Bjerrum Stephanie, Yang Bada, Åhsberg Johanna, Olbrich Laura, Damkjær Mathias Weis, Nathavitharana Ruvandhi R, Broger Tobias, Olaru Ioana Diana, Sweetser Brittney, Poore Hayley, Razid Alia, Kay Alexander W, Denkinger Claudia M, Schiller Ian, Dendukuri Nandini, Jaganath Devan, Lundh Andreas, Shah Maunank
Department of Clinical Research, Research Unit of Infectious Diseases, University of Southern Denmark, Odense, Denmark.
Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Cochrane Database Syst Rev. 2025 Jun 10;6(6):CD016070. doi: 10.1002/14651858.CD016070.pub2.
Low-complexity automated nucleic acid amplification tests (LC-aNAATs) are molecular World Health Organization (WHO)-recommended rapid diagnostic tests (also known as mWRDs) widely used to diagnose tuberculosis disease. The lateral flow urine lipoarabinomannan assay (LF-LAM) is recommended by the WHO to assist in diagnosing tuberculosis disease amongst people with HIV. Previous systematic reviews have assessed the diagnostic accuracy of LC-aNAATs and LF-LAM used in isolation for the detection of tuberculosis, but in clinical practice the tests may be used in parallel (i.e. LC-aNAAT in combination with LF-LAM).
To compare the diagnostic accuracy of the parallel use of LC-aNAAT on respiratory samples and LF-LAM on urine versus LC-aNAATs on respiratory samples alone for detection of tuberculosis disease in adults and adolescents with HIV who present with presumptive tuberculosis.
We searched Cochrane CENTRAL, MEDLINE, Embase, Science Citation Index-Expanded, Biosis Previews, Conference Proceedings Citation Index - Science, Scopus, WHO Global Index Medicus, ProQuest Dissertations & Theses, ClinicalTrial.gov, and the WHO International Clinical Trials Registry up to 3 November 2023.
We included studies that allowed assessment of the diagnostic accuracy of parallel testing and LC-aNAAT on respiratory samples in the same study group. Participants were adults and adolescents (defined as 10 years of age and older) with HIV who presented with presumptive tuberculosis. The reference standards we used for the detection of tuberculosis disease were microbiological or composite. As well as published studies, we included unpublished data if the data provided by study authors on request were the final data and could be used to compare diagnostic accuracy of parallel testing to one of the component tests.
Two review authors independently extracted data using a standardised form and assessed methodological quality using QUADAS-2 and QUADAS-C tools. We performed bivariate random-effects meta-analysis using a Bayesian approach to estimate sensitivity, specificity, and absolute differences between index tests. We performed subgroup analyses based on the presence of signs and symptoms, CD4 cell count, and clinical setting, as well as separate analyses for those with a positive screen for tuberculosis, advanced HIV, or serious illness.
In 27 studies involving 12,651 participants, of whom 2368 (19%) had tuberculosis based on a microbiological reference standard, the parallel use of respiratory LC-aNAAT and urine LF-LAM had a pooled sensitivity of 77.5% (95% credible interval (CrI) 73.4 to 81.3) and specificity of 89.4% (95% CrI 85.8 to 92.3). Compared to respiratory LC-aNAAT alone, parallel testing had 6.7 (95% CrI 3.8 to 10.7) percentage points higher sensitivity (low certainty) and -6.8 (95% CrI -9.5 to -4.7) percentage points difference in specificity (low-certainty evidence), using a microbiological reference standard. In 23 studies, 11,109 participants, of whom 3723 (34%) had tuberculosis based on a composite reference standard, parallel testing had a pooled sensitivity of 67.6% (95% CrI 59.9 to 74.6) and a pooled specificity of 96.2% (95% CrI 92.8 to 98.1). Compared to respiratory LC-aNAAT alone, parallel testing had 16.0 (10.7 to 22.9) percentage points higher sensitivity (low-certainty evidence) and -3.5 (95% CrI -6.6 to -1.7) percentage points difference in specificity (very low certainty evidence), using a composite reference standard.
AUTHORS' CONCLUSIONS: In the diagnosis of tuberculosis disease in people with HIV who present with presumptive tuberculosis, parallel testing (LC-aNAAT on respiratory samples and LF-LAM on urine) improves sensitivity at the cost of reduced specificity compared to LC-aNAAT on respiratory samples alone. The gain in sensitivity should be weighed against the loss of specificity, taking into consideration the varying tuberculosis prevalence in different settings. For low-prevalence settings, using the tests in parallel may lead to a large increase in false-positive results. In settings with high tuberculosis prevalence, the benefit of identifying additional patients with tuberculosis at the point-of-care likely outweighs the relatively lower risk of overtreatment of those without tuberculosis.
Internal sources: Liverpool School of Tropical Medicine, UK External sources: Foreign, Commonwealth and Development Office (FCDO), UK. Project number 300342-104; WHO, TB Prevention, Diagnosis, Treatment, Care & Innovation (PCI), Global TB Programme REGISTRATION: Protocol available via https://doi.org/10.1002/14651858.CD016070, version published 13 May 2024.
低复杂度自动化核酸扩增检测（LC-aNAATs）是世界卫生组织（WHO）推荐的分子快速诊断检测（也称为mWRDs），广泛用于诊断结核病。侧向流动尿液脂阿拉伯甘露聚糖检测（LF-LAM）被WHO推荐用于协助诊断HIV感染者中的结核病。以往的系统评价评估了单独使用LC-aNAATs和LF-LAM检测结核病的诊断准确性，但在临床实践中，这些检测可能会并行使用（即LC-aNAAT与LF-LAM联合使用）。
比较在疑似结核病的HIV感染成人和青少年中，并行使用呼吸道样本的LC-aNAAT和尿液的LF-LAM与单独使用呼吸道样本的LC-aNAAT检测结核病的诊断准确性。
我们检索了Cochrane中心对照试验注册库、MEDLINE、Embase、科学引文索引扩展版、生物学文摘数据库、会议论文引文索引 - 科学版、Scopus、WHO全球医学索引、ProQuest学位论文数据库、ClinicalTrial.gov以及WHO国际临床试验注册平台，检索截至2023年11月3日的数据。
我们纳入了在同一研究组中能够评估并行检测和呼吸道样本LC-aNAAT诊断准确性的研究。参与者为出现疑似结核病的HIV感染成人和青少年（定义为10岁及以上）。我们用于检测结核病的参考标准为微生物学标准或综合标准。除已发表的研究外，如果研究作者应要求提供的未发表数据为最终数据且可用于比较并行检测与其中一项组成检测的诊断准确性，我们也将其纳入。
两位综述作者使用标准化表格独立提取数据，并使用QUADAS-2和QUADAS-C工具评估方法学质量。我们采用贝叶斯方法进行双变量随机效应荟萃分析，以估计各指标检测的敏感性、特异性及绝对差异。我们根据体征和症状、CD4细胞计数及临床环境进行亚组分析，同时对结核病筛查阳性、HIV晚期或患有严重疾病的患者进行单独分析。
在27项涉及12651名参与者的研究中，根据微生物学参考标准，其中2368人（19%）患有结核病，并行使用呼吸道LC-aNAAT和尿液LF-LAM的合并敏感性为77.5%（95%可信区间（CrI）73.4至81.3），特异性为89.4%（95% CrI 85.8至92.3）。与单独使用呼吸道LC-aNAAT相比，使用微生物学参考标准时，并行检测的敏感性高6.7个百分点（95% CrI 3.8至10.7）（低确定性），特异性差异为-6.8个百分点（95% CrI -9.5至-4.7）（低确定性证据）。在23项涉及11109名参与者的研究中，根据综合参考标准，其中3723人（34%）患有结核病，并行检测的合并敏感性为67.6%（95% CrI 59.9至74.6），合并特异性为96.2%（95% CrI 92.8至98.1）。与单独使用呼吸道LC-aNAAT相比，使用综合参考标准时，并行检测的敏感性高16.0个百分点（10.7至22.9）（低确定性证据），特异性差异为-3.5个百分点（95% CrI -6.6至-1.7）（极低确定性证据）。
在诊断疑似结核病的HIV感染者的结核病时，与单独使用呼吸道样本的LC-aNAAT相比，并行检测（呼吸道样本的LC-aNAAT和尿液的LF-LAM）提高了敏感性，但特异性有所降低。应权衡敏感性的提高与特异性的降低，同时考虑不同环境下结核病的患病率差异。在低患病率环境中，并行使用这些检测可能会导致假阳性结果大幅增加。在结核病高患病率环境中，即时诊断出更多结核病患者的益处可能超过对未患结核病者过度治疗的相对较低风险带来的影响。
内部来源：英国利物浦热带医学院 外部来源：英国外交、联邦和发展办公室（FCDO）。项目编号300342 - 104；WHO，结核病预防、诊断、治疗、关怀与创新（PCI），全球结核病规划 注册信息：方案可通过https://doi.org/10.1002/14651858.CD016070获取，版本于2024年5月13日发布。
