Millions of cases of tuberculosis (TB) go undiagnosed each year. Better diagnostic tools are urgently needed. Biomarker-based or multiple marker biosignature-based tests, ideally performed on blood or urine, for the detection of active TB might help to meet target product profiles proposed by the World Health Organization for point-of-care testing. We conducted a systematic review to summarize evidence on proposed biomarkers and biosignatures and evaluate their quality and level of evidence. We screened the titles and abstracts of 7,631 citations and included 443 publications that fulfilled the inclusion criteria and were published in 2010–2017. The types of biomarkers identified included antibodies, cytokines, metabolic activity markers, mycobacterial antigens and volatile organic compounds. Only 47% of studies reported a culture-based reference standard and diagnostic sensitivity and specificity. Forty-four biomarkers (4%) were identified in high-quality studies and met the target product profile minimum criteria, of which two have been incorporated into commercial assays. Of the 44 highest-quality biomarkers, 24 (55%) were multiple marker biosignatures. No meta-analyses were performed owing to between-study heterogeneity. In conclusion, TB biomarker discovery studies are often poorly designed and findings are rarely confirmed in independent studies. Few markers progress to a further developmental stage. More validation studies that consider the intended diagnostic use cases and apply rigorous design are needed. The extracted data from this review are currently being used by FIND as the foundation of a dynamic database in which biomarker data and developmental status will be presented.
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We thank T. Togun (data quality checking), S. Huddart (graphics work) and R. Wyss (data curation). We also thank the New Diagnostic Working Group Biomarkers Task Force (for feedback on the design of this systematic review and on the manuscript). The New Diagnostics Working Group: D. M. Cirillo (San Raffaele Scientific Institute, Italy), C.M.D. (FIND, Switzerland), M. Doherty (SSI, Denmark), J. L. Gardiner (BMGF, USA), M. L. Gennaro (Rutgers, USA), S. A. Joosten (Leiden University, The Netherlands), M. Kaforou (Imperial College London, UK), E.M. (McGill University, Canada), P. Nahid (UCSF, USA), M.P. (McGill University, Canada), M. Schito (C-PATH, USA), T. J. Scriba (University of Cape Town, South Africa), R. S. Wallis (Aurum Institute, South Africa), G. Walzl (Stellenbosch University, South Africa), S.Y. (FIND, Switzerland), A. Zumla (UCL, UK) and T.B. (FIND, Switzerland). The work was funded by the Dutch Ministry of Foreign Affairs and the New Diagnostics Working Group of the Stop TB Partnership.
T.B., S.Y., B.L.F.-C. and C.M.D. are employed by FIND. FIND is a not-for-profit foundation that supports the evaluation of publicly prioritized TB assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for TB and other diseases. These agreements strictly define FIND’s independence and neutrality vis-a-vis the companies whose products get evaluated and describe roles and responsibilities. M.P. serves on the WHO SAGE IVD Group and is a member of the Scientific Advisory Committee of FIND. M.P. and E.M. have no industry or financial conflicts.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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MacLean, E., Broger, T., Yerlikaya, S. et al. A systematic review of biomarkers to detect active tuberculosis. Nat Microbiol 4, 748–758 (2019). https://doi.org/10.1038/s41564-019-0380-2
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