Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis,The Lancet Infectious Diseases

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Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis
The Lancet Infectious Diseases ( IF 36.4 ) Pub Date : 2021-11-17 , DOI: 10.1016/s1473-3099(21)00387-x
Ashar Dhana ₁ , Yohhei Hamada ₂ , Andre P Kengne ₃ , Andrew D Kerkhoff ₄ , Molebogeng X Rangaka ₅ , Tamara Kredo ₆ , Annabel Baddeley ₇ , Cecily Miller ₇ , Satvinder Singh ₈ , Yasmeen Hanifa ₉ , Alison D Grant ₁₀ , Katherine Fielding ₉ , Dissou Affolabi ₁₁ , Corinne S Merle ₁₂ , Ablo Prudence Wachinou ₁₃ , Christina Yoon ₁₄ , Adithya Cattamanchi ₁₄ , Christopher J Hoffmann ₁₅ , Neil Martinson ₁₆ , Eyongetah Tabenyang Mbu ₁₇ , Melissa S Sander ₁₈ , Taye T Balcha ₁₉ , Sten Skogmar ₂₀ , Byron W P Reeve ₂₁ , Grant Theron ₂₁ , Gcobisa Ndlangalavu ₂₁ , Surbhi Modi ₂₂ , Joseph Cavanaugh ₂₂ , Susan Swindells ₂₃ , Richard E Chaisson ₂₄ , Faiz Ahmad Khan ₂₅ , Andrea A Howard ₂₆ , Robin Wood ₂₇ , Swe Swe Thit ₂₈ , Mar Mar Kyi ₂₈ , Josh Hanson ₂₉ , Paul K Drain ₃₀ , Adrienne E Shapiro ₃₁ , Tendesayi Kufa ₃₂ , Gavin Churchyard ₃₃ , Duc T Nguyen ₃₄ , Edward A Graviss ₃₄ , Stephanie Bjerrum ₃₅ , Isik S Johansen ₃₆ , Jill K Gersh ₃₇ , David J Horne ₃₈ , Sylvia M LaCourse ₃₉ , Haider Abdulrazzaq Abed Al-Darraji ₄₀ , Adeeba Kamarulzaman ₄₀ , Russell R Kempker ₄₁ , Nestani Tukvadze ₄₂ , David A Barr ₄₃ , Graeme Meintjes ₄₄ , Gary Maartens ₄₄

Affiliation

Department of Medicine, University of Cape Town, Cape Town, South Africa.
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.
Non-communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa.
Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, CA, USA.
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.
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.
Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
Global HIV, Hepatitis and STIs Programme, World Health Organization, Geneva, Switzerland.
TB Centre, London School of Hygiene & Tropical Medicine, London, UK.
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.
Laboratoire de Référence des Mycobactéries, Cotonou, Benin.
UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, Geneva, Switzerland.
National Hospital for Tuberculosis and Pulmonary Diseases, Cotonou, Benin.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Center for Tuberculosis, University of California, San Francisco, CA, USA.
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.
Bamenda Regional Hospital HIV Treatment Center, Bamenda, Cameroon.
Tuberculosis Reference Laboratory Bamenda, Bamenda, Cameroon.
Clinical Infection Medicine, Lund University, Malmö, Sweden; Department of Translational Medicine, Lund University, Malmö, Sweden.
Department of Translational Medicine, Lund University, Malmö, Sweden.
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.
US Centers for Disease Control and Prevention, Atlanta, GA, USA.
University of Nebraska Medical Center, Omaha, NE, USA.
Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.
McGill International Tuberculosis Centre, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
ICAP at Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Department of Medicine, University of Medicine 2, Yangon, Yangon Division, Myanmar.
The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
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.
Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa.
School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; The Aurum Institute, Parktown, South Africa.
Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
Department of Clinical Research, Infectious Diseases, University of Southern Denmark, Odense, Denmark.
Research Unit for Infectious Diseases, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
University of Washington, Seattle, WA, USA.
Department of Medicine, Division of Infectious Diseases, University of Washington, Seattle, WA, USA.
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.
Centre of Excellence for Research in AIDS, University of Malaya, Kuala Lumpur, Malaysia.
Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.
National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
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.

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.

中文翻译：

流动艾滋病毒感染者的结核病筛查：系统评价和个体参与者数据荟萃分析

背景

世卫组织推荐的流动艾滋病毒感染者结核病筛查和诊断流程是先进行四种症状筛查（称为世卫组织推荐的四种症状筛查 [W4SS]），然后进行世卫组织推荐的分子快速诊断测试（例如 Xpert MTB/如果 W4SS 为阳性，则为 RIF [以下简称 Xpert]）。为了向更新的世界卫生组织指南提供信息，我们旨在评估替代筛查测试和结核病策略在该人群中的诊断准确性。

方法

在这次系统综述和个体参与者数据荟萃分析中，我们更新了对 PubMed (MEDLINE)、Embase、Cochrane 图书馆和 2011 年 1 月 1 日至 2018 年 3 月 12 日出版物的会议摘要的检索，这是在之前的系统综述中完成的审查范围包括截至 2019 年 8 月 2 日的时间。我们筛选了已识别作品的参考文献清单并联系了该领域的专家。我们纳入了成人和青少年（年龄≥10岁）流动艾滋病毒感染者的前瞻性横断面、观察性研究和随机试验，无论结核病的体征和症状如何。我们使用标准化数据提取表格提取研究级别的数据，并向研究作者请求个人参与者数据。我们的目的是将 W4SS 与替代筛查测试和策略以及 WHO 推荐的算法（即 W4SS 后接 Xpert）与 Xpert 在整体和关键亚组（例如，通过抗逆转录病毒治疗[ART]状态）。参考标准是文化。本研究已在 PROSPERO 注册，CRD42020155895。

发现

我们确定了 25 项研究，并从 22 项研究中获取了数据（包括 15 666 名参与者；15 663 名有数据的参与者中的 4347 名 [27·7%] 接受了 ART）。 W4SS 敏感性为 82% (95% CI 72–89)，特异性为 42% (29–57)。 C 反应蛋白 (≥10 mg/L) 与 W4SS 具有相似的敏感性 (77% [61–88])，但特异性较高 (74% [61–83]；n=3571)。咳嗽（持续≥2周）、血红蛋白（<10 id=32>2）和淋巴结肿大具有高特异性（80-90%），但敏感性低（29-43%）。 WHO推荐的算法的敏感性为58%（50-66），特异性为99%（98-100）； Xpert for all 的敏感性为 68% (57-76)，特异性为 99% (98-99)。在一项对两者进行评估的研究中，sputum Xpert Ultra 的敏感性高于 sputum Xpert（73% [62–81] vs 57% [47–67]），并且特异性相似（98% [96–98] vs 99） % [98–100]）。在接受 ART 的门诊患者中（接受 ART 的 4347 人中的 4309 人 [99·1%]），W4SS 敏感性为 53% (35–71)，特异性为 71% (51–85)。在该人群中，对任何胸部 X 射线异常进行 W4SS 的并行策略（同时进行两项测试）具有较高的敏感性 (89% [70–97]) 和较低的特异性 (33% [17–54]；n =2670) 比单独的 W4SS 强；在结核病患病率为 5% 的情况下，与 W4SS 相比，该策略每 1000 名艾滋病毒感染者需要进行 379 次快速诊断检测，但会多发现 18 例结核病例。在未接受 ART 的门诊患者中（15 541 名门诊患者中的 11 160 [71·8%]），W4SS 敏感性为 85% (76–91)，特异性为 37% (25–51)。单独的 C 反应蛋白 (≥10 mg/L) 与 W4SS 和序贯策略相比具有相似的敏感性 (83% [79–86])，但特异性更高 (67% [60–73]；n=3187) （均检测呈阳性）W4SS 则 C 反应蛋白（≥5 mg/L）与 (84% [75–90]) 具有相似的敏感性，但特异性高于 (64% [57–71]；n=3187 ），单独W4SS；在结核病患病率为 10% 的情况下，与 W4SS 相比，这些策略每 1000 名 HIV 感染者需要的快速诊断检测次数将减少 272 次和 244 次，但会分别多漏掉 2 例和 1 例结核病例。

解释

C反应蛋白减少了进一步快速诊断检测的需要，同时又不影响敏感性，并已被纳入更新的世界卫生组织结核病筛查指南中。然而，ART 门诊患者的 C 反应蛋白数据很少，因此需要进一步研究 C 反应蛋白在该组中的效用。与 W4SS 结合使用时，胸部 X 光检查对于接受 ART 的门诊患者非常有用。 WHO推荐的算法灵敏度不理想； Xpert for all 的灵敏度略有提高，但会产生重大的资源影响。

资金

世界卫生组织。

更新日期：2021-11-17

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