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

Abstract

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-1, 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 populationmore » 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. Keywords: host immune response; tuberculosis; biomarkers; clinical trials« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1439710
Report Number(s):
PNNL-SA-129994
Journal ID: ISSN 2352-3964; 49581; 453060036
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: EBioMedicine; Journal Volume: 25; Journal Issue: C
Country of Publication:
United States
Language:
English
Subject:
Environmental Molecular Sciences Laboratory

Citation Formats

Sigal, G. B., Segal, M. R., Mathew, A., Jarlsberg, L., Wang, M., Barbero, S., Small, N., Haynesworth, K., Davis, J. L., Weiner, M., Whitworth, W. C., Jacobs, J., Schorey, J., Lewinsohn, D. M., and Nahid, P. Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial. United States: N. p., 2017. Web. doi:10.1016/j.ebiom.2017.10.018.
Sigal, G. B., Segal, M. R., Mathew, A., Jarlsberg, L., Wang, M., Barbero, S., Small, N., Haynesworth, K., Davis, J. L., Weiner, M., Whitworth, W. C., Jacobs, J., Schorey, J., Lewinsohn, D. M., & Nahid, P. Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial. United States. doi:10.1016/j.ebiom.2017.10.018.
Sigal, G. B., Segal, M. R., Mathew, A., Jarlsberg, L., Wang, M., Barbero, S., Small, N., Haynesworth, K., Davis, J. L., Weiner, M., Whitworth, W. C., Jacobs, J., Schorey, J., Lewinsohn, D. M., and Nahid, P. Wed . "Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial". United States. doi:10.1016/j.ebiom.2017.10.018.
@article{osti_1439710,
title = {Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial},
author = {Sigal, G. B. and Segal, M. R. and Mathew, A. and Jarlsberg, L. and Wang, M. and Barbero, S. and Small, N. and Haynesworth, K. and Davis, J. L. and Weiner, M. and Whitworth, W. C. and Jacobs, J. and Schorey, J. and Lewinsohn, D. M. and Nahid, P.},
abstractNote = {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-1, 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. Keywords: host immune response; tuberculosis; biomarkers; clinical trials},
doi = {10.1016/j.ebiom.2017.10.018},
journal = {EBioMedicine},
number = C,
volume = 25,
place = {United States},
year = {Wed Nov 01 00:00:00 EDT 2017},
month = {Wed Nov 01 00:00:00 EDT 2017}
}