Meta-Analysis

. 2022 Apr;22(4):507-518.

doi: 10.1016/S1473-3099(21)00387-X. Epub 2021 Nov 17.

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

Ashar Dhana¹, Yohhei Hamada², Andre P Kengne³, Andrew D Kerkhoff⁴, Molebogeng X Rangaka⁵, Tamara Kredo⁶, Annabel Baddeley⁷, Cecily Miller⁷, Satvinder Singh⁸, Yasmeen Hanifa⁹, Alison D Grant¹⁰, Katherine Fielding⁹, Dissou Affolabi¹¹, Corinne S Merle¹², Ablo Prudence Wachinou¹³, Christina Yoon¹⁴, Adithya Cattamanchi¹⁴, Christopher J Hoffmann¹⁵, Neil Martinson¹⁶, Eyongetah Tabenyang Mbu¹⁷, Melissa S Sander¹⁸, Taye T Balcha¹⁹, Sten Skogmar²⁰, Byron W P Reeve²¹, Grant Theron²¹, Gcobisa Ndlangalavu²¹, Surbhi Modi²², Joseph Cavanaugh²², Susan Swindells²³, Richard E Chaisson²⁴, Faiz Ahmad Khan²⁵, Andrea A Howard²⁶, Robin Wood²⁷, Swe Swe Thit²⁸, Mar Mar Kyi²⁸, Josh Hanson²⁹, Paul K Drain³⁰, Adrienne E Shapiro³¹, Tendesayi Kufa³², Gavin Churchyard³³, Duc T Nguyen³⁴, Edward A Graviss³⁴, Stephanie Bjerrum³⁵, Isik S Johansen³⁶, Jill K Gersh³⁷, David J Horne³⁸, Sylvia M LaCourse³⁹, Haider Abdulrazzaq Abed Al-Darraji⁴⁰, Adeeba Kamarulzaman⁴⁰, Russell R Kempker⁴¹, Nestani Tukvadze⁴², David A Barr⁴³, Graeme Meintjes⁴⁴, Gary Maartens⁴⁵

Affiliations

¹ Department of Medicine, University of Cape Town, Cape Town, South Africa.
² Centre for International Cooperation and Global Tuberculosis Information, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, Japan; Institute for Global Health, University College London, London, UK.
³ Non-communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa.
⁴ Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, CA, USA.
⁵ Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Institute for Global Health, University College London, London, UK.
⁶ Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa; Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
⁷ Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
⁸ Global HIV, Hepatitis and STIs Programme, World Health Organization, Geneva, Switzerland.
⁹ TB Centre, London School of Hygiene & Tropical Medicine, London, UK.
¹⁰ TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Africa Health Research Institute, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.
¹¹ Laboratoire de Référence des Mycobactéries, Cotonou, Benin.
¹² UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland.
¹³ National Hospital for Tuberculosis and Pulmonary Diseases, Cotonou, Benin.
¹⁴ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Center for Tuberculosis, University of California, San Francisco, CA, USA.
¹⁵ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.
¹⁷ Bamenda Regional Hospital HIV Treatment Center, Bamenda, Cameroon.
¹⁸ Tuberculosis Reference Laboratory Bamenda, Bamenda, Cameroon.
¹⁹ Clinical Infection Medicine, Lund University, Malmö, Sweden; Department of Translational Medicine, Lund University, Malmö, Sweden.
²⁰ Department of Translational Medicine, Lund University, Malmö, Sweden.
²¹ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, Western Cape, South Africa.
²² US Centers for Disease Control and Prevention, Atlanta, GA, USA.
²³ University of Nebraska Medical Center, Omaha, NE, USA.
²⁴ Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.
²⁵ McGill International Tuberculosis Centre, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
²⁶ ICAP at Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
²⁷ Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
²⁸ Department of Medicine, University of Medicine 2, Yangon, Yangon Division, Myanmar.
²⁹ The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
³⁰ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
³¹ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
³² School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa.
³³ School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; The Aurum Institute, Parktown, South Africa.
³⁴ Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
³⁵ Department of Clinical Research, Infectious Diseases, University of Southern Denmark, Odense, Denmark.
³⁶ Research Unit for Infectious Diseases, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
³⁷ University of Washington, Seattle, WA, USA.
³⁸ Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, WA, USA.
³⁹ Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, WA, USA; Department of Global Health, Division of Infectious Diseases, University of Washington, Seattle, WA, USA.
⁴⁰ Centre of Excellence for Research in AIDS, University of Malaya, Kuala Lumpur, Malaysia.
⁴¹ Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.
⁴² National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
⁴³ Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
⁴⁴ Department of Medicine, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
⁴⁵ Department of Medicine, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: gary.maartens@uct.ac.za.

PMID: 34800394
PMCID: PMC8942858
DOI: 10.1016/S1473-3099(21)00387-X

Meta-Analysis

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

Ashar Dhana et al. Lancet Infect Dis. 2022 Apr.

. 2022 Apr;22(4):507-518.

doi: 10.1016/S1473-3099(21)00387-X. Epub 2021 Nov 17.

Authors

Affiliations

¹ Department of Medicine, University of Cape Town, Cape Town, South Africa.
² Centre for International Cooperation and Global Tuberculosis Information, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, Japan; Institute for Global Health, University College London, London, UK.
³ Non-communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa.
⁴ Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, CA, USA.
⁵ Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Institute for Global Health, University College London, London, UK.
⁶ Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa; Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
⁷ Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
⁸ Global HIV, Hepatitis and STIs Programme, World Health Organization, Geneva, Switzerland.
⁹ TB Centre, London School of Hygiene & Tropical Medicine, London, UK.
¹⁰ TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Africa Health Research Institute, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.
¹¹ Laboratoire de Référence des Mycobactéries, Cotonou, Benin.
¹² UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland.
¹³ National Hospital for Tuberculosis and Pulmonary Diseases, Cotonou, Benin.
¹⁴ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Center for Tuberculosis, University of California, San Francisco, CA, USA.
¹⁵ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.
¹⁷ Bamenda Regional Hospital HIV Treatment Center, Bamenda, Cameroon.
¹⁸ Tuberculosis Reference Laboratory Bamenda, Bamenda, Cameroon.
¹⁹ Clinical Infection Medicine, Lund University, Malmö, Sweden; Department of Translational Medicine, Lund University, Malmö, Sweden.
²⁰ Department of Translational Medicine, Lund University, Malmö, Sweden.
²¹ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, Western Cape, South Africa.
²² US Centers for Disease Control and Prevention, Atlanta, GA, USA.
²³ University of Nebraska Medical Center, Omaha, NE, USA.
²⁴ Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.
²⁵ McGill International Tuberculosis Centre, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
²⁶ ICAP at Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
²⁷ Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
²⁸ Department of Medicine, University of Medicine 2, Yangon, Yangon Division, Myanmar.
²⁹ The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
³⁰ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
³¹ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
³² School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa.
³³ School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; The Aurum Institute, Parktown, South Africa.
³⁴ Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
³⁵ Department of Clinical Research, Infectious Diseases, University of Southern Denmark, Odense, Denmark.
³⁶ Research Unit for Infectious Diseases, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
³⁷ University of Washington, Seattle, WA, USA.
³⁸ Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, WA, USA.
³⁹ Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, WA, USA; Department of Global Health, Division of Infectious Diseases, University of Washington, Seattle, WA, USA.
⁴⁰ Centre of Excellence for Research in AIDS, University of Malaya, Kuala Lumpur, Malaysia.
⁴¹ Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.
⁴² National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
⁴³ Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
⁴⁴ Department of Medicine, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
⁴⁵ Department of Medicine, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: gary.maartens@uct.ac.za.

PMID: 34800394
PMCID: PMC8942858
DOI: 10.1016/S1473-3099(21)00387-X

Erratum in

Correction to Lancet Infect Dis 2022; 22: 507-18.
[No authors listed] [No authors listed] Lancet Infect Dis. 2023 Jun;23(6):e198. doi: 10.1016/S1473-3099(23)00263-3. Epub 2023 Apr 17. Lancet Infect Dis. 2023. PMID: 37080230 Free PMC article. No abstract available.

Abstract

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.

© 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3·0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

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Conflict of interest statement

Declaration of interests 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.

Figures

**Figure 1**
Study selection W4SS=WHO-recommended four symptom screen. *One study (Hanifa and colleagues¹³) was incorporated into sensitivity analyses because the study's reference standard made it ineligible for the main analyses.

**Figure 2**
Summary ROC curves comparing C-reactive protein (≥10 mg/L) with W4SS in all participants* AUC=area under the ROC. ROC=receiver operating characteristic. W4SS=WHO-recommended four-symptom screen. *Data were extrapolated beyond observed datapoints.

**Figure 3**
Screening outcomes for selected screening tests and strategies in a hypothetical cohort of 1000 people living with HIV at 10% (all and not on ART) and 5% (on ART) tuberculosis prevalence ART=antiretroviral therapy. W4SS=WHO-recommended four-symptom screen.

See this image and copyright information in PMC

References

1. Gupta RK, Lucas SB, Fielding KL, Lawn SD. Prevalence of tuberculosis in post-mortem studies of HIV-infected adults and children in resource-limited settings: a systematic review and meta-analysis. AIDS. 2015;29:1987–2002. - PMC - PubMed
1. WHO . World Health Organization; Geneva: 2020. Global tuberculosis report 2020.
1. Getahun H, Kittikraisak W, Heilig CM, et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med. 2011;8 - PMC - PubMed
1. WHO . World Health Organization; Geneva: 2020. WHO consolidated guidelines on tuberculosis: tuberculosis preventive treatment: module 1: prevention: tuberculosis preventive treatment. - PubMed
1. Hamada Y, Lujan J, Schenkel K, Ford N, Getahun H. Sensitivity and specificity of WHO's recommended four-symptom screening rule for tuberculosis in people living with HIV: a systematic review and meta-analysis. Lancet HIV. 2018;5:e515–e523. - PubMed

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

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

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