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 - 25/01/24

Doi : 10.1016/S1473-3099(23)00491-7

Laura Olbrich, MD DPhil ^a,^c,^d,^e,^{*
Contributed equally}, Valsan P Verghese, ProfMD ^f,^{*
Contributed equally}, Zoe Franckling-Smith, MD ^g, Issa Sabi, MD PhD ^h, Nyanda E Ntinginya, MD PhD ^h, Alfred Mfinanga, MD ^h, Denise Banze, MD ⁱ, Sofia Viegas, PhD ⁱ, Celso Khosa, MD PhD ⁱ, Robina Semphere, MD ^j, Marriott Nliwasa, MD PhD ^j, Timothy D McHugh, ProfPhD ^k, Leyla Larsson, MSc ^a,^c, Alia Razid, BSc ^a,^c, Rinn Song, MD PhD ^e, Elizabeth L Corbett, ProfMD ^j,^l, Pamela Nabeta, MD ^m, Andre Trollip, PhD ^m, Stephen M Graham, ProfMD PhD ⁿ, Michael Hoelscher, ProfMD ^a,^b,^c,^d,^o, Christof Geldmacher, PhD ^a,^c,^d, Heather J Zar, ProfMD PhD ^g, Joy Sarojini Michael, ProfMD ^p,^{*
Contributed equally}, Norbert Heinrich, MD PhD ^a,^b,^c,^d,^{*
Contributed equally}⁎
on behalf of the
RaPaed-TB consortium^{^†}
Consortium members are listed at the end of the Article

Cynthia Biddle Baard, Jacinta Diane Munro, Margaretha Prins, Nolufefe Benzi, Linda Claire Bateman, Ashleigh Ryan, Kutala Booi, Nezisa Paulo, Anthenette Heydenrych, Wonita Petersen, Raquel Brookes, Michele Mento, Chad Centner, Craig Dalgarno, Friedrich Rieß, Sarah Mutuku, Elmar Saathoff, Kathrin Held, Marilyn Mary Ninan, Anila Chacko, Ramya Kumari, R Dhanabhagyam, Nithya Muniswamy, Marc P Nicol, Bariki Mtafya, Harieth Mwambola, Christina Manyama, Hellen Mahiga, Emanuel Sichone, Lwitiho Sudi, Cremildo Maueia, Carla Madeira, Justina Cambuie, Jorge Ribeiro, Lingstone Chiume, Alice Mnyanga, Tionge Sikwese, Happy Masakasa, Diana Kachere, Masheck Kosaka, Stefan Niemann, Novel Chegou, Lyn Horn

^a Division of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany

^b CIHLMU Center for International Health, LMU University Hospital, LMU Munich, Munich, Germany

^c German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany

^d Fraunhofer Institute ITMP, Immunology, Infection and Pandemic Research, Munich, Germany

^e Oxford Vaccine Group, Department of Paediatrics and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

^f Pediatric Infectious Diseases, Department of Pediatrics, Christian Medical College, Vellore, India

^g Department of Paediatrics and Child Health, SA-MRC Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa

^h Mbeya Medical Research Centre, National Institute for Medical Research, Mbeya, Tanzania

ⁱ Instituto Nacional de Saúde, Marracuene, Mozambique

^j Helse Nord Tuberculosis Initiative, Department of Pathology, Kamuzu University of Health Sciences, Blantyre, Malawi

^k Centre for Clinical Microbiology, University College London, London, UK

^l Clinical Research Department, London School of Hygiene & Tropical Medicine, London, UK

^m Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland

ⁿ Department of Paediatrics, University of Melbourne and Murdoch Children’s Research Institute, Melbourne, VIC, Australia

^o Unit Global Health, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany

^p Department of Clinical Microbiology, Christian Medical College, Vellore, India

^* Correspondence to: Dr Norbert Heinrich, Division of Infectious Diseases and Tropical Medicine, University Hospital, Ludwig Maximilian University of Munich, Munich 80802, Germany Division of Infectious Diseases and Tropical Medicine University Hospital Ludwig Maximilian University of Munich Munich 80802 Germany

Summary

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 59·8% (95% CI 50·8–68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7–48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4–34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5–94·0). 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 50·0%, 15·7–84·3) compared with those without HIV (61·0%, 51·6–69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% 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 für Bildung und Forschung; German Center for Infection Research (DZIF).

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Vol 24 - N° 2

P. 140-149 - février 2024 Retour au numéro

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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 - 25/01/24

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