Airway Infection Does Not Accelerate Decline in Lung Function in Chronic Obstructive Pulmonary Disease

William MacNee

Respiratory Medicine Unit University of Edinburgh, Edinburgh, Scotland

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An accelerated rate of decline in lung function is the hallmark of chronic obstructive pulmonary disease (COPD). Whether airway infection plays any role in this process is unclear because of the lack of necessary longitudinal studies to test this hypothesis. Confusion in this field arises from the term "chronic mucous hypersecretion," which is often used as a surrogate for "airway infection" (AI). Although, clearly, AI can be associated with chronic mucous hypersecretion, the latter can also occur in the absence of infection.

It has been recognized since the 1950s that the normal sterility of the bronchial tree is lost in smokers with the development of chronic cough and phlegm (1). From these studies the "British hypothesis" arose that chronic bronchitis could predispose to infection, which in turn damaged the airways and/or the alveoli, leading to progressive airflow limitation. Today, we know that bacterial colonization occurs in around 30% of patients with stable COPD (2). There is, however, still debate as to whether this colonization increases with increasing airflow limitation (2). Furthermore, the potential impact of bacterial colonization on the rate of decline of lung function has not been assessed appropriately in longitudinal studies. We know, however, that this percentage of positive bacteria in the airways appears to increase (to 50%) during exacerbations of the disease (5). Such exacerbations, whether infective in nature or not, are associated with an acute decline in FEV₁ for a few weeks after these episodes with usually complete recovery of ventilatory function, except in a minority of patients (6). There is no convincing evidence that exacerbations in COPD accelerate the decline in FEV₁ in COPD.

A further possible role of infection relates to the reasonably well-documented association between respiratory illnesses in the first year of life and impaired ventilatory function in adulthood (7). However, this association does not hold true for respiratory illnesses between ages 1 and 4 years (8). Furthermore, the association between respiratory illnesses in the first year of life and a reduction in subsequent lung function is unrelated to the effect of recurrent infections in adulthood, and may reflect an effect on lung development.

Chronic mucous hypersecretion is common, but not constant, in patients with COPD. Its relationship to the natural history of the disease remains controversial. Longitudinal epidemiological studies from Fletcher and coworkers (9), largely in working men in the UK in their fourth decade, demonstrated that chronic mucous hypersecretion and progressive airflow obstruction were independent entities, which may coexist in the same individual, both related to smoking, but with distinct natural histories. Other studies have since shown the lack of predictive value of chronic mucous hypersecretion, when controlling for the level of ventilatory impairment, in relationship to COPD mortality in some (10), but not all (11, 12), studies. For example, data from the Copenhagen City Heart Study (11)a prospective study of 14,000 men and women randomly selected from the general populationshowed that chronic mucous hypersecretion is associated with a small but significant increased risk of death from all causes. However, the association between chronic mucous hypersecretion and death from COPD varied with the level of the FEV₁, being weak in subjects with normal ventilatory function, but more pronounced in subjects with reduced ventilatory function. This relationship was explained on the basis that those with chronic mucous hypersecretion would be more prone to pulmonary infection and thus to death during exacerbations of COPD, a concept that remains unproven.

A hypothesis has been proposed, which again remains unproven, that bacterial colonization may lead to increased inflammation in the airways and hence increased airway damage and decline in FEV₁. There is considerable evidence that smokers have inflammation irrespective of the presence of infection in their airways (13). There is also some evidence to suggest that the presence of bacteria produces more inflammation (14). What is not clear is whether this enhanced degree of inflammation is associated with an accelerated decline in FEV₁ (14). Studies that do not support this hypothesis come from the 1950s, when the use of prophylactic antibiotics failed to show any improvement in the decline in FEV₁ (15, 16).

More recently, the Copenhagen City Heart Study (12) has produced data of potential interest in this context. This study showed a significant association between chronic mucous hypersecretion and admission to hospital for COPD exacerbations (a surrogate for airway infection) after adjusting for the FEV₁. The only difference between those who died with or without infection was indeed the presence of chronic mucous hypersecretion (12). There are, however, a number of sources of bias in this study. Thirty-eight percent of the total deaths occurred out of hospital and the presence or absence of infection at the time of death was not known in these individuals. In addition, the presence of increased and/or purulent mucus was one of the criteria employed to define infection and thus infection may have been more likely to be diagnosed in patients already producing sputum. Despite the proposed association between chronic mucous hypersecretion and FEV₁ decline in COPD morbidity the authors of the relevant article (17) suggest that chronic mucous hypersecretion should not be regarded as a marker of recurrent airway infection, but instead that "chronic mucous hypersecretion may act as a marker of airway inflammation often triggered by exogenous stimuli such as smoking." There is no doubt that with decrease in lung function in patients with COPD, infections occur with increasing frequency, but it is speculation that recurrent infections play a role in the natural history of the disease. Thus, despite the inherent plausibility of the hypothesis, there is little experimental evidence to support the concept that recurrent bronchopulmonary infections accelerate the decline in airflow limitation in patients with COPD.

	References

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