© 2004 American Thoracic Society
Does the Presence of Antibodies Justify the Use of Antibiotics in Exacerbations of Chronic Bronchitis?
Professor of Medicine, Vice-Chairman Department of Medicine State University of New York at Stony Brook Stony Brook, New York For many years there has been controversy about whether bacteria play a role in acute exacerbations of chronic bronchitis and thus whether antibiotics have a role in disease management (1). In a recent consensus conference, sponsoring societies stated that antibiotics have a limited role in this illness, and should only be used in patients with severe exacerbations (2, 3). Unfortunately, most evidence about the role of infection has been derived from bacteriologic cultures of respiratory secretions (collected either by expectoration or by bronchoscopy), which have been studied either qualitatively or quantitatively (4, 5). This information has not always been useful in addressing the role of infection, since patients with chronic bronchitis typically have chronic airway colonization and the presence of bacteria in airway secretions (even in high concentrations) does not establish an etiologic role in exacerbations. In this issue of the Journal (pp. 448–453), Sethi and colleagues report evidence of a strain-specific immune response to Haemophilus influenzae following exacerbation, and these findings add weight to the argument that bacteria are responsible for exacerbations, and are more than just colonizers, particularly because they are able to elicit a specific host response that appears to be intended to eliminate them (6). Previous studies of the immune response during acute exacerbations of chronic bronchitis have not shown convincing evidence of a host response to infection, and this has led to skepticism about the role of bacteria in this illness (1, 7). The study by Sethi and coworkers is different from previous studies in a number of important ways (6). First, the data were collected longitudinally from a population of patients with chronic bronchitis who were seen monthly and whenever a symptomatic exacerbation was present, with each patient serving as his own control. At each visit, the patient had an expectorated sputum sample collected and serum collected to measure antibody response. With this design, antibodies could be measured before and after an exacerbation (acute and convalescent) and the antibodies measured were of the IgG type, directed at surface-exposed epitopes of homologous strains of H. influenzae. This design means that antibodies directed at the actual strain that was present in the sputum at the time of exacerbation were measured, rather than looking for antibodies directed at a laboratory strain of bacteria (8). The presence of an antibody response was defined by comparing the pre- and postexacerbation antibody levels to similar data from patients without H. influenzae exacerbations. The antibodies measured were detected by both an ELISA assay and a bactericidal assay capable of detecting antibody-mediated complement-dependent killing of H. influenzae. This methodology differed from prior studies that often examined only a single serum sample and measured generic antibodies rather than antibodies directed to surface-exposed epitopes present on the actual strain in the airway during the exacerbation (8). The findings in this study complement other data reported by the same investigators showing that exacerbations are more common after patients acquire a new strain of either H. influenzae, pneumococcus, or Moraxella catarrhalis (defined by molecular methods) than if the airway persistently harbors the same strain (9). In a longitudinal study of outpatients, the authors found that 33% of clinic visits associated with acquisition of a new bacterial strain were accompanied by an exacerbation, as compared with 15.4% of visits without the acquisition of a new bacterial strain (9). Now the authors have shown that the acquisition of a new strain is also accompanied by an antibody response to this same new organism. In the current report, there were 35 patients who had acute exacerbations caused by H. influenzae and 46 without such exacerbations (6). Because patients often had multiple exacerbations, there were 69 strains of H. influenzae present during an exacerbation, and by molecular typing, 36 were new strains and 33 were persistent. Interestingly, if patients acquired a new strain at the time of an exacerbation, a specific antibody response to this strain (by ELISA assay) was present 58.3% of the time, while only 15.2% of exacerbations characterized by the presence of a persistent strain were accompanied by an antibody response. Similar findings were seen when bactericidal antibodies were measured. The specificity of the bactericidal antibody response was demonstrated because only 12% of heterologous strains of H. influenzae were killed by new bactericidal antibodies that developed after an exacerbation. These findings are consistent with previous studies that did not demonstrate an antibody response to laboratory strains of H. influenzae following an exacerbation since these strains can be viewed as heterologous, and not homologous. In the instance of persistence of a preexisting strain at the time of exacerbation, the absence of an antibody response implies that another bacteria (to which antibodies were not measured) or a virus could have caused the exacerbation. One limitation of the current study was the failure to study these patients for evidence of viral infection or infection with atypical pathogens. When the results of the current study are combined with other data, a cohesive mechanism for bacteria to cause exacerbation seems to emerge. Patients with chronic bronchitis are colonized by an organism such as H. influenzae and remain well, presumably because of the presence of an adequate host response to these organisms. Then, for unclear reasons, the strain of the organism changes and the patient becomes ill because protective antibodies are not present. The evidence that this change in strain is actually causing the exacerbation is now more compelling because the current study demonstrates that most patients who acquire a new strain of H. influenzae then develop a homologous antibody response to this organism. The development of an antibody response then protects the patient until either a new strain emerges again or another pathogen infects the patient. More data are needed in this area to determine if this paradigm also applies to pneumococcus, M. catarrhalis, and other pathogens implicated in exacerbations of chronic bronchitis. These new data are exciting and clearly advance our understanding of disease pathogenesis, supporting a role for bacteria in at least some episodes of acute exacerbations of chronic bronchitis. The fact that antibodies may be protective raises the interesting question of whether immunization strategies can be developed to prevent exacerbations. If such a strategy is used, it will likely be difficult because there does not appear to be a universally protective antibody against H. influenzae. Rather, protective antibodies are strain-specific, aimed at exposed surface epitopes, and generally not cross-reactive to other strains of H. influenzae. Nonetheless, these new data suggest that a focus on host antibody response is essential in the understanding and prevention of exacerbations of COPD. FOOTNOTES Conflict of Interest Statement: M.S.N. received honoria for consulting, lectures, or advisory boards of greater than $5,000 from Pfizer, Bayer, Glaxo-Smith Kline, Aventis, and Bristol-Myers in 2001, 2002, and 2003. REFERENCES
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