Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial

作者：George B. Sigal, Mark R. Segal, Anu Mathew, Leah G. Jarlsberg, M. Wang, Simone Barbero, Nicola Small, K. Haynesworth, J. Lucian Davis, Marc Weiner, W.C. Whitworth, Jon Jacobs, Jeffrey S. Schorey, David Lewinsohn, Payam Nahid · 发表于：EBioMedicine · 年份：2017 · DOI：10.1016/j.ebiom.2017.10.018 · 被引用次数：124 · 研究领域：Tuberculosis Research and Epidemiology、Diagnosis and treatment of tuberculosis、Infectious Diseases and Tuberculosis

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographica...