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

G. B. Sigal, M. R. Segal, A. Mathew, L. Jarlsberg, M. Wang, S. Barbero, N. Small, K. Haynesworth, J. L. Davis, M. Weiner, W. C. Whitworth, J. Jacobs, J. Schorey, David Lewinsohn, P. Nahid

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalEBioMedicine
Volume25
DOIs
StatePublished - Nov 1 2017

Fingerprint

Biomarkers
Tuberculosis
Randomized Controlled Trials
Assays
Therapeutics
Linear Models
Neopterin
Clinical Trials
Proteins
Osteocalcin
Matrix Metalloproteinases
Interleukin-1
Cavitation
Linear regression
Metabolism
Interleukin-6
Pulmonary Tuberculosis
Association reactions
Observation
Inflammation

Keywords

  • Biomarkers
  • Clinical trials
  • Host immune response
  • Tuberculosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Biomarkers of Tuberculosis Severity and Treatment Effect : A Directed Screen of 70 Host Markers in a Randomized Clinical Trial. / 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, David; Nahid, P.

In: EBioMedicine, Vol. 25, 01.11.2017, p. 112-121.

Research output: Contribution to journalArticle

Sigal, GB, Segal, MR, Mathew, A, Jarlsberg, L, Wang, M, Barbero, S, Small, N, Haynesworth, K, Davis, JL, Weiner, M, Whitworth, WC, Jacobs, J, Schorey, J, Lewinsohn, D & Nahid, P 2017, 'Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial', EBioMedicine, vol. 25, pp. 112-121. https://doi.org/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, David ; Nahid, P. / Biomarkers of Tuberculosis Severity and Treatment Effect : A Directed Screen of 70 Host Markers in a Randomized Clinical Trial. In: EBioMedicine. 2017 ; Vol. 25. pp. 112-121.
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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.

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