RT Journal Article
SR Electronic
T1 Baseline IL-6 is a biomarker for unfavorable tuberculosis treatment outcomes: a multi-site discovery and validation study
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2100905
DO 10.1183/13993003.00905-2021
A1 Akshay N. Gupte
A1 Pavan Kumar
A1 Mariana Araújo-Pereira
A1 Vandana Kulkarni
A1 Mandar Paradkar
A1 Neeta Pradhan
A1 Pradeep Menon
A1 Padmapriya Darasini Chandrasekaran
A1 Luke-Elizabeth Hanna
A1 Shri Vijay Bala Yogendra Shivakumar
A1 Neesha Rockwood
A1 Elsa Du Bruyn
A1 Rajesh Karyakarte
A1 Sanjay Gaikwad
A1 Robert Bollinger
A1 Jonathan Golub
A1 Nikhil Gupte
A1 Vijay Viswanathan
A1 Robert J. Wilkinson
A1 Vidya Mave
A1 Subash Babu
A1 Hardy Kornfeld
A1 Bruno B. Andrade
A1 Amita Gupta
YR 2021
UL http://erj.ersjournals.com/content/early/2021/08/19/13993003.00905-2021.abstract
AB 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Akshay N. Gupte has nothing to disclose.Conflict of interest: Pavan Kumar has nothing to disclose.Conflict of interest: Mariana Araújo-Pereira has nothing to disclose.Conflict of interest: Vandana Kulkarni has nothing to disclose.Conflict of interest: Mandar Paradkar has nothing to disclose.Conflict of interest: Neeta Pradhan has nothing to disclose.Conflict of interest: Pradeep Menon has nothing to disclose.Conflict of interest: P. Chandrasekaran reports funding from the Department of Biotechnology, Government of India, within the scope of the present manuscript.Conflict of interest: Luke-Elizabeth Hanna has nothing to disclose.Conflict of interest: Shri Vijay Bala Yogendra Shivakumar has nothing to disclose.Conflict of interest: Neesha Rockwood has nothing to disclose.Conflict of interest: Elsa Du Bruyn has nothing to disclose.Conflict of interest: Rajesh Karyakarte has nothing to disclose.Conflict of interest: Sanjay Gaikwad has nothing to disclose.Conflict of interest: R.C. Bollinger reports research support from the National Institutes of Health and the Ujala Foundation, within the scope of the present manuscript.Conflict of interest: J. Golub reports grants to their institution from the National Institutes of Health within the scope of the present manuscript.Conflict of interest: N. Gupte reports grants to their institution from the National Institutes of Health within the scope of the present manuscript.Conflict of interest: Vijay Viswanathan has nothing to disclose.Conflict of interest: Robert J. Wilkinson has nothing to disclose.Conflict of interest: Vidya Mave has nothing to disclose.Conflict of interest: Subash Babu has nothing to disclose.Conflict of interest: Hardy Kornfeld has nothing to disclose.Conflict of interest: Bruno B. Andrade has nothing to disclose.Conflict of interest: A. Gupta reports grants to their institution from the National Institutes of Health within the scope of the present manuscript; grants to their institution from CRDF outside the scope of the present manuscript; and membership of an NIH/NIAID Advisory Council and the IndoUS Science Technology Forum Board.