Elsevier

EBioMedicine

Volume 25, November 2017, Pages 112-121
EBioMedicine

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

https://doi.org/10.1016/j.ebiom.2017.10.018Get rights and content
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Highlights

  • Seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, show recurring strong associations with markers of baseline tuberculosis disease severity, smear grade and cavitation

  • These same proteins were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks.

  • Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response in our clinical trial cohort.

The identification of improved biomarkers of tuberculosis treatment effect has been recognized as a key research area by the WHO International Roadmap for Tuberculosis Research because it would accelerate the development of new drugs and regimens, and potentially improve approaches to patient monitoring. Our findings within a rigorously conducted phase 2 clinical trial are that across numerous analyses, seven proteins recur with strong associations with both baseline disease severity and treatment effect. The consistency with which these markers are identified provides impetus for their further study as well as the future pursuit of blood-based treatment monitoring assay development.

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-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.

Keywords

Host immune response
Tuberculosis
Biomarkers
Clinical trials

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