TY - JOUR
T1 - Biomarkers of Tuberculosis Severity and Treatment Effect
T2 - A Directed Screen of 70 Host Markers in a Randomized Clinical Trial
AU - Sigal, G. B.
AU - Segal, M. R.
AU - Mathew, A.
AU - Jarlsberg, L.
AU - Wang, M.
AU - Barbero, S.
AU - Small, N.
AU - Haynesworth, K.
AU - Davis, J. L.
AU - Weiner, M.
AU - Whitworth, W. C.
AU - Jacobs, J.
AU - Schorey, J.
AU - Lewinsohn, D. M.
AU - Nahid, P.
N1 - Funding Information:
We thank Drs. Susan Dorman, Jason Stout, Neil Schluger as protocol co-Chairs and the TBTC Study 29 protocol team for their support of embedding biomarker studies into the clinical trial. We thank Drs. Karen Dobos and Nicole Kruh-Garcia for input on biomarker interpretations. We thank R. Sivakamasundari, C. Frye, S. Grove, D. Bartlett, M. Navaratnam and M. Engle for assistance in sample handling, testing and data processing. Funding for recruitment, enrollment, and clinical and laboratory follow-up of TBTC Study 29 participants was provided by the United States Centers for Disease Control and Prevention. The biomarker assays and PN were supported by the National Institutes of Health through National Institute of Allergy and Infectious Diseases funding ( 1R01AI104589 : TB Surrogate Markers for Assessing Response to Treatment (TB SMART Study)), and by the Centers for Disease Control and Prevention , TB Trials Consortium Contract 200-2009-32597 (P.N.).
Publisher Copyright:
© 2017 The Authors
PY - 2017/11
Y1 - 2017/11
N2 - 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 8 weeks. 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 geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.
AB - 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 8 weeks. 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 geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.
KW - Biomarkers
KW - Clinical trials
KW - Host immune response
KW - Tuberculosis
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U2 - 10.1016/j.ebiom.2017.10.018
DO - 10.1016/j.ebiom.2017.10.018
M3 - Article
C2 - 29100778
AN - SCOPUS:85033711335
SN - 2352-3964
VL - 25
SP - 112
EP - 121
JO - EBioMedicine
JF - EBioMedicine
ER -