Identification of Sputum Biomarkers Predictive of Pulmonary Exacerbations in Chronic Obstructive Pulmonary Disease

Abstract Background Improved understanding of the pathways associated with airway pathophysiology in chronic obstructive pulmonary disease (COPD) will identify new predictive biomarkers and novel therapeutic targets. Research Question Which physiologic pathways are altered in the airways of subjects with COPD and predict exacerbations? Study Design and Methods We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the SPIROMICS multi-center COPD study. Biomarkers elevated in sputa from subjects with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. Results Sputum supernatants from 980 subjects (77 healthy non-smokers [NS], 341 smokers with preserved spirometry [SPS], and 562 COPD subjects [178 GOLD 1, 303 GOLD 2, and 81 GOLD 3]) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (at FDR 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were strongly associated with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. Interpretation Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiology. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum soluble phase biomarkers improves prediction of pulmonary exacerbations.