Airway Infection Accelerates Decline of Lung Function in Chronic Obstructive Pulmonary Disease

Jadwiga A. Wedzicha

Academic Respiratory Medicine, St. Bartholomew's and Royal London School of Medicine and Dentistry, London, United Kingdom

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Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in FEV₁ (forced expiratory volume in 1 s) with age. The most important cause of COPD is cigarette smoking, and smoking cessation is the only intervention that has been shown to slow decline in lung function, although only small numbers of patients with COPD manage to quit smoking (1). It is now recognized that COPD is associated with chronic inflammation both in the airways and in the lung parenchyma and airway inflammation has been related to the degree of airway obstruction, with an increased inflammatory process with worsening COPD (2). In COPD, decline of FEV₁ is variable among cigarette smokers, although factors causing this heterogeneity are largely unknown and thus airway infection may play an important role in the natural history of COPD.

It has been recognized for some time that patients with COPD develop lower airway bacterial colonization (LABC) in the stable state, in contrast to the airways of nonsmokers without COPD, which are sterile (3). Between 25 and 50% of patients with COPD have evidence of LABC and, once established, this persists as in other conditions where airway infection is a feature, such as bronchiectasis and cystic fibrosis. The organisms detected include most commonly nontypeable Haemophilus influenzae, but also Streptococcus pneumoniae, Moraxella catarrhalis, and Pseudomonas aeruginosa. A number of studies have now shown conclusively, using protected specimen brush catheters at bronchoscopy, that LABC does exist in COPD and may be detected right down to the peripheral airways and is not caused by contamination from nasopharyngeal commensals (3). Evaluation of risk factors for LABC in COPD shows that current cigarette smoking and the FEV₁ were related to colonization, suggesting that LABC is related to disease progression.

Bacteria have a number of important effects on airway epithelium, including stimulation of mucous production, reduction of mucociliary clearance, and airway epithelial cell injury (6, 7). These mechanisms lead to increased airway inflammation and production of neutrophil elastase, interleukin 8 (IL-8), and other chemoattractants that contribute to the neutrophil influx. Once LABC is established the process persists as described in the "vicious cycle hypothesis" (8). There is now evidence that H. influenzae, in addition to being present in the airway lumen, is also found in the submucosa and intracellularly; both these sites encouraging persistence of the organism and evasion from the effects of antibiotics (9). Although mucous hypersecretion was originally considered not to be related to disease progression in COPD, there is now evidence that chronic mucous hypersecretion is related to decline of FEV₁ in COPD (10), and one of the most important stimuli to hypersecretion may be LABC.

Evidence has shown conclusively that airway inflammation increases with higher airway bacterial loads determined from quantitative sputum cultures in patients with COPD (11). In this study the bacterial species also influenced the severity of airway inflammation, with colonization by P. aeruginosa showing the greatest effect on inflammatory markers. More direct evidence that bacterial colonization contributes to airflow obstruction comes from a study that showed that H. influenzae colonization was associated with increased airway inflammatory markers in patients with chronic bronchitis and airflow obstruction, compared with patients with chronic bronchitis without airflow obstruction, where airway inflammation was reduced (12).

Although there has been some previous controversy regarding isolation of bacteria at COPD exacerbation, data from Stockley and colleagues show that an exacerbation with purulent sputum is associated with increased airway bacterial load (13). In another study Sethi and colleagues showed that exacerbations associated with detection of H. influenzae are associated with higher levels of airway inflammatory markers, compared with pathogen-negative exacerbations; thus providing further evidence that airway infection leads to increased inflammation and thus decline in lung function (14). The majority of COPD exacerbations are associated with airway infection, either viral or bacterial. There is now evidence that not all COPD exacerbations recover to baseline with respect to symptoms and lung function (15) and as airway inflammatory markers are increased at exacerbation (16), this suggests that airway inflammation may persist and lead to progressive decline in the FEV₁.

Some patients with COPD develop frequent exacerbations and this susceptible patient group has increased stable airway IL-6 and IL-8 levels compared with those patients with infrequent exacerbations (16). Patients with frequent exacerbations are more likely to be colonized with H. influenzae when stable (17) and as COPD exacerbations increase with disease progression, then bacterial infection may play an important role in this process. Exacerbation frequency is an important determinant of health status (18) and eradication of bacterial colonization may have considerable impact on the consequences of COPD.

There has been increasing interest in chronic viral infection in the pathogenesis of COPD. Adenovirus E1A DNA has been detected in lung epithelial cells of patients with COPD and can regulate host gene expression by interacting with cellular transcription factors. Adenovirus E1A-producing epithelial cells exposed to lipopolysaccharide significantly increased IL-8 production compared with those without E1A (19). Thus the presence of chronic viral infection may augment the inflammatory response to agents such as oxidants and bacteria. Respiratory viruses have been isolated from the lower airway at COPD exacerbation (20) and it is possible that incomplete clearance of the virus may lead to persistence and thus "viral colonization." Viral infection, by causing epithelial disruption and mucous production, may facilitate the adherence and spread of bacteria in the respiratory tract. Thus there are complex interactions in the airway between bacteria and viruses and further study of these relationships in patients with COPD is warranted in carefully designed long-term studies.

The evidence is now compelling that airway infection, especially with bacteria, is associated with increased airway inflammation and susceptibility to decline in lung function. It is time that the respiratory community woke up to the fact that the presence of bacteria in COPD airways is not just an "innocent bystander" but plays an important role in disease progression. We have spent too many years debating this issue and now it is time to move forward and evaluate the effect of eradication of airway infection on health status and mortality in COPD.

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