To the Editors:
Few areas of respiratory medicine have generated as much controversy as the use and purpose of long-term corticosteroid treatment in chronic obstructive pulmonary disease (COPD). However, several recent large, placebo-controlled studies have clarified the role of long-term treatment with inhaled corticosteroids 1–3. There is now consistent evidence that inhaled corticosteroid treatment, even in high doses, is not associated with a clinically significant reduction in the rate of decline of forced expiratory volume in one second (FEV1). Treatment is associated with a modest reduction in the frequency of more severe exacerbations, particularly in patients with more severe disease 1, 4 and in those who have a good bronchodilator response to short-term treatment with oral prednisolone 5, 6.
The limited effects seen with inhaled corticosteroids is surprising, given that induced sputum evidence of corticosteroid-responsive eosinophilic airway inflammation is present in up to 40% of patients with stable moderate and severe COPD disease 7–10, and a higher proportion of patients studied at the time of an exacerbation 7. Moreover, short-term treatment with oral corticosteroids does seem to be associated with significant benefits in patients with exacerbations of COPD 11. Early, uncontrolled studies with long-term, low-dose prednisolone have suggested substantial treatment-associated reductions in exacerbation frequency and rate of decline in FEV1 12, 13.
These findings raise the possibility that COPD is an inhaled corticosteroid-resistant, oral corticosteroid-responsive condition. Two recent studies provide direct support for this view. Both studies were placebo-controlled crossover trials involving ∼60 patients with moderate and severe COPD. The first study investigated 2 weeks of prednisolone 30 mg·day−1 8 and the other inhaled mometasone 400 μg daily for 6 weeks 9. Both studies showed that the treatment-associated improvement in FEV1 and quality of life scores increased progressively from the lowest to highest tertile of baseline sputum eosinophil count, consistent with a close, and perhaps causal, association between eosinophilic airway inflammation and the response to corticosteroids. However, the beneficial effects of oral prednisolone were substantially greater than those of inhaled mometasone. This was particularly the case with the sputum eosinophil count, which was reduced six-fold by prednisolone, but was unaffected by mometasone. Another recent study has shown that a management approach with the additional aim of reducing the sputum eosinophil count below 3% is associated with a 62% reduction in severe exacerbations of COPD requiring hospitalisation, when compared to traditional symptom-based management 14. Anecdotally, we found in this study that it was often necessary to use oral prednisolone to achieve significant reductions in the sputum eosinophil counts in the intervention group.
A potential mechanism for the different effects of inhaled and oral corticosteroid resistance in COPD is that functionally important corticosteroid-responsive eosinophilic airway inflammation is confined to the distal lung, a site that is accessed by oral, but not inhaled, corticosteroids. Interestingly, studies in severe asthma show that oral, but not inhaled, corticosteroids reduce alveolar nitric oxide, strongly suggesting that this marker of distal lung inflammation reflects inflammation in a site that is differentially accessed by systemic and inhaled corticosteroids 15.
Other explanations consider a more absolute corticosteroid resistance in COPD, suggesting smoking and oxidative stress impair the ability of corticosteroids to recruit histone deactylase-2, which leads to transcription of pro-inflammatory genes 16. This is not consistent with the observed difference in the clinical and anti-inflammatory efficacy of oral and inhaled corticosteroids.
If COPD is associated with an inhaled corticosteroid-resistant but oral corticosteroid-responsive functionally important distal eosinophilic airway inflammatory response, it follows that long-term treatment with oral corticosteroids might be associated with improvements in meaningful longer-term outcomes in patients with COPD, such as exacerbation frequency and decline in lung function, particularly when there is evidence of eosinophilic airway inflammation. Of course, long-term therapy with oral corticosteroids has a high potential for adverse effects in an elderly frail population, although the risk benefit may be acceptable if the maintenance dose is low and if care is taken to monitor and prevent osteoporosis, especially in the context of patients with severe disease suffering an expected 5-yr survival of 24–30% 17. There is also the potential that effective anti-inflammatory therapy will be associated with a reduction in markers of systemic inflammation and reduced morbidity and mortality from associated conditions, such as coronary heart disease 18.
In a sense, experience with oral corticosteroid treatment in COPD parallels, but lags behind, experience with oral corticosteroid treatment in rheumatoid arthritis where opinion has swung from extreme enthusiasm to therapeutic nihilism and back to a view where they are helpful when used in low doses in selected patients 19.
We believe that the respiratory community will ultimately come to a similar conclusion. The time has come to investigate the effects and cost-effectiveness of long-term low-dose oral corticosteroid therapy in patients with chronic obstructive pulmonary disease who have evidence of eosinophilic airway inflammation.
- © ERS Journals Ltd
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