Systemic Inflammation in Predicting COPD Exacerbations

Abstract

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMOnary disease (COPD) involve inflammatory events in the airway caused mostly by infection— bacterial, viral, or both. During the last 2 decades, the understanding of exacerbations has improved, and these exacerbations are now regarded as major contributors to cost of care, health status deterioration, loss of lung function, and mortality in COPD. However, treatment of exacerbations has not evolved significantly, and clinical failure rates (need for additional treatment or hospitalization) of 20% to 40% within 1 month are still prevalent. Prevention of exacerbations is at the forefront as a therapeutic goal in COPD. However, to apply preventive therapies effectively, identifying patients at risk for future exacerbations is critical but not simple. Chronic obstructive pulmonary disease is a heterogeneous disease with multiple phenotypes. Although the frequency of exacerbations is related to the severity of airflow obstruction, some patients with severe disabling lung disease never have exacerbations, whereas other patients with much less airflow obstruction have frequent exacerbations. Other clinical risk factors associated with frequent exacerbations include a history of previous exacerbations, poor diseasespecific health status, chronic bronchitis, and gastroesophageal reflux, with the strongest predictive factor being a history of previous exacerbations. If exacerbations worsen lung function and health status over time in patients with COPD, current predictive factors may simply rely on the consequences of prior exacerbations to predict future episodes. The current approach for identifying a high-risk patient to prevent exacerbations is likely “too little, too late.” Further refinement and earlier detection of exacerbation risk in COPD is clearly needed. In this issue of JAMA, Thomsen et al report findings from 2 large, population-based, prospective studies demonstrating that elevated levels of systemic inflammatory biomarkers (C-reactive protein, fibrinogen, and leukocyte count) were associated with future exacerbations of COPD. This association was observed after accounting for other variables important for determining the risk of exacerbations, especially lung function and history of exacerbations. (Chronic bronchitis and gastroesophageal reflux apparently were not included as potential risk factors.) The association had a stepwise pattern; elevations in levels of all 3 biomarkers had the highest utility in predicting exacerbations, whereas the predictive value was minimal to moderate if only 1 or 2 biomarkers were elevated. This study has several strengths, including a large number of patients (6574 with COPD and a total of 3083 exacerbations), prospective follow-up with no loss to follow-up, and reliable capture of exacerbations through a single central health care system database. The biomarkers studied are simple to measure, inexpensive, and readily available, and specific values are provided. Several aspects of experimental design need to be considered in interpreting the results. Chronic obstructive pulmonary disease was diagnosed if the ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%. Patients younger than age 40 years and those with selfreported asthma were excluded. Nevertheless, 1435 participants (22%) were life-long nonsmokers. Whether these patients truly had COPD or were elderly individuals with normal age-related reduction in lung elasticity is uncertain. The predictive value of the inflammatory biomarkers was attenuated in the nonsmoker subgroup. Because of the population-based rather than disease-targeted enrollment in this study, the proportion of patients with mild to moderate COPD is substantially larger than in other studies. Generalizability of their observations to more severe COPD may therefore be limited. The COPD severity distribution also likely explains the low exacerbation rate observed of 0.5 episodes per patient per year. Another factor that may have contributed to the low rate is the definition of exacerbation used, which included either a short course of corticosteroids (with or without antibiotics) or a hospital admission due to COPD. Many exacerbations, particularly in mild COPD, are diagnosed as acute bronchitis and treated with antibiotics only, and these episodes were not captured in this analysis. Another con-