© 2008 American Thoracic Society doi: 10.1164/rccm.200711-1640ED
Acute Exacerbation of Chronic Obstructive Pulmonary DiseaseMore a Functional than an Inflammatory Problem?
Medizinische Hochschule Hannover Acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with upper and lower airway inflammation, as well as with systemic inflammation. Typical symptoms are airway edema, bronchospasm, and increasing sputum production (1). Frequent exacerbations may significantly worsen the long-term prognosis of patients with COPD (2). In addition to increased pulmonary inflammation, comorbid conditions, such as ischemic heart disease, pneumonia, and diabetes, may contribute to accelerated deterioration and early death, and may also be affected by the systemic inflammatory responses associated with exacerbations (3). Theoretically, antiinflammatory treatment should contribute to a reduction of exacerbations in COPD. In single studies with long-term use of inhaled steroids (e.g., the ISOLDE [Inhaled Steroids in Obstructive Lung Disease] trial) (4), a reduction in the frequency of exacerbations by about 20% was found in patients treated with inhaled corticosteroids, but this effect was primarily present in patients with advanced COPD (FEV1 < 60% predicted). Interestingly, in all studies investigating additional effects of long-acting β-agonists (LABAs), a marked reduction in the exacerbation rate was found (5). The underlying mechanisms may be inhibitory effects on plasma exudation into the lungs and neutrophil migration, possibly augmented by a reduction in the expression of adhesion molecules. In addition, the long-acting anticholinergic drug tiotropium appears to reduce exacerbation frequency by approximately 20% (6). Tiotropium is a pure bronchodilator without antiinflammatory properties (7). The mechanisms responsible for the exacerbation reduction with tiotropium are unknown. In this issue of the Journal (pp. 164–169), Washko and colleagues present an analysis of patients who were enrolled into the National Emphysema Treatment Trial (NETT), and who underwent lung volume reduction surgery (LVRS) (8). Compared with the control group, which received medical treatment only, patients who underwent surgery had a 30% lower exacerbation rate in the 3-year follow-up period, and a significantly longer time to first exacerbation. These improvements correlated closely with FEV1 after surgery, but not with parameters of lung capacity (RV, FRC), maximum expiratory force, or blood gas changes. Improvement in cough clearance as a potentially important reason for the reduction of exacerbations could be ruled out. This study has some limitations. All patients suffered from severe COPD (mean FEV1 < 30% of predicted), and not much can be concluded concerning patients with less advanced COPD disease. Patients who demonstrated improved lung function after LVRS had predominantly upper lobe emphysema and therefore represent a special subgroup of patients with COPD. Contrary to all expectations, the exacerbation rate per person-year was 0.36 in the surgical group and 0.34 in the control group, which was considerably lower than in pharmacologic studies (e.g., in the TORCH [Towards a Revolution in COPD Health] study [5], the exacerbation rate was 1.13 per year). This might be an indicator of good pharmacologic and nonpharmacologic management of the patients and underscores the highly selected cohort in the NETT. Before enrollment into the NETT, the majority of patients had been treated with inhaled or oral steroids, and nearly half of the patients received LABAs. Tiotropium was not available at the time of the study. No information is presented on medical treatment and smoking habits after surgery. Thus, it cannot be excluded that differences in these variables affected the overall exacerbation rate. Washko and colleagues' study offers important insights for our understanding of the pathophysiology of COPD exacerbation. Because the consequence of LVRS is improvement in lung mechanics, without obvious changes in the inflammatory status, it seems reasonable to conclude that alterations in the biomechanical situation have a major impact on the prognosis of patients with COPD. The excellent correlation between parameters of lung overinflation (IC/TLC) and prognosis of patients with COPD, as shown by Casanova and colleagues (9) in 2005, was the first indicator that reduction of overinflation might be important for the decrease in COPD exacerbations. However, the data presented by Washko and colleagues are not in line with this hypothesis. The resection of lung tissue by LVRS removes predominantly the most severely affected and overinflated lung areas. With the worst obstructive and overinflated regions resected, patients' ventilation during rest and during exercise takes place in reasonably well-preserved parts of the lungs. Therefore, dynamic lung overinflation during exercise should also be reduced. From several recently published in vitro and in vivo experiments, we learned that dynamic overinflation results in considerable inflammation and recruitment of inflammatory cells into the interstitium and the alveolar space, induced by the mechanical stretch of alveolar and bronchial epithelial cells (10). These changes are consistent with the inflammatory processes in patients with severe pulmonary emphysema, as described by Hogg (11). The correlation between the improvement of FEV1 and the reduction in numbers of exacerbations suggests that dynamic overinflation during exercise, which is associated with the airway diameter, may be the decisive underlying reason. Pure bronchodilators may therefore have an important impact on inflammation, despite the fact that they are not antiinflammatory in the pharmacologic sense. This should be recognized in future studies, and in the development of new treatment principles for COPD. FOOTNOTES Conflict of Interest Statement: T.W. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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