Acute Exacerbations of Chronic Obstructive Pulmonary Disease Identification of Biologic Clusters and Their Biomarkers

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. Objectives: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. Methods: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. Measurements and Main Results: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed pauciinflammatory. Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1 beta, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83-0.95); serum CXCL10, 0.83 (95% CI, 0.70-0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78-0.93), respectively. Conclusions: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1 beta, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.