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Distinct serum biosignatures are associated with different tuberculosis treatment outcomes.
Tuberculosis (Edinb) 2019; 118:101859T

Abstract

Biomarkers for TB treatment response and outcome are needed. This study characterize changes in immune profiles during TB treatment, define biosignatures associated with treatment outcomes, and explore the feasibility of predictive models for relapse. Seventy-two markers were measured by multiplex cytokine array in serum samples from 78 cured, 12 relapsed and 15 failed treatment patients from South Africa before and during therapy for pulmonary TB. Promising biosignatures were evaluated in a second cohort from Uganda/Brazil consisting of 17 relapse and 23 cured patients. Thirty markers changed significantly with different response patterns during TB treatment in cured patients. The serum biosignature distinguished cured from relapse patients and a combination of two clinical (time to positivity in liquid culture and BMI) and four immunological parameters (TNF-β, sIL-6R, IL-12p40 and IP-10) at diagnosis predicted relapse with a 75% sensitivity (95%CI 0.38-1) and 85% specificity (95%CI 0.75-0.93). This biosignature was validated in an independent Uganda/Brazil cohort correctly classifying relapse patients with 83% (95%CI 0.58-1) sensitivity and 61% (95%CI 0.39-0.83) specificity. A characteristic biosignature with value as predictor of TB relapse was identified. The repeatability and robustness of these biomarkers require further validation in well-characterized cohorts.

Authors+Show Affiliations

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. Electronic address: katharina.ronacher@mater.uq.edu.au.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: novel@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: leaniek@sun.ac.za.Specialised Diagnostics and Research Unit, National Public Health Laboratory (URDS/LNSP), Libreville, Gabon. Electronic address: joel.djoba@gmail.com.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: nelita@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: gl2@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: emaasdorp@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: gctromp@sun.ac.za.Centre for Statistical Consultation, Stellenbosch University, Stellenbosch, South Africa. Electronic address: mkidd@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: kstanley@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: daleen.kriel@gmail.com.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: angelamenezes83@gmail.com.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: andreag@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: gvds@sun.ac.za.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: rw1@sun.ac.za.Núcleo de Doenças Infecciosas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, Brazil. Electronic address: rdietze@ndi.ufes.br.Uganda-Case Western Reserve University Research Collaboration, Makerere University College of Health Sciences, Mulago Hospital, Kampala, Uganda. Electronic address: A_okwera@mucwru.or.ug.Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, United States. Electronic address: bonnie.thiel@case.edu.Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA. Electronic address: john.belisle@colostate.edu.Department of Immunology and Infection, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom. Electronic address: Jackie.Cliff@lshtm.ac.uk.Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, United States. Electronic address: w.boom@case.edu.Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center, Cleveland, United States. Electronic address: jlj@case.edu.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: pvh@sun.ac.za.Department of Immunology and Infection, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom. Electronic address: Hazel.Dockrell@lshtm.ac.uk.DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: gwalzl@sun.ac.za.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31434026

Citation

Ronacher, Katharina, et al. "Distinct Serum Biosignatures Are Associated With Different Tuberculosis Treatment Outcomes." Tuberculosis (Edinburgh, Scotland), vol. 118, 2019, p. 101859.
Ronacher K, Chegou NN, Kleynhans L, et al. Distinct serum biosignatures are associated with different tuberculosis treatment outcomes. Tuberculosis (Edinb). 2019;118:101859.
Ronacher, K., Chegou, N. N., Kleynhans, L., Djoba Siawaya, J. F., du Plessis, N., Loxton, A. G., ... Walzl, G. (2019). Distinct serum biosignatures are associated with different tuberculosis treatment outcomes. Tuberculosis (Edinburgh, Scotland), 118, p. 101859. doi:10.1016/j.tube.2019.101859.
Ronacher K, et al. Distinct Serum Biosignatures Are Associated With Different Tuberculosis Treatment Outcomes. Tuberculosis (Edinb). 2019 Aug 12;118:101859. PubMed PMID: 31434026.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinct serum biosignatures are associated with different tuberculosis treatment outcomes. AU - Ronacher,Katharina, AU - Chegou,Novel N, AU - Kleynhans,Léanie, AU - Djoba Siawaya,Joel F, AU - du Plessis,Nelita, AU - Loxton,André G, AU - Maasdorp,Elizna, AU - Tromp,Gerard, AU - Kidd,Martin, AU - Stanley,Kim, AU - Kriel,Magdalena, AU - Menezes,Angela, AU - Gutschmidt,Andrea, AU - van der Spuy,Gian D, AU - Warren,Robin M, AU - Dietze,Reynaldo, AU - Okwera,Alphonse, AU - Thiel,Bonnie, AU - Belisle,John T, AU - Cliff,Jacqueline M, AU - Boom,W Henry, AU - Johnson,John L, AU - van Helden,Paul D, AU - Dockrell,Hazel M, AU - Walzl,Gerhard, Y1 - 2019/08/12/ PY - 2019/06/06/received PY - 2019/08/09/revised PY - 2019/08/11/accepted PY - 2019/8/23/pubmed PY - 2019/8/23/medline PY - 2019/8/22/entrez KW - Biomarkers KW - Relapse KW - Treatment failure KW - Tuberculosis KW - Tuberculosis treatment SP - 101859 EP - 101859 JF - Tuberculosis (Edinburgh, Scotland) JO - Tuberculosis (Edinb) VL - 118 N2 - Biomarkers for TB treatment response and outcome are needed. This study characterize changes in immune profiles during TB treatment, define biosignatures associated with treatment outcomes, and explore the feasibility of predictive models for relapse. Seventy-two markers were measured by multiplex cytokine array in serum samples from 78 cured, 12 relapsed and 15 failed treatment patients from South Africa before and during therapy for pulmonary TB. Promising biosignatures were evaluated in a second cohort from Uganda/Brazil consisting of 17 relapse and 23 cured patients. Thirty markers changed significantly with different response patterns during TB treatment in cured patients. The serum biosignature distinguished cured from relapse patients and a combination of two clinical (time to positivity in liquid culture and BMI) and four immunological parameters (TNF-β, sIL-6R, IL-12p40 and IP-10) at diagnosis predicted relapse with a 75% sensitivity (95%CI 0.38-1) and 85% specificity (95%CI 0.75-0.93). This biosignature was validated in an independent Uganda/Brazil cohort correctly classifying relapse patients with 83% (95%CI 0.58-1) sensitivity and 61% (95%CI 0.39-0.83) specificity. A characteristic biosignature with value as predictor of TB relapse was identified. The repeatability and robustness of these biomarkers require further validation in well-characterized cohorts. SN - 1873-281X UR - https://www.unboundmedicine.com/medline/citation/31434026/Distinct_serum_biosignatures_are_associated_with_different_tuberculosis_treatment_outcomes L2 - https://linkinghub.elsevier.com/retrieve/pii/S1472-9792(19)30227-6 DB - PRIME DP - Unbound Medicine ER -