key: cord-0039094-ti2g0d93
authors: Hunter, Alan J.; Bryant, Richard E.
title: LOWER RESPIRATORY TRACT INFECTIONS IN ELDERLY PATIENTS WITH ASTHMA
date: 1997-11-01
journal: Immunol Allergy Clin North Am
DOI: 10.1016/s0889-8561(05)70337-4
sha: 8101e53122680bc29609db2bf5a3c86c29151be4
doc_id: 39094
cord_uid: ti2g0d93

Infection plays a significant role in the morbidity and mortality of the elderly. One population in which infection has not been adequately studied is the elderly asthmatic. This article examines the problems of lower respiratory tract infections in elderly asthmatics in the context of their host defenses, the severity of infection, and their risk of infection with specific organisms. The role of infection in the pathogenesis of asthma and consideration of prophylaxis and therapy are presented.

Infection plays a significant role in the morbidity and mortality of the elderly. One population in which infection has not been adequately studied is the elderly asthmatic. This article examines the problems of lower respiratory tract infections in elderly asthmatics in the context of their host defenses, the severity of infection, and their risk of infection with specific organisms. The role of infection in the pathogenesis of asthma and consideration of prophylaxis and therapy are presented.

Bronchial asthma is not generally considered to be a disease of the elderly. Population surveys, however, show that the prevalence of asthma in the elderly ranges from 2.4% to 12.2%.lSi 45, 48, 154 In a study comparing late-onset asthma and long-standing disease in nonsmoking elderly asthmatics, Braman et all9 noted that 48% of patients developed asthma after 65 years of age. In a review of 10 population studies, Enright et a145 found the prevalence of asthma to range from 2.4% to 6.6%. Banerjee et als noted that 61% of randomly selected geriatric dayhospital patients exhibited airflow obstruction on pulmonary function testing. Of those with airflow obstruction 41.2% demonstrated greater than 15% improvement in peak expiratory flow rate following inhalation In addition to chronic asthma, the incidence of new cases after 60 years of age appears to remain relatively constant, ranging from two to six cases per thousand. '8,21,22,39 Advances in technology, nutrition, and medicine have set the stage for profound increases in the geriatric populations, such that the over-85 age group is the fastest growing segment of society in North America. 28 Based on current trends, by the year 2020, the over-65 and over-75 age groups will constitute 22% and 14.2% of the populations in the industrialized nations. 30 Thus we can anticipate a sustained increase in geriatric asthmatics requiring care. The principles of managing asthma in elderly patients differ little from those of treating younger patients. The impaired excretion of drugs by the kidney and liver, however, and greater likelihood of comorbid diseases and adverse drug-drug interactions make the management of asthma in elderly patients complex. 178, 196 Infection-related mortality in the elderly is three-to 20-fold higher for given diseases compared with younger patients.h6, 17R Pneumoniaassociated mortality in the elderly ranges from 5.9% to 32.9%, accounting for 89% of all pneumonia and influenza deaths in the United States between 1979 and 1992,29, 60, 83, 111, Iz5 and with influenza is the fifth leading cause of death in patients over 65 years of age.29 A recent 2year prospective observational study of independent elderly individuals reported that 54% of those older than 65 years of age had respiratory tract infections, of which bronchitis, pneumonia, and influenza constituted 42% of the total respiratory infection^.'^^ The severity of lower respiratory tract infections is a function of host susceptibility, the virulence of the infecting agent, and the extent of disease at the start of therapy.

Resistance to microbial invasion of the lower respiratory tract is multifactorial and complex. The respiratory tract immune system is composed of both specific and nonspecific defense mechanisms that consist of a variety of anatomic, neurologic, cellular, and humoral mechanisms. The integrity of these mechanisms, pathogen virulence and the size of the bacterial inoculum play key roles in colonization and subsequent infection of the lower respiratory tract. A variety of conditions contributing to alveolar fluid accumulation place the host at an increased risk of pneumonia. Diminishing host, defenses increase the vulnerability of elderly 'asthmatic patients to more protracted and debilitating consequences of lung infections. Increased vulnerability may also reflect the increased prevalence of diseases associated with fluid retention, such as cardiac, renal, or liver failure, swallowing disorders, altered consciousness, deconditioning due to a sedentary lifestyle, or adverse effects of malnutrition, immunosuppression, or malignancy. Harford and Haras7 demonstrated the harmful effects of increased lung water on the survival of mice with experimental pneumonia. A 15-fold increase in mortality was described in mice inoculated with endobroncheal bacteria, following endobronchial infusion of saline or serum. Effective phagocytosis cannot occur under these conditions in the absence of opsonic antibodies. Disease-related pulmonary dysfunctions associated with an increased frequency of lower respiratory tract infection are as follows41: Chandra= noted that in previously healthy individuals, the presence of anergy, lymphopenia, or both was associated with 1-year survival rates of 72%, 58%, and 45%, respectively. In a 16-year longitudinal study of healthy elderly men, decreased absolute lympocyte counts were noted within 3 years of death.12 The leukopenia, however, was not age dependent and in both of these studies might have served as a marker of more severe comorbid disease(s). In predominately healthy patients with a mean age of 82 years, a normal inflammatory response to pneumonia was noted, as measured by appropriate rise in C-reactive protein, leukocytosis, and a neutrophil degranulation product, plasma neutrophil elastase a-1-antiproteinase ~omplex.~ In addition, despite having measurably lower numbers of cytotoxic T lymphocytes at baseline, elderly patients were able to mount an adequate response following inactivated influenza A virus ~accinati0n.l~~ These results support the notion that the healthy elderly are still able to mount an adequate immune response to pneumonia. Nasopharyngeal colonization with gram-negative bacteria has been reported to increase in elderly patients, but few studies have looked at the elderly living independently within the community.49, 50, 781, ls5 It is likely that the high rates of colonization are more representative of comorbid illnesses and therapy, in addition to the milieu in which these patients reside. The elderly have an increased incidence of bacteremia, urinary tract infection, diverticulitis, pneumonia, infective endocarditis, disseminated fungal infection, and reactivation of tuberc~losis.~~, Although immune dysfunction probably plays a role in these infections, the increased susceptibility of the elderly to infection may in part represent a synergistic effect of comorbid illnesses, nutritional stat~s,l"~, and age-dependent organ dysfunction.%, 178

Saltzman and Peterson"jl noted a 41% to 85% prevalence of proteincalorie malnutrition while reviewing immunodeficiency in the elderly.

Impaired T-cell responsiveness and anergy are known immunologic sequelae of malnutrition and may contribute to the immune dysfunction of the elderly.l'l* The provision of nutritional, vitamin, and trace element supplementation for 8 weeks resulted in improved skin test response, increased T-lymphocyte numbers, and responses to mitogen.3l Zinc may be especially important. Animal studies involving zinc-deficient mice have demonstrated reversible thymic involution and T-cell dysfunction with adequate zinc repla~ement.~~, 64 These studies have relevance in the elderly because the prevalence of deficient zinc intake and measurable zinc deficiency are 24% and 14%, respe~tively.~~ In a randomized controlled trial in institutionalized elderly, the administration of 220 mg of zinc sulfate twice daily resulted in increased numbers of circulating T lymphocytes, enhanced delayed cutaneous hypersensitivity, and immunoglobulin G response to tetanus vaccine.42 Four randomized, double-blind, placebo-controlled trials involving zinc administration for the common cold have demonstrated a decrease in symptoms when compared with pla~ebo.~, 43, 71, 137 Four additional randomized controlled trials failed to document any clinical improvement with administration of zinc gluconate for the common cold, and in addition found no change in viral shedding. 40, 54, 173, 190 There are numerous proposed mechanisms by which zinc might exert some antimicrobial action,137 but its clinical role has yet to be worked out. The precise role of vitamin replacement is not established, but clearly adequate caloric and nutritional support are important in the elderly.

Chronic obstructive lung disease is a predisposing factor for pneumonia in the elderly, but asthma is not generally considered a significant independent 133 Koivula et al,los however, in a population-based study of individuals more than 60 years of age in Finland, noted the prevalence of asthma to be 3.5%.'08 When compared with those patients who did not develop pneumonia, the adjusted relative risk for contracting pneumonia in asthmatics was 4.2 (95% confidence interval [CI], range 3.3-5.4), suggesting that asthma itself may predispose patients to develop infection. The presence of lung disease and bronchial asthma did not increase the risk of death. Postulated mechanisms by which asthma causes host immune system dysfunction have been reviewed (Table l) .l0, 25, 27, 84, 85, 97, 98, 148, 149 In addition, mucociliary transport may be slowed by as much as 72% during an acute exa~erbation.'~~ Multiple authors have described impaired mucociliary transport in asthmatic patients.'O! 25, 97, Io5, 'I7* 149 In addition, hypogammaglobulinemia was 4.8 times more likely to be identified in unselected asthmatics than in the normal p o p~l a t i o n .~~ Of note, 10 of the 12 patients with hypogammaglobulinemia received a cumulative prednisone dose (or its equivalent) of 2 5 mg/day for at least 2 years. Because asthma in the elderly is less likely to be responsive to conservative therapy, more elderly asthmatics will be at risk of suffering the combined immune-altering effects of age, comorbidity, and immunosuppression.Is In a survey of consecutive geriatric asthmatic patients in their pulmonary practice, Braman et all9 noted that 22 of 25 patients more than 70 years of age required oral steroids in addition to inhaled corticosteroids, highlighting the potential clinical significance of iatrogenic immune deficiencies. The previously described immune host defense dysfunction may be significant, but may be less important than the combined effects of comorbid disease(s). Asthmatic patients more than 65 years of age have been shown to have six-to 10-fold higher mortality than younger patients, partially attributable to complicating illnesses and therapies, but in addition attributable to delays in presentation, increased noncompliance with medications, poor nutrition, and isolated living situations that predispose them to poorer outcomes.18, 34, lS1, 162

The separate effects of age and comorbid disease on the susceptibility of the elderly to infection are complex. Many studies have attempted to identify historical, clinical, and laboratory parameters by which physicians could appropriately stratify patients with pneumonia with respect to their need for hospitalization and intensive care.17* 54, 61, 83* 120, Farr et a154 reviewed prognostic factors obtained by history that have been associated with death from pneumonia, and they identified 18 studies that showed an association between older age and death. Nine of the studies found an association using univariate analysis, and two studies found an association using multivariate analysis.20, 37 In a recent study evaluating the utility of radiographic presentation of community-acquired pneumonia, the overall mortality rate of patients 65 years of age or older was 10.2% as compared with the 1.8% mortality rate of patients 45 to 64 years of age, further highlighting the risk of age and infection. 83 In a metaanalysis, Fine et aP2 noted 14 cohort studies that evaluated the association of age and mortality, with a mean age difference in survivors versus nonsurvivors of 7.8 years. In the same study, logistic regression analysis performed on 85 cases noted an odds ratio of 1.05 (95% CI, range 1.01-1.09) of death for each 10-year increment in mean patient age. Although this metaanalysis found age to be significantly associated with death, the weight of comorbid illness was not addressed. Studies by Esposito et a1,% Black et al,I7 and Lipsky et a1,120 which corrected for comorbid factors, found that age was not a significant risk factor for mortality. Using retrospectively derived prognostic parameters, Black et all7 noted that ambulatory elderly patients were more likely to be admitted with pneumonia than younger patients. When a multivariate analysis was performed controlling for comorbid conditions, age was no longer predictive.17 In a retrospective case control study, Lipsky et noted dementia, seizure disorders, and institutionalization to be associated with acquiring pneumococcal infections. In the same study, age was not significantly associated with pneumococcal pneumonia when corrected for comorbidities. These observations support the overriding importance of an individual's physiologic status as a determinant for initiating invasive life-saving medical therapy.

The precise relationships between infection and asthma are unclear. As previously mentioned, Koivula et allos showed that elderly asthmatics have an increased risk of pneumonia when compared with the general age-matched population, suggesting that asthma per se may predispose elderly patients to pneumonia. Although this is a tenable hypothesis it is unclear whether comorbid illness or therapy with corticosteroids might have prevented detection of the separate effects of asthma as a risk factor for pneumonia. More extensive work has gone into trying to elucidate the mechanism by which infections may affect the risk of or perpetuate the course of asthma. Similarly it is not totally clear whether asthmatic patients have a different incidence or worsened prognosis with viral, bacterial, or combined infection.

Many studies have evaluated the role of preceding viral infection in the development of airway hyperresponsiveness in children. The role of infection in the pathogenesis of asthma and its exacerbations in adults continues to be controversial. Few studies have separated bronchial asthma from chronic obstructive pulmonary disease, hence there are few if any clinical data demonstrating whether asthma predisposes one to develop respiratory tract infections. In the only study addressing bronchial asthma as an independent comorbidity, Koivula et allos noted bronchial asthma to be second only to alcoholism as a risk for pneumonia. This study, involving elderly independent Finns, showed that asthmatics had an adjusted relative risk for pneumonia and hospitalization of 4.2 (95% CI, range 3.3-5.4) and 6.0 (95% CI, range 4.1-9.0), respectively, when compared with the remainder of the population. This increased risk remained statistically significant after a multivariate analysis for all significant comorbidities. There is a need for further studies in this area.

Bacterial infections have a minimal or inapparent role in asthma exacerbations except for the recently described association of Chlamydia pneumoniae and the development of asthma.8o In a study involving young asthmatics, McIntosh et found no difference in the bacterial isolation rates of pneumococcus, Hemophilus influenme, P-hemolytic streptococci, Staphylococci auyeus, or enteric bacteria when looking at symptomatic versus asymptomatic asthmatics. Several studies have suggested a possible role of Mycoplasma pneumoniae in the development of asthma exacerbations. In a study involving 77 wheezing asthmatics, from 8 months to 31 years of age, Gil et a17" were able to isolate M . pneumoniae in 24.7% of subjects compared with 5.7% of controls. Several studies have associated Mycoplasma sp with asthma, but its clinical importance is still uncertain.13,

In a study in adults, Hudgel et a193 confirmed these results, finding no difference in bacterial isolation rates when comparing symptomatic versus asymptomatic asthmatics. In addition, Berman et all4 using transtracheal biopsy, did not correlate bacterial isolation with exacerbations when comparing symptomatic versus asymptomatic asthmatics. Studies looking at antimicrobial therapy for acute exacerbations of asthma have found no difference in outcomes between those who received antibiotics and controls.13, y2, 168 Exclusive of secondarily infected upper respiratory infection, bacterial infection appears to play a minimal role in asthma exacerbations and therefore antimicrobials are seldom indicated.

C. pneumoniae causes a number of respiratory and nonrespiratory inflammatory condition^.^^ The seroprevalence in the population ranges from 30% to 50%, with about 50% positivity in older patients." In a prospective study involving 365 Wisconsin outpatients, Hahn et also assessed the association of C. pneumoniae infection with wheezing, asthmatic bronchitis, and adult-onset asthma. In the prospective phase, three (11%) of 27 patients with pneumonia and 16 (4.7%) of patients with bronchitis had positive serology for C. pneumoniae. Of these 19 infected patients, three (16%) had wheezing with their acute infection, and six (32%) developed bronchospasm during the ensuing 6 months. After controlling for confounding variables, a C. pneumoniae titer of 1:16 or more was associated with an odds ratio of 2.1 (95% CI, range 1.14.2) for developing wheezing. In the matched control phase of the study, 29 .6% of C. pneumoniae-positive patients compared with 7% of controls were diagnosed with asthma, with an odds ratio of 7.2 (95% CI, range 2.2-23.4). This finding was further substantiated by demonstrating a dose-response relationship between titers and the presence of wheezing. C. pneumoniae titers of 1:16 and 1:128 or more were associated with odds ratios for wheezing of 1.2 (not significant) and 3.5 (significant), respectively. Eighty percent of patients diagnosed with asthma following their illness had a C. pneurnoniae titer of more than or equal to 1:64, and of these six (75%) developed chronic asthma following bronchitis, and one (12.5%) following pneumonia. Asthmatic bronchitis was more likely to occur in older reinfected patients, raising the question whether C. pneumoniae might have exerted an immune-mediated effect on the lung. 73 ,

In a follow-up study composed of asthmatics with and without chronic obstructive pulmonary disease (COPD), Hahn and Golubjatnikov81 reported 100% C. pneumoniae seroreactivity in asthmatics, 80% seroreactivity in asthmatic bronchitis patients without antecedent asthma, and 52.8% seroreactivity in patients with nonwheezing respiratory illness. Additional studies have had similar results associating C. pneumoniae with asthma.5, 79-81,150 A recent community-based openlabel treatment trial involving asthmatic patients with a mean C. pneumoniae titer of 1:128 showed significant improvement in 54% of patients after 4 weeks of varying antimicrobial treatments (doxycycline, azithromycin, or erythromycin), as reflected by improvement in forced expiratory volume in 1 second (FEV,) and symptoms." Nonresponders were more likely to be receiving inhaled corticosteroids, to have a lower mean FEV,/forced vital capacity (FVC) ratio at baseline, and to have a significantly longer history of asthma symptoms prior to treatment. This is an interesting study, but it is hampered by the lack of a control arm and the association of significant impairment of pulmonary function tests prior to testing in the nonresponder arm. G r a y~t o n~~ found the incidence of wheezing and asthma to be no higher in C. pneumoniae than M. pneumoniae or viral respiratory disease (respiratory syncytial virus [RSV], influenza A and B, and adenovirus). This recent recognition of the association of C. pneurnoniae with asthma is yet another linkage of infection to an inflammatory condition. The exact implications of the Chlamydia-asthma association are yet to be defined and further study is needed to characterize improved diagnostic and therapeutic options available to clinicians.

In children, viral respiratory tract infections have been shown to play a significant role in the development of acute asthma, as well as contributing to the pathogenesis of airway hyperresponsiveness. Epidemiologic studies in children have established a convincing link between antecedent viral respiratory tract infection and acute asthma exacerbations, and as potential causative agent in the pathogenic process of airway hyperresponsiveness.118, 172 Table 2 summarizes proposed patho- genic mechanisms by which viral infections exacerbate pre-existing asthma, as well as cause airway hyperreactivity. Viral infections have been shown to decrease peak flow rates75,171 and induce airway epithelial damage, thereby potentially increasing antigenic exposure in the host,"J lx7, 159 which may result in increased airway reactivity in normal or genetically predisposed hosts.75, 82, I l 6 Viral infections and influenza vaccination have been shown to cause nonspecific bronchial hyperresponsiveness in asthmatic^.^^, 153 Hence, although clinical and experimental evidence support a causal link between neonatal and childhood RSV infections and bronchiolitis, and subsequent asthma, there is conflicting evidence that this occurs in adults.11s, 1 7~, 175~ 177, Epidemiologic studies have addressed the possible role of viral infection in asthma exacerbations. Pattemore et reviewed the epidemiology of viral illness and asthma and noted four studies in children that identified significantly elevated virus isolation rates in symptomatic asthmatics, compared with asymptomatic asthmatic^.^^, 93, loo, 132 Rhinoviruses have been associated with the majority of cases of virus-mediated infective asthma, with RSV, parainfluenza, adenovirus, influenza virus, and coronavirus comprising the remainder.'l, induced rhinovirus infections in 10 adults allergic to ragweed, noting increased airway reactivity to both allergen and histamine provocation. In addition, eight of 10 patients experienced a greater than 15% decline in FEV, within 6 hours of the antigen challenge. In a longitudinal study of adult asthmatics 19 to 46 years of age, Nicholson et identified nonbacterial pathogens in 44% of asthma exacerbations associated with cold symptoms. Twenty-four percent of laboratory-confirmed infections were associated with significant airflow obstruction. In this study, viral pathogens accounted for 93% of all infections, of which rhinovirus and coronavirus accounted for the majority. In children identification rates during exacerbation have approached /20% to 60%. 26, 91, 129, 131 Viral respiratory tract infections are likely to play a role in adult exacerbations but to a lesser extent. Viral identification rates during exacerbation in adults range between 10% and 19%.11, 93, 94, 146 Minor et and Hudgel et aly3 noted that viral isolation rates in adults were significantly lower than rates in children (10% to 13% versus 40% to 60°h).93,y4, lZy In a small 135, 146 Lemanske et prospective study involving adult asthmatics 15 to 59 years of age, Beasley et all1 reported an overall viral isolation rate of lo%, which increased to 36% in association with severe asthma exacerbations (FEV, < 60% or peak expiratory flow rate < 40%). Sixty percent of viral respiratory tract infections were associated with an acute asthma exacerbation. In a study of 253 exacerbations in 67 asthmatics, Kava106 found that 25% of asthma exacerbations were associated with symptomatic respiratory tract infections, and 55% of respiratory tract infections were associated with an asthma exacerbation. In the same study, viral-associated asthma exacerbations had a more protracted course then did exacerbations unassociated with a viral illness, or an uncomplicated viral respiratory tract infection: 11.4 days versus 8.1 days versus 4.9 days, respectively. Although the isolation rates in adults are significantly lower than those in children, these studies support the notion that viruses contribute to exacerbation of bronchial hyperreactivity in adults as well as children.

All studies have not reported an association between antecedent viral infections and asthma. Tarlo et allso isolated virus in only 3% of adults with asthma exacerbations presenting with symptoms of an upper respiratory tract infection, a rate identical to the isolation rate of asymptomatic individuals. Similarly, Sokhandan et obtained nasal swabs for viral isolation from 33 of 35 adults during asthma exacerbations that necessitated emergency room evaluation. In total, 55.9% of patients had symptoms consistent with an upper respiratory tract infection, yet by immunofluorescence, culture, or complement fixation testing, none of these had evidence of viral infection. Sokhandan and coworkers rationalized that despite expecting a higher isolation rate in emergency room presentations, as compared with the rates noted in ambulatory clinics, this lower rate raised significant questions about the role of viral infections in adult asthma exacerbations. Hence, there are solid yet conflicting data concerning viral-mediated exacerbation of asthma in adults, with little specific data in the elderly.

Aspergillus can affect the asthmatic host by several pathologic mechanisms. It may cause a profound allergic reaction in atopic individuals with preexisting bronchial asthma, it may coexist by colonizing the respiratory mucosa, or it may progress to more severe invasive aspergillosis. Allergic bronchopulmonary aspergillosis (ABPA) is the most common allergic bronchopulmonary mycosis. It is characterized by fever,, malaise, sputum production with brown mucous plugs, pulmonary eosinophilia, a significant allergic response in the bronchi and skin, and proximal bronchiectasis, in the setting of established asthma or another chronic lung disease such as cystic fibrosis.lo3, ls7 The clinical course varies from mild asthma exacerbations to severe pulmonary fibrosis following years of repeated inflammatory episodes. In 1952, Hinson et a190 first described ABPA syndrome in three patients with recurrent asthma, peripheral eosinophilia, fever, sputum production, and abnormal chest radi0gra~hs.I~~ Aspergillus fumigatus later grew out of sputum culture. This association of A. furnigatus and ABPA has subsequently been well documented. Although A. furnigatus is responsible for the majority of cases, the syndrome may occasionally be caused by other Aspergillus spp, as well as other Additional diagnostic considerations for A. fumigatus-negative patients with a compatible clinical syndrome are Pseudoallescheria boydii, Candida albicans, Curvularia lunata, Rhizopus spp., Helminthosporium spp, Penicillium spp, Stemphylium spp, Torulopsis glabrata, Bipolaris spp, hawaiiensis, and Fusarium vasinfec-No formal studies have evaluated the prevalence of ABPA in the elderly. In a recent study of asthmatics preselected for having positive immediate A. furnigatus skin tests, however, 28% of patients fulfilled clinical criteria for ABPA.l6-? Of these episodes, 36% had proximal bronchiectasis on radiographic interpretation. In this study, the over-60 age group accounted for 24% of the study population, yet was responsible for 39% of ABPA diagnoses. In addition, 46% of the over-60 patients had a diagnosis of ABPA during the study, compared with only 18% of patients younger than 60 years of age. This preliminary information highlights the potential clinical significance of ABPA in the elderly population, hence enforcing our need to consider ABPA in patient evaluation.

In summary, infection clearly has a significant role in asthma. Although the evidence linking viral infection to asthma exacerbations and pathogenesis is convincing in children, it is less convincing in adults. The epidemiologic studies reviewed did not focus on the elderly population, hence we are required to extrapolate the above association of virusmediated airway hyperresponsiveness in children and younger adults to consideration of the elderly patient. This area needs more work. At one time bacterial infections were considered a likely cause of asthmatic exacerbations; however, except for the recently proposed association of C. pneumoniae and asthma, and to a lesser degree M . pneumoniae, bacteria are considered to play a minor role in recurrent episodes of airway hyperresponsiveness in children and adults alike. Methodologic limitations of easily identifying infective agents causing lower respiratory tract infections severely limits progress in this area.

Perhaps the most important insight into the role of prior respiratory viral infection in secondary bronchial reactivity is provided by study of prior viral infections in patients with sinusitis or otitis media.**, 17" The very elegant studies available from the examination of cultures, antigen detection, or serologic confirmation of middle ear or sinus aspiration specimens have shown a clear association between primary viral and secondary bacterial infection of the sinuses or middle ear.2, 6y, 76, 86 Unlike the normally sterile milieu of the sinuses and middle ear, the lower respiratory tract lies distal to the heavily colonized oropharynx, thus impairing more precise microbiologic assessment. 16, 47 Clarification of the exact relationship between viral, bacterial, or combined infection in the bypass contamination from the oropharynx. Considering the multitude of infectious agents and the expense and methodologic complexity of defining infections of the nose, oropharynx, lung, and gastrointestinal tract, it is amazing that we know as much as we do. asthmatic awaits a better assessment of microbial infection that can

Waning immunity is cited as a potentially correctable host defense defect in the elderly.109 Despite the availability of vaccines for viral influenza, and Streptococcus pneumoniae, these important protective measures are often omitted. The viral influenza vaccine should be given each year in the late fall. The pneumococcal vaccine is especially important because it protects against invasive pneumococcal infection and its current formulation includes antigens from multidrug-resistant strains that would be more difficult to treat with antibiotics. Unfortunately, severely ill patients, those with comorbid diseases, and the immunocompromised elderly are substantially less likely to respond to this or other vaccines. Pneumococcal immunization is usually given at or about 65 years of age, but it should be given at a younger age to patients with cardiac, pulmonary, renal, or hepatic disease that would increase their susceptibility to invasive pneumococcal disease.", 138, 139 There is controversy over the desirability of repeated vaccination. Dermal reactivity to reimmunization is seldom a problem in those more than 65 years of age, however, and the elderly without comorbid disease show no statistical impairment of immunologic responsiveness to the vaccine.139, Fiveyear efficacy in immunocompetent 65-to 74-year-olds was 71% and in 75-to 84-year-olds was 67%.lh7 Considering that data and conceding that definitive studies with elderly asthmatics are unlikely to become available, it seems prudent to provide pneumococcal immunization to elderly asthmatic patients on the basis of their other underlying disease(s) (i.e., cardiovascular disorders, chronic pulmonary diseases, renal failure, alcoholism, or hematopoietic malignancies), to begin before 65 years of age in the most vulnerable patients with comorbid disease, and to consider repeating immunization at approximately 5-to 7-year intervals. Better vaccines and better instruments for testing their efficacy in the elderly are needed.

If elderly patients with asthma are at greater risk of serious sequelae from viral infections then measures likely to reduce the risk of viral infection should be beneficial.lo8 Societal practices also contribute to enhanced respiratory infection in the elderly. Vulnerable patients are grouped together in nursing homes and often subjected to affectionate and effusive reunions with families, children, grandchildren, and other carriers of infectious microbes that can then be circulated rapidly among the susceptible residents. Adults have approximately four viral infections per year and children average six to eight per year;7h thus, it is wise for grandparents and great-grandparents to avoid contact with children likely to have active viral infection, a logical but often unacceptable choice. Rhinoviral illness is often transmitted by infectious nasopharyngeal secretions and, therefore, is potentially amenable to reduction by barrier precautions, frequent hand washing, and returning babies to their parents if they need attention for their runny noses. 114 The lay press has suggested that improved handwashing practices in nursery schools can reduce colds in the home by nearly 50%.183*188 This thesis is given credibility by studies documenting the transmissibility of viruses on fomites and the hands of volunteers, the frequency with which children and adults pick their noses or rub their eyes, and the infectivity of viruses inoculated onto the nasal rnucosa or conj~nctiva.~~, 89, Thus appropriate attention to handwashing, disposal of soiled tissues, and interruption of the transmission of infected nasopharyngeal secretions should benefit the elderly. The common sense benefits from covering the mouth during a cough were recognized to reduce risks of transmission of tuberculosis in the 1 9 6 0~;~~ and are also applicable to reduce transmission of certain viral infections. We need to document and expand our repertoire of ways of interrupting transmission of viral infections to our elderly and infirm patients. Risks of respiratory infection can also be associated with vocational or recreational exposures. Geographic and exposure risk factors associated with respiratory disease that are not host-specific for asthmatic patients are shown in Table 3 .

It seems prudent to advise physicians caring for vulnerable elderly asthmatics to help prevent fluid retention secondary to cardiac, renal, or liver failure. Those at risk of aspiration due to hiatal herniae, gastroesophageal reflux, or presbyesophageal or other swallowing disorders should have thoughtful evaluation and advice as to precautions for eating, sleeping, and safe swallowing techniques. 

As discussed previously, asthmatic patients with respiratory disease usually have asthma that is not linked to bacterial infection and is not helped by antibiotics. Sputum purulence can be associated with eosinophil-rich exudates or with viral infection that confounds diagnostic assessment. Likewise, criteria for assessing the severity and need for hospitalization for an asthma attack are well defined and distinct from diagnostic assessment and criteria for hospitalization for pneumonia. This article addresses issues relevant to lower respiratory tract infection in elderly patients who happen to have asthma. In most instances concomitant asthma will have little effect on the most common bacterial causes of pneumonia in that group. In rare instances protracted therapy with high doses of corticosteroids may reactivate tuberculosis or opportunistic fungal or nocardia infections. Likewise Pneumocystis carinii infection can complicate high-dose corticosteroid therapy in relatively normal hosts. It is well to keep these situations in mind, but they are extremely rare ( Table 4) .

Diagnosis of respiratory infection in the elderly is based on the statistical probability of a specific infection considering host vulnerability, epidemiologic risks, and clinical presentation. Therapy is based on the clinical clues, laboratory evaluation, and the assessment of the severity of the patient's illness.

The cause of community-acquired pneumonia varies with the patient's age, comorbid disease, disability, and exposure to infectious agents. Pneumonia is generally attributed to S. pneumoniae (20% to 6O%), H . influenme (3% to lo%), gram-negative bacilli (3% to lo%), S. aureus (3% to 5%), legionella (2% to So/,), C. pneumoniae (4% to 6%), viral pneumonia (2% to 150/,), and aspiration (6% to 10°/0).9r 51, 112, 126 The cause of pneumonia is unknown in 20% to 30% of patients and the frequency of combined infection is probably higher than recognized. Kauppinen and coworkers suggested mixed infection may occur in more than a third of patients hospitalized with C. pneumoniae.lo4 Lieberman and cow o r k e r~'~~ reported age-specific etiologic data for pneumonia. Patients 13%) , legionella (8% to 15%), and C. pneurnoniae (24% to 28%). The latter statistic is comparable to figures cited by Grayston," who noted an increased incidence of C. pneurnoniae in the elderly. This finding has special relevance to the elderly asthmatic patient, who might be expected to have a higher likelihood of worsening asthma and a more prolonged illness after a C. pneurnoniae infection.

There have been a series of elegant studies documenting risk factors associated with severe pneumonia and a bad 142 The features of the history, physical examination, or laboratory assessment associated with severe pneumonia that requires hospitalization and often admission to an intensive care unit are as follows:

Age more than 65 years Comorbidity (COPD, diabetes mellitus, malignancy, immunode-Hospitalization within prior year Postsplenectomy Chronic alcoholism, malnutrition, immunosuppression Physical Examination Respiration more than 30 breaths per minute Shock (blood pressure 5 90/60 mm Hg) Temperature greater than 101°F Altered consciousness or confusion Extrapulmonary signs of disease; meningitis, endocarditis, arthritis White blood cell count less than 4000/mm3 or more than 30,000/ mm3; more than 5% bands Significant elevation in bands Pao, 5 60 mm Hg or Paco2 2 50 mm Hg on room air Elevated creatinine or BUN Hematocrit less than 30%, Hgb less than 9 g/dL Acidosis, disseminated intravascular coagulation, prolonged prothrombin time or partial thromboplastin time, thrombocytopenia Lobar pneumonia, multiple lobe pneumonia, cavitation, effusions, empyema, or rapid radiographic progression S. aureus, gram-negative bacilli, aspiration, or polymicrobic origin Labored breathing, inability to mobilize secretions, and a rapidly progressive course necessitate evaluation for intubation and ventilatory assistance. Sicker and more vulnerable patients require more aggressive ficiency, fluid retention from heart, liver, or renal disease) Laboratory Findings diagnostic work-up, including bronchoscopy, aspiration of parapneumonic effusions, and monitored assessment in an intensive care unit. A clinical prediction rule for 30-day mortality in patients with communityacquired pneumonia has recently been A weighted point system, based on the number of adverse indicators, can be applied to calculate the patient's mortality risk 6o This work is a significant advance and provides an improved structure for testing treatment decisions in patients with pneumonia.

Additional contributions have been made regarding indicators of mild disease that permit ambulatory treatment of patients with pneumonia.", 58, 59, la9 Criteria supporting the appropriateness of outpatient therapy include youth, lack of comorbid diseases, and absence of features indicating severe infection or an especially virulent pathogen:

Age less than 50 years who can and will take medication dependably (and will communicate if disease worsens) Lacks host defense defects associated with cardiac, renal, or liver failure, cerebrovascular disease, debility due to malignancy, chronic lung disease, immunosuppression, or nursing home residence Objective Features Suggesting Mild Disease Historical and Physical Findings Nonprogressive clinical course Normotensive, normothermic, alert, and oriented patient with normal respiratory rate, pulse less than 125, and no signs of extrapulmonic sepsis Laboratory Findings Normal oxygenation, acid-base balance and hemoglobin levels Postintervention PEFR or FEV, greater than 50% of baseline val-Normal platelet, white blood cell, and differential leukocyte Normal renal function and coagulation values Minimal bronchopneumonia without pleural effusion, cavita-Probability of low-risk pathogens ues count tion, or empyema

The authors58 emphasized that clinical judgment should supersede their guidelines and that broader applications await further testing. Interestingly, bronchial asthma was not associated with an adverse prognosis.58 Suggestions for antimicrobial therapy of patients requiring hospitalization for community-acquired pneumonia have been nicely summarized by the recent works of the American Thoracic Society and Bartlett and Mundy.Yr 142 Empiric therapy of elderly patients requiring hospitalization for pneumonia usually includes cephalosporins to treat pneumococcal or Hemophilus strains, and macrolides with or without rifampin for Legionella. Patients at risk of gram-negative bacillary, staphylococcal, or aspiration pneumonia are treated with regimens shown in Table 5 . Hypotensive or critically ill patients should also receive vancomycin. *Severely ill patients require broader coverage according to risk of specific diseases. Similarly, patients with risk of multiple pathogens like legionella, mycoplasma, or C. pneumoniae plus concomitant bacterial disease will require erythromycin, another macrolide, doxycycline, or a parenteral fluoroquinolone in addition to specific coverage for S. pneumoniae or other bacteria likely to be present. Antipneumococcal coverage is always necessary because of the frequency of pneumococcal pneumonia. Multidrug-resistant pneumococcal pneumonia can probably be treated adequately with high-dose cephalosporins but patients at risk of concomitant endocarditis, meningitis, or endophthalmitis may require concomitant parenteral vancomycin, meropenem, or rifampin. tErythromycin, azithromycin, or clarithromycin. *p-lactamase inhibitor combination: ampicillin-sulbactam, ticarcillin-ciavulanate, piperacillin-tazobac- §Parentera1 fluoroquinolones: ciprofloxacin, levofloxacin, Trovofloxacin. IlAminoglycoside or parenteral fluoroquinolone is added to ceftriaxone or cefotaxime. lflmipenem or meropenem is indicated for severely ill immunocompromised patients with risk of nosocomial infection. **Patients with comorbid disease are diagnosed and treated according to risks of specific diseases or complications of organ failure. Patients with AIDS, neutropenia, and leukemia or organ transplants require evaluation for opportunistic infections. Severely ili patients require more invasive diagnostic studies.

tt Patients with gram-negative bacillary pneumonia caused by Pseudornonas aefuginosa, Klebsiella pneumoniae, Enferobacter or Sefrafia spp should receive two antibiotics effective against the suspected pathogen (usually a p-lactam plus an aminoglycoside or parenteral ciprofloxacin (depending on renal dysfunction or prior antibiotic therapy). **Patients with organ failure or shock should receive two agents effective against the primaly pathogen plus therapy for intracellular pathogens like Legionella spp, M. pneumoniae, or C. pneumoniae. § §Victor Yu, MD, personal communication, April 1997.

((J(Patients with pneumonia and prominent wheezing or exacerbations of asthma during infection should have treatment that includes coverage for C. pneumoniae while that diagnosis is being confirmed.

lllIYoung, overtly healthy patients with minimal bronchopneumonia infiltrates and no indicators of serious disease can be treated with macrolides as outpatients.

***Only to be used in the elderly, nonmenstruating patient.

Hypotensive patients with organ failure or fulminant infection receive broadly based empiric therapy until diagnostic studies permit institution of pathogen-specific therapy. Patients with multidrug-resistant pathogens are an increasing problem; their therapy must be individualized. Of equal importance is the rapidly progressive pneumonia that may occur with bacteremia or with infection caused by S. pyogenes, plague, primary viral influenza, or staphylococcal pneumonia complicating viral influenza. Primary fungal pneumonia with blastomycosis, histoplasmosis, coccidioidomycosis, or cryptococcosis rarely causes fulminant infection. 126 Perhaps the most common fulminant pneumonia in the elderly is bacteremic pneumococcal pneumonia, which may present abruptly with shock in the absence of cough or sputum production.

In many areas of the country, 20% to 30% of strains will have intermediate to high-level resistance to penicillin and, therefore, penicillin is no longer the drug of choice for the primary treatment of suspected pneumococcal pne~monia.~, 2", 142, 169 Pneumococcal pneumonia caused by strains with intermediate penicillin sensitivities of 0.1 to less than 1.0 pg/mL can be treated with cephalosporins like ceftriaxone (1 to 2 g/day), or cefotaxime (3 to 6 &day). Patients with meningitis or fulminant pneumococcal infection should be treated with vancomycin plus cefotaxime or ceftriaxone until sensitivity data become available. It is important to remember that ceftizoxime is 10to 100-fold less active than cefotaxime or ceftriaxone against penicillin-resistant pneumoc~cci.~~ It has been suggested that cefotaxime dosage can be increased to 12 to 24 g daily to treat critically ill patients with marginally sensitive pneumococci.1s4 The applicability of this approach requires further study.

Elderly asthmatic patients with pneumonia are usually hospitalized because they are at greater risk of serious infection. The need for admission is based on the evidence of the severity of their infectious disease, and the severity of their asthma. Patients who are overtly well, who have indicators of mild disease, and who are clinically stable, however, may be treated as outpatients and followed c a r e f~l l y .~~ Although an algorithmic appr.oach to triaging the elderly patient may give a sense of false security, the "healthy" elderly patient with posttreatment FEV, or peak expiratory flow rate (PEFR) greater than 60% of previous best or of predicted may be considered for outpatient management.I5 Eligibility for ambulatory care requires a cooperative and dependable patient with an adequate support system to verify that the patient is taking and retaining medicines (i.e., not vomiting them up) and responding to ambulatory antibiotic therapy.

Oral antibiotics for the elderly asthmatic patient with pneumonia must provide adequate coverage for S. pneumoniae and H. infuen~ae.~ Broader-spectrum oral antibiotics like ampicillin-clavulanate, cefuroxime, or azithromycin meet this need. Alternative combination therapy with 1 g of parenteral ceftraxione and oral macrolide therapy provides substantial coverage until the patient's course and treatment can be reviewed the next day. Although oral fluoroquinolone treatment of pneumococcal pneumonia has been considered controversial in the past, the newer agent levofloxacin may be an acceptable alternative as experience is gained with its use.57~122 M . pneumoniae or C. pneumoniae can be treated with macrolides, doxycycline, or the fluoroquinolones cited previously.

Atypical pneumonia in the elderly asthmatic patient is less likely to be due to M . pneumoniae, but is often caused by C. pneumoniae. '19 The latter infection may exacerbate prior respiratory disease in the asthmatic patient or cause pneumonia presenting with new-onset asthma.79, Io6

The disease usually moves slowly through family members, causing complaints of pharyngitis, sinusitis, dry and poorly productive cough, headache, and malaise. The disease may cause a persistent illness with chronic circulating immune complexes that enhance atherosclerotic disease in elderly patients.la While the magnitude and frequency of that phenomena are being clarified scientifically, it seems prudent to initiate therapy early in the course of illness because of the potential benefits of shortening the duration of infection, ameliorating effects of asthma, and reducing risk of vascular disease.

Uncomplicated pneumonia caused by S. pneumoniae, H. infuenzae, or M . pneumoniae usually can be treated adequately in 7 to 10 days. C. pneumoniae generally is treated for 5 days with azithromycin or 10 to 14 days with other agents. Legionella pneumonia in the compromised patient may require 21 days of treatment.la There has been some concern over the use of fluoroquinolones as primary treatment of respiratory tract disease.186 Fluoroquinolones are contraindicated in pregnancy and therefore should not be used in sexually active women whose risk of pregnancy is uncertain. Ciprofloxacin is known to impair clearance of theophylline and can only be used with close monitoring of theophylline blood ls6 and sparfloxacin has an increased risk of photosensitivity. Levofloxacin and sparfloxacin do not affect theophylline metabolism but greater experience is required to demonstrate their efficacy as alternatives to parenteral therapy for elderly asthmatics with pneumonia.

The new fluoroquinolones are less active than ciprofloxacin against Pseudomonas aevuginosa and most fastidious gram-negative aerobic bacilli.lS6 Ciprofloxacin is the fluoroquinolone of choice against these pathog e n~~~ and is used in conjunction with another effective parenteral agent in hospitalized patients. As a class, the fluoroquinolones lack dependable efficacy against Stenotrophornonas and Nocardia spp. The fluoroquinolones have no antiviral or antifungal activity and should not be used as single-drug therapy for mycobacterial infection. The place of the new fluoroquinolones for treatment of polymicrobial anaerobic infection or fulminant pneumonia is not established. The breadth of the spectrum of activity of the fluoroquinolones has been responsible for their widespread misuse. Enthusiasm for their use has obscured the fact that their overuse increases the risk of emergence of fluoroquinolone resistance, thereby jeopardizing the future of even better fluoroquinolones currently under development. We need to reiterate the importance of defining the most likely microbial cause(s) of pneumonia prior to selecting an antibiotic to eradicate the pathogen causing infection. Focusing on the patient's risk of infection and the pathogen(s) causing it makes it easier to identify appropriate diagnostic studies and to remain alert to errors of diagnosis and treatment.

Viral respiratory diseases of elderly asthmatic patients are essentially the same as those of other patients of comparable age or debility. Illness from viral influenza A can be ameliorated by early treatment with either amantadine or rimantidine."', 135 Amantadine is primarily excreted by the kidneys, so the dose should be adjusted to reflect reduced renal function in the elderly.23 The ordinary amantadine dose of 100 mg twice daily is usually adjusted to 100 mg daily in the elderly or renally impaired patient. Rimantidine is excreted primarily by the liver, so its dosage need not be adjusted for renal dysfunction.

Patients with fulminant influenza A, influenza B, or respiratory syncytial viral (RSV) infection have been successfully treated with inhalational ribavirin.'07* 12', 128 This experience has been largely limited to severely ill patients requiring ventilatory assistance in an intensive care unit or patients with unusually severe host defense defects owing to liver, lung, or bone marrow transplantation, women in the third trimester of pregnancy, and a few very sick patients with ostensibly normal host ly3 The experience of RSV pneumonia in bone marrow transplant recipients suggests that treatment within the first 4 days of illness, prior to onset of clear-cut respiratory insufficiency, is required to modify the nearly 100% mortality seen in such patients.193 Treatment can be given as an 18-hour inhalation procedure or as a higher-dose treatment given four times daily. Current experience suggests that concomitant intravenous gamma globulin administration is helpful in bone marrow transplant patients with RSV pneumonia.4y, 193 Although elderly patients are known to be at increased risk of severe RSV, influenza A, or influenza B infection, most elderly patients with those infections will go undiagnosed, and will not receive ribavirin therapy. Ribavirin therapy should be thought of as a potentially useful therapeutic alternative for critically ill elderly patients whose course suggests RSV or influenza A or B infection.

Likewise, patients with primary herpes simplex, pneumonia, chickenpox pneumonia, or cytomegaloviral pneumonia can benefit from appropriate antiviral therapy with acyclovir, gancyclovir, or foscarnate. These illnesses are rare in the elderly asthmatic patient but need to be considered in the context of concomitant illness such as leukemia, lymphoma, and acquired immunodeficiency syndrome. 135, 195 Therapy for Fungal-Mediated Hypersensitivity ABPA may occur as a complication of asthma or cystic fibrosis. Patients usually require protracted therapy with prednisone, and their disease often relapses when the prednisone dose is reduced. Treatment with antifungal agents has been limited by the inability of current antimicrobials to eradicate aspergillus from bronchopulmonary tissues. At least three nonrandomized studies, however, have demonstrated a benefit from oral itraconazole therapy coupled with steroid 67, as reflected by reduction in serum immunoglobulin E, eosinophilia, and improvement in FEV, during therapy with itraconazole.", lZ4 These studies support an adjunctive role for itraconazole that may permit reduction, or rarely cessation, of prednisone ABPA therapy. Controlled trials are needed to document the validity of this contention. Likewise, evaluation of newer, more potent therapy for aspergillus pulmonary infection is badly needed.

In conclusion, asthma is underrecognized in the geriatric population and has some special considerations. Although data are lacking in the elderly, epidemiologic studies in younger age groups strongly suggest the causative and provocative roles of infection in asthma. Future evaluation must be performed to better characterize what role viral and bacterial infections have in the geriatric population. As the role of C. pneurnoniae and other infections in asthma is better defined, more specific therapy may be possible. The normal lung defense mechanisms decline with age, but clinical disease and therapeutic strategies are more dependent on organ dysfunction and underlying comorbid diseases. Thus assessment and specific therapy are dependent on an individual's physiologic health rather than chronologic age. For now, selection of therapy should be based on host vulnerability, the epidemiologic risk of infection, the severity of the patient's infection, and the virulence of potential pathogens. Although conceding the importance of antimicrobial therapy once infection occurs, one must continue to stress the importance of good hygiene, adequate nutrition, proper surveillance of the patient's asthma, and more vigilant use of vaccines to prevent infection in asthmatic patients. 

Legionella and Pneumocystis pneumonia in asthmatic children on high doses of systemic steroids

Influenza A virus-induced polymorphonuclear leukocyte dysfunction in the pathogenesis of experimental pneumococcal otitis media

Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges

Inflammatory markers of lower respiratory tract infection in elderly people

Acute exacerbations of asthma in adults: Role of Chlamydia pneumoniae in infection

Epidemiology and in vitro susceptibility of drug-resistant streptococcus pneumoniae

Allergic bronchopulmonary mycosis caused by Fusaviurn vasinfectum

Underdiagnosis of asthma in the elderly

Impaired tracheobronchial clearance in patients with mild stable asthma

Viral respiratory tract infection and exacerbations of asthma in adult patients

Absolute peripheral blood lymphocyte count and subsequent mortality of elderly men

The association of viral and mycoplasma infections with recurrence of wheezing in the asthmatic child

Transtracheal aspiration studies in asthmatic patients in relapse with "infective" asthma and in subjects without respiratory disease

Guidelines for the emergency management of asthma in adults

Sinusitis in children at home and in day-nurseries

Predicting the need for hospitalization of ambulatory patients with pneumonia

Asthma in the elderly patient

Asthma in the elderly: A comparison between patients with recently acquired and long-standing disease

British Thoracic Society and the Public Health Laboratory Service: Communityacquired pneumonia in adults in British hospitals in 1982-1983: A survey of aetiology, mortality, prognostic factors and outcome

Epidemiology of asthma and allergic rhinitis in a total community

Epidemiology of asthma and allergic rhinitis in a total community

lnfectious Disease and Microbiology

Effect of influenza A virus on leukocyte histamine release

Transbronchial clearance in patients with influenza

Respiratory virus infections and aeroallergens in acute bronchial asthma

Acquired ciliary defects in the nasal epithelium of children with acute viral upper respiratory tract infections

Geriatric Medicine

Centers for Disease Control: Pneumonia and influenza death rates-United States, 1979-1994

Nutritional regulation of immunity and risk of infection in old age

Nutrition and immunocompetence of the elderly. Effect of short-term nutritional supplementation on cell-mediated immunity and lymphocyte subsets

Severe varicella after low dose inhaled corticosteroids

Mycoplasma as a cofactor in severe respiratory infections

Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measured on a simple awareness scale

Rapidly progressive respiratory failure due to Aspergillus pneumonia: A complication of short-term corticosteroid therapy

Infections in the elderly

Predicting hospital-associated mortality for medicare patients: A method for patients with stroke, pneumonia, acute myocardial infarction, and congestive heart failure

et a1 Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole

The prevalence and incidence of asthma and asthma-like symptoms in a general population sample

Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infection in Australian adults

Spotting the pneumococcus in today's pneumonia milieu

Beneficial effects of oral zinc supplementation on immune response of old people

Halcomb WW Reduction in duration of common cold by zinc gluconate lozenges in a double-blind study

Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infections

age on manifestations and outcome

Chlamydia pneumoniae (TWAR)

Provocation of airflow limitation by viral infection: Implication for treatment

Acute community-acquired sinusitis

Immunology of the aging lung

et a1 Diminished activity of ceftizoxime in comparison to cefotaxime and ceftriaxone against Streptococcus pneumoniae

Treatment of Chlamydia pneumoniae infection in adult asthma: A beforeafter trial

Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma

Asthma and Chlamydia1 infection: A case series

Speers DM Respiratory syncytial virus infection in adults: Clinical, virologic, and serial pulmonary function studies

Do pulmonary radiographic findings at presentation predict mortality in patients with community-acquired pneumonia?

Adhesion molecules in lung disease

Hypogammaglobulinemia in asthmatic patients

Etiology and antimicrobial therapy of acute maxillary sinusitis

Pulmonary edema in influenza1 pneumonia of the mouse and the relation of fluid in the lung to the inception of pneumococcal pneumonia

A longitudinal study of respiratory viruses and bacteria in the etiology of acute otitis media with effusion

Mechanisms of transmission of rhinovirus infection

Bronchopulmonary aspergillosis

Respiratory viral infection and wheezy bronchitis in childhood

Role of viruses and bacteria in acute wheezy bronchitis in childhood: A study of sputum

et a1 Viral and bacterial infections in adults with chronic asthma

et a1 Association of viral and mycoplasma infections with exacerbations of asthma

et a1 Enhancement of IgE-mediated histamine release from human basophils by viruses

et a1 Deficiency of production of leukocyte interferon (interferon-a) in vitro and in vivo in children with recurrent respiratory tract infections

The pulmonary surfactant factor. Current knowledge, research trends and use in clinical practice

Bratislavske Lokarske Listy 95452455

Upper respiratory tract infections and airway reactivity in normal and asthmatic subjects

The association of viruses with acute asthma

Viral infections in exacerbations in schoolchildren with cough and wheeze: A longitudinal study

Disseminated strongyloidiasis: An unheralded risk of corticosteroid therapy

Review of fungus-induced asthmatic reactions

Pneumonia due to Chlamydia pneumoniae: Prevalence, clinical features, diagnosis, and treatment

Kava T Acute respiratory infection, influenza vaccination and airway reactivity in asthma

Kava T Effect of respiratory infections on exacerbation of asthma in adult patients

Ribaviran small-particle aerosol treatment of influenza

Kouradsen HB: Quality and avidity of pneumococcal antibodies before and up to five years after pneumococcal vaccination of elderly patients

Azithromycin for treatment of communityacquired pneumonia caused by legionella pneumophila: A retrospective study

Prospective study of pneumonia hospitalizations and mortality of US. older people: The role of chronic conditions, health behaviour, and nutritional status

Laforce MF Antimicrobial therapy for lower respiratory tract infections in adults: A review

et a1 Damage of the airway epithelium and bronchial reactivity in patients with asthma

A causal link between handwashing and risk of infection. Examination of the evidence

Fluoroquinolone toxicities-an update

Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions

Bronchial clearance of DTPA is increased in acute asthma but not in chronic asthma

Viral infections and asthma

Bolder I, et a1 Multiple pathogens in adult patients admitted with community-acquired pneumonia: A one year prospective study of 346 consecutive patients

Risk factors for acquiring pneumococcal infections

Amantadine effect on peripheral airways abnormalities in influenza. A study in 15 students with natural influenza infection

et a1 Treatment of community-acquired pneumonia: A randomized comparison of sparfloxacin, amoxycillin-davidamic acid and erythromycin

Lorber B: The common cold

Itraconazole allergic bronchopulmonary aspergillosis in twin brothers with cystic fibrosis

Community-acquired pneumonia requiring hospitalization: 5-year prospective study

Today's approach to community-acquired pneumonia

Distribution of Streptococcus pneumoniue resistant to penicillin in the USA and in vitro susceptibilities to selected oral antibiotics

Ribaviran aerosol treatment of influenza B virus infection

The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children

Mucociliary transport in allergic patients with antigen-induced bronchospasm

Viruses as precipitants of asthmatic attacks in children

Viral infections as a precipitant of wheeze in children: Combined home and hospital study

Severe community-acquired pneumonia: Etiology, epidemiology, and prognosis factors

Nutrition and asthma

Viral respiratory infections in the community: Epidemiology, agents, and interventions

Fatal varicella zoster infection in a severe steroid dependent asthmatic patient receiving methotrexate

Zinc gluconate lozenges for treating the common cold: A randomized, double-blind placebo-controlled study

Including diagnosis and therapy of infection caused by penicillin-resistant strains

The lack of association between aging and post-vaccination levels of IgG antibody to capsular polysaccharide of streptococcus pneumoniae

Antibody to capsular polysaccharide of streptococcus pneumoniae: prevalance, persistence, and response to revaccination

Respiratory viruses and exacerbations of asthma in adults

Guidelines for the initial management of adults with community-acquired pneumonia: Diagnosis, assessment of severity, and initial antimicrobial therapy

Severe community-acquired pneumonia: Factors influencing need of intensive care treatment and prognosis

Serologic response to itraconazole in allergic bronchopulmonary aspergillosis

Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease

Viruses as precipitants of asthma symptoms

Bronchopulmonary torulopsis

Catalytic activity of anti-ground state antibodies, antibody subunits, and known autoantibodies

Transbronchial mucociliary clearance in asthma: Impairment during remission

The role of Chlamydia pneumonia in acute exacerbations in asthma

Assessment and management of acute asthma in the elderly: A comparison with younger asthmatics

Effect of age on cytotoxic T lymphocytes memory as well as serum and local antibody responses elicited by inactivated influenza virus vaccine

Increased response of asthmatic subjects to methacholine after influenza vaccine

Prevalence and treatment of chronic airways obstruction in adults over the age of 45

Airborne infections

Nonresolving pneumonia in steroidtreated patients with obstructive lung disease

et a1 Pneumocystis carinii pneumonia in rheumatoid arthritis patients treated with methotrexate. A report of two cases

et a1 Clinical infections in the noninstitutionalized geriatric age group: Methods utilized and incidence of infections

Enhancement by parainfluenza-3 and capsaicin in airway smooth muscle from guinea pig

Chronic Chlamydia pneumoniae infection as a risk factor for coronary artery heart disease in the Helsinki study

Compliance with therapy: How great a problem?

The prevalence of allergic bronchopulmonary aspergillosis in patients with asthma, determined by serologic and radiologic criteria in patients at risk

Mycoplasma pneumoniae is a frequent cause of exacerbation of bronchial asthma in adults

Pulmonary complications of combination therapy with cyclophosphamide and prednisone

Pulmonary tuberculosis in patients treated with inhaled beclomethasone

The protective efficacy of polyvalent pneumococcal polysaccharide vaccine

et a1 Double-blind study of the effectiveness of broad spectrum antibiotic in status asthmaticus

Community-acquired pneumonia: It is time for the penicillin bullet to be replaced

Sinusitis and bronchial asthma

Aspirin-sensitive asthma

Childhood asthma following hospitalization with acute viral brochiolitis in infancy

Failure of zinc gluconate in treatment of acute upper respiratory tract infections

Asthma and atopy as diseases of unknown cause. A viral hypothesis possibly explaining the epidemiologic association of atopic diseases and various forms of asthma

et a1 The contribution of respiratory viruses to severe exacerbations of asthma in adults

Pulmonary mucormycosis in acute histiocytic leukemia

Virus-induced airway hyperresponsiveness in man

Infectious diseases

The beta-adrenergic theory of atopic abnormality in asthma

Bacterial colonization of nursing home residents on

IgE antibodies to mycoplasma pneumoniae in 183. Verespej MA

High doses of cefotaxime in treatment of adult meningitis due to Streptococcus pneumoniue with decreased susceptibilities to broad spectrum cephalosporins

et a1 A rhinovirus outbreak among residents of a longterm care facility

The fluoroquinolones

Allergic bronchopulmonary aspergillosis: A review

Identification of low-risk hospitalized patients with pneumonia: Implications for early conversion to oral antimicrobial therapy

Zinc gluconate lozenges for common cold: A double-blind clinical trial

Inhaled steroids and severe viral infection

The development of respiratory syncytial virusspecific IgE and the release of histamine in nasopharyngeal secretions after infection

Community respiratory viral infections among hospitalized adult bone marrow transplant recipients

Invasive aspergillosis. A complication of treatment of temporal arteritis

Prevention and treatment of cytomegalovirus pneumonia in transplant recipients

Ziment I Management of respiratory problems in the aged

Clin Allergy 9293-301, 1979 admission to an acute care hospital. J Hosp Infect 32127-133, 1996 asthma and other atopic diseases