Inhaled Corticosteroids Are Beneficial in Chronic Obstructive Pulmonary Disease

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Chronic obstructive pulmonary disease (COPD) is defined physiologically by the failure of the FEV₁ to change markedly after bronchodilator drugs (1). Exactly how much FEV₁ must change to exclude a diagnosis of COPD is not defined, but this is important in interpreting the data about the effects of inhaled corticosteroids in COPD. Both bronchial asthma and COPD result from chronic pulmonary inflammation and inhaled corticosteroids are remarkably effective in controlling this in asthma (2). Inevitably, clinicians have used inhaled corticosteroids in COPD, but until recently, the evidence to support this was limited.

Experimental studies looking at markers of chronic airway inflammation such as IL-8 and TNF- have failed to find any effect of inhaled or oral corticosteroids (3). However, other studies using different markers in different centers have reported reductions in visible bronchial inflammation and epithelial lining fluid albumen (4), chemotaxis (5) and airway neutrophila (6) after inhaled corticosteroids. Since no single biochemical or cellular marker adequately describes the airway inflammation of COPD it is clear that some aspects of this process, but not all, can be modified by inhaled corticosteroids.

Short-term oral corticosteroid treatment significantly increases FEV₁ in 10% of patients, usually those with larger bronchodilator responses (7). These patients have fewer symptoms and better lung function when treated with inhaled corticosteroids (8). Whether they have coexisting asthma is unresolved and the limited data available suggests that there is no clear separation of asthmatic and COPD pathologies in COPD patients responding substantially to corticosteroids (9). These patients have been rigorously excluded from clinical trials in COPD, although in real life they constitute around 20% of the patients seen. Omitting inhaled corticosteroid therapy will deprive them of important therapeutic benefits. In the remaining patients considerable efforts have been made to ensure that their FEV₁ does not improve with conventional therapy before using this as the outcome measure in clinical trials!

Methodological problems with the initial studies of inhaled corticosteroids in COPD make them hard to interpret. A recent meta-analysis of patients meeting current diagnostic criteria suggested that relatively high doses of inhaled corticosteroids over two years reduced the rate of decline in FEV₁ (10).

The results from three larger studies have now been reported. These differed in the severity of the disease studied, which meant that end-points other than FEV₁ were unavailable to two studies. Thus, the patients in the Copenhagen Study were older, had milder disease, and only 75% had ever smoked (11). Inhaled budesonide via a turbohaler did not change the rate of decline of FEV₁ over 3 yr. In the Euroscop study more than 1,200 patients were followed up for three years but these patients also had relatively mild cases of COPD with post-bronchodilator measurements of 80% of the predicted FEV₁. These patients were recruited by advertising in the mass media rather than through the medical system, and all continued to smoke (12). In this study, as in the Inhaled Steroids in Obstructive Lung DiseasE (ISOLDE) investigation (13), there was a small but significant increase in post-bronchodilator FEV₁ measurements with inhaled corticosteroids, but in neither investigation did the subsequent rate of decline in FEV₁ change.

Unlike the other studies, the ISOLDE trial studied patients with symptoms and a mean post-bronchodilator FEV₁ measurement of 50% of that predicted. Like many UK patients, just over half were receiving inhaled corticosteroids; when these were withdrawn there was a small but statistically significant fall in post-bronchodilator FEV₁ levels, which improved after the administration of oral prednisolone. In those randomized to placebo, FEV₁ returned to baseline values while those receiving inhaled fluticasone, the study drug, maintained the gain in FEV₁. Although the changes in lung function were small (approximately 80 ml) the group behavior was very consistent and indicated that this treatment has a biological effect.

Symptomatic COPD patients do not complain about their rate of decline of FEV₁ but are worried by disease exacerbations and the impact of COPD on their general well-being. Six months treatment with fluticasone propionate in symptomatic COPD patients reduced the number and severity of their exacerbations (14). Withdrawal of inhaled corticosteroids during the trial run-in was associated with a twelve-fold greater chance of exacerbation compared with patients with similar baseline function not taking this treatment (15). Patients receiving placebo dropped out significantly more often because of frequent exacerbations, and overall there were 25% fewer exacerbations with inhaled corticosteroids. This effect was seen in patients with more severe disease (post-bronchodilator FEV₁ < 1.5 L).

The ISOLDE study showed, for the first time, that like FEV₁, patient well-being or health status measured using the St. George's Respiratory Questionnaire declines with time in COPD. However, FEV₁ describes only about 5% of the impact of the disease on the patient's well-being (16), whereas exacerbation rate is much more important as a determinant of health status (17). The rate of decline of health status was slowed by inhaled corticosteroids, largely because of reduction in disease exacerbations.

There are theoretical risks with this treatment in COPD, but no conclusive data to support these claims are available. Plasma cortisol measurements were lower in patients receiving fluticasone in the ISOLDE study but neither this, nor the occurrence of skin bruising, was clinically significant. Objective assessment of bone structure in Euroscop found no problems with inhaled budesonide. The major confounding variable is the need for oral corticosteroids to control exacerbations (18). The adverse effects of oral corticosteroids outweigh any smaller improvements produced by inhaled therapy. However, reducing the number of exacerbations is likely to produce a net benefit.

Thus, a coherent picture is beginning to emerge about the benefits of inhaled corticosteroids in COPD. It is worthwhile in patients with more marked bronchodilator responsiveness (400 ml) and in those requiring regular courses of prednisolone for exacerbations. They are not the answer to all the problems of COPD, and more research into drugs which will modify the natural history of the disease is urgently needed. However, to claim that they are of no value to any patient is to throw the baby away with the bath water.

PETER M. A. CALVERLEY

Department of Medicine

University of Liverpool

Liverpool, United Kingdom

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