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-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.

Variation of some antioxidant biomarkers in Cameroonian patients treated with first-line anti-tuberculosis drugs

“…In our study, we noted that catalase activity was higher at the time of tuberculosis diagnosis, than the ones obtained during phase T2, and phase T3 of the treatment. Its evolution profile is different from the one reported in the literature, where a progressive increase in catalase activity is described during the first two months of antituberculosis antibiotic therapy (Sigal et al, 2017). The level of its activity before the initiation of treatment reflects the high reserve of catalase for the defense against EROs produced by the host facing the infection.…”

Can we predict tuberculosis cure? What tools are available?

“…Although promising, further research is needed to establish the efficacy of this new assay as marker for treatment monitoring and/or outcome. 166,195,196] [158] [172,173,197] [ 162,175] Markers of lung tissue repair (platelet activity VEGF, TGF-β, MMPs) [195,196] [135].…”

The prognosis model of treatment efficiency for pulmonary tuberculosis in intensive phase of antituberculosis therapy

“…Також, як моніторингові індикатори ЕЛ, можуть бути використані показники гострого та хронічного запалення, стану імунітету і метаболізму. Значна кількість наукових досліджень присвячена оцінці їх інформативності [5]. Проте в регулюючих лікарську діяльність документах використання таких показників не регламентоване, а клінічний мінімум, який використовується у практичній діяльності, не дає можливості провести оцінку ЕЛ, а також прогнозувати її.…”

“…Результати визначення неоптеріну у сироватці крові хворих на ТБ були значно варіабельні у групах порівняння, подібна розбіжність також описана у літературних джерелах [5,10]. У нашому дослідженні це може бути обумовлено формуванням груп за критерієм ЕЛ, а не певною характеристикою туберкульозного процесу.…”