleural fl uid may be classifi ed as exudative, if one or more of the following criteria are met: ■ pleural fl uid protein divided by serum protein > . (sensitivity %, specifi city %) ■ pleural fl uid lactate dehydrogenase (ldh) divided by serum ldh > . (sensitivity %, specifi city %) ■ pleural fl uid ldh is more than two-thirds of the upper limit of normal for serum ldh (sensitivity %, specifi city %) adapted from light ( ) human bocavirus and acute wheezing in children american academy of pediatrics subcommittee on diagnosis and management of bronchiolitis. diagnosis and management of bronchiolitis the yield of fl exible fi beroptic bronchoscopy in pediatric intensive care patients immunological mechanisms of severe respiratory syncytial virus bronchiolitis human metapneumovirus infection in young children hospitalized with acute respiratory tract disease: virologic and clinical features a multicenter, randomized, controlled trial of dexamethasone for bronchiolitis natural infection of infants with respiratory syncytial virus subgroups a and b: a study of frequency, disease severity, and viral load the use of albuterol in hospitalized infants with bronchiolitis advances in the treatment and prevention of severe viral bronchiolitis the presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically signifi cant congenital heart disease systemic corticosteroids in infant bronchiolitis: a meta-analysis drainage, fi brinolytics, or surgery: a comparison of treatment options in pediatric empyema does vats provide optimal treatment of empyema in children? a systematic review intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children clinical picture, diagnosis, treatment, and outcome of severe acute respiratory syndrome (sars) in children noninvasive therapy with helium-oxygen for severe bronchiolitis pleural effusion pleural effusions: the diagnostic separation of transudates and exudates nebulized % hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis development of wheezing disorders and asthma in preschool children heliox therapy in infants with acute bronchiolitis nasal continuous positive airway pressure with heliox versus air oxygen in infants with acute bronchiolitis: a crossover study diagnosis and management of pneumonia in children community-acquired pneumonia in children selected populations at increased risk from respiratory syncytial virus infection human metapneumovirus and human bocavirus in children mixed respiratory virus infections mycoplasma pneumoniae and chlamydia pneumoniae cause lower respiratory tract disease in paediatric patients children's hospital respiratory syncytial virus database: risk factors, treatment and hospital course in infants and young children infection with sin nombre hantavirus: clinical presentation and outcome in children and adolescents ribavirin for respiratory syncytial virus lower respiratory tract infection: a systematic overview risk of bacterial infection in previously healthy respiratory syncytial virus-infected young children admitted to the intensive care unit infl uenza in pediatric intensive cure unit do bronchodilators have an effect on bronchiolitis? comparison of conventional viral cultures with direct fl uorescent antibody stains for diagnosis of community-acquired respiratory virus infections in hospitalized children respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease respiratory syncytial virus in early life and risk of wheeze and allergy by age years h n infl uenza the impact-rsv study group. palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants high incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (rsv) bronchiolitis bench-to-bedside review: ventilator strategies to reduce lung injury -lessons from pediatric and neonatal intensive care etiological diagnosis of childhood pneumonia by use of transthoracic needle aspiration and modern microbiological methods a multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis respiratory syncytial virus and other respiratory viruses effect of exogenous surfactant (calfactant) in pediatric acute lung injury. a randomized controlled trial current concepts on pulmonary host defense mechanisms in children nebulized hypertonic saline solution for acute bronchiolitis in infants bronchiolitis: recent evidence on diagnosis and management key: cord- - wuvk cz authors: burns, katherine h.; saunders, barbara s.; burns, samuel a. title: nurturing visual social development in the nicu date: - - journal: j perinatol doi: . /s - - -w sha: doc_id: cord_uid: wuvk cz nan as hospital systems grapple with containing coronavirus disease (covid- ) while protecting healthcare providers and patients, developmental considerations of mask usage while caring for infants and young children with prolonged hospitalizations must be considered. we wish to propose developmental interventions to be implemented in nicus to mitigate the impact of exclusively masked interactions. it is assumed that infant visual acuity at birth is specifically developed to facilitate facial focus and recognition, contributing to development of "social networks"-a complex set of pathways involving many areas of the developing brain [ ] . although visual input is certainly not the only factor for these networks, denying infants the visual input reinforcing social interactions is not normal and cannot be without risk. we recommend the article neonatal transitions in social behavior and their implications for autism by shultz et al. as an excellent review of early social development [ ] . infants appear to be at very low risk for overall infection, illness, and transmission of covid- [ ] . however, infants with prolonged hospitalizations and perinatal complications are known to be at risk for significant neurodevelopmental delays and pathologies supporting the need to carefully nurture the social development of infants in nicus [ , ] . there is an urgency in early social development as many of these social milestones scaffold on each other and are typically obtained by months of age, and even newborn infants exhibit distress at unreciprocated interactions [ ] . we propose the following for consideration: ( ) placing higher risk infants in private rooms, especially as discharge approaches and/or the infant is post term. development should be a consideration in allocation of private rooms. this allows for social distancing and protection of the highest risk population for covid- in nicus-adults. ( ) considering infant visualization of adult faces as "therapeutic". it is standard for nicus to have developmental care plans [ ] . in light of covid- , extra attention should be paid to social development. this should vary by gestational age with more "passive" protocols for the younger and more fragile infants progressing to more interactive and stimulating protocols. for example, after months corrected age, caregiver-infant interactions should include more mirroring with a greater variety of facial expressions and vocalizations utilized [ , ] . we do not have data on the exact amounts or frequencies of masked/unmasked interactions necessary to optimize development, but our knowledge of infant development strongly suggests risk. we would, of course, not expect the above accommodations for caregivers with known, active covid- infections, and implementation may vary depending on current community spread. however, active consideration of a more nurturing long-term developmental approach to infants in this critical time of development needs to be undertaken. conflict of interest the authors declare that they have no conflict of interest. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. the development of the social brain in human infancy neonatal transitions in social behavior and their implications for autism systematic review of covid- in children shows milder cases and a better prognosis than adults neurodevelopmental outcomes in extremely preterm infants at . years after active perinatal care in sweden extremely preterm-born infants demonstrate different facial recognition processes at - months of corrected age innate intersubjectivity: newborns; sensitivity to communication disturbance individualised developmental care for babies and parents in the nicu: evidence-based best practice guideline recommendations early maternal mirroring predicts infant motor system activation during facial expression observation newborns' face recognition: role of inner and outer facial features visual following and pattern discrimination of face-like stimuli by newborn infants face processing at birth: a thatcher illusion study a comparison between preterm and fullterm infants' preferences for faces key: cord- -cyd msls authors: mallol, j.; aguirre, v.; wandalsen, g. title: common cold decreases lung function in infants with recurrent wheezing date: - - journal: allergol immunopathol (madr) doi: . /j.aller. . . sha: doc_id: cord_uid: cyd msls background: common acute viral respiratory infections (colds) are the most frequent cause of exacerbations in infants with recurrent wheezing (rw). however, there is no quantitative information about the effect of colds on the lung function of infants with rw. this study was undertaken to determine the effect of common cold on forced expiratory parameters measured from raised lung volume in infants with rw. methods: spirometric lung function (expiratory flows from raised lung volume) was randomly assessed in infants with rw while they had a common cold and when asymptomatic. results: it was found that during colds there was a significant decrease in all forced expiratory parameters and this was much more evident for flows (fef( %), fef( %) and fef( – %)) which were definitively abnormal (less than − . z-score) in the majority of infants. there was not association between family asthma, tobacco exposure, and other factors, with the extent of lung function decrease during colds. tobacco during pregnancy but not a history of family asthma was significantly associated to lower expiratory flows; however, the association was significant only when infants were asymptomatic. conclusion: this study shows that common colds cause a marked reduction of lung function in infants with rw. most wheezing episodes and asthma exacerbations in children and adults are caused by viruses responsible for upper respiratory tract infection (urti) or common colds. [ ] [ ] [ ] of the several known viruses which cause the disease, the role of rhinoviruses is most prominent but several other common respiratory viruses are associated with respiratory illness and wheezing in infants and children. [ ] [ ] [ ] [ ] experimental studies in adult asthmatics have demonstrated that rhinovirus, one of the most common causes of natural colds, can increase airway responsiveness, inflammation, and decrease lung function very early (in the first - days) after experimental inoculation, whereas other authors have not found significant changes in fev in asthmatics after rhinovirus inhalation. under clinical conditions, it has been demonstrated that airway inflammation occurred during natural cold caused by different viruses (influenza a, rhinovirus, adenovirus, respiratory syncytial virus, and coronavirus) is significantly greater in asthmatics than in healthy subjects. at present there is no information in infants with rw as to whether urti caused by common respiratory viruses results in significant airway obstruction, regardless of the fact that some mechanisms involved in virus-induced airway obstruction may also be present in infancy. , it has been found that viruses commonly causing urti can induce an asthmatic clinical response in infants during the first year of life and later during childhood, [ ] [ ] [ ] but the effect of urti on their lung function is unknown. the objective of this study was to quantify the effect of urti (common cold) on the spirometric lung function of infants with rw assessed with the raised volume rapid thoracic compression technique (rvrtc), a sensitive technique to assess bronchial obstruction in infants. subjects. thirty infants with recurrent wheezing (three or more previous episodes of physician diagnosed wheezing) and without antecedents of hospitalisations; severe lower respiratory infection in the last weeks; emergency room visits; or oral corticosteroids in the last weeks, were randomly recruited from our paediatric respiratory outpatient clinic to measure their spirometric lung function. lung function measurements were performed at random in two occasions for each patient (each one was its own control), either during the first days of an urti or when they had been asymptomatic during weeks and had normal physical examination at the measurement day. infants with fever; respiratory distress; rsv bronchiolitis; pneumonia; chronic lung diseases; neonatal respiratory illness requiring oxygen or mechanical ventilation; or any other condition potentially affecting airway responsiveness, were not eligible for the study. urti (common cold) was defined by the presence of runny nose (watery nasal rhinorrea), sneezing, nasal obstruction, without fever, and eventually cough, plus the antecedent of family members with similar symptoms at home (parent, siblings) or other children with a cold if they attended daycare. no viral determinations were done because they were not available at the hospital. infants were on treatment with inhaled salbutamol on-demand and regular budesonide delivered by valved holding chamber with mask; treatments were continued as prescribed by their doctors, excepting salbutamol which was withheld h prior to measurements. the study was approved by the hospital ethics committee and full informed written and signed consent was obtained from all parents. lung function testing. forced expiratory manoeuvres were obtained using the raised volume rapid thoracic compression technique (rvrtc) as previously described. [ ] [ ] [ ] infants were measured hrs postprandial and while sleeping under sedation with chloral hydrate ( - mg/kg). lung inflation pressure was set at cm h o, and after delivering several sequential inflations rapid thoracic compression was from raised lung volume and maintained until residual volume was reached. forced expiratory manoeuvres were repeated with increases of cm h o in jacket pressure until there was no further increase in flows with subsequent increase in jacket pressure. the best curve was selected from three reproducible curves, as the single best shaped curve with the highest product of forced vital capacity (fvc) and fef between % and % of fvc (fef - % ). the following parameters were recorded for all curves: fvc, fev . , fef % , fef % and fef - % . data analysis. values for each pulmonary function parameter were converted to z-scores using the equations of jones et al and the comparisons of spirometric values during urti and when asymptomatic were done using parametric test for paired samples; p o . was considered as statistically significant. for all computed lung function parameters a change of one or more z-score (increase or decrease) was considered as significant. abnormal lung function at the time of measurements was defined as a zscore of r À . for a given spirometric parameter in both occasions (symptomatic or asymptomatic patients). spearman correlation was used for continuous variables whereas chi-square tests and regression analysis were used to relate the change in lung function to history of a first-degree relative with asthma, gender, age, exposure to cigarette smoke during pregnancy or intra-domiciliary, order of measurement, time elapsed between measurements, age at onset of wheezing, and number of previous episodes of physician-diagnosed wheezing. technically satisfactory spirometric measurements on both occasions (when patients were with urti or asymptomatic) were obtained in wheezy infants ( males). in patients lung function was measured first when they were asymptomatic and in it was measured first when they were suffering from urti. the mean delay between tests was . weeks ( %ci, . - . ). anthropometric data, family history of asthma, and other characteristics of the studied infants are shown in table . there was no significant difference in baseline oxygen saturation between measurements when infants were asymptomatic or during urti [ . % ( %ci, . - . ) and . % ( %ci, . - . )], respectively. history of family asthma was present in / infants whereas exposure to tobacco during pregnancy was positive in / , table . mean values and % ci for lung function measurements in z-score are shown in table . urti caused a marked and significant decrease of lung function as compared with measurements performed when infants were asymptomatic. the percentage of infants with a lung function decrease of z z-score during urti was as follows: . % for fvc, . % for fef % , . % for fef % , . % for fef À % , and . % for fev . . when the abnormality criterion for any value of lung function was set at a z-score equal or less than À . , it was found that during urti % of infants ( / ) had one or more abnormal forced flow parameters. during urti, the most compromised parameters were fef % and fef - % , and forced expiratory flows were more affected than volumes (table and figure ) . two examples of flowvolume manoeuvres from two patient when they were suffering urti or asymptomatic are shown in figure . it was found that almost all infants had normal lung function (all the spirometric parameters assessed) when they were asymptomatic excepting two of them who remained under the À . z-score for one isolated parameter. there was no association between the extent of the lung function decrease during urti after adjusting for sex; age; perinatal tobacco exposure; history of family asthma; age of onset of recurrent wheezing; order of measurements; and number of previous wheezing episodes. however, there was a significant association between expiratory flows measured when infants were asymptomatic and tobacco during pregnancy. no significant association was found for lung function during urti. there were not unwanted side effects derived from sedation or measurement procedure in any of the studied infants. this study demonstrates that urti causes a notorious and significant decrease in spirometric parameters of infants - % . ( . - . ) À . (À . to À . ) . z-score (mean and % confidence interval). z score - % ic figure lung function parameters measured during urti and when asymptomatic (z-score, mean and % ci). with rw, and such an effect is predominantly on forced expiratory flows. an abnormal lung function during urti occurred in % of patients but all of them returned to normal lung function when asymptomatic. information about the quantitative effect of urti on the lung function of normal or asthmatic children is scarce. [ ] [ ] [ ] the latter is rather surprising since common viral infections account for - % of asthma exacerbations in children and are strong predictors for repeated asthma-like symptoms episodes in infancy and school age. , , [ ] [ ] [ ] , [ ] [ ] [ ] similarly, the effect of respiratory viral infections -the main cause of wheezing exacerbation in infancy-on lung function in infants who are or not at risk of asthma had not been reported. this study suggests that a positive history of family asthma and tobacco exposure during pregnancy would not be a risk factor for a higher degree of airway narrowing during urti in infants with rw; however, both factors have been found to be related with higher airway responsiveness in healthy infants. , . in the same direction, we also found a clear association between tobacco exposure during pregnancy and lower expiratory flows, but only when infants were asymptomatic. a possible explanation for this finding may be that in our infants the marked reduction of forced expiratory flows during urti may have obscured a potential effect of family asthma, perinatal tobacco and larger number of previous episodes of wheezing on the degree of decrease of lung function. another explanation is that common respiratory viruses can directly induce important mucosal oedema by increasing vascular permeability, particularly during the initial stage of a urti; in infants with rw it may be that the degree of such a response is unrelated to familiar predisposition or environmental exposures. recently, it has been found that both, decreased lung function and enhanced bronchial responsiveness, were associated to atopic sensitisation of the infant rather than to family history of asthma or allergies. we did not evaluate the response to an inhaled bronchodilator in our infants; therefore it is unclear whether the lower baseline airway function during urti reflects increased baseline airway tone, intraluminal airways obstruction due to mucosal oedema, or both. however, the significant increase of lung function achieving normal values when infants were asymptomatic, suggests that in this group of infants a pre-existing fixed smaller-sized airway calibre, as a determinant for the observed lung function decrease, could be ruled out. our results are limited because we only included infants with recurrent wheezing, we did not get viral determinations, and there was not a control group of healthy infants. however, the group was balanced regarding the antecedents of family asthma and tobacco exposure. other studies which assessed the effect of viral respiratory infections on pulmonary function in atopic and non-atopic patients, have not included a control group. , considering its limitations, this study provides, for the first time, information about the effect of urti or common cold on the spirometric lung function of infants with rw. in conclusion, this study shows a remarkable decrease in expiratory forced flows from raised lung volume during urti in infants with rw, and the degree of this decrease was unrelated with family asthma, tobacco exposure and the number of previous episodes of wheezing. furthermore, infants recovered a normal lung function when they were asymptomatic, although it was slightly decreased in the group exposed to tobacco during pregnancy. community study of role of viral infections in exacerbations of asthma in - year old children exacerbations: the asthma paradox frequency of detection of picornaviruses and seven other respiratory pathogens in infants the common cold the association of newly identified respiratory viruses with lower respiratory tract infections in korean children a diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants prevalence of viral respiratory tract infections in children with asthma experimental rhinovirus infection causes variable airway obstruction in subjects with atopic asthma rhinovirus inhalation causes long-lasting excessive airway narrowing in response to methacholine in asthmatic subjects in vivo inflammatory indices in induced sputum: a feasibility study virusinduced airway hyperresponsiveness and asthma allergens, viruses, and asthma exacerbations wheezing rhinovirus illnesses in early life predict asthma development in high-risk children serial viral infections in infants with recurrent respiratory illnesses variability of the raised volume rapid thoracic compresión technique in infants with recurrent wheezing forced expiratory flows and volumes in infants. normative data and lung growth raised volume forced expiration in infants. guidelines for current practice pulmonary function following mild respiratory tract infections (''common cold'') in teenagers respiratory symptoms or signs on the day of the study alter pulmonary function in teenagers spirometric changes in normal children with upper respiratory infections wheezing during the first year of life in infants from lowincome population: a descriptive study monocyte il- production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year follow-up study evidence of a causal role of winter virus infection during infancy in early childhood asthma the influence of a family history of asthma and parental smoking on airway responsiveness in early infancy parental smoking and airway reactivity in healthy infants analysis of nasal secretions during experimental rhinovirus upper respiratory infections expired nitric oxide and airway reactivity in infants at risk for asthma rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions duration of postviral airway hyperresponsiveness in children with asthma: effect of atopy the authors have no conflict of interest to declare. key: cord- -k pi sd authors: kliegman, robert m. title: neonatal necrotizing enterocolitis date: - - journal: pediatric gastrointestinal and liver disease doi: . /b - - - - . - sha: doc_id: cord_uid: k pi sd nan neonatal necrotizing enterocolitis (nec) is a disease of unknown origin that predominantly affects premature infants in level ii, or more often level iii, neonatal intensive care units during the infant's convalescence from the common cardiopulmonary disorders associated with prematurity. [ ] [ ] [ ] [ ] [ ] [ ] nec is the most common and most serious acquired gastrointestinal disorder among hospitalized preterm neonates and is associated with significant acute and chronic morbidity and mortality. , indeed, nec is the most common cause of gastrointestinal perforation (followed by isolated idiopathic focal intestinal perforation) and acquired short bowel syndrome among patients in the neonatal intensive care unit. , , it has been estimated that in the usa there are approximately to cases of nec annually. , [ ] [ ] [ ] nec is one of the most common nosocomial neonatal diseases; additional hospital charges for nec were estimated to be $ . million dollars at one neonatal system, with an average additional cost of $ per survivor. nec is a disease that affects premature infants during their convalescence from other diseases of immaturity. , it is unusual to see nec during the acute phase of respiratory distress syndrome, hypoxic-ischemic encephalopathy (birth asphyxia), heart failure from a patent ductus arteriosus and other acute neonatal disease processes. , although nec is noted predominantly in premature neonates, approximately % of cases occur in nearly full-term or full-term infants whose preceding risk factors have included polycythemia, cyanotic heart disease or heart disease producing low cardiac output (before or after surgery), chronic diarrhea, endocrine disorders (hypothyroidism, panhypopituitarism, congenital adrenal hyperplasia) or a prior anatomic obstructive gastrointestinal malformation (volvulus or gastroschisis). , , nec occurs predominantly in neonates after the onset of enteral alimentation, as % of affected infants have been fed for various amounts of time. , , the condition usually develops during the first weeks of life in relatively well neonates who have been fed enterally, but it may be delayed for days in infants of very low birthweight given nothing by mouth for long periods. nec tends to develop later among infants whose birthweight was less than g. thus, the more immature the infant at birth, the later the possible onset of nec. such findings suggest that immaturity of gastrointestinal function is a major risk factor. , , many case-control studies have suggested that immaturity is the only readily identifiable risk factor for the development of nec. immature function of host defense, gastrointestinal motility, digestion, healing and mucosal integrity (permeability), and intestinal circulation may contribute to the pathogenesis of nec (see below). , the incidence of nec varies among neonatal intensive care units, and some units have no cases. the overall incidence varies from % to % of all neonatal intensive care admissions. , the incidence among very-low-birthweight (less than g) infants who survive long enough to be fed approaches - %. the incidence is greatest among infants weighing between and g at birth ( - %) ; it declines to approximately - % among infants weighing more than g. , the incidence is affected by periodic outbreaks or epidemics of nec that become superimposed on an endemic case background. because infants of - g at birth represent a very small proportion of infants in neonatal intensive care units (less than % of all births), the mean birthweight of infants affected with nec is between and g and the mean gestational age is between and weeks. there is usually no association between nec and sex, race (other than the increased incidence of low birthweight among african americans), or inborn vs transport status. nec has very rarely been reported in successive pregnancies and among siblings in multiple gestations. because twins and triplets are often born prematurely, they seem to be over-represented among babies with nec. in contrast to what would be expected, the incidence of nec among twins appears to be higher in the well, first-born twin rather than in the second twin, who usually has a lower apgar score and a more complicated hospital course. nec is a disease of surviving neonates. most affected patients are considered 'gainers and growers' who, prior to the onset of nec, had few if any manifestations of gastrointestinal dysfunction, and few apparent sequelae of the previous diseases of prematurity from which they had been recovering. in many but not all instances, the affected pre-term infants had respiratory distress syndrome days to weeks before the onset of nec. with the advent of surfactant therapy for respiratory distress syndrome, more infants may survive this disorder and are now at risk for nec during their convalescence. because nec is seen in premature infants, many factors associated with prematurity were thought to be risk factors for nec. these were related to diseases, procedures or complications that may produce gastrointestinal ischemia, infection or altered digestion. mucosal injury following a combination of these risk factors was thought to produce nec. ischemic risk factors included birth asphyxia, respiratory distress syndrome, hypoxia, hypotension, patent ductus arteriosus, polycythemia, anemia, umbilical artery, catheter placement and exchange transfusion. because these risk factors were identified as part of a profile among affected infants, they were thought to contribute to the pathogenesis of nec. although each may contribute to mucosal injury, case-control studies suggest that these processes are equally prevalent among affected patients and unaffected controls. therefore, these risk factors merely describe the low-birthweight population and are no longer thought to be direct contributing factors in the pathogenesis of nec (see below). epidemiologic investigations emphasize that the predominant risk factor is prematurity, with associated immature host defense and gastrointestinal function. the pathologic appearance of nec has demonstrated varying features of inflammation and coagulation necrosis. the latter has been interpreted as being due to ischemia, but evidence also suggests that inflammatory mediators can produce lesions with coagulation necrosis similar to that following ischemia. , severe nec is a transmural process, involving all four layers of the bowel wall. nec often involves the terminal ileum, ileocecal area and ascending colon, and rarely only the rectal mucosa. eosinophilia may be noted in the rectal mucosal biopsies of patients with mild disease; this may represent only the early initiation phase of the illness, which later becomes masked by complicating peritonitis, secondary bacterial invasion and neutrophilic infiltration. eosinophilic intestinal infiltrates are not always suggestive of an allergic process and may be a non-specific response. superficial inspection of affected tissue reveals mucosal ulceration, hemorrhage, edema, and submucosal or subserosal gas-filled cysts typical of pneumatosis intestinalis ( fig. . ). approximately % of infants have involvement of both the small and large intestine (distal ileum and proximal colon), % have only colonic disease and % only ileal lesions. , involvement of the jejunum, stomach or entire length of bowel from the ligament of treitz to the rectum is less common (seen in % of surgical cases); the latter is present in fatal cases of nec (also known as pan-nec or nec totalis). approximately equal numbers of infants have either continuous segments of involvement or skip lesions. histologic examination of resected tissue reveals coagulation necrosis in approximately %, inflammation in approximately % and the presence of eosinophils ( %), ulceration ( %), hemorrhage ( %), peritonitis ( %), bacterial overgrowth ( %) and reparative process ( %). pneumatosis intestinalis is present in only % of pathology specimens. coagulation necrosis is the predominant lesion in most specimens. , coagulation necrosis, when present with inflammatory lesions, is often observed in an alternating manner in adjacent microscopic fields. inflammatory changes include acute and chronic signs of inflammation, including serositis, peritonitis, inflammatory pseudomembranes, crypt abscesses, and bacterial or fungal overgrowth. when coagulation necrosis is present with signs of inflammation, the coagulative process is often the dominant lesion. resected tissue also demonstrates extensive apoptosis, enterocyte expression of the inducible isozyme of nitric oxide synthase (inos), as well as increased tissue transcripts for tumor necrosis factor α, interleukins and , and increased messenger rna for stromelysin , a matrix metalloproteinase that can degrade the extracellular matrix. [ ] [ ] [ ] large-vessel thrombi are unusual autopsy findings in the mesenteric arteriole system of patients with nec. , small-vessel thrombi are present in %, but may represent secondary phenomena or autopsy artifacts. interestingly, reparative processes of both acute and chronic types are noted in over % of cases. such reparative changes include focal epithelial regeneration, granulation tissue formation and fibrosis. the latter two processes are usually noted in the mucosal and submucosal layers, but occasionally extend into the muscularis. such fibrotic processes may later be associated with development of strictures in recovering infants. early theories of the pathogenesis of nec proposed a relationship between gastrointestinal ischemia, enteral alimentation and micro-organisms. although the precise contributions of these variables remain ill defined, a multifactorial pathogenesis involving these risk factors plus immature gastrointestinal function and immature host defense mechanisms seems possible for the initiation and subsequent propagation of nec (figs . and . ). , hypoxic-ischemic injury potential alterations of mesenteric blood flow may occur at the large-vessel arterial level and may be associated with redistribution of systemic blood flow or may be within the gastrointestinal system itself with redistribution of local mucosal blood flow. , [ ] [ ] [ ] [ ] the possible systemic alterations may be associated with global hypoxia, asphyxia, exchange transfusion, arterial runoff lesions such as patent ductus arteriosus, shock or anemia. local alterations of the mucosal circulation may be associated with less severe perturbations of these systemic factors plus those local changes occurring during enteral alimentation, polycythemia, intestinal distention or luminal exposure to bacterial toxins or inflammatory mediators. potential events may be initiated during the prenatal period (cocaine exposure, placental insufficiency with intrauterine growth retardation) or may occur after birth. - infants exposed to cocaine prenatally may be at higher risk for the development of nec. although they tend to have higher birthweights and greater gestational age than others at risk for nec, these infants may develop nec sooner and have fewer traditionally identifiable risk factors. additional evidence linking prenatal intestinal ischemia and nec among intrauterine growth-retarded infants may be demonstrated by absent or reversed diastolic blood flow detected by fetal doppler ultrasonography. the regulation of postnatal mesenteric blood flow is complex. autoregulation of regional blood flow is determined by responses to luminal nutrients and autocrine effects of locally produced gut hormones. , these effects may be modified by disease states, medications, the autonomic and central nervous systems, and systemic processes producing vasoconstriction or hypotensive reduction of local tissue blood flow. regional intestinal hyperemia in response to local enteral nutrients is associated with increased local mucosal blood flow, oxygen delivery, oxygen consumption and oxygen extraction. oxygen-derived metabolic processes support aerobic energy-requiring intestinal mechanisms such as mucosal active transport, secretion, motility, digestion, macromolecule synthesis and cell growth. , the postprandial intestinal mucosal hyperemia of adults is due to selective vasodilation of the mesenteric artery and is regulated by central and local mechanisms (local hormones, nutrients). it is possible that an imbalance between oxygen delivery and oxygen consumption, together with inability to augment oxygen extraction (flow-dependent model), predisposes the immature intestine to hypoxic mucosal injury during alimentation. such hypoxic mucosal injury may alter energy-dependent processes, produce malabsorption, mucosal ulceration and ileus, increase mucosal permeability and predispose to secondary bacterial invasion. experiments in mature and immature models support each of these hypotheses as possible mechanisms for pathogenesis hypertonic formula or medication malabsorption, gaseous distention h gas production by nonpathogenic bacteria endotoxin production by nonpathogenic bacteria because % of infants with nec have been fed enterally before its onset, enteral alimentation has been proposed as a contributing factor in nec. , various hypotheses propose that it is the composition of the milk, the rate of milk volume increments, the immaturity of gastrointestinal motility, absorptive or host defense processes, or other variables (high luminal osmolality) that contribute to the pathogenesis of nec. , , human milk reduces the risk for nec. animal models support a role for the breast milk macrophage, but human data suggest that anti-inflammatory cytokines and enzymes as well as immunoglobulins, specifically iga, may have a protective advantage. indeed, both enterally administered serum-derived iga and human milk may reduce the incidence of nec. human milk may also reduce allergic reactions and facilitate the development of a favorable intestinal bacterial flora, while enhancing digestion and absorption of normal nutrients. the volume of milk fed to infants may also predispose the patient to nec. , , - excessively rapid increments of milk feeding may overcome the infant's intestinal absorptive capability, especially in the presence of altered motility, resulting in malabsorption. malabsorbed carbohydrates contribute to enhanced intestinal bacterial gas production, resulting in abdominal distention. , , high intraluminal pressure from gaseous distention may reduce mucosal blood flow, producing secondary intestinal ischemia. in addition, dissection of bacterial gas products from the intestinal lumen may produce pneumatosis intestinalis or, if gas enters the portal venous system, hepatic venous gas may be evident. analysis of gas from the intestinal lumen and cysts of pneumatosis intestinalis reveals a profile typical of intestinal bacterial fermentation of malabsorbed carbohydrates (e.g. hydrogen, methane, carbon dioxide). earlier hypotheses had suggested that giving patients at risk nothing by mouth might reduce the incidence of nec. delayed feeding for asphyxiated infants or those with umbilical arterial or venous catheters and respiratory distress syndrome has not reduced the incidence of nec. , , in fact, delayed feeding may do more harm than good by increasing the risk of intestinal mucosal atrophy, cholestatic jaundice, osteopenia of prematurity and hyperalimentation-related complications. large-volume milk feedings, increased too rapidly during the feeding schedule, may place undue stress on a previously injured or immature intestine. feeding increments in excess of - ml/kg per h were associated with an increased risk of nec in at least two studies. , two other studies have demonstrated the safety of - ml/kg per h feeding increments. , such information should temper enthusiasm for excessively rapid feeding protocols for low-birthweight infants. it suggests that daily increments should be based on the clinical examination, evidence of feeding intolerance and a recommended volume increment of - ml/kg per h. hypertonic formula and enteric medications may have direct adverse effects on mucosal blood flow and intestinal motility. subsequent injury may predispose to nec. , , alternatively, direct pharmacologic effects of an agent on systemic host defense (vitamin e), motility (morphine) or regional blood flow (indomethacin) may result in mucosal injury, increasing the risks for nec in susceptible neonates. h -blocking agents may decrease the risk of nec. there are multiple epidemiologic investigations that have provided circumstantial or direct evidence to suggest that nec is associated with one or more microbiologic agents. , nec has been reported to occur in epidemics or clustered episodes due to an identifiable enteric pathogen; more often no identifiable agent is discovered. , when no agent is identifiable, this may be due to the unculturable nature of the pathogen. the suspicion of a transmissible agent is corroborated by the observation that epidemics abate following the institution or reinforcement of specific infectious disease-control measures (gowning, gloving, nurse cohorts and, especially, careful hand-washing). , epidemics have been associated with the recovery of no specific agent, or with the recovery of a single pathogen such as escherichia coli, klebsiella, salmonella, staphylococcus epidermidis, clostridium butyricum, coronavirus, rotavirus and enteroviruses. , an outbreak of nec has been associated with enterobacter sakazakii-contaminated powdered milk formula. additional evidence suggesting that nec is due to an infectious agent includes the observation of related infantile diarrheal illnesses within a community or among personnel in the neonatal intensive care unit. furthermore, there are similarities between nec (pathology, symptoms, immature susceptibility) and many enterotoxemias of young animals and humans. such enteric toxin-mediated illnesses may be due to clostridium, s. epidermidis or other toxin-producing enteric pathogens. [ ] [ ] [ ] alternatively, endotoxin production by the `normal' gram-negative enteric flora during enteral alimentation may predispose the immature intestine to mucosal injury if endotoxin production exceeds elimination. in addition transcytosis (crossing of epithelial cells by e. coli, etc.) could initiate this process; e. coli from patients with nec has this capacity in animal models. endotoxin stimulates host inflammatory cells to produce various mediators such as tumor necrosis factor and platelet-activating factor. both of these and other inflammatory cytokines can initiate or propagate the pathologic process characterized by coagulation necrosis, inflammation, increased vascular permeability, edema, hemorrhage, local thrombosis and platelet consumption. indeed, the immature enterocyte (epithelial cell) tends to react with excessive local production of proinflammatory cytokines when stimulated with endotoxin or interleukin β. the resulting cytokine mediator-induced thrombocytopenia, neutropenia, hypotensive-hypovolemic shock (third-space fluid losses), metabolic acidosis and hemorrhagic diarrhea are quite similar to the clinical manifestations of nec in human neonates. the blood culture is positive in - % of patients with nec. , reports of the responsible bacteremic pathogens before demonstrated a predominance of e. coli and klebsiella. current reports of agents producing bacteremia in patients with nec suggest that s. epidermidis is another common blood isolate. it remains to be determined whether the organisms recovered in blood or peritoneal cultures are the primary pathogens or secondary invading organisms that gain access to the circulation or peritoneum through a compromised intestinal mucosa. the predominant risk factor for nec is prematurity, not the associated diseases of premature infants. nonetheless, multiple potentially adverse events may produce mucosal injury, the net result being manifest as nec. figure . provides potential initiating events, and figure . identifies additional pathologic factors that may propagate nec once mucosal injury exceeds the immature host's ability to repair the process. although it is hoped that one microbiologic agent or other process will be found to be responsible for nec, it is more probable that nec is a final common pathway for an immature intestinal response to injury. indeed, nec is a common cause of the systemic inflammatory response syndrome (sirs) in neonates. early signs and symptoms of nec are often non-specific; they include subtle signs of the 'sepsis syndrome' and more specific but equally subtle signs of gastrointestinal disease. non-specific extra-gastrointestinal manifestations include apnea, bradycardia, lethargy, temperature instability (hypothermia or the need to increase the isolette temperature to maintain normal body temperature), cyanosis, mottling, cool extremities and acidosis. more specific but not diagnostic gastrointestinal manifestations are related to ileus, third-space fluid losses, local coagulopathy and intestinal hemorrhage. gastrointestinal signs and symptoms include abdominal distention, abdominal tenderness, emesis, sudden increased gastric residual volume, hematemesis, bright red blood from the rectum, absent bowel sounds, abdominal guarding and diarrhea. the latter is an uncommon isolated manifestation of nec. monitoring pre-feed gastric residuals (gastric aspirates) is not helpful in predicting nec as many unaffected neonates have gastric residuals. a sudden change in the volume of gastric residuals plus abdominal distention is more ominous for nec. monitoring for subtle signs of gastrointestinal bleeding with stool guaiac testing is also not helpful as many unaffected premature infants have stools with occult blood, and patients with nec may have stools negative for occult blood. gross blood in the stool is more suggestive of nec but is not diagnostic. as the disease progresses in severity, there is disseminated intravascular coagulation, hypotensive (septic and hypovolemic) shock, ascites, peritonitis and intestinal perforation. focal findings may include erythematous streaking of the anterior abdominal wall around the umbilicus and the course of the subcutaneous umbilical vein, and erythema with a mass in the right lower quadrant, representing a local perforation, with matted bowel forming a local abscess. disease stage should be classified as noted in the diagnosis of nec is confirmed by the radiographic presence of pneumatosis intestinalis or hepatic venous gas (figs . and . ) . gastrointestinal perforation (pneumoperitoneum; figs . and . ) is strong evidence for nec, but the diagnosis must then be confirmed by histopathologic evidence. hepatic venous gas and ascites may also be demonstrated by abdominal ultrasonography or magnetic resonance imaging, and inapparent pneumatosis intestinalis may become more evident by performing a contrast enema. , , nonetheless, except under unusual circumstances (to rule out volvulus), contrast studies are not needed to determine the diagnosis of nec. ancillary laboratory evaluations may reveal thrombocytopenia with or without evidence of disseminated intravascular coagulation, anemia, neutropenia, metabolic acidosis from septic or hypovolemic shock, respiratory acidosis from increased intra-abdominal pressure and poor diaphragm excursion, increased breath hydrogen excretion, raised fecal calprotectin levels and radiographic signs of ileus, an isolated dilated intestinal loop or ascites. , the differential diagnosis of nec is outlined in table . . idiopathic, focal, spontaneous, isolated intestinal perforation is also a common cause of pneumoperitoneum in the pre-term and, less often, full-term neonate. the onset is usually sudden and occurs earlier in life than that of nec. prior feeding may not be present and pneumatosis intestinalis is absent. affected patients usually have respiratory distress syndrome and a lower birthweight and gestational age than patients with nec. the abdominal wall may appear blue, and radiography shows free air and a gasless abdomen. overall survival is better than patients with nec who develop pneumoperitoneum. , prevention nec may not be completely eliminated, but certain interventions have been demonstrated to lower the incidence. oral administration of an iga-igg preparation has been demonstrated to reduce the incidence of nec; however, intravenous or oral administration of igg has not affected the incidence. human milk significantly reduces the incidence of nec among pre-term infants fed donor or their mother's milk. , prenatal administration of corticosteroids lowers the incidence of nec. steroids enhance lung maturation and are thought to accelerate intestinal maturation, thus potentially reducing the 'immaturity' factor in the pathogenesis of nec. postnatal steroids may or may not affect the incidence of nec. judicious slow enteral feeding protocols (no volume increments exceeding - ml/kg per h) may reduce the occurrence of nec. , there is sufficient circumstantial evidence from multiple case-control studies to suggest that moderately slow feeding protocols are associated with a lower incidence of nec. initiation of days of small-volume feedings ( ml/kg daily) (gut stimulation, minimal enteric feeds) has been demonstrated to reduce the incidence of nec when compared to premature infants given advancing feeding (increments of ml/kg daily). in addition, arginine supplementation may reduce the incidence of nec, whereas enteral antibiotics (vancomycin or kanamycin) reduce the incidence of nec but also increases the incidence of microbial flora resistance to the chosen antibodies and thus cannot be recommended routinely. , finally, prevention of premature breath, for instance by administering α-hydroxyprogesterone caproate to the mother, also reduces the incidence of nec. nec has a wide spectrum of severity. the mildest form manifests as hemorrhagic colitis with or without pneumatosis coli; the more fulminant state is similar to that noted in patients with gram-negative septic shock, commonly referred to as sirs. abdominal distention is a universal feature of nec. significant abdominal distention may reduce the mesenteric arterial perfusion pressure, thus exacerbating a previously compromised intestinal blood flow. models of the effects of increased intra-abdominal pressure have reported such adverse consequences as increased systemic vascular resistance, decreased cardiac output, decreased urine output and 'apparent' hypovolemia. , surgical decompression of increased intra-abdominal pressure in human adults restores systemic arterial oxygenation, cardiac output and urine production within min of the procedure. increased intra-abdominal pressure in patients with nec is due to the development of tense ascites, marked intestinal gas production, stasis (ileus) and inflammatory fluid exudation with hemorrhage into the lumen of the small and large intestines. it is imperative to reduce abdominal distention with nasogastric tube placement and no further formula feeding (npo -nil per os). the decompression tube should be the largest that the patient can tolerate. paracentesis with placement of an intra-abdominal drain under local anesthesia has been helpful in stage ii or iii disease. finally, if the patient fails to respond to medical management or abdominal drain placement within - h of the onset of illness, exploratory laparotomy can result in abdominal decompression by removal of necrotic tissue and inflammatory exudate (table . ). the associated bacteremia in approximately - % of patients with nec is probably not the primary cause of the disease. nonetheless, appropriate antimicrobial therapy must be directed against these bacteria, even when the bacteremia is due to bowel injury and secondary bacterial invasion. patients with both nec and bacteremia usually have more severe disease and a higher mortality rate. although the precise antibiotic regimen for the treatment of nec has not been determined, the clinician must remain flexible, as there are changes in the pathogens recovered in patients with nec, and each neonatal intensive care unit has different bacteria with different antimicrobial resistent patterns. , , , this may reflect a bacterial shift in the fecal colonization of premature infants. nonetheless, the changing pattern of the agents recovered during bacteremia requires close scrutiny and appropriate modification of antimicrobial therapy. traditional antimicrobial treatment of nec employs systemic administration of a semisynthetic penicillin (ampicillin, ticarcillin) and an aminoglycoside (gentamicin, kanamycin). evidence suggests a beneficial response with the use of vancomycin and cefotaxime. many recommend anaerobic coverage with clindamycin or metronidazole. vigilant attention to the microbiology of blood, fecal and peritoneal cultures in patients with nec is needed for appropriate modification of antibiotic therapy (see table . for duration of antimicrobial therapy) , . perforation with subsequent bacterial peritonitis is managed with abdominal drain placement or surgery. the treatment of severe nec manifested as sirs is not unlike that of other causes of bacteremia-associated hypotension. endotoxin-stimulated production of inflammatory mediators such as bradykinin, tumor necrosis factor or platelet-activating factor results in increased vascular permeability, large transcapillary fluid loss, increased pulmonary artery pressure with hypoxia, lactic acidosis and hypotension. hypermetabolism increases oxygen requirements. once stabilized from the septic shock state, all patients require parenteral nutrition while npo. fluid losses plus the initial vasodilation increase water and electrolyte requirements. despite rapid killing of bacteria by antibiotics, the diverse effects of bacterial products (endotoxin, etc.) are still evident. the net result is a markedly reduced cardiopulmonary ability to meet the oxygen requirements of the peripheral tissues. [ ] [ ] [ ] the decreased cardiac output in septic shock (and nec) may be due to pooling of blood and fluid in the capacitance peripheral vessels and loss of fluid in third spaces as well as a specific myocardial dysfunction characteristic of severe bacteremic states. the myocardial depression is not due to ischemia but rather to various mediators released as a response to inflammation and hypotension. circulatory failure results in a flow-limited ability to provide the oxygen necessary to support energy metabolism (local tissue oxygen consumption). circulatory failure causes tissue hypoxia and metabolic (lactic) acidosis. some of the cellular defects of oxygen utilization may not be due to hypoxia-ischemia alone. tumor necrosis factor produced during endotoxemia has various metabolic consequences that may interfere with mitochondrial oxygen utilization. methods used to treat septic shock must take into consideration the linear relationship between oxygen delivery and local tissue oxygen consumption. this flow-dependent relationship can be improved by restoring the circulating blood volume (preload) with fluid resuscitation and by improving myocardial contractility with inotropic sympathomimetic agents. an acute 'adult' respiratory distress-like syndrome (ards) may be observed in patients with nec. this is due in part to inflammatory or vasoactive mediators producing non-cardiogenic pulmonary edema. hypoxia is exacerbated by increased pulmonary artery pressure, abdominal distention with reduced diaphragmatic excursion, and myocardial contractile failure. adequate oxygen delivery is closely dependent on appropriate ventilator management of patients with nec. methods that improve oxygen delivery also reduce local lactate production and improve metabolic acidosis. a successful outcome in patients with septic shock is related to the ability of the therapeutic measures to improve cardiac output. in addition to support for the failing circulation, careful attention must be given to the pulmonary problems associated with nec. the application of these principles to the therapy of nec must emphasize aggressive use of fluid resuscitation. if fluid administration is unsuccessful in restoring perfusion and urine production, or in correcting the metabolic acidosis, inotropic drugs (dopamine, dobutamine) can be used to improve oxygen delivery by improving myocardial contractility and occasionally by vasodilation. the administration of inotropic, vasodilator or vasopressor agents must be carefully titrated against peripheral perfusion, blood pressure, urine production, metabolic acidosis and central venous pressure if available. the therapeutic balance between vasopressor (myocardial contractility) agents and vasodilation (afterload reduction) is often difficult to achieve but may benefit from additional fluid therapy. abdominal drainage by percutaneous drain placement may acutely decompress the abdomen and improve many of the adverse cardiopulmonary complications of nec due to a tense abdomen and compromised diaphragms. it may be particularly helpful in improving oxygenation and ventilation. intestinal perforation is a traditional indication for exploratory laparotomy. in certain high-risk, unstable patients (often weighing less than g with stage iib or iii nec), percutaneous placement of an abdominal drain under local anesthesia has been performed. [ ] [ ] [ ] [ ] in many but not all patients with nec managed with paracentesis and a drain, exploratory laparotomy is necessary - h later. drain placement is even more beneficial for patients with isolated idiopathic intestinal perforations. fewer patients with isolated perforations may require immediate exploratory laparotomy in - h. additional indications for surgery include progressive clinical deterioration despite aggressive medical management (see table . ), and in the convalescent stages for the resection of strictures and enteric fistulae. all patients treated with abdominal drain placement must be considered at risk for stricture formation. if percutaneous drainage is used as the first surgical treatment, exploratory laparatomy is then indicated for deterioration, signs of intestinal obstruction or failure of a second drain to relieve pneumoperitoneum. surgical management should attempt to preserve as much viable bowel as possible, resecting only the most obviously necrotic and gangrenous tissue. in circumstances of nec totalis, a high diverting jejunostomy is recommended. a second laparotomy is performed within - h if the patient remains critically ill to determine whether what previously looked like non-viable tissue was actually viable. this approach may avoid massive resection and subsequent development of the short gut syndrome. for patients with minimal and well defined disease, some surgeons recommend that primary anastomosis be performed after resection of dead bowel, at the time of the initial laparotomy. such patients should be observed carefully for development of strictures (at the anastomosis and other sites) or recurrent nec. strictures may present with signs of obstruction (emesis, obstipation, abdominal distention), sepsis or gastrointestinal bleeding. neonatal necrotizing enterocolitis: pathogenesis, classification and spectrum of disease a regional study of underlying congenital diseases in term neonates with necrotizing enterocolitis necrotizing enterocolitis mortality in the united states, - outcome of neonatal necrotising enterocolitis: results of the bapm/cdsc surveillance study impact of necrotizing enterocolitis on length of stay and hospital charges in very low birth weight infants national nosocomial infections surveillance system. nosocomial infections among neonates in high-risk nurseries in the united states nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes gastrointestinal perforation and peritonitis in infants and children: experience with cases over ten years part : current controversies in the understanding of necrotizing enterocolitis epidemiology of neonatal necrotizing enterocolitis: a population-based study frequency of and risk factors for necrotizing enterocolitis in infants born before weeks of gestation neonatal necrotizing enterocolitis: bridging the basic science with the clinical disease necrotizing enterocolitis in neonates with congenital heart disease: risk factors and outcomes the relationship of neonatal feeding practices and the pathogenesis and prevention of necrotizing enterocolitis rapid versus slow rate of advancement of feedings for promoting growth and preventing necrotizing enterocolitis in parenerally fed lowbirth-weight infants pathology of neonatal necrotizing enterocolitis: a ten-year experience role of platelet-activating factor in the pathophysiology of necrotizing enterocolitis intestinal cytokine gene expression in infants with acute necrotizing enterocolitis: interleukin- mrna expression inversely correlates with extent of disease matrix metalloproteinases in necrotizing enterocolitis intestinal ischemia and necrotizing enterocolitis gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin time of onset of necrotizing enterocolitis in newborn infants with known prenatal cocaine exposure ultrasound predictors of neonatal outcome in intrauterine growth restriction donor human milk versus formula for preventing necrotizing enterocolitis in preterm infants: systematic review prevention of necrotizing enterocolitis in low-birth-weight infants by iga -igg feeding randomized trial of 'slow' versus 'fast' feed advancements on the incidence of necrotizing enterocolitis in very low birth weight infants prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants the incidence of necrotizing enterocolitis after introducing standardized feeding schedules for infants between and grams and less than weeks of gestation the effect of feeding volume on the clinical outcome in premature infants nosocomial necrotizing enterocolitis outbreaks: epidemiology and control measures outbreak of necrotizing enterocolitis associated with enterobacter sakazakii in powdered milk formula role of bacterial toxins in neonatal necrotizing enterocolitis analysis of enteric coagulase-negative staphylococci from neonates with necrotizing enterocolitis effect of lipopolysaccharide on intestinal intramucosal hydrogen ion concentration in pigs: evidence of gut ischemia in a normodynamic model of septic shock bacterial toxins and enteral feeding of premature infants at risk for necrotizing enterocolitis escherichia coli transcytosis in a caco- cell model: implications in neonatal necrotizing enterocolitis inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis a critical analysis of the routine testing of newborn stools for occult blood and reducing substances colonic pneumatosis intestinalis in preterm infants: different to necrotizing enterocolitis with a more benign course? pneumatosis coli -a benign form of necrotizing enterocolitis acidosis and hepatic portal venous gas: indications for surgery in necrotizing enterocolitis sonographic findings in necrotizing enterocolitis with paucity of abdominal gas as the initial symptom faecal calprotectin concentrations and diagnosis of necrotizing entercolitis a comparison of the clinical presentation and outcome of focal intestinal perforation and necrotizing entercolitis in very-low-birthweight neonates spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth-weight neonates breast milk and necrotising enterocolitis prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial arginine supplementation prevents necrotizing enterocolitis in the premature infant double blind, randomized, placebo controlled study of oral vancomycin in prevention of necrotizing enterocolitis in preterm, very low birthweight infants enteral antibiotics for preventing necrotizing enterocolitis in low birthweight or preterm infants prevention of recurrent preterm delivery by alpha-hydroxyprogesterone caproate cardiovascular, pulmonary, and renal effects of massively increased intraabdominal pressure in critically ill patients acute renal failure associated with increased intra-abdominal pressure comparison of two antibiotic regimens for neonatal necrotizing enterocolitis intraabdominal infections emergence of antibiotic-resistant bacteria in cases of peritonitis after intraabdominal surgery affects the efficacy of empirical antimicrobial therapy cellular oxygen metabolism during sepsis and shock: the relationship of oxygen consumption to oxygen delivery role of endotoxemia in cardiovascular dysfunction and mortality: escherichia coli and staphylococcus aureus challenges in a canine model of human septic shock sequential physiologic interactions in pediatric cardiogenic and septic shock primary peritoneal drainage for increasing ventilatory requirements in critically ill neonates with necrotizing enterocolitis controversies in the management of necrotizing enterocolitis peritoneal drainage as primary management in necrotizing enterocolitis: a prospective study a meta-analysis of peritoneal drainage versus laparotomy for perforated necrotizing enterocolitis is there a role for high jejunostomy in the management of severe necrotizing enterocolitis? complications after surgical intervention for necrotizing enterocolitis: a multicenter review gellis & kagan's current pediatric therapy, th edn key: cord- -o p ms authors: fenin, audrey; newman, jill c.; taylor, sarah n. title: very low birth weight infants receive full enteral nutrition within postnatal weeks date: - - journal: j perinatol doi: . /s - - - sha: doc_id: cord_uid: o p ms objective: identify whether an enteral nutrition goal of reaching full feeds by postnatal days for infants – . kg and by postnatal days for infants < kg was feasible and its associated outcomes. study design: very low birth weight infant cohort admitted in the first postnatal day and categorized as either epoch or epoch , months before and after implementation of a revised feeding protocol were compared. result: in epoch , % infants born – . kg and % infants born < kg reached full feeds by and days compared to % and %, respectively in epoch (p < . ). central line and parental nutrition days were significantly lower in epoch compared to epoch with sustained and potentially improved infant growth. conclusion: an evidence-based advancement feeding protocol was associated with achieving full feeds within the first postnatal weeks for very low birth weight infants. debate persists in very low birth weight (vlbw) infant care about the initiation and advancement of enteral nutrition [ ] [ ] [ ] . historically, early introduction to enteral feeding and rapid advancement of feeds were related to higher incidence of necrotizing enterocolitis (nec) [ ] [ ] [ ] . however, current evidence demonstrates no benefit to slower enteral feed advancement ( - ml/kg/day compared to - ml/kg/day) and potential harm including a delay in time to achieve full feeds, longer time to regain birth weight, and an increased chance of invasive infection risk with no reduction in the risk of nec [ , ] . on the other hand, no difference in nec or late-onset sepsis was observed in a recently published randomized, controlled trial [ ] . despite the lack of difference in -year outcomes including survival without moderate or severe neurodevelopmental disability in this trial [ ] , neonatal care centers may still find benefit if more rapid advancement of enteral feeds is associated with two common quality indicators in neonatal care-early discontinuation of central venous lines (cvl) and shorter duration of parenteral nutrition (pn), while maintaining infant growth. based on published guidelines recommending advancement of enteral nutrition to achieve full feeds by days in infants born - . kg and by days in infants born < kg [ ] , a nutrition-focused research team, whose work to initiate enteral nutrition in the first postnatal day has been published previously [ ] , aimed to investigate its ability to establish full enteral nutrition ( kcal/kg/day) by postnatal days for infants born - . kg and by postnatal days for infants born < kg after instituting practices that included discontinuation of routine gastric residual monitoring, decreased days of trophic feeding (minimal enteral nutrition), and faster feed volume advancement. despite evidence that early total enteral feeding of - ml/kg/day are tolerated on the first postnatal day in infants - . kg [ ] , concern existed that aggressive early feeding would lead paradoxically to feeding intolerance or fear of feeding intolerance and, therefore, would be associated with a greater delay to achieve full enteral nutrition. therefore, this cohort study, with a retrospective control, was performed with a primary aim to determine if infants were able to reach the full enteral nutrition goal and with secondary aims to determine whether this outcome was associated with changes in pn exposure, cvl days, or growth. after obtaining institutional review board exemption at the medical university of south carolina, this retrospective cohort study was performed at a single university-based tertiary care neonatal intensive care unit. data were retrospectively collected from a nutrition quality improvement database. subjects were selected if birth weight ≤ g and admitted within the first postnatal hours to the neonatal intensive care unit. infants with congenital anomalies, cardiac defects, or metabolic defects that precluded feeding within the first postnatal hours were excluded as were infants who died in the first postnatal hours, or those discharged home or transferred before postnatal days as their gv at days would not be calculated. infants born from march , to february , and meeting inclusion criteria were in the cohort labeled epoch . these dates were chosen as march , was the day of implementation of the new protocol. infants born march , to february , were included in the epoch cohort. data collected included birthweight, gestational age (ga), sex, race, and ethnicity. in addition, antenatal steroid exposure, small-for-gestational age (sga) status, respiratory support in the first postnatal days, feeding type, and hour of first feed were collected. sga was defined as birth weight < th percentile by fenton growth reference chart [ ] . feeding type was differentiated as mother's milk (mm) only, mm and donor human milk (dhm) combined, and dhm only. respiratory support was collected as any oxygen, conventional ventilator, or nasal continuous positive airway pressure (cpap) in the first postnatal days. occurrence of sepsis, bronchopulmonary dysplasia (bpd), and nec was collected through the hospitalization. sepsis was defined as any culture-positive blood infection during hospitalization. bpd was defined as oxygen support required at weeks' ga or at hospital discharge if prior to weeks' ga. nec was determined if modified bell's stage or greater was diagnosed during hospitalization. spontaneous perforation was determined if occurred in first postnatal days and without a diagnosis of nec. cvl and pn number of days and time to full feeds were calculated by finding the difference between the recorded times of initiation and discontinuation for each measure. growth trajectory was measured as -day gv, days to return to birth weight, and the change in weight z-score from birth to days as determined by the fenton growth reference chart [ ] . day gv was chosen as the primary indicator of growth and was calculated by the -point model (change in weight in grams from birth to days/the average weight between birth and days/ days) [ ] . days to return to birth weight was calculated as the first postnatal day at which the infant's weight was higher than the birth weight. infants in epoch had feeds initiated and advanced per a previous feeding protocol adopted in . infants in epoch had feed initiation and advancement per the revised protocol instituted on march , . the revised feeding protocol was the result of the vlbw infant feeding evidence and expert recommendations published prior to october , as reviewed by an institutional multidisciplinary team comprising neonatologists, nurses, neonatal nurse practitioners, and neonatal registered dietitians. the march revised protocol included continuation of the practice of initiating feeds at - postnatal hours, discontinuation of the practice of routine gastric residual monitoring, a decrease in days of trophic feeding of ml/ kg/day from to days in infants < kg and from to day in infants - . kg. the revised protocol also included institution of the practice of faster advancement of enteral feeds with infants < kg advanced at ml/kg/day divided into two daily steps (morning and evening) with fortification to kcal/oz at~ ml/kg/day and infants - . kg advanced at ml/kg/day also with two daily steps with fortification at~ ml/kg/day. in epoch , infants < kg advanced at~ ml/kg/day, also divided in two daily steps with a two-step fortification of kcal/oz for h followed by kcal/oz at ml/kg/day. for infants - . kg, advancement was also done in two daily steps of ml/kg/day, fortified at ml/kg/day in two steps also. the practice of introduction of enteral feeds at - postnatal hours was continued since an earlier study had shown this practice was associated with decreased central line infections, decreased feeding intolerance and improved gv [ ] . infants in both epoch and were either fed mm or dhm after obtaining parental assent if mm not available. to facilitate institution of the protocol, physicians, nursing, and dietary staff were educated prior to the protocol change by oral and visual presentations. see fig. for a schematic of the new protocol change. no other changes in nutrition delivery, including pn, occurred during the study period. power analysis demonstrated to achieve % power to detect a difference between the group proportions of . , subjects were needed in each epoch to identify whether the proportion of infants achieving full feeds differ by . from the . proportion at baseline. a two-sided z test with pooled variance was used with a targeted significance level at . . with an estimated eligible subjects born each year, -year pre-(epoch ) and -year post (epoch ) were chosen as the ranges for subject inclusion. descriptive statistics for demographic and outcome characteristics were reported as frequencies and percentages, means and standard deviations or median and interquartile ranges. for the primary aim, a dichotomous (yes/no) variable to indicate whether the infant met the goal for full enteral nutrition was defined. infants were stratified by birth weight (< kg and - . kg). for infants whose birth weight was < kg, the infant met goal if the number of days to full enteral nutrition was less than or equal to postnatal days. if the number of days was > postnatal days, then the infant did not meet the goal for full enteral nutrition. the same definition applied to birth weight - . kg with the cut-point for number of days being . chi-square tests or fisher's exact tests were used to test for associations between categorical measures. since the distributions for number of days cvl and pn were skewed, wilcoxon rank sum tests were used for unadjusted associations. student's t test was used to test for associations of normally-distributed continuous measures. multivariate linear and generalized mixed models were used to assess differences in epoch for gv, number of cvl days, and number of pn days, after controlling for birth ga, birth weight, race/ethnicity, sex, and antenatal steroid exposure. due to concern for collinearity, further comparisons were performed using sga status (yes or no) instead of birth weight in all models. weight z-score change from birth to -days also was assessed as the dependent variable in this second regression model. a bar chart was created to show the proportion of infants that met the goal for full enteral nutrition by epoch and weight group. histograms were used to show the distributions of continuous outcome measures by group. a p value < . was considered statistically significant and all analyses were performed using sas version . (cary, nc). a total of infants met inclusion criteria. in epoch , subjects were excluded ( due to discharge or transfer to another hospital, due to death, and with congenital anomaly affecting feeding). in epoch , subjects were excluded ( due to discharge or transfer to another hospital, due to death, and with congenital anomaly affecting feeding). the two groups were similar in baseline demographics, including sga status at birth, as shown in tables and . in comparison of feeding exposures which were not affected by the revised feeding guideline, the proportion of infants receiving a combination of dhm feeds, as well as those receiving only dhm were not significantly different between epochs. in addition, both epochs demonstrated initiation of feeds at a median of h. respiratory exposure in the first postnatal days did not significantly differ between groups except a significantly higher proportion of infants born to . kg received nasal cpap in epoch . in epoch , % of infants born - . kg achieved full enteral feeds by days and % of infants born < kg achieved full enteral feeds by days and these proportions were significantly higher than for similar infants in epoch (fig. ) . cvl and pn days were also significantly lower in epoch compared to epoch (table ) and the significant difference remained apparent when stratified by weight group (table ) . only infants out of the total infants in epoch had cvl and out of infants in epoch had cvl. the distribution of days with pn and cvl between epochs and by weight group is shown in fig. . in unadjusted analyses, no difference in the mean -day gv, weight z-score change from birth to postnatal days, or average days to return to birth weight were observed between epoch, even when stratified by weight group (tables and ). multivariate analyses were performed for three secondary outcomes, cvl and pn days and -day gv. initially, regression models were performed with independent variables ga, birth weight, sex, race and ethnicity, and antenatal steroid exposure with significantly lower cvl and pn day in epoch versus epoch (p value < . for both comparisons). in addition, in an adjusted model, gv from birth to days was significantly higher in epoch versus epoch (β estimate (β) = . , standard error (se) = . and p-value= . ). due to concern for collinearity with birth ga and weight in the same model, a second model was developed with sga versus non-sga as a covariate instead of birth weight. the results of significantly higher gv in epoch versus epoch did not differ in the new multivariate model (β = . , se = . and p value . ). consistent with previous findings, the number of cvl days remained significantly lower in epoch very low birth weight infants receive full enteral nutrition within postnatal weeks (β = − . , se = . and p value < . ). similarly, the analysis for the number of pn days was also significantly lower in epoch (β = − . , se = . and p value < . ). since growth velocity was significantly different between epochs in adjusted analysis, similar regression analysis including sga status to replace birth weight, was performed to identify whether weight z-score change from birth to postnatal days differed significantly by epoch when controlling for the other factors. it did not (p = . ). in comparison of morbidities between groups, no infants in this study experienced spontaneous intestinal perforation. no difference was observed between epochs in bpd, nec, or late onset-sepsis, except the proportion of infants born < kg who developed nec was significantly lower in epoch . this difference likely is not related to the revised feeding protocol and, instead, demonstrates the natural variation in nec incidence at a single institution over a -month period. after implementing an evidence based revised feeding guideline which included discontinuing the practice of gastric residual monitoring, decreasing number of days of trophic feeding and progressive enteral feeding advancement, % of infants - . kg and % of infants < kg superscript identify the descriptive statistics which is "b" for mean (standard deviation). c superscript identify the descriptive statistics which is "c" for median [interquartile range]. reached full feeds by and postnatal days, respectively. this change was associated with statistically and clinically significantly less days of cvl and pn in both unadjusted and adjusted comparisons. in addition, in adjusted models, mean -day growth velocity was significantly higher for the epoch receiving the revised feeding protocol (epoch ). however, weight z-score change from birth to -days was not significantly different between epochs in either univariate or multivariate analysis. this study focused specifically on how the revision of the feeding protocol, as compared by epochs, related to the outcomes of interest. investigation of how other parameters such as ga, sga status, and antenatal steroids was not performed in this study but may be of interest in future research of vlbw infant feeding. superscript identify the descriptive statistics which is "b" for mean (standard deviation). c superscript identify the descriptive statistics which is "c" for median [interquartile range]. the revised feeding protocol had multiple components based on evidence review. the revisions included a discontinuation of routine gastric residual monitoring which was based on recent evidence demonstrating no utility of this practice and the potential that it is associated with a delay in achievement of full enteral nutrition [ ] . recently, results of a randomized, controlled trial verified the results of earlier observational studies and showed increased enteral nutrition delivery and improved weight gain when gastric residuals were not routinely monitored [ ] . the revised guidelines in our study also included a shortened duration of trophic feeds to day for infants - . kg and to days for infants < kg. a previous retrospective cohort study demonstrated days of trophic feeds was associated with faster achievement of full enteral nutrition in extremely preterm infants [ ] . in our study, the increased daily feed advancement volume to - ml/kg/day was based on published systematic review of the evidence [ ] . more recently, the results of -year outcomes of a multicenter randomized trial comparing ml/kg/day with ml/kg/ day were published [ ] . in this recent publication, a more rapid advancement of volume was associated with shorter duration to achieve full feeds, but no significant difference in -year outcomes was observed except for infants receiving formula-only feeds who demonstrated better survival without moderate or severe neurodevelopmental disability in the slower feed volume advancement group. of note, the infants in this multi-center randomized trial did not start feeds on the first postnatal day [ ] . in this study with human milk feeds initiated on the first postnatal day, full feeds were achieved with lower cvl and pn days and higher growth velocity when adjusted for potential confounders. other retrospective cohort studies have demonstrated similar results but occurred in an older patient population [ ] , included parenteral nutrition revisions [ ], or compared a decrease in the number of days prior to feed progression. a decrease in the number of days prior to feed progression was associated with improved -day gv [ ] . a similar significant increase in gv was found in our study when adjusted for potential confounders. in addition in our results, the change in z-score for both epochs were similar to the change observed by rochow et al., though they measured change in z-scores from birth to postnatal days, instead of days, and included infants - weeks' ga [ ] . in our study, no difference in the number of days to return to birth weight was observed between epochs which may reflect the fact that pn practices did not differ between groups [ ] . the strengths of this study include [ ] the similarity of infants in both epochs in terms of sex, birthweight, and ga, and [ ] the inclusion of infants who were sga in these standard feeding protocols. days of exposure to pn were decreased in this study hence potentially decreasing the risks and costs associated with pn. days with a cvl were decreased hence decreasing the days on which line complications could occur as well as the risk for central line-associated blood stream infection. limitations of this study include that not every potential complication of a revised feeding potential was studied. for example, the number of abdominal radiographs to evaluate potential feeding intolerance was not measured. in addition, although the study center is a tertiary regional center covering an eight-county region of south carolina, this was still a single-center cohort study. gv was only measured at postnatal days. therefore, the effect on long-term growth is not known. despite clinical concern that "pushing" infants to feed earlier and more quickly would lead to more stops and starts of feeding and therefore longer time to full enteral feeds, this study shows that achieving full enteral nutrition within postnatal week for infants born - . kg and within postnatal weeks for infants born < kg is feasible and can be applied to clinical practice. the magnitude of the decrease in central line and parenteral nutrition demonstrates the potential for decreased patient morbidity and hospital cost associated with this strategy. postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants growth failure in the preterm infant: can we catch up? enteral feeding regimens and necrotising enterocolitis in preterm infants: a multicentre case-control study role of delayed feeding and of feeding increments in necrotizing enterocolitis prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. cochrane datab system rev controlled trial of two incremental milk-feeding rates in preterm infants guidelines for feeding very low birth weight infants early enteral feeding in very low birth weight infants early total enteral feeding in stable preterm infants: a systematic review and metaanalysis a systematic review and meta-analysis to revise the fenton growth chart for preterm infants an attempt to standardize the calculation of growth velocity of preterm infants-evaluation of practical bedside methods the value of routine evaluation of gastric residuals in very low birth weight infants effect of gastric residual evaluation on enteral intake in extremely preterm infants: a randomized clinical trial short versus extended duration of trophic feeding to reduce time to achieve full enteral feeding in extremely preterm infants: an observational study reducing time to initiation and advancement of enteral feeding in an all-referral neonatal intensive care unit very low birth weight infants receive full enteral nutrition within postnatal weeks . thoene mk, lyden e, anderson-berry a. improving nutrition outcomes for infants < grams with a progressive, evidenced-based enteral feeding protocol implementation of feeding guidelines hastens the time to initiation of enteral feeds and improves growth velocity in very low birthweight infants physiological adjustment to postnatal growth trajectories in healthy preterm infants effect of early parenteral nutrition discontinuation on time to regain birth weight in very low birth weight infants: a randomized controlled trial acknowledgements the authors acknowledge dr. julie ross for her leadership in quality improvement initiatives in the neonatal intensive care unit, the entire medical university of south carolina milky weigh nutrition quality improvement team, and the physicians, nurses, and dietitians who follow these evidence-based protocols in their care of vlbw infants. in addition, the authors acknowledge dr. martina mueller who assisted in the statistical methodology. the authors have no disclosures or sources of any support for this work such as grants and/or equipment and drugs.author contributions af and snt provided substantial contributions to the conception and design of the work. af performed data acquisition. all authors made substantial contributions in data analysis, data interpretation, and drafting the work with final approval of the version to be published. conflict of interest snt has received research funding from nih and the allen foundation. snt has served as a consultant for alcresta therapeutics and serves as a volunteer member of the mother's milk bank northeast medical advisory board. af and jcn have no potential conflict of interest to declare.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - g p vtm authors: wang, ting-ting; zhou, ming; hu, xue-feng; liu, jiang-qin title: perinatal risk factors for pulmonary hemorrhage in extremely low-birth-weight infants date: - - journal: world j pediatr doi: . /s - - - sha: doc_id: cord_uid: g p vtm background: pulmonary hemorrhage (ph) is a life-threatening respiratory complication of extremely low-birth-weight infants (elbwis). however, the risk factors for ph are controversial. therefore, the purpose of this study was to analyze the perinatal risk factors and short-term outcomes of ph in elbwis. methods: this was a retrospective cohort study of live born infants who had birth weights that were less than g, lived for at least hours, and did not have major congenital anomalies. a logistic regression model was established to analyze the risk factors associated with ph. results: there were elbwis born during this period. a total of infants were included, and infants were diagnosed with ph. risk factors including gestational age, small for gestational age, intubation in the delivery room, surfactant in the delivery room, repeated use of surfactant, higher fio( ) during the first day, invasive ventilation during the first day and early onset sepsis (eos) were associated with the occurrence of ph by univariate analysis. in the logistic regression model, eos was found to be an independent risk factor for ph. the mortality and intraventricular hemorrhage rate of the group of elbwis with ph were significantly higher than those of the group of elbwis without ph. the rates of periventricular leukomalacia, moderate-to-severe bronchopulmonary dysplasia and severe retinopathy of prematurity, and the duration of the hospital stay were not significantly different between the ph and no-ph groups. conclusions: although ph did not extend hospital stay or increase the risk of bronchopulmonary dysplasia, it increased the mortality and intraventricular hemorrhage rate in elbwis. eos was the independent risk factor for ph in elbwis. pulmonary hemorrhage (ph) is a life-threatening respiratory complication of newborns [ ] , especially in extremely lowbirth-weight infants (elbwis) who are vulnerable to conditions that require invasive ventilation and intensive care after birth. the incidence of clinical ph is estimated to be - per live births [ ] , whereas the rate of ph in very-lowbirth-weight infants (vlbwis) varies from - % [ ] [ ] [ ] [ ] . the variation in its incidence is mainly due to the unclear etiology and diagnostic criteria of ph. the pathophysiology of ph in newborns is hemorrhagic edema [ , ] . the severity may vary from a mild, self-limited disorder to a massive, deteriorating and end-stage syndrome. it is associated with significant morbidity and high mortality. usually, infants with ph need aggressive positive pressure ventilation, high oxygen supplementation, critical circulatory support and blood transfusions. asphyxia, prematurity, intrauterine growth restriction, infection, hypoxia and coagulopathy are considered as perinatal risk factors for ph in many studies [ , , ] . a few case reports have indicated that healthy term infants with ph are associated with inborn errors of metabolism. furthermore, risk factors associated with the care of preterm infants, including surfactant replacement, the management of patent ductus arteriosus (pda) and the fluid intake of ph, might be prominent in elbwis with ph [ ] [ ] [ ] . however, the risk factors for ph in elbwis are controversial, and more studies are needed to further enhance the understanding of the pathophysiology of ph in these extremely premature infants. therefore, the purpose of this study was to analyze the perinatal risk factors and short-term outcomes of ph in elbwis. this is a retrospective cohort study. infants were eligible for the analysis with birth weight less than g, living for at least hours and no extreme cogenital anomalies at a hospital between january st, and december st, . elbwis were excluded from the study if their parents decided to withdraw treatment of their newborns within the first hours of life due to extreme prematurity. infants transferred to other children's hospitals due to cardiac, gastrointestinal or other abnormalities within the first week of life were also excluded. this study was approved by the ethics committee of the hospital. all medical records/information were anonymized and deidentified prior to analysis. all elbwis were resuscitated by a pediatric team led by an attending pediatric physician according to the management guidelines of elbwis. briefly, the elbwis were wrapped with plastic bags under a radiant warmer and with respiratory support by a t-piece resuscitator. a peep cm h o and/or pip cm h o was provided through a face mask immediately after birth. intubation and/or prophylactic surfactant replacement was provided at the discretion of the attending physician in the delivery room. oxygen supplementation was given and adjusted according to the target saturation on a pulse oximeter [ ] . when the infants were transferred into the neonatal intensive care unit (nicu) and put on a ventilator or nasal continuous positive airway pressure (ncpap), a physician on duty at the nicu evaluated the respiratory severity and decided to extubate the infant to ncpap after giving surfactant if required. an umbilical venous catheter was inserted, and total parenteral nutrition (tpn) infusion was given. ph was defined as bright red blood secretion from the endotracheal tube that was associated with clinical deterioration, including increased ventilator support with a fraction of inspired oxygen (fio ) increase of > . from the baseline [ ] or an acute drop in hematocrit (> %) [ ] , in addition to multilobular infiltrates on chest radiography. the record of ventilation of every infant was reviewed by two attending neonatologists independently and confirmed the diagnosis of ph. when a clinical diagnosis of ph was made, the infant was intubated and ventilated with high-frequency oscillatory ventilation (hfov). the ventilation parameters were adjusted appropriately according to the oxygen saturation, the results of arterial blood gas assessment and the chest x-ray. surfactant replacement was considered if necessary. the perinatal data of all infants and their mothers were collected by retrospective chart review that contained sex, gestational age (ga), birth weight (bw), small for gestational age (sga), apgar score at and minutes, delivery method, maternal age, prenatal infection, pregnancy hypertension, gestational diabetes (gdm), prenatal antibiotics and corticosteroids, cause of premature birth, cervical cerclage, surgery during pregnancy, and placental abruption. the short-term outcomes of the infants were also recorded. neonatal respiratory distress syndrome (nrds) and its severity were diagnosed by the neonatologists of the nicu based on the clinical profile and chest radiograph. early onset sepsis (eos) was defined as infectious diseases within hours after birth as confirmed by blood culture. brain injury, including grade iii-iv intraventricular hemorrhage (ivh) and periventricular leukomalacia (pvl), was identified by serial head ultrasounds. bronchopulmonary dysplasia (bpd) was defined as the requirement for supplemental oxygen at weeks postmenstrual age among infants who survived to nicu discharge. retinopathy of prematurity (rop) was screened by an ophthalmologist. echocardiography was performed between days and by a cardiologist and repeated as appropriate. the hemodynamically significant pda was managed by neonatologists, and ibuprofen was given to close the patent ductus. the treatment was withheld if there was identification of gastrointestinal bleeding or oliguria (urine output of less than ml/kg/hour) according to the protocol for pda management in our nicu. the decision was made by the neonatologists to transfer the elbwi for surgical ligation if more than two courses of oral ibuprofen were given and the pda was still significant [ ] . the data were analyzed with spss version . . descriptive statistic analysis were used to describe the characteristics of mothers and infants. the normally distributed results are reported as the mean and standard deviation (sd); the remaining results are reported as the median, interquartile range (iqr) or percentage. chi-squared test, student's t-test and logistic regression model were used for statistical analysis. a total of elbwis were born in this hospital and admitted to the nicu between january st, , and december st, . six infants were transferred to other hospitals for surgical diseases, and two infants died (they were identical twins who were born at weeks and days of ga; their birth weights were g and g, respectively). their parents withdrew care within hours of life due to concerns about adverse long-term outcomes. among the infants included in this study, infants were diagnosed with ph (ph group), leading to an incidence of ph in these elbwis of . %. the median age of infants with ph occurrence was (iqr - . ) days. one elbwi had ph occurred within hours, on day , day and day after birth, respectively; had ph that occurred on day - after birth, three on day and two on day . the perinatal risk factors of ph are listed in table and . the ga of the infants with ph was significantly lower than that of the non-ph infants. there were fewer sga infants in the ph group than no-ph group. because most cases of ph occurred within days of life and the majority occurred in the first week of life, the average fluid intake within the first and days of life was also compared between the ph and no-ph group. unsurprisingly, the infants with ph were more likely to be intubated and treated with surfactant and oxygen supplementation. a multivariate analysis (including ga, sga, intubation in the delivery room, surfactant in the delivery room, repeated use of surfactant, higher fio during the first day, invasive ventilation during the first day, and eos) was performed by using the logistic regression model, which found that eos was an independent risk factor for ph (table ). the mortality of infants with ph was . % ( / ), which was significantly higher than that of infants without ph ( . %, / ). the rate of major ivh was higher in the ph group than that in the no-ph group. however, the rates of pvl, moderate-to-severe bpd, and severe rop were not significantly different between the ph and no-ph group (table ) . among the patients who were discharged home ( in the ph group and in the no-ph group), there were no significant differences of the duration of assisted ventilation, invasive mechanical ventilation, oxygen supplementation, hospital stay, or moderate-to-severe bpd between the two groups (table ). in this study, we found that elbwis with ph were likely to be intubated and require surfactant therapy, invasive ventilation and oxygen supplementation, whereas the mortality and major ivh rates were also increased. logistic regression analysis showed that eos could increase the risk of the incidence of ph is significantly higher in elbwis than that in other neonatal populations, and the precise etiology remains unclear. a -year retrospective study has shown that the rate of ph in vlbwis is % [ ] . another study reported that the rate of ph was approximately % in vlbwis but was - . % in elbwis [ , ] . in our cohort, the rate of ph in elbwis was . %. it has been shown that sga, eos, low birth weight (lbw), lower apgar scores at and minutes, severe rds and surfactant replacement are risk factors for ph [ ] . usually, smaller gestational age and lower birth weight increase the odds of eos in preterm infants. ph may occur as a result of unstable hemodynamics and coagulopathy in elbwis with eos. it has been proven that delayed cord clamping reduces the risk of ph [ ] . circulatory stabilization is the fundamental management strategy for elbwis and reduces the risk not only for pulmonary disease but also of mortality and ivh. many studies have shown that pda is associated with the occurrence of ph [ , , ] . as a result of decreased pulmonary vascular resistance, left-to-right shunting through pda increases blood flow and the pressure state of the pulmonary vessels, which may compromise cardiac function with an increased risk of ph [ ] . in our cohort, the rates of pda and requirement of treatment were higher in infants with ph than in those without, but the differences were not statistically significant. interestingly, the time of ph occurrence in our cohort was earlier than that of the development of hemodynamically significant pda [ ] . the other reason might be the active management of pda in elbwis [ ] . in our study, . % of the infants with pda in the ph group and . % in the no-ph group required oral ibuprofen or ligation. in addition, there was no significant gastrointestinal bleeding or oliguria observed in either the ph or no-ph group when ibuprofen was given, while the side effects of ibuprofen were fewer than those of indomethacin [ ] . in addition, the overload of fluid intake within the first week was associated with pda and ph [ , ] . polglase et al. [ ] demonstrated that immediately after an intravenous volume overload, lambs had increases in pulmonary blood flow and the left ventricular ejection volume; % of them developed ph. the elevation in pulmonary capillary pressure can lead to alveolar capillary wall injury, causing pulmonary edema due to increased permeability with the passage of proteins [ ] . in our study, the fluid intake of these elbwis was restricted to an average of - ml/kg/day to reduce the risk of bpd and hemodynamically significant pda [ ] and showed no difference between infants with ph and those without ph. surfactant replacement is a standard treatment for rds. it has been shown that surfactant replacement increases the risk of ph [ ] . in contrast, some studies have reported that the rates of ph are not different before or after surfactant replacement therapy [ ] . it is reasonable to postulate that the infants who need surfactant are sicker and more likely to have ph than those who do not need surfactant. although an in vitro study showed that the presence of surfactant impaired coagulation function [ ] , this finding was not proven clinically. on the other hand, infants with ph can be treated with surfactant because of the inhibition of surfactant function by blood. few retrospective and observational reports have demonstrated the benefits of surfactant on ph. however, the effect of this therapy remains to be established [ ] . it seems that the chemical composition of different surfactant types affects the risk of ph [ ] . infants given poractant alfa have a significantly higher rate of ph ( %) than infants treated with surfactant-ta ( %) [ ] . however, the clinical risk index for babies scores were higher in infants treated with poractant alfa than in infants treated with poractant alpha. in our cohort, the infants with ph were similar to the infants without ph in terms of surfactant administration in the delivery room or nicu. however, the infants with ph needed multiple doses of surfactant. infants who were given surfactant prophylactically in the delivery room did not have an increased risk of ph. ph is a life-threatening condition of hemorrhagic pulmonary edema with high mortality. in our study, the mortality of elbwis with ph was % (vs. % in the no-ph group), similar to previous reports [ ] . the rate of major intraventricular hemorrhage was significantly higher in the ph infants than in the non-ph infants ( % and %, respectively, p < . ). both ph and intraventricular hemorrhage are related to perinatal hemodynamic instability [ ] . the effective management of ph includes positive pressure ventilation [ ] , blood transfusion and circulation support. however, there were no significant differences in mechanical ventilation, oxygen supplementation, or hospital stay between surviving infants in the ph and no-ph groups, mainly because these factors, in addition to ph, are independently related to prematurity. this is a retrospective study in a single center of shanghai, which may not be able to highlight all the risk factors of ph in elbwis due to the limited data and small sample size. however, analyzing the risk factors of ph will help physicians to better understand why ph occurs and how to prevent it. in summary, ph is an adverse pathophysiological event of elbwis that occurs mostly within the first hours of life. ph increases the risk of mortality and major intraventricular hemorrhage, and early onset sepsis is an independent risk factor for ph. funding no funding was received. ethical approval this study was approved by ethics committee of the shanghai first maternity and infant hospital, tongji university school of medicine. no financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. open access this article is distributed under the terms of the creative commons attribution . international license (http://creat iveco mmons .org/licen ses/by/ . /), which permits unrestricted use, distribution, and reproduction in any medium, provided 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. pulmonary hemorrhage clinical course and outcomes among very low-birth-weight infants prevalence, risk factors and outcomes associated with pulmonary hemorrhage in newborns pulmonary hemorrhage in very low-birthweight infants: risk factors and management short-term outcome of pulmonary hemorrhage in very-low-birthweight preterm infants improvement in mortality of very low birthweight infants and the changing pattern of neonatal mortality: the -year experience of one perinatal centre risk factors of pulmonary hemorrhage in very low birth weight infants: a two-year retrospective study early versus delayed neonatal administration of a synthetic surfactant: the judgment of osiris ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage high-risk factors and clinical characteristics of massive pulmonary hemorrhage in infants with extremely low birth weight defining the reference range for oxygen saturation for infants after birth pda: to treat or not to treat pulmonary hemorrhage (ph) in extremely low birth weight (elbw) infants: successful treatment with surfactant circulatory management focusing on preventing intraventricular hemorrhage and pulmonary hemorrhage in preterm infants prevention and -month outcomes of serious pulmonary hemorrhage in extremely low birth weight infants: results from the trial of indomethacin prophylaxis in preterms intravenous paracetamol treatment in the management of patent ductus arteriosus in extremelylow birth weight infants failure of a repeat course of cyclooxygenase inhibitor to close a pda is a risk factor for developing chronic lung disease in elbw infants ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants fluid regimens in the first week of life may increase risk of patent ductus arteriosus in extremely low birth weight infants risk factor profile of massive pulmonary haemorrhage in neonates: the impact on survival studied in a tertiary care centre cardiopulmonary haemodynamics in lambs during induced capillary leakage immediately after preterm birth stress failure of pulmonarycapillaries: role in lung and heart disease neonatal research network. association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants comparison of two natural surfactants for pulmonary hemorrhage in very low-birthweight infants: a randomized controlled trial surfactant impairs coagulation in-vitro: a risk factor for pulmonary hemorrhage? surfactant for pulmonary haemorrhage in neonates efficacy of surfactant-ta, calfactant and poractant alfa for preterm infants with respiratory distress syndrome: a retrospective study acknowledgements we thank dr. po-yin cheung for his professional guidance for the preparation of this paper.author contributions ttw collected and analyzed the data, and drafted the manuscript. mz and xfh collected the data. jql designed the study. all authors approved the final version of the manuscript. key: cord- -fvdock authors: florin, todd a; plint, amy c; zorc, joseph j title: viral bronchiolitis date: - - journal: the lancet doi: . /s - ( ) - sha: doc_id: cord_uid: fvdock viral bronchiolitis is a common clinical syndrome affecting infants and young children. concern about its associated morbidity and cost has led to a large body of research that has been summarised in systematic reviews and integrated into clinical practice guidelines in several countries. the evidence and guideline recommendations consistently support a clinical diagnosis with the limited role for diagnostic testing for children presenting with the typical clinical syndrome of viral upper respiratory infection progressing to the lower respiratory tract. management is largely supportive, focusing on maintaining oxygenation and hydration of the patient. evidence suggests no benefit from bronchodilator or corticosteroid use in infants with a first episode of bronchiolitis. evidence for other treatments such as hypertonic saline is evolving but not clearly defined yet. for infants with severe disease, the insufficient available data suggest a role for high-flow nasal cannula and continuous positive airway pressure use in a monitored setting to prevent respiratory failure. acute bronchiolitis, a viral infection of the lower respiratory tract, is one of the most substantial health burdens for infants and young children worldwide. respiratory syncytial virus is the most prevalent viral cause of bronchiolitis in infants. estimates suggest that about million new cases of lower respiratory infection due to respiratory syncytial virus occur globally in children younger than years, with · million admissions to hospitals and about deaths per year, predominantly in the developing world. in developed countries such as the usa, bronchiolitis is the most common reason for admission to hospital in the fi rst months of life, accounting for approximately infant admissions annually. although admissions to hospital have declined from to , emergency department visits have increased, in addition to increased use of mechanical ventilation and hospital charges. , the clinical management remains challenging despite the frequency, global reach, economic cost, and morbidity and mortality associated with bronchiolitis. several treatment strategies (including bronchodilators and corticosteroids) showed no eff ect in pooled metaanalyses, making supportive care the hallmark of current therapy. in this seminar, we aim to summarise the current evidence for the epidemiology, pathophysiology, diagnostic approach, and management of acute viral bronchiolitis. bronchiolitis is a seasonal infection, with the season typically beginning in late october in the temperate northern hemisphere, peaking in january or february, and ending in april. globally, independent of region, respiratory syncytial virus infection peaks consistently during annual or biannual epidemics. although the peak and duration of these epidemics vary worldwide, they are consistent year-to-year within a country. some data suggest that climate might also be associated with prevalence of respiratory syncytial virus infection, with global surveillance suggesting that infection peaks during wet months in areas with high precipitation and during cooler months in hot regions. indoor crowding in population-dense areas during rainy seasons or cooler months might be one factor that facilitates viral transmission. additionally, weather-related factors, such as inhalation of cold and dry air that might impair ciliary function, the airway mucosa, and inhibition of temperature-dependent antiviral responses, might infl uence both disease transmission and severity. , altitude, climate, and meteorological conditions (such as wind speed and dew point) have been shown to have a modest association with bronchiolitis. , furthermore, air pollutants, such as ozone and traffi c pollutants, have been associated with exacerbations of respiratory infections in children younger than years. [ ] [ ] [ ] environmental tobacco smoke has been associated with increased risk for respiratory syncytial virus-attributable admission to hospital and disease severity in those admitted. , as with other respiratory viral infections, the risk of severe respiratory syncytial virus bronchiolitis might be greater in boys than in girls. , this diff erence might be due to diff erences in lung and airway development, and by genetic factors. , pathophysiology bronchiolitis is characterised by extensive infl ammation and oedema of the airways, increased mucus production, and necrosis of airway epithelial cells. respiratory syncytial virus binds to epithelial cells and replicates, resulting in epithelial necrosis and ciliary destruction. , the cell destruction triggers an infl ammatory response with proliferation of polymorphonuclear cells and lymphocytes. the submucosa and adventitial tissues become oedematous with increased mucus secretion. plugs composed of cellular debris and mucus form in the bronchiole lumens leading to bronchiolar obstruction, air trapping, and diff erent degrees of lobar collapse. microbiology molecular testing has led to an improved understanding of the viruses associated with bronchiolitis. respiratory syncytial virus remains the most commonly identifi ed virus, detected in - % of patients. [ ] [ ] [ ] [ ] [ ] [ ] other viruses associated with bronchiolitis include rhinovirus, metapneumovirus, coronavirus, human bocavirus, infl uenza virus, adenovirus, and parainfl uenza virus. , , , , studies have investigated whether severity of illness, as measured by need for hospital admission, length of hospital stay, intensive care unit admission, repeated emergency department visits, and apnoea, is associated with specifi c viral infections or co-infections, but the evidence is confl icting. data from some studies have shown that in infections involving a single virus, respiratory syncytial virus is associated with a more severe course compared with other viruses. , up to % of children with bronchiolitis are found to have co-infections with two other viruses, with the combination of respiratory syncytial virus and rhinovirus being the most commonly reported. some evidence suggests that co-infection in bronchiolitis, particularly respiratory syncytial virus in combination with rhinovirus or metapneumovirus, could be associated with a more severe disease course compared with infection by a single virus. , , , , however, other studies do not confi rm this association. , furthermore, although use of nucleic acid amplifi cation tests has greatly improved our ability to detect viruses present in respiratory infections, studies using these technologies have also found at least one respiratory virus in up to % of children younger than years with no respiratory symptoms. [ ] [ ] [ ] these viruses might be detected because of asymptomatic colonisation, incubation before clinical infection, or prolonged viral shedding post-infection. the confl icting evidence and high prevalence of respiratory viruses in asymptomatic children suggest no indication at this time that management should vary based on presumed viral cause and presence, or absence of viral co-infections. the diagnosis of bronchiolitis is clinical and thus requires a clinician to recognise signs and symptoms of viral lower respiratory tract infection in young children. peak incidence occurs between months and months of age. since the early clinical defi nition by court, and as noted in recent practice guidelines, the most specifi c defi nition is in infants. [ ] [ ] [ ] although the same physiology can occur in toddlers older than months, many clinical trials have excluded these children or have included them as a small subgroup of patients. bronchiolitis in toddlers can overlap with other conditions such as viral-induced wheezing and asthma, and application of evidence from trials predominantly assessing infants might not be appropriate. further eff orts to focus the defi nition might assist eff orts to standardise care. the classic clinical presentation of bronchiolitis starts with symptoms of a viral upper respiratory infection, such as nasal discharge, that progress to the lower respiratory tract over several days (fi gure ). timing of symptom progression can vary, and young infants can present with apnoea. lower respiratory tract symptoms of bronchiolitis include persistent cough, tachypnoea, and increased work of breathing, as shown by intercostal or supraclavicular retractions, use of abdominal muscles, grunting, or nasal fl aring. auscultatory fi ndings include crackles and wheeze. a hallmark characteristic of bronchiolitis is the minute-to-minute variation in clinical fi ndings, as mucus and debris in the airways are cleared by coughing or as the child's state changes from sleep to agitation. this variation can confound assessment, and often requires several examinations over a period of observation. nasal congestion can also confound the clinical assessment. nasal suctioning might help to ascertain which fi ndings are truly from the lower airways. fever can be present in about a third of infants with bronchiolitis, but it is usually present early in the illness with a temperature less than °c. the median duration of symptoms is about weeks, with - % of infants still having symptoms at weeks after onset. , various clinical scores have been shown in studies and clinical protocols to correlate with disease severity and improvement. , although documentation of a score can be useful as an objective measure, individual scores are not highly predictive, and they should be repeated and combined with other measures of severity for a universal assessment to guide decision making. the diff erential diagnosis for bronchiolitis includes considerations of various infectious and non-infectious causes. absence of upper respiratory symptoms should raise suspicion of other causes of respiratory distress in young infants, including cardiac disease, congenital airway abnormalities such as a vascular ring, or foreign body aspiration. other infections can resemble or complicate bronchiolitis. pertussis should be considered in infants with severe or paroxysmal cough, or with known exposure. bacterial infections complicating viral bronchiolitis, including otitis media or pneumonia, might present as a new fever or worsening status later in the course of illness. various risk factors have been associated with progression to severe bronchiolitis. those supported by the strongest evidence include presence of chronic lung disease of prematurity and haemodynamically important congenital heart disease, with immunodefi ciency and neuromuscular disorders also considered as high risk in practice guidelines. , young infants (aged < - months) and those with a history of premature birth (especially < weeks' gestation) are also at high risk for progression and can present with apnoea without other clinical fi ndings. studies assessing the risk for further apnoea in hospital have found it to be limited to infants less than month for full-term infants, weeks postconceptional age for preterm infants, or those with apnoea observed before admission. bronchiolitis is a clinical diagnosis based on history and physical examination, according to consensus across national guidelines. for infants with a typical presentation of bronchiolitis, routine imaging or laboratory testing is not recommended, as they increase costs without evidence for benefi t (table). appropriate use of pulse oximetry monitoring and initiation of oxygen for bronchiolitis have received increasing attention in studies and practice guidelines. findings suggest that arbitrary thresholds for oxygen administration might drive hospital admissions and prolong hospital length of stay. these outcomes represent only part of the morbidity of bronchiolitis, but developing evidence suggests that intermittent hypoxaemia might occur commonly in otherwise stable infants with bronchiolitis and raises questions as to whether this factor should be used as a sole indication for admission to hospitals. a canadian randomised trial found reduced admissions to hospital from the emergency department without any increase in revisits when pulse oximeters displayed values % higher than the actual value, suggesting that arbitrary pulse oximetry thresholds result in unnecessary admissions. a similar trial in the uk in the hospital setting found that reduction of the oxygen threshold from % to % resulted in earlier discharge from the hospital without any evidence of adverse outcomes. a us trial comparing intermittent versus continuous pulse oximetry in non-hypoxaemic infants in hospitals found similar outcomes between the groups. this us trial and other evidence supports recommendations in us practice guidelines that clinicians use a threshold of % for initiation of oxygen, whereas uk guidelines recommend %. , as the child improves, reduction in intensity of monitoring to intermittent checks is appropriate. a recent study using blinded oximetry at home showed that a substantial proportion of infants with bronchiolitis who are otherwise doing well have oxygen desaturations less than %, particularly during sleep, further calling into question arbitrary thresholds for hospital admissions and initiation of oxygen. this evidence will probably lead to eff orts to reduce continuous monitoring in children without other indications for monitoring. the majority of children with bronchiolitis have either normal radiographs or radiographic fi ndings consistent with simple bronchiolitis, - including peribronchial thickening, hyperinfl ation, and atelectasis. one prospective study of routine radiographs as part of the assessment for bronchiolitis in the emergency department reported airspace disease in ( %) of patients. despite the low prevalence of radiographic pneumonia, this and other studies have reported an increase in antibiotic prescription after radiographs are performed, because of non-specifi c fi ndings that infl uence clinicians' decisions. , factors that have been associated with defi nite focal infi ltrates consistent with pneumonia include hypoxia (oxygen saturation < %), [ ] [ ] [ ] grunting, persistently focal crackles, and fever (especially > °c). chest radiographs should only be considered in patients when the presentation is not classic for bronchiolitis. these situations include when another diagnosis (such as foreign body aspiration) is high on the diff erential diagnosis, when a child is severely ill and respiratory failure is imminent, and when symptoms are progressing or not resolving according to the typical disease course expected for bronchiolitis. lung ultrasound is increasingly used to assess cardiopulmonary conditions in adults and children. several studies have investigated the use of lung ultrasound in the diagnosis of bronchiolitis. two small studies found that ultrasound fi ndings in infants with bronchiolitis correlate with clinical fi ndings, and might be more specifi c than chest radiography, , but further studies are needed to establish whether there is a role for ultrasound in diagnosis or assessment of severity. with the development of pcr to detect respiratory viruses in the nasopharynx, interest in the use of viral testing for causative diagnosis in bronchiolitis has increased. virological testing, however, does not generally assist in management and is insuffi cient to predict outcomes. , many national guidelines therefore recommend against routine virological testing in bronchiolitis (table). recent studies suggest that higher respiratory syncytial virus genomic load, measured using quantitative pcr, might be associated with increased length of stay, use of respiratory support, and need for intensive care, in addition to recurrent wheezing, compared with lower viral loads. , , , further study is warranted to confi rm this association and clarify whether viral load measurement improves understanding of disease pathophysiology and severity. several guidelines recommend using respiratory syncytial virus testing to guide cohorting of patients; however, the viruses most likely to cause bronchiolitis are all transmitted in a similar fashion (close contact with large-particle aerosols or direct contact with contaminated fomites). [ ] [ ] [ ] thus, infection control might not be dependent on the identifi cation of specifi c viruses, but rather on following strict precautions including hand hygiene, separating infants in shared hospital rooms by more than m, and other infection control procedures. additionally, given the sensitivity of pcr testing, results should be interpreted with caution. certain viruses, such as rhinovirus, might be detected because of viral shedding from an unrelated illness or colonisation; whereas certain other viruses, such as respiratory syncytial virus and metapneumovirus, are almost always associated with an acute infection. blood and urine testing is not routinely recommended as part of standard practice in the diagnostic work-up of bronchiolitis (table) . a blood gas measurement should not be routinely obtained in infants with bronchiolitis, unless there are signs of impending respiratory failure or severe distress. proportions of serious bacterial infections, especially bacteraemia and meningitis, are very low in infants with bronchiolitis. abnormal white blood cell count is rarely useful in predicting serious bacterial infections in children infected with respiratory syncytial virus. guidelines universally do not recommend complete blood counts in infants with bronchiolitis unless blood count is part of assessment for a fever in infants younger than - months. similarly, given that bacteraemia is exceedingly rare (with cited proportions of < · % in the post-pneumococcal vaccine era), blood cultures should not be routinely performed, except in the septic work-up of infants younger than - months, , or in those with severe illness and signs of sepsis. hydration status is an important consideration in infants with bronchiolitis and should be determined by clinical examination. routine measurement of serum electrolytes is of little value in the majority of infants. urinary tract infections in infants with bronchiolitis occur with greater frequency than do bacteraemia and meningitis, with proportions ranging from % to %. , , it is reasonable to obtain a urinalysis and urine culture for infants aged less than days with fever and for older febrile infants who have risk factors for urinary tract infections, but urine should not be routinely obtained in all infants with bronchiolitis. current recommendations for management of bronchiolitis focus on agents to treat the patho physiological eff ects of viral lower respiratory infection (eg, bronchodilators and hypertonic saline). specifi c antivirals such as ribavirin to treat respiratory syncytial virus infection are not recommended in practice guidelines for typical cases of bronchiolitis because of challenging delivery methods, high cost, and potential health risks to caregivers. multiple new agents for prevention and treatment are under investigation and might become available in the future, including immunoglobulins, small interfering rna interference, fusion inhibitors, and small molecules. numerous studies have assessed the role of bronchodilators for the treatment of bronchiolitis, and systematic reviews have found no consistent benefi t. a cochrane collaboration systematic review identifi ed studies assessing bronchodilators, predominantly salbutamol and excluding epinephrine, and studies that looked specifi ally at clinical scores found no evidence of benefi t in any outcomes for infants admitted to hospitals. in outpatients, oxygen saturation, admission to hospital, or time to resolution of symptoms did not improve with bronchodilator usage compared with placebo. for outpatient studies assessing short-term change in pooled clinical scores, the reviewers found a small signifi cant diff erence in mean score (z= · ; p= · ) that was of small eff ect with minimal clinical importance (fi gure ). outpatient studies were heterogeneous (i²= %; p< · ), and those showing benefi t in scores tended to include older children and children with recurrent wheezing. nebulised epinephrine was assessed in another cochrane collaboration systematic review. this review found no benefi t for epinephrine compared with placebo for inpatients in hospital length of stay or other outcomes. a multicentre scandinavian study published after this cochrane review found that inpatients receiving standing doses of epinephrine had longer length of stay compared with inpatients receiving as-needed epinephrine or placebo. for outpatients, the cochrane review found a diff erence in the numbers of admissions associated with epinephrine treatment during the time of an emergency department visit, but not during the overall course of illness when assessed at week. clinical practice guidelines including those from the usa, uk, and canada do not recommend treatment with bronchodilators for bronchiolitis because of this evidence (table) . nebulised hypertonic saline is thought to reduce airway oedema, decrease mucus plugging, improve mucociliary clearance, and rehydrate the airway surface liquid in infants with bronchiolitis. these physiological changes are extrapolated from the cystic fi brosis literature, , and the pathophysiological processes in acute bronchiolitis are diff erent. therefore, the theoretical benefi ts of hypertonic saline seen in cystic fi brosis might not be present in infants with acute viral bronchiolitis. although initial trials demonstrated some ability of hypertonic saline to decrease hospital length of stay and transiently improve clinical severity score, - more recent trials demonstrated confl icting results. [ ] [ ] [ ] [ ] [ ] [ ] [ ] the trials that showed the largest benefi t were done in hospitals with lengths of stay more than h; thus, hypertonic saline for infants in countries and institutions in which the length of stay approaches or exceeds h might be benefi cial at reducing length of stay. the confl icting results are test for heterogeneity in the inpatient studies demonstrated low inconsistency between the nine studies (i²= %; p= · ) and the summary eff ect was not signifi cant (z= · ; p= · ), the outpatient studies demonstrated very high inconsistency between the studies (i²= %; p< · ) and the summary eff ect was signifi cant (z= · ; p= · ), and the overall heterogeneity of the meta-analysis demonstrated high inconsistency between the studies (i²= %; p< · ) and the overall summary eff ect was signifi cant (z= · ; p= · ). ipr=ipratropium. sal=salbutamol. neb=nebulised. reproduced from gadomski and scribani, refl ected in the diff erences in recommendations across national guidelines (table), with some countries not recommending hypertonic saline, some recommending use for all inpatients, and some recommending use only in moderate to severe illness. the largest systematic review and meta-analysis, published in , examined trials and patients. infants receiving hypertonic saline had a signifi cant diff erence in hospital length of stay of - · days ( % ci - · to - · ; p= · ) compared with those receiving · % saline or standard care. in seven trials, hypertonic saline reduced the risk of admission to hospital by % (risk ratio · ; % ci · - · ) compared with · % saline. no substantial adverse eff ects of hypertonic saline were noted in this systematic review. although the results of this meta-analysis were signifi cant, attention should be paid to the outer limits of the confi dence intervals, which approach no diff erence, and to the clinical relevance of these diff erences. a second meta-analysis of trials and patients found a smaller, but signifi cant, decrease in length of stay by - · days ( % ci - · to - · ; p< · ) in those who received hypertonic saline (fi gure ). this study found a discrepancy between the overall combined eff ect of all studies on length of stay and the negative results from the largest trials, allowing the authors to conclude that neither individual trials nor pooled estimates provide a strong evidence-based foundation for the use of hypertonic saline. both meta-analyses showed substantial heterogeneity across studies (i²= · %, p< · ; and i²= · %, p= · ). a recent reanalysis of the fi rst meta-analysis removed two outlying chinese studies and accounted for imbalances in day of illness at presentation. these analyses resolved the heterogeneity and found that hypertonic saline does not reduce length of stay in infants admitted to hospitals with bronchiolitis (mean diff erence in length of stay removing outliers - · days; % ci - · to · ; mean diff erence in length of stay accounting for day of illness imbalance · days; % ci - · to · ). large trials have not demonstrated benefi t for hypertonic saline and this meta-analysis found no eff ect of hypertonic saline on length of stay after adjustment for outliers and imbalances. the decision to undertake future trials is controversial given the positive results of some metaanalyses and negative results of others. multiple studies have examined the role of corticosteroids in the management of children with bronchiolitis. data from two large multicentre trials have shown no benefi t to corticosteroids alone in reducing admissions to hospital, , and a cochrane collaboration review supports the results of these studies. this review included only studies that enrolled children younger than months with a fi rst episode of wheezing and signs of a viral illness. among the included eight outpatient studies ( participants) comparing corticosteroids with placebo there was no reduction in admission at day (z= · ; p= · ) or day (z= · ; p= · ) after enrolment (fi gure ), clinical scores, length of stay in the emergency department, or length of time to resolution of symptoms. among the nine inpatient studies ( participants), length of hospital stay was not reduced. on the basis of this evidence, multiple clinical practice guidelines recommend against the use of corticosteroids for infants with bronchiolitis (table) . although clinicians report considering a family or personal history of atopy when deciding whether to treat infants with bronchiolitis with corticosteroids, there is no evidence that such infants receive any benefi t from corticosteroid treatment. [ ] [ ] [ ] evidence for the presence or absence of respiratory syncytial virus infection in these infants being associated with a response to corticosteroids is also unavailable. , authors from a large study with a factorial design have suggested, in an unadjusted analysis, that high-dose corticosteroids in combination with nebulised epinephrine might reduce admissions for outpatients with bronchiolitis by day , but these results are considered exploratory. , high-fl ow oxygen and respiratory support non-invasive technologies to improve oxygenation and ventilation for bronchiolitis include humidifi ed high-fl ow nasal cannula oxygen and continuous positive airway pressure. high-fl ow nasal cannula allows delivery of high fl ows (usually - l/kg per min) with humidifi cation and a cannula designed to improve patient tolerance. it has been used widely in premature infants, but the mechanisms of action are unclear, in particular whether it might deliver positive end-expiratory pressure in some conditions. evidence for effi cacy of high-fl ow nasal cannula is predominantly observational, with studies documenting corneli ( ) goebel ( ) kuyucu ( ) plint ( ) improved respiratory parameters and reduced intubation rates after implementation. one small randomised trial compared high-fl ow nasal cannula with hypertonic saline and found no diff erence in change in respiratory score. concerns about high-fl ow nasal cannula include the potential for rapid deterioration if the infant is not closely monitored and costs associated with overuse. continuous positive airway pressure has been studied in intensive care settings in observational studies and several small trials, with some evidence of improved respiratory parameters. the uk guidelines recommend considering continuous positive airway pressure in children with impending respiratory failure from bronchiolitis. antibiotic overuse in children with bronchiolitis probably occurs because of concerns about the presence of fever, the young age of aff ected patients, diffi culty diff erentiating atelectasis from infectious consolidation on chest radiograph, and concern for undetected secondary bacterial infection. bronchiolitis, however, has a clear viral cause and the occurrence of secondary bacterial infections is low, with a risk of bacteraemia or meningitis of less than %. a detailed review of randomised clinical trials found that routine use of antibiotics did not improve duration of symptoms, length of hospital stay, need for oxygen therapy, or hospital admission. overuse of antibiotics is known to result in unnecessary adverse eff ects on the patient, and the development of antimicrobial resistance. routine use should be avoided unless there is clear evidence of a secondary bacterial infection (table) . acute otitis media has been documented in up to % of infants with bronchiolitis. , antibiotic use for acute otitis media in bronchiolitis should follow established evidence and guidelines for acute otitis media. macrolide antibiotics have anti-infl ammatory properties that might have potential benefi t in mitigating the infl ammation present in bronchiolitis. two randomised trials found that there was no diff erence between azithromycin and placebo in hospital length of stay, need for oxygen, or hospital re-admission. , another randomised trial found that azithromycin lowered nasal interleukin- concentrations, prolonged time to subsequent wheezing episodes, and resulted in fewer days with respiratory symptoms in the year following the bronchiolitis episode compared with placebo. finally, a us multicentre study found that in children aged - months with a history of recurrent severe lower respiratory tract infections, early administration of azithromycin during a lower respiratory tract infection reduced the likelihood of progression to a severe infection, but it is not clear whether the underlying disease in these children was bronchiolitis or some other disease process. given the current evidence, routine use of macrolides is not recommended in bronchiolitis and more research is needed to clarify any potential role it might have in the future. hydration, suctioning, and chest physiotherapy have been suggested as supportive therapies. infants with bronchiolitis might have diffi culty feeding because of nasal congestion and increased work of breathing; thus, hydration remains a cornerstone of therapy. a multicentre study of infants younger than months admitted to hospital with bronchiolitis showed no benefi t of intravenous fl uids compared with administration of fl uids by nasogastric tube in mean length of stay, admission to the intensive care unit, need for ventilatory support, and adverse events. this trial also found that a nasogastric tube might be easier to place than an intravenous line in these infants. most guidelines recommend either nasogastric or intravenous fl uids to maintain hydration, with the uk and scottish guidelines preferring nasogastric or orogastric hydration in those that can tolerate it compared with intravenous hydration (table). if intravenous fl uids are used, isotonic fl uids are preferred to avoid risk of hyponatraemia. because infants are obligate nasal breathers, nasal suctioning has been suggested to help with clearing of the nares, improve the work of breathing, and improve feeding; however, suctioning might irritate the nasal mucosa and result in oedema. no randomised controlled trials have examined the role of nasal suctioning in bronchiolitis. the insuffi cient available evidence includes a retrospective cohort study of infants and a small observational study of infants. these studies suggest that deep suctioning might increase length of stay for inpatients, infrequent suctioning is associated with an increased length of stay, and oxygen saturation might increase after suctioning. to draw conclusions about causality from these observational studies is diffi cult, because the potential for confouding by indication exists (eg, sicker children might be more likely to receive deep suctioning). evidence suggests that oxygen saturation increases after nasal irrigation even without suctioning. current guidelines give diff ering recommendations with regard to suctioning; those that support its use recommend only superfi cial suctioning rather than deep suctioning (table) . , , chest physiotherapy use in bronchiolitis appears to vary by country. , a recent cochrane collaboration review of studies ( participants) demonstrated no evidence of benefi t to any type of chest physiotherapy among inpatients in length of stay, oxygen saturation, or respiratory parameters. no published guidelines routinely recommend chest physiotherapy for the management of uncomplicated bronchiolitis in otherwise healthy children without respiratory comorbidities (table) . , , prognosis much work has been published about the risk of developing recurrent wheezing and asthma following bronchiolitis in infancy. [ ] [ ] [ ] studies have followed birth cohorts to determine the risk of subsequent wheezing after lower respiratory tract infection in young childhood, and cohorts of children admitted to hospital with bronchiolitis. [ ] [ ] [ ] [ ] overall, admission to hospital with bronchiolitis at a young age is associated with an increased risk of recurrent wheezing. studies report that - % of children with bronchiolitis might develop recurrent wheezing in the years following their initial admission to hospital. a large study from taiwan that followed up children admitted with bronchiolitis before age years found that by age years, ( · %) of children with bronchiolitis had a diagnosis of asthma compared with ( · %) of controls (hazard ratio · ; % ci · - · ). one small cohort study of patients has suggested that ( %) of children admitted with bronchiolitis before months have asthma by years compared with eight ( %) of controls. however, another study that followed a birth cohort of children found that although lower respiratory tract infection in childhood was associated with an increased risk of recurrent wheezing, this association decreased with age and was not signifi cant by age years. most children in this cohort had mild illness not requiring hospital admission, and severity of illness might be associated with the increased risk of asthma. the question remains whether respiratory infection at a young age itself predisposes children to asthma through damage or alteration of lung function, or whether children with severe bronchiolitis might have individual risk factors (such as altered immune response or airway function) that predisposes them to both severe bronchiolitis and recurrent wheezing. substantial knowledge gaps and controversies exist in the management of acute bronchiolitis. the role of nebulised hypertonic saline in acute management is not clear, resulting in confl icting recommendations across clinical guidelines (table) . although meta-analyses suggest a small reduction of length of stay, these analyses are limited by heterogeneity, not accounting for duration of illness, and not considering the role of outlying study populations. two large multicentre trials do not support a clinically signifi cant diff erence in length of stay for inpatients and there is no clear evidence of cost benefi t. , [ ] [ ] [ ] while the same meta-analysis suggests a possible reduction in admissions for outpatients, the confi dence intervals were wide and the studies were also heterogeneous. no multicentre studies of nebulised hypertonic saline have been completed in outpatients. although the evidence is increasing that hypertonic saline has little role in meaningfully reducing the length of stay, its role in outpatients is less clear. a large outpatient multicentre study could clarify whether there is any benefi t. evidence also suggests that combined therapy with nebulised epinephrine and corticosteroids might reduce admissions to hospital. synergy between corticosteroids and β agonists is well documented in clinical trials of asthma management. [ ] [ ] [ ] [ ] basic science literature also shows that β agonists and corticosteroids enhance each other's eff ectiveness, particularly with regard to antiinfl ammatory gene expression. , because of the economic burden of bronchiolitis and the plausible basic and clinical evidence for synergy, a large and multicentre trial is needed to ascertain whether combined therapy with epinephrine and corticosteroids is benefi cial. oxygen saturation and the use of pulse oximetry play an important role in the decision to admit infants with bronchiolitis to hospital and in the length of their hospital stay. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] clinical practice guidelines also give confl icting guidance on the level of oxygen saturation at which admission should be considered. furthermore, a substantial proportion of discharged infants have episodes of transient desaturation. again, in view of the large health-care costs associated with hospital admission in bronchiolitis, further research is needed to clarify the level of oxygen saturation requiring admission, the role of continuous and spot measurements of oxygen saturation, and the clinical importance of transient desaturations in otherwise stable young infants. taf contributed to the design and coordinated the writing of this manuscript. all authors contributed to the literature search and writing of this manuscript. we declare no competing interests. taf, acp, and jjz have participated in trials of bronchiolitis funded by unrestricted public or academic institutional funding sources that had no infl uence on the conception and writing of this manuscript. viral bronchiolitis in children temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells nasal mucociliary transport in healthy subjects is slower when breathing dry air altitude and environmental climate eff ects on bronchiolitis severity among children presenting to the emergency department the relationship of meteorological conditions to the epidemic activity of respiratory syncytial virus air pollution and acute respiratory infections among children - years of age: a - year time-series study air pollution interacts with past episodes of bronchiolitis in the development of asthma exposure to traffi c and early life respiratory infection: a cohort study systematic literature review assessing tobacco smoke exposure as a risk factor for serious respiratory syncytial virus disease among infants and young children severity of respiratory syncytial virus bronchiolitis is aff ected by cigarette smoke exposure and atopy respiratory syncytial virus-associated hospitalizations among infants and young children in the united states respiratory syncytial virus-associated hospitalizations among children less than months of age interleukin- polymorphism in infants with respiratory syncytial virus infection: an opposite eff ect in boys and girls kendig and chernick's disorders of the respiratory tract in children pathological changes in virus infections of the lower respiratory tract in children bronchiolitis: lingering questions about its defi nition and the potential role of vitamin d detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study respiratory syncytial virus, human bocavirus and rhinovirus bronchiolitis in infants in very young infants severity of acute bronchiolitis depends on carried viruses viral etiologies of infant bronchiolitis, croup and upper respiratory illness during consecutive years virus type and genomic load in acute bronchiolitis: severity and treatment response with inhaled adrenaline prospective multicenter study of the viral etiology of bronchiolitis in the emergency department prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: multicenter cohort studies in the united states and finland evaluation of viral load in infants hospitalized with bronchiolitis caused by respiratory syncytial virus association of rhinovirus infection with increased disease severity in acute bronchiolitis dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis frequent detection of respiratory viruses without symptoms: toward defi ning clinically relevant cutoff values detection of respiratory syncytial virus and rhinovirus in healthy infants respiratory viral detection in children and adults: comparing asymptomatic controls and patients with community-acquired pneumonia bronchiolitis in children: diagnosis and management. nice guideline clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis the defi nition of acute respiratory illnesses in children bronchodilator and steroid use for the management of bronchiolitis in canadian pediatric emergency departments validity of bronchiolitis outcome measures severity scoring systems: are they internally valid, reliable and predictive of oxygen use in children with acute bronchiolitis? identifying hospitalized infants who have bronchiolitis and are at high risk for apnea bronchiolitis: recommendations for diagnosis, monitoring and management of children one to months of age bronchiolitis in children: a national clinical guideline inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants quality plan for the spanish national healthcare system of the spanish ministry for health and social policy; catalan agency for health technology assessment evidence based guidelines for the management of bronchiolitis prise en charge de la bronchiolite aiguë du nourrisson de moins an: actualization et consensus medical au sein des hôpitaux universitaires du grand ouest (hugo) eff ect of oximetry on hospitalization in bronchiolitis: a randomized clinical trial oxygen saturation targets in infants with bronchiolitis (bids): a double-blind, randomised, equivalence trial use of intermittent vs continuous pulse oximetry for non-hypoxemic infants and young children hospitalized for bronchiolitis: a randomized clinical trial eff ect of oxygen desaturations on subsequent medical visits in infants discharged from the emergency department with bronchiolitis chest radiographs in the pediatric emergency department for children < or = months of age with wheezing clinical predictors of pneumonia among children with wheezing clinical predictors of radiographic abnormalities among infants with bronchiolitis in a paediatric emergency department evaluation of the utility of radiography in acute bronchiolitis impact of chest radiography for children with lower respiratory tract infection: a propensity score approach clinical factors associated with focal infi ltrates in wheezing infants and toddlers lung ultrasound in bronchiolitis: comparison with chest x-ray lung ultrasound: a useful tool in diagnosis and management of bronchiolitis virologic testing in bronchiolitis: does it change management decisions and predict outcomes viral load in infants hospitalized for respiratory syncytial virus bronchiolitis correlates with recurrent wheezing at thirty-six-month follow-up the spread of infl uenza and other respiratory viruses: complexities and conjectures boston: exposure, epidemiology risk program. department of environmental health harvard school of public health transmission of infl uenza a in human beings risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections lack of usefulness of an abnormal white blood cell count for predicting a concurrent serious bacterial infection in infants and young children hospitalized with respiratory syncytial virus lower respiratory tract infection appropriateness of testing for serious bacterial infection in children hospitalized with bronchiolitis occult serious bacterial infection in infants younger than to days with bronchiolitis a systematic review assessing the utility of urine testing in febrile infants aged to months with bronchiolitis urinary tract infection: clinical practice guideline for the diagnosis and management of the initial uti in febrile infants and children to months lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics bronchodilators for bronchiolitis epinephrine for bronchiolitis racemic adrenaline and inhalation strategies in acute bronchiolitis hypertonic saline or high volume normal saline for viral bronchiolitis: mechanisms and rationale sodium chloride increases the ciliary transportability of cystic fi brosis and bronchiectasis sputum on the mucus-depleted bovine trachea hydrator therapies for cystic fi brosis lung disease nebulized % hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis nebulized hypertonic saline in the treatment of viral bronchiolitis in infants nebulized hypertonic saline/salbutamol solution treatment in hospitalized children with mild to moderate bronchiolitis nebulized hypertonic saline for bronchiolitis: a randomized clinical trial nebulized hypertonic saline for bronchiolitis in the emergency department: a randomized clinical trial the tale of trials: disentangling contradictory evidence on hypertonic saline for acute bronchiolitis % hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial a randomized trial of nebulized % hypertonic saline with salbutamol in the treatment of acute bronchiolitis in hospitalized infants sabre: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis the eff ect of % and % hypertonic saline in viral bronchiolitis: a randomised controlled trial nebulized hypertonic saline for acute bronchiolitis: a systematic review hypertonic saline (hs) for acute bronchiolitis: systematic review and meta-analysis association between hypertonic saline and hospital length of stay in acute viral bronchiolitis: a reanalysis of meta-analyses a multicenter, randomized, controlled trial of dexamethasone for bronchiolitis epinephrine and dexamethasone in children with bronchiolitis glucocorticoids for acute viral bronchiolitis in infants and young children cpap and high-fl ow nasal cannula oxygen in bronchiolitis high fl ow therapy versus hypertonic saline in bronchiolitis: randomised controlled trial antibiotics for bronchiolitis in children under two years of age acute otitis media in children with bronchiolitis the clinical course of bronchiolitis associated with acute otitis media the diagnosis and management of acute otitis media a single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial azithromycin therapy in hospitalized infants with acute bronchiolitis is not associated with better clinical outcomes: a randomized, double-blinded, and placebo-controlled clinical trial randomized trial to evaluate azithromycin's eff ects on serum and upper airway il- levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial emergency departments international collaborative (predict) nasogastric hydration versus intravenous hydration for infants with bronchiolitis: a randomised trial suctioning and length of stay in infants hospitalized with bronchiolitis is nasal suctioning warranted before measuring o saturation in infants with bronchiolitis? nasal irrigation with saline solution signifi cantly improves oxygen saturation in infants with bronchiolitis decreasing unnecessary utilization in acute bronchiolitis care: results from the value in inpatient pediatrics network eff ectiveness of chest physiotherapy in infants hospitalized with acute bronchiolitis: a multicenter, randomized, controlled trial chest physiotherapy for acute bronchiolitis in paediatric patients between and months old acute bronchiolitis: predisposing factors and characterization of infants at risk asthma and allergy patterns over years after severe rsv bronchiolitis in the fi rst year of life respiratory syncytial virus in early life and risk of wheeze and allergy by age years acute bronchiolitis in infancy as risk factor for wheezing and reduced pulmonary function by seven years in akershus county a longitudinal study on early hospitalized airway infections and subsequent childhood asthma the severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma saline in acute bronchiolitis rct and economic evaluation: hypertonic saline in acute bronchiolitis-randomised controlled trial and systematic review added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. allen & hanburys limited uk study group eff ect of inhaled formoterol and budesonide on exacerbations of asthma. formoterol and corticosteroids establishing therapy (facet) international study group scientifi c rationale for using a single inhaler for asthma control a holy grail of asthma management: toward understanding how long-acting beta( )-adrenoceptor agonists enhance the clinical effi cacy of inhaled corticosteroids long-acting beta -adrenoceptor agonists synergistically enhance glucocorticoiddependent transcription in human airway epithelial and smooth muscle cells beta -adrenoceptor agonist-induced rgs expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids taf receives funding from the national institutes of health-national institute of allergy and infectious diseases (grant k ai - ). the nih had no role in the writing of this manuscript, and in the decision to submit the paper for publication. we would like to thank kerry aicholtz for her administrative support. key: cord- - pymqxwq authors: hughes, michelle m; englund, janet a; kuypers, jane; tielsch, james m; khatry, subarna k; shrestha, laxman; leclerq, steven c; steinhoff, mark; katz, joanne title: population-based pertussis incidence and risk factors in infants less than months in nepal date: - - journal: j pediatric infect dis soc doi: . /jpids/piw sha: doc_id: cord_uid: pymqxwq background: pertussis is estimated to cause percent of childhood deaths globally and is a growing public health problem in developed countries despite high vaccination coverage. infants are at greatest risk of morbidity and mortality. maternal vaccination during pregnancy may be effective to prevent pertussis in young infants, but population-based estimates of disease burden in infants are lacking, particularly in low-income countries. the objective of this study was to estimate the incidence of pertussis in infants less than months of age in sarlahi district, nepal. methods: nested within a population-based randomized controlled trial of influenza vaccination during pregnancy, infants were visited weekly from birth through months to assess respiratory illness in the prior week. if any respiratory symptoms had occurred, a nasal swab was collected and tested with a multitarget pertussis polymerase chain reaction (pcr) assay. the prospective cohort study includes infants observed between may and august . results: the incidence of pcr-confirmed bordetella pertussis was . cases per infant-years ( % confidence interval, . – . ) in a cohort of infants with at least day of follow-up. conclusions: in a population-based active home surveillance for respiratory illness, a low risk for pertussis was estimated among infants in rural nepal. nepal’s immunization program, which includes a childhood whole cell pertussis vaccine, may be effective in controlling pertussis in infants. a resurgence of pertussis across age groups has occurred in several countries in recent years [ ] . middle-and high-income countries that use an acellular pertussis vaccine for the primary vaccination series have been particularly affected [ , ] , and infants and adolescents have experienced the greatest increase [ ] . factors that may contribute to the increased risk of pertussis include rapidly waning immunity from those vaccinated with acellular vaccines [ , , ] , asymptomatic transmission from individuals vaccinated with acellular vaccines [ ] , genetic adaption of bordetella pertussis [ ] , vaccination delay or refusal [ ] , improved surveillance and laboratory capabilities [ ] , and overall increased awareness of the continuing circulation of b pertussis [ ] . some countries experiencing epidemic pertussis, including the united states, united kingdom, and argentina, now recommend pertussis immunization in pregnancy and vaccination of close contacts [ , ] to protect the youngest infants from pertussis before they can be vaccinated themselves [ ] . recent data from maternal vaccination trials demonstrate the ability of antibodies to be transferred from mothers to their infants in pregnancy and their persistence in infants [ ] . global estimates of pertussis show the highest childhood burden in southeast asia [ ] . in this region, maternal pertussis vaccination during pregnancy may be a way to protect infants, similar to the approach using tetanus toxoid vaccine. however, globally only population-based estimate of pertussis in infants from birth has been conducted (senegal) [ ] , and surveillance and laboratory capabilities in asia are lacking [ , ] . the world health organization (who) recently recommended that countries using whole cell pertussis vaccines continue to do so in light of recent data indicating that acellular pertussis vaccines are less effective than whole cell pertussis vaccines [ ] . population-based data are needed, especially in low-income settings, to provide a more accurate estimate of the burden of pertussis in infants to inform childhood and maternal immunization policies [ , ] . we report on a prospective cohort study following infants weekly in their homes to monitor for pertussis disease from birth to age months. the objective was to provide a population-based estimate of laboratory-confirmed pertussis incidence in infants less than months of age in the sarlahi district, nepal. the study was nested within consecutive randomized controlled trials of maternal influenza vaccination during pregnancy set in the sarlahi district, located in the central terai (low-lying plains) region of nepal [ ] . at the start of the trial, prevalent pregnancies were identified through a census of all households in the catchment area. for the duration of the trial, field workers visited all households in the communities, every weeks, where married women ( - years) resided, for surveillance of incident pregnancies. once a pregnancy was identified, women provided consent and were enrolled. from april , through september , , women between and weeks gestation were randomized and vaccinated with either an influenza vaccine or placebo. the study was a population-based prospective cohort of infants followed from birth through months postpartum. approval for the study was obtained from the institutional review boards at the johns hopkins bloomberg school of public health, cincinnati children's medical center, the institute of medicine at tribhuvan university, kathmandu, and the nepal health research council. the trials are registered at clinicaltrials.gov (nct ). at baseline, information was collected on household structure, socioeconomic status, and demographics. at enrollment, date of last menstrual period and pregnancy history data were collected. as soon as possible after delivery, the mother and infant were visited to collect detailed birth information including infant weight and breastfeeding status. from birth through months, postpartum infants were visited weekly by a field worker, who recorded any infant respiratory symptoms in the past days. if an infant had any of the following symptoms, a mid-nasal nylon flocked swab was collected: fever, cough, wheeze, difficulty breathing, or ear infection. starting on august , , new symptoms, more specific for pertussis, were added to the weekly morbidity visit: apnea, cyanosis, cough with vomit, or whoop/whooping cough. the swabs were stored for up to week at room temperature in primestore molecular transport medium (longhorn diagnostics llc, bethesda, md). in addition to these signs, mothers were asked which, if any, infant vaccinations were received in the past days, including pertussis vaccination [ ] . mid-nasal swabs were also collected on a weekly basis from mothers from enrollment through months postpartum who reported fever plus one additional morbidity (cough, sore throat, nasal congestion, or myalgia). all nasal swabs collected from infants were tested for b pertussis, bordetella parapertussis, and bordetella bronchispetica. only the nasal swabs of mothers whose infants tested positive for any of these pathogens were tested for the same pathogens. real-time polymerase chain reaction (pcr) testing was conducted at the university of washington's molecular virology laboratory according to previously published methods [ ] . two-target pcr was used to assess the presence of bordetella species: b pertussis, b parapertussis, and b bronchiseptica. the amplified targets were chromosomal repeated insertion sequence is (is) and the polymorphic pertussis toxin ptxa promoter region (pt). after amplification, the melting points of the amplicons were measured in an icycler (bio-rad). a sample was interpreted as positive when the target(s) had a melting temperature within the species-specific acceptable range and a computed tomography ≤ . a sample was negative if none of the targets tested positive or a single positive target was not reproducible. maternal nasal swabs were tested for those mothers whose infants tested positive for any bordetella species polymerase chain reaction was also performed for several viral infections (influenza, rhinovirus [rv], respiratory syncytial virus [rsv], bocavirus [bov], human metapneumovirus, coronavirus, adenovirus, and parainfluenza [ ] [ ] [ ] [ ] ) as previously described [ ] . of women enrolled, infants were live born to women (supplementary figure ). infants were included in this analysis if they were followed for any length of the follow-up period ( to days); median total follow-up was days per infant (supplementary figure ) . the final dataset consists of infants, contributing infant-years of observation, with at least follow-up visit during the first months. this includes infants from the entire trial period, both before and after more pertussis-specific additions to the weekly symptom questionnaire. at baseline, data on household structure were gathered. at enrollment, women reported their literacy status (binary) and pregnancy history. the field workers identified their ethnicity into broad groups (pahadi, a group originating from the hills; or madeshi, a group originating from north india) from names and observation. women were categorized as nulliparous or multiparous. responses to questions about household construction, water and sanitation, and household assets were used to develop an index to measure the socioeconomic status of households. binary variables for each of the questions and a mean ses score were calculated for each household. gestational age was measured using a woman's report of date of last menstrual period during pregnancy surveillance. birth weight was collected as soon as possible after birth using a digital scale (tanita model bd- , precision to nearest grams). birth weights collected > hours after birth were excluded from the analysis. small for gestational age (sga) was calculated using the sex-specific th percentile cutoff described by alexander et al [ ] and the intergrowth- standards [ ] . women were asked within how many hours of birth breastfeeding was initiated and binary breastfeeding categories were created (≤ hour versus > hour postdelivery). incidence was calculated as the number of pertussis cases per infant-years at risk. poisson exact % confidence intervals (cis) were constructed. characteristics of infant pertussis cases were compared with nonpertussis cases using bivariate poisson regression. characteristics of all pertussis respiratory episodes were compared with nonpertussis respiratory episodes; t tests were used for continuous predictors and fisher's exact tests were used for categorical associations due to the low number of pertussis episodes. all statistical analyses were conducted in stata/se . . a total of infants had episodes of respiratory illness between may , and april , . thirty-nine percent (n = ) of infants experienced no respiratory episodes. the incidence of respiratory illness was . episodes per infant-year ( % ci, . - . ). mean episode duration was . days ( % ci, . - . ). a total of ( %) episodes were matched to or more pertussis-tested nasal swabs from infants (supplementary figure ) . seventeen cases of b pertussis were identified from nasal swabs (nasal swabs were positive on consecutive weeks for infants). the incidence of pcr-confirmed b pertussis was . cases per -infant years ( % ci, . - . ). five cases of b parapertussis were detected with an incidence of . cases per infant-years ( % ci, . - . ). no cases of b bronchiseptica were identified. the average pertussis episode duration was days (range, - ) ( table ). mean age of onset of symptoms was days (range, - ) (median, ; interquartile range, - ). the most common symptoms were cough, difficulty breathing, and cough with vomit. none of the additional symptoms related to pertussis that were added in year (cyanosis, apnea, cough with vomit, and whoop) resulted in collection of nasal swabs based solely on these additional symptoms. pertussis episodes were statistically significantly more likely to include difficulty breathing, cough with vomit, and whoop compared with other respiratory illness. six infants had at least pertussis vaccination before pertussis disease onset (three < weeks and three > weeks before pertussis illness) with a mean of days from vaccination to illness compared with days for nonpertussis episodes (p = . ). five infants received their first pertussis vaccination postpertussis disease onset, whereas infants received no pertussis vaccination in the first days. three fourths of pertussis episodes were coinfected with at least virus, with rv and bov the most common. cases of pertussis were more likely to be infected with bov than respiratory cases due to causes other than pertussis. the majority of cases occurred between february and january (figure ) . no statistically significant differences between risk factors for pertussis and nonpertussis cases ( table ) were documented. given the low number of pertussis cases, the lack of a statistical association is not evidence of nonassociation. no deaths occurred in infants who had pertussis. of the mothers of b pertussis-positive infants who had a nasal swab collected ( nasal swabs total) during their own follow-up, none were positive for any pertussis species. the b parapertussis cases were primarily male whose mothers were primiparous, literate, and pahadi ethnicity (supplementary table ). no mothers of infants who had b parapertussis had a nasal swab collected during follow-up. the average b parapertussis episode duration was days (supplementary table ). mean age of onset of symptoms was days with a range of - days. the most common symptoms were cough and wheeze. rhinovirus and rsv were the only coinfections observed. all b parapertussis cases occurred between september and february ( figure ). a low incidence of pertussis and generally mild clinical presentation were found in infants < months in nepal. to our knowledge, this represents one of the first population-based active surveillance of pcr-confirmed pertussis among young infants in asia. acellular pertussis vaccine trials conducted in the s found the average pertussis incidence in the whole cell vaccine groups ranged from to cases per infantyears [ ] . our finding of b pertussis cases per infantyears was on the lower end of this range. in the united states in , the estimated pertussis incidence in infants less than months was cases per infant-years [ ] , much lower than observed in our study; however, this passive surveillance system likely vastly underestimates pertussis incidence. thus, there is a need for active surveillance data such as ours. furthermore, given our highly sensitive case detection method, many of our pertussis cases would likely not have been detected in the previous acellular pertussis vaccine trials. more stringent respiratory symptom criteria would have lowered our incidence estimate even further. the low incidence was found in a population where pentavalent vaccine (pentavac: diphtheria, tetanus, pertussis [whole cell], hepatitis-b and haemophilus type b conjugate vaccine; serum institute of india pvt. ltd), scheduled for administration at , , and weeks, is received with significant delays ( % of infants received all recommended pertussis vaccines by months) [ ] . these data support the who's recommendation that countries using whole cell pertussis vaccine continue to do so given that the majority of outbreaks have been concentrated in countries using the acellular pertussis vaccine [ ] . recent studies suggest that protection from acellular pertussis vaccine is not as strong or long lasting as that conferred by the whole cell pertussis vaccine [ , ] . another contributing factor to the low pertussis incidence observed could be that surveillance was conducted during a period of low pertussis transmission. pertussis is a cyclical disease, thought to peak every to years, and we may have captured the burden at a low circulation period [ ] . we observed over % of our b pertussis cases over a -year period. this increase from earlier observation periods could indicate a temporary rise in pertussis consistent with its cyclical pattern or a true increase in the baseline burden. previous research on pertussis seasonality has in different places and time periods demonstrated various periods of peak transmission or no discernable patterns [ , ] . although our data do not support a seasonal pattern, the numbers observed are too low to be conclusive. pertussis symptom duration and severity were mild compared with the classic pertussis case presentation. only of the cases fulfilled the who criteria, which requires a minimum of weeks of cough, whoop, or posttussive vomiting [ ] . studies on pertussis in infants have generally been clinic-based, hospital-based, or in an outbreak, which therefore required a certain severity of illness for parents to recognize a need for medical attention [ , , ] . these study designs and passive surveillance efforts therefore may have missed milder pertussis cases [ ] . our study, which required only respiratory symptom for a nasal swab to be collected, had increased sensitivity to detect a range of pertussis case presentations. an alternative explanation for the mild cases seen could be an increase in the proportion of mild compared with severe pertussis cases in nepal. although cough, difficulty breathing, and cough with vomit were the most common symptoms, no symptom was present in all b pertussis cases. during an epidemic period in washington state, among infants < year, who had a minimum of days cough plus an additional symptom, % had posttussive emesis, % had apnea, % had whoop, and % had cyanosis [ ] . a study of us neonates with pertussis showed the symptom prevalence to be % for cough, % for cyanosis, % for apnea, and % for fever [ ] . our study found lower or equal symptom prevalence with the exception of fever. fever prevalence was higher in our study, similar to that found in peru [ ] . although not statistically significant, infants with pertussis were more likely to have been born preterm, low birth weight, and sga, and their mothers were more likely to be primiparous. these findings are similar to previous studies showing no difference in pertussis cases by sex [ , , ] or crowding [ ] but showing differences by birth weight [ ] . coinfections were common, consistent with findings from other hospital-based studies [ ] . codetection of b pertussis and b parapertussis with respiratory viruses may be due to asymptomatic pertussis carriage. the incidence of b parapertussis of cases per person-years was comparable to that of per person-years found in the italian acellular pertussis vaccine trial in - [ ] . the duration of illness was shorter for b parapertussis with a maximum duration of days compared with a maximum of days for b pertussis. a milder presentation is consistent with clinical knowledge of b parapertussis infection [ , ] . bordetella parapertussis cases occurred only during a -month period. there were several study design limitations. we cannot be certain whether the reported symptoms were caused by pertussis, another organism, or whether symptoms were related to or more etiologic agents. we were unable to perform multivariate regression modeling for characteristics associated with pertussis disease and pertussis cases due to the small number of cases we detected. infant respiratory symptoms were reported by parents, who may have missed signs that might have been observed by a healthcare worker. however, the criteria for collection of the nasal swab were broad and did not require sophisticated clinical skills. however, apnea and cyanosis may have been difficult for parents to identify. although the criteria for specimen collection changed in year , no infant experienced a pertussis-specific symptom in isolation without also having one of the originally specified respiratory symptoms. these data support our assumption that we were unlikely to have missed pertussis cases in year with our less sensitive respiratory symptom criteria. nasal swabs were collected in the mid-nasal region for influenza virus detection, which may have lowered the sensitivity of pertussis detection. in a field site, the acceptability of an additional nasopharyngeal swab would likely have increased the participant refusal rate. this would have decreased the generalizability of our results to the entire population. although nasopharyngeal swabs or nasopharyngeal aspirates are the recommended specimen collection method [ ] , the nasopharyngeal region was established as the collection area of choice when the diagnostic measure was culture, which has low sensitivity. recent data demonstrated the comparability of using mid-nasal versus nasopharyngeal swabs in pcr pertussis detection [ ] . strengths of the study included being a population-based, prospective study, with very low refusal rates. risk factors, clinical symptoms, and coinfections were prospectively identified without the potential bias that may occur when these data are collected retrospectively or in clinical settings. the community-based design allows generalizability of these results to the entire population and not just those seeking care at a health facility or in an outbreak situation. the sarlahi district is located in the terai region where the majority of nepalese reside, and it has similar demographics to the entire population of nepal [ ] . sarlahi's location near sea level and on the border with india supports the generalizability of these results to many populations living on the indian subcontinent. the weekly active surveillance with sensitive criteria for pertussis testing was able to detect mild and atypical pertussis cases, which may have been missed by previous traditional surveillance. the multitarget pcr method allowed highly sensitive and specific detection of additional bordetella species beyond the primary b pertussis target. we observed a low incidence of pertussis in infants in a whole cell vaccine environment. pertussis cases were generally milder than expected compared with traditional pertussis clinical definitions. these data support clinicians considering pertussis in their differential diagnosis of infants with mild respiratory symptoms. policymakers in nepal will need to weigh the benefit of an additional prenatal pertussis vaccine or a switch to acellular primary pertussis vaccine with the low burden of pertussis in infants less than months. our study demonstrated that mid-nasal swabs were able to detect pertussis using a sensitive multitarget pcr. the less invasive mid-nasal nasal swab is an attractive alternative for pertussis nasal swab collection, and further research is needed to compare this collection site with nasopharyngeal swabs. in the future, this method may enhance population-based surveillance efforts. epidemic pertussis in -the resurgence of a vaccine-preventable disease world health organization. revised guidance on the choice of pertussis vaccines pertussis across the globe: recent epidemiologic trends from changing pertussis epidemiology: everything old is new again comparison of three whole-cell pertussis vaccines in the baboon model of pertussis acellular vaccines and resurgence of pertussis asymptomatic transmission and the resurgence of bordetella pertussis genome-wide gene expression analysis of bordetella pertussis isolates associated with a resurgence in pertussis: elucidation of factors involved in the increased fitness of epidemic strains association between undervaccination with diphtheria, tetanus toxoids, and acellular pertussis (dtap) vaccine and risk of pertussis infection in children to months of age public health england maternal immunization in argentina: a storyline from the prospective of a middle income country maternal pertussis immunization: can it help infants? pertussis vaccination during pregnancy: antibody persistence in infants global, regional, and national causes of child mortality in : a systematic analysis a randomized double-blind trial comparing a two-component acellular to a whole-cell pertussis vaccine in senegal pertussis control in the asia-pacific region: a report from the global pertussis initiative vaccine preventable diseases: time to re-examine global surveillance data? pertussis vaccines: who position paper cost-effectiveness analysis of universal maternal immunization with tetanus-diphtheria-acellular pertussis (tdap) vaccine in brazil the burden of pertussis in low-and middle-income countries since the inception of the expanded programme on immunization (epi) in : a systematic review protocol designs of two randomized, community-based trials to assess the impact of influenza immunization during pregnancy on respiratory illness among pregnant women and their infants and reproductive outcomes in rural nepal infant vaccination timing: beyond traditional coverage metrics for maximizing impact of vaccine programs, an example from southern nepal multitarget pcr for diagnosis of pertussis and its clinical implications a united states national reference for fetal growth the likeness of fetal growth and newborn size across non-isolated populations in the intergrowth- st project: the fetal growth longitudinal study and newborn cross-sectional study pertussis vaccine trials in the s notice to readers: final reports of nationally notifiable infectious diseases reduced risk of pertussis among persons ever vaccinated with whole cell pertussis vaccine compared to recipients of acellular pertussis vaccines in a large us cohort high prevalence of bordetella pertussis in children under years old hospitalized with acute respiratory infections in incidence and diagnosis of pertussis in south african children hospitalized with lower respiratory tract infection who-recommended standards for surveillance of selected vaccine-preventable diseases world health organization infant pertussis epidemiology and implications for tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (tdap) vaccination: king county bordetella pertussis: an underreported pathogen in pediatric respiratory infections, a prospective cohort study clinical characteristics and outcomes of neonatal pertussis: a comparative study pertussis prevalence and its determinants among children with persistent cough in urban uganda pertussis in infants under one year old: risk markers and vaccination status-a case-control study bordetella parapertussis infection in children: epidemiology, clinical symptoms, and molecular characteristics of isolates clinical characteristics of illness caused by bordetella parapertussis compared with illness caused by bordetella pertussis laboratory manual for the diagnosis of whooping cough caused by bordetella pertussis/bordetella parapertussis. world health organization comparison of molecular detection methods for pertussis in children during a state-wide outbreak new era, icf international. nepal demographic and health survey supplementary materials are available at journal of the pediatric infectious diseases society online. disclaimer. neither of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.financial support. this work was supported by grants from the thrasher research fund ( ) and the bill and melinda gates foundation ( ).potential conflicts of interest. j. a. e. has been a consultant for pfizer, a member of a data safety monitoring board for glaxosmithkline (gsk) influenza antiviral studies, and her institution has received research support for clinical studies from gsk, gilead, chimerix, and roche.all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. key: cord- -n sq jz authors: chen, yan; peng, hua; wang, lin; zhao, yin; zeng, lingkong; gao, hui; liu, yalan title: infants born to mothers with a new coronavirus (covid- ) date: - - journal: front pediatr doi: . /fped. . sha: doc_id: cord_uid: n sq jz a novel viral respiratory disease caused by severe acute respiratory syndrome coronavirus (sars-cov- ), is responsible for an epidemic of the coronavirus disease (covid- ) in cases in china and worldwide. four full-term, singleton infants were born to pregnant women who tested positive for covid- in the city of wuhan, the capital of hubei province, china, where the disease was first identified. of the three infants, for who consent to be diagnostically tested was provided, none tested positive for the virus. none of the infants developed serious clinical symptoms such as fever, cough, diarrhea, or abnormal radiologic or hematologic evidence, and all four infants were alive at the time of hospital discharge. two infants had rashes of unknown etiology at birth, and one had facial ulcerations. one infant had tachypnea and was supported by non-invasive mechanical ventilation for days. one had rashes at birth but was discharged without parental consent for a diagnostic test. this case report describes the clinical course of four live born infants, born to pregnant women with the covid- infection. the new coronavirus (covid- ) is an epidemic in wuhan and the population is believed to be immunologically naïve. as the epidemic progresses, there remains little understanding of infant and childhood covid- infections and their clinical picture. as of february , , cases of novel covid- infections have been confirmed and , people have died (http:// ncov.chinacdc.cn/ -ncov/). during this epidemic, four live-born infants were born in our medical center, to pregnant women with the covid- infection. three of the four pregnant women gave birth by cesarean section due to concerns about symptomatic maternal infection. the other infant was born by vaginal delivery to a mother experiencing fever (highest temperature . • c), with a diagnostically confirmed infection. the most important question is whether the covid- could be transmitted vertically to the fetus from the pregnant mother and cause a clinically significant infection. recently, a finding from nine other cases suggested that there is no evidence for intrauterine infection caused by vertical transmission in women who develop covid- pneumonia in late pregnancy ( ) . we believe this present report is the second case report on vertical transmission between covid- pregnant women and their infants. moreover, this report will focus more on infants. this case report describes the clinical course of four live born infants born to pregnant women with the covid- infection. all four mothers were symptomatically infected with covid- during the rd trimester. on admission, the regular symptoms of pregnant mothers with covid- were fever (three out of four patients), cough (two out of four patients), myalgia or fatigue (two out of four patients), and headache (two out of four patients). only one patient felt reduced fetal movement and one experienced dyspnea. lymphocytes were below the normal range (lymphocyte count < . × /l) in all patients, and two patients showed lymphopenia (lymphocyte count < . × /l). both leucocytes and platelet counts were below the normal range (white blood cell count < × /l, platelet count < × /l) in the mother in case (shown in table ). the mother in case developed anemia (hemoglobin g/l) and dyspnea days after being admitted. there was a significant increase of the level of c-response protein in all pregnant mothers. coagulation function and blood biochemistry of all the mothers were normal. five respiratory pathogens (mycoplasma, chlamydia, respiratory syncytial virus, adenovirus, and coxsackie virus) and the nucleic acid of influenza viruses a and b of all patients were negative (laboratory findings shown in table ). an rt-pcr assay confirmed that the throat swab of the four pregnant women were positive for covid- . abnormalities in chest ct images and bilateral involvement were detected among all pregnant women. a cesarean section was performed for three patients in the acute phase of the disease while one patient underwent vaginal delivery because of the onset of labor. four full-term infants were born. all infants were isolated from their mother immediately after birth. we describe the clinical course of these four infants (laboratory findings shown in table ). three mothers of the infants recovered from their covid- infections and were released - days after delivery. however, one mother suffered severe dyspnea after delivery which required respiratory support-she did, however, survive. all four infants and their mothers were healthy upon a post-discharge follow-up. three male, and one female infant was born beyond weeks' gestation and had a birthweight above , g. all infants had a min apgar score of - and -min apgar score of - ( table ) . they were isolated from their mothers immediately after birth and received formula feeding. three of the four infants tested negative for covid- using a throat swab specimen in rt-pcr h after birth and one baby's parents did not provide consent for their baby to be tested for covid- . two of the four infants were healthy. two of the four infants had rashes after birth, however, the rash distribution and shape differed. the infant in case had some maculopapules scattered all over the body, and one facial skin ulceration on the forehead (size about . × . cm ). the rash disappeared and skin desquamation appeared the next day without any treatment. the rash of the infant in case was present on the forehead and seemed to diffuse small miliary red papules on day . the rash disappeared on day without treatment ( table ). the infant in case , the mother of whom had cholecystitis, developed edema of the lateral thigh on day , and the level of serum albumin was only g/l. the baby was taking full formula feeds on day . the baby was discharged from the nicu (neonatal intensive care unit) days after birth. the infant in case , the mother of whom had placenta previa, suffered transient tachypnea of the newborn (ttn) and required nasal-continuous positive airway pressure (ncpap) after birth. breathing became regular within days. the baby was taking full formula feeds on day and was discharged from the nicu on day ( table ). in this study, four pregnant women were confirmed to have the covid- infection. one mother experienced reduced fetal movement. one mother developed anemia and dyspnea after admission. of the three infants whose parents provided consent to be diagnostically tested, none tested positive for the virus. none of the infants developed serious clinical symptoms such as fever, cough, or diarrhea. two newborns had a rash, which disappeared spontaneously without treatment; one newborn had mild dyspnea, and was considered to suffer from ttn and supported by non-invasive mechanical ventilation for days. all of the four babies are doing well and have been formula feeding since birth. coronavirus (covs) ( ) is an enveloped positive-sense rna virus, which infects humans and a wide variety of animals, causing diseases in the respiratory, enteric, hepatic, and neurological systems with varying severity ( ). in the past few decades, newly evolved covs have posed a global threat to public health, such as severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov) that were implicated in the outbreak in guangdong, china and the outbreak in the middle east, respectively ( ). on january , a new coronavirus causing a pneumonia epidemic in wuhan city in central china was denoted as covid- by the world health organization (who) ( ). as of february , nearly , covid- infections in humans have been confirmed in china, with at least , reported deaths. as reported herein, four pregnant women were confirmed to have the covid- infection in our medical center, which is designated as one of the treatment centers for pregnant women with the covid- infection. importantly, we found neither sars-cov- diagnostic positivity nor immediate evidence of symptomatic covid- among the infants born to the symptomatic, test-positive mothers. on the basis of previous reports ( - ), sars-cov and mers-cov were associated with critical maternal illness, spontaneous abortion, or even maternal death. in these four pregnant women with the covid- infection, three had fever, two had a cough and experienced headache. in laboratory data, there was lower lymphocyte count and higher crp in blood analysis. typical ct images of covid- infection with ground glass changes were presented in these pregnant patients. these four pregnant women had no critical maternal illness. only one of them experienced reduced fetal movement and one had dyspnea. these symptoms, at onset of delivery, were similar to other populations ( ) . to prevent covid- intrauterine, perinatal, and postnatal transmission, three pregnant women received a cesarean section. one of the three pregnant women suffered placenta previa, which made it necessary to opt for a cesarean section. only one pregnant mother adopted a vaginal delivery because of an emergency labor process. shek et al. ( ) reported that perinatal transmission of the sars-associated coronavirus was not detected in any of the five live born infants who were born to pregnant women with sars during the community outbreak in hong kong in . in addition, none of the infants developed clinical, radiologic, hematologic, or biochemical evidence suggestive of sars. consistent with these reports, in our study, rt-pcr assay confirmed that the throat swab of the three cases were negative for covid- . we regret that the infant in case did not have a covid- diagnosis as the baby's guardian's did not provide consent. assiri et al. ( ) reported five cases of pregnant women infected with mers-cov from saudi arabia, and all pregnancies were in the second or third trimester. among the five pregnancies, two pregnant women died during their illnesses, two resulted in perinatal death (one pregnancy resulted in intrauterine fetal demise, and one infant died h after an emergency cesarean delivery). it was reported that pregnant women were diagnosed to have the sars infection during the outbreak in hong kong ( ) . seven mothers presented in the first trimester, and the rest were in their late second and third trimester. it was reported that the sars infection in pregnant women could lead to severe intrauterine growth retardation, which could be due to the prolonged usage of high dose systemic corticosteroids or antiviral agents and/or the impact of a severe maternal debilitating illness on normal fetal growth ( , ) . in this study, all four cases reported on were delivered during the acute phase of the illness, at - weeks of gestation, and the birth weight of all the babies were appropriate for their gestational age. throughout the clinical course, there were no manifestations or radiologic, hematologic, or biochemical evidence suggestive of covid- infection. this study is similar to reports of sars infection ( ) ( table ) . coronaviruses cause respiratory and intestinal infections in animals and humans ( ) . for adult patients, the clinical manifestations of covid- infection include fever, cough, shortness of breath, muscle ache, sore throat, diarrhea, and so on ( ) . the minority of patients showed severe and even fatal respiratory diseases such as acute respiratory distress syndrome. according to imaging examination, most patients showed bilateral pneumonia, multiple mottling, or ground-glass opacity. in this study, only the infant in case showed dyspnea and required oxygen therapy. a chest radiograph of the infant in case showed that the brightness of the left lung was slightly decreased, and the texture of the right lung was slightly blurred. his condition was relieved gradually after days of ncpap treatment. it has been confirmed that covid- gravely damages leucocytes, and could lead to multiple organ damage along with the respiratory system ( ) . in this study, blood assays of the three infant cases were normal, and all the blood cell counts and hemoglobin concentrations fluctuated within the normal reference range. it is worth noting that both case and case presented a transient skin rash after birth. whether this was attributable to the maternal inflammatory toxin effect requires further study. at follow up, the four newborns were health and had grown on formula feeding. this feature reveals that none of the four newborns of the mothers with covid- developed covid- infection. in this study, viral nucleic acid detection using real-time polymerase chain reaction (rt-pcr) remains, is taken as the standard of covid- infection. a recent retrospective analysis in adults showed that the sensitivity of rt-pcr is % for covid- infection ( ) . therefore, the reliability of diagnostic testing should be further evaluated, especially in children. another limitation of this report was the small number of cases, and imperfect clinic data. no covid- vertical transmission was detected. further studies for viral infection in placenta, amniotic fluid, neonatal blood, gastric fluid, and anal swab, and the viral depending receptor on children will be detected in future. the datasets generated for this study are available on request to the corresponding author. the studies involving human participants were reviewed and approved by the institutional review board of union hospital, huazhong university of science & technology. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article. yc and hp designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. lw, hg, yz, and lz designed the data collection instruments, collected the data, and reviewed and revised the manuscript. yl designed the study, coordinated, and supervised data collection, and critically reviewed the manuscript for important intellectual content. all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. this study was supported by the national natural science foundation of china ( , , and ). clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women:a retrospective review of medical records novel coronavirus: from discovery to clinical diagnostics global epidemiology of bat coronaviruses measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in wuhan sars and pregnancy: a case report severe acute respiratory syndrome and pregnancy middle east respiratory syndrome coronavirus infection during pregnancy: a report of cases from saudi arabia clinical features of patients infected with novel coronavirus in wuhan infants born to mothers with severe acute respiratory syndrome pregnancy and perinatal outcomes of women with severe acute respiratory syndrome mers-cov and now the -novel cov: have we investigated enough about coronaviruses? -a bibliometric analysis epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study sensitivity of chest ct for covid- : comparison to rt-pcr the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © chen, peng, wang, zhao, zeng, gao and liu. this is an openaccess article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -ex yi u authors: epalza, cristina; hallin, marie; busson, laurent; debulpaep, sara; de backer, paulette; vandenberg, olivier; levy, jack title: role of viral molecular panels in diagnosing the etiology of fever in infants younger than months date: - - journal: clin pediatr (phila) doi: . / sha: doc_id: cord_uid: ex yi u as infants with proven viral infection present lower risk of bacterial infection, we evaluated how molecular methods detecting viruses on respiratory secretions could contribute to etiological diagnostic of these febrile episodes. from november to may , we enrolled all febrile infants < days presenting to emergency room. standard workup included viral rapid antigenic test and viral culture on nasopharyngeal aspirate. samples negative by rapid testing were tested by molecular methods. from febrile episodes ( infants) with standard techniques, rate of documented microbiological etiology was % at emergency department, % during hospitalization, and % with viral cultures. molecular methods increased microbiologically documented etiology rate by %, to %. contribution of molecular methods was the highest in infants without clinical source of infection, increasing documentation by %, from % to %. making viral molecular results rapidly available could help identifying a higher proportion of infants at low risk of serious bacterial infection. the management of febrile infants younger than months in the emergency room (er) is challenging as they have a higher risk of serious bacterial infection (sbi) than older children and because clinical evaluation has a low sensitivity and specificity in identifying those infants with sbi. [ ] [ ] [ ] [ ] [ ] [ ] therefore, additional examinations are usually performed to diagnose sbi, or to identify those infants at higher and lower risk of sbi. accordingly, a large proportion of these infants considered at higher risk of sbi are admitted to the hospital and treated empirically with intravenous antibiotics while awaiting microbiological confirmation, whereas those at lower risk of sbi can be managed as outpatients, provided adequate surveillance can be ascertained. [ ] [ ] [ ] [ ] [ ] [ ] traditional viral and bacterial diagnostic techniques allow to find the etiology of febrile episodes in about half of the cases only. , with the development of molecular techniques, the ability to diagnose viral infections has improved substantially in recent years. multiple real-time polymerase chain reactions (pcrs) have been developed, increasing the detection rate for cultivable viruses or allowing the detection of non-or difficult-tocultivate viruses. more recently, techniques such as multiplex pcrs or microarrays allow the codetection of large panels of viruses in a single assay. furthermore, these new tools can now generate accurate results within a few hours. in several clinical situations, rapid report of microbial pathogens identification from clinical specimens has been shown to significantly improve the management and the outcome of infected patients, enabling rapid adjustment of antibiotic treatments, shortened hospital stay, and lower hospitalization costs. , regarding the management of febrile infants younger than months, several authors have shown that infants presenting a proven viral infection have a significantly lower risk of sbi. [ ] [ ] [ ] [ ] [ ] an early diagnosis of a viral infection could help consider a larger proportion of febrile infants at lower risk for sbi and lead to a more conservative approach regarding additional invasive procedures, antibiotic treatments, or hospital admission. while the molecular techniques allowing this early diagnosis are more expensive than conventional methods, their real clinical benefits remain poorly studied. the aims of this prospective study were to evaluate the analytical performances of a multiplex diagnostic tool detecting the most frequent respiratory viruses as compared with our set of homemade real-time pcrs and the potential contribution of these molecular methods to the etiologic diagnosis of febrile episodes in infants younger than months of life. the study was conducted at saint-pierre hospital, a university-affiliated hospital located in downtown brussels. about patients per year attend its pediatric er. all infants ≤ days of age admitted to the pediatric er from november , , to may , , reporting or presenting a rectal temperature ≥ . °c, were eligible for this study. according to published guidelines, - our standard procedure for these patients includes a thorough clinical interview, a complete physical examination, and the following laboratory tests: complete blood count, blood bacterial culture, viral rapid antigen testing and viral culture of nasopharyngeal aspirates (npa), urinalysis, and bacterial culture. cerebrospinal fluid is obtained for cytology, bacterial culture, and enterovirus (ev) detection by pcr in all infants < days or in those to days with toxic aspect or the following laboratory findings: white blood cell ≥ /mm or ≤ /mm or c-reactive protein ≥ mg/l or white cell count > / µl in urine sediment collected by catheterization. additional tests such as chest x-ray, stool culture, and stool viral antigen tests are performed whenever clinically indicated. for all patients, an admission is proposed; intravenous empirical antibiotic is started in nearly all infants < days and in those older than days with clinical or laboratory alterations. samples received in the laboratory during business hours were processed on receipt. sample arriving outside business hours were stored at °c and processed on the next working day. standard viral diagnostic procedures consisted in viral culture on confluent vero, mrc , and llc-mk cell lines (vircell, santa-fé, spain), and a combination of of the following rapid detection tests according to the season: lateral flow chromatography for influenza a and b (binaxnow influenza a/b, alere inc, waltham, ma), respiratory syncytial virus (rsv; binaxnow rsv, alere inc) and adenovirus (adv; adeno respi-strip, coris bioconcept, gembloux, belgium), and direct fluorescent immunoassays for human metapneumovirus (hmpv) and parainfluenza virus (piv; argene, biomérieux, marcy l'etoile, france). if rapid tests were negative, sets of molecular assays were performed: ( ) the clart pneumovir dna array (genomica, coslada, spain) detecting influenza a, b, and c; piv , , , and ; rsv a and b; hmpv a and b; adv; ev (solely echoviruses); rhinoviruses; coronavirus e; and bocaviruses and ( ) a homemade real-time pcrs detecting influenza a and b; piv , , , and ; rsv a and b; hmpv a and b; adv; ev; rhinoviruses; coronavirus e, nl , and oc ; and bocaviruses. extraction of nucleic acids was arried out with the magna pure lc extraction system (roche diagnostics) using the total nucleic acid large volume isolation kit (input volume µl, output volume µl). the pneumovir assay was performed according to the manufacturer's instructions; detection and interpretation of the results were conducted by a carreader (genomica). all these molecular techniques were performed once a week, except for the pcr targeting ev, which was performed twice a week. for npa with negative rapid tests, as the molecular tests used were presumably more sensitive than the reference standard (viral culture), we constructed, as recommended, a "composite" reference standard in order to avoid bias in establishing the specificity of the evaluated tests. this "composite" reference standard was constructed as follows: ( ) samples were considered as positive for a viral pathogen if they tested positive by at least of the assays used (viral culture, pneumovir, homemade pcrs) and ( ) they were considered negative if they tested negative by at least of the assays. the samples not fitting one of these categories were classified as undetermined. as a consequence, the analytical performances of our pcr detecting coronavirus nl and oc could not be evaluated, as it was the only method used here that was able to detect these viruses. for each patient, the following demographic, clinical, biological, and microbiological data were recorded: age, gender, duration of gestation, immunization status, duration and maximal documented temperature at home and in the er, symptoms, laboratory results, treatment administered and duration, destination after discharge from er, complications, and length of stay if hospitalized. all patients' files were reviewed by an infectious diseases senior pediatrician, and infants were classified into groups according to clinical symptoms at presentation: ( ) respiratory infection, ( ) suspected infection. viral or bacterial suspected infection was defined as clinical signs and nonspecific laboratory tests matching either with viral or bacterial infections but with no microbiological documentation. no etiology. no etiology was defined as the febrile episodes not matching with any of the definitions described above. if a febrile episode matched with diagnostic definitions, the most severe one was considered as the responsible of the fever. data were recorded on excel files (microsoft office, windows) and analyzed using descriptive statistics. verbal informed consent was obtained from all parents or legal guardians at inclusion. the study was approved by the local ethics committee. during the study period, infants were enrolled on admittance to the er for a total of febrile episodes: infants presented episodes (with a median of . days between episodes [ - days]). median age was days ( - days), . % were males, and . % were prematurely born babies. median measured for fever in the er was . °c and . °c at home, for a median duration of hours ( - hours) before arrival. for the . % of infants older than days, the immunization program was not yet started (belgian immunization program is free and starts at weeks of age). blood culture, urine culture, and npa were performed in . %, . %, and . % of patients, respectively. lumbar puncture was performed in . % of the infants ( . % of infants < days and % of older infants with toxic aspect or laboratory alterations), stool viral antigenic tests in %, stool culture in . %, and skin pus culture in . % ( patient). in of the episodes, an npa was available for complete viral evaluation ( patients were not sampled, samples were not analyzed with rapid test and viral culture, and others were not analyzed with molecular techniques due to technical issues). seventy-five out of npa ( . %) had a positive rapid antigen detection test ( figure ); positive results ( . %) were confirmed by culture. among the culture-negative rapid test-positive samples, were hmpv, whose culture growth is known to be difficult. the remaining cases were explored by molecular methods but, as previously said, were not analyzed with pneumovir assay. from the samples evaluable for analytical performances, the composite reference standard was negative for samples, positive for samples, and undetermined for samples (culture was negative and molecular tests were discordant). of note, among the "negative" samples, coronaviruses oc and coronaviruses nl were detected by pcr. as shown in table , culture was, as expected, the technique with the lowest sensitivity ( %), missing mainly hmpvs, rhinoviruses, and mixed infections; its specificity was %. the in-house real-time pcrs showed good specificity ( %) and positive predictive value ( %), but its sensitivity did not reach %. the pneumovir assay, on the other hand, achieved the best sensitivity ( %) and negative predictive value ( %) but lacked specificity ( %), mainly due to results considered as false positives for rhinoviruses according to the composite standard. eighty-four percent of episodes (n = ) led to hospitalization and episodes ( %) to intravenous empirical antibiotic treatment. using our standard protocol, the rate of documented microbiological etiology was % at er discharge, % at the end of hospitalization, and % when viral cultures results became available. molecular methods increased the documented etiology rate by %, to a total of % of all episodes (figure ). the highest rate of documented episodes was achieved for infants with respiratory symptoms at presentation ( . %), followed by those with gastrointestinal symptoms ( . %). the contribution of molecular methods to establish the etiology of the febrile episode was the highest for infants with fever without clinical focus, increasing the rate of microbiological documentation by %, to a total of % ( figure ). among the % of episodes with documented etiology, sbi was diagnosed in patients ( %): urinary tract infections (utis), bacterial enteritis, and finger cellulitis ( table ). viruses were detected in the npa of of these infants ( %): rsv, rhinovirus, piv, coronavirus nl , and cytomegalovirus. the remaining % were "documented viral infections." twentyone of the episodes ( %) with a proven viral etiology were suspected to have a bacterial coinfection on clinical basis or because they had laboratory signs of inflammation. these episodes occurred all in infants with respiratory symptoms at presentation. in episodes ( . %), infants were considered as low risk for bacterial infection after workup in the er ( figure ) ; ( %) of these infants were hospitalized, of them ( %) only for clinical observation, while required supportive treatment. one single episode classified as "low risk" at er discharge ended to be a "bacterial proven infection," namely, a campylobacter jejuni enteritis. among the infants with febrile episodes considered at low risk of sbi and hospitalized for observation, ( %) ended to have a documented viral infection. this is the first prospective study reporting the contribution of a large panel of techniques, including molecular methods for multiple respiratory viruses, to establish the etiology of febrile episodes in infants younger than months. we evaluated the possible contribution on clinical decisions in parallel with the chronology of the availability of the laboratory results that led to episode documentation. our study presents the limitation of having been conducted mainly during the autumn-winter season in a single center. this can explain the important rate of infants presenting respiratory symptoms. nevertheless, the rate of sbi is similar to those reported in the literature, , , as is the predominance of uti among our sbi, demonstrating that our cohort can be considered as representative of the etiologic case mix usually observed among febrile episodes in infants younger than months. identifying infants at risk of sbi among those presenting a febrile episode remains an important challenge, and several scales based on clinical, biological, and microbiological data have been recommended. - in the past years, important advances have been made in terms of laboratory techniques that either help better identify high-risk infants or confirm sbi more rapidly, such as procalcitonin level [ ] [ ] [ ] [ ] [ ] or rapid bacterial identification from blood culture by maldi-tof (matrixassisted laser desorption/ionization-time-of-flight mass spectrometry). other authors have focused on detecting infants at low risk of sbi using clinical scores. documenting a viral infection has also been shown to contribute to identify febrile infants at low risk of sbi. [ ] [ ] [ ] [ ] [ ] however, as having a proven viral infection does not fully rule out the risk of sbi (especially uti), - viral tests cannot replace blood or urine analysis but must be seen as additional tools in the management of these patients. current routine viral tests are rapid and relatively sensitive in pediatric population but are available for a limited number of viruses only. as a consequence, viral infection is not always documented on time to affect the clinical care. in our study, the infants considered at "low risk of sbi" when discharged from the er that finally turned out to have a proven viral infection represented about % of the total cohort (n = ). these numbers are similar to those published by huppler et al, who identified in a large meta-analysis of studies a similar rate of infants ( %) that were observed without receiving empiric antibiotic therapy or sent back home, after being identified at "low-risk." this population, namely, "low risk" infants with a presumed viral infection, is probably the population that could benefit the most from adding molecular tools to their management, sparing them the bundle of downsides associated with hospitalization and empiric antibiotic therapy, including costs, adverse effects, development of resistant organisms, nosocomial infections, and psychosocial stress on family dynamics. the present evaluation demonstrates that molecular techniques greatly improve the detection rate of viral infections, especially in the challenging group of febrile infants without clinical source, among which the increase in microbiological documentation was nearly %. the clart pneumovir was the most powerful tool tested, multiplexing viral targets with a sensitivity rate of % and a negative predictive value of %. however, it also presented potential drawbacks: its lack of specificity (false-positive results for rhinoviruses) and the fact it does not target all circulating coronaviruses. unfortunately, as the molecular methods used here are expensive and need trained staff, they are not yet routinely used in the management of febrile infants younger than months. furthermore, to be useful in clinical practice, the results of these techniques should be available during the timespan in which patient's management, treatment, and follow-up are decided. new "sample-in, answer-out" point-of-care platforms that enable fully automated detection of comprehensive panels of respiratory pathogens in about hour are now available and should soon enable this expected improvement of patient's management. in conclusion, our study demonstrates that the use of molecular techniques increases to % the proportion of documented etiology in febrile episodes in infants younger than months. we have also identified the population in which these techniques have the highest contribution. making these tests available hours/ and days/ could help lightening the management of these patients. our study provides adequate information to design a prospective study that could fully assess the contribution of new, rapid, point-of-care, multiplex molecular tools to the management of febrile infants younger than months. the authors gratefully thank the fondation vésale for supporting the molecular analyses used in this study. the authors also thank jerôme de marchin for his contribution to the design of data collection instruments and beatriz epalza for her help in analyzing the data. ce: conceptualized and designed the study, coordinated patient's recruitment, designed the data collection instruments, coordinated and supervised data collection, drafted the initial manuscript, and approved the final manuscript as submitted. mh: supervised the molecular techniques, carried out the laboratory data analysis, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. lb: supervised the laboratory techniques, reviewed the manuscript, and approved the final manuscript as submitted. sd: helped in patient's recruitment, reviewed the manuscript, and approved the final manuscript as submitted. pdb: helped in patient's recruitment, reviewed the manuscript, and approved the final manuscript as submitted. ov: reviewed the manuscript and approved the final manuscript as submitted. jl: conceptualized and designed the study, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the fondation vésale supported the molecular analyses used in this study. cristina epalza https://orcid.org/ - - - supplemental material for this article is available online. febrile infant working group of the pediatric emergency care applied research network. accuracy of complete blood cell counts to identify febrile infants days or younger with invasive bacterial infections predictive model for serious bacterial infections among infants younger than months of age febrile infants at low risk for serious bacterial infectionan appraisal of the rochester criteria and implications for management. febrile infant collaborative study group c-reactive protein as a marker of serious bacterial infections in hospitalized febrile infants markers that predict serious bacterial infection in infants under months of age presenting with fever of unknown origin risk stratification and management of the febrile young child outpatient management without antibiotics of fever in selected infants management and outcomes of care of fever in early infancy detection of respiratory viruses by molecular methods simultaneous detection and high-throughput identification of a panel of rna viruses causing respiratory tract infections comparison of the filmarray assay and in-house real-time pcr for detection of respiratory infection clinical and financial benefits of rapid bacterial identification and antimicrobial susceptibility testing clinical impact of rapid identification and susceptibility testing of bacterial blood culture isolates serious bacterial infections in febrile infants to days old with and without viral infections risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections prevalence of serious bacterial infections in febrile infants with respiratory syncytial virus infection influenza virus infection and the risk of serious bacterial infections in young febrile infants low prevalence of invasive bacterial infection in febrile infants under months of age with enterovirus infection evaluation of diagnostic tests for infectious diseases: general principles procalcitonin in young febrile infants for the detection of serious bacterial infections diagnostic value of procalcitonin in well-appearing young febrile infants validation of a laboratory risk index score for the identification of severe bacterial infection in children with fever without source european group for validation of the step-by-step approach. validation of the "step-by-step" approach in the management of young febrile infants use of procalcitonin assays to predict serious bacterial infection in young febrile infants impact of rapid microbial identification directly from positive blood cultures using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry on patient management febrile infant working group of the pediatric emergency care applied research network (pecarn). a clinical prediction rule to identify febrile infants days and younger at low risk for serious bacterial infections performance of lowrisk criteria in the evaluation of young infants with fever: review of the literature detection of viruses in young children with fever without an apparent source rapid point of care diagnostic tests for viral and bacterial respiratory tract infections-needs, advances, and future prospects key: cord- -phtmgy g authors: nan title: vaccination schedule for infants and covid- date: - - journal: bull acad natl med doi: . /j.banm. . . sha: doc_id: cord_uid: phtmgy g nan eleven vaccines have been made mandatory for children q born from january , . this measure significantly improved the vaccination coverage of infants in , particularly against hepatitis b and meningitis, has significantly reduced the incidence of invasive meningococcal infections in younger infants. the spread of the covid- pandemic in france has interrupted this beneficial development. many parents have cancelled vaccination appointments for their infants as well as their older children. fear of contagion in waiting rooms, doubts about the effects of vaccination on immunity in a pandemic period, and then containment, has led to a sharp decrease in vaccinations, mainly in infants. on april , , the french health authority issued an opinion so that the vaccination schedule would not be delayed. the epi-phare report on the use of city drugs during the covid- period reveals that penta and hexavalent vaccines for infants have fallen by % and that deliveries of mmr and hpv vaccines have dropped by to % during the last two weeks of march [ ] . this situation cannot continue. infants must imperatively be vaccinated from the nd month, in order to acquire an effective protection as soon as possible against frequent and serious diseases at this age, particularly the author declares that he has no competing interest. usage des médicaments de ville en france durant l'épidémie de covid- -point de situation à la fin mars key: cord- - g regv authors: neu, josef title: the microbiome and its impact on disease in the preterm patient date: - - journal: current pediatrics reports doi: . /s - - - sha: doc_id: cord_uid: g regv emerging technologies derived largely from the human genome project are being applied to evaluating the intestinal microbiota in preterm infants. the microbial ecology of the developing intestine is highly related to health and disease and new discoveries are emerging that will help us understand disorders in the development of the intestinal microbial ecosystem and how to eventually manipulate them to prevent diseases such as necrotizing enterocolitis and late onset sepsis. here, a brief overview of the developing microbiome as it pertains to several aspects of health and disease in the preterm infant is presented. the intestinal microbiota, a complex ecosystem shaped by the millennia of evolution, normally exists in a commensal and/or symbiotic relationship with the host [ , ] . this relationship promotes a delicate equilibrium with the capability to modulate immune responses and promote health. in the past few years, emerging technologies derived largely from the human genome project are applied to evaluating the intestinal microbiota, and new discoveries using these techniques have prompted new initiatives such as the human microbiome roadmap designed to evaluate the role of the intestinal microbiome in health and disease [ ] . our current state of knowledge suggests that the neonatal intestinal microbiota is highly variable in its composition and depends on factors such as gestational age, mode of delivery, type of feeding and other environmental exposures [ ] . the host's need for intestinal microbiota is demonstrated by studies showing that germ-free animals do not develop normal lymph node architecture, with extensive defects in the development of gut-associated lymphoid tissue, arrested capillary network development in the gut and reduced antibody production [ ] . the traditional view of the human is that it is composed of ten trillion cells, which are the product of * , genes. however, it has long been known that in various niches of the human body, there resides a number of species of microbes and microbial genes that vastly outnumber the cells and genes of the human ''host''. until the beginning of the last decade, culture-based techniques were the mainstay of evaluating intestinal microbes. however, it has long been recognized that the majority of bacterial cells seen microscopically in feces are not currently cultured in the laboratory. recently developed high throughput molecular techniques analyze microbial dna and rna and have moved beyond culture-based technologies. there are two general approaches, both of which comprise several variants. one commonly used general approach is to utilize the s rrna gene, and the other is a more complex metagenomic approach in which community dna is subject to shotgun (whole genome) sequencing. a detailed description of these techniques is beyond the scope of this review and can be found elsewhere [ • , , ] . even if the taxonomy of a particular microbial community is identified, the functional expression as it relates to physiology and interaction with the host is not clarified. simple identification of individual microbes or microbial genotypes often does not clarify their phenotypic expression. thus, in addition to microbiome identification based technologies, it is important to clarify the function of the microbial communities of interest within a particular niche. it, thus, is of interest to identify the mrna and protein expression of the genes as well as the metabolites that result before and after interaction of the microbial gene products with the host. additional ''omic'' disciplines are, thus, being applied to augment studies of the microbiome. metatranscriptomics, metaproteinomics, and metabolomics identify gene expression products (mrna), proteins and metabolites resulting from the genes within a complex microbial community, such as that found in a fecal sample. metaproteomics is the study of proteins collectively expressed within microbial communities that usually employ mass spectrometry based analyses to detect proteins associated with the microbiota identified within a given niche. these studies usually also employ a systems biology approach to evaluate the likely functions of the proteins produced by the microbiota. a recent study employed a nontargeted, shotgun mass spectrometry-based whole community proteomics, or metaproteomics, approach for the first deep proteome measurements of thousands of proteins in human fecal samples [ ] . the resulting metaproteomes had a distribution that was unexpected relative to the metagenome, with more proteins for translation, energy production and carbohydrate metabolism when compared to what was earlier predicted from metagenomics. the intestinal microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory processes connecting the intestine, liver, muscle, and brain. these interactions begin at birth and likely even during fetal life. the microbiota shapes the development of the immune system, and the immune system in turn shapes the composition of the microbiota through a cross talk between the microbes and the host immune system. the signaling processes, together with direct chemical interactions between the microbe and host, act upon multiple organs such as the gut, liver, muscle, and brain. although a commonly held belief is that the intestinal tract of the fetus is sterile, recent studies using a combination of culture and non-culture-based techniques suggest that many preterm infants are exposed to microbes found in the amniotic fluid, even without a history of rupture of membranes or culture-positive chorioamnionitis [ • , ] . this has led to speculation that the microbial ecology of the swallowed amniotic fluid may have a role not only in the fetal intestinal physiology and inflammation but also perhaps in premature labor [ • ]. studies of microbial ecology in premature infants using non-culture-based techniques remain few, but this is an area of active investigation. recent polymerase chain reaction (pcr)-based studies estimate the prevalence of microbial invasion of the amniotic cavity to be c - % higher than that detected by cultivation-based methods [ ] . from these studies we now know that cultivation-resistant anaerobes belonging to the family fusobacteriaceae (particularly sneathia sanguinegens, and leptotrichia spp.) are also commonly found in amniotic fluid. other diverse microbes detected by pcr of amniotic fluid include as yet uncultivated and uncharacterized species. a causal relationship between diverse microbes, as detected by pcr, and preterm birth is supported by types of association (e.g., space, time, and dose) proposed as alternatives to koch's postulates for inferring causality from molecular findings. whether this colonization affects the gastrointestinal tract of the fetus is not known. we do know, however, that the fetus is known to swallow large quantities of amniotic fluid during the last trimester of pregnancy, and there have been recent findings that microbial dna is present in meconium. these both suggest that the fetal intestine is exposed to the amniotic fluid microbes. the high sensitivity of the fetal intestine to inflammatory mediators such as lps [ , ] suggests that microbes may trigger intestinal inflammation in utero. furthermore, one can speculate that exposure of the intestinal tract to toll like receptor agonists such as lps, flagellin or microbial cpg in low quantities may also ''tolerize'' the intestine to further inflammatory stimuli [ • ]. one study used high-throughput s-based techniques to analyze intestinal microbial ecology in premature neonates in neonates born at - weeks' gestational age [ ] . surprisingly, microbial dna was detected in meconium, suggesting an intrauterine origin. differences in diversity were detected in infants whose mothers intended to breast feed (but had not yet fed their babies, suggesting other factors such as socioeconomic or educational status to be important), babies born to mothers treated with antibiotics prior to delivery and in babies born at\ weeks' gestation. postnatally, many factors can influence intestinal bacterial colonization as well as the responses to colonization. some studies have shown that the mode of delivery, vaginal versus c-section, type of milk (human milk vs. formula), and antibiotics influence the intestinal flora [ ] [ ] [ ] . those infants born via c-section, fed formula milk and exposed to antibiotics have a decrease in diversity of intestinal microbiota and abnormal patterns of colonization with suppression of ''healthy'' bacteria such as lactobacillus and bifidobacteria. epidemiologic data showing a relationship between increased c-section rate and risk for development of subsequent diseases was recently reviewed [ ] . ''in the united states the rate of cesarean delivery (cd) has risen % since , reaching a level of . % in . this trend is reflected in many parts of the world, with the most populous country in the world, china, approaching % and some private clinics in brazil approaching %.'' in association with the trend of increasing c-section deliveries, there has been an epidemic of both autoimmune diseases such as type diabetes, crohn's disease, multiple sclerosis, and allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. the occurrence of these diseases is higher in more affluent, western, industrialized countries. as reviewed [ ] , several previous studies have demonstrated differences in microbial colonization after c-section and vaginal deliveries. a more recent study by domingiuez-bello et al. [ ] , where non-culture-based sequencing technology was used, offers a detailed look at the early stages of the body's colonization by microbes. during birth and rapidly thereafter, bacteria from the mother and from the surrounding environment colonize the infant's gut. during vaginal delivery, the contact with the mother's vaginal and intestinal flora is an important source of the infant's colonization with a predominance of lactobacillus, prevotella and other bifidobacterium [ , ] during cesarean delivery, direct contact of the mouth of the newborn with vaginal and intestinal microbiota is absent, and nonmaternally derived environmental bacteria have a more important role in the infants' intestinal colonization, which has a less diverse flora and a bacterial community similar to those found on the skin surface dominated by staphylococcus and with a delayed intestinal colonization by lactobacillus, bifidobacterium and prevoltella [ , ] . some authors have speculated that the composition of the very first human microbiota could have lasting effects on the intestine [ ] . gronlund et al. [ ] showed that the primary gut flora in infants born by cesarean delivery may be disturbed for up to months after birth. another study using culture-based techniques showed that the mode of delivery was associated with differences in intestinal microbes seven years after delivery [ ] . there is accumulating evidence that intestinal microbiota has an important role in the postnatal development of the immune system [ ] . available epidemiological data show that atopic diseases, asthma, type diabetes and food allergies appear more often in infants after cesarean delivery than after vaginal delivery [ ] [ ] [ ] [ ] . studies in adults using nonculture-based analysis of the intestinal microbiota show that antibiotics may perturb the gastrointestinal tract for years. [ ] since many mothers delivered by c-section also receive antibiotics, whether they have a role in perturbing the newborn intestinal microecology remains unknown but is a confounding factor when one evaluates the epidemiology studies showing atopic disease, type diabetes and food allergies in c-section versus vaginally delivered infants. the composition of enteric microbiota in the early days of life may be a very important factor for achieving and maintaining good health in the years to come. it follows that it is fundamental to identify more thoroughly the intestinal ecosystem during the early developmental stages of life. studies in animals and premature infants have shown that human milk decreases the incidence of necrotizing enterocolitis (nec) [ , ] . beneficial factors of breast milk include immunoglobulins, cytokines, lactoferrin, lysozyme, growth factors, and oligosaccharides (hmo) [ , ] . human milk oligosaccharides (hmos) contain a lactose core and act as prebiotics, stimulating growth of bifidobacterium species [ , ] . at birth a rapid colonization of intestinal flora occurs in the newborn, with aerobic or facultative anaerobic bacteria such as enterobacteria, enterococci and staphylococci represented. these consume oxygen during growth, allowing the proliferation of anaerobic bacteria such as bacteroides, bifidobacterias and clostridia [ , ] . in the formula-fed infant this transition does not occur, and the newborn intestinal flora differs in its pattern of colonization, with a predominance of gram negative bacteria and fewer anaerobes [ , ] . if grouped by phyla, breast-fed infants have a predominance of 'healthy' firmicutes, mainly lactobacillus, bacteroides and actinobacteria (bifidobacterium). formula-fed infants have a predominance of proteobacteria such as escherichia coli, and firmicutes, some of which have pathogenic characteristics such as clostridia and staphylococcus. in one study of preterm infants it was speculated that the abnormal pattern of colonization at birth coupled with a delayed bloom of more pathogenic bacteria could potentially lead to the development of nec [ ] . sullivan et al. [ ] in one multicenter study utilizing donor human milk showed that an exclusively human milk-based diet (including human milk based fortifier) is associated with significantly lower rates of nec, including surgical nec, when compared with a mother's milk-based diet that also includes bovine milk-based products. the reduction in nec utilizing strategies of only human milk was % for medical nec and almost % for surgical nec. the number needed to treat to prevent one case of nec was estimated to be ten. in a recent aap policy statement regarding breastfeeding and the use of human milk, the recommendation was to offer donor milk to all preterm infants in which mother's own milk is unavailable [ ] . the use of antibiotics is widespread in the intensive care units (nicu), most commonly for a diagnosis of ''rule out'' infection. often, their use is justified, but other times it's the product of fear of infections on the part of the care providers. nevertheless, the use of antibiotics in neonates and especially in the preterm infant has unintended and sometimes adverse consequences. antibiotic exposure may reduce the diversity of intestinal microbiota, delay the colonization of beneficial bacteria and potentially predispose preterm neonates to nec. one recent retrospective study found that the duration of antibiotic exposure is associated with an increased risk of nec among neonates without prior sepsis [ • ]. indeed, studies have shown that overgrowth of pathogenic species is increased after three days of antimicrobial exposure [ ] . in the u.s. most mothers giving birth prematurely are treated with antibiotics and most very low birth weight infants are treated with a course of broad spectrum antibiotics such as ampicillin and gentamicin. studies have shown the detrimental effects of antibiotics to the intestinal flora, even after one dose of antibiotics with alterations in the intestinal microbiota that could take years to recover [ ] . one study showed a decrease in diversity, a predominance of less desirable bacteria and highly resistant clones with abundance of specific resistance genes as a result of antibiotic exposure that did not recover after two years post exposure [ ] . cotten et al. [ ] found that each empirical treatment day with antibiotic was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death. they concluded that prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution. caution should be exercised when deciding to start antibiotics in preterm infants. there are long lasting consequences and life threatening morbidities associated with the indiscriminate use of antibiotics. necrotizing enterocolitis (nec) is an enigmatic disease that has been recognized for over a century. with the advent of neonatal intensive care, it has become one of the most common and devastating diseases in neonates [ ] [ ] [ ] . complicating the literature is the fact that the causes are multifactorial, and it is not a single disease [ ] . for example, when an infant born at term with a hypoplastic left ventricle presents with pneumatosis intestinalis at two days of age, the etiology and pathophysiology of this baby's ''nec'' is likely different than the week gestation preterm who presents with pneumatosis intestinalis at fiveweeks of age. the first is more likely related to ischemic injury due to hemodynamic insufficiency and hypoxicischemic injury [ ] rather than a coalescence of factors that result in intestinal inflammation and injury related to intestinal immaturity, as in the preterm infant. in the latter case, sometimes referred to as ''classic'' nec [ ] , the interactions of a predisposing genetic background, an immature intestinal barrier and a microbial environment that is conducive to the development of nec are thought to play an interactive and critical role in pathogenesis [ , , ] . the linkage of nec to bacterial colonization was recognized by santulli et al. [ ] over three decades ago. additional observations showing clusters of cases, outbreaks in institutions, the finding of pneumatosis intestinalis, which likely represents submucosal gas produced by bacterial fermentation, and the common findings of bacteremia and endotoxinemia in affected neonates, supports a microbial role in the pathogenesis of this disease [ ] . numerous bacteria have been related to nec, but none of them have been found to fulfill koch's postulates because they are commonly found among patients without nec [ ] . viruses have also been implicated in the pathogenesis of nec and coronavirus within fecal samples and resected intestinal segments were reported in patients with nec [ ] , but their actual roles in the causation of the disease have not been substantiated. the intestinal microbiota normally exists in a commensal and/or symbiotic relationship with the host [ ] , but in the neonate and especially in the premature infant, this relationship is underdeveloped and many factors will define its delicate equilibrium with the capability to modulate immune responses and promote health (fig. ) [ ] . as previously mentioned, a specific pathogen that fulfills koch's postulates for the etiology of nec has not been found. whether the use of a new generation of sequencing technologies will help in this search is unknown, although some preliminary studies are offering clues. in a study by wang et al. [ ] , fecal samples from preterm infants, ten with nec and ten matched controls (including four twin pairs), were obtained from patients in a single site level iii neonatal intensive care unit. bacterial dna was subjected to terminal restriction fragment length polymorphism analysis and library sequencing of the s rrna gene. the distribution of samples from nec patients was distinctly different from that of controls, though intestinal bacterial colonization in all of these preterm infants was notable for low diversity. patients with nec had previously received a higher mean number of days of antibiotics and had even less diversity with an increase in abundance of gammaproteobacteria and a decrease in other bacteria species. these results suggest a relationship with prior use of antibiotics in patients with nec, though in this study infants may have been on antibiotics with nec when the cultures were collected. in another study by mai et al. [ ] , stool specimens were collected prospectively from infants with gestational ages b completed weeks or birth weights b g, starting with the first stool and continuing weekly until discharge. high throughput s rrna sequencing was used to compare the diversity of microbiota and the prevalence of specific bacterial signatures in nine nec infants and in nine matched controls. a bloom ( % increase) of proteobacteria and a decrease ( %) in firmicutes in nec cases between the week and\ h was detected. no significant change was identified in the controls. several molecular signatures were increased in the nec cases one week before and within h of nec development. one of the bacterial signatures detected more frequently in nec cases (p \ . ) matched closest to c-proteobacteria, also noted in the wang study [ ] . although this sequence grouped with the well studied enterobacteriaceae family, it did not match any sequence in genbank by more than %, suggesting that novel pathogens contribute to the etiology of nec. the current evidence highlights the importance of the development of a healthy intestinal microbiota in the neonate. many aspects that promote health or disease are related to the homeostasis of this intestinal microbiota. especially in the preterm infant, the delicate equilibrium of the intestinal microbiota could be strongly influenced by the intervention that we as physicians routinely perform as part of the medical care of the neonate. as the awareness of the importance of the development and maintenance of the intestinal flora increases and the development of newer molecular techniques allows us to identify, monitor and modify this microbiota we will be able to improve the care of our infants with interventions with long lasting effects. conflict of interest josef neu is on the scientific advisory board for medela and mead johnson, has consulted for biogaia, was a mentor to a postdoctoral fellow who received a research grant from gerber and has been supported to travel to meetings by nestle, danone and abbott. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by any of theauthors bacterial contributions to mammalian gut development commensal host-bacterial relationships in the gut the human microbiome project factors influencing the composition of the intestinal microbiota in early infancy developmental regulation of intestinal angiogenesis by indigenous microbes via paneth cells this review discusses the advantages over culture based techniques and challenges of studying microbes using next-generation sequencing technologies. it provides an overview and comparison of techniques such as s sequencing versus shotgun and some of the bioinformatics software available to analyze data generated by these technologies microbial community profiling for human microbiome projects: tools, techniques, and challenges genomic approaches to studying the human microbiota shotgun metaproteomics of the human distal gut microbiota discusses various microbes found in association with microbial invasion of amniotic fluid without rupture of membranes and raises numerous questions of whether these microbes may be responsible for preterm labor and postnatal diseases where early colonization may have an effect on development of the immune system microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation microbial invasion of the amniotic cavity in pregnancies with small-for-gestationalage fetuses the mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis disease tolerance as a defense strategy this is a ''distinct host defense strategy, which has been largely overlooked in animal and human studies intestinal microbial ecology in premature infants assessed with non-culture-based techniques analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods long-term ecological impacts of antibiotic administration on the human intestinal microbiota fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis development of the human gastrointestinal microbiota and insights from high-throughput sequencing delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns cesarean delivery may affect the early biodiversity of intestinal bacteria fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery influence of mode of delivery on gut microbiota composition in seven year old children effects of intestinal microflora and the environment on the development of asthma and allergy mode of delivery and development of atopic disease during the first years of life childhood asthma hospitalization risk after cesarean delivery in former term and premature infants caesarean section and gastrointestinal symptoms, atopic dermatitis, and sensitisation during the first year of life is delivery by cesarean section a risk factor for food allergy? long-term ecological impacts of antibiotic administration on the human intestinal microbiota an exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products an experimental study of acute neonatal enterocolitis-the importance of breast milk breast-feeding, infant formulas, and the immune system in vitro fermentation of breast milk oligosaccharides by bifidobacterium infantis and lactobacillus gasseri a strategy for annotating the human milk glycome reduced enterobacterial and increased staphylococcal colonization of the infantile bowel: an effect of hygienic lifestyle? intestinal flora in very low-birth weight infants breast-v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects factors influencing the composition of the intestinal microbiota in early infancy fecal microbiota in premature infants prior to necrotizing enterocolitis breastfeeding and the use of human milk a case control study that shows a link between antibiotic usage and the development of necrotizing enterocolitis. this is an example of how manipulation of of the microbiome may have inadvertent consequences bacterial colonization of neonates admitted to an intensive care environment short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants necrotizing enterocolitis- years of fruitless search for the cause necrotizing enterocolitis necrotising enterocolitis. the lancet ischemia-reperfusion and neonatal intestinal injury hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis acute necrotizing enterocolitis in infancy: a review of cases molecular koch's postulates applied to bacterial pathogenicity-a personal recollection years later isolation and propagation of a human enteric coronavirus commensal host-bacterial relationships in the gut immunomodulation by commensal and probiotic bacteria s rrna gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis key: cord- - ev w ko authors: unger, sharon; stintzi, alain; shah, prakeshkumar; mack, david; o'connor, deborah l title: gut microbiota of the very-low-birth-weight infant date: - - journal: pediatr res doi: . /pr. . sha: doc_id: cord_uid: ev w ko the microbiome, of which the bacterial component alone (microbiota), is estimated to include times more cells than human cells of the body, blooms immediately after birth and evolves in composition and complexity throughout childhood. the gut microbiome has a profound impact on gastrointestinal tract development, maintenance of mucosal surface integrity, and contributes to the nutritional status of the host and thus plays a pivotal role in health and disease. new technologies have enabled the detailed characterization of normal microbial symbionts and dysbiosis–disease associations. this review summarizes the stepwise establishment of the intestinal microbiota, influential environmental factors, and how this may be perturbed in preterm very-low-birth-weight infants. the contribution of the microbiota to provision of energy and nutrients for intestinal development and the nutritional status of the host are reviewed. in addition, the crucial role of the gut microbiota in maintaining mucosal integrity is explored along with how its breakdown can lead to sepsis, necrotizing enterocolitis, and systemic inflammatory response syndrome. finally, the role of enteral feeding type (human milk, formula, and nutrient fortification) in mediating these processes is discussed, and guidance is provided for nutritional strategies to promote health in these fragile infants. supplementary information: the online version of this article (doi: . /pr. . ) contains supplementary material, which is available to authorized users. t he microbiome describes the totality of the microbes in an environment, including bacteria, protozoa, viruses, fungi, and their genetic elements. the human microbiota describes the bacteria colonizing every surface of the body from the skin to the respiratory tract, genitourinary tract, and gastrointestinal tract (git). the intestinal microbiota constitutes the most abundant microbial community in humans with times more cells and times more genes than human cells. until recently, little was known of the git microbiota of very-low-birth-weight (vlbw, < , g) infants as traditional culture-based techniques identified only % of git microbes ( ) . advances in molecular technologies have allowed a rapid expansion of knowledge of the human microbiome. the git microbiota is crucial in maintaining mucosal integrity, and its breakdown can lead to sepsis, necrotizing enterocolitis (nec), and systemic inflammatory response syndrome ( ) . distal organ damage in systemic inflammatory response syndrome has been linked to severe morbidities associated with preterm birth including brain damage (periventricular leukomalacia) and lung damage (chronic lung disease) ( ) . the git microbiota best associated with optimal health is unknown; however, an overarching finding in vlbw infants is decreased git microbiota diversity and a higher pathogen load ( , ( ) ( ) ( ) ( ) . in the past century, investigations of the git microbiota were cultured based with the identification of the genus, species, and even strain using a battery of morphological and biochemical tests. however, up to % of gut microbes remain very difficult to culture ( ) . a number of new molecular-based approaches have been developed over the past decade revolutionizing the study of microbial communities. high-throughput sequencing of the s ribosomal rna gene is the most widely employed approach used to characterize a microbial community. the s rrna is part of the small ribosomal unit that is preserved in all organisms and contains highly conserved sequence domains interspersed with hypervariable regions. selective amplification of these hypervariable regions followed by high-throughput sequencing is an efficient way to characterize the microbial community ( ) . beyond s rdna-based sequencing, metagenomic, metatranscriptomic, metaproteomic, metabolomic, and non- s rdna-targeted approaches are increasingly employed to generate functional and quantitative information on microbial communities ( ) . the metagenome refers to the totality of the genomes from the whole community including bacteria, fungi, viruses, and protozoa. to analyze a metagenome, dna is extracted and shotgun sequenced to determine functional and biochemical capabilities of the microbial community. two strains of any given bacterial species may differ in dna content by as much as % allowing for the same species but different strains to be harmless, commensal, or harmful. a further step is to identify not only which genes are present in a microbiome but which genes have been expressed into mrna (metatranscriptomics) or proteins (metaproteomics) ( ) . at present, metatranscriptomics of the git microbiome is limited by the inherent instability of rna and difficulties extracting it from stool. metaproteomics is an attractive alternative but has been limited because of analytical challenges, incomplete reference databases, and highly redundant protein sequences between different microbes. metabolomic analyses use mass spectrometry or nuclear magnetic resonance spectrometry to monitor the whole set of small molecules produced by microbes or the host cells within a sample ( ) . predominant gut organisms from the kingdom bacteria are presented in figure . more than , bacterial species have been identified in the adult git with the three phyla being prominent: bacteroides, actinobacteria, and firmicutes. in any single individual, % of the git microbiota is made up of - species ( ) . until recently, we believed that the git of a healthy-term newborn was sterile; however, meconium is now known to contain microbial rdna ( ) , suggesting that infants are colonized before birth. oral administration of genetically labeled enterococcus faecium to pregnant mice led to their presence in the meconium of born pups by cesarean, demonstrating the possibility of prenatal maternal microbial transmission ( ) . immediately after birth, bacterial colonization of the git proceeds rapidly (phase i, - wk) with aerotolerant microbes. it continues through exclusive breastfeeding (phase ii) until weaning (phase iii) in a stepwise manner with the appearance of strict anaerobes such that by - mo of age, the microbiota resembles the extremely dense and complex microbial colonization of an adult (phase iv) ( , , ) . the infant microbiota is more variable day-to-day in its composition and less stable over time compared with that of the adult ( , , , ) . the relative stability of the adult microbiota has been challenged by a recent study demonstrating that a single week of dietary change is sufficient to alter the intestinal microbiota ( ) . infant microbial colonization can be significantly affected by exogenous factors including the mode of delivery, feeding type, antibiotics, and introduction of solid food. colonization of the git is perturbed by a number of factors prevalent among vlbw infants including: cesarean delivery, antibiotics (mother or infant), prolonged rupture of the membranes, parenteral feeding, delayed enteral feeding, slower git transit time, gestational age, birth weight, living in a populated neonatal intensive care unit with an enriched pathogen load, and lack of exposure to mother's skin and breast milk microbiome ( , ( ) ( ) ( ) ( ) , ( ) ( ) ( ) ( ) ( ) ( ) . table summarizes studies describing the git microbiota of vlbw infants using molecular techniques. there appear to be significant differences in the composition of the intestinal microbiota of preterm compared to term infants, with decreased bacterial diversity, increased pathogens potentially related to nec, and a surprising increase in eukaryotic and viral diversity ( , , - ). as described in both tables and , these studies represent small numbers of patients and samples with between and patients per study in the vlbw group and between and patients in the nec group. other limiting factors in studying these data are the heterogeneity (or lack of reporting) of patient characteristics, diet, mode of delivery, antibiotic course, and sampling frequency and timing (some samples only collected after the onset of nec). infants born by cesarean have a different git microbiome compared with those born vaginally, and some of these differences are sustained throughout early childhood ( , , , , , ) . vaginal birth leads to an inoculation of infants with maternal fecal and vaginal bacteria. in contrast, cesarean-born infants are exposed initially to bacteria originating from the hospital environment, health care workers, and their mother's skin. in term infants, vaginal delivery results in a higher git bacterial richness (number of different species) and diversity (richness and evenness of their distribution) ( , ) . while study-tostudy differences exist, most recently, azad et al. ( ) reported that escherichia-shigella is underrepresented, and the phylum bacteroidetes was undetectable in -mo-old term-born infants born by cesarean compared with vaginal delivery. contrary to previous studies, this group did not observe differences by mode of delivery in prevalence of clostridium difficile or the relative abundance of bifidobacterium or clostridium. most vlbw infants receive broad-spectrum antibiotics during their early postnatal course possibly resulting in inadequate phase i colonization ( ) with an apparent inverse review correlation between the number of days of antibiotics in the first month postnatally and microbial diversity as well as total bacterial load in stools ( ) . early studies suggested that colonization with beneficial bacteria such as lactobacillus is specifically affected ( , ) and that antibiotic usage promotes a bloom of staphylococcus. more recently, it was shown term infants treated with parenteral ampicillin and gentamicin within the first h of birth demonstrated significant reductions in the phyla actinobacteria (including bifidobacterium) and firmicutes (including lactobacillus) which were replaced by proteobacteria (including enterobacteriaceae) ( ) . the dominance of proteobacteria and reduced microbial diversity remained for at least wk after treatment. in an adult human study, exposure to clindamycin for d led to a decline in bacterial diversity that persisted for up to y ( ) . given the instability of the newborn git microbiota, antibiotics exposure could be expected to induce profound alterations of the microbial community with long-term consequences ( , , ) . healthy-term newborns appear to be initially colonized by large numbers of enterobacter and streptococcus, regardless of feeding type ( ) . it is proposed that these bacteria are responsible for creating a reduced environment in the git which favors establishment of the anaerobes bacteroides, bifidobacterium, and clostridium by day to . in the term breastfed infant, it has been shown that by d, the beneficial bifidobacteria and lactobacillus predominate ( ) . in formula-fed infants, a more adult-type flora is most prevalent ( , , , ) along with an abundance of potentially pathogenic bacteria (clostridium difficile and escherichia coli) ( , , ) . most recently, azad et al. ( ) reported lower bacterial richness and diversity in the stools of -mo-old breastfed infants compared with formula-fed infants; further formula-fed infants had increased richness and overrepresentation of c. difficile compared with breastfed infants. the differences in colonization of human milk-fed compared with formula-fed infants are believed due, in part, to breast milk inoculating the git with its own rich microbiome and abundant source of oligosaccharides that selectively stimulate the growth and/or activity of beneficial bacteria ( , ) . it has been shown that during breastfeeding a significant volume of milk flows from the baby's mouth back into the mammary ducts providing an opportunity for bacteria from the baby's mouth to make its way into breast milk ( ) . even after cleansing the breast using an iodine solution to minimize bacterial contamination, pyrosequencing of the s rrna gene from milk reveals the microbial community in human milk to be highly diverse and complex ( , ) . data from human and animal studies suggest that bacteria or their components may actively migrate from the maternal git, by way of macrophages or dendritic cells, to the mammary gland and breast milk ( , ) , thereby providing another mechanism for different colonization patterns of human milk-fed compared with formula-fed infants. preliminary data also suggest that maternal obesity and elective cesarean section may also be associated with microbial diversity and composition in breast milk ( ) . human beings are born with a naive immune system that must develop tolerance to its environment and mature to develop an appropriate immunological response to pathogens. the git represents the largest surface area exposed to the external environment and contains - % of the body's immune cells ( ) . the microbiota communicates with host cells via toll-like receptors (tlr) which are transmembrane proteins present throughout the git that sense microbes by their conserved molecular patterns. for example, tlr- recognizes peptidoglycan and lipoteichoic acid from grampositive bacteria, tlr- recognizes lipopolysaccharide, the endotoxin of gram-negative bacteria, and tlr- recognizes flagellin ( ) . paradoxically, signaling induced by commensal bacteria is required for development of gut epithelial cell protection against inflammatory mediator injury as well as for cell repair ( ) . the effects of commensal bacteria include enhancement of tight junctions, stimulation of mucin production, and downregulation of cytokine production. evidence exists for induction of enterocyte protection by lactobacillus, bifidobacterium, bacteroides thetaiotaomicron, and streptococcus thermophiles ( ) . the microbiota may impact not only epithelial cell development but also endothelial cell ontogenesis. intestinal angiogenesis is ongoing at the time of acquisition of the microbiome, and a perturbation of angiogenesis may be implicated in intestinal inflammatory conditions such as nec. in a laboratory model, fibroblasts have been shown to produce proangiogenic factors in response to microbial cell products, and endothelial cells have demonstrated proliferation, migration, tube formation, and vessel sprouting ( ) . further evidence for the role of the microbiome on gastrointestinal development comes from experiments with germfree animals as well as from alteration of the microbiome with antibiotics. germ-free rodents have a decrease in transcription of mucin genes and a decreased thickness of the mucus layer along with fewer goblet cells and less iga production ( ) . suckling rats exposed to wk of antibiotics at the time of weaning show significant downregulation of genes encoding paneth cell products (important in host defense) and the major histocompatibility complex ib and ii proteins (antigen presentation), thus potentially altering the development of tolerance to food antigens ( ) . several lines of evidence suggest that the microbiota of the distal small intestine and colon make a substantial contribution to the nutrition of the host (up to - % of energy intake). germ-free animals have a higher dietary requirement for energy than those with an intact microbiota and when the microbiota of conventionally reared mice are transplanted into review unger et al. to lean germ-free mice, their body weight increases dramatically ( ) . many bacterial species in the distal intestine can ferment undigested carbohydrates (e.g., breast milk oligosaccharides) to produce the short-chain fatty acids acetate, propionate, and butyrate ( ) . butyrate is a major energy source for colonocytes, and propionate and acetate are absorbed and enter the portal circulation where they are used by a variety of body tissues, particularly the liver, in energy metabolism, lipogenesis, and gluconeogenesis. additionally, short-chain fatty acids are believed to influence energy metabolism by binding to and activating g protein-coupled receptors on colonic epithelial and enteroendocrine cells resulting in the release of peptide yy and glucagon-like peptide. we reported piglets fed formulas containing a mixture of inulin (fructooligosaccharide source) and galactooligosaccharides for the first d had colons that weighed ~ % more than piglets fed the same formulas but without a source of oligosaccharides ( ) . increased bacterial load supported by the provision of undigested carbohydrates and the resultant microbial synthesis of butyrate is thought to play a role in increased intestinal cell proliferation. these findings highlight the importance of the microbiota for the vlbw infant with increased energy requirements whose colon must double in length before reaching wk corrected age. differences in microbial community composition between normal weight and obese children and adults have been observed ( ) . important in reference to the vlbw infant, new data from developing countries suggest that the git microbial composition is altered in both marasmus (malnutrition due to insufficient energy) and kwashiorkor (malnutrition due to insufficient protein) ( ) . interestingly, transplantation of the microbiota of malawian children with kwashiorkor to gnotobiotic mice fed a rodent diet patterned after the malawian diet resulted in significant perturbation of both amino acid and carbohydrate metabolism ( ) . it has long been recognized that intestinal bacteria are critical in synthesizing a number of vitamins, vitamin k being the classic example. routine vitamin k prophylaxis of healthy newborns is required to prevent hemorrhagic disease as a result of minimal placental transfer of the vitamin but also due to the low concentrations of vitamin k producing bacteria in the git at birth. our own work in this area suggests that the total amount of the b-vitamin folate synthesized by bacteria in the colon may approach or even exceed dietary intake in both infants and adults and it can be absorbed ( , ) . folate plays an important role in dna and rna biosynthesis, amino acid synthesis, and cell division, all processes important for healthy git development. other vitamins thought to be synthesized by bacteria include vitamin b , biotin, thiamine, riboflavin, and pyridoxine. although beyond the scope of this review, the git microbiota also contributes a wide variety of other small molecules which have important functions. these metabolites include bile acids (facilitate fat absorption), choline metabolites (modulate lipid and glucose homeostasis), phenolic, benzoyl, and phenyl derivatives (detoxification of xenobiotics), indole derivatives (protect against stress-induced lesions in the gut), lipids, and many more ( ) . the interaction between the vlbw infant and their microbiome is presented in figure . the vlbw baby is at elevated risk for feeding intolerance, nec, and sepsis. the pathophysiology of these disorders is likely multifactorial involving a combination of intestinal mucosal barrier immaturity, an imbalance in microvascular tone, aberrant microbial colonization and an unbalanced immune response ( ) . infectious causes for nec have been sought for more than years with the implication of several bacteria (namely several species of clostridium, klebsiella pneumoniae, escherichia coli, and cronobacter sakazakii) and viruses (namely coronavirus, coxsackie, rotavirus, adenovirus, and torovirus) ( ) . with the advent of molecular technologies, it has become possible to not only study the bacterial species present but also the metabolic differences in the git microbiota of infants with and without nec. table summarizes the molecular studies of git microbiota for vlbw infants with nec or sepsis. in summary, these studies demonstrate lower bacterial diversity, less bifidobacteria and bacteroidetes, and a bloom of the γ-proteobacteria - wk prior to the diagnosis of nec ( ) ( ) ( ) ( ) ( ) ( ) . a metagenomic analysis on stool samples from a set of twins discordant for the diagnosis of nec demonstrated significant differences in the genes mapping to carbohydrate metabolism leading to speculation that microbial communities may metabolize milk through different pathways resulting in differing substrates available to the microbiota and thus differential effects on the host ( ) . similar perturbations in the git microbiota development have been reported for infants with late-onset sepsis ( ) . the git microbiome plays a pivotal role in balancing the inflammatory system in the immature git. a breakdown of the mucosal barrier can result in translocation of inflammatory mediators producing systemic inflammatory response syndrome. in addition to sepsis and nec, systemic inflammatory response syndrome plays a key role in downstream organ inflammation and damage that may result in severe long-term morbidities such as periventricular leukomalacia, chronic lung disease, and retinopathy of prematurity ( ) . the vlbw infant is at elevated risk of metabolic syndrome including type ii diabetes, hypertension, and obesity in later life. this may commence with an altered growth during the neonatal period related to suboptimal nutritional intake, illness, and potentially an aberrant microbiota with altered metabolic capacity, resulting in a greater percentage of body fat and considerably less lean mass at term-corrected age ( , ) . evidence for the role of the microbiota in obesity comes from rodent studies with induction of hepatic lipogenesis and increased lipid storage in adipocytes of germ-free mice after colonization with normal gut microbiota ( ) . in human twin studies, evidence suggests that physiological phenotype such as adiposity may be better associated with a core microbiome at the gene level rather than at the organismal lineage level with a decrease in bacterial diversity and an alteration in metabolically active genes found in obese patients ( ) . dysregulation of the developing immune system has been implicated in a wide array of diseases in childhood and adult life including atopy ( ) and food allergy ( ), inflammatory bowel disease ( ) , and cancer ( ) . animal studies have demonstrated that both changes in diet and in the gut microbiota alter the development of autoantibodies to pancreatic β-cells, a precursor to the development of type i diabetes ( ) , but whether these translate to human conditions remains speculative. an emerging area of interest is the impact of the gut microbiota on the developing human brain which may be of particular importance for the preterm infant who is at elevated risk for behavioral issues including attention-deficit disorder and autism spectrum disorder. the central nervous system communicates bidirectionally with the gut via the enteric nervous system. studies in germ-free mice have revealed important changes in neurotrophin factors related to brain plasticity as well as in behavior with increased stress responses and anxiety-like behavior. these abnormal behaviors can be reversed with transplantation of a normal gut microbiota ( ) . the portfolio of evidence indicates that mother's own milk is the optimal way to feed every infant, including vlbw infants. this principle is internationally endorsed based on extensive literature, primarily derived from studies with healthy-term infants, associating provision of own mother's milk with decreased incidence of diarrhea, otitis media, hospitalization for lower respiratory tract infection in the first week of life, sudden infant death syndrome, improved neurodevelopment, and perhaps decreased risk of type ii diabetes and a small decrease in childhood obesity ( ) ( ) ( ) . additionally, among vlbw infants, provision of own mother's milk is associated with lower incidence of nec and sepsis, improved feeding tolerance, and a reduction in colonization by pathogens. for vlbw infants at risk of nec, when own mother's milk is not available, pasteurized donor human milk is recommended. a cochrane review reported a higher incidence of nec (relative risk of . ( % confidence interval: . , . )) and feeding intolerance (relative risk: . ( . , . )) among infants supplemented with formula compared with donor human milk ( ) . in north america, donor milk provided to vlbw infants is pasteurized to remove the possibility of transmission of harmful agents including hiv and known pathogens. pasteurization, however, destroys all live cells, and hence inoculation of the infant gut with bacteria may be diminished. however, pasteurized donor milk remains a rich source of oligosaccharides which are seemingly unaffected by heat treatment ( ) . in order to meet the nutritional requirements of vlbw infants, it is standard of care to add energy and essential nutrients to human milk after tolerance to enteral feeds has been established. there is strong evidence that early nutrient deficits and suboptimal growth, common in the neonatal intensive care unit, are independent risk factors for poor vlbw outcome ( ) . human milk for the majority of vlbw infants is fortified using nutrient fortifiers whose protein source is bovine based although a human milk-derived fortifier is commercially available. the impact of human milk fortification on the gut microbiota has not been systematically investigated, although two industry-sponsored trials have demonstrated at least a % reduction in nec and nec requiring surgical intervention was almost eliminated ( , ) . unfortunately, the study design does not allow for determination of whether it was the absence of bovine-based fortifier, formula, or both that reduced the incidence of nec. a variety of probiotics have been studied in preterm infants, most commonly lactobacillus and bifidobacterium. a cochrane meta-analysis of randomized or quazi-randomized trials (n = , infants) reported that probiotic supplementation of preterm infants reduced both all-cause mortality (relative risk: . ( . , . )) and nec (relative risk: . ( . , . )) ( ). furthermore, probiotic supplementation improved the antecedent of severe nec, feeding intolerance, as well as reduced the number of days of hospitalization. unlike in europe and other parts of the world, probiotic supplementation has not been widely adopted as a nec prevention strategy in north american neonatal intensive care units due to concerns about the limited safety data for infants born < , g and a domestically available probiotic formulation with demonstrated efficacy, safety, and regulatory approval. there remains some concerns that the regulatory framework for approval of probiotics does not approach the rigor for drugs. the canadian pediatric society committee recently recommended that physicians consider recommending probiotics for the prevention of nec for at-risk preterm infants ( ) . an in-depth understanding of the microbial community composition and metabolic functions in the git of the "well" vlbw infant fed mother's own milk will leverage the incorporation into clinical practice of therapeutics such as probiotics because at a very practical level, we will know what the "gold standard" is for microbial composition and function ( ) . a growing body of evidence suggests that perturbed colonization of the microbiota in the preterm vlbw infant is associated with increased morbidity and mortality during initial hospitalization and beyond. the potential to develop strategies to reduce morbidities associated with very preterm birth through manipulation of the microbiome appear tremendous. while the microbial community composition and related metabolic functions best associated with optimal health in vlbw infants are unknown, characterization of the git microbiome of the "well" exclusively own mother's milk-fed vlbw infant seems a reasonable starting point. high-throughput sequencing of the s ribosomal rna gene has already begun to yield critical information on the microbial community in the git of the vlbw infant, and newer emerging technologies including metatranscriptomics, metaproteomics, and metabolomics show much promise in the future of helping to define the complex metabolic environment in the git. this will facilitate a sophisticated understanding of the microbiome in relation to optimal health and provide a basis against which to assess novel nutritional therapies. this study was supported through a grant from the canadian institutes for health research, mrc operating grant program (mop) and . disclosures: no disclosures. the infant intestinal microbiome: friend or foe? microbes and the developing gastrointestinal tract microbes in the neonatal intensive care unit resemble those found in the gut of premature infants nichd neonatal research network. prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants factors influencing the composition of the intestinal microbiota in early infancy development of the intestinal bacterial composition in hospitalized preterm infants in comparison with breast-fed, full-term infants intestinal microbiota development in the premature neonate: establishment of a lasting commensal relationship? redefining the role of intestinal microbes in the pathogenesis of necrotizing enterocolitis diversity of the human intestinal microbial flora bacterial diversity in meconium of preterm neonates and evolution of their fecal microbiota during the first month of life is meconium from healthy newborns actually sterile? developmental microbial ecology of the neonatal gastrointestinal tract potential roles and clinical utility of prebiotics in newborns, infants, and children: proceedings from a global prebiotic summit meeting fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery influence of mode of delivery on gut microbiota composition in seven year old children diet rapidly and reproducibly alters the human gut microbiome intestinal microflora in early infancy: composition and development stool microflora in extremely low birthweight infants factors influencing the presence of faecal lactobacilli in early infancy mode of delivery -effects on gut microbiota and humoral immunity bacterial imprinting of the neonatal immune system: lessons from maternal cells? neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome deep s rrna metagenomics and quantitative pcr analyses of the premature infant fecal microbiota establishment and development of intestinal microbiota in preterm neonates microbiome assembly across multiple body sites in low-birthweight infants beyond bacteria: a study of the enteric microbial consortium in extremely low birth weight infants gut microbial colonisation in premature neonates predicts neonatal sepsis low species diversity and high interindividual variability in faeces of preterm infants as revealed by sequences of s rrna genes and pcr-temporal temperature gradient gel electrophoresis profiles distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants strain-resolved community genomic analysis of gut microbial colonization in a premature infant gut microbiota of healthy canadian infants: profiles by mode of delivery and infant diet at months development of the intestinal flora in very low birth weight infants compared to normal full-term newborns the intestinal bacterial colonisation in preterm infants: a review of the literature high-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin long-term ecological impacts of antibiotic administration on the human intestinal microbiota analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods diet and faecal flora in the newborn: breast milk and infant formula the microbial ecology of the large bowel of breast-fed and formula-fed infants during the first year of life quantification of bifidobacterium spp., escherichia coli and clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time pcr the human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery carbohydrates in milks: analysis, quantities and significance ultrasound imaging of milk ejection in the breast of lactating women characterization of the diversity and temporal stability of bacterial communities in human milk human milk: a source of more life than we imagine effect of intestinal microbial ecology on the developing brain the altered gut microbiome and necrotizing enterocolitis recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis pro-angiogenic activity of tlrs and nlrs: a novel link between gut microbiota and intestinal angiogenesis the gut microbiota as an environmental factor that regulates fat storage role of the gut microbiota in human nutrition and metabolism dietary oligosaccharides increase colonic weight and the amount but not concentration of bacterially synthesized folate in the colon of piglets gut microbiomes of malawian twin pairs discordant for kwashiorkor folate is absorbed across the colon of adults: evidence from cecal infusion of ( )c-labeled [ s]- -formyltetrahydrofolic acid a large pool of available folate exists in the large intestine of human infants and piglets host-gut microbiota metabolic interactions necrotizing enterocolitis bacterial community structure and functional contributions to emergence of health or necrotizing enterocolitis in preterm infants early intestinal bacterial colonization and necrotizing enterocolitis in premature infants: the putative role of clostridium application of s rrna gene pcr to study bowel flora of preterm infants with and without necrotizing enterocolitis intestinal microbial ecology in premature infants assessed with non-culture-based techniques intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis s rrna gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis long-term programming effects of early nutrition -implications for the preterm infant early postnatal life as a critical time window for determination of long-term metabolic health intestinal microbiota during infancy and its implications for obesity a core gut microbiome in obese and lean twins gut microbiota composition and development of atopic manifestations in infancy: the koala birth cohort study food allergy: a glimpse into the inner workings of gut immunology the intestinal microbiota in health and disease human gut microbiome and risk for colorectal cancer is the origin of type diabetes in the gut? world health organization. global strategies for infant and young child feeding section on breastfeeding. breastfeeding and the use of human milk human milk banking formula milk versus donor breast milk for feeding preterm or low birth weight infants effects of holder pasteurization on human milk oligosaccharides randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants an exclusively human milkbased diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products probiotics for prevention of necrotizing enterocolitis in preterm infants using probiotics in the paediatric population key: cord- -zqm egei authors: drall, kelsea m.; field, catherine j.; haqq, andrea m.; de souza, russell j.; tun, hein m.; morales-lizcano, nadia p.; konya, theodore b.; guttman, david s.; azad, meghan b.; becker, allan b.; lefebvre, diana l.; mandhane, piush j.; moraes, theo j.; sears, malcolm r.; turvey, stuart e.; subbarao, padmaja; scott, james a.; kozyrskyj, anita l title: vitamin d supplementation in pregnancy and early infancy in relation to gut microbiota composition and c. difficile colonization: implications for viral respiratory infections date: - - journal: gut microbes doi: . / . . sha: doc_id: cord_uid: zqm egei in canada and the us, the infant diet is supplemented with vitamin d via supplement drops or formula. pregnant and nursing mothers often take vitamin d supplements. since little is known about the impact of this supplementation on infant gut microbiota, we undertook a study to determine the association between maternal and infant vitamin d supplementation, infant gut microbiota composition and clostridioides difficile colonization in , mother-infant pairs of the child (canadian healthy infant longitudinal development) cohort study over – . logistic and maaslin regression were employed to assess associations between vitamin d supplementation, and c. difficile colonization, or other gut microbiota, respectively. sixty-five percent of infants received a vitamin d supplement. among all infants, infant vitamin d supplementation was associated with a lower abundance of genus megamonas (q = . ) in gut microbiota. among those exclusively breastfed, maternal prenatal supplementation was associated with lower abundance of bilophila (q = . ) and of lachnospiraceae (q = . ) but higher abundance of haemophilus (q = . ). there were no differences in microbiota composition with vitamin d supplementation among partially and not breastfed infants. neither infant nor maternal vitamin d supplementation were associated with c. difficile colonization, after adjusting for breastfeeding status and other factors. however, maternal consumption of vitamin-d fortified milk reduced the likelihood of c. difficile colonization in infants (adjustedor: . , % ci: . – . ). the impact of this compositional difference on later childhood health, especially defense against viral respiratory infection, may go beyond the expected effects of vitamin d supplements and remains to be ascertained. most infants in north america are supplemented with vitamin d subsequent to recommendations that all breastfed infants receive iu/day, an amount that is also present in commercial infant formulas. , however, infant vitamin d supplementation during breastfeeding is not common practice in australia and several european countries, including italy and spain, , and compliance rates in canada and the us are moderate. , vitamin d has shown protective activity against the development of preschool wheeze when provided as a maternal prenatal supplement. supplementation of preterm infants with vitamin d has reduced recurrent wheeze in a randomizedcontrolled trial. independent of gestational age and breastfeeding status, infant supplementation before -months has shown future benefit in raising serum vitamin d levels and reducing hospital length-of-stay of infants hospitalized for bronchiolitis, a respiratory infection often caused by respiratory syncytial virus contact : anita l kozyrskyj kozyrsky@ualberta.ca - edmonton clinic health academy, edmonton, ab t g c , canada supplemental data for this article can be accessed here. (rsv). of note, low vitamin d levels has been associated with susceptibility to other viral respiratory infections, including sars-cov- (covid- disease). furthermore, the high rates of food allergy and recurrent wheeze in australian children have been attributed to vitamin d insufficiency during infancy. while the immunological roles (both innate and adaptive) of vitamin d have been extensively studied, vitamin d has many physiological roles important for the maintenance of gut microbiota and exclusion of opportunistic microbes. vitamin d receptors (vdrs) are found on immune cells including t cells, b cells and dendritic cells, but are also highly expressed in intestinal enterocytes where they act as transcription factors for the secretion of antimicrobial peptides and tight junction proteins that maintain intestinal epithelial barrier function. , asystematic review of in vivo research has summarized the impact of vitamin d on mammalian gut microbiota but only included evidence from two studies in human infants. meanwhile, anewer human study identified prenatal vitamin d supplementation as an important predictor of variance in gut microbial profiles of infants. in the koala birth cohort, clostridioides difficile counts in -month old infants were reduced following maternal prenatal supplementation with multivitamins containing vitamin d. although asymptomatic c. difficile colonization occurs in approximately % of young infants, it is less common in breastfed infants and it has been associated with a disrupted gut microbiota composition and later childhood allergic disease. in adults, vitamin d deficiency has also been correlated with c. difficile infection, while community incidence of c. difficile has been associated with rsv and influenza virus circulation. notwithstanding that infant feeding type shapes the infant gut microbiome, , attention is shifting to specific micronutrients. if vitamin d influences the gut microbiome, supplementation during breastfeeding may confer additional benefits. , the primary objective of this study was to determine the association between maternal perinatal and infant vitamin d supplementation, and infant gut microbiota composition at months of age, including c. difficile colonization. at an average age of . months (sd: . months), . % of our , infants received a vitamin d supplement (referred to as vitamin d throughout) in the form of vitamin d drops (table ) . a high proportion ( . %) of exclusively breastfed infants received vitamin d supplements. supplementation was less frequent in partially ( . %) and exclusively formula fed infants ( . %) ( table ). the manitoba site had the lowest prevalence of infant vitamin d supplementation ( . % overall, . % in exclusively breastfed infants). fifteen percent of infants were born to mothers who did not report taking vitamin d supplements or took < iu/day during pregnancy and lactation, compared to % whose mothers reported taking vitamin d supplements (≥ iu/day) both pre and postnatally. overall, . % of infants were colonized with c. difficile, but less among exclusively breastfed infants ( . %, table ). among those infants who were colonized with c. difficile, mothers were usually younger, had a higher bmi, and were less frequently of asian ethnicity (table ) . asmaller proportion of infants colonized with c. difficile were born to mothers who consumed at least cups of fortified milk a day, were more frequently living in homes with furry pets, born in edmonton and less likely to receive vitamin d drops. in all infants, direct vitamin d supplementation (or: . , % ci: . - . , p = . ), as well as postnatal supplementation (≥ sources of vitamin d, (or: . , % ci: . - . , p = . ), were associated with lower odds of c. difficile colonization compared to the absence of supplementation; however, these associations were lost upon adjustment for covariates, notably infant feeding mode. prenatal maternal vitamin d supplementation was not associated with within exclusively breastfed infants, the crude odds ratios for c. difficile colonization were not statistically significant with infant vitamin d supplementation (or: . , % ci: . - . , p = . ) nor with maternal supplementation (table s ). these null associations were unchanged following adjustment for birth mode, maternal milk consumption, household pets, study center and infant age at sample collection ( figure a , table s ). no significant interaction terms were discovered between variables. asensitivity analysis was conducted to ensure that results were not affected by site variations in infant supplementation. no deviations from the main findings were noted for associations between vitamin d supplementation and infant c. difficile colonization after the manitoba site was excluded (data not shown). independent of infant or maternal prenatal vitamin d supplementation, prenatal maternal milk consumption greater than or equal to cups per day, compared to or less cups per day, was significantly associated with lower odds (aor: . , % ci: . - . , p = . , table s ) of c. difficile colonization in exclusively breastfed infants. in this final adjusted model, c. difficile colonization was twice more likely in infants born via elective cesarean and in the presence of household pets (table s ) . no associations between vitamin d supplementation and c. difficile colonization were observed (summary table ) within partially (figure b) or exclusively formula fed infants ( figure s ). following adjustment for birth mode and feeding mode, microbiota of the genus megamonas (veillonellaceae family) were of significantly lower abundance in all infants supplemented with vitamin d (q = . , table ). furthermore, peptostreptococcus (peptostreptococcaceae family) were lower in supplemented infants and eubacterium (eubacteriaceae family) were depleted in infants whose mothers took a pre and postnatal vitamin d supplement (> iu/day); however statistical significance for these two genera was lost upon fdr correction (table ) . exclusively breastfed infants born to mothers who were taking ≥ iu/day both pre and postnatally exhibited a lower relative abundance of proteobacteria, specifically those of the genus bilophila (q = . , table ). furthermore, bacteria belonging to the lachnospiraceae family (q = . ) were depleted and microbes belonging to the pasteurellaceae family (haemophilus spp., q = . ) were enriched compared to infants nursed by mothers taking < iu/day ( table ). the same modeling procedure was followed for partially and exclusively formula fed infants but none of the associations survived fdr correction (summary table ). with the aim to address a gap in emerging discussions on vitamin d and intestinal homeostasis in infants, we undertook this gut microbiome study in a general population of , canadian mothers and infants. three-quarters of breastfed infants were supplemented with vitamin d drops and % of mothers took vitamin supplements containing ≥ iu of vitamin d daily during pregnancy and postnatally. at - months of age, c. difficile colonization of the infant gut was less prevalent with infant vitamin d supplementation but this was explained by the extent of breastfeeding, a strong deterrent of c. difficile. within exclusively breastfed infants, neither infant nor maternal vitamin d supplementation were related to c. difficile colonization status. whereas c. difficile counts were reportedly lower in colonized, breastfed infants of mothers with prenatal vitamin d intake ≥ iu/day in the koala study, infant c. difficile colonization rates in this cohort did not differ by infant vitamin d supplement intake. our findings agree with those of the koala study regarding direct vitamin d supplementation of breastfed infants, for which there were no associations with c. difficile colonization of their gut microbiota. however, we found direct vitamin d supplementation of infants to be associated with a lower abundance of megamonas in gut microbiota. this association was found in all study infants and was independent of feeding mode. while little is known about megamonas in infancy, this genus was enriched in the gut microbiota of male infants born to mothers with prenatal asthma in a previous publication from the child cohort. in addition to childhood asthma, maternal history of asthma is a risk factor for greater severity of viral bronchiolitis in offspring. megamonas has recently been reported to be more abundant in the gut microbiota of adult males with higher testosterone levels and the role of this sex steroid is currently being scrutinized in asthma pathogenesis. in view of reported benefits of the vitamin d supplementation of high risk mothers and of infant populations where supplementation is not the norm, , the megamonas genus of veillonellaceae may be a possible link between vitamin d and asthma or viral respiratory infection that merits further examination. it would also further support recommendations for the supplementation of formula-fed infants. vitamin d plays a crucial role in both innate immunity, via toll-like figure ). adjusted for maternal milk consumption during pregnancy, household pets, age at stool sample collection, study center and other supplement categories; d-drop use adjusted for maternal d supplementation (pre/post); post-natal supplements adjusted for pre-natal supplement use; and pre-natal supplement use adjusted for post-natal supplement use (maternal and infant). adjusted odds ratios (aor) and % confidence intervals (error bars) calculated using logistic regression in stata (version . ). receptor signaling of macrophages in response to pathogens, and adaptive immunity, by inhibiting proliferation of t cells and secretion of inflammatory cytokines. , further, there is emerging evidence for its role in the lung microbiome and gutlung axis. we also found associations with maternal pre and postnatal vitamin d supplementation (≥ iu/day) in exclusively breastfed infants, namely a lower relative abundance of bilophila spp. bilophila have been linked to inflammation and colitis in mice, , and colic in infants. genus bilophilia produce secondary bile acids, ligands for vdrs, and levels of these microbiota are elevated in the presence of taurine or bile. [ ] [ ] [ ] vitamin d receptors are highly expressed in the proximal colon and involved in the production of defensins, cathelicidins, claudins and zonulin occludens, important to gut barrier integrity. , , newborns conjugate bile acids with taurine but have the capacity to utilize glycine, especially when fed formula. [ ] [ ] [ ] this may explain why bilophila species were uniquely altered among exclusively breastfed infants. maternal supplementation with vitamin d was also associated with depletion of lachnospiraceae but enhancement of haemophilus spp, both of which are reported to be altered in mammalian studies of vitamin d. the reduction in abundance of bilophila and other changes to infant gut microbiota following maternal vitamin d supplementation points to pathways involving production of secondary bile acids. interestingly, maternal prenatal consumption of or more cups of fortified milk per day reduced the likelihood of c. difficile colonization in exclusively breastfed infants by %, even after adjustment for infant vitamin d supplementation, maternal vitamin d supplementation and other covariates (aor: . , table . gut microbiota composition in all study infants. multivariate linear regression (maaslin) predicting arcsine square root transformed relative abundances of microbiota in all study infants (n = , ) , exclusively breastfed infants (n = ), partially breastfed (n = ) and exclusively formula fed (n = ) according to postnatal maternal and infant vitamin d supplementation practices. table s ). transitioning to cow's milk after exclusive breastfeeding seems to have an inhibitory influence on c. difficile colonization in infants, whereas c. difficile infection is more common in children with cow's milk intolerance. furthermore, greater maternal dietary intake of vitamin d during pregnancy has been reported to reduce risk of cow's milk allergy in offspring. our findings suggest a putative role of vitamin d fortified-milk consumption during pregnancy but maternal milk consumption may be equally correlated with other maternal dietary patterns [ ] [ ] [ ] or lifestyle factors (i.e. cleaning product use ) that influence the composition of infant gut microbiota. an important limitation of this work is that we could not distinguish between those with darker skin pigmentation and other ethnicities, beyond caucasian and asian. these populations have been shown to produce less subcutaneous vitamin d, making them at greater risk of low vitamin d. we also observed study site differences specifically that the prevalence of manitoban infant supplementation was lower, in just over % of exclusively breastfed infants. according to the sensitivity analysis we conducted, study findings were unchanged if the manitoba site was excluded. finally, we did not have access to maternal or infant serum vitamin d levels. however, for microbiome research, intestinal levels are likely more important than serum levels and reference values for intestinal vitamin d concentrations have yet to be determined. instead, this study relied on selfreport questionnaires for reporting of vitamin d supplementation. questionnaire response categories did not allow us to explore potential differences within the group of mothers taking more than iu/day. future studies would benefit from a more specific nutrition/supplement question, such as the one administered in the alberta pregnancy outcomes and nutrition (apron) study, which was pilot-tested to ensure efficient and detailed collection of vitamin intake and dosing in the canadian context. however, this limitation is not likely to have a large effect on our findings as the apron study found that the average vitamin d intake during pregnancy from supplements and diet combined was iu/day. ultimately, this study found evidence of an association between maternal vitamin d supplementation with the gut microbiota composition of all study infants, notably a lower abundance of megamonas, with its potential implications for host defense against viral respiratory infections. in exclusively breastfed infants, we found evidence of an association between direct vitamin d supplementation and lower abundance of bilophila and members of the lachnospiraceae, and a higher abundance of haemophilus at -months of age. yet, vitamin d supplementation did not appear to be associated with c. difficile colonization in any of the feeding groups. it is essential to confirm our findings to fully comprehend the relationship between vitamin d and the gut microbiota of infants, and to understand how current standards of care around vitamin d supplementation support healthy development. this observational study included , families participating in the child cohort study. mothers were recruited during their second trimester of pregnancy between january and december from the vancouver, edmonton or manitoba sites (inclusion and exclusion criteria outlined at www. childstudy.ca). all study infants provided a fecal sample and data on breastfeeding status and infant vitamin d supplement intake ( figure s ). mothers provided informed consent upon enrollment and the human research ethics boards at the university of manitoba, university of alberta, and university of british columbia approved this study. fecal samples were collected at - months of age using a standardized protocol during a planned home visit. methods of sample collection, dna extraction and amplification, s ribosomal rna sequencing, and microbial taxonomic classification are described elsewhere. briefly, collected samples were aliquoted stored at − °c until analyzed. dna extraction was performed using - mg of frozen sample using the qiaamp dna stool mini kit (qiagen inc, valencia ca). bacterial s rrna genes were amplified at the hypervariable v region and sequenced using the illumina miseq platform (san diego, ca). sequences were clustered with usearch (version . ) at > % similarity against the greengenes reference database (version . ) for taxonomic classification in qiime . and excluded if < % similarity. taxon relative abundance was the outcome variable for the microbiota composition analysis. a specific s primer was used for targeted amplification and quantification of c. difficile, as described elsewhere. multiplex assays were prepared using the quantinova multiplex pcr kit (qiagen) with appropriate primers and probes. each qpcr reaction cycle consisted of an initial denaturation for min at . •c, cycles of denaturation for s at •c and annealing/extension/reading for s at •c and was performed on the miniopticontm real-time pcr system (bio-rad, hercules, ca, usa). the outcome variable for c. difficile presence was fecal colonization status, yes/no. maternal vitamin d supplementation from various sources (prenatal vitamins, multivitamins or vitamin d supplements, including dose and frequency of intake) was collected in questionnaires during pregnancy ( figure s ) and -months postpartum ( figure s ). mothers were asked about infant supplementation with vitamin d drops (referred to as vitamin d throughout) during the first three months ( figure s ). maternal and infant supplementation variables were created following this algorithm: i. maternal prenatal vitamin d intake: a -category exposure variable was created from the relevant questionnaire information: ) one supplement or no supplements containing vitamin d, ) two supplements containing vitamin d and ) three or more supplements containing vitamin d. ii. postnatal vitamin d intake: a -category exposure variable was created from the relevant questionnaire information: ) low (i.e. one maternal source, no infant direct) or no vitamin d from supplements, ) two maternal supplements with vitamin d or infant direct vitamin d, ) infant direct and one maternal supplement, and ) two or more maternal supplements and infant direct vitamin d. iii. maternal perinatal intake based on the dosing information. based on current dietary reference intakes for vitamin d supplementation of iu/day, and a recommended dietary allowance of iu/day during pregnancy and breastfeeding, , a final category variable was created: ) no maternal vitamin d or less than iu/day, ) prenatal only maternal vitamin d supplementation ≥ iu/day, ) postnatal only maternal vitamin d supplementation ≥ iu/day and ) prenatal and postnatal supplementation ≥ iu/day. furthermore, mothers reported their milk intake in a food frequency questionnaire administered during pregnancy as milk/fortified substitute beverage consumption ( cup), milk/fortified substitute use on cereal ( / cup) and milk/fortified substitute in tea/coffee ( tbsp). to measure dietary sources of vitamin d through fortified milk and/or plant-based alternatives, a -category variable was created: ) or fewer cups/day, ) cups/ day, ) or more cups/day. data from study questionnaires or medical charts were obtained and used to create the following covariates: season of birth (low uvb season, october -march); high uvb season, april -september), maternal pre-pregnancy age and body-mass-index (bmi), infant age at stool collection, hospital length of stay at birth, mode of delivery, infant sex, feeding mode at stool collection (exclusively breastfed [no non-human milk, juices, formula or solids], partially breastfed or exclusively formula fed), antibiotics use, household income, ethnicity, maternal depressive symptoms, pets in the home and study center. all descriptive (fisher's exact tests, t-tests, anova) and regression tests were completed using stata (version . ) statistical software and the online galaxy platform (version . . ). logistic regression models were used to determine the association between vitamin d supplement use and c. difficile colonization and were built using purposeful selection of covariates. models were run in all infants, then stratified by feeding mode due to the strong association between breastfeeding and infant vitamin d supplementation. one infant did not have data on feeding mode (stratified analyses, n = , ). microbial taxon abundance was compared using multivariate association with linear models (maaslin), which was adjusted for covariates and subjected to false discovery rate (fdr) correction with q ≤ . . the data and analysis code that support the findings of this study can be made available from the corresponding author and child cohort study coordinators upon reasonable request. these data, including study participant data, are securely stored in the https://childdb.ca database. supplementation: recommendations for canadian mothers and infants centers for disease control and prevention. vitamin d [internet variations in infant and childhood vitamin d supplementation programmes across europe and factors influencing adherence vitamin d and health in pregnancy, infants, children and adolescents in australia and new zealand: a position statement adherence to vitamin d recommendations among us infants aged to adherence to complementary feeding recommendations for infants and implications for public health vitamin d and childhood asthma: causation and contribution to disease activity effect of vitamin d supplementation on recurrent wheezing in black infants who were born preterm: the d-wheeze randomized clinical trial vitamin d status at the time of hospitalization for bronchiolitis and its association with disease severity the role of vitamin d in the prevention of coronavirus disease infection and mortality differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: a latent class analysis role of vitamin d in the hygiene hypothesis: the interplay between vitamin d, vitamin d receptors, gut microbiota, and immune response vitamin d regulation of immune function in the gut: why do t cells have vitamin d receptors? vitamin d and the gut microbiome: a systematic review of in vivo studies temporal development of the gut microbiome in early childhood from the teddy study influence of vitamin d on key bacterial taxa in infant microbiota in the koala birth cohort study seasonal variations in clostridium difficile infections are associated with influenza and respiratory syncytial virus activity independently of antibiotic prescriptions: a time series association of exposure to formula in the hospital and subsequent infant feeding practices with gut microbiota and risk of overweight in the first year of life meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations maternal supplementation for prevention and treatment of vitamin d deficiency in exclusively breastfed infants clostridioides difficile colonization is differentially associated with gut microbiome profiles by infant feeding modality at - months of age sex-specific impact of asthma during pregnancy on infant gut microbiota epidemiological and genetic characteristics associated with the severity of acute viral bronchiolitis by respiratory syncytial virus serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome periconception endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in offspring: protocol for a systematic review and meta-analysis vitamin d and lung infection the gut-lung axis in health and respiratory diseases: a place for inter-organ and inter-kingdom crosstalks a human stool-derived bilophila wadsworthia strain caused systemic inflammation in specific-pathogenfree mice influence of diet on the gut microbiome and implications for human health luminal contents from the gut of colicky infants induce visceral hypersensitivity in mice enrichment of sulfidogenic bacteria from the human intestinal tract the 'in vivo lifestyle' of bile acid α-dehydroxylating bacteria: comparative genomics, metatranscriptomic, and bile acid metabolomics analysis of a defined microbial community in gnotobiotic mice a narrative role of vitamin d and its receptor: with current evidence on the gastric tissues vitamin d and mucosal immune function vitamin d receptor negatively regulates bacterialstimulated nf-κb activity in intestine the association between gut microbiota development and maturation of intestinal bile acid metabolism in the first y of healthy japanese infants rapid change of fecal microbiome and disappearance of clostridium difficile in a colonized infant after transition from breast milk to cow milk five years experience of clostridium difficile infection in children at a uk tertiary hospital: proposed criteria for diagnosis and management maternal dietary folate, folic acid and vitamin d intakes during pregnancy and lactation and the risk of cows' milk allergy in the offspring maternal micronutrients can modify colonic mucosal microbiota maturation in murine offspring impact of maternal nutrition on breast-milk composition: a systematic review harmonization of food-frequency questionnaires and dietary pattern analysis in ethnically diverse birth cohorts postnatal exposure to household disinfectants, infant gut microbiota and subsequent risk of overweight in children food nutrition board. dri dietary reference intakes calcium vitamin d use of micronutrient supplements among pregnant women in alberta: results from the alberta pregnancy outcomes and nutrition (apron) cohort: supplement use during pregnancy the current recommended vitamin d intake guideline for diet and supplements during pregnancy is not adequate to achieve vitamin d sufficiency for most pregnant women the canadian healthy infant longitudinal development (child) study: examining developmental origins of allergy and asthma open-source sequence clustering methods improve the state of the art vitamin d and calcium: updated dietary reference intakes vitamin d -effects on skeletal and extraskeletal health and the need for supplementation applied logistic regression: chapter dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment key: cord- -g rmzsv authors: wynn, james l.; wong, hector r. title: pathophysiology of neonatal sepsis date: - - journal: fetal and neonatal physiology doi: . /b - - - - . - sha: doc_id: cord_uid: g rmzsv nan a successful immune response is critically necessary to eradicate infectious challenges and prevent dissemination of the infection in the host. however, if inflammation is not limited and becomes generalized, it can result in the constellation of signs and symptoms of a systemic inflammatory response syndrome (sirs). if the infection is not contained, the spread of the pathogen from its local origin through the blood may result in systemic endothelial activation and precipitate sepsis, severe sepsis, and septic shock. progression of sepsis to shock may lead to multiple organ dysfunction syndrome (mods) and ultimately death. host immunity is divided into innate and adaptive immune systems for purposes of discussion and teaching but there is a great deal of interaction between the two systems. innate immunity is rapid, largely nonspecific, and composed of barriers, phagocytic cells, the complement system, and other soluble components of inflammation. after breech of a barrier, cellular elements of the innate immune response are the first line of defense against the development and progression of infection. adaptive immunity, which is antigen specific, is long lived, and often takes several days to develop, provides immunologic specificity and memory. these systems work together to protect the host from pathogenic challenge but may also precipitate host injury through aberrant responses. the outcome of infection is dependent on at least four major factors: ( ) the pathogen, ( ) the pathogen load, ( ) the site of infection, and ( ) the host response. less is known about the host response in neonates compared with adults for a number of reasons, the principal one being a highly variable definition of disease. our understanding of the pathophysiology of sepsis is largely from investigations in adult populations, including both humans and animals. there is clear evidence from both preclinical models of sepsis and humans that neonates manifest different host immune responses as compared with adults. [ ] [ ] [ ] [ ] even in comparison with children, neonates manifest a unique host immune response to septic shock. thus neonatal-specific clinical investigations, particularly in very preterm infants, are required to improve both survival and long-term outcomes for these populations. a better understanding of the pathophysiology will uncover new opportunities for interventional studies ultimately aimed at improving outcomes. to this end, in this chapter we explore the pathophysiology of sepsis in the neonate, with special attention paid to the immunobiology of sepsis. adult and pediatric intensivists currently use generally accepted definitions for sepsis for goal-based therapeutic interventions. [ ] [ ] [ ] [ ] these definitions are critical to facilitate epidemiologic studies, to accurately determine disease prevalence, to select patients for clinical trials, and ultimately to improve the delivery of care. the generally accepted pediatric definition for sepsis, established in , was intended for all children (< years old), including term neonates (≥ weeks' completed gestation). preterm neonates (< weeks' completed gestation) were specifically excluded from the pediatric generally accepted definitions, and neonatal-perinatal subspecialists were not represented among the pediatric consensus experts. to investigate whether the pediatric generally accepted definitions for sirs and sepsis applied to term infants, hofer and colleagues retrospectively examined term neonates and found that the generally accepted definitions applied to only % of cases of culturepositive early-onset sepsis. neonatal sepsis has been inconsistently defined on the basis of a variety of clinical and laboratory criteria, which makes the study of this condition very difficult. diagnostic challenges and uncertain disease epidemiology necessarily result from a variable definition of disease. the lack of a generally accepted definition for neonatal sepsis remains a significant hindrance towards improving outcomes and accurately describing disease pathophysiology. thus working definitions for the sepsis continuum, specific for preterm and term neonates, are needed to provide a uniform basis for clinicians and researchers to study and diagnose severe sepsis. the addition of immune biomarker-based staging of disease to clinical sign staging is highly likely to increase the accuracy of patient classification for future multicenter clinical trials that will test novel interventions. sepsis or serious infection within the first weeks of life kills more than million newborns globally every year. , the incidence of neonatal sepsis is variable (from less than % to more than % of live births) on the basis of gestational age and time of onset (early-onset sepsis [< hours after birth] or late-onset sepsis [≥ hours after birth]). [ ] [ ] [ ] [ ] [ ] [ ] [ ] preterm neonates have the greatest sepsis incidence and mortality rates among all agegroups [ ] [ ] [ ] [ ] [ ] [ ] (figure - ) . risk factors for developing sepsis in neonates, particularly the very premature, have been well described. , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] prematurity, low birth weight (especially infants weighing less than , g), male sex, a maternal vaginal culture positive for group b streptococcus (gbs), prolonged rupture of membranes, maternal intrapartum fever, and chorioamnionitis are strongly associated with an increased risk for early-onset sepsis. chorioamnionitis is associated with the greatest risk for subsequent clinical or culture-proven sepsis. recent studies demonstrate the risk for sepsis in newborn infants born to women with clinical chorioamnionitis is strongly dependent on gestational age, with minimal risk in neonates aged weeks or older and greater risk with increasing degrees of prematurity. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the risk for neonatal sepsis conferred by maternal gbs colonization is significantly reduced with adequate intrapartum antibiotic prophylaxis. section xxvi pathophysiology of neonatal diseases ated with sepsis-like syndromes (e.g., echovirus, enterovirus, parechovirus, coxsackie virus, adenovirus, parainfluenza virus, rhinovirus, and coronavirus). , [ ] [ ] [ ] physical barriers, including skin and mucosal surfaces, are the first point of contact between the host and potential pathogens. thus a successful immune defense in addition to epithelial barrier function is critical to prevent the development of local infection. multiple immune elements are present to prevent attachment and propagation of pathogens while simultaneously permitting the presence of commensal organisms required for homeostasis. vernix enhances skin barrier function in late-preterm and term neonates. vernix is a complex material comprising water ( . %), lipids ( . %), and proteins ( . %) produced by fetal sebaceous glands during the last trimester and is largely absent in preterm neonates born before weeks' gestation. vernix provides a barrier to water loss, improves temperature control, and serves as a shield containing antioxidants and innate immune factors such as antimicrobial proteins and peptides (apps). the apps on the surface of the newborn's skin (and replete in the amniotic fluid [ ] [ ] [ ] ) are capable of killing/inactivating common neonatal pathogens, including gbs, e. coli, and candida species. erythema toxicum is an immune-mediated manifestation that results from bacterial colonization of the skin occurring shortly after birth. , this common cutaneous immune response is less common in preterm infants than in term infants, highlighting the impact of developmental age on host immune capabilities. in contrast to the moist mucosal surfaces of the respiratory and gastrointestinal (gi) tracts, the skin is arid, which further reduces the chances for microbial invasion. the outermost layer of the skin, the stratum corneum, prevents microbial invasion, maintains temperature, and reduces the risk for dehydration through prevention of transcutaneous water loss. the immature and incompletely developed stratum corneum of preterm newborns takes at least to weeks after birth to become fully functional and may take up to weeks in the extremely preterm neonate, significantly increasing the risk for barrier dysfunction. disruption of the cutaneous barrier by trauma (e.g., placement of an intravenous catheter or heel stick) or chemical burn allows microorganisms to enter the subcutaneous tissue, increasing the likelihood of their establishing a local infection ( figure - ). the likelihood of a microbial breach of the cutaneous barrier rises in the presence of intravenous catheters, which are essential for critical care. emollients, aimed at enhancing the barrier function of preterm newborn skin, increase the risk for nosocomial infection and their use is not recommended. mucosal barriers contain multiple components that serve to prevent infection, including acidic ph, mucus, cilia, proteolytic enzymes, apps, opsonins such as surfactant proteins, sentinel immune cells such as macrophages, dendritic cells, polymorphonuclear neutrophils (pmns), and t cells, as well as commensal organisms. like the skin, the gi mucosa is quickly colonized after birth and contains a significant repository of microorganisms. [ ] [ ] [ ] gi barrier integrity, paramount for prevention of spread of microorganisms out of the intestinal compartment, is dependent on the interaction between commensal organisms and host epithelium. interleukin (il)- , produced by type intestinal innate lymphoid cells in the presence of the microbiota, drives granulocytosis and may protect the neonatal host from infectious challenge. a loss of intestinal barrier integrity likely plays a role in the development of necrotizing enterocolitis (nec) and late-onset sepsis. , prolonged antibiotic treatment, hypoxia, and remote infection are factors known to despite the efficacy of this intervention, the incidence of invasive gbs disease in african american neonates is still more than twice that in white babies, and the incidence of escherichia coli sepsis may be rising in very-low-birth-weight (vlbw) neonates. vaginal delivery in the presence of maternal active primary herpes simplex virus significantly increases the risk for a neonatal herpes simplex virus infection, which has a fulminant course and high mortality. [ ] [ ] [ ] preexisting maternal immunodeficiency or sepsis also increases the risk for sepsis in the neonate. in addition, care practices after birth, such as intubation, mechanical ventilation, and placement of central venous lines, increase the risk for the development of sepsis. a number of pathogens have been associated with sepsis in the neonatal period. the predominant cause is bacterial; however, certain viral infections are associated with a fulminant course and significant mortality. [ ] [ ] [ ] in a large (n = , ), multicenter study of vlbw infants (< g), gram-positive organisms accounted for % of pathogens causing early-onset sepsis and % of those causing late-onset sepsis. in contrast, gram-negative organisms were responsible for % of early-onset sepsis and % of late-onset sepsis. candida species accounted for % of cases of early-onset sepsis and % of cases of late-onset sepsis. infection by gram-negative organisms, particularly pseudomonas species, carries a higher risk for fulminant course and death than infection by other pathogen groups. , , , [ ] [ ] [ ] gram-positive causes of sepsis are dominated by gbs and coagulase-negative staphylococci (cons). , although the high mortality rate for gbs has been well described (especially among infants born prematurely), mortality rates associated with cons are significantly lower. , fungi may also be associated with fulminant neonatal sepsis and predominantly affect vlbw infants. , , independent predictors of in-hospital neonatal mortality after late-onset sepsis were pseudomonas infection (adjusted odds ratio [or], . ; % confidence interval [ci], . % to . %) and fungemia (or, . ; % ci, . % to . %). the limited sensitivity of current methods to identify causative organisms is partially due to an inability to take a large sample of blood from newborn infants with suspected sepsis. blood culture-negative ("clinical") sepsis is estimated to occur at a nearly -fold greater rate than blood culture-positive sepsis. in some of these infants, sepsis may also be due to novel viral pathogens associ- y e a r s - y e a r s - y e a r s - y e a r s - y e a r s - y e a r s - y e a r s the production of mucus and mucociliary clearance of pathogens and debris. premature neonates have relatively more goblet cells than do maturer neonates, leading to a decrease in mucociliary clearance. respiratory mucosal function can be impaired by surfactant and saliva deficiency, altered mucus production, and mechanical ventilation. ventilation is associated with decreased mucociliary clearance, airway irritation, and parenchymal lung injury (see figure - ). intubation is also associated with the progressive accumulation of colonizing bacteria and bacterial endotoxin in respiratory fluids, with concomitant mobilization of endotoxin-modulating apps to the airway. neonates with surfactant deficiency lack apps such as surfactant proteins a and d, which are also absent in commercially available surfactant preparations. there is an age-dependent maturation in the ability of respiratory epithelium to elaborate apps (cathelicidin and β-defensins), such that the respiratory epithelium of preterm newborns mounts a deficient app response. disrupt or injure the neonatal intestinal barrier (see figure - ). [ ] [ ] [ ] under these circumstances, the gut may become the motor of systemic inflammation. mechanistically, paneth cells and intestinal lymphoid cells may release excessive amounts of il- , which, in turn, plays a critical role in the development of sirs. many interventions aimed at reducing the frequency of sepsis in neonates via enhancement of mucosal barrier integrity have been evaluated. neither probiotics nor glutamine supplementation has reduced the incidence of neonatal sepsis. in contrast, human milk feeding is associated with a reduction in the risk for sepsis and nec , and is strongly encouraged, especially in preterm infants. respiratory mucosa is defended in utero by amniotic fluid and pulmonary apps, surfactant proteins a and d, alveolar macrophages, and pmns, among other immune elements. the surface and submucosal gland epithelium of the conducting airways is a constitutive primary participant in innate immunity through c the cell surface and in endosomes, whereas rlrs and nlrs detect pathogens only intracellularly. the discovery that tlr was integral for a robust lipopolysaccharide (lps)-mediated inflammatory response after gram-negative sepsis may be why tlrs have been more thoroughly investigated in the setting of sepsis than other prrs. each of the known tlrs in humans, present on and within multiple cell types, recognizes extracellular and intracellular pathogens via specific pamps. , multiple tlrs may be activated in concert by intact or partial microorganisms and in turn activate multiple second-messenger pathways simultaneously. , lps is the prototypic mediator of systemic inflammation and generates many of the clinical findings of sepsis and septic shock, including mods and death. lps signals through tlr in conjunction with the adaptor proteins cd and myeloid differentiation factor . in adults a reduction in mortality and improvement in hemodynamics were demonstrated when the level of serum lps was reduced. the level of lps is elevated in blood from infected neonates and those with nec even in the absence of gram-negative bacteremia. high levels of circulating endotoxin found during sepsis and nec are associated with multiorgan failure, thrombocytopenia, neutropenia, and death. administration of anti-lps antibodies to a small number of these deficiencies as well as those related to cellular function in combination with invasive procedures lead to a reduction in respiratory barrier function that increases the risk for sepsis. once the local barrier function has been compromised, pathogen recognition by local immune sentinel cells is the first step towards the development of an immune response (figure - ) . elegant sensing mechanisms have evolved to facilitate detection of potentially pathogenic microorganisms. multiple classes of pathogen recognition receptors (prrs) have been discovered that serve as detectors of pathogen-associated molecular patterns (pamps), including cell wall and membrane components, flagellum, nucleic acids, and carbohydrates. a litany of prr classes have been discovered, including the toll-like receptors (tlrs), nod-like receptors (nlrs), retinoic acid-inducible protein i like receptors (rlrs), peptidoglycan recognition proteins, β -integrins, and c-type lectin receptors. the tlrs, β integrins, and c-type lectin receptors detect pathogens both on neonates with sepsis (n = ) with serum endotoxin present reduced the time to recovery but not mortality as compared with the values in placebo-treated neonates. reduction of serum lps levels by exchange transfusion in infected neonates (n = ) was associated with improved survival. bacterial cell wall components (such as lipoteichoic acid) signal primarily through tlr , tlr , and tlr , flagellin signals through tlr , and cpg double-stranded dna signals through tlr . common viral pamps such as double-stranded rna or single-stranded rna signal through tlr , and tlr and tlr , respectively. agonist-tlr binding results in a signaling cascade of intracellular second-messenger proteins ultimately leading to production of cytokines and chemokines, as well as activation of other antimicrobial effector mechanisms. signaling through tlrs typically leads to the production of nuclear factor κb (nf-κb)-dependent inflammatory cytokines and chemokines, whereas signaling through toll/il- receptor-domain-containing adapter inducing interferon (ifn)-β (trif) induces production of type i ifns, as well as nf-κb-related inflammatory cytokines. in neonates of all gestational ages, up-regulation of tlr and tlr messenger rna (mrna) occurs during gram-positive and gram-negative infection, respectively. dysregulation or overexpression of tlr is involved in the development of nec in experimental animal models, implicating the importance of tlrs in the initial immune response to pathogens and their role in neonatal sepsis. other important intracellular prrs include nlrs and rlrs. for nlrs, multiple cytosolic proteins are able to act as pamp sensors (e.g., nlrp , nlrp , and nlrc ) and coalesce with adaptor proteins and procaspase to form a multimeric protein complex termed the inflammasome. the formation of the inflammasome results in the conversion of procaspase to active caspase , which cleaves the inactive precursor proteins il- β and il- to their active forms. rlrs are cytoplasmic rna helicases that, like tlr , sense double-stranded rna of viral origin and induce type i ifn production and nf-κb activation. to date, the impact of rlr and nlr signaling has not been specifically examined in neonates with sepsis. in addition to its roles in leukocyte function (adhesion, phagocytosis, migration, and activation) and complement binding, complement receptor (cr , also known as mac- and cd b-cd ) functions as a pathogen sensor on the surface of phagocytes. cr binds lps, as well as a broad range of other microbial products, in cooperation with or independently of cd , leading to up-regulation of inducible nitric oxide (no) synthase and no production. diminished expression of l-selectin and cr on stimulated neonatal pmns impairs activation and accumulation at sites of inflammation. , , decreased expression of l-selectin and cr persists for at least the first month of life in term infants, possibly contributing to an increased risk for infection. the expression of cr (cd b) may be reduced further in preterm neonates as compared with term neonates. in umbilical cord blood from neonates of less than weeks' gestation, pmn cr content was similar to levels found in patients with type leukocyte adhesion deficiency (failure to express cd ). , thus decreased leukocyte cr surface expression increases the likelihood of suboptimal pathogen detection and cellular activation, particularly in the preterm neonate. c-type lectin receptors are prrs that recognize bacterial, viral, fungal, and parasitic carbohydrate moieties. c-type lectin receptors may be expressed on the cell surface (e.g., macrophage mannose receptor, mincle receptor, dectin , and dectin ) or secreted as soluble proteins (e.g., mannose-binding lectin [mbl], (which is also named mannan-binding protein or mannanbinding lectin) as one of the acute-phase reactants. once bound to its carbohydrate ligand, mbl initiates activation of complement via the lectin pathway to promote opsonization and phagocytic clearance of pathogens. plasma mbl concentrations are low at birth (especially in preterm infants) but rise steadily throughout infancy and childhood. low levels of mbl are associated with the increased incidence of sepsis in neonates. [ ] [ ] [ ] in addition to decreased concentrations at birth, certain genetic polymorphisms of mbl (namely, mbl ), have been associated with an increased risk for infection in some, but not all, studies. - m-ficolin activates the complement system in a manner similar to mbl and its level is elevated in neonates with sepsis. prr stimulation results in rapid inflammatory mediator transcription and translation directed at cellular activation and clearance of pathogenic organisms (see figure - ). during sepsis and septic shock, multiple proinflammatory cytokines have been identified, including il- β, il- , il- (cxcl ), il- , il- , ifn-γ, and tumor necrosis factor (tnf)-α. compared with adults with sepsis, neonates with sepsis produce less il- β, tnf-α, ifnγ, and il- . [ ] [ ] [ ] [ ] [ ] [ ] the decreased cytokine production is due in part to decreased production of important intracellular mediators of tlr signaling, including myeloid differentiation factor , ifn regulatory factor , and p , which exhibit gestational age-specific decrements. recent studies have demonstrated impaired inflammasome activation and mature il- β production by neonatal mononuclear cells. , in a comprehensive study (> analytes) of serum from neonates evaluated for late-onset sepsis, il- emerged as a predictive biomarker to differentiate infected neonates from uninfected neonates. il- reduces pmn apoptosis, drives ifn-γ production, and induces production of tnf-α, il- β, and cxcl . il- primes pmns for degranulation with production of reactive oxygen intermediates on subsequent stimulation. dysregulation of many of these functions linked to il- are seen in sepsis and septic shock. increased il- levels have been demonstrated in premature neonates with brain injury and also in an experimental model of nec, [ ] [ ] [ ] highlighting activation pathways common with those in ischemia and inflammation. excessive levels of il- β, tnf-α, il- , cxcl , il- , and il- , such as those seen with advanced-stage nec, severe sepsis, or septic shock, correlate with poor survival. , [ ] [ ] [ ] [ ] altered cytokine levels (increased il- and il- levels and decreased ccl levels) may identify those neonates at highest risk for the development of sepsisassociated disseminated intravascular coagulation (dic). proinflammatory cytokine production leads to activation of endothelial cells, including increased expression of cell adhesion molecules that facilitate leukocyte recruitment and diapedesis ( figure - ) . up-regulation of cell adhesion molecules (soluble intercellular adhesion molecule, vascular cell adhesion molecule, l-selectin, p-selectin, e-selectins, and cd b-cd ) during sepsis facilitates rolling and extravascular migration of leukocytes. [ ] [ ] [ ] [ ] decreased production of l-selectin and expression of c in pmns and monocytes derived from neonates may impair accumulation at sites of inflammation. , chemokine gradients produced by endothelial cells and local macrophages are necessary for effective and specific leukocyte attraction and accumulation (see figure - ). without adequate leukocyte recruitment, there is increased risk for propagation from a localized to a systemic infection. although poor cellular chemotaxis in the neonate has been observed, it is not likely a result of reduced serum concentrations of chemokines as baseline levels are similar in preterm and term neonates as compared with adults. suboptimal cellular chemotaxis may be related to other mechanisms, such as poor complement receptor translocation. the role of hmgb- and rage signaling in human neonates with sepsis has not been well characterized but has been shown to be involved in the pathophysiology of nec in an experimental model. significantly lower soluble rage levels were found in human fetuses that mounted robust inflammatory responses and hmgb- levels correlated significantly with the levels of il- and s β calcium-binding protein in the fetal circulation. other specific damage-associated molecular patterns, including heat shock proteins and uric acid, may also stimulate tlrs, regulate pmn function, and serve as immune adjuvants. heat shock protein production in infected neonates has not been evaluated but polymorphisms in heat shock proteins increase the risk for acute renal failure in preterm neonates. the levels of heat shock proteins are significantly elevated in infected adults and children. elevated heat shock protein and heat shock protein level measured within hours of pediatric intensive care unit admission were associated with septic shock and there was a strong trend towards increased mortality. , uric acid can increase cytokine production, pmn recruitment, and dendritic cell stimulation and may also serve as an antioxidant. the level of uric acid is reduced in the serum of neonates with sepsis as compared with control neonates. in addition to facilitating leukocyte attraction, proinflammatory stimuli result in production of vasoactive substances that decrease or increase vascular tone and alter vascular permeability (see figure - ). these include platelet-activating factor, thromboxane, leukotrienes, no, histamine, bradykinin, up-regulation after stimulation, deficiencies in another downstream signaling process, or inhibition by bacterial products. the levels of a wide variety of chemokines are increased during sepsis, including cxcl (ip- ), ccl (rantes), ccl (monocyte chemoattractant protein ), ccl (macrophage inflammatory protein α), and cxcl . the levels of other chemoattractive molecules also increase with sepsis, including complement proteins c a and c a, apps, including cathelicidins and defensins, and components of invading bacteria themselves. , the importance of chemoattractive substances in the pathogenesis of severe sepsis is highlighted by studies showing that cxcl can be used as a stratifying factor for survival in children, and c a is implicated in sepsis-associated organ dysfunction in adults. chemokine investigations in infected neonates revealed that cxcl is a sensitive early marker of infection, and low ccl levels may predict development of dic. damage-associated molecular patterns (or alarmins), such as intracellular proteins or mediators released by dying or damaged cells, may also active prrs. for example, the damage-associated molecular pattern high-mobility group box (hmgb- ) is involved in the progression of sepsis to septic shock in adults. , macrophages or endothelial cells stimulated with lps or tnf-α produce hmgb- , which signals through tlr , tlr , and receptor for advanced glycation end products (rage). hmgb- results in cytokine production, activation of coagulation, and pmn recruitment. , hmgb- mediates disruption of epithelial junctions within the gut via the induction of reactive nitrogen intermediates, leading to increased bacterial a twin study which assessed the frequency of infections among monoygotic and dizygotic prematurely born twins concluded that . % (p = . ) of the variance in susceptibility to lateonset sepsis was due to genetic factors alone. the impact of genetics in the host response is also underscored by the increased risk for death from infection seen with african american race or male sex among low-birth-weight infants. an ethnically unique single nucleotide polymorphism in the tlr promoter region was significantly associated with gram-negative bacterial infections in preterm infants. several recent studies in newborn infants have demonstrated an association between small variations in dna, specifically single nucleotide polymorphisms, and infection development and outcomes. , [ ] [ ] [ ] [ ] [ ] because tlrs play an essential role in recognition and response to pathogens, alterations in their expression, structure, signaling pathways, and function can have consequences for host defense. polymorphisms or mutations in tlrs are associated with increased risk for infection in adults [ ] [ ] [ ] [ ] and children , , but are less well characterized in neonates. after confounders had been controlled for, the presence of a tlr single nucleotide polymorphism was associated with a three-fold increase in the risk for gram-negative infections in vlbw infants. polymorphisms in the tlr , tlr , il , and pla g a (which encodes pla ) genes were associated with the development of neonatal sepsis. modifications in expression or function of costimulatory molecules necessary for tlr activation are also associated with an increased risk for infection. for example, the levels of lpsbinding protein (lbp; which binds intravascular lps) and the lps coreceptor cd are both increased during neonatal sepsis. , , furthermore, genetic variations in these proteins have been associated with increased risk for sepsis in adults. [ ] [ ] [ ] genetic polymorphisms in myeloid differentiation factor , a small protein involved in lps signaling through tlr , increase the risk for organ dysfunction and sepsis in adults but the significance in neonates is unknown. polymorphisms in post-tlr activation intracellular signaling molecules, including myeloid differentiation factor , il- receptor-associated kinase , and nf-κb essential modulator, are associated with invasive bacterial infection in older populations. additional genetic polymorphisms in intracellular second-messenger inflammatory signaling systems with impact on neonatal sepsis risk and progression are likely to be uncovered with the implementation of biobanking and mining of stored samples. mutations have been identified in nlrs that are involved in the pathogenesis of crohn's disease (nod ) and neonatalonset multisystem inflammatory disease (nlrp ). rlr mutations have been identified but have unknown clinical significance. no mutations in specific domains of nlrs have been found in neonates with sepsis or nec. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the importance of nlrs in listeria monocytogenes infections in neonates is unknown. complement is an important component of early innate immunity that facilitates killing of bacteria through opsonization and direct microbicidal activity. complement components also possess chemotactic or anaphylactic activity that increases leukocyte aggregation and local vascular permeability. furthermore, complement reciprocally activates a number of other important processes, such as coagulation, proinflammatory and prostaglandins. , these substances are produced predominantly by host endothelium and mast cells. activated pmns produce phospholipase a (pla ), the level of which is increased in the serum of neonates with sepsis and leads to generation of vasoactive substances, including prostaglandins and leukotriene. thromboxane produced by activated platelets and endothelin produced by activated endothelium are potent vasoconstrictors that participate in the development of pulmonary hypertension. [ ] [ ] [ ] [ ] overproduction of cytokines and vasoactive substances is associated with circulatory alterations and organ failure seen in severe sepsis and septic shock ( figure - ) . , [ ] [ ] [ ] [ ] if the pathogen is not contained locally and inflammatory homeostasis is not restored, sirs may develop, and lead to mods and death (see figure - ). the traditional paradigm for understanding the host response to sepsis consists of an intense proinflammatory response, or sirs, temporally followed by a compensatory antiinflammatory response syndrome. this paradigm has been challenged by the failure of multiple antiinflammatory strategies to improve sepsis outcomes in adults. new data in adults and children demonstrate simultaneous proinflammatory/antiinflammatory responses where the magnitude of either response may determine outcome. , near simultaneous increases in antiinflammatory cytokine production (transforming growth factor β, il- , il- , il- , and il- ) occur in neonates during infection, countering the actions of proinflammatory cytokines. , , these mediators blunt the activation and recruitment of phagocytic cells, reduce fever, modify coagulation factor expression, and decrease production of reactive oxygen and nitrogen intermediates, no, and other vasoactive mediators. [ ] [ ] [ ] [ ] [ ] [ ] soluble cytokine and receptor antagonists produced during sepsis also modulate proinflammatory mediator action. elevation of the levels of tnf receptor (which regulates the concentration of tnf-α), soluble il- receptor, soluble il- , and il- receptor antagonist have been documented in neonatal sepsis with resolution after effective treatment. , , the role of these regulatory cytokine inhibitors in the immune response to neonatal sepsis and septic shock has been incompletely characterized. soluble rage competes with cell-bound rage for the binding of hmgb- and other rage ligands. soluble rage has antiinflammatory effects and its level is elevated in adults during sepsis. furthermore, soluble rage improved survival and reduced inflammation when given to infected adult rodents. serum soluble triggering receptor expressed on myeloid cells may reduce inflammatory signaling for triggering receptor expressed on myeloid cells , and predict mortality in preterm neonates. micrornas may regulate inflammation at the level of gene expression via several putative mechanisms. several pilot studies in rodents and humans have demonstrated regulatory functions for microrna in neonates. [ ] [ ] [ ] [ ] [ ] [ ] the impact of regulatory micrornas and their effects on the host inflammatory response in neonates with sepsis are unclear. endogenous cortisol is induced by proinflammatory cytokines and attenuates the intensity of sirs associated with severe sepsis and septic shock. the use of cortisol in adults with sepsis has been controversial. , cortisol production in newborn infants is significantly increased early in shock. however, very preterm neonates may have relative adrenal insufficiency that may contribute to hemodynamic instability and hypotension. cortisol replacement may be critical in these infants and deserves further study. it is important to note, however, that in children with septic shock, adjunctive corticosteroid therapy is associated with repression of gene programs corresponding to the adaptive immune system. complement-mediated activation of leukocytes during sepsis occurs via up-regulated cell surface receptors (complement receptor [cd ] and cr ). , c b and c a facilitate opsonization (primarily c b), redistribute blood flow, and increase inflammation, platelet aggregation, and release of reactive oxygen intermediates (primarily c a). , c a-mediated local leukocyte activation also results in increased cytokine production with subsequent up-regulation of adhesion molecules on vascular endothelium and increased cell recruitment to the site of infection. data in adults link elevated c a levels with multiple facets of sepsis-associated disease, such as dic, cardiac dysfunction, increased proinflammatory cytokine levels, sirs, apoptosis of adrenal medullary cells leading to adrenal cytokine production, and leukocyte activation. contrary to its name, the alternative pathway is the primary mechanism of amplification of complement activation after c convertase assembly (which cleaves c to c a and c b). dysregulation of complement activation may contribute to adverse effects in individuals with severe sepsis or septic shock. neonates, particularly the very premature, exhibit decreased basal levels of complement proteins and function for both the alternative pathway and the classical pathway. , moreover, as compared with adults, neonates exhibit gestational age-related degrees of depressed complement-mediated opsonic capabilities. as such, complement-mediated opsonization is poor in premature neonates and limited in term neonates. nization and pathogen clearance may help explain the lack of efficacy of intravenous immunoglobulin to prevent sepsis or death from sepsis in neonates. [ ] [ ] [ ] [ ] [ ] [ ] [ ] apps are the most phylogenetically ancient means of innate immune defense against microbial invasion. present in nearly every organism, including bacteria, plants, insects, nonmammalian vertebrates, and mammals, these small, often cationic peptides are capable of killing microbes of multiple types, including viruses, bacteria, parasites, and fungi, largely by disruption of the pathogen membrane. constitutive expression of apps occurs in humans on barrier areas with consistent microbial exposure such as skin and mucosa. after microbial stimulation, both release of preformed apps and inducible expression are thought to contribute to early host defense. importantly, there is no evidence for the development of microbial resistance to apps that target fundamental components of the microbial cell wall. some apps can bind and neutralize microbial components such as endotoxin, precluding engagement with tlrs and other prrs, and diminish inflammation. many apps can potentially reduce the intensity of the inflammatory response associated with the presence of bacterial toxins. [ ] [ ] [ ] because endotoxemia is an important contributor to neonatal mods and death with sepsis and nec, lps-binding/blocking strategies, including use of synthetic apps, may have a significant positive impact on outcomes. , bactericidal/permeability-increasing protein (bpi) is a -kda protein present in the respiratory tract, pmn primary granules, and plasma. bpi exerts selective cytotoxic, antiendotoxic, and opsonic activity against gram-negative bacteria. plasma bpi concentrations were higher in critically ill children with sepsis syndrome or organ system failure than in critically ill children without sepsis syndrome or organ system failure, and bpi levels positively correlated with the pediatric risk for death score. pmns from term neonates are deficient in bpi, potentially contributing to the increased risk for infection. whereas term neonates demonstrate up-regulation of plasma bpi during infection, premature neonates showed a decreased ability to mobilize bpi on stimulation, which may contribute to their risk for infection with gram-negative bacteria. polymorphisms in bpi increase the risk for gram-negative sepsis in children, but the impact of these polymorphisms in neonates is unknown. compared with pmns from adults, pmns from term neonates produce similar quantities of defensins but reduced quantities of bpi and elastase. , , recombinant bpi (rbpi ) treatment was associated with improved functional outcome, reduced amputation, but no difference in mortality in a multicenter study of children with severe systemic meningococcal disease. lactoferrin is the major whey protein in mammalian milk (in particularly high concentrations in colostrum) and is important in innate immune host defenses. lactoferrin is present in tears and saliva and has antimicrobial activity both via binding iron and by direct membrane disruption activity via a portion of its amino-terminal lactoferricin. lactoferrin is also an alarmin (e.g., hmgb- or il- ), capable of activating leukocytes, binding endotoxin, and modifying the host response by acting as a transcription factor that regulates mrna decay. , bovine lactoferrin has been shown to reduce the incidence of bacterial and fungal sepsis , and nec in preterm infants. lysozyme is present in tears, tracheal aspirates, skin, and pmn primary and secondary granules and contributes to degradation of peptidoglycan in bacterial cell walls. secretory pla can destroy gram-positive bacteria through hydrolysis of their membrane lipids. pmn elastase is a serine protease released by activated pmns with microbicidal function and is believed to play a role in the inflammatory damage seen with pmn recruitment, particularly in the lung. , cathelicidin and the insufficiency, and pmn dysfunction. septic shock in adult humans was associated with extensive complement activation, c-reactive protein-dependent loss of c a receptor on neutrophils, and the appearance of circulating c a receptor in serum, which correlated with a poor outcome. deficiencies in c a receptor found in term neonates as compared with adults may limit the ability to respond to c a and therefore increase the likelihood of infection. the expression of c a receptor on preterm pmns is unknown. the extent to which c a or other complement proteins play a role in the development of disease in septic neonates remains to be determined. complement regulatory proteins modify the effects of complement and prevent potential damage due to overactivation. in particular, cd blocks c polymerization and target lysis, cd destabilizes cd and c and c convertases, and cd accelerates the deactivation of c b. dysregulation of complement activation can lead to a vicious activation cycle that results in excessive cellular stimulation, cytokine production, endothelial cell activation, and local tissue damage promulgating sirs and septic shock (see figure - ). in addition to the initial inflammatory response including complement activation, molecular detection of pamps promotes il- β and il- production, which in turn increases the production of multiple other innate proteins that possess valuable immune function and serve to reduce pathogen load. acutephase reactant proteins, produced predominantly in the liver, include c-reactive protein (opsonin), serum amyloid a (cellular recruitment), lactoferrin (reduces the level of available iron/ antimicrobial peptide lactoferricin), procalcitonin (unknown function), haptoglobin, fibronectin (opsonic function), pentraxin (binds c q and activates the classical complement pathway), mbl, and lps-binding protein. , , , [ ] [ ] [ ] [ ] [ ] [ ] acutephase reactant proteins have been studied in neonates with sepsis primarily to assess them for diagnostic utility rather than immunologic function. in particular, elevated plasma concentrations of c-reactive protein and lps-binding protein are often associated with early-onset sepsis. , the levels of il- and c-reactive protein were significantly higher in preterm infants who did not survive sepsis, pneumonia, or nec. a lack of sustained increase in the production of c-reactive protein and serum amyloid a during sepsis has also been associated with a fulminant course. the fetus receives antibodies from the mother via active placental transfer, with a significant increase beginning around weeks' gestation. as a result of a shorter period of gestation, preterm neonates have lower igg subclass levels as compared with term neonates, particularly igg and igg subclasses. preterm neonates ( to weeks' gestation) with low igg levels (serum total igg levels below mg/dl at birth) were at increased risk for development of late-onset sepsis but not death compared to those with levels above mg/dl. however, igg titers and opsonic activity to cons were not predictive of late-onset cons sepsis. reliance on other means of innate immune defense likely provides the premature neonate with alternative microbial control mechanisms. despite the presence of maternally derived immunoglobulin and acute-phase reactant proteins, neonates exhibit impaired opsonizing activity compared with adults, which likely increases the risk for progression of infection. complement plays a critical role in immunoglobulin-mediated opsonization and effector cell phagocytosis. although immunoglobulin has many putative beneficial immunologic functions, most of these have not been demonstrated or examined in preterm infants. the dependence on complement for effective immunoglobulin-based opso-thrombocytopenia in neonates, which is attributed to reduced megakaryopoiesis in the setting of consumption with clot formation. decreased platelet function in preterm neonates with sepsis further increases the risk for bleeding. in extremely low-birth-weight infants, platelets are hyporeactive for the first few days after birth, complicating the ability of the immune system to contain a microbiologic threat and increasing the risk for hemorrhage. clotting can lead to propagation of inflammation via thrombin-induced production of platelet-activating factor. pmns activated by platelet-activating factor or platelet tlr may then contribute to further endothelial injury and dysfunction, leading to the development of a vicious clottinginflammation-clotting cycle. activated platelets may be consumed in clot formation and/or may also be removed from the circulation by the liver, potentially resulting in thrombocytopenia, particularly during gram-negative and fungal infections. , , systemic activation of coagulation is associated with consumption of clotting factors and increased risk for bleeding, prolonged proinflammatory responses, and dic. , , this finding is consistent with the elevated serum levels of il- and high frequency of dic seen with disseminated herpes simplex virus infection. in adult mice, protease-activated receptor plays a major role in orchestrating the interplay between coagulation and inflammation. protease-activated receptor may modify the endothelial response during neonatal sepsis and thus is a target for therapeutic intervention. recent studies have shown the critical importance of vascular endothelial activation in the early recognition and containment of microbial invasion. in transgenic mice, it was shown that pulmonary endothelial cells sense blood-borne bacteria and their products, whereas alveolar macrophages patrol the air spaces. these data illustrate the role of endothelium and help to explain in part the occurrence of acute respiratory distress syndrome (ards) and persistent pulmonary hypertension of the newborn associated with severe sepsis in the absence of a primary pulmonary infectious focus. expression of tlrs allows endothelium to become activated in the presence of microbial components, leading to production of cytokines, chemokines, and adhesion molecules (e.g., vascular cell adhesion molecule, intercellular cell adhesion molecule, l-selectin, p-selectin, and e-selectin). these substances are all necessary to attract immune cells (primarily pmns) to the site of infection and to facilitate pathogen containment. [ ] [ ] [ ] [ ] vasoactive substances released from activated leukocytes, platelets, and endothelial cells include platelet-activating factor, thromboxanes, leukotrienes, no, histamine, bradykinin, and prostaglandins. , the balance of no and endothelin , a vasoconstrictor, may be disrupted with endothelial damage, favoring the constrictive effects of endothelin and leading to ischemia and injury. this phenomenon may explain in part why no inhibitors increased mortality in adults with septic shock. stimulated endothelium can be a doubleedged sword, however, because excessive activation can lead to systemic overproduction of cytokines and vasoactive substances (including no). endothelial cell apoptosis, detachment from the lamina, and alterations in vascular tone combine to promote capillary leak, leading to hypovolemia, shock, and organ failure , , (see figure - ). release of myeloperoxidase from pmns may also injure surrounding endothelium. activated or damaged endothelium establishes a prothrombotic environment that can result in local microvascular occlusion or progress to dic. the glucocorticoid receptor is the target for cortisol, the primary endogenous glucocorticoid in humans, produced in the zona fasciculata of the adrenal glands. endothelial glucocorticoid defensins are other apps that possess antimicrobial properties. cathelicidin is present in the amniotic fluid, vernix, skin, saliva, respiratory tract, and leukocytes. α-defensins are cysteine-rich -kda peptides found in amniotic fluid, vernix, spleen, cornea, thymus, paneth cells, and leukocytes. β-defensins are found in the skin, gi tract, urinary system, reproductive organs (placenta, uterus, testes, kidney), respiratory tract, breast milk, mammary gland, and thymus. in addition to microbicidal action, apps have a wide range of immunomodulatory effects on multiple cell types from both the innate immune system and the adaptive immune system. , , these immunomodulatory effects include altered cytokine and chemokine production, improved cellular chemotaxis and recruitment, improved cell function (maturation, activation, phagocytosis, reactive oxygen intermediate production), enhancement of wound healing (neovascularization, mitogenesis), and decreased apoptosis. the cytosolic granules of pmn are rich in apps, including α-defensins, lactoferrin, lysozyme, cathelicidin, soluble pla , and bpi. gestational age-related decreases in the umbilical cord blood concentration of several apps (cathelicidin, bpi, calprotectin, soluble pla , α-defensins) in comparison with maternal serum levels have been drescibed. plasma app deficiencies may contribute to the increased risk for infection associated with prematurity, and their absence may increase the risk for endotoxemia. compared with term neonates, preterm neonates showed lower human β-defensin levels in umbilical cord blood. up-regulation of apps (defensins) occurs in blood of infected adults and children (defensins, lactoferrin). the effect of sepsis on the production of plasma apps in neonates has not been investigated in detail. the development of a procoagulant state in the surrounding microvasculature allows the trapping of invading pathogens and prevents further dissemination (see figure - ). in general, the intrinsic pathway amplifies coagulation after initiation by the extrinsic pathway. reduced levels of vitamin k-dependent factors (factors ii, vii, ix, and x), reduced thrombin generation, reduced consumption of platelets with formation of microthrombi, and reduced levels of counterregulatory elements (inhibitors) increase the risk for bleeding in infants and children. during sepsis, a microvascular procoagulant state develops via stimulation of phagocytes, platelets, and endothelium, resulting in expression of tissue factor. , tissue factormediated activation of the coagulation cascade results in activation of thrombin-antithrombin complex, plasminogen activator inhibitor type , and plasmin-α -antiplasmin complex, as well as inactivation of protein s and depletion of the anticoagulant proteins antithrombin iii and protein c. [ ] [ ] [ ] decreased activated protein c levels were associated with increased risk for death from sepsis in preterm neonates. a randomized controlled trial of activated protein c revealed no change in mortality among pediatric patients with sepsis, but term infants younger than days old experienced increased bleeding. the coagulation cascade is intimately tied to inflammation and complement activation. cytokine production increases expression of endothelial tissue plasminogen activator inhibitor type . plasminogen activator inhibitor type inhibits fibrinolysis by inhibiting the conversion of plasminogen to plasmin, which in turn is important for the breakdown of fibrin. deposition of fibrin in small vessels leads to inadequate tissue perfusion and organ failure. increased plasminogen activator inhibitor type excessive local inflammation and tissue damage. high early levels of circulating free pmn-derived dna produced by nets are associated with mods and death. nets contain destructive proteases capable of killing bacteria even after the pmn has died. formation of nets is reduced in pmns from preterm neonates and nearly absent in term neonates but may occur with sustained cellular stimulation. net formation may result in collateral damage to surrounding tissues when the target microbe is too large to be effectively phagocytosed (e.g., fungal hyphae). the contribution of net production to detrimental outcomes in infected neonates is unknown but excessive net formation with collateral tissue injury may contribute to the poor outcomes seen in preterm neonates with fungal infections. rapid depletion of bone marrow pmn reserves during infection, particularly in neonates, can lead to neutropenia, with consequent impaired antimicrobial defenses and significantly increased risk for death. in a multivariate analysis, neutropenia and metabolic acidosis were associated with fatal neonatal sepsis. neutropenia is particularly common in gram-negative sepsis in neonates. release of immature pmn forms (bands), which exhibit greater dysfunction than mature pmns, may further predispose to adverse outcomes. murine neonates with experimental sepsis exhibit delayed emergency myelopoiesis (a process by which the host repopulates peripheral myeloid cells lost early during sepsis), that is independent of trif and myeloid differentiation factor . interventions aimed at addressing reduced pmn numbers in neonates have included provision of mature pmns and prophylaxis or treatment with colonystimulating factors (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor). despite strong biologic plausibility, these interventions have been unsuccessful at reducing the neonatal infectious burden. [ ] [ ] [ ] in a metaanalysis, treatment with colony-stimulating factor therapy (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor) in a subgroup (n = ) of neutropenic neonates (absolute neutrophil count less than /µl) with culture-positive sepsis (largely gram-negative and gbs) significantly reduced the risk for death (relative risk, . ; % ci, . to . ). therefore, stimulation of granulopoiesis may be beneficial under these specific circumstances, although further studies focused on this subpopulation and outcomes are needed. irreversible aggregation and accumulation of newborn pmns in the vascular space after stimulation leads to decreased diapedesis, rapid depletion of bone marrow reserves, vascular crowding, and increased likelihood of microvascular occlusion. neonatal pmn deformation compared with adult pmn deformation is reduced at the baseline, which increases the risk for occlusion. furthermore, low blood pressure/flow states seen during septic shock further exacerbate existing microvascular ischemia. in combination, these deficiencies increase the propensity for systemic spread of infection, and set the stage for microvascular occlusion. many other cells besides pmns are involved in the development of an immune response to infection. monocytes, macrophages, and dendritic cells amplify cellular recruitment through production of inflammatory mediators, activation of endothelium, phagocytosis and killing of pathogens, and antigen presentation to t and b cells of the adaptive immune system. the primary functions of monocytes are the synthesis of crucial inflammatory proteins and antigen presentation to naïve cd + t cells. the patterns of cytokine production can promote the differentiation of naïve cd + t cells into distinct subtypes of t cells that serve important roles in the clearance of pathogens. for example, t-helper (t h ) cells are produced from naïve cd + t cells after exposure to ifn-γ and il- , and support cellmediated immunity against intracellular pathogens through production of ifn-γ, tnf-α, and lymphotoxin. t-helper (t h ) cells receptor is a critical negative regulator of inducible no synthase expression and nf-κb activation, demonstrating a protective role of the endothelium during sepsis. studies have revealed a potential role of plasma angiopoietin during pediatric septic shock. the level of angiopoietin , which protects against vascular leak, was reduced, whereas the level of angiopoietin , which promotes vascular permeability, was elevated, highlighting a novel potential therapeutic opportunity to reduce endorgan injury. the roles for endothelial glucocorticoid receptor and angiopoietin in neonatal sepsis are unknown. the role of endothelium activation during sepsis and septic shock in neonates, particularly in premature neonates, has been less well investigated. toxins from gbs have been shown to damage pulmonary endothelium and likely participate in pulmonary complications associated with gbs pneumonia such as ards and the development of persistent pulmonary hypertension of the newborn. the levels of the adhesion molecules e-selectin and p-selectin, expressed and secreted by activated endothelium, are increased in the serum of neonates with sepsis and likely reflect significant endothelial activation. endothelial tlr activation impaired intestinal perfusion in an experimental model of nec, via endothelial no synthasenitrite-no signaling. the pmn is the primary effector of innate immune cellular defense. endothelial cells produce activating cytokines and chemokine gradients that recruit circulating pmns to the site of infection. expression of cell adhesion molecules by pmns and endothelium allows cells to roll and extravasate into surrounding tissues. activated pmns phagocytose and kill pathogens via oxygen-dependent and oxygen-independent mechanisms. il- β is produced by activated pmns largely via an nlrp -asccaspase -dependent* mechanism that amplifies the recruitment of additional pmns from the bone marrow to the site of infection. activated pmns may release reactive nitrogen species, reactive oxygen species, and proteolytic enzymes via activation of membrane-associated nadph oxidase. these reactive intermediates and enzymes can lead to destruction of nonphagocytosed bacteria but can also cause local tissue destruction, including neonatal endothelial and lung injury, as well as surfactant inactivation, , and thus play a role in progression from sepsis to mods. neonatal pmns exhibit quantitative and qualitative deficits as compared with adult pmns. , respiratory burst activity is suppressed in pmns during neonatal sepsis and may contribute to poor microbicidal activity. [ ] [ ] [ ] compared with adult pmns, neonatal pmns exhibit delayed apoptosis, , as well as sustained capacity for activation (cd b up-regulation) and cytotoxic function (reactive oxygen intermediate production) that contributes to tissue damage. reduced apoptosis with prolonged survival of pmns may result in improved bacterial clearance but may also paradoxically increase the risk for sustained pmn-mediated tissue damage. increased serum pmn elastase, urokinase plasminogen activator, and urokinase plasminogen activator receptor levels are found at the time of presentation in infected neonates. with pmn death, dna (chromatin), histones, and apps are expelled into the environment and serve to trap bacteria (neutrophil extracellular traps [nets]). the formation of nets can occur after activation of platelet tlr and may lead to *asc, apoptosis-associated speck-like protein containing a carboxyterminal card. eosinophils phagocytose antigen-antibody complexes and release cytokines, chemokines, cytotoxic molecules, apps, and other substances (prostaglandins, thromboxanes, leukotrienes) when stimulated. eosinophilia is commonly observed in neonates with sepsis due to candida sp. and bacteria, and is seen in infants with nec. in infants of less than weeks' gestation, eosinophilia (absolute eosinophil count more than /mm ) may predict bacterial sepsis. eosinophilia in premature infants is not associated with production of ige. studies have demonstrated an integral role for eosinophils in adult intestinal integrity and revealed a novel innate bactericidal nonphagocytic function via extracellular catapulting of mitochondrial dna nets with associated bound toxic proteins. the precise role of eosinophils in the neonatal immune response to sepsis and in maintenance of intestinal integrity has yet to be determined. mast cells play a role in the response to pathogen invasion as a part of the innate cellular immune system via production of histamines (which promote vasodilation and up-regulation of p-selectin), cytokines, pmn recruitment, bacterial phagocytosis, and antigen presentation. , mast cell involvement was demonstrated in infants with erythema toxicum, where mast cell recruitment, degranulation, and expression of apps occurs. adult rodents deficient in mast cells exhibit impaired pmn influx, impaired clearance of enteric organisms, and decreased sepsis survival. mast cell production of histamine likely contributes to the vasodilation associated with sepsis and septic shock. like eosinophils and pmns, mast cells are capable of killing bacteria via generation of extracellular traps in adults. this means of immune protection has not been investigated in neonates. mast cells may also alter adaptive immune function by patterning the t h immunophenotype seen in the neonate and therefore contribute to the increased risk for infection. immature dendritic cells exposed to histamine during maturation (with lps) exhibit altered t-cell polarizing activity with predominance towards the t h phenotype via increased production of il- and decreased production of il- . furthermore, mast cells from neonates were shown to secrete significantly more histamine after stimulation as compared with adults, which may contribute to the development of shock. the role of natural killer (nk) cells in neonatal bacterial sepsis is incompletely defined. nk cell numbers increase with increasing gestational age, furthermore, a reduced percentage of nk cells present at birth may be a risk factor for late-onset sepsis in preterm infants. it is noteworthy that the numbers of circulating nk cells are not significantly different in neonates with or without infection , ; however, the numbers of circulating nk cells are decreased in newborn infants with shock. the mechanisms used by nk cells to destroy bacteria include secretion of apps (defensins), direct contact and lysis, antibody-dependent cellular cytotoxicity, and ifn-γ production. in neonates with bacterial sepsis, nk cells are activated, as evidenced by up-regulation of cd . , despite activation, nk cell cytotoxicity is deficient in infants with sepsis and recurrent infections. , although neonatal macrophages exhibit impaired baseline activation in response to ifn-γ, nk cell-mediated production of ifn-γ can enhance their phagocytic capability. further studies are necessary to more clearly define the role of nk cells in neonatal bacterial sepsis. cd + ter + (erythroid) cells may contribute to the increased susceptibility of the neonate to infection by reducing the inflammatory response associated with bacterial colonization of the gut. for example, ex vivo tnf-α production by stimulated adult effector cells was reduced in the presence of murine neonatal splenic cd + erythroid cells via an arginase -dependnent mechanism. the cd + erythroid population represents a large portion of murine fetal liver, neonatal spleen/bone marrow, and adult bone marrow. [ ] [ ] [ ] furthermore, the murine neonatal spleen contains large numbers of colony-forming progenitor cells for to weeks after birth. of note and in stark contrast arise in the presence of il- and il- , produce il- , il- , and il- , down-regulate t h responses, and support humoral immunity, as well as defense against extracellular parasites. a third subset of t h cells, t-helper cells, are generated in the presence of transforming growth factor β, il- , il- , and il- . these cells produce il- and il- , which are important for defense against extracellular bacteria and fungi. neonatal mononuclear cells exhibit a bias away from t h cell-polarizing activity because of increased il- and low tnf-α production. this may be beneficial because of mobilization of antiinfective proteins/ peptides that serve to protect the newborn during microbial colonization and development of immune tolerance. the adverse consequence is a reduced ability to respond to infection with microorganisms; particularly intracellular pathogens such as listeria sp. and mycobacteria. preterm infants (< weeks) may have greater attenuation of tnf-α and il- secretion compared with term infants and adults. there is decreased monocytic recruitment to areas of inflammation during sepsis because of decreased chemotactic ability. although the levels of peripheral monocytes decrease early during sepsis (between nd hours), secondary to extravasation and differentiation into macrophages, sepsis-related elevation of macrophage colony-stimulating factor results in a late increase in the number of peripheral monocytes (> hours). in addition to altered cytokine production and suboptimal recruitment, monocyte phagocytic function is reduced during sepsis. antigen presentation to naïve cd + t cells is an important immune function performed by monocytes. the decreased antigen-presenting function in monocytes from newborn infants is in part due to decreased mhc class molecule expression and decreased expression of costimulatory molecules, including cd and cd . monocytes leave the bloodstream, enter the tissues, and differentiate into macrophages and dendritic cells. monocytes and macrophages are closely related to pmns (common myeloid progenitor) and can kill pathogens by similar means. circulating monocytes differentiate into macrophages after exposure to maturing cytokines, and exit the bloodstream into tissues. important substances produced by stimulated monocytes/macrophages include complement components, cytokines (both proinflammatory and antiinflammatory), coagulation factors, and extracellular matrix proteins. located just below epithelial borders, macrophages encounter pathogens immediately after entry. macrophages are avidly phagocytic and generate apps to reduce bacterial burden, such as lactoferrin, defensins, transferrin, and lysozyme. in addition, macrophages play an important role in the amplification of the immune response through the production of cytokines and chemokines, as well as in antigen presentation to naïve cd + t cells. macrophages are poorly responsive to several tlr agonists. dendritic cells are antigen-presenting cells that function as a liaison between the innate immune system and the adaptive immune system through induction of antigen-specific t cellmediated immunity. dendritic cells from newborn infants exhibit a reduced antigen-presenting function when compared with adult cells and require increased stimulation for activation. evaluations of neonatal dendritic cell function suggest a tendency towards poor up-regulation of costimulatory molecules (cd /cd ) and activation markers (cd ), poor stimulation of t-cell proliferation, and a tendency towards the induction of immune tolerance. although preterm and term infants and adults have similar numbers of "plasmacytoid" dendritic cells in their blood, the capacity to produce ifn-α on tlr challenge was significantly decreased in preterm neonates and may increase susceptibility to viral infections. dendritic cells in umbilical cord blood can effectively induce cytotoxic lymphocyte responses. depletion of dendritic cells has been reported in adult animals and adult patients with sepsis; their role in the immune response to neonatal sepsis is not well characterized. pmn and γδ t cells. these data show that neonatal t cells are activated and are capable of playing a role in the host response to bacterial sepsis in vivo. neonatal lymphocyte function is skewed towards t h responses, setting the stage for immune tolerance (t h ) rather than immune priming for infection (t h ). newborn infants must overcome that immune modulation in order to mount effective responses to specific infectious challenges and respond to vaccination. examples of the impact of this immunopolarization include decreased ifn-γ production by cd + and cd + t cells as compared with production in children and adults. , the likely significance of decreased ifn-γ production is a reduction in activation of other immune cells, such as macrophages. reports of lymphocyte function in infected newborns are very limited. expansion of lymphocytes after antigenic stimulation is important for development of sustained immunity. decreased lymphocyte proliferative responses have been shown during the first weeks of life in vlbw neonates, and may predispose the premature neonate to development of late-onset sepsis. for example, t-lymphocyte function was depressed in infected newborn infants, and especially in those with multiorgan failure, versus healthy term or growing preterm infants. similarly, production of lymphocyte-associated cytokines after stimulation of umbilical cord blood peripheral blood mono nuclear cells with gbs was significantly deficient in preterm and term infants compared with adults. cytomegalovirus infection in utero leads to the expansion and differentiation of mature cytomegalovirusspecific cd + t cells, which have characteristics similar to adult cd + t cells. these cells showed potent perforin-dependent cytolytic activity and produce antiviral cytokines, highlighting the potential for adult-like immunocompetence of neonatal t cells under specific circumstances. an important location for effective lymphocytic function during systemic bacterial infection is the spleen. the marginal zone of the spleen facilitates the clearance of bacteria, particularly encapsulated organisms, from the bloodstream. these functions are accomplished via the interaction of multiple leukocytes, including macrophages, dendritic cells, b cells, and t cells, within follicles of the spleen. the neonatal splenic marginal zone is immature, owing to a lack of antecedent antigen exposure and is virtually devoid of cd + b cells. as a result of this functional asplenia, there is decreased clearance of pathogens from the blood and potential for a more fulminant course with bacteremia. , b cells are critically important in the adult host response to sepsis. data suggest antibody-independent and antibodydependent roles for b cells in the outcome of sepsis. studies deciphering the role of b cells in neonatal sepsis are very limited, and thus the role b cells play in the neonatal host response is unclear. after gbs meningitis, the level of igm was increased, suggesting b cells from neonates can respond to pathogenic challenge. premature neonates with perinatal infection or nosocomial infection may show signs of humoral immunoparalysis, manifested by decreased igm/igg production ex vivo as compared with production in their healthy age-matched counterparts. sepsis in early life did not reduce serum antibody titers in preterm infants after heptavalent pneumococcal conjugate vaccine exposure but was associated with a reduced opsonization titer to a single serotype, suggesting the capacity to respond to vaccination or other immune challenge may be altered. in the setting of reduced classic adaptive immune function seen in early life as compared with the function in adults, innate lymphoid populations (which lack b cell receptor and t cell receptor) may play a significant role in protecting the neonate from infectious challenge. [ ] [ ] [ ] [ ] [ ] [ ] [ ] examples of innate lymphoid cells include γδ t cells, intestinal lymphoid cells, invariant nk t cells, mucosa-associated invariant t cells, and b cells. to the lymphoid and reticuloendothelial system roles of the spleen in the healthy adult, the spleen is normally a major site of erythropoiesis during fetal and neonatal life, to support rapid fetal and postnatal growth in the setting of significantly reduced erythroid reservoirs as compared with the adult reservoirs. , , a lack of effect on neonatal murine survival to polymicrobial sepsis after adoptive transfer or diminution of cd + erythroid splenocytes suggests that the impact of these cells on neonatal infection risk and progression may be limited. the contribution of the adaptive immune system in the neonatal host response to sepsis is uncertain. the -to -day interval required for development of an adaptive immune responsenamely, the selection and amplification of specific clones of lymphocytes (b cells and t cells) that results in immunologic memory-argues against a central role for adaptive immunity in the protective response to early neonatal bacterial sepsis. as a result, the neonate is thought to largely depend on innate immunity for protection from infection during the first days of life. in adults, absence or dysfunction of the adaptive immune system has a profound impact on survival in preclinical models. b cells (and in particular b-cell cytokine production) and not t cells were shown to be important in the early host response to experimental sepsis. studies using neonatal mice lacking an adaptive immune system showed no difference in polymicrobial sepsis survival as compared with survival of wild-type mice with an intact adaptive immune system. furthermore, there are many quantitative and qualitative differences in lymphocytes from neonates compared with lymphocytes from adults, each with a respective proposed clinical impact. as these findings illustrate, the contribution of adaptive immunity for protection and response against sepsis, and in particular which components are protective, is unclear in the most immature and requires further investigation. peripheral blood examination has yielded inconsistent changes in the percentage, number, and type of circulating lymphocytes during sepsis. , [ ] [ ] [ ] [ ] [ ] [ ] moreover, changes related to the timing of sepsis onset (early-onset or late-onset sepsis) and prematurity have been incompletely characterized. t regulatory cells are abundant and potent at birth, facilitating inhibition of t h cell immunity, and perhaps mediating a state of immunologic tolerance. although the numbers of splenic t regulatory cells are increased in murine neonates and adults with sepsis, depletion of t regulatory cells had no effect on survival of murine adults. , alterations in the number or function of t regulatory cells in human neonatal sepsis have not been reported. examination of peripheral blood to identify markers of sepsis has yielded a number of lymphocyte cell-surface molecules whose levels increase during sepsis. activation of neonatal t cells is evidenced by increased cd ro expression (present on t cells after antigenic stimulation) at the time of sepsis diagnosis, , , and with congenital infection, although changes in number may take several days to occur after stimulation. other markers of lymphocyte activation may be found at different time points during the course of infection. for example, expression of the activation marker cd is increased on t cells (cd + ) early in the infectious process, whereas cd and cd ro expression persists for several days. increased expression of cd + t-cell carcinoembryonic antigen-related cell adhesion molecule (cd a) in preterm infants with lateonset sepsis may contribute to sepsis-associated immune suppression. hla-dr expression is increased on multiple cell types during neonatal sepsis. in contrast to adults, a large portion of neonatal t cells produce cxcl , which activates of genes for innate immune and metabolic pathways with decreased levels of adaptive immune transcripts. using a proteomics approach, ng and colleagues identified proapolipoprotein cii and a desarginine variant of serum amyloid a as promising biomarkers for late-onset sepsis and nec in preterm infants. it is very likely that implementation of unbiased "omic" approaches will reveal critical age-appropriate pathways and opportunities for therapeutic interventions aimed at improving neonatal sepsis outcomes. sepsis that leads to shock and organ failure carries the worst prognosis. sirs contributes to the development of organ failure in neonates (see figure - ). , , , persistent decreases in capillary perfusion are associated with mods and death in adults. lethargy, shock, and birth weight less than g were independent predictors of sepsis-related death. in neonates, impairment of the cardiovascular system, manifested by poor perfusion or hypotension, is invariably associated with septic shock. sustained poor organ perfusion in neonatal sepsis and septic shock due to cardiovascular dysfunction is associated with mods affecting the kidney, , liver, gut, and central nervous system (see figure - ) . the mechanism of organ failure may be decreased oxygen utilization associated with mitochondrial dysfunction rather than poor oxygen delivery to tissue. , on the basis of available evidence, it has been speculated that the prolonged sirs associated with severe sepsis and shock leads to organ failure via a cessation of energy-consuming processes. , development of severe nec is also associated with severe sepsis, shock, mods, and death. , the need for intubation or initiation of vasoactive medications, and hypoglycemia, thrombocytopenia, increased prothrombin time, or excessive bleeding as presenting laboratory signs of sepsis are risk factors for sepsis-related death. , , independent predictors of in-hospital late-onset sepsis death during the birth hospitalization were the presence of congenital anomalies (or, . ; % ci, . to . ), neuromuscular comorbidities (or, . ; % ci, . to . ), and secondary pulmonary hypertension with/without cor pulmonale (or, . ; % ci, . to . ), underscoring the impact of organ-level comorbidities that increase neonatal sepsis mortality. the most common organ dysfunction associated with sepsis is cardiovascular dysfunction. cardiovascular dysfunction associated with sepsis may lead to shock that is a composite of hypovolemic, cardiogenic, and distributive shock. distributive shock is related to endothelial no production that leads to excessive vasodilation. cardiogenic shock may be related to mitochondrial death (induced by reactive nitrogen and reactive oxygen intermediates) with subsequent myocardial dysfunction. abnormalities in peripheral vasoregulation and myocardial dysfunction may play a larger role in hemodynamic derangements in pediatric patients, especially infants and neonates. in children, a non-hyperdynamic state with reduced cardiac output and increased systemic vascular resistance is most commonly observed in the setting of sepsis. [ ] [ ] [ ] [ ] [ ] the hemodynamic presentation in neonates is much more variable and is complicated by an unclear association between a normal blood pressure and adequate systemic blood flow. , microcirculatory flow is impaired in term neonates even with mild to moderate severity of infection. preterm neonates with sepsis have relatively high left and right cardiac outputs and low systemic vascular resistances. however, a decrease in right or left ventricular output of more than % has been associated with increased mortality in neonatal sepsis. an elevated left ventricular output mechanistic investigations that fully explore the role of these newly discovered populations in the neonatal host response to sepsis are likely to uncover novel therapeutic opportunities. systems biology and the use of "omic" approaches have the potential to produce significant insights into the pathogenesis of sepsis. genomic and proteomic approaches have yielded important data associated with septic shock in older populations. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the use of these modern techniques in the study of neonatal inflammation and response to pathogen challenge has only just begun. , , , the ability to profile genome-wide expression has significantly enhanced our understanding of the complexity of the host immune response to sepsis in children. , , , , for example, genome-wide expression profiling revealed zinc homeostasis as an important feature of pediatric sepsis. , , prophylactic zinc supplementation reduced bacterial load and mortality in a murine model of peritoneal sepsis. however, oral zinc supplementation did not alter mortality in neonates with probable sepsis. in a study of pediatric patients who met the criteria for septic shock, a unique whole-blood transcriptomic response was found in neonates as compared with infants, toddlers, and school-age children. neonates manifested the largest number of uniquely regulated genes, representing both innate and adaptive immune system pathways, and showed a predominance of down-regulated transcripts representing the adaptive immune system. the number of up-regulated genes increased in proportion with developmental age. investigation of the murine circulating leukocyte transcriptome revealed significant differences in the host immune response to sepsis across the age spectrum (neonate, young adult, elderly), despite similar increases in mortality among the neonates and elderly mice as compared with young adult mice. these data underscore the impact of developmental age on the host immune response and suggest that therapeutics, which may have efficacy in older populations, may be ineffective in or possibly detrimental to neonates. because the transition to extrauterine life is associated with dramatic changes in physiology, the whole-blood transcriptome is likely to be quite different between both uninfected infants and in the host response to sepsis by timing after birth. indeed, an unsupervised analysis of the whole-blood genome-wide transcriptome on prospectively collected peripheral blood samples from infants evaluated for sepsis revealed the major node of separation between groups (infected or uninfected) was the timing of evaluation relative to birth (early, lass than days or late, more than days). principal component analyses revealed significant differences between patients with early or late sepsis despite the presence of similar key immunologic pathway aberrations in both groups. this study highlights both the uninfected state and the host responses to sepsis are significantly affected by timing relative to birth. a study of vlbw infants with blood culture-proven late-onset sepsis ( % cons) identified a -gene signature associated with sepsis, with increased expression of the tnf-α network, including matrix metalloproteinase and cd among the most commonly up-regulated genes. elevated matrix metalloproteinase mrna expression and activity in septic shock correlated with decreased survival and increased organ failure in pediatric patients. matrix metalloproteinase is a direct activator of nf-κb. inhibition (genetic or pharmacologic) of matrix metalloproteinase leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. most recently, a -gene network was uncovered and validated that accurately identified infected infants, who exhibited increased expression phosphorylation, ubiquitination, sumoylation) may occur after sepsis. , these dna alterations may modify transcription factor access of gene-specific promoter regions, ultimately leading to short-term and long-term changes in gene expression and immune function. the dna methylation pattern in the promoter region of the calca gene varied in different types of bacterial sepsis in preterm infants, suggesting its potential use as an epigenetic biomarker. trained immunity, the term coined to describe an adaptive innate immune response, may also be a positive or negative consequence of sepsis in early life. mechanisms that underlie trained immunity are beginning to emerge, and include dna methylation and modification of energy utilization pathways. , nonspecific vaccine benefits and resistance to subsequent pathogen challenge after innate immune priming or previous infection are likely manifestations of trained immunity in neonates. , , the cell types, extent, and duration of trained immunity-based modifications in neonates with sepsis have not been studied. myeloid suppressor cells manifest immunosuppressive activity with sepsis and were recently described in neonates. myeloid suppressor cells are present at high frequency at birth and decline in number with postnatal age. they inhibit t-cell proliferative responses and ifn-γ production. reactivation of viral infection that may contribute to morbidity and mortality has been demonstrated in infected adults. the impact of this phenomenon in neonates is unknown. acute hypoxic respiratory failure, ards, and acute lung injury are common pulmonary complications associated with severe sepsis. destruction of the alveolar capillary membrane leads to refractory hypoxemia. after direct or indirect insults to the lung, alveolar macrophages produce chemokines that mitigate pmn influx to lung parenchyma. activated pmns release reactive oxygen and reactive nitrogen intermediates that damage endothelial and epithelial barriers, leading to leakage of protein-rich edema fluid into the air spaces. other pulmonary complications with severe sepsis may include secondary surfactant deficiency, primary or secondary pneumonia, and reactive pulmonary hypertension. , infants with sepsis and persistent pulmonary hypertension of the newborn may require inhaled no in addition to optimized ventilation strategies such as highfrequency oscillatory ventilation. if oxygenation or tissue perfusion remains severely compromised despite optimal medical management, extracorporeal membrane oxygenation should be considered in neonates weighing more than kg without contraindications. , the detrimental neurodevelopmental long-term impact of sepsis has been demonstrated in multiple studies and has been reviewed in detail. [ ] [ ] [ ] [ ] [ ] central nervous system injury is predominantly white-matter injury (loss of pre-oligodendrocytes), manifested by focal cystic periventricular leukomalacia, diffuse necrosis, or a combination of these entities. , central nervous system injury is, in part, mediated by inflammation with or without direct pathogen invasion. , , the impact of sepsis on central nervous system injury is intensified with lower gestational ages, highlighting the detrimental effects of sepsis on the developing brain. the importance of evaluating the preterm infant for disseminated infection that may include meningitis cannot be overemphasized. a complete evaluation, including cultures of blood, urine and cerebrospinal fluid, is uncommon, although one third of the cases of culture-positive meningitis in vlbw infants are associated with negative concurrent blood cultures. clinically apparent seizures may occur in % of vlbw preterm infants with meningitis. low-voltage background pattern, sleep-wake cycling, and seizure activity on but normal ejection fraction in preterm neonates with septic shock suggests that septic shock in preterm neonates is predominantly due to vasoregulatory failure. neonatal sepsis may or may not be associated with left ventricular diastolic dysfunction; however, cardiac injury as manifested by elevated levels of cardiac troponin t may complicate the clinical picture. , abnormal peripheral vasoregulation with or without myocardial dysfunction is the primary mechanism for the hypotension accompanying septic shock in the neonate. therefore, infected neonates may present with hypotension and adequate perfusion (warm shock) or inadequate perfusion (cold shock). myocardial dysfunction can lead to ventricular wall stretch that in turn elevates b-type natriuretic peptide levels. b-type natriuretic peptide levels are elevated in children with septic shock, and increased levels have utility as prognostic indicators of death. plasma no level is elevated in neonates with sepsis and shock compared wit those with shock alone. elevated serum lactate level (> mmol/l) distinguished nonsurvivors from survivors in a pediatric study that included neonates. after severe sepsis or septic shock, there is an increased risk for subsequent infection and death in children and adults. this phenomenon is termed immunoparalysis and is associated with reduced mhc class expression and tnf-α production by mononuclear cells after endotoxin stimulation. in addition to altered monocytic responses, there is significant loss of lymphoid cd + t and b cells via caspase-dependent apoptotic pathways. , whether by clonal selection, apoptosis, or elevated endogenous glucocorticoid levels, [ ] [ ] [ ] lymphocyte loss may lead to a state of immune compromise after the acute phase of sepsis. , , [ ] [ ] [ ] [ ] [ ] new data suggests that il- may play an important role in promoting t-cell activation and prevention of apoptosis. the importance of immunoparalysis has been convincingly demonstrated in infected adults - and children. however, the clinical impact in the preterm neonate in whom adaptive immune function is less well developed is uncertain. , in examinations of peripheral blood and postmortem spleens from infected adults, there is significant loss of b and cd + t lymphocytes and dendritic cells, , resulting in decreased antigen presentation, antibody production, and macrophage activation. circulating peripheral absolute lymphocyte counts can drop significantly in adults with sepsis but this phenomena is also seen in critically ill adults who are not infected. sustained lymphopenia significantly increases the risk for secondary infection, mods, and death in children. extensive loss of lymphocytes (both b and t lymphocytes) has been described in postmortem specimens from the thymus and spleen in infected preterm and term infants. , , [ ] [ ] [ ] [ ] the number and the size of the follicles in the spleen decreased significantly and the total number of cells decreased by more than three times; similar changes were found in lymph nodes. however, these histopathologic splenic findings are in contradiction to earlier reports where no differences were described in infected and uninfected infants. splenomegaly may occur in infants with late-onset sepsis and may be due to splenic congestion in the absence of hyperplasia of white pulp. the mechanisms responsible for immune alterations after sepsis are beginning to emerge. the intensity of the inflammatory response may be modified by neural-based mechanisms. t cell-secreted acetylcholine acts on macrophages to reduce production of tnf, il- , il- , hmgb- , and other cytokines. the role of vagal tone in the neonatal host response to sepsis is unclear. discovery and characterization of the impact of epigeneticmediated immune system functional alterations after sepsis is an area of intense research. dna methylation and posttranslational modification of histone proteins (methylation, acetylation, prevented hmgb- level elevation, and was associated with longer survival times. increased plasma nitrite and nitrate concentrations are associated with the development of multiple organ failure in pediatric patients with sepsis , but have not been investigated in neonates. the incidence of neonatal sepsis remains high and outcomes remain poor despite considerable technologic advances in the field of neonatology. much remains to be learned about the impact of developmental age on the host response to sepsis and what facets are critically important. important considerations for future investigations include the development and implementation of a generally accepted definition for neonatal sepsis, the use of homogeneous systems (only neonatal components) for human ex vivo studies, and transgenic approaches in preclinical models, alongside observational studies in humans to ensure meaningful findings. complete reference list is available at www.expertconsult.com. the amplitude-integrated electroencephalogram may be helpful to predict neurologic outcome in infants with sepsis or meningitis. significantly lower resistance, vasodilatation, and higher blood flow were noted in all the cerebral arteries of infants with sepsis. increase in cerebral blood flow velocity was correlated with elevated il- concentrations. alterations in blood flow in preterm infants, in addition to factors associated with sepsis, such as respiratory distress, hypercarbia, hypotension, and patent ductus arteriosus, contribute to the risk for intracerebral hemorrhage. endocrine abnormalities may include altered thyroid function and adrenal insufficiency associated with refractory hypotension. inadequate adrenocortical responses are associated with increased mortality. , cortisol production in the neonate is significantly increased early in septic shock. however, very preterm neonates can have relative adrenal insufficiency that may contribute to hemodynamic instability and hypotension. hydrocortisone has not been evaluated in large prospective randomized clinical trials for the treatment of septic shock in the neonate but it has been shown to increase blood pressure, decrease heart rate, and decrease vasoactive medication requirements in preterm and term neonates in addition to its cytokine-suppressing effects. [ ] [ ] [ ] if hydrocortisone treatment is considered, the obtaining of a pretreatment serum cortisol level is prudent in order to differentiate contributing causes of hypotension. sepsis was the most common cause ( %) of acute kidney injury in term neonates and was associated with high mortality ( %) (n = ). the frequency of acute renal failure (defined as a blood urea nitrogen level greater than mg/dl) in infected neonates was % and oliguria occurred in % of acute kidney failure cases. acute kidney injury in preterm neonates is associated with high mortality. hepatic injury and dysfunction are frequent associations with severe sepsis. the mechanisms include reduced hepatic perfusion associated with septic shock and mitochondrial energy failure. reductions in coagulation and complement factors, acute-phase reactant proteins, and increases in the levels of transaminases and bilirubin are commonly seen, especially in association with decreased perfusion states. energy expenditure and oxygen consumption are increased during sepsis, and decreased mitochondrial oxidative function precipitated by hypoxia and the presence of reactive oxygen intermediates may lead to impaired growth, caloric deficiency, and energy failure. , sepsis that leads to mods carries a dismal prognosis. inadequate cardiac output and microcirculatory failure, which may be combined with formation of microthrombi and dic, can lead to poor perfusion to the kidney, , liver, gut, and central nervous system. , , , , recent studies suggest that the mechanism of organ failure in sepsis may relate to decreased oxygen utilization associated with mitochondrial dysfunction rather than poor oxygen delivery to tissues. , mitochondrial dysfunction can initiate activation of cell death pathways, including apoptosis, pyroptosis, necrosis, and netosis (i.e. cell death mediated by nets). damage-associated molecular patterns (including nucleosomes and microparticles) created by activation of these cell death programs further amplify the host inflammatory response. free radicals play an important role in the inflammatory process of sepsis. in a sepsis model in neonatal piglets, edaravone, a novel free radical scavenger, increased mean arterial pressure and cardiac output, lowered heart rate, reduced hydroperoxide, nitrite, and nitrate levels, delayed the tnf-α surge, . jackson gl, rawiki p, sendelbach d, et al: hospital course and short-term outcomes of term and late preterm neonates following exposure to prolonged rupture of membranes and/or chorioamnionitis. pediatr infect dis j ( ) protective immunity and defects in the neonatal and elderly immune response to sepsis increased mortality and altered immunity in neonatal sepsis produced by generalized peritonitis defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by tlr agonists the host response to sepsis and developmental impact the influence of developmental age on the early transcriptomic response of children with septic shock international pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: update from the american college of critical care medicine surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates time for a neonatal-specific consensus definition for sepsis global, regional, and national causes of child mortality: an updated systematic analysis for with time trends since million neonatal deaths: when? where? why? changes in pathogens causing early-onset sepsis in very-low-birth-weight infants late-onset sepsis in very low birth weight neonates: the experience of the nichd neonatal research network very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the national institute of child health and human development neonatal research network pattern of culture-proven neonatal sepsis in a district general hospital in the united kingdom outcome of early-onset sepsis in a national cohort of very low birth weight infants protective immunity and defects in the neonatal and elderly immune response to sepsis increased mortality and altered immunity in neonatal sepsis produced by generalized peritonitis defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by tlr agonists the host response to sepsis and developmental impact the influence of developmental age on the early transcriptomic response of children with septic shock international pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: update from the american college of critical care medicine surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates time for a neonatal-specific consensus definition for sepsis global, regional, and national causes of child mortality: an updated systematic analysis for with time trends since million neonatal deaths: when? where? why? changes in pathogens causing earlyonset sepsis in very-low-birth-weight infants late-onset sepsis in very low birth weight neonates: the experience of the nichd neonatal research network very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the national institute of child health and human development neonatal research network pattern of culture-proven neonatal sepsis in a district general hospital in the united kingdom outcome of early-onset sepsis in a national cohort of very low birth weight infants late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births early onset neonatal sepsis: the burden of group b streptococcal and e. coli disease continues causes of death in the extremely low birth weight infant early and late onset sepsis in late preterm infants insights into severe sepsis in older patients: from epidemiology to evidence-based management the effect of age on the development and outcome of adult sepsis neonatal outcomes of extremely preterm infants from the nichd neonatal research network the epidemiology of severe sepsis in children in the united states risk factors in early neonatal sepsis risk factors for early neonatal sepsis risk factors for neonatal sepsis risk factors for early-onset group b streptococcal sepsis: estimation of odds ratios by critical literature review incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case-control study neonatal sepsis workups in infants >/= grams at birth: a population-based study association of maternal hypertension and chorioamnionitis with preterm outcomes outcomes of very-low-birth-weight infants exposed to maternal clinical chorioamnionitis: a multicentre study are complete blood cell counts useful in the evaluation of asymptomatic neonates exposed to suspected chorioamnionitis? hospital course and short-term outcomes of term and late preterm neonates following exposure to prolonged rupture of membranes and/or chorioamnionitis role of guidelines on length of therapy in chorioamnionitis and neonatal sepsis chorioamnionitis and early childhood outcomes among extremely low-gestational-age neonates a multicenter study on the clinical outcome of chorioamnionitis in preterm infants morbidity and mortality among very-low-birth-weight infants born to mothers with clinical chorioamnionitis a population-based comparison of strategies to prevent early-onset group b streptococcal disease in neonates active bacterial core surveillance (abcs) report: emerging infections program network: group b streptococcus changing patterns in neonatal escherichia coli sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis predictors of morbidity and mortality in neonates with herpes simplex virus infections neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor clinical management guidelines for obstetriciangynecologists intravenous gamma globulin administration to common variable immunodeficient women during pregnancy: case report and review of the literature outcome and prognostic factors in neonates with septic shock clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a -year period severe neonatal parechovirus infection and similarity with enterovirus infection evaluation of systemic inflammatory responses in neonates with herpes simplex virus infection early and late onset sepsis in very-lowbirth-weight infants from a large group of neonatal intensive care units fulminant late-onset sepsis in a neonatal intensive care unit, - , and the impact of avoiding empiric vancomycin therapy neonatal gram-negative bacteremia hospital-acquired infection surveillance in a neonatal intensive care unit trends in incidence and antimicrobial resistance of early-onset sepsis: population-based surveillance in san francisco and atlanta mortality following blood culture in premature infants: increased with gram-negative bacteremia and candidemia, but not gram-positive bacteremia neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at to months incidence, clinical characteristics and risk factors for adverse outcome in neonates with late-onset sepsis volume of blood required to detect common neonatal pathogens clinical sepsis in neonates and young infants rt-pcr detection of respiratory pathogens in newborn children admitted to a neonatal medium care unit an echovirus type outbreak in a neonatal intensive care unit viral outbreaks in neonatal intensive care units: what we do not know vernix caseosa as a multi-component defence system based on polypeptides, lipids and their interactions vernix caseosa in neonatal adaptation differential expression pattern of genes encoding for anti-microbial peptides in the fetal membranes of patients with spontaneous preterm labor and intact membranes and those with preterm prelabor rupture of the membranes innate immune defences in the human uterus during pregnancy surfactant protein d in the female genital tract neonatal skin in mice and humans expresses increased levels of antimicrobial peptides: innate immunity during development of the adaptive response the newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa erythema toxicum neonatorum is an innate immune response to commensal microbes penetrated into the skin of the newborn infant relationship between toxic erythema and infant maturity clinical consequences of an immature barrier development of the epidermis in the newborn development of skin barrier function in premature infants topical ointment for preventing infection in preterm infants developmental immunology and role of host defenses in fetal and neonatal susceptibility to infection probiotics: role in pathophysiology and prevention in necrotizing enterocolitis patterned progression of bacterial populations in the premature infant gut oral microbial profile discriminates breast-fed from formula-fed infants the microbiota regulates neutrophil homeostasis and host resistance to escherichia coli k sepsis in neonatal mice neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants gastrointestinal maturation and implications for infant feeding potential of immunomodulatory agents for prevention and treatment of neonatal sepsis association of intrapartum antibiotic exposure and late-onset serious bacterial infections in infants multiple-organ-failure syndrome il- produced by paneth cells drives tnf-induced shock parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants impact of early human milk on sepsis and health-care costs in very low birth weight infants role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death breast milk and neonatal necrotising enterocolitis jr: innate immune functions of the airway epithelium endotoxin-directed innate immunity in tracheal aspirates of mechanically ventilated human neonates new synthetic surfactants: the next generation? jr: expression and activity of beta-defensins and ll- in the developing human lung impaired transendothelial migration by neonatal neutrophils: abnormalities of mac- (cd b/cd )-dependent adherence reactions defective lps signaling in c h/hej and c bl/ sccr mice: mutations in tlr gene pathogen recognition by innate receptors cooperation of toll-like receptor signals in innate immune defence combined toll-like receptor agonists synergistically increase production of inflammatory cytokines in human neonatal dendritic cells harmful molecular mechanisms in sepsis the roles of tlrs, rlrs and nlrs in pathogen recognition early use of polymyxin b hemoperfusion in abdominal septic shock: the euphas randomized controlled trial septicaemic low birthweight neonates treated with human antibodies to endotoxin endotoxin clearance by exchange blood transfusion in septic shock neonates changes and clinical significance of toll-like receptor and expression in neonatal infections a critical role for tlr in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair activation and regulation of the inflammasomes cr : a general purpose adhesion-recognition receptor essential for innate immunity total cell content of cr (cd b/ cd ) and lfa- (cd a/cd ) in neonatal neutrophils: relationship to gestational age l-selectin is down-regulated in umbilical cord blood granulocytes and monocytes of newborn infants with acute bacterial infection comparison of l-selectin and cd b on neutrophils of adults and neonates during the first month of life neutrophil activation in preterm infants who have respiratory distress syndrome procalcitonin in detecting neonatal nosocomial sepsis the role of mannose-binding lectin in susceptibility to infection in preterm neonates low mannose-binding lectin (mbl) levels in neonates with pneumonia and sepsis high prevalence of mannosebinding lectin (mbl) deficiency in premature neonates impaired nlrp inflammasome activity during fetal development regulates il- β production in human monocytes mannose-binding lectin (mbl) genotype in relation to risk of nosocomial infection in pre-term neonates in the neonatal intensive care unit role of mannose-binding lectin in nosocomial sepsis in critically ill neonates mannan-binding lectin- (mbl ) gene polymorphisms in prenatal and perinatal cytomegalovirus infections m-ficolin concentrations in cord blood are related to circulating phagocytes and to early-onset sepsis mechanisms and regulation of the gene-expression response to sepsis diagnostic markers of infection in neonates proinflammatory and anti-inflammatory cytokine responses in preterm infants with systemic infections selective impairment of tlr-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte tnf-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to r- cytokine profiles as markers of disease severity in sepsis: a multiplex analysis rapid simultaneous measurement of multiple cytokines using microl sample volumes-association with neonatal sepsis evaluation of serum c-reactive protein, procalcitonin, tumor necrosis factor alpha, and interleukin- levels as diagnostic and prognostic parameters in patients with community-acquired sepsis, severe sepsis, and septic shock serum tumor necrosis factor-alpha in neonatal sepsis immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling imidazoquinoline toll-like receptor agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase- -dependent pathways identification of diagnostic biomarkers for infection in premature neonates a role for il- in human neutrophil apoptosis interleukin- is an essential element in host resistance to experimental group b streptococcal disease in neonates interleukin- (ifngamma-inducing factor) induces il- and il- beta via tnfalpha production from non-cd + human blood mononuclear cells interleukin- primes the oxidative burst of neutrophils in response to formyl-peptides: role of cytochrome b translocation and n-formyl peptide receptor endocytosis role of cytokines in preterm labour and brain injury up-regulation of il- and il- in the ileum of neonatal rats with necrotizing enterocolitis genetic variants of the interleukin- promoter region (- ) influence the course of necrotising enterocolitis in very low birth weight neonates decreased development of necrotizing enterocolitis in il- -deficient mice neonatal interleukin- beta, interleukin- , and tumor necrosis factor: cord blood levels and cellular production cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis serum tumour necrosis factor in newborns at risk for infections cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality early prediction of sepsis-induced disseminated intravascular coagulation with interleukin- , interleukin- , and rantes in preterm infants early diagnostic markers for neonatal sepsis: comparing c-reactive protein, interleukin- , soluble tumour necrosis factor receptors and soluble adhesion molecules increased cd b-density on circulating phagocytes as an early sign of late-onset sepsis in extremely lowbirth-weight infants serum soluble icam- , vcam- , l-selectin, and p-selectin levels as markers of infection and their relation to clinical severity in neonatal sepsis soluble l-selectin, a marker of immune activation, in neonatal infection circulating concentrations of chemokines in cord blood, neonates, and adults rac concentrations in umbilical cord neutrophils intravascular immunity: the host-pathogen encounter in blood vessels ip- is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants interleukin- as a stratification tool for interventional trials involving pediatric septic shock high-mobility group box protein (hmgb ): nuclear weapon in the immune arsenal activation of human umbilical vein endothelial cells leads to relocation and release of highmobility group box chromosomal protein role of toll-like receptors and , and the receptor for advanced glycation end products in high-mobility group box -induced inflammation in vivo hmgb b box increases the permeability of caco- enterocytic monolayers and impairs intestinal barrier function in mice high-mobility group box protein is an inflammatory mediator in necrotizing enterocolitis: protective effect of the macrophage deactivator semapimod characterization of rage, hmgb , and s beta in inflammation-induced preterm birth and fetal tissue injury genetic polymorphisms and risk for acute renal failure in preterm neonates heat-shock protein acts as an effective adjuvant in neonatal mice and confers protection against challenge with herpes simplex virus extracellular heat shock protein (hsp ) levels in children with septic shock extracellular hsp levels in children with septic shock how dying cells alert the immune system to danger alterations in antioxidant status during neonatal sepsis lipid peroxidation and antioxidants in neonatal septicemia such stuff as dreams are made on: mediator-directed therapy in sepsis nitric oxide levels in preterm and term infants and in premature infants with bacteremia secretory phospholipase a in newborn infants with sepsis group b streptococcus isolates from septic patients and healthy carriers differentially activate platelet signaling cascades plasma endothelin- and clinical manifestations of neonatal sepsis endogenous formation of prostanoids in neonates with persistent pulmonary hypertension elevated immunoreactive endothelin- levels in newborn infants with persistent pulmonary hypertension endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction lipid mediators in the pathophysiology of critical illness the fetal inflammatory response syndrome plasma nitric oxide levels in newborn infants with sepsis platelet-activating factor concentrations in healthy and septic neonates the immunology of sepsis why have clinical trials in sepsis failed? a genomic storm in critically injured humans toward a clinically feasible gene expression-based subclassification strategy for septic shock: proof of concept characterisation of the host inflammatory response to staphylococcus epidermidis in neonatal whole blood proinflammatory cytokines (il- , il- ), cytokine inhibitors (il- sr, stnfrii) and anti-inflammatory cytokines (il- , il- ) in the pathogenesis of sepsis in newborns and infants bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis interleukin (il)- inhibits nuclear factor κb (nfκb) activation in human monocytes. il- and il- suppress cytokine synthesis by different mechanisms role of interleukin- in innate and adaptive immunity recombinant human il- attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production termination of acute-phase response: role of some cytokines and antiinflammatory drugs tlr -induced il- production impairs neutrophil recruitment to infected tissues during neonatal bacterial sepsis soluble interleukin- receptor as a predictor of neonatal sepsis inflammatory mediators in umbilical plasma from neonates who develop early-onset sepsis using proteomics in perinatal and neonatal sepsis: hopes and challenges for the future srage is elevated in septic patients and associated with patients outcome receptor for advanced glycation end products (rage) regulates sepsis but not the adaptive immune response circulating soluble triggering receptor expressed on myeloid cells- (strem- ) as diagnostic and prognostic marker in neonatal sepsis diversifying microrna sequence and function human neonatal naive cd + t cells have enhanced activation-dependent signaling regulated by the microrna mir- a identification of micrornas changed in the neonatal lungs in response to hyperoxia exposure mirna- b regulates tnf-alpha production in cd + neonatal monocytes via post-transcriptional regulation microrna- : tiny player in neonatal innate immunity mir- a mediates protective innate immune tolerance in the neonate intestine microrna- expression in neonatal blood associated with antenatal immunoglobulin e production and development of allergic rhinitis corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis human toll-like receptor mutations are associated with susceptibility to invasive meningococcal disease in infancy lipopolysaccharide binding protein in preterm infants interactions of endotoxin with cortisol and acute phase proteins in septic shock neonates relative adrenal insufficiency in the preterm and term infant corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock the impact of environmental and genetic factors on neonatal late-onset sepsis risk factors for infectious disease death among infants in the united states toll-like receptor polymorphisms in gramnegative bacterial infections of han chinese neonates role of polymorphic variants as genetic modulators of infection in neonatal sepsis mannose-binding lectin gene polymorphism and early neonatal outcome in preterm infants il- , il- and cd polymorphisms and sepsis outcome in ventilated very low birth weight infants tumor necrosis factor alpha− polymorphism associated with increased sepsis mortality in ventilated very low birth weight infants toll-like receptor genetic variants are associated with gram-negative infections in vlbw infants toll-like receptor polymorphisms and aspergillosis in stem-cell transplantation toll-like receptor polymorphisms affect innate immune responses and outcomes in sepsis human toll-like receptor mutations but not cd polymorphisms are associated with an increased risk of gramnegative infections a novel polymorphism in the toll-like receptor gene and its potential association with staphylococcal infection tlr deficiency in patients with herpes simplex encephalitis toll-like receptor (tlr) polymorphisms in african children: common tlr- variants predispose to severe malaria elevated levels of lipopolysaccharide-binding protein and soluble cd in plasma in neonatal early-onset sepsis serum levels of cd in neonatal sepsis by gram-positive and gram-negative bacteria c>t cd genotype-functional effects on innate immune responses in term neonates increased expression and internalization of the endotoxin coreceptor cd in enterocytes occur as an early event in the development of experimental necrotizing enterocolitis gene variants of the bactericidal/ permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis functional significance of gene polymorphisms in the promoter of myeloid differentiation- pyogenic bacterial infections in humans with myd deficiency pyogenic bacterial infections in humans with irak- deficiency irak and nemo mutations in otherwise healthy children with recurrent invasive pneumococcal disease neonatal-onset multisystem inflammatory disease responsive to interleukin- β inhibition reduced expression of c a receptors on neutrophils from cord blood mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants interleukin- (- c) polymorphism and the risk of sepsis in very low birth weight infants: meta-analysis the role of mannose-binding lectin in susceptibility to infection in preterm neonates interleukin- - -genotype, sepsis and cerebral injury in very low birth weight infants genetic association studies in vlbw infants exemplifying susceptibility to sepsis-recent findings and implications for future research interleukin- polymorphism is associated with chorioamnionitis and neonatal infections in preterm infants prevalence of two tumor necrosis factor gene polymorphisms in premature infants with early onset sepsis lower prevalence of il- receptor alpha-chain gene g variant in very-low-birth-weight infants with necrotizing enterocolitis genetic variants of tnf-α, il- β, il- receptor α-chain, il- and il- genes are not risk factors for sepsis in lowbirth-weight infants genetic variants of the tumour necrosis factor-alpha promoter gene do not influence the development of necrotizing enterocolitis genetic basis for necrotizing enterocolitisrisk factors and their relations to genetic polymorphisms prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective the development of the complement system after weeks' gestation activity of classical and alternative pathways of complement in preterm and small for gestational age infants concentrations of main serum opsonins in early infancy phagocytic, opsonic and immunoglobulin studies in newborns neutrophil cd b expression and circulating interleukin- as diagnostic markers for early-onset neonatal sepsis human neutrophils increase expression of c bi as well as c b receptors upon activation molecular and cellular mechanisms of leukocyte chemotaxis anaphylatoxins: possible roles in disease the role of complement in inflammatory diseases from behind the scenes into the spotlight changes and regulation of the c a receptor on neutrophils during septic shock in humans different expression and mobilisation of the complement regulatory proteins cd , cd and cd in neonatal and adult neutrophils meconium aspiration syndrome induces complement-associated systemic inflammatory response in newborn piglets plasma bactericidal/permeabilityincreasing protein concentrations in critically ill children with the sepsis syndrome innate immunity of the newborn: basic mechanisms and clinical correlates the value of immunoglobulin and complement levels in the early diagnosis of neonatal sepsis decreased plasma fibronectin concentrations in preterm infants with septicaemia proteomics mapping of cord blood identifies haptoglobin "switch-on" pattern as biomarker of early-onset neonatal sepsis in preterm newborns serial serum c-reactive protein levels in the diagnosis of neonatal infection plasma levels of interleukin- and interleukin- in preterm neonates evaluated for sepsis the prognostic virtue of inflammatory markers during late-onset sepsis in preterm infants maternal-fetal transport of immunoglobulin g and its subclasses during the third trimester of human pregnancy antibody responses and opsonic activity in sera of preterm neonates with coagulase-negative staphylococcal septicemia and the effect of the administration of fresh frozen plasma surgery, sepsis, and nonspecific immune function in neonates preterm infants have deficient monocyte and lymphocyte cytokine responses to group b streptococcus does ivig administration yield improved immune function in very premature neonates? a blinded, randomized, multicenter study of an intravenous staphylococcus aureus immune globulin treatment of neonatal sepsis with intravenous immune globulin clinical trial of safety and efficacy of inh-a for the prevention of nosocomial staphylococcal bloodstream infection in premature infants phase / double-blind, placebo-controlled, dose escalation, safety, and pharmacokinetic study of pagibaximab (bsyx-a ), an antistaphylococcal monoclonal antibody for the prevention of staphylococcal bloodstream infections, in very-low-birthweight neonates role of pentoxifylline and/or igmenriched intravenous immunoglobulin in the management of neonatal sepsis intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants intravenous immunoglobulin for suspected or proven infection in neonates defensins: antimicrobial peptides of innate immunity first line of defense in early human life enhancement of neonatal innate defense: effects of adding an n-terminal recombinant fragment of bactericidal/ permeability-increasing protein on growth and tumor necrosis factor-inducing activity of gram-negative bacteria tested in neonatal cord blood ex vivo the novel beta-defensin defb prevents lipopolysaccharide-mediated effects in vitro and in vivo augmentation of the lipopolysaccharideneutralizing activities of human cathelicidin cap /ll- -derived antimicrobial peptides by replacement with hydrophobic and cationic amino acid residues cd receptor occupancy in severe sepsis: results of a phase i clinical trial with a recombinant chimeric cd monoclonal antibody (ic ) impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeabilityincreasing protein extracellular release of bactericidal/permeability-increasing protein in newborn infants bactericidal permeability increasing protein gene variants in children with sepsis neutrophil function in preterm and term infants granules and secretory vesicles in human neonatal neutrophils bactericidal/permeability-increasing proteinlessons learned from the phase iii, randomized, clinical trial of rbpi for adjunctive treatment of children with severe meningococcemia antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment lactoferrin, a bird's eye view proteomic approach to the identification of novel delta-lactoferrin target genes: characterization of dcps, an mrna scavenger decapping enzyme multiple-center, randomized, placebocontrolled, double-blind study of the nitric oxide synthase inhibitor c : effect on survival in patients with septic shock molecular basis of endothelial dysfunction in sepsis monitoring of endothelial dysfunction in critically ill patients: the role of endothelial progenitor cells the role of paneth cells and their antimicrobial peptides in innate host defense host antimicrobial proteins as endogenous immunomodulators mammalian defensins in the antimicrobial immune response reduced levels of antimicrobial proteins and peptides in human cord blood plasma association of human beta-defensin- serum levels and sepsis in preterm neonates* elevated concentrations of human neutrophil peptides in plasma, blood, and body fluids from patients with infections plasma concentrations of defensins and lactoferrin in children with severe sepsis vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis developmental hemostasis: pro-and anticoagulant systems during childhood the expression of surface tissue factor apoprotein by blood monocytes in the course of infections in early infancy complement and coagulation: strangers or partners in crime? indications of coagulation and/ or fibrinolytic system activation in healthy and sick very-low-birth-weight neonates coagulation, fibrinolytic and kallikrein systems in neonates with uncomplicated sepsis and septic shock plasma antithrombin iii and protein c levels in early recognition of late-onset sepsis in newborns study of protein c, protein s, and antithrombin iii in newborns with sepsis low plasma protein c values predict mortality in low birth weight neonates with septicemia drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase iii randomised controlled trial the tissue factor and plasminogen activator inhibitor type- response in pediatric sepsis-induced multiple organ failure evaluation and treatment of thrombocytopenia in the neonatal intensive care unit low immature platelet fraction suggests decreased megakaryopoiesis in neonates with sepsis or necrotizing enterocolitis whole blood platelet deposition on extracellular matrix under flow conditions in preterm neonatal sepsis the platelet hyporeactivity of extremely low birth weight neonates is age-dependent the ashwell receptor mitigates the lethal coagulopathy of sepsis platelet count and sepsis in very low birth weight neonates: is there an organism-specific response? disseminated intravascular coagulation in the newborn natural history of neonatal herpes simplex virus infections in the acyclovir era protease-activated receptor- : key player in the sepsis coagulation-inflammation crosstalk increased numbers of macrophages in tracheal aspirates in premature infants with funisitis neutrophil-derived microparticles induce myeloperoxidase-mediated damage of vascular endothelial cells coagulation dysfunction in sepsis and multiple organ system failure endothelial glucocorticoid receptor is required for protection against sepsis admission angiopoietin levels in children with septic shock group b streptococcal beta-hemolysin promotes injury of lung microvascular endothelial cells pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn endothelial tlr activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via enos-no-nitrite signaling neutrophil-derived il- β is sufficient for abscess formation in immunity against staphylococcus aureus in mice correlation between susceptibility of infants to infections and interaction with neutrophils of escherichia coli strains causing neonatal and infantile septicemia innate cellular immune responses in newborns impact of prematurity, stress and sepsis on the neutrophil respiratory burst activity of neonates functional analysis of neutrophil granulocytes from healthy, infected, and stressed neonates decreased bactericidal activity of leukocytes of stressed newborn infants spontaneous and fas-mediated apoptosis are diminished in umbilical cord blood neutrophils compared with adult neutrophils mechanisms underlying reduced apoptosis in neonatal neutrophils neonatal neutrophils with prolonged survival exhibit enhanced inflammatory and cytotoxic responsiveness neutrophil extracellular traps kill bacteria platelet tlr activates neutrophil extracellular traps to ensnare bacteria in septic blood netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus neutrophil-derived circulating free dna (cf-dna/nets): a potential prognostic marker for posttraumatic development of inflammatory second hit and sepsis novel cell death program leads to neutrophil extracellular traps impaired neutrophil extracellular trap (net) formation: a novel innate immune deficiency of human neonates delayed but functional neutrophil extracellular trap formation in neonates neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens outcomes following candiduria in extremely low birth weight infants exhaustion of mature marrow neutrophils in neonates with sepsis neutrophil storage pool depletion in neonates with sepsis and neutropenia evaluation of risk factors for fatal neonatal sepsis can neutrophil responses in very low birth weight infants predict the organisms responsible for late-onset bacterial or fungal sepsis? the leukocyte left shift in clinical and experimental neonatal sepsis delayed emergency myelopoiesis following polymicrobial sepsis in neonates granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropaenia granulocyte-macrophage colony stimulating factor administered as prophylaxis for reduction of sepsis in extremely preterm, small for gestational age neonates (the programs trial): a single-blind, multicentre, randomised controlled trial for treating or preventing neonatal infections a multicenter, randomized, placebocontrolled trial of prophylactic recombinant granulocyte-colony stimulating factor in preterm neonates with neutropenia passive deformability of mature, immature, and active neutrophils in healthy and septicemic neonates irreversible neutrophil aggregation. a mechanism of decreased newborn neutrophil chemotactic response secretory products of macrophages evaluation of natural killer cells as diagnostic markers of early onset neonatal sepsis: comparison with c-reactive protein and interleukin- innate immunity of the human newborn is polarized toward a high ratio of il- /tnf-alpha production in vitro and in vivo down-regulation of th responses in human neonates human deficiencies in type- cytokine receptors reveal the essential role of type- cytokines in immunity to intracellular bacteria decreased mononuclear and polymorphonuclear chemotaxis in human newborns, infants, and young children association between serum macrophage colony-stimulating factor levels and monocyte and thrombocyte counts in healthy, hypoxic, and septic term neonates neonatal blood cell count in health and disease. ii. values for lymphocytes, monocytes, and eosinophils monocyte phagocytosis as a reliable parameter for predicting early-onset sepsis in very low birthweight infants phenotype of fetal monocytes and b lymphocytes during the third trimester of pregnancy defective antigen-presenting cell function in human neonates molecular mechanisms underlying antiinflammatory phenotype of neonatal splenic macrophages efficient maturation and cytokine production of neonatal dcs requires combined proinflammatory signals differential responses of cord and adult blood-derived dendritic cells to dying cells preterm neonates display altered plasmacytoid dendritic cell function and morphology efficient priming of antigen-specific cytotoxic t lymphocytes by human cord blood dendritic cells cd c+ dendritic cells are required for survival in murine polymicrobial sepsis depletion of dendritic cells, but not macrophages, in patients with sepsis evaluation of eosinophilia in hospitalized preterm infants perinatal hematological profile of newborn infants with candida antenatal infections eosinophilia in newborn infants eosinophilia in premature neonates. phase of a biphasic granulopoietic response catapult-like release of mitochondrial dna by eosinophils contributes to antibacterial defense mast cells in innate immunity mast cells and neutrophils release il- through extracellular trap formation in psoriasis urticaria neonatorum: accumulation of tryptase-expressing mast cells in the skin lesions of newborns with erythema toxicum mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through tnf-alpha critical protective role of mast cells in a model of acute septic peritonitis phagocytosisindependent antimicrobial activity of mast cells by means of extracellular trap formation histamine regulates cytokine production in maturing dendritic cells, resulting in altered t cell polarization mast cells from the umbilical cord matrix and basophils from cord blood molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin nk cell increase in neonates from the preterm to the full-term period of gestation reduced nk cell percentage at birth is associated with late onset infection in very preterm neonates alterations in lymphocyte phenotype of infected preterm newborns natural killer cell cytotoxicity is deficient in newborns with sepsis and recurrent infections multiple leucocyte activation markers to detect neonatal infection immunosuppressive cd + erythroid cells compromise neonatal host defence against infection transferrin receptor is differentially required in lymphocyte development transferrin therapy ameliorates disease in beta-thalassemic mice ineffective erythropoiesis in stat a −/− b −/− mice due to decreased survival of early erythroblasts roles of spleen and liver in development of the murine hematopoietic system immaturity of the human splenic marginal zone in infancy. possible contribution to the deficient infant immune response fetal and neonatal development of human spleen: an immunohistological study neonatal cd + erythroid cells do not modify murine sepsis mortality caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte b cells enhance early innate immune responses during bacterial sepsis neonatal adaptive immunity comes of age lymphocyte subpopulations in full-term septic neonates neonates with culture proven sepsis have lower amounts and percentage of cd ra+ t cells pre-inflammatory mediators and lymphocyte subpopulations in preterm neonates with sepsis analysis of lymphocyte proliferative response subpopulations in very low birth weight infants and during the first weeks of life hla-dr+, t lymphocytes and cd + cells in eutrophic full-term neonates with staphylococcal septicemia peripheral blood cells with expression of the interleukin- receptor (cd +) in severely infected fullterm neonates cord blood cd + cd + -derived t regulatory cell lines express foxp protein and manifest potent suppressor function regulatory t cells mediate maternal tolerance to the fetus increased natural cd +cd + regulatory t cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis transient increase in cd ro expression on t lymphocytes in infected newborns surface activation markers of t lymphocytes: role in the detection of infection in neonates can expression of cd ro, a t-cell surface molecule, be used to detect congenital infection? increased cd + t cell co-inhibitory immune receptor ceacam in neonatal sepsis and soluble-ceacam in meningococcal sepsis: a role in sepsis-associated immune suppression? interleukin- (cxcl ) production is a signatory t cell effector function of human newborn infants increase of cord blood cytokineproducing t cells in intrauterine infection age-related changes in intracellular th /th cytokine production, immunoproliferative t lymphocyte response and natural killer cell activity in newborns, children and adults identification of t-lymphocyte function in healthy vs. septic preterms and its relation to candidal infections in the hospital setting mature cd + t lymphocyte response to viral infection during fetal life asplenic-hyposplenic overwhelming sepsis: postsplenectomy sepsis revisited hyposplenism: a comprehensive review. part i: basic concepts and causes demonstration of circulating group b streptococcal immune complexes in neonates with meningitis in vitro immunoglobulin response of fetal b-cells is influenced by perinatal infections and antibiotic treatment: a study in preterm infants blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants shades of grey-the blurring view of innate and adaptive immunity a critical role of t-cell receptor gamma/delta cells in antibacterial protection in mice early in life in vivo and in vitro activation and expansion of gammadelta t cells during listeria monocytogenes infection in humans gamma delta t cells respond directly to pathogen-associated molecular patterns influence of perinatal risk factors on cd +/tcr αβ and cd +/tcr γδ lymphocytes in cord blood of preterm neonates tcr usage and functional capabilities of human gamma delta t cells at birth il- activates innate lymphoid cells to promote neonatal intestinal pathology identification of pediatric septic shock subclasses based on genome-wide expression profiling genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum divergence of canonical danger signals: the genome-level expression patterns of human mononuclear cells subjected to heat shock or lipopolysaccharide validating the genomic signature of pediatric septic shock genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock gene-expression profiling of grampositive and gram-negative sepsis in critically ill patients the use of gene-expression profiling to identify candidate genes in human sepsis gene-expression profiling of peripheral blood mononuclear cells in sepsis recent progress of proteomics in critical illness proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis optimized dna extraction from neonatal dried blood spots: application in methylome profiling validation of a gene expressionbased subclassification strategy for pediatric septic shock genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis oral zinc supplementation for reducing mortality in probable neonatal sepsis: a double blind randomized placebo controlled trial post-natal age is a critical determinant of the neonatal host response to sepsis genome-wide expression profiles in very low birth weight infants with neonatal sepsis a novel role for matrix metalloproteinase- in sepsis identification of a human neonatal immune-metabolic network associated with bacterial infection host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants fetal thymic involution: a sonographic marker of the fetal inflammatory response syndrome persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock risk factors and predictors of mortality in culture proven neonatal sepsis anatomical study of the kidneys of newborn infants dying after a septic state renal failure, comorbidity and mortality in preterm infants liver perfusion in sepsis, septic shock, and multiorgan failure neonatal sepsis in karachi: factors determining outcome and mortality association of septic shock caused by early-onset group b streptococcal sepsis and periventricular leukomalacia in the preterm infant accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways pathology of lymphoid organs in low birth weight infants subjected to antigen-related diseases: a morphological and morphometric study advances in pathogenesis and management of sepsis molecular biology of inflammation and sepsis: a primer multisystem organ failure and capillary leak syndrome in severe necrotizing enterocolitis of very low birth weight infants clinical and laboratory factors that predict death in very low birth weight infants presenting with late-onset sepsis heart failure in pediatric septic shock: utilizing inotropic support circulatory shock in children: an overview hemodynamic support in fluidrefractory pediatric septic shock clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care which inotrope for which baby? relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation microcirculatory changes in term newborns with suspected infection: an observational prospective study hemodynamics in preterm infants with late-onset sepsis echocardiogram done early in neonatal sepsis: what does it add? el-arman mm: myocardial dysfunction in neonatal sepsis: a tissue doppler imaging study diagnosis and treatment of neonatal hypotension outside the transitional period elevation of brain natriuretic peptide levels in children with septic shock brain natriuretic peptide for prediction of mortality in patients with sepsis: a systematic review and meta-analysis predictors of mortality and multiple organ failure in children with sepsis sepsis-induced apoptosis causes progressive profound depletion of b and cd + t lymphocytes in humans acute thymus involution in infancy and childhood: a reliable marker for duration of acute illness thymus size and its relationship to perinatal events the grade of acute thymus involution in neonates correlates with the duration of acute illness and with the percentage of lymphocytes in peripheral blood smear. pathological study clinicopathological differences between early-onset and late-onset sepsis and pneumonia in very low birth weight infants spleen depletion in neonatal sepsis and chorioamnionitis acute thymic involution in fetuses and neonates with chorioamnionitis prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach prevention of lymphocyte apoptosisa potential treatment of sepsis? mutations in genes required for t-cell development: il r, cd , il rg, jak , rag , rag , artemis, and ada and severe combined immunodeficiency: huge review early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome immunosuppression in patients who die of sepsis and multiple organ failure immunoparalysis and adverse outcomes from critical illness very low birth weight neonates who survive early-onset sepsis do not have an increased risk of developing late-onset sepsis early sepsis does not increase the risk of late sepsis in very low birth weight neonates the pathophysiology and treatment of sepsis nicotinic acetylcholine receptor α subunit is an essential regulator of inflammation neural reflexes in inflammation and immunity epigenetic regulation of immune cell functions during post-septic immunosuppression dna methylation pattern of calca in preterm neonates with bacterial sepsis as a putative epigenetic biomarker a prime time for trained immunity: innate immune memory in newborns and infants epigenetic programming of monocyteto-macrophage differentiation and trained innate immunity mtor-and hif- alpha-mediated aerobic glycolysis as metabolic basis for trained immunity nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges myd -dependent expansion of an immature gr- + cd b + population induces t cell suppression and th polarization in sepsis myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro t cell responses reactivation of multiple viruses in patients with sepsis surfactant-replacement therapy for respiratory distress in the preterm and term neonate diminished inducible nitric oxide synthase expression in fulminant early-onset neonatal pneumonia the paradox of adult respiratory distress syndrome in neonates bench-to-bedside review: developmental influences on the mechanisms, treatment and outcomes of cardiovascular dysfunction in neonatal versus adult sepsis inhaled nitric oxide and persistent pulmonary hypertension of the newborn the diseases treated with ecmo: focus on pphn extracorporeal membrane oxygenation and sepsis neurodevelopment of extremely preterm infants who had necrotizing enterocolitis with or without late bacteremia neonatal infection and -year neurodevelopmental outcome of very preterm infants impact of sepsis on neurodevelopmental outcome in a swiss national cohort of extremely premature infants infection-induced inflammation and cerebral injury in preterm infants postnatal sepsis, necrotizing entercolitis, and the critical role of systemic inflammation in white matter injury in premature infants postnatal infection is associated with widespread abnormalities of brain development in premature newborns adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term association between high cytokine levels with white matter injury in preterm infants with sepsis the relationship of csf and plasma cytokine levels to cerebral white matter injury in the premature newborn to tap or not to tap: high likelihood of meningitis without sepsis among very low birth weight infants the prognostic value of amplitude integrated eeg in neonatal sepsis and/or meningitis cerebral blood flow velocity in earlyonset neonatal sepsis and its clinical significance serum cortisol and thyroid hormone levels in neonates with sepsis refractory hypotension in preterm infants with adrenocortical insufficiency hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns circulating adrenocorticotropic hormone (acth) and cortisol concentrations in normal, appropriate-forgestational-age newborns versus those with sepsis and respiratory distress: cortisol response to low-dose and standard-dose acth tests hemodynamic changes after low-dosage hydrocortisone administration in vasopressor-treated preterm and term neonates cardiovascular effects of hydrocortisone in preterm infants with pressor-resistant hypotension dose-related inhibition of proinflammatory cytokine release from neutrophils of the newborn by dexamethasone, betamethasone, and hydrocortisone the main etiologies of acute kidney injury in the newborns hospitalized in the neonatal intensive care unit acute renal failure in neonatal sepsis acute kidney injury in preterm infants admitted to a neonatal intensive care unit effect of sepsis syndrome on neonatal oxygen consumption and energy expenditure nitric oxide inhibits neonatal hepatocyte oxidative metabolism impaired energy metabolism during neonatal sepsis: the effects of glutamine bench-to-bedside review: neonatal sepsis -redox processes in pathogenesis edaravone, a novel free radical scavenger, reduces high-mobility group box and prolongs survival in a neonatal sepsis model inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure plasma nitrite and nitrate concentrations and multiple organ failure in pediatric sepsis key: cord- -ungitgh authors: sergueef, nicette title: clinical conditions date: - - journal: cranial osteopathy for infants, children and adolescents doi: . /b - - - - . - sha: doc_id: cord_uid: ungitgh nan this chapter addresses some clinical conditions than can be effectively treated using manipulative procedures. such treatment, however, is not intended to replace defi nitive medical or surgical treatments. rather this therapeutic option is offered as a gentle, alternative, non-invasive approach, with essentially no untoward side effects, to be employed as a fi rst line of therapy. patients respond quickly to a specifi c technique when it is appropriately applied following a precise diagnosis. it is the responsibility of the practitioner to ensure that underlying pathologies requiring more aggressive medical or surgical treatment have been ruled out or appropriately addressed. it should also be borne in mind that when a patient fails to respond to treatment as anticipated, they should be completely reassessed. if the osteopathic practitioner does not see a signifi cant functional change in the patient's condition by the third to fi fth treatment, the probability of misdiagnosis is likely. for each clinical condition, the specifi c features of the condition are addressed. for the basic treatment protocols and descriptions of individual procedures, see chapters (examination of the patient) and (treatment of the patient). congenital muscular torticollis and plagiocephaly are the most frequently occurring asymmetries of infancy. brachial plexus injury, fracture of the clavicle, pectus excavatum and carinatum, scoliosis, kyphosis and vertebral somatic dysfunctions are other commonly encountered conditions with structural and functional consequences that can be addressed with osteopathic manipulative treatment. torticollis may be subdivided into congenital torticollis and congenital muscular torticollis (cmt). the patient with congenital torticollis presents at birth with their head tilted toward the involved side and rotated toward the opposite side. they commonly have associated medical conditions, such as osseous malformations, basilar impression or atlantooccipital anomalies, and neurologic disorders such as arnold-chiari malformations. these underlying conditions should be diagnosed and appropriate treatment initiated before osteopathic manipulation is considered. the patient with cmt, on the other hand, is symmetric at birth, and the asymmetry develops in the fi rst weeks of life. cmt presents with a tight sternocleidomastoid (scm) muscle, causing the child's head to be tilted toward the side of the tight muscle and rotated in the opposite direction. a mass, or fi bromastosis colli, can eventually be palpated within the muscle. the incidence of cmt ranges from . to . %, but is as high as . % when cases are diagnosed sonographically. cmt occurs more often among boys than girls. , some authors report a higher incidence on the right side, , whereas others report that it is more frequently encountered on the left. primiparity, assisted delivery , and breech presentation , frequently appear in the birth history. the larger the infant, birth body length and shoulder width, with more associated delivery trauma, the higher the incidence of cmt. multiple theories to explain the etiology of cmt have been proposed. van roonhysen ( ) postulated abnormal uterine pressure as a cause of torticollis. pommerol, in the th century, attributed the unilateral shortening of the scm to abnormal fetal position. these 'intrauterine' theories have also attempted to explain the presence of several other deformities present at birth. many authors have commented on aberrant constraint of the infant within the uterus and the association between torticollis, plagiocephaly, bat ears, scoliosis and congenital hip dislocation, [ ] [ ] [ ] [ ] or hip dysplasia. other theories link cmt to birth trauma. the high incidence of breech presentation associated with cmt may document the role of birth trauma in its occurrence. others suggest that intrauterine torticollis predisposes the infant to breech presentation or forceps delivery. it has been proposed that birth trauma with injury of the scm and a resultant hematoma, which is then replaced with fi brous tissue, causes cmt. histologic studies have, however, failed to support this proposition. proposed compressive arterial occlusion as an etiology has also been dismissed. vascular compromise does not occur because there is abundant arterial and venous supply to the scm that follows no regular or segmental pattern and has multiple anastomoses. among more recent theories, cmt is proposed as the sequela of an intrauterine or perinatal compartment syndrome. a bilateral imbalance of structures responsible for control of head posture may play a role -for example, as may be the case for the interstitial nucleus of cajal, a neural integrator for head posture. because the torticollis is not present at birth but appears later, it is possible that it results from improper handling of the child or incorrect positioning as in a car seat. resultant dysfunction of the occipito-atlanto-axial joints may, therefore, occur and has been proposed as a cause for cmt. several clinical variants are observed. the scm mass is not always present. smaller masses may be found on the occipital bone below the superior nuchal line. when an scm mass is palpable, usually in the fi rst months of life, it appears well circumscribed within the muscle, is located in the midportion of the scm and ranges in size from to . mm on maximal transverse diameter and from . to . mm in length (measured with ultrasound). this mass typically disappears during the st year of life without any correlation with the resolution of the cmt. although the fi ndings of head tilt toward the involved side with head rotation toward the opposite side are consistent, the amount of rotation can differ between subjects. contractures of the semispinalis capitis and the splenius capitis are sometimes present. cmt is probably the consequence of several concomitant factors. the problem may begin with a faulty intrauterine position that weakens the scm, making it vulnerable to birth trauma and thus creating the dysfunction. osteopathic practitioners use their knowledge of anatomy to develop a rationale for treatment. the scm arises, by two heads, from the sternum and clavicle ( fig. . . ). the medial (or sternal) head has its origin on the upper part of the anterior surface of the manubrium sterni and the lateral (or clavicular) head arises from the anterior surface and superior border of the medial third of the clavicle. initially, the two heads are separated from one another. they gradually join, below the middle of the neck, to form the body of a thick, rounded muscle. the scm is inserted into the lateral surface of the mastoid process by a strong tendon and into the lateral half of the superior nuchal line of the occipital bone by a thin aponeurosis. the two heads of the scm consist of different types of fi ber, the sternal head being more tendinous and the clavicular head being composed of fl eshy and aponeurotic fi bers. the clavicle is more mobile than the sternum and is subject to signifi cant stress during the birth process, which may explain a different strain being put on the two parts of the scm. a distinction between 'sternal torticollis' and 'clavicular torticollis' has been proposed. the insertion of the scm covers the occipitomastoid suture; therefore, scm tightness should be released whenever attempting to treat this suture. conversely, somatic dysfunction between the temporal and the occipital bones will affect the scm. the jugular foramen -located at the anterior end of the occipitomastoid suture, between the petrous portion of the temporal bone and the occiput -will also be affected. the jugular foramen contains the inferior petrosal sinus and the sigmoid sinus that unite to form the internal jugular vein. it also contains the glossopharyngeal (cn ix), the vagus (cn x) and the accessory (cn xi) nerves. cn xi provides the motor supply to the scm, its proprioceptive fi bers passing through branches from the anterior divisions of the second and third cervical nerves to innervate the scm. thus, sutherland stated: 'you will probably fi nd the source of the torticollis to be entrapment neuropathy of the eleventh cranial nerve at the jugular foramen.' jacquemart and piedallu, in , recommended that osteopathic manipulation for cmt be directed at somatic dysfunction of the occiput and upper cervical spine. the mastoid process is not fully developed in the newborn and is totally covered by the tendon of the scm from its apex to its superior border. the development of the mastoid process is linked to the traction of the scm; asymmetric sidebending and rotation of the head, as in cmt, will cause the mastoid processes to develop asymmetrically. cephalometric analysis demonstrates that, left untreated, persistent torticollis can lead to skull and facial asymmetry. when it occurs, the cranial base deformation appears early, the changes being more signifi cant in the posterior cranial fossa, whereas the facial deformity will develop later in childhood. both the cranial base and facial deformities tend to increase with age. furthermore, the asymmetric function of the neck muscles stresses the mechanisms of postural control. abnormal sensory input to the cns and a sense of instability occurs that has to be compensated for with vision. this can affect the infant's developing visual function. to prevent these sequelae, osteopathic procedures should be employed to address cmt as early as possible. observe the child for spontaneous rotation and sidebending of the cervical region. a good way to evaluate the range of motion in rotation and sidebending is to have the baby visually follow a toy moved in the directions to be tested. the child can also be held in the arms of the practitioner, facing the parents. the practitioner then pivots to the right and to the left, holding the infant in such a way that, in order to continue to observe their parents, the child must actively turn their head fi rst to the left in response to the practitioner's pivoting right, and then to the right in response to the practitioner's pivoting left. having the parents participate in this procedure allows them to understand the extent of the child's restriction of motion; repeating the procedure after treating the child allows one to evaluate the effect of the treatment. the size of the scm mass (when present) and the tension of the muscle fi bers should be evaluated. palpate the infant to identify membranous, myofascial and interosseous somatic dysfunction, particularly in the upper thoracic spine, pectoral girdle, cervico-occipital area and cranium (temporal bone, occiput, occipitomastoid suture and jugular foramen). treatment should use indirect principles. because the mass associated with cmt often develops at the conjunction of the two heads of the scm, in order to release the dysfunction the bones to which the muscle is attached (clavicle, sternum, occiput and temporal bone) should be balanced. indirect myofascial release of the scm may be employed. if the infant is treated early, before a dysfunctional pattern becomes engrained, osteopathic manipulation can rapidly alleviate the asymmetry of scm. the caregiver should be taught an active positioning program to be employed at home. for example, approaching the infant from the side opposite the rotation during daily activities, such as feeding and playing, head turning and lengthening of the scm can be facilitated. the infant should be placed in a sleeping position that avoids reinforcement of the scm shortening. it is improper to attempt to accomplish this by propping the infant's head with a pillow in such a way as to lengthen the scm. although this may appear to hold the head in the desired position, it induces a stretch refl ex in the tight muscle, maintaining the shortening. gentle stretching exercises that induce active scm stretching can be taught. these should be employed to rotate the head toward, and sidebend the neck away, from the side of the tight scm. such exercises are indicated until a full range of movement has been obtained. the term plagiocephaly -derived from the greek plagios (oblique) and kephalê (head) -indicates distortion of the head and refers clinically to cranial asymmetry. cranial deformations have been (and still are) produced intentionally, depending on the period and country, as signs of distinction, beauty, health, courage, freedom and nobility. the oldest known example is from iraq, c. bc, and the earliest written reference is from hippocrates, around bc (airs, waters, places), describing the macrocephales who practiced head deformation. inten-tional plagiocephaly was obtained by pressure applied to an infant's skull, either through manual molding or with boards, pads or stones. different deformities were induced depending on the methods employed. the use of cradleboards and the wearing of headdresses are examples of other traditions that also resulted in head deformation. non-intentional plagiocephaly can be associated with premature sutural closure or craniosynostosis. premature synostosis of one or several cranial sutures may be the result of genetic or metabolic conditions. , the fused suture does not allow bone growth and the shape of the skull refl ects this anomaly: a brachycephaly develops when the coronal suture fuses, a dolichocephaly or a scaphocephaly when the sagittal suture fuses, and a trigonocephaly when the metopic suture fuses. unilateral synostosis of the lambdoid or coronal suture (fig. . . ) results in a posterior or anterior plagiocephaly, respectively. although any suture may be involved in synostotic plagiocephaly, true lambdoid synostosis with posterior plagiocephaly rarely occurs and represents only . % of all synostoses. in the general population, the incidence of craniosynostosis has been estimated to be as low as in - live births; , however, it is imperative that the diagnosis of synostotic plagiocephaly, which is most specifi cally accomplished by radiologic means, be made when the condition is present. children presenting with craniosynostosis should be monitored closely by a pediatric neurosurgeon for signs and symptoms of increased intracranial pressure. treatment may require surgery, particularly for severe cases. non-synostotic plagiocephaly (nsp), also referred to as functional plagiocephaly, must be differentiated from craniosynostosis. the prevalence of nsp is estimated to be as high as . % of all children under the age of months. nsp is identifi ed as either frontal or occipital (figs . . and . . ) depending on the site of the deformation. in , the 'back to sleep' campaign was instituted in the usa for prevention of sudden infant death syndrome (sids). parents were encouraged to put infants to sleep in the supine position. following this, a shift occurred in the location of the deformity of nsp, from frontal plagiocephaly being more frequently encountered before the 'supine' directive, to occipital plagiocephaly more commonly encountered now. nsp results from a variety of extrinsic and intrinsic factors affecting the infant before, during and after birth. these various factors may be isolated or may exert a cumulative effect. associated risk factors for nsp include premature birth, fi rstborn, , prolonged labor, unusual birth position, use of forceps and vacuum extraction. male gender is also a risk factor because fetal distress during labor, with a consequently higher incidence of operative delivery, is more common with males than with females. before birth, nsp may result from abnormal constraint on the fetal head in the intrauterine environment, as with a unicornuate uterus, uterine fi broids or oligohydramnios. multiple births are another risk factor, with deformational plagiocephaly being frequently encountered in these children. extrauterine constraints placed on the fetus can be responsible for nsp. this may be the result of pressure from neighboring abdominal organs. with athletic mothers, increased tonus of the abdominal muscles can compress the uterus back against the spine. lack of abdominal muscle strength, on the other hand, will produce an increase in the already increased lumbar lordosis that is very common in late pregnancy. the increased lordosis is associated with anatomic fl exion of the sacrum that displaces the sacral promontory forward, with resultant external pressure on the uterus. during the birth process, the uterus contracts regularly to allow the descent of the fetus through the birth canal. prolonged periods of uterine contraction may increase the mechanical forces applied to the infant's head. when the head enters the pelvic cavity, anatomic extension between the sacrum and the pelvic bones normally occurs to increase the diameters of the pelvic outlet. dysfunction of the maternal sacroiliac joints can result in a reduction of that increase and further constraint on the infant's head. in the left occiput-anterior position -the most frequent birth presentation -the right side of the infant's occipital bone is in contact with the maternal pubic symphysis while the left frontal bone is compressed against the sacrum (fig. . . ). asynclitism further increases the pressure of the infant's head against the pelvic bones with resulting occipital fl attening on the right and frontal fl attening on the left. the reverse -occipital fl attening on the left and frontal fl attening on the right -would result from the left occiput-posterior position. at the end of the descent, the head contacts the pelvic fl oor and turns in such a way as to position the occiput under the pubic symphysis. in the left occiput-anterior position, the right side of the occiput and the occipitomastoid area can be exposed to greater pressure. later, during expulsion, compressive forces are applied on the occiput by the pubic symphysis. after birth the pressure of the mattress on the infant's head is thought to contribute to occipital fl attening. sleeping habits affect the cranial shape. when infants consistently sleep supine, as in asiatic countries, posterior fl attening of the skull occurs. babies should be able to turn their head symmetrically to both sides. asymmetric cervical rotation should be considered anomalous and, if present, should be resolved by weeks of age. although a preferred rotation of the head to the right side is present at birth in % of infants, this does not seem to be related to the fetal position. often, infants may demonstrate asymmetric preferential motions, but a preferred motion should be differentiated from somatic dysfunction. concern should arise when a rotational dysfunction is present. early restriction of cervical motion is an identifi ed risk factor for positional plagiocephaly, particularly if the child is less active, staying in the same position to the point where an area of alopecia develops on the scalp. upper thoracic and cervical restrictions, and scm imbalance or torticollis, very often accompany plagiocephalies. , , furthermore, when the fl attening has developed, it reinforces the preferential positional pattern with automatic positioning of the head on the fl at area. by defi nition, plagiocephalic children have irregularly shaped heads. since infants now sleep supine because of the 'back to sleep' campaign, the most commonly encountered forms of plagiocephaly are posterior, with either medial or lateral occipital deformity. when compressive forces are applied to the squamous portion of the occiput, usually in the area of the lambda (superior angle of the occiput), the posterior portion of the head is fl attened and assumes a brachycephalic shape. in severe cases, the fl attening can demonstrate a slight depression, usually near the superior part of the occiput. an asymmetric plagiocephaly results when dysfunctional rotation of the head is associated with the compressive forces. because of the rotation, pressure from the weight of the infant's head on the mattress is asymmetric, and the occipitoparietal area on the side toward which the head is chronically rotated becomes fl attened, while the other side develops excessively. this results in occipital fl attening on one side and occipital bossing on the other. anteriorly, the skull demonstrates frontal bossing on the same side as the occipital fl attening, with frontal fl attening on the opposite side. when the head is seen from above, it has a 'parallelogram' shape ( fig. . . ) . the parallelogram cranial shape is commonly described in allopathic medical literature , , [ ] [ ] [ ] [ ] as well as in osteopathic medical literature. [ ] [ ] [ ] this pattern is also referred to as 'cranial obliquity'. in the cranial concept, the parallelogram cranial shape is associated with a pattern of lateral strain in the sphenobasilar synchondrosis (sbs) (fig. . ) . shearing between the posterior part of the body of the sphenoid, which is displaced laterally, and the anterior part of the occiput, displaced in the opposite direction, is lateral strain of the sbs and is found in children with nsp. the temporal bones of three parts. when occipital fl attening occurs, the deformity is obvious in the squamous portion of the occiput where the compression has occurred; however, the compressive forces have also been directed against the non-visible parts of the occipital bone, i.e. the anterior intraoccipital synchondrosis that lies between the two parts of the condylar facets. when such a compression of the occipital condyles occurs, it most often occurs asymmetrically. the hypoglossal canals are located bilaterally in the anterior intraoccipital synchondroses, between the basiocciput and the bilateral exocciputs. they contain the hypoglossal nerves that provide the motor supply to the tongue. compressive force on one side can have an impact on tongue motor function, with resultant problems such as suckling diffi culties. asymmetry of the cranial base can also affect the shape of the foramina therein, with potential for various entrapment neuropathies and vascular compressions. the jugular foramen, the right usually being larger than the left, contains the glossopharyngeal nerve (cn ix), the vagus nerve (cn x), the accessory nerve (cn xi) and the inferior petrosal and sigmoid venous sinuses. a broad spectrum of functions depends on these structures. compression of cn ix is associated with altered sensation of the pharynx, fauces, palatine tonsil, pharyngotympanic tube (pt) and the posterior third of the tongue. disturbances of cn x result in a wide range of symptoms including dysautonomia, colic and regurgitation. according to magoun, 'the occipitomastoid suture and the jugular foramen should be considered as of signifi cance with "pukey" parallelogram shape of the head, with the basilar portion of the occiput displaced away from the side of the posterior fl attening. the relationship between the cranial bones is disturbed, as described in lateral strain of the sbs, but this is not the only dysfunction associated with nsp. the compressive forces responsible for nsp can affect the relationship between different portions of the cranial bones, producing intraosseous dysfunctions. the occiput and temporal bones are the most common bones that demonstrate intraosseous dysfunction in the presence of nsp. at birth, the occipital bone is composed of four parts and each of babies'. compression of cn xi can compromise the motor supply to the upper and middle portions of the trapezius and to the scm. the trapezius receives a portion of its motor supply from cn xi; the scm depends mainly on cn xi. cn xi can also affect swallowing through its impact on the pharyngeal constrictor muscles that receive their nervous supply from the cranial portion of the accessory nerve. with the resultant asymmetry in the cranial base, a difference in tension between the two scm muscles is palpable. there are multiple myofascial attachments on the cranial base that can be similarly affected, resulting in a multiplicity of dysfunctional patterns in distant areas. asymmetric tensions in the trapezius and semispinalis capitis muscles can cause thoracic spine dysfunction, asymmetries of the stylopharyngeus and stylohyoideus muscles can affect the pharynx, and the styloglossus muscle can dysfunctionally infl uence the tongue. the compressive forces applied to the fetal head also affect the temporal bones. when occipital fl attening occurs on one side, the ipsilateral temporal bone and attached ear are moved forward and the mastoid portion is compressed. this deformation can be demonstrated with computerized tomography of the skull base. the long axis of the petrous portion of the temporal bone is displaced in the direction of the coronal plane, thus placing the temporal bone in a position resembling external rotation. embedded in the petrous portion of the temporal bone are the bony portion of the pt and the vestibular apparatus. compressive forces affecting the temporal bone may increase the risk of otitis. the bony portion of the pt, the vertical portion of the tensor veli palatini and the mastoid air cell system have been found to be smaller than normal in children with secretory otitis. temporal bone dysfunction may have further implications. children with nsp present with a higher risk of auditory processing disorders, which is thought to lead to subtle problems of cerebral dysfunction later at school. these problems include language disorders and learning disabilities, as well as attention defi cits. plagiocephalic children also have a higher incidence of sleep disorders. nsp infants have been described as less active when sleeping on their backs than non-nsp infants, who move actively, turning their head and torso when developmental landmarks are achieved. on the other hand, infants who sleep supine do not need to use their upper trunk and shoulder girdle muscles as much. consequently, there is a delay in acquisition of early motor milestones. tripod sitting, creeping and crawling are particularly delayed, which contributes further to weakening of the core muscles. scoliosis has been associated with plagiocephaly where sleeping supine was identifi ed as a causative factor. , , in the netherlands, where the supine sleeping position has been encouraged since , approximately . % of - -yearold children have cervical restriction of motion and/or plagiocephaly. interestingly, the habit of always bottle feeding a child on the same side seems to contribute to the pattern of asymmetric cervical rotation. alternating right-and left-sided bottle feeding is consequently an imperative for every baby, particularly nsp infants. the facial skeleton adapts to the cranial base asymmetry. facial asymmetries and facial disharmonies are associated with nsp. , , on the side of the occipital fl attening, the maxillary bone develops less well, with less distance separating the nasion and the temporomandibular joint. this reduction is proportional to the amount of posterior occipital deformation. the growth of the neurocranium and the viscerocranium occurs at different rates. consequently, compensatory developmental disorders of the viscerocranium will appear later in childhood than the original nsp, and the association, therefore, is not commonly recognized. it is a common observation that infants will sleep preferentially with their head turned toward one side, and that will be the side of the occipital fl attening of the nsp. daily activities such as diffi culty nursing or accepting bottle feeding bilaterally will also refl ect dysfunctions because of diffi culty in turning the head to both sides. associated disorders such as regurgitation, colic or sleep disorders are also often present. otitis media can be part of the picture if the child is over months of age. while taking the history, the infant's appearance, posture and range of motion are studied. when observing the child, the osteopathic practitioner assesses what dysfunctional mechanics are involved in the present nsp. where is the dysfunction? is it only in the cervical spine or are other areas involved? what is the primary dysfunction? three mechanisms are quite frequent: occipitocervical somatic dysfunction, thoracic somatic dysfunction and cranial somatic dysfunction: . is there a pattern of restricted cervical spinal rotation that has obliged the child to lay their head on one side that explains the head fl attening? if the head moves freely in all clinical conditions directions, no cervical spinal dysfunction is present. . is there a pattern of thoracic somatic dysfunction? does the child rotate their head with a movement involving only one side of the pectoral girdle, indicative of thoracic dysfunction? in this case, asymmetry of the movements of the arms may also be present. . is there a cranial dysfunction, such as a lateral strain of the sbs that explains the parallelogram shape of the head? these questions should be kept in mind in the following examination. observe the relationship between the head and the pelvis. in the presence of a 'total body' dysfunctional pattern, the pelvis and the head of the child are rotated in opposite directions on the vertical axis of the spine. palpation and motion testing will confi rm these observations and treatment should be applied accordingly. evaluate the skull. infants usually do not present with thick hair as encountered in most adults, making observation of the neurocranium easier. look for any bald spots that indicate chronic contact between that area of the head and the bed during sleep. look for posterior and anterior fl attening; in the presence of posterior plagiocephaly these are usually on opposite sides. this results in a parallelogram-shaped head that is easier to see from above when the child is held on the practitioner's or parent's lap. observe the child's face and frontal bones. a pattern of compressive forces applied directly to the frontal bone, with no occipital deformity, would indicate a frontal dysfunction. frontal fl attening opposite to the occipital fl attening is consistent with a pattern of lateral strain of the sbs. symmetry of the frontal bone with occipital deformity on one side is an indication of synostotic posterior plagiocephaly, where the forehead may be symmetric or fl attened on the side of the occipital fl attening. when a frontal dysfunction is present, this may affect the eyes. observe the size and shape of the orbital cavities, as well as the ocular bulbs. the orbital diameter is the distance between the superior medial and inferior lateral angles of the orbit. an increase in the orbital diameter results in an orbital cavity that appears to be wider than it is high and is associated with a cranial fl exion-external rotation pattern. conversely, if the orbital cavity appears to be narrower, this is associated with a cranial extension-internal rotation pattern. frontal dysfunction, in turn, affects the rest of the facial bones and is particularly important when problem solving dysfunctions of the nasal bones and the maxillae. observe the positions of the ears. they are very indicative of the positions of the temporal bones. in cases of nsp, the ear located on the side of the occipital fl attening is displaced more anteriorly than the contralateral ear. if the ear is displaced more posteriorly on the fl attened side, further diagnostic investigation is warranted because the displacement might be a sign of synostotic plagiocephaly. this sign, however, is not an exclusive indicator and synostotic plagiocephaly may also present with an anterior ear position. , observe the size and shape of the ears. usually, on the side of the occipital fl attening of nsp, the ear may, for example, have been compressed against the uterine wall and, therefore, may be smaller. in this instance, expect to fi nd intraosseous dysfunctions of the temporal bone on that side. this is the ear that the child will usually rub and that eventually may present with an otitis media. after observation, the osteopathic practitioner gently palpates (i.e. caresses) the child's head, looking for depressions, bossing and irregularities of contour. sutures are palpated for ridges, overlapping or irregularities in shape. a thick ridge over a suture calls for attention, because it may be a sign of a synostotic suture. flattenings are the result of compressive forces. tissues are palpated to evaluate for tissue texture abnormality and increased tenderness. palpation of osseous tissues gives a sense of density that might be different between the two sides of the suture; increased tenderness is usually proportional to the strength of the compressive forces. posterior occipital muscles are evaluated by palpation for tension and asymmetry. although the vault and the back of the head, the parietals and the squamous portion of the occiput are quite accessible to palpation, palpation of the frontal and facial bones necessitates a little more patience and delicacy in order to avoid disturbing the child. the base of the skull is not directly accessible to palpation for structure. the lateral parts of the occiput or exocciputs and the basilar part, as well as the sphenoid bone and the petrous portions of the temporal bones, should be assessed by palpating for function. to visualize these areas correctly while palpating them, knowledge of anatomy is of paramount importance. motion testing will confi rm the fi ndings of palpation and observation. dysfunctional head rotation is a treatment priority. it is of considerable importance that the child leaves the offi ce with a freer range of motion and an increased ability to turn their head. if not treated, the dysfunctional rotation will maintain the nsp. look for any somatic dysfunction of the occipitocervical junction and the cervical and thoracic spine, and treat utilizing indirect principles. structure will follow function, and if bilateral rotation is recovered, the traction of the muscles that insert on the occipital squama will help to reshape the fl attened areas. membranous patterns of the cranial mechanism should be assessed and dysfunctions balanced. particular attention should be given to the poles of attachment of the dura, the falx cerebri on the occipital squama and the tentorium cerebelli on the superior borders of the petrous portions of the temporal bones. motion of the sbs, occipitomastoid and lambdoid sutures should be assessed and treated accordingly. check the frontal bones and their relationships with the facial bones. any dysfunction should be treated. special attention should be directed at the cranial base, with the assessment and treatment of the compressed occipital condyles and compressed jugular foramina, when present. molding procedures can be applied, with intraosseous balancing of the occiput, temporal bones, frontal bones, sphenoid and parietal bones as dictated by the patient's needs. very often parents will comment on the fact that the fl attening was not present at birth and say that they do not understand why nsp has developed. to succeed in the treatment of plagiocephaly, it is worthwhile explaining the mechanism of nsp and stressing the importance of parental participation in the following months. explain that the initial asymmetry may have been present at birth in a very subtle way that has been exacerbated by a persistent positional preference. explain that it is of paramount importance to encourage the child in activities that promote bilateral cervical rotation, as well as promoting sleeping positions that avoid pressure on the already fl attened area. successful treatment depends on this. proper sleeping position may be obtained by elevating one side of the bed approximately cm ( inches). this can be accomplished by placing a rolled bath towel beneath the entire length of the mattress, on the side of the occipital fl attening. this will encourage the infant to turn their head in the other direction. toys and other attention-getting objects, soliciting the rotation of the child's head when lying supine, should be placed on the side opposite to the occipital fl attening. encourage play in the prone position. it can be explained to the parents that activities in the prone position stimulate the posterior axial musculature. muscular extension of the neck results in traction on the squamous portion of the occiput, helping to create a round head. to stimulate the child's curiosity and open them to the world, while encouraging them to turn their head symmetrically left and right, carry the child facing forward, held in the midline of the parent's chest. one parental hand should support the child's bottom while the other hand contacts the front of the child's torso, holding them against the parent's chest. the prolonged use of a car seat or other similar such carrying device should be discouraged because it tends to maintain the child in a chronic position, usually that of the dysfunctional asymmetry. thumb sucking should be discouraged because the child assumes an asymmetric position while preferentially sucking one thumb. if oral gratifi cation is necessary, an orthodontically shaped pacifi er should be employed. encourage the parents to gently caress the child's head bilaterally, behind the ears, in the areas over the occipitomastoid sutures and over the superior nuchal line of the occiput. this will help to reduce any dysfunctional tenderness. scoliosis is a lateral deviation of the spine. a structural scoliosis is a spinal deformation that is not totally reducible, while a functional scoliosis is totally reducible. the diagnosis of scoliosis is confi rmed by radiographic analysis. a functional scoliosis is usually associated with pelvic or postural asymmetry, a difference in the length of the lower limbs or vestibular or visual disorders. a structural scoliosis presents a spinal deformation in the three planes of space involving sidebending, rotation and fl exion or extension of the vertebrae. the side of convexity of the spinal curve defi nes the scoliosisfor example, a left scoliosis consists of a spinal curve that is convex on the left side. cobb's angle is a measurement of the degree of scoliosis between the most tilted vertebrae above and below the apex of the curve. this angle is obtained by measuring the angle of intersection between lines drawn perpendicular to the top of the most superior vertebra, and the bottom of the most inferior vertebra, of the curve. a scoliosis is identifi ed as idiopathic when no recognizable pathology explains its origin. it is identifi ed as secondary in the presence of spinal anomaly or neuromuscular dysfunction. the classifi cation of scoliosis is based on the age of the patient when the spinal curvature is fi rst identifi ed: congenital scoliosis is present at birth, infantile scoliosis is diagnosed under the age of years, juvenile idiopathic scoliosis between and years, and adolescent idiopathic scoliosis (ais) between years and the end of skeletal growth. the cause of idiopathic scoliosis has not been established, but seems to be a multifactorial interaction of environmental and genetic factors. studies have shown scoliosis as a single-gene disorder that follows the simple patterns of mendelian genetics. , traits can be dominant or recessive. genetic links exist, with % of parents and % of siblings having a scoliosis. further, a correlated incidence of scoliosis has been described in twins. older maternal age is a risk factor for greater progression of the curve of ais. maternal age of years or more at the time of the child's birth is associated with a higher incidence of ais, whereas paternal age has no significant effect. changes in the extracellular matrix of the connective tissues (e.g. collagen distribution and elastic fi bers) have been found among patients with scoliosis, but most researchers do not consider these changes to be the etiology of the deformity. similarly, a change in muscle fi ber composition or chronic muscle overuse might explained the hyperintense signal intensity shown on mri in the multifi dus muscle on the concave side of the scoliosis associated with greater degrees of curve severity. myopathy involving impaired calcium pump activity is among other proposed etiologies that require further study. the progression of ais is associated with increased calmodulin (calcium-binding receptor protein) levels in platelets, with a possible modulation of the calcium-activated calmodulin by melatonin. the level of melatonin has been proposed as a predictor for progression of spinal curvature in idiopathic scoliosis. melatonin is produced and released by the pineal body at night, and its production is inhibited by environmental light. it is proposed that a deficiency of melatonin could disturb equilibrium and postural mechanisms. neurologic origins have also been proposed as etiologies of scoliosis. hearing-impaired children who have a high incidence of vestibular dysfunction have signifi cantly less idiopathic scoliosis than children with normal hearing, resulting in the suggestion that idiopathic scoliosis has a neural etiology. a sensory input defi ciency of the spatial orientation system, involving visual and vestibular dysfunction, is believed to cause motor cortex and axial posture control disturbances. , another hypothesis is that developmental disorders in the central nervous system, followed by asymmetry of the spinal rotators and other trunk muscles, results in ais. a less effi cient postural regulation system with a diminished quality of standing stability has been demonstrated in some scoliotic patients. developmental disorders have also been considered at the level of the spinal cord. differences between the growth of the vertebral column and the growth of the spinal cord -'uncoupled neuro-osseous growth' -either with asymmetric nerve root tension or with reduced growth of the cord, are suggested etiologies for scoliosis. more rapid growth of vertebral bodies that occurs through endochondral ossifi cation, as well as slower circumferential growth of the vertebral bodies and pedicles that occurs through membranous ossifi cation, is observed in ais patients. furthermore, the length of the vertebral canal is shorter than the length of the vertebral column. this leads to the hypothesis that the thoracic spine is tethered by a tight spinal cord, with a resultant diminution of the kyphosis. this, in turn, results in a displacement of the spinal cord to one side of the vertebral canal with an associated sidebending of the spine and lastly a rotation of the vertebral bodies to allow for their growth while the vertebral canal stays in the midline. the base of the vertebral canal remains at a right angle to the sagittal plane of the patient, in its original position, and does not follow the rotation of the vertebral body. the tension of the core link -the strong dural membranes covering the cord, between the pelvic and cranial bowls -may play a role in this mechanism. the relationships between the different parts of the craniosacral mechanism, therefore, should be considered, and any dysfunction of the dura and/or the vertebral ligaments should be treated. biomechanical factors can affect spinal alignment. sidebending-rotation and torsion of the sbs, for example, can modify the level position of the orbits through the sphenoid and thereby modify the occipital neutral position, again altering balance mechanics in the spine below. pelvic obliquity is considered a cause of imbalance in the axial skeleton. pelvic obliquity has been associated with unequal leg length. if this imbalance appears early in the growth process, it will result in abnormal asymmetric weight-bearing pressures on the vertebrae. a 'dangerous triad' of joint laxity, delayed growth and persistence of asymmetric overloading of the spine has been described in rhythmic gymnasts who develop scolioses. this group shows an incidence of scoliosis of %, compared to . % in the general population of the same age group. pelvic obliquity has also been associated with the 'molded baby syndrome', where intrauterine molding determines a vertebral curve, having a sacral tilt inferiorly on the side of the spinal convexity. mechanical compressive forces acting on the infant during the prenatal, perinatal and postnatal periods have been proposed as an etiology for scoliosis. more breech presentations have been found among infants developing scoliosis during the fi rst months of life. plagiocephaly is frequently associated with infantile scoliosis. , - a facial and cranial distortion, always on the side of the curve of the scoliosis and linked to the intrauterine position, has been described. mcmaster noted that the scoliosis was rarely present at birth and, like plagiocephaly, develops very often within the fi rst months of life. he proposed an explanation for the association between plagiocephaly and scoliosis, as follows. infants prefer to turn toward their right side when in a supine position. light but asymmetric pressures from the mattress on the skull as well as on the growing spine can create asymmetries, particularly when applied over a prolonged time or during a critical period of growth. with chronic right rotation of the head, the back of the head will fl atten on the right, allowing growth of the skull on the left. the thorax follows the same pattern, the left side expanding freely backwards with a left rotation of the thoracic vertebrae. infantile scoliosis is sometimes found in association with imbalance of the occiput or with dysfunction of the sbs. intraosseous dysfunction of the occiput can produce asymmetry of the occipital condylar parts, resulting in altered balance mechanics in the spine below. the compressive forces applied to the occipital bone at the time of delivery have been described and suggested to be the causes for future compensatory scoliotic curves. , thus, the child may prefer to sidebend their head slightly to one side and, as time goes on, with potential new injuries and therefore more diffi culties for compensation, the adolescent will develop a scoliosis. ventura et al. state: 'even small deformities present at, or soon after, birth may get worse in infants whose connective tissues do not have a potential for recovery.' to this we could add one or more of the components described above -the etiology is multifactorial. congenital scoliosis may be associated with neurologic pathology or a vertebral structural defect (failure of formation and/or segmentation), as well as associated abnormalities of the head, neck, pelvis and hips. a thorough medical examination should be performed to rule out these disorders. hemivertebra is the most common anomaly that causes nonidiopathic congenital scoliosis and is sometimes associated with posterior midline cutaneous abnormalities. neural axis abnormalities have been demonstrated in . % of otherwise asymptomatic patients with infantile scoliosis. congenital scoliosis is more common in females than in males, occurring in the ratio of . : . among children with congenital spinal anomalies, - % have other anomalies located most commonly in the genitourinary tract, cardiovascular system, spinal cord or cervical spine. since the time of hippocrates, congenital and infantile scolioses have been described as potentially the result of mechanical factors operating during fetal life. these scolioses are more common in males, presenting more often as a left thoracic curve. , some resolve spontaneously, while others progress. harrenstein in , quoted by mehta, stated: 'spontaneous correction does occur without treatment but at the moment it is not possible to distinguish between the two at the time of the diagnosis.' thus, in order to differentiate between progressive and non-progressive congenital and infantile idiopathic scoliosis, mehta proposed a method of measurement of the rib-vertebra angle (rva). in an anteroposterior radiograph, the rva is 'the angle formed between each side of the apical thoracic vertebra and its corresponding rib'. the rvas are equal on a normal spine and a gap of - mm normally separates the head of the rib and the upper corner of the adjacent vertebra. mehta states that the most progressive infantile scoliosis presents an rva difference between the two sides equal to or greater than °. when this radiographic measurement is repeated after months, the rva remains unchanged or increases with a progressive scoliosis, whereas it decreases with a resolving curve. furthermore, with time, in the anteroposterior radiograph, a progressive scoliosis demonstrates overlap of the rib shadow with the upper corner of the vertebra. the relationship between the rib and the vertebra and the tissue response to any stress during growth periods is of great importance. curve progression is the major concern in every type of scoliosis, and the differentiation between progressive and non-progressive congenital scoliosis and infantile idiopathic scoliosis has been confi rmed through sequential comparisons of rvas over time. , when spontaneous resolution occurs in non-progressive infantile scoliosis, it does so between the ages of and months. spontaneous resolution of infantile idiopathic scoliosis varies between % and %. therefore, it is appropriate to detect the scoliosis at its earliest stage and to treat all affected babies within the fi rst months of life. it is typical to employ a wait-and-watch approach to the progressive category because orthopedic treatment is complex and diffi cult to initiate before the age of months. osteopathic procedures, on another hand, may be begun immediately, with potentially good results being obtained in cases of congenital and infantile idiopathic scoliosis. observe the baby for spontaneous positioning and areas of restricted mobility. look for positional asymmetries of the torso, head and neck, arms and legs. look also for a bulky back on the convex side of the thorax and creases in the skin laterally on the concave side. skin creases are a sign of fi xed scoliosis. observe the baby for clumsy movement in the maintenance of head position and in general coordination. palpate the infant to identify membranous, myofascial and interosseous somatic dysfunction contributing to the visually observed functional restrictions. the infant may be treated utilizing indirect principles to release any restriction of motion, particularly in the pelvis, upper thoracic spine, ribs, sternum, thoracic diaphragm, pectoral girdle, cervico-occipital area and cranium. intraosseous dysfunctions -most commonly encountered in the sacrum, lumbar and thoracic vertebrae and occiput -may be addressed using molding procedures. at home, following treatment, it is important to avoid movements and positions that will reinforce the scoliotic pattern. in considering daily activities, such as feeding and play, and when putting the infant to sleep, encourage the parents to position the infant correctly and to solicit movement from the infant that promotes symmetry. a child should sleep on their back to prevent sids, but should play in the prone position to develop the vertebral musculature of tonic posture. prevention is the best therapy. osteopathy, as a non-invasive treatment, facilitates the spontaneous recovery process or regression as quickly as possible. this allows the child to progress through the developmental milestones of infancy without interference from a dysfunctional musculoskeletal system. scoliosis is present between and years of age in - % of children. these patients differ from those with infantile scoliosis in that there is predominance among females and for the curvature to be a right thoracic curve. , the vertebral rotation is associated with a 'rib hump' on the side of the convexity, with most curves convex on the right in the thoracic area and on the left in the lumbar area. cobb's angle is sometimes debated as a true assessment of the scoliosis. ais is a three-dimensional deformity of the spine, with morphologic changes in the trunk and rib cage. vertebral rotation should be considered in the evaluation. the presence of severe pain or neurologic symptoms would be atypical for idiopathic scoliosis and should raise concern for spinal cord pathology. idiopathic scoliosis, if left untreated, increases in adult life. the period of puberty should be considered as a high-risk interval, and regular screening is recommended. a signifi cant correlation between growth in height and progression of cobb's angle has been found, with a possible increase until . years after menarche. current studies have indicated that the younger the patient at the time of diagnosis by pubertal or skeletal maturation landmarks, the greater the chance of curve progression. a curve measuring less than ° at skeletal maturity is least likely to progress, whereas curves measuring - ° may gain another - °. thoracic curves deteriorate most, followed by thoracolumbar curves and double curves. less than % of adolescent idiopathic scoliosis resolves without treatment. orthopedic treatment with a cast or a brace might be indicated to limit the progression of the curve and to employ surgery to correct the scoliosis. bracing for at least hours per day appears to be optimal for interdicting progression of the curve. watchful waiting is suggested as an alternative treatment to bracing because bracing does not decrease the incidence of surgery and often results in adverse psychological effects. manipulative treatment associated with exercise has been shown to stop curve progression in ais. , exercise may be used to effectively reverse the signs and symptoms of scolioses and to prevent progression of spinal curves in children and adults. as scoliosis is a risk factor for the impairment of physical wellbeing and quality of life, treatment is important. the physical examination begins with observation of the patient standing. observe placement of the feet for asymmetries. from behind, note the level of the iliac crests and the symmetry of the pelvis and waist triangles. leg length discrepancy as a contributing factor should be considered. further, observe the relationship between the pelvic and pectoral girdles, and look for shoulder and scapular asymmetries. elevation of the right shoulder compared to the left is associated with a thoracic curve convex on the right. note the position of the patient's head. a vertical line dropped from the external occipital protuberance should fall in the middle of the intergluteal crease. the patient is next observed in profi le for increased or decreased thoracic kyphosis, forward head posture and lumbar lordosis. the adam's forward bending test is employed to help identify scoliosis. the child bends forward, holding palms together with arms extended. the examiner looks from behind and from the side, along the horizontal plane of the back, to detect an asymmetry as a rotational deformity or 'rib hump' (fig. . . ) . this deformity is associated with spinal curves and may be further delineated with radiographic evaluation. with the child remaining forward bent, observe the distance between tips of the fi ngers and the ground as an indication of general spinal fl exibility. the palpatory examination of the patient with ais is directed at the identifi cation of membranous, myofascial and interosseous somatic dysfunction. the patient may be treated utilizing indirect principles to address any identifi ed dysfunction. begin by treating the area of greatest motion restriction. this will often be in the upper thoracic and craniocervical regions. the presence of proprioceptive sensory endings in the ligaments and fascia of the upper cervical area contributes to postural balance. primary high cervical somatic dysfunction can consequently impact postural balance. somatic dysfunction in the upper thoracic region can result in compensatory dysfunction in the upper cervical spine. once these areas have been treated, dysfunction of the thoracic spine, ribs, lumbar spine, sacrum and pelvis should be addressed. normalization of the diaphragm, to increase vital capacity, should always be part of the treatment of scolioses. dysfunction of the thoracic diaphragm, because of the attachments of the crura on the lumbar spine, affects the mobility of the spine and may be linked to dysfunction in the pelvic and cranial diaphragms through the core link. any dysfunctional pattern present in the skull should be treated. dysfunction in the occiput can affect the proprioceptive input from the craniocervical region. the vestibular apparatus located inside the petrous portions of the temporal bones contributes to balance mechanics and symmetric muscle tension. dysfunction between the sphenoid, occiput and temporal bones should, therefore, be treated. by virtue of the fact that fusion of the sbs does not typically occur before late adolescence, there remains mobility in the base of the skull of younger ais patients, making them particularly receptive to cranial treatment. cranial dysfunction may also affect the scoliotic patient through the reciprocal tension membranes. dysfunctional tensions in the dura have been proposed as an etiology of scoliosis. equilibration of intracranial and intraspinal membranes should, therefore, be employed. in younger patients where active bone growth is still present, intraosseous dysfunctions -most commonly encountered in the sacrum, lumbar and thoracic vertebrae and occiput -may be addressed using molding procedures. exercises are an important component of the treatment protocol. a properly employed exercise program should teach the patient to breathe effectively, increasing vital capacity and enhancing thoracic cage mobility. it should facilitate the establishment of the fullest range of motion possible and the development of symmetry of movement, particularly spinal rotation, while strengthening the core musculature and stabilizing the spine. it should allow the patient to develop proprioception and establish good postural habits. kyphosis is an increase of the spinal curve in the sagittal plane that results in a greater than normal posterior convexity (anterior concavity). an increased kyphotic curve is encountered more often in the thoracic spine, where it produces a rounded upper back, or 'humped back'. in the cervical and lumbar spines, normal curves present with posterior concavity or lordosis. under dysfunctional circumstances, the lumbar and cervical curves are reversed and become kyphotic. at the lower portion of the spine, a kyphosis can be ascribed to the sacrum, when its usual posterior convexity is increased. a thoracic kyphosis of > ° is considered pathologic. congenital kyphotic deformities are infrequent and can be caused by a failure of formation of the vertebral body or a failure of segmentation, for which the treatment is surgical. in the infant, tumor of the spine is also a potential cause of kyphosis that requires specifi c medical attention. in the juvenile period, scheuermann's disease is a cause of kyphosis resulting from an alteration of the vertebral development. wedging of the vertebral bodies, the posterior height being greater than the anterior height, produces the kyphotic deformity. boys are more frequently affected and the resultant back pain might be the trigger for an x-ray where the diagnosis is made. irregularities in the endplates of the vertebrae can be observed, particularly at the level of the lower thoracic and upper lumbar spine. scheuermann's disease may also be associated with scoliosis. because kyphosis is a spinal deformity, it should not be confused with poor posture. when examining an infant who is seated without support, it is normal to fi nd a kyphosis of the thoracic and lumbar spine. proprioception and muscular tone develop with age to maintain adequate sagittal balance. sagittal spinal curves change as a child grows. , the thoracic kyphosis is more pronounced in males, at a mean age of . years. more often, the exaggerated kyphotic curve is associated with dysfunctional posture. juvenile and adolescent kyphosis can be the result of poor posture, as a compensatory pattern to an extension dysfunction elsewhere. anterior displacement of the occipital bone on the superior articular surface of the atlas will project the chin forward, and the ensuing postural compensation will result in an increased thoracic kyphosis. this pattern is commonly found in individuals who demonstrate oral breathing. when encountered in a child, an apparent kyphosis may also be the result of protraction of the pectoral girdle. in this case, the thoracic curve is not fi xed in the kyphotic position and spinal backward bending can be achieved on demand, although lack of fl exibility is common. the child is usually shy, and an extension-internal rotation pattern may be present, either at the level of the pelvis or at the level of the sbs, the temporal or occipital bones. a thoracoabdominal diaphragmatic dysfunction is very often associated with diminished thoracic fl exibility and reduced vital capacity. the areas of the diaphragmatic attachments onto the inferior portion of the sternum and adjacent ribs might be the causative dysfunctional agents. an increased thoracic kyphotic curve is usually compensated for by an increase in the lumbar lordosis. kyphosis and lumbar lordosis generally compensate each other. a correlation between these two spinal curves has been found in most age groups. the cervical and lumbar regions are normally lordotic. hyperlordosis is an increase of the lumbar lordosis and is considered pathologic. it can be associated with other conditions, such as developmental dysplasia of the hip or neuromuscular disorders. there may be a family history of hyperlordosis, but it can also follow trauma, commonly from athletic activities, particularly highly competitive sports, during periods of growth. adolescents may also present with hyperlordosis as a consequence of a developmental spondylolisthesis. with this disorder, studies have shown an increase of hyperlordosis and sacral inclination, but a decrease of thoracic kyphosis. the degree of lumbar lordosis is correlated with sacral position. sacral anatomic extension (craniosacral fl exion) is normally associated with decreased lordosis; sacral anatomic fl exion (craniosacral extension) is associated with increased lordosis. the global amplitude of the vertebral curves, cervical lordosis, thoracic kyphosis and lumbar lordosis changes with growth, but the association with the position of the sacrum is constant under normal conditions. the relationship between the cranial and the pelvic bowls, through the core link, is a fundamental principle within the cranial concept. cranial fl exion is associated with sacral craniosacral fl exion, and cranial extension is associated with sacral craniosacral extension. the vertebral anteroposterior curves are decreased when fl exion of the cranial base is present; conversely, there is an increase of the lordotic or kyphotic curves with extension of the cranial base. early detection of kyphotic and lordotic curves is important for successful treatment. the child should be considered from a total body approach and the posture of the whole body should be evaluated in the standing position: • observe the pattern of weight-bearing mechanics. • observe the feet for a pattern of inversion or eversion. a pattern toward eversion of the feet, and eventually fl at feet, is consistent with increased sagittal curves and cranial extensioninternal rotation. • observe the knees. genu valgum is consistent with increased sagittal curves and cranial extension-internal rotation. • observe the pelvis for an increase of anterior tilt, with the sacrum in craniosacral extension. • observe for pelvic asymmetry and any difference in the greater trochanter and innominate crest heights. • observe the spine for an increase of the anterior-posterior curves. a pattern involving all of the curves might be the consequence of a cranial or sacral dysfunction with extension and internal rotation. a pattern of increased curvature limited to a portion of the spine may be associated with a dysfunction within the curve, in an adjacent spinal curve or adjacent junctions between the spinal ap curves. • observe the pectoral girdle for protraction or an associated asymmetric pattern. a difference in shoulder heights is common. this suggests somatic dysfunction in the thoracic spine with associated sidebending and rotational components. • observe the position of the head in relation of the rest of the body, in both the frontal and the sagittal plane. forward displacement of the head is often associated with somatic dysfunction of the craniocervical or upper thoracic vertebrae. next, observe the child while they are moving. if necessary, have the child demonstrate active fl exion-extension, sidebending and rotation of the spine to confi rm previous observations. muscles may show a difference in tension between anterior and posterior groups. hyperlordotic children will present with increased tension in the hamstrings and hip fl exors, while at the same time their abdominal muscles will lack tension. tests of listening are performed on the innominates, the sacrum, the lumbar and cervical vertebrae and the cranium. the treatment of any identifi ed dysfunctional areas should follow using indirect principles. the postural response to effective manipulation is almost immediate. you should be able to see improvement in the posture of the child after the fi rst treatment. simple exercises may be recommended, particularly if poor posture is present. pelvic tilt is useful, as are stretching the hamstrings and proprioceptive exercises to increase body posture awareness. the child should be encouraged to judiciously practice athletic activities, such as swimming and tai chi, which will strengthen and balance the core muscles and improve fl exibility and coordination. advice should be given that appropriately addresses daily living conditions. for example, the patient should avoid carrying a backpack on one shoulder; rather, they should carry it using both shoulders. they should avoid reading and writing on a fl at horizontal surface and should work instead on a surface that is tilted approximately ° to limit cervicothoracic fl exion. once the problem has been effectively addressed, the child may then be treated as needed, but they should be followed on a regular basis, at least annually, until they have stopped growing. pectus excavatum is a deformity of the anterior thoracic cage in which the sternum is depressed in a concave shape, whereas in pectus carinatum the sternum is protruded in a convex shape. these deformities may or may not be associated with genetic disorders or with scolioses. decreased thoracic cage compliance and reduced vital capacity may be present, although the heart and lungs develop normally. pectus excavatum and pectus carinatum are present at birth, but the parents usually do not become aware of the deformity until it becomes more apparent with growth. severe cases often result in signifi cant psychological impact, usually in early adolescence. pectus excavatum is frequently associated with an sbs extension pattern. this results in internal rotation of the paired structures, specifi cally the pectoral girdle. these individuals may also demonstrate direct mechanical derangement of the internal fascial structure of the thoracic cage and intraosseous dysfunction of the ribs and sternum. a diaphragmatic dysfunction is almost always associated with this condition. in pectus carinatum, similar mechanisms exist but with a tendency for sbs fl exion. the evaluation of the patient commences by examining the interrelationship between the sternum and the thoracic spine, and between the sternum and the occiput. next, examine all myofascial structures attached to the sternum, including the pectoral girdle and the diaphragm. the anterior abdominal wall should be evaluated for dysfunctional tension, and, if present, contributory mechanics should be sought out in the lumbar spine, sacrum and pelvis. visceral abdominal dysfunction should also be considered. treatment consists of myofascial release applied to identifi ed dysfunctions. if possible, molding procedures directed at the sternum should be employed simultaneously with the myofascial release modalities to enhance the effi cacy of both. the application of these procedures should be done in synchrony with, and with the intent to enhance, the inherent motility of the body. the younger the patient when treatment is initiated, the greater the potential for positive outcome. vertebral somatic dysfunction in infants and children can be found at any level of the spine. it will, however, be more commonly encountered in the lumbar, upper thoracic and cervical regions. it usually results from the day-to-day physical activities and traumas of childhood. in younger children, dysfunction in the cervical region will often present as cervical pain and, eventually, as torticollis. in the lumbar region, somatic dysfunction may remain quiescent for a protracted period, in time manifesting through a somatovisceral mechanism as abdominal pain. in older children and adolescents, the initial complaint from vertebral dysfunction is usually localized or referred musculoskeletal pain. because of the young patient's ability to compensate for somatic dysfunction, any vertebral somatic dysfunction should be thoroughly evaluated to rule out a viscerosomatic origin. the mechanics of vertebral somatic dysfunction manifest in children and adolescents is the same as that encountered in adults, showing the coupled relationships between fl exion-extension, sidebending and rotation as described by fryette. however, because of the fl exibility of the soft tissues in these young patients, dysfunctional barriers are more compliant, lending to the application of indirect techniques in their treatment. somatic dysfunction may also exist as a refl ex manifestation of visceral dysfunction and disease. although the precise locations of viscerosomatic refl exes in infants and young children have not been specifi cally reported, it is reasonable to anticipate locations similar to those in adults. the facilitated state of the segmental spinal cord in the presence of visceral input can, in turn, result in a somatovisceral response. a listing of viscerosomatic locations as they have been reported in the osteopathic literature is summarized in box . . . because of the growth potential of these patients, vertebral somatic dysfunction can exert disproportionate impact on their developing posture as well as on the viscera through somatovisceral refl exes. -the parasympathetic refl ex from the gastrointestinal tract proximal to the mid-transverse colon is vagal, occiput, c , c ; the parasympathetic refl ex from the distal half of the transverse colon to the rectum is sacropelvic s -s -the esophagus has a right-sided sympathetic refl ex from t to t -the stomach has a left-sided sympathetic refl ex from t to t -the duodenum has a right-sided sympathetic refl ex from t to t -the small intestine sympathetic refl ex is bilateral from t to t -the appendix and cecum sympathetic refl ex is from t to t on the right -the ascending colon sympathetic refl ex is from t to l on the right -the descending colon to rectum sympathetic refl ex is from l to l on the left. the clavicle is the bone most frequently fractured during the birth process. clavicular fractures occur in about . % of all vaginal deliveries , and . % when considering all live births. both males and females are affected equally, with equal left versus right-sided incidence. there is, however, a slightly increased incidence of right-sided fractures in left occiput-anterior deliveries. reported risk factors for clavicular fractures include increased duration of the second stage of labor, increased birth weight and neonatal length (macrosomia), instrumental delivery and shoulder dystocia. in cephalic presentation, the compression of the infant's anterior shoulder against the maternal symphysis is responsible for the trauma. direct pressure or torsion applied to the clavicles to facilitate delivery can also result in fracture. complete or incomplete greenstick fractures are most frequent. they present with edema, crepitus, a palpable bony bump and tissue texture changes over the fracture site. decreased or absent movement of the affected arm is present, as may become apparent when eliciting the moro refl ex. asymptomatic or incomplete clavicular fractures may not be initially identifi ed until after discharge from the hospital. usually, the caregiver will notice that the child demonstrates irritability with discomfort and pain when putting the child's arm through the sleeve of a garment or when lifting the child by holding them under their arms. they are also liable to report that the child cries when positioned on the affected side. shoulder dislocation, humeral fracture and brachial plexus injury are part of the differential diagnoses. the diagnosis is confi rmed radiographically. associated complications, such as erb's palsy, are present in . % of newborns with fractures of the clavicle, although clavicular fracture may actually reduce the potential nerve injury from traction on the brachial plexus. usually no orthopedic treatment is necessary for asymptomatic and incomplete clavicular fractures. when the neonate presents with pain or discomfort, the affected arm may be immobilized by pinning the sleeve to the front of the shirt for - days. a large callus typically forms at the fracture site within a week, and recovery is usually considered to be complete. osteopathic procedures may be employed to assist the recovery process and address the dysfunctions usually associated with a fracture of the clavicle. the clavicle is of importance because of its myofascial attachments. it serves as a junction between the fasciae of the thorax, arm and neck. the investing layer of the deep cervical fascia completely surrounds the neck. superiorly, it is attached to the external occipital protuberance and the superior nuchal line, the mastoid processes, zygomatic arches and the inferior borders of mandible. it splits to surround the trapezius and sternocleidomastoid muscles. inferiorly, it is attached to the manubrium of the sternum, the acromion and the spine of the scapula. the clavicle is the link in the fascial continuity between the investing layer of the deep cervical fascia and the fascia of the thorax and the arm. the clavipectoral fascia attaches on the clavicle, as does the deltoid fascia. the deltoid fascia is in continuity with the brachial fascia. the clavicle, therefore, plays an important role in the equilibrium of the fascia of the thorax, arm and neck, and should be balanced, as should the myofascial structures attached to it. forces applied during the delivery that are great enough to fracture the clavicle also affect the neck and upper thoracic vertebrae of the neonate. therefore the osteopathic practitioner should evaluate these structures and treat any dysfunctions accordingly, using indirect principles. furthermore, because of pain from the fractured clavicle, the child will prefer to lie on the opposite side, thereby fostering the development of asymmetric fascial tensions. these asymmetries can, in turn, induce the child to select a chronic position of comfort, long after the clavicle has healed. the chronic asymmetric positioning can then predispose the child to the development of plagiocephaly. fractures of the clavicle that occur during childhood are usually the result of rough play or athletic activities. in childhood, the forces that result in clavicular fractures are usually violent, most often involving impact on the hand with the arm extended or impact on the shoulder. in % of cases the site of fracture involves the medial third of the bone. the standard orthopedic treatment reduces the displacement at the fracture site by maintaining the shoulder in an upward and backward position with a bandage or plaster. osteopathic procedures applied to the older child follow the same anatomic principles as for the infant, i.e. to alleviate myofascial imbalances and upper thoracic and cervical dysfunction. the acromioclavicular junction may demonstrate somatic dysfunction; it should, therefore, be evaluated and treated following indirect principles. it is of importance to allow for normal function of the growing upper extremity. acromioclavicular dysfunction is the source of many adult shoulder disorders. a brachial plexus injury occurs most commonly as a result of a diffi cult birth, fetal malpresentation, shoulder dystocia, macrosomia or assisted vaginal delivery. fracture of the clavicle(s) or humerus, shoulder dislocation, torticollis, hematomas of the sternocleidomastoid muscle or paralysis of the diaphragm may be associated with injury of the brachial plexus. a commonly believed etiology of brachial plexus injury is excessive traction on the fetal head during birth. in vaginal delivery, during the attempt to deliver the anterior shoulder, the applied downward traction can damage the brachial plexus. this theory, however, is questionable because, in almost half the cases of brachial plexus injury, delivery of the shoulders occurs without diffi culty. therefore, an in utero, atraumatic theory is also proposed. when asymmetry and diminished movement of the arm are observed on the fetal ultrasound, a vulnerable plexus may be injured without traction during delivery. the brachial plexus is formed by the union of the anterior divisions of the lower four cervical nerves and part of the anterior division of the fi rst thoracic nerve. in addition, the fi fth cervical nerve frequently receives a branch from the fourth cervical, and the fi rst thoracic a branch from the second thoracic. the plexus extends from the inferior aspect of the side of the neck to the axilla. the fi fth and sixth cervical nerves unite to form the upper trunk; the eighth cervical and fi rst thoracic nerves form the lower trunk, while the seventh cervical nerve runs out alone as the middle trunk. these three trunks pass beneath the clavicle and split into the anterior and posterior divisions. the plexus is attached to the fi rst rib and to the coracoid process by the costocoracoid membrane and is subject to any force that disturbs the relationship between the cervical vertebrae, the fi rst thoracic vertebra and ribs, the clavicle and the scapula (fig. . . ) . most of the time brachial plexus injury is unilateral and immediately recognizable. brachial plexus injury can affect different spinal nerve roots and is identifi ed as follows: • upper type, with involvement of c and c , or erb-duchenne palsy that affects muscles of the shoulder and elbow. the child presents with adduction of the upper extremity and internal clinical conditions rotation of the shoulder, but grasp remains intact. it represents most of the brachial plexus paralyses and is considered to have a good prognosis. • lower type, with involvement of c , c and t , or klumpke's palsy that affects muscles of the forearm and hand. the child presents with a paralysis of the hand and wrist. the presence of an ipsilateral horner's syndrome (anhidrosis, miosis and ptosis) indicates an involvement of the sympathetic fi bers associated with an intraspinal avulsion of the root of t . • whole arm type, with involvement of c -t , with no movement of the upper extremity and often associated with sensory loss. extreme lateral fl exion and traction of the head may be responsible for the stretch applied to the brachial plexus. the injury results in anything from a mild edema or hemorrhage within the affected nerves, to tearing of the nerve(s) that could be as extensive as to produce a total avulsion of the complete plexus. the c and c spinal nerves are located in the sulcus nervi spinali of the transverse processes. in that location they are strongly attached by various fi brous slips as extensions of the prevertebral fascia and surrounding structures attached to the spinous processes, and are, therefore, more likely to be ruptured. the c and t spinal nerves may, more often, be subject to avulsion. neuronal injury associated with brachial plexus injury may be of different degrees of severity: • neuropraxic lesions are failure of conduction without the axon having been affected, and are reversible. • axonotmetic lesions involve disruption of both the myelin sheath and the axon, but with the surrounding neuronal elements kept intact. wallerian degeneration of the axon distal to the injury occurs. • neurotmetic lesions are total sectioning of the nerve with its myelin sheath and supporting connective tissue. • avulsion is a separation of the plexus from the spinal cord. obstetric brachial plexus palsy occurs in . - . per live births with an upper root (c -c ) involvement in % of cases; c , c and c involvement in %; and the whole plexus in %. , , neuropraxic and axonotmetic lesions have better prognoses. the diagnosis is made by physical examination. the moro refl ex is asymmetric and the biceps' deep tendon refl ex is absent. the grasp refl ex is, however, normal. the child should be moved very gently: the injuries are painful and the tissues very fragile. initial treatment is usually conservative with regular assessment. if the patient fails to show signifi cant improvement by months of age, surgical opinion should be sought. physical therapy, consisting of gentle passive mobilization, may be employed to maintain range of motion and prevent contractures while the infant is recovering active motion. specifi c motor training can be initiated within the fi rst weeks, with facilitation of active movement. the persistent neurologic defi cits may result in the development of internal rotation and adduction contractures of the arm. gentle stretching of internal rotators should be performed to reduce this risk while avoiding reinforcement of forearm supination. osteopathic procedures should be employed as early as possible in the treatment of brachial plexus injury. traumatic forces may have injured the brachial plexus, but other areas, such as the upper thoracic spine, the fi rst rib, the cervical spine, clavicle and all of the myofascial components of the thoracic outlet, have been stressed as well. dysautonomia may also be present because somatic dysfunction of the cranial base and occipitoatlantal region can affect the parasympathetic tone through the vagus nerve, while somatic dysfunction in the upper thoracic spine can affect sympathetic nervous function. direct compression of the venous and lymphatic drainage of the brachial plexus, as well as somatovisceral refl exes, should be considered when attempting to facilitate nerve regeneration. osteopathic procedures aim to promote fl uid, electrolyte and metabolic exchange within the tissues to facilitate drainage of edema and to prevent or reduce tissue scarring. treatment is intended to optimize nerve regeneration and prevent the development of muscular imbalance. recuperation of the common motor defi cits, such as the absence of active external rotation, fl exion and abduction of the shoulder, and function of the biceps should be addressed to minimize bony deformities and joint contractures. the neonate with possible brachial plexus injury may be examined on the treatment table. observe for spontaneous movements of the head, trunk, pelvis and limbs. check for subtle facial palsy that may be found as a concomitant result of birth trauma. inspect shoulders and limbs for deformities. evaluate range of motion of every joint of the affected limb. palpate for tissue texture changes in the upper extremities. look for signs of shoulder instability such as a palpable or audible click during movement. palpate for tissue texture changes in the suboccipital, neck and upper thoracic areas. the connective tissues are responsible for the maintenance of shape against both external and internal stresses. mechanical forces contribute to the development and evolution of the extracellular matrices found in the connective tissues. as tissue texture changes follow trauma, osteopathic procedures should help in resetting structure and function of traumatized connective tissues. evaluate, through tests of listening, the function of the humerus, scapula, clavicle, sternum, upper thoracic spine, fi rst ribs, cervical spine and craniocervical joints. this method of assessment is of particular value with this type of pathology because it is so gentle. anatomic visualization is, as always, important. as you evaluate the patient, visualize the different layers of soft tissue: fascia superfi cialis, cervical fascia, costocoracoid membrane, sternocleidomastoid and scalene muscles. evaluate and visualize the different bones involved. listen to the inherent motions in order to defi ne the dysfunctional area. study the relationship between the shoulder and the vertebral column. for instance, in the case of a klumpke's palsy, place the pad of the fi ngers of one hand on the spinous processes of c , c , t and t , and place the other hand on the ipsilateral shoulder. listen, and look for dysfunctional motion. one vertebral segment may be more dysfunctional than others. the relationship between the humerus and the shoulder should also be balanced. treat the dysfunctions you identify by applying indirect principles. improvement should be rapid and most cases have a favorable prognosis. injuries involving the fi fth and sixth cervical nerve roots have the best prognosis, whereas lower plexus and total plexus injuries have a poorer prognosis. signifi cant defi cit persisting after months should be explored surgically. prognosis is excellent if antigravity movement of biceps and shoulder abductor is present by months of age. assessment may be performed by testing the biceps' strength in a supine position while simultaneously palpating the muscle. bicipital activity should not be confused with fl exion of the elbow obtained by the action of the supinator muscle. surgery is considered by some authors when antigravity movement of the biceps is not present by months of age. surgery is considered to be justifi ed by others when an initial involvement of the c nerve root is present, with a birth weight above the th percentile and there is only poor elbow fl exion at and months of age. the plasticity of the glenohumeral joint in the newborn makes it subject to shoulder dysplasia and, in more severe cases, dislocation. these disorders may be compared to similar disorders occurring in the hip joint -hip dysplasia and hip dislocationand in some cases the etiology may be similar. intrauterine forces applied to the fetus can result in shoulder dysplasia. during the latter part of pregnancy any compression of the upper fetal torso within the uterus may affect the glenohumeral joint and the surrounding soft tissues. stresses during the birth process can also contribute to the development of shoulder dysplasia. increased duration of the second stage of labor, greater than hours, has been described as a factor contributing to shoulder dystocia. additionally, macrosomia that results in a size discrepancy between the fetal shoulders and the maternal pelvic inlet can, in severe cases, lead to signifi cant neonatal morbidity including asphyxia and trauma, particularly to the brachial plexus. a large fetal trunk, or increased bisacromial diameter, prevents the rotation of the fetal shoulders into the oblique pelvic diameter during delivery. as a consequence, certain obstetrical maneuvers may have to be employed to alleviate the impaction of the fetal shoulders within the maternal pelvis. as stressful as such a disproportionate relationship between the fetus and the maternal pelvis can be, it does not always result in overt trauma to the brachial plexus. it can, however, cause injury to the shoulder that can lead to shoulder dysplasia. this type of injury to the shoulder can occur even from the stresses of an otherwise normal delivery. dysplasia of the shoulder may also result from postpartum conditions. the presence of dysfunctional asymmetries in the newborn, congenital muscular torticollis, non-synostotic plagiocephaly and brachial plexus injuries may contribute to abnormal development of the glenohumeral joint. contractures of the muscles of internal rotation in neonatal brachial plexus palsy are responsible for posterior dislocation of the humerus from the glenoid fossa, - requiring orthopedic repair. milder cases of dysplasia without dislocation may be treated using osteopathic procedures. if untreated, these glenohumeral dysfunctions can increase with age, becoming the cause of adult scapulothoracic problems. therefore, the scapula and the glenohumeral joint should be evaluated at birth for any signs of dysplasia, as precisely as the pelvis is evaluated. particular attention should be directed at the identifi cation of signs of shoulder instability, such as a palpable or audible click during movement. observe and compare the size and shape of both shoulders. the examination may reveal asymmetry in the number of skin folds in the proximal part of the arms. observe the freedom and range of motion of both shoulders. note any restriction, stiffness of movement and asymmetry in movement, particularly external rotation and abduction of the arm. the malposition of the humeral head may result in an apparent difference in the length of the arms, with the arm on the side of the dysplasia appearing to be shorter. compare the anterior and posterior aspects of the shoulders and look for any posterior fullness that may be indicative of a posteriorly displaced humeral head, necessitating orthopedic attention. treat any somatic dysfunction identifi ed using indirect principles. stabilization of the humeral head in the glenoid fossa may be facilitated when myofascial procedures are applied to the periarticular muscles of the shoulder. nursemaid's elbow, also called pulled elbow, is a radial head subluxation that occurs in younger children when traction is applied suddenly to their hand or forearm. this commonly occurs when an adult is attempting to lift a child up by pulling upward while holding the child's hand. traumas such as falls or when the infant initiates rolling over are other possible causes of this condition. the head of the radius articulates with the radial notch of the ulna and the surrounding annular ligament. under normal conditions, the annular ligament encircles the head of the radius with a certain amount of tension that maintains the contact with the radial notch. the normal movements of the head of the radius, within the ring formed by the annular ligament and the radial notch of the ulna, are anterior and posterior motion. pronation is associated with posterior radial motion and supination with anterior radial motion. in nursemaid's elbow a subluxation of the developing radial head from the annular ligament of the elbow joint occurs. a combination of pronation and traction on an extended elbow causes a proximal slip of the annular ligament over the top of the radial head with resultant interposition of some fi bers of the anterior joint capsule between the two bones. the most common symptoms of nursemaid's elbow are immediate pain and an inability to move the arm. the child will have a partially fl exed elbow with pronation of the forearm. most of the time anxiety is also present. the intention of osteopathic treatment is to restore motion between the head of the radius and the radial notch of the ulna and surrounding annular ligament. ligamentous articular strains may be balanced utilizing indirect principles that apply perfectly to this condition. balancing the annular ligament and the radial collateral ligament of the elbow may prevent recurrence of a posterior radial head subluxation. the caregiver should be told to avoid pulling or lifting their child by the arms or hands. a frequent complaint in an osteopathic practice is intoeing, i.e. the child's feet turn in when walking or running. malposition of the feet, developmental dysplasia of the hip and toe walking are among the other complaints encountered with infants, while sprains are more frequently encountered with the older children and teenagers. metatarsus adductus is an adduction of the forefoot that occurs in : live births. the classic view of it resulting from intrauterine positioning is debated, since genetic factors may contribute. sleeping in the prone position also seems to promote it. this is a frequent cause of intoeing during the fi rst year of life and is more frequently encountered on the left side. normally, in the neutral position, the heel-bisector line drawn through the midline axis of the hindfoot passes through the forefoot at the second web space. in cases of metatarsus adductus, the line passes lateral to the third toe. therefore, an angulation exists medially between the forefoot, or metatarsals, and the hindfoot. sometimes a transverse crease is present on the medial side of the foot and the lateral border of the foot is convex (fig. metatarsus adductus associated with an inversion of the foot is named metatarsus varus and adduction of the fi rst metatarsal is metatarsus primus varus. metatarsus adductus is frequently associated with internal tibial torsion. metatarsus adductus associated with retracted equinus -the inability to dorsifl ex at the ankle -is indicative of a diagnosis of clubfoot. dysfunctions of the feet might not seem grave, but left untreated they will lead to postural dysfunctions and compensatory dysfunctions of the feet, with diffi culty wearing shoes and the development of bunions and hammer toes. a group of children with metatarsus varus, followed an average of years, showed that % maintained a moderate, although asymptomatic, deformity and % demonstrated residual deformity and dysfunction (stiffness). the opinion is that metatarsus adductus left untreated will persist into adulthood in - % of cases. , furthermore, some cases only appear to be clinically improved because of a compensatory pronation of the midtarsal joints and rearfoot. metatarsus adductus is classifi ed according to its fl exibility. normally, an infant should extend and abduct the foot when being tickled (e.g. with a toothbrush) along the lateral border of the foot, particularly over the fi fth metatarsal head. the inability of the infant to react in such a way is indicative of metatarsus adductus. the physician should consider the total body approach and treat any dysfunctional mechanics, particularly of lisfranc's joints (tarsometatarsal) following the principles of functional procedures. the parents should be encouraged to stimulate abduction of the forefoot, using a toothbrush or similar stimulus, as described above. in more severe cases it should be proposed that stretching exercises be practiced several times a day (e.g. at each diaper change). the calcaneus is maintained between the thumb and index fi nger, while the forefoot is gently pulled into a corrected position, holding the correction for seconds and repeating the process about fi ve times. it should be stressed that this exercise should be done properly, without creating a valgus of the hindfoot. if these treatments fail, and also in cases of clinical conditions severely rigid feet, a series of casts are used to gradually straighten out the deformity. ctev, or clubfoot, is a complex deformity of unknown pathogenesis with several etiologic hypotheses that range from genetic to intrauterine factors. the head-body angle of the talus (declination angle) which normally increases after the th week of gestation has been found to be decreased in ctev, associated with hypoplasia of the talus. more recently, studies indicate that talar deformity is not the primary lesion, but follows loss of spatial orientation of the deltoid and spring ligaments and tibialis posterior tendon insertion, with contracted soft tissues. ctev is a relatively common congenital deformity that occurs with geographical differences ranging from . : live births in japan to : in the south pacifi c ( . : live births among caucasians). about % of the cases are bilateral. the male-to-female ratio for affected children is . : . , clubfoot deformity presents with different components: hindfoot equinus (inability to dorsifl ex), hindfoot varus and metatarsus adductus. the fl exibility of the deformity is important to determine the degree of severity. classic treatment consists of manipulation of the foot followed by casting. generally, casting is attempted for months; if unsuccessful, surgery is planned. osteopathic procedures should be employed as early as possible for best results. every bone of the hindfoot -the calcaneus, talus, navicular and cuboid bones -should be evaluated and treated to release any dysfunctional relationships between them and to equilibrate the soft tissues surrounding them. the deltoid and plantar calcaneonavicular (spring) ligaments are of particular importance and should be balanced with gentle fascial release procedures. pes cavus, or high-arched or hollow foot, should fi rst make you think of ruling out an underlying neurologic disorder as the primary etiology. anterior pes cavus, where both the medial and lateral longitudinal arches are high, is benign. medial pes cavus is more severe, often with claw foot deformity of the toes. the two may be differentiated by dorsifl exing the foot. in the presence of medial pes cavus the claw foot deformity of the toes increases with dorsifl exion of the foot. the position and range of motion of the hindfoot bones, particularly the talus, should be evaluated. hollow foot is often associated with a fl exionexternal rotation pattern of the craniosacral mechanism. you must differentiate total fl at foot or total hollow foot from partially fl at foot or partially hollow foot. in the latter, only the posterior portion of the longitudinal arch is involved, resulting from an imbalance of the subtalar, calcaneocuboid or cuneocuboid articulation. a rigid pes planus is a pathologic fl at foot, also named tarsal coalition, in which one or more of the tarsal bones that should have a joint between them become fused. in infants the fused joints are cartilaginous and are still relatively fl exible. thus the condition is typically not symptomatic before adolescence. physiologic pes planus is a loss or reduction of the longitudinal arch ( fig. . . ) that can be reestablished when the child stands on their toes. physiologic pes planus is fl exible and often associated with generalized ligamentous laxity. in a sample of primary school children, . % demonstrated fl at feet, and being overweight was shown to increase the prevalence of the condition. because of ligamentous laxity and/or obesity, the child's ankles cave in. the plantar calcaneonavicular ligament plays an important role in maintaining the arch of the foot ( fig. . . ). it supports the head of the talus and is part of the astragalonavicular joint. any dysfunction of the plantar calcaneonavicular ligament affects the head of the talus that tends to be displaced downward, medially and forward by the weight of the body. the tibialis posterior, an inversion muscle, lies directly below the plantar calcaneonavicular ligament and participates considerably in maintaining the longitudinal arch of the foot. in cases of dysfunction of these structures, the foot becomes fl attened, expanded and turned laterally. this condition has been suggested as a cause for tarsal tunnel syndrome. it has also been suggested as contributing to back and knee problems later in life, but no evidence supports this contention. flat feet and dysfunction of the spine are, however, very often two components of the same problem, where postural mechanics are involved. flat foot is usually associated with an extension-internal rotation pattern of the craniosacral mechanism. the treatment of physiologic pes planus with orthotic devices is controversial. insole arch supports diminish some of the muscular activity that maintains the arch and tend to weaken the muscles. two studies suggest an association between wearing shoes at an early age and fl at feet. , this stresses the importance of allowing the feet to grow and develop without constraint. parents should be reassured about their concerns regarding the child's appearance and gait. this condition tends to improve between and years of age. to promote optimal growth without dysfunctional mechanics, the osteopathic practitioner should consider the global posture of the child. check for rearfoot valgus by assessing the position and freedom of the calcaneus and talus. check also for internal rotation dysfunction of any of the tarsal bones. encourage the child, through their parents, to maintain a healthy lifestyle, to go barefoot as much as possible and not to become overweight. physical activities that strengthen foot inversion, such as walking on the lateral borders of the feet or picking objects with the toes, should be recommended. positional calcaneovalgus, the result of intrauterine malposition, is a fl exible dorsifl exion of the ankle with a mild subtalar joint eversion. it is frequently associated with external tibial torsion and has the appearance of fl at feet. treatment follows the principles of functional procedures to address the subtalar dysfunction. sprains and strains are common in the pediatric population. young athletes are particularly vulnerable. activities that involve jumping and landing, as in skateboarding, often result in such injuries. these injuries are, however, not limited to young athletes. young children can sustain sprains and strains with activities of daily living, such as ascending or descending stairs. these injuries may be overlooked because of the child's tendency to get up and resume activity unless severely injured; however, if not properly addressed, such injuries can be the source of functional asymmetry and somatic dysfunction, often with sequelae in other anatomic areas at a later date. following a foot or ankle sprain that causes excessive or prolonged midfoot pronation, abnormal patellofemoral mechanics may result. traumatic twisting of the forefoot, most often inversion, commonly causes ankle injuries, often resulting in, but not limited to, sprains or strains involving the tibia, fi bula and talus. it should be remembered that these stresses may also result in specifi c dysfunctions between the fi bula and talus, the talus and calcaneus, the talus and navicular bone, and the calcaneus and cuboid, as well as dysfunctions between any of the other adjacent tarsal and metatarsal bones (figs . . , . . ). on physical examination, the acutely injured ankle presents with pain and swelling and, with more severe injuries, ecchymosis. ecchymosis indicates possible ligamentous tears or bony fracture necessitating radiographic evaluation. further, if the subject is not willing to bear weight on the injured ankle, or if signifi cant edema is present, radiographic evaluation is also appropriate to evaluate the extent of injury. once bony fracture has been ruled out, soft tissue injuries may be treated with osteopathic manipula-tion by employing indirect principles. under these circumstances, the patient should experience no aggravation of discomfort during the treatment procedure and will often feel a signifi cant reduction of pain and swelling following the intervention. posttreatment reduced weight bearing and avoidance of stressful activities should be recommended. immobilization of the injured area with strapping methods should be considered for adolescents and individuals likely to be involved in weight-bearing activities. when there is no more pain for a week, a rehabilitation program can be organized to work the injured ankle in full range of motion with progressive resistance exercises. exercises with a balance board, to strengthen proprioception, function and coordination, are also indicated. the patient places the foot on the board and fi rst does fl exion-extension movements, followed by rotation of the ankle around the ball (fig. . . ) . a thorough history and physical examination should be performed to rule out diagnoses such as cerebral palsy, which can present with rotational misalignment of the legs. internal tibial torsion is said to be the result of intrauterine positioning or from the child's habit of sitting on their feet. this is often noticed by the parents between and years of age and is a common cause of intoeing in children under years of age. internal tibial torsion is more often bilateral; when unilateral, the deformity most commonly affects the left side. parents complain that their child is clumsy, trips and falls easily, although intoeing in athletes has been suggested as benefi cial in activities like sprinting. about - % of all torsional deformities resolve spontaneously by maturity. when it does not resolve, however, dysfunctional rotation results in improper alignment of the lower limb and is associated with arthrosis of the hip, knee and ankle. external tibial torsion is usually diagnosed later and demonstrates a tendency to increase with age. it is associated with conditions of the extensor apparatus as unstable patellofemoral joints and osgood-schlatter disease. , examination of rotation of the tibia is best done with the child in the prone position with their knee fl exed to °. this allows measurement of the footthigh angle, the angle formed between the long axes of the femur and the foot. the osteopathic practitioner should consider a total body approach with specifi c attention to intraosseous and myofascial tensions in the lower limbs. the relationships between the fi bula and the tibia, as well as between the tibia and the femur and the tibia and the talus, should be balanced. osteopathic procedures directed at functional alignment and balance of the lower extremity improve function and should reduce stressful compensatory patterns that may later result in patellar tendonitis and arthritis. femoral torsion is defi ned by the angle between the femoral neck axis and the transcondylar axis of the distal femur. femoral torsion can be internal (femoral anteversion) or external (femoral retroversion) and results in the knees pointing toward or away from each other, respectively. a normal femur is anteverted, i.e. the femoral head and neck are rotated anteriorly with respect to the femoral condyles. babies have ° of femoral anteversion. this decreases by about . ° per year to reach ° in adult life. femoral anteversion is also a very common cause of intoeing in children under years of age, the child being obliged to internally rotate the femurs in order to re-center the femoral heads in the acetabula. observation of the child's gait allows one to differentiate between intoeing that is the result of internal tibial torsion as compared to femoral anteversion where the patellae are positioned more medially on the knees. the child trips and falls frequently and does not like to sit with their legs crossed, preferring to sit in a 'w' position (fig. . . ) . parents note that the child's shoes are very quickly worn out in an asymmetric pattern. studies in adults in whom the condition remained uncorrected found a correlation between femoral anteversion and arthritis of the knee. normally, hip range of motion shows greater amplitude in medial rotation than in lateral rotation. abnormal femoral anteversion can be predicted (± sd from the mean) if the difference between medial and lateral rotation is ° or more. the osteopathic practitioner should consider a total body approach and release intraosseous and myofascial tension in the lower limbs. the pelvis should be diagnosed and treated if necessary, as well as the coxofemoral joint. somatic dysfunction of the innominate, particularly during periods of growth, is signifi cant because of the infl uence it can have on the position of the femur. genu varum and genu valgum -also known as bowlegs and knock-knees, respectively -are common angular deformities of the lower extremities in children. all babies are born bowlegged. between the ages of and years the bowlegging gradually decreases, and by years the average child is maximally knock-kneed. the knock-kneeing straightens minimally over the next several years and, by age years, most children have reached the typical adult confi guration, which is slightly knock-kneed. persistent genu varum is better tolerated functionally than valgus, which causes stress to the medial aspect of the knee joint with the subsequent development of pain. the wider the varus or the valgus, the greater the shear stress (lateral-medial forces) on the joint. an angular deformity is not physiologic when it is asymmetric or painful and radiographs might be necessary. bilateral varus is associated with craniosacral fl exion of the sacrum, and bilateral valgus with a sacrum in craniosacral extension. unilateral varus problems are very often associated with fl exion-external rotation patterns on the same side at the level of the pelvis, the temporal bone or the occipital bone. similarly, unilateral valgus problems are associated with extension-internal rotation patterns of these same areas. using indirect procedures from a total body perspective, treatment is directed at specifi cally diagnosed dysfunctional mechanics. the distance between the knees (with the ankles together) of children who have varus, or between the ankles (with the knees together) of children who have valgus, can be measured to follow the response to treatment. the knee can also present minor strains. a commonly found pattern occurs when an increased medial femoral torsion is combined with excessive lateral torsion of the tibia. this is found more often as the result of physical activities, such as in skiing, when the ski is stuck in the snow, slightly abducted, and the rest of the body moves forward. the relationship between the tibia and the femur should be balanced to address these strains. congenital dislocation of the patella is rare and may be isolated or associated with other limb malformations. patellar instability is not a congenital condition, although anatomic confi gurations such as patella alta, trochlear dysplasia and ligamentous laxity are thought to participate in the instability. mri permits visualization of the nonosseous components of the patellofemoral articulation in the child. the cartilaginous composition of the articulation provides less restraint to lateral movement of the patella that allows instability. the trilaminar soft-tissue structures surrounding the patella present interconnections with the fi bers of the iliotibial tract, lateral hamstrings and lateral quadriceps retinaculum. tightness in these structures has been suggested as causing excessive posterior and lateral pull, contributing to patellar instability, especially if the medial patellofemoral ligament is injured and cannot stabilize the knee. these structures are linked to the pelvic bone, and recurrent dislocation of the patella can be associated with pelvic dysfunctions that interfere with the balance transmission of weight-bearing forces. osgood-schlatter disease occurs mainly in athletic adolescent boys. it is suggested that a welldeveloped and inelastic quadriceps creates a traction apophysitis on the tibia, with the development of loose ossicles and elongation of the patellar ligament leading to patella alta. patients with osgood-schlatter disease also present with increased external tibial torsion that, in association with other factors, has been suggested to predispose to the onset of the disease. the osteopathic practitioner will consider a total body approach and release the pelvis, the hips, the knees and the patellofemoral articulations ( fig. . . ). myofascial release should be considered for the thigh and patella. gentle and pain-free stretch-ing exercises should be done at home on a regular basis and should address tension in the quadriceps, the upper and lower iliotibial tract, the hamstrings, the hip fl exors, the hip abductors, the gastrocnemius and the soleus. a long-term maintenance program should include strengthening in terminal knee extension in association with isometric exercises of the above muscles. patellar knee sleeves are sometimes useful. they might have proprioceptive effects offering support. patients feel less pain and the support provides some kind of reassurance. different terms describe hip dysfunctions. 'developmental displacement of the hip' (ddh) is proposed in replacement for 'congenital dislocation of the hip' to stress the fact that the condition can occur prenatally or postnatally. the different variants of the abnormalities of the hip joint include shallowness of the acetabulum and capsular laxity with resultant instability and propensity for dislocation. ddh refers to a defi cient development of the acetabulum that could lead to subluxation and dislocation. the femoral head remains well covered by the acetabulum in the early fetal period (between and weeks) and dislocation does not occur at this early time. however, at birth, the human acetabulum is shallower than at any other time during development and is consequently vulnerable for hip instability. mechanical factors seem to play a role in neonatal hip instability. moderate loading of the hips at ° of fl exion maintained for hours has been shown to distend the articular capsule and to produce deformation and dislocation of the joint resembling that found in ddh. modifi cations in the pressure on the cartilaginous acetabulum are thought to interfere with normal bone growth. uterine constraint is proposed by numerous authors as an explanation for the association between ddh and other deformations. foot deformity, congenital torticollis, congenital postural scoliosis , and plagiocephaly are frequently associated with ddh. the sleeping position of the infant, with a preference to lie on one side (the 'side-lying syndrome'), has also been proposed as a contributing factor to ddh. leg postures, associating extension and lateral rotation, critically predispose the infant to hip dislocation during fetal life and at birth. interestingly, the newborn psoas muscle is totally relaxed in full abduction, fl exion and lateral rotation. this muscle is always a lateral rotator of the hip, but exerts a much greater effect when the femur is abducted. extending the hip results in a levering action that is potentially critical if associated with other contributing factors such as acetabular or femoral ante-version and dysplasia. caution should, therefore, be exerted when moving the leg into combined extension and lateral rotation. ddh occurs in : live births and is more frequently encountered on the left side. being female, fi rst-born, having been carried or delivered in the breech position , , and having a family history of acetabular dysplasia or ligamentous laxity are the main risk factors. dislocation of the hip requires orthopedic attention. clinical examination reveals asymmetries in the number of skin folds on the thigh and the inability to completely abduct the thigh when the knee and hip are fl exed. the malposition of the femoral head may cause the leg on that side to look shorter than the other. barlow and ortolani positive tests confi rm the diagnosis and are performed with the child supine on a fl at pad, placing the fi ngers on the baby's greater trochanters and the thumbs on the inside of the lower portion of the thighs and knees. the hips and knees are fl exed to °. the barlow test consists of adducting the legs and pushing down gently on the knees in an attempt to disengage the femoral head from the acetabulum. a 'clunk' will be felt as the femoral head dislocates. the ortolani test relocates a dislocated hip and is performed by slowly abducting the thighs while maintaining axial pressure. the fi ngers on the greater trochanter exert a movement in the opposite direction to assist the return of the femoral head to the acetabulum. the examiner will again feel, and hear, a 'clunk.' diagnostic ultrasonography may be carried out after - weeks and radiographs after - months; before these ages there is insuffi cient ossifi cation for the tests to be diagnostic. different methods of treatment are proposed for ddh, with good results. abduction devices (pavlik harness) and traction followed by plaster immobilization are always done with special care because of the risk of aseptic necrosis of the femoral head. a program of home abduction-adduction exercises administered by the parents has been successful in infants with limited abduction and acetabular dysplasia without dislocation. developmental dysplasia of the hip -insuffi cient depth of the acetabulum to accommodate the femoral head -in the infant can be associated with pelvic imbalance, such as intraosseous dysfunction of the innominates and sacrum, coxofemoral dysfunctions and eventually with craniosacral dysfunctions. the innominate bone needs to be in a neutral position in order to provide a satisfactory acetabular placement. an internally rotated innominate results in a higher position of the acetabulum, leading to an apparently shorter leg on that side. this can be confused with the apparent inequity of leg length found in association with hip dislocation. osteopathic procedures attempt to balance the craniosacral mechanism of these children. the relationship between the sacrum and the occiput, the temporal bones and the innominates should be balanced. special care is given to myofascial structures responsible for pelvic tensions or pelvic asymmetry. myofascial procedures should be applied to the periarticular muscles of the hip, in particular the iliopsoas, the adductors and the abductors, to release contracture of the joint and improve restrictions of motion in adduction or abduction. the treatment of dysplasia is intended to stabilize the femoral head in the acetabulum and to allow the growth of a symmetric pelvis with a balanced sacrum, innominates and hips. dysfunctional interosseous relationships between the sacrum and the innominates, and between the innominates and the femurs, should be identifi ed and treated. any dysfunctional intraosseous relationship between the ilium, ischium and pubes should be also balanced, and, if present, intraosseous dysfunction of the sacrum treated. clinical examination of these children should be repeated during the st year, with an annual follow-up, until full skeletal maturity. dysplasia may result in early development of osteoarthritis of the hip. [ ] [ ] [ ] [ ] treatment should be directed at promotion of function and prevention of future degenerative changes. by the age of years children should be walking with a heel-toe gait. after this age, toewalking is abnormal and can be due to an underlying neurologic disorder. a tight achilles tendon may be present, but in other cases nothing will be found. look for any extension dysfunction of the craniosacral mechanism. balance the sacrum and the craniocervical junction. release the posterior myofascial components of the spine and inferior limbs. teach the child to walk heel-toe. because serious medical and orthopedic conditions may be responsible for limping, any such underlying pathology should be ruled out before using manipulation as a primary treatment. for example, a limp or a waddling gait between the ages of and years might be associated with a congenital coxa vara, where the angle between the femoral neck and the femoral shaft is less than normal (< °). coxa valga is an increase in that angle (> °) and, in this case, the child may present with increased internal rotation and adduction of the hips. observation of the child while walking allows one to determine what area is dysfunctional. it is better to have the child bare legged to best visualize the different components of the lower extremity. observe the foot angle, the direction in which the child's feet point when they walk. observe for tibial and femoral torsions and the movements of the hips. determine which part is not following the global movement of the limb or if one side does not contact the fl oor in the same fashion. the postural balance should be evaluated and any dysfunctional asymmetries treated. an asymmetry of leg length might be present as the cumulative result of several dysfunctions. for example, an innominate in external rotation on the right side, combined with an innominate in internal rotation on the left side, will give the appearance of a longer leg on the right side. evaluate the range of motion of the different joints of the lower limbs and, utilizing appropriate manipulative procedures, treat any dysfunction identifi ed. otitis media (om) is among the most common of illnesses affecting preschool children. almost every child experiences om at least once before their third birthday and % of children experience recurrent om. its prevalence has increased considerably recently, resulting in an enormous economic burden to society. clinical classifi cations include acute otitis media (aom) and chronic otitis media with effusion (come). aom is a viral or bacterial infection, commonly secondary to an upper respiratory infection and usually occurring in young children from the age months to years. it presents with a sudden infl ammation in the middle ear, fever, pain and irritability. an incomplete resolution of aom or an obstruction of the pharyngotympanic tube (pt), also called the eustachian or auditory tube, may lead to an effusion in the middle ear containing common pathogenic bacteria. repeated episodes of acute symptoms are considered to be recurrent aom. come is a chronic infl ammation of the middle ear mucosa, with the retention of fl uid within the middle ear space that lasts more than months. it is a condition wherein irreversible changes have occurred, affecting the tympanic membrane, the pt or the middle ear. the multitude of studies attempting to identify the causative factors of om have provided multiple, and often opposite, results. this is probably because the etiology of individual cases of om is often multifactorial, including genetic, environmental, nutritional and behavioral factors. thus, the number of variables necessary for consideration makes such studies extremely diffi cult. the following have, however, been identifi ed as risk factors for the onset of om: genetic predisposition, , low birth weight, male gender, number of siblings, day-care attendance, not being breastfed, use of a pacifi er, , season of the year, , passive exposure to smoking and low socioeconomic status. on the other hand, breastfeeding, even for periods as short as months, has been shown to reduce the incidence of om in childhood. anatomic factors should also be considered. the ear, particularly the middle ear, and adjacent structures provide a site where genetic, environmental, nutritional and behavioral factors can interact, resulting in the development of om. the three parts of the ear -external, middle and internal ( fig. . . ) -are related anatomically and functionally to the temporal bone. the external ear consists of the auricle (pinna) and external acoustic meatus. the auricle on the lateral aspect of the head, at the level of the temporal bone, refl ects the global position of the temporal bone. a protruding auricle, for example, are often associated with external rotation of the homolateral temporal bone. the auricle functions to collect sound waves. the external acoustic meatus terminates in the tympanic membrane. its lateral part is membranous, continuous with the auricle. the medial part is surrounded by the squamous portion of the temporal bone above and the tympanic portion in front and below. the middle ear or tympanic cavity, an air-fi lled space, is located between the tympanic membrane laterally and the lateral wall of the internal ear medially. it contains three bones, or ossicles -the malleus, incus and stapes -that transmit vibrations from the tympanic membrane to the cochlea of the internal ear. the tympanic cavity is open posteriorly to the mastoid antrum, an air sinus located in the petrous portion of the temporal bone, and to the interconnected mastoid air cells. anteriorly, the tympanic cavity communicates with the nasopharynx through the pt. a mucosa covers the complete cavity, including its contents, the three ossicles and the two muscles (tensor tympani and stapedius), and forms the inner layer of the tympanic membrane. this mucosa is in continuity with that of the pharynx. the mastoid cavity, mastoid antrum and auditory ossicles are nearly completely developed at birth. the internal ear consists of several bony cavities, the vestibule, the semicircular canals and the cochlea that form the bony labyrinth. it contains the membranous labyrinth with the organ of hearing (the cochlear duct) and the organs of balance (the semi-circular ducts). the membranous labyrinth fl oats in the perilymph, the fl uid fi lling the bony labyrinth. the structures that form the internal ear are also nearly completely developed at birth. most of the above structures of the ear can be found nesting within the petrous portion of the temporal bone. in diseases of the ear such as om, as well as in balance and hearing disorders, this anatomic relationship confers great signifi cance on the temporal bone and its function and dysfunction. the temporal bone is formed by the squamous, petromastoid, tympanic and styloid parts. the petromastoid part develops in the cartilaginous otic capsule of the cranial base. the squamous and the tympanic portions are ossifi ed from mesenchyme. the tympanic portion (the tympanic ring) unites with the squama just before birth. total fusion of the temporal bone, except the distal part of the styloid, is complete by the end of the st year. nevertheless, the mastoid portion is completely fl at at birth. the mastoid process, a postnatal petrous development, begins to develop with the growth of the mastoid air cells and because of the traction from the tendon of the sternocleidomastoid (scm) muscle. the development of the mastoid process is dependent on the child's ability to lift their head (extend their cervical spine) and to rotate their cervical spine symmetrically. for this reason the prone position, recommended in the statement 'back to sleep, prone to play' is important. in this case, function determines structure, and children with torticollis will present with asymmetry in the shape and size of the mastoid processes. alternatively, infants with non-synostotic plagiocephaly may present with a fl attening in the area of the occipitomastoid suture, where compressive forces inhibit mastoid development. the expansion of the mastoid process is of particular signifi cance. the mastoid air cells that develop inside the mastoid during the growth period are important components of the complex system that regulates and buffers the fl uctuations of middle ear pressure. the volume of the mastoid air cells is about times the volume of the tympanic cavity. often compared to an air reservoir, the mastoid cavity is an active space for gas exchange through its submucosal capillary network the submastoid cell structure in humans is histologically similar to that found in the pulmonary alveolar and nasal membranes, and, therefore, is suitable for gaseous effusion and diffusion. the production of gas within the tympanomastoid cavity keeps the internal pressure at the same level, or higher, than atmospheric pressure. swallowing allows gas to be expelled through the pt into the pharynx. this positive pressure gradient prevents bacteria from entering the tympanomastoid cavity. the depth of the mastoid air cell system has been found to be shorter in children with secretory om compared with healthy individuals. decreased mastoid pneumatization has been proposed as a prognostic indicator for chronic infl ammation of the middle ear, as has poor outcome with om when the mastoid is poorly pneumatized. the mastoid cells connect to the tympanic cavity and through the pt to the nasopharynx. both mastoid cells and pt are of paramount importance in the normal function of the ear and, consequently, the pathogenesis of om. the pt connects the middle ear to the nasopharynx, balances pressure between the middle ear and ambient air, clears debris and secretions toward the nasopharynx and also protects the middle ear against nasopharyngeal secretions and noxious agents from the airways. it begins on the anterior wall of the tympanic cavity and extends forward, medially and downward to the nasopharynx posterior to the inferior meatus of the nasal cavity (figs . . , . . ). because of these close relationships between the middle ear and the nasopharynx, om, frequently described as a complication of rhinitis, may be considered to be a disease of the upper respiratory tract. descriptive and functional anatomy of the nose and nasopharynx is discussed in 'rhinitis' and 'sinusitis' below. the pt is shaped like two cones joined together at their apices. the posterolateral cone, shorter, approximately one-third of the pt, is osseous (protympanum), located inside the petrous temporal bone. it ends at the junction of the petrous and squamous parts of the temporal bone, immediately posterior to the foramen spinosum. the remaining two-thirds of the pt are fi brocartilaginous, partially fi xed to the cranial base, in a furrow following the sphenopetrosal synchondrosis, between the petrous portion of the temporal bone and the posterior border of the greater wing of the sphenoid. the upper border of the cartilaginous pt is arched laterally and looks like a hook on transverse section. a fi brous membrane completes the tube. the tubal isthmus, where the pt diameter is smallest, joins the two cones of the pt. the cartilaginous portion has a greater vertical inclination than the osseous portion. the length of the pt in the adult is approximately - mm. the pt in the newborn is approximately half its adult length and reaches approximately % of its adult length by years of age. the ratio of the length of the cartilaginous and junctional portions of the pt to the length of the bony portion is : in infants and : in adults. the pt in infants is not only shorter, it is also more horizontal, and, therefore, the clearance function is less effective. additionally, when the bony portion of the pt of children with secretory om is compared to that of healthy children, it is found to be even shorter. the pt connecting the middle ear and nasopharynx has been compared to the bronchial tree connecting the lung to the nasopharynx. the mucosal lining of the pt contains mucus-producing cells, ciliated cells, infants and children demonstrate an increase in the density and size of the folds in the tissues lining the pt and it has been suggested that this plays a role in protecting the middle ear. the gas exchange through the submucosal connective tissue seems to be accelerated when the submucosal vasculature dilates and blood fl ow is augmented due to middle ear infl ammation. alternatively, gas exchange can be diminished when the mucosa thickens and submucosal tissue proliferates due to extended infl ammation. in normal tubal function at rest, the pt is usually collapsed, fulfi lling its protective role against retrograde infection from the nasopharynx. the tensor veli palatini (tvp), the dilatator tubae (dt), the levator veli palatini (lvp) and the salpingopharyngeus muscles are all attached to the pt. the tvp arises from the scaphoid fossa, from the spina angularis of the sphenoid and from the lateral wall of the cartilage of the auditory tube. it then descends verti-cally, becomes tendinous and inserts onto the pterygoid hamulus, the lower extremity of the medial pterygoid plate of the sphenoid, and medially onto the posterior border of the hard palate to form part of the palatine aponeurosis. the dt is attached above to the pt, particularly to its membranous portion. it intermingles below with the tvp and rounds the pterygoid hamulus. most authors agree that contraction of the tvp opens the pt lumen and therefore ventilates the middle ear; , this action is particularly signifi cant for the fi bers of the dt. the lvp arises from the medial lamina of the cartilaginous pt and from under the apex of the petrous portion of the temporal bone. it extends into the palatine velum, its fi bers broadening to the middle line, where they blend with those of the opposite side. the salpingopharyngeus arises from the inferior part of the pt, is directed downward and blends with the posterior fasciculus of the pharyngopalatinus ( fig. open it -for example, swallowing, crying or yawning. this balances the pressure gradient between the atmosphere and the tympanic cavity. when the mechanism of swallowing is dysfunctional, opening of the pt is not effi cient. sustained collapse follows with the development of negative middle ear pressure and retraction of the tympanic membrane. the subsequent potential for aspiration of nasopharyngeal secretions into the middle ear may result in om. furthermore, dysfunctional swallowing may also cause gastroesophageal refl ux, another risk factor for om. in addition, if present, the frequent use of a pacifi er may encourage infantile deglutition, i.e. forward tongue thrust when swallowing. although the use of a pacifi er does not increase the incidence of respiratory infections, there is evidence that constant use affects the occurrence of aom, possibly because of alteration in the pressure equilibrating function of the pt. dysfunction of the pt may result in negative middle ear pressure that, in turn, impairs auditory sound conduction to the cochlea of the internal ear affecting hearing. pt dysfunction can also affect hearing through its impact on the tensor tympani muscle. the tensor tympani muscle is continuous with the tvp. it arises from the cartilaginous portion of the pt and the adjoining sphenoid, and inserts on the manubrium of the malleus. , tensor tympani contraction draws the malleus medially, increasing tympanic membrane tension while pushing the incus and stapes medially against the fenestra vestibuli. this results in an increased intravestibular pressure that, under normal circumstances, serves to dampen violent noises. consequently, dysfunction of the pt may be associated with both negative middle ear pressure and spasm of the tensor tympani with resultant disturbance of hearing. anatomic developmental delays such as immaturities of the pt and surrounding structures or of the neuromuscular system may result in dysfunctional opening of the pt in infants and children. most of the time, the dysfunctional opening of the pt improves with age as the base of the neurocranium and the viscerocranium develop. this too, however, can contribute to the complex interaction of phenomena that predispose the child to develop om. the base of the skull (figs . . , . . ) goes through signifi cant developmental changes during the fi rst years of life. two critical phenomena participate in this development. first, the diverse stimulation produced by normal orofacial functions, such as suckling and swallowing, spurs the growth of structures, particularly the pterygoid processes in which the involved muscles insert. secondly, but concomitant with the above, the progressive fl exion of the cranial base, associated with the anteroposterior growth of the skull, contributes to positional changes of both the pterygoid processes, which become longer and more vertical, and the petrous portions of the temporal bones, which become externally rotated. additionally, several changes occur in the viscerocranium, such as the increase in height of the vomer that accompanies the expansion of the nasal cavity. these developmental changes are concomitant with the development of the pt and its associated muscles. therefore, any structural imbalance that develops in association with the development of the base of the skull or viscerocranium may adversely affect the ventilation and drainage of the ear. a dysfunctional tongue posture may affect the tongue's pumping function on the palatine aponeurosis and, therefore, the associated pt ventilation that occurs during swallowing. tongue posture adapts to oral development and pt function appears to be diminished in long-faced adenoidal children. additionally, children with signifi cant overbites are found to be more predisposed to develop pt dysfunction. body position also seems to infl uence pt opening. evidence shows a correlation between the lateral recumbent position, where one ear is positioned downwards, and a lower pt opening function on that side. this reinforces the need to avoid the repeated use of the same sleep position for infants. any cranial somatic dysfunction of the base of the skull may disrupt its developmental sequence as well as affecting tongue posture, with resultant impact on pt growth and function. this may be a cranial somatic dysfunction of the bony constituents of the cranial base, the occiput, sphenoid and temporal bones, or dysfunction of any component linked to the vascular supply and innervation of the myofascial structures involved in suckling and swallowing. the tvp and the tensor tympani are innervated by branches from the otic ganglion, located immediately below the foramen ovale, on the medial surface of the mandibular nerve (cn v ). the glossopharyngeal nerve (cn ix) innervates the stylopharyngeus, and the accessory nerve (cn xi) innervates the palatal muscles through the pharyngeal plexus. they both exit the skull through the jugular foramen. the hypoglossal nerve (cn xii) innervates the intrinsic and extrinsic tongue muscles. it exits the skull through the anterior intraoccipital synchondrosis, the site of the hypoglossal canal of the occipital bone when ossifi cation occurs. consequently, effi cient pt function requires equilibrium among surrounding bony structures, such as the temporal bones, occiput, sphenoid and mandible. it also requires that associated myofascial structures be free of dysfunction. a dysfunctional pt creates a terrain where other risk factors are reinforced. recurrent bilateral om with effusion develops when poor pt function is allied with diminished immune status. the allergic infl ammatory response that often occurs in the nasopharynx also occurs in the middle ear, and the prevalence of allergic rhinitis is signifi cantly higher in children with om with effusion than in healthy children. , the allergic infl ammation in atopic children is not localized in one area only, but manifests itself in the middle ear on both sides, as well as in the nasopharynx, demonstrating totally the united airways concept. mucosal infl ammation with release of histamine and other mediators following nasopharyngeal exposure to an allergen may, consequently, be responsible for pt obstruction and dysfunction. chronic allergic infl ammation of the upper airway may lead to lymphoid hypertrophy with increased size of adenoidal and tonsillar tissue. in such a case, with edema and infl ammation of the posterior nasopharynx, the enlarged adenoids may obstruct the pharyngeal ostium of the pt. tubal tonsil hypertrophy is a possible etiology for om, when recurrence appears after adenoidectomy. the pt mucociliary apparatus contains components that have an important role in eliminating middle ear debris by moving it toward the nasopharyngeal orifi ce. additionally, specialized epithelial cells express and secrete surface-active materials that appear to facilitate the muscular action of the pt opening and to protect the middle ear against infections. conversely, many viruses impair the mucociliary function of the pt epithelium and perturb the nasopharyngeal bacterial fl ora, increasing the adherence of bacteria to the epithelial cells. bacteria and respiratory viruses (e.g. the respiratory syncytial virus or infl uenza viruses) are common causes of middle ear infection. [ ] [ ] [ ] because of the connection between the upper and lower airways, the pathophysiologic site of origin is frequently the nasal pathway. babies born in the fall begin their lives during the peak seasons for viral exposure and the development of respiratory infections, a risk factor for om. additionally, impaired or decreased nasal mucociliary activity may also cause pt mucociliary dysfunction. thus osteopathic procedures that facilitate the clearance of secretions and the mucociliary action of the pt and upper airways are indicated. blood fl ow to the region should also be improved. gastroesophageal refl ux may also predispose to bacterial infection. possibly because of refl ux, infants fed in the supine position demonstrate abnormal postfeeding tympanographic results compared to infants fed in the semi-upright position. signs of aom include fever, insomnia and the presence of pus in the middle ear with a tympanic membrane that appears bulging and erythematous when observed by otoscopic examination. ear infections may be painful, causing irritability, rubbing of the affected ear, loss of balance and impaired hearing with lack of response to moderate sounds. although it is generally thought that om causes permanent hearing loss, this has not been demonstrated. transient mild to moderate hearing loss associated with om has, however, been shown to cause delays in communicative development. osteopathic considerations for the treatment of om are directed at augmenting the body's defenses against infection and its recuperative power after infection is present. mainstream medical interventions are often fraught with controversy. because the infectious agents responsible for om are both viral and bacterial, antibiotic therapy, although appropriate for bacterial infection, is not universally effective. guidelines for determining when to employ antibiotics and other modalities are available. , , , the use of tympanostomy tubes is controversial. , consequently, non-toxic interventions like osteopathic treatment, which appear to reduce the need for antibiotics, have been shown to be of potential benefi t as adjuvant therapy for children with recurrent aom. diagnosis should begin with observation. start with an overall evaluation of the child's posture. look at the pectoral girdle, often protracted in patients with ent infections. observe the cervicothoracic junction, the cervical spine and its relationship to the skull for lack of mobility and vertical compression. these patients may demonstrate a shrugged shoulder posture, with the appearance of a shortened neck. observe the auricles of the ear bilaterally for deformity, asymmetry of position and relative external or internal rotation. the appearance of the ear follows the temporal bone which, in turn, affects the function of the pt. examine the parietomastoid and occipitomastoid sutures bilaterally. look for fl attening or compression of the area. because ear position refl ects temporal bone position, asymmetry of the ears is often associated with asymmetry of cranial shape. non-synostotic plagiocephaly has been shown to be associated with an increased incidence of om. enquire if the child repeatedly pulls at one ear. this will often occur on the side of compression of the parietomastoid and occipitomastoid suture. study the face. open mouth facies are indicative of mouth breathing and nasal obstruction, predisposing to om. diagnosis and treatment of dysfunction in this area is discussed in part . , 'mouth breathing'. next, perform a palpatory examination. begin by evaluating the upper thoracic spine, ribs and pectoral girdle for somatic dysfunction. the viscerosomatic refl exes from the upper respiratory tract, including the ear, are to be found at level of t -t . somatic dysfunction in this area results in increased sympathetic tone with vasoconstriction affecting the ears, nose and throat through somatovisceral refl exes. mechanical dysfunction of the upper thoracic spine (t and t ), associated ribs, sternum and clavicles impairs lymphatic drainage from the head and neck. further evaluate the remainder of the thoracic cage and thoracoabdominal diaphragm which, when dysfunctional, can also impair lymphatic circulation. utilizing indirect principles, treat any dysfunction identifi ed in the above areas. examine the cervical region for somatic dysfunction. pay particular attention to the occipitoatlantal and atlantoaxial articulations, to the myofascial structures for their relation to lymphatic nodes and vasculature, and to the scm muscles that, when dysfunctional, impact the function of the temporal bone. treat any identifi ed dysfunction. evaluate the skull. begin by assessing the cranial base, paying attention to the sphenobasilar synchondrosis and temporal bones. the articulations of the temporal bones should be examined. the occipitomastoid sutures are important for their impact on the contents of the jugular foramen: cranial nerves ix, x and xi. the petrobasilar suture and sphenopetrosal synchondrosis are often dysfunctional in the infant's skull. dysfunction of these articulations may affect the petrous portion of the temporal bone containing the osseous part of the pt. furthermore, the cartilaginous portion of the pt is located beneath the sphenopetrosal synchondrosis and free motion of the petrous portion of the temporal bone, in external and internal rotation, facilitates the clearance of secretion from the pt. next, evaluate the temporal bones for intraosseous dysfunctions between the petrous, squamous and tympanic portions. palpate for the cranial rhythmic impulse (cri) at the level of the mastoid. intraosseous mastoid cranial respiration may promote mastoid cell function. examine the relationship between the mandible and the temporal bones. there is usually tenderness in the area. any temporomandibular dysfunction can affect the mobility of the temporal bones and the myofascial structures of the anterior neck below. the pt is commonly cleared by the actions of swallowing and yawning. these actions can be impaired by dysfunction of the mandible and its relationship to the tongue and soft palate. treat identifi ed dysfunction. specifi c attention should be paid to the effi cient clearance of secretions from the pt and mastoid cavities. this activity may be stimulated by the mastoid pump procedure and the galbreath technique. when possible, the rate and amplitude of the cri should be monitored during the above procedures. following the cri during the mastoid pump enhances the effi cacy of the procedure. the specifi c treatment of cranial dysfunctional patterns will augment the amplitude of the cri, improving fl uid mobility and affecting low frequency oscillations in autonomic nervous system (ans) physiology. counsel the caregivers to maintain a healthy lifestyle for the child. maintain a regular sleep-wake cycle. provide a balanced diet with adequate hydration and avoiding refi ned carbohydrate as much as possible. bottle feed and nurse in a semi-upright position and never put the infant to bed with a bottle. as much as possible, limit pacifi er use to moments when the infant falls asleep and try to eliminate its use after the age of months. avoid exposure to passive smoke. when bathing the infant, limit the amount of water entering their ears. caregivers should be instructed to lay the child on their side, with the problem ear up. they should then massage the mandibular region, applying gentle skin traction from the area anterior to the ear in the direction of the chin. this tends to open the pt and the position employs gravity to facilitate drainage. they can also gently caress around the ear, particularly over the mastoid region. these actions allow the caregiver to actively participate in the child's recovery. they sensitize the caregiver to the health status of the child and promote relaxation for the child. encourage the caregiver to play with the child in a fashion that promotes mimicry of the production of sounds in the throat and the clicking of the tongue by pulling it quickly from the hard palate. all activities encouraging action of the myofascial structures connected to the pt will tend to open it and facilitate its drainage. rhinitis is the infl ammation of the nasal mucous membranes. acute rhinitis may be the consequence of a viral infection, whereas allergic rhinitis is caused by an immune-mediated response to any one or more of a myriad of allergens. other classifi cations include atrophic rhinitis and vasomotor rhinitis. although these conditions are the result of differing etiologies, they are all affected by the presence of somatic dysfunction. it is an established osteopathic dictum that the body possesses the inherent ability to heal itself. the presence of somatic dysfunction can predispose the individual to develop rhinitis or interfere with the body's recuperative mechanisms. knowledge of the anatomy and physiology of the nasal cavities and the mucosa lining their walls is absolutely necessary to understand the etiologies of nasal dysfunction and how osteopathic principles may be applied to promote health in this area. the nose is divided by the nasal septum into two cavities, or fossae. the two nasal cavities open anteriorly by way of the anterior naris, or nostril. they are continuous posteriorly by way of the posterior nasal apertures, or choanae, into the nasopharynx. the nasal septum represents the medial wall of each nasal cavity. it is formed by the perpendicular plate of the ethmoid, the vomer and the septal cartilage ( fig. . . ) . the roof of the nasal cavities is formed anteriorly by the nasal spine of the frontal bone and the two nasal bones. the cribriform plate of the ethmoid, with numerous perforations for the olfactory nerves, is located behind the nasal bones. more posteriorly, the anterior aspect of the body of the sphenoid causes the roof of the nasal cavities to slope downward. the sphenoidal sinuses open into the nasal cavities from above, on each side of the nasal septum ( fig. . . ). the fl oor of the nasal cavities is the upper surface of the osseous palate. the maxillary palatine processes form the anterior two-thirds, while the palatine horizontal plates form the posterior one-third ( fig. . . ). the lateral walls of the nasal cavities demonstrate numerous structures. they are formed anteriorly by the maxilla, posteriorly by the palatine bone and superiorly by the ethmoid labyrinth and lacrimal bone. the inferior, middle and superior nasal conchae (turbinates), the most central portion of this lateral wall, by virtue of their curled shape add a great amount of surface area to the nasal cavities. the space below each turbinate is referred to as a meatus (fig. . . ) . the nasal vestibules, just inside the nares, are the anterior-most aspect of the nasal cavities. the nares and vestibules are bounded laterally by the alar and lateral cartilages, and medially by the cartilaginous septum and the connective tissue septum, the columella (fig. . . ) . the vestibule is lined with skin that contains sebaceous and sweat glands and coarse hairs (vibrissae) that assist in air fi ltration. the nasal cavities are completely covered with a lining that varies histologically in different areas. at the anterior part of the nasal cavities, in the vestibules, the lining is continuous with the facial skin. above, at the level of the upper border of the alar cartilages, the limen nasi defi nes the beginning of a lining formed by a non-keratinizing stratifi ed squamous transitional epithelium that evolves further into a pseudostratifi ed ciliated epithelium, the respiratory mucosa. this mucosa covers the remaining surface of the nasal cavities, except for the olfactory area that is covered with olfactory epithelium. this mucosa is also present in many other parts of the upper respiratory tract. several additional cavities communicate with the nasal cavities and demonstrate a continuum of the nasal respiratory mucosa. each of the nasal cavities communicates directly with the nasopharynx below, the nasopharynx continues to become the oropharynx, the laryngopharynx and the esophagus. the mucous membrane of the pharynx is continuous with that lining the mouth and larynx, as well as, through the trachea and bronchi, into the lungs. this continuum is a perfect example of the interrelationship between the different structures of the human body and exemplifi es the concept of the body as a unit. the respiratory mucosa plays a signifi cant part in the physiology of the nose, as well as in its pathologies, as is the case in rhinitis. the mucosa acts as a selective barrier, essential for the defense of the airways against inhaled pathogens. the respiratory pseudostratifi ed ciliated epithelium is formed by ciliated columnar or cuboidal epithelia with goblets cells, non-ciliated columnar cells and basal cells. mast cells and migrating lymphocytes, mainly t cells, are also present. under the basal lamina of this epithelium, the submucosa is adherent to the periosteum of the adjacent cranial bones and includes a fi brous layer with diffuse lymphoid tissue and a layer of mucous, seromucous and serous glands. an abundant mucous fi lm is produced by these glands and by the goblets cells. additional plasma exudation may occur, particularly in the presence of infl ammatory states. this fi lm gathers the particles and debris from the air that is inspired to sweep them away. almost all particles greater than μm and about % of those between and μm are collected. they end up either in the nasopharynx and oropharynx to be periodically swallowed, or in the anterior nasal vestibules. mucociliary clearance depends on the beating function of the respiratory cilia. they beat about times per minute. the frequency of the mucociliary transport rate is subject to various infl uences, such as mucus viscoelastic properties, airway epithelia alkalization that appears to be a stimulator or airway epithelia acidifi cation that decreases the rate. healthy function of the respiratory cilia results in constant motion of the mucous fi lm. the nasal ciliary beating propels the mucus secretions posteriorly in the direction of the nasopharynx. conversely, dysfunction of the drainage of the nasal respiratory epithelium leads to stasis and the accumulation of secretions within the nasal cavities. cranial somatic dysfunction -particularly of the frontal bones, sphenoid, ethmoid, maxillae and vomer, with resultant loss of their inherent motility -is a possible cause of mucociliary stasis. septal deviations are known to infl uence the dynamics of the nasal cavity and are often associated with a 'stuffy' nose. histologic studies confi rm this observation. loss of cilia, increased infl ammation and decreased density of the glandular acini are reported affecting the mucosa on the concave side of the septal deviation. the vasculature of the respiratory epithelium contributes signifi cantly to the function and dysfunction of the nasal cavities. the nasal mucosa contains a profuse subepithelial capillary network that supplies nutrients and water that through its evaporation contributes to the conditioning of inspired air. the vascular supply also includes a number of different capacitance vessels, i.e. the veins, venules and cavernous sinusoids that modulate blood fl ow. constriction and relaxation of these sinusoid vessels produce shrinkage or swelling of the mucosal surfaces that consequently regulates airfl ow and alters nasal patency. most of the venous cavernous sinusoids are located on the inferior conchae, major sites for nasal congestion. air conditioning is a major function of the nose. on inspiration, the air contacts the nasal mucosa and is brought to the appropriately conditioned temperature and humidity. by virtue of their contour, the conchae, located on the lateral walls of the nasal cavities, provide an increased surface area for the fl owing air to be in contact with the nasal mucosa. during expiration, some of the heat may be returned to the mucosa. when an individual is in a setting of °c, the nasal cavities warm the inspired air to °c. the air is also humidifi ed and this allows gas exchange within the alveoli of the lungs that takes place at °c and % relative humidity. therefore, nasal air conditioning requires large amounts of heat and water for conditioning the inspired air and the capacitance vessels seem perfectly designed to fulfi ll that need. they might also operate as a short-term reservoir, either for heat or for water. special conditions (e.g. hyperventilation) call for these reserves in order to provide cooling and evaporation. under normal circumstances and normal vasculature, a healthy nose succeeds in warming and humidifying the inspired air in order to protect the lungs. conversely, paucity in blood supply or moistening may reduce the effi ciency of the air conditioning system of the nasal cavity. the nasal vasculature also contains an extensive system of arteriovenous anastomoses. this allows for the rapid passage of blood through the mucosa without reducing the nasal patency. great amounts of arterial blood may fl ow through these anastomoses, providing heat exchange similar to hot water in a radiator. brain cooling appears to be the result of several mechanisms including a possible nasal and paranasal convection process. this latter process involves the transfer of cool venous blood from the respiratory mucosa to venous structures of the brain, such as the superior sagittal sinus between the parietal bones or the cavernous sinuses on each side of the body of the sphenoid, where arterial thermoregulation may then occur. on both sides, the cavernous sinus drains venous blood from the skin of the face and from the nose and mouth areas, and is in intimate contact with the internal carotid artery. the direction of fl ow in these sinuses is reversible. countercurrent mechanisms are suggested, where the arteriovenous anastomoses, present in the nasal vasculature, may also participate, allowing enhanced thermoregulation and brain cooling in hot conditions. changes in craniofacial morphology have been observed as adaptations to weather conditions. wider nasal cavities and larger paranasal sinuses are considered to be adaptive mechanisms that, under hot conditions, offer more evaporating surface and consequently greater cooling capacity, thus protecting the brain. orofacial dysfunction may alter nasal breathing and consequently the above functions. body position also affects the nasal vasculature. the supine position increases vascular congestion, thus decreasing nasal patency and the ability of the clinical conditions nose to condition cold, dry air. conversely, the upright position decreases vascular congestion. consequently, it is appropriate to enquire if the patient experiences excessive increased nasal congestion when they lie down as it may result in snoring and sleep disorders. furthermore, the nasal vascular supply is under the infl uence of hormones, psychological stress and diverse substances (e.g. gases or infl ammatory molecules) that once in contact with the nasal mucosa seem to produce vascular congestion with edema and plasma exudation. it should be noted that children and teenagers often report nasal vascular congestion as nasal obstruction. an alternation of breathing between the two nares is known as the nasal cycle. it has been observed as early as years of age, with the duration of a cycle ranging from to minutes. alternation of the side of nasal breathing has been associated with the central mechanism regulating the dominance of the cerebral hemispheres. increased sympathetic activity in the nasal mucosa appears to be linked to greater sympathetic tone in the ipsilateral hemisphere and thus with decreased blood fl ow and mental activity in that hemisphere. changes in the tone of the nasal vascular supply are regulated by the ans. parasympathetic nerves are vasodilator, sympathetic nerves are vasoconstrictor. therefore, predominance of parasympathetic activity causes a vasodilatation and nasal congestion, whereas increased sympathetic activity produces a vasoconstriction that decreases nasal airfl ow resistance. the preganglionic fi bers of the cranial portion of the sympathetic nervous system originate from axons of somata in the lateral gray column of the upper thoracic spinal segments. the fi bers enter the superior cervical ganglion adjacent to the second and third cervical vertebrae where they synapse. the postganglionic fi bers ascend, following the course of the internal carotid artery, forming the internal carotid plexus. the greater petrosal nerve, a branch of the facial nerve (cn vii), contains the preganglionic parasympathetic fi bers traveling to the pterygopalatine (sphenopalatine) ganglion. located deeply in the pterygopalatine fossa, between the pterygoid process and maxilla, anterior to the pterygoid canal, the pterygopalatine ganglion is one of the major peripheral parasympathetic ganglia. at the level of the foramen lacerum, the greater petrosal nerve is joined by the deep petrosal nerve from the internal carotid plexus (sympathetic) to form the nerve of the pterygoid canal (vidian nerve). these fi bers synapse in the pterygopalatine ganglion; the postganglionic parasympathetic fi bers are secretomotor and supply the glands of the nasal mucosa. additionally, the nasal cavities are densely innervated by the sensory nervous system. nerves are present in respiratory mucosa, particularly in the walls of the venous vessels and the gland acini. glands are innervated by both parasympathetic and sensory nerve fi bers. sensory nerves are stimulated by mechanical, thermal or chemical stimulation and afferent fi bers run in the trigeminal nerve. sensory nerve stimulation instigates different refl exes, such as the sneeze refl ex. nasal thermal stimulation, as occurs with inhalation of cold dry, dry or moist air, produces a nasopulmonary bronchoconstrictor refl ex in normal healthy individuals, inducing changes in airway resistance. activation of temperaturesensitive nerve endings in the nasal mucosa generates this response and the decrease of airfl ow through the nose and trachea protect the lungs from insufficiently conditioned air. the ans controls several aspects of nasal function, i.e. nasal secretions, mucociliary function, blood fl ow, microvascular permeability, release of infl ammatory cells and nasal patency. the modulation and balance of nasal functions necessitate an interaction between the sympathetic and parasympathetic systems, as well as a well-tuned sensory nervous system. dysfunction may lead to pathologic nasal syndromes. because of the relationships between the sympathetic nervous system and the upper thoracic spinal segments, the second and third cervical vertebrae, and between the parasympathetic nervous system and the sphenoid, maxilla or palatine bones, somatic dysfunction of any of these vertebral and cranial areas can result in dysfunction of the ans with impact on nasal function. furthermore, because of the role of the trigeminal nerve, particularly the fi rst and second divisions, in the sensory function of the nose, the temporal bone should be added to that list. osteopathic procedures may be applied to balance the ans and promote healthy nasal functions. unpaired and paired structures form the nasal cavities, as in the remainder of the skull. as such, during the prm inspiratory phase, the midline unpaired structures of the nasal cavities (i.e. the sphenoid, ethmoid, vomer and septal cartilage) demonstrate cranial fl exion and the paired structures (i.e. maxillae, palatine, nasal and lacrimal bones and conchae) externally rotate. in the reciprocal prm expiratory phase, the midline structures move in the direction of cranial extension and the paired structures internally rotate. therefore, in health, the nasal cavities follow each cycle of the prm, with a resultant widening of the cavities during fl exionexternal rotation of the inspiratory phase and narrowing during extension-internal rotation of the expiratory phase. cranial somatic dysfunction very frequently follows asymmetric patterns. thus, the nasal cavity will be wider on one side than on the other. this can be observed by nasoscopic examination, as well as by simply looking at the patient to note asymmetry in the facial features. it may also be observed by comparing the relative size of the nares. one side is usually more open than the other. the open side is the side of the external rotation, whereas the other side is associated with internal rotation. the patient often reports more nasal congestion on the smaller side and in cases of small children the mothers comment on the increase of nasal secretion on that side. the alternation of cranial fl exion and extension, with all cranial structures free to follow this movement, is necessary to ensure effective tissue perfusion of the nasal mucosa. it also promotes venous and lymphatic drainage of the nose, as well as the removal of secretions from the nasal cavities and sinuses. under these circumstances, mucosal infl ammation and hyperreactivity associated with rhinitis may be reduced. in neurogenic infl ammation of the upper airway mucosa, such as in chronic rhinosinusitis, sensory nerves are excited and mediators are released, including histamine, prostaglandins and various neuropeptides such as substance p. they may then cause vasodilatation, vascular congestion, extravasation of plasma with edema, and recruitment and activation of infl ammatory cells. secretion from the submucosal glands may also be increased. these exaggerated sensory and parasympathetic defensive refl exes form the pathophysiologic basis of rhinitis. acute rhinitis, one of the symptoms of the common cold, is the result of a viral infection. numerous viruses cause infections in the respiratory tract and any region of the tract may be infl amedthe nose, the paranasal sinuses, the throat, the larynx, the trachea and the bronchi. acute rhinitis represents one of the most frequent upper respiratory infections. allergic rhinitis is considered to be the most common allergic airway disease, with about % of the population experiencing this condition. allergic rhinitis is common in children and most of the time this condition fi rst develops during childhood or adolescence. typical behaviors are usually observed such as grimacing and picking of the nose. older children are likely to blow their noses more often than younger children who present with constant clearing of the throat because of postnasal drip, frequent sniffi ng or snorting. rhinorrhea, nasal obstruction, sneezing, itching of the eyes, nose and palate, and watery eyes are typical symptoms associated with allergic rhinitis. the disease results from exposure to various allergens including foods, pollens, molds, dust mites and animal dander. two groups are described: seasonal allergic rhinitis, often the result of pollen exposure, and perennial allergic rhinitis, lasting for at least months of the year. allergic individuals demonstrate a decreased capacity to warm and humidify inhaled air. they also are prone to develop other diseases of the upper and lower respiratory tract such as sinusitis, otitis media with effusion and asthma that may complicate allergic rhinitis. although the reason why individuals develop allergic rhinitis is uncertain, a genetic predisposition to develop the allergic response has been suggested. it is thought that these individuals probably have a greater sensitivity to allergens and are predisposed to develop mucosal infl ammation and hyperreactivity. a 'microfl ora hypothesis' has also been suggested. it is thought that the disturbance of the normal microbiota in the gastrointestinal tract, in part due to the use of antibiotics and dietary changes in industrialized countries over the past two decades, is a factor that may lead to modifi ed airway tolerance to allergens and atopic disorders. genetics and microbiotic disruption would then be considered as predisposing factors, increasing an individual's susceptibility to develop airway hypersensitivity and allergy. the nasal dysfunction associated with allergic rhinitis results in various symptoms. nasal congestion with increased airfl ow resistance, particularly in the supine position, causes sleep-disordered breathing. it is a risk factor for snoring, affecting teenage males more frequently than females. it is also linked to various systemic symptoms such as headaches, irritability and fatigue that diminish functional capacity. thus, allergies are one of the main reasons for missed school days in the us. school performance may be decreased because of inattention and decreased concentration. physical and emotional impairments associated with the allergic condition make it a whole body dysfunction. because allergic rhinitis can affect the patient's quality of life to such an extent, and because of its economic impact, prevention and treatment are essential. osteopathic procedures may be seen as a valuable complement to traditional medical treatment. the examination for somatic dysfunction is begun by observing the global postural pattern and/or how the cervical and thoracic regions are, or are not, integrated into this pattern. the child should be observed from behind, from the side and from the front. from behind, observe upper body postural mechanics. look for cervical and thoracic sidebending, occipitocervical rotation and slumping of the pectoral girdle. from the side, observe cervical and thoracic anteroposterior mechanics. there is often upper thoracic fl exion with increased cervical lordosis. in this position, the head will very commonly be thrust forward with signifi cant tension placed on the anterior cervical soft tissues. observe specifi cally the submandibular myofascial structures and the position of the hyoid bone. the child with rhinitis may have to compensate by mouth breathing. as such, they may demonstrate the associated mouth breathing posture to a variable degree, depending on the chronicity of the condition. a double-chin appearance and the demonstration of a slack-jawed posture are indicative of chronic mouth breathing. from the front, observe and confi rm the sidebending and rotation observed from behind. again look for the presence of mouth breathing and the associated orofacial characteristics. children who mouth breath demonstrate a lack of tonicity of their facial tissues. the lower lip is typically everted and the tongue slightly protruded. observe the relationship between the tongue and the teeth. persistent protrusion of the tongue results in anterior displacement of the upper incisors with an eventual overbite. the child with allergic rhinitis will demonstrate puffi ness of the facial soft tissues, particularly noticeable around the eyes, as well as darkening of the tissues beneath the eyes. the nasion is often recessed in the face. because of the chronic lack of nasal breathing, the bony structures of the nasal cavities are small, resulting in narrowed nasal apertures. children with persistent nasal congestion demonstrate an observable transverse crease in the skin across the lower third of the nose, at the junction between the nasal bones and cartilages. this develops as the result of repeatedly rubbing and pushing the tip of the nose vertically or laterally with their fi ngers or hand in response to nasal itching -the 'allergic salute'. following observation, the palpatory examination is best performed with the child supine. begin by palpating the upper thoracic region for structure and employ the tests of listening to assess function, paying particular attention to the motion of the vertebrae and ribs. examine the clavicles in similar fashion. next, evaluate the cervical spine, with attention to the structural and functional relationships between the occiput, c , c , c and c . palpate the soft tissues in this area for the presence of edema. in acute upper respiratory conditions, the trigeminally mediated upper cervical refl ex (occiput, c ) will result in acute tissue texture changes. assess the anterior cervical soft tissues and midline structures with attention to the hyoid bone. identify somatic dysfunction and treat it using the principles of indirect technique. examine the cranial base. note the pattern demonstrated between the sphenoid and occiput. sbs compression and inferior vertical strain are often encountered in association with nasal dysfunction. note the relationship between the occiput and temporal bone. visualize how this relationship impacts the jugular foramina and consequently cn x. the functional status of the sphenoid bone exerts significant infl uence on the frontal bone and the facial bones below, and should be assessed. also assess the frontal bone. any dysfunctional motion restriction will result in diminished movement, and consequently diminished drainage, of the nasal cavities. in particular, dysfunctional frontal internal rotation causes the ethmoidal notch to be narrowed, restricting the movement of the ethmoid below. when evaluating the relationships between the sphenoid, frontal bone and the facial bones with the tests of listening, fi rst assess the global motion of the region and then proceed to assess the individual bones and their interosseous relationships. during this assessment, localized motion restriction may be perceived that requires further identifi cation through visualization. the following sutures are potential sites of interosseous dysfunctions: frontoethmoidal, frontomaxillary, frontonasal and sphenoethmoidal. the relationships between the vomer and the sphenoid, ethmoid, maxillae and palatine bones, as well as the articulation between the two maxillae, should be evaluated. the nasal cartilages should be assessed in their relationship with the nasal bones and perpendicular plate of the ethmoid. following indirect principles, treat any dysfunctions found. address the upper thoracic and cervical regions for their effect on the ans. treat cranial dysfunctions for their effect on the autonomic and sensory nervous systems, venous and lymphatic drainage, and to promote the production and drainage of nasal secretions. treatment of nasal structures will affect the total body through the cranial mechanism. the nasal septum consists of the vomer and the perpendicular plate of the ethmoid. posteriorly, it is continuous with the sphenoidal sagittal septum that divides the body of the sphenoid into two sinus cavities. posteriorly and superiorly, it is continuous with the falx cerebri and falx cerebelli. these structures combined constitute a vertical septum that separates the paired structures of the head and unites the viscerocranium and the neurocranium and, through the core link, the body below. the nasal mucosa contains a rich supply of nerve endings and a dense network of microvasculature. for these reasons, it is highly sensitive. this should be kept in mind during the physical examination and treatment. it makes tests of listening and methods of treatment employing indirect principles the techniques of choice. further, to follow the prm, its rhythm and potency within nasal tissue, and to employ treatment when appropriate to enhance its potency, may help to modulate the autonomic dysfunction present in rhinitis, as well as help to reduce stasis and edema on a macro level in the mucosa and a micro level in the neuronal synapses. recurrent and chronic rhinitis is commonly triggered or aggravated by environmental circumstances. as such, the caregiver should be provided with information as to potentially irritating conditions and substances that will allow them to identify and remove these triggers from the child's environment. allergens should be sought out, identifi ed and, if possible, removed. the most common allergens include pollens, foods, molds, dusts and animal dander. a detailed list of these substances may be found by doing an internet search. conversely, dietary considerations and respiratory exercises may be employed to improve the function of the immune system. it has been suggested that disruption of the normal microbiota in the gastrointestinal tract contributes to decreased airway tolerance to allergens. refi ned foods should be avoided as much as possible, while a diet rich in fresh fruit and vegetables and antioxidants such as vitamins c and e should be recommended. a diet high in probiotics that promote the growth of benefi cial bacteria (bifi dobacterium, lactobacillus, bacteroides) is recommended. this includes prebiotic carbohydrates such as inulin and oligofructose, plant carbohydrates that are not digestible in the small intestine but rather are fermented by bac-teria in the colon. lactose intolerance should be considered. respiratory exercises are intended to enhance nasal breathing, promote mucus drainage and reduce vascular stasis in the nasal mucosa. they should be initiated in such a way that they can be successfully performed and yet avoid frustrating the child. nasal congestion impairs nasal respiration and if the child is simply told to breathe through their nose, the diffi culty of the experience usually limits the success of the exercise. the child will feel frustrated at best, and at worst may experience anxiety and a sense of suffocation. and they will stop doing the exercises. begin by explaining to the child the importance of nasal breathing. explain that breathing through their nose cleans the air they breathe and gives them more oxygen in their blood, and that this will, in turn, enhance their performance in school and in sports. next, have the child breathe through their nose and become aware of the sensation of nasal airfl ow. have them palpate the lateral aspects of the nasal cartilages as they breathe. teach them to actively fl are the nose by contracting the dilatator nostril muscles as they inhale. palpating the nose during this process reinforces their awareness of nasal fl aring. after or minutes of active nasal breathing the child should observe the difference in the sensation of nasal airfl ow. they may now be instructed to repeat the above process at home, exercising for minutes at least three times daily. the child should also be taught to breathe using their thoracoabdominal diaphragm. successfully implementing these exercises not only allows the child to improve nasal respiratory function, it further teaches them a sense of control over their own respiration. this will reduce and eventually eliminate the sense of suffocation the child experiences when they attempt to breathe through congested nasal passages because, even thought they may experience nasal congestion, they will have been empowered to alleviate it. it is estimated that children get an average of six to eight colds annually, and that - % of all upper respiratory tract infections are complicated by sinusitis. the application of osteopathic principles in the treatment and prevention of sinusitis in children should be utilized, as it is particularly effi cient. it is based on an understanding of the anatomic and functional aspects of the nasal cavities and sinuses as part of the upper respiratory tract. a description of the nasal cavities, mucosa and its main characteristics has already been provided in 'rhinitis' above. we shall, therefore, only consider the description of the paranasal sinuses and the pathophysiology that explains their dysfunction. many speculative theories exist concerning the function of paranasal sinuses. some years ago, galen hypothesized that they were 'porous bones' reducing the skull's weight. since then, other theories have described the paranasal sinuses as shock absorbers, resonance chambers, air conditioning areas or the result of the evolutionary process and parts of the facial development. there are four paranasal air sinuses associated with each nasal cavity: the ethmoidal, frontal, sphenoidal and maxillary sinuses, all of which open into the lateral walls of the nasal cavities by small apertures that differ from one individual to another. the lateral wall of the nasal cavity is formed anteriorly by the frontal process of the maxilla and the lacrimal bone; centrally by the ethmoid, maxilla and inferior nasal concha; and posteriorly by the vertical plate of the palatine bone and the medial pterygoid plate of the sphenoid. three meatuses are located in this wall. they consist of three irregular passages directed anteroposteriorly -the superior, middle and inferior meatuses of the nose. the superior meatus is the smallest. located between the superior and middle nasal conchae, it occupies the middle third of the lateral wall of the nasal cavity. the middle meatus is between the middle and inferior conchae. the inferior meatus is the largest of the three. it lies in the space between the inferior concha and the fl oor of the nasal cavity. only the nasolacrimal duct drains into the inferior meatus in the anterior part of the nasal cavity. the ethmoidal sinuses, on each side, are formed by - air cells, fi lling the ethmoidal labyrinth. they are divided into three groups: anterior, middle and posterior. the anterior and middle ethmoidal cells drain into the middle meatus, whereas the posterior ethmoidal cells drain into the superior meatus. the frontal sinuses are the highest. each frontal sinus develops from an anterior ethmoidal cell that extends posteriorly along the medial part of the orbital roof and laterally above the internal part of the eyebrow at about or years of age. on each side, through the frontonasal duct and the ethmoidal labyrinth, the frontal sinus drains into the middle meatus. the maxillary sinuses are the largest. they form large pyramidal cavities within the bodies of the maxillae and drain into the middle meatus on each side. the sphenoidal sinuses are within the body of the sphenoid, their apertures being on the upper portion of the anterior walls of the sphenoidal body. the sphenoid sinuses drain into the superior meatus, near the roof of the nasal cavities (figs . . , . . ). the pneumatization of the paranasal sinuses occurs at different rates, with a great deal of variation between individuals. the maxillary and sphenoidal sinuses are the fi rst ones to develop in the fourth gestational month, followed by the frontal and ethmoid cells that appear in the sixth month. at birth, the parasinuses are quite small. the ethmoid cells measure - mm in diameter while the maxillary sinuses appear as furrows mm in length and mm in width. the sphenoid sinuses are usually pneumatized around years of age and the frontal sinuses have developed to the extent that they are radiographically apparent by about the age of . around this time, the growth of the cerebral mass slows down. the inner table of the frontal bone is stabilized while the outer table is still dragged forward by nasomaxillary growth. a space forms between both plates, where the frontal sinus expands. mechanical forces associated with mastication and the actions of growth hormones are linked with the increase in the size of the sinus. sinusal development normally continues until late adolescence. the paranasal sinuses are innervated by branches from the trigeminal nerve (cn v). the frontal and sphenoidal sinuses are innervated by branches from the ophthalmic nerve (cn v ), the maxillary sinuses from the maxillary nerve (cn v ), and the ethmoid cells from both the ophthalmic and maxillary nerves. as in the remainder of the nasal cavity, described previously, the paranasal sinuses are lined with a respiratory mucosa, ciliated and mucus-secreting, that is continuous with that of the respiratory tract. additionally, the paranasal sinuses seem to be an anatomic source for the excretion of nasal nitric oxide (no). mammals lacking paranasal sinuses (e.g. baboons) demonstrate lower exhaled concentrations of this molecule. no is involved in vasodilatation, neural transmission and immunologic activity, and appears also to participate in local host defense, even before allergens reach the respiratory mucosa. it may also regulate the mucociliary motility of the respiratory mucosa, thereby participating in the drainage of nasal secretions and the defense mechanisms of the mucosa. from the paranasal sinuses, no may also play distal functions. throughout normal nasal breathing, no is constantly excreted into the upper airway, acting as an 'aerocrine' messenger. it follows the airfl ow to the lungs where it modulates pulmonary function through regulation of blood fl ow and oxygen uptake. nasal breathing, therefore, becomes crucial for these vital functions. when compared to oral breathing in healthy individuals, nasal breathing results in an improvement of arterial oxygenation with a reduction of pulmonary vascular resistance. in this manner, no would be an airborne messenger. it is of prime importance to improve nasal respiration in infants and children as soon as possible. nasal breathing promotes healthier conditions in association with inspiration. additionally, it stimulates the development of the maxillofacial skeleton and, therefore, of the nasal cavities. the paranasal sinuses are a common site for infection in children and adolescents. the most common sinusitis is maxillary, followed by ethmoidal and then frontal sinusitis. the tendency to develop sinusitis can be explained in part by anatomy. proper ventilation is critical for preservation of sinus integrity. the maxillary sinuses are ventilated, but the ostium of each sinus is positioned high on the lateral wall of the nasal cavity. this encumbers gravitational drainage and probably predisposes patients to infections of the maxillary sinus. the frontal sinus is ventilated and because of the location of its ostium at its base, this sinus benefi ts the most from gravity. sphenoidal sinusitis rarely occurs as an isolated infection, being found more often as a part of complete sinusal involvement. viral infections of the upper respiratory tract commonly result in an infl ammation of the sinuses and nasal mucosa to produce the rhinosinusitis. bacterial infections with purulent nasal drainage are most often located in the paranasal sinuses. viral rhinosinusitis precedes about % of bacterial sinus infections while the remaining % most often follow allergic rhinitis. persistence of nasal symptoms, such as discharge or congestion, cough and headaches, particularly when awakening, for more than days is defi ned as chronic sinusitis. the sinus ostium is a common structure shared by all of the paranasal sinuses. its function has been compared to that of the pharyngotympanic tube. they both permit drainage. the ostia of the sinuses allow drainage of the paranasal sinuses whereas the pts drain the tympanic cavities. therefore, following the same principles as those used to treat otitis media, osteopathic procedures may be applied to affect the bones of the paranasal sinuses to improve their compliance and promote sinus drainage. interand intraosseous techniques for the frontal bones, ethmoid, sphenoid and maxillae are very effi cient in the treatment of sinusitis. the normal size of the sinus ostia is approximately . mm. the ostia are lined with mucosa and infl ammation and swelling of that mucosa may decrease or occlude ostial patency and consequently the drainage of the paranasal sinuses. obstruction of a paranasal sinus ostium will initially produce an increase of the pressure within the sinus. this is followed by intrasinusal gas absorption that consequently results in negative pressure within the sinus. this condition predisposes aspiration of bacterialaden secretions into the ethmoid or maxillary sinuses from the nasal cavity, particularly when an individual sniffs or blows their nose. obstructed drainage generates stasis of mucus in the paranasal sinuses that, in turn, becomes an ideal culture medium for bacteria. more infl ammation follows, with a self-perpetuating condition that leads to chronicity. additionally, somatic dysfunction may contribute to impaired nasal secretion. parasympathetic stimulation results in vasodilatation and increased activity of the seromucous glands and goblet cells, with symptoms such as rhinorrhea and nasal congestion. on the other hand, increased sympathetic activity produces vasoconstriction and dryness of the nasal mucosa. cranial somatic dysfunction of the maxilla, palatine bone and sphenoid can affect the pterygopalatine ganglion and both parasympathetic and sympathetic supply of the nose and paranasal sinuses (see 'rhinitis' above). dysfunction of the cranial base and craniocervical junction will refl exly affect the trigeminal nerve and, through it, sympathetic and parasympathetic refl exes. somatic dysfunction in the cervical and upper thoracic spine can affect sympathetic activity, as well as lymphatic drainage of the facial area. once again, normal motion of skeletal structures, functional ciliary motion and autonomic regulation are required for a healthy upper respiratory system. it should be stressed that cranial somatic dysfunction, although it may originate very early in life, may not manifest until years later. nasal septal asymmetry may affect as many as % of newborns as the result of compression of the tip of the baby's nose during vaginal delivery. nasal suction bulbs or nasogastric tubes may also be traumatic to the nose. a nasal septal deviation may affect the middle concha and predispose to the obstruction of the osteomeatal area. cranial base dysfunction and vertebral somatic dysfunction may result from diffi cult labor. obviously, for all these reasons, a whole body osteopathic evaluation and treatment of the newborn should be performed, including attention to the facial bones, particularly those of the nose. left untreated, facial somatic dysfunction may restrict full development of the paranasal sinuses. furthermore, nasal obstruction will lead to mouth breathing and sleep-disordered breathing. sore throat and sinusitis may follow. nasal obstruction is frequently associated with chronic maxillary sinusitis, adenotonsillar hypertrophy and otitis media as well as dental malocclusion and facial maldevelopment. later in childhood and adolescence, somatic dysfunction can occur as the result of traumatic forces from physical bumps, falls, athletic strains and the like. the resultant dysfunction, depending on the direction of the traumatic force, may be established in the pattern of the individual's underlying postural balance or completely independent of it. somatic dysfunctions of the facial bones and upper thoracic region are of particular consequence in the development and maintenance of sinus dysfunction. the cranial respiration of the prm differs from the thoracoabdominal respiration. however, they may entrain each other. this happens during states of relaxation, where the rate of the pulmonary respiration decreases to that approximating the rate of the prm. thereby, the two respirations combine their action to affect the entire body. this principle is particularly signifi cant in the upper airway to promote movement of the nasal secretions, the gaseous contents of the paranasal sinuses, blood and lymph. the normal cranial motion associated with the prm consists of an inspiratory phase (fl exionexternal rotation) during which the paranasal sinuses as paired structures expand laterally and decrease in height. conversely, during the expiratory phase of the prm (extension-internal rotation), the sinuses decrease their lateral dimension and increase their height. during cranial inspiration, the maxilla and the zygomatic bone move in external rotation, but at the same time a slight twisting occurs between them that contributes to the drainage of the maxillary sinus. the movements of all bones in association with the biphasic prm may be described as the result of the combined movements in the three cardinal planes. the twisting between the zygomatic bone and the maxilla occurs predominantly in the sagittal plane. during external rotation, the zygoma demonstrates a component of anterior rotation, while the maxilla simultaneously demonstrates posterior rotation. the reverse occurs during internal rotation. this motion may be compared to the wringing out of a wet rag. the zygomatic bones are an interface between the greater wing of the sphenoid, the maxilla, the frontal and the temporal bones. their position is strategic and they play a key role in the balance of the face. the vomer is located between the sphenoidal body and the hard palate. its inferior border articulates anteriorly with the intermaxillary suture between the palatine processes of the maxillae and posteriorly with the interpalatine suture between the horizontal plates of the palatine bones. the vomer rotates posteriorly during cranial fl exion or inhalation, when the body of the sphenoid rotates anteriorly. conversely, the vomer rotates anteriorly during cranial extension or expiration, when the body of the sphenoid rotates posteriorly. accordingly, sutherland stated: 'during inhalation the zygomatic bones and the vomer function somewhat like a plumber's plunger on the sphenoidal sinus and the maxillary sinuses.' every component of the facial skeleton is involved as part of the global functional pattern and should be assessed. again according to sutherland, even the smallest structures should be considered: 'see the turbinates on the side of the nose as they are in the living body, curling and uncurling during inhalation and exhalation.' the treatment of sinusitis is intended to promote the prm. the osseous structures as well as the potency of the prm should be considered. manipulative treatment of the somatic dysfunction associated with sinusitis should be employed in conjunction with standard medical treatments. the sooner it is initiated, the more rapid and successful the response. failure to treat chronic sinusitis effectively will result in altered growth patterns of the viscerocranium. nasal breathing will be impaired with concomitant malposition of the tongue and resultant dental malalignment. osteopathic examination and treatment of sinusitis are very similar to that of rhinitis. examination is directed at the identifi cation of somatic dysfunction that affects normal mucociliary clearance and impairs blood and lymphatic circulation, as well as ans function. for this and the associated treatment discussion, the reader is directed to 'rhinitis' above. manipulative treatment for sinusitis should focus on the reduction of mucosal edema, which will increase osteal patency. procedures should be employed to drain the sinuses and provide symptomatic relief. treatment should also include procedures that address sympathetic and parasympathetic somatovisceral refl ex activity affecting the sinuses. the sympathetic supply of the paranasal sinuses emanates from the upper thoracic spine. when examining the child with sinusitis, it is all too easy to become focused on dysfunction of the viscerocranium and forget this signifi cant area. additionally, when working with children it is less intrusive to begin in an area away from the face. perform tests of listening to evaluate the motion of the upper thoracic vertebrae and associated ribs. because of its relationship with the trigeminal nerve, the occipitocervical region should also be assessed. the rhythmic motion of the cranial bones under the infl uence of the prm signifi cantly facilitates sinus drainage. it is, therefore, appropriate to examine the global cranial pattern, looking specifically for dysfunction that reduces the motion of the sphenoid, ethmoid, vomer, palatine and zygomatic bones, maxillae and conchae. observe the face of the child, looking for puffi ness in the nasal area. look for asymmetry of the nares and asymmetric nasal respiration. compare the degree of nasal alar fl are with inspiration. in addition, inspect the nasal cavity, noting secretions, edema and erythema of the mucosa. observe the child for open mouth posture that may be indicative of enlarged adenoids. listen to the child's speech for hyponasality. utilizing tests of listening, evaluate the sphenoid and frontal bones. proceed to assess the facial bones, paying particular attention to the ethmoid, maxillae and zygomatic bones. the function of the vomer, palatine bones and conchae should also be considered. the zygomatic bones are easily accessible and their manipulation readily results in drainage of the maxillary sinuses. this procedure (see chapter ) is straightforward and easily mastered by the novice. manipulation of the zygoma, in turn, affects the ipsilateral maxilla and greater wing of the sphenoid. the motion of the sphenoid should be assessed. it exerts signifi cant infl uence on the facial bones and on proper drainage of the sphenoid sinuses whose ostia are located in the upper portion of the anterior walls of the sphenoidal body. the ethmoid bone is a common site of dysfunction in children and adolescents, and should be assessed in its relationships with the frontal bones, sphenoid and maxillae. proper motion of the ethmoid bone is necessary to facilitate the emptying of secretions from the ethmoid air cells. intra-and interosseous motion of the maxilla should be assessed because it is necessary for the effective drainage of the maxillary sinus. additionally, in conjunction with the pterygoid process of the sphenoid and the palatine bone, it forms the pterygopalatine fossa where the pterygopalatine (sphenopalatine) ganglion is located. any dysfunc-tion of these bones may affect the ganglion and its effects on mucosal secretions. the vomer's contribution is very important to the mechanism of the pumping action of the paranasal sinuses. its assessment is often performed with one fi nger placed intraorally. when treating very young children, this procedure should be done only when absolutely necessary and then only with the greatest delicacy. the examiner should never attempt intraoral palpation of the vomer if the child is not completely cooperative. an alternative procedure is to employ visualization of the vomer while palpating the anterior edge of the nasal septal cartilage. treat any dysfunctional areas identifi ed. treatment is normally performed in continuity with assessment. because indirect treatment procedures are used preferentially for children and adolescents, the effective treatment of a given area results in further relaxation of the patient, thereby facilitating the treatment of the next area to be evaluated and treated. furthermore, when performing indirect techniques, tissue responses are continuously monitored, so that in acute conditions the patient's tolerance to the procedure is also continuously assessed. the tissues dictate the treatment; they guide your actions and determine the dosage. the upper thoracic region should be treated for its sympathetic somatovisceral effects, to facilitate lymphatic drainage of the head and neck, and for functional reasons because it is the foundation on which the above structures rest. the occipitocervical junction should be treated for its refl ex impact on the trigeminal nerve and its relationship to the cranial base. the sphenoid, frontal and facial bones should be treated for their direct effect on the paranasal sinuses. paranasal sinuses are intraosseous cavities and their drainage is dependent on the inherent motility of their respective bones: frontal, sphenoid, ethmoid and maxillae. as such, intraosseous dysfunctions of any of these bones can impact the associated sinus. specifi cally pumping the individual bones may be employed to facilitate drainage of their sinuses. positioning the patient contributes to the drainage of the paranasal sinuses by using gravity. drainage of the sinuses is best performed as follows: • drainage of the frontal sinus in the seated position • drainage of the sphenoidal sinus in the seated position with the head of the patient bent forward • drainage of the maxillary sinus in the supine position with the patient's head rotated to the opposite side so that the sinus to be drained is up. when treating the vomer, if the child resists the digital intraoral approach, the child's pacifi er, if they have one, may be utilized. by allowing the child to actively suck on the pacifi er the resultant alternation of intraoral pressure and tongue movement, pressing the pacifi er on the roof of the child's mouth, may be employed to manipulate the vomer, while the practitioner works on the adjacent sphenoid and ethmoid bones. the caregiver should be encouraged to maintain a healthy lifestyle for the child, including a balanced diet with adequate hydration and the avoidance, as much as possible, of refi ned carbohydrate. respiratory exercises including nasal respiration and diaphragmatic breathing may be taught. vocal activities such as humming can be benefi cially employed to increase sinus ventilation. the pharynx is a musculomembranous half-cylinder that connects the nasal and oral cavities with the larynx and esophagus. it extends from the base of the skull to the level of the sixth cervical vertebra where it joins the esophagus. the pharynx is divided into three portions: the nasopharynx located above the hard palate, the oropharynx that extends from the hard palate to the base of the epiglottis and the laryngopharynx from the base of the tongue to the larynx. the oropharynx can be further subdivided into the retropalatal or velopharynx from the hard palate to the caudal margin of the soft palate and retroglossal from the most inferior tip of the soft palate to the base of the epiglottis (fig. . . ) . the pharyngeal wall consists of an internal mucous layer, an intermediate fi brous layer and an external layer of skeletal muscle. in the superior part of the pharynx, the pharyngobasilar fascia is the thickest portion of the intermediate fi brous layer of the pharyngeal wall and is fi rmly attached to the base of the skull. the attachment forms an irregular u-shaped line. the anterior part inserts on the posterior margin of the medial plate of the sphenoidal pterygoid process. it then curves under the cartilaginous part of the pts where it inserts onto the petrous part of the temporal bone and continues to the pharyngeal tubercle of the occipital basilar part to meet the attachment from the other side (fig. . . ) . the anterior part of the pharyngeal wall is not continuous; rather, it has multiple attachments to the medial pterygoid plate, the pterygomandibular raphe, the mandible, the tongue, the hyoid bone, and the thyroid and cricoid cartilages. six muscles contribute to constitute the pharyngeal wall. the bilateral superior, middle and inferior constrictor muscles constrict the pharyngeal cavity and, on each side, three longitudinal muscles -the stylopharyngeus, salpingopharyngeus and palatopharyngeus -elevate the pharyngeal wall and participate in swallowing (figs . . , . . ) . the fi bers of the three constrictor muscles fan out posteriorly into the median pharyngeal raphe, a fi brous band that is attached above to the pharyngeal tubercle of the occipital basilar part. the pharyngeal raphe descends to the level of the sixth cervical vertebra where it blends into the posterior wall of the esophagus. a thin retropharyngeal space fi lled by loose areolar tissue connects the pharynx with the cervical portion of the vertebral column and the prevertebral fascia covering the longus colli and longus capitis muscles. the pharynx is the common route for air and food, and seven cavities communicate with it: the two nasal cavities, the mouth, the larynx, the two tympanic cavities and the esophagus (fig. . . ) . the nasal cavities open posteriorly into the nasopharynx through the choanae. the oral cavity also opens posteriorly through the oropharyngeal isthmus the internal mucous layer of the pharyngeal cavity is continuous with that of the mouth and larynx and that lining the nasal cavities and pts. it contains a large collection of lymphoid tissue, arranged in a circular orientation around the wall of the throat, the waldeyer's tonsillar ring that represents the primary defense against pathogens at the entry of the upper respiratory and alimentary tract. the constituent parts of this defensive annulus are the nasopharyngeal, palatine, tubal and lingual tonsils, plus lymphoid tissue in the intertonsillar intervals. the nasopharyngeal tonsil is located in the area of the nasopharyngeal roof and posterior wall, where the mucosa covers the inferior part of the sphenoidal body and the basilar part of the occipital bone. the palatine tonsil constitutes the major part of waldeyer's ring. the paired palatine tonsils are located in the lateral wall of the oropharynx, in the tonsillar fossae, posterior to the base of the tongue between the anterior and posterior pillars, the palatoglossal and palatopharyngeal folds, respectively. they can be observed through the open mouth with the tongue depressed (fig. . . ). they are located slightly higher in the neonate and descend during the nd and rd years of age. the lingual tonsils are multiple lymphoid nodules situated on the posterior one-third of the tongue while additional small nodules beneath the mucosa of the pt form the tubal tonsils. the nasopharyngeal tonsil increases in size in the fi rst years of life to reach its peak around years of age. thereafter, it starts to involute until almost completely atrophied by puberty. when the nasopharyngeal tonsil is enlarged it is referred to as adenoid or adenoids; 'tonsils' is usually the common name for the palatine tonsils. waldeyer's tonsillar ring is located at a strategic point where numerous antigens, both foodsupported and airborne, fi rst come into contact with the body. thus, it plays an important role in the immune system as a site of antigen recognition and synthesis of antibodies, including ige. the nasopharyngeal and palatine tonsils are major sources of t lymphocytes that participate in cell-mediated immunity and b lymphocytes that produce immunoglobulins. the nasopharyngeal tonsil also seems to participate in immune peripheral tolerance to harmless foreign antigens commonly inhaled or present in digested nutrients. bacterial, or less frequently viral, infections are most often responsible for tonsillitis, where the tonsils may be acutely infl amed. bacterial infections are often streptococcal, usually from group a streptococci, the most virulent species in humans. differential diagnosis between viral and bacterial infection, based on physical examination alone, is diffi cult. tonsillitis is characterized by sore throat and pain, particularly during swallowing, which may involve the ears. headaches, vomiting and high fever may be associated. it should be noted that bacterial infections are correctly treated with appropriate antibiotics and that in these instances the diagnosis and treatment of somatic dysfunction should be considered as adjunctive. pharyngitis, an acute infl ammation of the pharynx, is usually the result of a viral infection, although it may be bacterial. the pharyngeal mucous membranes may be infl amed with purulent exudates. sore throat and pain during swallowing are also present, associated with fever, cervical adenopathy and leukocytosis. susceptibility to infections differs between individuals. host genetic components that adjust immune responses to pathogens seem to play an important role. , nevertheless, the peritonsillar location is the most common of head and neck space infections in children in % of cases. the american academy of otolaryngology-head and neck surgery currently proposes adenoidectomy as a guideline after ' or more infections of tonsils and/ or adenoids per year despite adequate medical therapy'. adenoidectomy is currently one of the most common operations performed on children in the united states. , besides bacterial and viral infections, allergies such as allergic rhinitis are considered to be common risk factors for adenoid hypertrophy. the continuity between the internal mucous layer of the pharyngeal cavity, the nasal cavities, the mouth, the larynx, the tympanic cavities and the esophagus explains the interrelationship and diversity of clinical presentations in allergic conditions. increased immune activity results in hypertrophy of waldeyer's tonsillar ring, in particular at the level of the nasopharyngeal tonsil. chronic nasal airway obstruction may follow a condition quite common in childhood that leads to a persistent mouth-open posture and mouth breathing. adenotonsillar hypertrophy has also been associated with a myriad of symptoms such as obstructive sleep disorder syndrome, nocturnal snoring, rhinosinusitis, hyponasal speech and impairment of the ability to smell. furthermore, hypertrophy of the nasopharyngeal tonsil or adenoids predisposes the individual to recurrent otitis media or otitis media with effusion, in part because of the diminution of the patency of the orifi ces of the pt, located just laterally to the nasopharyngeal tonsil. tonsillectomy and adenoidectomy in children is reported to improve symptoms associated with obstructive sleep apnea syndrome, such as snoring and restless sleep, as well as behavioral, emotional and neurocognitive diffi culties. these procedures are also associated with improvement of the nasal cavity geometry by reducing the venous stasis and congestion of the inferior turbinate present in adenotonsillar hypertrophy. nasopharyngeal tonsil hypertrophy and the associated mouth breathing are usually believed to impact craniofacial development. experiments conducted in primates have established that a persistent mouth-open posture and associated oral respiration leads to dental malocclusions such as cross-bite. mouth-breather children may present with a narrow, elevated palate and a decreased nasopharyngeal space. in such cases, they may demonstrate a receding chin (retrognathia) with crowding of the maxillary and mandibular teeth, and increased lower anterior vertical face height. following adenoidectomies and establishment of nasal breathing, changes are reported, with a more anterior growth of the mandible, improvement of retrognathia and diminution of lower anterior vertical face height. the commonly used terminology 'adenoid' facies to describe longer lower face heights, open mouth and more retrognathic mandibles has led people to believe that adenoid hypertrophy was solely responsible for mouth breathing and associated disorders. this is an overly simplifi ed conclusion. once again, a multifactorial approach to diagnosis and, consequently, treatment may be necessary. a study of children years after adenotonsillectomy showed that upper airway narrowing during sleep was still present, although some resolution of sleep disturbance was obtained months postoperatively. not all children who snore demonstrate adenotonsillar hypertrophy and such hypertrophy is not the only cause of sleep apnea. pharyngeal collapsibility is implicated with anatomic predisposition such as changes in the longitudinal tension within the pharyngeal airway. although adenoidectomy is considered to be an effective treatment for children who are mouth breathers, recurrence of breathing diffi culties in these individuals occurs and has been attributed to their craniofacial anatomic pattern. in upper airway narrowing, sleep apnea, mouth breathing and adenotonsillar hypertrophy, the craniocervical membranous, myofascial, ligamentous and interosseous somatic dysfunction may contribute to the pharyngeal dysfunction. the upper part of the pharynx is attached to the sphenoid, the temporal bones and the occiput. through the prevertebral fascia the pharynx is linked to the cervical spine and movements of the cervical spine are associated with changes of pharyngeal size: cervical fl exion decreases clinical conditions oropharyngeal size; cervical extension does the opposite. [ ] [ ] [ ] any dysfunction of the cervical spine or of any of the structures on which the pharynx is inserted can impair normal pharyngeal function. movement is necessary to mobilize body fl uids, particularly lymph, and somatic dysfunction affecting the structures surrounding lymph nodes and vessels is associated with impaired motion and can thus interfere with lymph fl ow. lymphatic vessels from the pharynx drain into the deep cervical lymph nodes through the retropharyngeal, paratracheal and infrahyoid nodes. the retropharyngeal nodes consist of a median and two lateral groups located in front of the lateral masses of the atlas. they are positioned between the pharyngeal and prevertebral fasciae and drain the nasopharynx and pt, as well as the two upper cervical joints. the deep cervical lymph nodes are beneath the scm muscle. among them, a large node surrounded with several small ones forms the jugulodigastric group that receives drainage from most of the lymphatic vessels from the tonsil. the tonsils differ from the lymph nodes in that they do not receive afferent lymphatic vessels. small lymphatic vessels organize as efferents from the tonsils that traverse the superior constrictor muscle before draining to the jugulodigastric nodes. located against the posterior belly of the digastric muscle, these nodes swell during tonsillitis and may be palpable in front of the anterior border of the digastric muscle, below the mandibular angle. the vessels that supply the pharyngeal wall come from the external carotid artery. the tonsillar branch of the facial artery (external maxillary) is the main blood supply to the palatine tonsil. the veins of the pharynx drain through the pterygoid plexus in the infratemporal fossa and into the facial and internal jugular veins. because the pharynx is so intimately linked to the cervical spine and the cranial base, as well as associated muscles and fasciae, optimal pharyngeal function necessitates that these areas are unimpaired. the upper thoracic spine is the anatomic origin of the sympathetic supply to the pharynx and, consequently, along with associated ribs, should also be considered when addressing pharyngeal dysfunction and disease. finally, the functional freedom of the clavicles, thoracic inlet and cervical spine, together with associated soft tissues above, is necessary to facilitate lymphatic drainage of the pharynx. having performed a total body structural examination to identify the global postural pattern and its relationship to the pharyngeal complaint, with the child in a supine position, it is appropriate to begin the local examination by evaluating the cervical and upper thoracic regions. first, palpate for tissue texture abnormalities in the paravertebral muscles and superfi cial soft tissues, looking for areas of muscular tension and subcutaneous edema. similarly, palpate the anterior and lateral aspects of the neck. observe and palpate the location of the hyoid bone and larynx that should be in the midline. palpation of the anterior neck structures should be done with great delicacy to prevent irritating already infl amed tissues and because this is an area of increased sensitivity, particularly in infants who were born with a nuchal cord. assess the anterior and lateral cervical musculature, paying specifi c attention to the scm muscle because of its relationship to the deep cervical lymph nodes. follow the scm inferiorly to its attachment on the clavicles and assess clavicular motion. evaluate the cervical vertebrae, noting the alignment of the spinous processes. clinical experience has shown a strong association between pharyngitis and cervical articular somatic dysfunction that, when treated, appears to prevent recurrent pharyngitis. next, evaluate the upper thoracic vertebrae and associated ribs. assess the functional status of the cranial base, noting the relationships between the occiput, temporal bones and sphenoid. the pharynx is suspended beneath the skull and tone of the pharyngeal musculature is impacted by cranial dysfunction. for proper function, the pharyngeal muscles require precise interrelationships between their origins and insertions. dysfunctional mechanics that affect these relationships will impair function of the pharynx and associated waldeyer's tonsillar ring. the pharyngeal tonsil is located directly beneath the cranial base, at the level of the sphenobasilar junction. as such, freedom of motion of the cranial base may facilitate lymphatic drainage of the adenoids. mandibular function should also be examined. dysfunction of the mandible may impact anterior cervical myofascial function, contribute to impaired lymphatic drainage of the jugulodigastric node and participate in chronic mouth breathing. apply indirect principles to treat any identifi ed articular dysfunction of the spine, ribs and clavicles. myofascial release techniques may be employed to address pharyngeal, anterior cervical and spinal muscular dysfunctions. normalizing the cranial and thoracoabdominal diaphragms and the thoracic inlet may be employed to promote lymphatic and venous circulation. following the inherent motility of the prm may enhance all of these interventions. this slow, gentle rhythm is soothing to the child and is integral in the maintenance of homeostasis. . humans may breathe through their noses, mouths or intermittently through both. it is commonly held that, between birth and at least months of age, infants breathe exclusively through their noses. this belief has, however, been challenged and some authors propose that infants are 'preferential nasal breathers' rather than 'obligate nasal breathers'. in older children and adults, under normal conditions and at rest, the nasal respiratory route is used, and oronasal breathing occurs typically when a higher degree of ventilation is necessary, as during exercise. in order to breathe through the nose, the nasal airway (nostril, nasal cavity and nasopharynx) should be patent. nasal obstruction consists of partial or complete blockage of one or more of these components of the air passages. in the newborn, the posterior nasal aperture may be blocked by choanal atresia. because of the infant's preferential nasal breathing route, such total nasal obstruction is a medical emergency. in the young infant, and later in life, several other factors can cause nasal airway obstruction. 'stuffy nose' or rhinitis is a common cause of nasal obstruction in young infants that results in mouth breathing (see p. ). viral upper respiratory tract infections, foreign body, deviated nasal septum, hypertrophy of the inferior turbinates and nasal polyps are other factors that can also predispose to mouth breathing and produce an open mouth posture. nasal endoscopy may be necessary to assess children with severe nasal obstruction that may require surgical repair. tonsillar hypertrophy is believed by many to be the main cause of nasal obstruction in children. the pharyngeal tonsil, or adenoids, is a large collection of lymphoid tissue located beneath the roof of the nasopharynx, at the level of the sbs. enlargement of the pharyngeal tonsil commonly occurs as the result of frequent bacterial or viral infections and can obstruct the nasopharyngeal route so that mouth breathing is the only possible alternative. 'tonsils' is the common name for the palatine tonsils, which are lymphoid tissue located laterally on the oropharyngeal walls, just posterior to the base of the tongue. children with enlarged adenoids are described as having 'adenoidal facies' (long faces). they share common features with other mouth breathers, having low body weight and short stature, circles around their eyes, receding chins, small mouths, dry, large lower lips and short upper lips that are held apart from one another. they also tend to have multiple allergies and to demonstrate a specifi c postural confi guration, the most commonly described feature of which is the anteriorly displaced or extended position of the head. effi cient respiration is the result of multiple intricate neurophysiologic processes and several anatomic structures contribute to this complex system. the extended, or forward, head posture may follow nasal obstruction as a solution to compromised nasal breathing. experimental studies have shown that cervical extension increases maximum oropharyngeal airway size. therefore, children with nasal obstruction will spontaneously tend to assume the extended or forward head posture. an extended head position is associated with an anterior displacement of the condyles of the occiput on the superior articular surfaces of the atlas, while the squamous portion of the occiput is lowered. the distance between the occiput and dorsal arch of the fi rst cervical vertebra has been shown to be decreased in mouth breathers. the condyles of the occiput are convex and the superior articular surfaces of the atlas are concave. extension of the head for the shift from nasal to mouth breathing results in anterior and ascending displacement of the occipital condyles on the superior articular surfaces of the atlas. this causes the horizontal line of sight of the orbits to be angled upward, with resultant shift of the visual fi eld and the need for postural compensation. one way to accomplish this, which is commonly observed in mouth breathers, is to increase the thoracic kyphosis. another way -possible with young children when the synchondroses of the cranial base are still patent -is to increase the amount of fl exion in the cranial base. such an increase of cranial base fl exion is present in mouth-breathing children. interestingly, an increase in cranial base fl exion in primates has been shown to result in a decrease of the anteroposterior length of the nasopharynx and shortening of the anteroposterior length of the mandibular ramus. the decrease of the anteroposterior length of the nasopharynx reinforces the tendency for mouth breathing, while the shortening of the anteroposterior length of the mandibular ramus correlates with the receding of the chin (retrognathia) that is observed in children who are mouth breathers. adenoidectomy is considered to be an effective treatment for children with enlarged adenoids who are mouth breathers. however, recurrence of breathing diffi culties in these children has been observed and is attributed to their craniofacial anatomic pattern. an extended craniocervical junction, or any dysfunctional pattern in the surrounding myofascial structures, may, therefore, be considered a primary dysfunction that could, in turn, predispose the child to chronic mouth breathing. this is confi rmed by clinical observations that some children present with chronic mouth breathing secondary to nasal airway obstruction, while others tend to be mouth breathers without any obvious obstruction of the nasal airway. mouth breathing has also been correlated with an inferoposterior displacement of the hyoid bone and an anteroinferior positioning of the tongue. , , the hyoid bone, a 'u-shaped' bone with an anterior convexity, is not directly articulated with any other skeletal structures. through its myofascial attachments it acts as an interface between the tongue, the pharynx, the larynx and the skull and thorax. therefore its position is infl uenced by dysfunction of any of these related structures and it can, in turn, exert infl uence on them. in mouth breathers, both the hyoid bone and the tongue are displaced to a position lower than normal. chronic mouth breathers often demonstrate premature molar eruption. mouth breathing also infl uences the growth of the mandible, resulting in anterior mandibular rotation and increase of the gonial angle between the ramus and the body of the mandible. consequently, the vertical height of the lower face of mouth breathers is usually increased, with a resultant open bite that is an augmentation of the vertical dimension separating the jaws. nose breathing performs several functions of importance, such as warming and humidifi cation of the inspired air, facilitation of arterial oxygenation and regulation of pulmonary function. nasal obstruction is linked to obstructive sleep apnea in children as well as in adults. therefore, nasal obstruction is a signifi cant dysfunction and osteopathic procedures can often be applied to improve the patency of the nasal airway. preventive treatment should be carried out for infants and toddlers to ensure normal development of the cranial base and craniocervical junction. mouth breathing is present with and without nasal obstruction and the child should be evaluated to determine if nasal obstruction is present. in severe cases, nasal endoscopy and medical treatment may be necessary. hyponasal speech usually indicates an obstructed airway. a simple way to check for nasal patency is to ask the child to breathe, at least times, through their nose while keeping their mouth closed. the child should be able to perform this test without becoming short of breath. diffi culty in achieving the test may be associated with rhinitis or chronic sinusitis. successfully completing the test indicates that the prognosis for a positive response to manipulative treatment is good. an alternative method to assess nasal patency is to hold a mirror under the nostrils of the subject. normally patent nasal respiration will fog the mirror. if nasal obstruction is not demonstrated, the child should be examined to defi ne somatic dysfunction possibly responsible for mouth breathing. identifi ed somatic dysfunction should be treated and then procedures to establish nasal breathing should be taught to the child. the objective of treatment is to obtain optimal posture, improve function of the cervical and thoracic spine, balance the cranial base and its relationships with the hyoid bone and mandible, and facilitate nasal passage patency. as the pharyngeal tonsil is located immediately below the cranial base, at the level of the sphenobasilar junction, augmentation of the motion of the cranial base may increase tonsilar lymphatic drainage. when treating the child it is best to begin by addressing their global standing posture. observe the relationship between the head and the remainder of the body. look for any asymmetries of cervical rotation and sidebending. look for an exaggerated position of cervical extension or fl exion and for increased thoracic kyphosis and lumbar lordosis. next, with the child in the supine position, palpate for tissue texture change in the suboccipital area and in the cervical and thoracic spine below. palpate the soft tissue in the submandibular area; look for any lack of tonicity of the genioglossus muscles. palpate for texture change in the tissues surrounding the mouth and the nose. assess the motion of the suboccipital area, cervical and thoracic spine. the cranial base, sphenobasilar synchondrosis and sphenoid should be evaluated next. the motions of the frontal bone, ethmoid and facial bones, particularly the maxillae, are considered next. identify any membranous myofascial dysfunction that might also be present and treat accordingly, following indirect principles. teaching the child activities for the rehabilitation of normal breathing habits should complete the treatment. the child should be trained to breathe through their nose. they should be taught to control the nasalis muscle that compresses the nasal aperture with its transverse part and laterally opens the nostril with its alar part. with their index fi nger and thumb bilaterally contacting their nose, lateral to the nasal ala, they can be taught to feel the expansion of the nares when breathing. next, they can be encouraged to open their nostrils more dynamically during inhalation while palpating the resultant nasal expansion. encouraging them to smell pleasant odors such as fl owers or favorite foods may further increase awareness of nasal function. small children may be taught to intermittently fl are and relax their nostrils by telling them to move their noses as a rabbit does, while keeping their mouths closed, but not so tight as to purse their lips by constricting the orbicularis oris muscle. the upper airway is a very complex area that participates in several physiologic functions as diverse as deglutition, vocalization and respiration. multiple anatomic structures take part in the mechanics of respiration. consequently, more than one specifi c site of the upper airway can be blocked in obstructive disorders such as sleepdisordered breathing (sdb) where the different parts of the pharynx, the base of the tongue and the esophagus may be involved. in sdb, several factors may be present along with the obstructive phenomenon. these include abnormalities or diseases of the paranasal sinuses, tonsilses, soft palate and tongue, as well as obesity. [ ] [ ] [ ] a review of the development and relationships between the multiple constituents of the upper respiratory system is helpful in understanding the dysfunctional patterns of the region. the respiratory system consists of the larynx, trachea, bronchi, lungs and pleura. the larynx is situated between the trachea and the root of the tongue. it forms the lower part of the anterior wall of the pharynx and is the organ of voice. in the infant, during the fi rst months of life, the larynx is located in a high position and, throughout both deglutition and respiration, contact is maintained between the epiglottis and the soft palate. by approximately months of age, however, this contact is maintained only during deglutition and separation occurs during respiration. the larynx progressively descends from a high position in the neck at the level of c -c during the fi rst ½- years of life to a lower position in the adult, where it is located between the upper border of c and the upper border of c . during the fi rst years of life the descent of the larynx is associated with important changes in the relationships of the structures that constitute the pharynx. in the newborn and the very young infant, the tongue is located totally within the oral cavity. as the larynx descends, the posterior part of the tongue is drawn posteriorly and inferiorly to participate in the constitution of the superior part of the anterior wall of the pharynx, i.e. the oropharynx. the pharynx is shaped like a funnel, having a length of about . cm. the upper wide end of the pharynx is tipped forward and consists of the oral and nasal cavities, whereas the lower part, at about the level of c , is continuous with the esophagus. superiorly, it is attached above to the base of the skull on the posterior borders of the medial plates of the pterygoid processes of the sphenoid bone, on the petrous parts of the temporal bones and on the pharyngeal tubercle of the occipital bone. laterally, the pharynx is connected to the styloid processes of the temporal bones and posteriorly to the cervical spine and the prevertebral fascia that envelops the longus colli and longus capitis muscles. the anterior portions of the pharynx are attached to the medial pterygoid plates of the sphenoid bone, the pterygomandibular raphes, the mandible, the tongue, the hyoid bone, and the thyroid and cricoid cartilages. the pharyngeal wall consists of two groups of muscles, the constrictor muscles and the longitudinal muscles, grouped according to the arrangement of the muscle fi bers. the three constrictor muscles -the inferior, middle and superior -function to constrict the pharyngeal cavity. the longitudinal muscles are the paired stylopharyngeus muscles that connect the pharynx with the styloid processes of the temporal bones, the salpingopharyngeus muscles that connect the pharynx with the cartilaginous part of the pharyngotympanic tubes and the palatopharyngeus muscles that connect the pharynx with the soft palate. the three longitudinal muscles elevate the pharyngeal wall. the pharyngeal muscles are innervated by the vagus nerve (cn x), except for the stylopharyngeus muscles that are innervated by the glossopharyngeal nerve (cn ix). the pharynx consists of three parts: the nasopharynx into which the choanae of the nasal cavity open, the oropharynx that constitutes the posterior portion of the oral cavity and the laryngopharynx into which the superior portion of the larynx opens. the soft palate is located between the nasopharynx and the oropharynx. the soft palate is a determining factor in the establishment of the breathing route. it is compared to a curtain hanging from the posterior border of the hard palate, i.e. the posterior borders of the two palatine bones. the soft palate extends downwards and backwards between the mouth and pharynx. it consists of muscular fi bers, aponeurosis, vasculature, nerves, adenoid tissue and mucous glands enclosed in a fold of mucous membrane. its posterior surface is convex and is continuous with the fl oor of the nasal cavities. its anterior surface is concave and is continuous with the roof of the mouth (fig. . . ) . the position of the soft palate determines the route of breathing. it acts as a valve hanging over the oropharyngeal isthmus. in its more horizontal position it separates the nasopharynx from the oropharynx, its posterior tip being closer to the posterior wall of the pharynx, facilitating the oral route of breathing. when it is depressed against the base of the tongue, the oropharyngeal isthmus is closed and the nasal breathing route is made possible. when respiration is through both mouth and nose, the position of the soft palate is shown to be between the tongue and the posterior pharyngeal wall. the soft palate is under the control of fi ve pairs of muscles. the levator veli palatini (lvp) and tensor veli palatini (tvp) arise from the base of the skull. the lvp originates from the apex of the petrous part of the temporal bone and from the cartilage of the pt and spreads in the palatine velum to blend with the muscle of the opposite side. the tvp arises from the scaphoid fossa of the medial pterygoid plate, from the spina angularis of the sphenoid and from the lateral wall of the cartilage of the pt. it descends vertically and then turns around the pterygoid hamulus to insert into the palatine aponeurosis. the musculus uvulae is related to the uvula. the palatopharyngeus arises from the pharynx and the palatoglossus from the tongue. all the soft palate muscles are innervated by the vagus nerve (cn x) except the tvp that is innervated by the mandibular nerve (cn v ) . the tvp muscles tense the soft palate; the lvp muscles elevate the soft palate and, therefore, close the nasopharynx. the palatopharyngeus muscles depress the soft palate and participate in the closing of the oropharyngeal isthmus. the palatoglossus muscles depress the soft palate caudally and ventrally and elevate the root of the tongue. the function of the soft palate is supposed to be actively determined, with dominant activity of the palatoglossus muscle when a subject is breathing quietly, and more activity from the lvp muscle during forced expiration. some activities such as breathing exercises or singing require both the nasal and oral breathing routes and the position of the soft palate consequently adapts to the situation. normal breathing relies on a patent nasal and pharyngeal airway. this patency depends on neural regulatory mechanisms as well as normal anatomic structures. the neural regulation is in part under the control of refl exes mediated through the trigeminal nerve (cn v) or the vagus nerve (cn x). the role of the vagus nerve is of paramount importance in the preservation of pharyngeal airway patency and any dysfunction of the upper cervical spine, in particular at the level of the jugular foramen, should be considered when airway patency is functionally compromised. considering the anatomic structures, the soft palate has been found to be the most common site of obstruction in infants presenting with signifi cant obstructive sleep apnea (osa). furthermore, an increase of cranial base fl exion has also been demonstrated in mouth breathing or sdb children. one can assume that, because of the insertion of the soft palate muscles, a dysfunction of the cranial base would lead to modifi ed soft palate mechanics. the soft palate occupies a strategic position, an intersection between the muscles arising from the base of the skull and the muscles connected to the tongue and the pharynx. considering these relationships, it is logical that any disturbance in the anatomic features infl uencing the soft palate, the tongue and the pharynx may also play a role in the development of sdb. adenotonsillar hypertrophy is described as being the most common cause of osa in children; its importance correlates with the dimension of the adenoids. osa, the result of airfl ow obstruction, occurs in older children as well as in infants, where symptoms may include apneic spells. pharyngeal collapse is involved and it is proposed that airway muscle dysfunction or anatomic alterations predispose to that collapse. loss of longitudinal tension within the pharyngeal airway is suggested as being responsible for the collapsibility. subtle abnormalities in upper airway neuromuscular function or structure are proposed additions to the etiology of adenotonsillar hypertrophy. , the craniocervical junction is under great stress in the infant and dysfunction of the pharynx, which is attached to the base of the skull and to the cervical spine and prevertebral fascia, may be associated with any somatic dysfunction of the craniocervical junction and cranial base. the position of the cervical spine is correlated with pharyngeal changes: cervical fl exion reduces oropharyngeal size; cervical extension increases it. , , studies have demonstrated that patients with obstructive sdb present a narrower or more obstructed oropharynx and laryngopharynx than controls, particularly during sleep. besides the effect of cervical posture, alteration of refl exes due to sleepiness may play a role. when present, nasal obstruction also disturbs nasopharynx refl exes, mediated through the trigeminal or vagus nerves, which may result in decreased patency of the oropharynx. multiple sites are considered as potential causes for sdb. in view of the intricate anatomic relationships of the soft palate, the pharyngeal wall, the tongue and the mandible, any dysfunction of one affects the associated structures and their positions. biomechanical interactions between the tongue and lateral pharyngeal walls have been described and displacement of the mandible also affects oropharyngeal size. mouth opening reduces oropharyngeal size. the modifi ed mandible position affects the function of the genioglossus, one of the tongue muscles that protrude the anterior part of the tongue out of the mouth. this, in turn, increases upper airway collapsibility, the position of the tongue being a strong determinant of the patency of the oropharynx. this explains why mouth breathers present with snoring and sdb. alterations in the electromyographic activity of the geniohyoid and genioglossus muscles follow experimental nasal obstruction in monkeys with affected mandibular growth as a result. similar mechanisms are believed to exist in humans where mouth breathing in children, associated with sdb, may cause developmental facial abnormalities. maxillary and mandibular protrusions are smaller in children with osa and the position of the hyoid bone is lower. mouth breathing generates the development of a craniofacial type that includes an increased value of the anterior facial height and an open bite. the increased respiratory effort that these children must exert is responsible for functional impairment and eventually structural changes in their craniofacial anatomy. osa is also associated with poor sleep quality, failure to thrive, impaired daytime psychomotor performance, irreversible developmental delay and enuresis. osteopathic procedures should consequently be employed at the earliest possible time to avoid the establishment of dysfunctional patterns and their sequelae. begin by assessing for, and treating, any dysfunctional imbalances in the global postural pattern, particularly the craniocervical junction and upper aspects of the thoracic region including clavicle, sternum, upper thoracic vertebrae and associated ribs. next, attention should be paid to the mechanics of the hyoid bone, including the infra-and suprahyoid muscles because of their relationship with the pharynx and tongue. the synchondroses of the cranial base, the occipitomastoid sutures and the relationship between the sphenoid and temporal bones should be considered next. any dysfunction of the temporal bones should be addressed in the treatment of sdb because of the connection between the longitudinal muscles of the pharynx and the styloid processes of the temporal bones. evaluate the temporomandibular joint, the mandible and surrounding myofascial elements. the inferior part of the pharynx is continuous with the esophagus that connects the pharynx to the stomach. possible stomach as well as tracheal visceral dysfunctions may affect the pharynx, either through mechanical imbalance or through disturbed vagal refl ex; therefore, they should be treated if present. teaching the child activities that strengthen and tone the soft palate and tongue can complete the treatment. vocal exercises employed in singing are benefi cial. the tongue, particularly the genioglossus muscles, can be strengthened by having the child alternately attempt to touch the tip of their tongue up to the tip of their nose and down to their chin. bronchiolitis is an acute viral infection of the lower respiratory tract that affects infants and young children. in europe, australasia and north america, an average of % of all children born every year present with bronchiolitis. respiratory syncitial virus (rsv) and infl uenza a virus are the most important viral causes of lower respiratory tract infection in young children. infections with infl uenza viruses b and coronavirus may also be common. infl uenza viruses are highly contagious and are responsible for epidemics presenting various degrees of severity, although only a small proportion of children infected with the virus develop severe disease. risk factors are childcare attendance, exposure to environmental pollutants, school-aged siblings, congenital abnormalities of the airways and neuromuscular disease. rsv is so named because, in tissue culture, it grows as a giant syncytia, a mass of protoplasm containing several nuclei. multiple genotypes of rsv cocirculate every year, along with an important variability in infl uenza virus occurrence from year to year. the infecting virus fi rst establishes in the upper respiratory tract and then spreads to the medium and small bronchi and bronchioles, resulting in infl ammation of the epithelium with edema and bronchial obstruction that manifests principally during expiration. air is trapped within the alveoli and hyperinfl ation of the lungs follows. respiratory distress appears with tachypnea and tachycardia. expiration is diffi cult and prolonged, and when the infant presents with severe tachypnea, breath is rapid and short, with poor air exchange. wheezing, crepitus and fever may be present. rsv is an important childhood pathogen in infants younger than months of age. once infected, an infant does not develop complete immunity and recurrence of infection is common. pneumonia and bacterial superinfections of the respiratory tract are frequent complications. rsv may be severe in infants under months of age and is an important cause of hospitalization for acute lower respiratory tract infection in infants and young children. bronchiolitis, particularly when due to rsv, may be a precursor of the later development of asthma. allergic rhinitis also exacerbates bronchial infl ammation and may be a risk factor for the development of asthma. young children who have more than three episodes of infectious bronchiolitis, and those with a family history of asthma who have more than two episodes of infectious bronchiolitis, may also be predisposed to asthma. widespread respiratory viruses like rsv are also possible factors in the cause of acute otitis media in young children. , consequently, preventive considerations should be applied. the primary defense against common pathogens of acute lower respiratory infections is waldeyer's (circumpharyngeal) tonsillar ring, a collection of lymphoid tissue in the mucosa of the nasopharynx. it consists of the pharyngeal tonsil, the palatine tonsils and the lingual tonsil that are the multiple lymphoid nodules located on the posterior part of the tongue, plus small other nodules in the pt and lymphoid tissue in the intertonsillar intervals. the nasopharyngeal tonsil increases in size in the fi rst years of life, are largest at years and atrophies by the time of puberty. the efferent lymphatics of these mucosa-associated lymphoid tissues start in plexuses surrounding every lymphoid follicle and drain through the retropharyngeal lymph nodes or directly into the upper deep cervical nodes. the retropharyngeal nodes consist of three groups, two of which are located on either side, anterior to the lateral masses of c , following the lateral borders of the longi capitis. somatic dysfunction of the cervical spine, the frontal bone, the maxillae, the ethmoid bone, the nasal bones and the zygomatic bones can alter the function of the upper respiratory tract as a primary defense against common pathogens. dysfunction of the thoracic cage and diaphragm can impair effi cient return of lymph to the general circulation and the ciliary clearance current of mucus in the bronchial tree. thus, somatic dysfunction can contribute to the creation of a fertile environment wherein pathogens can thrive. it has been shown that osteopathic manipulative treatment (omt), particularly the lymphatic pump, results in decreased morbidity and mortality in patients with infl uenza. , the ans is of prime importance in the regulation of bronchial secretion and its dysfunction may facilitate bronchiolitis. the sympathetic postganglionic fi bers between t and t stimulate bronchial and bronchiolar dilatation and decrease fl uidity of the secretions. the pulmonary branches of the vagus nerve are motor to the muscles fi bers of the bronchi and bronchioles and are consequently bronchoconstrictor. thus, somatic dysfunction of the upper thoracic, upper cervical and cranial regions can affect the lower respiratory tract through somatovisceral refl ex action. the objective of osteopathic treatment in the acutely ill, non-emergent child with bronchiolitis is to stimulate the expectoration of mucus, reduce air trapping and promote homeostasis by balancing the ans and enhancing the venous and lymphatic drainage of the lungs. furthermore, it is important to reduce somatic dysfunction that can predispose the child to the recurrence of the illness. observe the chest and the way the child is breathing, paying particular attention to the mobility of the ribs and sternum. children with respiratory obstruction may demonstrate suprasternal, infrasternal, subcostal and intercostal retraction when breathing. on percussion, the chest is hyperresonnant. prolonged expiration, wheezing, and fi ne moist crackles may be observed at auscultation. it is important to auscult the lungs before and after the osteopathic treatment. using indirect principles, restore thoracic spine and rib motion. thoracic pumping may be used to loosen mucus, stimulate expectoration and decrease bronchial obstruction. the thoracic diaphragm and thoracic inlet should be evaluated and treated as fi ndings dictate. rib raising and sternal molding may be applied to further mobilize the thoracic cage, increase ventilation, loosen mucus and stimulate expectoration. sympathetic activity should be balanced by treating any dysfunction of the upper thoracic spine (t -t ). parasympathetic tone can be normalized with treatment of the suboccipital area. using indirect principles, treat any cervical somatic dysfunction that is present. improve lymphatic drainage from the upper deep cervical lymph nodes with soft tissue techniques applied to the cervical myofascial structures. observe the child's face. the frontal bone, the maxillae, the ethmoid bone, the nasal bones and the zygomatic bones form the upper respiratory tract. look for asymmetries of these structures and for any tissue texture change. palpation and motion testing will confi rm these observations and treatment should be applied accordingly. it is imperative that the child is breathing through their nose, so any dysfunction that impairs nasal respiration should be addressed. following manipulative treatment it is important to re-evaluate the child. re-evaluate the musculoskeletal areas treated and auscult the lungs again to check clearance of the secretions and progress of airfl ow. it is important to maintain hydration of the respiratory tract. the caregivers should be advised to encourage consumption of fl uids and to maintain suffi cient humidifi cation of the child's environment. asthma is the most frequently encountered chronic disease in childhood. allergic disorders and asthma in childhood have increased in prevalence in many countries over the past - years. , asthma is characterized by chronic infl ammation leading to airway hyperreactivity and recurrent reversible airfl ow obstruction. a multifaceted interaction of genetic and environmental factors appears to cause asthma. a genetic predisposition seems to exist , , and the risk is greater if both parents present with the disease. in the predisposed host, immune responses to different exposures such as allergens and air pollutants may trigger pathogenic infl ammation. children from lower socioeconomic groups more often present with asthma, rhinitis and allergic sensitization, especially to food allergens. different factors may explain this susceptibility, the quality of food being one of them. evaluation of different diets demonstrates the asthma preventive effect of dietary management for children with a family history of asthma. of demonstrable benefi t are diets with increased anti-infl ammatory 'n- ' polyunsaturated fatty acids (omega- polyunsaturated fatty acids), alone and in combination with house dust mite allergen prevention. there is also some evidence that dietary omega- polyunsaturated fatty acid supplementation during pregnancy and early childhood may potentially reduce infant atopy and asthma. , the controversial 'hygiene hypothesis' was developed in the late s to explain the high prevalence of allergic diseases and asthma in industrialized countries. the attention to hygiene in these countries is associated with reductions in microbial exposures and decreased incidence of infectious diseases. microbial encounters in infancy and early childhood stimulate the development of the immune system and the 'hygiene hypothesis' states that atopic disorders are the consequences of the lack of early life infections. alternatively, the use of antibiotics in the st year of life may increase the risk of asthma. opposite to the hygiene hypothesis, however, there is evidence that the pathogenesis of asthma may include early exposure to viruses and bacteria. , a high frequency of respiratory tract infections in the st year of life is a predictor of asthma between the ages of and years. , elevated ige levels at months are also a predictor. alternatively, the association of atopy with asthma is controversial and the onset of eczema during the st year of life is not always found to be associated with the later development of asthma in childhood. a clinical association between rhinosinusitis and asthma is strongly suggested. furthermore, effective treatment of rhinosinusitis has a positive effect on concomitant asthma. elements that contribute to the concept of 'united airway' disease include the dissemination of postnasal drip of infl ammatory cells into the lungs. a vascular circulatory route with the migration of infl ammatory cells to the lungs is another suggested pathway to explain the connection. another possible link between the upper and lower airways is through the nervous system, with naso-pharyngo-bronchial refl exes involving the trigeminal and the vagus nerves. upper airway infl ammation may have an effect on receptors in the nose and pharynx. afferent (sensory) fi bers from these receptors participate in the constitution of the trigeminal nerve that connects with the dorsal vagal nucleus in the brainstem through the reticular formation. the vagus sends parasympathetic efferent fi bers to the bronchi to preserve bronchial muscle tone and modulate bronchospastic responses. in asthmatic children, bronchoconstriction and mucus secretion is increased due to augmented parasympathetic nerve activity. a neurogenic infl ammation activated by infl ammatory mediators and environmental irritants along the neural refl ex pathway may be the cause of a neuronal dysfunction. the osteopathic principle of holistic integration of the different parts of the body applies perfectly to this hypothesis where an initial body reaction is followed by distant manifestations. the theory of 'one airway -one response' states that the common histopathology in both upper and lower airways results in a global allergic infl ammation of the whole airway. the total body allergic response is also illustrated through interactions between the respiratory system, the skin and the gastrointestinal tract. the lung and the gut are part of a unifi ed mucosal system. the circulation of cells of the blood, from the bone marrow and the mucosal lymphoid tissue explain a possible interaction between these different areas and allergens. the intestine is one of the most signifi cant immune organs of the body. the composition of its microfl ora differs between infants with and without atopy, and the differences are verifi able before the occurrence of some clinical manifestation such as asthma. alternatively, there is a link between the mode of obstetrical delivery and the maturation of the humoral immune system. infants delivered by cesarean section demonstrate a delay in intestinal colonization. the initial stimulation by the gut microfl ora may possibly be more signifi cant than that of a sporadic infection and there is evidence of a relationship between cesarean section delivery and increased occurrence of atopic asthma. there is another connection between the lung and the guts with asthmatic patients. about - % of adults and children with asthma present with gastroesophageal refl ux -refl ux of gastric contents into the esophagus -which may not be clinically obvious. intracellular acidifi cation diminishes the ciliary beat frequency of the epithelial cells of the human tracheobronchial apparatus. this point is signifi cant in asthma, as well as in other respiratory dysfunction, as a factor contributing to decreased mucociliary clearance. the lungs and esophagus are both innervated by the vagus and upper thoracic distribution of the sympathetic nervous system. autonomic dysfunction may explain symptoms related to both gastroesophageal refl ux and asthma. under normal conditions, the parasympathetic nervous system through the vagus sustains bronchial muscle tone while sympathetic fi bers evoke bronchodilatation. sympathetic nerve fi bers also innervate the bronchial and gutassociated lymphoid tissue that seems to be essential in neuroimmune interactions. the parasympathetic visceral sensory system collects internal information that, in turn, infl uences emotions as much as emotional states impact autonomic function. the infl uence of stress is potentially negative on neuroimmunoregulation. in asthmatic patients, there is evidence that stress experienced prenatally or in the st years of life may participate in the development of asthma. , increased psychological stress may impact respiratory illnesses in children and contribute to immune deregulation. there is evidence that stress facilitates susceptibility to infections and may be associated with the development of asthma. very often, asthmatic children present with anxious facial expression. most of the time, an asthmatic reaction is triggered by exposure to numerous environmental agents. asthmatic children have hyperresponsive or hyperreactive airways. various stimuli such as dust mites, pollutants and tobacco smoke produce an exaggerated bronchoconstrictor response with sensations of shortness of breath and chest tightness. there is evidence that the pathogenic development occurs early in the lungs, producing architecturally altered lungs later in life. treatment, therefore, should be initiated as soon as possible. asthma presents in different forms. the patient may demonstrate prodromal symptoms such as itching over the upper part of the chest and associated dry cough. this can be followed by episodes of dyspnea, tachypnea and tightness in the chest with wheezing and coughing that result from exposure to allergens, air pollution or exercise. in asthmatic patients, a bronchoconstrictor response follows nasal inhalation of cold air. other patients present with chronic coughing and wheezing, associated with shortness of breath and decrease of vital capacity. anxiety may occur related to the sensations of shortness of breath and chest tightness. osteopathic considerations for the treatment of asthma, although directed as a whole body intervention, are specifi cally focused on somatic dysfunctions of the thoracoabdominal diaphragm, thoracic cage, upper thoracic spine, cervical spine, sacrum, cranium and face. the goals of treatment are to encourage expectoration of mucus, reduce the mechanical impact of somatic dysfunction, enhance the recuperative effect of balanced sympathetic and parasympathetic tone, and facilitate the arterial, venous and lymphatic components of tissue perfusion. because signs and symptoms are often observed fi rst by the parents, these children may present to the osteopathic practitioner before the diagnosis of asthma has been formally made. it must be stressed that asthma is a potentially life-threatening condition, and although the treatment of somatic dysfunction can greatly benefi t the patient, , the need for other methods of medical management should never be dismissed. the earlier somatic dysfunction is effectively addressed, the better the possible outcome. manipulative treatment should begin with the area most easily accessible without distressing the child. the sequence of treatment is determined by the patient's acceptance of the intervention. older children are commonly tolerant and treatment may be begun on the treatment table. for younger children, it is often easier to begin with the evaluation and treatment of the upper thoracic cage because this can be done with the child seated, even in the caregiver's lap. after a trusting physicianpatient relationship has been established, the child may then be transferred to the treatment table for further treatment. with the child seated or supine, observe the upper thoracic cage, looking for decreased compliance to respiratory excursion, i.e. tension of the scalene, trapezius and sternocleidomastoid muscles in the region of the supraclavicular triangle. evalu-ate sternoclavicular motion and fl exibility of the sternum for dysfunction. articular motion of this region becomes mechanically discrete as the skeletal structures become more developed around years of age. palpate the thoracic spine and ribs for somatic dysfunction, paying attention to the area from t to t because of viscerosomatic input and somatovisceral impact with the lungs in this region. utilizing indirect principles, treat identifi ed somatic dysfunctions. following this, with the child, if possible, in the supine position, evaluate the lower thoracic cage and thoracoabdominal diaphragm. observe the mechanical pattern of respiration. asthmatic children tend to demonstrate forced expiration. palpate for lower thoracic cage compliance, comparing the inspiratory and expiratory phases of respiration. greater resistance will typically be appreciated during the expiratory phase and the child will often manifest shallow, rapid respiration. palpating the lower thoracic cage bilaterally, evaluate for general tension and asymmetry in the excursion of the thoracoabdominal diaphragm. assess the lumbar spine for dysfunction that can impact the diaphragm through the diaphragmatic crura. examine the sacrum and pelvis to identify dysfunctional mechanics that can affect the asthmatic through the core link. treat identifi ed somatic dysfunction with indirect procedures. entraining the movement of the manipulative treatment with the patient's breathing allows the practitioner to follow and gradually augment the amplitude of respiratory excursion. next, evaluate the cervical spine and myofascial structures of the neck. after general screening for dysfunction, attention should be directed at the upper cervical spine because of the viscerosomatic and somatovisceral vagal infl uence of the area. treat identifi ed dysfunction. examination can now proceed to the cranial base. using your preferred hand placement, evaluate the motion of the sbs. anecdotally, children with asthma and eczema seem to present frequently with sbs compression and decreased amplitude of the cri. assess the relationship between the occiput and temporal bones for compromise of the jugular foramen with its potential to interfere with vagal function. evaluate the temporal bones where part of the tentorium cerebelli attaches. dysfunction at this level affects the respiratory breathing pattern. an external rotation of one temporal bone tends to limit the freedom of expiration. examine the relationship between the sphenoid, frontal and facial bones. the bones of the face -ethmoid, lacrimal, maxillary and nasal bones, which contribute to the structure of the nasal airway -are suspended beneath the frontal bones. additionally, the ethmoid bone articulates posteriorly with the sphenoid. it is not uncommon to encounter compression between the frontal bones and the bones of the face. treat specifi cally identifi ed dysfunctional patterns. it is important that the nasal airway is unobstructed because of the effect of nasal respiration on inspired air and thoracopulmonary function. the interrelationship between rhinosinusitis and asthma further stresses the importance of appropriate function of the facial bones in asthmatic children. treatment of the cranial mechanism with attention to the inherent rhythm augments the cri with a resultant total body effect. following manipulative treatment, various activities can be prescribed to facilitate the results of the intervention. for small children the caregiver should be encouraged to regularly gently stroke the thoracic paravertebral region, particularly t -t , bilaterally. the child can be encouraged to perform expiratory activities like blowing soap bubbles. older children can be taught breathing exercises to improve lung function to increase vital capacity, facilitate the clearing of airway secretions and enhance the quality of life. begin by encouraging the child to breathe slowly and deeply, employing the thoracoabdominal diaphragm and with the least possible utilization of the accessory muscles of respirationscalene, sternocleidomastoid, trapezius and abdominal wall muscles. they should learn to breathe on demand with particular attention to control of expiration. further, they should be taught to hold their breath in the most relaxed possible way. this allows them to experience apnea without anxiety. as they become experienced in these activities, they can be encouraged to practice this method of respiratory relaxation at the fi rst perception of an asthma attack. because controlled breathing is an integral part of singing, they may benefi t from participation in a choral group. teach them to maintain good posture. a simple procedure is to have the child walk with a book balanced on the top of their head. finally, children and adolescents with asthma should participate in regular physical activity. , diet considerations should be initiated. daily intake of fresh fruit and vegetables should be recommended. processed sugars and foods that increase gastric acidity should be limited. dairy products (e.g. ice cream) which increase mucus production should be consumed moderately and preferably before p.m. to facilitate gastric emptying before bedtime and avoid gastroesophageal refl ux. approximately % of infants demonstrate symptoms of imperfect lacrimal drainage during their fi rst months of life. most of the time spontaneous resolution takes place and by their st birthday only about . % of infants still present with the condition. congenital nasolacrimal duct obstruction (dacryostenosis) may result from an abnormality in the lacrimal drainage system or from an infection. the diagnosis of congenital nasolacrimal duct obstruction is clinical. it is based on a history of epiphora (tearing), mucopurulent discharge, or both, in the presence of non-infl amed conjunctiva, usually affecting only one eye and occurring in the fi rst few weeks of life. the condition may be continuous or intermittent and crusting on the lid margins is common. parents will often report that the eyelids are stuck together on the child's awakening or that the child has a persistently watering or sticky eye. digital pressure applied medial to the eye over the lacrimal sac will produce increased discharge from the excretory puncta. there is much debate regarding a standard medical approach for the management of congenital nasolac-rimal duct obstruction. the availability of multiple therapeutic approaches for any given condition indicates that none of them works particularly well in all cases. the list of procedures that are employed as standard to correct symptomatic nasolacrimal duct obstruction includes probing and irrigation, intubation with a silicone tube, balloon dilatation of the nasolacrimal duct and infracture of the inferior turbinate. osteopathic manipulation offers an alternative approach and, since it is benign, it should be attempted before more aggressive procedures are employed. the earlier the infant or child is treated, the better the chance of rapid resolution of the obstruction. additionally, a good mental image of the anatomy of the nasolacrimal duct and lacrimal drainage system, on the part of the practitioner, will provide the basis necessary to improve the effi cacy of manipulation. the lacrimal apparatus consists of several parts that develop simultaneously. the lacrimal gland secretes the tears and the excretory ducts (lacrimal canaliculi) deliver the fl uid to the surface of the eye, while the lacrimal sac and the nasolacrimal duct collect and transport the fl uid into the nasal cavity. the lacrimal gland consists of two portions: the superior orbital part and the inferior lacrimal part. the superior orbital part is located in the lacrimal fossa, in the superolateral part of the orbit, on the medial side of the zygomatic process of the frontal bone. shaped like an almond, it is connected to the periosteum of the orbit and rests on the levator palpebrae superioris and the lateral rectus. the inferior lacrimal gland is separated from the superior by a fi brous septum and projects into the lateral part of the upper eyelid. although the lacrimal gland reaches full development at about - years of age, the production of tears in infants is similar to that in adults. on each eyelid, the lacrimal canaliculus originates at a lacrimal punctum, a minuscule orifi ce on the medial margins of the lids. the superior canaliculus is the smaller and shorter. first it goes up, then turns at an acute angle to meet the lacrimal sac, while the inferior canaliculus descends, then turns upward toward the lacrimal sac ( fig. . . ). at their angles the canaliculi are dilated and form ampullae. their mucous lining is covered by stratifi ed squamous epithelium, positioned on a basement membrane. the external wall consists of a layer of skeletal muscle fi bers, continuous with the lacrimal part of the orbicularis oculi. the lacrimal sac is the upper dilated end of the nasolacrimal duct. it is located in a fossa formed by the lacrimal bone, the frontal process of the maxilla and the lacrimal fascia. it measures from to mm in length and extends to form the nasolacri-mal duct. its superfi cial surface is sheltered by the lacrimal fascia (an extension of the orbital periosteum) and by the medial palpebral ligament. its deep surface is crossed by the lacrimal part of the orbicularis oculi, which is attached to the posterior lacrimal crest on the lacrimal bone. the lacrimal sac is lined by a mucosal membrane continuous with the conjunctiva through the lacrimal canals and with the nasal cavity through the nasolacrimal duct. the relationship with the orbicularis oculi is of particular interest. this muscle surrounds the circumference of the orbit, with osseous attachments on the frontal bone, the frontal process of the maxilla and the lacrimal bone. when it contracts, as during 'blinking', compression of the lacrimal sac occurs through the lacrimal part of the muscle, pushing fl uid into the nasolacrimal duct to drain into the inferior meatus of the nasal cavity. during muscular relaxation, fl uids are drawn into the canaliculi and the expanded lacrimal sac. the nasolacrimal duct extends from the lacrimal sac caudally to open in the inferior nasal meatus. both ends of the duct are wider than its middle portion, where it is enclosed in an osseous canal formed by the maxilla, the lacrimal bone and the inferior nasal concha. it is directed downward, backward and slightly laterally. the nasolacrimal duct is formed embryologically from ectodermal cells enclosed between the maxillary and lateral nasal processes. during the rd month of gestation a canal appears in the center of this epithelial cord. it will develop progressively in a cephalocaudal direction from the th month of gestation until birth. in the third trimester of gestation the lower portion of the duct opens into the inferior meatus of the nasal cavity to constitute the nasolacrimal duct, while the epithelium from the nasal cavity invests the duct in a caudocephalad direction. a mucosal fold -the valve of hasner -is located just above the nasal opening of the nasolacrimal duct. total canalization of the epithelial cord may fail to occur with the persistence of membranous tissue that should normally disappear at birth or in the fi rst days of life. in congenital nasolacrimal duct obstruction, the lower part of the duct may be closed at birth by fusion of the mucosa covering the nasal folds. the resultant obstruction is usually observed in infants at about the th or th day of life. nasolacrimal duct obstruction is frequently associated with dysfunction of the bones forming the osseous canal in which the nasolacrimal duct is located, i.e. the maxilla, the lacrimal bone and the inferior nasal concha. it frequently follows compression of the frontal bone and may also be associated with an inferior vertical strain of the sbs. consequently, the relationships between the frontal bone, maxilla and lacrimal bone are affected, potentially modifying the patency of the nasolacrimal duct. this type of compression occurs frequently during pregnancy, diffi cult labor or delivery and appears to be a prediposing factor. furthermore, dysfunction of the frontal bone, maxilla and lacrimal bone changes the relationship between the points of attachment of the orbicularis oculi, predisposing to muscular dysfunction. when treating nasolacrimal duct obstruction, the delicacy of the intervention necessitates that the infant moves as little as possible. this may be accomplished by arranging to see the infant at a time that coincides with their nap time. the best approach is to have the caregiver arrive with the infant about minutes before the scheduled appointment. place the infant and caregiver in a quiet examining room and allow the infant to have their bottle or to nurse. allow suffi cient time thereafter for the infant to go to sleep, preferably in a supine position on the examining table. once the infant is asleep, quietly commence treatment. first observe the frontal bones. often the frontal bone on the side of the lacrimal duct obstruction will be found to be lower than the other side. look next at the area of the nasion, nasal bones and frontal processes of the maxillae, noting asymmetry and compression of these structures. the forces commonly involved in lacrimal duct obstruction are most often vertical compression between the frontal and nasal bones, sometimes with sidebending and rotation of the facial block beneath the frontal bone, with the obstruction on the side of the facial concavity. confi rm the observations with tests of listening, paying close attention to the frontal bones, nasal bones, maxillae and lacrimal bones. keep a mental picture of the minute details of the area to help this process. defi ne areas of restricted motility and employing the inherent forces of the prm and its rhythm, utilize the most delicate indirect treatment procedure. the treatment procedure should be so gentle as not to awaken the infant. encourage the caregiver to regularly clean the secretions from the eye to avoid the development of an infection. to promote drainage into the nasolacrimal duct, the caregiver can milk the lacrimal sac by intermittently applying gentle digital pressure medial to the punctum of the eye in a superior to inferior direction. actively playing with the child to encourage facial expression stimulates the function of the orbicularis oculi. if the child is old enough, have them blink tightly and make faces. contracting the orbicularis oculi promotes drainage by placing pressure on the lacrimal sac. strabismus -the deviation of the alignment of one eye in relation to the other -is a condition frequently encountered in infants and children. it is a very complex subject and its complete discussion is beyond the focus of this text. however, the treatment of somatic dysfunction can prove very beneficial in certain presentations of the condition. strabismus must be taken seriously and signifi cant underlying pathologies, such as congenital cataract and retinoblastoma, ruled out. it is imperative that, on presentation, every case of strabismus, no matter what the age of the patient, has a thorough ocular examination, including cornea, lens, retina and optic nerve, as well as the neurologic status of the eye and extraocular muscles (eom). treatment of strabismus should be initiated at the earliest possible time to avoid loss of the ocular stimulation that normally contributes to the maturation of the visual system. the eyeball -the organ of sight -is contained in the skeletal cavity of the orbit, which provides a protective space for the eyeball and associated structures, i.e. fasciae, eyelids, conjunctiva, lacrimal apparatus and eom. the eyeballs start to develop from neuroectoderm of the lateral aspects of the forebrain as a pair of diverticulae at approximately the nd day of gestation. at the th day, two optic vesicles are formed. around the th week, they invaginate and create the optic cups in which mesenchymal and vascular tissues enter the globe. the different parts of the future eyeball and surrounding orbital cavity are intimately interrelated. at the beginning of the fetal period -the end of the nd month of gestation -eom are present, surrounding the eyeball. growth will continue with a signifi cant correlation between gestational age and fetal eye biometry, including lens, orbital diameters, circumferences and surfaces. surrounding the eyeball, the constituents of the orbital cavity consist of the frontal, lacrimal, palatine and zygomatic bones, ethmoid, maxilla and sphenoid. they develop in membrane and are quite responsive to the growth stimulation of the eyeball. thus, the orbital cavity is growing as a result of the increase of the volume of the eyeball and the activity of the eom, with more and more elaborate eye movements. from this time up to years of age, the eyeballs will continue to grow, acting continuously as a growth stimulator for the skeletal cavity of the orbit. at birth, the orbit height is already % of its adult height. at years of age it is %, while at years of age it is about %, nearly its adult size. evidence of the importance of this stimulating factor is demonstrated by conditions like microphthalmia, where the development of the eyeball does not occur correctly, or when an individual is enucleated in early childhood. underdevelopment of the orbital cavity is typically associated with these conditions. an anophthalmic bony orbit may be . % smaller when compared to the other orbit. the concept that function affects structure, one of the basic osteopathic principles, is perfectly illustrated in this instance. at the same time, structure affects function. in this case, the structures forming the orbital cavity may affect the ocular function of sight, associated vascular and neurologic aspects, and extra-and intraocular muscular activity. therefore, it is appropriate to consider the protective case for the eye, i.e. the orbital cavity, and to see how its osseous components play a part in the etiology of ocular dysfunction. the orbits are located in the upper and anterior part of the viscerocranium. they are shaped like pyramids, with their apices and long axes directed backward and medially. each orbit consists of a roof, a fl oor, a medial and a lateral wall, a base and an apex. the roof is concave, directed downward and slightly forward. the orbital plate of the frontal bone forms most of the roof, while the lesser wing of the sphenoid forms its posterior part. therefore, there is a suture on the roof of the orbital cavity between the frontal bone and the lesser wing of the sphenoid. the lacrimal fossa for the lacrimal gland is located laterally on the orbital surface of the frontal plate. medially, below and behind the end of the supraorbital margin of the frontal bone, is the trochlear fovea for the attachment of the cartilaginous pulley of the superior oblique muscle. this feature is of particular interest in understanding ocular dysfunction, since the frontal bone is frequently under stress from fetal positioning, diffi cult labor or trauma sustained by young children, such as a fall on the head. although most of this anatomy is not directly palpable, the supraorbital margin of the frontal bone is completely accessible and its position should always be evaluated in strabismus. the fl oor of the orbit is directed upward and laterally. it consists mostly of the orbital surface of the maxilla; behind that and medially, the orbital process of the palatine; and in front and laterally, the orbital process of the zygomatic bone (fig. . . ) . the maxilla articulates with both the palatine and the zygomatic bones. the lacrimal notch is located anteriorly, on the medial border of the maxilla, and provides the superior opening of the nasolacrimal canal. on this border the maxilla articulates with the lacrimal bone and the ethmoid's orbital plate behind. a depression situated just lateral to the lacrimal notch is the location of the origin of the inferior oblique muscle. the posterior border of the maxilla forms most of the anterior edge of the inferior orbital fi ssure, discussed further below. the medial wall of the orbit is formed anteriorly by the frontal process of the maxilla, the lacrimal bone, the orbital plate of the ethmoid and a tiny part of the body of the sphenoid in front of the optic foramen. the lacrimal groove for the lacrimal sac is located anteriorly. it is limited behind by the posterior lacrimal crest, from which the lacrimal part of the orbicularis oculi arises. three vertical sutures -the lacrimomaxillary, lacrimoethmoidal and sphenoethmoidal -are present, while the frontomaxillary, frontolacrimal, and frontoethmoidal sutures are situated between the superior border of the medial wall and the orbital roof. the lateral wall of the orbit is directed medially and forward. it consists of the orbital process of the zygomatic and the orbital surface of the greater wing of the sphenoid. the sphenozygomatic suture unites them. this is another site of particular interest since the zygomatic bone is easily palpable. through palpation of the zygoma one can visualize, indirectly assess and treat the less accessible greater wing of the sphenoid. the sphenozygomatic suture ends below at the anterior end of the inferior orbital fi ssure. the upper end of the sphenozygomatic suture meets with two other sutures, creating a sutural crossroads for consideration in the treatment of any ocular dysfunction. anteriorly, the frontozygomatic suture can be observed, and posteriorly the suture between the frontal bone and the greater wing of the sphenoid. just under the frontozygomatic suture, on the orbital process of the zygomatic bone, is a tubercle for the attachment of the levator palpebrae superioris' aponeurosis. the inferior orbital fi ssure lies between the lateral wall and fl oor of the orbit, posterior to the zygomaticomaxillary suture. it communicates with the pterygopalatine and infratemporal fossae, and transmits the infraorbital vessels, the maxillary nerve (cn v ) and the ascending branches from the pterygopalatine ganglion. the superior orbital fi ssure separates the roof and lateral wall of the orbit in its medial portion. the oculomotor (cn iii), the trochlear (cn iv), the ophthalmic division of the trigeminal (cn v ) and the abducent (cn vi) nerves enter the orbital cavity through this fi ssure, accompanied by some fi laments from the cavernous sympathetic plexus and the orbital branches of the middle meningeal artery. additionally, the superior ophthalmic vein drains into the cavernous sinus through this fi ssure. the apex of the orbit corresponds to the medial end of the superior orbital fi ssure, close to the origin of the eom, just below the optic foramen. the cylindrical optic canal forms by surrounding the optic nerve and ophthalmic artery where the two roots of the lesser wing of the sphenoid join the sphenoidal body. through the optic canal and superior orbital fi ssure, the cranial cavity communicates with the orbital cavity. the cranial dura mater lines the internal surface of every cranial bone, with a fi rm adhesion at the sutures, and extends outside the cranial cavity through foramina and fi ssures, forming tubular sheaths for the cranial nerves as they leave the neurocranium. thus, the endosteal layer of the cranial dura mater is continuous through the superior orbital fi ssure with the orbital periosteum. in addition, a tubular dural sheath from the meningeal layer of the dura surrounds the optic nerve as it passes through the optic canal. this dural layer blends with the ocular sclera and adheres intimately to the common annular tendon of the four recti muscles. there is an anatomic continuity between the dura and the lining and structures of the orbital cavity, such as the eyeball and the eom. the seven extraocular, or extrinsic, muscles include the levator palpebrae superioris, superior rectus, inferior rectus, medial rectus, lateral rectus, superior oblique and inferior oblique muscles (fig. . . ) . they control the movements of the upper lid and eyeball. all the eom are tied together in a complex fashion by fascial sheaths. there are also intrinsic muscles within the eyeball that are responsible of the shape of the lens and size of the pupil. the levator palpebrae superioris arises from the lesser wing of the sphenoid, above and in front of the optic foramen, from which it is separated by the origin of the rectus superior. from a narrow tendon it soon broadens into a fl at, triangular shape that ends anteriorly in a wide aponeurosis. the superficial fi bers are prolonged forward, piercing the orbicularis oculi muscle, to insert on the deep surface of the skin of the upper eyelid. the deepest fi bers blend with an expansion from the sheath of the rectus superior. some fi bers also attach to the upper margin of the superior tarsus and are referred to as the superior tarsal muscle. a thickening of the sheath of the levator palpebrae superioris is referred to as the superior transverse ligament of whitnall. it extends laterally and medially to insert in the orbital walls just behind the superior orbital rim. medially, it attaches to the trochlea of the superior oblique muscle and to the frontal bone. laterally, it is fi xed to the capsule of the lacrimal gland and to the frontal bone. when the levator palpebrae superioris contracts, it raises the upper eyelid. it is innervated by a superior branch of the oculomotor nerve (cn iii). interestingly, the superior tarsal muscle is innervated by postganglionic sympathetic fi bers from the superior cervical ganglion. therefore, a complete ptosis refl ects the loss of oculomotor function, whereas a partial ptosis is associated with loss of sympathetic supply. the four rectus muscles arise from a fi brous ring -the common tendinous annulus of zinn -that extends across the superior orbital fi ssure and clinical conditions surrounds the upper, medial and lower margins of the optic foramen, where it adheres strongly to the tubular dural sheath surrounding the optic nerve. the common tendinous annulus consists of two parts. superiorly, the tendon of lockwood gives origin to the superior rectus muscle, part of the medial rectus and the upper fi bers of the lateral rectus; inferiorly, the tendon of zinn gives origin to the inferior, medial and lateral rectus muscles. at their origin, the rectus muscles are tightly set in zinn's annulus and start to separate at about mm anterior to the optic canal. the medial rectus is the broadest while the lateral rectus is the longest. the four rectus muscles go forward and insert through tendinous expansions into the sclera, the superior and inferior recti passing anterolaterally. the superior oblique muscle originates from the body of the sphenoid, above and medial to the margin of the optic foramen and origin of the superior rectus. it passes forward, ending in a round tendon, which goes through a fi brocartilaginous ring or trochlea attached to the frontal bone. from that point, the tendon turns backward, laterally and downward beneath the superior rectus to insert into the sclera, behind the equator of the eyeball in its superolateral posterior quadrant. the inferior oblique muscle originates from the orbital surface of the maxilla, just posterior to the orbital rim and lateral to the lacrimal groove. it tra-verses the fl oor of the orbit in a lateral, backward and upward direction, and inserts into the inferolateral posterior quadrant of the eyeball. the eom produce mobility of the eyeball with extreme amplitude in all directions (fig. . . ) . this is because the type of attachment they demonstrate to the periorbita -an interlocking of tendinous and muscular fi bers -provides them with a strong anchor. the contraction of the eom rotates the eyeball according to their insertions and the orientation of their fi bers. however, in all cases it should be remembered that these muscles function together and not as isolated entities. the ocular movements of individual muscles can be simplifi ed as follows: • the superior and inferior recti adduct the eyeball, in association with elevation and intorsion from the superior rectus and depression and extorsion from the inferior rectus. • the medial rectus adducts the eyeball while abduction is the result of contraction of the lateral rectus. • the superior oblique is considered to act from the trochlea. • both the superior and inferior oblique abduct the eye, with a component of depression and intorsion from the superior oblique and elevation and extorsion from the inferior oblique. being described in . this capsule is a fascial sheath completely covering the eyeball. it extends from the optic nerve to the corneoscleral junction and separates the eyeball from the orbital fat. it is perforated by the tendons of the eom on which it refl ects to form tubular sheaths. tenon described this capsule as a 'muscle pulley'. after much controversy, this theory is again accepted, and further studies have established that each rectus and inferior oblique muscle passes through a pulley formed by a ring or sheath of collagen, elastin and smooth muscle that is located close to the equator of the eyeball, in tenon's capsule. in this manner, the rectus and the inferior oblique muscles have their paths constrained by pulleys that serve as functional origins for the muscles, in a fashion similar to that of the trochlea for the superior oblique muscle. thus, the position of a pulley insertion relative to the eyeball affects the forces of the eom, and a translation of the eyeball of . mm modifi es the pulling direction of the rectus muscle by °. these pulleys are under active muscular control, allowing for constant ocular adjustments. conversely, their instability and modifi cation of location are associated with ocular dysfunction. the eom connective tissue sleeves that act as pulleys are fi rmly attached to each other and, through extensions, to the orbital walls. those from the lateral and medial rectus are anchored to the orbital tubercle of the zygomatic bone and posterior to the lacrimal crest of the lacrimal bone, respectively. they are referred to as check ligaments. this point is of great signifi cance. the zygomatic bone should not be overshadowed as a site of insertion for the eom sheaths by the sphenoid on which the common tendinous annulus of zinn inserts. in subjects with it should be noted that while the longitudinal axis of the orbit deviates laterally in a posterior to anterior direction, the axis of the eyeball approximates the sagittal plane (fig. . . ) . therefore, muscular activity between medial and lateral muscles is not equal. at birth, infants tend to demonstrate intermittent ocular misalignments. this is associated with lack of maturity in visual function. it should disappear by months of age when orthotropic ocular alignment and sensory binocularity should be present. transitory esotropic misalignments are usually considered to be typical in infants. however, if the condition is permanent with a fi xed restriction of any of the eom movements, or if it persists after months of age, further evaluation is necessary. in any case, osteopathic examination and treatment are indicated to balance the bony components of the orbit and their relationship with other parts of the skull. dysfunction can also manifest through myofascial and membranous components. entrapment neuropathy can result. evaluation and treatment of these components are indicated to promote the best possible muscular activity and ocular function. although the study of eom function is complex, it is imperative that it includes the orbital connective tissues that sheath the muscles. these tissues have long been recognized, the capsule of tenon clinical conditions strabismus or other ocular misalignments, the consideration of the orbital bones on which the eom insert should include the zygomatic bone. its location makes it vulnerable to being struck during the course of normal childhood activities. this may, in turn, affect the diameter of the orbit and the functional balance of the eom, particularly the lateral rectus. another site of importance is the trochlea for the superior oblique muscle on the frontal bone. frontal dysfunctions are often found in infants, with one side lower than the other resulting in frontal trochlear asymmetry. this may be seen with a superior-medial deviation of the eye encountered with dysfunction of the superior oblique muscle. dysfunction of the maxilla can also infl uence visual activity through its effect on the insertion of the inferior oblique muscle. through these complex interactions the orbit functions as a unit and each part, when dysfunctional, is a potential site for muscular instability and resultant ocular dysfunction. the somatic components of ocular dysfunction also involve oculomotor supply. the oculomotor nerve (cn iii) exits the brain medially to the cerebral peduncles. it traverses the dura at the top of the clivus, enters the cavernous sinus and courses forward in the lateral wall of the cavernous sinus where it receives sympathetic fi bers from the internal carotid plexus and connects with the ophthalmic division of the trigeminal nerve (cn v ). it then divides into two branches that enter the orbit through the superior orbital fi ssure. the general somatic efferent fi bers of the oculomotor nerve innervate nearly all of the eom. the superior division innervates the superior rectus and the levator palpebrae muscles, whereas the inferior division innervates the medial and inferior rectus and inferior oblique muscles. the general visceral efferent fi bers of cn iii are part of the parasympathetic ans and supply the sphincter of the iris that regulates the size and shape of the pupil and the ciliary muscle that modulates the shape of the lens. the trochlear nerve (cn iv) is the only cranial nerve to emerge from the dorsal surface of the brainstem. it curves around the midbrain, pierces the dura between the lesser and greater circumferences of the tentorium cerebelli, enters the lateral border of the cavernous sinus, receives sympathetic fi bers from the internal carotid plexus and traverses the superior orbital fi ssure to the orbit. it carries somatic efferent fi bers to the superior oblique muscle. the abducent nerve (cn vi) emerges from the brainstem between the pons and medulla oblongata. it pierces the dura covering the clivus and passes over the ridge of the petrous apex of the temporal bone through an osteofi brous canal underneath gruber's petrosphenoidal ligament. it then enters the cavernous sinus where it receives sympathetic fi bers from the internal carotid plexus and the orbit through the medial end of the superior orbital fi ssure and within the annulus of zinn. cn vi carries somatic efferent fi bers to the lateral rectus muscle. additionally, the eom contain proprioceptive receptors that provide input as to the position and movement of the eye in the orbit. this contributes to the control of eye's movements and facilitates central control of the direction of gaze and the relationship of the child to their environment. these afferent fi bers appear to travel with the motor cn iii, iv and vi before joining the ophthalmic branch of cn v to enter the cns. afferent input from these receptors not only affects static eye position but can also modify linear visual tracking, saccadic eye movement and the vestibulo-ocular refl ex. each of these nerves is subject to intracranial entrapment from osseous compression, membranous tension, ligamentous pull or the pressure of edema from venous congestion. the anterior attachments of the tentorium cerebelli are a site with particularly great potential to cause such neurologic dysfunction. the ganglion of the trigeminal nerve may become entrapped by the tentorium in the trigeminal cave formed at the apex of the petrous part of the temporal bone. bilaterally, the anterior fi bers of the tentorium twine on each side as the fi bers of the lesser circumference attach to the anterior clinoid processes and the fi bers of the greater circumference attach to the posterior clinoid processes. between these two attachments, the fi bers of the tentorium cerebelli are oriented horizontally and contribute to the formation of the roof of the cavernous sinus. cn iii and iv pierce the dura at this level to enter the cavernous sinus. any dural membranous strains in these areas can result in entrapment neuropathy and each bone on which the tentorium cerebelli attaches should be considered as potentially critical in the development of ocular dysfunction. the petrosphenoidal ligament is another signifi cant site under which cn vi may be compressed. furthermore, as the nerve bends sharply in its course over the petrous ridge, it is, therefore, vulnerable to the changes in position of the petrous portion of the temporal bone. adequate arterial supply and drainage are necessary for healthy nervous function. edema and stasis encumber this function, as is the case with a jugular foramen dysfunction and impediment of the drainage from the cavernous sinus, resulting in venous congestion. this, in turn, will affect the cranial nerves passing through the cavernous sinuses to the orbits. the same rationale applies to the superior orbital fi ssure. intraosseous dysfunction in infants between the greater and lesser wings of the sphenoid, or narrowing of the fi ssure because of greater wing dysfunction with surrounding structures, such as the temporal bone, impairs venous drainage or impulse conduction of the nerves passing through the fi ssure. additionally, lymphatic stases outside the skull can also entrap nerves at their foramina of exit. multiple theories exist concerning the cause of non-paralytic or concomitant strabismus, including sensorimotor, anatomic and mechanical or muscular origins. prematurity and diffi cult labor are considered to be risk factors. a supranuclear developmental abnormality in the cns is thought to be the cause of strabismus occurring in the fi rst months of life. impaired vision and amblyopia may also cause strabismus. it is abnormal for an infant or child to have strabismus and, if present, a thorough ocular and neurologic examination by a specialist should be performed. osteopathic procedures may, however, be applied to provide balance to the musculoskeletal and nervous systems. such balance improves the self-healing capacities of the body and contributes to the success of other treatments. osteopathic treatment should be initiated at the earliest possible time because the prognosis of strabismus is correlated to the time when the strabismus fi rst appears and the time when treatment is initiated. additionally, early treatment may positively impact the vestibulo-ocular refl exes and thereby the child's posture. young children and infants are most likely to present for the treatment of strabismus. as such the following treatment description must be appropriately adapted to fi t the age of the patient. the following is not intended to treat organic pathologies of the eye; it is directed at problems of functional balance. the examination and treatment for the eye should address different levels of anatomic dysfunction. these include osseous, myofascial, neurologic and vascular dysfunction and the intrinsic structure of the eye. observation and palpation are directed at determining on which of these levels treatment should focus. observe the relationship between the eye and the functional pattern of the skull. if the functional pattern of eye position and movement is consistent with the dysfunctional pattern of the skull, the focus of treatment should be on the cranial dysfunction. if eye position and movement is not consistent with the pattern of the skull, treatment should focus directly on the eye, eom and associated fascial structures. start with observation of the bony orbit, relative to how it fi ts the global pattern of the skull. look at the shape of the face and skull of the child to determine if a global pattern of cranial fl exion-external rotation, extension-internal rotation, sidebendingrotation or torsion is present. observe the orbital diameter, the distance between the superior medial and inferior lateral angles of the orbit. it is increased with cranial fl exion-external rotation, resulting in an orbital cavity that is wider. cranial extensioninternal rotation decreases the orbital diameter, with a resultant orbital cavity that is narrower. look for asymmetry between the visible constituents of the bony orbits, specifi cally the frontal bones, zygomae and maxillae. look at the eyes and observe for difference in size and shape. cranial fl exion-external rotation is associated with a prominent eyeball and an almondshaped eye. in cranial extension-internal rotation, the eyeball is less prominent, with a smaller, rounder shaped eye. epicanthus -a vertical fold of skin covering the medial portion of the eye -may give the impression of esotropia. active motion testing will, however, demonstrate normal function of the eye. next, observe the spontaneous movements and neutral resting position of the eyes. note the direction of gaze, the presence of esotropia or exotropia. the easiest way to evaluate the ocular movement of younger children is to hold a toy or some interesting object in front of the child to catch their attention. move the object horizontally, vertically and in both diagonals, and observe the movement of the child's eyes as they follow the moving object. note any asymmetric movement of the cervical spine that can be employed to compensate for the absence of ocular movement. this may be a sign of amblyopia that requires further evaluation. if possible, assess both eyes together and each eye separately by covering one eye with the child's or caregiver's hand and pretending to play 'peek-a-boo'. comparatively note the speed and ease with which the eyes move to follow the object. convergence may be determined by observing as the toy is brought closer to the infant's face. this procedure tests the actions of the eom and normal responses are illustrated in figure . . . determine if a correlation exists between the dysfunction of the eom and the pattern of cranial dysfunction. the two most commonly encountered types of strabismus that are amenable to cranial clinical conditions manipulation are the consequence of dysfunction involving the superior oblique muscle and the lateral rectus. a superior-medial-oblique deviation of the eye resulting from dysfunction of the superior oblique muscle may be associated with ipsilateral dysfunction of the frontal bone affecting its relationship to the muscle at the trochlea. medial deviation of the eye resulting from dysfunction of the lateral rectus may be associated with ipsilateral temporal bone or sphenoid dysfunction that affects cn vi as it passes beneath the petrosphenoidal ligament. palpate for function to confi rm the above observations. tests of listening should be performed with specifi c attention to the anatomic structures associated with the eyes in order to defi ne the dysfunctional area responsible for ocular deviation. areas of specifi c interest include the bones on which the eom are attached: the sphenoid, frontal, maxillae and zygomae. assess the anatomic areas of neurovascular passage to the orbital cavity. these include the superior orbital fi ssure between the greater and lesser wing of the sphenoid and the cavernous sinus for their contents. also evaluate the apex of the petrous portion of the temporal bone and the sphenoid for their relationship to the petrosphenoidal ligament. in actual practice, these assessments and the treatment of identifi ed dysfunction fl ow seamlessly into one another. diagnostic palpation of the sphenoid, and to a lesser degree of the frontal bone, is complex because the movements of the eom are transmitted to these bones. these additional movements on top of the biphasic prm create multifaceted palpatory sensations that can be confusing to the inexperienced examiner. consequently, it is desirable to evaluate the child when they are quiet with minimal eye movement. this occurs most readily when the child is sleeping. if the examiner is skilled with indirect procedures, the act of palpation will often soothe the child enough to bring them to a quiet state. complete examination of the sphenoid is somewhat diffi cult because of the limited surface area of the bone that is available for direct palpation. the areas of contact over the lateral-most aspects of the membranous greater wings, because of their fl exibility, transmit an incomplete representation of the movement of the body of the sphenoid. for this reason, the lightest touch must be employed when evaluating the sphenoid and even then information about the body must be obtained indirectly. to assess the sphenoid body and associated lesser wings more effectively, visualize the relationship between the frontal bone and the sphenoid behind. the body and lesser wings of the sphenoid are in continuity with the orbital plates of the frontal bone. when palpating, one hand can be placed transversely on the frontal bone with the thumb and middle fi nger contacting the greater wings on either side. the movement of the lesser wings and body of the sphenoid is transmitted through the orbital plates of the frontal bone. this provides a method of augmenting the palpatory sensations from the body of the sphenoid through the frontal bone. similarly, the sensation of movement of the greater wings of the sphenoid may be enhanced through the zygomatic bones and their relationship with the greater wings at the sphenozygomatic sutures. these visualization procedures may be employed during both tests of listening and treatment, and require that the bones being palpated in association with the sphenoid are themselves free of somatic dysfunction. in infants and younger children, intraosseous dysfunctions of the frontal bone and sphenoid should be considered. listen to the movement between the two halves of the frontal bone. palpate for deformation affecting the trochlea of the superior oblique muscle. visualize and listen to the synchondroses between the greater wings and the body of the sphenoid. listen to the relationship between the greater and lesser wings at the superior orbital fi ssure, visualizing the neurovascular content, and try to promote the inherent forces of the prm in the area. similarly, assess the cavernous sinus because of its relation with the nerves and venous drainage of the eyes. visualize the dura that constitutes the walls of the cavernous sinus and its relationship to the remainder of the reciprocal tension membranes. finally, if the child permits, and while utilizing the gentlest of indirect methods, palpate the globes of the eyes. evaluate the tone and quality of the myofascial structures surrounding the eyeballs. identify the functional point of balance between the eom. treat any dysfunction as identifi ed above, using indirect principles. only after any osseous, membranous and fascial dysfunctions have been treated, and the eom have been balanced, employ myofascial rehabilitation. in the patient with ocular deviation, the eom provide dysfunctional proprioception to the cns. the child should learn to experience the sensations of the normal range of ocular movements. older children can be taught to move their eye while the practitioner gently applies digital contact intended to guide the eye through the normal range of ocular movements. in this exercise, particular attention should be directed at establishing awareness of the sensation of eye movements in the directions that they are defi cient. the process of myofascial rehabilitation is accomplished with greater ease once pre-existing osseous, membranous and fascial dysfunctions have been treated. a description of the anatomy of the bony orbit and the eom has already been provided in 'strabismus' above. we shall, therefore, only consider the description of the eyeball and somatic dysfunction as they relate to the pathophysiology of astigmatism, myopia and hyperopia. the eyeball occupies the anterior part of the cavity of the orbit. it is surrounded by the eom and embedded in the fat of the orbit. two spheres of different diameters form the eyeball. the anterior cornea is smaller, transparent, bulging outward and represents approximately one-sixth of the eyeball. posteriorly, a larger opaque sphere constitutes the rest of the eyeball. anatomically, the eyeball may be described as being formed by three tunics or walls that are, from front to back, the fi brous tunic, the vascular pigmented tunic and the nervous tunic, and by internal components or refracting media, the aqueous humor, the vitreous body and the crystalline lens. the outside fi brous tunic of the eyeball is formed by the sclera and cornea. in the front, the sclera is continuous with the cornea at the sclerocorneal junction. the sclera is a dense and fi rm membrane that preserves the shape of the eyeball. it is covered with a fascial membrane, the capsule of tenon, posteriorly from the optic nerve to the corneoscleral junction anteriorly. this fascial membrane refl ects onto each of the eom tendons as they perforate tenon's capsule to attach on the sclera. posteriorly, the sclera is pierced by the nervous fi laments of the optic nerve (cn ii), forming the lamina cribrosa sclerae. the sclera is continuous with the fi brous sheath of cn ii and, therefore, with the meningeal layer of the dura mater. several small apertures exist around the lamina cribrosa sclerae for the ciliary vessels and nerves. the central artery and vein of the retina pass through cn ii. the cornea projecting in front of the sclera is almost circular, with its width slightly greater than its height. its anterior convexity demonstrates varying degrees of curvature throughout life and between individuals. a rapid change in the corneal curvature occurs during the fi rst - weeks of life. this rate of change then decreases considerably after the th week. the corneal curvature usually stabilizes at approximately the end of the st year of life. its coating of tears constitutes the most important site of refraction of the eyeball. the middle tunic of the eyeball is a vascular pigmented layer consisting of the choroid posteriorly and the ciliary body and iris anteriorly. the choroid is a thin, highly vascular membrane that constitutes approximately the posterior fi ve-sixths of the globe. its outer surface adheres fi rmly to the sclera while its inner surface is attached to the retina. this layer provides a signifi cant percentage of the vascular supply to the retina. the ciliary body consists of the ciliary processes and the ciliary muscle. the ciliary processes are circularly arranged as a ruche behind the iris surrounding the lens. they are continuous at their periphery with the layers of the choroid and anteriorly with the periphery of the iris. posteriorly, they are connected with the zonule that is the suspensory ligament of the lens. the ciliary muscle plays an important role in accommodation. it adjusts the shape of the lens in order to change the focus of the eye. when the ciliary muscle contracts, it draws forward the ciliary body, thus reducing tension in the fi bers of the suspensory ligament. this results in a relaxation of the lens' capsule with resultant increased convexity of the lens. the parasympathetic stimulation of fi bers from cn iii produces contraction of the ciliary muscle. the iris is a thin, circular, contractile disk, located between the cornea and lens, and continuous peripherally with the ciliary body. the iris differs in color among individuals, and at birth is light blue because of a lack of pigment. iris pigmentation is well developed at months of age. the iris divides the space between the cornea and lens into an anterior and a posterior chamber that communicates through the center of the iris, the pupil. pupillary dilatation or constriction results from the contraction of the dilatator or sphincter pupillae. responses to light and accommodation produce the two dominant pupilloconstrictor refl exes. axons from preganglionic parasympathetic fi bers course with cn iii to the ciliary ganglion, located behind the eyeball. from there, postganglionic fi bers supply the smooth muscle of the iris; this may result in pupillary constriction. inhibition of the tonic activity of the oculomotor system in the midbrain edinger-westphal nucleus leads to pupillary dilatation. extreme pupillary dilatation is referred to as mydriasis, extreme constriction as miosis. the nervous tunic, i.e. the retina or inner layer of the walls of the eyeball, is truly a sensory extension of the brain. during embryogenesis, the optic vesicles develop from the lateral aspects of the forebrain. when they invaginate, forming two optic cups, the inner walls of the cups become the retinal sensory mesh and send axons back to the optic stalk. on activation of the receptors of this sensory stratum, brain activity starts the visual sensory processing. light and images of external objects are received on the retinal receptors, stimulating a chemical reaction and action potentials transmitted through the optic nerve to the visual cortex within the occipital lobe. the vascular supply of the retina comes partly from the choroid that is in contact with the external layer of the retina. internally, the retina lies in contact with the vitreous body. the thickness of the retina varies, its thickest portion being located in the back of the eye, near the central retinal area or macula lutea. the fovea centralis, the center of the macula lutea, is a point of maximum vision and could be considered as the posterior point of the eyeball's axis. it is approximately - mm lateral and mm inferior to the center of the optic disc, a point where the retina is insensitive to light, referred to as the blind spot. the macula continues to develop until - weeks after birth. fully developed visual acuity is normally established by years of age. light passes through various refracting media in the eye, the aqueous humor, the lens and the vitreous body. the aqueous humor fi lls the anterior and posterior chambers of the eyeball. it is secreted into the posterior chamber by the ciliary processes. it fl ows into the anterior chamber through the pupil and is absorbed into the scleral venous sinus between the iris and cornea. the lens is situated directly behind the iris and in front of the vitreous body. it is a transparent, biconvex structure surrounded by a capsule and is connected to the ciliary muscle through the suspensory ligament. it measures approximately mm in diameter at birth and from the fi rst years of life offers excellent refractive power. as the child grows, more layers are added on the lens periphery, and around years of age it reaches its adult size. from then on, progressively, it will loose its hydration and thereby its fl exibility and refractive power. accommodation, normally occurring when tension of the lens' capsule decreases, becomes more diffi cult. this leads, for most individuals in their fi fties, to the need for glasses to compensate. the postrenal (vitreous) chamber forms about four-fi fths of the eyeball and is fi lled with the vitreous body (vitreous humor) that is situated between the retina and the lens. it is transparent, of a gel-like consistency, and is composed of about % water. when light enters the eye, the cornea and crystalline lens normally focus the rays of light through accommodation specifi cally on the retina. when properly functioning, this is referred to as the emmetropic state and requires that normal ocular growth occurred resulting in normal eye biometry. the central point of the anterior curvature of the eyeball is referred to as the anterior pole; the central point of the posterior curvature is the posterior pole. a line joining the two poles is referred to as the optic axis. the optic axes of the two eyeballs are almost parallel, approximating in the sagittal plane, while the longitudinal axes of the orbits are directed forward and laterally (fig. . . ) . therefore, for each eye, these two axes are aligned in different directions. the optic nerves enter the orbit with the ophthalmic artery, through the optic canal, and follow the direction of the axes of the orbits. this explains why the optic disc is medial to the fovea centralis in the center of the macula lutea. the transverse and anteroposterior diameters of the eyeball are slightly greater ( mm) than its vertical diameter ( . mm). at birth the anteroposterior diameter is about . mm and at puberty is between and mm. ocular growth and refraction are dynamic processes evolving during infancy and childhood, well through adult life. color vision develops rapidly after birth and in most individuals some color vision is usually present at months of age. although diffi cult to evaluate in infants, normal visual acuity is thought to be present by years of age. even though complete anatomic and functional maturity of the visual system is reached around years of age, many important milestones occur during the fi rst years of life. for these reasons, when examining and treating infants and children, an osteopathic practitioner should pay close attention to any somatic dysfunction that may potentially alter the normal shift of the refractive state of the eye to emmetropia. the sites of dysfunction with potential for alteration of the visual system are the different bony components of the orbit, the eyeball, eom and surrounding fascial and dural sheaths. because the vestibulo-ocular refl exes link the individual's posture with ocular function, the axial skeleton and postural balance of the child should also be addressed. any disturbance in the visual components may alter vision, usually asymmetrically. if this occurs during the developmental process, the resulting absence of stimulation in the visual part of the cortex will cause partial loss of sight, or amblyopia. this could be associated with an important difference of visual acuity between both eyes. normally orthotropic ocular alignment and sensory binocularity should be present by months of age. if there are signs of misalignment and lack of sensory binocularity, further evaluation should be carried out. emmetropization allows a distant object to be projected as a focused image on the retina without accommodative effort. this is possible when the optical power and the axial length of the eye are balanced. normally, in the emmetropic eye with relaxed accommodation, objects are focused on the retina. if the point of focus falls behind the retina, increased accommodation is necessary to bring the point of focus on the retina. this occurs with hyperopia and has been associated with decrease of the axial length of the eyeball. conversely, in myopia, the point of focus falls in front of the retina and this is associated with increase of the axial length of the eyeball (fig. . . ). some compensation usually occurs in these conditions, since eyes with decreased axial length are associated with a more rounded cornea, whereas increased axial length is associated with fl attening of the cornea. typically, infants demonstrate hyperopic eyes that tend to improve with ocular growth and, by the age of - years, they are emmetropic. by age years, only a few children are myopic, but between the ages of and years, myopic children have the fastest progression of all age groups. myopia is a common condition affecting approximately . % of caucasian children, . % of hispanics and demonstrates the highest prevalence in asians ( . %). this condition and its progression are infl uenced by various factors such as demography and the environment . the etiology of myopia seems to be multifactorial, with a genetic component since myopic individuals are more likely to have myopic parents. a greater reading exposure in childhood has often been suggested as a contributing factor and is especially associated with myopia in asian children, more often encountered around - years. intrinsic ocular factors are also associated with myopias. greater dimensions are present in myopic eyes than in emmetropic eyes when the vitreous chambers are measured along the axial direction, i.e. the optical and visual axes. , heavier newborns with large heads have longer optical axial lengths, deeper vitreous chambers and fl atter corneas. however, refraction is maintained and satisfactory, suggesting the presence of accommodative mechanisms in the cornea that compensate for the longer axial length. myopia usually develops because of a lack of coordination between postnatal growth and the refractive power of the eyeball components. there is some probability that the cns infl uences the development of myopia. unequal curvature(s) along the meridians of the refractive surfaces of the eye -cornea, anterior or posterior surfaces of the lens -result in astigmatism. thus, when light enters the eye, instead of having the cornea and the crystalline lens focusing the rays of light at a single point on the retina, they are spread out as a line in one direction or another. the orientation of the axis of corneal astigmatism is affected by the mode of delivery. infants delivered vaginally when compared to those delivered by cesarean section demonstrate a higher frequency of with-the-rule astigmatism, with the greater curvature of that astigmatism tending to be in the vertical meridian. these astigmatic corneas usually fl atten signifi cantly by the age of months. because astigmatism, myopia and hyperopia are associated with anatomic variations in the biometry of the eye, any form of treatment that may affect the refractive power and shape of the eye is desirable. this is particularly important in children less than year of age, when the eye is still growing and the ocular refl exes are not totally developed. prevention of the ocular complications of myopia, such as retinal detachment and glaucoma, may be facilitated by relaxation of tension in surrounding ocular structures. addressing somatic dysfunction of the upper thoracic and cervical vertebrae may further assist relaxation of ocular tension. for these reasons, osteopathic procedures may be applied directly to the eyeball itself or the structures surrounding the eyeball including the orbit and its myofascial contents. procedures may also be employed to affect the control of refractive mechanisms through the impact that the ans has on the intrinsic ocular muscles. the osteopathic structural examination of the eye and orbit for the patient with astigmatism, myopia and hyperopia is essentially the same as that described above for strabismus. the patient should be thoroughly evaluated for dysfunction affecting the component bones of the orbit, the eom and associated fascial sheaths. in addition, because these ocular conditions involve changes in the shape of the eyeball, the physical evaluation of the individual with myopia or hyperopia should specifi cally include the search for any somatic dysfunction that affects the axial length of the eyeball. for the patient with astigmatism, somatic dysfunction responsible for changes in orbital shape and tension of myofascial structures that affect the curvatures along the meridians of the refractive surfaces of the eye should be identifi ed. cranial fl exion-external rotation is associated with a decrease of the orbital depth, whereas extension-internal rotation is associated with increased orbital depth. for these reasons, potentially contributory craniosacral somatic dysfunction should be sought out and treated. this includes dysfunction involving the sbs and bony components of the orbit as well as all components of the craniosacral mechanism, including, but not limited to, the sacrum and pelvis. a posture in which the child projects their head forward may be the result of poor sight. on the other hand, dysfunction affecting the posture, because of its effect on the cervical myofascial structures, particularly those attaching to the base of the skull, will tend to impair the inherent motility of the skull and potentially the components of the orbit. a craniosacral somatic dysfunction of the sacrum in fl exion will produce a decrease of spinal ap curves and a tendency toward cranial fl exion. this can, in turn, favor decreased orbital depth that is particularly signifi cant in infants and young children at a time when ocular growth is occurring. as such, a complete postural assessment is appropriate when examining a child with ocular dysfunction. it is also appropriate in these individuals to begin working on the global postural pattern because vestibulo-ocular refl exes link posture with ocular function. using an indirect approach, begin with the treatment of postural dysfunction. because of their action on the prm, the use of indirect techniques will relax the patient. the treatment of ocular dysfunction requires the most delicate touch and as the patient relaxes it becomes easier to treat the eyes. after addressing the global postural pattern, proceed to the examination of the neurocranium and viscerocranium. assess the sbs with tests of listening, then progress to observe the size and shape of the orbit. look at the relationship of the eyeball to the orbit. prominence of the eyeball is associated with a wider orbit and a pattern of cranial fl exion-external rotation, whereas a recessed eye is associated with a narrower orbit and cranial extension-internal rotation. also observe the patient in profi le bilaterally, comparing the amount of corneal curvature. determine if the dysfunctional mechanics identifi ed at the sbs is consistent with the pattern of orbit and eyeball. if so, treat the sbs; if not, look for dysfunction in the orbit. (note: in infants the state of development of the frontal bone with small brow ridges causes the eyeballs to appear as if they are bulging.) next, assess the different bones that constitute the orbit, particularly the frontal bone, zygomae, maxillae and sphenoid. the effect of cranial dysfunction on the depth and shape of the orbit is signifi cant in astigmatism, myopia and hyperopia. the apex of the orbit is situated at the medial end of the superior orbital fi ssure between the lesser and greater wings of the sphenoid, near the origin of the eom and inferior to the optic foramen. thus, the length and direction of the orbital axes are infl uenced by the sphenoid. dysfunctions of the sphenoid that can affect the orbit include dysfunction of the sbs, dysfunction between the sphenoid and the bones articulating with its wings and intraosseous dysfunction. with cranial fl exion the apex of the orbit moves forward, thus decreasing the ap orbital diameter, whereas in extension the apex is displaced posteriorly, increasing the ap orbital diameter. with sbs torsion or sidebending-rotation, on the side of associated external rotation, the ap orbital diameter is decreased and on the side of associated internal rotation it is increased. intraosseous dysfunctions of the sphenoid have variable effects on the orbit and eyeball. they must be identifi ed and treated as early as possible, sphenoid ossifi cation being essentially complete by year of age. dysfunction of the frontal bones, zygomae and maxillae, either individually or in conjunction with the sphenoid, can affect the shape of the orbit and, when present, should be treated using indirect principles. an extension of the dura surrounds the optic nerve and is attached to the optic canal. intraosseous dysfunction of the sphenoid can affect the cylin-drical optic canal that is formed where the two roots of the lesser wing of the sphenoid join the sphenoidal body. the dura also extends through the superior orbital fi ssure and blends with the orbital periosteum. consequently, membranous strain can affect the sphenoid and through the sphenoid the shape of the orbit. dural membranous dysfunction should thus be sought out and treated at the youngest possible age. to ensure autonomic balance for the orbital contents, the rhythmic motility of the orbit and neurocranium is necessary. change of the ap diameter of the orbit is associated with altered tension of the intraorbital soft tissues with resultant stasis, edema and compression. this, in turn, will affect the function of nervous structures, in this case cn iii and the ciliary ganglion. treatment of regional dysfunction, ensuring the rhythmic fl exion-extension of the prm in the orbit, fi ssures and foramina, provides a pumping action mobilizing the extracellular fl uids surrounding the nerves and facilitating their function. the sympathetic supply to the orbit originates in the upper thoracic spine and, through the upper cervical ganglia, reaches the ciliary ganglia via the carotid plexus. somatic dysfunction affecting these structures in the upper thoracic and cervical spine and the cranial base should be sought out and treated to ensure optimal sympathetic function. sucking and swallowing are complex activities that are partially conscious and partially unconscious. they require the participation of many structures, including a signifi cant percentage of the cranial nerves, and should be considered in the context of a sensory-motor complex that begins to develop well before birth. swallowing appears in utero after weeks with movements of the fetal tongue visible after weeks. at that time, fetuses suck their thumbs refl exively in response to oral stimulation from the digital extremities. protrusion of the upper lip appears after the th week of gestation and protrusion of the lower lip at the th week. the real activity of sucking is seen at the th week. after that time, sucking and swallowing become more and more developed and appear as coordinated movements around weeks. at term, the fetus swallows about - ml of amniotic fl uid per day. this daily exercise stimulates the maturation of oral structures, including the tongue, lips, soft palate and pharynx, and, therefore, prepares the fetus to perform the orofacial functions that will be vital at birth. sucking is one of the primitive refl exes that are totally present at birth in term infants. in the fi rst days of life, oral feeding is almost entirely refl ex, apparently without suprabulbar activity for rooting, latching, sucking and swallowing. these refl exes are functionally important in infants to ensure successful ingestion. the primitive sucking refl ex lasts for about a year, and then becomes more diffi cult to obtain because of central nervous system maturation and the development of voluntary motor activity. the tongue is one of the major participants in the process of sucking. it is a muscular structure with intrinsic and extrinsic muscles. the intrinsic muscles allow the precise movements necessary for sucking, swallowing and speech. they are the superior longitudinal, inferior longitudinal, transverse and vertical muscles. the extrinsic muscles originate from other parts of the skull and hyoid bone, and consist of four paired muscles: • the genioglossus muscles originate from the mandible, attach to the hyoid bone and blend with the intrinsic muscles of the tongue • the hyoglossus muscles originate from the hyoid bone and insert into the tongue • the styloglossus muscles originate from the styloid processes of the temporal bones and insert into the lateral part of the tongue • the palatoglossus muscles originate from the soft palate aponeurosis and insert into the lateral part of the tongue. a midline fi brous sagittal septum divides the tongue into two halves and attaches to the body of the hyoid bone. additionally, on the undersurface of the tongue, the frenulum linguae -a vertical fold of mucous membrane -connects the tongue to the fl oor of the mouth. as such, although anchored at its root, the tongue is mobile, allowing the different functions of sucking, suckling, latching, swallowing and eating, and later speech. in infants, the tongue is totally contained in the oral cavity, although it is quite wide in proportion to the container and protrudes beyond the alveolar gum pads. however, its development is far from being complete and its position will go through many changes before the end of adolescence. one of the biggest changes occurs in the fi rst years of life, as the child grows, the posterior third of the tongue descends following the larynx. when evaluating tongue malposition in children, the bony attachments of the tongue muscles should be evaluated for somatic dysfunction. dysfunction of the mandible, the temporal bones through the styloid processes and the hyoid bone may potentially interfere with the position of the tongue. one of the most common lingual dysfunctions is forward and inferior displacement of the tongue. this predisposes to malocclusion and mouth breathing. mouth breathing and a low posture of the tongue are also associated with an inferoposterior displacement of the anterior convexity of the hyoid bone. [ ] [ ] [ ] to ensure the lingual mobility necessary in the infant for feeding and the development of proper speech, the frenulum linguae should not be too short. ankyloglossia, or tongue-tie, is a congenital anomaly characterized by an unusually short frenulum linguae. breastfeeding is more diffi cult in the presence of ankyloglossia, and children have more diffi culty pronouncing lingual and sibilant sounds such as t, d, z, s, th, n and l. furthermore, the tongue affects the growth and development of the maxillae and mandible and, therefore, the teeth in the alveolar processes, acting as a natural orthodontic appliance 'for better or for worse'. its position should be unencumbered as early in life as possible in order to play a satisfactory functional role. as such, clipping of the frenulum (frenuloplasty) may be necessary in association with osteopathic procedures to ensure a correct tongue placement. sucking has been classifi ed in two categories: nutritive and non-nutritive sucking (nns). nutritive sucking results in the delivery of milk and exhibits a slower rate of sucks that are continuous, whereas nns consists of a series of bursts of rapid sucks, approximately twice the rate of nutritive sucking, followed by rest periods. during breastfeeding, before the initiation of sucking, the tongue protrudes beyond the lower gum and then retracts, repeating this protrusive and retrusive displacement of the tongue to draw the nipple into the mouth. if the newborn recognizes the odor of the breast's nipple, frequent sucking is initiated that, in turn, will stimulate the mechanism of lactation. the mother's milk odor results in increased sucking and stronger pressure than when the infant is fed formula or water. successful sucking is produced by a peristaltic wave in the medial portion of the tongue moving from the front to the back of the tongue. , this is the result of successive contraction and relaxation of the genioglossus and transverse muscles of the tongue. at the same time, a repetitive thrust of the mandible participates in the compressive action on the nipple to produce milk. sucking results from the combined actions of the masseters, orbicularis oris and buccinator muscles, as well as from the muscles of the tongue and the mandible, in particular the lateral pterygoid muscles. this activity of the pterygoid muscles is important. at birth the pterygoid processes of the sphenoid are not fully developed, and because the activity of sucking requires a signifi cant effort from the infant, the stimulation produced contributes to their development. at approximately the th month of life, a new sucking pattern appears. it resembles that of later years, as when sucking from a straw, and demonstrates less movement of the tongue. refl exes are of paramount importance in the actions of the oral cavity. they facilitate various vital functions, including suckling and swallowing, but also breathing, eating and drinking. sucking elicits a swallowing refl ex in the infant by stimulating the lips and the oral cavity. this refl ex results from sensory input that induces a series of motor responses. it is mediated through neural receptors located on sensory fi bers, the afferent pathway of sensory fi bers, central synaptic connections and interneurons, and the efferent pathway composed of motoneurons or autonomic postganglionic neurons innervating the effector organ. in a somatic refl ex, the effector is the striated muscle innervated by the alpha motoneuron. in an autonomic refl ex, the effector includes a peripheral neuron extending its postganglionic axon to visceral structures. in sucking and swallowing, the sensory receptors -the tongue, gums, palate and pharynx -are located in the oral cavity. the sensory input passes through the superior laryngeal nerve, trigeminal nerve (cn v) and glossopharyngeal nerve (cn ix) to the brainstem, in the nucleus tractus solitarius (nts) and adjacent reticular formation. from there, second order neurons engage brainstem deglutitive pharyngeal and laryngeal motoneurons in the nucleus ambiguus and in the facial, trigeminal and hypoglossal nuclei. the palate and palatopharyngeal muscles respond, separating the mouth from the nasal cavity to prevent passage of food from the oral cavity to the nasal cavity during the swallowing process. the integrity of the infant's oral cavity is of signifi cance when considering the development of orofacial refl exes. the concept that structure affects function, and vice-versa, is perfectly illustrated in this area. the different structures that constitute the oral cavity evolve as the infant is developing, thus producing changes in function that will, in turn, further affect those structures. conversely, malposition of any of the structures contributing to the oral cavity, such as lingual malposition, will affect function and consequently viscerocranial development in infants and children. breastfeeding differs from bottle feeding. breastfed infants have better control of the amount of milk obtained than bottle-fed infants. bottle feeding is greatly infl uenced by the force of gravity, with higher volumes resulting in faster fl ow of milk. in order to control this increased fl uid fl ow, the newborn tends to adapt with a lingual and mandibular posture that is less protrusive. this decreases muscular participation and bottle-fed infants demonstrate a reduction of masseter muscle activity. the positive effect of muscular traction on bony development and thus on orofacial development is decreased and may, in turn, contribute to malocclusion. the type of nipple employed during bottle feeding, i.e. its material, density and location of holes, requires different adaptive patterns from the infant. most of the time, the root of the tongue does not come up to the tip of the nipple, as is the case with breastfeeding, but rather demonstrates a more posterior position. sucking is considered to be a determining factor in orofacial morphogenesis. it infl uences mandibular growth through the traction of myofascial attachments. the upper head of the lateral pterygoid muscle inserts into the developing condyle of the mandible. active sucking as produced by breastfeeding is considered to be of paramount importance in mandibular development. it contributes to the change from the retrognathic mandibular posture seen in infants to a more centered position at year of age. , during breastfeeding, the shape of the breast and the sucking pressure of the infant's tongue against their palate has a modeling effect on the palate. the pressure of the tongue on the anterior portion of the palate produces a pattern of cranial fl exion-external rotation. the rhythmic sucking pressure on the infant's palate results in a pumping action that may contribute to the balancing of their skull and cranial mechanism. additionally, breastfeeding seems to have a positive effect on orofacial morphogenesis, and a protective effect for the development of posterior cross-bite in deciduous dentition. human milk is a complex fl uid that contains more than components and is highly effective for the health and wellbeing of the infant. breastfeeding provides multiple benefi ts, such as decreased gastrointestinal and respiratory infections in childhood, in particular otitis media, as well as protection against atopic disease. , it also seems to reduce pain in infants and to enhance cognitive and visual development, as well as to have a potentially positive impact on the mother's health. breastfeeding is thus recommended as the optimal source of nutrition for infants during the fi rst months of life. although thought of as a natural process, it is not always easy, and some infants demonstrate diffi culties. such is the case for preterm infants, or infants with developmental anomalies such as micrognathia or ankyloglossia. nursing diffi culties may also be related to developmental anomalies of the mother's breast or variations of nipple size or shape that reduce the effectiveness of sucking. when developmental anomalies are not present, but nursing diffi culties persist, an evaluation for somatic dysfunction should be performed. the oral structures, including the mandible, should be assessed, and the function of the tongue should be checked. the intrinsic muscles of the tongue are all innervated by the hypoglossal nerve (cn xii), as are all the extrinsic muscles, with the exception of the palatoglossus muscle which is innervated by the vagus nerve (cn x). the hypoglossal nerve leaves the skull through the hypoglossal canal, situated in the anterior intraoccipital synchondrosis, between the basiocciput and the exocciput. the hypoglossal nerve may be subject to compressive forces during a diffi cult labor, with consequent impact on tongue motor function and resultant suckling diffi culties. feeding is a highly complex activity in young infants since it requires the integration of sucking, swallowing and breathing. normally, coordination of the buccopharyngeal functions takes place by weeks postconceptional age, although refl ex swallowing occurs when sucking stimulates the lips and the oral cavity. a spoon of food placed on the tongue of term infants will also produce a refl ex where the tongue pushes against the spoon. it is only around the th or th month of age that infants open their mouth when a spoon is brought before them or touches their lips, and approximately weeks later that they use their tongue to move food to the back of the mouth to swallow. the mechanism of deglutition is divided into oral, pharyngeal and esophageal stages. the oral stage occurs when the milk or food is in the mouth and when the child tastes, plays, experiments with the food and forms a bolus to be pushed into the pharynx and esophagus. at that time, the anterior part of the tongue presses against the hard palate, while in infants the buccinator muscles participate with resultant suction. next, the tongue propels the bolus in the back of the mouth into the pharynx and the swallowing refl ex is elicited. multiple receptors around the opening of the pharynx are stimulated by the bolus, resulting in sensory impulses conducted to the swallowing center via cn v, ix and x. consequent motor activity is triggered by cn ix and x. during this pharyngeal stage, while the tongue propels the bolus posteriorly, the hyoid is displaced anteriorly, the larynx superiorly and anteriorly toward the base of the tongue, and the epiglottis moves to cover the superior opening of the larynx. the displacement of the epiglottis and the approxi-mation of the vocal cords of the larynx combine to prevent the passage of food into the trachea. thus, the bolus passes into the pharynx, dividing around the epiglottis while the soft palate moves against the posterior pharyngeal wall to close the nasopharyngeal entrance. the stylopharyngeus muscles draw the sides of the pharynx superiorly and laterally. this stretches the opening of the esophagus, and the bolus, always under the infl uence of gravity and contractions of the pharyngeal constrictors, enters into the esophagus. this third stage of the mechanism of swallowing -the esophageal phase -is totally under the infl uence of the ans via the vagus nerves and the cervical and thoracic sympathetic ganglia. several differences in the coordination of swallowing are observed between infants and adults. human infants, like non-human primates, demonstrate the ability to breathe and suckle simultaneously with swallowing phases between respirations ( fig. . . ). they will keep this ability until approximately years of age when the neuromuscular system matures. at that time, the larynx and tongue have completed their descent and the posterior third of the tongue is more vertical, forming the upper anterior wall of the pharynx. the larynx and hyoid bones are involved in the descent, with separation of the epiglottis away from the uvula of the soft palate. the tip of the epiglottis is located at the level of the fi rst cervical vertebra at months of age and at the level of the third vertebra between and months of age. nasal cavity in infants, swallowing is immature, different from that of the adult and characterized by an important anterior displacement of the posterior pharyngeal wall. during immature swallowing, the tongue protrudes over the lower lip with active contraction of the facial muscles, in particular the orbicularis oris and mentalis muscles. with progression of time, the teeth erupt in surroundings that can have an infl uence on their development, as much as they can infl uence the adjacent structures. therefore, with maturation, the tongue rests lower in the mouth and is located between the teeth. now, during swallowing, the tip of the tongue is posterior to the incisors, the lips are sealed and facial muscles relaxed. infantile or immature swallowing should disappear around - years of age, and the positioning of the tongue against the palate will contribute to the development of a broad palate and a well-developed facies. the act of swallowing is complex, involving the lips, jaw, tongue, palate, pharynx, larynx and esophagus, and each of these structures may be affected by somatic dysfunction. conversely, the functions of sucking and swallowing are of paramount importance for the development of structures to which they are related. oropharyngeal development is infl uenced by the functional posture of the tongue, lips and jaws. the pharynx is attached superiorly to the base of the skull, the pterygoid processes of the sphenoid bone, the petrous portions of the temporal bones and the pharyngeal tubercle of the occipital bone. laterally, the pharynx is connected to the styloid processes of the temporal bones and posteriorly to the cervical spine. consequently, any dysfunction of the cranial base, cervical spine, hyoid bone and mandible should be considered when evaluating dysfunctional swallowing. craniocervical dysfunctions are very frequently associated with an anterior displacement of the tongue, predisposing the individual to tongue thrusting. furthermore, because cn ix and x trigger the motor activity of swallowing, the relationship between the occiput and temporal bones should be assessed for its effect on the jugular foramina. the process of maturation of swallowing is not always established, leading to swallowing dysfunction or immature swallowing. many individuals swallow with their tongues barely touching the palate or with their tongues between their teeth, in a dysfunctional manner. swallowing occurs between and times a day, and, when dysfunctional, the thrusting force applied on the incisors with every swallow results in labial tilting. the child or adolescent who swallows immaturely also demonstrates some contraction in the orbicularis oris and mentalis muscles, failure to contact the molars and tongue protrusion when swallowing. furthermore, they have a narrow, high, palatal arch, and thus do not benefi t from the pumping action of the tongue on the palate, and the palatine aponeurosis, which is suggested as being necessary for aeration of the pharyngotympanic tube (eustachian tube). begin by observing the face, specifi cally noting the proportion between the upper, middle and lower thirds of the face. the lower two regions are proportionately smaller in newborns than in older children, adolescents and adults. observe the tonicity of the lips and note whether or not pursing is present. observe the tonicity of the perioral musculature. have the child open the mouth and observe the position of the tongue; note any protrusion and if the tongue is at rest or demonstrates slight muscular activity. assess the length of the frenulum linguae. it may be too short, inserting near the tip of the tongue, sometimes giving the tongue a heart-shaped appearance due to it. observe the movements of the tongue and, if the child is old enough, have them protrude the tongue to note its mobility. ask them to pretend they are going to touch the tip of their nose with their tongue to observe its undersurface. with severe ankyloglossia, the tongue will tend to curl under during protrusion and will not be able to protrude because the tip is tied down by the short frenulum. in infants, test the suck response by introducing a cotted fi nger, with the palmar surface in the direction of the hard palate, into the infant's mouth and allow them to suckle. the infant should respond by latching tightly. feel coordination and strength of tongue movements. note any oral habits, such as tongue sucking, thumb or fi nger sucking, pacifi er sucking or nail biting. when present, observe the position the child assumes when sucking a fi nger, thumb or pacifi er and note in what direction the object being sucked is oriented. these positions will usually be taken to reinforce a dysfunctional pattern. for example, placement of an index fi nger relatively vertically in the mouth is associated with a narrow, high, palatal arch. thumb sucking with the index fi nger curled over the nose is consistent with a cranial pattern in extension because the ethmoid bone is placed in anterior rotation as during extension. utilizing tests of listening, assess the cranial base, noting the movement of the occiput and the temporal bones. intraosseous dysfunction of the occipital bone at the anterior intraoccipital synchondrosis will compress cn xii in the hypoglossal canal, while interosseous dysfunction between the occiput and temporal bones can affect the jugular foramen, entrapping cn ix and x. also examine the temporal bones because they affect the position of the mandible and because of the insertion of the styloglossus muscles on the styloid processes. assess the mandible, temporomandibular joint, hyoid bone and cervical spine. these areas should be balanced to ensure satisfactory function of the associated myofascial structures. patient education should be approached in three steps: . instruct them to consciously keep their tongue in their mouth. . they must learn to swallow with their lips closed. . while keeping their lips closed, they must learn to swallow with the tip of their tongue resting against the palate behind their upper incisors. an exercise to accomplish this is to place a small piece of food between the tongue and palate and keep it there while attempting to swallow several times. this may be repeated up to the point where swallowing with the tip of the tongue resting against the palate becomes an automatic refl ex. in young children with minor ankyloglossia, have them perform exercises to mobilize the tongue as much as possible in order to stretch the frenulum. stress that mispronunciation often associated with baby talk may appear to be cute, but that it is actually dysfunctional and should not be encouraged. insist, when speaking, that the child repeats incorrectly articulated sounds as correctly as possible to improve tongue mobility. have them play soundmaking games where they repeat certain sounds that cause the tongue to make a clicking noise against the palate. be aware that functional asymmetries are often associated with repetitive asymmetric activities, such as unilateral bottle feeding or thumb sucking. educate the caregiver and patient to lose these habits. the use of a pacifi er should be limited as much as possible. suggest that pacifi ers should be used only during the fi rst months of life, when the need for sucking is strongest. gastroesophageal refl ux (ger) is the retrograde fl ow of gastric contents into the esophagus and above. it is rather frequent during infancy and is often considered as 'physiologic' under months of age with a benign prognosis in the majority of cases. however, it is a problem of considerable concern for the parents that ranges from minimal regurgitation with the bringing up of small amounts after feeds, to signifi cant vomiting with failure to thrive. because the latter may be indicative of a serious condition, it requires further medical evaluation. ger is one of the most recurrent symptomatic clinical disorders affecting the gastrointestinal tract of infants and children, and regurgitation in infancy is a complaint in . % of children seen in osteopathic practice. daily regurgitation is present in % of infants in the fi rst months of life, with a peak incidence at months. most of the time, the condition resolves before the end of the st year and only % of infants still bring up their food between and months of age; however, when the condition is present for at least days before years of age, children are predisposed to demonstrate ger symptoms into middle childhood. there is no association with gender, , nor with the mode of feeding the infant, breast or bottle; nevertheless, a genetic component seems to be present and a correlation exists between maternal symptoms of ger and the occurrence of regurgitation in infancy and ger in middle childhood. additionally, there is a stronger prevalence of ger among caucasian infants. , normal gastroesophageal function is a complex mechanism where the relaxation and contractility of the lower esophageal sphincter are important factors. the esophagus is a tube connecting the pharynx and stomach, with muscular sphincters -the upper and lower esophageal sphincters. the upper portion of the esophagus (the cervical esophagus) consists of skeletal muscle; the remainder (the thoracic esophagus) consists of smooth muscle. after swallowing, the bolus of food passes through the pharynx to enter the esophagus. a primary wave of contraction starts in the pharynx and travels along the whole length of the esophagus, reinforced by secondary waves in the body of the esophagus. these peristaltic waves assist gravity to propel the bolus through the esophagus and into the stomach. normally, at the gastroesophageal junction (gej), the lower esophageal sphincter (les) relaxes to allow the bolus of liquid or food to pass into the stomach. in ger, the gej is a critical site. the les is formed by circular smooth muscle surrounding the terminal esophagus. the les is under tonic contraction that relaxes during swallowing as well as following esophageal distension by a bolus of liquid or food. additionally, the crura of the diaphragm participate in this sphincteric mechanism. the esophagus traverses the diaphragm through an opening in the right diaphragmatic crus, the esophageal hiatus, which is located between the central tendon and the hiatus aorticus. the two vagus nerves (cn x) also traverse the diaphragm through the esophageal hiatus. at this hiatus, one crus, most often the right crus, surrounds the esophagus forming an external sphincter; however, the fi bers from the crus are not directly connected to the esophageal wall. rather, fi bers coming from the transversalis fascia, and thus continuing to form a fascia under the diaphragm, pass into the esophageal hiatus and surround the esophagus to blend into its walls - cm above the gej. some of the elastic fi bers of the fascia extend into the esophageal submucosa. this connection between the diaphragm and esophagus is called the phrenoesophageal ligament. this ligament simultaneously allows gej mobility, permitting the displacement associated with respiration and swallowing, while providing restriction of upward movement of the esophagus. additionally, during pulmonary inspiration, the diaphragmatic esophageal hiatus contracts in response to increased intra-abdominal pressure. the fascial relationships between the esophagus and the diaphragm must be balanced when addressing dysfunction of the gej. the transversalis fascia is a vast layer of fascia lying between the peritoneum and the abdominal walls, in continuation below with the pelvic fasciae, behind with the thoracolumbar fascia and above with the fascial sheet covering the undersurface of the diaphragm. the phrenoesophageal ligament, described above, consists of fi bers extending from this layer to form the cone surrounding the gej. furthermore, the stomach is connected to the diaphragm through the gastrophrenic ligament, i.e. the portion of the greater omentum that extends from the greater curvature of the stomach to the inferior surface of the diaphragm. from a functional point of view, the diaphragm must be balanced to allow satisfactory gej function. the smooth muscle of the les generates a tonic pressure at the gej that is the major barrier to refl ux of gastric contents into the esophagus. thus, refl ux of acidic fl uid backward, out of the stomach and into the esophagus, is normally controlled at the gej. at birth, neuromuscular activity and esophageal and les peristalsis are undeveloped, resulting in frequent retrograde spilling out of gastric contents. the achievement of full development of the les occurs as the infant matures, with the pressure at the les reaching adult levels between and months of age. at the same time, the average capacity of the stomach at birth, i.e. around ml, will rise to ml at the end of the fi rst month and will reach ml in the adolescent. in order to act as a protective barrier against refl ux from the stomach, pressure in the gej has to be higher than in the adjacent stomach or esophagus. inhibitory and excitatory factors infl uence the tone of the les. as mentioned above, a bolus of liquid or food initiates the relaxation of the sphincter in response to esophageal distension. this mechanism is under the control of intramural plexuses of the enteric nervous system. the motor fi bers start in the dorsal motor nucleus of the vagus and the nucleus ambiguus, and the neural release of nitric oxide and vasoactive intestinal peptide among others by postganglionic fi bers triggers the relaxation of the les. additionally, neurological activity from the dorsal motor nucleus of the vagus and nucleus ambiguus is also sent to the crura of the diaphragm. thus, both the esophageal and crural musculature are inhibited. embryologically, both the esophagus and stomach develop from the foregut. the dilatation of the foregut for the stomach starts in the sagittal plane at weeks of gestation. several spatial changes occur before the stomach reaches its fi nal position. because growth is greater along the dorsal border of the stomach, the greater and lesser curvatures are formed. this is followed by rotation, with the greater curvature moving to the left and the lesser curvature moving to the right. the two vagus nerves follow this rotation. thus, the right vagus becomes posterior and supplies the dorsal part of the stomach, while the left vagus is anterior and supplies the ventral part of the stomach. some torsion of the stomach occurs between the lower part of the esophagus and the pyloric canal, which are consequently no longer in the same plane. this has been suggested as a risk factor for ger. this developmental process results in what is felt when the stomach is palpated. the identifi cation of a strong torsional sensation in this region of the gut is an indication for osteopathic treatment that should be directed at the alleviation of the identifi ed torsional dysfunction. the etiology of ger is multifactorial, with often more than one factor being present in children with this condition. however, a transient les relaxation (tlesr) as the result of a vasovagal refl ex appears to be frequently associated with ger, producing a complete relaxation of the les without pharyngeal swallowing. , other factors for ger include ineffective esophageal motility or delayed gastric emptying. a high fat diet can contribute to an increase in the number of episodes of tlesr. additionally, in infants, gravitational and positional factors associated with the supine position may exacerbate the refl ux. most infants spend more time in this recommended position since the 'back to sleep' campaign to prevent sudden infant death syndrome (sids). the return of the gastric acid contents into the esophagus predisposes the infant and the child to esophagitis; for these patients, crying becomes common. acid refl ux into the esophagus can reach the upper esophagus, the pharynx and larynx, and may possibly be aspirated into the trachea. chemoreceptors in the mid or upper esophageal mucosa are stimulated, resulting in refl ex respiratory inhibition, hypertension and bradycardia. approximately % of infants demonstrate refl ux-induced apnea with airway closure or laryngospasm. the severity of these reactions may lead to sids. bronchospasm may also occur and, in turn, accentuate the symptoms of asthma, although ger does not seem to increase the risk of developing asthma. recurrent bronchitis or pneumonia is frequent and can be caused by repeated pulmonary aspiration of acid refl ux. ent problems such as nasal obstruction are sometimes related to ger, with secondary infl ammation and narrowing of the posterior nasal apertures. , with premature infants, the most common complication of recurrent ger is failure to thrive. in children and adolescents, ger is frequently associated with abdominal pain in the midepigastrium, eventually substernal heartburn and possible chronic irritative coughing. furthermore, regurgitation of gastric contents into the oral cavity is responsible for dental erosion and dental caries. the vagus nerve (cn x) is essential in the control of les tone. it contains both motor and sensory fi bers, with a course and distribution more widespread than any of the other cranial nerves, passing through the neck and thorax to the abdomen. about % of vagal fi bers are afferent fi bers and may be general somatic, general visceral or special afferent. they provide signifi cant sensory input from the viscera. in infants, children and adolescents with ger, there is a defi nitive dysfunctional viscerosomatic and/or somatovisceral component. this may, in turn, lead to altered behavioral responses. possible dysfunction affecting cn x in its extensive course may facilitate ger. critical sites are the jugular foramina and the passages through the diaphragm at the esophageal hiatus. additionally, the stomach and esophagus may demonstrate visceral dysfunction in relation to somatic dysfunction in the surrounding structures, i.e. diaphragm, fasciae and ligaments. the osteopathic approach to ger consists, therefore, of addressing any dysfunction that can impede the vagus, balancing the stomach and esophagus together and in their relationships with surrounding structures -the diaphragm, fasciae and ligaments. inspect the abdomen, noting its shape, contour and movement with respiration. the abdomen should be rounded and dome-shaped in infants because of the lack of abdominal muscular tone. observe for abdominal asymmetry, noting areas of tension under the inferior border of the thoracic cage, in particular under the xiphoid process. note if the umbilicus is centered or displaced or if it is protruded. in children and adolescents, observe the inside of the mouth for dental caries. examine and treat the craniocervical junction, with particular attention to the relationship between the occiput and temporal bones because compression of the jugular foramen can impact the exit of cn x. check and balance the cervical area (c , c , c ) because of the phrenic nerve and its action on the diaphragm. examine and treat identifi ed somatic dysfunction affecting the thoracolumbar junction because of its potential to affect the crura of the diaphragm. evaluate and treat the diaphragm, paying particular attention to the freedom and symmetry of its excursion and its attachment around the xiphoid process as well as its anterior costal attachments. balance the fasciae at the level of the les by balancing the area below the xiphoid process with the diaphragm. balance the relationship between the stomach and diaphragm. the stomach itself demonstrates curling and uncurling movements, similar to those that created its curvatures. palpation should reveal a balance between these curling and uncurling movements. a predominance of one phase can be treated using indirect procedures. balance the torsional relationship between the stomach and the esophagus. address somatic dysfunction related to both viscerosomatic and somatovisceral refl exes: occiput, c , c for the vagus; upper thoracic for the esophagus; midthoracic for the stomach. infants should have small and frequent feeds, and should be fed in a semi-upright position. feeding should occur under calm circumstances. instruct children and adolescents to eat slowly and to avoid swallowing air. they should eat and drink small amounts to prevent distension of the stomach. they should also be instructed to avoid the consumption of fatty foods, caffeinated beverages and chocolate. lifestyle changes such as avoiding eating before bedtime and, if appropriate, weight loss should be encouraged. the term colic is derived from the greek, kblikos, meaning in relation to the colon. in the list of the most frequent gastrointestinal (gi) dysfunctions encountered in infants, colic is second only to regurgitation. it occurs in - % of infants [ ] [ ] [ ] and is one of the most common complaints for which parents seek professional advice. the colicky infant presents with abdominal distension, frequent gas emissions, apparent abdominal pain, irritability and excessive crying. the mechanisms that explain this disorder are not entirely understood. they may be discussed in anatomic or physiologic terms, refl ecting dysfunction at one or more levels of the brain-gut axis. additionally, because the ontogeny of the gi system is under multiple infl uences -genetic heritage, intrinsic development, endogenous regulatory mechanisms and the environment -the etiology of colic is commonly multifactorial. thus, various etiologies have been proposed, including gi diseases such as allergy to cow's milk protein, lactose intolerance and intestinal hyperperistalsis, as well as neurodevelopmental dysmaturation or psychological diffi culties in the parent-child relationship. on average, it is estimated that infants cry for . hours per day during the fi rst months of life, with a peak around weeks of age. crying time then slowly decreases to less than hour a day by weeks of age. the 'rule of three' proposed by wessel et al. in is usually the reference employed to identify colicky children. these children are said to cry for more than hours per day, more than days per week and for longer than weeks. colic usually starts in the st month of life and may persist until or months of age. crying is commonly concentrated in the late afternoon and evening, occurs in prolonged bouts and is unpredictable and spontaneous. colicky children are described as crying without identifi able cause, fussing and hard-to-soothe, although being otherwise healthy infants, well fed and showing no signs of failure to thrive. individual variation may be present in the cries, such as duration or intensity, associated fussing or the resulting parental distress, adding complexity to the defi nition. colic cries convey acoustic information that the infant is highly aroused or distressed. during a crying episode, the infant usually positions their legs fl exed over their abdomen, in association with a hard distended abdomen, gurgling noises from the abdomen (borborygmi), sometimes gas and regurgitation, as well as facial grimacing and clenched fi sts. this presentation is indicative of a gi etiology for colic. when evaluating the colicky infant, several aspects of gi development and associated neurohormonal factors should be considered. bacterial colonization of the sterile gi tract of the neonate starts quickly on delivery. a fl ora develops, resulting from microbial and host interactions. the main factors that infl uence this developing microbial population are the maternal intestinal fl ora, the use of antibiotics by the mother during pregnancy and when nursing, the mode of delivery (vaginal or cesarean) and the mode of feeding (bottle feeding or breastfeeding). the bacterial fl ora in breastfed infants is composed typically of bifi dobacteria, whereas in bottle-fed infants anaerobic bacteria as well as aerobic species are present. it is also recognized that the fl ora of breastfed infants includes far fewer species that are liable to be pathogenic. the developing bacterial fl ora usually becomes stable by the end of the fi rst week of life. by years of age the infantile fl ora resembles that of the normal adult. this process is one of the main components, along with host cells and nutrients, that form the complex ecosystem of the intestine. the intestinal lumina are lined by a very large surface of mucosa that is the principal interface with the external environment. besides its function of digestion and absorption of the nutrients contained in food, the intestinal mucosa forms a protective barrier against foreign substances and potentially pathogenic microorganisms from the external environment. the mucosal barrier consists of cellular and stromal components covered by a mucus layer. within the mucosal barrier various secretions form a viscoelastic gel, creating a site for bacteria-bacteria interactions. thus, the microbiota play an important role in the development of the endogenous barrier mechanism in the gut and are involved in the maturation of humoral immunity in humans. the intestine can be considered the primary immune organ, housing more than % of all immune cells. the gut-associated lymphoid tissue (galt) develops through innate and acquired immunity and consists of organized and diffuse lymphoid tissues that constitute the aggregated lymphoid follicles (peyer's patches) and the mesenteric lymph nodes. this arrangement permits rapid response to any challenge in order to maintain the integrity and protective functions of the immune barrier at the gi mucosal surface. the galt contains b lymphocytes, implicated in the synthesis of secretory antibodies of the immunoglobulin a (iga) class, and t lymphocytes. in this ecosystem, the equilibrium of the microbiota is important in the maintenance of homeostasis and intestinal immune responses. it is also of paramount importance in the prevention of food allergies, and it is during the fi rst years of life, when the infantile fl ora is not well diversifi ed, that food allergies and enteropathies are more apt to be established. particular circumstances in infants, such as prematurity, cesarean section delivery and antimicrobial treatment, delay intestinal colonization and its important immunostimulating effect. , on the other hand, breastfeeding is considered to confer benefi cial effects on the microbiota, explaining its protective role against atopic disease, although it does not appear to have a protective effect on the development of colic. differences in the gut microbiota of breastfed colicky infants have been shown to exist when compared to non-colicky, and lactobacilli are present less than in controls. that breastfed infants may suffer from colic might be explained by the fact that breast milk contains intact proteins similar to those of cow's milk and that colic often appears to be related to a food allergy, particularly to cow's milk protein. , this exposure would trigger the production of specifi c ige to milk protein and may be considered a manifestation of an allergic predisposition. this is, however, subject to debate because no data support the hypothesis that infantile colic leads to an increased risk for subsequent allergic disease or atopy, although more irritability during the th week and colic-type crying during the th week has been observed in children with atopic disease at years of age. furthermore, lactose intolerance also contributes to infantile colic. incomplete lactose absorption encourages bacterial growth with resultant fl atulence and cramping. as the etiology of infantile colic is multifactorial, cow's milk protein elimination may be an effective treatment for infantile colic, and for colicky breastfed infants a maternal diet free of cow's milk may be considered. other maternal dietary modifi cations during breastfeeding should include reduction of cruciferous vegetables, onion and chocolate, foods that are associated with colic symptoms in infants. hyperperistalsis is another theory included in the gi disorder etiology to explain abdominal cramping and colic. intestinal smooth muscle normally generates rhythmic peristaltic activity. movements of the intestine with the regulation of gut motility are the result of complex neural and muscular interactions that take place at several levels and under the infl uence of neurotransmitters and hormones. the innervation of the gut consists of intrinsic and extrinsic nerves. ganglionated and non-ganglionated plexi, part of the enteric nervous system (ens), form the intrinsic innervation, while the vagus, splanchnic and pelvic nerves form the extrinsic innervation. the intrinsic afferent neurons project within the myenteric and submucous plexuses and information from activated sensory receptors reaches the cns through vagal and spinal afferent nerves. the gut interacts constantly with the cns through either somatic or autonomic neurons (brain-gut axis). consequently, the cns modulates the gut motor activity through the ans (sympathetic and parasympathetic), maintaining the normal rhythm of activity in the gi tract as well as adjusting autonomic output to accommodate any external challenge. the release of acetylcholine by the parasympathetic fi bers increases gut motility, whereas the release of norepinephrine, somatostatin and neuropeptide y by sympathetic fi bers decreases the motility. multiple factors, such as emotion, stress, nervousness, fasting or eating, can also infl uence the activity of the ans. additionally, communication occurs between the different parts of the gi tract through myogenic and neurogenic signals along the gut, and through refl ex arcs transmitted via autonomic neurons. individual differences are present in the functioning of the cns. accordingly, an increased sensitivity to stimuli, such as distension of the gut, is demonstrable in patients with functional gi disorders, and excessive crying in colicky infants may be the result of hypersensitivity in the perception of gut stimuli or excessive afferent responses to these stimuli. genetic susceptibility to functional gi disorders may exist. supporting this theory, a correlation is found between high responsiveness of the newborn during neurobehavioral assessment in the fi rst days of life and crying behavior at home. additionally, intestinal hypersensitivity may alter motility of the gi tract by increasing intestinal afferent-efferent refl exes. cranial osteopathy offers a therapeutic option for these patients. osteopathic treatment of colicky infants has been demonstrated to decrease crying and increase sleep time. somatic dysfunction affects the ans. the resulting state of facilitation, in turn, increases the perception of either mechanical or chemical intestinal stimuli, and visceral hypersensitivity or dysfunction follows. somatic dysfunction can involve any osseous, articular, ligamentous, membranous, fascial, muscular, visceral and vascular component associated with the gi tract. vagal viscerosensory neurons have their cell bodies in the inferior ganglion located under the jugular foramen. the spinal sensory input takes place through perivascular nerves passing through the prevertebral ganglia to the dorsal horn of the spinal cord, and these neurons have their cell bodies in the dorsal root ganglia. pain perception is thought to be mediated essentially by the spinal innervation. the craniocervical junction (parasympathetic), the thoracic and thoracolumbar spine (sympathetic) and sacropelvic region (parasympathetic) may be sites of somatic dysfunction resulting in somatovisceral dysfunction. treating these areas may contribute to balance the gut function of the colicky infant. changes in internal sensory states, acting in a bidirectional manner between the viscera and the brain, are obviously related to interoception and visceral hypersensitivity, and are considered as the key pathogenetic factors underlying the emotional state present in subjects with functional gi disorders. stress, in a broad sense, as with any menace to one's individual homeostasis, may come from the external or internal environment. as such, visceral hypersensitivity, milk allergy or somatic dysfunction may be stressful, and colicky infants are quite often described as demonstrating diffi cult temperament. an infant who is crying is expressing distress without indication of its origin. this can be a signifi cant source of stress for parents and caregivers. they respond differently to these cries according to cultural and sociodemographic factors that, in turn, may affect the amount of infant crying. responses of mothers to infant crying diverge from putting the child to bed, to holding and carrying them, riding around in the car, rocking or swaddling. globally, fi rst-born babies are usually reported as crying more excessively, and the western caregiving style is associated with a higher incidence of reported crying. , touching, holding and caressing a child results in positive effects on the emotion regulation and stress reactivity in the infant. maternal care facilitates the development of central corticotropin-releasing factor (crf) systems which regulate the expression of behavioral, endocrine and autonomic responses to stress. it is well established that infant-maternal contact is of paramount importance in mediating infant emotional reactivity. gut-brain peptide cholecystokinin (cck) and endogenous opioid analgesic agent production are increased following contact. this contributes to the development of attachment through the 'interactive regulation of biological synchronicity between organisms'. under normal conditions, this relationship between mother and infant contributes to the wellbeing of both. conversely, infantile irritability can prove to be a major source of distress to caregivers. in extreme circumstances the irritability of the child can prove so stressful as to create an impulse to shake the child. a potential psychosocial etiology for colic in the st year of life is associated with pre-existing maternal anxiety. if the caregiver is stressed, the child will cry more, and the caregiver will be further worried by their incapacity to help the child. furthermore, a baby is frequently described as crying excessively when the crying distresses the parents. infants' cries can also be indicative of a behavioral problem resulting from a less than optimal parentinfant interaction. this complex interrelationship between the child and caregiver has led to a behavioral hypothesis for the etiology of colic where interventions such as modifying parental responsiveness, using motion and sound to calm the baby, and reducing stimuli have been suggested. these caregivers do not need to be told that they are bad parents; they need to be supported and managed with understanding. the circumstances must be discussed and the caregiver given the opportunity to vent their anxiety and frustration. behavioral adaptations, when appropriate, should be encouraged. maternal smoking may contribute to the disorder. one hypothesis for colic suggests that it is the result of transient developmental dysmaturation based on the fact that infantile colic often stops after or months. it is important, nonetheless, to treat these children and help the parents, because persistent behavioral diffi culties, including crying, sleeping or feeding behavior in infancy, are precursors of hyperactivity or behavioral problems and academic diffi culties in childhood. it is important to perform a thorough physical examination to rule out other causes for persistent crying to ensure that there is no organic cause for the crying. once this has been done, osteopathic manipulation may be employed to reduce the somatic afferent load of somatovisceral refl exes into the cns as well as to alleviate the mechanical impact that somatic dysfunction can have on the gi tract. treatment is appropriate not only for infants, but also for children and adolescents, because colic may persist later in life as a functional gi disorder. the osteopathic component of the examination should begin with observation of the infant's posture. the infant may position themselves with their legs fl exed to their chest. if the patient is a child, they might present with an apparent increased lumbar lordosis that occurs when bowel dysfunction creates a distended abdomen with consequent relaxation of the abdominal muscles. observe the abdomen to see if it is tense with bowel distension from fl atulence. note the power and rhythm of the inherent motility of the prm in the head and throughout the body, particularly noting the abdomen. somatic dysfunction should be sought out, especially in the regions of, but not limited to, the posterior neurocranium; the occipitocervical junction and upper cervical spine; the thoracic spine, ribs and upper lumbar spine; the thoracoabdominal diaphragm, the anterior abdominal wall and the sacrum and pelvis. treatment should employ indirect principles and manipulation should be directed at somatic dysfunction, when identifi ed, involving the temporooccipital relationship for its impact on the jugular foramen, and the occipitocervical junction and upper cervical spine for their effect on the vagus and parasympathetic somatovisceral refl exes. somatic dysfunction of the thoracic spine, ribs and upper lumbar spine may be treated to affect sympathetic somatovisceral refl exes. in acute cases, practice inhibition in the lumbothoracic area. avoid active massage of the abdomen which can be irritating. dysfunction of the thoracic spine, ribs and thoracoabdominal diaphragm should be addressed for its impact on the lymphatic and venous drainage of the contents of the abdomen. diaphragmatic, abdominal wall and pelvic dysfunction should be treated to alleviate the impact of dysfunctional fascial tensions on the gi tract. dysfunction of the thoracoabdominal diaphragm is related to the function of the mesenteric plexus. sacropelvic somatic dysfunction may be treated to affect pelvic splanchnic parasympathetic somatovisceral refl exes. using indirect principles, release the periumbilical area and intestine. in every treatment procedure pay attention to the inherent motility of the prm as manifest throughout the body. treating this mechanism affects the ans and probably facilitates tissue perfusion, reducing congestion. the caregiver should be encouraged to create an environment of comfort, calm and relaxation for the infant. gently caressing the frontal area of the neurocranium will often facilitate this. obtaining relaxation of the infant will also have a calming effect on the caregiver(s) that will, in turn, further relax the infant. this relaxation will often make it easier to obtain such a state of calm in the future and will also demonstrate to the caregiver(s) that it can be obtained. avoid, however, active massage of the abdomen which can be irritating. dietary considerations may be employed to improve the function of the gi and the immune system. breastfeeding should, if at all possible, be encouraged. the mother should pay attention to her diet, avoiding cow's milk, cruciferous vegetables, onion and chocolate. in colicky children, lactose intolerance should be considered. a diet rich in fresh fruit and vegetables and antioxidants such as vitamins c and e should be recommended, while refi ned foods should be avoided as much as possible. constipation is the chief complaint in % of all pediatric outpatient visits and defecation disorder is present in - % of children referred to pediatric gastroenterologists. constipation in children is usually defi ned as abdominal pain, diffi culty or pain when passing stool, with the passage of feces that are either large and too hard or in small pebble-like pieces, with diffi culty defecating and a frequency of two times or less per week. the fi rst intestinal discharge, meconium, is passed in healthy newborns within hours. after that, the mode of feeding determines the frequency and quality of stools. bottle-fed infants demonstrate less frequent stools than breastfed infants, who have soft yellow stools up to fi ve times a day. however, breastfed infants may go for or more days without defecation. weaning -the commencement of nourishment with food other than milk -usually occurs between and months of age and results in fi rmer feces. although the frequency of bowel evacuation varies from one infant to another, it is generally admitted that a frequency of less than one stool a day before months of age, and three times or less per week after months, may be considered as pathologic. in preschool children, constipation is present when the child has less than two stools per week. most of the time, constipation is functional, without any objective evidence of an underlying pathologic condition and a thorough history and physical examination are suffi cient to make the diagnosis. it is, however, important to rule out failure to thrive or endocrine, metabolic or structural disease such as hirschsprung's disease. children presenting with this latter condition, characterized by the total absence of ganglion cells in meissner's and auerbach's plexuses, suffer from constipation with massive colonic dilatation proximal to the segment of affected bowel. the onset, however, occurs at birth with delayed passage of meconium and children suffering from the disease demonstrate poor growth. functional constipation has also been described as functional fecal retention, voluntary withholding, psychogenic megacolon or idiopathic constipation. it affects boys more often than girls, contrary to the adolescent and adult populations where women suffer more often from constipation. another difference between children and the adult population is the presence of fecal incontinence in children, which is not present in adults with functional constipation. during the fi rst months of life, infants may present with dyschezia, i.e. diffi culty in defecation. in this case they experience severe problems when trying to defecate and strain and scream during prolonged endeavors. this behavior may last up to minutes, until they successfully pass stools that are usually soft or liquid. the cause is hypothesized to be the failure to coordinate the augmentation of intra-abdominal pressure with the relaxation of the pelvic muscles. painful defecation quite often results in chronic fecal retention with fecal impaction (the immovable collection of compressed or hardened feces in the colon or rectum) and resultant fecal soiling (the passage of liquid stool around the impaction). more than % of school-aged children suffering constipation have a history of painful defecation before months of age. toddlers may succeed in avoiding defecation for several days. the evacuation that then occurs is often painful and may be associated with bleeding, thereby strengthening the behavior of fear and retention. fecal retention, in turn, is associated with subsequent abnormal contraction of the anal sphincters (anismus) and contraction of the pelvic fl oor during attempted retention. the child develops a retentive posture with contraction of the gluteal muscles. with overstretching of the rectal wall and muscle fatigue in the pelvic fl oor, incompetent anal function results in spontaneous relaxation of the sphincters, with consequent fecal soiling with soft or liquid stool. fecal soiling often follows constipation facilitated by rectal distension. constipated children demonstrate several associated symptoms including irritability, abdominal cramps and decreased appetite. most of the time, children with constipation have a withholding type of behavior and very often feel ashamed. they demonstrate more behavioral problems than children who are not constipated; however, these accompanying symptoms disappear immediately following the effective treatment of constipation. the role of psychological and emotional components in the etiology of defecation disorders is subject to debate. it is uncertain which problem comes fi rst: the emotional disorder or the defecation disorder. toilet training is normally initiated between the ages of months and years. when conducted in an overly coercive and stressful fashion, the associated stress has been proposed as a cause of fecal retention. however, when hard bowel movements or painful defecation are present in association with stool toilet training refusal, constipation should be considered because the fi rst episode of constipation in children usually occurs before stool toilet training refusal. familial environmental factors, or added parental anxiety because they want their child to be able to go to school, may add a psychological factor to a physical predisposition to constipation. a decrease in colonic peristalsis has been proposed as a cause of constipation in childhood. it is well recognized that reduction of physical activity and reduction of fl uid intake in adults can be associated with constipation. because children tend to be normally physically active, inactivity is not a major cause of constipation for this population. however, food allergy, particularly cow's milk allergy with cow's milk protein hypersensitivity, seems to be associated with constipation in children. , constipation may certainly be multifactorial. the behavioral approach does not explain every case of constipation. furthermore, children with constipation demonstrate a higher incidence of bladder disorders such as urinary incontinence, bladder overactivity, dyscoordinated voiding, large bladder capacity, poorly emptying bladder, recurrent urinary tract infection and vesicoureteral refl ux. this constitutes a syndrome, an aggregate of associated symptoms and signs that may be addressed by an osteopathic approach. most cases of functional constipation respond well to osteopathic manipulative procedures. defecation is a complex process that involves a mixture of voluntary and involuntary actions. it is triggered by the excitation of anorectal mechanoreceptors sensitive to distension of the rectum. it is followed by coordinated voluntary activity of the abdominal and pelvic musculature and involuntary relaxation of anal sphincters. as the fecal mass moves, the pelvic fl oor muscles relax in order to allow alignment of the rectum with the anal canal. defecation can be inhibited by voluntary contraction of the external anal sphincter and pelvic fl oor muscles. normally, the anal canal is occluded by the internal and external anal sphincters. additionally, the puborectalis muscle, the medial part of the levator ani muscle, contributes to the loop surrounding the anorectal junction by mixing some of its fi bers with the deep part of the external sphincter of the anal sphincters. additional fi bers of the levator ani muscle join the conjoint longitudinal coat that surrounds the anal canal between the internal and external canal. behind the rectum, the pubococcygeal fi bers of the levator ani muscles attach to the anterior surface of the coccyx. the internal anal sphincter has an autonomic innervation: the sympathetic fi bers are from the hypogastric plexus and the plexuses located around the superior rectal artery; the parasympathetic fi bers are from the pelvic splanchnic nerves (s -s ). the external sphincter has a voluntary motor supply that comes from the inferior rectal branch of the pudendal nerve (s -s ) and the perineal branch of the fourth sacral nerve. if the child is old enough to be standing and walking, observe their postural mechanics, noting particularly the degree of abdominal protrusion, thoracolumbar mechanics as they relate to psoas muscle mechanics, the degree of lumbar lordosis as it relates to abdominal protrusion and psoas muscle mechanics. with the patient supine, observe the abdomen, noting its contour and possible distension. palpate the abdomen, looking for tension in the abdominal wall and for palpable stool. in many cases of chronic constipation, stool will be palpable throughout the colon. defi ne stool consistency and assess the quantity of the rectal fecal mass by looking at the height of transabdominally palpable stool above the pelvic brim. diagnostic digital rectal examination should be performed gently to avoid perpetuation of dyschezia. maneuvers that result in rectal stimulation produce potentially noxious sensory experiences and should be discouraged. specifi cally look for somatic dysfunction affecting the thoracolumbar junction that can be associated with psoas muscle dysfunction and sympathetic somatovisceral refl exes. examine the sacrum, coccyx and pelvis for dysfunction that can affect the pelvic fl oor and also be the source of parasympathetic somatovisceral refl exes. the general medical treatment approach includes dietary changes with behavioral modifi cation techniques (cognitive and behavioral interventions such as toilet training, which diminishes phobia and provides positive reinforcement through a rewards system). this approach is often combined with prolonged courses of laxatives. treatment is usually successful, but may take up to - months. when somatic dysfunction has been identifi ed, the correct osteopathic treatment can result in signifi cantly faster results with a resolution of constipation, often in one or two treatments. therefore, treat any somatic dysfunction as identifi ed. treat somatic dysfunction of the sacrum for its relation with pelvic splanchnic nerves and the pudendal nerve. release sacroiliac joints and surrounding myofascial structures. it is important to remember that the sacrum is not completely ossifi ed in infants and children and that intraosseous dysfunction may be present between the different sacral segments. in the infant the sacral molding procedure often provides good results. treat somatic dysfunction of the coccyx, paying attention to its relationship to the insertion of the levator ani muscles. treat somatic dysfunction of the thoracolumbar area for its somatovisceral effect on the sympathetic output to the intestine. with hypersympathetic drive, the bowel becomes less active and may result in constipation. it is also important to be sure that child's posture is balanced, without dysfunctional tension at the level of the psoas for its relationship with the sympathetic chain near the psoas muscle origin. it is important to increase the amount of fl uid that the child drinks every day. infants may be given fruit juices such as prune and pear which contain fructose and sorbitol for their mild laxative effect. if the child is old enough to be eating solid foods, increase bran cereal and fruits and vegetables that are high in fi ber. encourage the consumption of meals at regular times. if the child is relatively sedentary, as tends to occur these days with the playing of computer games, encourage increased physical activity. tell the parents to watch for infrequent, diffi cult or painful defecation that heralds the recurrence of constipation. when identifi ed, they should respond quickly, encouraging the child to go to the bathroom more frequently and modifying the child's diet and physical activities. in a holistic approach to health care, any one area of the body is linked directly or indirectly to all the other areas of the body. consequently, observation of the oral cavity not only provides information about the mouth, it also provides knowledge as to many other aspects of the individual. the oral cavity provides access to the posterior nasal cavity, pharynx, esophagus and lower respiratory tract. it contains an ecosystem that refl ects the overall health status of the individual. dental occlusion refl ects the functional balance of the musculoskeletal system, both locally and at distant areas of the body. muscular tone, facial expression and orofacial habits mirror the individual's psychoemotional status. the oral cavity is also an area that allows communication with others through facial expression and speech. it is the major point of entry for nutrition and hydration and a secondary portal for respiration. optimal function of the area is essential for the very survival of the individual. the main osseous structures of the oral cavity are the mandible, maxillae and palatine bones. the latter two bones are part of the viscerocranium and as such their growth and development extend through adolescence. this process is under genetic infl uence as well as epigenetic factors in which orofacial functions play a signifi cant part. the long period through which development occurs allows extensive opportunities for dysfunction to be established. thus, a thorough understanding of the structure and function involved in this evolution, combined with attentive observation of the infant and growing child, is imperative to identify somatic dysfunction, the effective treatment of which is necessary to promote health and balance. the oral cavity, the mouth, is surrounded by the lips and cheeks and consists of two parts: the oral cavity proper and the vestibule. the oral cavity proper is limited anteriorly and laterally by the alveolar arches, teeth and gums, and above by the hard and soft palate; posteriorly, it communicates with the pharynx through the oropharyngeal isthmus. it includes the tongue, which is totally contained in the oral cavity in infants. as the child grows, only the anterior two-thirds remain in the oral cavity while the posterior third descends following the larynx. the vestibule is located between the lips and cheeks externally, and the gums and teeth internally. it connects with the outside through the oral fi ssure between the lips. the entire oral cavity is covered by mucosa, starting at the labial margins and consisting of three portions: the lining and the masticatory and specialized mucosae. these portions demonstrate different properties according to their location. the oral mucosa is in continuity with the pharyngeal mucosa at the oropharyngeal isthmus. several bones within the viscerocranium defi ne the oral cavity. the maxillae are the fi rst to come to mind; together with the mandible, they are among the largest of the facial bones. nevertheless, all of the components that constitute the skeletal framework of the oral cavity must be taken into consideration. myofascial structures attached to this framework affect it and are, in turn, affected by it. besides the mandible and maxillae, these bony boundaries include the paired palatine and temporal bones, and unpaired sphenoid and hyoid bones. the maxilla consists of a body with zygomatic, frontal, alveolar and palatine processes. bilaterally their bodies contain the maxillary sinuses, the largest of the paranasal sinuses. although these cavities are large in the adolescent, at birth they are small furrows mm in length and mm in width. consequently, in the infant, the vertical diameter of the maxilla is smaller than the transverse and anteroposterior diameters. the maxillary body is shaped as a pyramid, having four surfaces: anterior, posterior (infratemporal), superior (orbital) and medial (nasal). the lower part of the anterior surface demonstrates multiple eminences above the roots of the teeth. several facial muscles insert on the anterior surface of the maxilla and their traction during orofacial activities such as sucking and chewing contributes to the development of the maxilla. the depressor septi nasi muscle arises above the eminences of the incisor teeth. a slip of the orbicularis oris muscle is attached on the alveolar border below this incisive fossa, and the nasalis muscle is attached superiorly. the levator anguli oris muscle arises from the canine fossa, lateral to the incisive fossa. above the canine fossa is the infraorbital foramen, the anterior end of the infraorbital canal, which transmits the infraorbital vessels and nerve. above the foramen on the margin of the orbit is attached part of the levator labii superioris. the nasal notch medially limits the anterior surface of the maxilla and nearby the nasalis and depressor septi muscles are attached. bilaterally the two nasal notches join to form a pointed process, the anterior nasal spine. laterally, the convex infratemporal surface of the maxilla forms the inferior part of the infratemporal fossa. the maxillary tuberosity forms the lower part of this surface and on its medial side articulates with the pyramidal process of the palatine bone. inconstantly, it articulates with the lateral pterygoid plate of the sphenoid and gives origin to a few fi bers of the medial pterygoid muscle. just above this is the pterygopalatine fossa, with a groove for the maxillary nerve. the maxillary orbital surface forms part of the fl oor of the orbit. medially, behind the lacrimal notch, the margin articulates with the lacrimal bone, the ethmoid's orbital plate and the palatine's orbital process. posteriorly, it constitutes the poste-rior border of the inferior orbital fi ssure. anteriorly it forms part of the orbital margin, which is continuous medially with the frontal process and laterally with the zygomatic process. anteriorly and medially, the inferior oblique muscle originates just lateral to the lacrimal groove. on the nasal surface is the maxillary hiatus, the large opening of the maxillary sinus. the superior border of the maxillary nasal surface articulates with the ethmoid and lacrimal bones. the inferior meatus of the nasal cavity is located below the maxillary hiatus and behind a surface for articulation with the perpendicular plate of the palatine bone. a groove crosses this surface, running obliquely downward and forward, and forms, with the palatine bone, the greater palatine canal. anterior to the maxillary hiatus a deep groove forms part of the nasolacrimal canal. the zygomatic process of the maxilla is triangular and is situated at the convergence of the anterior, posterior and orbital surfaces. the frontal process forms part of the lateral boundary of the nose projecting posterosuperiorly. it gives attachment to part of the orbicularis oculi and levator labii superioris alaeque nasi. its medial surface forms part of the lateral wall of the nasal cavity. the upper border articulates with the frontal bone, the anterior border with the nasal bone and the posterior border with the lacrimal bone. the alveolar process is very thick, being broader behind than it is in front. it contains eight deep cavities for the roots of the teeth. these cavities vary in size and depth: the cavities for the canine teeth are the deepest; the cavities for the molars are the widest. the alveolar processes of the maxillae articulated together form the alveolar arch. the buccinator muscle arises from the lateral surface of the alveolar process, as far forward as the fi rst molar. the palatine process projects horizontally and medially from the nasal surface of the maxilla. it constitutes an important part of the fl oor of the nasal cavity and the roof of the mouth. its inferior surface is concave and forms, with the palatine process of the opposite side, the anterior three-quarters of the osseous plate of the palate. in young skulls, a fi ne linear suture, the incisive suture, may be observed. it extends from the incisive fossa, behind the incisor teeth, to the space between the lateral incisor and canine teeth. the small part in front of this suture forms the premaxilla (os incisivum) that contains the sockets of the incisor teeth. the two palatine processes join to form the median intermaxillary palatal suture. the margins are sometimes raised and form a prominent palatine torus. the medial border of the superior surface of the palatine process forms a ridge, the nasal crest. with the opposite side, it forms a groove for the vomer. the posterior border is articulated with the horizontal plate of the palatine bone (figs . . , . ) . the maxilla ossifi es in a mesenchymatous sheet. the number of ossifi cation centers is debated and between two and four such centers may appear during the th week of fetal life. they form a premaxilla (os incisivum) and a maxilla that start to unite at the beginning of the rd month of development. the identifi cation of the junction between these two parts as a suture is also debated, and information is lacking to demonstrate its role as a growth site. a line or cleft, however, may be observed in the anterior part of the palate until the middle decades of life. this site -be it suture, line or cleft -is of consequence in osteopathic practice because it provides a hinge-like location where intraosseous maxillary somatic dysfunction can develop. such dysfunction is commonly found in infants and children as the result of activities such as thumb sucking and from falls where the area is injured. if not treated, this dysfunction will have a signifi cant impact that can only increase as the structures grow. orofacial dysfunctions such as malocclusion or speech disorders may follow. the maxillary sinus, described as a small furrow at birth, reaches its full size after the second dentition. as such, the size of the maxillary body at birth is small, the teeth sockets located almost at the level of the fl oor of the orbit. the relatively small length of the maxillary vertical dimension, when compared to that of the adult, gives the infant the appearance of having large eyes. augmentation in volume of the maxillary sinus and development of the alveolar processes will contribute to an increase in the vertical dimension of the maxillary body ( fig. . ). the maxilla articulates with nine bones including the frontal, ethmoid, zygomatic, nasal, lacrimal, inferior nasal concha, palatine, vomer and the opposite maxilla. the articulation with the orbital surface or with the lateral pterygoid plate of the sphenoid is inconstant. on the other hand, the mandible articulates only with the two temporal bones. it consists of a curved horizontal body and two perpendicular portions, the rami. it is the largest and strongest bone of the face and contains the alveoli for the roots of the lower teeth. its shape and position determine the positional arrangement of the lower teeth and as such it contributes to the relationship between the occlusal surfaces of the maxillary and mandibular teeth when they are in contact. the mandibular body has two surfaces and two borders. in the midline of the external surface is a small ridge, the remnant of the line of fusion between the two halves of the mandible at the symphysis menti. this ridge divides inferiorly to surround the mental protuberance. the mentalis muscle and a small portion of the orbicularis oris are inserted below the incisor teeth on either side of the ridge. laterally, the depressor labii inferioris, depressor anguli oris and platysma muscles are attached. the internal surface is concave and the paired superior and inferior mental spines are situated on either side of the symphysis menti. the genioglossi muscles have their origins on the superior spines and insert on the lingual fascia beneath the mucous membrane and on the hyoid bone. they depress and protrude the tongue. if their origin on the mandible is dysfunctionally positioned, their leverage will be altered and consequently their effect on the tongue will, in turn, be dysfunctional. the geniohyoid muscles insert on the inferior mental spines, and the anterior belly of the digastric insert below the mental spines, on either side of the midline. on either side, an oblique line, the mylohyoid line, runs from a point inferior to the mental spine upward and backward to the ramus behind the third molar tooth. it gives attachment to the mylohyoid muscle, the lower-most part of the superior constrictor of the pharynx, and the pterygomandibular raphe. the superior constrictor, pterygomandibular raphe and buccinator are intimately joined together to the mandibular periosteum. furthermore, they form a continuous band that unites the orofacial structures with the cranial base and cervical spine (fig. . . ) . thus, postural imbalances in the axial skeleton can affect the orofacial structures, potentially leading to orofacial dysfunction and malocclusion. the upper or alveolar border contains cavities for the roots of the teeth. on either side, the buccinator muscle is attached on the outer lip of the superior border, as far forward as the fi rst molar tooth. the buccinator has its origin posteriorly on the lateral aspect of the maxilla and oblique line of the mandible, the pterygoid hamulus and pterygomandibular raphe (figs . . , . . ). it inserts anteriorly on the angle of the mouth, the middle fi bers of the muscle crossing in the region of the modiolus, the lower set passing to the upper lip, the upper set to the lower lip. the modiolus located near the corner of the mouth represents a convergence of several muscles of facial expression and, as such, observation of this area is highly indicative of the psychoemotional state of the individual. the fi bers of the buccinator muscle are interspersed with more horizontal portions of the orbicularis oris muscle. the buccinator fl attens the cheek, retracts the angle of the mouth and plays an important role in mastication in conjunction with the tongue and orbicularis oris muscle to form a belt on each side of the oral cavity, preventing food from accumulating in the oral vestibule. the quadrilaterally shaped mandibular ramus consists of two surfaces, four borders and two processes. the lateral surface is fl at and gives attachment to the masseter muscle. the masseter muscle is attached above on the inferior border of the anterior two-thirds of the zygomatic arch and the medial surface of the zygomatic arch. it inserts inferiorly on the lateral surface of the ramus and the coronoid process of the mandible. it elevates the mandible and its function is of paramount importance in the development, growth and maturation of the mandibular condyles and fossae. a reduction of masseter muscle activity in bottle-fed babies has been observed and, with the loss of chewing behavior, may predispose to chewing/swallowing disorders and malocclusions. located on the medial surface of the mandibular ramus, approximately in its center, is the mandibular foramen leading to the mandibular canal. it contains the alveolar nerve and vessels. a sharp spine on the anterior margin of the foramen, the lingula (spix spine), provides attachment for the sphenomandibular ligament. this site is of particular interest in mandibular kinematics because mandibular motion is centered on a point located near the lingula. the vascular-neural bundle is, therefore, protected from injury caused by normal mandibular motion. the medial pterygoid muscle inserts below the mandibular foramen, on the medial surface of the mandibular angle. thus, the mandibular angle is affected by the action of the masseter laterally and medial pterygoid medially. traction from these muscles dynamically infl uences the growth of the mandible. this infl uence has to be balanced unilaterally between the masseter and medial pterygoid, as well as bilaterally. the coronoid process is a thin, fl attened piece that forms the anterior limit of the mandibular incisure. the temporalis and masseter muscles are attached on its lateral surface; the temporalis also covers part of the medial surface and anterior border of the ramus. the temporalis muscle has its origin on the temporal fossa and functions to elevate the mandible and close the jaw. its posterior, almost horizontally oriented fi bers are the primary retractors of the protruded mandible. these muscles determine chewing action and, when dysfunctional, can have signifi cant impact on the mandible. the condylar process provides an articular surface with the disk of the temporomandibular joint (tmj). its long axis is slightly oblique and directed medially and posteriorly. the neck that unites the head or condylar process to the ramus has the pterygoid fovea (anteriorly) for the attachment of the lateral pterygoid muscle. this masticatory muscle has two heads: the inferior head has its origin on the lateral plate of the pterygoid process; the superior head originates on the infratemporal crest and adjacent greater wing of the sphenoid. in addition to its insertion on the mandible, some of its fi bers join the articular disk and capsule of the tmj. it acts to protrude the lower jaw and also contributes to the opening of the mouth. unilateral pterygoid contraction deviates the chin laterally, enabling grinding motion for chewing. this muscle is important in the development of children's orofacial structures, where unilateral functional patterns will stimulate growth in an asymmetric fashion. alternatively, structural asymmetries may, in turn, prevent the individual from having symmetric functional patterns. ossifi cation of the mandible occurs in the fi brous membrane covering the outer surfaces of meckel's cartilages. these cartilages develop bilaterally in the fi rst pharyngeal arches. the primitive tmj starts to organize during the th week of development, concomitantly with the emergence of muscular activity in the masticatory apparatus. at birth the mandible consists of two parts separated by a cartilaginous symphysis menti not yet ossifi ed. the body, although rather underdeveloped, is much larger than the rami. it consists of relatively thin cortices with tooth buds almost totally occupying its volume. each side contains the sockets of the two incisors, the canine and the two deciduous molar teeth. the angle between the body and the ramus is obtuse ( °), and the coronoid process, of rather large size, projects above the level of the condyle. at birth, the tmj is slack. the mandibular fossa of the temporal bone in which the condylar process of the mandible is located is almost fl at, providing little stability. during the fi rst years of life growth will occur through bony deposition and resorption. bone deposition occurs on the mandibular labial side, whereas resorption occurs on the lingual side, thus allowing for elongation of the mandible and more space for the deciduous dentition. the two halves of the mandible join during the st year, although a line of separation may still be seen in the beginning of the nd year. concomitant development of mastication stimulates growth of the alveolar and subdental portions of the mandibular body, allowing in turn more powerful traction from the masticatory muscles. during the fi rst years of life, mandibular bicondylar width grows rapidly, in synchrony with cranial base growth. it is the fastest growth period of the mandible. with the development of permanent dentition, the angle becomes less obtuse - ° at about the th year. crown formation of the permanent teeth, and their following eruption, is a time of possible occlusal instability, lasting up to - years of age when the majority of the permanent teeth have erupted. after puberty, the mandibular angle is ° (fig. . . ) . development of the teeth, like the development of the other components of the craniofacial complex -jaws, dental arches, tongue and myofascial structures -is under the infl uence of genetic and environmental factors. this development is largely infl uenced by the surrounding structures of the cranium, particularly the temporal bones with which the mandible articulates, and the sphenoid and hyoid bones that are part of the skeletal framework of the oral cavity. at the root of the zygomatic process, in the squamous portion of the temporal bone, is the mandibular fossa, with which the condylar process of the mandible articulates. this fossa, also called the glenoid cavity, is a deep hollow in the adult but is almost fl at in the infant. a disk separates the mandibular condylar process from the temporal glenoid cavity, and a fi brous capsule and synovial membrane surround the joint. the position of the condylar process of the mandible is greatly infl uenced by the position of the mandibular fossa of the temporal bone. the relationship can be potentially dysfunctional if one or several components of the tmj demonstrate somatic dysfunction. in the cranial concept, during cranial external rotation, the mandibular condyles move somewhat posteromedially, following the mandibular fossae of the temporal bones, and the chin recedes. concomitantly, the mandibular angles move laterally. the opposite occurs during cranial internal rotation when the mandibular fossae of the temporal bones move anteriorly. as a result, the mandible moves anteriorly, with the chin becoming more prominent. the deep cervical fascia and stylomandibular ligament also contribute to the relationship between the temporal bones and mandible. the deep fascia of the neck is divided into an external or investing layer and a pretracheal layer. the former surrounds the neck and encloses the trapezius and sternocleidomastoid muscles. above, it fuses with the periosteum along the superior nuchal line of the occipital bone, on the mastoid and styloid processes of the temporal bone and the complete base of the mandible. the stylomandibular ligament, a condensation of the deep cervical fascia, extends from the tip of the styloid process of the temporal bone to the posterior border of the angle of the mandible. this fascia links the mandible to the base of the skull. thus, dysfunction of the cranial base may affect the mandible, and vice versa. it is of great signifi cance in the fi rst years of life, when structures have not yet completed their growth. as such, torticollis or plagiocephaly, if untreated, may predispose to somatic dysfunction of the mandible and viscerocranium, leading to malocclusion. as it belongs to the cranial base, the sphenoid also infl uences the mandible through its muscular and ligamentous relations. the sphenomandibular ligament is of particular importance. this fi brous band, a remnant of meckel's cartilage, runs from the spine of the sphenoid's greater wing to the lingula of the mandible. it constitutes the primary passive support of the mandible, with the area of the lingula acting as an anchor. an artifi cial axis passing through the two lingulae may be proposed, around which motions of the mandible occur. these motions include depression of the mandible during opening of the mouth and elevation during closure, as well as protraction and retraction. the mandible may be compared to a swing hanging under the sphenoid's greater wings. this comparison is particularly valid in infants and young children, where the tmj is quite loose and the sphenomandibular ligament well defi ned. other links between the mandible and sphenoid include the bilateral pterygomandibular raphe and pterygoid muscles joining the pterygoid process to the mandible. the pterygomandibular raphe, also referred to as the pterygomandibular ligament, is a thickening of the buccopharyngeal fascia. it separates and gives origin to the buccinator muscle anteriorly and the superior constrictor of the pharynx posteriorly. the pterygomandibular raphe is attached superiorly to the pterygoid hamulus, the hookshaped inferior extremity of the medial plate of the pterygoid process. below, it is attached above the mylohyoid line behind the third molar tooth. indeed, multiple infl uences exist between the cranial base and the facial bones, potentially affecting the orofacial structures. the human profi le and the position of the mandible have been correlated postnatally with the basicranial shape. furthermore, facial morphology is more related to variation of the lateral part of the basicranium than to fl exion occurring in the midline. epigenetic factors play a signifi cant role in this process. this role is largely fulfi lled by several orofacial functions that start as early as the fi rst weeks of development. it is hypothesized that, around weeks of development, early mandibular movement participates in the differentiation of the primary mandible from meckel's cartilage. consideration of orofacial function is of great signifi cance in the understanding and treatment of any orofacial disorder or malocclusion. to a large extent, orofacial function, interconnected with the musculoskeletal apparatus in a complex system, contributes to the formation of the oral cavity and viscerocranium. deglutition, sucking, ventilation, facial expression, mastication and speech are the sequential events that, through dynamic processes, constantly infl uence the growth and development of the orofacial components. for most of these activities, the tongue plays a central and vital part. in feeding, it moves food through the oral cavity for chewing and then to the pharynx for swallowing. in respiration, its position, relative to the posterior pharyngeal wall, determines the dimensions and shape of the airway for air to fl ow between the palate and the posterior tongue. with the larynx, the tongue contributes to the production of sounds and speech. finally, the tongue seems to play an important proprioceptive role that, in turn, functionally or dysfunctionally regulates all of these activities. the tongue consists of a mass of muscle covered by mucous membrane, where the papillae of the gustatory organ are located. the lingual musculature is divided into intrinsic and extrinsic muscles. the intrinsic muscles, which are totally contained inside the tongue, are the bilateral superior and inferior longitudinal, the transverse and the vertical lingual muscles. conversely, the extrinsic muscles extend outside the tongue and consist of the genioglossus, hyoglossus, styloglossus and palatoglossus muscles. the lingual musculature matures quite early in life, transforming the tongue into a powerful growth stimulator for the surrounding structures. at birth, the infant tongue is totally intraoral and its extrinsic muscles are short. in the infant, the tongue fi lls the oral cavity, contacting the soft and osseous palates, the cheeks and lower lip. although mobile, the tongue is solidly anchored at its base on the mandible by the paired genioglossi and on the hyoid bone by the genioglossi and hyoglossi muscles. in addition, the lateral surfaces of the tongue are suspended from the soft palate by the palatoglossi and from the styloid processes of the temporal bones by the styloglossi muscles. the fi bers of these muscles blend with the superior portion of the tongue. as in other primates, the larynx of the newborn is positioned high, with the epiglottis in direct contact with the soft palate. during the fi rst years of life, in association with the growth of the cervical spine, the hyoid bone migrates from the level of c -c at birth to c -c after puberty. the posterior third of the tongue follows this caudal migration, consequently stretching its superior attachments. this contributes to change the orientation of the soft palate from horizontal in the infant to more vertical in the adult. although the positional changes occur mainly during the fi rst years of life, the reciprocal infl uences, from the cranial base and hyoid bone acting on the tongue and soft palate, should be kept in mind, no matter the age of the patient. normally, at about or years of age, after the descent of the larynx and tongue, the tongue rests lower in the mouth. at this time it forms part of the fl oor of the oral cavity and part of the anterior wall of the oropharynx. it is contained inside the mandibular arch and the functions of swallowing, sucking, ventilation, facial expression, chewing and phonation should be performed without diffi culty. dysfunction develops when lingual mobility and function are impaired. this may be the result of somatic dysfunction affecting the cranial base, hyoid bone or mandible, or accommodation of these areas to dysfunction in more distant body areas. tongue-tie, or ankyloglossia, is a partial or complete adhesion of the tongue to the fl oor of the mouth. because of abnormal shortness, the frenulum linguae tethers the tongue to the fl oor of the mouth, impairs lingual mobility and, in severe cases, prohibits its extension beyond the lower gum. although it may present as part of several craniofacial syndromes, in most cases the child is perfectly healthy. ankyloglossia is, however, associated with up to . % of serious breastfeeding problems. it is also a potential etiology for speech disorders and dental problems, such as diastasis between the lower incisors due to the lingual pressure. furthermore, impaired lingual mobility is related to diffi culty with intraoral toileting and later with the playing of wind instruments. although surgical treatment (frenuloplasty or tongue-tie division) remains debated, in specifi c indications it is reported to improve diffi cult breastfeeding and to protect the maternal nipple, and to alleviate speech disorders and improve tongue mobility. swallowing, or deglutition, is one of the fi rst orofacial functions to appear in utero and has been observed after weeks, when the child refl exively swallows amniotic fl uid. at birth, new habits develop with feeding, allowing the evolution of the pattern of deglutition. in the infant, sucking and swallowing are the results of a pumping action in the hyolingual complex, with a rhythmic tongue thrust, the tip of the tongue showing regularly between the alveolar processes. musculoskeletal growth and maturation of the neuromuscular system result in the development of a more mature or adult swallowing pattern. at around - years of age, at rest and during swallowing, the apex of the tongue is normally located on the palate, behind the upper incisor teeth. when swallowing, the lips are closed, but the perioral musculature, particularly the orbicularis oris and mentalis muscles, is relaxed. lingual pressure applied against the palate contributes to the development of a broad palate and well-developed maxillae. the tongue works as a natural orthodontic appliance 'for better or for worse'. in the cheeks, the muscular bands formed by the buccinator and superior constrictor muscles, joined together through the pterygomandibular raphe, bilaterally act to constrain the tongue within the oral cavity. thus, functional balance or dysfunction of the cervical spine and cranial base, the sites of origin of the superior constrictor, contributes significantly to lingual posture. in addition, because the tongue is anchored on the mandible, it affects and is affected by mandibular position and growth. when mature or adult swallowing does not develop successfully, immature or atypical swallowing will continue. chewing forces also contribute to maxillofacial growth. first, mastication occurs purely in the sagittal plane, with the mandible moving up and down, and demonstrating propulsion and retraction. then, progressively, an alternating unilateral chewing pattern appears, with diagonal movements of the mandible. the masticatory muscles develop in response to this demand. at around months of age, a child can chew soft food and keep it in their mouth; year later they can chew more solid foods. as such, their diet should include food that requires suffi cient chewing to allow satisfactory occlusal force per chew that can, in turn, stimulate periosteal growth. symmetric chewing is a requisite for adequate muscular stimulation of the digastric, temporal and pterygoid muscles. the traction of these muscles will, in turn, stimulate bone growth. at this time cranial balance is necessary to facilitate the establishment of symmetric masticatory patterns that are learned and practiced throughout the rest of life, making early identifi cation and treatment of somatic dysfunction essential. besides swallowing and chewing, ventilation, speech and facial expression also contribute to the development and growth of the maxillofacial structures. ventilation, as a vital function, is present from birth onwards. in the fi rst months, the infant is normally a nasal breather. at this time, observed respiration should be unencumbered. it is imperative that airfl ow be quiet and through both nares equally. dysfunctional nasal respiration will impact the development of the orofacial structures, potentially leading to mouth breathing. establishment of the route of respiration is partly under the control of the soft palate. this muscular fold, suspended from the posterior border of the bony palate, extends inferiorly and posteriorly into the oropharynx. under normal circumstances the soft palate and tongue act in apposition to close the oropharyngeal isthmus; conversely, when the soft palate rises and contacts the posterior pharyngeal wall, the nasopharynx is closed. thus, the position of the soft palate determines the route of respiration and regulation of airfl ow through the nose or mouth. the soft palate is united with the tongue through the palatoglossi muscles and with the pharynx through the palatopharyngei muscles. for optimal function of all of the structures that contribute to upper airway respiration, somatic dysfunction affecting the sites of origin of these muscles should be identifi ed and treated. for optimal breathing, the cranial base, hyoid bone and mandible should be balanced. it is well established that an inferoposterior displacement of the hyoid bone and an anteroinferior positioning of the tongue are correlated with mouth breathing. [ ] [ ] [ ] normally, the tongue demonstrates large movements in all three planes of space. in the production of sounds and speech, the tongue must change shape and the dorsum of the tongue must contact the palate. shortening of the base of the tongue results from anterior displacement of the hyoid bone, whereas lengthening of the base of the tongue results from its posterior displacement. by employing the activity of the lingual muscles, speech contributes to the overall function and development of the orofacial cavity. although the hyoid bone has no direct articulation with other skeletal structures, it is an interface between the mandible and tongue above and the upper thoracic area below. consequently, its position and motion are infl uenced by changes occurring at the level of the mandible or anywhere in the thorax. a hyolingual complex -a 'kinetic chain' -may be described, part of a more global oropharyngeal complex where every structure is interdependent with others as part of the system. begin by noting the relationship between the head and the remainder of the body. the skull should be centered above the spine. note any tension in the posterior, lateral and anterior (submandibular) cervical musculature. divide the viscerocranium into three regions: frontal, nasal and buccal. observe the relationship between these three regions and the relative harmony between them. in newborns, the lower two regions are proportionately smaller than in older children, adolescents and adults because the paranasal sinuses are not yet developed and the teeth have not erupted. observe facial expression and orofacial functions such as breathing, sucking (in infants) and swallowing. look for coordination of the tongue and orofacial musculature, the rate of sucking if the patient is a baby, and possible tongue sucking or tongue thrusting. note the ease of swallowing without any concomitant inappropriate muscular contraction if the patient is a child. if they are old enough to respond, ask them to describe the location of the tip of their tongue during swallowing; normally it should contact the hard palate behind the upper incisors. observe the resting respiration. nasal patency of airfl ow can be assessed easily with a wisp of cotton held adjacent to each nasal aperture or look for fogging with exhalation on the convex side of a cold metal spoon or a cold mirror. observe the midline of the face, the metopic suture, nose and symphysis menti. all of these landmarks should be aligned in a straight line observe the maxillae and compare size and shape: in external rotation the maxilla appears wider; in internal rotation it appears narrower. observe the position of the mandible. note its relationship with the maxillae, particularly its centric position. observe the location of the gnathion; newborns are normally retrognathic. with the infant, an open mouth posture with tongue forward may be observed with dysfunction of the cranial base, mandible or hyoid bone. with children, observe the mouth area and the lips for symmetry and tonicity. the upper lip refl ects the functional pattern of the maxillae, whereas the lower lip refl ects the mandible. look for the capacity to keep the lips closed and in soft contact. there should be no tension, in particular in the orbicularis oris or mentalis muscle, and no protrusion, retraction or pursing of the lips. note any abnormal perioral muscle function or nervous habits such as fi nger and nail picking or nail biting. compare the nasolabial sulci for depth and obliquity. increased sulcus depth is associated with external rotation of the ipsilateral maxilla and/or the zygoma, whereas decreased depth is associated with internal rotation of these bones. look inside the mouth. assess the position and function of the tongue. note the presence of a large frenulum linguae. if the child is old enough to voluntarily open the mouth, look at the relative position of the tongue within the oral cavity. it should be inside the mandibular arch and should not cover the lower teeth. again, if possible, have the child slightly protract their tongue to look for the presence of dental imprints on the lateral aspects of the tongue, unilateral or bilateral, indicating lingual malposition and/or dental malalignment. with the tongue protracted, look for tongue deviation. assess the mobility of the tongue, looking for limitation of movement. dysfunctional tongue posture is often accompanied by decreased tone and eversion of the lower lip. observe the teeth as to position, dental attrition and progression of dental development according to the child's age. observe clenching of the teeth and observe the occlusion of the teeth. the upper and lower midline between the incisors should be in alignment. normally, the upper incisors should slightly override the lower incisors and upper molars should rest on the lower molars. note misalignment or protrusion of the upper or lower incisors. note any crowding of the teeth. if asymmetric crowding is present, look to see if there is ipsilateral cranial internal rotation. note the potential association with impaired ipsilateral nasal breathing and/or dysfunctional mastication. observe the shape and symmetry of the palate: a lower, fl attened palate with everted teeth is associated with external rotation; a high arched palate with inwardly directed teeth is associated with internal rotation. observe the mandible. it should appear balanced under the cheeks. if not, differentiate between asymmetry of position and asymmetry of size and shape. asymmetry of mandibular position is associated with asymmetry of the temporal bones: external rotation of the temporal bone results in posterior displacement of the mandibular fossa; internal rotation results in anterior fossa displacement. the chin will be displaced toward the side of temporal external rotation. if asymmetry of mandibular size and shape is noted, look for a potential cause. structural asym-metry may result from intraosseous mandibular dysfunction, dental malalignment or asymmetric orofacial function, such as mastication occurring only on one side. note the consistency between orofacial fi ndings and the cranial pattern. if they are in concordance, a cranial osteopathic approach may be indicated. palpation for function and treatment of identifi ed dysfunction should follow. when treating orofacial problems, don't forget to check and treat somatic dysfunction of other areas, frequently the cranial base, craniocervical junction and upper thoracic area. cranial procedures directed at release of the global membranous strain pattern, the sbs, vault and facial bones to ensure optimal freedom of movement are anecdotally associated with facilitation of the teething process. it is also important to remember that all tooth buds are present in the maxillae and mandible, even though not yet erupted. any fi nger or object placed inside the mouth of a child can act as an orthodontic device and move the teeth. therefore, it is inappropriate to employ force when examining the patient or using osteopathic manipulation to treat children's orofacial somatic dysfunction. the earlier osteopathic treatment of orofacial dysfunction is initiated, the better. results may be enhanced when osteopathic treatment is employed in conjunction with appropriate orthodontic treatment. dental development begins in the rd month of intrauterine life and ends at approximately years of age. throughout this period profound occlusal events occur, resulting in potential sources of stress for the orofacial structures. to understand the evolution of the occlusal mechanism, it is important to begin with the infant and to follow the eruption and arrangement of the teeth along the dental arches. during the fi rst months, the absence of teeth allows total freedom in the displacement of the mandible and the child can experiment and discover objects surrounding them by bringing everything to their mouth. the lower central incisors are normally the fi rst to appear between and months of age. when the upper central incisors emerge, the fi rst occlusal relationship appears, associated with new constraint for mandibular mobility. the upper and lower lateral incisors are almost completely erupted at around months, the time when the fi rst molars appear. just before the end of the nd year of life, the central and lateral incisors and the fi rst molars are in occlusion, the canines have erupted and the second molars are beginning to emerge. in the nd year of life, the deciduous teeth are present, with occlusion between the incisors, canines and fi rst molars. at the same time, the child's orofacial functions have matured and their food is becoming more solid. mouthing (active oral interaction with the environment by sucking different objects) is still quite frequent up to years of age. several explanations -from a means of exploring their environment to proactively exposing the naive gi tract to environmental antigens -have been offered for this behavior. whatever the reason, mouthing effectively contributes to dental attrition, thereby eliminating any dysfunctional occlusal contact and facilitating functional adaptation. smoothing of the occlusal surfaces results in proprioception important in establishing functional balance of mandibular motion patterns. conversely, any dysfunctional occlusal contact will result in dysfunctional mandibular motion patterns and stimulate abnormal mandibular and maxillary growth. it will also prevent the establishment of alternating unilateral mastication. the teeth develop in sockets in the alveolar parts of the maxillae and mandible. they are each held in their respective socket by a periodontal ligament. this anchors the teeth solidly while still allowing micromovements. it is also the site for periodontal innervation that is of paramount importance in the development and control of orofacial praxis. proprioceptive input from the periodontal ligament in association with proprioception from the tmj and surrounding myofascial structures provides constant information to the cns. this allows the individual to adjust to the challenges of mastication as well as to global postural mechanics. deciduous teeth are small, with thin enamel coverage, allowing rapid wearing out. on the other hand, permanent teeth are the hardest of all tissues in the body. each consists of a crown and a root, meeting at the cervical margin. dentine forms most of the tooth, with a central pulp cavity ending in a pulp chamber and canal. the side of the tooth in contact with the lips and cheeks is the labial or buccal surface while the side in contact with the tongue is the lingual or palatal surface. when the jaws are brought together the teeth meet, or occlude; thus, dental occlusion occurs. occlusion is qualifi ed according to the respective positions of the teeth. a centric occlusion takes place when the relation of opposing occlusal surfaces of mandibular and maxillary teeth provides the maximum contact, or inter-cuspation. in such circumstances, the mandible is in centric relation to the maxillae. infants usually demonstrate a retrusive mandibular position. when the fi rst teeth erupt, the relationship will tend to show a horizontal protrusion, or overjet, of upper incisors beyond the lower incisors. however, at this early age tongue thrusting will result in a functional edge-to-edge repositioning of the teeth. in the fi rst years of life, during eruption of the deciduous teeth, changes in the orofacial osseous and myofascial structures normally allow suffi cient space for the teeth to emerge. typically, by approximately years of age, there is occlusion between all deciduous teeth that already gives a good idea of the occlusal pattern of the future permanent teeth. the overjet and overbite relationship should have resolved in order to allow for freedom of mandibular diduction, which is only possible if the mandible can slide forward slightly. this sequence occurs as the result of an alternating chewing pattern, enhanced by chewing the solid foods found in the correct type of diet. it is important for the osteopathic practitioner to observe the oral cavity and teeth in order to identify their eruptive pattern, position, occlusal contacts and any asymmetric wear that may be associated with cranial somatic dysfunction. in addition, any asymmetry of function that predisposes the child to mouth and then chew using only one side, as might occur with a neurologic impairment, a child with one handicapped upper extremity or simply a child with a torticollis, will result in asymmetric wear of the occlusive surfaces of the teeth and eventually asymmetric mandibular growth. the permanent incisors are signifi cantly wider than the deciduous incisors that they have replaced by approximately years of age. there might be a tendency for overjet or overbite, either positive or negative. while a horizontal protrusion of upper incisors beyond the lower ones is named overjet, a vertical overlap is named overbite (fig. . . ). at this age, the child's temporary canines, the two temporary molars and the fi rst permanent molars are in occlusion. around years of age, occlusion exists between the permanent incisors, the temporary canines and the fi rst permanent molars. at years of age, occlusion is typically present between the permanent incisors, permanent canines and fi rst permanent molars. in mixed dentition, if the child has developed an asymmetric pattern of chewing, with a tendency to chew only on one side, they may wear out the teeth in a way that will not allow functional and symmetric development. unsatisfactory occlusal contact will create points of resistance that will, in turn, control and guide the movement of the mandible in asymmetric patterns. the masticatory, perioral and craniocervical muscles, as well as the highly elaborate tmj structures, result in engrams of the repetitive dysfunctional pattern. if no change occurs, this will be the permanent pattern ingrained in the cns. thus, it is important to recognize asymmetric patterns and to identify and treat any underlying somatic dysfunction. because patterns of function become fi xed as the child ages, for the best therapeutic outcomes the cranial osteopathic approach should be employed at the earliest opportunity. at the end of the th century, edward angle proposed that a defi nitive nomenclature was necessary in orthodontia as in anatomy. he felt that the term malocclusion was far more expressive than 'irregularities of the teeth' to describe not only the relationship between the maxillary and mandibular arches, but also of the individual teeth to one another. as a result, a classifi cation was born, referred to as angle's classifi cation. angle's classifi cation is based on the mesiodistal relationship of the permanent molars. in dentistry, distal means away from the median sagittal plane of the face, following the curvature of the dental arch, while mesial means proximal. three classes of dental arrangement are described. class i identifi es the normal relationship of the jaws, where the mesiobuccal cusp of the maxillary fi rst molar occludes in the buccal groove of the mandibular fi rst molar. in the individual with normal dentition and centric occlusion, the lower incisors bite against the lingual surfaces of the upper incisors, the crowns of the lower incisors being covered in their superior third. in addition, from the canine teeth backwards, each lower tooth is slightly in front of its upper fellow. classes ii and iii categorize variations of malocclusion. in class ii, all the lower teeth occlude distal to normal, wherein the distobuccal cusp of the maxillary fi rst molar occludes in the buccal groove of the mandibular fi rst molar. in addition, this class is further subdivided into division , labioversion of maxillary incisor teeth, and division , linguoversion of maxillary central incisors. this may occur unilaterally of bilaterally. class ii is the most frequently encountered type of malocclusion. in class iii, all the lower teeth occlude mesial to normal, wherein the mesiobuccal cusp of the maxillary fi rst molar occludes in the embrasure between the mandibular fi rst and second permanent molars. class iii may further be classifi ed as a unilateral condition. the origin of malocclusion is highly debated, again with multifactorial origins proposed. besides the genetic aspect of malocclusion, in particular for class iii, malocclusal patterns are felt to result from an imbalance between intrinsic forces such as from the tongue and lips and extrinsic forces such as stressful orofacial habits. a large number of studies have considered the infl uence of epigenetic factors such as the orofacial functions of deglutition, sucking, ventilation, mastication and phonation (see below). in fact, it is more the orofacial dysfunctions and parafunctions or orofacial habits that are the source of malocclusion. edward angle said: 'orthodontic treatments are very unlikely to succeed, if the functional disorders are still going on.' class ii malocclusion represents a heterogeneous collection of conditions with malocclusion that may be the result of purely skeletal or combined skeletal and dental origin; they are, however, more often purely dental in nature. the teeth and alveolar bone constitute an interface between opposing forces and pressures, primarily from muscular function -the perioral musculature of the lips and cheeks on the one hand and intraoral forces from the tongue on the other. pressures are applied to the teeth with varying distribution according to the oral function involved. under appropriate circumstances these pressures should affect the teeth from multiple, yet balanced, directions. when dysfunction results in chronically repeated patterns of activity, limiting the directions that these muscular pressures are applied to the teeth, dental malocclusion can be the result. the development of class ii malocclusion has also been correlated with non-nutritive sucking habits such as thumb sucking. [ ] [ ] [ ] [ ] [ ] in the early years of life the premaxillae may be easily pushed forward by non-nutritive sucking, pushing the upper incisors along with them. thumb sucking creates an anterior opening between the dental arches, which facilitates the forward displacement of the tongue that occurs during tongue thrusting. it consequently results in dysfunctional forward placement of the tongue. this will, in turn, promote maxillary prognathism because, with every deglutition, which occurs approximately times per day, the tip of the tongue will move forward between the teeth, applying pressure to the premaxillae and upper incisors, pushing them forward. for similar reasons, the sucking of a pacifi er is also commonly associated with malocclusion, followed by the practice of sucking fi ngers. prolonged pacifi er habits result in changes to the dental arches with a prevalence of posterior cross-bite and increased amount of overjet. until the age of - years the risk of developing a dysfunctional occlusion may be reduced proportionally to the reduction of time that the child uses the pacifi er, and under these circumstances the dental arches should be regularly evaluated. signifi cant maxillary prognathism has also been correlated with persistent digit sucking habits. , among other sucking habits, a trend toward association of bottle feeding with the need for orthodontic treatment has been found. on the other hand, breastfeeding seems to have a positive effect on orofacial morphogenesis, , with a protective effect for the development of posterior crossbite in deciduous dentition. not only the mode of feeding but also the type of food is associated with malocclusion. there are suggestions that changes in diet and food processing are associated with variations in facial size and shape. the prevalence of occlusal disorders in subjects born in the s has been found to be lower than in individuals born in the s. it is thought that this is probably because of dietary habits resulting from the increased consumption of processed foods. at the same time, there is an increased prevalence of allergies that result in mouth breathing. there is a % incidence of mouth breathers in individuals born in the s and % in those born in the s. when mouth breathing is associated with nasal obstruction, it results in an inferior position of the mandible. in addition, the tongue is maintained lower in the oral cavity (fig. . . ). this posture is associated with compensations in the perioral musculature, such as hypotonicity, as well as compensations at the level of the vertebral spine. mouth breathers tend to assume an extended or forward head posture. respiratory dysfunctions are also associated with malocclusion. premature molar eruption is often present in chronic mouth breathers. mandibular growth is affected, with resulting anterior mandibular rotation and an increase of the mandibular angle. thus, the vertical dimension of the lower face is increased, with resultant open bite. the term 'adenoidal facies' (long faces) describes infants with an open mouth, a short upper lip and prominent and crowded anterior teeth. lip hypotonicity -decreased tonicity of the orbicularis oris muscle -is typically found in patients with class ii, division malocclusion. in this presentation, hypotonicity of the orbicularis oris muscle is balanced by compensatory contraction in the mentalis muscles. it is this aspect that can be observed in patients with 'adenoidal facies' syndrome. in addition, the maxillae are narrow and the palate high arched with concomittant increase in the mandibular angle; thus the face appears longer. these individuals also demonstrate a lack of development of the masseter muscles as well as of the maxillary bones. alternatively, hypertonic and bulbous masseter muscles with reduced facial height are correlated with a tendency to clench the teeth. these fi ndings are commonly identifi ed in association with cranial somatic dysfunction involving the temporal bones and/or tmjs. the cranial concept lends itself well to the understanding of functional orofacial disorders. children who have dysfunctional extension of the sbs will present with a long narrow head. the resultant internal rotation of the maxillae is associated with a palate that is narrow and high arched. this orofacial cranial pattern fails to provide suffi cient space for the teeth in the dental arches, predisposing the child to dental crowding. in young children, class ii malocclusion may be found in association with an intraosseous dysfunction between the premaxilla and the maxilla. the premaxilla can be pushed forward or backward as the result of stress patterns occurring during intrauterine life or at the time of delivery. postpartum behaviors, such as thumb sucking, can also push the premaxilla forward, while a fall forward striking the face, particularly the upper incisors, will push the premaxilla in a posterior direction. cranial maxillary dysfunction can be the beginning of a sequence of events that act to reinforce each other. maxillary dysfunction can reduce nasal patency and predispose to mouth breathing. it can affect the dental arch with potential consequences for occlusion. maxillary dysfunction can also trigger a compensatory pattern in the position and development of the mandible. the mandible itself may demonstrate several types of dysfunction. similar to maxillary dysfunction, mandibular dysfunction may result from strains or traumas. it can also occur as accommodation to internal or external rotation dysfunction of the temporal bones. temporal bone dysfunction may be unilateral or bilateral, with the mandible moving anteriorly on the side of temporal internal rotation or posteriorly on the side of temporal external rotation. the resultant mandibular displacement will, in turn, affect occlusion. in fact, any facial strain or trauma may impact the symmetry of the occlusal pattern. the area of the nasion -the junction between the frontonasal and internasal sutures -as well as the frontomaxillary sutures, may suffer compression from intrauterine pressures or as the result of a diffi cult delivery. the nasal bones should be attentively evaluated. with the maxillae, they are suspended from the frontal bone and as such will demonstrate restriction of movement following any trauma of the frontal bone. furthermore, an impact on the frontal bone may result in a decrease in the vertical height of the maxillae with potential intraosseous dysfunction and resultant compromise of nasal respiration. discrepancy in size between the maxilla and mandible may result from insuffi cient growth of these structures, potentially producing overjet or overbite. positioning of the child during the fi rst months of life infl uences the growth pattern of the cranial bones. non-synostotic plagiocephaly is associated with chronic sleep position and is most often visible in the fi rst months of life. it has also been shown that when a child sleeps in the same position for months, changes in the dental arches are observed. deformation of the face, however, because the growth of the viscerocranium continues later in life than the growth of the neurocranium, is not common rotational variations in children predictive model for congenital muscular torticollis: analysis of infants with sonography sternocleidomastoid pseudotumor and congenital muscular torticollis in infants: a prospective study of cases sternomastoid tumour and muscular torticollis breech deformation complex in neonates endocranial suture closure. its progress and age relationship. part i. adult males and white stock a study of the relationship between fetal position and certain congenital deformities relationship between side of plagiocephaly, dislocation of hip, scoliosis, bat ears and sternomastoid tumors congenital postural deformities the hip in the moulded baby syndrome congenital muscular torticollis in infancy; some observations regarding treatment pathologic changes in muscle as a result of disturbances of circulation congenital' muscular torticollis congenital muscular torticollis: sequela of intrauterine or perinatal compartment syndrome midbrain control of three-dimensional head orientation le torticolis 'congénital' est-il simplement un torticolis obstétrical? clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. a prospective study of eight hundred and twenty-one cases fracture of the clavicle in the newborn following normal labor and delivery reappraisal of neonatal clavicular fracture: relationship between infant size and neonatal morbidity newborn clavicle fractures clavicle fractures in the newborn management of birth injuries associated factors in cases of brachial plexus injury the effect of sequential use of vacuum and forceps for assisted vaginal delivery on neonatal and maternal outcomes brachial plexus injury: a -year experience from a tertiary center intrauterine shoulder weakness and obstetric brachial plexus palsy birth trauma in the head and neck mechanisms of cervical nerve root avulsion in injuries of the neck and shoulder obstetrical brachial plexus palsy. prediction of outcome in upper root injuries management of infant brachial plexus injuries supramolecular organization of extracellular matrix glycosaminoglycans, in vitro and in the tissues invited review: role of mechanophysiology in aging of ecm: effects of changes in mechanochemical transduction paralysie obstétricale du membre supérieur is abnormal labor associated with shoulder dystocia in nulliparous women? shoulder dystocia: prevention and management comparing mcroberts' and rubin's maneuvers for initial management of shoulder dystocia: an objective evaluation glenoid deformity secondary to brachial plexus birth palsy glenohumeral deformity secondary to brachial plexus birth palsy posterior shoulder dislocation in infants with neonatal brachial plexus palsy pulled elbow in childhood common rotational variations in children the natural history of hooked forefoot intoeing -fact, fi ction and opinion foot deformities at birth: a longitudinal prospective study over a year period guidelines for evaluation and management of fi ve common podopediatric conditions the newborn foot congenital club foot. an anatomical study the pathogenesis of club foot. a histomorphometric and immunohistochemical study of fetuses congenital idiopathic talipes equinovarus common lower extremity problems in children the ponseti technique for correction of congenital clubfoot flexible fl at feet in children: a real problem planovalgus foot deformity. current status the infl uence of footwear on the prevalence of fl at foot. a survey of children the infl uence of footwear on the prevalence of fl at foot. a survey of skeletally mature persons footprint analysis during the growth period acute and recurrent patellar instability in the young athlete sprain or fracture? an analysis of ankle injuries sprinting and intoeing torsional and angular deformities effect of limb malrotation on malalignment and osteoarthritis the effect of tibial torsion of the pathology of the knee increased external tibial torsion in osgood-schlatter disease femoral anteversion and arthritis of the knee femoral anteversion related to side differences in hip rotation. passive rotation in children aged - years congenital dislocation of the patella. part i: pathologic anatomy soft-tissue anatomy anterior to the human patella does osgood-schlatter disease infl uence the position of the patella? congenital dislocation of the hip -a misleading term: brief report the fetal acetabulum. a histomorphometric study of acetabular anteversion and femoral head coverage increasing prevalence of recurrent otitis media among children in the united states otitis media surfactant proteins a and d in eustachian tube epithelium american academy of pediatrics subcommittee on management of acute otitis media. diagnosis and management of acute otitis media susceptibility to otitis media: strong evidence that genetics plays a role the genetic component of middle ear disease in the fi rst years of life upper respiratory morbidity in preschool children: a cross-sectional study otitis media and eustachian tube dysfunction: connection to allergic rhinitis prognostic factors for persistent otitis media with effusion in infants epidemiology of otitis media onset by six months of age a pacifi er increases the risk of recurrent acute otitis media in children in day care centers pacifi er as a risk factor for acute otitis media: a randomized, controlled trial of parental counseling risk factors for chronic otitis media with effusion in infancy. each acute otitis media episode induces a high but transient risk accumulation of factors infl uencing children's middle ear disease: risk factor modelling on a large population cohort otitis media in pittsburgh-area infants: prevalence and risk factors during the fi rst two years of life exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media gray's anatomy, th edn selective hemispheric stimulation by unilateral forced nostril breathing neuropeptides and nasal secretion changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals chronic rhinosinusitis and neuropeptides neuronal plasticity in persistant perennial allergic rhinitis allergic rhinitis: defi nition, epidemiology, pathophysiology, detection, and diagnosis complications of allergic rhinitis the 'microfl ora hypothesis' of allergic diseases allergic rhinitis as a risk factor for habitual snoring in children economic impact and quality-of-life burden of allergic rhinitis allergic rhinitis and impairment issues in schoolchildren: a consensus report assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials infants are not obligatory nasal breathers consultation with the specialist: diagnosis and management of the newborn and young infant who have nasal obstruction endoscopy in the assessment of children with nasal obstruction posture of the head, the hyoid bone, and the tongue in children with and without enlarged tonsils infl uences of head positions and bite opening on collapsibility of the passive pharynx hyoid bone and atlas vertebra in established mouth breathers: a cephalometric study anatomical basis of sleep-related breathing abnormalities in children with nasal obstruction posterior maxillary (pm) plane and anterior cranial architecture in primates upper airway obstruction and craniofacial morphology oronasal obstruction, lung volumes, and arterial oxygenation decreased pulmonary vascular resistance during nasal breathing: modulation by endogenous nitric oxide from the paranasal sinuses site of upper airway obstruction in obstructive apnoea and infl uence of sleep stage soft palate and oronasal breathing in humans upper airway imaging anatomy of oral respiration: morphology of the oral cavity and pharynx developmental change in the upper respiratory system of human infants site and mechanics of spontaneous, sleep-associated obstructive apnea in infants polysomnographic studies in children undergoing adenoidectomy and/or tonsillectomy upper airway stability and apnea during nasal occlusion in newborn infants pharyngeal airway obstruction in obstructive sleep apnea: pathophysiology and clinical implications upper airway collapsibility in children with obstructive sleep apnea syndrome evidence for persistence of upper airway narrowing during sleep, years after adenotonsillectomy factors infl uencing regional patency and confi guration of the human infant upper airway tracheal and neck position infl uence upper airway airfl ow dynamics by altering airway length the nose and sleep-disordered breathing: what we know and what we do not know state-related changes in upper airway caliber and surrounding soft-tissue structures in normal subjects nasal obstruction in sleep-disordered breathing adenotonsillar hypertrophy and skeletal morphology of children with obstructive sleep apnea syndrome craniofacial modifi cations in children with habitual snoring and obstructive sleep apnoea: a case-control study enuresis in children with sleep apnea preventing respiratory syncitial virus bronchiolitis surveillance of communityacquired viral infections due to respiratory viruses in rhone-alpes (france) during winter to respiratory syncytial virus activity -united states molecular epidemiology of respiratory syncytial virus infections among children with acute respiratory symptoms in a community over three seasons rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. ige and eosinophil analyses respiratory syncytial virus infection in children hospitalised with acute lower respiratory tract infection the unifi ed immune system: respiratory tract-nasobronchial interaction mechanisms in allergic airway disease detection of rhinovirus, respiratory syncytial virus, and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction otitis media one hundred thousand cases of infl uenza with a death rate of one-fortieth of that reported under conventional medical treatment more about the use of omt during infl uenza epidemics genetics of allergic disease british thoracic society research committee. asthma prevalence in impact of il and il -receptor alpha polymorphisms on the genetics of bronchial asthma and severe rsv infections advances in adult and pediatric asthma onset and persistence of childhood asthma: predictors from infancy consider the child: how early should we treat? low socioeconomic status as a risk factor for asthma, rhinitis and sensitization at years in a birth cohort dietary supplementation with fi sh oil rich in omega- polyunsaturated fatty acids in children with bronchial asthma three-year outcomes of dietary fatty acid modifi cation and house dust mite reduction in the childhood asthma prevention study diet as a risk factor for atopy and asthma fish oil supplementation in pregnancy modifi es neonatal allergen-specifi c immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial infection, allergy and the hygiene hypothesis: historical perspective infections and autoimmunity -good or bad? infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood clinical patterns and natural history of asthma respiratory infections and asthma infl uence of early life exposures on incidence and remission of asthma throughout life rhinosinusitis and pediatric asthma systemic effects of local allergic disease muscarinic acetylcholine receptors and airway diseases the role of nerves in asthma the unifi ed immune system: respiratory tract-nasobronchial interaction mechanisms in allergic airway disease allergy development and the intestinal microfl ora during the fi rst year of life importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged - months mode of delivery and asthma -is there a connection? gastroesophageal refl ux: a potential asthma trigger regulation of human airway ciliary beat frequency by intracellular ph refl ex mechanisms in gastroesophageal refl ux disease and asthma the sympathetic nerve -an integrative interface between two supersystems: the brain and the immune system the central autonomic nervous system: conscious visceral perception and autonomic pattern generation stress and atopic disorders socioeconomic status, stress, and immune markers in adolescents with asthma streptococcal infections in families. factors altering individual susceptibility asthma, genes, and air pollution changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals quantifi able effects of osteopathic manipulative techniques on patients with chronic asthma effects of osteopathic manipulative treatment on pediatric patients with asthma: a randomized controlled trial training of aerobic and anaerobic fi tness in children with asthma physical activity and exercise in asthma: relevance to etiology and treatment epiphora during the fi rst year of life outcome of probing for congenital nasolacrimal duct obstruction in older children a simple model for practicing surgery on the nasolacrimal drainage system development of tearing in preterm and term neonates gray's anatomy, th edn growth of the fetal lens and orbit the growth of human face bony orbital development after early enucleation in humans anatomy of the orbital apex and cavernous sinus on high-resolution magnetic resonance images the origins and insertions of the extraocular muscles: development, histologic features, and clinical signifi cance the development of eye alignment, convergence, and sensory binocularity in young infants effect of developmental status on the approach to physical examination la fonction de la capsule de tenon revisitée evidence for active control of rectus extraocular muscle pulleys pivotal role of orbital connective tissues in binocular alignment and strabismus: the friedenwald lecture incomitant strabismus associated with instability of rectus pulleys the functions of the proprioceptors of the eye muscles does extraocular muscle proprioception infl uence oculomotor control? entrapment neuropathy of the central nervous system. ii factors associated with childhood strabismus: fi ndings from a population-based study the rapid change of corneal curvature in the neonatal period and infancy anatomy, development, and physiology of the visual system development of visual sensitivity to light and color vision in human infants: a critical review the relation between birth size and the results of refractive error and biometry measurements in children relationship of age, sex, and ethnicity with myopia progression and axial elongation in the correction of myopia evaluation trial collaborative longitudinal evaluation of ethnicity and refractive error study group. refractive error and ethnicity in children a synopsis of the prevalence rates and environmental risk factors for myopia iq and the association with myopia in children prevalence and risk factors for refractive errors in adult chinese in singapore nearwork in earlyonset myopia baseline refractive and ocular component measures of children enrolled in the correction of myopia evaluation trial (comet) eye shape in emmetropia and myopia corneal topography of neonates and infants gray's anatomy, th edn acquisition et exercice de la fonction masticatrice chez l'enfant et l'adolescent. première partie the development of normal feeding and swallowing posture of the head, the hyoid bone, and the tongue in children with and without enlarged tonsils upper airway obstruction and craniofacial morphology anatomical basis of sleep-related breathing abnormalities in children with nasal obstruction ankyloglossia: does it matter? la langue, appareil naturel d'orthopédie dentofaciale 'pour le meilleur et pour le pire the serial organization of sucking in the young infant antenatal olfactory learning infl uences infant feeding ultrasound demonstration of tongue motions during suckle feeding ultrasonographic analysis of sucking behavior of newborn infants: the driving force of sucking pressure neonatal sucking behaviour and its development until months relationship between respiratory control and feeding in the developing infant reduction of masseter muscle activity in bottle-fed babies infl uence of breast feeding on facial development approche fonctionnelle de l'allaitement et malocclusions morphogenèse temporo-mandibulaire structure fonctionnelle du condyle mandibulaire humain en croissance does breast-feeding protect against malocclusion? an analysis of the child health supplement to the national health interview survey breast feeding, bottle feeding, and non-nutritive sucking; effects on occlusion in deciduous dentition exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media promotion of breastfeeding intervention trial (probit): a randomized trial in the republic of belarus the 'microfl ora hypothesis' of allergic diseases breastfeeding reduces pain in neonates feeding behaviors and other motor development in healthy children ( - months) developmental change in a basicranial line and its relationship to the upper respiratory system in living primates postnatal descent of the epiglottis in man. a preliminary report oral habits -studies in form, function, and therapy middle ear effusion: an orthodontic perspective a pacifi er increases the risk of recurrent acute otitis media in children in day care centers palpatory diagnosis of plagiocephaly prevalence of symptoms of gastroesophageal refl ux during infancy. a pediatric practice-based survey. pediatric practice research group natural history and familial relationships of infant spilling to years of age ethnicity and gender related differences in extended intraesophageal ph monitoring parameters in infants: a retrospective study gastroesophageal refl ux disease: review of presenting symptoms, evaluation, management, and outcome in infants embryonic origins of the relation of gastroesophageal refl ux disease and airway disease transient lower esophageal sphincter relaxation overview of the mechanisms of gastroesophageal refl ux gastric emptying: a contributory factor in gastro-oesophageal refl ux activity? the natural course of infantile refl ux regurgitation: a non-western perspective gastroesophageal refl ux in childhood an overview of refl ux-associated disorders in infants: apnea, laryngospasm, and aspiration gastroesophageal refl ux disease and asthma: a longitudinal study in uk general practice consultation with the specialist: diagnosis and management of the newborn and young infant who have nasal obstruction humans are born too soon: impact on pediatric otolaryngology dental erosion in children: a literature review osteopathic family practice: an application of the primary care model eléments cliniques du diagnostic de coliques du nourrisson. enquête chez nourrissons âgés de à jours systematic review of the occurrence of infantile colic in the community paediatric study group on gastrointestinal symptoms in infancy. gastrointestinal symptoms in infancy: a population-based prospective study the ontogeny of the small intestinal epithelium crying in infancy paroxysmal fussing in infancy, sometimes called colic excessive infant crying: the impact of varying defi nitions what is distinct about infants' 'colic' cries? intestinal microfl ora in early infancy: composition and development the intestine and its microfl ora are partners for the protection of the host: report on the danone symposium "the intelligent intestine importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged - months factors infl uencing the composition of the intestinal microbiota in early infancy infant colic: empirical evidence of the absence of an association with source of early infant nutrition intestinal microfl ora in breastfed colicky and non-colicky infants effectiveness of treatments for infantile colic: systematic review infantile colic and small intestinal function: a nutritional problem? relation between infantile colic and asthma/atopy: a prospective study in an unselected population extent of fussing and colic type crying preceding atopic disease improvement of symptoms in infant colic following reduction of lactose load with lactase cow's milk as a cause of infantile colic in breast-fed infants maternal intake of cruciferous vegetables and other foods and colic symptoms in exclusively breast-fed infants neurohumoral control of gastrointestinal motility principles of applied neurogastroenterology: physiology/motility-sensation changing our understanding of infant colic individual differences in responsivity to a neurobehavioural examination predict crying patterns of -week-old infants at home role of the brain and sensory pathways in gastrointestinal sensory disorders in humans a preliminary assessment of the impact of cranial osteopathy for the relief of infantile colic understanding and controlling the enteric nervous system central nervous system involvement in functional gastrointestinal disorders mothers' reports of infant crying and soothing in a multicultural population crying, feeding and sleeping patterns in to -month-old infants emotion regulation and touch in infants: the role of cholecystokinin and opioids the role of corticotropin-releasing factor-norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress attachment and the regulation of the right brain infantile colic: maternal smoking as potential risk factor colic and crying syndromes in infants persistent infant crying and hyperactivity problems in middle childhood clinical conditions the clinical signifi cance of disaccharide maldigestion the primary respiratory mechanism childhood functional gastrointestinal disorders times of fi rst void and fi rst stool in newborns gastrointestinal motility in neonatal and pediatric practice painful defecation and fecal soiling in children constipation and toileting issues in children colonic transit times and behaviour profi les in children with defecation disorders during toilet training, constipation occurs before stool toileting refusal intolerance of cow's milk and chronic constipation in children review article. chronic constipation and food hypersensitivity -an intriguing relationship functional constipation in children gray's anatomy, th edn pediatric skull base surgery. . embryology and developmental anatomy incisive suture (fi ssure) in the human fetus: radiographic and histologic study prémaxillaire et croissance faciale ans après the anatomy of buccinator -insights from functional casts of the oral vestibule reduction of masseter muscle activity in bottle-fed babies approche fonctionnelle de l'allaitement et malocclusions acquisition et exercice de la fonction masticatrice chez l'enfant et l'adolescent the pediatric mandible: i. a primer on growth and development a propos de l'articulation temporo-mandibulaire du nouveau-né. les relations oto-méniscales remodeling reversals in anterior parts of the human mandible and maxilla skeletal and functional craniofacial adaptations in plagiocephaly post-natal growth of the human skull base facial heights: evolutionary relevance of postnatal ontogeny for facial orientation and skull morphology in humans and chimpanzees prenatal development of the human mandible developmental change in the upper respiratory system of human infants développement de l'oropharynx: évolution de la paroi ventrale du pharynx developmental change in a basicranial line and its relationship to the upper respiratory system in living primates orodigitofacial syndromes type i and ii: clinical and surgical studies ankyloglossia: assessment, incidence, and effect of frenuloplasty on the breastfeeding dyad the effect of ankyloglossia on speech in children tongue-tie ankyloglossia: does it matter? tongue tie division in infants with breast feeding diffi culties ankyloglossia: the adolescent and adult perspective la langue, appareil naturel d'orthopédie dentofaciale 'pour le meilleur et pour le pire feeding behaviors and other motor development in healthy children ( - months) posture of the head, the hyoid bone, and the tongue in children with and without enlarged tonsils upper airway obstruction and craniofacial morphology anatomical basis of sleep-related breathing abnormalities in children with nasal obstruction the part played by the tongue in mastication and deglutition tongue movements in feeding and speech infant mouthing behavior: the immunocalibration hypothesis deciduous dentition and the establishment of functional occlusal patterns the effect of occlusal alteration and masticatory imbalance on the cervical spine classifi cation of malocclusion morphologic determinants in the etiology of class iii malocclusions: a review angle's system, th edn. philadelphia: s.s. white dental manufacturing company skeletal maturation and cephalofacial development muscular forces exerted on the normal deciduous dentition tongue thrust classifi cation oral habits -studies in form, function, and therapy cephalometric characteristics of class ii division and class ii division malocclusions: a comparative study in children effects of oral habits' duration on dental characteristics in the primary dentition breast feeding, bottle feeding, and non-nutritive sucking; effects on occlusion in deciduous dentition relação entre hábitos bucais e má oclusão em pré-escolares duration of nutritive and nonnutritive sucking behaviors and their effects on the dental arches in the primary dentition sucking, chewing, and feeding habits and the development of crossbite: a longitudinal study of girls from birth to years of age a cephalometric evaluation of patients presenting with persistent digit sucking habits bottle-feeding and malocclusion: is there an association? does breast-feeding protect against malocclusion? an analysis of the child health supplement to the national health interview survey early weaning: implications to oral motor development effects of food processing on masticatory strain and craniofacial growth in a retrognathic face tooth wear in the mixed dentition: a comparative study between children born in the s and the s effects of upper lip closing force on craniofacial structures the nose and sleep-disordered breathing: what we know and what we do not know middle ear effusion: an orthodontic perspective observations on a recent increase in plagiocephaly without synostosis skull morphology affected by different sleep positions in infancy cranio-facial surgery: international society for craniomaxillofacial surgery importance of early recognition and treatment of deformational plagiocephaly with orthotic cranioplasty diagnosis and management of positional head deformity artifi cial deformation and cranio-facial asymmetry in ancient peruvians head posture and craniofacial morphology growth changes in head posture related to craniofacial development the application of cephalometrics to cinefl uorography: comparative analysis of hyoid movement patterns during deglutition in class i and class ii orthodontic patients commonly observable by the non-trained examiner before several years of age. facial asymmetries are, however, frequently associated with plagiocephalies. [ ] [ ] [ ] with asymmetric occipital deformation, compensatory changes may occur in the maxillae, with resultant mandibular asymmetry. the relationship between the neurocranium, cranial base and viscerocranium has been studied extensively. an increase in anterior facial height is observed in subjects maintaining a forward-bent head position; a decrease is associated with a backward-bent head posture. , changes in the position of the hyoid bone are observed in class ii malocclusion where the hyoid bone is higher and more forward relative to the mandible. the posture of the cervical spine changes in response to changes in the occlusal plane as well as to imbalance between right and left masticatory muscles. modifi cations of the cranial base are linked to class iii malocclusion where a decrease in the angle between the clivus (surface from the dorsum sellae of the body of the sphenoid to the foramen magnum) and the cribriform plate of the ethmoid has been observed. the child's occlusal pattern should be assessed. if abnormal occlusion or malocclusion is identifi ed, the somatic dysfunction that may be responsible should be sought out and treated. the etiology of malocclusion is multifactorial and osteopathic procedures may be employed when cranial somatic dysfunction contributing to the establishment of the malocclusive pattern is present. to be effective, these procedures should be employed at the earliest possible age. cranial manipulation is in no way intended to be a replacement for standard orthodontic treatment. however, orthodontic treatments are less likely to be fully successful if somatic dysfunction affecting the child's occlusal pattern persists.when examining the child with malocclusion, the principles of examination discussed above in 'oral cavity and orofacial functions' apply. in addition, when looking for contributory somatic dysfunction, the practitioner should pay attention to the standing postural mechanics and their impact, particularly on the upper thoracic and occipitoatlantal areas. even in cases where orthodontic treatment has been initiated, the child's posture should be addressed. the identifi cation and treatment of dysfunctional postural mechanics resulting in functional balance of the orofacial complex will accelerate the effect of the orthodontic treatment. furthermore, orthodontic treatment in itself serves as a source of stress, affecting the overall mechanics of the body. thus, the release of existing dysfunctional mechanics will provide comfort to the child, making the orthodontic process more tolerable, as well as facilitating the effect of the orthodontic procedure.with the child seated, it is appropriate to observe the occlusal pattern. have the child actively open their mouth while observing for displacement of the symphysis menti. this motion normally should follow a straight vertical path, without a distorted pattern. next, have the child move their mandible laterally to the right and left sides to compare ease of movement and degree of displacement bilaterally. if appropriate, give the child some chewing gum to observe the presence or absence of an alternating masticatory pattern. observe and note the presence of a dominant side to the masticatory pattern. check the presence of immature swallowing by observing and asking the child to describe the location of the tip of their tongue within their mouth during swallowing. assess the musculature of the lips and cheeks by placing your thumbs inside the child's mouth, such that their palmar surfaces are in contact with the inside of the cheeks. ask the child to close their mouth and swallow, and with your thumbs appreciate the strength of contraction of the buccinator muscles. next, with the child lying supine, palpate the clavicles, sternum and hyoid bone, assessing their myofascial attachments. go on to assess the myofascial structures of the upper thoracic and cervical spine for somatic dysfunction, noting the relationship between the occiput and atlas. palpate the myofascial structures of the skull, paying attention to the orofacial muscles and tmj area for dysfunctional asymmetric tension. check the tmjs and proceed with tests of listening. evaluate the cranial base, looking for patterns of predominant cranial fl exion or extension, as well as torsion, sidebending-rotation, compression and strain patterns. by placing one hand on the frontal bone with the index and middle fi ngers controlling the greater wings of the sphenoid and the other hand cradling the mandible, note the balance between the mandible and greater wings of the sphenoid. listen to the different bones of the skull that may be involved in the malocclusion, paying particular attention to the temporal bones, sphenoid, frontal bones and maxillae, looking for intra-and interosseous cranial somatic dysfunctions. treat all identifi ed somatic dysfunction using indirect principles. intraosseous molding may be considered if the child is young enough.all of these relationships are often reciprocal and illustrate the integration of all parts of the body, local and distant, into a united system. osteopathic treatment may be employed to address the somatic dysfunction that is found in association with orofacial dysfunction. when indirect principles of treatment are respectfully employed, these procedures may be used to treat from the very youngest patient on through adolescence. the earlier the dysfunction is recognized, the younger the patient and the more plastic the tissues, the greater the possibility to affect the structure and to re-establish satisfactory functional patterns, thereby activating the body's inherent ability to heal itself. involve the parents or caregivers; empower them to help the child to succeed in dealing with the dysfunction. take the time to explain to the child why it is necessary to breathe through the nose and eat slowly. encourage the child to promote correct function, such as nasal breathing and learning how to blow their nose. encourage the child to practice activities that promote breathing, such as singing with good articulation of the words.young children with dysfunctional tongue mechanics or with minor cases of ankyloglossia can perform exercises to mobilize the tongue and to stretch the frenulum as much as possible. encourage the parents or caregivers to correct the child when there is mispronunciation. it may appear to be cute, but is actually dysfunctional. the child should repeat incorrectly pronounced words as correctly as possible to improve tongue mobility. infants can be encouraged to play sound-making games by repeating sounds that cause the tongue to make a clicking noise against the palate.teach effi cient swallowing without tongue thrusting by instructing the child to consciously keep their tongue in their mouth and to learn to swallow with the tip of their tongue resting against the palate behind their upper incisors. to practice this, the child can hold a small piece of food between the tongue and palate while attempting to swallow several times. this exercise should be repeated until the act of swallowing with the tip of the tongue resting against the palate becomes automatic.insist on alternate unilateral mastication and that the child takes suffi cient time to chew their food thoroughly. those children who are old enough should be encouraged to eat food that is as unrefi ned as possible. soft refi ned junk food often does not require suffi cient chewing.caution the parent or caregiver to watch for functional asymmetries that are associated with repetitive asymmetrical activities, such as unilateral bottle feeding or thumb sucking. instruct the parent or caregiver and the patient, when old enough to understand, to avoid these activities or perform them in a fashion that alternates sides. key: cord- -bv udg k authors: lawrence, robert m. title: chapter transmission of infectious diseases through breast milk and breastfeeding date: - - journal: breastfeeding doi: . /b - - - - . - sha: doc_id: cord_uid: bv udg k nan a large body of evidence clearly demonstrates the protective effects of breastfeeding and documents the transmission of specific infections to infants through breast milk. the fear and anxiety that arise with the occurrence of any infectious disease are even greater in the situation of the breastfeeding mother-infant dyad. uncertainty and lack of knowledge often lead to proscribing against breastfeeding out of fear, which then deprives the infant of the potential protective, nutritional, and emotional benefits of breastfeeding exactly at the time when they are most needed (see the discussion of immunologic benefits of human milk in chapter ). decisions concerning breastfeeding in a mother with an infectious illness should balance the potential benefits of breastfeeding versus the known or estimated risk for the infant acquiring a clinically significant infection via breastfeeding and the potential severity of the infection. documenting transmission of infection from mother to infant by breastfeeding requires not only the exclusion of other possible mechanisms of transmission but also the demonstration of the infectious agent in the breast milk and a subsequent clinically significant infection in an infant that was caused by a plausible infectious process. the first step is to establish the occurrence of a specific infection (clinically or immunologically evident) in a mother and demonstrate the persistence of the infectious agent such that it could be transmitted to the infant. isolation or identification of the infectious agent from the colostrum, breast milk, or an infectious lesion of the breast is important but not necessarily proof of transmission to an infant. epidemiologic evidence of transmission must be considered, including identifying characteristics of the organism that relate an isolate from an infant to the maternal isolate. infectious organisms can reach the breast milk either by secretion in the fluid or cellular components of breast milk or by contamination of the milk at the time of or after expression. a reasonable mechanism of infection via breast milk should be evident and proved through either animal or human studies. demonstration of a subclinical or clinically evident infection in an infant should follow these outlined steps. exclusion of other possible mechanisms of transmission (exposure to mother or other persons/ animals via airborne, droplet, arthropod, or vector modes of transmission or through direct contact with other infectious fluids) would complete the confirmation of transmission of infection via breastfeeding. it is essential to exclude prenatal or perinatal transmission of infection to a fetus/infant, but doing this can often be difficult. clinical case reports or studies confirming the isolation of an infectious agent from the milk are important. to determine a reasonable estimate of the risk for infection via breast milk, larger epidemiologic studies are needed that compare infection rates in breastfed infants versus formula-fed infants, robert m. lawrence addressing the issues just identified. timing of breastfeeding is important relative to the timing of maternal infection and to the presence of a pathogen in colostrum or breast milk. the duration of breastfeeding is another important variable to consider in the estimate of risk because shedding of a pathogen in breast milk may be intermittent. these considerations are only some of the variables to be taken into account, in general, to assess the risk for transmission of an infectious agent from mother to infant via breast milk or breastfeeding. efforts to prove transmission of infection in a particular maternal-infant dyad can be just as difficult and must consider many of the same factors. this chapter focuses on a discussion of specific, clinically relevant, infectious agents and diseases, with reasonable estimates of the risk for infection to infants from breastfeeding. the basic tenet concerning breastfeeding and infection is that breastfeeding is rarely contraindicated in maternal infection. the few exceptions relate to specific infectious agents with strong evidence of transmission and to the association of an infant' s illness with significant morbidity and mortality. the risk or benefit of breastfeeding relative to immunization of a mother or infant is discussed for certain microorganisms. appendix d addresses drugs in breast milk and includes table d- , on antiinfective agents, and chapter reviews how breastfeeding may protect against infection. chapter addresses specific concerns relating to banked breast milk and includes standards developed by the human milk banking association of north america to guide the appropriate handling of banked human milk relative to possible infectious agents. isolation precautions have undergone some revisions in terminology and conceptualization. understanding that the transmission of microorganisms can occur with a known infection and with unrecognized sources of infection, recommendations have been made for standard precautions to be applied to all patients to protect health care workers from potentially infectious body fluids. additionally, precautions based on the predominant modes of transmission have been recommended to protect against infection through the airborne route, direct contact, or contact with droplets. although these precautions are intended to be used in clinical situations to protect health care workers, they may be applied in certain situations to the mother-infant dyad to prevent transmission of infectious agents from one to the other or to other hospitalized mothers and infants. these precautions are useful most often when a mother and infant are still hospitalized. the use of such precautions within the home is not meant to limit breastfeeding. they are intended to allow breastfeeding in the majority of cases and to facilitate the continuation of breastfeeding with some additional safeguards in certain situations, after short temporary periods of stopping breastfeeding, and when to safely use expressed breast milk (see appendix f). standard precautions include preventing contact with blood, all body fluids, secretions and excretions, nonintact skin, and mucous membranes by ( ) careful handwashing before and after every patient contact; ( ) use of gloves when touching body fluids, nonintact skin, or mucous membranes or any items contaminated with body fluids (linens, equipment, devices, etc.); ( ) use of nonsterile gowns to prevent contact of clothing with body fluids; ( ) use of masks, eye protection, or face shields when splashing with body fluids is possible; and ( ) appropriate disposal of these materials. standard precautions should be applied to all patients regardless of actual or perceived risks. the centers for disease control and prevention (cdc) does not consider breast milk a body fluid with infectious risks and thus these policies do not apply to breast milk. (see section on misadministration of breast milk later in this chapter as a possible exception to this concept.) in considering breastfeeding infant-mother dyads and standard precautions, body fluids other than breast milk should be avoided, and only in specified situations should breast milk also be avoided. in general, clothing or a gown for the mother and bandages, if necessary, should prevent direct contact with nonintact skin or secretions. avoiding infant contact with maternal mucous membranes requires mothers to be aware of and understand the risks and to make a conscious effort to avoid this type of contact. the use of gloves, gowns, and masks on infants for protection is neither practical nor appropriate. the recommendations concerning the appropriateness of breastfeeding and breast milk are addressed for specific infectious agents throughout this chapter. human immunodeficiency virus (hiv) infection is an example of one infection that can be prevented by the use of standard precautions, including avoiding breast milk and breastfeeding. the recommendations concerning breastfeeding and hiv and the various variables and considerations involved are discussed later. airborne precautions are intended to prevent transmission via droplet nuclei (dried respiratory particles smaller than mcm that contain microorganisms and can remain suspended in the air for long periods) or dust particles containing microorganisms. airborne precautions include the use of a private room with negative-air-pressure ventilation and masks at all times. in the case of pulmonary tuberculosis (tb), respiratory protective devices (requiring personal fitting and seal testing before use) should be worn. airborne precautions are recommended with measles, varicella or disseminated zoster, and tb. breastfeeding in the presence of these maternal infections is prohibited for the infectious period. this is to protect against airborne transmission of the infection from the mother and to allow the infant to be fed the mother' s expressed breast milk by another individual. the exception to allowing breast milk would be local involvement of the breast by varicella-zoster lesions or mycobacterium tuberculosis, such that the milk becomes contaminated by the infectious agent. transmission via droplets occurs when an individual produces droplets that travel only a short distance in the air and then contact a new host's eyes, nose, mouth, or skin. the common mechanisms for producing droplets include coughing, sneezing, talking (singing or yelling), suctioning, intubation, nasogastric tube placement, and bronchoscopy. in addition to standard precautions applied to all patients, droplet precautions include the use of a private room (preferred) and a mask if within feet ( . m) of the patient. droplet precautions are recommended for adenovirus, diphtheria, respiratory infections, haemophilus influenzae, neisseria meningitidis or invasive infection, influenza, mumps, mycoplasma, parvovirus, pertussis, plague (pneumonic), rubella, and streptococcal pharyngitis, pneumonia, or scarlet fever. the institution of droplet precautions with a breastfeeding mother who has these infections should be specified for each particular infection. this may require some period of separation for the infant and mother (for duration of the illness, for short-term or complete treatment of the mother, for the infectious period) with use of expressed breast milk for nutrition in the interim. prophylactic treatment of the infant, maternal use of a mask during breastfeeding or close contact combined with meticulous handwashing, and the mother's avoidance of touching her mucous membranes may be adequate and reasonable for certain infections. contact precautions are meant to prevent transmission of infection via direct contact (contact between the body surfaces of one individual with another) and indirect contact (contact of a susceptible host with an object contaminated with microorganisms from another individual). contact precautions include cohorting or a private room, gloves and gowns at all times, and handwashing after removal of gown and gloves. contact precautions are recommended for a long list of infections, such as diarrhea in diapered or incontinent patients with clostridium difficile infection, escherichia coli o :h , shigella, rotavirus, hepatitis a, respiratory illness with parainfluenza virus or respiratory syncytial virus (rsv), multidrug-resistant (mdr) bacteria (e.g., enterococci, staphylococci, gramnegative organisms), enteroviral infections, cutaneous diphtheria, impetigo, herpes simplex virus (hsv) infection, herpes zoster (disseminated or in immunocompromised individuals), pediculosis, scabies, staphylococcus aureus skin infection, viral hemorrhagic fevers (e.g., ebola, lassa), conjunctivitis and abscesses, cellulitis, or decubitus that cannot be contained by dressings. for a breastfeeding infant-mother dyad, implementation of precautions for each of these infections in a mother requires meticulous attention to gowning and handwashing by the mother and a specialized plan for each situation. each of these transmission-based precautions can be used together for organisms or illnesses that can be transmitted by more than one route. they should always be used in conjunction with standard precautions, which are recommended for all patients. the red book: report of the committee on infectious diseases by the american academy of pediatrics (aap) remains an excellent resource for infection control guidelines and recommendations to prevent transmission in specific situations and infections. routine culturing of breast milk or culturing breast milk to screen for infectious agents is not recommended except when the milk is intended as donor milk to another mother' s child directly or through human milk banks. see chapter for specific bacterial count standards for raw donor milk and for pasteurization of donor milk. breastfeeding and the expression of or pumping of breast milk (referred to as expressed breast milk) for later use are not sterile activities. in general expressed breast milk should not contain large numbers of microorganisms (less than for raw milk and less than for milk to be pasteurized), nor should it contain potential pathogens such as s. aureus, β-hemolytic streptococci, pseudomonas species, proteus species, or streptococcus faecalis or faecium. few studies have examined "routine" culturing of milk and the significance of specific bacterial colony counts relative to illness in infants. the studies have been primarily concerned with premature or low-birth-weight (lbw) infants who remain hospitalized and are commonly fed via enteral tubes. a study from canada tested samples of milk for use in preterm infants. the study did not identify any adverse events in the infants attributed to organisms growing in the milk samples, and routine bacteriological testing of expressed breast milk was not recommended. a study from chicago examined gram-negative bacilli in the milk used in premature infants. samples were tested before feeding and from the nasogastric tubes during feeding. milk samples from before feeding were less likely to contain gram-negative bacilli ( %) than milk samples from the nasogastric tubing ( %). feeding intolerance was observed when there were more than colony-forming units per milliliter (cfu/ml), and episodes of sepsis were identified when the bacterial counts in the milk were greater than or equal to cfu/ml. this study recommended the routine bacteriologic testing of expressed breast milk. another study from arkansas focused on contamination of feeding tubes during administration of expressed breast milk or formula. ten infants in the neonatal intensive care unit (nicu) were exposed to greater than gram-negative bacteria in their feeding tubes. the three infants who were fed expressed breast milk with contamination at greater than organisms remained well, but the seven formula-fed infants with high levels of bacterial contamination in the feeding tubes developed necrotizing enterocolitis. the gram-negative bacteria with high level contamination in the feeding tubes were either enterobacter or klebsiella in all cases. many nicus consider to cfu/ml as the significant bacterial count for gram-negative bacilli in breast milk that places premature and lbw infants at greater risk for infection. even less data are available concerning specific bacterial colony counts for gram-positive organisms and the risk to the infant. generally less than gram-positive organisms per ml of milk is considered acceptable, with only case reports and no controlled trials to support this cutoff. when the presence of an infectious illness in an infant and/or the breastfeeding mother' s breast when breast milk is seriously considered as a possible mechanism of transmission to the infant, culturing breast milk to identify the organism may be warranted and useful. more important than hurrying to culture breast milk is the careful instruction of mothers on the proper technique for collecting expressed breast milk, storing it, and cleaning the collection unit. the reinforcement of proper technique from time to time, especially when a question of contamination arises, is equally important. many small reports comment on the contamination of breast milk with different collection methods. relative comparisons suggest decreasing contamination of expressed breast milk when collected by the following methods; drip milk, hand pumped milk, manual expression, modern electric pumped milk. one group from malaysia published results showing no difference in contamination between milk collected by electric pump versus manual expression when collected in the hospital. expressed breast milk collected at home by breast pump had higher rates of contamination with staphylococci and gram-negative bacteria. discussion continues about the need to discard the first few milliliters of milk to lower bacteria numbers in expressed breast milk without any evidence to suggest if this is truly necessary. , no evidence shows that cleansing the breast with anything other than tap water decreases the bacterial counts in cultured expressed breast milk. if an infant is directly breastfeeding, collecting milk for culture by manual expression and trying to obtain a "midstream" sample (as is done with "midstream" urine collection for culture) is appropriate. if an infant is being fed expressed breast milk, collecting and culturing the milk at different points during collection (utilizing the same technique the mother uses [manual expression, hand pump, or electric pump]) and administration is appropriate. this might include a sample from immediately after collection, another of stored expressed breast milk, and a sample of milk from the most recent infant feeding at the time the decision to culture is made. please see box - for the basic steps in culturing expressed breast milk. interpretation of such culture results can be difficult and should involve a pediatric infectious disease expert, a microbiologist, and hospital epidemiologist. additional organism identification is often required, utilizing antibiogram patterns or molecular fingerprinting by various techniques to correlate a bacterial isolate from breast milk with an isolate causing disease in infant or mother. misadministration of breast milk, also known as misappropriation, breast milk exposure, and accidental ingestion of breast milk, and other terms, is a medical-legal issue when it occurs in a hospital. this scenario occurs when one infant receives breast milk from another mother by mistake. this occurrence can be very distressing to the families (recipient patient, recipient parent, and donor mother) and medical staff involved. the actual risk for transmission of an infectious agent to an infant via a single ingestion of expressed breast milk (the most common occurrence) from another mother is exceedingly low. in this scenario, the cdc recommends treating this as an accidental exposure to a body fluid, which could be infectious. bacterial, fungal, or parasitic infection from the one exposure is highly unlikely. the concern is about viral pathogens, known to be blood-borne pathogens, which have been identified in breast milk and include but are not limited to hepatitis b virus (hbv), hepatitis c virus (hcv), cytomegalovirus (cmv), west nile virus, human t-cell lymphotropic virus (htlv), and hiv. most hospitals have protocols for managing the situation from both the infection control/prevention and the medical-legal perspectives. these protocols advise informing both families about what occurred, discussing the theoretical risks of harm from the exposure, and reviewing test results and/ or recommending testing to determine the infectious status of each mother relative to the above mentioned viruses. hcv is not a contraindication to breastfeeding and west nile virus infection in lactating women is rare. , neither infection has a documented effective form of prevention or acute treatment. testing either mother (donor or of recipient infant) for these agents is not warranted. prenatal testing for hiv is more commonplace throughout the world. the incidence of hiv among women of childbearing age is low, although it varies significantly by geographic location, and the hospital or locale-specific incidence would be important to know to estimate risk. most women and medical staff are aware that hiv can be transmitted by breastfeeding; therefore breast milk from hiv-positive women is rarely if ever stored in hospitals. the risk for transmission of hiv via breastfeeding is due to the volume of feedings over months (estimated at to feedings in the first months of life) compared with the small "dose of exposure" from one or two "accidental feedings." transmission of hiv from a single breast milk exposure has never been documented. immunologic components in breast milk, along with time and cold of storage, inactivate the hiv in expressed breast milk. for these reasons, the risk for transmission of hiv via expressed breast milk consumed by another child is thought to be extremely low. htlv-i/ii infection in childbearing women is uncommon except in certain geographic regions (japan, africa, the caribbean, and south america). transmission of htlv via breast milk does occur and, like hiv, appears to be related to the volume and duration of breastfeeding. limiting the duration of breastfeeding is effective in decreasing transmission. , , freezing and thawing expressed breast milk decreases the infectivity of htlv-i. in areas of low prevalence, a positive test in a mother should be suspected to be a false positive test, and retesting with both antibody and polymerase chain reaction (pcr) testing should be performed. for these reasons the transmission of htlv-i/ii via accidental expressed breast milk exposure is thought to be extremely low. although the majority of women are cmv positive by childbearing age and cmv transmission occurs via breastfeeding, the risk for cmv in a full-term infant is low. premature or lbw infants are at greater risk for developing disease with cmv infection. freezing expressed breast milk (at − ° c) for to days significantly decreases the infectivity of cmv. here again the risk for cmv transmission from a single accidental exposure to cmv-positive expressed breast milk is extremely low. with a discussion of theoretical risk should be a discussion of possible preventive interventions, such as vaccination or antimicrobial postexposure prophylaxis. if donor mothers are positive for hbv, it is appropriate to give recipient infants hepatitis b virus immunoglobulin (hbig) and hbv vaccines if they have not already received them. if a box - . culturing breast milk . wash hands as per routine. . wash breast with warm tap water and a clean washcloth. . manually express breast milk ("midstream" collection is not required) or attach breast pump flange (previously cleaned as per routine) for collection and collect milk. . place a to ml sample of expressed breast milk in a sterile container with a nonleakable top. . deliver to the labatory in less than hour or refrigerate at ° c until delivery. before sending samples to the viral lab or for nucleic acid/ po lymerase chain reaction (pcr) testing, confirm that the laboratory will accept and process the sample as requested and that the appropriate collection container and prelaboratory management of the specimen are utilized. it may also be appropriate to consult a pediatric infectious disease specialist. additional important components of the hospital-based protocols for managing accidental expressed breast milk exposure include ongoing psychosocial support for the families and staff, documentation of medical discussions with the families, investigative steps, consents and interventions, and the demonstration of ongoing infection control efforts to prevent additional events of misadministration of breast milk. microorganisms produce a whole spectrum of clinical illnesses affecting mothers and infants. many situations carry the risk for transmission of the involved organism from a mother to the infant, or vice versa; in general, however, infants are at greater risk because of such factors as inoculum size and immature immune response. as always, an infection must be accurately diagnosed in a timely manner. empiric therapy and initial infection control precautions should begin promptly based on the clinical symptoms and the most likely etiologic agents. when dealing with a maternal infection, clarifying the possible modes of transmission and estimating the relative risk for transmission to the infant are essential first steps to decision-making about isolating a mother from her infant and the appropriateness of continuing breastfeeding or providing expressed breast milk. breastfeeding infrequently is contraindicated in specific maternal infections. often the question of isolation and interruption of breastfeeding arises when symptoms of fever, pain, inflammation, or other manifestations of illness first develop in a mother and the diagnosis is still in doubt. a clinical judgment must be made based on the site of infection, probable organisms involved, possible or actual mechanisms of transmission of these organisms to the infant, estimated virulence of the organism, and likely susceptibility of the infant. additionally, by the time the illness is clearly recognized or diagnosed in a mother, the infant has already been exposed. given the dynamic nature of the immunologic benefits of breast milk, continuation of breastfeeding at the time of diagnosis or illness in a mother can provide the infant protection rather than continued exposure in most illnesses. stopping breastfeeding is rarely necessary. many situations associated with maternal fever do not require separation of mother and infant, such as engorgement of the breasts, atelectasis, localized nonsuppurative phlebitis, or urinary tract infections. appendix f lists a number of clinical syndromes, conditions, and organisms that require infection control precautions in hospitals. this appendix also includes short lists of possible etiologic agents for these conditions and appropriate precautions and recommendations concerning breastfeeding for different scenarios or organisms. this chapter considers specific infectious agents that are common, clinically significant, or of particular interest. bacillus anthracis, a gram-positive, spore-forming rod, causes zoonotic disease worldwide. human infection typically occurs due to contact with animals or their products. three forms of human disease occur: cutaneous anthrax (the most common), inhalation anthrax, and gastrointestinal (gi) disease (rare). person-to-person transmission can occur as a result of discharge from cutaneous lesions, but no evidence of human-to-human transmission of inhalational anthrax is available. no evidence of transmission of anthrax via breast milk exists. standard contact isolation is appropriate for hospitalized patients or patients with draining skin lesions. the issue of anthrax as a biologic weapon has exaggerated its importance as a cause of human disease. the primary concerns regarding anthrax and breastfeeding are antimicrobial therapy or prophylaxis in breastfeeding mothers and the possibility that infant and mother were exposed by intentional aerosolization of anthrax spores. the cdc published recommendations for treatment and prophylaxis in infants, children, and breastfeeding mothers. the recommendations include the use of ciprofloxacin, doxycycline, amoxicillin, and several other agents without discontinuing breastfeeding. little available is information on ciprofloxacin and doxycycline in breast milk for prolonged periods of therapy or prophylaxis ( days) and possible effects on infants' teeth and bone/cartilage growth during that time period. depending on the clinical situation and sensitivity testing of the identified anthrax strain, other agents can be substituted to complete the -day course. the cdc has approved the use of ciprofloxacin and doxycycline for breastfeeding women for short courses of therapy (less than several weeks). simultaneous exposure of infant and mother could occur from primary aerosolization or from spores "contaminating" the local environment. in either case decontamination of the mother-infant dyad' s environment should be considered. breastfeeding can continue during a mother' s therapy for anthrax as long as she is physically well. open cutaneous lesions should be carefully covered and, depending on the situation, simultaneous prophylaxis for the infant may be appropriate. considerable justifiable concern has been expressed because of the reports of sudden infant death from botulism. infant botulism is distinguished from food-borne botulism from improperly preserved food containing the toxin and from wound botulism from spores entering the wound. infant botulism occurs when the spores of clostridium botulinum germinate and multiply in the gut and produce the botulinal toxin in the gi tract. the toxin binds presynaptically at the neuromuscular junction, preventing acetylcholine release. the clinical picture is a descending, symmetric flaccid paralysis. not every individual who has c. botulinum identified in the stool experiences a clinical illness. the age of infants seems to relate to their susceptibility to illness. the illness is mainly in children younger than months of age; the youngest patient described in the literature was days old. most children become ill between weeks and months of age. the onset of illness seems to occur earlier in formula-fed infants compared with breastfed infants. when a previously healthy infant younger than months of age develops constipation, then weakness and difficulty sucking, swallowing, crying, or breathing, botulism is a likely diagnosis. the organisms should be looked for in the stools, and electromyography may or may not be helpful. in a group reviewed by arnon et al, of patients hospitalized in california were still being nursed at onset of the illness. a beneficial effect of human milk was observed in the difference in the mean age at onset, with breastfed infants being twice as old as formula-fed infants with the disease. the breastfed infants' symptoms were milder. breastfed infants receiving iron supplements developed the disease earlier than those who were breastfed but unsupplemented. of the cases of sudden infant death from botulism, no infants were breastfed within weeks of death. all were receiving iron-fortified formulas. in most cases, no specific food source of c. botulinum can be identified, but honey is the food most often implicated, and corn syrup has been implicated in infants older than months of age. honey may contain botulism spores, which can germinate in the infant gut. however, botulin toxin has not been identified in honey. it has been recommended that honey not be given to infants younger than months of age. this includes putting honey on a mother' s nipples to initiate an infant' s interest in suckling. arnon reviewed the first years of infant botulism monitoring worldwide. the disease has been reported from of the states in the united states and from eight countries on four continents. the relationship to breastfeeding and human milk is unclear. in general the acid stools (ph . to . ) of human milk fed infants encourage bifidobacterium species. few facultative anaerobic bacteria, or clostridia, existing as spores, are present in breastfed infants. in contrast, formula-fed infants have stool phs ranging from . to . , with few bifidobacteria, primarily gram-negative bacteria, especially coliforms and bacteroides species. c. botulinum growth and toxin production decrease with declining ph and usually stops below ph . . breast milk also contains additional protective immunologic components, which purportedly have activity against botulinum toxin. the relationship between the introduction of solid foods or weaning in both formula-fed and breastfed infants and the onset of botulism remains unclear. for a breastfed infant, the introduction of solid food may cause a major change in the gut with a rapid rise in the growth of enterobacteria and enterococci followed by progressive colonization by bacteroides species, clostridia, and anaerobic streptococci. feeding solids to formula-fed infants minimally changes the gut flora as these organisms already predominate. although more hospitalized infants have been breastfed, sudden-death victims are younger and have been formula fed, which supports the concept of immunologic protection in the gut of a breastfed infant. much work remains to understand this disease. clinically, constipation, weakness, and hypotonicity in a previously healthy child constitute botulism until ruled out, especially with recent dietary changes. at this time, no reason exists to suspect breastfeeding as a risk for infant botulism, and some evidence suggests a possible protective effect from breastfeeding. breastfeeding should continue if botulism is suspected in mother or infant. brucella melitensis has been isolated in the milk of animals. foods and animals represent the primary sources of infection in humans. brucellosis demonstrates a broad spectrum of illness in humans, from subclinical to subacute to chronic illness with nonspecific signs of weakness, fever, malaise, body aches, fatigue, sweats, arthralgia, and lymphadenitis. in areas where the disease is enzootic, childhood illness has been described more frequently. the clinical manifestations in children are similar to those in adults. infection can occur during pregnancy, leading to abortion (infrequently), and can produce transplacental spread, causing neonatal infection (rarely). the transmission of b. melitensis through breast milk has been implicated in neonatal infection. , there have been eight cases of brucellosis in infants that were possibly associated with breastfeeding, but brucella was not isolated from the breast milk in any of those cases.* one case of brucellosis in an infant caused by breast milk transmission, with b. melitensis isolated from the breast milk, before antibiotic treatment was given to the mother has been documented. additionally, brucella melitensis has been cultured from women with breast lumps and abscesses. only one of six women described in this report was lactating at the time of diagnosis, and no information about the infant was given. brucellosis mastitis or abscess should be considered in women presenting with appropriate symptoms and occupational exposure to animals, contact with domestic animals in their environment, or exposure to animal milk or milk products (especially unpasteurized products). the breast inflammation tends to be granulomatous in nature (without caseation) and is often associated with axillary adenopathy; occasionally systemic illness in the woman is evident. treatment of brucellosis mastitis or abscess should be treated with surgery or fine needle aspiration as indicated and to weeks of combination antibiotic therapy with two or three medications. temporary interruption of breastfeeding with breast pumping and discarding the milk to continue stimulation of milk production is appropriate. breastfeeding should then continue after an initial period of to hours of therapy in the mother. acceptable medications for treating the mother while continuing breastfeeding include gentamicin, streptomycin, tetracycline, doxycycline, trimethoprim-sulfamethoxazole, and rifampin (see appendix d). chlamydial infection is the most frequent sexually transmitted disease (std) in the united states and is a frequent cause of conjunctivitis and pneumonitis in an infant from perinatal infection. the major determinant of whether chlamydial infection occurs in a newborn is the prevalence rate of chlamydial infection of the cervix. chlamydial immunoglobulin a (iga) has been found in colostrum and breast milk in a small number of postpartum women who were seropositive for chlamydia. no information is available on the role of milk antibodies in protection against infection in infants. it is not believed that chlamydia is transmitted via breast milk. use of erythromycin or tetracycline to treat mothers and oral erythromycin and ophthalmic preparations of tetracyclines, erythromycin, or sulfonamides to treat suspected infection in infants are appropriate during continued breastfeeding. separating infants from mothers with chlamydial infections or stopping breastfeeding is not indicated. simultaneous treatment of mothers and infants may be appropriate in some situations. corynebacterium diphtheriae causes several forms of clinical disease, including membranous nasopharyngitis, obstructive laryngotracheitis, and cutaneous infection. complications can include airway obstruction from membrane formation and toxinmediated central nervous system (cns) disease or myocarditis. the overall incidence of diphtheria has declined even though immunization does not prevent infection but does prevent severe disease from toxin production. fewer than five cases are reported annually in the united states. transmission occurs via droplets or direct contact with contaminated secretions from the nose, throat, eye, or skin. infection occurs in individuals whether they have been immunized or not, but infection in those not immunized is more severe and prolonged. as long as the skin of the breast is not involved, no risk for transmission exists via breast milk. no toxin-mediated disease from toxin transmitted through breast milk has been reported in an infant. breastfeeding, along with chemoprophylaxis and immunization of affected infants, is appropriate in the absence of cutaneous breast involvement (see appendix f). maternal infection with neisseria gonorrhoeae can produce a large spectrum of illness ranging from uncomplicated vulvovaginitis, proctitis, pharyngitis, conjunctivitis, or more severe and invasive disease, including pelvic inflammatory disease, meningitis, endocarditis, or disseminated gonococcal infection. the risk for transmission from mother to infant occurs mainly during delivery in the passage through the infected birth canal and occasionally from postpartum contact with the mother (or her partner). risk for transmission from breast milk is negligible, and n. gonorrhoeae does not seem to cause local infection of the breasts. infection in neonates is most often ophthalmia neonatorum and less often a scalp abscess or disseminated infection. mothers with presumed or documented gonorrhea should be reevaluated for other stds, especially chlamydia trachomatis and syphilis, because some therapies for gonorrhea are not adequate for either of these infections. with the definitive identification of gonorrhea in a mother, empiric therapy should begin immediately, and the mother should be separated from the infant until completion of hours of adequate therapy. treatment of the mother with ceftriaxone, cefixime, penicillin, or erythromycin is without significant risk to the infant. single-dose treatment with spectinomycin, ciprofloxacin, ofloxacin, or azithromycin has not been adequately studied but presumably would be safe for the infant given the -hour separation and a delay in breastfeeding without giving the infant the expressed breast milk (pump and discard). doxycycline use in a nursing mother is not routinely recommended. careful preventive therapy for ophthalmia neonatorum should be provided, and close observation of the infant should continue for to days, the usual incubation period. empiric or definitive therapy against n. gonorrhoeae may be necessary depending on an infant' s clinical status and should be chosen on the basis of the maternal isolate' s sensitivity pattern. the mother should not handle other infants until after hours of adequate therapy, and the infant should be separated from the rest of the nursery population, with or without breastfeeding. haemophilus influenzae type b can cause severe invasive disease such as meningitis, sinusitis, pneumonia, epiglottitis, septic arthritis, pericarditis, and bacteremia. shock can also occur. because the increased utilization of the h. influenzae type b conjugate vaccines, invasive disease caused by haemophilus has decreased dramatically, more than %, in the united states. most invasive disease occurs in children months to years of age. older children and adults rarely experience severe disease but do serve as sources of infection for young children. children younger than months of age seem to be protected because of passively acquired antibodies from the mothers, and some additional benefits may be received from breast milk. transmission occurs through contact with respiratory secretions, and droplet precautions are protective. no evidence suggests transmission through breast milk or breastfeeding. evidence supports that breast milk limits the colonization of h. influenzae in the throat. in the rare case of maternal infection, an inadequately immunized infant in a household is an indication to provide rifampin prophylaxis and close observation for all household contacts, including the breastfeeding infant. expressed breast milk can be given to an infant during the -hour separation after the mother' s initiation of antimicrobial therapy, or if the mother' s illness prevents breastfeeding, it can be reinitiated when the mother is able (see appendix f). although uncommon in the united states, leprosy occurs throughout the world. this chronic disease presents with a spectrum of symptoms depending on the tissues involved (typically the skin, peripheral nerves, and mucous membranes of the upper respiratory tract) and the cellular immune response to the causative organism, mycobacterium leprae. transmission occurs through long-term contact with individuals with untreated or multibacillary (large numbers of organisms in the tissues) disease. leprosy is not a contraindication to breastfeeding, according to jeliffe and jeliffe. the importance of breastfeeding and urgency of treatment are recognized by experts who treat infants and mothers early and simultaneously. no mother-infant contact is permitted except to breastfeed. dapsone, rifampin, and clofazimine are typically and safely used for infant and mother regardless of the method of feeding (see appendix d). listeriosis is a relatively uncommon infection that can have a broad range of manifestations. in immunocompetent individuals, including pregnant women, the infection can vary from being asymptomatic to presenting as an influenza-like illness, occasionally with gi symptoms or back pain. severe disease occurs more frequently in immunodeficient individuals or infants infected in the perinatal period (pneumonia, sepsis, meningitis, granulomatosis infantisepticum). although listeriosis during pregnancy may manifest as mild disease in a mother and is often difficult to recognize and diagnose, it is typically associated with stillbirth, abortion, and premature delivery. it is thought that transmission occurs through the transplacental hematogenous route, infecting the amniotic fluid, although ascending infection from the genital tract may occur. early and effective treatment of a woman can prevent fetal infection and sequelae. , neonatal infection occurs as either early-or late-onset infection from transplacental spread late in pregnancy, ascending infection during labor and delivery, infection during passage through the birth canal, or, rarely, during postnatal exposure. no evidence in the literature suggests that listeria is transmitted through breast milk. treatment of the mother with ampicillin, penicillin, or trimethoprim-sulfamethoxazole is not a contraindication to breastfeeding as long as the mother is well enough. expressed colostrum or breast milk also can be given if the infant is able to feed orally. the management of lactation and feeding in neonatal listeriosis is conducted supportively, as it is in any situation in which an infant is extremely ill, beginning feeding with expressed breast milk or directly breastfeeding as soon as reasonable. n. meningitidis most often causes severe invasive infections, including meningococcemia or meningitis often associated with fever and a rash and progressing to purpura, disseminated intravascular coagulation, shock, coma, and death. transmission occurs via respiratory droplets. spread can occur from an infected, ill individual or from an asymptomatic carrier. droplet precautions are recommended until hours after initiation of effective therapy. despite the frequent occurrence of bacteremia, no evidence indicates breast involvement or transmission through breast milk. the risk for maternal infection to an infant after birth is from droplet exposure and exists whether the infant is breastfeeding or bottle feeding. in either case the exposed infant should receive chemoprophylaxis with rifampin, mg/kg/dose every hours for days ( mg/kg/dose for infants younger than month of age), or ceftriaxone, mg intramuscularly (im) once, for children younger than years of age. close observation of the infant should continue for days, and breastfeeding during and after prophylaxis is appropriate. the severity of maternal illness may prevent breastfeeding, but it can continue if the mother is able, after the mother and infant have been receiving antibiotics for hours. a period of separation from the index case for the first hours of effective therapy is recommended; expressed breast milk can be given during this period. respiratory illness caused by bordetella pertussis evolves in three stages: catarrhal (nasal discharge, congestion, increasing cough), paroxysmal (severe paroxysms of cough sometimes ending in an inspiratory whoop, i.e., whooping cough), and convalescent (gradual improvement in symptoms). transmission is via respiratory droplets. the greatest risk for transmission occurs in the catarrhal phase, often before the diagnosis of pertussis. the nasopharyngeal culture usually becomes negative after days of antibiotic therapy. chemoprophylaxis for all household contacts is routinely recommended. no evidence indicates transmission through breast milk, with similar risk to breastfed and bottle-fed infants. in the case of maternal infection with pertussis, chemoprophylaxis for all household contacts, regardless of age or immunization status, is indicated. in addition to chemoprophylaxis of the infant, close observation and subsequent immunization (in infants older than weeks of age) are appropriate. despite chemoprophylaxis, droplet precautions and separation of mother and infant during the first days of effective maternal antibiotic therapy are recommended. expressed breast milk can be provided to the infant during this period. staphylococcal infection in neonates can be caused by either s. aureus or coagulase-negative staphylococci (most often s. epidermidis) and can manifest in a wide range of illnesses. localized infection can be impetigo, pustulosis in neonates, cellulitis, or wound infection, and invasive or suppurative disease includes sepsis, pneumonia, osteomyelitis, arthritis, and endocarditis. s. aureus requires only a small inoculum ( to organisms) to produce colonization in newborns, most often of the nasal mucosa and umbilicus. by the fifth day of life, % to % of the infants in the nursery will be colonized with s. aureus. the organism is easily transmitted to others from mother, infant, family, or health care personnel through direct contact. outbreaks in nurseries were common in the past. mothers, infants, health care workers, and even contaminated, unpasteurized, banked breast milk were sources of infection. , careful use of antibiotics, changes in nursery layout and procedures, standard precautions, and cohorting as needed decreased the spread of s. aureus in nurseries. now the occurrence of methicillin-resistant s. aureus (mrsa) is again a common problem, requiring cohorting, occasionally epidemiologic investigation, and careful infection control intervention. there are numerous reports of mrsa outbreaks in nicus.* the significance of colonization with staphylococcus and the factors leading to development of disease in individual patients are not clear. the morbidity and mortality related to s. aureus infection in neonates is well described. , , management of such outbreaks has been reviewed. , little has been written about the role of breastfeeding in colonization with s. aureus in nicus, wellbaby nurseries, or at home. mrsa is an important pathogen worldwide. community-acquired mrsa is different from hospital-acquired mrsa. community-acquired mrsa is usually defined as occurring in an individual without the common predisposing variables associated with hospital-acquired mrsa, lacking a mdr phenotype (common with hospital-acquired mrsa), frequently carrying multiple exotoxin virulence factors (such as panton-valentine leukocidin toxin), as well as carrying the smaller type iv staphylococcal cassette cartridge for the meca gene on a chromosome (hospital-acquired mrsa carries types i-iii staphylococcal cassette cartridge) and as being molecularly distinct from the common nosocomial strains of hospital-acquired mrsa. community-acquired mrsa is most commonly associated with skin and soft tissue infections and necrotizing pneumonia and less frequently associated with endocarditis, bacteremia, necrotizing fasciitis, myositis, osteomyelitis, or parapneumonic effusions. community-acquired mrsa is so common, it is now being observed in hospital outbreaks. , , , community-acquired mrsa transmission to infants via breast milk has been reported. , , , , premature or small-forgestational-age infants are more susceptible to and at increased risk for significant morbidity and mortality due to mrsa due in part to prolonged hospitalization, multiple courses of antibiotics, invasive procedures, and intravenous (iv) lines, their relative immune deficiency due to prematurity and illness, and altered gi tract due to different flora and decreased gastric acidity. therefore colonization with mrsa may pose a greater risk to infants in nicus in the long run. full-term infants develop pustulosis, cellulitis, and soft tissue infections, but rarely has invasive disease been reported. , , fortunov et al from texas reported infections in term or late-preterm previously well infants including with pustulosis, with celluliltis or abscesses, and invasive infections. family history of soft tissue skin infections and male sex were the only variables associated with risk for infection; cesarean delivery, breastfeeding, and circumcision were not. nguyen et al reported mrsa infections in a well-infant nursery from california. the eleven cases were all in full-term boys with pustularvesicular lesions in the groin. the infections were associated with longer length of stay, lidocaine injection use in infants, maternal age older than years, and circumcision. breastfeeding was not an associated risk factor for mrsa infection. the question of the role of circumcision in mrsa outbreaks was addressed by van howe and robson. they reported that circumcised boys are at greater risk for staphylococcal colonization and infection. others report that s. aureus carriage in infants (and subsequent infection) is most likely affected by multiple variables including infant factors (antibiotics, surgical procedures [circumcision being the most common], duration of hospital stay as a newborn), maternal factors (previous colonization, previous antibiotic usage, mode of delivery, length of stay), and environmental factors (mrsa in the family or hospital, nursery stay versus rooming-in, hand hygiene).* gerber et al from the chicago area published a consensus statement for the management of mrsa outbreaks in the nicu. the recommendations, which were strongly supported by experimental, clinical, and epidemiologic data, included using a waterless, alcohol-based hand hygiene product, monitoring and enforcing hand hygiene, placing mrsa-positive infants in contact precautions with cohorting if possible, using gloves and gowns for direct contact and masks for aerosolgenerating procedures, cohorting nurses for care of mrsa-positive infants when possible, periodic screening of infants for mrsa using nares or nasopharyngeal cultures, clarifying the mrsa status of infants being transferred into the nicu, limiting overcrowding, and maintaining ongoing instruction and monitoring of health care workers in their compliance with infection control and hand hygiene procedures. evaluation of the outbreak could include screening of health care workers and environmental surfaces to corroborate epidemiologic data and laboratory molecular analysis of the mrsa strains if indicated epidemiologically. the use of mupirocin or other decolonizing procedures should be determined on an individual basis for each nicu. s. aureus is the most common cause of mastitis in lactating women. , , , recurrence or persistence of symptoms of mastitis is a well described occurrence and an important issue in the management of mastitis. communityacquired mrsa has been associated with mastitis as well. pasteurization, s. aureus was not detected in any of the samples of expressed breast milk. colonization of one infant with mrsa was identified, but no mrsa infections were identified in any of the hospitalized infants in the nicu during the months of the study. novak et al identified mrsa in of samples ( %) of expressed fresh-frozen milk from different donors from five brazilian milk banks. only of the samples were positive with high-level bacterial counts of mrsa: greater than , cfu/ml. these were the only samples that would not have been acceptable by bacteriological criteria according to brazilian or american criteria for raw milk use. they did not investigate other epidemiologic data to identify possible variables associated with low or high level contamination of expressed breast milk with mrsa. management of an infant and/or mother with mrsa infection relative to breastfeeding or use of breast milk should be based on the severity of disease and whether the infant is premature, lbw, very-lowbirth-weight (vlbw), previously ill, or full term. full-term infants who themselves or their mothers develop mild to moderate infections (impetigo, pustulosis, cellulitis/abscess, mastitis/breast abscess, or soft tissue infection) can continue breast feeding after a short period of interruption ( to hours). during this time, pumping to maintain the milk supply should be supported, an initial evaluation for other evidence of infection should be done in the maternalinfant dyad, the infected child and/or mother should be placed on "commonly" effective therapy for the mrsa infection, and ongoing observation for clinical disease should continue. the mother and infant can "room-in" together in the hospital, if necessary, with standard and contact precautions. culturing the breast milk is not necessary. empiric therapy for the infant may be chosen based on medical concerns for the infant and the known sensitivity testing of the mrsa isolate. appropriate antibiotic choices include short-term use of azithromycin (erythromycin use during infancy [less than weeks of age], or breastfeeding associated with an increased risk for hypertrophic pyloric stenosis), sulfamethoxazoletrimethoprim (in the absence of g pd deficiency and older than days of age), clindamycin, and perhaps linezolid for mild to moderate infections. infants in nicus (premature, lbw, vlbw, and/ or previously ill), who themselves or their mothers have a mrsa infection, should have the breast milk cultured and suspend breastfeeding or receiving breast milk from their mother until the breast milk is shown to be culture negative for mrsa. the infant should be treated as indicated for their infection or empirically treated if symptomatic (with pending culture results) and closely observed for development of new signs or symptoms of infection. pumping to maintain the milk supply and the use of banked breast milk are appropriate. the infant should be placed on contact precautions, in addition to the routine standard precautions. the infant can be cohorted with other mrsa-positive infants with nursing care cohorted as well. for the mother with mrsa infection, she should be instructed concerning hand hygiene, the careful collection, handling, and storage of breast milk, contact precautions to be used with her infant, and the avoidance of contact with any other infants. the mother can receive several possible antibiotics for mrsa that are compatible with breastfeeding when used for a short period. if the mother remains clinically well, including without evidence of mastitis, but her breast milk is positive for mrsa greater than cfu/ml, empiric therapy to diminish or eradicate colonization would be appropriate. various regimens have been proposed to "eradicate" mrsa colonization, but none have been proven to be highly efficacious. these regimens usually include systemic antibiotics with one or two medications (rifampin added as the second medication), nasal mupirocin to the nares twice daily for to weeks with routine hygiene, with or without the usage of hexachlorophene (or similar topical agent or cleanser) for bathing during the to week treatment period. there is no clear information concerning the efficacy of using similar colonization eradication regimens for other household members or pets in preventing recolonization of the mother or infant. before reintroducing the use of the mother' s breast milk to the infant at least two to three negative breast milk cultures should be obtained after completion of therapy. routine screening of breast milk provided by mothers for their infants in nicus for the presence of mrsa is not indicated in the absence of mrsa illness in the maternal-infant dyad, an mrsa outbreak in nicus, or a high frequency of mrsa infection in a specific nicu. one case of staphylococcal scalded skin syndrome was reported by katzman and wald in an infant breastfed by a mother with a lesion on her areola that did not respond to ampicillin therapy for days. subsequently the infant developed conjunctivitis with s. aureus, which produced an exfoliative toxin, and a confluent erythematous rash without mucous membrane involvement or nikolsky sign. no attempt to identify the exfoliative toxin in the breast milk was made, and the breast milk was not cultured for s. aureus. the child responded to iv therapy with nafcillin. this emphasizes the importance of evaluating mother and infant at the time of a suspected infection and the need for continued observation of the infant for evidence of a pyogenic infection or toxin-mediated disease, especially with maternal mastitis or breast lesions. this case also raises the issue of when and how infants and their mothers become colonized with s. aureus and what factors lead to infection and illness in each. the concern is that staphylococcus can be easily transmitted through skin to skin contact, colonization readily occurs, and potentially serious illness can occur later, long after colonization. in the case of staphylococcal scalded skin syndrome or toxic shock syndrome (tss), the primary site of infection can be insignificant (e.g., conjunctivitis, infection of a circumcision, or simple pustulosis), but a clinically significant amount of toxin can be produced and lead to serious disease. toxic shock syndrome can result from s. aureus or streptococcus pyogenes infection and probably from a variety of antigens produced by other organisms. tss- has been identified as a "superantigen" that affects the t lymphocytes and other components of the immune response, producing an unregulated and excessive immune response and resulting in an overwhelming systemic clinical response. tss has been reported in association with vaginal delivery, cesarean delivery, mastitis, and other local infections in mothers. mortality rate in the mother may be as high as %. the case definition of staphylococcal tss includes meeting all four major criteria: fever greater than . ° c, rash (diffuse macular erythroderma), hypotension, and desquamation (associated with subepidermal separation seen on skin biopsy). the definition also includes involvement of three or more organ systems (gi, muscular, mucous membrane, renal, hepatic, hematologic, or central nervous system); negative titers for rocky mountain spotted fever, leptospirosis, and rubeola; and lack of isolation of s. pyogenes from any source or s. aureus from the cerebrospinal fluid (csf). a similar case definition has been proposed for streptococcal tss. aggressive empiric antibiotic therapy against staphylococci and streptococci and careful supportive therapy are essential to decreasing illness and death. oxacillin, nafcillin, first-generation cephalosporins, clindamycin, erythromycin, and vancomycin are acceptable antibiotics, even for a breastfeeding mother. the severity of illness in the mother may preclude breastfeeding, but it can be reinitiated when the mother is improving and wants to restart. standard precautions, but allowing breastfeeding, are recommended. staphylococcal enterotoxin f has been identified in breast milk specimens collected on days , , and from a mother who developed tss at hours postpartum. s. aureus that produced staphylococcal enterotoxin f was isolated from the mother' s vagina but not from breast milk. infant and mother lacked significant antibody against staphylococcal enterotoxin f in their sera. the infant remained healthy after days of follow-up. staphylococcal enterotoxin f is pepsin inactivated at ph . and therefore is probably destroyed in the stomach environment, presenting little or no risk to the breastfeeding infant. breastfeeding can continue if the mother is able. coagulase-negative staphylococcal infection (the predominant isolate is staphylococcus epidermidis) produces minimal disease in healthy, full-term infants but is a significant problem in hospitalized or premature infants. factors associated with increased risk for this infection include prematurity, high colonization rates in specific nurseries, invasive therapies (e.g., iv lines, chest tubes, intubation), and antibiotic use. illness produced by coagulasenegative staphylococci can be invasive and severe in high-risk neonates, but rarely in mothers. there are reports of necrotizing enterocolitis associated with coagulase-negative staphylococcus. at weeks of age, for infants still in the nursery, s. epidermidis is a frequent colonizing organism at multiple sites, with colonization rates as high as % to %. serious infections with coagulase-negative staphylococci (e.g., abscesses, iv line infection, bacteremia/sepsis, endocarditis, osteomyelitis) require effective iv therapy. many strains are resistant to penicillin and the semisynthetic penicillins, so sensitivity testing is essential. empiric or definitive therapy may require treatment with vancomycin, gentamicin, rifampin, teicoplanin, linezolid, or combinations of these for synergistic activity. transmission of infection in association with breastfeeding appears to be no more common than with bottle feeding. as with s. aureus infection control includes contact and standard precautions. occasionally, during presumed outbreaks, careful epidemiologic surveillance may be required, including cohorting, limiting overcrowding and understaffing, surveillance cultures of infants and nursery personnel, reemphasis of meticulous infection control techniques for all individuals entering the nursery, and, rarely, removal of colonized personnel from direct infant contact. s. epidermidis has been identified as part of fecal microbiota of breastfed infants. s. epidermidis has also been identified in the breast milk of women with clinical evidence of mastitis. nevertheless, s. epidermidis is rarely associated with infection in full-term infants. conceivably breast milk for premature infants could be a source of s. epidermidis colonization in the nicus. the other factors associated with hospitalization in a nicu noted previously presumably play a significant role in both colonization and infection in premature infants. the benefits of early full human milk feeding potentially outweigh the risk for colonization with s. epidermidis via breast milk. ongoing education and assistance should be provided to mothers about the careful collection, storage, and delivery of human breast milk for their premature infants. s. pyogenes (β-hemolytic group a streptococcus [gas]) is a common cause of skin and throat infections in children, producing pharyngitis, cellulitis, and impetigo. illnesses produced by gas can be classified in three categories: ( ) impetigo, cellulitis, or pharyngitis without invasion or complication; ( ) severe invasive infection with bacteremia, necrotizing fasciitis, myositis, or systemic illness (e.g., streptococcal tss); and ( ) autoimmune-mediated phenomena, including acute rheumatic fever and acute glomerulonephritis. gas can also cause puerperal sepsis, endometritis, and neonatal omphalitis. significant morbidity and mortality rates are associated with invasive gas infection; mortality rate is % to %, with almost half the survivors requiring extensive tissue débridement or amputation. infants are not at risk for the autoimmune sequelae of gas (rheumatic fever or poststreptococcal glomerulonephritis). transmission is through direct contact (rarely indirect contact) and droplet spread. outbreaks of gas in the nursery are rare, unlike with staphylococcal infections. either mother or infant can be initially colonized with gas and transmit it to the other. in the situation of maternal illness (extensive cellulitis, necrotizing fasciitis, myositis, pneumonia, tss, mastitis), it is appropriate to separate mother and infant until effective therapy (penicillin, ampicillin, cephalosporins, erythromycin) has been given for at least hours. breastfeeding should also be suspended and may resume after hours of therapy for the mother. group b streptococcus (gbs, streptococcus agalactiae) is a significant cause of perinatal bacterial infection. in parturient women, infection can lead to asymptomatic bacteriuria, urinary tract infection (often associated with premature birth), endometritis, or amnionitis. in infants, infection usually occurs between birth and months of age ( to cases per live births). it is routinely classified by the time of onset of illness in the infant: early onset ( to days, majority less than hours) and late onset ( to days, generally less than weeks). infants may develop sepsis, pneumonia, meningitis, osteomyelitis, arthritis, or cellulitis. early-onset gbs disease is often fulminant, presenting as sepsis or pneumonia with respiratory failure; three quarters of neonatal disease is early onset. type iii is the most common serotype causing disease. transmission is believed to occur in utero and during delivery. colonization rates of mothers and infants vary between % and %. postpartum transmission is thought to be uncommon, although it has been documented. risk factors for early-onset gbs disease include delivery before weeks' gestation, rupture of membranes for longer than hours before delivery, intrapartum fever, heavy maternal colonization with gbs, or low concentrations of anti-gbs capsular antibody in maternal sera. the common occurrence of severe gbs disease before hours of age in neonates has lead to prevention strategies. revised guidelines developed by the aap committees on infectious diseases and on the fetus and newborn have tried to combine various variables for increased risk for gbs infection (prenatal colonization with gbs, obstetric and neonatal risk factors for early-onset disease) and provide intrapartum prophylaxis to those at high risk ( figure - ) the utilization of these guidelines and intrapartum prophylaxis across the united states has decreased the incidence of early-onset disease by approximately %. in , the incidence of early-onset disease was . cases per live births. late-onset gbs disease is thought to be the result of transmission during delivery or in the postnatal period from maternal, hospital, or community sources. dillon et al demonstrated that of infants with late-onset disease were colonized at birth, but the source of colonization was unidentified in the others. gardner et al showed that only . % of children who were culture negative for gbs at discharge from the hospital had acquired gbs by months of age. anthony et al noted that many infants are colonized with gbs, but the actual attack rate for gbs disease is low and difficult to predict. acquisition of gbs through breast milk or breastfeeding is uncommon. cases of late-onset gbs disease associated with gbs in the maternal milk have been reported. , , , , some of the mothers had bilateral mastitis, at least one had delayed evidence of unilateral mastitis, and the others were asymptomatic. it was not clear when colonization of the infants occurred or when infection or disease began in the infants. the authors discussed the possibility that the infants were originally colonized during delivery, subsequently colonized the mothers' breasts during breastfeeding, and then became reinfected at a later time. butter and demoor showed that infants initially colonized on their heads at birth had gbs cultured from their throat, nose, or umbilicus days later. whenever they cultured gbs from the nipples of mothers, the authors also found it in the nose or throat of the infants. byrne et al presented a review of gbs disease associated with breastfeeding and made recommendations to decrease the risk for transmission of gbs to infants via breastfeeding or breast milk. some of their recommendations included confirming appropriate collection and processing procedures for gbs cultures in medical facilities to decrease false-negative cultures, reviewing proper hygiene for pumping, collection, and storage of expressed breast milk with mothers, reviewing the signs and symptoms of mastitis with mothers, and utilizing banked human milk as needed instead of mother' s milk. when a breastfed infant develops late-onset gbs disease, it is appropriate to culture the milk. (see discussion of culturing breast milk earlier in this chapter.) consider treatment of the mother to prevent reinfection if the milk is culture positive for gbs (greater than cfu/ml), with or without clinical evidence of mastitis in the mother. withholding the mother' s milk until it is confirmed to be culture negative for a pathogen is appropriate and should be accompanied by providing ongoing support and instruction to the mother concerning pumping and maintaining her milk supply. serial culturing of expressed breast milk after treatment of the mother for gbs disease or colonization would be appropriate to insure the ongoing absence of a pathogen in the expressed breast milk. there are reports of reinfection of the infant from breast milk. , eradication of gbs mucosal colonization in the infant or the mother may be difficult. some authors have recommended using rifampin prophylactically in both the mother and infant at the end of treatment to eradicate mucosal colonization. (see chapter for management of mastitis in the mother.) a mother or infant colonized or infected with gbs should be managed with standard precautions while in the hospital. ongoing close evaluation of the infant for infection or illness and empiric therapy for gbs in the infant are appropriate until the child has remained well and cultures are subsequently negative at hours. occasionally, epidemiologic investigation in the hospital will utilize culturing medical staff and family members to detect a source of late-onset gbs disease in the nursery. this can be useful when more than one case of late-onset disease is detected with the same serotype. cohorting in such a situation may be appropriate. selective prophylactic therapy for colonized infants to eradicate colonization may be considered, but unlike gas or staphylococcus infection, gbs infection in nurseries has not been reported to cause outbreaks. no data support screening all breastfeeding mothers and their expressed breast cbc including wbc count with differential and blood culture. applies only to penicillin, ampicillin, or cefazolin and assumes recommended dosing regimens. a healthy-appearing infant who was ≥ weeks' gestation at delivery and whose mother received ≥ hours of iap before delivery may be discharged home after hours if other discharge criteria have been met and a person able to comply fully with instructions for home observation will be present. if any one of these conditions is not met, the infant should be observed in the hospital for at least hours and until criteria for discharge are achieved. milk for gbs as a reasonable method for protecting against spread of gbs infection via expressed breast milk. selective culturing of expressed breast milk may be appropriate in certain situations. the face of tuberculosis (tb) is changing throughout the world. in the united states the incidence of tb rose during through and has been declining since then. increased rates of tb were noted in adults between and years of age, and because these are the primary childbearing years, the risk for transmission to children increased. tb during pregnancy has always been a significant concern for patients and physicians alike. it is now clear that the course and prognosis of tb in pregnancy are less affected by the pregnancy and more determined by the location and extent of disease, as defined primarily by chest radiograph, and by the susceptibility of the individual patient. untreated tb in pregnancy is associated with maternal and infant mortality rates of % to %. effective therapy is crucial to the clinical outcome in both pregnant and nonpregnant women. tb during pregnancy rarely results in congenital tb. any individual in a high-risk group for tb should be screened with a tuberculin skin test (tst). no contraindication or altered responsiveness to the tst exists during pregnancy or breastfeeding. interpretation of the tst should follow the most recent guidelines, using different sizes of induration in different-risk populations as cutoffs for a positive test, as proposed by the cdc. figure - outlines the evaluation and treatment of a pregnant woman with a positive tst. treatment of active tb should begin as soon as the diagnosis is made, regardless of the fetus' gestational age, because the risk for disease to mother and fetus clearly outweighs the risks of treatment. isoniazid, rifampin, and ethambutol have been used safely in all three trimesters. isoniazid and pyridoxine therapy during breastfeeding is safe, although the risk for hepatotoxicity in the mother may be a concern during the first months postpartum. congenital tb is extremely rare if one considers that to million cases of tb occur each year worldwide and that less than cases of congenital tb have been reported in the literature. as with other infectious diseases presenting in the perinatal period, distinguishing congenital infection from perinatal or postnatal tb in infants can be difficult. postnatal tb infection in infancy typically presents with severe disease and extrapulmonary extension (meningitis, lymphadenopathy, and bone, liver, spleen involvement). airborne transmission of tb to infants is the major mode of postnatal infection because of close and prolonged exposure in enclosed spaces, especially in their own household, to any adult with infectious pulmonary tb. potential infectious sources could be the mother or any adult caregiver, such as babysitters, day care workers, relatives, friends, neighbors, and even health care workers. the suspicion of tb infection or disease in a household with possible exposure of an infant is a highly anxiety-provoking situation ( figure - ). although protection of an infant from infection is foremost in everyone' s mind, separation of the infant from the mother should be avoided when reasonable. every situation is unique, and the best approach will vary according to the specifics of the case and accepted principles of tb management. the first step in caring for the potentially exposed infant is to determine accurately the true tb status of the suspected case (mother or household contact). this prompt evaluation should include a complete history (previous tb infection or disease, previous or ongoing tb treatment, tst status, symptoms suggestive of active tb, results of most recent chest radiograph, sputum smears, or cultures), physical examination, a tst if indicated, a new chest radiograph, and mycobacterial cultures and smears of any suspected sites of infection. all household contacts should be evaluated promptly, including history and tst with further evaluation as indicated. continued risk to the infant can occur from infectious household contacts who have not been effectively evaluated and treated. an infant should be separated temporarily from the suspected source if symptoms suggest active disease or a recent tst documents conversion, and separation should continue until the results of the chest radiograph are seen. because of considerable variability in the course of illness and the concomitant infectious period, debate continues without adequate data about the appropriate period of separation. this should be individualized given the specific situation. hiv testing and assessment of the risk for mdr tb should be done in every case of active tb. sensitivity testing should be done on every mycobacterium tuberculosis isolate. table - summarizes the management of the newborn infant whose mother (or other household contact) has tb. initiation of prophylactic isoniazid therapy in the infant has been demonstrated to be effective in preventing tb infection and disease in the infant. therefore continued separation of infant and mother is unnecessary after therapy in both mother and child has begun. the real risk to an infant requiring separation is from airborne transmission. separation of the infant from a mother with active pulmonary tb is appropriate, regardless of the method of feeding. however, in many parts of the world, after therapy in the mother and prophylaxis with isoniazid in the infant has begun, the infant and mother are not separated. with or without separation, the mother and infant should continue to be closely observed throughout the course of maternal therapy to ensure good compliance with medication by both mother and infant and to identify, early on, any symptoms in the infant suggestive of tb. tuberculous mastitis occurs rarely in the united states but does occur in other parts of the world* and can lead to infection in infants, frequently involving the tonsils. a mother usually has a single breast mass and associated axillary lymph node swelling and infrequently develops a draining sinus. tb of the breast can also present as a painless mass or edema. involvement of the breast can occur with or without evidence of disease at other sites. evaluation of extent of disease is appropriate, including lesion cultures by needle aspiration, biopsy, or wedge resection and milk cultures. therapy should be with multiple anti-tb medications, but surgery should supplement this, as needed, to remove extensive necrotic tissue or a persistently draining sinus. neither breastfeeding nor breast milk feeding should be done until the lesion is healed, usually weeks or more. continued anti-tb therapy for months in the mother and isoniazid for the infant for to months is indicated. in the absence of tuberculous breast infection in the mother, transmission of tb through breast milk has not been documented. thus even though temporary separation of infant and mother may occur pending complete evaluation and initiation of adequate therapy in the mother and prophylactic isoniazid therapy ( mg/kg/day as a single daily dose) in the infant, breast milk can be expressed and given to the infant during the short separation. breastfeeding can safely continue whether the mother, infant, or both are receiving anti-tb therapy. anti-tb medications (isoniazid, rifampin, pyrazinamide, aminoglycosides, ethambutol, ethionamide, p-aminosalicylic acid) have been safely used in infancy, and therefore the presence of these medications in smaller amounts in breast milk is not a contraindication to breastfeeding. although conflicting, reports indicate that breastfeeding by tst-positive mothers does influence infants' responses to bacille calmette-guérin notes: further workup should always include evaluation of tb status of all other household (or close) contacts by tuberculin skin testing (tst), review of symptoms, physical examination, and chest x-ray (cxr). sputum smears and cultures should be done as indicated. separation should occur until interpretation of cxr film confirms absence of active disease, or, with active disease, separation should continue until individual is no longer considered infectious: three negative consecutive sputum smears, adequate ongoing empiric therapy, and decreased fever, cough, and sputum production. separation means in a different house or location, not simply separate rooms in a household. duration of separation should be individualized for each case in consultation with tb specialist. this assumes no evidence of breast involvement, suspected tb mastitis, or lesion (except in status , when breast involvement is considered). risk to infant is via aerosolized bacteria in sputum from the lung. expressed breast milk can be given even if separation of mother and infant is advised. tst positive, no symptoms or physical findings suggestive of tb, negative cxr film. prophylactic therapy: isoniazid mg/kg/day, maximum mg for months; pyridoxine to mg/day for months. empiric therapy: standard three-or four-drug regimens for months, and treatment should continue for total of months with isoniazid and rifampin when organism is shown to be sensitive. suspected multidrug-resistant (mdr) tb requires consultation with tb specialist to select optimum empiric regimen and for ongoing monitoring of therapy and clinical response. vaccine, the tst, and perhaps the m. tuberculosis bacillus. despite efforts to identify either a soluble substance or specific cell fractions (gamma/delta t cells) in colostrum and breast milk that affect infants' immune responsiveness, no unified theory explains the various reported changes and no evidence has identified a consistent, clinically significant effect. , , , viral infections arboviruses arboviruses were originally a large collection of viruses grouped together because of the common mode of transmission through arthropods. they have now been reclassified into several different families: bunyaviridae, togaviridae, flaviviridae, reoviridae, and others. they include more than human pathogens. these organisms primarily produce either cns infections (encephalitis, meningoencephalitis) or undifferentiated illnesses associated with fever and rash, severe hemorrhagic manifestations, and involvement of other organs (hepatitis, myalgia, polyarthritis). infection with this array of viruses may also be asymptomatic and subclinical, although how often this occurs is uncertain. some of the notable human pathogens include bunyaviridae (california serogroup viruses), hantavirus, hantaan virus, phlebovirus (rift valley fever), nairovirus (crimean-congo hemorrhagic fever), alphavirus (western, eastern, and venezuelan equine encephalomyelitis viruses, chikungunya virus), flavivirus (st. louis encephalitis virus, japanese encephalitis virus, dengue viruses, yellow fever virus, tick-borne encephalitis viruses), and orbivirus (colorado tick fever). other than for crimean-congo hemorrhagic fever and for reported cases of colorado tick fever associated with transfusion, direct person-to-person spread has rarely been described. recent outbreaks of chikungunya virus infection in reunion island and in india described infection in young infants probably secondary to vertical spread from mother to infant transplacentally. , , a few cases of early fetal deaths were associated with infection in pregnant women. the cases of vertical transmission occurred with near-term infection in the mothers, and the infants developed illness within to days of delivery. , no evidence for transmission via breast milk or breastfeeding is available. little evidence indicates that these organisms can be transmitted through breast milk. the exceptions to this include evidence of transmission of two flaviviruses via breast milk, west nile virus, and yellow fever vaccine virus. standard precautions are generally sufficient. with any of these infections in a breastfeeding mother, the severity of the illness may determine the mother' s ability to continue breastfeeding. providing the infant with expressed breast milk is acceptable. (see the discussion of west nile virus and yellow fever vaccine virus later in this chapter.) in general, treatment for these illnesses is supportive. however, ribavirin appears to decrease the severity of and mortality from hantavirus pulmonary syndrome, hemorrhagic fever with renal failure, and crimean-congo hemorrhagic fever. ribavirin has been described as teratogenic in various animal species and is contraindicated in pregnant women. no information is available concerning ribavirin in breast milk, with little information available on the use of iv or oral ribavirin in infants. arenaviruses are single-stranded ribonucleic acid (rna) viruses that infect rodents and are acquired by humans through the rodents. the six major human pathogens in this group are ( ) lymphocytic sensitivity testing should be done on any positive culture. isoniazid mg/kg/day for to months depending on mother's or contact's status; repeat tst at months and obtain normal cxr in infant before stopping isoniazid. before beginning therapy, workup of infant for congenital or active tb may be appropriate. this workup should be determined by clinical status of infant and suspected potential risk, and may include tst after weeks of age, with cxr, complete blood count, and erythrocyte sedimentation rate, liver function tests, cerebrospinal fluid analysis, gastric aspirates, sonography/computed tomography of liver/spleen, and chest if congenital tb is suspected. breastfeeding is proscribed when separation of mother and infant is indicated because of risk for aerosolized transmission of bacteria. expressed breast milk given to infant via bottle is acceptable in absence of mastitis or breast lesions. consult with tb specialist about mdr tb. empiric therapy will be chosen based on the most recent culture sensitivities of index patient or perhaps suspected source case, if known, as well as medication toxicities and other factors. tb mastitis usually involves a single breast with associated axillary lymph node swelling and, infrequently, a draining sinus tract. it can also present as a painless mass or edema of breast. with suspected mastitis or breast lesion caused by tb, even breast milk is contraindicated until lesion or mastitis heals, usually weeks or more. patient has a documented, recent tst conversion but has not been completely evaluated. evaluation should begin and cxr done and evaluated in less than hours to minimize separation of this person from infant. further workup should proceed as indicated by symptoms, physical findings, and cxr results. choriomeningitis virus, ( ) lassa fever virus, ( ) junin virus (argentine hemorrhagic fever), ( ) machupo virus (bolivian hemorrhagic fever), ( ) guanarito virus (venezuelan hemorrhagic fever), and ( ) sabia virus. the geographic distribution of these viruses and the illness they cause are determined by the living range of the host rodent (reservoir). the exact mechanism of transmission to humans is unknown and hotly debated. , , direct contact and aerosolization of rodent excretions and secretions are probable mechanisms. lymphocytic choriomeningitis virus is well recognized in europe, the americas, and other areas. perinatal maternal infection can lead to severe disease in the newborn, but no evidence suggests transmission through breast milk. , standard precautions with breastfeeding are appropriate. lassa fever (west africa) and argentine hemorrhagic fever (argentine pampas) are usually more severe illnesses with dramatic bleeding and involvement of other organs, including the brain. these fevers more frequently lead to shock and death than do the forms of hemorrhagic fever caused by the other viruses in this group. person-to-person spread of lassa fever is believed to be common, and transmission within households does occur. this may relate to prolonged viremia and excretion of the virus in the urine of humans for up to days. the possibility of persistent virus in human urine, semen, and blood after infection exists for each of the arenaviruses. the possibility of airborne transmission is undecided. current recommendations by the cdc are to use contact precautions for the duration of the illness in situations of suspected viral hemorrhagic fever. no substantial information describes the infectivity of various body fluids, including breast milk, for these different viral hemorrhagic fevers. considering the severity of the illness in mothers and the risk to the infants, it is reasonable to avoid breastfeeding in these situations if alternative forms of infant nutrition can be provided. as more information becomes available, reassessment of these recommendations is advisable. a vaccine is in clinical trials in endemic areas for junin virus and argentine hemorrhagic fever. preliminary studies suggest it is effective, but data are still being accumulated concerning the vaccine' s use in children and pregnant or breastfeeding women. cytomegalovirus (cmv) is one of the human herpesviruses. congenital infection of infants, postnatal infection of premature infants, and infection of immunodeficient individuals represent the most serious forms of this infection in children. the time at which the virus infects the fetus or infant and the presence or absence of antibodies against cmv from the mother are important determinants of the severity of infection and the likelihood of significant sequelae (congenital infection syndrome, deafness, chorioretinitis, abnormal neurodevelopment, learning disabilities). about % of all infants are born excreting cmv at birth, and approximately % of these congenitally infected infants will demonstrate evidence of infection at birth (approximately five symptomatic cases per , live births). approximately % of infants born after primary infection in a pregnant woman will manifest at least one sequela of prenatal infection. various studies have detected that % to % of pregnant women have cmv in cervical cultures and that % to % of pregnant women have cmv in their urine. , perinatal infection certainly occurs through contact with virus in these fluids but usually is not associated with clinical illness in fullterm infants. the lack of illness is thought to result from transplacental passive transfer of protective antibodies from the mother. postnatal infection later in infancy occurs via breastfeeding or contact with infected fluids (e.g., saliva, urine) but, again, rarely causes clinical illness in full-term infants. seroepidemiologic studies have documented transmission of infection in infancy, with higher rates of transmission occurring in daycare centers, especially when the prevalence of cmv in the urine and saliva is high. cmv has been identified in the milk of cmv-seropositive women at varying rates ( % to %) using viral cultures or cmv deoxyribonucleic acid (dna) pcr. , , , cmv is more often identified in the breast milk of seropositive mothers than in vaginal fluids, urine, and saliva. the cmv isolation rate from colostrum is lower than that from mature milk. , the reason for the large degree of variability in identification of cmv in breast milk in these studies probably relates to the intermittent nature of reactivation and excretion of the virus in addition to the variability, frequency, and duration of sampling of breast milk in the different studies. some authors have hypothesized that the difference in isolation rates between breast milk and other fluids is caused by viral reactivation in cells (leukocytes or monocytes) in the breast leading to "selective" excretion in breast milk. vochem et al reported that the rate of virolactia was greatest at to weeks postpartum, and yeager et al reported significant virolactia between and weeks postpartum. antibodies (e.g., secretory iga) to cmv are present in breast milk, along with various cytokines and other proteins (e.g., lactoferrin). these may influence virus binding to cells, but they do not prevent transmission of infection.* several studies have documented increased rates of postnatal cmv infection in breastfed infants ( % to %) compared with bottle-fed infants ( % to %) observed through the first year of life , , , in these same studies, full-term infants who acquired cmv infection postnatally were only rarely mildly symptomatic at the time of seroconversion or documented viral excretion. also, no evidence of late sequelae from cmv was found in these infants. postnatal exposure of susceptible infants to cmv, including premature infants without passively acquired maternal antibodies against cmv, infants born to cmv-seronegative mothers, and immunodeficient infants, can cause significant clinical illness (pneumonitis, hepatitis, thrombocytopenia).* in one study of premature infants followed up to months, vochem et al found cmv transmission in of infants ( %) exposed to cmv virolactia and breastfed compared with no infants infected of exposed to breast milk without cmv. no infant was given cmv-seropositive donor milk or blood. five of the infants who developed cmv infection after months of age had mild signs of illness, including transient neutropenia, and only one infant had a short increase in episodes of apnea and a period of thrombocytopenia. five other premature infants with cmv infection before months of age had acute illness, including sepsis-like symptoms, apnea with bradycardia, hepatitis, leukopenia, and prolonged thrombocytopenia. vollmer et al followed premature infants with early postnatal cmv infection acquired through breast milk for to . years to assess neurodevelopment and hearing function. none of the children had sensorineural hearing loss. there was no difference between the cmv-infected children and matched premature control cmv-negative infants in terms of neurologic, speech and language, or motor development. neuberger et al examined the symptoms and neonatal outcome of cmv infection transmitted via human milk in premature infants in a case-control fashion; cmv-infected premature infants were compared with cmv-negative matched premature infants. neutropenia, thrombocytopenia, and cholestasis were associated with cmv infection in these infants. no other serious effects or illnesses were found directly associated with the infection including intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, duration of mechanical ventilation or oxygen therapy, duration of hospital stay or weight, gestational age, or head circumference at the time of discharge. exposure of cmv-seronegative or premature infants to cmv-positive milk (donor or natural mother' s) should be avoided. various methods of inactivating cmv in breast milk have been reported, including holder pasteurization, freezing (− ° c for days), and brief high temperature ( ° c for seconds). , , , , one small, prospective study suggests that freezing breast milk at − °c for hours protects premature infants from cmv infection via breast milk. sharland et al reported on premature infants (less than weeks) who were uninfected at birth and exposed to breast milk from their cmv seropositive mothers. only one of ( %) infants became positive for cmv at days of life, and this infant was clinically asymptomatic. this transmission rate is considerably lower than others reported in the literature. cmvseronegative and leukocyte-depleted blood products were used routinely. banked breast milk was pasteurized and stored at − ° c for various time periods and maternal expressed breast milk was frozen at − ° c before use whenever possible. the infants received breast milk for a median of days (range to days) and they were observed for a median of days (range to days). breast milk samples pre-or postfreezing were not analyzed by pcr or culture for the presence of cytomegalovirus. buxmann et al demonstrated no transmission of cmv in premature infants receiving thawed frozen breast milk until weeks (gestational age + postnatal age) (less than or equal to weeks gestational age) born to mothers who were cmv-igg negative. cmv infection was found in five premature infants of infants born to mothers who were cmv-igg positive and who provided breast milk for their infants. three of the five children remained asymptomatic. one child development a respirator-dependent pneumonia and the second developed an upper respiratory tract infection and thrombocytopenia in association with their cmv infections. yasuda et al reported on preterm infants (median gestational age weeks) demonstrating a peak in cmv dna copies, detected by a real-time pcr assay, in breast milk at to weeks postpartum. thirty of the infants received cmv dna-positive breast milk. three of the had cmv dna detected in their sera, but none of the three had symptoms suggestive of cmv infection. much of the breast milk had been stored at − ° c before feeding, which the authors propose is the probable reason for less transmission in this cohort. lee et al reported on the use of maternal milk frozen at − °c for a minimum of hours before feeding to premature infants in a nicu; infants had cmv-seropositive mothers and infants had cmv-seronegative mothers. two infants developed cmv infection, which was symptomatic. they were both fed frozen thawed milk from cmv-seropositive mothers. others have reported individual cases of cmv infection in premature infants despite freezing and thawing breast milk. , simple freezing and thawing of breast milk does not completely prevent transmission of cmv to premature infants. the efficacy of freezing and thawing breast milk for varying lengths of time to prevent cmv infection in premature infants has not been studied prospectively in a randomized controlled trial. eleven of neonatal units in sweden ( of which have their own milk banks) freeze maternal milk to reduce the risk for cmv transmission to premature infants. a prominent group of neonatologists and pediatric infectious disease experts in california who recognize the significant benefits of providing human milk to premature and lbw infants recommend screening mothers of premature infants for cmv igg at delivery and, when an infant' s mother is cmv igg positive at delivery, using either pasteurized banked human milk or frozen then thawed maternal breast milk for premature infants until they reach the age of weeks. in consideration of the low rates of cmv virolactia in colostrum , and the predominant occurrence of virolactia between and weeks (peak at to weeks) postpartum, , they reasonably propose beginning colostrum and breast milk feedings for all infants until the maternal cmv serologic screening is complete. they appropriately recommend close observation and follow-up of premature infants older than weeks of age for signs, symptoms, and laboratory changes of cmv infection until discharge from the hospital. cmv-seropositive mothers can safely breastfeed their full-term infants because, despite a higher rate of cmv infection than in formula-fed infants observed through the first year of life, infection in this situation is not associated with significant clinical illness or sequelae. dengue viruses (serotypes dengue to ) are flaviviruses associated primarily with febrile illnesses and rash; dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. the mosquito aedes aegypti is the main vector of transmission of dengue virus in countries lying between latitudes degrees north and degrees south. more than . billion people live in areas where transmission occurs; dengue virus infects over million individuals a year and casuses approximately , deaths a year. , although dengue hemorrhagic fever and dengue shock syndrome occur frequently in children younger than year of age, they are infrequently described in infants younger than months of age. there are also differences in the clinical and laboratory findings of dengue virus infection in children compared with adults. boussemart et al reported on two cases of perinatal/prenatal transmission of dengue and discussed eight additional cases in neonates from the literature. prenatal or intrapartum transmission of the same type of dengue as the mother was confirmed by serology, culture, or pcr. phongsamart et al described three additional cases of dengue virus infection late in pregnancy and apparent transmission to two of the three infants with passive acquisition of antibody in the third infant. sirinavin et al reported on cases in the literature of vertical dengue infection, all presenting at less than weeks of age, but no observations or discussion of breast milk or breastfeeding as a potential source of infection were published. watanaveeradej et al presented an additional three cases of dengue infection in infants documenting normal growth and development at follow-up at months of age. it has been postulated that more severe disease associated with dengue disease occurs when an individual has specific igg against the same serotype as the infecting strain in a set concentration, leading to antibody-dependent enhancement of infection. the presence of preexisting dengue serotype specific igg in an infant implies either previous primary infection with the same serotype, passive acquisition of igg from the mother (who had a previous primary infection with the same serotype), or perhaps acquisition of specific igg from breast milk. watanaveeradej et al documented transplacentally transferred antibodies against all four serotypes of dengue virus in % of cord sera at delivery. follow-up of infants documented the loss of antibodies to dengue virus over time with losses of %, %, %, %, and % at , , , , and months of age, respectively. no evidence is available in the literature about more severe disease in breastfed infants compared with formula-fed infants. no interhuman transmission of dengue virus in the absence of the mosquito vector and no evidence of transmission via breast milk are known. only one report of a factor in the lipid portion of breast milk, which inhibits the dengue virus, is available, and no evidence for antibody activity against dengue virus in human breast milk is known. breastfeeding during maternal or infant dengue disease should continue as determined by the mother' s or infant' s severity of illness. epstein-barr virus (ebv) is a common infection in children, adolescents, and young adults. it is usually asymptomatic but most notably causes infectious mononucleosis and has been associated with chronic fatigue syndrome, burkitt lymphoma, and nasopharyngeal carcinoma. because ebv is one of the human herpesviruses, concern has been raised about lifelong latent infection and the potential risk for infection to a fetus and neonate from the mother. primary ebv infection during pregnancy is unusual because few pregnant women are susceptible. , although abortion, premature birth, and congenital infection from ebv are suspected, no distinct group of anomalies is linked to ebv infection in fetus or neonate. also, no virologic evidence of ebv as the cause of abnormalities was found in association with suspected ebv infection. culturing of ebv from various fluids or sites is difficult. the virus is detected by its capacity to transform b lymphocytes into persistent lymphoblastoid cell lines. pcr and dna hybridization studies have detected ebv in the cervix and in breast milk. one study, which identified ebv dna in breast milk cells in more than % of women donating milk to a breast milk bank, demonstrated that only % had antibody to ebv (only igg, no igm). another study examining serologic specimens from breastfed and bottle-fed infants showed similar seroprevalence of ebv at to months of age ( / [ . %] and / [ . %]) in the breastfed and bottle-fed children, respectively. the question of the timing of ebv infection and the subsequent immune response and clinical disease produced requires continued study. differences exist among the clinical syndromes that manifest at different ages. infants and young children are asymptomatic, have illness not recognized as related to ebv, or have mild episodes of illness, including fever, lymphadenopathy, rhinitis and cough, hepatosplenomegaly, or rash. adolescents or young adults who experience primary ebv infection more often demonstrate infectious mononucleosis syndrome or are asymptomatic. chronic fatigue syndrome is more common in adolescents and young adults. burkitt lymphoma, observed primarily in africa, and nasopharyngeal carcinoma, seen in southeast asia, where primary ebv infection usually occurs in young children, are tumors associated with early ebv infection. these tumors are related to "chronic" ebv infection and tend to occur in individuals with persistently high antibody titers to ebv viral capsid antigen and early antigen. the questions of why these tumors occur with much greater frequency in these geographic areas and what cofactors (including altered immune response to infection associated with coinfections, immune escape by ebv leading to malignancy, or increased resistance to apoptosis secondary to ebv gene mutations) may contribute to their development remain unanswered. , it also remains unknown to what degree breast milk could be a source of early ebv infection compared with other sources of ebv infection in an infant' s environment. similar to the situation of postnatal transmission of cmv in immunocompetent infants, clinically significant illness rarely is associated with primary ebv infection in infants. more data concerning the pathogenesis of ebv-associated tumors should be obtained before proscribing against breastfeeding is warranted, especially in areas where these tumors are common but the protective benefits of breastfeeding are high. in areas where burkitt lymphoma and nasopharyngeal carcinoma are uncommon, ebv infection in mother or infant is certainly not a contraindication to breastfeeding. marburg and ebola viruses cause severe and highly fatal hemorrhagic fevers. the illness often presents with nonspecific symptoms (conjunctivitis, frontal headache, malaise, myalgia, bradycardia) and progresses with worsening hemorrhage to shock and subsequent death in % to % of patients. personto-person transmission through direct contact, droplet spread, or airborne spread is the common mode of transmission. however, the animal reservoir or source of these viruses in nature for human infection has not been identified. attack rates in families are % to %. no postexposure interventions have proved useful in preventing spread, and no treatment other than supportive is currently available. a recent report documented the presence of ebola virus in numerous body fluids including in breast milk. one acute breast milk sample on day after the onset of illness and a "convalescent" breast milk sample on day from the same woman were positive for ebola virus by both culture and pcr testing. in the same study, saliva remained virus positive for a mean of days after disease onset, urine was positive for a mean of days, and semen for a mean of days after the onset of disease. no information is available concerning the risk for transmission of these viruses in breast milk or additional risks or benefits from breastfeeding. contact precautions are recommended for marburg virus infections and contact and airborne precautions for ebola virus infection. given the high attack and mortality rates, these precautions should be carefully instituted and breastfeeding not allowed. if any other suitable source of nutrition can be found for an infant, expressed breast milk should also be proscribed for the infant of a mother with either of these infections for at least weeks postrecovery. the diagnosis of hepatitis in a pregnant woman or nursing mother causes significant anxiety. the first issue is determining the etiology of the hepatitis, which then allows for an informed discussion of risk to the fetus/infant. the differential diagnosis of acute hepatitis includes ( ) common causes of hepatitis, such as hepatitis a, b, c, and d; ( ) , igm anti-hbcag, anti-hcv) as the initial diagnostic tests. simultaneous consideration of other etiologies of acute liver dysfunction is appropriate depending on a patient' s history. if the initial diagnostic tests are all negative, subsequent additional testing for anti-hepatitis d virus (hdv), hcv rna, hepatis g virus (hgv) rna, anti-hepatis e virus (hev), or hev rna may be necessary. if initial testing reveals positive hbsag, testing for anti-hdv, hbeag, and hbv dna is appropriate. these additional tests are useful in defining the prognosis for a mother and the risk for infection to an infant. during the diagnostic evaluation, it is appropriate to discuss with the mother or parents the theoretic risk for transmitting infectious agents that cause hepatitis via breastfeeding. the discussion should include an evaluation of the positive and negative effects of suspending or continuing breastfeeding until the exact etiologic diagnosis is determined. the relative risk for transmission of infection to an infant can be estimated and specific preventive measures provided for the infant (table - ) . hepatitis a virus (hav) is usually an acute selflimited infection. the illness is typically mild, and generally subclinical in infants. occasionally, hav infection is prolonged or relapsing, extending to months, and rarely it is fulminant, but hav infection does not lead to chronic infection. the incidence of prematurity after maternal hav infection is increased, but no evidence to date indicates obvious birth defects or a congenital syndrome. , hav infection in premature infants may lead to prolonged viral shedding. transmission is most often person to person (fecal-oral), and transmission in food-borne or water-borne epidemics has been described. transmission via blood products and vertical transmission (mother to infant) are rare. transmission in daycare settings has been clearly described. infection with hav in newborns is uncommon and does not seem to be a significant problem. the usual period of viral shedding and presumed contagiousness lasts to weeks. acute maternal hav infection in the last trimester or in the postpartum period could lead to infection in an infant. symptomatic infection can be prevented by immunoglobulin (ig) administration, and % to % of disease can be prevented by ig administration immune serum globulin within weeks of exposure. hav vaccine can be administered simultaneously with ig without affecting the seroconversion rate to produce rapid and prolonged hav serum antibody levels. transmission of hav via breast milk has been implicated in one case report, but no data exist on the frequency of isolating hav from breast milk. because hav infection in infancy is rare and usually subclinical without chronic disease and because exposure has already occurred by the time the etiologic diagnosis of hepatitis in a mother is made, no reason exists to interrupt breastfeeding with maternal hav infection. the infant should receive ig and hav vaccine, administered simultaneously. hepatitis b virus (hbv) infection leads to a broad spectrum of illness, including asymptomatic seroconversion, nonspecific symptoms (fever, malaise, fatigue), clinical hepatitis with or without jaundice, extrahepatic manifestations (arthritis, rash, renal involvement), fulminant hepatitis, and chronic hbv infection. chronic hbv infection occurs in up to % of infants infected via perinatal and vertical transmission and in % of children infected between to years of age. given the increased risk for significant sequelae from chronic infection (chronic active hepatitis, chronic persistent hepatitis, cirrhosis, primary hepatocellular carcinoma), prevention of hbv infection in infancy is crucial. transmission of hbv is usually through blood or body fluids (stool, semen, saliva, urine, cervical secretions). vertical transmission either transplacentally or perinatally during delivery has been well described throughout the world. vertical transmission rates in areas where hbv is endemic (taiwan and japan) are high, whereas transmission to infants from hbv carrier mothers in other areas where hbv carrier rates are low is uncommon. transmission of hbv to infants occurs in up to % of infants when the mothers are acutely infected immediately before, during, or soon after pregnancy. hbsag is found in breast milk, but transmission by this route is not well documented. beasley and beasley et al demonstrated that although breast milk transmission is possible, seroconversion rates are no different between breastfed and nonbreastfed infants in a long-term follow-up study of hbsag-positive mothers. hill et al followed breastfed infants and formula-fed infants born to women who were chronically hbsag positive. all infants received hepatitis b immunoglobulin at birth and a full series of hepatitis b vaccine. none of the breastfed infants and nine of the formulafed infants were positive for hbsag after completion of the hbv vaccine series. breastfeeding had occurred for a mean of . months (range weeks to year). transmission, when it does happen, probably occurs during labor and delivery. another report from china followed infants born to hbsag-positive women. the infants received appropriate dosing and timing of hbig and hbv vaccine. at year of age, anti-hbs antibody was present in . % of the breastfed infants and . % of the bottle-fed infants. risk factors associated with immunoprophylaxis failure against vertical transmission of hbv include hbeag-seropositive mothers and elevated hbv dna "viral loads" in the mothers. in the aap committee on infectious diseases stated that "that breastfeeding of the infant by a hbsag-positive mother poses no additional risk for acquisition of hbv infection by the infant with appropriate administration of hepatitis b vaccine and hbig." screening of all pregnant women for hbv infection is an essential first step to preventing vertical transmission. universal hbv vaccination at birth and during infancy, with administration of hepatitis b immunoglobulin (hbig) immediately after birth to infants of hbsag-positive mothers, prevents hbv transmission in more than % of cases. breastfeeding by hbsag-positive women is not contraindicated, but immediate administration of hbig and hbv vaccine should occur. two subsequent doses of vaccine should be given at appropriate intervals and dosages for the specific hbv vaccine product. this decreases the small theoretic risk for hbv transmission from breastfeeding to almost zero. when acute peripartum or postpartum hepatitis occurs in a mother and hbv infection is a possibility, with its associated increased risk for transmission to the infant, a discussion with the mother or parents should identify the potential risks and benefits of continuing breastfeeding until the etiology of the hepatitis can be determined. if an appropriate alternative source of nutrition is available for the infant, breast milk should be withheld until the etiology of the hepatitis is identified. hbig and hbv vaccine can be administered to the infant who has not already been immunized or has no documented immunity against hbv. if acute hbv infection is documented in a mother, breastfeeding can continue after immunization has begun. acute infection with hcv can be indistinguishable from hepatitis a or b infection; however, it is typically asymptomatic or mild. hcv infection is the major cause of blood-borne non-a, non-b hepatitis (nanbh). chronic hcv infection is reported to occur % to % of the time regardless of age at time of infection. sequelae of chronic hcv infection are similar to those associated with chronic hbv infection. bortolotti et al the two commonly identified mechanisms of transmission of hcv are transfusions of blood or blood products and iv drug use. however, other routes of transmission exist because hcv infection occurs even in the absence of obvious direct contact with significant amounts of blood. other body fluids contaminated with blood probably serve as sources of infection. transmission through sexual contact occurs infrequently and probably requires additional contributing factors, such as coinfection with other sexually transmitted agents or high viral loads in serum and other body fluids. studies of transmission in households without other risk factors have demonstrated either low rates of transmission or no transmission. the reported rates of vertical transmission vary widely. in mothers with unknown hiv status or known hiv infection, the rates of vertical transmission were % to %, whereas the rates varied between % and % in known hiv-negative mothers. these same studies suggest that maternal coinfection with hiv, hcv genotype, active maternal liver disease, and the serum titer of maternal hcv rna may be associated with increased rates of vertical transmission. , , the correlation between hcv viremia, the hcv viral load in a mother, and vertical transmission of hcv is well documented. , , , the clinical significance and risk for liver disease after vertical transmission of hcv are still unknown. the timing of hcv infection in vertical transmission is also unknown. in utero transmission has been suggested by some studies, whereas intrapartum or postpartum transmission was proposed by ohto et al when they documented the absence of hcv rna in the cord blood of neonates who later became hcv rna positive at to months of age. more recently, gibb et al reported two pieces of data supporting the likelihood of intrapartum transmission as the predominant time of vertical transmission: (a) low sensitivity of pcr for hcv rna testing in the first month of life with a marked increase in sensitivity after that for diagnosing hcv infection in infants and (b) a lower transmission risk for elective cesarean delivery (without prolonged rupture of membranes) compared with vaginal or emergency cesarean delivery. another group, mcmenamin et al, analyzed vertical transmission in mother-infant pairs. the overall vertical transmission rate was . % ( / ), with another infants not tested or lost to follow-up. comparison of the vertical transmission rate was no different for vaginal delivery or emergency cesarean in labor versus planned cesarean ( . % vs. . %). this held true even when mothers had hepatitis c rna detected antenatally ( . % vs. . %). the authors did not support planned cesarean delivery to decrease vertical transmission of hepatitis c infection. no prospective, controlled trials of cesarean versus vaginal delivery and the occurrence of vertical hepatitis c transmission are available. the risk for hcv transmission via breast milk is uncertain. anti-hcv antibody and hcv rna has been demonstrated in colostrum and breast milk, although the levels of hcv rna in milk did not correlate with the titers of hcv rna in serum. , , , nevertheless, transmission of hcv via breastfeeding (and not in utero, intrapartum, or from other postpartum sources) has not been proven in the small number infants studied. transmission rates in breastfed and nonbreastfed infants appear to be similar, but various important factors have not been controlled, such as hcv rna titers in mothers, examination of the milk for hcv rna, exclusive breastfeeding versus exclusive formula feeding versus partial breastfeeding, and duration of breastfeeding.* zanetti et al including infants whose mothers were seropositive for hcv rna. eight infants in that study were infected with hcv, their mothers had both hiv and hcv, and three of these eight infants were infected with both hiv and hcv. the hcv rna levels were significantly higher in the mothers coinfected with hiv compared with those mothers with hcv alone. overall, the risk for hcv infection via breastfeeding is low, the risk for hcv infection appears to be more frequent in association with hiv infection and higher levels of hcv rna in maternal serum, no effective preventive therapies (ig or vaccine) exist, and the risk for chronic hcv infection and subsequent sequelae with any infection is high. it is therefore appropriate to discuss the theoretic risk for breastfeeding in hcv-positive mothers with the mother or parents and to consider proscribing breast milk when appropriate alternative sources of nutrition are available for the infants. hiv infection is a separate contraindication to breastfeeding. additional study is necessary to determine the exact role of breastfeeding in the transmission of hcv, including the quantitative measurement of hcv rna in colostrum and breast milk, the relative risk for hcv transmission in exclusively or partially breastfed infants versus the risk in formulafed infants, and the effect of duration of breastfeeding on transmission. the current position of the cdc is that no data indicate that hcv virus is transmitted through breast milk. therefore breastfeeding by a hcvpositive, hiv-negative mother is not contraindicated. infants born to hcv rna-positive mothers require follow-up through to months of age to determine infants' hcv status, regardless of the mode of infant feeding. infants should be tested for alanine aminotransferase and hcv rna at months and to months of age. alanine aminotransferase and anti-hcv antibody should be tested at to months of age to confirm an infant' s status: uninfected, ongoing hepatitis c infection, or past hcv infection. hepatitis d virus (hdv) is a defective rna virus that causes hepatitis only in persons also infected with hbv. the infection occurs as either an acute coinfection of hbv and hdv or a superinfection of hbv carriers. this "double" infection results in more frequent fulminant hepatitis and chronic hepatitis, which can progress to cirrhosis. the virus uses its own hbv rna (circular, negative-strand rna) with an antigen, hdag, surrounded by the surface antigen of hbv, hbsag. hdv is transmitted in the same way as hbv, especially through the exchange of blood and body fluids. hdv infection is uncommon where the prevalence of hbv is low. in areas where hbv is endemic, the prevalence of hdv is highly variable. hdv is common in tropical africa and south america as well as in greece and italy but is uncommon in the far east and in alaskan inuit despite the endemic occurrence of hbv in these areas. transmission of hdv has been reported to occur from household contacts and, rarely, through vertical transmission. no data are available on transmission of hdv by breastfeeding. hdv infection can be prevented by blocking infection with hbv; therefore hbig and hbv vaccine are the best protection. in addition to hbig and hbv vaccine administration to the infant of a mother infected with both hbv and hdv, discussion with the mother or parents should include the theoretic risk for hbv and hdv transmission through breastfeeding. as with hbv, once hbig and hbv vaccine have been given to the infant, the risk for hbv or hdv infection from breastfeeding is negligible. therefore breastfeeding after an informed discussion with the parents is acceptable. hepatitis e virus (hev) is a cause of sporadic and epidemic, enterically transmitted nanbh, which is typically self-limited and without chronic sequelae. hev is notable for causing high mortality rate in pregnant women. transmission is primarily via the fecal-oral route, commonly via contaminated water or food. high infection rates have been reported in adolescents and young adults (ages to years). tomar reported that % of cases of hev infections in the pediatric population in india manifest as acute hepatitis. maternal-neonatal transmission was documented when the mother developed hepatitis e infection in the third trimester. although hev was demonstrated in breast milk, no transmission via breast milk was confirmed in the report. five cases of transfusion-associated hepatitis e were reported. epidemics are usually related to contamination of water. person-to-person spread is minimal, even in households and day care settings. although ig may be protective, no controlled trials have been done. animal studies suggest that a recombinant subunit vaccine may be feasible. hev infection in infancy is rare, and no data exist on transmission of hev by breastfeeding. no evidence of clinically significant postnatal hev infection in infants or of chronic sequelae in association with hev infection and no documented hev transmission through breast milk is available. currently no contraindication exists to breastfeeding with maternal hev infection. ig has not been shown to be effective in preventing infection, and no vaccine is available for hev. hepatitis g virus (hgv) has recently been confirmed as a cause of nanbh distinct from hepatitis viruses a through e. several closely related genomes of hgv, currently named gbv-a, -b, and -c, appear to be related to hcv, the pestiviruses, and the flaviviruses. epidemiologically, hgv is most often associated with transfusion of blood, although studies have identified nontransfusion-related cases. hgv genomic rna has been detected in some patients with acute and chronic hepatitis and a small number of patients with fulminant hepatitis. gbv-c/hgv has also been found in some patients with inflammatory bile duct lesions, but the pathogenicity of this virus is unconfirmed. hgv rna has been detected in % to % of healthy blood donors in the united states. feucht et al described maternal-to-infant transmission of hgv in three of nine children. two of the three mothers were coinfected with hiv and the third with hcv. none of these infants developed signs of liver disease. neither the timing nor the mode of transmission was clarified. lin et al reported no hgv transmission in three mother-infant pairs after cesarean delivery and discussed transplacental spread via blood as the most likely mode of hgv infection in vertical transmission. wejstal et al reported on perinatal transmission of hgv to of infants born to hgv viremic mothers, identified by pcr. hgv did not appear to cause hepatitis in the children. fischler et al followed eight children born to hgv-positive mothers and found only one to be infected with hgv. that child remained clinically well, while his twin, also born by cesarean delivery and breastfed, remained hgv negative for years of observation. five of the other six children were breastfed for variable periods without evidence of hgv infection. ohto et al examined hgv mother-to-infant transmission. of pregnant japanese women who were screened, were identified as positive for gbv-c/hgv rna by pcr; of infants born to the hgv positive women were shown to be hgv rna positive. reportedly, none of the infants demonstrated a clinical picture of hepatitis, although two infants had persistent mild elevations (less than two times normal) of alanine aminotransferase. the viral load in mothers, who transmitted hgv to their infants, was significantly higher than in nontransmitting mothers. infants born by elective cesarean delivery had a lower rate of infection ( in ) compared with infants born by emergency cesarean delivery ( of ) or born vaginally ( of ) . in this study, hgv infection in breastfed infants was four times more common than in formula-fed infants, but this difference was not statistically significant because only four infants were formula fed. the authors report no correlation between infection rate and duration of breastfeeding was seen. testing of the infants was not done frequently and early enough routinely through the first year of life to determine the timing of infection in these infants. schröter et al reported transmission of hgv to of infants born to hgv rna positive mothers at week of age. none of breast milk samples were positive for gbv-c/hgv rna, and all of the children who were initially negative for hgv rna in serum remained negative at follow-up between to months of age. the foregoing data suggest that transmission is more likely to be vertical, before, or at delivery rather than via breastfeeding. the pathogenicity and the possibility of chronic disease due to hgv infection remain uncertain at this time. insufficient data are available to make a recommendation concerning breastfeeding by hgv-infected mothers. herpes simplex virus types and (hsv- , hsv- ) can cause prenatal, perinatal, and postnatal infections in fetuses and infants. prenatal infection can lead to abortion, prematurity, or a recognized congenital syndrome. perinatal infection is the most common form of infection ( in to live births, to cases per year in the united states) and is often fatal or severely debilitating. the factors that facilitate intrapartum infection and predict the severity of disease have been extensively investigated. postnatal infection is uncommon but can occur from a variety of sources, including oral or genital lesions and secretions in mothers or fathers, hospital workers and home caregivers, and breast lesions in breastfeeding mothers. a number of case reports have documented severe hsv- or hsv- infections in infants associated with hsvpositive breast lesions in the mothers. , , , cases of infants with hsv gingivostomatitis inoculating the mothers' breasts have also been reported. in the absence of breast lesions breastfeeding in hsv-seropositive or culture-positive women is reasonable when accompanied by careful handwashing, covering the lesions, and avoiding fondling or kissing with oral lesions until all lesions are crusted. breastfeeding during maternal therapy with oral or iv acyclovir can continue safely as well. inadequate information exists concerning valacyclovir, famciclovir, ganciclovir, and foscarnet in breast milk to make a recommendation at this time. breastfeeding by women with active herpetic lesions on their breasts should be proscribed until the lesions are dried. treatment of the mothers' breast lesions with topical, oral, and/or iv antiviral preparations may hasten recovery and decrease the length of viral shedding. human herpesvirus (hhv- ) is a cause of exanthema subitum (roseola, roseola infantum) and is associated with febrile seizures. hhv- appears to be most similar to cmv based on genetic analysis. no obvious congenital syndrome of hhv- infection has been identified, although prenatal infection has been reported. seroepidemiologic studies show that most adults have already been infected by hhv- . therefore primary infection during pregnancy is unlikely, but reactivation of latent hhv- infection may be more common. no case of symptomatic hhv- prenatal infection has been reported. the significance of reactivation of hhv- in a pregnant woman and the production of infection and disease in the fetus and infant remains to be determined. primary infection in children occurs most often between and months of age, when maternally acquired passive antibodies against hhv- are waning. febrile illnesses in infants younger than months of age have been described with hhv- infection, but infection before months or after years is uncommon. various studies involving serology and restriction enzyme analysis of hhv- isolates from mother/infant pairs support the idea that postnatal transmission and perhaps perinatal transmission from the mothers are common sources of infection. one study was unable to detect hhv- in breast milk by pcr analysis in samples, although positive control samples seeded with hhv- -infected cells did test positive. given the limited occurrence of clinically significant disease and the absence of sequelae of hhv- infection in infants and children, the almost universal acquisition of infection in early childhood (with or without breastfeeding) and the absence of evidence that breast milk is a source of hhv- infection, breastfeeding can continue in women known to be seropositive for hhv- . human herpesvirus (hhv- ) is closely related to hhv- biologically. primary infection with hhv- occurs primarily in childhood, usually later in life than hhv- infection. the median age of infection is months, with % of children becoming hhv- positive by years of age. seroprevalence of hhv- antibody has been reported to be % to % in adults, and passive antibody is present in almost all newborns. , like hhv- , hhv- infection can be associated with acute febrile illness, febrile seizures, and irritability, but in general it is a milder illness than with hhv- with fewer hospitalizations. virus excretion of hhv- occurs in saliva, and pcr testing of blood cells and saliva are frequently positive in individuals with past infection. congenital infection of hhv- was detected via dna pcr testing in of of cord blood samples ( %), but hhv- was not detected in any of cord blood specimens. hhv- dna was detected by pcr in of breast milk mononuclear cell samples from women who were serum positive for hhv- antibody. in the same study, small differences were seen in the hhv- seropositive rates between breastfed infants and bottle-fed infants at months of age ( . % versus %), at months of age ( % versus . %), and at months of age ( . % versus . %, respectively,). none of these differences were statistically significant. given that, in general, hhv- infection occurs earlier than hhv- infection in most infants and that hhv- is rarely found in breast milk, it seems unlikely that hhv- in breast milk is a common source of infection in infants and children. the infrequent occurrence of significant illness with hhv- infection, with the absence of sequelae except in patients who had transplantation surgery at older ages and the common occurrence of infection in childhood argue, that no reason to proscribe against breastfeeding for hhv- positive women exists. human papillomavirus (hpv) is a dna virus with at least different types. these viruses cause warts, genital dysplasia, cervical carcinoma (types and ), and laryngeal papillomatosis. transmission occurs through direct contact and sexual contact. laryngeal papillomas are thought to result from acquiring the virus in passage through the birth canal. infection in pregnant women or during pregnancy does not lead to an increase in abortions or the risk for prematurity, and no evidence indicates intrauterine infection. hpv is one of the most common viruses in adults and one of the most commonly sexually transmitted infections. diagnosis is usually by histologic examination or dna detection. spontaneous resolution does occur, but therapy for persistent lesions or growths in anatomically problematic locations is appropriate. therapy can be with podophyllum preparations, trichloroacetic acid, cryotherapy, electrocautery, and laser surgery. interferon is being tested in the treatment of laryngeal papillomas, with mixed results. prevention against transmission means limiting direct or sexual contact, but this may not be sufficient because lesions may not be evident and transmission may still occur. rintala et al examined the occurrence of hpv dna in the oral and genital mucosa of infants during the first years of life. hpv dna was identified in % to % of the oral scrape samples and in % to % of the genital scrape samples by pcr. oral hpv infection was acquired by % of children, cleared by %, and persisted in % of children; % of the children were never infected. they did not report on breast milk or breastfeeding in that study. the question of the source of the infection remains undetermined. the breast is a rare site of involvement. hpv types and can immortalize normal breast epithelium in vitro. hpv dna has been detected in breast milk in of ( . %) of milk samples from mothers, collected days postpartum. no attempt was made to correlate the presence of hpv dna in breast milk with the hpv status of an infant or to assess the "viral load" of hpv in breast milk or its presence over the course of lactation. a second study found dna of cutaneous and mucosal hpv types in of human milk samples and of colostrum samples. no reports of hpv lesions of the breast or nipple and documented transmission to an infant secondary to breastfeeding are available. no increased risk for acquiring hpv from breast milk is apparent, and breastfeeding is acceptable. even in the rare occurrence of an hpv lesion of the nipple or breast, no data suggest that breastfeeding or the use of expressed breast milk is contraindicated. measles is another highly communicable childhood illness that can be more severe in neonates and adults. measles is an exanthematous febrile illness following a prodrome of malaise, coryza, conjunctivitis, cough, and often koplik spots in the mouth. the rash usually appears to days after exposure. complications can include pneumonitis, encephalitis, and bacterial superinfection. with the availability of vaccination, measles in pregnancy is rare ( . in , pregnancies), although respiratory complications (primary viral pneumonitis, secondary bacterial pneumonia), hepatitis, or other secondary bacterial infections often lead to more severe disease in these situations. prenatal infection with measles may cause premature delivery without disrupting normal uterine development. no specific group of congenital malformations have been described in association with in utero measles infection, although teratogenic effects of measles infection in pregnant women may rarely manifest in the infants. perinatal measles includes transplacental infection when measles occurs in an infant in the first days of life. infection from extrauterine exposure usually develops after days of life. the severity of illness after suspected transplacental spread of virus to an infant varies from mild to severe and does not seem to vary with the antepartum or postpartum onset of rash in the mother. it is uncertain what role maternal antibodies play in the severity of an infant's disease. more severe disease seems to be associated with severe respiratory illness and bacterial infection. postnatal exposure leading to measles after days of life is generally mild, probably because of passively acquired antibodies from the mother. severe measles in children younger than year of age may occur because of declining passively acquired antibodies and complications of respiratory illness and rare cases of encephalitis. measles virus has not been identified in breast milk, whereas measles-specific antibodies have been documented. infants exposed to mothers with documented measles while breastfeeding should be given immunoglobulin (ig) and isolated from the mother until hours after the onset of rash, which is often only a short period after diagnosis of measles in the mother. the breast milk can be pumped and given to the infant because secretory iga begins to be secreted in breast milk within hours of onset of the exanthem in the mother. table - summarizes management of the hospitalized mother and infant with measles exposure or infection. mumps is an acute transient benign illness with inflammation of the parotid gland and other salivary glands and often involves the pancreas, testicles, and meninges. mumps occurs infrequently in pregnant women ( to cases in , pregnancies) and is generally benign. mumps virus has been isolated from saliva, respiratory secretions, blood, testicular tissue, urine, csf in cases of meningeal involvement, and breast milk. the period of infectivity is believed to be between days before and days after the onset of parotitis, with the usual incubation period being to days. prenatal infection with the mumps virus causes an increase in the number of abortions when infection occurs in the first trimester. a small increase in the number of premature births was noted in one prospective study of maternal mumps infection. no conclusive evidence suggests congenital malformations are associated with prenatal infection, not even with endocardial fibroelastosis, as originally reported in the s. perinatal mumps (transplacentally or postnatally acquired) has rarely if ever been documented. natural mumps virus has been demonstrated to infect the placenta and infect the fetus, and live attenuated vaccine virus has been isolated from the placenta but not from fetal tissue in women vaccinated days before induced abortion. antibodies to mumps do cross the placenta. postnatal mumps in the first year of life is typically benign. no epidemiologic data suggest that mumps infection is more or less common or severe in breastfed infants compared with formula-fed infants. although mumps virus has been identified in breast milk and mastitis is a rare complication of mumps in mature women, no evidence indicates that breast involvement occurs more frequently in lactating women. if mumps occurs in the mother breastfeeding can continue because exposure has already occurred throughout the days before the development of symptoms in the mother and secretory iga in the milk may help to mitigate the symptoms in the infant. human parvovirus b causes a broad range of clinical manifestations, including asymptomatic infection (most frequent manifestation in all ages), erythema infectiosum (fifth disease), arthralgia and arthritis, red blood cell (rbc) aplasia (less often decreased white blood cells or platelets), chronic infection in immunodeficient individuals, and rarely myocarditis, vasculitis, or hemophagocytic syndrome. vertical transmission can lead to severe anemia and immune-mediated hydrops fetalis, which can be treated, if accurately diagnosed, by intrauterine transfusion. inflammation of the liver or cns can be seen in the infant, along with vasculitis. if the child is clinically well at birth, hidden or persistent abnormalities are rarely identified. no evidence indicates that parvovirus b causes an identified pattern of birth defects. postnatal transmission usually occurs person to person via contact with respiratory secretions, saliva, and rarely blood or urine. seroprevalence in children at years of age is less than %, with the peak age of infection occurring during the schoolage years ( % to % of children infected). the majority of infections are asymptomatic or undiagnosed seroconversions. severe disease, such as prolonged aplastic anemia, occurs in individuals with hemoglobinopathies or abnormal rbc maturation. attack rates have been estimated to be % to % in casual contacts but up to % among household contacts. in one study of susceptible pregnant women, the annual seroconversion rate was . %. no reports of transmission to an infant through breastfeeding are available. excretion in breast milk has not been studied because of limitations in culturing techniques. rat parvovirus has been demonstrated in rat milk. the very low seroconversion rate in young children and the absence of chronic or frequent severe disease suggest that the risk for parvovirus infection via breast milk is not significant. the possibility of antibodies against parvovirus or other protective constituents in breast milk has not been studied. breastfeeding by a mother with parvovirus infection is acceptable. poliovirus infections (types , , and ) cause a range of illness, with % to % subclinical, % to % abortive, and % to % manifest as paralytic poliomyelitis. a review by bates from of cases of poliomyelitis in infants younger than month of age demonstrated paralysis or death in more than % and only one child without evidence of even transient paralysis. more than half the cases were ascribed to transmission from the mothers, although no mention was made of breastfeeding. breastfeeding rates at the time were approximately %. prenatal infection with polioviruses does cause an increased incidence of abortion. prematurity and stillbirth apparently occur more frequently in mothers who developed paralytic disease versus inapparent infection. although individual reports of congenital malformations in association with maternal poliomyelitis exist, no epidemiologic data suggest that polioviruses are teratogenic. also, no evidence indicates that live attenuated vaccine poliovirus given during pregnancy is associated with congenital malformations. , perinatal infection has been noted in several case reports of infants infected in utero several days before birth who had severe disease manifesting with neurologic manifestations (paralysis) but without fever, irritability, or vomiting. additional case reports of infection acquired postnatally demonstrate illness more consistent with poliomyelitis of childhood. these cases were more severe and involved paralysis, which may represent reporting bias. no data are available concerning the presence of poliovirus in breast milk, although antibodies to poliovirus types , , and have been documented. in this era of increasing worldwide poliovirus vaccination, the likelihood of prenatal or perinatal poliovirus infection is decreasing. maternal susceptibility to poliovirus should be determined before conception and poliovirus vaccine offered to susceptible women. an analysis of the last great epidemic in italy in was done using a population-based case-control study. in , births, infants were reported with paralytic poliomyelitis. a group of matched control subjects was selected from infants admitted to the hospital at the same time. using the dichotomous variable of never breastfed and partially breastfed, never-breastfed infants were among the cases and among the control group. the authors determined an odds ratio of . , with % confidence interval of . to , demonstrating that the risk for paralytic poliomyelitis was higher in infants never breastfed and lowest among those exclusively breastfed. because by the time the diagnosis of poliomyelitis is made in a breastfeeding mother, the exposure of the infant to poliovirus from maternal secretions has already occurred, and because the breast milk already contains antibodies that may be protective, no reason exists to interrupt breastfeeding. breastfeeding also does not interfere with successful immunization against poliomyelitis with oral or inactivated poliovirus vaccine. the occurrence of human t-cell leukemia virus type i (htlv-i) is endemic in parts of southwestern japan, , , , the caribbean, south america, and sub-saharan africa. htlv-i is associated with adult t-cell leukemia/lymphoma and a chronic condition with progressive neuropathy. the progressive neuropathy is called htlv-i associated myelopathy or tropical spastic paraparesis. other illnesses have been reported in association with htlv-i infection including dermatitis, uveitis, arthritis, sjögren syndrome in adults, and infective dermatitis and persistent lymphadenitis in children. transmission of htlv-i occurs most often through sexual contact, via blood or blood products, and via breast milk. infrequent transmission does occur in utero or at delivery and with casual or household contact. seroprevalence generally increases with age and varies widely in different regions and in populations of different backgrounds. in some areas of japan, seropositivity can be as high as % to %, but in south america, africa, and some caribbean countries the rates are % to %. in latin america seropositive rates can be as high as % to % among female sex workers or attendees to std clinics. in blood donors in europe, the seroprevalence of htlv-i has been reported at . % to . %. the seroprevalence in pregnant women in endemic areas of japan is as high as % to % and in nonendemic areas as low as . % to . %. htlv- is not a major disease in the united states. in studies from europe the seroprevalence in pregnant women has been noted to be up to . %. these pregnant women were primarily of african or caribbean descent. htlv-i antigen has been identified in breast milk of htlv-i positive mothers. another report shows that basal mammary epithelial cells can be infected with htlv-i and can transfer infection to peripheral blood monocytes. human milk from htlv-i positive mothers caused infection in marmosets. , htlv-i infection clearly occurs via breastfeeding and a number of reports document an increased rate of transmission of htlv-i to breastfed infants compared with formula-fed infants.* ando et al , in two separate reports demonstrated a parallel decline in antibodies against htlv-i in both formula-fed and breastfed infants to a nadir at approximately year of age and a subsequent increase in antibodies from to years of age. the percentage of children seropositive at year of age in the breastfed and formula-fed groups, respectively, was . % and . %, at . years of age it was . % and . %, and at years of age it was . % and . %. a smaller group of children followed through to years of age demonstrated no newly infected children after years of age and *references , , , , - , . no loss of antibody in any child who was seropositive at years of age. , transmission of htlv-i infection via breastfeeding is also clearly associated with the duration of breastfeeding. , , , it has been postulated that the persistence of passively acquired antibodies against htlv-i offers some protection through months of life (table - ) . other factors relating to htlv-i transmission via breast milk have been proposed. yoshinaga et al presented data on the htlv-i antigen producing capacity of peripheral blood and breast milk cells and showed an increased mother-to-child transmission rate when the mother' s blood and breast milk produced large numbers of antigen-producing cells in culture. hisada et al reported on mothers and infants in jamaica, demonstrating that a higher maternal provirus level and a higher htlv-i antibody titer were independently associated with htlv-i transmission to the infant. ureta-vidal et al reported an increased seropositivity rate in children of mothers with a high proviral load and elevated maternal htlv-i antibody titers. various interventions have been proposed to decrease htlv-i transmission via breastfeeding. complete avoidance of breastfeeding was shown to be an effective intervention by hino et al , in large population of japanese in nagasaki. avoiding breastfeeding led to an % decrease in transmission. breastfeeding for a shorter duration is another effective alternative. ando et al showed that freezing and thawing breast milk decreased the infectivity of htlv-i. sawada et al demonstrated in a rabbit model that htlv-i immunoglobulin protected against htlv-i transmission via milk. it is reasonable to postulate that any measure that would decrease the maternal provirus load or increase the anti-htlv-i antibodies available to infants might decrease the risk for transmission. the overall prevalence of htlv-i infection during childhood is unknown because the majority of individuals do not manifest illness until much later in life. the timing of htlv-i infection in a breastfeeding population has been difficult to assess because of passively acquired antibodies from the mother and issues related to testing. furnia et al in areas where the prevalence of htlv-i infection (in the united states, canada, or europe) is rare, the likelihood that a single test for antibody against htlv-i would be a false positive test is high compared with the number of true positive tests. repeat testing is warranted in many situations. quantification of the antibody titer and the proviral load is appropriate in a situation when mother-to-child transmission is a concern. a greater risk for progression to disease in later life has not been shown for htlv-i infection through breast milk, but early-life infections are associated with the greatest risk for adult t-cell leukemia. the mother and family should be informed about all these issues. if the risk for lack of breast milk is not too great and formula is readily available and culturally acceptable, then the proscription of breastfeeding, or at least a recommendation to limit the duration of breastfeeding to months or less, is appropriate to limit the risk for htlv-i transmission to the infant. freezing and thawing breast milk before giving it to an infant might be another reasonable intervention to decrease the risk for transmission, although no controlled trials document the efficacy of such an intervention. neither ig nor antiviral agents against htlv-i are available at this time. human t-cell leukemia virus type ii (htlv-ii) is endemic in specific geographic locations, including africa, the americas, the caribbean, and japan. transmission is primarily through intravenous drug use, contaminated blood products, and breastfeeding. sexual transmission occurs but its overall contribution to the prevalence of htlv-ii in different populations remains uncertain. many studies have examined the presence of htlv-i and ii in blood products. pcr testing and selective antibody tests suggest that about half of the htlv seropositivity in blood donors is caused by htlv-ii. htlv-ii has been associated with two chronic neurologic disorders similar to those caused by htlv-i, tropical or spastic ataxia. a connection between htlv-ii and glomerulonephritis, myelopathy, arthritis, t-hairy cell leukemia, and large granulocytic leukemia has been reported. mother-to-child transmission has been demonstrated in both breastfed and formula-fed infants. it appears that the rate of transmission is greater in breastfed infants.* htlv-ii has been detected in breast milk. nyambi et al reported that htlv-ii transmission did correlate with the duration of breastfeeding. the estimated rate of transmission was %. the time to seroconversion (after the initial loss of passively acquired maternal antibodies) for infected infants seemed to range between and years of age. at this time avoidance of breastfeeding and limiting the duration of breastfeeding are the only two possible interventions with evidence of effectiveness for preventing htlv-ii mother-to-child transmission. with the current understanding of retroviruses, it is appropriate in cases of documented htlv-ii maternal infection to recommend avoiding or limiting the duration of breastfeeding and provide alternative nutrition when financially practical and culturally acceptable. mothers should have confirmatory testing for htlv-ii and measurement of the proviral load. infants should be serially tested for antibodies to htlv-ii and have confirmatory testing if seropositive after to months of age. further investigation into the mechanisms of transmission via breast milk and possible interventions to prevent transmission should occur as they have for hiv- and htlv-i. human immunodeficiency virus type (hiv- ) is transmitted through human milk. refraining from breastfeeding is a crucial aspect of preventing perinatal hiv infection in the united states and many other countries. the dilemma is the use of replacement feeding versus breastfeeding in countries where breastfeeding provides infants with significant protection from illness and death due to malnutrition or other infections. the question of the contribution of breastfeeding in mother-to-child hiv- transmission is not a trivial one when one considers the following: . the who estimates that . million people were newly infected with hiv- in , with children younger than years old making up , of that . million. (this number has declined due to increasing access to interventions to prevent mother-to-infant transmission. availability of antiretroviral therapy for prevention of mother-to-child hiv transmission in developing countries in was estimated to reach % of the mothers who needed it.) . breastfeeding contributes an estimated % to % increase in the overall mother-to-child transmission rates, over and above intrauterine and intrapartum transmission, when no specific interventions to prevent transmission via breastfeeding are utilized. . despite a dramatic increase in the number of people receiving antiretroviral therapy in developing countries ( million), this represented only % of the individuals who needed treatment. the evidence of hiv transmission via breastfeeding is irrefutable. multiple publications summarize the current evidence for hiv transmission via breastfeeding in the literature. , , since , case reports have documented hiv transmission via breast milk to children around the world. , , , primary hiv infection in breastfeeding mothers, with the concomitant high viral load, is associated with a particularly high rate of hiv transmission via breast milk. palasanthiran et al estimated that risk at %.large observational studies have demonstrated higher rates of hiv transmission in breastfed infants of mothers with chronic hiv infection compared with formula-fed infants. , , a systematic analysis of published reports estimated the additional risk for perinatal hiv transmission due to breastfeeding to be % ( % confidence interval % to %). more recently published cohort studies similarly attributed additional risk for hiv transmission due to breastfeeding at % to % over and above the risk from prenatal and intrapartum transmission. , , laboratory reports demonstrate the presence of cell-free virus and cell-associated virus in breast milk as well as various immunologic factors that could block or limit infection.* a dose-response relationship has been observed, correlating the hiv viral load in human milk as well as a mother' s plasma viral load with an increased transmission risk for the breastfed infant. , , , many of the potential risk factors associated with human milk transmission of hiv is higher the longer the duration of breastfeeding. , , , , maternal characteristics related to transmission of hiv via human milk include younger maternal age, higher parity, lower cd + counts, higher plasma viral loads, and breast abnormalities (mastitis, abscess, or nipple lesions). characteristics of human milk that relate to a higher risk for transmission include higher viral load in the milk, lower concentrations of antiviral substances (lactoferrin, lysozyme), and lower concentrations of virus-specific cytotoxic t-lymphocytes, levels of various interleukins (il- , il- ), , secretory iga, and igm. mixed breastfeeding is also associated with a higher risk for hiv transmission compared with exclusive breastfeeding. , , the measurable benefits of breast milk versus the relative risk for hiv transmission to the infant due to exclusive breastfeeding (with optimization of other factors to decrease hiv transmission) have been reported in a couple of studies. , the measurable benefits of receiving breast milk versus the relative increased risk for hiv transmission will need to be determined in a prospective fashion in different locales. a number of potential interventions to prevent breastfeeding transmission of hiv- can be utilized (box - ) . the simplest and most effective is the compete avoidance of human milk. this is a practical solution in places like the united states and other countries where replacement feeding as well as other strictly medical interventions are feasible and reasonable, and the risk for not providing breast milk to the infant is negligible. in resourcepoor situations, where the risk for other infections is high without the benefits of breast milk, exclusive breastfeeding is appropriate, with any other reasonable and culturally acceptable interventions to decrease hiv transmission via breast milk. potentially effective interventions include exclusive breastfeeding, early weaning versus breastfeeding for longer durations, education, and support to decrease the likelihood of mastitis or nipple lesions. other possible interventions include treating a mother with antiretroviral therapy for her own health (cd counts less than ) or prophylactically to decrease the human milk viral load, treating an infant prophylactically for a prolonged period of time ( weeks to months) to protect against transmission via breastfeeding, treating the milk itself to decrease the viral load (by pasteurization or other methods), , treating acute conditions in mothers and infants (e.g., mastitis, breast lesions, infant candidiasis), and enhancing an infant' s own defenses via vitamins, immunization, or antiretroviral therapy. some of these may not be feasible in certain settings such as pasteurization or maternal antiretroviral therapy. others may not be culturally acceptable, such as treating expressed breast milk before giving it to an infant or even exclusive breastfeeding. significant data demonstrate the advantage of breastfeeding, even for hiv-infected or hivexposed infants. the complete avoidance of breastfeeding in certain situations may lead to increased risk for illness and death due to other reasons besides hiv transmission. a study from kenya showed improved hiv- -free survival rates in a formula-fed group of children born to hiv-positive mothers, but the breastfed and formula groups had similar mortality rates ( . % versus . %, respectively) and similar incidences of diarrhea and pneumonia in the first years of life. no difference in the two groups was seen in the prevalence of malnutrition, but the breastfed infants had better nutritional status in the first months of life. arpadi et al recommend additional nutritional interventions to complement breastfeeding in this population after months of age. two reports from zambia document the benefit of exclusive breastfeeding for decreasing late hiv transmission and the lower mortality at months in infants who had continued breastfeeding rather than had discontinued breastfeeding at months of age. , in malawi, hiv-infected and hiv-exposed infants who were breastfed (exclusive breastfeeding for months and mixed feeding after that) had lower mortality at months than those who were not breastfed. a report from botswana examined breastfeeding plus infant zidovudine prophylaxis for months versus formula feeding plus infant zidovudine for month; this study showed a decreased risk for vertical transmission with formula feeding, but also increased cumulative mortality for the hiv-infected infants at months of age who were in the formula-fed group. a study from south africa examining the use of vitamin a also demonstrated less morbidity in hiv-infected children who were breastfed than not breastfed. other abstract reports have shown increased morbidity in hiv-infected children due to diarrhea, gastroenteritis, and hospitalization after weaning from breastfeeding. , , , exclusive breastfeeding in most areas of the world is essential to infant health and survival, even in the situation of maternal hiv infection. , , , the duration of exclusive breastfeeding is crucial to decreasing the risk for hiv infection in infants versus the risk for malnutrition and other infections with early weaning. in the mashi study in botswana, thior et al evaluated infants randomized to breastfeeding plus infant zidovudine for months or formula feeding plus month of infant zidovudine. the cumulative infant mortality was significantly higher at months for the formula-fed group but at months it was similar between the two groups. the breastfed infants were more likely to become hiv infected despite the months of zidovudine prophylaxis. becquet et al analyzed data from cote d'ivoire for to ; % of the hivexposed infants were breastfed for a median of months, and % were formula fed and observed for years. no significant difference in the rate of hiv infection was seen in the two groups, and no significant difference between the two groups was seen for morbid events (diarrhea, acute respiratory infections or malnutrition) or hospitalization or death. the authors attributed these good outcomes to effective nutritional counseling and care, access to clean water, and the provision of a safe and continuous supply of breast milk substitute. coovadia et al studied exclusive breastfeeding in the first months of life as an intervention in south africa. of the exclusively breastfed infants, . % at weeks of age and . % at months of age were hiv infected. breastfed infants who also were fed solids or formula milk were more likely to acquire infection than exclusively breastfed infants. the cumulative mortality at months of age was markedly lower for exclusively breastfed infants ( . %) versus . % in the infants receiving mixed feedings. kuhn et al examined the effects of early, abrupt weaning on hiv-free survival of children in zambia. infants were randomly assigned to two different counseling programs that advised either abrupt weaning at months or prolonged breastfeeding. in the weaning intervention group, % of mothers stopped breastfeeding by months compared with a median duration of breastfeeding of months in the control group. the study found no significant difference in hiv-free survival at • women and their health care providers need to be aware of the potential risk for transmission of hiv infection to infants during pregnancy and in the peripartum period and through breast milk. • documented, routine hiv education and routine testing with the consent of women seeking prenatal care are strongly recommended so that each woman knows her hiv status and the methods available both to prevent the acquisition and transmission of hiv and to determine whether breastfeeding is appropriate. • at delivery, education about hiv and testing with the consent of women whose hiv status during pregnancy is unknown are strongly recommended. knowledge of a woman' s hiv status assists in counseling on breastfeeding and helps each woman understand the benefits to herself and her infant of knowing her serostatus and the behaviors that would decrease the likelihood of acquisition and transmission of hiv. • women who are known to have hiv infections must be counseled not to breastfeed or provide their milk for the nutrition of their own or other' s infants. • in general, women who are known to be hiv seronegative should be encouraged to breastfeed. however, women who are hiv seronegative but at particularly high risk for seroconversion (e.g., injection drug users and sexual partners of known hiv-positive persons or active drug users) should be educated about hiv with an individualized recommendation concerning the appropriateness of breastfeeding. in addition, during the perinatal period, information should be provided on the potential risk for transmitting hiv through breast milk and about methods to reduce the risk for acquiring hiv infection. • each woman whose hiv status is unknown should be informed of the potential for hiv-infected women to transmit hiv during the peripartum period and through breast milk and the potential benefits to her and her infant of knowing her hiv status and how hiv is acquired and transmitted. the health care provider needs to make an individualized recommendation to assist the woman in deciding whether to breastfeed. months in the two groups ( . % versus . %). children already infected by months of age had a higher mortality if they were assigned to the early weaning group ( . % versus . %). additional analysis showed that in mothers with less severe hiv disease early weaning was clearly harmful to the infant. arpadi et al studied the growth of hiv-exposed, uninfected children who were exclusively breastfed for months with rapid weaning to replacement foods or exclusively breastfed until months and then continued breastfeeding with complementary foods. weight-for-age z scores dropped markedly in both groups from to months of age but less so in the continued breastfeeding group. length-for-age z score also dropped dramatically, but was not influenced by continued breastfeeding. even in this hiv-exposed, uninfected group of children, additional nutritional interventions are essential to complement breastfeeding beyond months of age. in recent years the discussion around preventing hiv transmission via breastfeeding and in the number of studies examining the important issues have increased. , , the fact that intrapartum and perinatal transmission of hiv from mothers to infants has decreased markedly due to the increased utilization of antiretroviral therapy during pregnancy, delivery, and postnatally for prevention emphasizes the importance of now working harder to decrease breast milk transmission of hiv. in considering different possible interventions to decrease mother-infant hiv transmission, it is crucial to reemphasize the goals of optimizing maternal health and survival and optimizing infant health and survival at the same time. a laboratory report shows that mothers receiving highly active antiretroviral therapy (haart) while breastfeeding do have decreased whole breast milk hiv- viral loads ( / mothers had less than copies/ml) compared with mothers who did not receive haart ( / with less than copies/ml). however, the whole milk hiv- dna load (measured as "undetectable" at less than copies/ cells) was not significantly different in the haart ( of mothers)] and non-haart ( of ) groups. hiv- dna is incorporated into cells found in breast milk. another group showed significantly lower hiv rna levels in the breast milk of women treated with nevirapine, zidovudine, and lamivudine compared with women not receiving antiretroviral therapy. the use of maternal haart seems to decrease hiv- transmission via breastfeeding. one group working in mozambique, malawi, and tanzania working with mother-infants pairs receiving haart as prevention during pregnancy compared one cohort ( mother-infant pairs) who received supplementary formula and water filters for the first months of life with a second cohort ( motherinfant pairs) breastfeeding exclusively and the mothers receiving haart for the first months. the cumulative incidence rate of hiv infection at months of age was . % for the formula-fed infants and . % for breastfed infants. through months of age no apparent additional risk for late postnatal transmission of hiv was observed. the petra study team working in tanzania, south africa, and uganda examined the efficacy of three shortcourse regimens of zidovudine and lamivudine in preventing early and late hiv transmission in this predominantly breastfeeding population. there were four regimens: a, zidovudine and lamivudine starting at weeks' gestation plus intrapartum medication and -days' postpartum treatment; b, same as a without the prepartum component; c, intrapartum zidovudine and lamivudine only; d, placebo. at week the hiv transmission rates were . % in group a, . % in group b, . % in group c, and . % in group d. at months the hiv infection rates were % in group a, % in group b, % in group c, and % in group d. although a measurable decrease in transmission at weeks of age was observed, limited protection was seen at months of age. an observational study from tanzania compared maternal haart for months with exclusive breastfeeding and abrupt weaning at to months of age with a historical control of the same feeding schedule without the postnatal maternal haart. in the treatment group the cumulative hiv transmission was . % at weeks, . % at months, and . % at months of age. the cumulative hiv infection or death rate was . % at months and . % at months of age. the cumulative risk for hiv transmission was . % between and months. the hiv transmission in this treatment group was half the transmission rate in the historical control group. another study in sub-saharan africa with months of maternal haart and exclusive breastfeeding for months demonstrated % hiv-free survival at months of age; the maternal and infant mortality rates for the treated mother-infant pairs were significantly lower than the country' s maternal and infant mortality rates. antiretroviral therapy prophylaxis for infants is another investigated intervention to decrease hiv transmission via breastfeeding. in a study from cote d'ivoire comparing different groups over time, infants received zidovudine (zdv) alone as zdv prophylaxis, a single dose of nevirapine (nvp), and days of zidovudine (zdv) as nvp/ zdv prophylaxis, or a single dose of nevirapine plus zidovudine and lamivudine ( tc) for days as nvp/zdv/ tc prophylaxis. formula feeding (ff) was compared with exclusive shortened breastfeeding (esb) upto months of age and prolonged breastfeeding (pb). the cumulative transmission rates at months were . % in infants in the zdv + pb group, . % in infants in the nvp/zdv + esb group, . %, in the infants in the nvp/zdv +ff group, . % in the infants in the nvp/zdv/ tc + esb group, and . % in the infants in the nvp/zdv/ tc + ff group. kumwenda et al working in malawi demonstrated decreased hiv transmission with breastfeeding and two different infant prophylaxis regimens. at months of age, they observed a . % occurrence of hiv transmission for infants receiving a single dose of nevirapine plus week of zidovudine compared with . % in the group receiving a single dose of nevirapine plus week of zidovudine plus weeks of daily nevirapine, and . % in the group receiving a single dose of nevirapine plus week of zidovudine plus weeks of nevirapine and zidovudine. in the mitra study in tanzania in which the median time of breastfeeding was weeks, the hiv transmission rate at months in the infants who received zidovudine plus tc for week plus tc alone for breastfeeding through months of age was less than % of the transmission rate for those infants receiving only week of zidovudine plus tc. a summary of three trials in ethiopa, india, and uganda compared a single dose of nevirapine at birth for infants with weeks of daily nevirapine in predominantly breastfed infants whose mothers were counselled regarding feeding per the who/ unicef guidelines. at months of infants in the single-dose group and of in the extended-dose group were hiv infected, which was not statistically significant. the authors suggested that a longer course of infant antiretroviral prophylaxis might be more effective. the potential effect of breastfeeding on the hivpositive mother needs to be adequately assessed in relation to the mother's health status. from uganda and zimbabwe mbizvo et al reported no difference in the number of hospital admissions or mortality between hiv-positive and hiv-negative women during pregnancy. in the years after delivery the hiv-positive women had higher hospital admission (approximately two times increased risk) and death rates (relative risk greater than ) than hiv-negative women. chilongozi et al reported on hiv-positive mothers from four sub-saharan sites followed for months. serious adverse events occurred in women ( . %); deaths occurred in the hiv-positive women, and no deaths occurred in hiv-negative women. several studies have examined breastfeeding relative to mothers' health and reported conflicting results. the first study from kenya demonstrated a significantly higher mortality rate in breastfeeding mothers compared with a formula-feeding group in the years after delivery. the hypothesized explanation offered by the authors for this difference was increased metabolic demands, greater weight loss, and nutritional depletion. a second study from south africa showed an overall lower mortality rate in the two groups with no significant difference in mortality rate in the months of observation. kuhn et al reported no difference in mortality at months after delivery between women randomly assigned to a short breastfeeding group ( women, median breastfeeding duration months, % still breastfeeding at months) and a long breastfeeding group ( women, % breastfeeding at months, % breastfeeding at months, median months). the hiv-related mortality rates were high ( . %), but not associated with prolonged lactation. walson et al followed hiv-positive women for to years in kenya. the mortality risk was . % at year and . % at years of follow-up. although less than % of women reported a hospitalization during the years, they experienced various common infections (pneumonia, diarrhea, tb, malaria, stds, urinary tract infections, mastitis). breastfeeding was a significant cofactor for diarrhea and mastitis but not for pneumonia, tb, or hospitalization. in summary, breastfeeding of infants by hiv-positive mothers does lead to an increased risk for hiv infection in the infants. much remains to be understood about the mechanisms of hiv transmission via breast milk and the action and efficacy of different interventions to prevent such transmission. the complete avoidance of breastfeeding is a crucial component for the prevention of perinatal hiv infection in the united states and many other countries. in resource-poor settings, where breastfeeding is the norm and where it provides vital nutritional and infection protective benefits, the who, unicef, and the joint united nations programme on hiv/ aids (unaids) recommend education, counseling, and support for hiv-infected mothers so they can make an informed choice concerning infant feeding. mothers choosing to breastfeed should receive additional education, support, and medical care to minimize the risk for hiv transmission and to optimize their own health status during and after breastfeeding. mothers choosing to use replacement feedings should receive parallel education, support, and medical care for themselves and their infants to minimize the effect of the lack of breastfeeding. good evidence now shows that antiretroviral prophylactic regimens for mothers or infants while continuing breastfeeding does decrease postnatal hiv transmission. early weaning is associated with increased morbidity and mortality. further carefully controlled research is indicated to adequately assess the risks and benefits to infants and mothers of prolonged breastfeeding with antiretroviral prophylaxis for either or both mothers and infants. along with this, hiv testing rates must be improved at the same time as increased availability and access to antenatal care, hiv prevention services, and hiv medical care for everyone must be increased. the availability and free access to antiretroviral medications must also improve. the decision about infant feeding for hivpositive mothers remains a difficult one, but this is slowly changing with increasing options. the goals remain % hiv transmission prevention, optimal maternal health and survival, and long-term infant health and survival. human immunodeficiency virus type (hiv- ) is an rna virus in the nononcogenic, cytopathic lentivirus genus of retroviruses. it is genetically closer to simian immunodeficiency virus than to hiv- . the clinical disease associated with hiv- has similar symptoms to hiv- infection but progresses at a slower rate to severe immunosuppression. hiv- is endemic in western africa and parts of the caribbean and found infrequently in europe and north and south america. , it is transmitted via sexual contact, blood, or blood products and from mother to child. routine testing for hiv- is recommended in blood banks. antibody tests used for hiv- are only % to % sensitive for detecting hiv- . specific testing for hiv- is appropriate whenever clinically or epidemiologically indicated. vertical transmission occurs infrequently. ekpini et al followed a large cohort of west african mothers and infants: hiv- positive women, hiv- positive women, women seropositive for both hiv- and , and hiv seronegative women. a few cases of perinatal hiv- transmission occurred, but no case of late postnatal transmission was observed. it is probable that hiv- transmission via breast milk is less common than with hiv- , but insufficient data support that the risk for transmission is zero. mothers who test positive for hiv- should be tested for hiv- , and guidelines for breastfeeding should follow those for hiv- until additional information is available. rabies virus produces a severe infection with progressive cns symptoms (anxiety, seizures, altered mental status) that ultimately proceeds to death; few reports of survival exist. rabies occurs worldwide except in australia, antarctica, and several island groups. in more than , cases of rabies were reported to the who, a number that is probably a marked underestimate of the actual cases. between and , cases of human rabies were reported in the united states. , postexposure prophylaxis is given to thousands of patients each year. rabies virus is endemic in various animal populations, including raccoons, skunks, foxes, and bats. because of aggressive immunization programs, rabies in domesticated dogs and cats in the united states is uncommon. the virus is found in the saliva and tears and nervous tissue of infected animals. transmission occurs by bites, licking, or simply contact of oral secretions with mucous membranes or nonintact skin. many cases of rabies in humans now lack a history of some obvious contact with a rabid animal. this may be a result of the long incubation period (generally to weeks, but can be up to year, with reports of incubation periods of several years), a lack of symptoms early in an infectious animal, or airborne transmission from bats in enclosed environments (caves, laboratories, houses). person-to-person transmission via bites has not been documented, although it has occurred in corneal transplants. rabies viremia has not been observed in the spread of the virus. no evidence exists indicating transmission through breast milk. in the case of maternal infection with rabies, many scenarios can occur before the onset of progressive, severe cns symptoms. the progression and severity of maternal illness can preclude breastfeeding, but separation of an infant from the mother is appropriate regardless of the mother' s status and method of infant feeding (especially to avoid contact with saliva and tears). breastfeeding should not continue when the mother has symptoms of rabies, and the infant should receive postexposure immunization and close observation. an infant may received expressed breast milk, but the expression must occur without possible contamination with saliva or tears from the mother. depending on the scenario, the nature of a mother' s illness, the possible exposure of an infant to the same source as the mother, and the exposure of a child to the mother, postexposure immunization of an infant may be appropriate. a more common scenario is a mother' s apparent exposure to rabies (without exposure for the infant), necessitating postexposure immunization of the mother with rabies vaccine. in the majority of cases, in the absence of maternal illness, breastfeeding can reasonably continue during the mother' s five-dose immunization series in days. in a rare situation in which apparent exposure of mother and infant to rabies occurs together, postexposure treatment of both mother and infant should be instituted, and breastfeeding can continue. respiratory syncytial virus (rsv) is a common cause of respiratory illness in children and is relatively common in adults, usually producing milder upper respiratory tract infection in adults. no evidence indicates that rsv causes intrauterine infection, adversely affects the fetus, or causes abortion or prematurity. rsv does produce infection in neonates, causing asymptomatic infection, afebrile upper respiratory tract infection, bronchiolitis, pneumonia, and apnea. mortality rate can be high in neonates, especially in premature infants and ill full-term infants, particularly those with preexisting respiratory disease (hyaline membrane disease, bronchopulmonary dysplasia) or cardiac disease associated with pulmonary hypertension. rsv is believed to be transmitted via droplets or direct contact of the conjunctiva, nasal mucosa, or oropharynx with infected respiratory secretions. documentation of rsv infection is rarely made in adults, and spread from a mother or other household contacts probably occurs before a diagnosis can be made. therefore risk for rsv transmission from breast milk is probably insignificant compared with transmission via direct or droplet contact in families. in nurseries, however, it is appropriate to make a timely diagnosis of rsv infection in neonates to isolate infants from the others and prevent spread in the nursery. ribavirin is not recommended for routine use. it is infrequently used in patients with potentially life-threatening rsv infection. rsv infection should be suspected in any infant with rhinorrhea, nasal congestion, or unexplained apnea, especially in october through march in temperate climates. prophylaxis against rsv with rsv-specific immunoglobulin iv (rsv-igiv) during this season for infants at highest risk for severe disease is appropriate. debate surrounds the topic of the effect of passively acquired antibodies (in infants from mothers before birth) against rsv on the occurrence and severity of illness in neonates and infants. it appears that a higher level of neutralizing antibody against rsv in neonates decreases the risk for severe rsv disease. , some controversy remains concerning the measurable benefit of breastfeeding for preventing serious rsv disease. , , some studies have shown benefit and others no effect. controlling for possible confounding factors (e.g., smoking, crowded living conditions) in these studies has been difficult. at this point, no reason exists to stop breastfeeding with maternal rsv infection; a potential exists for benefit from nonspecific factors in breast milk against the rsv. infants with rsv infection should breastfeed unless their respiratory status precludes it. rotavirus infections usually result in diarrhea, accompanied by emesis and low-grade fever. in severe infections the clinical course can include dehydration, electrolyte abnormalities, and acidosis and can contribute to malnutrition in developing countries. generally, every child will have at least one episode of rotavirus infection by years of age. in developed countries, rotavirus is often associated with diarrhea requiring hospitalization in children younger than years of age, but rarely associated with death. worldwide rotavirus is the leading cause of diarrhea-related deaths in children younger than years old. estimates suggest that in children younger than years old rotavirus infection leads to more than million occurrences of diarrhea, million hospital admissions, and , deaths each year. fecal-oral transmission is the most common route, but fomites and respiratory spread may also occur. spread of infection occurs most often in homes with young children or in daycare centers and institutions. in hospitalized infants or mothers with rotavirus infection, contact precautions are indicated for the duration of the illness. no evidence indicates prenatal infection from rotavirus, but perinatal or postnatal infection from contact with the mother or others can occur. no case of transmission of rotavirus via breast milk has been documented. breast milk does contain antibodies to rotavirus for up to years. human milk mucin has been demonstrated to inhibit rotavirus replication and prevent experimental gastroenteritis. the mechanisms of rotavirus immunity are not well understood. they are thought to be multifactorial with cell-mediated immunity limiting severity and the course of infection, while humoral immunity protects against subsequent infections. innate and adaptive responses at the level of the mucosa are probably the most important. exclusive breastfeeding may decrease the likelihood of severe rotavirus-related diarrhea by as much as %. , although breastfeeding does not prevent infection with rotavirus, it seems to decrease the severity of rotavirus-induced illness in children younger than years old. , , at least one study suggested that this may represent simply the postponement of severe rotavirus infection until an older age. one study suggested that protection against rotavirus rapidly declines upon discontinuation of breastfeeding. this delay in rotavirus infection until the child is older may be beneficial in that the older child may be able to tolerate the infection or illness with a lower likelihood of becoming dehydrated or malnourished. continuing breastfeeding during an episode of rotavirus illness with or without vomiting is appropriate and often helpful to the infant. no reason to suspend breastfeeding by a mother infected with rotavirus is apparent. two rotavirus vaccines (rotateq and rotarix) have been licensed for use in more than countries, but less than countries have routine immunization programs. additional types of rotavirus vaccines are undergoing study in various countries, specifically examining the efficacy of the vaccines in low and medium income countries. some of the explanations for the slow implementation of an effective vaccine globally include differences in protection with specific vaccines in high income countries compared with low or medium income countries, the unfortunate association with intussusception in the united states, the delayed recognition of the significant rotavirus-related morbidity and mortality, and the cost of the new vaccines. the question of variable efficacy of the specific rotavirus vaccines in developed and developing countries remains an important one. several trials are examining this issue and attempting to address factors such as maternal transplacentally transferred antibodies, breastfeeding practices (especially immediately before immunization with a live oral rotavirus vaccine), stomach acid, micronutrient malnutrition, interfering gut flora, and differences in the epidemiology of rotavirus in different locations. evidence indicates that maternal immunization with rotavirus vaccine can increase both transplacental acquisition of antibodies and secretory iga in breast milk. additionally, oral rotavirus vaccines have been able to stimulate a good serologic response in both formula-fed and breastfed infants, although the antigen titers may need to be modified to create an optimal response in all infants. the actual protective effect of these vaccines in different situations and strategies will require measurement in ongoing prospective studies. congenital rubella infection has been well described, and the contributing variables to infection and severe disease have been elucidated. the primary intervention to prevent congenital rubella has been to establish the existence of maternal immunity to rubella before conception, including immunization with rubella vaccine and reimmunization if indicated. perinatal infection is not clinically significant. postnatal infection occurs infrequently in children younger than year of age because of passively acquired maternal antibodies. the predominant age of infection is to years old, and more than half of those with infections are asymptomatic. postnatal rubella is a self-limited, mild viral infection associated with an evanescent rash, shotty adenopathy, and low-grade transient fever. it most often occurs in the late winter and spring. infants with congenital infection shed the virus for prolonged periods from various sites and may serve as a source of infection throughout the year. contact isolation is appropriate for suspected and proved congenital infection for at least year, including exclusion from day care and avoidance of pregnant women, whereas postnatal rubella infection requires droplet precautions for days after the onset of rash. rubella virus has been isolated from breast milk after natural infection (congenital or postnatal) and after immunization with live attenuated vaccine virus. both iga antibodies and immunoreactive cells against rubella have been identified in breast milk. breastfed infants can acquire vaccine virus infection via milk but are asymptomatic. because postpartum infection with this virus (natural or vaccine) is not associated with clinically significant illness, no reason exists to prevent breastfeeding after congenital infection, postpartum infection with this virus, or maternal immunization with rubella vaccine. severe acute respiratory syndrome (sars) is a term that could be applied to any acute serious respiratory illness caused by or associated with a variety of infections agents; since , however, it has been linked with sars-associated coronavirus (sars-cov). in the global outbreak of to , more than probable cases of sars and more than deaths occurred. more than the actual number of affected individuals or its associated mortality rate (approximately % overall, and closer to % in persons older than years of age), it was what we did not know about this new unusual illness, and the tremendous publicity surrounding it, that made sars such a sensation. we now know the cause of this illness, known as the sars-cov. sars-cov was shown not to be closely related to the previously characterized coronavirus groups. , despite intense international collaboration to study the illness and the virus, many things are not known, such as the degree of infectiousness, the actual period of transmissibility, all the modes of transmission, how many people have an asymptomatic infection compared with those with symptoms or severe illnesses, how to make a rapid diagnosis of confirmed cases, and where it originated. at least cases of probable sars in children have been described in the literature. , , , in general, the illness in children is a mild, nonspecific respiratory illness, but in adolescents and adults it is more likely to progress to severe respiratory distress. it has been reported that children are less likely to transmit sars than adults. the overall clinical course, the radiologic evolution, and the histologic findings of these illness are consistent with the host' s immune response playing a significant role in disease production. five infants were born to mothers with confirmed sars. the infants were born prematurely ( to weeks), presumably due to maternal illness. although two of the five infants had serious abdominal illnesses (other coronaviruses have been associated with reported outbreaks of necrotizing enterocolitis), the presence of sars-cov could not be demonstrated in any of these infants. no evidence of vertical transmission of sars is available. the mode of feeding for any of the reported cases of young children with sars or the infants born to mothers with sars was not mentioned. as with other respiratory viruses predominantly transmitted by droplets, transmission via breast milk is an insignificant mode of transmission, if it occurs at all. the benefits of breastfeeding being what they are, mothers with sars should continue breastfeeding if they are able, or expressed breast milk can be given to an infant until the mother is able to breastfeed. in this era of worry about biologic terrorism, smallpox is an important concern. the concern for infants (breastfed or formula-fed) is direct contact with mothers or household members with smallpox. smallpox is highly contagious in the household setting due to person-to-person spread via droplet nuclei or aerosolization from the oropharynx and direct contact with the rash. additional potential exposures for infants include the release of a smallpox aerosol into the environment by terrorists, contact with a smallpox-contaminated space or the clothes of household members exposed to an aerosol, and infection via contact with a mother' s or a household member' s smallpox vaccination site. these risks are the same for breastfed and formulafed infants. no evidence for transmission of the smallpox virus via breast milk exists. a contact is defined as a person who has been in the same household or had face-to-face contact with a patient with smallpox after the onset of fever. patients do not transmit infection until after progression from the fever stage to the development of the rash. an exposed contact does not need to be isolated from others during the postcontact observation period (usually days) until the person develops fever. temperature should be monitored daily in the exposed contact. personal contact and breastfeeding between mother and infant can continue until the onset of fever, when immediate isolation (at home) should begin. providing expressed breast milk for the infant of a mother with smallpox should be avoided because of the extensive nature of the smallpox rash and the possibility of contamination (from the rash) of the milk during the expression process. no literature documents transmission of the smallpox virus via expressed breast milk. the other issue for breastfeeding infants is the question of maternal vaccination with smallpox in a preexposure event vaccination program. children older than year of age can be safely and reasonably vaccinated with smallpox in the face of a probable smallpox exposure. smallpox vaccination of infants younger than year of age is contraindicated. breastfeeding is listed as a contraindication to vaccination in the preevent vaccination program. it is unknown whether vaccine virus or antibodies are present in breast milk. the risk for infection due to contact or aerosolization of virus from a mother' s smallpox vaccination site is the same for breastfed and formula-fed infants. the advisory committee on immunization practices also does not recommend preevent smallpox vaccination of children younger than years old. a report documents tertiary contact vaccinia in a breastfeeding infant. a united states military person received a primary smallpox vaccination and developed a local reaction at the inoculation site. despite reportedly observing appropriate precautions, the individual' s wife developed vesicles on both areolae (secondary contact vaccinia). subsequently, the breastfeeding infant developed lesions on her philtrum, cheek, and tongue. both the mother and infant remained well and the infections resolved without therapy. culture and pcr testing confirmed vaccinia in both the mother' s and the infant' s lesions. the breast milk was not tested. in a review from to , sepkowitz reported on cases of secondary vaccinia in households. the cdc reported suspected cases of secondary/tertiary vaccinia with of those cases confirmed by culture or pcr. the cases were related to , vaccinated military personnel. this is an incidence of . cases per , vac cinees and . cases per , primary vaccinees. in a separate report on the civilian preevent smallpox vaccination program, , individuals were vaccinated between january and june , and no cases of contact vaccinia were reported. the risk for contact vaccinia is low. the risk is from close or intimate contact. in the above-mentioned case, the risk for the infant was contact with the mother' s breasts, the inadvertent site of her contact vaccinia. breastfed and formulafed infants are equally at risk from close contact in the household of a smallpox vaccinee or a case of secondary vaccinia, and separation from the individual is appropriate in both situations. if the breast of the nursing mother is not involved, expressed breast milk can be given to the infant. tt virus (ttv) is a recently identified virus found in a patient (tt) with posttransfusion hepatitis not associated with the other hepatitis-related viruses a through g. ttv has been described as an unenveloped, circular, single-stranded dna virus. this virus is prevalent in healthy individuals, including healthy blood donors, and has been identified in patients with hepatitis. ttv dna has been detected in infants of ttv-positive and ttvnegative mothers. ohto et al reported no ttv dna was detected in cord blood from infants, and it was detected in only of samples taken at month of age. they noted an increasing prevalence from months ( %) to years ( %), which they ascribed to acquisition via nonparenteral routes. in comparisons of the ttv dna in ttvpositive mothers and their ttv-positive infants, of showed high level nucleotide sequence similarity, and of differed by greater than %. schröter et al reported on ttv dna in breast milk examined retrospectively. notably, ttv dna was detected in of serum samples of infants at week of age, who were born to women viremic for ttv dna. twenty-four women who were negative for ttv dna gave birth to children who were initially negative for ttv dna and remained negative throughout the observation period (mean . months, range to months). ttv dna was detected in % of breast milk samples from ttv viremic women and in none of the breast milk samples from ttv-negative women. no clinical or laboratory evidence of hepatitis was found in the children who were observed to be ttv dna positive during the period of the study. other authors have reported ttv in breast milk detected by pcr. they describe the absence of ttv dna in infants at days and months of age, and of infants were positive for ttv dna at months of age, suggesting the late acquisition of infection via breastfeeding. tt virus is transmitted in utero and is found in breast milk. no evidence of clinical hepatitis in infants related to ttv infection and no evidence for a late chronic hepatitis exist. given the current available information, no reason to proscribe breastfeeding by ttv-positive mothers is compelling. certainly more needs to be understood concerning the chronic nature of this infection and the possible pathogenesis of liver disease. no documented evidence indicates that women with breast cancer have rna of tumor virus in their milk. no correlation between rna-directed dna polymerase activity has been found in women with a family history of breast cancer. rna-directed dna polymerase activity, a reserve transcriptase, is a normal feature of the lactating breast. , , epidemiologic data conflict with the suggestion that the tumor agent is transmitted through the breast milk. the incidence of breast cancer is low among groups who had nursed their infants, including lower economic groups, foreign-born groups, and those in sparsely populated areas. the frequency of breast cancer in mothers and sisters of a woman with breast cancer is two to three times that expected by chance. this could be genetic or environmental. cancer actually is equally common on both sides of the family of an affected woman. if breast milk were the cause, it should be transmitted from mother to daughter. when mother-daughter incidence of cancer was studied, no relationship was found to breastfeeding. sarkar et al reported that human milk, when incubated with mouse mammary tumor virus, caused degradation of the particular morphology and decreased infectivity and reverse transcriptase activity of the virions. they suggest that the significance of this destructive effect of human milk on mouse mammary tumor virus may account for the difficulty in isolating the putative human mammary tumor agent. sanner showed that the inhibitory enzymes in milk can be removed by special sedimentation technique. he ascribes the discrepancies in isolating virus particles in human milk to these factors, which inhibit rna-directed dna po lymerase. the fear of cancer in breastfed female offspring of a woman with breast cancer does not justify avoiding breastfeeding. breastfed women have the same breast cancer experience as nonbreastfed women, and no increase is seen in benign tumors. daughters of breast cancer patients have an increased risk for developing benign and malignant tumors because of their heredity, not because of their breastfeeding history. , unilateral breastfeeding (limited to the right breast) is a custom of tanka women of the fishing villages of hong kong. ing et al investigated the question, "does the unsuckled breast have an altered risk for cancer?" they studied breast cancer data from to . breast cancer occurred equally in the left and the right breasts. comparison of patients who had nursed unilaterally with nulliparous patients and with patients who had borne children but not breastfed indicated a highly significantly increased risk for cancer in the unsuckled breast. the authors conclude that in postmenopausal women who have breastfed unilaterally, the risk for cancer is significantly higher in the unsuckled breast. they thought that breastfeeding may help protect the suckled breast against cancer. others have suggested that tanka women are ethnically a separate people and that left-sided breast cancer may be related to their genetic pool and not to their breastfeeding habits. no mention has been made of other possible influences, such as the impact of their role as "fishermen" or any inherent trauma to the left breast. in , lane-claypon stated that a breast that had never lactated was more liable to become cancerous. nulliparity and absence of breastfeeding had been considered important risk factors for breast cancer. macmahon et al reported in that age at first full-term pregnancy was the compelling factor, and the younger the mother, the less the risk. in a collective review of the etiologic factors in cancer of the breast in humans, papaioannou concludes, "genetic factors, viruses, hormones, psychogenic stress, diet, and other possible factors, probably in that order of importance, contribute to some extent to the development of cancer of the breast." wing concluded in her review on human milk and health that "in view of the complete absence of any studies showing a relationship between breastfeeding and increased risk of breast cancer, the presence of virus-like particles in breast milk should not be a contraindication to breastfeeding." henderson et al gradually, studies have appeared challenging the dogma. brinton et al, mctiernan and thomas, and layde et al showed the clearly protective effects of breastfeeding. another example is a study conducted to clarify whether lactation has a protective role against breast cancer in an asian people, regardless of confounding effects of age at first pregnancy, parity, and closely related factors. in a hospital-based case-control study of women without breast cancer, statistical adjustment for potential confounders and a likelihood ratio test for linear trend were done by unconditional logistic regression. total months of lactation regardless of parity was the discriminator. regardless of age of first pregnancy and parity, lactation had an independent protective effect against breast cancer in japanese women. although breast cancer incidence is influenced by genetics, stress, hormones, and pregnancy, breastfeeding clearly has a protective effect. "there is a reduction in the risk of breast cancer among premenopausal women who have lactated. no reduction in the risk of breast cancer occurred among postmenopausal women with a history of lactation," according to newcombe et al, reporting a multicenter study in . varicella-zoster virus infection (varicella/chickenpox, zoster/shingles) is one of the most communicable diseases of humans, in a class with measles and smallpox. transmission is thought to occur via respiratory droplets and virus from vesicles. varicella in pregnancy is a rare event, although disease can be more severe with varicella pneumonia, and can be fatal. congenital varicella-zoster virus infection occurs infrequently, causing abortion, prematurity, and congenital malformations. a syndrome of malformations has been carefully described with congenital varicella-zoster virus infection, typically involving limb deformity, skin scarring, and nerve damage, including to the eye and brain. perinatal infection can lead to severe infection in infants if maternal rash develops days or less before delivery and within days after delivery. illness in infants usually develops before days of age and is believed to be more severe because of the lack of adequate transfer of antibody from the mother during this period and transplacental spread of virus to the fetus and infant during viremia in the mother. varicella in a mother occurring before days before delivery allows sufficient formation and transplacental transfer of antibodies to the infant to ameliorate disease even if the infant is infected with varicella-zoster virus. mothers who develop varicella rash more than days after delivery are less likely to transfer virus to the infant transplacentally; they pose a risk to the infants from postnatal exposure, which can be diminished by the administration of varicellazoster ig to the infant. postnatal transmission is believed to occur through aerosolized virus from skin lesions or the respiratory tract entering the susceptible infant's respiratory tract. airborne precautions are therefore appropriate in the hospital setting. infants infected with varicella-zoster virus in utero or in the perinatal period (younger than month of age) are more likely to develop zoster (reactivation of latent varicella-zoster virus) during childhood or as young adults. postnatal varicella from nonmaternal exposure can occur but is generally mild when it develops after weeks of age or when a mother has passed on antibodies against varicella-zoster virus via the placenta. severe postnatal varicella does occur in premature infants or infants of varicella-susceptible mothers. when a mother' s immune status relative to varicella-zoster virus is uncertain and measurement of antibodies to varicella-zoster virus in mother or infant cannot be performed promptly (less than hours), administration of vzig or ivig to the infant exposed to varicella or zoster in the postnatal period is indicated. ideally a mother' s varicella status should be known before pregnancy, when varicella virus vaccine could be given if indicated. varicella-zoster virus virus has not been cultured from milk, but varicella-zoster virus dna has been identified in breast milk. antibody against varicella-zoster virus has also been found in breast milk. breast milk from mothers who had received the varicella vaccine in the postpartum period was tested for varicella-zoster virus dna. varicella dna was not detected in any of the breast milk samples from the women, all of whom seroconverted after vaccination. one case of suspected transfer of varicella-zoster virus to an infant via breastfeeding has been reported, but virus may have been transmitted by respiratory droplet or exposure to rash before the mother began antiviral therapy. isolation of an infant from the mother with varicella and interruption of breastfeeding should occur only while the mother remains clinically infectious, regardless of the method of feeding. as soon as the infant has received varicella-zoster ig, expressed breast milk can be given to an infant if no skin lesions involve the breasts. persons with varicella rash are considered noninfectious when no new vesicles have appeared for hours and all lesions have crusted, usually in to days. immunocompetent mothers who develop zoster can continue to breastfeed if the lesions do not involve the breast and can be covered because antibodies against varicella-zoster virus are provided to the infant via the placenta and breast milk and will diminish the severity of disease, even if not preventing it. conservative management in this scenario would include giving an infant varicella-zoster ig as well (see table - ). it is estimated that to asymptomatic cases of west nile infection occur for every febrile illnesses and for every one case of meningoencephalitis associated with west nile virus. west nile fever is usually a mild illness of to days' duration. the symptoms are relatively nonspecific, including malaise, nausea, vomiting, headache, myalgia, lymphadenopathy, and rash. west nile disease is characterized by severe neurologic symptoms (e.g., meningitis, encephalitis, or acute flaccid paralysis, and occasionally optic neuritis, cranial nerve abnormalities, and seizures). children are infrequently sick with west nile virus infection and infants younger than year of age have rarely been reported. the case-fatality rate for in the united states was approximately . %, but has been reported as high as % to % in hospitalized patients. the case-fatality rate for persons older than years of age is considered to be higher, % to % among hospitalized patients in outbreaks in romania and israel. the primary mechanism of transmission is via a mosquito bite. mosquitoes from the genus culex are primary vectors. the bird-mosquito-bird cycle serves to maintain and amplify the virus in the environment. humans and horses are incidental hosts. the pathogenesis of the infection is believed to occur via replication of the virus in the skin and lymph nodes, leading to a primary viremia that seeds secondary sites before a second viremia causes the infection of the cns and other affected organs. , transmission has been reported in rare instances during pregnancy , via organ transplant and percutaneously in laboratory workers. a study of west nile virus infection in pregnancy documented four miscarriages, two elective abortions, and live births. cord blood samples were tested in infants and of were negative for anti-west nile virus igm. three infants had west nile virus infection, which could have been acquired congenitally. three of infants who had congenital malformations might have been caused by maternal west nile virus infection based on timing in pregnancy, but no evidence of west nile virus etiology is conclusive. west nile virus transmission occurs via blood and blood product transfusion, and the incidence has been estimated to be as high as per , donations during epidemics in specific cities. no evidence of direct person-to-person transmission without the mosquito vector has been found. one case of possible west nile virus transmission via breastfeeding has been documented. the mother acquired the virus via packed rbc transfusions after delivery. the second unit of blood she received was associated with other blood products from the same donation causing west nile infection in another transfusion recipient. eight days later the mother had a severe headache and was hospitalized with fever and a csf pleocytosis on day after delivery. the mother' s csf was positive for west nile virus-specific igm antibody. the infant had been breastfed from birth through the second day of hospitalization of the mother. samples of breast milk were west nile virus-specific igg and igm positive on day after delivery and west nile virus-specific igm positive on day . the same milk was west nile virus rna positive by pcr testing on day , but not on day after delivery. the infant tested positive for west nile virus-specific igm in serum at day of age, but remained well without fever. no clear-cut exposure to mosquitoes for the infant were reported. the cord blood and placenta were not available to be tested. igm antibodies can be found in low concentrations in breast milk, but this is not common or as efficient as the transfer of iga, secretory iga, or igg into breast milk. a review of west nile virus illness during the breastfeeding identified six occurrences of breastfeeding during maternal west nile virus illness. five of the six infants had no illness or detectable antibodies to west nile virus in their blood. one infant developed a rash and was otherwise well after maternal west nile virus illness, but was not tested for west nile virus infection. two infants were identified who developed west nile virus illness while breastfeeding, but no preceding west nile virus infection was demonstrated in their mothers. two other breastfeeding infants developed west nile virus-specific antibodies after their mothers acquired west nile virus illness in the last week of pregnancy, but congenital infection could not be ruled out. live virus was not cultured from samples of breast milk from mothers infected with west nile virus during pregnancy, but west nile virus rna was detected in two samples and samples had igm antibodies to west nile virus. the above data suggest that west nile virus infection through breastfeeding is rare. to date evidence of significant disease due to west nile virus infection in young breastfeeding children is lacking. at this time, no reason exists to proscribe breastfeeding in the case of maternal west nile virus infection if a mother is well enough to breastfeed. as with many other maternal viral illnesses, by the time the diagnosis is made in a mother, the infant may have already been exposed during maternal viremia and possible virolactia. the infant can and should continue to receive breast milk for the potential specific and nonspecific antiviral immunologic benefits. yellow fever virus is a flavivirus which is transmitted to humans by infected aedes and haemogogus mosquitos in tropical areas of south america and africa. large outbreaks occur when mosquitos in a populated area become infected from biting viremic humans infected with yellow fever virus. transmission from the mosquitos to other humans occurs after an incubation period in the mosquito of days. direct person-to-person spread has not been reported. illness due to yellow fever virus usually begins after an incubation period of to days, with acute onset of headache, fever, chills, and myalgia. photophobia, back pain, anorexia, vomiting, and restlessness are other common symptoms. the individual is usually viremic for the first days of illness until the fever and other symptoms diminish. liver dysfunction and even failure can develop as can myocardial dysfunction. cns infection is uncommon but symptoms can include seizures and coma. medical care should include intensive supportive care and fluid management. one case of congenital infection after immunization of a pregnant woman with the attenuated vaccine strain has been reported. one of infants whose mothers had inadvertently received the yellow fever virus vaccine during pregnancy developed igm and elevated neutralizing antibodies against the yellow fever virus without any evidence of illness or abnormalities. a more recent study from brazil examined inadvertent yellow fever virus immunization during pregnancy during a mass vaccination campaign in ; pregnant women received the yellow fever virus at a mean of . weeks' gestation, the majority of whom did not know their pregnancy status at the time. seroconversion occurred in . % of the women after at least weeks after vaccination. mild postvaccination illness (headache, fever, or myalgia) was reported by . % of the women. the frequency of malformations, miscarriages, stillbirths, and premature deliveries was similar to that found in the general population. at the -month follow-up point, % of the infants still demonstrated neutralizing antibodies against yellow fever virus, but after months only one child was still seropositive. transmission of the yellow fever vaccine virus through breastfeeding was recently reported from brazil. the mother was immunized during a yellow fever epidemic in a nonendemic area in brazil; days after delivering a healthy female infant ( weeks' gestational age) the mother received the dd yellow fever vaccine, and days later the mother reported headache, malaise, and low-grade fever that persisted for days. the mother continued breastfeeding and did not seek medical care for herself. at days of age the infant became irritable, developed fever, and refused to nurse. the infant developed seizures and subsequent evaluation of the infant demonstrated an abnormal csf and ct of the brain showed bilateral areas of diffuse low density suggestive of inflammation and consistent with encephalitis. yellow fever-specific igm antibodies were identified in the infant' s serum and csf. reverse-transcriptase polymerase chain reaction (rt-pcr) testing of the csf also demonstrated yellow fever virus rna identical to the dd yellow fever vaccine virus. breast milk and maternal serum were not tested for yellow fever virus. yellow fever virus, wild or vaccine type, has not been identified in human breast milk, although another flavivirus, west nile virus, has been detected in milk from a few lactating women with west nile virus infection. (see the section on west nile virus.) yellow fever vaccine-associated neurologic disease occurs at different rates in different age-groups, including . to . cases per infants younger than months of age. the d-derived yellow fever vaccines are contraindicated in infants younger than months of age. since , the advisory committee on immunization practices has recommended, based on theoretical risk, that yellow fever vaccine be avoided in nursing mothers, except when exposure in highrisk yellow fever endemic areas is likely to occur. no case of transmission of yellow fever virus from an infected mother to her infant via breastfeeding or breast milk has been reported. published information on the severity of yellow fever virus infection in infants younger than year of age, potential protection from passively acquired antibodies, or protection from breast milk is limited. no information on a differential risk in breastfed versus formula-fed infants is available. given the well documented method of transmission of yellow fever virus via mosquitos, and the lack of evidence of transmission via breast milk, it makes more sense to protect all infants against mosquito bites than to proscribe breastfeeding, even in the mother infected with yellow fever virus. continued breastfeeding or use of expressed breast milk will depend on a mother's health status and ability to maintain the milk supply while acutely ill. if another source of feeding is readily available then temporarily discarding expressed breast milk for at least days of acute illness in the mother is a reasonable precaution. lyme disease, as with other human illnesses caused by spirochetes, especially syphilis, is characterized by a protean course and distinct phases (stages) of disease. lyme borreliosis was described in europe in the early twentieth century. since the s, tremendous recognition, description, and investigation of lyme disease have occurred in the united states and europe. public concern surrounding this illness is dramatic. lyme disease is a multisystem disease characterized by involvement of the skin, heart, joints, and nervous system (peripheral and central). stages of disease are identified as early localized (erythema migrans, often accompanied by arthralgia, neck stiffness, fever, malaise, and headache), early disseminated (multiple erythema migrans lesions, cranial nerve palsies, meningitis, conjunctivitis, arthralgia, myalgia, headache, fatigue, and, rarely, myocarditis), and late disease (recurrent arthritis, encephalopathy, and neuropathy). the varied manifestations of disease may relate to the degree of spirochetemia, the extent of dissemination to specific tissues, and the host' s immunologic response. the diagnosis of lyme disease is often difficult in part because of the broad spectrum of presentations, inapparent exposure to the tick, and the lack of adequately standardized serologic tests. culture of the spirochete, borrelia burgdorferi, is not readily available. enzyme-linked immunosorbent assay (elisa), immunofluorescent assay, and immunoblot assay are the usual tests. pcr detection of spirochetal dna requires additional testing in clinical situations to clarify and standardize its utility. gardner reviewed infection during pregnancy, summarizing a total of adverse outcomes from cases reported in the literature. the adverse outcomes included miscarriage and stillbirth ( % of cases), perinatal death ( %), congenital anomalies ( %), and both early-and late-onset progressive infection in the infants. silver reviewed published reports and concluded that lyme disease during pregnancy is uncommon, even in endemic areas. although the spirochete can be transmitted transplacentally, a significant immune response in the fetus is often lacking, and the association of lyme infection with congenital abnormalities is weak. , little published information exists on whether b. burgdorferi can be transmitted via breast milk. one report showed the detection of b. burgdorferi dna by pcr in the breast milk of two lactating women with untreated erythema migrans, but no evidence of lyme disease or transmission of the spirochete in the one infant followed for year. no attempt to culture the spirochete was made, so it is not possible to determine if the detectable dna was from viable spirochetes or noninfectious fragments. in that same study of women with untreated erythema migrans who had detectable b. burgdorferi dna in the urine, still had detectable dna in the urine to days after starting treatment, but none had it months after initiating therapy. ziska et al reported on the management of nine cases of lyme disease in women associated with pregnancy; seven of the nine women were symptomatic at conception and six received antibiotics throughout pregnancy. follow-up of the infants showed no transmission of lyme disease, even in the seven infants who had been breastfed. the lack of adequate information on transmission of b. burgdorferi via breast milk cannot be taken as proof that it is not occurring. if one extrapolates from data on syphilis and the treponema pallidum spirochete, it would be prudent to discuss the lack of information on the transmission of b. burgdorferi via breast milk with the mother or parents and to consider withholding breast milk at least until therapy for lyme disease has begun or been completed. if the infection occurred during pregnancy and treatment has already been completed, an infant can breastfeed. if infection occurs postpartum or the diagnosis is made postpartum, infant exposure may have already occurred. again, discussion with the mother or parents about withholding versus continuing breastfeeding is appropriate. after prenatal or postnatal exposure, an infant should be closely observed and empiric therapy considered if the infant develops a rash or symptoms suggestive of lyme borreliosis. treatment of mother and infant with ceftriaxone, penicillin, or amoxicillin is acceptable during breastfeeding relative to the infant' s exposure to these medications. doxycycline should not be administered for more than days while continuing breastfeeding because of possible dental staining in the neonate. continued surveillance for viable organisms in breast milk and evidence of transmission through breastfeeding is recommended. a large body of information is available on various "lyme vaccines" used in dogs, but these vaccines are only partially protective and must be repeated yearly. preliminary information suggests that a vaccine for use in humans safely produces good serologic responses, but protective efficacy has not been demonstrated, and no information exists on its use during pregnancy or breastfeeding. syphilis is the classic example of a spirochetal infection that causes multisystem disease in various stages. both acquired syphilis and congenital syphilis are well-described entities. acquired syphilis is almost always transmitted through direct sexual contact with open lesions of the skin or mucous membranes of individuals infected with the spirochete, treponema pallidum. congenital syphilis occurs by infection across the placenta (placentitis) at any time during the pregnancy or by contact with the spirochete during passage through the birth canal. any stage of disease (primary, secondary, tertiary) in a mother can lead to infection of the fetus, but transmission in association with secondary syphilis approaches %. infection with primary syphilis during pregnancy, without treatment, leads to spontaneous abortion, stillbirth, or perinatal death in % of cases. similar to acquired syphilis, congenital syphilis manifests with moist lesions or secretions from rhinitis (snuffles), condylomata lata, or bullous lesions. these lesions and secretions contain numerous spirochetes and are therefore highly infectious. postnatal infection of an infant can occur through contact with open, moist lesions of the skin or mucous membranes of the mother or other infected individuals. if the mother or infant has potentially infectious lesions, isolation from each other and from other infants and mothers is recommended. if lesions are on the breasts or nipples, breastfeeding or using expressed milk is contraindicated until treatment is complete and the lesions have cleared. spirochetes are rarely identified in open lesions after more than hours of appropriate treatment. penicillin remains the best therapy. evaluation of an infant with suspected syphilis should be based on the mother' s clinical and serologic status, history of adequate therapy in the mother, and the infant' s clinical status. histologic examination of the placenta and umbilical cord, serologic testing of the infant' s blood and csf, complete analysis of the csf, long bone and chest radiographs, liver function tests, and a complete blood cell count are all appropriate given the specific clinical situation. treatment of the infant should follow recommended protocols for suspected, probable, or proven syphilitic infection. no evidence indicates transmission of syphilis via breast milk in the absence of a breast or nipple lesion. when a mother has no suspicious breast lesions, breastfeeding is acceptable as long as appropriate therapy for suspected or proven syphilis is begun in the mother and infant. giardiasis is a localized infection limited to the intestinal tract, causing diarrhea and malabsorption. immunocompetent individuals show no evidence of invasive infection, and no evidence exists that documents fetal infection from maternal infection during pregnancy. giardiasis is rare in children younger than months of age, although neonatal infection from fecal contamination at birth has been described. human milk has an in vivo protective effect against giardia lamblia infection, as documented by work from central africa, where the end of breastfeeding heralds the onset of giardia infection. this has been reaffirmed in undeveloped countries around the world. the protective effect of breast milk has been identified in the milk of noninfected donors. the antiparasitic effect does not result from specific antibodies but rather from lipase enzymatic activity. the lipase acts in the presence of bile salts to destroy the trophozoites as they emerge from their cysts in the gi tract. hernell et al demonstrated that free fatty acids have a marked giardiacidal effect, which supports the conclusion that lipase activity releasing fatty acids is responsible for killing g. lamblia. g. lamblia have also been reported to appear in the mother' s milk, and the parasite has been transmitted to newborns via that route. the exact relationship of breastfeeding to transmission of g. lamblia and the effect on infants continue to be studied, even though symptomatic infection in breastfed infants is rare. one report from the middle east suggests that even partial breastfeeding is protective against infection with intestinal parasites, including cryptosporidium and giardia lamblia. breastfeeding by mothers with giardiasis is problematic mainly because of the medications used for therapy. metronidazole' s safety in infants has not been established, and little information is available on quinacrine hydrochloride and furazolidone in breast milk. paromomycin, a nonabsorbable aminoglycoside, is a reasonable alternative recommended for treatment of pregnant women. breastfeeding by a mother with symptomatic giardiasis is acceptable when consideration is given to the presence of the therapeutic agents in the breast milk. hookworm infection, most often caused by ancylostoma duodenale and necator americanus, is common in children younger than the age of years, and there is at least one report on infantile hookworm disease from china. this publication from the chinese literature reports hundreds of cases of infantile hookworm disease that include the common symptoms of bloody stools, melena, anorexia, listlessness, and edema. anemia, eosinophilia and even leukemoid reactions occur as part of the clinical pictures in young children. they also note at least cases of hookworm diseases in newborn infants younger than month of age. in the discussion of infantile hookworm infection, they note four routes of infection: direct contact with contaminated soil, "sand-stuffed" diapers, contaminated "washed/wet" diapers, and vertical equal to transmammary transmission or transplacental transmission. they postulated that infection of infants before to days of age would most likely be due to transplacental transmission and infection before environmental contact would most likely be due to transmammary transmission. ample evidence is available in veterinary medicine of transmammary spread of helminths. , at least two reports suggest the possibility of transmammary transmission of hookworms in humans. setasuban et al described the prevalence of necator americanus in nursing mothers as % and identified n. americanus in breast milk in one case. nwosu documented positive stool samples for hookworms in of neonates ( %) at to weeks of age in southern nigeria. the majority of neonatal infections were due to ancylostoma duodenale although necator americanus is more prevalent in that area of nigeria. examination of colostral milk did not demonstrate any hookworm larvae. additional epidemiologic work is necessary to determine the potential significance of transmammary spread of helminths in humans, and more careful examination of breast milk as a source of hookworm infection is required before reasonable recommendation are possible. malaria is recognized as a major health problem in many countries. the effect of malaria infection on pregnant and lactating women and thus on the developing fetus, neonate, and growing infant can be significant. the four species of malaria, plasmodium vivax, p. ovale, p. malariae, and p. falciparum, vary in the specific aspects of the disease they produce. p. vivax exists throughout the world, but p. falciparum predominates in the tropics and is most problematic in its chloroquine-resistant form. malaria in the united states is most often seen in individuals traveling from areas where malaria is endemic. the parasite can exist in the blood for weeks, and infection with p. vivax and p. malariae can lead to relapses years later. transmission occurs through the bite of the anopheline mosquito and can occur via transfusion of blood products and transplacentally. congenital malaria is rare but seems to occur more often with p. vivax and p. falciparum. it usually presents in the first days of life (range day to months). it may resemble neonatal sepsis, with fever, anemia, and splenomegaly occurring in the most neonates and hyperbilirubinemia and hepatomegaly in less than half. malaria in infants younger than months of age generally manifests with less severe disease and death than in older children. possible explanations include the effect of less exposure to mosquitoes, passive antibody acquired from the mother, and the high level of fetal hemoglobin in infants at this age. the variations in the infection rates in children younger months of age during the wet and dry seasons support the idea that postnatal infection is more common than congenital infection. no evidence indicates that malaria is transmitted through breast milk. the greatest risk to infants is exposure to the anopheline mosquito infected with malaria. the main issues relative to malaria and breastfeeding are how to protect both mothers and infants effectively from mosquitoes and what drugs for treating malaria in mothers are appropriate during lactation. protection from mosquito bites includes screened-in living areas, mosquito nets while sleeping, protective clothing with or without repellents on the clothes, and community efforts to eradicate the mosquitoes. chloroquine, quinine, and tetracycline are acceptable during breastfeeding. sulfonamides should be avoided in the first month of an infant' s life, but pyrimethamine-sulfadoxine (fansidar) can be used later. mefloquine is not approved for infants or pregnant women. however, the milk/plasma ratio for mefloquine is less than . , there is a large volume of distribution of the drug, high protein binding of the drug limits its presence in breast milk, and the relative importance of breastfeeding in areas where malaria is prevalent shifts the risk/benefit ratio in favor of treatment with mefloquine. the single dose recommended for treatment or the onceweekly dose for prevention allows for continued breastfeeding with discarding of the milk for short periods after a dose ( to hours). maternal plasma levels of primaquine range from to ng/ml, but no information is available on levels in human milk. primaquine is used in children, and once daily dosing in the mother would allow discarding milk with peak levels of drug. therefore breastfeeding during maternal malaria even with treatment is appropriate with specific medications. strongyloides stercoralis is a nematode (roundworm). most infections are asymptomatic, but clinically significant infection in humans can include larval skin invasion, tissue migration, intestinal invasion with abdominal pain and gi symptoms, and a loeffler-like syndrome due to migration to the lungs. immune-compromised individuals can develop dissemination of larvae systemically, causing various clinical symptoms. humans are the principal hosts, but other mammals can serve as reservoirs. infection via the skin by filariform larvae is the most common form of transmission; ingestion is an uncommon occurrence. transmammary transmission of strongyloides species has been described in dogs, ewes, and rats. , , only one report of transmammary passage of strongyloides larvae in humans is available. in infants younger than days of age, % demonstrated the presence of strongyloides fuelleborni on stool examination. the clinical significance of this was not elucidated. strongyloides larvae was identified in only one sample of milk from nursing mothers. in the absence of an understanding of the clinical significance of strongyloides in the stools of young infants, given the lack of exclusion of the most common mechanism of transmission (through the skin) in the single report and the apparent infrequent evidence of these larvae in human milk, it is difficult to make any recommendations concerning breastfeeding and strongyloides. toxoplasmosis is one of the most common infections of humans throughout the world. the infective organism, toxoplasma gondii, is ubiquitous in nature. the prevalence of positive serologic test titers increases with age, indicating past exposure and infection. the cat is the definitive host, although infection occurs in most species of warmblooded animals. postnatal infection with toxoplasmosis is usually asymptomatic. symptomatic infection typically manifests with nonspecific symptoms, including fever, malaise, myalgia, sore throat, lymphadenopathy, rash, hepatosplenomegaly, and occasionally a mononucleosis-like illness. the illness usually resolves without treatment or significant complications. congenital infection or infection in an immunodeficient individual can be persistent and severe, causing significant morbidity and even death. although most infants with congenital infection are asymptomatic at birth, visual abnormalities, learning disabilities, and mental retardation can occur months or years later. the syndrome of congenital toxoplasmosis is clearly defined, with the most severe manifestations involving the cns, including hydrocephalus, cerebral calcifications, microcephaly, chorioretinitis, seizures, or simply isolated ocular involvement. the risk for fetal infection is related to the timing of primary maternal infection, although transmission can occur with preexisting maternal toxoplasmosis. in the last months of pregnancy the protozoan is more readily transmitted to the fetus, but the infection is more likely to be subclinical. early in pregnancy the transmission to a fetus occurs less frequently but does result in severe disease. treatment of documented congenital infection is currently recommended, although duration and optimal regimen have not been determined, and reversal of preexisting sequelae generally does not occur. prevention of infection in susceptible pregnant women is possible by avoiding exposure to cat feces or the organism in the soil. pregnant or lactating women should not change cat litter boxes, but if they must, it should be done daily and while wearing gloves. the oocyst is not infective for the first to hours after passage. mothers can avoid ingestion of the organism by fully cooking meats and carefully washing fruits, vegetables, and food preparation surfaces. in various animal models, t. gondii has been transmitted through the milk to the suckling young. the organism has been isolated from colostrum as well. the newborn animals became asymptomatically infected when nursed by an infected mother whose colostrum contained t. gondii. only one report has identified t. gondii in human milk, and some question surrounds the reliability of that report. transmission during breastfeeding in humans has not been demonstrated. breast milk may contain appropriate antibodies against t. gondii. given the benign nature of postnatal infection, the absence of documented transmission in human breast milk, and the potential antibodies in breast milk, no reason exists to proscribe breastfeeding by a mother known to be infected with toxoplasmosis. trichomonas vaginalis is a flagellated protozoan that can produce vaginitis (see chapter for a discussion of vaginitis) but frequently causes asymptomatic infection in both men and women. the parasite is found in % to % of women in the childbearing years. it is transmitted predominantly by sexual intercourse, but it can be transmitted to the neonate by passage through the birth canal. this parasite often coexists with other stds, especially gonorrhea. infection during pregnancy or while taking oral contraceptives is more difficult to treat. some evidence suggests that infection with and growth of the parasite are enhanced by estrogens or their effect on the vaginal epithelium. no evidence indicates adverse effects on the fetus in association with maternal infection during pregnancy. occasionally female newborns have vaginal discharge during the first weeks of life caused by t. vaginalis. this is thought to be influenced by the effect of maternal estrogen on the infant' s vaginal epithelium and acquisition of the organism during passage through the birth canal. the organism does not seem to cause significant disease in a healthy infant. no documentation exists on transmission of t. vaginalis via breast milk. the difficulty encountered with maternal infection during lactation stems from metronidazole (flagyl), the drug of choice, being contraindicated for infants. case reports describe treatment of neonates with metronidazole without adverse effect. although topical agents containing povidone-iodine (betadine) or sodium lauryl sulfate (trichotine) can be effective when given as douches, creams, or suppositories, metronidazole remains the treatment of choice. the aap advises using metronidazole only with a physician' s discretion and considers its effect on a nursing infant unknown but possibly a concern. the potential concerns are metronidazole' s disulfiram-like effect in association with alcohol, tumorigenicity in animal studies, and leukopenia and neurologic side effects described in adults. on the other hand, metronidazole is given to children beyond the neonatal period to treat serious infections with various other parasites, such as entamoeba histolytica. the current recommendation for lactating women is to try local treatment first, and if these fail, then to try metronidazole. a -g single-dose treatment produces peak levels after hour, and discarding expressed breast milk for the next to hours is recommended. if this treatment also fails, a -g twice-daily regimen for days or a -g single daily dose for to days is recommended, with discarding of breast milk close to the dose and timing of feedings distant from the dose. infants who exclusively breastfeed are presumed at greater risk from exposure to metronidazole than those who are only partially breastfed. candida consists of multiple species. the most common species affecting humans include c. albicans as the dominant agent and c. tropicalis, c. krusei, and c. parapsilosis, as well as many other uncommon species. in general, candida exists as a commensal organism colonizing the oropharynx, gi tract, vagina, and skin without causing disease until some change disrupts the balance between the organism and the host. mild mucocutaneous infection is the most common illness, which can lead to vulvovaginitis, mastitis, or, uncommonly, oral mucositis in a mother, and thrush (oral candidiasis) and candidal diaper rash in an infant. invasive candidal infection occurs infrequently, usually when a person has other illness, impaired resistance to infection (hiv, diabetes mellitus, neutropenia; decreased cell-mediated immunity in premature infants or lbw or vlbw infants), or disrupted normal mucosal and skin barriers and has received antibiotics or corticosteroids. invasive disease can occur through local spread, and may occur more often in the genitourinary tract (urethra, bladder, ureters, kidneys), but usually develops in association with candidemia. the bladder and kidney are more frequently involved, but when dissemination occurs via candidemia, a careful search for other sites of infection should be made (e.g., retina, liver, spleen, lung, meninges). transmission usually occurs from healthy individuals colonized with candida through direct contact with them or through contact with their oral or vaginal secretions. intrauterine infection can occur through ascending infection through the birth canal but is rare. no distinct syndrome of congenital candidal infection exists. most often an infant is infected in passing through the birth canal and remains colonized. postnatal transmission can occur through direct contact with caregivers. the mother and infant serve as an immediate source of recolonization for each other, especially during the direct contact of breastfeeding. for this reason, an infant and breastfeeding mother should be treated simultaneously when treating thrush, vulvovaginitis, diaper candidiasis, or mastitis. colonization with this organism usually occurs in the absence of any clinical evidence of infection. simultaneous treatment should occur even in the absence of any clinical evidence of candida infection or colonization in the apparently uninvolved individual of the breastfeeding dyad. no well-controlled clinical trials define the most appropriate or most effective method(s) of treatment for candidal infection in breastfeeding mother-infant pairs. the list of possible treatment products is extensive and includes many anecdotal and empirical regimens. in the face of this absence of data, brent conducted a survey of members of the academy of breastfeeding medicine concerning the respondents' approach to diagnosis and treatment of thrush in the breastfeeding dyad. most of the respondents relied on the history and physical examination of the infant, but only a third rated the examination of the mother as very important in making a diagnosis. only % reported using laboratory testing to make the diagnosis. twentyone percent of the respondents reported using only oral nystatin for the infant when the mother was asymptomatic. almost half treated the infant and the mother with topical nystatin, and % used oral nystatin for the infant and oral fluconazole for the mother when the mother had breast pain. less than % used oral fluconazole for both infant and mother, and other therapies were used by about % of the respondents. for recurrence of persistence of the thrush, more respondents reported treating the mother or both the infant and mother with fluconazole, and almost a quarter reported using other therapies. considerable discussion of mammary candidosis/candidiasis, the clinical diagnosis of candidal involvement of the breast, the significance of pain with breastfeeding, and the presence or absence of candida albicans in milk samples is ongoing. , , this topic will continue to be debated because additional prospective studies are necessary to clarify specific issues. data are inadequate to make specific recommendations about various clinical situations regarding candida and breastfeeding. clinical practice will vary with experience, especially for the more problematic clinical situations. some general guidelines follow. (see chapter for a discussion of mastitis.) the treatment of mucocutaneous candidiasis should probably begin with a topical agent, such as nystatin, clotrimazole, miconazole, econazole, butaconazole, terconazole, or ciclopirox. treatment should continue for at least weeks, even with obvious improvement in or days. failures most often result from inadequate therapy involving the frequency of application, careful washing and drying before application, or, in the case of diaper candidiasis, decreasing the contact of the skin with moisture. nystatin oral suspension is less effective for the treatment of oral candidiasis in infants, now compared with the past, supposedly due to increasing resistance. gentian violet (diluted to . % to . %) applied to the breast or painted onto an infant' s mouth is being recommended more frequently. other topical preparations have been recommended for the mother' s breast including mupirocin, grapefruit seed extract, or mixtures of mupirocin, betamethasone ointments, and miconazole powder. controlled clinical trials for efficacy and toxicity are not available. when good adherence to the proposed regimen with topical agents fails, or when infant or mother are severely affected by pain and decreased breastfeeding, systemic therapy is appropriate. fluconazole and ketoconazole are the most commonly used systemic agents for oral or diaper candidiasis and vulvovaginitis or mastitis. fluconazole has a better side effect profile than ketoconazole, and more data are available concerning its safe use in children younger than months of age and even neonates and premature infants. , , fluconazole is not currently approved for use in infants younger than months of age. for severe invasive infections in infants, amphotericin b with or without oral flucytosine, iv fluconazole, voriconazole or caspofungin are reasonable choices in different situations. use of itraconazole in infants has not been adequately studied to date. maternal use of fluconazole during breastfeeding is not contraindicated because only a small amount of medicine compared with the usual infant dose reaches the infant through breast milk. amphotericin or caspofungin therapy in mothers is also not contraindicated because these are both poorly absorbed from the gi tract. whenever a mother is treated for candidal mastitis or vulvovaginitis, the infant should be treated simultaneously, at least with nystatin oral suspension as the first choice of medication. any predisposing risk factors for candidal infection in mothers and infants should be reduced or eliminated to improve the chance of rapid, successful treatment and to decrease the likelihood of chronic or recurrent disease. for mothers, such interventions might include decreasing sugar consumption, stopping antibiotic use as soon as possible, and consuming some form of probiotic bacteria, such as acidophilus (in yogurt, milk, or pill form), to reestablish a normal colonizing bacterial flora. for infants, breastfeeding can enhance the growth of specific colonizing bacterial flora such as lactobacillus, which can successfully limit fungal growth. breastfeeding should continue with appropriate support and problem-solving with a professional who is knowledgeable about breastfeeding. hiv- , hiv- , htlv-i, and htlv-ii are the only infectious diseases that are considered absolute contraindications to breastfeeding in developed countries. when the primary route of transmission is via direct contact or respiratory droplets/particles, temporary separation of mother and infant may be appropriate (whether the infant is breastfed or formula fed), but expressed breast milk should be given to the infant for the organism-specific immunologic benefits in the mother' s milk. in most instances, by the time a specific diagnosis of infection is made for a mother, the infant has already been exposed to the organism and providing expressed breast milk to the infant should continue. (refer to appendix f for specific exceptions, such as lassa fever.) regarding antimicrobial therapy for mothers and continued breastfeeding, the majority of the medications commonly used in adults can be used to treat the same infection in infants. the additional amount of medication received by infants via breast milk is usually insignificant. in almost all instances, an appropriate antimicrobial agent for treating mothers that is also compatible with breastfeeding can be chosen. unless the risk to infants for transmission of an infectious agent via breast milk that leads to a clinically significant illness in the infants is documented, breastfeeding should continue. measles antibodies in the breast milk of nursing mothers spectrum of breast tuberculosis respiratory syncytial virus infection among young children with acute respiratory tract infection in iraq probable breast milk borne brucellosis in a young infant breast milk transmission of cytomegalovirus (cmv) infection congenital and perinatal cytomegalovirus infections intrauterine west nile virus: ocular and systemic findings the cloning and clinical implications of hgv and hgbv-c bottle feeding can prevent transmission of htlv-i from mothers to their babies transmission of adult t-cell leukemia retrovirus (htlv-i) from mother to child: comparison of bottle-with breastfed babies effect of freezethawing breast milk on vertical htlv-i transmission from seropositive mothers to children long-term follow up study of vertical htlv-i infection in children breastfed by seropositive mothers long-term followup study of htlv-i infection in bottle-fed children born to seropositive mothers the yeast connection: is candida linked to breastfeeding associated pain? epidemiology of group b streptococcus: maternal and nosocomial sources for acquisition tuberculosis and pregnancy and tuberculous mastitis infant botulism infant botulism: anticipating the second decade protective role of human milk against sudden death from infant botulism growth faltering due to breastfeeding cessation in uninfected children born to hiv-infected mothers in zambia other viral infections of the fetus and newborn protozoan and helminth infections (including pneumocystis carinii) recurrent group b streptococcal disease in infants: who should receive rifampin? methicillin-resistant staphylococcus aureus sccmec type iv: nosocomial transmission and colonisation of healthcare workers in a neonatal intensive care unit stringent precautions are advisable when caring for patients with viral hemorrhagic fevers prevalence of methicillin-resistant staphylococcus aureus in expressed breast milk in a neonatal intensive care unit transmision de brucelosis por lactancia materna: presentacion de dos casos congenital lymphocytic choriomeningitis virus infection in twins poliomyelitis in pregnancy, fetus and newborn assessment of the risk of ebola virus transmission from bodily fluids and fomites transmission of hepatitis by breastfeeding evidence against breast feeding as a mechanism for vertical transmission of hepatitis b two-year morbidity-mortality and alternatives to prolonged breast feeding among children born to hiv infected mothers in cote d'ivorie transmission of methicillin-resistant staphylococcus aureus to preterm infants through breast milk a new staphylococcal enterotoxin, enterotoxin f, associated with tss staphylococcus aureus isolate mother-to-infant transmission of hepatitis c outbreak of methicillin-resistant staphylococcus aureus colonization and infection in a neonatal intensive care unit epidemiologically linked to a healthcare worker with chronic otitis estimating the timing of mother-to-child transmission of human immunodeficiency virus in a breast-feeding population in kinshasa mycobacteriareactive t cells are present in human colostrum from tuberculin-positive, but not tuberculin-negative nursing mothers estimated risk of transmission of the west nile virus through blood transfusion in the us partial breastfeeding protects bedouin infants from infection morbidity: prospective cohort study children hospitalized with severe acute respiratory syndrome-related illness in toronto a prospective study of infants born to women seropositive for human immunodeficiency virus type . hiv infection in newborns french collaborative study group clinical virology postpartum varicella vaccination: is the vaccine virus excreted in breast milk? contamination of breast milk obtained by manual expression and breast pumps in mothers of very low birth weight hepatitis c virus infection and related liver disease in children of mothers with antibodies to the virus clinical and laboratory observations, gram-negative bacilli in human milk feedings: quantitation and clinical consequences for premature infants prenatal transmission of dengue: two new cases community associated methicillin-resistant staphylococcus aureus in hospital nursery and maternity units thrush in the breastfeeding dyad: results of a survey on diagnosis and treatment reproductive factors in the aetiology of breast cancer transmammary passage of strongyloides sp. larvae in the human host alaska rsv study group: risk factors for severe respiratory syncytial virus infection among alaska native children detection of human immunodeficiency virus type (hiv- ) proviral dna in breast milk and colostrum of seropositive mothers streptococcus agalactiae as a cause of meningitis in the newborn and bacteraemia in adults incidence and clinical outcome of cytomegalovirus transmission via breast milk in preterm infants </= weeks neonatal group b streptococcal infection related to breast milk epidemiology of tuberculosis in the united states probable transmission of brucellosis by breast milk does discarding the first few milliliters of breast milk improve the bacteriological quality of bank breast milk? primary human herpes virus infection: a comparison of human herpes virus and human herpes virus infections in children analysis of the presence of cutaneous and mucosal papillomavirus types in ductal lavage fluid, milk and colostrum to evaluate its role in breast carcinogenesis centers for disease control and prevention: testing for antibodies to hiv- in the united states public health service working group: recommendations for counseling persons infected with human t-lymphotropic virus, types i and ii centers for disease control and prevention: screening for tuberculosis and tuberculosis infection in high-risk populations update: management of patients with suspected viral hemorrhagic fever-united states poliomyelitis prevention in the united states: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine-united states prevention: recommendations for antimicrobial prophylaxis for children and breastfeeding mothers and treatment of children with anthrax prevention: possible west nile virus transmission to an infant through breastfeeding-michigan prevention: yellow fever vaccine; recommendations of the advisory committee on immunization practices (acip) update: cardiac and other adverse events following civilian smallpox vaccination-united states centers for disease control and prevention: secondary and tertiary transfer of vaccinia virus among u.s. military personnel-united states and worldwide centers for disease control and prevention: a new product (varizig) for post exposure prophylaxis of vericells available under an investigational new drug application expanded access protocol centers for disease control and prevention: communityassociated methicillin-resistant staphylococcus aureus infection among healthy newborns: chicago and los angeles county centers for disease control and prevention: what to do if an infant or child is mistakenly fed another woman' s expressed breast milk prevention: transmission of yellow fever vaccine through breast feeding: brazil take of rhesushuman reassortment tetravalent rotavirus vaccine in breastfed infants candida infections in the neonate prevalence of methicillin-sensitive and methicillin-resistant staphylococcus aureus in pregnant women coxsackieviruses, and enteroviruses morbidity and mortality among a cohort of human immunodeficiency virus type infected and uninfected pregnant women and their infants from malawi, zambia, and tanzania electron microscopic detection of simian-type virus particles in human milk staphylococcus aureus outbreaks among newborns: new frontiers in an old dilemma breastfeeding and the risk of life-threatening rotavirus diarrhea: prevention or postponement? committee on infectious diseases: american academy of pediatrics: red book report of the committee on infectious disease committee on infectious diseases: american academy of pediatrics: red book report of the committee on infectious disease committee on infectious disease: american academy of pediatrics: red book report of the committee on infectious disease mother-tochild transmission of hiv- infection during exclusive breastfeeding in the first months of life: an intervention cohort breastfeeding, hiv transmission and infant survival: balancing pros and cons influence of infantfeeding patterns on early mother-to-child transmission of hiv- in durban, south africa: a prospective cohort study. south african vitamin a study group method of feeding and transmission of hiv- from mothers to children by months of age: prospective cohort study from durban are hivinfected women who breastfeed at increased risk of mortality? morbidity in children born to women infected with human immunodeficiency virus in south africa: does mode of feeding matter? pilot epidemiologic study of transmission of cytomegalovirus from mother to preterm infant by breastfeeding mother-to-child transmission of human immunodeficiency virus type: report from the nairobi study human milk and hiv infection: epidemiologic and laboratory data hiv, breastfeeding and under mortality: modelling the impact of policy decisions for or against breastfeeding staphylococcus epidermidis strains isolated from breast milk of women suffering infectious mastitis: potential virulence traits and resistance to antibiotics hiv- transmission through breast-milk: appraisal of risk according to duration of feeding task force on recurrent respiratory papillomatosis presence of papillomavirus in condylomatous lesions of the mamillae and in invasive carcinoma of the breast variations in biological features of west nile viruses group b streptococcal carriage and disease: a year prospective study hepatitis in the obstetric patient prophylactic isoniazid protection of infants in a tuberculosis hospital breast-feeding protects against respiratory syncytial virus infections neonatal herpes simplex infection possibly acquired via maternal breast milk risk of human immunodeficiency virus type transmission through breastfeeding serologic evidence for congenital transmission of human herpesvirus examination of human breast milk for evidence of human herpesvirus by pcr cytomegalovirus infection of breast milk and transmission in infancy late postnatal mother-to-child transmission of hiv- in abidjan listeriosis during pregnancy and in neonates rotavirus infections in young nicaraguan children european collaborative study: children born to women with hiv- infection: natural history and risk of transmission european paediatric hepatitis c virus network: effects of mode of delivery and infant feeding on the risk for motherto-child transmission of hepatitis c virus flora of the umbilical stump: cultures a lipid inhibitor of dengue virus in human colostrum and milk, with a note on the absence of anti-dengue secretory antibody vertical transmission of hepatitis g nonspecific antiviral substances in human milk against arbovirus and murine leukemia virus genetic evidence for mother-to-infant transmission of hepatitis g virus stringent precautions are not advisable when caring for patients with viral hemorrhagic fevers evalution and treatment of community acquired staphylococcus aureus infections in term and late-preterm previously healthy neonates diagnostic value of signs and symptoms of mammary candidosis among lactating women immunity and correlates of protection for rotavirus vaccines rate of inactivation of cytomegalovirus in raw banked milk during storage at degrees c and pasteurisation htlv-i transmission from mother to child detection of human herpesvirus (hhv- ) dna in breast milk by polym erase chain reaction and prevalence of hhv- antibody in breast-fed and bottle-fed children a new endemic focus of human t-lymphotropic virus type ii carriers among orinoco natives in colombia estimating the time of htlv-i infection following mother-to-child transmission in a breast-feeding population in jamaica tertiary contact vaccinia in a breastfeeding infant community acquisition of group b streptococcus by infants of colonized mothers infectious diseases of the fetus and newborn infant hospital infection control practices advisory committee: guidelines for isolation precautions in hospitals transmission of community-associated methicillian-resistant staphylococcus aureus from breast milk in the neonatal intensive care unit giardiasis and breastfeeding in urban africa multidisciplinary prospective study of mother-to-child chikungunya virus infections on the island of la reunion management of outbreaks of methicillin-resistant staphylococcus aureus infection in the neonatal intensive care unit: a consensus statement chickenpox, measles and mumps seroepidemiology in various population groups of the greater montreal area mother-to-child transmission of hepatitis c virus: evidence for preventable peripartum transmission cholate-dependent killing of giardia lamblia by human milk triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load: a study within the drug resource enhancement against aids and malnutrition program risk of respiratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level comparison of fluconazole and nystatin oral suspensions for treatment of oral candidiasis in infants rapid high temperature treatment of human milk htlv-i: a new problem for latin america rotavirus vaccines opportunities and challenges detection of human immunodeficiency virus type (hiv- ) dna and p antigen in breast milk of hiv- -infected ugandan women and vertical transmission denuge and denuge hemorrhagic fever tubercular mastitis child to mother transmission of herpes simples virus- infection at an unusal site vertical transmission of hepatitis c virus dengue: an update epidemiology and diagnosis of hospital acquired conjunctivitis among neonatal intensive care unit patients congenital infections with human herpes virus (hhv ) and human herpes virus (hhv ) the absence of candida albicans in milk samples of women with clinical symptoms of ductal candidiasis dengue hemorrhagic fever in infants: research opportunities ignored epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding cytomegalovirus transmission to preterm infants during lactation congenital malformations and oral poliovirus vaccination during pregnancy mammary tuberculosis: analysis of thirty-eight patient cytomegalovirus in human milk an epidemiologic study of breast cancer detection of htlv-ii in breast milk of htlv-ii infected mothers killing of giardia lamblia by human milk lipases: an effect mediated by lipolysis of milk lipids risk of hepatitis b transmission in breast-fed infants of chronic hepatitis b carriers transmission of west nile virus through human breast milk seems to be rare milk-borne transmission of htlv-i as a major route in the endemic cycle primary prevention of htlv-i in japan primary prevention of htlv- in japan apparent vertical transmission of human immunodeficiency virus type by breast-feeding in zambia virus markers associated with vertical transmission of human t lymphotropic virus type in jamaica rotavirus antibodies in the mother and her breastfed infant incidence of haemophilus influenzae in the throats of healthy infants with different feeding methods transfusion transmission of west nile virus: a merging of historical and contemporary perspectives clinical presentations and outcomes of severe acute respiratory syndrome in children poliomyelitis in pregnancy: a twenty-year report from long-term serologic follow-up of patients for epstein-barr virus after recovery from infectious mononucleosis the global distribution of human immunodeficiency virus type (hiv- ) infection interventions for preventing late postnatal mother-to-child transmission of hiv methicillin-resistant staphylococcus aureus colonization and its association with infection among infants hospitalized in neonatal intensive car units staphylococcus aureus in the infant upper respiratory tract. i. observations on hospital-born babies unilateral breast feeding and breast cancer staphylococcus aureus in australasian neonatal nurseries identification of human t-cell lymphotropic virus type iia infection in the kayapo, an indigenous population of brazil mother-to-infant transmission of tt virus in japan italian register for hiv infection in children: hiv- infection and breast milk transmission of west nile virus from an organ donor to four transplant recipients tuberculosis mastitis methicillin-resistant staphylococcus aureus infections among healthy full-term newborns human milk in the modern world staphylococcus epidermidis: a differential trait of the fecal microbiota of breastfed infants epstein-barr virus shedding in breast milk post weaning gastroenteritis and mortality in hiv- uninfected african infants receiving antiretroviral prophylaxis to prevent mtct of hiv- successful antepartum treatment of listeriosis low risk for motherto-child transmission of human t lymphotropic virus type ii in non-breastfed infants staphylococcal scalded skin syndrome in a breastfed infant fluconazole prophylaxis against fungal colonization and infection in preterm infants transmission of staphylococus aureus between healthy lactating mothers and their infants by breastfeeding transmammary transmission of strongyloides ratti case-control study of mastomys natalensis and humans in lassa virusinfected households in sierra leone transfer of tuberculin immunity from mother to infant recurrent group b streptococcal disease in an infant associated with the ingestion of infected mother' s milk mammary tuberculosis: report on cases eradication of methicillin-resistant staphylococcus aureus from a neonatal intensive care unit by active surveillance and aggressive infection control measures prevention of mother-to-child transmission of hiv- through breast feeding by treating infants prophylactically with lamivudine in dar es salaam prevention of mother-to-child transmission of hiv through breastfeeding by treating mothers with triple antiretroviral therapy in dar es salaam, tanzania: the mitra plus study clinical outcomes in methicillin-resistant staphylococcus aureus colonized neonates in the neonatal intensive care unit demonstration of adult t-cell leukemia virus antigen in milk from three seropositive mothers oral infection of a common marmoset with human t-cell leukemia virus type i (htlv-i by fresh human milk of htlv-i carrier mothers the differences of clinical manifestations and laboratory findings in children and adults with dengue virus infection human parvovirus b infection in women of childbearing age and within families lymphocytic choriomeningitis in the newborn late-onset and recurrent neonatal group b streptococcal disease associated with breast-milk transmission diarrhoea in uninfected infants of hiv-infected mothers who stop breastfeeding at months: the ban study experience accessed / prolonged breastfeeding and mortality up to two years postpartum among hiv positive women in zambia hiv specific secretory iga in breast milk of hiv-positive mothers is not associated with protection against hiv transmission among breast-fed infants high uptake of exclusive breastfeeding and reduced postnatal hiv transmission; prospective results from the zambia exclusive breastfeeding study accessed / effect of early, abrupt weaning on hiv-free survival of children in zambia differential effects of early weaning for hiv-free survival of children born to hiv-infected mothers by severity of maternal disease breastfeeding and aids in the developing world hiv prevention is not enough: child survival in the context of prevention of mother to child hi transmission congenital and postnatally acquired cytomegalovirus infections: long-term follow-up extended antiretroviral prophylaxis to reduce breast milk hiv- transmission breast milk is not a significant source for early epstein-barr virus or human herpes virus infection in infants: a seroepidemiologic study in endemic areas of human t-cell lymph tropic virus type i in japan evidence for mother-to-child transmission of human t-lymphotropic virus type ii mother-to-child transmission of human t-lymphotropic virus type ii (htlv-ii) role of maternal antibody in pneumonia and bronchiolitis due to respiratory syncytial virus a further report on cancer of the breast repeated congenital infection with toxoplasma gondii is ingestion of milk associated bacteria by premature infants fed raw human milk controlled by routine bacteriologic screening? maternal and child health technical information bulletin cytomegalovirus in human breast milk: risk to the premature infant the independent associations of parity, age at first full term pregnancy, and duration of breastfeeding with risk for breast cancer epstein-barr virus estimating infant mortality from hiv and other causes in breastfeeding and bottle-feeding populations postnatal cytomegalovirus infection from frozen breast milk in preterm low birth weight infants postntal transmission of hiv from mother to child eradication of methicillin-resistant staphylococcus aureus in a neonatal intensive care unit: which measures for which success? international multicentre pooled analysis of late postnatal mother-to-child transmission of hiv- infection. ghent international working group on mother-to-child transmission of hiv month effectiveness of short-course antiretroviral regimens combined with alternatives to breastfeeding to prevent hiv mother-tochild transmission breast milk transmission of a panton-valentine leukocidin-producing staphylococcus aureus strain causing infantile pneumonia mammary epithelial cells support and transfer productive human t cell lymphotropic virus infections mechanism of vertical transmission of hepatitis g absence of infection in breast fed infants born to hepatitis c virus-infected mothers intrauterine listeria infection: prenatal diagnosis by biophysical assessment and amniocentesis ejpidemiologic features of htlv-ii: serologic and molecular evidence neonatal brucellosis probable transmission of brucellosis from breast milk to a newborn a multicenter therapeutic study of children with brucellosis lactation and cancer of the breast: a summary of an international study human immunodeficiency virus infection as risk factor for mother-to-child hepatitis c virus transmission: persistence of anti-hepatitis c virus in children is associated with the mother' s antihepatitis c virus immunoblotting pattern increased infant human immunodeficiency virus type one free survival at one year of age in sub-saharan africa with maternal use of highly active antiretroviral therapy during breast feeding the genome sequence of the sars-associated coronavirus diagnostic approach cytomegalovirus infection of extremely low-birth weight infants via breast milk freezethawing of breast milk does not prevent cytomegalovirus transmission to a preterm infant human milk siga binds to botulinum type b s toxin and limits toxin adherence on t cells antimicrobial factors and microbial contaminants in human milk: recent studies morbidity and mortality patterns in hiv- seropositive/seronegative women in kampal and harare during pregnancy and in the subsequent two years morbidity and mortality in breastfed and formula-fed infants of hiv- -infected women: a randomized clinical trial predominance of left-sided breast tumors obstetric management of hepatitis c-positive mothers: analysis of vertical transmission in mother-infant pairs evidence for a protective effect of lactation on risk of breast cancer in young women: results from a case-control study prospective study of the incidence and complications of bacterial contamination of enternal feeding in neonates effect of treatment on the contagiousness of patients with active pulmonary tuberculosis infectious diseases of the fetus and newborn infant does breast feeding increase the child' s risk of breast cancer? role of breast milk in acquisition of cytomegalovirus infection hiv transmission through breastfeeding: a study in malawi prevention of breast milk tranmission of hiv: the time is now mother-to-infant transmission of hepatitis c virus: rate of infection and assessment of viral load and igm anti-hcv as risk factors yellow fever vaccine nosocomial transmission of methicillin-resistant staphylococus aureus from a mother to her preterm quadruplet infants breastfeeding family history and breast disease transmission of hepatitis c virus from mothers to infants: its frequency and risk factors revisited immune escape by epstein-barr virus associated malignancies the duration of breastfeeding by hiv- infected mothers in developing countries: balancing benefits and risks search for possible routes of vertical and horizontal transmission of adult t-cell leukemia virus outbreak of invasive disease caused by methicillin-resistant staphylococcus aureus in neonates and prevalence in the neonatal intensive care unit human immunodeficiency virus type -infected cells in breast milk: association with immunosuppression and and vitamin a deficiency effect of breastfeeding on mortality among hiv- infected women: a randomised trial breast brucellosis in taif, saudi arabia: cluster of six cases with emphasis on fna evaluation case control study of symptoms and neonatal outcome of human milktransmitted cytomegalovirus infection in premature infants human milk glycosaminoglycans inhibit hiv glycoprotein gp binding to its host cell cd receptor risk factors for neonatal methicillin-resistant staphylococcus aureus infection in a well-infant nursery lactation and a reduced risk of premenopausal breast cancer contamination of expressed human breast milk with an epidemic multiresistant staphylococus aureus clone human cytomegalovirus infection of breast milk strongyloides papillosus: prenatal and transmammary infection in ewes human neonatal infections with hookworms in an endemic area of southern nigeria. a possible transmammary route mother-to-child transmission of human t-cell lymphotoropic virus types i and ii (htlv-i/ii) in gabon: a prospective follow-up of years transfer of human herpes virus and antibodies from mother to their offspring vertical transmission of hepatitis c virus transmission of hepatitis c virus from mothers to infants for the vertical transmission of hepatitis viruses collaborative study group, motherto-infant transmission of gb virus type c/hgv for the vertical transmission of hepatitis viruses collaborative study group: tt virus infection during childhood tt virus: virological and genomic characteristics and disease associations birth outcomes following west nile virus infection of pregnant women in the united states neonatal group b streptococcal disease associated with infected breast milk transmission of cytomegalovirus to extremely preterm infants through breast milk early breastfeeding cessation among hiv-exposed negative infants and risk of serious gastroenteritis: findings from a perinatal prevention trial in kampala, uganda inactivation of human immunodeficiency virus type i in human milk: effects of intrinsic factors in human milk and of pasteurization lactation mastitis: bacterial cultivation of breast milk, symptoms, treatment, and outcome human immunodeficiency virus and other viruses in human milk: placing the issues in broader prospective effect of breast-feeding on immune response to bcg vaccination brucellosis in a mother and her young infant: probable transmission by breast milk brucellar arthritis of knee in a child breast-feeding during primary maternal human immunodeficiency virus infection and risk of transmission from mother to infant treatment acceleration program and the experience of the dream program in prevention of mother-to-child transmission of hiv updated u.s. public health service guidelines for the management of occupational exposures to hiv and recommendations for post exposure prophylaxis etiologic factors in cancer of the breast in humans: collective review methicillin-resistant staphylococcus aureus in milk oral rotavirus vaccines: how well will they work were they are needed most? determinants of acquisition and carriage of staphylococcus aureus in infancy early acquisition of cytomegalovirus infection clinical virology west nile virus: a primer for the clinician petra study team: efficancy of three short course regimens of zidovudine and lamivudine in preventing early and late transmission of hiv- from mother to child in tanzania, south africa, and uganda (petra study): a randomized, double-blind, placebo-controlled trial dengue virus infection in late pregnancy and transmission to the infants effect of maternal rotavirus immunization on milk and serum antibody titers cell-free virus in breast milk of hiv- -seropositive women role of breastfeeding in paralytic poliomyelitis bacterial contamination of human milk: container type and method of expression maternal herpetic breast infection: another hazard of neonatal herpes simplex mother-to-child transmission of chikungunya virus infection care of the pregnant woman with tuberculosis and her newborn infant: a pediatrician' s perspective read jsand the committee on pediatric aids: human milk, breastfeeding, and transmission of human immunodeficiency virus type in the united states postpartum mastitis and community-acquired methicillin-resistant staphylococcus aureus infectious diseases of the fetus and newborn infant hepatitis e virus breastmilk infectivity in human immunodeficiency virus type -infected mothers high risk types of human papillomavirus (hpv) dna in oral and genital mucosa of infants during their first years of life: experience from the finnish hpv family study streptococcal toxic shock syndrome, including necrotizing fasciitis and myositis late-onset septicemia in a norwegian national cohort of extremely premature infants receiving very early full human milk feeding hepatitis a outbreak in a neonatal intensive care unit: risk factors for transmission and evidence of prolonged viral excretion among preterm infants characterization of a novel corona virus associated with severe acute respiratory syndrome longitudinal analysis of human immunodeficiency virus type rna in breast milk and of its relationship to infant infection and maternal disease attempts to detect rna tumour virus in human milk is breast milk collected at home suitable for raw consumption by neonates in brizilian public neonatal intensive care units? prevalence of hiv- dna and p antigen in breast milk and correlation with maternal factors follow-up of transmission of hepatitis c to babies of human immunodeficiency virus-negative women: the role of breastfeeding in transmission occurrence of acute diarrhea in atopic and nonatopic infants: role of prolonged breast-feeding an outbreak of methicillin-resistant staphylococcus aureus in a neonatal intensive care unit hospital transmission of community acquired methicillin-resistant staphylococcus aureus among postpartum women removal of inhibitors against rna-directed dna polymerase activity in human milk effect of human milk on mouse mammary tumor virus human papillomavirus dna detected in breast milk control of a cluster of a community-associated methicillin-resistant stahpylococcus aureus in neonatology immunoglobulin prophylaxis against milkborne transmission of human t cell leukemia virus type in rabbits chlamydial infections pregnancy and pulmonary tuberculosis possible breast milk transmission of group b streptococcal infection evidence for transmission of lymphocyte responses to tuberculin by breast-feeding, lancet i: toxic shock syndrome detection of borrelia burgdorferi dna by pcr in the urine and breast milk of patients with lyme borreliosis prevention of perinatal group b streptococcal disease. revised guidelines from cdc detection of tt virus dna and gb virus type c/hepatitis g virus rna in serum and breast milk: determination of mother-to-child transmission effects of hepatitis a and b in pregnancy on the mother and fetus human immunodeficiency virus load in breast milk, mastitis and mother-to-child transmission of human immunodeficiency virus type how contagious is vaccinia? transmammary transmission of necator americanus larva in the human host a study of infectious intestinal disease in england: risk factors associated with group a rotavirus in children highly active antiretroviral therapy started during pregnancy or postpartum suppresses hiv- rna, but not dna, in breast milk prevention of postnatal cytomegalovirus infection in preterm infants infants born to mothers with severe acute respiratory syndrome tuberculosis of the breast masquerading as carcinoma: a study of patients transmammary transmission of strongyloides stercolis in dogs low birth weight and maternal virus diseases: a prospective study of rubella, measles, mumps, chickenpox, and hepatitis lyme disease during pregnancy no benefit of early cessation of breastfeeding at months on hiv-free survival of infants born to hiv-infected mothers in zambia: the zambia exclusive breastfeeding study vertical dengue infection: case reports and reviews a young infant with severe acute respiratory syndrome six week extended-dose neviapine (swen) study team: extended-dose nevirapine to weeks of age for infants to prevent hiv transmission via breastfeeding in ethiopia, india, and uganda: an analysis of three randomized controlled trials chlamydial secretory iga antibodies in human milk hepatitis d virus factors associated with immunoprophylaxis failure against vertical transmission of hepatitis b virus phagocytosis-associated oxidative metabolism in human milk macrophages management of mastitis in breastfeeding women communityacquired methicillin-resistant staphylococcus aureus among patients with puerperal mastitis requiring hospitalization working parents: the impact of day care and breast-feeding on cytomegalovirus infection in offspring breast milk and the risk of cytomegalovirus infection tuberculosis, an old disease but a new threat to mother, fetus, and neonate vertical transmission of hepatitis b antigen in taiwan yeast-recombinant hepatitis b vaccine: efficacy with hepatitis b immune globulin in prevention of perinatal hepatitis b virus transmission maternal lyme disease and congenital heart disease: a case-control study in an endemic area significance of postnatal mother-to-child transmission of htlv-i on the development of adult t-cell leukemia/lymphoma disseminated neonatal herpes simplex virus type i from a maternal breast lesion the effects of yellow fever immunization ( dd) inadvertently used in early pregnancy during a mass campaign in brazil the impact of breastfeeding on the health of hiv positive mothers and their children in sub-saharan africa prospective study of mother-to-infant transmission of hepatitis c virus inhibitory effect of maternal antibody on mother-to-child transmission of human t-lymphotropic virus type i seroepidemiological study of human herpes virus and in children of different ages and detection of these two viruses throat swabs by polymerase chain reaction short-term breast-feeding may reduce the risk of vertical transmission of htlv-i. the tsushima atl study group infant feeding and risk of mother-to-child transmission of hiv- in sao paulo state, brazil. sao paulo collaborative study for vertical transmission of hiv- breast feeding plus infant zidovudine prophylaxis for months vs. formula feeding plus infant zidovudine for month to reduce mother-to-child hiv transmission in botswana: a randomized trial: the mashi study isolation of the aids virus from cell-free breast milk of three healthy virus carriers rates of diarrhoea associated with early weaning among infants in kisumu, kenya. in program and abstracts of the th conference on retroviruses and opportunistic infections contamination in expressed breast milk following breast cleansing brucellar meningitis in an infant-evidence for human breast milk transmission hepatitis e in india human parvovirus b congential yellow fever virus infection after immunization in pregnancy unaids/who: report on the global hiv/aids epidemic a review of hiv transmission through breastfeeding mother-to-child transmission of human t-cell leukemia/ lymphoma virus type i: implication of high antiviral antibody titer and high proviral load in carrier mothers clinical profile of chikungunya in infants infective and antiinfective properties of breast milk from hiv- infected women postnatal transmission of the human immunodeficiency virus type from mother to infant: a prospective cohort study in kigali, rwanda mother-tochild transmission of human t-lymphotropic virus type ii the possible role of circumcision in newborn outbreaks of community associated methicillin-resistant staphylococcus aureus brucellosis chez un nourrisson de mois recovery of staphylococcal enterotoxin f from the breast milk of a woman with toxic-shock syndrome evidence for sexual and mother-to-child transmission of human t lymphotrophic virus type ii among guaymi indians transmission of cytomegalovirus to preterm infants through breast milk postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants pregnancy and lactation in relation to breast cancer risk morbidity among hiv- -infected mothers in kenya: prevalence and correlates of illness during -year postpartum follow-up high concentrations of interleukin in breast milk are associated with protection against postnatal hiv transmission low and undectable breast milk interleukin- concentrations are associated with reduced risk of postnatal hiv transmission lactation mastitis: a descriptive study of the experience breastfeeding does not pose any additional risk of immunoprophylaxis failure on infants of hbv carrier mothers recurrent neonatal group b streptococcal disease associated with infected breast milk transplacentally transferred maternal-infant antibodies to dengue virus vertical transmission of hepatitis a resulting in an outbreak in a neonatal intensive care unit immortalization of distinct human mammary epithelial cell types by human papilloma virus e or e perinatal transmission of hepatitis g virus (gb virus type c) and hepatitis c virus infections: a comparison advisory committee on immunization practices; healthcare infection control practices advisory committee: recommendations for using smallpox vaccine in a pre-event vaccination program global rotavirus surveillance: determining the need and measuring the impact of rotavirus vaccines recommendations for minimizing cmv exposure in breast milk fed very low birth weight (vlbw) preterm infants. available at www.breastfeeding. org/articals/cmvpremi.pdf maternal-infant transmission of htlv-i: frequency and time course of seroconversion. abstract w- mother-to-child transmission of human t-cell lymphotropic virus type i associated with prolonged breast-feeding maternal lyme disease and congenital malformations: a cord blood serosurvey in endemic and control areas human versus cow' s milk in infant nutrition and health human t-lymphocyte retroviruses working group on severe streptococcal infections: defining gas streptococcal toxic shock syndrome: rationale and consensus definition acquired cytomegalovirus infection of breast milk in infancy oral transmission of human t-cell leukemia virus type into a common marmoset as an experimental model for milk-borne transmission evaluation of cytomegalovirus infections transmitted via breast milk in preterm infants with a real-time polymerase chain reaction assay sequelae of maternally derived cytomegalovirus infections in premature infants mother-to-infant transmission of hepatitis c virus human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis independent protective effect of lactation against breast cancer: a case-control study in japan a maternal factor for mother-to-child transmission: viral antigen-producing capacities in culture of peripheral blood and breast milk cells mother-to-infant transmission of hepatitis c virus infectious diseases of the fetus and newborn infant sensitive method for detection of human herpes viruses and in saliva collected in field studies survey of pregnant women with hepatitis a and their neonates postnatal transmission of aids-associated retrovirus from mother to infant disseminated lyme disease and pregnancy. th annual international scientific conference on lyme disease and other tick-borne disorders a. siblings at home have active chickenpox when neonate and mother are ready for discharge from hospital.no no . mother: if she has a history of chickenpox, she may return home. without a history, she should be tested for varicellazoster virus antibody titer.* if test is positive, she may return home. if test is positive, she may return home. if test is negative, varicella-zoster ig † is administered and she is discharged home. . neonate: may be discharged home with mother if mother has history of varicella or is varicella-zoster virus-antibody positive. if mother is susceptible, administer varicella-zoster ig to infant and discharge home or place in protective isolation. b. mother has no history of chickenpox; exposed during period - days antepartum. ‡ ‡if exposure occurred less than days antepartum, mother would not be potentially infectious until at least hours postpartum. §considered noninfectious when no new vesicles have appeared for hours and all lesions have crusted. ¶dosage of acyclovir for pregnant woman is mg/kg/day; for seriously ill infant with varicella, to mg/m /day. elisa, enzyme-linked immunosorbent assay; fama, fluorescent antibody to membrane antigen; la, latex agglutination. key: cord- -rcv pl d authors: o’ryan, miguel l.; nataro, james p.; cleary, thomas g. title: microorganisms responsible for neonatal diarrhea date: - - journal: infectious diseases of the fetus and newborn infant doi: . /b - - - / - sha: doc_id: cord_uid: rcv pl d nan at the beginning of the st century, diari..eal disease continues to be a significant cause of morbidity and mortality worldwide. during the period of to , an estimated . billion children younger than years suffered an episode of acute diarrhea every year in developing countries; among these, . million required outpatient medical care, and million required hospitalization. approximately million diarrhea-associated deaths occurred in this age group annually, primarily in the most impoverished areas of the world.' these estimates are somewhat lower than the more than million annual deaths from diarrhea reported in the prior years? indicating progress in prevention and treatment of acute diarrhea. in the united states, approximately childhood deaths per year were reported during the late ~,~*~ although the actual number may be higher: accurate incidence rates for acute diarrhea in neonates from different populations are not readily available. the relative sparing of the newborn probably results from low exposure to enteropathogens and protection associated with brea~t-feeding.~-' after the first few months of life, increasing interaction with other individuals and the environment, including introduction of artificial feeding, increases the risk of exposure to enteropathogens. for most pathogens, the incidence of acute diarrhea peaks in children between months and years old? neonatal diarrhea is more common in underdeveloped areas, where low educational levels, crowding, and poor standards of medical care, environmental sanitation, and personal hygiene favor early contact with enteropathogens. as the incidence of neonatal gastroenteritis rises, there is a proportional increase in neonatal deaths because medical care for the poor often is inadequate.' *" for very low birth weight infants (< g), the death rate from diarrhea is -fold greater than for higher-birth-weight infants. this chapter discusses the pathogenesis, diagnosis, treatment, and prevention of gastroenteritis based on the available knowledge about pathogens that can cause neonatal diarrhea. pathogens that rarely or never cause acute diarrhea in neonates are not discussed. after an overview of host defense mechanisms and protective factors in human milk, the remainder of the chapter is devoted to specific pathogens that cause inflammatory or noninflammatory diarrhea. the neonate is a host that is uniquely susceptible to enteric infections. neonates have not had the opportunity to develop local or systemic immune responses, and in the first few days of life, they have not acquired the highly important enteric flora that protects the normal adult gastrointestinal tract.i -" still less is known about the barrier effect of the neonate's gastric acidity," intestinal mucus,z or each of which provides protection against gastrointestinal tract infections in older infants, children, and adults. the gastric acid barrier appears to be least effective during the first months of life. the average gastric ph level of the newborn is high (ph to ; mean, ). , although the ph falls to low levels by the end of the first day of life (ph to ), it subsequently rises again; by to days of life, the hydrochloric acid output of the neonatal stomach is far less than that of older infants and ~hildren.~~.'~ the buffering action of frequent milk feedings and the short gastric emptying interpose additional factors in the neonate that would be expected to permit viable ingested organisms to reach the small intestine. the intestinal epithelium serves as a nutrient absorptive machine, barrier to pathogen entry, and regulator of inflammation. intestinal epithelial cells have receptors for bacterial products and produce chemokines (e.g., interleukm [ il]- , monocyte chemotactic protein type [ mcp- , granulocyte macrophage-cell stimulating factor [ gm-csf] ) and proinflammatory cytokines (e.g., il- , tumor necrosis factor-a [tnf-a], il- ) in response to invasion by enteropathogens." the gut epithelium orchestrates the immune response. however, in the newborn, phagocytic, chemotactic, and complement functions are immature. b and t lymphocyte functions are impaired, resulting in a preferential igm production in response to antigenic stimulation. igg is actively transferred from mother to infant across the placenta at about weeks' gestation and peaks by about weeks; premature neonates, especially those born before weeks' gestation, are deficient in these maternally derived serum antib~dies.~' h e - the importance of breast-feeding infants for the prevention of diarrheal disease has long been e m p h a s i~e d .~~~~* -~~ published studies reporting the association between breastfeeding and diarrhea are extensive and suggest that infants who are breast-fed suffer fewer episodes of diarrhea than those who are not. this protection is greatest during a child's first months of life and declines with increasing age, during the period of weaning, partial breast-feeding confers protection that is intermediate between that gained by infants who are exclusively breast-fed and that by those who are exclusively bottle-fed. a striking demonstration of the protection afforded by breast-feeding of newborns has been provided by mata and urrutiai in their studies of a population of infants born in a rural guatemalan village. despite extremely poor sanitation and the demonstration of fecal organisms in the colostrum and milk of almost one third of diarrheal disease did not occur in any newborns. the incidence of diarrhea rose significantly only after these infants reached to months old, at which time solids and other fluids were used to supplement the human milk feedings. at that time, escherichia coli and gram-negative anaerobes (e.g., bacteroides) were found to colonize the intestinal tract.i in contrast, urban infants of a similar ethnic background who were partly or totally artificially fed frequently acquired diarrheal disease caused by enteropathogenic e. coli (epec) . multiple mechanisms by which breast-feeding protects against diarrhea have been postulated. breast-feeding confers protection by active components in milk and by decreased exposure to organisms present on or in contaminated bottles, food, or water. many protective components have been identified in human milk and generally are classified as belonging to the major categories of cells, antibody, antiinflammatory factors, and glycoconjugates and other nonantibody f a~t o r s .~~-~' examples of milk antibodies are summarized in table - . for any given pathogen, multiple milk factors may help protect the infant. human milk typically targets a major pathogenic mechanism using multiple, redundant strategies. redundancy of milk protective factors and targeting of complex virulence machinery have created a formidable barrier to enteropathogens. despite the fact that pathogens can rapidly divide and mutate, milk continues to protect infants. for example, human milk has secretory antibodies to shigellu virulence antigens and lipopoly-saccharide^,^^.^^ neutral glycolipid gb to bind shiga and lactoferrin to disrupt and degrade the surface-expressed virulence antigen^.^^-^^ in a similar way, milk contains antibodies directed toward the surface expressed virulence antigens of epec, ' oligosaccharides that block cell attachment? and lactoferrin that disrupts and degrades the surface expressed epec antigens ' human milk can initiate and maintain the growth of bifidobacterium and low ph in the feces of newborn infants, creating an environment antagonistic to the growth of e. ~o l i . ' the protective effect of human milk antibodies against enteropathogen-specific disease has been described for vibrio cholerae, campylobacter j e j~n i , ~~ epec, enterotoxigenic e. coli (etec), shigella, ' and giardia lamblia , and for bovine milk concentrate against etec, rota~irus,~' and shigella. in , the nonlactose carbohydrate fraction of human milk was found to consist mainly of oligosa~charides.~~ in , montreuil and mullet determined that up to . % of colostrum and up to . % of mature milk are oligosaccharides. human milk contains a larger quantity of the oligosaccharides than does milk from other mammals, and its composition is singularly complex. the metabolic fate of the oligosaccharides is of interest. only water, lactose, and lipids are present in greater amounts than the oligosaccharides. despite the fact that substantial energy must be expended by the mother to synthesize the many hundreds of different milk oligosaccharides, the infant does not use them as food. most of the oligosaccharides pass through the gut undigested. it is thought that they are present primarily to serve as receptor analogues that misdirect enteropathogen attachment factors away from gut epithelial carbohydrate receptors. likewise, enteropathogens use the oligosaccharide portion of glycolipids and glycoproteins as targets for attachment of whole bacteria and toxins. evidence is emerging that these glycoconjugates may have an important role in protection of the breast-fed infant from disease. human milk protects suckling mice from the heat-stable enterotoxin (st) of e. coli; on the basis of its chemical stability and physical properties, the protective factor has been deduced to be a neutral fucosyloligosaccharide. ~ experiments have shown that epec attachment to hep- cells can be inhibited by purified oligosaccharide fractions from human milk. oligosaccharides also may be relevant to protection from norwalk virus and other caliciviruses, because these viruses attach to human abo, lewis, and secretor blood group antigens. ' human milk contains large amounts of these carbohydrates. the ganglioside fraction in human milk has been shown to inhibit the action of heat-labile toxin (lt) and cholera toxin on ileal loops more effectively than secretory iga. s lactadherin in human milk has been shown to bind rotavirus and to inhibit viral replication in vitro and in v~v o . ~~ a study of infants in mexico showed that lactadherin in human milk protected infants from symptoms of rotavirus infection. e. coli organisms promptly colonize the lower intestinal tracts of healthy infants in their first few days of life - and constitute the predominant aerobic coliform fecal flora throughout life in humans and in many animals. the concept that this species might cause enteric disease was first suggested in the late th and early th centuries, when several veterinary workers described the association of diarrhea (i.e., in , m r '~ observed that bacterium (now escherichia) coli was found more often in the small intestines of children with diarrhea than in children without diarrhea. adam * confirmed these findings and noted the similarity with asiatic cholera and calf scours. he further extended these observations by suggesting that e. coli strains from patients with diarrhea could be distinguished from normal coliform flora by certain sugar fermentation patterns. although he called these disease-producing organisms dyspepsicoli and introduced the important concept that e. coli could cause enteric disease, biochemical reactions have not proved to be a reliable means of distinguishing nonpathogenic from pathogenic e. coli strains. there are now at least six recognized enteric pathotypes of e. ~oli.'~ the pathotypes can be distinguished clinically, epidemiologically, and pathogenetically (table - ) . - etec organisms are defined by their ability to secrete the lt or the st enterotoxin, or both. lt is closely related to cholera toxin and similarly acts by means of intestinal adenylate c y c l a~e , '~~~'~~ prostaglandin s y n t h e~i s , '~~~'~~ and possibly platelet activating f a c t~r . '~~' '~~ st (particularly the variant sta) causes secretion by specifically activating intestinal mucosal guanylate cyclase.' "-' l the stb toxin causes noncyclic, nucleotide-mediated bicarbonate secretion and appears to be important only in animals. ' -" enteroinvasive e. coli (eiec) has the capacity to invade the intestinal mucosa, thereby causing an inflammatory enteritis much like shigellosi~.'~~~''~ epec elicits diarrhea by a signal transduction m e~h a n i s m~~~'~~~~~'~'~~ which is accompanied by a characteristic attaching-and-effacing histopathologic lesion in the small intestine. ' enterohemorrhagic e. coli (ehec) also induces an attaching-and-effacing lesion, but in the colon?' ehec also secretes shiga toxin, which gives rise to the sequela of hemolytic-uremic syndrome (hus). diffusely adherent e. coli executes a signal transduction effect, which is accompanied by the induction of long cellular processes. enteroaggregative e. coli (eaec) adheres to the intestinal mucosa and elaborates enterotoxins and a major problem in the recognition of etec, eiec, epec, and ehec strains of e. coli is that they are indistinguishable from normal coliform flora of the intestinal tract by the usual bacteriologic methods. serotyping is of value in recognizing epec serotypes' and eiec, because these organisms tend to fall into a limited number of specific serogroups (see table - ).' ' eiec invasiveness is confirmed by inoculating fresh isolates into guinea pig conjunctivae, as described by sereny. ' the ability of organisms to produce enterotoxins (lt or st) is encoded by a transmissible plasmid that can be lost by one strain of e. coli or transferred to a previously unrecognized although the enterotoxin plasmids appear to prefer certain serogroups (different from epec or invasive serogro~ps),'~~ etec is not expected to be strictly limited to a particular set of serogroups. instead, these strains can be recognized only by examining for the enterotoxin. this is done in ligated animal or by enzyme-linked immunosorbent assay (elisa)' for lt or in suckling mice for st. , specific dna probes also are available for lt and st. whether there are other mechanisms involved in the ability of the versatile e. coli species to cause enteric disease, such as by producing other types of enterotoxins"' or by fimbriate adherence traits a l~n e , '~~. '~' remains to be elucidated. cytoto~ns. ~ , in tissue although early work on the recognition of e. coli as a potential enteric pathogen focused on biochemical or serologic distinctions, there followed a shift in emphasis to the enterotoxins produced by previously recognized and entirely "new" strains of e. coli. beginning in the mid- s with work by de and colleague^'^^^'^^ in calcutta, e. coli strains from patients with diarrhea were found to cause a fluid secretory response in ligated rabbit ileal loops analogous to that seen with v; cholerue. work by taylor and associate^'^"^^ showed that the viable e. coli strains were not required to produce this secretory response and that this enterotoxin production correlated poorly with classically recognized epec serotypes. in sho paulo, trabulsi'& made similar observations with e. coli isolated from children with diarrhea, and several veterinary workers demonstrated that etec was associated with diarrhea in piglets and cal~es.'~~-'~o a similar pattern was described in with acute undifferentiated diarrhea in adults in bengal from whom e. coli could be isolated from the upper small bowel only during acute i l l n e~s . '~' "~~ these strains of e. coli produced a nondialyzable, lt, ammonium sulfate-precipitable enterotoxin.' analogous to the usually short-lived diarrheal illnesses of e. coli reported by several workers, a short-lived course of the secretory response to e. coli culture filtrates compared with the secretory response of cholera toxin was de~cribed."~ however, like responses to cholera toxin, secretory responses to e. coli were associated with activation of intestinal mucosal adenylate cyclase that paralleled the fluid secretory r e~p o n s e . '~~. '~~ the two types of enterotoxins produced by e. have been found to be plasmid-encoded traits that are potentially separable from each other and from the equally important plasmid-encoded adherence traits for patho-st causes an immediate and reversible secretory whereas the effects of lt (e.g., cholera toxin) follow a lag period necessitated by its intracellular site of a~t i o n . '~~' '~' '~~ only lt appears to cause fluid secretion by activating adenylate cyclase, which is accomplished by toxininduced adp-ribosylation of the gsa signaling p r~t e i n .~' "~~ the activation of adenylate cyclase by lt and by cholera toxin is highly promiscuous, occurring in many cell types and resulting in development of nonintestinal tissue culture assay systems such as the chinese hamster ovary (cho) cell assay' and y adrenal cell assay.' the antigenic similarity of lt and cholera toxin and their apparent binding to the monosialoganglioside gm, have enabled development of elisas for detection of lt and cholera t~x i n . '~~, '~' -'~~ st is a much smaller molecule and is distinct antigenically from lt and cholera t~x i n . '~~, '~'~'~' al though it fails to alter camp levels, st increases intracellular intestinal mucosal cyclic guanosine monophosphate (cgmp) concentrations and specifically activates plasma membrane-associated intestinal guanylate cy~lase."'-"~ like camp analogues, cgmp analogues cause intestinal secretion that mimics the response to st."' the receptor for sta responds to an endogenous ligand called guunylin, of which sta is a structural homologue.'" because the capacity to produce an enterotoxin may be transmissible between different organisms by a plasmid or even a bacteri~phage,''~-'~' interstrain gene transfer genesis. [ ] [ ] [ ] may be expected to be responsible for occasional toxigenic non-e. coli. enterotoxigenic klebsiella and citrobacter strains have been associated with diarrhea in a few reports, often in the same patients with etec.' ,' likewise, certain strains of salmonella appear to produce an lt, cho cellpositive toxin that may play a similar role in the pathogenesis of the watery, noninflammatory diarrhea sometimes seen with salmonella enteritidis i n f e c t i~n . '~~"~ at least equally important as enterotoxigenicity for e. coli to cause disease is the ability of these organisms to colonize the upper small bowel, where the enterotoxin produced has its greatest effect. a separable, plasmid-encoded colonization trait was first recognized in porcine e. coli. veterinary workers demonstrated that the fimbriate k- surface antigen was necessary for etec to cause disease in piglets. ' an autosomal dominant allele appears to be responsible for the specific intestinal receptor in piglets. in elegant studies by gibbons and c o -~o r k e r s , '~~ the homozygous recessive piglets lacked the receptor for k- and were resistant to scours caused by etec. at least analogous colonization factors have been described for human e. coli isolate^^^"^'"^^ against which local iga antibody may be produced. these antigens potentially may be useful in vaccine development. data on the epidemiology and transmission of etec remain scanty for the neonatal period. in the past decades, these strains have been recognized among adults with endemic, cholera-like diarrhea in calcutta, india, and in dacca, banglade~h,''~*'~' and among travelers to areas such as mexico and central a f r i~a . '~~-'~~ the isolation of etec is uncommon in sporadic diarrheal illnesses in temperate climates where sanitation facilities are good and where winter viral patterns of diarrhea predominate. etec is commonly isolated from infants and children with acute watery summer diarrhea in areas where sanitary facilities are less than optimal. - *' -' these include areas such as afria, ~~~il, , , , , gentir~a,'~~ bengal,' '' mexico,' o and native american reservations in the southwestern united state^."^"'^ in a multicenter study of acute diarrhea in infants and children in china, india, mexico, myanmar, and pakistan, % of cases (versus % of controls) had etec.le a case-control study from northwestern spain showed a highly significant association of etec with . % of neonatal diarrhea, often acquired in the ho~pital.''~ although all types of etec (lt and/or st producers) are associated with cholera-like, non inflammatory, watery diarrhea in adults in these areas, they probably constitute the major cause (along with rotaviruses) of dehydrating diarrhea in infants and young children in these areas. in this setting, peaks of illnesses tend to occur in the summer or rainy season, and dehydrating illnesses may be life threatening, especially in infants and young ~h i l d r e n . ~~'~'~'~ humans are probably the major reservoirs for the human strains of etec, and contaminated food and water probably constitute the principal vector^.''^"^^ although antitoxic immunity to lt and asymptomatic infection with ltproducing e. coli tends to increase with age, st is poorly immunogenic, and st-producing e. coli continues to be associated with symptomatic illnesses into adulthood in endemic area~.l'~>l'~ the association of etec with outbreaks of diarrhea in newborn nurseries is well documented. ryder and colleagues'g isolated an st-producing e. coli from % of infants with diarrhea, from the environment, and in one instance, from an infant's formula during a -month period in a prolonged outbreak in .a special care nursery in texas. another st-producing e. coli outbreak was reported in by gross and a~sociates'~~ from a maternity hospital in scotland. etec and epec were significantly associated with diarrhea among infants younger than year in bang ade~h.l~ ' an outbreak of diarrhea in a newborn special care nursery that was associated with enterotoxigenic organisms that were not limited to the same serotype or even the same species has been reported.lg the short-lived etec, klebsiella, and citrobacter species in this outbreak raised the possibility that each infant's indigenous bowel flora might become transiently toxigenic, possibly by receiving the lt genome from a plasmid or even a bacteriophage. the clinical manifestations of etec diarrhea tend to be mild and self-limited, except in small or undernourished infants, in whom dehydration may constitute a major threat to life. in many parts of the developing world, acute diarrheal illnesses are the leading recognized causes of death. there is some suggestion that the diarrheal illnesses associated with st-producing etec may be particularly severe.' most probably the best definition of the clinical manifestations of etec infection comes from volunteer studies with adults. ingestion of ' to '' human etec isolates that produce lt and st or st alone resulted in a % to % attack rate of mild to moderate diarrheal illnesses within to hours that lasted to days.' these illnesses, typical for traveler's diarrhea, were manifested by malaise, anorexia, abdominal cramps, and sometimes explosive diarrhea. nausea and vomiting occur relatively infrequently, and up to one third of patients may have a low-grade fever. although illnesses usually resolve spontaneously within to days, they occasionally may persist for week or longer. the diarrhea is noninflammatory, without fecal leukocytes or blood. in outbreaks in infants and neonates, the duration has been in the same range ( to days), with a mean of approximately days. as in cholera, the pathologic changes associated with etec infection are minimal. from animal experiments in which thiry-vella loops were infected with these organisms and at a time when the secretory and adenylate cyclase responses were present, there was only a mild discharge of mucus from goblet cells and otherwise no significant pathologic change in the intestinal tract.lo unless terminal complications of severe hypotension ensue, etec organisms rarely disseminate beyond the intestinal tract. like cholera, etec diarrhea is typically limited to being an intraluminal infection. the preliminary diagnosis of etec diarrhea can be suspected by the epidemiologic setting and the noninflammatory nature of stool specimens, which reveal few or no leukocytes. although the ability of e. coli to produce enterotoxins may be lost or transmitted to other strains, there is a tendency for the enterotoxin plasmids to occur among certain predominant serotypes, as shown in table - ."' these serotypes differ from epec or invasive serotypes, but their demonstration does not prove that they are enterotoxigenic. the only definitive way to identify etec is to demonstrate the enterotoxin itself by a specific gene probe for the toxin codon, by a bioassay such as tissue culture or ileal loop assays for lt or the suckling mouse assay for st, or in the case of lt, by immunoassay such as elisa. however, even these sensitive bioassays are limited by the unavailability of any selective media for detecting etec by culture. even though substantial improvements have been made in enterotoxin assay (particularly for lt), the necessary random selection of e. coli from a relatively nonselective stool culture plate resulted in a sensitivity of only % of epidemiologically incriminated cases in an outbreak when to isolates were randomly picked and tested for enter~toxigenicity."~ by also examining paired serum samples for antibody against lt, only % demonstrated significant serum antibody titer rises, for a total sensitivity of etec isolation or serum antibody titer rises of only %. some have suggested that isolates may be pooled for lt or st assay. the capacity to prove with radiolabeled or enzyme-tagged oligonucleotide gene sequences for the enterotoxins (lt or st) further facilitates the identification of enterotoxigenic organisms.' s a novel method of combining immunomagnetic separation (using antibodycoated magnetic beads) followed by dna or polymerase chain reaction (pcr) probing may enhance the sensitivity of screenin fecal or food specimens for etec or other the mainstay of treatment of any diarrheal illness is rehydration."' this principle especially pertains to etec diarrhea, which is an intraluminal infection. the glucose absorptive mechanism remains intact in e. coli enterotoxininduced secretion, much as it does in cholera, a concept that has resulted in the major advance of oral glucose-electrolyte therapy. this regimen can usually provide fully adequate rehydration in infants and children able to tolerate oral fluids, replacing the need for parented rehydration in most cases . , its use is particularly critical in rural areas and developing nations, where early application before dehydration becomes severe may be lifesaving. the standard world health organization solution contains . g nacl, . g nahco,, . g kcl, and g glucose per liter of clean or boiled drinking water.i ' this corresponds to the following concentrations: mmoyl of sodium, mmovl of potassium, mmoyl of bicarbonate, mmol/l of chloride, and mmol/l of glucose. a variety of recipes for homemade preparations have been described?" but unless the cost is prohibitive, the premade standard solution is preferred. each ounces of this solution should be followed by ounces of plain water. if there is concern about hypertonicity, especially in small infants in whom a high intake and constant direct supervision of feeding cannot be ensured, the concentration of salt can be reduced.' a reduced osmolality solution with mmol/l of sodium and mmoyl of glucose and a total osmolality of (instead of ) mosm/kg has been found to reduce stool output by % and illness duration by % in a multicenter trial involving children in four countries. commercially available rehydration solutions are increasingly available ~orldwide.'~' pathogens. lf , the role of antimicrobial agents in the treatment or prevention of etec is controversial. this infection usually resolves within to days in the absence of antibacterial therapy. moreover, there is concern about the potential for coexistence of enterotoxigenicity and antibiotic resistance on the same plasmid, and co-transfer of multiple antibiotic resistance and enterotoxigenicity has been well d~cumented."~ widespread use of prophylactic antibiotics in areas where antimicrobial resistance is common has the potential for selecting for rather than against enterotoxigenic organisms. the prevention and control of etec infections would be similar to those discussed under epec serotypes. the use of breast-feeding should be encouraged. eiec causes diarrhea by means of shigella-like intestinal epithelial invasion (discussed later). s ' the somatic antigens of these invasive strains have been identified and seem to fall into of recognized groups (see table - ). most, if not all, of these bacteria share cell wall antigens with one or another of the various shigelza serotypes and produce positive reactions with antisera against the cross-reacting antigen."* however, not all strains of e. coli belonging to the serogroups associated with dysentery-lke illness are pathogenic, because a large ( mda) invasive plasmid is also required. additional biologic tests, including the guinea pig conjunctivitis (sereny) test or a gene probe for the plasmid, are used to confirm the property of inva~iveness."~ although an outbreak of foodborne eiec diarrhea has been well documented among adults who ate an imported cheese,"' little is known about the epidemiology and transmission of this organism, especially in newborns and infants. whether the infectious dose may be as low as it is for shigella is unknown; however, studies of adult volunteers suggest that attack rates may be somewhat lower after ingestion of even large numbers of eiec than would be expected with shigella. the outbreak of eiec diarrhea resulted in a dysentery-like syndrome with an inflammatory exudate in stool and invasion and disruption of colonic mucosa."' descriptions of extensive and severe ileocolitis in infants dying with e. coli diarrhea indicate that neonatal disease also can be caused by invasive strains capable of mimicking the pathologic features of shigellosis. the immunofluorescent demonstration of e. coli together with an acute inflammatory infiltrate " in the intestinal tissue of infants tends to support this impression, although it has been suggested that the organisms may have invaded the bowel wall in the postmortem ~e r i d . l '~ there is still little direct evidence concerning the role of invasive strains of e. coli in the cause of neonatal diarrhea. the infrequency with which newborns manifest a dysentery-like syndrome makes it unlikely that this pathogen is responsible for a very large proportion of the diarrheal disease that occurs during the first month of life. the diagnosis should be suspected in infants who have an inflammatory diarrhea as evidenced by fecal polymorphonuclear neutrophils or even bloody dysenteric syndromes from whom no other invasive pathogens, such as campylobacter, shigella, salmonella, vibrio, or yersinia, can be isolated. in this instance, it may be appropriate to have the fecal e. coli isolated and serotyped or tested for invasiveness in the sereny test. plasmid pattern analysis and chromosomal restriction endonuclease digestion pattern analysis by pulsed-field gel electrophoresis have been used to evaluate strains involved in outbreaks. the management and prevention of eiec diarrhea should be similar to those for acute shigella or other e. coli enteric infections. the serologic distinction of e. coli strains associated with epidemic and sporadic infantile diarrhea was first suggested by goldschmidt in and confirmed by dulaney and michelson in . these researchers found that certain strains of e. coli associated with institutional outbreaks of diarrhea would agglutinate with antisera on slides. in , bra?" isolated a serologically homogeneous strain of e. coli (subsequently identified as serogroup ) from % of infants with summer diarrhea in england. he subsequently summarized a larger experience with this organism isolated from only % of asymptomatic controls but from % of infants with diarrhea, one half of which was hospital this strain (initially called e. coli-gomez by varela in ) also was associated with infantile diarrhea in a second type of e. coli (called beta by giles in and subsequently identified as ) was associated with an outbreak of infantile diarrhea in aberdeen, s~o t l a n d .~'~*~'~ from this early work primarily with epidemic diarrhea in infants has developed an elaborate serotyping system for certain e. coli strains that were clearly associated with infantile these strains first were called enteropathogenic e. coli by neter and colleagues in , and the association with particular serotypes can still be observed. as shown in table - , these organisms are distinct from the enterotoxigenic or enteroinvasive organisms or those that inhabit the normal gastrointestinal tract. they exhibit localized adherence to hep- cells, a phenotype that has been suggested to be useful for diagnosis and pathogenesis research. 'i epec is an important cause of diarrhea in infants in developing or transitional c~u n t r i e s .~"~~' -~~~ outbreaks have become rare in the united states and other industrialized countries, but they still ccur. ~~ some have attributed the rarity of this recognition of illness in part to the declining severity of diarrheal disease caused by epec within the past years, resulting in fewer cultures being obtained from infants with relatively mild symptom^.^^^^^^ however, several other variables influence the apparent incidence of this disease in the community. a problem arises with false-positive epec on the basis of the nonspecific cross-reactions seen with improper shortening of the serotyping p r o c e d~r e .~~~,~~~ because of their complexity and relatively low yield, neither slide agglutination nor hep- cell adherence or dna probe tests are provided as part of the routine identification of enteric pathogens by most clinical bacteriology laboratories. failure to recognize the presence of epec in fecal specimens is the inevitable consequence. the apparent incidence of epec gastroenteritis also varies with the epidemiologic circumstances under which stool cultures are obtained. the prevalence of enteropathogenic strains is higher among infants from whom cultures are obtained during a community epidemic compared with those obtained during sporadic diarrheal disease. neither reflects the incidence of epec infection among infants involved in a nursery outbreak or hospital epidemic. epec gastroenteritis is a worldwide problem, and socioeconomic conditions play a significant role in determining the incidence of this disease in different populations. s for instance, it is unusual for newborn infants born in a rural environment to manifest diarrheal disease caused by epec; most infections of the gastrointestinal tract in these infants occur after the first months of conversely, among infants born in large cities, the attack rate of epec is high during the first months of life. this age distribution reflects in large part the frequency with which epec causes crossinfection outbreaks among nursery populations' '~ ~ ; however, a predominance of epec in infants in the first months of life also has been described in community epidemic^^^'-^^^ and among sporadic cases of diarrhea acquired outside the h~s p i t a l . '~' -~~~ the disparity in the incidence of neonatal epec infection between rural and urban populations has been ascribed to two factors: the trend away from breast-feeding among mothers in industrialized societies and the crowding together of susceptible newborns in nurseries in countries in which hospital deliveries predominate over home d e l i~e r i e s . '~~~'~~ although the predominant serogroup can vary from year to year, , , ,z . ~ the same strains have been prevalent during the past years in great britain? puerto r~c o ?~~ guatemala: panama, newfoundland, indonesia, thailand, and south when living conditions are poor and overcrowding of susceptible infants exists, there is a rise in the incidence of neonatal diarrhea in general and epec gastroenteritis in p a r t i c~l a r .~'~~~~~~~~~ a h igher incidence of asymptomatic family carriers is found in such situations. b newborn infants can acquire epec during the first days of life by one of several routes: ( ) organisms from the mother ingested at the time of birth; ( ) bacteria from other infants or toddlers with diarrheal disease or from asymptomatic adults colonized with the organism, commonly transmitted on the hands of nursery personnel or parents; ( ) airborne or droplet infection; ( ) fomites; or ( ) organisms present in formulas or solid food supplements. only the first two routes have been shown conclusively to be of any real significance in the transmission of disease or the propagation of epidemics. most neonates acquire epec at the time of delivery through ingestion of organisms residing in the maternal birth canal or rectum. stool cultures taken from women before, during, or shortly after delivery have shown that % to % carry epec at some time during this period. ~s ~ ~ ~ ' use of fluorescent antibody techniquesz ' or cultures during a community outbreak of epec gastroenteritis" revealed twice this number of persons excreting the organism. virtually none of the women carrying pathogenic strains of e. coli had symptoms referable to the gastrointestinal tract. many of the mothers whose stools contain epec transmit these organisms to their infant~, ~*~' resulting in an asymptomatic infection rate of % to % among newborns cultured at random in nursery surveys. ~ ~ '~ these results must be considered conservative and are probably an artifact of the sampling technique. one study using antisera to identify as many e. coli as possible in fecal cultures showed a correlation between the coliform flora in % of motherinfant pairs? of particular interest was the observation that the groups of e. coli isolated from the infants' mucus immediately after delivery correlated with those subsequently recovered from their stools, supporting the contention that these organisms were acquired orally at the time of birth. in mothers whose stools contained the same group as their offspring, the mean time from rupture of membranes to delivery was about hours longer than in those whose infants did not acquire the same serogroups, suggesting that ascending colonization before birth also can play a role in determining the newborn's fecal flora. the contours of the epidemiologic curves in nurse$ - and communi@ - outbreaks are in keeping with a contact mode of spread. transmission of organisms from infant to infant takes place by way of the fecal-oral route in almost all cases, most likely on the hands of persons attending to their care. * , , ill infants represent the greatest risk to those around them because of the large numbers of organisms found in their stools - and crossinfection also has been initiated by infants who were healthy at the time of their admission to the nursery. , - a newborn exposed to epec is likely to acquire enteric infection if contact with a person excreting the organism is intimate and prolonged, as in a hospital or family setting. stool culture surveys taken during outbreaks have shown that between % and % of term neonates residing in the nursery carry epec in their intestinal tracts.' , , 'm despite descriptions of nursery outbreaks in which virtually every neonate or low-birth-weight infant became infected, there is ample evidence that exposure to pathogenic strains of e. coli does not necessarily result in greater likelihood of illness for premature infants than for term infants. , * , any increased prevalence of cross-infections that may exist among premature infants can be explained more readily by the prolonged hospital stays, their increased handling, and the clustering of infants born in different institutions than by a particular susceptibility to epec based on immature defense mechanisms. the most extensive studies on the epidemiology of gastroenteritis related to e. coli have dealt with events that took place during outbreaks in newborn nurseries. unfortunately, investigations of this sort frequently regard the epidemic as an isolated phenomenon and ignore the strong interdependence that exists between community-and hospital-acquired ~~~~~~ , , n ot surprisingly, the direction of spread is most often from the reservoir of disease within the community to the hospital. when the original source of a nursery outbreak can be established, frequently it is an infant born of a carrier mother who recently acquired her epec infection from a toddler living in the home. cross-infection epidemics also can be initiated by infected newborns who have been admitted directly into a clean nursery unit from the surrounding d i s t r i~t~~~~~~~*~~~ or have been transferred from a nearby hospital. after a nursery epidemic has begun, it generally follows one of two major patterns. some are explosive, with rapid involvement of all susceptible infants and a duration that seldom exceeds or months. * , * the case-fatality rate in these epidemics may be very high. other nursery outbreaks have an insidious onset with a few mild, unrecognized cases; the patients may not even develop illness until after discharge from the hospital. during the next few days to weeks, neonates with an increased number of loose stools are reported by the nurses; shortly thereafter, the appearance of the first severely ill infants makes it apparent that an epidemic has begun. unless oral antimicrobial therapy is instituted (see "therapy"), nursery outbreaks like these may continue for months - or with cycles of illness followed by periods of relative quiescence. this pattern can be caused by multiple strains (of different phage or antibiogram types) sequentially introduced into the nursery? * . the nursery can be a source of infection for the community. the release of infants who are in the incubation stages of their illness or are convalescent carriers about to relapse may lead to secondary cases of diarrheal disease among young siblings living in widely scattered areas. , , these children further disseminate infection to neighboring households, involving playmates of their own age, young infants, and mothers. as the sickest of these contact cases are admitted to different hospitals, they contaminate new susceptible persons, completing the cycle and compounding the outbreak. this feedback mechanism has proved to be a means of spreading infantile gastroenteritis through entire ~o~n t i e s , ~~~~~~,~~~ and even provinces. one major epidemic of diarrhea related to epec :b that occurred in the metropolitan chicago and northwestern indiana region during the winter of involved more than children and community hospitals during a period of months. , almost all of the patients were younger than years old, and % were younger than month, producing an age-specific attack rate of nearly % of neonates in the community. the importance of the hospital as a source of cross-infection in this epidemic was demonstrated through interviews with patients' families, indicating that a minimum of % of infants had direct or indirect contact with a hospital shortly before the onset of their illness. it has been suggested, but not proved, that asymptomatic carriers of epec in close contact with a newborn infant, such as nursery personnel or family members, might play an important role in its t r a n s m i~s i o n .~~~'~"~~~ stool culture surveys have shown that at any one time about % of and % to % of young who are free of illness harbor epec strains. higher percentages have been recorded during community epidemics? * s be cause this intestinal carriage is transitory: the number of individuals who excrete epec at one time or another during the year is far higher than the % figure recorded for single specimens. nursery personnel feed, bathe, and diaper a constantly changing population of newborns, about % to % of whom excrete epec. * despite this constant exposure, intestinal carriage among nursery workers is surprisingly low. even during outbreaks of diarrheal illness, when dissemination of organisms is most intense, less than % of the hospital personnel in direct contact with infected neonates are themselves excreting pathogenic strains of e. coli. ', , although adult asymptomatic carriers generally excrete fewer organisms than patients with acute illness large numbers of pathogenic bacteria may nevertheless exist in their stools? s however, no nursery outbreak and few family cases o have been traced to a symptomless carrier. instead, passive transfer of bacteria from infant to infant by the hands of personnel appears to be of primary importance in these outbreaks. cities, . , epec can be recovered from the throat or nose of % to % of infants with diarrheal illness p and from about % of asymptomatic the throat and nasal mucosa may represent a portal of entry or a source of transmission for epec. environmental studies have shown that epec is distributed readily and widely in the vicinity of an infant with active diarrheal disease, often within day of admission to the ~a r d . '~' , '~~ massive numbers of organisms are shed in the diarrheal stool or vomitus of infected e. coli organisms may survive to weeks in dust . and can be found in the nursery air when the bedding or diapers of infected infants are disturbed during routine nursing procedure^^^^^^^ or on floors, walls, cupboards, and nursery equipment such as scales, hand towels, bassinets, incubators, and oxygen tents of other infant^?^,'^^,'^^ documentation of the presence of epec in nursery air and dust does not establish the importance of this route as a source of cross-infection. one study presented evidence of the respiratory transmission of epec; however, even in the cases described, the investigators pointed out that fecal-oral transmission could not be completely ruled additional clinical and experimental data are required to clarify the significance of droplet and environmental infection. coliform organisms have also been isolated in significant numbers from human mi k, ~ ~ prebottled infant f rmulas, ~~ and formulas prepared in the home. epec in particular has been found in stool cultures obtained from donors of human milk and workers in a nursery formula room. o in one instance, epec :b was isolated from a donor, and subsequently, the same serogroup was recovered in massive amounts in almost pure culture from her milk. pathogenic strains of e. coli have also been isolated from raw cow's milk '' and from drinking ~a t e r .~" likewise, epec has been isolated from flies during an epidemic, but this fact has not been shown to be of epidemiologic significance. ' infection of the newborn infant with epec takes place exclusively by the oral route. attempts to induce disease in adult volunteers by rectal instillation of infected material have been unsuc~essful.~~ there are no reports of disease occurring after transplacental invasion of the fetal bloodstream by enteropathogenic or nonenteropathogenic strains of e. coli. ascending intrauterine infection after prolonged rupture of the membranes has been reported only once; the neonate in this case suffered only from mild diarrhea. bacterial cultures of the meconium and feces of newborns indicate that enteropathogenic strains of e. coli can colonize effectively the intestinal tract in the first days of although e. coli may disappear completely from stools of breast-fed children during the ensuing weeks, this disappearance is believed to be related to factors present in the human milk rather than the gastric secretions. ~ ~ the use of breast-feeding or expressed human milk has even been effective in terminating nursery epidemics caused by epec :b , probably by reducing the incidence of crossinfections among infants. although dose-effect studies have not been performed among newborns, severe diarrhea has occurred after ingestion of ' epec organisms by very young the high incidence of cross-infection outbreaks in newborn nurseries suggests that a far lower inoculum can often effect spread in this setting. the role of circulating immunity in the prevention of gastrointestinal tract disease related to epec has not been clearly established. virtually % of maternal sera have been found to contain hemaggl~tinating, '~~~''~~'~ or bacteriostatic ' ~ ' antibodies against epec. the passive transfer of these antibodies across the placenta is extremely inefficient. titers in blood of newborn infants are, on average, to times lower than those in the corresponding maternal sera. group-specific hemagglutinating antibodies against the antigen of epec are present in % to % of cord blood samp es, ~ ~ whereas b a~t e r i c i d a l~'~~~~~ or bacterio-static " activity against these organisms can be found much more frequently. tests for bacterial agglutination, which are relatively insensitive, are positive in only a small percentage of neonate^.'^^'^" the importance of circulating antibodies in the susceptibility of infants to epec infection is unknown. experiments with suckling mice have failed to demonstrate any effect of humoral immunity on the establishment or course of duration of intestinal colonization with e. coli in mothers or their infants. similar observations have been made in epidemiologic studies among premature human infants using enteropathogenic ( :b ) and nonenteropathogenic ( :h ) strains of e. coli as the indicator organisms. in a cohort of mothers and their infants followed from birth to months old, cooper and associate^'^ were able to show a far higher incidence of clinical epec disease in infants of epec-negative mothers than in infants born of mothers with epec isolated from stool cultures. this finding suggested to the investigators the possibility that mothers harboring epec in their gastrointestinal tracts transfer specific antibodies to their infants that confer some protection during the first weeks of life. protection against enteric infections in humans often correlates more closely with levels of local secretory than serum antibodies. although it is known that colonization of newborns with e. coli leads to the production of coproantibodies against the ingested the clinical significance of this intestinal immunity is uncertain. the previously mentioned experiment with mice showed no effect of active intestinal immunity on enteric col~nization.~'~ in human infants, the frequency of bacteriologic and clinical relapse related to epec of the same and the capacity of one strain of epec to superinfect a patient already harboring a different train^^^,^^^,^^^ also cast some doubt on the ability of mucosal antibodies to inhibit or alter the course of intestinal infection. studies of the protective effects of orally administered epec vaccines could help to resolve these question^.'^' the mechanism by which epec causes diarrhea involves a complex array of plasmid and chromosomally encoded traits. epec serotypes usually do not make one of the recognized enterotoxins (lt or st) as usually measured in tissue culture or animal r n~d e l s ,~'~~~'~ nor do these serotypes cause a typical invasive colitis or produce a positive sereny test only uncommonly do epec strains invade the bloodstream or disseminate. nevertheless, epec strains that test negative in these tests are capable of causing diarrhea; inocula of '' e. coli or organisms caused diarrhea in of adult volunteers. some epec strains may secrete weak enterot~xins,~~''~'~ but the consensus opinion is that the attaching and effacing lesion constitutes the critical secretory virulence pheno-clinical pathologic reports reveal the characteristic attachin and effacing lesion in the small intestine of infected infants? the lesion is manifested by intimate (about nm) apposition of the epec to the enterocytes plasma membrane, with dissolution of the normal brush border and rearrangement of the cyto~keleton.'''~~~~ in some instances, the bacteria are observed to rise up on pedestal-like structures, which are diagnostic of the infection.i ' villus blunting, crypt hypertrophy, histiocytic infiltration in the lamina propria, and a reduction in the brush border enzymes may also be ~bserved.~'~'~'~ two major epec virulence factors have been described; strains with both factors are designated as typical epec. * * ' one such factor is the locus of enterocyte effacement (lee), a type secretion system encoded by the lee chromosomal pathogenicity i~land.~'~-~'* the lee secretion apparatus injects proteins directly from the cytoplasm of the infecting bacterium into the cytoplasm of the target enter~cytes.~'~ the injected proteins constitute cytoskeletal toxins, which together elicit the close apposition of the bacterium to the cell, cause the effacement of microvilli, and most likely give rise to the net secretory one critical secreted protein, called towinterleukin- receptor (tir),"' inserts into the plasma membrane of the epithelial cell, where it serves as the receptor for a lee-encoded epec outer membrane protein called intimin.'" animals infected with attaching and effacin pathogens mount antibody responses to intimin and t i r ! and both are considered potential immunogens. the lack of protection from epec reinfection suggests that natural antibody responses to tir and intimin are not protective. the second major virulence factor of typical epec is the bundle-forming pilus (bfp), which is encoded on a partially conserved mda virulence plasmid called epec adherence factor bfp, a member of the type iv pilus family, mediates aggregation of the bacteria to each other and probably to enterocytes themselves, thereby facilitating mucosal colonization. a bfp mutant was shown to be attenuated in adult volunteers. the principal pathologic lesion with epec is the focal destructive adherence of the organism, effacing the microvillous brush border with villus blunting, crypt hypertrophy, histiocytic infiltration of the lamina propria, and reduced brush border enzymes. rothbaum and colleagues described similar findings with dissolution of the glycocalyx and flattened microvilli with the nontoxigenic epec strain :b . there has been a wide range of pathologic findings reported in infants dying of epec gastroenteritis. most newborns dying with diarrheal disease caused by epec show no morphologic changes of the gastrointestinal tract by gross or microscopic examination of tiss~es.~'~'~'' bra?" described such "meager" changes in the intestinal tract that "the impression received was that the term gastroenteritis is incorrect." at the other extreme, extensive and severe involvement of the intestinal tract, although distinctly unusual among neonates with epec diarrhea, has been discussed in several reviews of the pathologic anatomy of this disease. v , changes virtually identical to those found in infants dying with necrotizing enterocolitis have been reported. drucker and c o -~o r k e r s~'~ found that among infants who were dying of epec diarrhea, "intestinal gangrene, and/or perforation, andlor peritonitis were present in five, and intestinal pneumatosis in five." the reasons for such wide discrepancies in epec disease pathology are not clear. the severity of intestinal lesions at the time of death does not correlate with the birth weight of the patient, the age of onset of illness, the serogroup of the infecting strain, or the prior administration of oral or systemic antimicrobial agents. the suggestion that the intensity of inflammatory changes may depend on the duration of the diarrhea '' cannot be corroborated in autopsy s t~d i e s~'~*~"~~~ or small intestinal it is difficult to reconcile such a thesis with the observation that a wide range of intestinal findings can be seen at autopsy among newborns infected by a single serotype of epec during an epidemic. the nonspecific pathologic picture described by some researchers includes capillary congestion and edema of the bowel wall and an increase in the number of eosinophils, plasma cells, macrophages, and mononuclear cells in the mucosa and submucosa. , , villous patterns are generally well preserved, although some flattening and broadening of the villi are seen in the more severe cases. almost complete absence of villi and failure of regeneration of small bowel mucosa have been reported in an extreme case. edema in and around the myenteric plexuses of auerbach, a common associated finding, has been suggested as a cause of the gastrointestinal tract dilatation often seen at autopsy in infants with epec infection^.^^^'^^^'^^^ in general, the distal small intestine shows the most marked alterations; however, the reported pathologic findings may be found at all levels of the intestinal tract. several complications of epec infection have been reported. candidal esophagitis accounted for significant morbidity in two series collected before'" and the antibiotic era. oral thrush has been seen in % of epecinfected infants treated with oral or systemic antib i o t i c~. '~~,~~"~~ some degree of fatty metamorphosis of the liver has been reported by several investigators" i ' ; however, these changes are nonspecific and probably result from the poor caloric intake associated with persistent diarrhea or vomiting. some degree of bronchopneumonia, probably a terminal event in most cases, exists in a large proportion of newborns dying of epec i n f e~t i o n .~" " '~'~~~ in one reported series of infant cases, epec was demonstrated by immunofluorescent staining in the bronchi, alveoli, and interalveolar septa. mesenteric lymph nodes are often swollen and congested with reactive germinal centers in the lymphoid f o l l i~l e s . '~~~~, '~~ severe lymphoid depletion, unrelated to the duration or severity of the antecedent illness, also has been de~cribed.'~~ the kidneys frequently show tubular epithelial toxic changes. various degrees of tubular degeneration and cloudy swelling of convoluted tubules are common finding^.^'^,'^^,^^^ renal vein thrombosis or cortical necrosis may be observed in infants with disseminated intravascular coagulation in the terminal phases of the illness. the heart is grossly normal in most instances but may show minimal vacuolar changes of nonspecific toxic myocarditis on microscopic examinati n. ~~'~~' candidal abscesses of the heart and kidneys' , , have been described. with the exception of mild congestion of the pia arachnoid vessels and some edema of the meninges, examination of the central nervous system reveals few changes? despite the observation of braf l that "inflammation of the middle ear [is] exceptional," strains of epec have been isolated from a significant number of specimens of the middle ear in case series in which dissection of the temporal bone has been performed. exposure of newborns to epec may be followed by one of several possible consequences: no infection, infection without illness, illness with gastroenteritis of variable severity and duration, and rarely, septicemia with or without metastatic foci of infection accompanying gastroenteritis. when infants are exposed to epec, a significant number become colonized as temporary st , or pharyngeal carriers with no signs of clinical disease. although l a~r e l l~~' showed that the percentage of asymptomatic infections rises steadily as age increases, this observation has not been confirmed by other investigator^.^'^.^^^ similarly, the suggestion that prematurity per se is associated with a low incidence of inapparent epec infection has been documented in several clinical but refuted in others. , most neonates who acquire infection with epec eventually show some clinical evidence of gastroenteritis. the incubation period is quite variable. its duration has been calculated mostly from evidence in outbreaks in newborn nurseries, where the time of first exposure can be clearly defined in terms of birth or admission dates. in these circumstances, almost all infants show signs of illness between and days after exposure, and most cases show signs within the first days. , , in some naturally and experi-menta infections with heavy exposure, the incubation period may be as short as hours; the stated upper limit is days. the first positive stool culture and the earliest recognizable clinical signs of disease occur simultaneously in most although colonization may precede symptoms by to days. , th e gastroenteritis associated with epec infection in the newborn is notable for its marked variation in clinical pattern. clinical manifestations vary from mild illness manifest only by transient anorexia and failure to gain weight to a sudden explosive fulminating diarrhea causing death within hours of onset. prematurity, underlying disease, and congenital anomalies often are associated with the more severe forms of illness. , , , experienced clinicians have observed that the severity of epec gastroenteritis has declined markedly during the past decades. the onset of illness usually is insidious, with vague signs of reluctance to feed, lethargy, spitting up of formula, mild abdominal distention, or even weight loss that may occur for or days before the first loose stool is passed. diarrhea usually begins abruptly. it may be continuous and violent, or in milder infections, it may run an intermittent course with or more days of normal stools followed by or more days of diarrhea. emesis sometimes is a prominent and persistent early finding. stools are loose and bright yellow initially, later becoming watery, mucoid, and green. flecks or streaks of blood, which are commonly seen with enterocolitis caused by salmonella, campylobacter, or shigella, are rarely a feature of epec diarrheal disease. a characteristic seminal smell may pervade the environment of infants infected with epec :b , , , and an odor variously described as "pungent," "musty," or "fetid" often surrounds patients excreting other strains in their stool^.^^','^^ because the buttocks are repeatedly covered with liquid stools, excoriation of the perianal skin can be an early and persistent problem. fever is an inconstant feature, and when it occurs, the patient's temperature rarely rises above " c. convulsions occur infrequently; their occurrence should alert the clinician to the possible presence of electrolyte disturbances, particularly hypernatremia. prolonged hematochezia, distention, edema, and jaundice are ominous signs and suggest an unfavorable p r o g n o~i s .~'~,~~~*~*~ m ost infants receiving antimicrobial agents orally show a cessation of diarrhea, tolerate oral feedings, and resume weight gain within to days after therapy has been those with mild illness who receive no treatment can continue to have intermittent loose stools for to weeks. in one outbreak related to epec :k , more than one third of the untreated or inappropriately treated infants had diarrhea for more than days in the absence of a recognized enteric pathogen on repeated culturing. recurrence of diarrhea and vomiting after a period of initial improvement is characteristic of epec e n t e r i t i~. '~'~~~~~~~ though seen most often in newborns who have been treated inadequately or not treated at all, clinical relapses also occur after appropriate therapy. occasionally, the signs of illness during a relapse can be more severe than those accompanying the initial attack of illness. , , not all clinical relapses result from persistent infection. a significant number of relapses, particularly those that consistently follow attempts at reinstitution of formula fee ding^?^^.^^^ are caused by disaccharide intolerance rather than bacterial proliferation. intestinal superinfections, caused by another serotype of epecz or by completely different enteric pathogens, such as salmonella or shigella, also can delay the resolution of symptoms. rarely, infants suffer a "relapse" caused by an organism from the same group as the original strain but differing in its h antigen. unless complete serotyping is performed on all epec isolates, such an event easily could be dismissed as being a recurrence rather than a superinfection with a new ~r g a n i s m . '~~*~~~ antimicrobial agents to which the infecting organisms are susceptible often may not eradicate epec: , , which may persist for weeks , , or months after the acute illness has subsided. although reinfection cannot always be excluded, a significant number of infants are discharged from the hospital with positive rectal dehydration is the most common and serious complication of gastroenteritis caused by epec or a toxin-producing e. coli. virtually all deaths directly attributable to the intestinal infection are caused by disturbances in fluids and electrolytes. when stools are frequent in number, large in volume, and violent in release, as they often are in severe infections with abrupt onset, a neonate can lose up to % of body weight in a few h o~r s .~~~,~~~ rarely, fluid excretion into the lumen of the bowel proceeds so rapidly that reduction of circulating blood volume and shock may intervene before passage of even a single loose before the discovery of the etiologic agent, epidemic diarrhea of the newborn was also known by the term cholera infantum. mild disease, particularly when aggravated by poor fluid intake, can lead to a subtle but serious deterioration of an infant's metabolic status. sometimes, a week or more of illness elapses before it becomes apparent that an infant with borderline acidosis and dehydration who seemed to be responding to oral fluids alone requires parenteral therapy for impr~vement?~~ it is incumbent on the clinician caring for small infants with gastroenteritis to follow them closely, with particular attention to serial weights, until full recovery can be confirmed. there are few other complications, with the possible exception of aspiration pneumonia, directly related to epec gastroenteritis. protracted diarrhea and nutritional failure may occur as a consequence of functional damage to the small intestinal mucosa, with secondary intolerance to dietary necrotizing enterocolitis, which occasionally results in perforation of the bowel and peritonitis, has not been causally related to infection with epec. , , a review of most of the large clinical series describing epec disease in infants who ranged in age from neonates to children aged years revealed only three proven instances of ba~teremia:~~**~~ one possible urinary tract infection: and one documented case of meningitis in an infant of unspecified age. focal infections among neonates were limited to several cases of otitis and a subcutaneous abscess from which epec was isolated. additional complications include interstitial pneumonia, gastrointestinal bleeding with or without disseminated intravascular coagulatio , ~.~~~ and methemoglobinemia caused by a mutant of epec :b that was capable of generating large quantities of nitrite from proteins present in the gastrointestinal tract. the gold standard of epec diagnostics is identification in the stool of e. coli carrying genes for bfp and lee. identification of these genes can be accomplished by molecular methods (discussed later), but lack of access to these methods has led many labs to rely on surrogate markers, such as serotyping." classic epec has been recovered from the vomitus, stool, or bowel contents of infected newborns. isolation from bile and the upper respiratory t r a~t~~~~~~*~~~ ha s been described in those instances in which a specific search has been made. less commonly, epec is isolated from ascetic fluid'" or purulent exudates * * , occasionally, the organism has been recovered from blood c u l t~r e s ?~~,~~~ urine: and cerebrospinal fluid. stool cultures generally are more reliable than rectal swabs in detecting the presence of enteric pathogens, although a properly obtained swab should be adequate to demonstrate epec in most cases. ' , * specimens should be obtained as early in the course of the illness as possible because organisms are present in virtually pure culture during the acute phase of the enteritis but diminish in numbers during convalescence. because of the preponderance of epec in diarrheal stools, two cultures are adequate for isolation of these pathogens in almost all cases of active disease. studies using fluorescent antibody methods for identification of epec in stool specimens have demonstrated that during the incubation period of the illness, during convalescence, and among asymptomatic carriers of epec, organisms can be excreted in such small numbers that they escape detection by standard bacteriologic methods in a significant proportion of as many as to specimens may be required to detect epec using methods that identify individual epec isolates in the ~t . ~~~ after a stool specimen is received, it should be plated as quickly as possible onto noninhibiting media or placed in a preservative medium if it is to be held for longer periods. deep freezing of specimens preserves viable epec when a prolonged delay in isolation is necessary?" no selective media, biochemical reactions, or colonial variations permit differentiation of pathogenic and nonpathogenic strains. certain features may aid in the recognition of two important serogroups. cultures of serogroups :b and :b , unlike many other coliforms, are sticky or stringy when picked with a wire loop and are rarely hemolytic on blood whereas :b colonies emit a distinctive evanescent odor commonly described as "~e m i n a l . ' '~~~,~~~ this unusual odor first led b r a y to suspect that specific strains of e. coli might be responsible for infantile gastroenteritis. because serotyping is simpler than molecular detection and because epec have long been known to belong to certain highly characteristic serotypes, serotyping can be used to identify likely epec strains, especially in outbreaks? e. coli, like other enterobacteriaceae members, possesses cell wall somatic antigens (o), envelope or capsular antigens (k), and if motile, flagellar antigens (h). many of the groups may be further divided into two or more subgroups (a, b, c), and the k antigens are divisible into at least three varieties (b, l, a) on the basis of their physical behavior. organisms that do not possess flagellar antigens are nonmotile (designated nm). the epec b capsular surface antigen prevents agglutination by antibodies directed against the underlying antigen. heating at °c for hour inactivates the agglutinability and antigenicity of the b antigen. slide agglutination tests with polyvalent or ob antiserum may be performed on suspensions of colonies typical of e. coli that have been isolated from infants with diarrhea, especially in nursery outbreaks. however, because of numerous false-positive "cross-reactions:' the and k (or b) type must be confirmed by titration with the specific a n t i~e r a .~~~ the presence of epec does not prove that epec is the cause of diarrhea in an individual patient. mixed cultures with two or three serotypes of epec have been demonstrated in % to % of patients. * * this need not mean that two or three serotypes are causative agents. secondary infection with hospital-acquired strains can occur during convalesand some infants may have been asymptomatic carriers of one serotype at the time that another produced diarrheal disease. a similar explanation may pertain to mixed infections with epec and salmonella or shigella. * nelson reported the presence of these pathogens in combination with epec in % of infants who were cultured as part of an antibiotic therapy trial. salmonella and shigella that had not been identified on cultures obtained at admission were isolated only after institution of oral therapy with neomycin. the investigator postulated that the alteration in bowel flora brought about by the neomycin facilitated the growth of these organisms, which had previously been suppressed and obscured by coliform over- the importance of seeking all enteric pathogens in primary and follow-up cultures of infantile diarrhea is apparent, particularly when the specimen originates from a patient in a newborn nursery or infants' ward. although epec gastroenteritis was once considered to be synonymous with "summer diarrhea," community outbreaks have occurred as frequently, if not more frequently, in the colder seasons. , * it has been suggested that the increased incidence at that time of year might be related to the heightened chance of contact between infants and toddlers cence,l , , , that is bound to occur when children remain indoors in close contact.z nursery epidemics, which depend on the chance introduction and dissemination of epec within a relatively homogeneous population and stable environment, demonstrate no seasonal prevalence. average relative humidity, temperature, and hours of daylight have no significant effect in determining whether an outbreak will follow the introduction of enteropathogenic strains of e. coli into a ward of infants. there are no clinical studies of the variations in peripheral leukocyte count, urine, or cerebrospinal fluid in neonatal enteritis caused by epec. microscopic examination of stools of infants with acute diarrheal illness caused by these organisms usually has revealed an absence of fecal polymorphonuclear l e~k o c y t e s~'~~~~~~~~~*~~~ although data on fecal lactoferrin in human volunteers suggest that an inflammatory process may be important in epec diarrhea. , stool ph can be neutral, acid, or alkaline. serologic methods have not proved to be useful in attempting to establish a retrospective diagnosis of epec infection in neonates. rising or significantly elevated agglutinin titers rarely could be demonstrated in early investigation^^'^"'^^^'; hemagglutinating antibodies showed a significant response in no more than % to % of cases. , fluorescent antibody techniques have shown promise for preliminary identification of epec in acute infantile diarrhea. this method is specific, with few false-positive results, and it is more sensitive than conventional plating and isolation t e c h n i q~e s .~~~,~~' .~~~ the rapidity with which determinations can be performed makes them ideally suited for screening ill infants and possible carriers in determining the extent and progression of a n~r s e r f '~,~~~ or om mu nit$^^^^'' outbreak. because immunofluorescence does not depend on the viability of organisms and is not affected by antibiotics that suppress growth on culture plates, it can be used to advantage in following bacteriologic responses and relapses in patients receiving oral the rap^.^","^ the use of fluorescent antibody techniques offers many advantages in the surveillance and epidemiologic control of epec gastroenteritis. immunofluorescent methods should supplement but not replace standard bacteriologic and serologic methods for identification of enteric pathogens. specific gene probes and pcr primers for the bfp adhesin, the intimin-encoding gene (eue) and for a cryptic plasmid locus (eaf) are a~ailable.~~ detection of bfp or eaf are superior to detection of eue, because many non-epec, including nonpathogens, carry the eae gene. b pcr and gene probe analysis can be performed directly on the stools of suspect infants. however, confirmation of infection by the identification of the organism in pure culture should be pursued. before widespread use of molecular methods, the hep- cell adherence assay was proposed for epec diagnosis."' the presence of a focal or localized adherence (la) pattern on the surface of hep- or hela cells after -hour coincubation is a highly sensitive and specific test for detection of epec. the requirement for cell culture and expertise in reading this assay limits its utility to the research setting. an elisa for the bfp has been described but is not readily available? the capacity of la + epec to polymerize f-actin can be detected in tissue culture cells stained with rhodamine-labeled phall~idin.~~' this fluorescence-actin staining (fas) test is cumbersome and impractical for routine clinical use. the mortality rate recorded previously in epidemics of epec gastroenteritis is impressive for its variability. during the s and s, when organisms later recognized as classic enteropathogenic serotypes were infecting infants, the case-fatality ratio among neonates was about %. during the s and s, many nursery epidemics still claimed about one of every four infected infants, but several outbreaks involving the same serotypes under similar epidemiologic circumstances had fatality rates of less than h. in th e s, reports appeared in the literature of a nursery epidemic with a % neonatal mortality rate and of an extensive outbreak in a nursery for premature infants with % fatalities ; another report stated that among " consecutive infants admitted to the hospital for epec diarrheal disease, none died of diarrheal disease per se." a significant proportion of the infants who died during or shortly after an episode of gastroenteritis already were compromised by preexisting disease , , or by congenital m a l f~r m a t i o n s~'~,~~'~~~~ at the time they acquired their illness. these underlying pathologic conditions appear to exert a strongly unfavorable influence, probably by reducing the infant's ability to respond to the added stresses imposed by the gastrointestinal tract infection. although prematurity is often mentioned as a factor predisposing to a fatal outcome, the overall mortality rate among premature infants with epec gastroenteritis has not differed significantly over the years from that recorded for term the management of epec gastroenteritis should be directed primarily toward prevention or correction of problems caused by loss of fluids and electr ytes.i~~ most neonates have a relatively mild illness that can be treated with oral rehydration. infants who appear toxic, those with voluminous diarrhea and persistent vomiting, and those with increasing weight loss should be hospitalized for observation and treatment with parenteral fluids and careful maintenance of fluid and electrolyte balance and possibly with antimicrobial therapy. clinical studies suggest that slow nasogastric infusion of an elemental diet can be valuable in treating infants who have intractable diarrhea that is unresponsive to standard modes of therapy. there is no evidence that the use of proprietary formulas containing kaolin or pectin is effective in reducing the number of diarrheal stools in neonates with gastroenteritis. attempts to suppress the growth of enteric pathogens by feeding lactobacillus to the infant in the form of yogurt, powder, or granules have not been shown to be of value. a trial of cholestyramine in newborns with epec gastroenteritis had no effect on the duration or severity of the diarrhea. the use of atropine-like drugs, paregoric, or loperamide to reduce intestinal motility or cramping should be avoided. inhibition of peristalsis interferes with an efficient protective mechanism designed to rid the body of intestinal pathogens and may lead to fluid retention in the lumen of the bowel that may be sufficient to mask depletion of extracellular fluid and electrolytes. the value of antimicrobial therapy in management of neonatal epec gastroenteritis, if any, is uncertain. there are no adequately controlled studies defining the benefits of any antibiotic in eliminating epec from the gastrointestinal tract, reducing the risk of cross-infection in community or nursery outbreaks, or modifymg the severity of the illness. proponents of the use of antimicrobial agents have based their claims for efficacy on anecdotal observations or comparative studies. nonetheless, several clinical investigations have provided sufficient information to guide the physician faced with the dilemma of deciding whether to treat an individual infant or an entire nursery population suffering from epec diarrheal disease. it should be emphasized, however, that these guidelines must be considered tentative until rigidly controlled, double-blind studies have established the efficacy of antibiotics on a more rational and scientific basis. oral therapy with n e o m y~i n ,~'~'~~' ~olistin,'~~or chloram-phenic ~~~ appears to be effective in rapidly reducing the number of susceptible epec organisms in the stool of infected infants. studies comparing the responses of infants treated orally with ne~mycin?~' gentamicin: p~l p y x i n :~~ or kanamy~in'~' with the responses of infants receiving supportive therapy alone have shown that complete eradication of epec occurs more rapidly in those receiving an antimicrobial agent. in most cases, stool cultures are free of epec to days after the start of therapy. bacteriologic failure, defined as continued isolation of organisms during or after a course of an antimicrobial agent, can be expected to occur in % to % of patients? s such relapses generally are not associated with a recurrence of ~y m p t~m~.~~i *~~~*~~~ the effectiveness of oral antimicrobial therapy in reducing the duration of epec excretion serves to diminish environmental contamination and the spread of pathogenic organisms from one infant to another. breaking the chain of fecal-oral transmission by administering antimicrobial agents simultaneously to all carriers of epec and their immediate contacts in the nursery has appeared to be valuable in terminating outbreaks that have failed to respond to more conservative m e a s~r e s .~'~,~~,~~~ the apparent reduction in morbidity and mortality associated with oral administration of neomycin, . , colistin, . . p o l y m y x i r~,~~~ or gentamicin & during nursery epidemics has led to the impression that these drugs also exert a beneficial clinical effect in severely or moderately ill infants. reports describing bacteriologic: or histopathol~gic~'~ evidence of tissue invasion by epec have persuaded some investigators to suggest the use of parenteral rather than oral drug therapy in debilitated or malnourished infants. on the basis of these data, there appears to be sufficient evidence to recommend oral administration of nonabsorbable antibiotics in the treatment of severely or moderately ill newborns with epec gastroenteritis. the drug most frequently used for initial therapy is neomycin sulfate in a dosage of mg/kg/day administered orally every hours in three divided doses. s in communities in which neomycin-resistant epec has been prevalent, treatment with colistin sulfate or polymyxin b in a dosage of to mglkglday orally and divided into three equal doses may be appropriate. however, it is rarely necessary to use this approach. treatment should be continued only until stool cultures become negative for epec. because of the unavoidable delay before cultures can be reported, most infants receive therapy for to days. if fluorescent antibody testing of rectal swab specimens is available, therapy can be discontinued as soon as epec no longer is identified in smears; this takes no more than hours in more than % of cases. after diarrhea and vomiting have stopped and the infant tolerates formula feedings, shows a steady weight gain, and appears clinically well, discharge with outpatient follow-up is indicated. bacteriologic relapses do not require therapy unless they are associated with illness or high epidemiologic risks to other young infants in the household. because the infecting organisms in these recurrences generally continue to show in vitro susceptibility to the original drug, it should be reinstituted pending bacteriologic re~ults. ~~ when clinical judgment suggests that a neonate may be suffering from bacterial sepsis and epec diarrheal disease, parenteral antimicrobial therapy is indicated after appropriate cultures have been obtained. the routine use of systemic therapy in severe cases of epec enteritis is not appropriate on the basis of current clinical experience. antimicrobial susceptibility patterns of epec are an important determinant of the success of therapy in infections with these organism^.^^',^^'^^^ these patterns are unpredictable, depending on the ecologic pressures exerted by local antibiotic and on the incidence of transmissible resistance factors in the enteric flora of the particular population served by an i n s t i t~t i o n .~~~"~~ for these reasons, variations in susceptibility patterns are apparent in different n~r s e r i e s~~~, '~~ and even from time to time within the same institution. , , sudden changes in clinical response may even occur during the course of a single epidemic as drugsusceptible strains of epec are replaced by strains with multidrug r e~i s t a n c e .~~~'~~' ,~~' because differences can exist in the susceptibilities of different epec serogroups to various antimicrobial agents, regional susceptibility patterns should be reported on the basis of ob group or serotype rather than for epec as a whole. knowledge of the resistance pattern in one's area may help in the initial choice of antimicrobial therapy. the prevention of hospital outbreaks of epec gastroenteritis is best accomplished by careful attention to infection control policies for a nursery. all infants hospitalized with diarrhea should have a bacteriologic evaluation. if the laboratory is equipped and staffed to perform fluorescent antibody testing, infants transferred from another institution to a newborn, premature, or intensive care nursery and all infants with gastroenteritis on admission during an outbreak of epec diarrhea or in a highly endemic area can be held in an observation area for or hours until the results of the fluorescent antibody test or pcr are received. because of the difficulty in diagnosing epec infection, reference laboratories, such as those at the centers for disease control and prevention (cdc), should be notified when an outbreak is suspected. infants suspected to be excreting epec, even if healthy in appearance, then can be separated from others and given oral therapy until the test results are negative. some experts have suggested that when the rapid results obtainable with fluorescent antibody procedures are not available, all infants admitted with diarrhea in a setting where epec is common may be treated as if they were excreting epec or some other enteric pathogen until contrary proof is obtained. stool cultures should be obtained at admission, and contact precautions should be enforced among all who come into contact with the infant. additional epidemiologic studies are needed to establish the advantages of careful isolation and nursing techniques, particularly in smaller community hospitals in which the number of infants in a "gastroenteritis ward may be small. the use of prophylactic antibiotics has been shown to be of no value and can select for increased r e~i s t a n c e .~~~"~~ unfortunately, it can be difficult to keep a nursery continuously free of epec. specific procedures have been suggested for handling a suspected outbreak of bacterial enteritis in a newborn nursery or infant care ~n i t .~~~l~~~*~~~ evidence indicating that a significant proportion of e. coli enteritis may be caused by nontypeable strains has required some modification of these earlier recommendations. the following infection control measures may be appropriate: . the unit is closed, when possible, to all new admissions. . cultures for enteric pathogens are obtained from nursing personnel assigned to the unit at the time of the outbreak. . stool specimens obtained from all infants in the nursery can be screened by the fluorescent antibody or another technique and cultured. identification of a classic enteropathogenic serotype provides a useful epidemiologic marker; however, failure to isolate one of these strains does not eliminate the possibility of illness caused by a nontypeable epec. . antimicrobial therapy with oral neomycin or colistin can be considered for all infants with a positive fluorescent antibody test or culture result. the initial drug of choice depends on local patterns of susceptibility. depending on the results of susceptibility tests, subsequent therapy may require modification. . if an identifiable epec strain is isolated, second and third stool specimens from all infants in the unit are reexamined by the fluorescent antibody technique or culture at -hour intervals. if this is not practical, exposed infants should be carefully followed. . early discharge for healthy, mature, uninfected infants is advocated. . an epidemiologic investigation should be performed to seek the factor or factors responsible for the outbreak. a surveillance system may be established for all those in contact with the nursery, including physicians and other health care personnel, housekeeping personnel, and postpartum mothers with evidence of enteric disease. a telephone, mail, or home survey may be conducted on all infants who were residing in the involved unit during the weeks before the outbreak. . when all patients and contacts are discharged and control of the outbreak is achieved, a thorough terminal disinfection of the involved nursery is mandatory. above all, personnel and parents should pay scrupulous attention to hand hygiene when handling infants. ' since a multistate outbreak of enterohemorrhagic colitis was associated with e. coli :h , shiga toxin-producing e. coli (stec) have been recognized as emerging gastrointestinal pathogens in most of the industrialized world. a particularly virulent subset of stec, ehec, causes frequent and severe outbreaks of gastrointestinal the most virulent ehec belong to serotype :h . ehec has a bovine reservoir and is transmitted by undercooked meat, unpasteurized milk, and contaminated vegetables such as lettuce, alfalfa sprouts, and radish sprouts (as occurred in more than schoolchildren in japan). it also spreads directly from person to the clinical syndrome is that of bloody, noninflammatory (sometimes voluminous) diarrhea that is distinct from febrile dysentery with fecal leukocytes seen in shigellosis or eiec infection^.^^ most cases of ehec infections have been recognized in outbreaks of bloody diarrhea or hus in daycare centers, schools, nursing homes, and c o m m~n i t i e s .~~~-~~~ although ehec infections often involve infants and young children, the frequency of this infection in neonates remains unclear; animal studies suggest that receptors for the shiga toxin may be developmentally regulated and that susceptibility to disease may be age related. the capacity of ehec to cause disease is related to the phage-encoded capacity of the organism to produce a vero cell cytotoxin, subsequently shown to be one of the shiga toxins. - shiga toxin is neutralized by antiserum against shiga toxin, whereas shiga toxin , although biologically similar, is not neutralized by anti-shiga toxin. , like shiga toxin made by shigella dysenteriae, both e. coli shiga toxins act by inhibiting protein synthesis by cleaving an adenosine residue from position in the s ribosomal rna (rrna) to prevent elongation factor- -dependent aminoacyl transfer rna (trna) from binding to the s rrna. the virulence of ehec also may be determined in part by a -mda plasmid that encodes for a fimbrial adhesin in and . , this phenotype is mediated by the lee pathogenicity island, which is highly homologous to the island present in epec strains. ehec and other stec infections should be suspected in neonates who have bloody diarrhea or who may have been exposed in the course of an outbreak among older individuals. because most cases are caused by ingestion of contaminated food, neonates have a degree of epidemiologic protection from the illness. diagnosis of stec diarrhea is made by isolation and identification of the pathogen in the feces. e. coli :h does not ferment sorbitol, and this biochemical trait is commonly used in the detection of this s e r~t y p e .~~. '~~ because some nonpathogenic e. coli share this characteristic, confirmation of the serotype by slide agglutination is required. these techniques can be performed in most clinical laboratories. however, detection of non- serotypes is problematic and relies on detection of the shiga toxin; available methods include shiga toxin elisa, latex agglutination, and molecular method^.^^,^^^ these should be performed by a reference laboratory. hus in infants is not necessarily caused by stec infection. even in older patients, however, the stool is typically negative for stec at the time the that hus develops. ' serum and fecal detection of cytotoxin has been performed in such patients, but no diagnostic modality is definitive once hus has s~pervened!~~,~~~ antimicrobial therapy should not be administered to patients who may have stec infection, although their role in inducing hus remains c o n t r o~e r s i a l .~~~'~~~ management of the diarrhea and possible sequelae is supportive, with proper emphasis on fluid and electrolyte replacement. aggressive rehydration is helpful in minimizing the frequency of serious sequelae. the hep- adherence assay is useful for the detection of epec, which exhibit a classic la pattern."' two other adherence patterns can be discerned in this assay: aggregative (aa) and diffuse (da). these two patterns have been suggested to define additional pathotypes of diarrheogenic e. coli." strains exhibiting the aa pattern (i.e., eaec) are common pathogens of infants.lz eaec cause diarrhea by colonization of the intestinal mucosa and elaboration of enterotoxins and c y t o t o~i n s .~~~~~ many strains can be shown to elicit secretion of inflammatory cytokines in vitro, which may contribute to growth retardation associated with prolonged otherwise asymptomatic colonization.io several virulence factors in eaec are under the control of the virulence gene activator aggr. presence of the aggr regulator or its effector genes has been proposed as a means of detecting truly virulent eaec strains (called typical eaec), , and an empirical gene probe long used for eaec detection has been shown to correspond to one gene under aggr the mode of transmission of eaec has not been well established. in adult volunteer studies, the infectious dose is high (> lo colony-forming units [ cfu] ), suggesting that in adults at least, person-to-person transmission is unlikely. .m several outbreaks have been linked to consumption of contaminated f~o d . "~~,~'~ the largest of these outbreaks involved almost schoolchildren in japan "; a contaminated school lunch was the implicated source of the outbreak. some studies have demonstrated contamination of condiments or milk, which could represent vehicles of foodborne transmission. several nursery outbreaks of eaec have been bserved, ~'~~'~ although in no case has the mechanism of transmission been established. the fist reported nursery outbreak involved infants in nis, serbia, in . because these infants did not ingest milk from a common source, it is presumed that horizontal transmission by environmental contamination or hands of health care personnel was possible. most of the infants were full term and previously well, and they were housed in two separate nursery rooms. the earliest epidemiologic studies of eaec implicated this organism as a cause of endemic diarrhea in developing c o~n t r i e s .~'~-~'~ in this setting, eaec as defined by the m pattern of adherence to hep- cells can be found in upward of % of the population at any one time>l newer molecular diagnostic modalities have revised this figure downward, although the organism remains highly prevalent in many areas. several studies from the indian subcontinent implicated eaec among the most frequent enteric pathogen^.^'^.^'^.^^^ other sites reproducibly reporting high incidence rates include and bra~il."~'*~~' there is evidence that eaec may be emerging in incidence. a study from spo paulo, brazil, implicated eaec as the prevalent e. coli pathotypes in infants i ; epec had previously been shown to be the most common pathogen in this community. many other sites in developing countries of africa:" asia, ° ~ and south america " have described high endemic rates. several studies have suggested that eaec is also a common cause of infant diarrhea in industrialized c~u n t r i e s . "~~~~~~ using molecular diagnostic methods, a large prospective study in the united kingdom implicated eaec as the second most common enteric bacterial pathogen after cumpylob~cter.~~~ a similar study from switzerland found eaec to be the most common bacterial enter~pathogen.~'~ studies from the united states also have demonstrated a high rate of eaec diarrhea in infants; using molecular diagnostic methods, eaec was implicated in % and % of outpatient and inpatient diarrhea cohorts, respectively, compared with less than % of asymptomatic control infants (p < . ). although epidemiologic studies have shown that eaec can cause diarrhea in all age groups, several studies suggest that the infection is particularly common in infants younger than months d. * descriptions from outbreaks and volunteer studies suggest that eaec diarrhea is watery in character with mucus but without blood or frank pus. o o patients typically are afebrile. several epidemiologic studies have suggested that many infants may have bloody diarrhea, i but fecal leukocytes are uncommon. the earliest reports of eaec infection suggested that this pathogen may be particularly associated with persistent diarrhea (> days). - however, later studies suggest that persistent diarrhea may occur in only a subset of infected infants!" in the serbian outbreak of infected infants, the mean duration of diarrhea was . days ''; diarrhea persisted more than days in only three patients. infants in this outbreak had frequent, green, odorless stools. in three cases, the stools had mucus, but none had visible blood. eleven babies developed temperatures in excess of oc; only one had vomiting. despite a lack of clinical evidence suggesting inflammatory enteritis, several clinical studies have suggested that eaec is associated with subclinical inflammation, including the shedding of fecal cytokines and la~toferrin.'~~.~'~ studies in fortaleza, brazil, suggest that children asymptomatically excreting eaec may exhibit growth shortfalls compared with uninfected peers.lo a study from germany reported an association between eaec isolation and infant colic in infants without diarrhea. z this observation has not been repeated. eaec should be considered in the differential diagnosis of persistent diarrhea and failure to thrive in infants. diagnosis of eaec requires identification of the organism in the patient's feces. the hep- adherence assay can be used for this purpose"'; some reports suggest that the adherence phenotype can be observed using formalin-fixed cell^^^'^^^' thereby obviating the need to cultivate eukaryotic cells for each assay. pcr and gene probe for typical eaec are available. successful antibiotic therapy has been reported using fluoroquinolones in adult although preliminary studies suggest that a~ithrornycin~~~ or r i f a~i m i n~~~ also may be effective. therapy in infected infants should be guided by the results of susceptibility testing, as eaec frequently is antibiotic re~istant.~" additional e. coli pathotypes have been described, including diffusely adherent e. coli (daec), and cytodetaching e. c i .~~~ daec has been specifically associated with diarrhea outside of infancy, as infants may have some degree of inherent resistance to infection. cytodetaching e. coli represent organisms that secrete the e. coli hem~lysin.~~' it is not clear whether these latter organisms are true enteric pathogens. there are differences in invasiveness of salmonella strains related to serotype. s. typhi, s. choleraesuis, salmonella heidelberg, p and salmonella dub inm are particularly invasive, with bacteremia and extraintestinal focal infections occurring frequently. salmonella species possess genes closely related to those for the shigella invasion plasmid anti ensthese genes are probably essential to intestinal infection. virulence plasmids, which increase invasiveness in some serotypes, have been recognized, although the precise mechanisms of virulence remain to be elucidated; resistance to complement-mediated bacteriolysis by inhibition of insertion of the terminal c b- membrane attack complex into the outer membrane may be laboratory studies have demonstrated dramatic strain-related difference in the ability of s. typhimurium t o evoke fluid secretion, to invade intestinal mucosa, and to disseminate beyond the production of an enterotoxin immunologically related to cholera toxin by about two thirds of salmonella strains may be related to the watery diarrhea often seen. part because of the properties of their lipopolysaccharide~~~~~~~~ persistence of the organism within phagolysosomes of phagocytic cells may occur with any species of salmonella. it is not completely clear how the organisms have adapted to survive in the harsh intracellular environment, but their survival has major clinical significance. it accounts for relapses after therapy. it explains the inadequacy of some antimicrobial agents that do not penetrate phagolysosomes. it perhaps is the reason for prolonged febrile courses that occur even in the face of appropriate therapy. although humoral immunity and cell-mediated immunity are stimulated during salmonella infections, it is believed that cell-mediated immunity plays a greater role in eradication of the ba~teria. '~ t cell activation of macrophages appears to be important in killing intracellular salmonella. defective interferon-y production by monocytes of newborns in response to s. typhimurium lipopolysaccharide may explain in part the unusual susceptibility of infants to salmonella infection. studies in mice suggest that helper t cell (th ) responses in peyer's patches and mesenteric lymph nodes may be central to protection of the intestinal m~c o s a .~~~ humans who lack the il- receptor and therefore have impaired th responses and interferon-y production are at increased risk for salmonella infe~tion.~~' in typhoid fever, presence of an envelope antigen, vi, is known to enhance virulence. patients who develop classic enteric fever have positive stool cultures in the first few days after ingestion of the organism and again late in the course after a period of bacteremia. this course reflects early colonization of the gut, penetration of gut epithelium with infection of mesenteric lymph nodes, and reseeding of the gut during a subsequent bacteremic pha~e. ~' studies of s. typhimurium in monkeys suggest similar initial steps in pathogenesis (e.g., colonization of gut, penetration of gut epithelium, infection of mesenteric lymph nodes) but failure of the organism to cause a detectable level of ba~teremia. ~~ although both salmonella and shigella invade intestinal mucosa, the resultant pathologic changes are different. shigella multiplies within and kills enterocytes with production of ulcerations and a brisk inflammatory response, whereas salmonella passes through the mucosa and multiplies within the lamina propria, where the organisms are ingested by phagocytes; consequently, ulcer formation is less striking, although villus tip cells are sometimes sloughed. acute crypt abscesses can be seen in the stomach and small intestine, but the most dramatic changes occur in the colon, where acute diffuse inflammation with mucosal edema and crypt abscesses are the most consistent findings. v with s. typhi there also is hyperplasia of peyer's patches in the ileum, with ulceration of overlying tissues. salmonella strains, with the exception of s. typhi, are well adapted to a variety of animal hosts; human infection often can be traced to infected meat, contaminated milk, or contact with a specific animal. half of commercial poultry samples are contaminated with salmonella. definition of the serotype causing infection can sometimes suggest the likely source. for example, s. dublin is closely associated with cattle; human cases occur with a higher-than-predicted frequency in people who drink raw milk.@' for s. typhimurium, which is the most common serotype and accounts for more than one third of all reported human cases, a single source has not been established, although there is an association with cattle. despite the ban by the u.s. food and drug administration (fda) on interstate commercial distribution of small turtles, these animals continue to be associated with infection, as illustrated by a series of cases in puerto ~i~~.~~~ various pet reptiles are an important source of a variety of unusual salmonella serotypes such as salmonella marina, salmonella chameleon, salmonella arizonae, salmonella java, salmonella stanley, salmonella poona, salmonella jangwain, salmonella tilene, salmonella pomona, salmonella miami, salmonella manhattan, salmonella litchfield, salmonella rubislaw, and salmonella w a~s e n a a r .~~-~~ salmonella organisms are hardy and capable of prolonged survival; organisms have been documented to survive in flour for nearly a year? salmonella tennessee has been shown to remain viable for many hours on non-nutritive surfaces (i.e., glass, hours; stainless steel, hours; enameled surface, hours; rubber mattress, hours; linen, hours; and rubber tabletop, infection with salmonella is, like most enteric infections, more common in young children than in adults. the frequency of infection is far greater in the first years of life; roughly equal numbers of cases are reported during each decade beyond years of age. although the peak incidence occurs in the second through sixth months of life, infection in the neonate is relatively common. researchers at the cdc have estimated the incidence of salmonella infection in the first month of life at nearly cases per , infants? adult volunteer studies suggest that large numbers of salmonella ( lo to lo ) need to be ingested to cause di~ease. ~' however, it is likely that lower doses cause illness in infants. the occurrence of nursery ~u t b r e a k s~"~~~~~ and intrafamilial spread suggests that organisms are easily spread from person to person; this pattern is typical of low-inoculum diseases transmitted by the fecal-oral route. the neonate with salmonella infection infrequently acquires the organism from his or her mother during delivery. although the index case in an outbreak can often be traced to a mother, - , subsequent cases result from contaminated objects in the nursery e n~i r o n m e n t~~"~~~ serving as a reservoir coming in contact with hands of attending p e r~o n n e l .~~.~'~ the mother of an index case may be symptomatic ~ i ~ or asymptomatic with preclinical infecti n, '~ convalescent infedon, , , or chronic carriage. the risk of the newborn becoming infected once salmonella is introduced into a nursery has been reported to be as high as % to %, , but the frequency of infection may be lower because isolated cases without a subsequent epidemic are unlikely to be reported. gastric acidity is an important barrier to salmonella infection. patients with anatomic or functional achlorhydria are at increased risk of developing salmonellosis. ~ the hyp~chlorhydria'~ and rapid gastric emptying typical of early lifez may in part explain the susceptibility of infants to salmonella. premature and low-birth-weight infants appear to be at higher risk of acquiring salmonella infection than term whether this reflects increased exposure because of prolonged hospital stays or increased susceptibility on the basis of intestinal or immune function is unclear. contaminated food or water is often the source of salmonella infection in older patients; the limited diet of the infant makes contaminated food a less likely source of infection. although human milk? - raw milk? powdered milk, - formula: and cereal i have been implicated in transmission to infants, more often fomites, such as delivery room resu~citators, ~' rectal thermometer~, '~>~'~ oropharyngeal suction device^,^^^'^^' water baths for heating formula? soap dispenser^,^" " clean" medicine airconditioning mattresses, radiant and serve as reservoirs. one unusual outbreak involving premature and term infants was traced to faulty plumbing, which caused massive contamination of environment and personnel. after salmonella enters a nursery, it is difficult to eradicate. epidemics lasting to week^,'@^,^^' weeks,& months, b year:' " and to months b have been reported. spread to nearby pediatric wards has the incubation period in nursery outbreaks has varied widely in several studies where careful attention has been paid to this variable. in one outbreak of salmonella oranienburg involving newborns, % of cases occurred within days of in an outbreak of s. typhimurium, each of the ill infants presented within days of birth. these incubation periods are similar to those reported for salmonella newport in older children and adults, % of whom have been reported to be ill within days of e~p o s u r e .~'~'~~' conversely, one outbreak of salmonella nienstedten involving newborns was characterized by incubation periods of to days. the usual incubation period associated with fecal-oral nursery transmission is not found with congenital typhoid. during pregnancy, typhoid fever is associated with bacteremic infection of the fetus. the congenitally infected infants are symptomatic at birth. they are usually born during the second to fourth week of untreated maternal illness. usually, the mother is a carrier; fecal-oral transmission of s. typhi can occur with delayed illness in the newborn. several major clinical syndromes occur with nontyphoidal salmonella infection in young infants. colonization without illness may be the most common outcome of ingestion of salmonella by the neonate. such colonization usually is detected when an outbreak is under investigation. most infected infants who become ill have abrupt onset of loose, green, mucus-containing stools, or they have bloody diarrhea; an elevated temperature is also a common finding in salmonella gastroenteritis in the first months of life. o grossly bloody stools are found in the minority of patients, although grossly bloody stools can occur in the first hours of life. hematochezia is more typically associated with noninfectious causes (e.g., swallowed maternal blood, intestinal ischemia, hemorrhagic diseases, anorectal fissures) at this early age. there appear to be major differences in presentation related to the serotype of s. enteritidis causing infection. for example, in one epidemic of s. oranienb~rg~'~ involving newborns, % had grossly bloody stools, % were febrile, % had mucus in their stools, and only % were healthy. in a series of s. newport infections involving premature infants; % of infants with gastroenteritis had blood in their stools, % had fever, % had mucus in their stools, and % were asymptomatic. in an outbreak of s. typhim~rium~~' involving ill and healthy infants, none had bloody stools; all of the symptomatic infants were febrile and usually had loose, green stools. of infants infected by salmonella virchow, % were asymptomatic; the rest had mild diarrhea! seals and colleagues described infants with s. nienstedten, all of whom had watery diarrhea and low-grade fever; none had bloody stools. in a large outbreak in zimbabwe of s. heidelberg infection reported by bannerman, % of infants were asymptomatic, % had diarrhea, % had fever, % had pneumonia, and % developed meningitis. an outbreak of salmonella worthington was characterized primarily by diarrhea, fever, and jaundice, although of infants developed meningitis and % died. in dramatic contrast to these series, none of infants with positive stool cultures for s. tennessee had an illness in a nursery found to be contaminated with that organism. a few infants with salmonella gastroenteritis have developed necrotizing e n t e r o c o l i t i~, ~~~~~~ but it is not clear whether salmonella was the cause. although gastroenteritis is usually self-limited, chronic diarrhea has sometimes been attributed to s a l r n~n e l l a .~~~~~~~ whether chronic diarrhea is caused by salmonella is uncertain. although some infants develop carbohydrate intolerance after a bout of salmonella and salmonella is typically listed as one of the causes of postinfectious protracted diarrhea, it is difficult to be sure that the relationship is causal. the prolonged excretion of salmonella after a bout of gastroenteritis may sometimes cause non-specific chronic diarrhea to be erroneously attributed to salmonella. major extraintestinal complications of salmonella infection may develop in the neonate who becomes bacteremic. extraintestinal spread may develop in infants who initially present with diarrhea and in some who have no gastrointestinal tract signs. bacteremia appears to be more common in the neonate than in the older a study of more than children with salmonella infection showed that extraintestinal infection occurred significantly more often ( . % versus . %) in the first months of life. several retrospective studies suggest that infants in the first month of life may have a risk of bacteremia as high as % to %. one retrospective suggests that the risk is not increased in infancy and estimates that the risk of bacteremia in childhood salmonella gastroenteritis is between . % and . %. prospective studies of infants in the first year of life suggest that the risk of bacteremia is . % to . %. * although selection biases in these studies limit the reliability of these estimates, the risk is substantial. the salmonella species isolated from infants include some serotypes that appear to be more invasive in the first months of life than in older children or healthy adults (s. newport, s. agona, s. blockley, s. derby, s. enteritidis, s. heidelberg, s. infantis, s. javiana, s. saint-paul, and s. typhimurium) and serotypes that are aggressive in every age group (s. choleraesuis and s. dublin). other serotypes appear more likely to cause bacteremia in adults (s. typhi, s. paratyphi a, and s. paratyphi b). virtually any salmonella serotype can cause bacteremic disease in neonates. a few infants with salmonella gastroenteritis have died with e. coli or pseudomonas aeruginosa sepsis; but the role of salmonella in these cases is unclear. unlike the situation in older children in whom bacteremic salmonellosis often is associated with underlying medical conditions, bacteremia may occur in infants who have no immunocompromising conditions. salmonella bacteremia is often not suspected clinically because the syndrome is not usually d i s t i n~t i v e . ~~~~~ even afebrile, well-appearing children with salmonella gastroenteritis have been documented to have bacteremia that persists for several days. although infants with bacteremia may have spontaneous resolution without therapy: a sufficient number develop complications to warrant empirical antimicrobial therapy when bacteremia is suspected. the frequency of complications is highest in the first month of life. meningitis is the most feared complication of bacteremic salmonella disease. between % and % of all cases of nontyphoidal salmonella meningitis occur in the first months of life. the serotypes associated with neonatal meningitis (s. typhimurium, s. heidelberg, s. enteritidis, s. saint-paul, s. newport, and s. panama) are serotypes frequently associated with bacteremia. meningitis has a high mortality rate, in part because of the high relapse rates. relapse has been reported in up to % of ca~es. ~' in some studies, more than % of patients with meningitis have died, although more typically, % to % of infants die. * the survivors suffer the expected complications of gram-negative neonatal meningitis, including hydrocephalus, seizures, ventriculitis, abscess formation, subdural empyema, and permanent neurologic impairment. neurologic sequelae have included retardation, hemiparesis, epilepsy, visual impairment, and a t h e t o~i s .~~~ in large nursery outbreaks, it is common to find infants whose course is complicated by pneum~nia?'~ osteo-myeliti~, ">~~~ or septic arthriti~. '~,~'~ othe r rare complications of salmonellosis include p e r i~a r d i t i s ,~~ p y e l i t i~,~~ peritonitis: otitis media: mas ti ti^,^^^ chole~ystitis,~~' endophthalmiti~,~~~ cutaneous abscesses, and infected cephal~hematoma?~' other focal infections seen in older children and adults, such as endocarditis and infected aortic aneurysms, rarely or never have been reported in neonates. , altho ugh the mortality rate in two reviews of nursery outbreaks was . % to . %," in some series, it reached %. enteric fever, most often related to s. typhi but also occurring with s. paratyphi a, s. paratyphi b, s. paratyphi c, and other salmonella species, is reported much less commonly in infants than in older patients. infected infants develop typical findings of neonatal sepsis and meningitis. current data suggest that mortality is about y .~~' in utero infection with s. typhi has been described. typhoid f e~e r~" *~~' and nontyphoidal salmonella infections during pregnancy put women at risk of aborting the fetus. premature labor usually occurs during the second to the fourth week of maternal typhoid if the woman is untreated. in a survey of typhoid fever in pregnancy during the preantibiotic era, of women with well-documented cases delivered prematurely, with resultant fetal death; the rest delivered at term, although only infants survived. the outlook for carrying the pregnancy to term and delivering a healthy infant appears to have improved dramatically during the antibiotic era. however, one of seven women with typhoid in a series still delivered a dead fetus with extensive liver necrosis. in the preantibiotic era, about % of pregnant women with typhoid fever died. with appropriate antimicrobial therapy, pregnancy does not appear to put the woman at increased risk of death. despite these welldescribed cases, typhoid fever is rare early in life. of cases of typhoid fever that osler and m~c r a e~~~ reported, only were in the first year of life. in areas where typhoid fever is still endemic, systematic search for infants with enteric fever has failed to find many cases. the few infections with s. typhi documented in children in the first year of life often present as a brief nondescript "viral syndrome" or as p n e~r n o n i t i s ?~~*~~' fever, diarrhea, cough, vomiting, rash, and splenomegaly may occur; the fever may be high, and the duration of illness may be many weeks. the current practice of early discharge of newborn infants, although potentially decreasing the risk of exposure, can make recognition of a nursery outbreak difficult. diagnosis of neonatal salmonellosis should trigger an investigation for other cases. other than diarrhea, signs of neonatal salmonella infection are similar to the nonspecific findings seen in most neonatal infections. lethargy, poor feeding, pallor, jaundice, apnea, respiratory distress, weight loss, and fever are common. enlarged liver and spleen are common in those neonates with positive blood cultures. laboratory studies are required to establish the diagnosis because the clinical picture is not distinct. the fecal leukocyte examination reveals polymorphonuclear leukocytes in % to % . of persons with salmonella infection, but it has not been evaluated in neonates. obviously, the presence of fecal leukocytes is consistent with colitis of any cause and therefore is a nonspecific finding. routine stool cultures usually detect salmonella if two or three different enteric media (i.e., macconkey's, eosin-methylene blue, salmonella-shigella, tergitol , xylose-lysine-deoxycholate, brilliant green, or bismuth sulfite agar) are used. stool, rather than rectal swab material, is preferable for culture, particularly if the aim of culture is to detect carriers. on the infrequent occasions when proctoscopy is performed, mucosal edema, hyperemia, friability, and hemorrhages may be seen.*' infants who are bacteremic often do not appear sufficiently toxic to raise the suspicion of b a~t e r e m i a .~~~ blood cultures should be obtained as a routine part of evaluation of neonates with suspected or documented salmonella infection. ill neonates with salmonella infection should have a cerebrospinal fluid examination performed. bone marrow cultures also may be indicated when enteric fever is suspected. there are no consistent abnormalities in the white blood cell count. serologic studies are not helpful in establishing the diagnosis, although antibodies to and flagellar antigens develop in many infected newborns. if an outbreak of salmonellosis is suspected, further characterization of the organism is imperative? determination of somatic and flagellar antigens to characterize the specific serotype may be critical to investigation of an outbreak. when the serotype found during investigation of an outbreak is a common one (e.g., s. typhimurium), antimicrobial resistance testing , and use of molecular techniques such as plasmid chara~terization~~~ can be helpful in determining whether a single-strain, common-source outbreak is in progress. and ampicillin or amoxicillin versus placebo. in contrast to these studies, data suggest that there may be a role for quinolone antibiotics in adults and ~h i l d r e n ,~~~,~~~ but these drugs are not approved for use in neonates, and resistance has been en~ountered.~'~ because these studies have few data as to the risk-benefit ratio of therapy in the neonate, it is uncertain whether they should influence treatment decisions in neonates. studies that have included a small number of neonates suggest little benefit from antimicrobial therapy. * * however, because bacteremia is common in neonates, antimicrobial therapy for infants younger than months who have salmonella gastroenteritis often is recommended, v v especially if the infant appears toxic. premature infants and those who have other significant debilitating conditions also should probably be treated. the duration of therapy is debatable but should probably be no more than to days if the infant is not seriously ill and if blood cultures are sterile. if toxicity, clinical deterioration, or documented bacteremia complicates gastroenteritis, prolonged treatment is indicated. even with antimicrobial therapy, some infants develop complications. the relatively low risk of extraintestinal dissemination must be balanced against the well-documented risk of prolonging the carrier state. for infants who develop chronic diarrhea and malnutrition, hyperalimentation may be required; the role of antimicrobial agents in this setting is unclear. the infant with typhoid fever should be treated with an antimicrobial agent; relapses sometimes occur after therapy. colonized healthy infants discovered by stool cultures during evaluation of an outbreak ought to be isolated but probably should not receive antimicrobial therapy. such infants should be discharged from the nursery as early as possible and followed carefully as outpatients. antimicrobial treatment of neonates who have documented extraintestinal dissemination must be prolonged. bacteremia without localization is generally treated with at least a -day course of therapy. therapy for salmonella meningitis must be given for at least weeks to lessen the risk of relapse. about three fourths of patients who have relapses have been treated for three weeks or less? similar to meningitis, treatment for osteomyelitis must be prolonged to be adequate. although cures have been reported with weeks of therapy, to weeks of therapy is recommended. in vitro susceptibility data for salmonella isolates must be interpreted with caution. the aminoglycosides show good in vitro activity but poor clinical efficacy, perhaps because of the low ph of the phagolysosome. aminoglycosides have poor activity in an acid environment. the stability of some drugs in this acid environment also may explain in vitro and in vivo disparities. the intracellular localization and survival of salmonella within phagocytic cells also presumably explains the relapses encountered with virtually every regimen. resistance to antibiotics has long been a problem with salmonella i n f e c t i~n .~~,~~~,~~' there has been a steady increase in resistance to salmonella in the united states over the last years. with the emergence of typhimurium type dt , resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline has increased from . % in and to % in . resistance plasmids have been selected and transmitted, partly because therapy has been given for mild illness that should not have been treated and partly because of use of antibiotics in animal feeds. resistance to chloramphenicol and ampicillin has made trimethoprim-sulfamethoxazole increasingly important for the treatment of salmonella infection in those patients who require therapy. however, with increasing resistance to all three of these agents in asia? the middle e~r o p e ,~~~,~'~ ar gentina, and north america, , the third-generation cephalosporins and quinolones represent drugs of choice for invasive salmonellosis. the quinolones currently are not approved for persons younger than years. cefotaxime, ceftriaxone, and cefoperazone represent acceptable alternative drugs for typhoidal and nontyphoidal salmonellosis when resistance is e n c o~n t e r e d .~~"~~~ because the second-generation cephalosporins, such as cefuroxime, are less active in vitro than the third-generation cephalosporins and are not consistently clinically effective, they should not be data suggest that cefoperazone may sterilize blood and cause patients with typhoid fever to become afebrile more rapidly than with chl~ramphenicol,~~~ perhaps because cefoperazone is excreted into bile in high concent r a t i o n~.~~~ the third-generation cephalosporins may have higher cure and lower relapse rates than ampicillin or chloramphenicol in children with salmonella meningitis. the doses of ampicillin, chloramphenicol, or cefotaxime used in infants with gastroenteritis pending results of blood cultures are the same as those used in treatment of sepsis. because of the risk of gray baby syndrome, chloramphenicol should not be used in neonates unless other effective agents are not available. trimethoprim-sulfamethoxazole, although useful in older children and adults, is not used in neonates because of the risk of kernicterus. nosocomial infection with strains of salmonella resistant to multiple antibiotics, including third-generation cephalosporins, has emerged as a problem in south america. nonantibiotic interventions are important in the control of salmonella infections. limited data suggest that intravenous immune globulin (igiv) ( mg/kg on days , , , and of therapy) along with antibiotic therapy may decrease the risk of bacteremia and death in preterm infants with salmonella ga~troenteritis.~~~ early recognition and intervention in nursery outbreaks of salmonella are crucial to control. when a neonate develops salmonellosis, a search for other infants who have been in the same nursery should be undertaken. when two or more cases are recognized, environmental cultures, cultures of all infants, cohorting and contact isolation of infected infants, rigorous enforcement of hand hygiene, early discharge of infected infants, and thorough cleaning of all possible fomites in the nursery and delivery rooms are important elements of control. if cases continue to occur, the nursery should be closed to further admissions. cultures of nursery personnel are likely to be helpful in the unusual situation of an s. typhi outbreak in which a chronic carrier may be among the caretakers. culture of health care personnel during outbreaks of salmonellosis caused by other salmonella species is debatable, although often recommended. data suggest that nurses infected with salmonella rarely infect patients in the hospital setting. the fact that nursing personnel are sometimes found to be colonized during nursery outmay be a result rather than a cause of those epidemics. the potential role of vaccines in control of neonatal disease is minimal. for the vast number of non-s. ryphi serotypes, there is no prospect for an immunization strategy. multiple doses of the commercially available oral live attenuated vaccine (ty la; vivotif, berna), has been shown in chilean schoolchildren to reduce typhoid fever cases by more than %. , however, the vaccine is not recommended for persons younger than years, in part because immunogenicity of ty la is age dependent; children younger than months fail to respond with development of immunity!" vi capsular polysaccharide vaccine is available for children older than years and is effective in a single dose. whether some degree of protection of infants could the virulence of shigellae has been studied extensively since their recognition as major pathogens at the beginning of the th century. the major determinants of virulence are encoded by a -to -mda p l a~m i d .~~~.~~~ this plasmid, which is found in all virulent shigellae, encodes the synthesis of proteins that are required for invasion of mammalian cells and for the vigorous inflammatory response that is characteristic of the d i s e a~e .~~*~~ shigellae that have lost this plasmid, have deletions of genetic material from the region involved in synthesis of these proteins, or have the plasmid inserted into the chromosome lose the ability to invade eukaryotic cells and become aviru ent o ; maintenance of the plasmid can be detected in the clinical microbiology lab by ability to bind congo red. the ability to invade cells is the basic pathogenic property shared by all ~h i g e l l a e~~'~~~~ and by the shigella-like invasive e. coli, which also possesses the shigella virulence plasmid. ~ ~ ~ ~ in the laboratory, shigella invasiveness is studied in tissue culture (hela cell invasion), in animal intestine, or in rabbit or guinea pig eye, where instillation of the organism causes keratoconjunctivitis (sereny test)."' animal model studies have shown that bacteria penetrate and kill colonic mucosal cells and then elicit a brisk inflammatory response. in addition to the virulence plasmid, several chromosomal loci enhance virulence. v this has been best studied in s. flexneri in which multiple virulence-enhancing regions of the chromosome have been defined. s - the specific gene products of some of the chromosomal loci are not known; one chromosomal virulence segment encodes for synthesis of the repeat units of lipopolysaccharide. intact lipopolysaccharide is necessary but not sufficient to cause virulence. at least two cell-damaging cytotoxins that also are chromosomally encoded are produced by shigellae. one of these toxins (shiga toxin) is made in large quantities by s. dysenteriae serotype (the shiga bacillus) and is made infrequently by other shigellae. shiga toxin is a major virulence factor in s. dysenteriae, enhancing virulence at the colonic mucosa and also giving rise to sequelae similar to those caused by stec (discussed earlier). this toxin kills cells by interfering with peptide elongation during protein ~y n t h e s i s .~'~-~'~ additional toxins may also be secreted by shigellae, although their roles in virulence are not established. although much of the epidemiology of shigellosis is predictable based on its infectious dose, certain elements are unexplained. shigellae, like other organisms transmitted by the fecal-oral route, are commonly spread by food and water, but the low infecting inoculum allows person-to-person spread. because of this low inoculum, shigella is one of the few enteric pathogens that can infect swimmers. the dose required to cause illness in adult volunteers is as low as organisms for s. dysenteriae serotype , " about organisms for s. f l e~n e r i ,~~~ and organisms for s. ~o n n e i .~'~ personto-person transmission of infection probably explains the continuing occurrence of shigella in the developed world. enteropathogens that require large inocula and hence are best spread by food or drinking water are less common in industrialized societies because of sewage disposal facilities, water treatment, and food-handling practices. in the united states, daycare centers currently serve as a major focus for acquisition of shigell~sis.~'~ numerous outbreaks of shigellosis related to crowding, poor sanitation, and the low dose required for diseases have occurred in this setting. given the ease of transmission, it is not surprising that the peak incidence of disease is in the first years of life. it is, however, paradoxical that symptomatic infection is uncommon in the first year of life. - the best data on the age-related incidence of shigellosis come from mata'~~'~ prospective studies of guatemalan infants. in these studies, stool cultures were performed weekly on a group of children followed from birth to years old. the rate of infection was more than -fold lower in the first months of life than (fig. - ) . the same age-related incidence has been described in the united states and in a rural egyptian village. this anomaly has been explained by the salutary effects of brea~t-feeding.~~'-~~' however, it is likely that breast-feeding alone does not explain the resistance of infants to shigellosis. a review of three large case series - suggests that about . % ( of ) of shigellosis cases occur in infants in the neonatal period. the largest series of neonatal ~higellosis~~~ suggests that the course, complications, and etiologic serogroups are different in neonates than in older children. although newborns are routinely contaminated by maternal feces, neonatal shigellosis is rare. other aspects of the epidemiology of shigellosis elude simple explanation. the seasonality (summer-fall peak in the united states, rainy season peak in the tropics) is not well explained. the geographic variation in species causing infection likewise is not well understood. in the united states, most shigella infections are caused by s. sonnei or, less commonly, s. flexneri. in most of the developing world, the relative importance of these two species is reversed, and other shigella serotypes, especially s. dysenteriae serotype , are identified more frequently. as hygiene improves, the proportion of s. sonnei increases and that of s. flexneri decreases. data from bangladesh suggest that s. dysenteriae is less common in neonates, but s. sonnei and s. boydii are more c mmon. ~~ there appear to be some important differences in the relative frequencies of various complications of shigella infection related to age. some of these differences and estimates are based on data that are undoubtedly compromised by reporting biases. s. dysenteriae serotype characteristically causes a more severe illness than other shigellae with more complications, including pseudomembranous colitis, hemolysis, and hus. however, illnesses caused by various shigella serotypes usually are indistinguishable from each other and conventionally are discussed together. the incubation period of shigellosis is related to the number of organisms ingested, but in general, it is between and hours. volunteer studies have shown that after ingestion, illness may be delayed for a week or more. neonatal shigellosis seems to have a similar incubation period. more than one half of the neonatal cases occur within days of birth, consistent with fecal-oral transmission during parturition. mothers of infected neonates are sometimes carriers, although more typically they are symptomatic during the perinatal period. intrauterine infection is rare. in the older child, the initial signs are usually high fever, abdominal pain, vomiting, toxicity, and large-volume watery stools; diarrhea may be bloody or may become bloody. painful defecation and severe, crampy abdominal pain associated with frequent passage of small-volume stools with gross blood and mucus are characteristic findings in older children or adults who develop severe colitis. many children, however, never develop bloody diarrhea. adult volunteer studies have demonstrated that variations in presentation and course are not related to the dose ingested because some patients develop colitis with dysentery but others develop only watery diarrhea after ingestion of the same i n o c u l~m .~~~ the neonate with shigellosis may have a mild diarrheal syndrome or a severe ~o l i t i s .~~~~~~~-~~ fever in neonates is usually low grade (< " f) if the course is uncomplicated. the neonate has less bloody diarrhea, more dehydration, more bacteremia, and a greater likelihood of death than the older ~h i l d . ~~ physical examination of the neonate may show signs of toxicity and dehydration, although fever, abdominal tenderness, and rectal findings are less striking than in the older complications of shigellosis are common. although the illness is self-limited in the normal host, resolution may be delayed for a week or more. in neonates and malnourished children, chronic diarrhea may follow a bout of shigello~is. ~',~~ between % and % of hospitalized children with shigella have convulsions before or during the course of usually, the seizures are brief, generalized, and associated with high fever. seizures are uncommon in the first months of life, although neonates have been described with seizures. the cerebrospinal fluid generally reveals normal values in these children, but a few have mild cerebrospinal fluid pleocytosis. the neurologic outcome generally is good even with focal or prolonged seizures, but fatalities do occasionally occur, often associated with toxic encephalpa thy.^^' although the seizures had been postulated to result from the neurotoxicity of shiga toxin, this explanation was proved to be incorrect because most shigellae make little or no shiga toxin and the strains isolated from children with neurologic symptoms do not produce shiga t~x i n .~'~,~~' hemolysis with or without development of uremia is a complication primarily of s. dysenteriae serotype infection. sepsis during the course of shigellosis may be caused by the shigella itself or by other gut flora that gain access to the bloodstream through damaged mucosa. ' * the risk of sepsis is higher in the first year of life, particularly in neo-nates, . - , , in malnourished children, and in those with s. dysenteriae serotype infection. sepsis occurs in up to % of neonates with given the infrequency of neonatal shigellosis, it is striking that % of reported cases of shigella sepsis have involved infants in the first month of life. one of the infants with ba~teremia~~' reportedly had no discernible illness. disseminated intravascular coagulation may develop in those patients whose course is complicated by sepsis. meningitis has been described in a septic neonate. colonic perforation has occurred in n e o n a t e~, ~"~~~ older children,@' and adults. although this complication of toxic megacolon is rare, it appears to be more common in neonates than in older individuals. bronchopneumonia may complicate the course of shigellosis, but shigellae are rarely isolated from lungs or tracheal secretions." the syndrome of sudden death in the setting of extreme toxicity with hyperpyrexia and convulsions but without dehydration or sepsis (i.e., ekiri ~yndrome)~~'"~ is rare in neonates. in the nonbacteremic child, other extraintestinal foci of infection, including ~a g i n a~~~. "~ and eye,"' rarely occur. reiter's syndrome, which rarely complicates the illness in children, has not been reported in neonates. although infection is less common in infants than in toddlers, case fatality rates are highest in infant^.^^'^^' the mortality rate in newborns appears to be about twice that of older children. in industrialized societies, less than % of children with shigellosis die, whereas in developing countries, up to % die. these differences in mortality rates are related to n~t r i t i o n . ~~ availability of medical care, antibiotic resistance of many shigellae, the frequency of sepsis, and the higher frequency of s examination of stool for leukocytes as an indication of colitis is useful in support of the clinical suspicion of shigellosis. the white blood cell count and differential count also are used as supporting evidence for the diagnosis. leukemoid reactions (white blood cells > , /mm ) occur in almost % of children with s. dysenteriae serotype but in less than % of children with other ~h i g e l l a e .~~~ leukemoid reactions are more frequent in infants than in older ~hildren. ~' even when the total white blood cell count is not dramatically elevated, there may be a striking left shift. almost % of children with shigellosis have greater than % bands on the differential cell few reports address the white blood cell count in newborns, but those that do suggest that normal or low rather than elevated counts are more common. although serum and fecal antibodies develop to lipopolysaccharides and the virulence plasmid-associated polypeptide~, ~~ serologic studies are not useful in the diagnosis of shigellosis. pcr can identify shigella and eiec in feces. colonoscopy typically shows inflammatory changes that are most severe in the distal segments of therapy because dehydration is particularly common in neonatal shigellosis, attention to correction of fluid and electrolyte disturbances is always the first concern when the illness is suspected. although debate continues over the indications for antimicrobial therapy in the patient with shigellosis, the benefits of therapy generally appear to outweigh the risks. the chief disadvantages of antimicrobial therapy include cost, drug toxicity, and emergence of antibiotic-resistant shigellae. because of the self-limited nature of shigellosis, it has been argued that less severe illness should not be treated. however, children can feel quite ill during the typical bout of shigellosis, and appropriate antimicrobial therapy shortens the duration of illness and eliminates shigellae from stool, decreasing secondary spread. complications are probably decreased by antibiotics. given the high mortality rates of neonatal shigellosis, therapy should not be withheld. the empirical choice of an antimicrobial agent is dictated by susceptibility data for strains circulating in the community at the time the patient's infection occurs. multiresistant shigellae complicate the choice of empirical therapy before availability of susceptibility data for the patient's isolate. plasmid-encoded resistance (r factors) for multiple antibiotics has been observed frequently in s. dysenteriae serotype outbreaks and with other ~higellae.~'~.~'~ antimicrobial resistance patterns fluctuate from year to year in a given locale. however, despite the guesswork involved, early preemptive therapy is indicated when an illness is strongly suggestive of shigellosis. in vitro susceptibility does not always adequately predict therapeutic responses. cefa~lor, ~~ furazolidone, ~ephalexin, '~ amo~icillin, ~' kanam~cin, ~' and ~e f a m a n d o l e~~~ all are relatively ineffective agents. the optimal duration of therapy is debatable. studies in children older than years and in adults suggest that singledose regimens may be as effective in relieving symptoms as courses given for days. the single-dose regimens generally are not as effective in eliminating shigellae from the feces as are the longer courses. a third-generation cephalosporin, such as ceftriaxone, may be the best empirical choice. optimal doses for newborns with shigellosis have not been established. trimethoprim at a dose of lomg/kg/day (maximum, mg/day) and sulfamethoxazole at a dose of mg/kg/day (maximum, mg/day) in two divided doses for a total of days are recommended for the older child if the organism is s~s c e p t i b l e . ~~-~~~ if the condition of the infant does not permit orally administration, the drug usually is divided into three doses given intravenously over ampicillin at a dose of mg/kg/day in four divided doses taken orally for days may be used if the strain is susceptible. for the rare newborn who acquires shigellosis, appropriate therapy often is delayed until susceptibility data are available. this occurs because shigellosis is so rare in newborns that it is almost never the presumptive diagnosis of the child with watery or bloody diarrhea. although a sulfonamide is as efficacious as ampicillin when the infecting strain is sus~eptible, ~~ sulfonamides are avoided in neonates because of concern about the potential risk of kernicterus. the risk of empirical ampicillin therapy is that shigellae are frequently resistant to the drug; % of shigellae currently circulating in the united states are ampicillin resistant. for the neonate infected with ampicillin-resistant shigella, there are few data on which to base a recommendation. ceftriaxone is generally active against shigellae, but in the neonate, this drug can displace bilirubin-binding sites and elicit clinically significant cholestasis. data on children and adults suggest that clinical improvement occurs with c e f t r i a x~n e .~~~*~~~ quinolones, such as ciprofloxacin and ofloxacin, have been shown to be effective agents for treating s h i g e l l o s i~~~~~~~~ in adults, but they are not approved for use in children younger than years. other drugs sometimes used to treat diarrhea pose special risks to the infant with shigellosis. the antimotility agents, in addition to their intoxication risk, may pose a special danger in dysentery. in adults, diphenoxylate hydrochloride with atropine has been shown to prolong fever and excretion of the ~rganism.~" the response to appropriate antibiotic therapy is generally gratifying. improvement is often obvious in less than hours. complete resolution of diarrhea may not occur until a week or more after the start of treatment. in those who have severe colitis or those infected by s. dysenteriae serotype , the response to treatment is somewhat delayed. for most of the developing world, the best strategy for prevention of shigellosis during infancy is prolonged breastfeeding. specific antibodies in milk appear to prevent symptomatic shigellosis ' ; nonspecific modification of gut flora and the lack of bacterial contamination of human milk also may be important. breast-feeding, even when other foods are consumed, decreases the risk of shigellosis; children who continue to consume human milk into the third year of life are still partially protected from in the united states, the best means of preventing infection in the infant is good hand hygiene when an older sibling or parent develops diarrhea. even in unsanitary environments, secondary spread of shigellae can be dramatically decreased by hand hygiene after defecation and before meals. spread of shigellae in the hospital nursery can presumably be prevented by the use of contact isolation for infants with diarrhea and attention to thorough hand hygiene. although nursery personnel have acquired shigellosis from infected newborns, further transmission to other infants in the nursery, although is rare. in contrast to salmonella, large outbreaks of nosocomial shigellosis in neonates are rare. unfortunately, good hygiene is a particularly difficult problem in daycare centers. the gathering of susceptible children, breakdown in hand hygiene, failure to use different personnel for food preparation and diaper changing, and difficulty controlling the behavior of toddlers all contribute to daycare-focused outbreaks of shigellosis. immunization strategies have been studied since the turn of the th century, but no satisfactory immunization has been developed. even if immunizations are improved, a role in managing neonates seems unlikely. campylobacter was first recognized in an aborted sheep fetus in the early o s o and was named vibrio fetus by smith and taylor in . this organism subsequently was identified as a major venereally transmitted cause of abortion and sterility and as a cause of scours in cattle, sheep, and goats. s it was not until , when it was isolated from the blood culture of a pregnant woman who subsequently aborted at months' gestation, that the significance of campylobacter as a relatively rare cause of bacteremia and perinatal infections in humans was a~preciated.~l'-~'~ during the s, campylobacter was recognized to be an opportunistic pathogen in debilitated in , v fetus and related organisms were separated from the vibrios (such as v cholerae and v parahaemolyticus) and placed in a new genus, campylobacter (greek word for "curved rod"). since , several campylobacter species have been recognized as a common cause of e n t e r i t i~~l~.~~~ and, in some cases, extraintestinal infections. the genus campylobacter contains species, most of which are recognized as animal and human pathogens. the most commonly considered causes of human disease are campylobacter fetus, campylobacter jejuni, campylobacter coli, campylobacter lari, and campylobacter upsaliensis (table - ),' - although campylobacter mucosalis has been isolated from stool of children with diarrhea. dna hybridization studies have shown that these species are distinct, sharing less than % dna homology under stringent hybridization ~o n d i t i o n s .~~~,~~~ helicobacter pylori was originally named campylobacter pylori, but because of differences in dna, it was reclassified and is no longer considered in the campylobacter genus. strains of c. fetus are divided into two subspecies: c. fetus subsp. fetus and c. fetus subsp. venerealis. the first subspecies causes sporadic abortion in cattle and sheep ; in by far the most common syndrome caused by a campylobacter species is enteritis. c. jejuni and c. coli cause gastroenteritis and generally are referred to collectively as c. jejuni, although dna hybridization studies show them to be different. in the laboratory, c. jejuni can be differentiated from c. coli because it is capable of hydrolyzing hippurate, whereas c. coli is not. most isolates that are associated with diarrhea ( % to %) are identified as c. jejuni, - and in some cases, individuals have been shown to be simultaneously infected with c. jejuni and c. ~o l i . ~~~ because of the fastidious nature of c. jejuni, which is difficult to isolate from fecal flora, its widespread occurrence was not recognized until . - previously called related vibrios by this organism had been associated with bloody diarrhea and colitis in infants and adults only when it had been associated with a recognized b a~t e r e m i a .~~~-~~~ in the late s, development of selective fecal culture methods for c. jejuni enabled its recognition worldwide as one of the most common causes of enteritis in persons of all ages. it is an uncommon infection in neonates who generally develop gastroenteritis when i n f e~t e d .~'~-~~~-~~' bacteremia with c. jejuni enteritis also is uncommon. ~ , l* * - maternal symptoms considered to be related to c. jejuni infection generally are mild and include fever ( %) and diarrhea ( %). in contrast to the serious disease in newborns that is caused by c. fetus, neonatal infections with although meningitis occurs in rare third trimester infection related to c. fetus or c. jejuni may results in abortion or stillbirth. pathogenesis c. fetus does not produce recognized enterotoxins or cytotoxins and does not appear to be locally invasive by the sereny instead, these infections may be associated with penetration of the organism through a relatively intact intestinal mucosa to the reticuloendothelial system and blo~dstream.~'~ whether this reflects a capacity to resist serum factors or to multiply intracellularly remains to be determined. c. jejuni is capable of producing illness by several mechanisms. these organisms have been shown to produce an lt enterotoxin and a c y t o t o x i r~.~~~~~~~ this enterotoxin is known to be a heat-labile protein with a molecular mass of to mda. it shares functional and immunologic properties with cholera toxin and e. coli lt. c. jejuni and c. coli also elaborate a cytotoxin that is toxic for a number of mammalian cells. - the toxin is heat labile, trypsin sensitive, and not neutralized by immune sera to shiga toxin or the cytotoxin of clostridium dificile. the role of these toxins as virulence factors in diarrheal disease remains unpr~ved.'~~,~~ several animal models have been tested for use in the study of this pathogen. potential models for the study of c. jejuni enteritis include dogs, which may acquire symptomatic infection ; -to -day old ~h i c k s~~' -~~; chicken embryo cells, which are readily invaded by c. jejuni "; rhesus monkeys ; and rabbits by means of the removable intestinal tie adult rabbit technique. an established small mammal model that mimics human disease in the absence of previous treatment or surgical procedure has not been successful in adult mice. an infant mouse mode , and a hamster of diarrhea appear promising. c. jejuni is negative in the sereny test for invasivenes~,~~~ and most investigators report no fluid accumulation in ligated rabbit ileal loops. the pathologic findings of c. fetus infection in the perinatal period include placental necrosis '' and, in the neonate, widespread endothelial proliferation, intravascular fibrin deposition, perivascular inflammation, and hemorrhagic necrosis in the brain. the tendency for intravascular location and hepatosplenomegaly in adults infcctcd with c. fetus has been the pathologic findings in infants and children infected with c. fetus can include an acute inflammatory process in the colon or rectum, as evidenced by the tendency for patients to have bloody diarrhea with numerous fecal leukocytes. there also can be crypt abscess formation and an ulcerative colitis or pseudomembranous colitis-like or a hemorrhagic jejunitis or ileitis. b , , mesenteric lymphadenitis, ileocolitis and acute appendicitis also have been described. infection with campylobacter species occurs after ingestion of contaminated food, including unpasteurized milk, poultry, and contaminated water.' , - m any farm animals and pets, such as chickens, dogs, s and cats (especially young animals), are potential sources. the intrafamilial spread of infection in h o~s e h o l d s ,~~~,~~~ the occurrence of outbreaks in and the apparent laboratory acquisition of c. jejuni all suggest that c. jejuni infection may occur after person-to-person transmission of the organism. outbreaks of c. jejuni in the child daycare setting are not common. volunteer studies i have shown a variable range in the infecting dose, with many volunteers developing no illness. the report of illness after ingestion of lo organisms in a glass of milk and production of illness in a single volunteer by organisms i substantiate the variation in individual susceptibility. the potential for low-inoculum disease has significant implications for the importance of strict enteric precautions when infected persons are hospitalized, particularly in maternity and nursery areas. when diarrhea in neonates caused by c. jejuni has been r e p~r t e d ,~~~-~~' maternal-infant transmission during labor has generally been documented. ~ * ~ p ~ the lior serotyping system, restriction length polymorphism, and pulse-field gel electrophoresis have been used to confirm the identity of the infant and maternal isolates. most mothers gave no history of diarrhea during pregnancy. * , outbreaks have occurred in neonatal intensive care units because of person-to-person spread. z the frequency of asymptomatic carriage of c. jejuni ranges from % to . % ' , to as high as % to %. , , , - in a cohort study in mexico, % of all infections related to c. jejuni were asymptomatic. infected children, if untreated, can be expected to excrete the organisms for or weeks; however, more than % are culture negative after ~e e k s .~~~,~~~a~ ymptomatic excreters pose a significant risk in the neonatal period, in which acquisition from an infected mother can be clinically important. , s , c. jejuni has increasingly been recognized as a cause of watery and inflammatory diarrhea in temperate and tropical climates throughout the world. it has been isolated from % to % of all fecal cultures from patients with diarrheal illnesses in various parts of the world. - , * - there is a tendency for c. jejuni enteritis to occur in the summer in countries with temperate climates. the reservoir of campylobacter is the gastrointestinal tract of domestic and wild birds and animals. it infects sheep, cattle, goats, antelope, swine, chickens, domestic turkeys, and pet dogs. c. fetus often is carried asymptomatically in the intestinal or biliary tracts of sheep and cattle. during the course of a bacteremic illness in pregnant animals, c. fetus organisms, which have a high affinity for placental tissue, invade the uterus and multiply in the immunologically immature fetus. the infected fetuses generally are aborted. whether this organism is acquired by humans from animals or is carried asymptomatically for long periods in humans, who may then transmit the organism through sexual contact as appears to occur in animals, is unclear. it is believed that this subspecies rarely is found in the human intestine and that it is not a cause of human enteriti~?'~ c. fetus infections predominantly occur in older men with a history of farm or animal exposure and in pregnant women in their third trimester. ~ , , symptomatically or asymptomatically infected women may have recurrent abortions or premature deliveries and are the source of organisms associated with life-threatening perinatal infections of the fetus or newborn infant. , - in several instances of neonatal sepsis and meningitis, c. fetus was isolated from culture of maternal cervix or vagina. , s a n osocomial nursery outbreak has been associated with carriage in some healthy infants. ' other outbreaks have been associated with meningitis , cervical cultures have remained positive in women who have had recurrent abortions and whose husbands have antibody titer elevations. the most commonly incriminated reservoir of c. jejuni is poultry. ,s , , m ost chickens in several different geographic locations had a large number (mean, x /g) of c. jejuni in the lower intestinal tract or feces. this occurred in some instances despite the use of tetracycline, to which the campylobacter was susceptible in vitro, in the chicken feed. the internal cavities of chickens remain positive for carnpylobacter even after they have been cleaned, packaged, and fr zen. ~~ however, unlike salmonella, c. jejuni organisms that survive usually do not multiply to high concen-tration~?~' domestic puppies or kittens w i t h c. jejuni diarrhea also can provide a source for spread, especially to infants or c. jejuni enteritis also has been associated in a number of outbreaks with consumption of unpasteurized in retrospect, the first reported human cases of c. jejuni enteritis were probably in a milk-borne outbreak reported in . because campylobacter infections of the udder are not seen, milk is probably contaminated from fecal shedding of the organism. these organisms are killed by adequate heating. fecally contaminated water is a potential vehicle for c. jejuni infections. several phenotypic and genotypic methods have been used for distinguishing c. jejuni strains from animals and humans involved in epidemics. clinical manifestations of infection caused by campylobacter depend on the species involved (see table - ). human infections with c. fetus are rare and generally are limited to bacteremia in patients with predisposing condition^^^^.^^^ or to bacteremia or uterine infections with prolonged fever and pneumonitis that lasts for several weeks in women during the third trimester of pregnancy. unless appropriately treated, symptoms usually resolve only after abortion or delivery of an infected infant? j , - * these infected neonates, who are often premature, develop signs suggesting sepsis, including fever, cough, respiratory distress, vomiting, diarrhea, cyanosis, convulsions, and jaundice. the condition typically progresses to meningitis, which may be rapidly fatal or may result in serious neurologic ~equelae.~" additional systemic manifestations include pericarditis, pneumonia, peritonitis, salpingitis, septic arthritis, and abscesses. c. jejuni infection typically involves the gastrointestinal tract, producing watery diarrhea or a dysentery-like illness with fever and abdominal pain and stools that contain blood and ~u c u s .~~~~~~'~~' " ' older infants and children generally are affected, but neonates with diarrhea have been reported. infection in neonates generally is not clinically apparent or is mild. stools can contain blood, mucus, and pus p * * ; fever often is ab~ent. ~~"~' the illness usually responds to appropriate antimicrobial which shortens the period of fecal shedding. extraintestinal infections related to c. jejuni other than bacteremia are rare but include cholecystitis, urinary tract and meningitis. bacteremia is a complication of gastrointestinal infe~tion, ~' especially in malnourished children. meningitis that appears to occur secondary to intestinal infection also has been reported in premature infants who have had intraventricular needle aspirations for neonatal hydrocephalus.'i complications in older children and adults that have been associated with c. jejuni enteritis include reiter's syndrome, guillain-barre ~y n d r o m e , ~~~~~* and reactive persistent c. jejuni infections have been described in patients infected with human immunodeficiency extraintestinal manifestations generally occur in patients who are immunosuppressed or at the extremes of age.' campybbacter zari has caused chronic diarrhea and bacteremia in a neonate!% most important in the diagnosis of campylobacter infection is a high index of suspicion based on clinical grounds. c. fetus and c. jejuni are fastidious and may be overlooked on routine fecal cultures. isolation of campylobacter from blood or other sterile body sites does not represent the same problem as isolation from stool. growth occurs with standard blood culture media, but it may be slow. in the case of c. fetus infecting the bloodstream or central nervous system, blood culture flasks should be blindly subcultured and held for at least days or the organism may not be detected because of slow or inapparent the diagnosis of c. fetus infection should be considered when there is an unexplained febrile illness in the third trimester of pregnancy or in the event of recurrent abortion, prematurity, or neonatal sepsis with or without meningitis. a high index of suspicion and prompt, appropriate antimicrobial therapy may prevent the potentially serious neonatal complications that may follow maternal c. fetus infection. campylobacter is distinguished from the vibrio organisms by its characteristics of carbohydrate nonfermentation and by its different nucleotide base omp position.^^^^^^^-^^^*^^^ campylobacter is . to . fm wide and . to . long. it is a fastidious, microaerophilic, curved, motile gram-negative bacillus that has a single polar flagellum and is oxidase and catalase positive, except for c. upsaliensis, which is generally catalase negative or weakly positive. c. jejuni and c. fetus are separated by growth temperature (c. fetus grows best at ' c but can be cultured at ' c; c. jejuni grows best at ' c) and by nalidixic acid and cephalosporin susceptibilities, because c. jejuni is susceptible to nalidixic acid and resistant to cephalosporins. c. jejuni grows best in a microaerobic environment of % oxygen and % carbon dioxide at ' c. it grows on a variety of media, including brucella and mueller-hinton agars, but optimal isolation requires the addition of selective and nutritional supplements. growth at ' c in the presence of cephalosporins is used to culture selectively for c. jejuni from fecal specimens. in a study of six media, charcoal-based selective media and a modified charcoal cefoperazone deoxycholate agar were the most selective for identification of campylobacter species. extending the incubation time from to hours led to an increase in the isolation rate regardless of the medium its typical darting motility may provide a clue to identification, even in fresh fecal specimens, when viewed by phase-contrast microscopy. when the organism has been cultured, it is presumptively identified by motility and by its curved, sometimes sea gulllike appearance on carbolfuchsin stain. polymorphonuclear leukocytes are usually found in stools when bloody diarrhea occurs and indicate the occurrence of ~o l i t i s .~~~*~~* to avoid potentially serious c. jejuni infection in the newborn infant, careful histories of any diarrheal illnesses in the family should be obtained, and pregnant women with any enteric illness should have cultures for this and other enteric pathogens. detection of c. jejuni and c. coli by pcr has been reported and in the future may be useful for the rapid and reliable identification of this organism. the differential diagnosis of c, fetus infections include the numerous agents that cause neonatal sepsis or meningitis, especially gram-negative bacilli. diagnostic considerations for inflammatory or bloody enteritis include necrotizing enterocolitis, allergic proctitis, and salmonella; rarely shigellu, and other infectious agents occur. agglutination, complement fixation, bactericidal, immunofluorescence, and elisa tests have been used for serologic diagnosis of c. jejuni infection and to study the immune response, but these assays are of limited value in establishing the diagnosis during an acute infection. the prognosis is grave in newborn infants with sepsis or meningitis caused by c. fetus. in infants with c. jejuni gastroenteritis, limited data suggest that appropriate, early antimicrobial therapy results in improvement and rapid clearance of the organism from stool. campylobacter species are often resistant to p-lactams, including ampicillin and cephalosporins. v mo st strains are susceptible to erythromycin, gentamicin, tetracycline, chloramphenicol, and the newer quinolones, although resistance to these agents has been r e p~r t e d .~~' ,~~~ it appears that a parenteral aminoglycoside is the drug of choice for c. fetus infections, pending in vitro susceptibility studies. in the case of central nervous system involvement, cefotaxime and chloramphenicol are potential alternative drugs. depending on in vitro susceptibilities, which vary somewhat with locale, erythromycin is the drug of choice for treating c. jejuni e n t e r i t i~.~~~~~"~~' ' if erythromycin therapy is initiated within the first days of illness, a reduction in excretion of the organism and resolution of symptoms occur. although data regarding treatment of asymptomatic or convalescent carriers are not available, it seems appropriate to treat colonized pregnant women in the third trimester of pregnancy when there is a risk of perinatal or neonatal infection. the failure of prophylactic parenteral gentamicin in a premature infant has been documented, followed by successful resolution of symptoms and fecal shedding with erythromycin. because there appears to be an increased risk of toxicity with erythromycin estolate during pregnancy and other forms of erythromycin should probably be used in these settings. azithromycin appears to be effective if the organism is susceptible. strains that are erythromycin resistant often are resistant to azithromycin. cumpylobucter tends to have higher minimal inhibitory concentrations for clarithromycin than for a~ithromycin.~~~ furazolidone has been used in children and ciprofloxacin in nonpregnant patients older than years. contact precautions should be employed during any acute diarrheal illness and until the diarrhea has subsided. hand hygiene after handling raw poultry and washing cutting boards and utensils with soap and water after contact with raw poultry may decrease risk of infection. pasteurization of milk and chlorination of water are critically important. infected food handlers and hospital employees who are asymptomatic pose no known hazard for disease transmission if proper personal hygiene measures are maintained. ingestion of human milk that contains anti<. jejuni antibodies has been shown to protect infants from diarrhea due to c. j e j~n i .~~,~~~ c. dificile is a spore-forming, gram-positive, anaerobic bacillus that produces two toxins. in the presence of antibiotic pressure, c. dificile colonic overgrowth and toxin production occur. the virulence properties of c. dificile are related to production of an enterotoxin that causes fluid secretion (toxin a) and a cytotoxin detectable by its cytopathic effects in tissue culture (toxin b). * both the usual manifestations of c. dificile disease in older children and adults include watery d&rhea, abdominal pain and tenderness, nausea, vomiting, and low-grade fever. grossly bloody diarrhea is unusual, although occult fecal blood is common. leukocytosis is present during severe illness. diarrhea usually begins to days into a course of antimicrobial therapy but may be delayed until several weeks after completion of the therapeutic course. usually, the illness is mild and self-limited if the offending drug is discontinued. severe colitis with pseudomembranes is less common now than in previous years because the risk of diarrhea developing during antimicrobial therapy is recognized and the antimicrobial agent typically is stopped. it is unclear whether this organism causes disease in newborns. one study from a newborn intensive care unit suggests that toxin a in stools is associated with an increased frequency of abnormal stools. endoscopic findings of pseudomembranes and hyperemic, friable rectal mucosa suggest the diagnosis of pseudomembranous colitis. pseudomembranes are not always present in c. dificile colitis; mild cases are often described as nonspecific colitis. several noninvasive techniques are used to establish the diagnosis, including enzyme immunoassay (eia) for toxin detection and pcr. - isolation of c. dificile from stool does not distinguish between toxigenic and nontoxigenic isolates. if c. dificile is isolated, testing for toxin by cell culture or eia should be performed to confirm the presence of a toxigenic strain. there are multiple commercially available eias that detect either toxin a or both toxins a and b. - these assays are sensitive and easy to perform. other assays are available for epidemiologic investigation of outbreaks of disease due to c. d i f i~i l e .~~~ in older children and adults, the diagnosis is confirmed by culture of c. dificile and demonstration of toxin in feces. in neonates, these data are inadequate to prove that an illness is related to c. dificile. when the clinical picture is consistent, the stool studies are positive for c. dificile and no other cause for illness is found, a diagnosis of "possible" c. dificile is made. a favorable response to eradication of c. dificile is supportive evidence that the diagnosis is c rrect. ~~ because of the uncertainty implicit in the ambiguity of neonatal diagnostic criteria, other diagnoses must be considered. when the decision is made that a neonate's illness might be related to c. difjcile, the initial approach should include fluid and electrolyte therapy and discontinuation of the offending antimicrobial agent. if the illness persists or worsens or if the patient has severe diarrhea, specific therapy with r n e t r o n i d a z~l e~~~*~~~ should be instituted. metronidazole is considered to be the treatment of choice for most patients with c. difjcile ~olitis. ~' rarely is there a need to consider orally administered vancomycin or bacitracin in after initiation of therapy, signs of illness generally resolve within several days, titers decrease, and fecal toxins disappear eventually. recurrence of colitis after discontinuation of metronidazole or vancomycin has been documented in % to % of adults.g relapses are treated with a second course of metronidazole or vancomycin. drugs that decrease intestinal motility should not be administered. neutralizing antibody against c. dificile otoxin has been demonstrated in human colostrum.' secretory component of siga binds to toxin a to inhibit its binding to receptors data show that there are nonantibody factors present in milk that interfere with the action of toxin b in addition to secretory iga directed at toxin a. breast-feeding appears to decrease the frequency of colonization by c. d i f j~i l e .~'~ in addition to standard precautions, contact precautions are recommended for the duration of illness. meticulous hand hygiene techniques, proper handling of contaminated waste and fomites, and limiting the use of antimicrobial agents are the best available methods for control of c. dificile infection. b! cholerue is a gram-negative, curved bacillus with a polar flagellum. of the many serotypes, only enterotoxin-producing organisms of serotype and cause epidemics. b! cholerue is divided into two serotypes, inaba and ogawa, and two biotypes, classic and el tor; the latter is the predominant biotype. nontoxigenic strains and non- strains of v cholerae can cause diarrhea and sepsis but do not cause outbreaks? ~ a pathogenesis b! cholerue group is the classic example of an enteropathogen whose virulence is caused by enterotoxin production. cholera toxin is an -mda protein whose five b subunits cause toxin binding to the enterocyte membrane ganglioside gm, and whose a subunit causes adenosine diphosphate ribosylation of a guanosine triphosphate-binding regulatory subunit of adenylate cy~lase."~~~'~ the elevated camp levels that result from stimulation of enterocytes by cholera toxin cause secretion of salt and water with concomitant inhibition of absorption. two other toxins are also encoded within the virulence cassette that encodes cholera toxin. these toxins, zona occludens toxin (zot) and accessory cholera toxin (ace), are consistently found in illness-causing strains of and but not usually in v; cholerae organisms that are less virulent. since , v cholerae , biotype el tor, has spread from india and southeast asia to africa, the middle east, southern europe, and the southern, western, and central pacific islands in the aquatic environment. the usual reported vehicles of transmission have included contaminated water or ice; contaminated food, particularly raw or undercooked shellfish; moist grains held at ambient temperature; and raw or partially dried fish. the usual mode of infection is ingestion of contaminated food or water. boiling water or treating it with chlorine or iodine and adequate cooking of food kill the organism. asymptomatic infection of family contacts is common but direct person-to-person transmission of disease has not been documented. persons with low gastric acidity are at increased risk for cholera infection. cholera acquired during pregnancy, particularly in the third trimester, is associated with a high incidence of fetal miscarriage can be attributed to a fetal acidosis and hypoxemia resulting from the marked metabolic and circulatory changes that this disease induces in the mother. it is not surprising that the likelihood of delivering a stillborn child is closely correlated with the severity of the maternal illness. the inability to culture v; cholerue from stillborn infants of infected mothers, together with the usual absence of bacteremia in cholera, suggests that transplacental fetal infection is not a cause of intrauterine death. neonatal cholera is a rare disease. this generalization also applies to the new strains, although mild '* and severe forms of illness have rarely been described in newborns. among neonates admitted to a cholera research hospital in dacca, bangladesh, there were infants ill with ~holera.~" even infants born to mothers with active diarrheal disease may escape infection, despite evidence that rice-water stools, almost certain to be ingested during the birth process, may contain as many as lo organism~/ml.~~~ the reason for this apparently low attack rate among newborns is not certain; however, it probably can be attributed in large part to the protection conferred by breast-feedingg ' human milk contains antibodies and receptor-like glycoprotein that inhibit adherence of v choleraeu and gangliosides that bind cholera toxin. the role of transplacentally acquired vibriocidal maternal antibodies has not been determined. because v cholerae causes neither bacteremia nor intestinal invasion, protection against illness is more likely to be a function of mucosal rather than serum additional factors that may reduce the incidence of neonatal cholera include the large inoculum required for infection and the limited exposure of the newborn to the contaminated food and water. clinicians should request that appropriate cultures be performed for stool specimens from persons suspected of having cholera. the specimen is plated on thiosulfate citrate bile salts sucrose agar directly or after enrichment in alkaline peptone water. isolates of v cholerae should be confirmed at a state health department and then sent to the cdc for testing for production of cholera toxin. a fourfold rise in vibriocidal antibody titers between acute and convalescent serum samples or a fourfold decline in titers between early and late (> months) convalescent serum specimens can confirm the diagnosis. probes have been developed to test for cholera toxin. * the most important modality of therapy is administration of oral or parented rehydration therapy to correct dehydration and electrolyte imbalance and maintain h y d r a t i~n .~~ antimicrobial therapy can eradicate vibrios, reduce the duration of diarrhea, and reduce requirements for fluid replacement. one cholera vaccine, which is administered parenterally, is licensed in the united states but is of very limited value. several experimental oral vaccines are being t e~t e d ? *~-~~' i.: enterocolitica is a major cause of enteritis in much of the industrialized enteritis due to this organism primarily occurs in infants and young children, and infections in the united states are reported to be more common in the north than in the s o~t h .~~~-~~~ h i m als, especially swine, have been shown to serve as the reservoir for y. enterocolitica. a history of recent exposure to chitterlings (i.e., pig intestine) is common. transmission has also occurred after ingestion of contaminated milk and infusion of contaminated blood p r o d~c t s .~~~,~~~ virulence of y. enterocolitica is related primarily to a virulence plasmid, which is closely related to the virulence plasmids of yersinia pseudotuberculosis and yersinia p e s t i~.~~'~~~~ an st enterotoxin, which is closely related to the st of etec, may also be important. infection with y. enterocolitica is recognized as one of the causes of bacterial gastroenteritis in young children, but knowledge of neonatal infection with this organism is fragmentary. even in large series, isolation of yersinia from newborns is rare? , the youngest infants whose clinical course has been described in detail were days to several months old at the onset of their illness. , - there were no features of the gastroenteritis to distinguish it from that caused by other invasive enteric pathogens such as shigella or salmonella. infants presented with watery diarrhea or with stools containing mucus with streaks of blood. sepsis was common in these infants particularly in the first months of life when % of enteritis was complicated by sepsis. , , , fever is not a consistent finding in children with bacteremia, and meningitis is rare. in older children, fever and right lower quadrant pain mimicking appendicitis are often found. diagnosis y enterocolitica can be recovered from throat swabs, mesenteric lymph nodes, peritoneal fluid, blood, and stool. because laboratory identification of organisms from stool requires special techniques, laboratory personnel should be notified when yersinia is suspected. because avirulent environmental isolates occur, biotyping and serotyping are useful in assessing the clinical relevance of isolates. pcr has been used to detect pathogenic strain^.^^^'^^^ the effect of antimicrobial therapy on the outcome of gastrointestinal infection is uncertain. it has been recommended that antibiotics be reserved for sepsis or prolonged and severe gastroenteritisg '; however, there are no prospective studies comparing the efficacy of various antimicrobial agents with each other or with supportive therapy alone. most strains of y. enterocolitica are susceptible to trimethoprimsulfamethoxazole, the aminoglycosides, piperacillin, imipenem, third-generation cephalosporins, amoxicillin-clavulanate potassium, and chloramphenicol, and resistant to amoxicillin, ampicillin, carbenicillin, ticarcillin, and m a c r o l i d e~.~~~-~~~ therapy in individual cases should be guided by in vitro susceptibility testing, although cefotaxime has been successfully used in bacteremic infants? aerornonas hydrophila is widely distributed in animals and the environment. although wound infection, pneumonia, and sepsis (especially in immunocompromised hosts) represent typical aeromonas infections, gastroenteritis increasingly is being recognized. the organism is a gramnegative, oxidase-positive, facultatively anaerobic bacillus belonging to the family vibrionaceae. like other members of this family, it produces an enter~toxin~~' that causes fluid secretion in rabbit ileal loops.%' some strains cause fluid accumulation in the suckling mouse model,"' whereas other strains are i n~a s i v e~~~ or cytotoxic. the enterotoxin is not immunologically related to cholera toxin or the heat lt of although volunteer studies and studies with monkeys have failed to provide supportive evidence for enteropathog e n i~i t y ?~~,~~ there is good reason to believe that a. hydrophila does cause diarrhea in children. the earliest description of aeromonas causing diarrhea was an outbreak that occurred in a neonatal unit. although several studies have failed to show an association with diarrhea,% - most studies have found more aeromonas isolates among children with gastroenteritis than among ~o n t r o l s ?~~-~~~ part of the controversy may be caused by strain differences; some strains possess virulence traits related to production of gastroenteritis, whereas others do not. , the diarrhea described in children is a disease of summer, primarily affecting children in the first years of life. in one study, ( %) of cases of aeromonas detected during a -month period occurred in infants younger than month. typically, watery diarrhea with no fever has been described; although there are descriptions of watery diarrhea with fever? however, in %, a dysentery-like illness occurred. dysentery-like illness has been described in the neonate. in one third of children, diarrhea has been reported to last for more than ~eeks. ~' there may be species-related differences in clinical features of aeromonas-associated gastroenteritis in children. organisms that were formerly classified as a. hydrophila are now sometimes labeled as aeromonas sobria or aeromonas ~a v i a e .~~'~~~' fever and abdominal pain appear to be particularly common with a. sobria. one series of a. hydrophila isolates from newborns in dallas showed more blood cultures than stool cultures positive for a e r o m o n a~.~~~ diagnosis of enteric infection associated with aeromonas often is not made because this organism is not routinely sought in stool cultures. when the organism is suspected, the laboratory should be notified so that oxidase testing can be performed. the organism is usually susceptible to aztreonam, imipenem, meropenem, third-generation cephalosporins, trimethoprim-sulfamethoxazole, and chloramphenicol.q ~ plesiomonas shigelloides is a gram-negative, facultative anaerobic bacillus that, like aeromonas, is a member of the vibrionaceae family. it is widely disseminated in the environment; outbreaks of disease are usually related to ingestion of contaminated water or seafood. although it has been associated with outbreaks of diarrheal disease and has been found more commonly in ill than well controls, the role of i? shigelloides in diarrheal disease has remained contro~ersial.~~~ if it is a true enteropathogen, the mechanism by which it causes disease is ~n c l e a r . ~~'~~' the role of this organism in neonatal diarrhea has not been extensively investigated. infections of neonates have been r e p~r t e d ?~' .~~~ but most cases of enteric disease currently reported in the united states are in adults. typical illness consists of watery diarrhea and cramps; sometimes, fever, bloody stools, and emesis occur and last for to days. diagnosis is not usually made by clinical microbiology laboratory testing because, as with aeromonas, coliforms can be confused with l ? shigelloides unless an oxidase test is performed. the true frequency of infection is unknown. the organism has antibiotic susceptibilities similar to those of a e r~m o n a s .~~~'~~~ proving that an organism causes diarrhea is difficult, particularly when it may be present in large numbers in stools of healthy persons. bacteria that have been associated with acute gastroenteritis may be considered causative when the following criteria are met: . a single specific strain of the organism should be found as the predominant organism in most affected infants by different investigators in outbreaks of enteric disease in different communities. . this strain should be isolated in a significantly lower percentage and in smaller numbers from stool specimens of healthy infants. . available methods must be used to exclude other recognized enteropathogens, including viruses and parasites, enterotoxigenic agents, and fastidious organisms such as ca mpylobacter. . demonstration of effective specific antimicrobial therapy and specific antibody responses and, ultimately, production of experimental disease in volunteers are helpful in establishing the identity of a microorganism as a pathogen. optimally, the putative pathogen should have virulence traits that can be demonstrated in model systems. most bacteria that have been suggested as occasional causes of gastroenteritis in neonates fail to fulfill one or more of these criteria. their role in the cause of diarrheal disease is questionable. this is particularly true of microorganisms described in early reports in which the possibility of infection with more recently recognized agents could not be excluded. much of the clinical, bacteriologic, and epidemiologic data collected earlier linking unusual enteropathogens to infantile diarrhea must be reevaluated in light of current knowledge and methodology. several reports of acute gastroenteritis believed to have been caused by klebsiella suggest that, rather than playing an etiologic role, these organisms had probably proliferated within an already inflamed b~w e l .~~~-' '~' the recovery of klebsiella-enterobacter in pure culture from diarrheal stools has led several investigators to suggest that these bacteria may occasionally play a causative role in infantile gastroenteritis and enterocoliti~.'~~~~'"~ ingestion of infant formula contaminated with enterobacter sakazakii has been associated with development of bloody diarrhea and sepsis.'oo however, klebsiella species also may be isolated in pure culture from stools of newborns with no enteric s y m p t o m~. '~~~~'~' ' in one study, certain capsular types of klebsiella were more often isolated from infants with diarrheal disease than from normal infants.ioo later work has shown that klebsiella pneumoniae, enterobacter cloacae, and citrobacter species are capable of isolation of citrobacter species, such as those of klebsiella species, describe associations with enteric illnesses in up to % of cases. - there is inadequate evidence to define the roles of klebsiella, enterobacter, and citrobacter species as etiologic agents of enteric illnesses. listeria monocytogenes, one of the classic causes of neonatal sepsis and meningitis (see chapter ), has been linked to outbreaks of febrile diarrheal disease in immunocompetent adults and ~h i l d r e n . '~'~~'~~' seventy-two percent of ill individuals have had fever.ioz outbreaks have been related to ingestion of contaminated foods. listeria has rarely been described as a cause of neonatal gastroenteriti~.'~~~-~~~~ infection with enterotoxin-producing bacteroides fragilis has been associated with mild watery diarrhea.' these infections have a peak incidence in -to -year-old infants. these toxin-producing organisms cannot be detected in routine hospital laboratories. a variety of organisms has been isolated from infant stools during episodes of diarrhea. most of these reports have failed to associate illness with specific organisms in a way that has stood the test of time. for example, i? aeruginosa - and have been associated with diarrhea, but proteus , [ ] [ ] [ ] [ ] [ ] [ ] [ ] there are few convincing data suggesting that either is a true enteropathogen. these organisms generally are recovered as frequently from healthy infants as from infants with diarrheal disease, suggesting that their presence in stool cultures is significant. , - an association between providencia and neonatal enteritis has been substantiated largely by anecdotal reports of nursery outbreaks. . ~ @' these bacteria are rarely isolated from infants with sporadic or community-acquired diarrheal disease.' ~' m" b~ candida albicans usually is acquired during passage through the birth canal and is considered a normal, although minor, component of the fecal flora of the neonate (see chapter ).' ' intestinal overgrowth of these organisms frequently accompanies infantile gastroenteriti~, "~~~~~'~~~*'~~~ particularly after antimicrobial therapy. , ,' - the upper small gut may become colonized with candida in malnourished children with diarrhea ; whether the presence of the organism is cause or effect is unclear. stool cultures obtained from infants with diarrheal disease are therefore inconclusive, and although candida enteritis has been reported in adults,' the importance of this organism as a primary cause of neonatal gastroenteritis has been difficult to prove. clinical descriptions of nursery epidemics of candidal enteritis are poorly documented, generally preceding the recognition of epec and rotaviruses as a cause of neonatal diarrhea. even well studied cases of intestinal involvement add little in the way of substantive proof because secondary invasion of candida has been shown to be a complication of coliform enteritis. , producing e n~e r o~o~n s~ ~~~~ ~ ~ ' " ~ reports of although diarrhea has sometimes been described as a finding in neonatal disseminated candidiasis, more typically, gastrointestinal tract involvement with disseminated candida is associated with abdominal distention and bloody stools mimicking necrotizing enterocoliti~.~~~"~~~-~~~~ typically, affected infants are premature and have courses complicated by antibiotic administration, intravascular catheter use, and surgical procedures during the first several weeks of life. a trial of oral anticandidal therapy may be helpful in neonates suffering from diarrhea in the presence of oral or cutaneous candidiasis. if the therapy is appropriate, a response should be forthcoming within to days. diarrhea sometimes occurs as a manifestation of systemic infection. patients with staphylococcal toxic shock syndrome, for example, often have diarrhea. loose stools sometimes occur in sepsis, but it is unclear whether the diarrhea is a cause or an effect. the organisms isolated from blood cultures in a group of bangladeshi infants and children with diarrhea included staphylococcus aureus, haemophilus inpuenzae, streptococcus pneumoniae, r aeruginosa, and various gramnegative enteric bacilli.' it is unknown whether the bacteriology of sepsis associated with diarrhea is similar in the well-nourished infants seen in industrialized countries. acute diarrhea associated with intestinal parasites is infrequent during the neonatal period. in areas with high endemicity, infection of the newborn is likely to be associated with inadequate maternal and delivery care, insufficient environmental sanitation, and poor personal hygiene standards. the occurrence of symptomatic intestinal parasitic infection during the first month of life requires acquisition of the parasite during the first days or weeks; the incubation period for e. histolytica and g. larnblia is to weeks, and for cryptosporidium parvum, it is to days. the newborn can be infected during delivery by contact with maternal feces, o in the hospital through contact with the mother or personnel, or in the household through contact with infected individuals in close contact with the child. contaminated water can be an important source of infection for g. lamblia and c. parvum. organisms formerly identified as e. histolytica have been reclassified into two species that are morphologically identical but genetically distinct: e. histolytica and e. dispar. the former can cause acute nonbloody and bloody diarrhea, necrotizing enterocolitis, ameboma, and liver abscess, and the latter is a noninvasive parasite that does not cause disease. early acquisition of disease tends to be more severe in young infants; rarely, amebic liver abscess and rapidly fatal colitis have been reported in infant^."^^-'^^^ for example, a -dayold child from india who presented with to episodes of watery and mucous diarrhea, lethargy, jaundice, and mildly elevated liver enzymes has been described; the child recovered completely after days of intravenous o m i d a~o l e . '~~~ however, asymptomatic colonization of neonates with various species of ameba is common in areas of high endemi~ity."~~ diagnosis can be established by stool examination for cysts and trophozoites and by serologic studies.' through the use of pcr, isoenzyme analysis, and antigen detection assays, e. histolytica and e. dispar can be differentiated. ' serum antibody assays may be helpful in establishing the diagnosis of amebic dysentery and extraintestinal amebiasis with liver involvement. the efficacy of treatment with metronidazole for colitis or liver abscess has not been established for the newborn period, although this therapy has been used with success. o patients with colitis or liver abscess caused by e. histolytica are treated also with iodoquinol, as are asymptomatic carriers. g. lamblia is a binucleate, flagellated protozoan parasite with trophozoite and cyst stages. it is spread by the fecal-oral route through ingestion of cysts. child-care center outbreaks reflecting person-to-person spread have demonstrated high i n f e~t i v i t y . "~~~'~~~ foodborne transmission and waterborne transmission also occur. infection is often asymptomatic or mildly symptomatic; cases of severe symptomatic infection during the immediate newborn period have not been reported. symptoms in giardiasis are related to the age of the patient, with diarrhea, vomiting, anorexia, and failure to thrive typical in the youngest children. seroprevalence studies have demonstrated evidence of past or current infection in % of peruvian children by the age of months.io ' in a study of lactating bangladeshi mothers and their infants, % of women and % of infants excreted giardia once during the study; in some infants, this occurred before they were months old.'o of these infected infants, % had diarrhea, suggesting that the early exposure to the parasite resulted in disease. in a prospective study of diarrhea conducted in mexico, infants frequently were infected with giardia from birth to months, with a crude incidence rate of first giardia infection of . infections per child-year in this age group. the symptom status of these children was not reported but this study strongly suggests that g. lamblia may be more common than currently recognized among newborns living in developing areas. the diagnosis of giardiasis can be made on the basis of demonstration of antigen by eia or by microscopy of feces, duodenal fluid or, less frequently, duodenal b i~p~y . ' '~~~' '~' breast-feeding is believed to protect against symptomatic g i a r d i a~i s .~-~~* '~~~ this protection may be mediated by cellular and humoral i nrnunity ~~"~~*"~~ and nonspecifically by the antigiardial effects of unsaturated fatty acids.iob giardia infections causing severe diarrhea may respond to metronidazole or furazolidone.' c. parvum is a coccidian protozoon related to toxoplasma gondii, lsospora belli, and plasmodium species. s' the life cycle involves ingestion of thick-walled oocysts; release of sporozoites, which penetrate intestinal epithelium; and development of merozoites. there is asexual and sexual reproduction, with the latter resulting in formation of new oocysts that can be passed in stools. cryptosporidium species are ubiquitous. infection often occurs in persons traveling to endemic areas.'o because cryptosporidium infects a wide variety of animal species, there is often a history of animal contact among infected individ~als."~' person-to-person spread, particularly in household c~n t a c t s '~~'~' '~~ and daycare center^,"^^"'^^ is well documented and suggests that the organism is highly infectious. waterborne outbreaks of cryptosporidiosis occur and can be of massive proportion^."^^ the clinical manifestations of illness in immunocompetent persons resemble those of giardia infection but are somewhat shorter in d~ration'"~; asymptomatic carriage is rare. symptoms and signs include watery diarrhea, abdominal pain, myalgia, fever, and weight loss. * ~ ~' " ~' infection in the first month of life has been described.""~"" because symptoms resolve before excretion of oocysts ceases, a newborn whose mother has been ill with cryptosporidiosis in the month before delivery might be at risk even if the mother is asymptomatic at the time of the child's birth."'* with the increasing frequency of human immunodeficiency virus infection, it is likely that women with symptomatic cryptosporidiosis occasionally will deliver an infant who will become infected. infants infected early in life may develop chronic diarrhea and maln~trition."'~ the diagnosis of cryptosporidiosis is most typically made by examination of fecal smears using the giemsa stain, ziehl-neelsen stain, auramine-rhodamine stain, sheather's sugar flotation, an immunofluorescence procedure, a modified concentration-sugar flotation method, or an eia.' io , lo nitazoxanide is effective therapy of immunocompetent adults and children ill with cryptosporidiosis.'io because illness is usually self-limited in the normal host, attention to fluid, electrolyte, and nutritional status usually suffices. enteric isolation of hospitalized infants with this illness is appropriate because of the high infectivity. several studies suggest that the risk of infection early in life may be decreased by breast-feeding. ' '"j viruses that infect the intestinal mucosa and cause primarily gastroenteritis are referred to as enteric viruses; they should not be confused with enteroviruses, members of picornaviridae family that are associated primarily with systemic illnesses. enteric viruses include rotaviruses, enteric adenoviruses, human caliciviruses, and astroviruses. other viruses such as coronaviruses, breda viruses, pestiviruses, parvoviruses, toroviruses, and picobirnaviruses have been sporadically associated with acute diarrhea but are currently considered of uncertain relevance. extensive reviews on the role of enteric viruses in childhood diarrhea can be found elsewhere." -"" all four enteric viruses could conceivably infect the newborn, but the extent of exposure and clinical manifestations are largely unknown for astrovirus, enteric adenovirus, and human caliciviruses. rotavirus is the most extensively studied enteric virus. neonatal rotavirus infections have similar virologic and clinical characteristics to infection in older children, although some differences exist. rotavirus is a -nm, nonenveloped virus composed of three concentric protein shells: a segmented genome ( segments), an rna-dependent polymerase, and enzymes required for messenger rna synthesis are located within the inner core. each segment codes for at least one viral protein (vp). the vp can be part of the structure of the virus, or it may be a nonstructural protein (nsp) required for replication, viral assembly, budding, determination of host range, or viral pathogenesis."" six distinct rotavirus groups (a through f) have been identified serologically based on common group of which three (a, b, and c) have been identified in humans.'io because group a rotaviruses represent more than % of isolated strains in humans worldwide, further discussion focuses on this group. group a rotaviruses are subclassified into serotypes based on neutralization epitopes located on the outer capsid. both rotavirus surface proteins, vp and vp , can induce production of neutralizing antibodies. at least vp types (g serotypes: gi to g , g to g , and g ) and nine vp types (p serotypes: pia, plb, p a, p , p b, p , p , p , and p ) have been detected among human r o t a v i r u~e s .~~~~-~~~~ by sequencing the vp -coding gene, eight genomic p types (genotypes) have been identified that correspond to one or more of the described p antigenic types (genotype to antigenic type pla, to plb, to p a, to p , to p b, to p , to p , and to p )."" combining g antigenic with p antigenic and genetic typing, a specific rotavirus strain can be identified p antigenic type (p genetic type), g type. as an example, the human neonatal m strain is described as p a[ ], gi. from newborn nurseries, some of which seem to be endemic to the newborn units with high rates of asymptomatic infe~tion,"~~-"~' and less commonly, outbreaks of symptomatic infection.iiz these findings suggest that specific conditions of the newborn environment (e.g., child, nursery, personnel) may increase the possibility of reassortments between human strains; such strains may persist in these settings possibly through constant transmission involving asymptomatic newborns, adults, and contaminated surfaces. rotavirus primarily infects mature enterocytes located in the mid and upper villous e p i t h e l i~m .~~~~-"~~ lactase, which is present only on the brush border of the differentiated epithelial cells at these sites, may act as a combined receptor and uncoating enzyme for the virus, permitting transfer of the particles into the cell. perhaps for this reason, infection is limited to the mature columnar enterocytes; crypt cells and crypt-derived cuboidal cells, which lack a brush border, appear to be resistant to rotaviral i n f e~t i o n . "~~' "~~ this concept also may explain why rotavirus infection is less common in infants younger than weeks' gestational age than in more mature infants ; between and weeks' gestational age, lactase activity is approximately % of that found in term infants. the upper small intestine is most commonly involved, although lesions may extend to the distal ileum and rarely to the ~ l n .~~~~ ~~~~ interaction between intestinal cell and rotavirus structural and nonstructural proteins occurs, resulting in death of infected villous enter~cytes."~~ once infected, the villous enterocyte is sloughed, resulting in an altered mucosal architecture that becomes stunted and flattened. the gross appearance of the bowel is usually normal; however, under the dissecting microscope, scattered focal lesions of the mucosal surface are apparent in most cases. light microscopy also shows patchy changes in villous morphology, compatible with a process of infection, inflammation, and accelerated mucosal renewal. the villi take on a shortened and blunt appearance as tall columnar cells are shed and replaced by less mature cuboidal entero-ischemia may also play a role in the loss and stunting of villi" and activation of the enteric nervous system; active secretion of fluid and electrolytes may be another pathogenic mechanism. during the recovery phase, the enteroblastic cells mature and reconstruct the villous structure. because of the loss of mature enterocytes on the tips of the villi, the surface area of the intestine is reduced. diarrhea that occurs may be a result of this decrease in surface area, disruption in epithelial integrity, transient disaccharidase deficiency, or altered countercurrent mechanisms and net secretion of water and electrolytes. ' ~ ~ ~ ~ ~ nsp has been found to induce age-dependent diarrhea in cd mice by triggering calcium-dependent chloride and water secretion. the potential role of this "viral enterotoxin" in human disease is not yet clear. , infants with asymptomatic rotavirus infections in the nursery are less likely than uninfected nursery mates to experience severe rotavirus infection later in life - ; this finding suggested protective immunity and supported vaccine development. most studies have indicated that serum and intestinal antirotavirus antibody levels are correlated with protection against i n f e~t i o n "~~-"~~ although this correlation has not been ~n i v e r s a l .~~~~-~~~~ breast-feeding protects against rotavirus disease during the first year of life, probably including newborns. the high prevalence of antirotaviral antibodies in colostrum and human milk has been demonstrated by numerous investigators in widely diverse geographic areas. maternal rotavirus infection or immunization is accompanied by the appearance of specific antibodies in milk, probably through stimulation of the enteromammary immune between % and % of women examined in london, bangladesh, guatemala, costa rica, and the united states had antirotaviral iga antibodies in their milk for up to years of rotavirus-specific igg antibodies have been found during the first few postpartum days in about one third of human milk samples a~s a y e d ,~~@~"~~ whereas i@ antibodies were detectable in about one half. glycoproteins in human milk have been shown to prevent rotavirus infection in vitro and in an animal model." the concentration of one milk glycoprotein, lactadherin, was found to be significantly higher in human milk ingested by cytes.l , , infants who developed asymptomatic rotavirus infection than in milk ingested by infants who developed symptomatic infe~tion. ~ rotaviruses probably infect neonates more commonly than previously recognized, although most infections seem to be asymptomatic or mildly symptomatic. " ~ - in a prospective study, the prevalence of rotavirus infection among neonatal intensive care unit patients was . %. rotavirus has a mean incubation period of days, with a range of to days in children and in experimentally infected adults. fecal excretion of virus often begins a day or so before illness and maximal excretion usually occurs during the third and fourth days, and generally diminishes by the end of the first week, although low concentrations of virus have been detected in neonates for up to weeks. , [ ] [ ] [ ] [ ] rotavirus infections are markedly seasonal (autumn and winter) in many areas of the world, although in some countries seasonality is less striking; the reason for this is u n~l e a r .~~~" '~~ in nurseries in which persisting endemic infection has permitted long-term surveillance of large numbers of neonates, rotavirus excretion can follow the seasonal pattern of the community but can also show no seasonal it is not clear how units in which infection remains endemic for months or years differ from those with a low incidence of rotavirus. some nurseries are free of rotavirus infection' or minimally a f f e~t e d~~"~" whereas others have rotavirus diarrheal disease throughout the year or in outbreaks that involve % to % of low birth weight does not seem to be an important factor in determining the attack rate among infants at risk but may be important in rn rta ity.i~~~ infants in premature or special-care nurseries, despite their prolonged stays and the increased handling necessary for their care, do not demonstrate a higher susceptibility to infection; data regarding shedding of the virus are inconsi~tent!~*~~~~ after infection is introduced into a nursery, rotavirus probably will spread steadily and remain endemic until the nursery is closed to new admissions or nursing practices permit interruption of the cycle. exactly how the virus is introduced and transmitted is uncertain, although limited observations and experience with other types of enteric disease in maternity units suggest several possibilities. the early appearance of virus in stools of some neonates indicates that infection probably was acquired at delivery. virus particles can be detected on the first v s or second" day of life in a significant number of infected infants. by day or , most infected infants who will shed virus, with or without signs of illness, are doing so. , the large numbers of virus particles e x~r e t e d "~~,~~~~ suggest a fairly large and early oral inoculum. it is unlikely that contamination from any source other than maternal feces could provide an inoculum large enough to cause infection by the second day. transfer of particles from infant to infant on the hands of nursing and medical staff is probably the most important means of viral spread. with ' to " viral particles usually present in g of stool, the hands of personnel easily could become contaminated after infection is introduced into a nursery. there are numerous reports of nosocomial and daycare center rotavirus gastroenteritis outbreaks that attest to the ease with which this agent spreads through a hospital or institutional setting.'io admission of a symptomatic child usually is the initiating event, although transfer of a neonate with inapparent infection from one ward to another also has been incriminated. the most important factors influencing the incidence of rotavirus diarrhea in a nursery are the proximity to other newborns and the frequency of handling. during a -month study, infants cared for by nursing staff and kept in communal nurseries experienced three epidemics of diarrhea with attack rates between % and %. during the same period, only % of infants rooming in with their mothers became ill, even though they had frequent contact with adult relatives and siblings. there is no clear evidence of airborne or droplet infection originating in the upper respiratory tract or spread by aerosolization of diarrheal fluid while diapers are changed. indirect evidence of airborne transmission includes the high infection rate in closed settings, the isolation of the virus from respiratory secretions,izo and the experimental observation of transmission by aerosol droplets in mice.' however, the respiratory isolation achieved by placin an evidence indicates that transplacental or ascending intrauterine infection occurs. transmission of virus through contaminated fomites, formula, or food is possible but has not been documented in newborns. rotavirus particles have not been found in human milk or c o l o~t r u m .~~~~~~~~ exposure of a newborn to rotavirus can result in asymptomatic infection or cause mild or severe gastro-outbreaks with high attack rates as measured by rotavirus excretion have been described but the extent of symptomatic infection severe rotavirus infection is seldom reported during the newborn period but the extent of underreporting of severe disease, especially in the less developed areas of the world, has not been evaluated. it has been hypothesized that asymptomatic infections during the newborn period are the result of naturally attenuated strains circulating in this environment. rna electrophoretic patterns of rotaviruses found in certain nurseries have shown uniform and it has been suggested that these strains may be attenuated. the presence of unusual antigenic types such as the p a[ ] type within nurseries also suggests "less virulent strains." at least rotavirus strains were documented to co-circulate in a tertiary care center during a -month period " and in a different setting the same rotavirus strains by electropherotype produced asymptomatic infection in neonates and symptomatic infection in older infants. newborns within a nursery exposed to a given rotavirus strain can develop symptomatic or asymptomatic infection. ~ ~ i because newborns routinely have frequent relatively loose stools, it is possible that mild diarrhea episodes caused by rotavirus are being wrongly labeled as asymptomatic episodes. no clinical feature is pathognomonic of rotaviral gastroenteritis. early signs of illness, such as lethargy, irritability, vomiting, and poor feeding, usually are followed in a few hours by the passage of watery yellow or green stools free of blood but sometimes containing mucus. , - diarrhea usually decreases by the second day of illness and is much infant in a closed incubator is not fully protective. s no enteritisel . . . , ,l , , varies. . . . , improved by the third or fourth day. occasionally, intestinal fluid loss and poor weight gain may continue for or weeks, particularly in low-birth-weight infants. although reducing substances frequently are present in early fecal ~a m p l e s "~~~'~~~' ~ this finding is not necessarily abnormal in neonates, particularly those who are breast-fed. nevertheless, infants with prolonged diarrhea should be investigated for monosaccharide or disaccharide malabsorption or intolerance to cow's milk protein or in a prospective % of newborns with gastrointestinal symptoms in a neonatal intensive care unit had rotavirus detected in their stools. frequent stooling (present in %), bloody mucoid stool ( %), and watery stools ( %) were risk factors for a rotavirus infection. bloody mucoid stools, intestinal dilatation, and abdominal distention were significantly more common in preterm infants, but severe outcomes such as necrotizing enterocolitis and death did not differ among infected term and preterm infants. longitudinal studies in newborn nurseries and investigations of outbreaks among neonates rarely describe a severe adverse outcome or death. , , because these infants are under constant observation, early detection of excessive fluid losses and the availability of immediate medical care are probably major factors in determining outcome. rotavirus gastroenteritis causes almost , deaths of infants every year,i i concentrated largely in the poorest regions of the world. it is likely that in places where hospital-based care is uncommon, rotavirus causes neonatal deaths secondary to dehydration. group a rotavirus has been associated with a wide array of diseases in infants and children; reye syndromes, encephalitis-aseptic meningitis, sudden infant death syndrome, inflammatory bowel disease, and kawasaki syndrome have been described but not systematically studied. case reports and small case series have associated neonatal rotavirus infection with necrotizing e n t e r o c~l i t i s .~~'~"~~~ rotavirus infection may play a role in a small proportion of cases of necrotizing enterocolitis, although it probably represents one of many potential triggering factors. a significant association between neonatal rotavirus infection and bradycardia-apnea episodes was detected in one prospective study. the possible association between natural rotavirus infection and i n t u s s u~c e p t i o n~~~~~~~~~ gained support after the association was made between the human-simian reassortant vaccine and intussusception in infants older than months (attributable risk = : , ). intussusception is extremely uncommon in the newborn; it is highly unlikely that rotavirus triggers this disease in neonates. there are many methods used for detection of rotavirus in stool specimens, including electron microscopy, immune electron microscopy, elisa, latex agglutination, gel electrophoresis, culture of the virus, and reverse transcriptasepolymerase chain reaction. elisa and latex agglutination currently are the most widely used diagnostic techniques for detection of rotavirus in clinical samples. many commercial kits are available that differ in specificity and ~e n s i t i v i t y . '~~~-'~~~ in general, latex agglutination assays are more rapid than elisas but are less sensitive. the sensitivity and specificity of the commercially available elisas surpass %. checking of the elisa by another method such as gel electrophoresis or pcr amplification may be desirable if there is concern about false-positive results. fecal material for detection of rotavirus infection should be obtained during the acute phase of illness. whole-stool samples are preferred, although suspensions of rectal swab specimens have been adequate for detection of rotavirus by rotavirus are relatively resistant to environmental temperatures, even tropical temperatures, although °c is desirable for short-term storage and - °c for prolonged storage.'io excretion of viral particles may precede signs of illness by several days' ; maximal excretion by older infants and children usually occurs to days after onset of symptoms. neonates can shed virus for to weeks after onset of symptoms. the primary goal of therapy is restoration and maintenance of fluid and electrolyte balance. despite the documented defect in carbohydrate digestion with rotavirus diarrhea, rehydration often can be accomplished with glucoseelectrolyte or sucrose-electrolyte solutions given orally . , - intravenous fluids may be needed in neonates who are severely dehydrated, who have ileus, or who refuse to feed. persistent or recurrent diarrhea after introduction of milkbased formulas or human milk warrants investigation for secondary carbohydrate or milk protein i n t~l e r a n c e . '~~~~~~" disaccharidase levels and xylose absorption return to normal within a few days to weeks after infe~tion."~~ intractable diarrhea related to severe morphologic and enzymatic changes of the bowel mucosa is possible although rare in the newborn; it may require an elemental diet or parenteral nutrition. efficacy of anti-rotavirus antibodies (e.g., hyperimmune colostrum, antibody-supplemented formula, human serum immunoglobulin) and of probiotics has been p~s t u l a t e d , '~~~~'~~' although not convincingly shown ; the widespread clinical use of these measures seems remote. one study suggests that use of lactobacillus during the diarrheal episode may decrease the duration of rotavirus-associated hospital stays, especially when used early in the course of the disease, although more studies are needed before recommending widespread use. hand hygiene before and after contact with each infant remains the single most important means of preventing the spread of infection. because rotavirus is often excreted several days before illness is recognized, isolation of an infant with diarrhea may be too late to prevent cross-infection unless all nursing personnel and medical staff have adhered to this fundamental precaution. infants who develop gastroenteritis should be moved out of the nursery area if adequate facilities are available and the infant's condition permits transfer. the use of an incubator is of value in reducing transmission of disease only by serving as a reminder that proper hand-hygiene and glove techniques are required, but is of little value as a physical barrier to the spread of encouraging rooming-in of infants with their mothers has been shown to be helpful in preventing or containing nursery epidemics.' temporary closure of the nursery may be required for clinically significant outbreaks that cannot be controlled with other measures. development of rotavirus vaccines began in the early s. candidate vaccines included bovine and rhesus monkey elisa. , attenuated strains, human attenuated strains, and bovinehuman and rhesus-human reassortant strains."" in august , the first licensed rotavirus vaccine, rotashield, an oral formulation of a simian-human quadrivalent reassortant vaccine, was recommended for use in children when they were , , and months old. after approximately , children were vaccinated with more than million doses, a significantly increased risk of intussusception was observed among vaccinated children, with an overall odds ratio of . .iz use of this vaccine was terminated. two new vaccine candidates are undergoing phase i clinical trials: a "pentavalent" bovine-human reassortant vaccine including g types gl-g and p type pla[ ] and a monovalent human attenuated pla[ ]g vaccine. the epidemiology of rotavirus infection will change significantly if one or both candidates become widely available in the future. the impact on neonatal infection will depend on the effect of herd immunity in decreasing circulation of rotavirus strains. stools from breast-fed neonates are typically watery and yellow, green, or brown. the frequency of stooling can vary from one every other day to eight evacuations per day. in an active, healthy infant who is feeding well, has no vomiting, and has a soft abdomen, these varied patterns of stooling are not a cause for concern. physicians need to consider the child's previous frequency and consistency of stools and establish a diagnosis of acute diarrhea on an individual basis. close follow-up of weight increase in infants with nonformed stools can help confirm the clinical impression. a normal weight gain should direct medical action away from stool exams or treatment. diarrhea during the neonatal period is a clinical manifestation of a wide variety of disorders (table - ). the most common initiating factor is a primary infection of the gastrointestinal tract that is mild to moderate in severity, chapter self-limited, and responsive to supportive measures. acute diarrhea can also be an initial manifestation of a systemic infection, including bacterial and viral neonatal sepsis. infants with moderate to severe diarrhea require close monitoring until the etiologic diagnosis and the clinical evolution are clarified. there are noninfectious diseases leading to chronic intractable diarrhea that may result in severe nutritional disturbances or even death unless the specific underlying condition is identified and treated appropriately. the differential diagnosis of a diarrheal illness requires a careful clinical examination to determine whether the child has a localized or a systemic process. lethargy, abnormalities in body temperature, hypothermia or hyperthermia, decreased feeding, abdominal distention, vomiting, pallor, respiratory distress, apnea, cyanosis, hernodynamic instability, hypotension, hepatomegaly or splenomegaly, coagulation or bleeding disorders, petechiae, and exanthemas should lead to an intense laboratory investigation directed at systemic viral or bacterial infection. if the process is deemed a localized intestinal infection, initial evaluation can be focused on differentiating an inflammatory-invasive pathogen from those that cause a noninflammatory process. for this, stool examination for fecal leukocytes, red blood cells, and lactoferrin can be a helpful indicator of the former. inflammatory diarrhea can be caused by shigella, salmonella, carnpylobacter, v parahaemolyticus, k: enterocolitica, eiec, eaec, c. difjcile, necrotizing enterocolitis, antibioticassociated colitis, and allergic colitis (i.e., milk or soy intolerance). noninflammatory causes of diarrhea include etec, epec, rotaviruses, enteric adenoviruses, calicivirus, astrovirus, g. larnblia and cryptosporidium. although supportive fluid therapy is mandatory for all types of diarrhea, the brief examination for fecal leukocytes and red blood cells can direct the diagnostic and therapeutic approach. pathogens such as shigella, salmonella, and ehec can cause watery or bloody diarrhea, depending on the specific host-pathogen interaction and the pathogenic mechanisms involved. some of the noninfectious diseases responsible for neonatal diarrhea are listed in table the united states and panama food based oral rehydration salt solutions for acute childhood diarrhoea international study group on reduced osmolality ors solution. multicentre evaluation of reduced-osmolality oral rehydration salts solution antimicrobial resistance and enterotoxin production among isolates of escherichia coli in the far east high-molecular-weight plasmid correlates with escherichia coli invasiveness shigella guanabara, tip serologico destacado do grupo b ceylonensis-dispar a study of specific e. coli infections occurring in a unit for surgical neonates molecular characterization of strains of enteroinvasive escherichia coli untersuchungen zur kiologie der durchfallserkrankungen des sauglings a study of e. coli mutable from an outbreak of diarrhea in the new-born isolation of antigenically homogenous strains of bart. coli neopolitanum from summer diarrhea of infants slide agglutination of bacterium coli var. neopolitanum in summer diarrhea a complete somatic antigen common to sahone~la adelaide, escherichia coli-gomez and escherichia coli ll:b an outbreak of infantile gastroenteritis in aberdeen epidemic gastroenteritis of infants in aberdeen during escherichia strains from infantile epidemic gastroenteritis identification of enterobacteriaceae association of escherichia coli sero- . gastroenteritis due to escherichia coli enteropathogenic escherichia coli serotype ol :hnt isolated from preterm neonates in nairobi, kenya bray's discovery of pathogenic esch. coli as a cause of infantile gastroenteritis cross-infection in infantile gastroenteritis acute intestinal infections of nondysenteric etiology protracted diarrhea of infancy treated by intravenous alimentation. . clinical studies of infants the association of escherichia coli (serotypes olll:b and :bs) with cases of acute infantile gastroenteritis in jerusalem die mehrfachinfektionen mit dyspepsie-coli, ihre beurteilung in statistischer, bakteriologischer und klinischer sicht epidemic of infantile gastroenteritis due to eschm'chia coli :bs with methemoglobinemic cyanosis treatment of diarrhea in malnourished infants and children. a double-blind study comparing ampicillin and placebo prophylactic antimicrobial agents-panel. statement of panelist serotypes of escherichia coli in normal stools gastroenteritis in infants associated with specific serotypes of escherichia coli. i. incidence of specific escherichia coli serotypes and :b in the pittsburgh area multiple intestinal infection fecal leukocytes in diarrheal illness measurement of fecal lactoferrin as a marker of fecal leukocytes and inflammatory enteritis a rapid test for infectious and inflammatory enteritis fluorescent antibody techniques for salmonella and other enteric pathogens colistin suppression of escherichia coli in stools. i. control of a nosocomial outbreak of diarrhea caused by neomycin-resistant escherichia coli olll:b genetic and phenotypic analysis of escherichia coli with enteropathogenic characteristics isolated from seattle children comparison of two assay methods for patterns of adherence to hep- cells of escherichia coli from patients with diarrhea an elisa for the detection of localized adherent classic enteropathogenic escherichia coli serogroups actin accumulation at sites of bacterial adhesion to tissue culture cells: basis of a new diagnostic test for enteropathogenic and enterohemorrhagic escherichia coli yearbook of pediatrics use of an oral elemental diet in infants with severe intractable diarrhea controlled trial of orally administered lactobacilli in acute infantile diarrhea use of antibiotics in acute gastroenteritis among infants in hospital incidence of antibiotic resistance and r-factors among gram-negative bacteria isolated from the neonatal intestine antibiotic resistance of fecal escherichia coli. a comparison of samples from children of low and high socioeconomic groups transferable antibiotic resistance in enterobacteriaceae: relationship to the problems of treatment and control of coliform enteritis changing pattern of the antimicrobial susceptib of escherichia coli in neonatal infections resistance to antimicrobial drugs-a worldwide calamity discovery and development of new antibiotics: the problem of antibiotic resistance american academy of pediatrics and american college of obstetricians and gynecologists antibacterial effectiveness of routine handwashing mdtistate outbreak of escherichia coli :h infections from hamburgers. mmwr morb mortal wkly rep the emergence of escherichia coli h infection in the united states outbreaks of enterohemorrhagic escherichia coli :h infection by two different genotype strains in japan a nationwide case-control study of escherichia coli h infection in the united states environmental and food safety aspects of escherichia coli :h infections in cattle epidemiology and spectrum of disease of escherichia coli hemolytic-uremic syndrome associated with escherichia coli :h enteric infections-united states transmission of escherichia coli :h infection in minnesota child day-care facilities an outbreak of diarrhea and hemolytic uremic syndrome from escherichia coli :h in freshpressed apple cider pathogenesis of shigella diarrhea: evidence for a developmentally regulated glycolipid receptor for shigatoxin involved in the fluid secretory response of rabbit small intestine pathogenesis of shiga toxin-induced hemolytic uremic syndrome shiga-toxin-converting bacteriophages two distinct toxins active on vero cells from escherichia coli antigenic heterogeneity of escherichia coli verotoxins a plasmid of enterohemorrhagic escherichia coli :h is required for expression of a new h b r i a l antigen and for adhesion to epithelial cells a dna probe to identlfy enterohemorrhagic escherichia coli of :h and other serotypes that cause hemorrhagic colitis and hemolytic uremic syndrome methods for detection of stec in humans. an overview shiga toxin-producing escherichia coli in children with diarrhea: a prospective point-of-care study escherichia coli :h : clinical, diagnostic, and epidemiological aspects of human infection the risk of the hemolyticuremic syndrome after antibiotic treatment of escherichia coli :h infections risk of hemolytic uremic syndrome after antibiotic treatment of escherichia coli h enteritis: a meta-analysis enteroaggregative escherichia coli typical enteroaggregative escherichia coli are the most prevalent pathotypes causing diarrhea in mongolian children a sensitive and specific dna probe to identify enteroaggregative escherichia coli, a recently discovered diarrheal pathogen the export of coat protein from enteroaggregative escherichia coli by a specific atp-binding cassette transporter system pathogenicity of enteroadherent escherichia coli in adult volunteers heterogeneity of enteroaggregative escherichia coli virulence demonstrated in volunteers laboratory investigation of enteroaggregative escherichia coli untypeab e:hlo associated with a massive outbreak of gastrointestinal illness enteroaggregative escherichia coli and outbreaks of gastroenteritis in uk enteroaggregative e. coli associated with an outbreak of diarrhea in a neonatal nursery ward identification of a protein with toxigenic activity produced by enteroaggregative escherichia coli. abstracts of the general meeting of the enteroaggregative escherichia coli associated with persistent diarrhea in a cohort of rural children in india enteroaggregative escherichia coli and salmonella associated with non-dysenteric persistent diarrhea association of escherichia coli hep- adherence patterns with type and duration of diarrhoea persistent diarrhea in northeast brazil: etiologies and interactions with malnutrition use of pcr to identify enteroaggregative escherichia coli as an important cause of acute diarrhoea among children living in calcutta, india hep- -adherent escherichia coli strains associated with acute infantile diarrhea, siio paulo age-specific prevalence of escherichia coli with localized and aggregative adherence in venezuelan infants with acute diarrhea heterogeneous virulence of enteroaggregative escherichia coli strains isolated from children in southwest nigeria adherence of non-enteropathogenic escherichia coli to hela cells prevalence of enteroaggregative escherichia coli among children with and without diarrhea in switzerland enteroaggregative and enterotoxigenic escherichia coli among isolates from patients with diarrhea in austria acute and chronic diarrhoea and abdominal colic associated with enteroaggregative escherichia coli in young children living in western europe a study of infectious intestinal disease in england microbiological findings in cases and controls unpublished observations markers of enteric inflammation in enteroaggregative escherichia coli diarrhea in travelers detection of enteroaggregative escherichia coli with formalin-preserved hep- cells improved detection of enteroaggregative escherichia coli using formalin-fixed hep- cells successful treatment of diarrheal disease associated with enteroaggregative escherichia coli in adults infected with human immunodeficiency virus azithromycin found to be comparable to levofloxacin for the treatment of u s travelers with acute diarrhea acquired in mexico rifaximin versus ciprofloxacin for the treatment of traveler's diarrhea: a randomized, double-blind clinical trial molecular characterization of a fimbrial adhesin, f , mediating diffuse adherences of diarrheaassociated escherichia coli to hep- cells diffuse and enteroaggregative patterns of adherence of enteric escherichia coli isolated from aboriginal children from the kimberley region of western australia enteropathogens associated with acute and persistent diarrhea in bangladeshi children < years of age characterization of the roles of hemolysin and other toxins in enteropathy caused by alpha-hemolytic escherichia coli linked to human diarrhea edwards and ewing's identification of enterobacteriaceae salmonella enteritidis bacteremia in childhood salmonella bacteremia in the first year of life salmonella dublin infections in the united states, - salmonella entry into host cells: the work in concert of type secreted effector proteins molecular pathogenesis of salmonella enterica serotype typhimurium-induced diarrhea functions and effectors of the salmonella pathogenicity island type secretion system salmonella typhirnun'um bacteremia: association with the virulence plasmid pathogenesis of salmonellosis: studies of fluid secretion, mucosal invasion, and morphologic reaction in the rabbit ileum probing for enterotoxigenicity among the salmonellae: an evaluation of biological assays pathogenesis of experimental salmonellosis: inhibition of protein synthesis by cytotoxin cytotoxin production by salmonella strains: quantitative analysis and partial characterization electron microscope studies of experimental salmonella infection. i. penetration into the intestinal epithelium by s. typhimurium bactericidal activity of fractionated granule contents from human polymorphonuclear leukocytes: antagonism of granule cationic proteins by lipopolysaccharide role of charge and hydrophobic interaction in the action of the bactericidallpermeability increasing protein of neutrophils on gram-negative bacteria resistance to intraceuular infection host parasite relations in mouse typhoid enhancement in vitro of the low interferon-gamma production of leukocytes from human newborn infants generation of gamma interferon responses in murine peyer's patches following oral immunization severe mycobacterial and salmonella infections in interleukin- receptor-deficient patients typhoid fever: pathogenesis and immunologic control salmonella gastroenteritis in rhesus monkeys pathology of the alimentary tract of s. typhimurium food poisoning the rectal biopsy appearances in salmonella coliris isolation of salmonella from poultry, poultry products and poultry processing plants in massachusetts pet turtle-associated salmonellosis-puerto rico salmonella infection acquired from reptilian pets iguanas and salmonella marina infection in children: a reflection of the increasing incidence of reptileassociated salmonellosis in the united states human salmonellosis associated with exotic pets paratyphoid fever and baker's confectionery: analysis of epidemic in south wales salmonellosis in a premature nursery unaccompanied by diarrheal diseases salmonella isolates from humans in the united states a review of human salmonellosis. i. infective dose. rev infect dis salmonellosis of the newborn with transmission by delivery room resuscitators salmonella typhimurium infection dustborne in a children's ward cross-infection in hospital due to salmonella derby outbreak of s. ryphimurium gastroenteritis due to an imported strain resistant to ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole in a nursery a salmonella newport outbreak in a premature nursery with a one year follow up salmonella infections of the newborn infant infections with s. typhimurium in the newborn an epidemic of s. panama infections in infants studies of the acute diarrheal diseases. xvi. an outbreak of s. typhimurium infection among newborn premature infants an outbreak of paratyphoid b fever in a nursery of a small hospital mass invasion of salmonellae in a babies' ward outbreak of gastroenteritis due to s. virchow in a maternity hospital typhimurium epidemic in newborn nursery nosocomial infection of nurslings caused by multiple drug-resistant strain of s. typhimuriumutilization of a new typing method based on iysogeny of strains heidelberg enteritis-an outbreak in the neonatal unit of harare central hospital outbreak of s. eimsbuettel in newborn infants spread by rectal thermometers epidemic salmonellosis: a -month study of cases of s. oranienburg infection nursery salmonellosis: delayed recognition due to unusually long incubation period analises clinico-epidemiologica de un brote de infeccion por s. bredeney en recien nacidos a nursery outbreak with s. newport. indian pediatr salmonella enteritidis infections in infancy with special reference to a small nosocomial epidemic nosocomial s. typhimurium epidemic in a neonatal special care unit protracted infection with s. bareilly in a maternity hospital salmonella muenchen infections in newborns and small infants institutional salmonellosis epidemic salmonellosis in hospitals and institutions salmonellosis in infants: the importance of i n t r a f a d a l transmission multiple-resistant salmonella group g outbreak in a neonatal intensive care unit nosocomial outbreak of salmonella typhimurium infection in a nursery intensive care unit (nicu) and paediatric ward neonatal diarrhea due to s. paratyphi b salmonellosis as a public health problem in wartime observation on the transmission of salmonellosis in man chronic salmonellosis in infancy association of salmonella enteritis with operations on the stomach severe salmonella gastroenteritis associated with hypochlorhydria infektion eines neugeborenen durch s. typhimurium-haltige muttermilch human milk contaminated with s. konbus. a cause of nosocomial illness in infants transmission of lethal salmonella senftenberg from mother's breast-milk to her baby a milkborne outbreak of s. dublin an island-wide epidemic of salmonellosis in trinidad traced to contaminated powdered milk salmonella anatum infection in infants linked to dried milk interregional foodborne salmonellosis outbreak due to powdered infant formula contaminated with lactose-fermenting salmonella virchow an epidemic among infants caused by s. muenchen rectal thermometer-mediated crossinfection with s. wadnvorth in a pediatric ward transmission of s. worthington by oropharyngeal suction in hospital neonatal unit an outbreak of salmonella enteritidis in a maternity and neonatal intensive care unit plasmid profiles and salmonella epidemiology etude clinique et bacttriologique d'une tpidemie de salmonellose en milieu hospitalier (s. oranienburg) a protracted hospitalassociated outbreak of salmonellosis due to a multiple antibioticresistant strain of s. indiana an extensive outbreak of gastroenteritis caused by s. newport a large outbreak of foodborne salmonellosis on the navajo nation indian reservation: epidemiology and secondary transmission typhoid fever in children typhoid carriage in pregnancy with infection of neonate salmonella infection presenting as hematochezia on the first day of life gastroenteritis with necrotizing enterocolitis in premature babies etiology and risk factors of severe and protracted diarrhea monosaccharide intolerance and hypoglycemia in infants with diarrhea. . clinical course of infants acquired carbohydrate intolerance and cow milk protein-sensitive enteropathy in young infants chronic protracted diarrhea of infancy: a nutritional disease salmonella bacteremia: reports to the centers for disease control, - extraintestinal salmonellosis in a children's hospital salmonella sepsis in infancy incidence of salmonella bacteremia in infants with salmonella gastroenteritis predictors for extraintestinal infection of salmonella enteritis in thailand predictors of persistently positive blood cultures in children with "occult" salmonella bacteremia salmonella infections in infants in hawaii extraintestinal manifestations of salmonella infections neonatal salmonella meningitis complicated by cerebral abscesses salmonella meningitis in infants lisferia and gram-negative bacillary meningitis in new york city - salmonelln meningitis in infancy isolation of s. typhimurium from cephalohematoma and osteomyelitis ober eine salmonella-osteomyelitis in rahmen einer s. typhimurium epidemie auf einer neugeborenen station infectious diarrhea of the newborn caused by an unclassified species of salmonella the microbiological and epidemiological properties of infections caused by s. enteritidis suppurative mastitis in infants infections with bacterium enteritidis in infancy with the triad of enteritis, cholecystitis and meningitis endophthalmitis due to s. enteritidis nontyphoidal salmonella pericarditis: a case report and review of the literature neonatal typhoid fever typhoid clinical analysis of cases salmonella septic abortion typhoid fever in pregnancy typhoid fever complicating pregnancy typhoid fever and pregnancy with special references to fetal infection typhoid fever benign bacteremia caused by s. typhi and s. paratyphi in children younger than two years typhoid and paratyphoid fever in hospitalized children in thailand fecal leukocytes in enteric infections efficiency of cultures of rectal swabs and fecal specimens in detecting salmonella carriers: correlation with numbers of salmonella excreted treatment of salmonella gastroenteritis in infants. the significance of bacteremia antibody response to the somatic antigen of s. newport in premature infants production of and h agglutinins by a newborn infant infected with s. saint-paul an outbreak of salmonellosis associated with a fatality in a healthy child a large dose and severe illness molecular and epidemiological study of salmonella clinical isolates effect of antibiotic therapy in acute salmonellosis on the fecal excretion of salmonellae effect of antibiotic treatment on duration of excretion of s. typhimurium by children. bmw a controlled trial comparing trimethoprimlsulfamethoxazole, ampicillin, and no therapy in the treatment of salmonella gastroenteritis in children failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis: experience during an outbreak in health care workers treatment of acute cases of salmonella infection and salmonella carriers with ampicillin and neomycin association for study of infectious diseases. effect of neomycin in noninvasive salmonella infections of the gastrointestinal tract treatment of salmonella gastroenteritis with ampicillin, amoxicillin, or placebo quinolone antibiotics in the treatment of salmonella infections a review of human salmonellosis. . duration of excretion following infection with nontyphi salmonella ciprofloxacin for treatment of severe typhoid fever in children ciprofloxacin resistance in clinical isolates of salmonella typhimurium obtained from two patients infection with s. heidelberg. an outbreak presumably not foodborne s. heidelberg enteritis and bacteremia. an epidemic on two pediatric wards changes in antimicrobial resistance of salmonella isolated from humans in the united states multiply resistant nontyphoidal salmonella gastroenteritis in children increase in antimicrobialresistant salmonella infections in the united states, - emergence of multidrugresistant salmonella enterica serotype typhimurium dt infections in the united states alarming increases in multi-drug resistant s. typhimurium in southern india clonal distribution of resistance plasmid carrying s. typhimurium, mainly in the middle east problems of salmonella infections in a hospital in kenya antimicrobial resistance among salmonella isolates from hospitals in rome plasmid encoded trimethoprim resistance in multi-resistant epidemic s. typhimurium phagotypes and in britain trimethoprim-resistant salmonella salmonella strains resistant to multiple antibiotics: therapeutic implications treatment of typhoid fever and other systemic salmonellosis with cefotaxime, ceftriazone, cefoperazone, and other newer cephalosporins once daily ceftriaxone vs. chloramphenicol for treatment of typhoid fever in children cefamandole treatment of salmonella bacteremia typhoid fever: successful therapy with cefoperazone biliary excretion and pharmacokinetics of cefoperazone in humans treatment of salmonella meningitis and brain abscess with the new cephalosporins: two case reports and a review of the literature intravenous immunoglobulin in the treatment of salmonella typhimurium infections in preterm neonates salmonellosis in nurses: lack of transmission to patients comparison of enteric coated capsules and liquid formulation of ty la typhoid vaccine in randomised controlled field trial safety and immunogenicity of salmonella typhi ty la vaccine in young thai children immunogenicity of s. typhi ty la vaccine for young children breast-feeding and salmonella infection polynucleotide sequence divergence among strains of e. coli and closely related organisms involvement of a plasmid in the invasive ability of shigellaflexneri host-pathogen interactions: the seduction of molecular cross talk shigella interaction with intestinal epithelial cells determines the innate immune response in shigellosis identification and characterization of virulence associated, plasmid-coded proteins of shigella spp. and enteroinvasive e. coli molecular alteration of the -megadalton plasmid associated with the loss of virulence and congo red binding activity in shigellaflexneri epithelial cell penetration as an essential step in the pathogenesis of bacillary dysentery experimental approach in studies on pathogenesis of bacillary dysentery-with special reference to the invasion of bacilli into intestinal mucosa plasmid-mediated invasiveness of "shigella-like" escherichia coli molecular comparison of virulence plasmids in shigella and enteroinvasive escherichia coli alterations in the pathogenicity of escherichia coli k- after transfer of plasmids and chromosomal genes horn shigelhflerneri complete genome sequence and comparative genomics of shigella flexneri serotype a strain virulence associated chromosomal loci of s. j aneri identified by random tn insertion mutagenesis hela cell invasiveness and antigen of shigella fkxneri as separate and prerequisite attributes of virulence to evoke keratoconjunctivitis in guinea pigs production of shiga toxin and other cytotoxins by serogroups of shigella shigella toxin inhibition of binding and translation of polyuridylic acid by escherichia coli ribosomes inhibition of protein synthesis in intact hela cells by shigelln dysenteriae toxin the siga gene which is borne on the she pathogenicity island of shigella flexneri a encodes an exported cytopathic protease involved in intestinal fluid accumulation the relation between production of cytotoxin and clinical features in shigellosis shigellosis outbreak associated with swimming pathogenesis of shigella dysenteriae (shiga) dysentery the response of man to virulent shigellaflexneri a shigella infections and vaccines: experiences from volunteer and controlled field studies management and prevention of infectious diseases in day care the children of santa maria cauque: a prospective field study of health and growth surveillance of patients attending a diarrhoeal disease hospital in bangladesh studies in shigellosis. v. the relationship of age to the incidence of shigella infections in egyptian children, with special reference to shigellosis in the newborn and infant in the first six months of life breast-feeding as a determinant of severity in shigellosis shigella infections in breast fed guatemalan indian neonates shigellosis in neonates and young infants neonatal shigellosis shigella infection in african and indian children with special reference to shigella septicemia enteric infection due to campylobacrer, ersinia, salmonella and . kraybill en, controni g. septicemia and enterocolitis due to . moore ee. shigella sonnei septicemia in a neonate s. sonnei septicemia in a neonate: a case report shigellosis in the first week of life bacillary dysentery in a newborn infant sonnei infection at term and its transfer to the newborn an isolated case of shigellosis in the newborn nursery bacillary dysentery acquired at birth shigellosis in a neonate extraintestinal manifestations of shigellosis convulsions as a complication of shigellosis in children convulsions in childhood shigellosis meningitis and septicemia due to shigella in a newborn infant lethal toxic encephalopathy due to childhood shigellosis in a developed country the association of shiga toxin and other cytotoxins with the neurologic manifestations of shigellosis shiga bacillus dysentery associated with marked leukocytosis and erythrocyte fragmentation shigella dysentery with secondary klebsiella sepsis shigella septicemia: prevalence, presentation, risk factors, and outcome coliform septicemia complicating shigellosis in children shigella septicemia in the newborn infant shigellosis with bacteremia: a report of two cases and a review of the literature blood-stream invasion with s. sonnei in an asymptomatic newborn infant neonatal shigellosis with bowel perforation colonic perforation in shigella dysenteriae infection fatal s. sonnei septicemia in an adult complemented by marrow aplasia and intestinal perforation association of pneumonia with under-nutrition and shigellosis fulminating, rapidly fatal shigellosis in children clinical, statistical observations on ekiri and bacillary dysentery. a study of cases the etiology of ekiri, a highly fatal disease of japanese children chronic vulvovaginitis in children due to s. flexneri shigella vaginitis: report on patients and review of the literature shigella keratitis: a report of two cases and a review of the literature causes of death and the histopathologic findings in fatal shigellosis. pediatr infect dis j : , . pediatric population in a newborn infant death in shigellosis: incidence and risk factors in hospitalized patients differential clinical features and stool findings in shigellosis and amoebic dysentery isolation of shigellae. . comparison of plating media and enrichment broths shigellosis: a continuing global problem. dacca, bangladesh, international centre for diarrhoeal disease research double-blind treatment study of shigellosis comparing ampicillin, sulfadiazine, and placebo optimal dosage of ampicillin in shigellosis comparative efficacy of nalidixic acid and ampicillin for severe shigellosis serum immune response to shigella protein antigens in rhesus monkeys and humans infected with shigella spp detection of shigella in feces using dna amplification distribution and spread of colonic lesions in shigellosis: a colonoscopic study fluorescent antibody and histological studies of vaccinated control monkeys challenged with shigella flexneri experimental shigella infections. iv. fluorescent antibody studies of an infection in guinea pigs plasmid characterization in the investigation of an epidemic caused by multiply resistant s. dysenteriae type in central africa plasmid characterization of shigelh spp. isolated from children with shigellosis and asymptomatic excretors antimicrobial resistance of shigella isolates in the usa the importance of international travelers shigellae with transferable drug resistance: outbreak in a nursery for premature infants antimicrobial resistance of shigella isolates in bangladesh, - increasing frequency of strains multiply resistant to ampicillin, trimethoprimlsulfamethomle, and nalidixic acid comparison of cefador and ampicillin in the treatment of shigellosis failure of furazolidone therapy on shigellosis comparative efficacy of cephalexin and ampicillin for shigellosis and other types of acute diarrhea in infants and children amoxicillin less effective than ampicillin against shigella in vitro and in vivo: relationship of efficacy to activity in serum clinical and bacteriological evaluation of antibiotic treatment in shigellosis antibiotic treatment of acute shigellosis: failure of cefamandole compared to trimethopriml sulfamethoxazole and ampicillin comparative treatment of shigellosis with trimethoprindsulfamethoxazole and ampicillin trimethoprid sulfamethoxazole therapy for shigellosis comparison of trimethopriml sulfamethoxazole and ampicillin for shigellosis in ambulatory patients single dose ampicillin therapy for severe shigellosis in bangladesh comparative efficacy of ceftriaxone and ampicillin for treatment of severe shigellosis in children comparative efficacies of single intravenous doses of ceftriaxone and ampicillin for shigellosis in a placebo-controlled trial treatment of shigellosis. . comparison of one-or two-dose ciprofloxacin with standard -day therapy activities of new fluoroquinolones against shigella sonnei adverse effect of lomotil therapy in shigellosis community based evaluation of the effect of breast feeding on the risk of microbiologically confirmed or clinically presumptive shigellosis in bangladeshi children interruption of shigellosis by handwashing interbacterial transfer of r-factor in the human intestine: in vitro acquisition of r-factor mediated kanamycin resistance by a multi-resistant strain of s. sonnei report of the departmental committee appointed by the board of agriculture and fisheries to inquire into epizootic abortion some morphological and biochemical characters of the spirilla (vibriofetus, n. spp.) associated with disease of the fetal membranes in cattle vibrios (vibrio jejuni, n. spp.) associated with intestinal disorders of cows and calves infectivity of three vibrio fetus biotypes for gallbladder and intestines of cattle, sheep, rabbits, guinea pigs, and mice septicemie grave au cours de la grossesse due un vibrion. avortement consecutif perinatal mortality caused by vibrio fetus: review and analysis campylobacter fetus infections in children vibriofetus infection in man. i. ten new cases and some epidemiologic observations campylobacteriosis in man: pathogenic mechanisms and review of bloodstream infections teneur en bases de i'adn et classification des vibrions related vibrio in stools campylobacter enteritis: a "new" disease communicable disease surveillance centre and the communicable diseases (scotland) unit. campylobacter infections in britain campylobacter enteritis in central africa campylobacter enteritis in sweden cumpylobacter enteritis in children campylobacter gastroenteritis in children campylobacter enteritis acute enteritis due to related vibrio: first positive stool cultures campylobacter enteritis campylobacter enteritis: clinical and epidemiologic features campylobacter enteritis campylobacter enteritis in south australia campylobacter colitis in infants the genus campylobacter: a decade of progress cohort study of intestinal infection with campylobacter in mexican children two cases of campylobacter mucosalis enteritis in children relationships among catalase-positive campylobacters determined by deoxyribonucleic acid-deoxyribonucleic acid hybridization nucleic acids in the classification of campylobacters bovine campylobacteriosis: a review bovine vibriosis: a brief review une affection meconnue de la grossesse: i'infection placentaire a "vibrio fetus campylobacter infection in the neonate: case report and review of the literature vibrio f e t u j a cause of human abortion vibrio fetus vibrio fetus meningoencephalitis human vibrio fetus infection: report of two dissimilar cases septicemia due to campylobacter fetus in a newborn infant with gastroenteritis campylobacter spp. isolated from the cervix during septic abortion. case report. br i obstet gynaecol campylobacter meningitis in childhood abortion and perinatal sepsis associated with campylobacter infection early onset campylobacter sepsis in a neonate human infections with vibrio fetus and a closely related vibrio campylobacter fetus subspeciesfetus bacteremia the biotype and biotype distribution of clinical isolates of campylobacter jejuni and campylobacter coli over a three-year period serotype distribution of campylobacter jejuni and campylobacter coli isolated from hospitahzed patients with diarrhea in central australia results of the first year of national surveillance of campylobacter infections in the united states distribution and serotypes of campylobacter jejuni and campylobacter coli in enteric campylobacter strains isolated from children in the central african republic vibrionic enteritis in infants lnfection due to a "related vibrio human infection with vibriofetus campylobacter infection of premature baby campylobacter in a mother and baby neonatal campylobacter enteritis campylobacter jejuni/coli meningitis in a neonate campylobacter gastroenteritis in neonates perinatal campylobacter fetus ss. jejuni enteritis a case of premature labour due to campylobacter jejuni infection campylobacter jejuni in newborns: a cause of asymptomatic bloody diarrhea campylobacter enterocolitis in a neonatal nursery campylobacter enteritis and bloody stools in the neonate hospital epidemic of neonatal campylobacter jejuni infection nosocomial outbreak of campylobacter jejuni meningitis in newborn infants campylobacter jejuni diarrhea in a -day old male neonate an outbreak of campylobacter jejuni infection in a neonatal intensive care unit carnpylobacter infections in pregnancy: case report and literature review midtrimester abortion associated with septicaemia caused by campylobacter jejuni campylobacter septic abortion campylobacter jejuni infection as a cause of septic abortion campylobacter enteritis associated with recurrent abortions in agammaglobulinemia campylobacrer coli septicaemia associated with septic abortion rectal bleeding caused by campylobacter jejuni in a neonate cholera-like enterotoxin produced by campylobacter jejuni: characterization and clinical significance toxins produced by campylobacter jejuni and campylobacter coli production of a unique cytotoxin by campylobacter jejuni campylobacter jejuni and campylobacter coli production of a cytotonic toxin immunologically similar to cholera toxin purification of carnpylobacter jejuni enterotoxin pathogenic properties of campylobacterjejuni: assay and correlation with clinical manifestations detection of a novel campylobacter cytotoxin experimental studies of campylobacter enteritis campylobacterjejuni colitis in gnotobiotic dogs experimental campylobacter diarrhea in chickens campylobacrer jejuni diarrhea model in infant chickens experimental gastroenteritis in newly hatched chicks infected with campylobacter jejuni experimental infection of rhesus monkeys with a human strain of campylobacter jejuni the role of gut flora and animal passage in the colonization of adult mice with campylobacter jejuni colonization of mice by campylubacter jejuni animal-passed, virulenceenhanced campylobacter jejuni causes enteritis in neonatal mice experimental infection of hamsters with campylobacter jejuni dohoo ir pathogenicity of c. jejuni isolates from animals and humans vibriofetus meningitis in a newborn infant fecal leucocytes in campylobacterassociated diarrhoea in infants campylobacter colitis acute colitis caused by campylobacterfetus spp. jejuni the laboratory recognition of vibrio fetus and a closely related vibrio isolated from cases of human vibriosis campylobactet: pathogenicity and significance in foods contamination of red meat carcasses by campylobacter fetus subsp. jejuni water-borne outbreak of campylobacter gastroenteritis water-borne outbreaks of campylobacter enteritis carnpylobacter jejuni: incidence in processed broilers and biotype distribution in human and broiler isolates the extent of surface contamination of retailed chickens with campylobacter jejuni serogroups campylobacter jejuni enteritis associated with raw goat's milk a point-source outbreak of campylobacteriosis associated with consumption of raw milk campylobacter infection associated with raw milk campylobacter enteritis at a university: transmission from eating chicken and from cats risk factors for campylobacter infection in infants and young children: a matched case-controled study isolation of campylobacterfetus from recent cases of human vibriosis neonatal sepsis by campylobacter jejuni: genetically proven transmission from a household puppy outbreaks of campylobacter enteritis in two extended families: evidence for person-to-person transmission enteritis due to "related vibrio" in children attempts to transmit campylobacter enteritis to dogs and cats experimental campylobacter jejuni infection in humans molecular typing of campylobacter jejuni isolates involved in a neonatal outbreak indicates nosocomial transmission prospective study of enteric campylubacter infections in children from birth to months in the central african republic campylobacter infections in human beings campylubacter enteritis: clinical and epidemiological features related vibrios in africa campylobacter en enteritis campylobacter infections in soweto campylobacter infections in pregnancy. case report and literature review epidemiologic application of pulsed-field gel electrophoresis to an outbreak of campylobacterfetus meningitis in a neonatal intensive care unit nosocomial meningitis due to campylobacterfetus subspecies fetus in a neonatal intensive care unit nosocomial meningitis due to campylobacter fetus subspecies fetus in a neonatal intensive care unit campylobacter fetus subspecies jejuni (vibrio fetus) from commercially processed poultry broiler chickens as potential source of campylobacter infections in humans campylobacter enteritis associated with a healthy cat campylobacter jejuni enteritis transmitted from cat to man campylobacter enteritis associated with canine infection campylobacter fetus infection in human subjects: association with raw milk campylobacter enteritis in a household olorado campylobacter enteritis associated with the consumption of unpasteurized milk a gastroenteritis outbreak probably due to bovine strain of vibrio campylobacter enteritis associated with contaminated water evaluation of methods to distinguish epidemic-associated campylobacter strains early treatment with erythromycin of campylobacter jejuni associated dysentery in children campylobacter urinary tract infection campylobacter jejuni bacteraemia in children with diarrhea in bangladesh report of six cases campylobacter bacteremia in children hla-b -negative arthritis related to campylobacter jejuni enteritis in three children and two adults guillain-barre syndrome and campylobacter jejuni: a serological study guillain-barre syndrome associated with campylobacter infection section i bacterial infections acute erosive reactive arthritis associated with cammlobacter jejuni-induced colitis reactive arthritis associated with campylobacter enteritis persistent campylobacter jejuni infections in patients infected with human immunodeficiency virus (hiv) chronic diarrhea and bacteremia caused by campylobacter lari in a neonate comparison of six media, including a semisolid agar for the isolation of various campylobacterspecies from stool specimens darkfield microscopy of human feces for presumptive diagnosis of campylobacter fetus subsp. jejuni enteritis specific detection of campylobacter jejuni and campylobacter coli by using polymerase chain reaction in vitro susceptibilities of aerotolerant campylobacter isolates to antimicrobial agents susceptibilities of f -lactamase-positive and -negative strains of campylobacter coli to b-lactam agents characterization of erythromycin resistance in campylobacter jejuni and campylobacter coli high-level quinolone resistance in clinical isolates of campylobacter jejuni complete biliary obstruction due to erythromycin estolate administration in an infant use of azithromycin for the treatment of campylobacter enteritis in travelers to thailand, an area where ciprofloxacin resistance is prevalent azithromycin resistance in campylobacter jejuni and campylobacter coli in vitro susceptibility of quinolone-resistant campylobacterjejuni to new macrolide antibiotics immunoglobulin a antibodies directed against campylobacter jejuni flagellin present in breast-milk virulence factors of clostridium diflicile enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion molecular characterisation of clostridium diflicile toxins a and b nonantibiotic-associated enterocolitis caused by closrridium dificile in an infant pseudomembranous colitis: presence of clostridial toxin role of clostridium diflicile in a case of nonantibiotic-associated pseudomembranous colitis nonantibiotic-associated pseudomembranous colitis due to toxin producing clostridia clostridium diflicile associated with pseudomembranous colitis cultures for c. dificile in stools containing a cytotoxin neutralized by c. sordellii antitoxin epidemiologic markers of clostridium diflicile isolation of c. diflicile from the environment and contacts of patients with antibiotic-associated colitis the prevalence of c. dificile and toxin in a nursery population: a comparison between patients with necrotizing enterocolitis and an asymptomatic group acquisition of clostridium diflicile and clostridium diflicile-associated diarrhea in hospitalized patients receiving tube feeding a randomized crossover study of disposable thermometers for prevention of clostridium diflicile and other nosocomial infections prospective controlled study of vinyl glove use to interrupt clostridium dificile transmission nosocomial c. dificile reservoir in a neonatal intensive care unit clostridium diflicile-associated diarrhea diagnosis and treatment of clostridium diflicile colitis shigella dysenteriae . a forgotten cause of pseudomembranous colitis dificile toxin in asymptomatic neonates incidence and origin of c. diflicile in neonates is c. dificile pathogenic in infants? neonatal antibiotic-associated colitis is clostridium difficile a pathogen in the newborn intensive care unit? a prospective evaluation multicenter evaluation of the clostridiurn diflicile tox n b test identification of toxin a-negative, toxin b-positive clostridium diflicile by pcr comparison of restriction enzyme analysis, arbitrarily primed pcr, and protein profile analysis typing for epidemiologic investigation of an ongoing clostridium dificile outbreak prospective randomized trial of metronidazole vs. vancomycin for c. difficile associated diarrhoea and colitis comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of clostridum difficile-associated diarrhea antibiotic-associated colitis due to c. difficile: double-blind comparison of vancomycin with bacitracin oral bacitracin vs. vancomycin therapy for c. diflicile-induced diarrhea relapse following oral vancornycin therapy of antibiotic-associated pseudomembranous colitis neutralizing activity against c. diflicile toxin in the supernatants of cultures of colostral cells binding of clostridium dificile toxin a to human milk secretory component in vitro and in vivo neutralizing activity of c. diflicile purified toxins a and b by human colostrum and milk diflicile in normal infants and sudden death syndrome: an association with infant formula feeding and the gulf coast vibrio working group. vibrio infections on the gulf coast: results of first year of regional surveillance cholera in the americas: guidelines for the clinician epidemic cholera in the americas the molecular epidemiology of cholera in latin america emergence of a new epidemic strain of vibrio cholerae in bangladesh. an epidemiological study vibrio cholerae in karachi vibrio cholerae bengal in bangkok large epidemic of cholera-like disease in bangladesh caused by vibrio cholerae synonym bengal clinical profile of acute diarrhoea cases infected with the new epidemic strain of vibrio cholerae : designation of the disease as cholera nationwide prevalence of the new epidemic strain of vibrio cholerae bengal in india cholera-a possible endemic focus in the united states cholera in pregnant women neonatal diarrhea caused by vibrio cholerae bengal vibrio cholerae diarrhea and acute renal failure in a three day old infant neonatal diarrhea in a diarrhea treatment center in bangladesh clinical presentation, breastfeeding management and outcome bottle feeding as a risk factor for cholera in infants characteristics of the serum vibriocidal and agglutinating antibodies in cholera cases and in normal residents of the endemic and non-endemic cholera areas maternal cholera immunisation and secretory iga in breast milk response of man to infection with vibrio cholerae. i. clinical, serologic and bacteriologic responses to a known inoculum cholera, non-vibrio cholera, and stomach acid development and testing of a nonradioactive dna oligonucleotide probe that is specific for vibn'o cholerae cholera toxin development of an enzymelabeled oligonucleotide probe for the cholera toxin gene safety and immunogenicity in north americans of a single dose of live oral cholera vaccine cvd -hgr results of a randomized, placebocontrolled, double-blind crossover trial evidence that inactivated oral cholera vaccines both prevent and mitigate vibrio cholerae infections in a cholera-endemic area a review of the current status of enteric vaccines ersinia enterocolitica infections in children ersinia enterocolitica gastroenteritis: a prospective study of clinical, bacteriologic, and epidemiologic features ersinia enterocolitica infections in infants and children, associated with the household preparation of chitterlings clinical and microbiologic characteristics of cutaneous infection with yersinia enterocolitica ersinia enterocolih'ca : an emerging cause of pediatric gastroenteritis in the united states incidence of and lack of correlation between illness and proposed virulence factors ersinia enterocolitica: a frequent seasonal stool isolate from children at an urban hospital in the southeast united states yersinia enterocolitica causing pneumonia and empyema in a child and a review of the literature epidemic yersinia enterocolitica infection due to contaminated chocolate milk prevention of yersinia enterocolitica growth in red blood cell concentrates plasmid-mediated surface fibrillae of y. pseudotuberculosis and y. enterocolitica. relationship to the outer membrane protein yopl and possible importance for pathogenesis factors promoting acute and chronic diseases caused by yersiniae primary structure of heatstable enterotoxin produced by y. enterocolitica neonatal yersinia enterocolitica enteritis yersinia enterocolitica septicemia in normal infants infections due to yersinia enterocolitica serotypes , and : acquired in south florida yersinia enterocolitica septicemia in infants younger than three months of age neonatal yersinia enterocolitica enteritis yersinia enterocolitica septicemia in an infant presenting as fever of unknown origin yersinia enterocolitica septicemia in a normal child yersinia enterocolitica infections in children presentation of yersinia enterocolitica enteritis in children yersinia enterocolitica infection in children polymerase chain reactiongene probe detection system specific for pathogenic strains of yersinia enterocolitica detection of pathogenic yersinia enterocolitica by polymerase chain reaction and digoxigenin-labeled polynucleotide probes in-vitro antimicrobial susceptibility of ersinia enterocolitica isolates from stools of patients in thenetherlandsfrom - yersinia enterocolitica : . antimicrobial resistance patterns, virulence profiles and plasmids antimicrobial susceptibility of pathogenic yersinia enterocolitica isolated in canada from to immunological cross-reactivity of enterotoxins of a. hydrophila and cholera toxin enteropathogenicity of a. hydrophila and e! shigelloides virulence characteristics of aeromonas spp. in relation to source and biotype lnvasiveness of aeromonas spp. in relation to biotype, virulence factors, and clinical features clinical and biochemical sigdcance of toxin production by a. hydrophila cytotonic enterotoxin from aeromonas hydrophila lack of correlation between known virulence properties of a. hydrophila and enteropathogenicity for humans enteropathogenicity of a. hydrophila and i? shigelloides: prevalence among individuals with and without diarrhea in thailand zur frage der bedeutung von aeromonasstammen bei saiiglingsenteritis prevalence, species differentiation, and toxigenicity of aeromonas strains in cases of childhood gastroenteritis and in controls aeromonas-associated gastroenteritis a survey of the incidence of aerornonas in human feces travelers' diarrhea among american peace corps volunteers in rural thailand the characterization and significance of j? shigelloides and a. hydrophila isolated from an epidemic of diarrhea. lndian clinical and microbiological features of a. hydrophila-associated diarrhea diarrhea associated with a. hydrophila aeromonas spp. and their association with human diarrheal disease faecal aeromonas spp. in balinese children gastroenteritis due to aeromonas in pediatrics a. hydrophila-associated diarrhea in a neonate aeromonas-associated gastroenteritis in children phenotypic characteristics of aerornonas species isolated from adult humans recent advances in the study of the taxonomy, pathogenicity, and infectious syndromes associated with the genus aeromonas aeromonas: biology of the organism and diseases in children in vitro susceptibilities of a. hydrophila against new antibiotics antimicrobial susceptibility of aeromonas species isolated from patients with diarrhea aeromonas infections and their treatment plesiomonas enteric infections in the united states two epidemics of diarrhoeal disease possibly caused by i? shigelloides a. hydrophila and j? shigelloides as causes of intestinal infections in vitro and in vivo pathogenicity of i! shigelloides clinical disease spectrum and pathogenic factors associated with p. shigelloides infections in humans neonatal septicemia and meningitis due to plesiomonas shigelloides neonatal plesiomonas shigelloides septicemia and meningitis: a case review plesiomonas shigelloides sepsis and meningoencephalitis in a neonate plesiomonas shigelloides meningitis and septicaemia in a neonate: report of a case and review of the literature biochemical characteristics and a simple scheme for the identification of aeromonas species and plesiomonas shigelloides comparative in vitro activities of selected antimicrobial agents against aeromonas species and i? shigelloides antimicrobial therapy in plesiomonas shigelloide~associated diarrhea in thai children bacillus mucosus infection of the newborn klebsiella strains isolated from diarrheal infants. human volunteer studies klebsiella pseudomembranous enterocolitis beobachtungen a e r die bitiologie der gastroenterocolitiden des sauglings-und kindesalters. . untersuchung der rolle der klebsiella-stamme ober eine enteritis-epidemie bei friihgeborenen,verursacht durch den bacillus klebsiella bacillus mucosus capsulatus" in infantile diarrhea bacillus lactis aerogenes infection in the newborn stomatitis and diarrhea in infants caused by bacillus mucosus capsulatus a new klebsiella type (capsular type ) isolated from feces and urine enterobacter sakazakii infections in neonates associated with intrinsic contamination of a powdered infant formula contamination of infant feeds in a milton milk kitchen nosocomial colonization with kanamycin-resistant klebsiella pneumoniae, types and , in a premature nursery nosocomial colonization with klebsiella, type , in a neonatal intensive-care unit associated with an outbreak of sepsis, meningitis, and necrotizing enterocolitis enterotoxigenic klebsiella pneumoniae in acute childhood diarrhea production of e. coli stalike heat stable enterotoxin by citrobacter freundii isolated from humans citrobacter infections in humans: experience at the seattle veterans administration medical center and a review of the literature kahlich r, webershinke . a contribution to incidence and evaluation of citrobacter findings in man an outbreak of diarrhea due to citrobacter freundii in a neonatal special care nursery gastroenteritis caused by listeria monocytogenes in a private day-care facility series of incidents of listeria monocytogenes non-invasive febrile gastroenteritis involving ready-to-eat meats listeria gastroenteritis-dd syndrome, new pathogen listeria monocytogenes: clinical and experimental update an outbreak of febrile gastroenteritis associated with corn contaminated by listeria monocytogenes an outbreak of gastroenteritis and fever due to listeria monocytogenes in milk noscomial listeria gastroenteritis in a newborn, confirmed by random amplification of polymorphic dna listeria monocytogenes causing hospital-acquired enterocolitis and meningitis in newborn infants listeria meningitis presenting as enteritis in a previously healthy infant: a case report fetal chronic nonspecific enterocolitis with peritonitis in uniovular twins after listeria infection in the mother isolation of enterotoxigenic bacteroides jragilis from bangladeshi children with diarrhea: a controlled study enterotoxigenic bacteroides fragilis: epidemiologic studies of its role as a human diarrhoeal pathogen an enterotoxin of pseudomonas aeruginosa neonatal infections with pseudomonas aeruginosa associated with contaminated resuscitation equipment an epidemic of diarrhea in the newborn nursery caused by a milk-borne epidemic in the community nursery outbreak of severe diarrhoea due to multiple strains of pseudomonas aeruginosa pseudomonas in a glasgow baby unit an outbreak of pseudomonas aeruginosa (pyocyanea) infection in a premature baby unit, with observations on the intestinal carriage of pseudomonas aeruginosa in the newborn serological and biochemical examination of citrobacter koseri strains from clinical specimens concerning the etiological role of bacteria belonging to citrobacter and hafiia genera in children suffering from diseases accompanied by diarrhea, and some of their epidemiological peculiarities the role of paracolobactrum and proteus in infantile diarrhea peritonitis due to the morgani bacillus. with a brief review of literature on the pathogenicity of this organism proteus vulgaris and proteus morgani in diarrheal disease of infants bacillus morgani, type i, in enterocolitis of infants beobachtungen iiber die atiologie der gastroenterocolitiden des sauglings-und kindesalters. . untersuchung der roue der proteus vulgaris-und der proteus mirabilis-stamme epidemiology and etiology of severe infantile diarrhea bacteriological and clinical studies in infantile diarrhoea. . doubtful pathogens: enterobacteriaceae, pseudomonas, alcaligenes and aeromonas the intestinal flora in the etiology of infantile infectious diarrhea the bacteriological considerations of infantile enteritis in sydney beobachtungen iiber die atiologie der gastroenterocolitiden des sauglings-und kindesalters. iv. untersuchung der rolle der proteus morgani-stamme group d streptococci in the faeces of healthy infants and of infants with neonatal diarrhea neonatal enteritis due to providencia organisms infection with the providence type of paracolon bacillus in a residential nursery providence group of organisms in the aetiology ofjuvenile diarrhoea microbial flora of stomach and small intestine in infantile gastroenteritis diarrhoea associated with candida spp.: incidence and seasonal variation prevalence of candida species in nigerian children with diarrhea infantile diarrhea and malnutrition associated with candida in a developing community role of candida in indirect pathogenesis of antibiotic associated diarrhea in infants upper small intestine microflora in diarrhea and malnutrition in nigerian children diarrhea caused by candida beitrage zur frage der moniliasis in sauglingdter recovery from disseminated candidiasis in a premature neonate systemic candida infections in infants in intensive care nurseries: high incidence of central nervous system involvement disseminated fungal infections in very low birth weight infants: clinical manifestations and epidemiology bacteremia during diarrhea: incidence, etiology, risk factors, and outcome prevalence and risk factors associated with intestinal parasitoses in pregnant women and their relation to the infant's birth weight amebiasis in the newborn amoebic proctocolitis and liver abscess in a neonate amoebic appendicitis in a newborn infant amebiasis of the newborn: report of three cases extraintestinal amebiasis in infancy: report of three patients and epidemiologic investigations of their families amebic liver abscess in newborn fuliminant amebic colitis in a ten-day-old infant acquisition of intestinal parasites in newborn human infants comparison of use of enzyme-linked immunosorbent assay-based kits and pcr amplification of rrna genes for simultaneous detection of entamoeba histolytica and e. dispar comparison of pcr, isoenzyme analysis, and antigen detection for diagnosis of entamoeba histolytica infection giardiasis in day care centers. evidence of person-to-person transmission person-to-person transmission of g. lamblia in day care nurseries diarrhea caused by shigella, rotavirus, and giardia in day care centers: prospective study occurrence of g. lnmblia in children in day care centers the biology of giardia spp age-related rate of seropositivity and antibody to giardia lambliu in four diverse populations giardia lamblia infections in a cohort of bangladeshi mothers and infants followed for one year giardiasis and breastfeeding in urban africa local immunity in murine giardiasis: is milk protective at the expense of maternal gut? protection against infection with giardia muris by milk containing antibody to giardia killing of g. lamblia by human milk mediated by unsaturated fatty acids immunology of giardia and cryptosporidium infections cryptosporidiosis in immunocompetent patients cryptosporidiosis in animals and humans shedding of oocysts in immunocompetent individuals infected with cryptosporidium cryptosporidiosis travelers' diarrhea in two families cryptosporidiosis after marrow transplantation, person-to-person transmission and treatment with spiramycin cryptosporidiosis in humans: review of recent epidemiologic studies outbreak of cryptosporidiosis in a day care center cryptosporidiosis outbreak in a day care center cryptosporidiosis-associated mortality following a massive waterborne outbreak in milwaukee, wisconsin cryptosporidium: a frequent finding in patients with gastrointestinal symptoms human cryptosporidiosis in immunocompetent and immunodeficient persons: studies of an outbreak and experimental transmission cryptosporidium infections in mexican children: clinical, nutritional, enteropathogenic, and diagnostic evaluations cryptosporidiosis in children from some highland costa rican rural and urban areas timing of symptoms and oocyst excretion in human cryptosporidiosis schmid , et al. cryptosporidium, malnutrition and chronic diarrhea in children evaluation of nine immunoassay kits (enzyme immunoassay and direct fluorescence) for detection of giardia lnrnblio and cryptosporidium parvurn in human fecal specimens cryptosporidiosis: multiattribute evaluation of six diagnostic methods treatment of diarrhea caused by cryptosporidium parvum: a prospective of randomized, double-blind, placebo-controlled study of nitazoxanide cryptosporidiosis in northeastern brazilian children: association with increased diarrhea morbidity rotavirus, enteric adenoviruses, caliciviruses, astroviruses, and other viruses causing gastroenteritis fields virology rotaviruses and their replication viruses causing gastroenteritis non-group a rotavirus molecular epidemiology of rotavirus infection immunity of piglets to either vp or vp outer capsid protein confers resistance to challenge with a virulent rotavirus bearing the corresponding antigen reassortant rotavirus containing structural proteins vp and vp from different parents are protective against each parental strain distribution of human rotaviruses, especially g strains molecular epidemiology of rotavirus in children attending day care centers in houston unusual diversity of human rotavirus g and p genotypes in india evidence of high-frequency genomic reassortment of group a rotavirus strains in bangladesh emergence of type g in detection of rotavirus types g and g among brazilian children with diarrhea genetic an antigenetic characterization of a serotype g human rotavirus isolated in melbourne, australia detection of a human rotavirus with g and p[ ] specificity in thailand review of g and p typing results from a global collection of rotavirus strains: implications for vaccine development neonatal rotavirus infection in bangladesh strain characterization and risk factors for nosocomial infection distinct population of rotaviruses circulating among neonates and older infants epidemiology of rotavirus in india detection and characterization of rotavirus g and p types from children participating in a rotavirus vaccine trial in belen an outbreak of diarrhea in a neonatal medium care unit caused by a novel strain of rotavirus: investigation using both epidemiologival and microbiological methods characterization of rotavirus infection in a hospital neonatal unit in pretoria, south africa neonatal rotavirus infection in belem, northern brazil: nosocomial transmission of a p[ ] g strain detection and characterization of rotaviruses in hospitalized neonates in blantyre, malawi importance of a new virus in acute sporadic enteritis in children virus particles in epithelial cells of duodenal mucosa from children with acute nonbacterial gastroenteritis infantile enteritis viruses: morphogenesis and morphology reovirus-like particles in jejunal mucosa of a japanese infant with acute infectious nonbacterial gastroenteritis comparison of methods for immunocytochemical detection of rotavirus infections is lactase the receptor and uncoating enzyme for infantile enteritis (rota) viruses? the mucosal lesion in viral enteritis. extent and dynamics of the epithelial response to virus invasion in transmissible gastroenteritis of piglets noncultivable viruses and neonatal diarrhea. fifteen-month survey in a newborn special care nursery lactose malabsorption and milk consumption in infants and children mechanisms of mucosal injury: human studies determinants of diarrhea in viral enteritis. the role of ion transport and epithelial changes in the ileum in transmissible gastroenteritis in piglets identification of group a rotavirus genes associated with virulence of a porcine rotavirus and host range restriction of a human rotavirus in the gnotobiotic piglet model chronic rotavirus infection in immunodeficiency functional abnormalities in the intestine role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea transmissible gastroenteritis: sodium transport and the intestinal epithelium during the course of viral gastroenteritis age-dependent diarrhea induced by a rotaviral nonstructural glycoprotein attenuation of a human rotavirus vaccine candidate did not correlate with mutations in the nsp protein gene mutations in nonstructural glycoprotein nsp are associated with altered virus virulence clinical immunity after neonatal rotavirus infection. a prospective longitudinal study in young children protection conferred by neonatal rotavirus infection against subsequent rotavirus diarrhea protective effect of naturally acquired homotypic and heterotypic rotavirus antibodies identification of vp epitopes associated with protection against human rotavirus illness or shedding in volunteers protective effect of preexisting rotavirus-specific immunoglobulin a against naturally acquired rotavirus infection in children characterization of serum antibody responses to natural rotavirus infections in children by w -specific epitope-blocking assays relative concentrations of serum neutralizing antibody to vp and vp protein in adults infected with human rotavirus seroepidemiologic evaluation of antibodies to rotavirus as correlates of the risk of clinically significant rotavirus diarrhea in rural bangladesh fecal antibody responses to symptomatic and asymptomatic rotavirus infections anti-rotavirus g type-specific and isotype-specific antibodies in children with natural rotavirus infections prospective study of communityacquired rotavirus infection evidence that protection against rotavirus diarrhea after natural infection is not dependent on serotype-specific neutralizing antibody cord blood and breast milk antibodies in neonatal rotavirus infection epidemiology of human rotavirus types and as studied by enzyme-linked immunosorbent assay transfer of anti-rotaviral antibodies h-om mothers to their infants effects of antibodies, trypsin, and trypsin inhibitors on susceptibility of neonates to rotavirus infection antibodies to seven rotavirus serotypes in cord sera, maternal sera, and colostrum of german women rotavirus-inhibitory activity in serial milk samples from mexican women and rotavirus infections in their children during their first year of life secretory antibody directed against rotavirus in human milk-measurement by means of enzymelinked immunosorbent assay human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis clinical immunity after neonatal rotavirus infection. a prospective longitudinal study in young children stool viruses in babies in glasgow. . investigation of normal newborns in hospital nosocomial rotavirus gastroenteritis in a neonatal nursery new virus associated with diarrhoea in neonates rotavirus infections in a special-care baby unit rotavirus infections in newborns: an epidemiological and clinical study a prospective study of rotavirus infections in neonatal and maternity wards serotypic characterization of rotaviruses derived from asymptomatic human neonatal infections further studies on neonatal rotavirus infection rotavirus shedding by newborn children molecular epidemiology of rotavirus infection in a room for convalescing newborns neonatal rotavirus infections rotavirus: a cause of nosocomial infection in a nursery prevalence of rotavirus infection in neonates diarrhea and rotavirus infection associated with differing regimens for postnatal care of newborn babies asymptomatic rotavirus before and after rotavirus diarrhea in children in day care centers quantitative aspects of rotavirus excretion in childhood diarrhoea influence of temperature and relative humidity on human rotavirus infection in japan rotavirus in infant-toddler day care centers: epidemiology relevant to disease control strategies serotype variation of human group a rotaviruses in two regions of the united states hospital admissions attributable to rotavirus infection in england the epidemiology of rotavirus diarrhea in the united states: surveillance and estimates of disease burden rotavirus-associated medical visits and hospitalizations in south america: a prospective study at three large sentinel hospitals modulation of rotavirus enteritis during breast-feeding tilleman . rotavirus and other viruses in the stool of premature babies rotavirus infections in neonates acute diarrhea and rotavirus infection in newborn babies and children in yogyakarta a search for faecal viruses in newborn and other infants rotavirus and coronavirus-like particles in aboriginal and non-aboriginal neonates in kalgoorlie and alice springs rotavirus infections in newborns: an epidemiological and clinical study clinical range of neonatal rotavirus gastroenteritis epidemiology of diarrheal disease among children enrolled in four west coast health maintenance organizations rearing regimen producing piglet diarrhea (rotavirus) and its relevance to acute infantile diarrhea detection of rotavirus in respiratory secretions of children with pneumonia aerosol transmission of experimental rotavirus infection molecular epidemiology of rotavirus in black infants in south africa use of electrophoresis of rna from human rotavirus to establish the identity of stains involved in outbreaks in a tertiary care nursery rotavirus infection in a normal nursery: epidemic and surveillance nosocomial outbreak of neonatal gastroenteritis caused by a new serotype , subtype human rotavirus clinical, laboratory, and epidemiologic features of a viral gastroenteritis in infants and children comparison of human rotavirus disease in tropical and temperate settings epidemiology of acute gastroenteritis in early childhood in kenya. vi. some clinical and laboratory characteristics relative to the aetiological agents pennock c k faecal excretion of oligosaccharides and other carbohydrates in normal neonates lactose malabsorption following rotavirus infection in young children global illness and deaths caused by rotavirus disease in children a case of neonatal necrotizing enterocolitis due to rotavirus epidemic outbreak of necrotizing enterocolitis coincident with an epidemic of neonatal rotavirus gastroenteritis rotavirus infection and bradycardia-apnoea-episodes in the neonate human rotavirus infection in infants and young children with intussusception a two-part study of the aetiological role of rotavirus in intussusception a one-year virological survey of acute intussusception in childhood intussusception among infants given an oral rotavirus vaccine evaluation of the inmunocardstat. rotavirus assay for detection of group a rotavirus in fecal specimens comparison of seven kits for detection of rotavirus in fecal specimens with a sensitive, specific enzyme immunoassay detection of rotavirus in stool specimens with monoclonal and polyclonal antibody-based assay systems evaluation of seven immunoassays for detection of rotavirus in pediatric stool samples comparative efficacy of commercial immunoassays for the diagnosis of rotavirus gastroenteritis during the course of infection comparison of direct electron microscopy, immune electron microscopy, and rotavirus enzyme-linked immunosorbent assay for detection of gastroenteritis viruses in children enzyme-linked immunosorbent assay (elisa) for detection of human reovirus-like agent of infantile gastroenteritis rotavirus particles can survive storage in ambient tropical temperatures for more than months epidemiological aspects of rotavirus infection in hospitalized venezuelan children with gastroenteritis practice parameter: the management of acute gastroenteritis in young children oral hydration in rotavirus diarrhoea: a double-blind comparison of sucrose with glucose electrolyte solution glucose vs. sucrose in oral rehydration solutions for infants and young children with rotavirusassociated diarrhea chronic rotavirus infection in immunodeficiency passive immunizations of suckling mice and infants with bovine colostrum containing antibodies to human rotavirus enteral immunoglobulins for treatment of protracted rotaviral diarrhea field trial of an infant formula containing anti-rotavirus and anti-escherichia coli milk antibodies from hyperimmunized cows effect of probiotic lactobacillus strains in young children hospitalized with acute diarrhea oral immunoglobulin for the treatment of rotavirus infection in low birth weight infants a study of the prevalence of rotavirus infection in children with gastroenteritis admitted to an infectious disease hospital intussusception, infection, and immunization: summary of a workshop on rotavirus intractable diarrhea in a newborn infant: microvillous inclusion disease persistent diarrhea as the predominant symptom of hirschsprung's disease (congenital dilatation of colon) factors correlating with a successful outcome following extensive intestinal resection in newborn infants intractable diarrhea of infancy due to lymphangiectasis small intestinal disaccharidase deficiency sucrase-isomaltose deficiency-a frequently misdiagnosed disease fordtran . . glucose-galactose malabsorption sugar intolerance as a cause of protracted diarrhea following surgery of the gastrointestinal tract in neonates virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis enteric microflora and carbohydrate intolerance in infants with diarrhea transient monosaccharide intolerance in a newborn infant cow's milk proteinsensitive enteropathy. an important contributing cause of secondary sugar intolerance in young infants with acute infective enteritis malabsorption syndromes in infancy and childhood. i, faecal excretion of oligosaccharides and other carbohydrates in normal neonates report of patients diagnosed under months of age over a year period schwachman's syndrome. a review of cases physiologic deficiency of pancreatic amylase in infancy: a factor in iatrogenic diarrhea enterokinase and trypsin activities in pancreatic insufficiency and diseases of the small intestine a new syndrome of bile acid deficiency-a possible synthetic defect disorders of the serum lipoproteins. i. lipoprotein deficiency states acrodermatitis enteropathica: defective metabolism of unsaturated fatty acids acrodermatitis enteropathica without hypozincemia congenital chloride diarrhea prostaglandin synthetase inhibitor in an infant with congenital chloride diarrhea primary hypomagnesemia with secondary hypocalcemia, diarrhea and insensitivity to parathyroid hormone congenital adrenal hyperplasia with disturbed electrolyte regulation watery diarrhoea with a vasoactive intestinal peptide-producing ganglioneuroblastoma chronic diarrhea of infancy: nonbeta islet cell hyperplasia wolman's disease in an infant neonatal megaloblastic anemia due to inherited transcobalamin i deficiency in siblings tricho-hepato-enteric syndrome: further delineation of a distinct syndrome with neonatal hemochromatosis phenotype, intractable diarrhea, and hair anomalies circumvention of defective neutral amino acid transport in hartnup disease using tryptophan ethyl ester congenital na+ diarrhea: a new type of secretory diarrhea cow's milk allergy: manifestations, diagnosis and management colitis, persistent diarrhea, and soy protein intolerance milk-and soy-induced enterocolitis of infancy. clinical features and standardization of challenge regional enteritis in early infancy bloody diarrhea in the newborn infant of a mother with ulcerative colitis ulcerative colitis in children under one year: a twenty-year review intractable diarrhoea of infancy acquired immunodeficiency syndrome in infants the irritable colon of childhood (chronic nonspecific diarrhea syndrome) gut transit time and lactose malabsorption during phototherapy. i, neonatal diagnosis of familial dysautonomia familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villous atrophy lethal familial protracted diarrhea infantile gastroenteritis due to water with high sulfate content diarrhea, red diapers, and child abuse management of children with infection-associated persistent diarrhea 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.