© 2005 American Thoracic Society doi: 10.1164/rccm.2504004
Bacteria and Airway Inflammation in Chronic Obstructive Pulmonary DiseaseMore EvidenceRoyal Brompton Hospital, London, United Kingdom Most of the bacterial species isolated from sputum during exacerbations of chronic obstructive pulmonary disease (COPD) colonize the nasopharynx of healthy individuals, and can be found in the lower airways of patients with COPD during stable phases of their disease (1, 2). The most commonly isolated species are nontypable Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. About half of exacerbations yield positive sputum cultures, and the isolation rate may be increased by the selection of purulent samples (1, 3). In this issue of the Journal (pp. 195–199), Murphy and coworkers (4) report that M. catarrhalis was cultured from sputum in approximately 10% of patients with COPD with exacerbations. Studies that have used bronchoscopy to sample the lower airways directly have shown that approximately 25% of patients with stable COPD have lower airway bacterial colonization with a potential pathogenic species, and the proportion increases to approximately 50% during an exacerbation. Bacterial counts are much higher during an exacerbation (5–8). Bacteria have been associated with airway inflammation both in the stable state, when the level of inflammation is related to the size of the bacterial load, and during exacerbations, when resolution of bronchial inflammation is related to bacterial eradication (9–11). However, mucosal damage releases nutrients for bacterial growth, and bacteria could be viewed as passengers "along for the ride," taking advantage of the mucosal environment created by another insult, such as viral infection or air pollution (12). Some of the answers to this "chicken and egg" argument are provided by the study of Murphy and colleagues. Murphy and colleagues (4) studied a cohort of patients with COPD, seeing them at monthly intervals, with extra visits arranged for exacerbations. Samples were taken at each visit, allowing longitudinal bacteriologic and immunologic investigations to be performed. A similar approach was adopted by Gump and coworkers (2) many years ago, and concluded that bacteria were isolated with identical frequency whether the patient was stable or having an exacerbation. Murphy and colleagues have made two important advances in methodology compared with older studies: they have used molecular techniques to identify bacteria and differentiate newly acquired strains from those that have been carried for longer periods, and they have tested the immune response to the patient's own bacterial isolate and related this to the patient's previous results. In a previous study, they showed that 33% of clinic visits associated with acquisition of a new strain were accompanied by an exacerbation, as compared with 15.4% of visits without a new strain being found (13). One hypothesis to explain this observation would be that the new strain, not being recognized by the immune system, can multiply and invade the mucosa, thereby stimulating systemic inflammation and symptoms of an exacerbation. They went on to show that, when a new strain was associated with an exacerbation, a specific systemic antibody response occurred that gave positive results in a bactericidal assay (14). That finding adds weight to the argument that the bacteria are playing a causative role in the exacerbation by participating in the generation of a host response intended to eliminate them. In their present publication, Murphy and colleagues (4) concentrate on patients from whom M. catarrhalis was isolated. The characteristics of these patients did not differ from the COPD cohort as a whole, suggesting that all patients with COPD are susceptible to this bacterial infection. There were 120 episodes in 50 patients of the bacterium being acquired and subsequently cleared; 47.5% of such cases were associated with an exacerbation. The majority of patients made new systemic and/or mucosal antibodies to their homologous strain after acquisition, and subsequently developed strain-specific protection. The study also informs the debate about the importance of bacterial infection in COPD. In contrast to H. influenzae, which can be carried by patients for long periods, M. catarrhalis was eliminated quickly, even in the absence of antibiotic treatment. Most strains were cleared by the time of the next visit, and because there was a month between visits, clearance may be even more rapid than Murphy and coworkers (4) report. This host–bacterial interaction is very striking, and a better understanding of the differences between the two species could be important in developing new treatment strategies. The rapid clearance of M. catarrhalis by host defenses also explains the apparent success of amoxicillin treatment for ß-lactamase–producing strains in clinical trials, because this might be unrelated to the antibiotic treatment. Although lower airway bacterial colonization has been associated with airway inflammation, there is some evidence that this wanes with time (14, 15). Therefore, carriage of a bacterial strain to which tolerance has developed might protect against acquisition of a new strain (which would be more likely to provoke an exacerbation) by occupying an ecologic niche in the airway (16). However, contrary to this hypothesis, Murphy and coworkers (4) did not find that the presence of a concomitant pathogen had an effect on whether an exacerbation occurred when a new strain of M. catarrhalis was isolated. Their study also found a difference in the local IgA and systemic IgG immune responses to M. catarrhalis, which occurred independently. Asymptomatic colonization was more often associated with development of a mucosal antibody response compared with an exacerbation. Such local antibody production might have protected the airway against progression from bacterial colonization to infection. In contrast, exacerbations were associated with a greater intensity of systemic antibody response, suggesting that local bacterial invasion had occurred. Thus, if antigens could be identified that induce protective mucosal immune responses, this could lead to future vaccines. Unfortunately, in the present study, a new antibody response had no effect on the time to subsequent acquisition of another strain of M. catarrhalis. This finding does not bode well for a vaccine-based approach unless conserved antigens common to most strains can be identified. The debate about the importance of bacteria in COPD will continue. The presence of bacteria in sputum does not indicate causation, and the study by Murphy and colleagues (4) did not exclude alternative causes of exacerbations, such as infections with viruses or atypical species. Indeed, viral infection might alter the host–bacterial interaction by disrupting the integrity of the epithelium, which could also influence the antibody response to subsequent bacterial infection. A further concern of all studies using sputum is the lack of information about small airway biology, which might not be accurately reflected in sputum. However, the success of the longitudinal study design adopted by Murphy and coworkers should lead to future work using a similar approach that would include the influence of therapy in the study design as well as clinical outcomes. In the present article, neither antibiotic nor corticosteroid administration had an effect on the frequency and/or intensity of new serum and local antibody responses (4). This result is surprising in that one might have expected these agents to curtail the exacerbation and so reduce the antibody response. FOOTNOTES Am J Respir Crit Care Med Vol 172. pp 147–148, 2005 Internet address: www.atsjournals.org Conflict of Interest Statement: R.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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