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

Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study. Gupte, A. N, Kumar, P., Araújo-Pereira, M., Kulkarni, V., Paradkar, M., Pradhan, N., Menon, P., Chandrasekaran, P. D., Hanna, L., Yogendra Shivakumar, S. V. B., Rockwood, N., Du Bruyn, E., Karyakarte, R., Gaikwad, S., Bollinger, R., Golub, J., Gupte, N., Viswanathan, V., Wilkinson, R. J, Mave, V., Babu, S., Kornfeld, H., Andrade, B. B, & Gupta, A. European Respiratory Journal, 59(4):2100905, European Respiratory Society, apr, 2022.

Paper doi abstract bibtex

Background Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear. Methods We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. Results Pre-treatment interferon-$γ$, interleukin (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 with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08–4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48–11.57; p\textless0.001) and death (aOR 4.62, 95% CI 1.95–10.95; p\textless0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66 versus 0.76; p=0.02). Conclusions Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction. Pre-treatment IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes independent of disease severity and improves the performance of risk prediction models comprised of established clinical predictors \textlesshttps://bit.ly/38394xE\textgreater

@article{Gupte2022,
abstract = {Background Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear. Methods We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. Results Pre-treatment interferon-$\gamma$, interleukin (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 with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95{\%} CI 1.08–4.33; p=0.02), recurrence (aOR 5.36, 95{\%} CI 2.48–11.57; p{\textless}0.001) and death (aOR 4.62, 95{\%} CI 1.95–10.95; p{\textless}0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15{\%} (C-statistic 0.66 versus 0.76; p=0.02). Conclusions Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction. Pre-treatment IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes independent of disease severity and improves the performance of risk prediction models comprised of established clinical predictors {\textless}https://bit.ly/38394xE{\textgreater}},
author = {Gupte, Akshay N and Kumar, Pavan and Ara{\'{u}}jo-Pereira, Mariana and Kulkarni, Vandana and Paradkar, Mandar and Pradhan, Neeta and Menon, Pradeep and Chandrasekaran, Padmapriya Darasini and Hanna, Luke-Elizabeth and {Yogendra Shivakumar}, Shri Vijay Bala and Rockwood, Neesha and {Du Bruyn}, Elsa and Karyakarte, Rajesh and Gaikwad, Sanjay and Bollinger, Robert and Golub, Jonathan and Gupte, Nikhil and Viswanathan, Vijay and Wilkinson, Robert J and Mave, Vidya and Babu, Subash and Kornfeld, Hardy and Andrade, Bruno B and Gupta, Amita},
doi = {10.1183/13993003.00905-2021},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gupte et al. - 2022 - Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes a multisite discovery and validation.pdf:pdf},
issn = {0903-1936},
journal = {European Respiratory Journal},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
number = {4},
pages = {2100905},
pmid = {34711538},
publisher = {European Respiratory Society},
title = {{Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study}},
url = {https://erj.ersjournals.com/content/59/4/2100905 https://erj.ersjournals.com/content/59/4/2100905.abstract},
volume = {59},
year = {2022}
}

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Methods We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. Results Pre-treatment interferon-$γ$, interleukin (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 with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08–4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48–11.57; p\\textless0.001) and death (aOR 4.62, 95% CI 1.95–10.95; p\\textless0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66 versus 0.76; p=0.02). Conclusions Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction. 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