Validation and Optimization of Host Immunological Bio-Signatures for a Point-of-Care Test for TB Disease

Frontiers in Immunology

Hazel M. Dockrell¹  Kim Stanley¹  Emmanuel Nepolo¹  Novel N. Chegou²  Jacob A. Sheehama³  Gunar Günther³  Paul L. A. M. Corstjens³  Rawleigh Howe⁴  Adane Mihret⁴  Gerhard Walzl⁵  Annemieke Geluk⁶  Harriet Mayanja-Kizza⁷  Stephanus T. Malherbe⁸  Hygon Mutavhatsindi⁸  Gian D. van der Spuy⁸  the AE-TBC ScreenTB Consortia⁸  Desta Kassa⁹  Amelia C. Crampin^1,10  Jayne S. Sutherland^1,11 

[1] Microbiology, School of Medicine, University of Namibia, Windhoek, Namibia;0Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, Netherlands;;Department of Biochemistry &Department of Immunology, Armauer Hansen Research Institute, Addis Ababa, Ethiopia;Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom;Department of Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands;Department of Internal Medicine and Immunology, School of Medicine, Makerere University, Kampala, Uganda;Department of Science and Innovation - National Research Foundation (DSI-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;Infectious and Non-Infectious Diseases Research Directorate, Ethiopian Health and Nutrition Research Institute, Addis Ababa, Ethiopia;Karonga Prevention Study, London School of Hygiene and Tropical Medicine, Karonga, Malawi;TB Research Group, Medical Research Council Gambia at London School of Hygiene and Tropical Medicine (LSHTM), Banjul, Gambia;

关键词: bio-signature;    diagnostic;    validation;    blood;    biomarkers;    point of care;   

DOI  :  10.3389/fimmu.2021.607827

来源: DOAJ

【 摘 要 】

The development of a non-sputum-based, point-of-care diagnostic test for tuberculosis (TB) is a priority in the global effort to combat this disease, particularly in resource-constrained settings. Previous studies have identified host biomarker signatures which showed potential, but there is a need to validate and refine these for development as a test. We recruited 1,403 adults presenting with symptoms suggestive of pulmonary TB at primary healthcare clinics in six countries from West, East and Southern Africa. Of the study cohort, 326 were diagnosed with TB and 787 with other respiratory diseases, from whom we randomly selected 1005 participants. Using Luminex® technology, we measured the levels of 20 host biomarkers in serum samples which we used to evaluate the diagnostic accuracy of previously identified and novel bio-signatures. Our previously identified seven-marker bio-signature did not perform well (sensitivity: 89%, specificity: 60%). We also identified an optimal, two-marker bio-signature with a sensitivity of 94% and specificity of 69% in patients with no history of previous TB. This signature performed slightly better than C-reactive protein (CRP) alone. The cut-off value for a positive diagnosis differed for human immuno-deficiency virus (HIV)-positive and -negative individuals. Notably, we also found that no signature was able to diagnose TB adequately in patients with a prior history of the disease. We have identified a two-marker, pan-African bio-signature which is more robust than CRP alone and meets the World Health Organization (WHO) target product profile requirements for a triage test in both HIV-negative and HIV-positive individuals. This signature could be incorporated into a point-of-care device, greatly reducing the necessity for expensive confirmatory diagnostics and potentially reducing the number of cases currently lost to follow-up. It might also potentially be useful with individuals unable to provide sputum or with paucibacillary disease. We suggest that the performance of TB diagnostic signatures can be improved by incorporating the HIV-status of the patient. We further suggest that only patients who have never had TB be subjected to a triage test and that those with a history of previous TB be evaluated using more direct diagnostic techniques.

【 授权许可】

Unknown