Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries

Background Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. Methods RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. Findings 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59 center dot 8% (95% CI 50 center dot 8-68 center dot 4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41 center dot 6% (34 center dot 7-48 center dot 7), and using a composite clinical reference standard, sensitivity was 29 center dot 6% (25 center dot 4-34 center dot 2). Specificity for all three reference standards was 90 center dot 3% (95% CI 85 center dot 5-94 center dot 0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50 center dot 0%, 15 center dot 7-84 center dot 3) compared with those without HIV (61 center dot 0%, 51 center dot 6-69 center dot 9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71 center dot 2% of children with microbiologically confirmed tuberculosis. Interpretation MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. Funding European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium fur Bildung und Forschung; German Center for Infection Research (DZIF). Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.