REBUTTAL FROM DR. BARNES

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Dr. Calverley accepts that inhaled corticosteroids do not influence the progressive decline in lung function in patients with COPD and emphasizes a beneficial effect in reducing the number of exacerbations. This benefit was not seen in the two large studies (Copenhagen Lung Study and EUROSCOP) that studied patients with mild-to-moderate COPD (1, 2), but was apparently seen in the ISOLDE study of patients with more severe COPD. The results of the ISOLDE study have yet to be published in a peer review publication, and are therefore difficult to evaluate. The only study that has specifically investigated the effect of inhaled corticosteroids on exacerbations in COPD showed no overall reduction in exacerbations with a high dose of inhaled corticosteroid compared to placebo, although a subanalysis showed a reduced number of severe exacerbations (3). Thus, results to date with inhaled corticosteroids suggest that their main benefit in the treatment of COPD may be to reduce (by a small amount) the number of severe exacerbations. As this could result in health cost savings, further studies in patients who have frequent exacerbations are indicated.

We both agree that a subpopulation of patients with COPD (approximately 10%) have some response to short-term oral corticosteroids. My own prejudice is that this is owing to concomitant asthma, as is supported by the fact that these patients have some inflammatory features of asthma, with increased numbers of eosinophils in mucosal biopsies and induced sputum (4, 5). For the benefit of the patient it is best to classify these patients as asthmatic and treat them with inhaled corticosteroids

Dr. Calverley cites studies that have shown beneficial effects of corticosteroids on inflammatory indices in COPD. Closer examination of these studies, however, show defects in study design (no placebo group, small numbers) or very small but statistically significant effects.

The issue of safety of high-dose inhaled corticosteroids in the vulnerable population with COPD has still not been adequately studied, and specific investigations of systemic side effects are now indicated in this "at risk" population of patients. Any benefit of high-dose inhaled corticosteroids must be weighed against the relatively high risk of adverse effects and the high cost of treatment in this vulnerable population.

	References

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1. Vestbo, J., T. Sorensen, P. Lange, A. Brix, P. Torre, and K. Viskum. 1999. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 353: 1819-1823 [Medline].

2. Pauwels, R. A., C. G. Lofdahl, L. A. Laitinen, J. P. Schouten, D. S. Postma, N. B. Pride, and S. V. Ohlsson. 1999. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N. Engl. J. Med 340: 1948-1953 [Abstract/Free Full Text].

3. Paggiaro, P. L., R. Dahle, I. Bakran, L. Frith, K. Hollingworth, and J. Efthimou. 1998. Multicentre randomized placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 351: 773-780 [Medline].

4. Chanez, P., A. M. Vignola, T. O'Shaugnessy, I. Enander, D. Li, P. K. Jeffery, and J. Bousquet. 1997. Corticosteroid reversibility in COPD is related to features of asthma. Am. J. Respir. Crit. Care Med. 155: 1529-1534 [Abstract].

5. Pizzichini, E., M. M. Pizzichini, P. Gibson, K. Parameswaran, G. J. Gleich, L. Berman, J. Dolovich, and F. E. Hargreave. 1998. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am. J. Respir. Crit. Care Med. 158: 1511-1517 [Abstract/Free Full Text].