Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study
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Akshay N Gupte Pavan Kumar Mariana Araújo-Pereira Vandana Kulkarni Mandar Paradkar Neeta Pradhan Pradeep Menon Chandrasekaran Padmapriyadarasini Luke-Elizabeth Hanna Shri Vijay Bala Yogendra Shivakumar Neesha Rockwood Elsa Du Bruyn Rajesh Karyakarte Sanjay Gaikwad Robert Bollinger Jonathan Golub Nikhil Gupte Vijay Viswanathan Robert Wilkinson Vidya Mave Subash Babu Hardy Kornfeld Bruno B Andrade Amita GuptaAbstract
Pre-treatment IL-6 is a biomarker for unfavorable tuberculosis treatment outcomes independent of disease severity and, improves the performance of risk-prediction models comprising of established clinical predictors. BACKGROUND: Biomarkers of unfavorable tuberculosis treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavorable tuberculosis treatment outcomes is unclear. METHODS: We identified and internally validated the association between 20 a-priori selected plasma inflammatory markers and unfavorable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary tuberculosis in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV coinfected tuberculosis patients in India and South Africa, respectively. RESULTS: Pre-treatment IFN-γ, IL-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared to controls. External validation among predominantly diabetic tuberculosis patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV coinfected tuberculosis patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 tuberculosis cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted odds ratio [aOR]=2.16, 95%CI 1.08-4.33, p=0.02), recurrence (aOR=5.36, 95%CI 2.48-11.57, p<0.001) and death (aOR=4.62, 95%CI 1.95-10.95, p<0.001). Adding baseline IL-6 to a risk-prediction model comprising of low BMI, high smear grade and cavitation improved model performance by 15 percent (C-statistic of 0.66 versus 0.76, p=0.02). CONCLUSION: Pre-treatment IL-6 is a biomarker for unfavorable tuberculosis treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction.
Journal details
Journal European Respiratory Journal
Volume 59
Issue number 4
Pages 2100905
Available online
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Publisher website (DOI) 10.1183/13993003.00905-2021
Europe PubMed Central 34711538
Pubmed 34711538
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