Steroids for Treatment of COPD Exacerbations

Abstract

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is a common, progressive lung condition, characterized by cough and dyspnea and punctuated by episodes of acute exacerbations or “lung attacks” during which these symptoms significantly increase. These lung attacks can induce severe symptoms, causing patients to seek urgent medical care and can result in respiratory failure and death. In the United States, COPD exacerbations are responsible for more than 800 000 hospital admissions each year and 143 000 deaths annually, making it the third leading cause of mortality. Furthermore, acute exacerbations accelerate decline in lung function, reduce patients’ quality of life, and increase health care use (with exacerbation management accounting for up to 70% of the total direct costs of COPD management). Acute exacerbations are common among patients with COPD, with nearly 1 in 2 patients experiencing at least 1 exacerbation annually. Although the pathophysiology of exacerbations is poorly understood, in most cases, it is thought to be provoked by an acute respiratory tract infection (by either a virus or bacteria), which suborns a hyperinflammatory state in the airways, causing patients to experience paroxysms of cough, sputum production, and shortness of breath. Accordingly, these episodes are usually treated with systemic corticosteroids in varying doses and duration. Over the past 30 years, randomized trials have demonstrated the benefits of systemic (usually oral) corticosteroids in providing symptom relief, accelerating lung function recovery, and preventing respiratory failure and treatment relapses in patients experiencing exacerbations. However, prior clinical trials have used different dosing regimens, leading to significant practice variation across physicians, hospitals, and countries. Some trials have used high doses of systemic corticosteroids and tapered the dose over several weeks to months, and others have used fixed (short duration) therapy without any tapering. Currently, there is no firm consensus on the dose or duration of therapy but most national and international guidelines recommend a 10to 14-day course of oral prednisone (approximately40 mg/d). However, even using this conservative regimen, patients frequently experience adverse effects of corticosteroids including hyperglycemia, weight gain, and insomnia. Moreover, because approximately 10% of patients experience frequent exacerbations (defined as 2 or more exacerbations annually), cumulative exposure to oral corticosteroids may be substantial in some patients, leading to serious long-term steroid toxicity, including weight gain, diabetes, osteoporosis, fractures, adrenal suppression, and ocular complications. Because steroid toxicity is dose and duration dependent, ascertainment of a minimal effective dose to treat acute exacerbations is of critical clinical importance for millions of patients with COPD who experience frequent exacerbations. This important but unresolved question is addressed by Leuppi and colleagues in this issue of JAMA. In this rigorous, high-quality, randomized noninferiority clinical trial involving 314 patients with acute exacerbations of COPD, a 5-day course of oral prednisone (at 40 mg daily) was compared with the conventional 14-day course of prednisone as recommended by most guidelines. The study found no significant differences in the primary outcome of treatment relapse (ie, reexacerbation) rate within 180 days (37.2% in the 5-day treatment group vs 38.4% in the 14-day treatment group). There were also no significant differences in lung function or in any of the subjective outcomes such as dyspnea or quality of life between the 2 groups. Thus, the 5-day treatment was noninferior to the 14-day treatment despite a 65% reduction in the cumulative steroid exposure over 6 months in the short-term treatment group (560 mg in the conventional group vs 200 mg median prednisone exposure in the short-term group). While the risk of acute steroid toxicity, including hyperglycemia, was similar between the 2 groups, there were fewer occurrences of hypertension in the short-term treatment group, but this difference was not statistically significant. In addition, patients in the short-term treatment group had significantly shorter hospital stays than those in the con-