Frequent Exacerbations in Patients with COPD May Indicate a Distinct Susceptibility Phenotype

Results of an observational study [N Engl J Med. 2010;363(12):1128-1138] suggest that patients with chronic obstructive pulmonary disease (COPD) who have more frequent exacerbations appear to have a distinct susceptibility phenotype that is relatively stable over time. This is based on the findings that show that, although exacerbations in patients with COPD become more frequent and more severe as the severity of COPD increases, some patients appear to be susceptible to exacerbations irrespective of disease severity. Exacerbations in patients with COPD appear to accelerate the decline in lung function in these patients that leads to reduced physical activity, quality of life, and increased mortality risk. Data show that a history of exacerbations is the most reliable predictor of exacerbations. Based on this, the investigators of the current study proposed the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. To test this hypothesis, the investigators used data collected from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) observational study to analyze the frequency and associations of exacerbations in 2138 patients in that study. Patients were included in the analysis who were between 40 and 75 years of age, had a history of ≥10 pack-years of smoking, a forced expiratory volume in 1 second (FEV1) of <80% of predicted value after bronchodilator use, and a ratio of FEV1 to forced vital capacity of ≤0.7 after bronchodilator use. In accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, the patients in the study were categorized based on disease severity. Of the 2138 patients, 945 had moderate COPD (Gold stage 2), 900 had severe COPD (Gold stage 3), and 293 had very severe COPD (Gold stage 4). The study found that exacerbations were more frequent and more severe as the severity of COPD increased. In the first year of follow-up, the exacerbation rates were 0.85 per person for patients with stage 2 COPD disease, 1.34 for patients with stage 3 disease, and 2.00 for patients with stage 4 disease. Overall, the study found frequent exacerbations (≥2 in the first year of follow-up) in 22% of patients with stage 2 disease, 33% with stage 3 disease, and 47% with stage 4 disease. The study also found that a history of exacerbations was the best predictor of exacerbations for all disease stages based on a univariate logistic-regression analysis that found that the best predictor of an exacerbation in the first year was being treated for an exacerbation in the year prior to the study (odds ratio, 4.30; 95% confidence interval, 3.58-5.17; P<.001). Using data from patients who completed all 3 years of the study, the investigators assessed the stability of the frequent-exacerbation phenotype over time. They found that the phenotypes for exacerbation susceptibility and resistance became stronger over time. Among 296 patients who had frequent exacerbations in the first 2 years of the study, 210 (71%) had frequent exacerbation in the third year, and among 521 patients with no exacerbations in the first 2 years, 388 (74%) had no exacerbations in the third year. Based on a multinomial regression model, the study also found that phenotype was independently associated with poorer quality of life, a history of gastroesophageal reflux or heartburn, and elevated white blood cell count. According to the authors, the results of their study “suggest that the frequent-exacerbation phenotype can be identified on the basis of a history of exacerbations, potentially allowing for appropriate targeting of patients for interventions and making it possible to selectively recruit patients for clinical trials.”