Inhaled Corticosteroids Are Not Beneficial in Chronic Obstructive Pulmonary Disease

	INTRODUCTION

TOP INTRODUCTION COPD AS AN INFLAMMATORY... WHY ARE INHALED CORTICOSTEROIDS... ADVERSE EFFECTS OF INHALED... CONCLUSIONS REFERENCES

Inhaled corticosteroids are now widely used in the treatment of chronic obstructive pulmonary disorder (COPD). In my opinion this is incorrect and, indeed, patients may suffer from systemic side effects.

	COPD AS AN INFLAMMATORY DISEASE

TOP INTRODUCTION COPD AS AN INFLAMMATORY... WHY ARE INHALED CORTICOSTEROIDS... ADVERSE EFFECTS OF INHALED... CONCLUSIONS REFERENCES

There is increasing evidence that COPD is associated with chronic inflammation in the airways and parenchyma. This has been used as a rationale for the use of inhaled corticosteroids in COPD, by analogy with the striking suppressive effects of inhaled corticosteroids on airway inflammation and symptoms in asthma. But the inflammatory pattern in COPD differs markedly from that seen in asthma, with preponderance of macrophages and CD8⁺ T-lymphocytes in the airways and lung parenchyma, and an increase in macrophages and neutrophils in sputum and bronchoalveolar lavage, in contrast to the increase in eosinophils and activation of mast cells and CD4⁺ T-cells that are characteristic of asthma (1, 2). In both chronic diseases there is an increased production of cytokines, but the pattern differs with interleukin-8 (IL-8) and tumor necrosis factor- (TNF-) predominating in COPD, compared to IL-4, IL-5, and IL-13 in asthma.

Corticosteroids Do Not Suppress Inflammation in COPD

Corticosteroids are very effective at suppressing airway inflammation in asthma and have potent inhibitory effects on eosinophilic inflammation, with reduced production, recruitment, activation, and, particularly, survival of eosinophils (3). By contrast, our own double-blind placebo-controlled studies in carefully characterized patients with COPD have shown that even high doses of inhaled corticosteroids do not reduce inflammatory cell numbers, concentrations of cytokines, or proteases (4, 5). Even high doses of oral corticosteroids, given because there was concern that the inhaled steroid may not reach inflammatory sites in patients with severe COPD, were without any effect (5). Another study found a small inhibitory effect of inhaled corticosteroids on neutrophil counts in induced sputum of patients with COPD, but this study was not controlled and there was a high eosinophil count, suggesting that asthmatic patients had been included (6). The lack of effect of corticosteroids on inflammatory markers in induced sputum has been confirmed in a preliminary study that showed no effect in bronchial biopsies (7). It appears that COPD is a steroid-resistant disease.

Clinical Studies with Inhaled Corticosteroids in COPD

Since inhaled corticosteroids are so clearly effective in asthma, it is important that patients with asthma be rigorously excluded from any trial of inhaled corticosteroids. Approximately 10% of patients are likely to have both asthma and COPD and share features of the two diseases; these patients may show a beneficial response to steroids and should be labeled as asthmatic. Indeed, a 2-wk course of oral steroids and perhaps a 3-mo trial of inhaled corticosteroids are indicated in order to exclude any asthmatic component. Several studies that purport to show a benefit of inhaled steroids in COPD include a large proportion of patients with asthma (8, 9). The remaining patients, with "pure" COPD, do not appear to respond to corticosteroids. Several studies have failed to show any beneficial effect of inhaled corticosteroids in patients with COPD when asthma has been rigorously excluded. Inhaled steroids do not improve airway responsiveness to bronchoconstriction and have little or no effect on spirometry in COPD (10, 11). Three recent studies examined the effects of inhaled corticosteroids in controlled trials of large numbers of patients over 2 to 3 yr and showed no significant reduction in the accelerated decline in lung function, indicating that there is no effect of inhaled steroids on the progressive inflammatory disease process (12). A high dose of inhaled steroids does not reduce the total number of acute exacerbations in patients with severe COPD, although they are less severe (15).

	WHY ARE INHALED CORTICOSTEROIDS INEFFECTIVE IN COPD?

TOP INTRODUCTION COPD AS AN INFLAMMATORY... WHY ARE INHALED CORTICOSTEROIDS... ADVERSE EFFECTS OF INHALED... CONCLUSIONS REFERENCES

There are several possible reasons why corticosteroids may not be effective in suppressing the inflammatory disease process in COPD, although they are highly effective in asthma. Neutrophilic inflammation is generally resistant to corticosteroids, whereas eosinophilic inflammation is suppressed. Corticosteroids decrease the survival of eosinphils in vitro, whereas they prolong the survival of neutrophils by inhibiting apoptosis (16, 17). In normal subjects ozone inhalation induces a neutrophilic inflammatory response (with an increase in neutrophils of a similar magnitude to that seen in patients with COPD), and this is unaffected by high doses of inhaled corticosteroids (18). There may even be an active resistance to the effects of inhaled corticosteroids in COPD, since corticosteroid therapy fails to suppress cytokines, such as TNF- and IL-8, that are inhibited by steroids in vitro. The molecular mechanisms underlying this resistance are currently being elucidated.

	ADVERSE EFFECTS OF INHALED CORTICOSTEROIDS

TOP INTRODUCTION COPD AS AN INFLAMMATORY... WHY ARE INHALED CORTICOSTEROIDS... ADVERSE EFFECTS OF INHALED... CONCLUSIONS REFERENCES

As patients with COPD respond so poorly to inhaled corticosteroids, they are commonly prescribed high doses that may be associated with systemic side effects. Patients with COPD may be particularly vulnerable to these systemic effects as they are often elderly, immobile, and have poor nutrition, thus increasing the risks of osteoporosis. Elderly patients may also have an increased risk of developing cataracts, glaucoma, and diabetes. In a recent large study of inhaled corticosteroids in patients with mild COPD, 10% of patients developed skin bruising compared to 4% in the control group (13). Any discussion of the use of inhaled corticosteroids in patients with COPD must weigh the real risk of systemic side effects against the minimal clinical value provided by this treatment. High doses of inhaled corticosteroids are expensive and, as they provide little or no benefit, cannot be justified in terms of cost-effectiveness.

	CONCLUSIONS

TOP INTRODUCTION COPD AS AN INFLAMMATORY... WHY ARE INHALED CORTICOSTEROIDS... ADVERSE EFFECTS OF INHALED... CONCLUSIONS REFERENCES

There is now overwhelming evidence that long-term treatment with inhaled corticosteroids provide no significant clinical benefit to patients with COPD. The disease process in COPD appears to be steroid resistant. Yet patients with COPD are often treated with high doses of inhaled corticosteroids for want of any effective therapy in this disease. This must be associated with a high risk of adverse systemic effects and involves unnecessary expense. Inhaled corticosteroids treatment should not be routinely recommended for the management of COPD, unless there is coexisting asthma. There is a pressing need for the development of new therapies in COPD and there are some promising developments in this area (19).

PETER J. BARNES

National Heart and Lung Institute

Imperial College

London, United Kingdom

	References

TOP INTRODUCTION COPD AS AN INFLAMMATORY... WHY ARE INHALED CORTICOSTEROIDS... ADVERSE EFFECTS OF INHALED... CONCLUSIONS REFERENCES

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