• Charles R Esther, Wanda K O'Neal, Wayne H Anderson, Mehmet Kesimer, Agathe Ceppe, Claire M Doerschuk, Neil E Alexis, Annette T Hastie, R Graham Barr, Russell P Bowler, J Michael Wells, Elizabeth C Oelsner, Alejandro P Comellas, Yohannes Tesfaigzi, Victor Kim, Laura M Paulin, Christopher B Cooper, MeiLan K Han, Yvonne J Huang, Wassim W Labaki, Jeffrey L Curtis, Richard C Boucher, and Subpopulations and Intermediate Outcome Measures in COPD Study.
• Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address: charles_esther@med.unc.edu.
• Chest. 2022 May 1; 161 (5): 123912491239-1249.

BackgroundImproved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets.Research QuestionWhich physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations?Study Design And MethodsWe applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations.ResultsSputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations.InterpretationBiomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. 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.Trial RegistryClinicalTrials.gov; No.: NCT01969344; URL: www.Clinicaltrialsgov.Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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