© 2002 American Thoracic Society
Inhaled Glucocorticosteroids and Chronic Obstructive Pulmonary DiseaseHow Full Is the Glass?Department of Respiratory Diseases Ghent University Hospital Ghent, Belgium The role of inhaled glucocorticosteroids in the management of chronic obstructive pulmonary disease (COPD) is debated but evidence is accumulating to support therapeutic recommendations (1). The evidence is coming from well-controlled clinical trials and supported by mechanistic studies. Large scale clinical studies have shown that inhaled glucocorticosteroids have no influence on the long term decline in lung function in COPD, but a similar statement can be made for all pharmacologic therapies currently used to counter this disease. The major benefits from inhaled glucocorticosteroids in COPD are a decrease in the number of exacerbations, an inhibition of the progressive decline in health status, and an additive effect with long-acting inhaled ß2 agonists on lung function and symptoms. There is also indirect evidence that inhaled glucocorticosteroids might decrease mortality in COPD (2). A large prospective controlled study on this issue, the TORCH (Towards a Revolution in COPD Health) study, is currently ongoing, but the results will not be available for another 5 years. Many investigators have studied the effect of inhaled glucocorticosteroids on the airway pathology of COPD. For evident reasons, these studies have been small compared with the clinical studies. The results have differed and are somewhat contradictory. Inhaled glucocorticosteroids have been shown to have either no effect or to decrease various indices of airway inflammation in COPD, such as extravasation, chemotactic activity, or neutrophil count, or to increase antiproteolytic activity. None of these studies, however, revealed a clinical correlate for the changes in pathology. The unique quality of the study by Hattotuwa and coworkers (3) in this issue of AJRCCM (pp. 1592–1596) is that the investigators were able to show both an effect on relevant clinical outcomes (symptoms and exacerbations) and on aspects of airway pathology, namely the ratio of CD8/CD4 T lymphocytes in the epithelium and numbers of subepithelial mast cells. The main reason that Hattotuwa and colleagues (3) succeeded in finding a clinical correlate for the changes in pathology was probably that their study population and treatment regimen resembled those in the ISOLDE (Inhaled Steroids in Chronic Obstructive Lung Disease in Europe) trial (4), where inhaled glucocorticosteroids were shown to have clear-cut benefits. We should be careful in the interpretation of the findings by Hattotuwa and coworkers (3). The association between change in pathology and clinical efficacy does not necessarily mean that the two are causally related. The major site of the chronic airflow limitation in COPD is the small airways. Bronchial biopsies are unlikely to reflect the pathological abnormalities at this more peripheral location. Very few studies have investigated the pathology of acute exacerbations in COPD and the data are again confined to larger airways (5, 6). These studies suggest an increase in airway eosinophilia during a COPD exacerbation. A possible explanation for the effect of inhaled glucocorticosteroids on the rate of exacerbation is their well-known effects on eosinophilic inflammation. Further research is required to determine how inhaled glucocorticosteroids would prevent the increase in eosinophilic inflammation in COPD and how this hypothesis may be linked with the findings of Hattotuwa and coworkers (3). The role of mast cells in COPD is equally unclear. Their number is increased in the bronchiolar epithelium (7), and bronchial challenges with indirect mast cell activating agents cause airway narrowing in patients with COPD (8, 9). There might thus be a link between the effect of inhaled glucocorticosteroids on mast cells and the symptomatic benefit in COPD. As in many disease areas, mechanistic studies on the effects of treatments are informative both with regard to the drug and the disease. The limited clinical efficacy of inhaled glucocorticosteroids in COPD and the variable effects on airway pathology point to a more striking conclusion: we do not understand the pathogenesis of COPD, and have not yet identified the responsible cells and molecules. Airway inflammation in COPD is clearly different from that in asthma (10). It can also be expected that it will be hard to control the airway inflammation in patients with COPD who continue to smoke. The high morbidity and mortality due to COPD justifies major efforts in finding new approaches to avoiding risk factors, especially cigarette smoking, and to develop treatments that modify the underlying disease. Should we use inhaled glucocorticosteroids in COPD at all? I believe that the clinical data are sufficiently convincing to justify their use in patients with more advanced disease. There is currently very little evidence to support the generalized use of inhaled glucocorticosteroids in mild to moderate COPD. Accumulating evidence, however, supports their use in patients with more advanced COPD (FEV1 less than 50% predicted) with a history of repeated exacerbations. We have very little to offer to these patients. Of course we should repeatedly try to convince and help them to stop smoking. Regular treatment with long-acting bronchodilators and pulmonary rehabilitation will decrease symptoms and improve exercise tolerance. Several clinical studies now demonstrate that inhaled glucocorticosteroids in this category of patients can improve symptoms, and reduce exacerbations and the decline in health status. There is no evidence that such an approach would be harmful. The controversy on the effect of inhaled glucocorticosteroids on mineral bone density is probably irrelevant for this population, in view of their limited life expectancy. Inhaled glucocorticosteroids also decrease the number of courses of oral corticosteroids that these patients might need. And although the glass might be more than half empty, a little water is better than nothing for the thirsty. REFERENCES
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