Rationale: C-reactive protein (CRP)-based tuberculosis (TB) screening is recommended for people with HIV (PWH). However, its performance among people without HIV and in diverse settings is unknown. Objectives: In a multi-country study, we aimed to determine whether CRP meets the minimum accuracy targets (sensitivity ≥90%, specificity ≥70%) for an effective TB triage test. Methods/Measurements: Consecutive outpatient adults with cough ≥2 weeks from five TB endemic countries in Africa and Asia had baseline blood collected for point-of-care CRP testing and HIV and diabetes screening. Sputum samples were collected for Xpert MTB/RIF Ultra (Xpert) testing and culture. CRP sensitivity and specificity (5 mg/L cut-point) was determined in reference to sputum test results and compared by country, sex, and HIV and diabetes status. Variables affecting CRP performance were identified using a multivariate receiver operating characteristic (ROC) regression model. Results: Among 2904 participants, of whom 613 (21%) had microbiologically-confirmed TB, CRP sensitivity was 84% (95% CI: 81-87%) and specificity was 61% (95% CI: 59-63%). CRP accuracy varied geographically, with higher sensitivity in African countries (≥91%) than Asian countries (64-82%). Sensitivity was higher among men than women (87% vs. 79%, difference +8%, 95% CI: 1-15%) and specificity was higher among people without HIV than PWH (64% vs. 45%, difference +19%, 95% CI: 13-25%). ROC regression identified country and measures of TB disease severity as predictors of CRP performance. Conclusions: Overall, CRP did not achieve the minimum accuracy targets and its performance varied by setting and in some sub-groups, likely reflecting population differences in mycobacterial load.

William Worodria, Charles Yu, Nhung Viet Nguyen, Devasahayam Jesudas Christopher, Grant Theron, Patrick P.J. Philips, Payam Nahid, Claudia M. Denkinger, Adithya Cattamanchi, and Christina Yoon declare support from the underlying R2D2 TB Network to their institutions from the National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes of Health (NIH). CMD also declares research grants from the German Ministry of Education and Research, German Alliance for Global Health Research, US Agency for International Development, FIND, German Center for Infection Research, and WHO. AC declares research funding to his institution from NIH, Bill and Melinda Gates Foundation, and Global Health Labs. CY declares research grants from NIH/NIAID and NIH/National Heart Lung Blood Institute, with CRP test strips and analyzers donated by Boditech Med Inc, South Korea. CY serves as a Scientific Advisory Board member for an EDCTP-funded cluster randomized trial. All other authors declare no competing interests. CRP test strips and analyzer were donated by Boditech Med Inc, South Korea.

NCT04923958

Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health under award number U01AI152087.

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IRBs of University of California San Francisco (USA), Heidelberg University (Germany), Makerere University (Uganda), Stellenbosch University (South Africa), Christian Medical College (India), National Lung Hospital (Vietnam) and De La Salle Medical and Health Sciences Institute (Philippines) gave ethical approval for this work.

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