Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study

Effect of Diabetes on Tuberculosis Severity study (EDOTS) Summary of the Study Background: Unfavorable treatment outcomes, including bacteriological failure, death, and tuberculosis (TB) recurrence, continue to pose a significant challenge to global TB elimination efforts. Although shortening the duration of chemotherapy would substantially strengthen TB control programs, progress is hindered by the lack of reliable biomarkers capable of predicting treatment response . Recurrence rates, for instance, vary widely, with estimates ranging from 4.9% to 47% , reflecting regional differences in TB epidemiology as well as variability in outcome definitions across TB control programs. These challenges underscore the urgent need for biomarkers measurable at treatment initiation that can distinguish individuals at high risk of adverse outcomes from those likely to be cured with the standard 6-month regimen or potentially shorter regimens. Early identification of patients at increased risk of treatment failure would enable targeted intensification of monitoring during and after therapy and help define populations most likely to benefit from novel intensified or extended treatment strategies, including higher doses of standard antimicrobials, additional drugs, or adjunctive host-directed therapies. Furthermore, treatment-associated mortality remains a major concern and could potentially be reduced through baseline risk stratification followed by more intensive treatment and follow-up for high-risk individuals. Study Cohort: The test cohort consisted of 446 participants enrolled in the prospective Effect of Diabetes on Tuberculosis Severity study conducted in Chennai, India, from 2014 to 2019. Of these, 68 individuals experienced unfavorable treatment outcomes, including treatment failure, relapse, or death, while 10% (n = 44) were lost to follow-up. Eligibility criteria included newly diagnosed pulmonary tuberculosis confirmed by positive smear and culture, age between 18 and 75 years, and no prior history of tuberculosis treatment. Participants were excluded if they had previously received TB treatment, had drug-resistant TB, were HIV-seropositive, or were receiving immunosuppressive therapy. Pulmonary tuberculosis was diagnosed based on positive sputum culture results on solid media in conjunction with compatible chest radiographic findings. All participants were treated under the Directly Observed Treatment, Short-course (DOTS) strategy. Follow-up assessments were conducted monthly during the 6-month treatment period and every three months thereafter for up to one year following treatment completion. A nested case–control design was used, with cases experiencing adverse treatment outcomes matched in a 1:2 ratio to control participants who achieved a recurrence-free cure by the end of the study. Cure was defined as negative sputum culture results at months 5 and 6 of treatment without evidence of recurrence during follow-up. Adverse outcomes included treatment failure (positive sputum cultures at months 5 or 6), all-cause mortality, or recurrent tuberculosis within 12 months after initial cure. Within the test cohort, 18 treatment failures, 16 deaths, and 34 recurrences were documented. Case–control matching was performed based on age, sex, body mass index (BMI), and diabetes status. Exact matching was achieved for age and sex, BMI was matched within one unit, and diabetes status was determined by participant self report. Peripheral blood samples were collected at baseline prior to treatment initiation in heparinized tubes, and plasma was separated by centrifugation and stored at −80 °C until analysis. Findings : The present study leverages well-characterized sample collections from individuals with unfavorable tuberculosis treatment outcomes to identify baseline predictors of poor prognosis. Our findings demonstrate that IL-6 exhibits significant differences between cases and controls, providing additional predictive value beyond established clinical and bacteriological parameters for identifying individuals at risk of treatment failure, recurrence, or death. While prior studies have largely depended on clinical and bacteriological indicators—such as baseline time to culture positivity and culture status at month 2—to predict unfavorable outcomes, our study specifically evaluated IL-6 to assess differences in its expression kinetics between cases and controls.