Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis

Ashar Dhana, Yohhei Hamada, Andre P. Kengne, Andrew D. Kerkhoff, Molebogeng X. Rangaka, Tamara Kredo, Annabel Baddeley, Cecily Miller, Satvinder Singh, Yasmeen Hanifa, Alison D. Grant, Katherine Fielding, Dissou Affolabi, Corinne S. Merle, Ablo Prudence Wachinou, Christina Yoon, Adithya Cattamanchi, Christopher J. Hoffmann, Neil Martinson, Eyongetah Tabenyang MbuMelissa S. Sander, Taye T. Balcha, Sten Skogmar, Byron W.P. Reeve, Grant Theron, Gcobisa Ndlangalavu, Surbhi Modi, Joseph Cavanaugh, Susan Swindells, Richard E. Chaisson, Faiz Ahmad Khan, Andrea A. Howard, Robin Wood, Swe Swe Thit, Mar Mar Kyi, Josh Hanson, Paul K. Drain, Adrienne E. Shapiro, Tendesayi Kufa, Gavin Churchyard, Duc T. Nguyen, Edward A. Graviss, Stephanie Bjerrum, Isik S. Johansen, Jill K. Gersh, David J. Horne, Sylvia M. LaCourse, Haider Abdulrazzaq Abed Al-Darraji, Adeeba Kamarulzaman, Russell R. Kempker, Nestani Tukvadze, David A. Barr, Graeme Meintjes, Gary Maartens*


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Background: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population. Methods: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895. Findings: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72–89) and specificity was 42% (29–57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61–88]), but higher specificity (74% [61–83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had high specificities (80–90%) but low sensitivities (29–43%). The WHO-recommended algorithm had a sensitivity of 58% (50–66) and a specificity of 99% (98–100); Xpert for all had a sensitivity of 68% (57–76) and a specificity of 99% (98–99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62–81] vs 57% [47–67]) and specificities were similar (98% [96–98] vs 99% [98–100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35–71) and specificity was 71% (51–85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70–97]) and lower specificity (33% [17–54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76–91) and specificity was 37% (25–51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79–86]), but higher specificity (67% [60–73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75–90]), but higher specificity than (64% [57–71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively. Interpretation: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications. Funding: World Health Organization.

TidsskriftThe Lancet Infectious Diseases
Udgave nummer4
Sider (fra-til)507-518
StatusUdgivet - apr. 2022

Bibliografisk note

Funding Information:
AC reports grants from National Institutes of Health (NIH), Global Health Labs, and Stop TB Partnership, and consulting fees from the US Centers for Disease Control and Prevention (CDC). AK reports grants from Sanofi. FAK reports grants from WHO, Canadian Institutes of Health Research, Fonds de Recherche Quebec, and McGill Interdisciplinary Initiative on Infection and Immunity. GT reports receipt of consumables and equipment from Boditech and Cepheid. NM reports grants from Pfizer and Roche. REC reports grants from NIH, CDC, and Unitaid, and consulting fees from Sanofi. SML reports grants from NIH and CDC. SSk reports grants from Swedish Heart-Lung Foundation. TKr reports consulting fees from WHO. All other authors declare no competing interests.

Funding Information:
This work was supported by WHO. AD received training in research that was supported by the Fogarty International Center of the National Institutes of Health under award number D43 TW010559 and the National Research Foundation (NRF) of South Africa. GT acknowledges funding from the South African Medical Research Council (SAMRC Flagship Project MRC-RFA-IFSP-01-2013), the EDCTP2 programme supported by the EU ( grant SF1401 , OPTIMAL DIAGNOSIS), and the Faculty of Medicine and Health Sciences, Stellenbosch University. GN acknowledges that the work reported herein was made possible through funding by the South African Medical Research Council (SAMRC) through its Division of Research Capacity Development, under the Internship Scholarship Programme, from funding received from the South African National Treasury. The content of this paper is the sole responsibility of the authors and does not necessarily represent the official views of the SAMRC or the funders. GMe and GMa were supported by core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). GMe was supported by the Wellcome Trust (214321/Z/18/Z) and the South African Research Chairs Initiative of the Department of Science and Technology and NRF of South Africa (grant number 64787). AB, CM, SSi, and CSM work for WHO; the authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy, or views of WHO. The findings and conclusions in this manuscript are those of the author(s) and do not necessarily represent the official position of the CDC.


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