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The Proceedings of the American Thoracic Society 1:109-114 (2004)
© 2004 The American Thoracic Society

Bacteria in Exacerbations of Chronic Obstructive Pulmonary Disease

Phenomenon or Epiphenomenon?

Sanjay Sethi

Department of Medicine, University of Buffalo SUNY, and VA WNY Healthcare System, Buffalo, New York

Correspondence and requests for reprints should be addressed to Sanjay Sethi, M.D., VA WNY Healthcare System, Medical Research 151, 3495 Bailey Avenue, Buffalo, NY 14215. E-mail: ssethi{at}buffalo.edu


   ABSTRACT
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 ABSTRACT
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Our understanding of the pathogenesis and consequences of acute exacerbations of chronic obstructive pulmonary disease (COPD) has increased considerably in the past decade. Several new lines of evidence support bacterial causation of approximately half of the exacerbations in COPD. Acquisition of new strains of bacterial pathogens in patients with COPD is associated with a substantial increase in risk of exacerbation. Bacterial pathogens are isolated in significant concentrations from bronchoscopic samples obtained during acute exacerbation. Neutrophilic airway inflammation is associated with isolation of bacterial pathogens from sputum. A specific immune response to the infecting strains of bacterial pathogens isolated from sputum during exacerbations has been demonstrated. Future work should strive to understand better the host–pathogen interaction that leads to an exacerbation and to develop novel therapeutic and preventive measures.

Key Words: chronic obstructive pulmonary disease • exacerbation • bacteria • surface antigen • infection

Exacerbations of chronic obstructive pulmonary disease (COPD) were long regarded as a nuisance that had little impact on the course of the disorder. With increasing realization of the significant impact of exacerbations on morbidity and mortality in COPD, they are now receiving well deserved attention (1–4). Opinion regarding the contribution of bacterial infection to the pathogenesis of exacerbations has ranged from a preeminent role as embodied in the "British Hypothesis" in the 1950s and 1960s to the idea that the infection is a mere epiphenomenon in 1970s and 1980s (5, 6). In the last decade, new research methods have been applied to this question that have led to a better delineation of the contribution of bacterial infection to exacerbations of COPD.

Potential pathways by which bacteria could contribute to the pathogenesis of acute exacerbation include (1) primary infection of the lower airways, (2) secondary infection of the airways after an antecedent viral infection, and (3) bacterial antigens inducing bronchial hyperreactivity and eosinophilic inflammation (7). In this review, evidence for bacteria as a primary cause of exacerbations in COPD is discussed, with an emphasis on information gained from research techniques developed over in the last decade.


   METHODS TO DETERMINE THE ROLE OF BACTERIA IN EXACERBATIONS OF COPD
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The methods used to determine the role of bacteria in exacerbations of COPD can be categorized as either conventional or new (Table 1). Each of these approaches has contributed to our understanding of the disease.


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  		TABLE 1. Research methods used to understand the role of bacteria in exacerbations of chronic obstructive pulmonary disease

 
Conventional Methods
Sputum cultures.
Bacteria are isolated from sputum in 40–60% of acute exacerbations of COPD. Table 2 summarizes the sputum bacteriology obtained in 14 clinical trials of antibiotics in acute exacerbation published in the last few years (7). A variation in the relative incidence of specific pathogens is seen and may relate to patient inclusion criteria and sputum culture techniques. The three predominant bacterial species isolated from patients experiencing exacerbation of COPD are nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. These three species are also the predominant bacterial pathogens implicated in other respiratory mucosal infections, otitis media, and sinusitis. Other less frequently isolated potential pathogens are Haemophilus parainfluenzae, Staphylococcus aureus, Pseudomonas aeruginosa, and gram-negative Enterobacteriaceae. H. parainfluenzae and S. aureus are rarely implicated in other respiratory mucosal infections and are frequently a part of normal oral flora. This would suggest that they are unlikely to be pathogens of major importance in acute exacerbations of COPD.


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  		TABLE 2. Relative frequency of bacterial pathogens isolated from 14 recent antibiotic comparison trials in acute exacerbations of chronic obstructive pulmonary disease

 
In the past, isolation from sputum of a potential pathogen along with the presence of symptoms consistent with an acute infection was often accepted to represent a causal relationship. This proposed relationship between sputum pathogen isolation and symptoms of an exacerbation, however, was called into question when several longitudinal cohort studies demonstrated that the incidence of bacterial isolation from sputum during exacerbations of COPD was not different from their incidence during stable COPD (8, 9).

Advances in our understanding of bacterial pathogenesis in the past several decades have shown that sputum culture, when used alone as a research tool to delineate the cause of exacerbations of COPD, has major limitations. Contamination by upper airway secretions that may often contain potential pathogens is a major concern. This limitation can be overcome when uncontaminated lower respiratory secretions are obtained by bronchoscopy and cultures are performed quantitatively (discussed later here). Identification of pathogens as species by sputum culture, in the absence of strain differentiation, does not distinguish between preexisting colonization and acquisition of a new infecting strain. This limitation can be overcome by strain differentiation using molecular typing of the pathogens recovered from sputum (discussed later here). These new approaches have been extremely useful in research settings to delineate the role of bacterial infection in exacerbations of COPD. However, because of their complexity, they are not applicable to routine clinical practice.

Sputum cultures are still useful in researching the pathogenesis of exacerbations of COPD, as they provide the pathogens to be studied further. It is important to note that all studies to date of bacterial causation of exacerbations have used a single culture of sputum at the time of presentation and standard or semiquantitative culture techniques. No study has studied multiple sputum samples from each exacerbation or applied more sensitive techniques such as polymerase chain reaction for bacterial antigens to sputum samples. It is quite possible that such studies may reveal that a larger proportion of exacerbations has a bacterial origin than the current data suggest.

Serologic studies to bacterial antigens.
Studies of immune response to microbial pathogens have been widely used to determine whether the potential pathogen is responsible for an infectious syndrome. This approach in the past was mainly applied to the study of H. influenzae in exacerbations of COPD (10). A critical analysis of eight of these studies demonstrates their limitations in light of current knowledge of bacterial pathogenesis (Table 3) (11–18). Four of these studies compared antibodies in single sera obtained from patients with sera obtained from healthy control subjects rather than between paired sera obtained from individual patients before and after the exacerbation, potentially failing to detect significant immune responses (11–14). In the other four studies, where paired sera were used, the acute sera were obtained at the time of presentation rather than before the onset of infection (15–18).


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  		TABLE 3. Limitations of published studies of immune response to bacterial pathogens in acute exacerbations of chronic obstructive pulmonary disease

 
Because the presentation of exacerbations can be subacute over days to weeks, using acute sera as preinfection sera can confound the results, as a substantial immune response could be present by the time of presentation of the exacerbation. Seven of the eight studies used a single or a small panel of laboratory strains of H. influenzae as antigen instead of the strains recovered from sputum during the exacerbations (11–16, 18). In view of the considerable variation in the surface antigenic structure among H. influenzae strains, such a method fails to detect strain-specific immune responses (7). Furthermore, immunoassays used in seven of the eight studies were not specific for antibodies to epitopes exposed on the bacterial surface, an approach that will not detect potentially protective antibodies in the background of antibodies to nonsurface-exposed or cross-reactive epitopes (11–16, 18).

In view of these limitations, the results of these studies, unsurprisingly, were contradictory. Of the studies discussed, only that by Musher and colleagues using homologous strains, assays for surface-exposed epitopes, and paired sera demonstrated an unequivocal immune response (new opsonophagocytic antibodies) to H. influenzae after exacerbation of COPD (17). This study, however, was limited to a small number of patients hospitalized for febrile acute tracheobronchitis because of this pathogen, and it may not be appropriate to use the results to make generalizations about exacerbations that are not associated with fever and that are treated on an outpatient basis. Studies can be designed to address the limitations of previous work and provide a more accurate picture of the immune response to bacterial pathogens after exacerbations of COPD (discussed later here). Such studies would use the infecting strains as antigen, immunoassays specific for antibodies to surface-exposed epitopes, and paired patient serum samples, with the preinfection samples obtained before the exacerbation.

Antibiotic trials in exacerbation of COPD.
It has been suggested that if bacteria are important in acute exacerbations of COPD, antibiotics would show dramatic benefits over placebo in randomized double-blind trials. However, the results of placebo-controlled antibiotic trials in exacerbations have been inconsistent, demonstrating either a small benefit or no benefit (19). This lack of efficacy with antibiotics does not necessarily translate to the absence of bacterial causes of exacerbations (Table 4). Instead, several potential explanations for trials showing no benefit with antibiotics in acute exacerbations include the following: (1) An exacerbation may be due to a mucosal infection, and the use of antibiotics in other mucosal infections such as otitis media and sinusitis is also not associated with dramatic efficacy over placebo. This does not imply that mucosal infections are nonbacterial. (2) The expected benefits from antibiotics in a mucosal infection primarily are a more rapid resolution of symptoms and prevention of complications. Unfortunately, most studies of antibiotics in exacerbations have not measured the speed of resolution of symptoms. Rather, the endpoint has been the success of treatment at 3 weeks after onset of the exacerbation. The systemic immune–inflammatory response would be expected to resolve a large proportion of bacterial exacerbations in this time period, disguising any potential effect of antibiotics. (3) Many studies include patients with mild impairment of lung function who are likely to have a low rate of complications, making a difference from placebo prone to a type 2 error. (4) Exacerbations are nonbacterial in 50% of the patients, with no expected benefit from antibiotics, again predisposing studies to a type 2 error. (5) Antibiotic resistance in some of these pathogens, compounded by a lack of penetration into the bronchial tissues and fluids by some drugs, is likely to diminish the effects of antibiotics in exacerbations.


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  		TABLE 4. Limitations of published placebo-controlled antibiotic trials in acute exacerbations of chronic obstructive pulmonary disease

 
A metaanalysis of nine trials demonstrated a small but significant beneficial effect of antibiotics over placebo in exacerbation in COPD (19). In addition, two trials have since been published, as well as a trial originally published in Italian in 1991 that has been analyzed further and published in English (20–22). These three studies differed in patient populations, antibiotics used, and endpoints measured and, not surprisingly, yielded conflicting results. Sachs and colleagues enrolled 71 patients with relatively mild COPD, included subjects with asthma, and had an incidence of bacterial exacerbations that was 11% (20). All subjects received oral steroids and were randomized to amoxicillin, cotrimoxazole, or placebo. The rate of treatment success in this study was 91.5%, but no benefit was seen with antibiotics. When the size of the study, the patient population, the etiology of exacerbation, and the choice of antibiotics are considered, it would have been a surprise to see a benefit with antibiotics.

In contrast, Nouira and colleagues enrolled a very different spectrum, 93 patients with exacerbations of severe COPD requiring ventilatory support in an intensive care unit (21). Patients were randomized to receive ofloxacin or placebo, although no corticosteroids were administered. The tracheobronchial aspirates revealed potential bacterial etiology in 61% of these exacerbations. There was a dramatic benefit in this study, with antibiotics reducing the risk of mortality and need for additional antibiotics by 17.5-fold and 28.4-fold, respectively.

Finally, Allegra and colleagues compared amoxicillin/clavulanate to placebo in 414 exacerbations in 369 patients with varying severity of underlying COPD (22). This study measured outcome at 5 days, instead of the more traditional 3 weeks. Amoxicillin/clavulanate resulted in clinical success or improvement in 86.4% of patients compared with 50.6% of patients on placebo. Although antibiotics were superior to placebo irrespective of the severity of underlying airway obstruction, the impact of antibiotics was greater with more severe underlying COPD.

In summary, therefore, placebo-controlled antibiotic trials appear to demonstrate benefits with antibiotic therapy, especially if patients are enrolled in adequate numbers or have more severe underlying COPD or if the primary endpoint is determined early in the course of treatment (21–23). Systemic corticosteroids also provide benefit in exacerbations of COPD, albeit such benefit is not dramatic (24). Whether the benefits of antibiotics are independent and possibly additive to the benefit with systemic corticosteroids is an important question that has not yet been addressed in well designed and conducted trials. Another important question, as yet not addressed in trials in exacerbations of COPD, is whether the choice of antibiotics, specifically the choice of an antibiotic with greater microbiologic efficacy in vitro, results in better outcome than an antibiotic with limited microbiologic efficacy in vitro.

Realizing the limitations of the previously mentioned techniques in understanding the role of bacteria in exacerbations of COPD, in the last decade, several investigators have reexamined the issue using either new diagnostic modalities or research techniques (Table 1) and have provided exciting new data and a more rigorous evaluation of the etiology of exacerbations.

Newer Methods
Bronchoscopic sampling of lower respiratory tract in exacerbations of COPD.
One major limitation of sputum samples is the invariable contamination by saliva during expectoration, thereby decreasing the specificity of the results of culture of these samples. Samples obtained of distal airway secretions by protected specimen brush or by bronchoalveolar lavage are uncontaminated by upper respiratory tract secretions, and bacterial concentrations above certain thresholds on quantitative culture correlate with tissue infection (25). Four studies using this method in exacerbations have shown consistently significant bacterial infection of the distal airways in approximately 50% of the patients experiencing exacerbation (26–29). The bacterial species isolated from distal airway secretions represent the same spectrum of pathogens commonly isolated from cultures of sputum samples obtained from COPD patients suffering acute exacerbation.

Monso and colleagues (26) included a control group of 29 patients with stable COPD and demonstrated that exacerbation was associated twice more often with distal airway infection with 103 or more cfu/ml of pathogenic bacteria and four times more often with 104 or more cfu/ml of pathogenic bacteria. In a more severely ill population of 50 COPD patients who were placed on mechanical ventilation for an exacerbation, Soler and colleagues demonstrated that a large proportion (28%) of pathogens isolated were P. aeruginosa and other Gram-negative bacilli (28). Recently, two studies using sputum cultures have also demonstrated an increasing frequency of isolation of Pseudomonas species and other Gram-negative bacilli in exacerbations of underlying very severe COPD (30, 31). Whether this is due to environmental factors (such as antibiotic selection pressure or exposure to hospital flora from frequent exacerbations) or is related to a greater degree of host immune compromise is not clear. The consistent results of these studies, coupled with the increased rate of isolation of pathogenic bacteria in exacerbations than in stable COPD, support the pathogenic role of bacteria in a proportion of exacerbations.

Molecular epidemiology of bacterial pathogens.
Sputum culture studies that have included only species identification of the bacterial pathogens isolated and that have expected to find a difference in the isolation rate of bacterial pathogens during exacerbation and in stable COPD have yielded consistently negative results (8, 9). Such studies, however, do not take into account the genetic diversity among the individual strains of a bacterial species, including alterations in surface antigenic structures. Such variation in the surface antigenic structure of bacterial pathogens allows these organisms to evade pre-existing host immunity and to cause recurrent infection. A recent longitudinal cohort study in COPD combined clinical information, sputum culture, and molecular typing of the pathogens isolated from sputum to determine whether acquisition of a strain of a pathogen that was new to the patient was associated with the development of an exacerbation (32). Indeed, the acquisition of a strain that the patient had not been infected with earlier was associated with a more than twofold increase in the risk of exacerbation. This increased risk of exacerbation was seen with three of the four major pathogens implicated in acute exacerbation (Table 5 and Figure 1). These results provide further support for the role of bacteria in causing a substantial proportion of exacerbations and suggest that the mechanism of recurrent exacerbations in these patients is not a periodic increase in bacterial load but, rather, infection with a bacterial strain with an antigenic structure new to the host. Such an infection leads to an immune and inflammatory response that presents clinically as an acute exacerbation.


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  		TABLE 5. Isolation of a new strain of a bacterial pathogen increases the risk of exacerbation of chronic obstructive pulmonary disease

 


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  		Figure 1. Timeline and molecular typing for a patient with chronic obstructive pulmonary disease. The horizontal line is a timeline, with each number indicating a clinic visit. The arrows indicate exacerbations. Isolates of Haemophilus influenzae were assigned types based on banding patterns on gel electrophoresis. The gel on the right shows whole bacterial cell lysates of isolates recovered at visits 5 through 9. A, B, and C indicate the molecular types based on banding patterns. Molecular mass standards are noted on the left of the gel in kilodaltons. Modified by permission from Sethi and colleagues (32).

 
In the same study, not every exacerbation was associated with acquisition of a new strain and neither was every new strain acquisition associated with an exacerbation (32). This is not surprising, however, because of the complex biology of the host–pathogen interaction that determines the clinical consequences of a new strain acquisition in a patient with COPD. As strains of bacterial pathogens differ in virulence, it is possible that less virulent new strains do not induce a host inflammatory response of sufficient intensity to elicit symptoms that reach the threshold of a clinical exacerbation. Even when infected with new bacterial strains of comparable virulence, the intensity of the inflammatory response and the threshold of respiratory symptoms at which they perceive the need to be treated may differ among patients with COPD. Adding to the complexity of the situation, strains that preexist in the patient may undergo antigenic variation, and the new variant that emerges may evade the host immune response, proliferate, and cause increased symptoms. Demonstration of an association between new strain acquisition and increased rate of exacerbation for all of the three major pathogens implicated in exacerbations provides strong evidence that bacteria do indeed cause a substantial proportion of exacerbations.

Immune responses to bacterial pathogens in acute exacerbations of COPD.
Older studies of the immune response to bacterial pathogens in COPD had several limitations as discussed previously here. Recent investigations have explored the immune response to bacterial pathogens in acute exacerbations with methods that would avoid the pitfalls of earlier studies (33, 34). Bakri and colleagues have shown that after exacerbation associated with M. catarrhalis, new serum IgG antibodies and/or new sputum IgA antibodies directed at the infecting strain developed in two-thirds of exacerbations (34). The mucosal and serosal immune response occurred concurrently as well as independently of each other. In another study of the immune response to H. influenzae in two patients, serum bactericidal antibody to the infecting strain developed after acute exacerbation (33). Furthermore, the major antigenic targets of these bactericidal antibodies were surface-exposed epitopes on outer membrane protein (OMP) P2, a major OMP of this pathogen. The surface epitopes on OMP P2 are considerably variable among strains of H. influenzae (7). Not surprisingly, the bactericidal antibodies to OMP P2 were able to kill only the infecting strain and not the other patient's strain. When animals are immunized with H. influenzae, antibodies that develop also bind variable epitopes on OMP P2 and therefore are strain specific (35, 36).

Although most studies of immune response to respiratory pathogens have focused on antibody production, lymphocyte proliferative response to these pathogens is also important. Abe and colleagues recently examined the blood lymphocyte proliferative response to OMP P6 of H. influenzae in patients with COPD who had experienced an H. influenzae exacerbation in the past 12 months and compared this with patients who had not experienced such an exacerbation and also with healthy control subjects (37). They demonstrated that susceptibility to H. influenzae exacerbation was associated with a specific decrease in T-lymphocyte proliferation with OMP P6. This suggests that failure to recognize OMP P6 as an important antigen may contribute to repeated H. influenzae exacerbations in patients with COPD. These studies have demonstrated the development of specific immune response to infecting strains of nontypeable H. influenzae and of M. catarrhalis and support the role of bacterial infection in exacerbations of COPD. Similar evidence with other bacterial species would help us better define their role in acute exacerbations.

Airway inflammation measurement and correlation with bacteriology.
An exciting development in airway disease research has been the recognition that sputum measurements of cells and mediators reflect the milieu of the lower airways quite accurately. This has led to several studies in exacerbations of COPD in which the effect of bacterial infection on the airway milieu has been examined systematically. In one such study, bacterial exacerbation was associated with significantly greater neutrophilic inflammation than nonbacterial exacerbation, with higher levels of sputum interleukin-8, tumor necrosis factor-{alpha}, and neutrophil elastase during bacterial exacerbation (38). Gompertz and colleagues (39) measured markers of neutrophilic inflammation in serial sputum samples obtained from patients experiencing exacerbation over 8 weeks and demonstrated that in those exacerbations associated with purulent sputum there is a significant decline in neutrophilic airway inflammation over time. This decline is especially significant in the first 5 days, a finding that substantiates measuring benefit with antibiotics in the treatment of exacerbations at time points earlier than the conventional 3 weeks. In contrast to these studies, Aaron and colleagues (40) were not able to demonstrate a difference in granulocyte inflammatory markers in sputum in bacterial and nonbacterial exacerbations. However, their study was hampered by a small sample size of 1 bacterial, 2 viral, and 11 exacerbations of unknown etiology. The association between neutrophilic airway inflammation and presence of bacteria on sputum culture supports a bacterial cause of exacerbations. In addition, as neutrophil elastase is a major driver of lung injury, elevated levels of this enzyme seen in bacterial exacerbations could contribute significantly to the loss of lung function seen in COPD.

CONCLUSIONS
The current evidence indicates that bacterial infection causes approximately 40–50% of acute exacerbations of COPD. The complexity of the host–pathogen interaction that determines the outcome of each encounter between a potential respiratory pathogen and a patient with COPD is being increasingly appreciated. Further studies should attempt to understand this interaction better. Specifically, the virulence determinants of the pathogens that induce host inflammatory responses need to be better understood. Among patients with COPD, there is a large variability in the incidence of exacerbations. We need to elucidate the host defense factors that protect some of these patients from exacerbations with these pathogens. In addition, protective host immune response that develops after exacerbations needs to be characterized to facilitate vaccine development. The interplay between different etiologic factors, for example, the environment, viruses, atypical pathogens, and bacteria, needs to be better understood to treat exacerbations better and develop novel preventive and therapeutic strategies.


   FOOTNOTES
 
Supported by Merit Review from the Department of Veterans Affairs.

(Received in original form June 25, 2003; accepted in final form September 24, 2003)


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