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

Dhana A 1 , Hamada Y 2 , Kengne AP 3 , Kerkhoff AD 4 , Rangaka MX 5 , Kredo T 6 Show all authors , Baddeley A 7 , Miller C 7 , Singh S 8 , Hanifa Y 9 , Grant AD 10 , Fielding K 9 , Affolabi D 11 , Merle CS 12 , Wachinou AP 13 , Yoon C 14 , Cattamanchi A 14 , Hoffmann CJ 15 , Martinson N 16 , Mbu ET 17 , Sander MS 18 , Balcha TT 19 , Skogmar S 20 , Reeve BWP 21 , Theron G 21 , Ndlangalavu G 21 , Modi S 22 , Cavanaugh J 22 , Swindells S 23 , Chaisson RE 24 , Ahmad Khan F 25 , Howard AA 26 , Wood R 27 , Thit SS 28 , Kyi MM 28 , Hanson J 29 , Drain PK 30 , Shapiro AE 31 , Kufa T 32 , Churchyard G 33 , Nguyen DT 34 , Graviss EA 34 , Bjerrum S 35 , Johansen IS 36 , Gersh JK 37 , Horne DJ 38 , LaCourse SM 39 , Al-Darraji HAA 40 , Kamarulzaman A 40 , Kempker RR 41 , Tukvadze N 42 , Barr DA 43 , Meintjes G 44 , Maartens G 45

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
Lancet Infect Dis, 2022 Apr;22(4):507-518.
PMID: 34800394 DOI: 10.1016/S1473-3099(21)00387-X

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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