Division of Infectious Disease and Tropical Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Field Epidemiology Department, Epicentre, Paris, France.
Lancet Glob Health. 2023 Jun;11(6):e903-e916. doi: 10.1016/S2214-109X(23)00135-3.
Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests.
In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337.
We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15-66) for AlereLAM, 61% (95% Crl 25-88) for Xpert, and 32% (95% Crl 10-55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies.
AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples.
FIND, the Global Alliance for Diagnostics.
痰液是诊断活动性肺结核最常用的样本，但许多 HIV 感染者无法产生痰液。相比之下，尿液则更容易获得。我们假设样本的可获得性会影响各种结核病检测的诊断效果。
在这项基于个体参与者数据的系统评价和荟萃分析中，我们比较了即时尿液脂阿拉伯甘露聚糖检测与基于痰液的核酸扩增检测（NAAT）和痰液涂片显微镜检查（SSM）的诊断效果。我们以阳性培养或任何部位的 NAAT 为诊断依据，将微生物学确诊的结核病作为分母，并考虑了样本提供情况。我们从数据库建立到 2022 年 2 月 24 日，在 PubMed、Web of Science、Embase、African Journals Online 和 clinicaltrials.gov 上检索了随机对照试验、横断面研究和队列研究，这些研究评估了即时尿液脂阿拉伯甘露聚糖检测和痰液 NAAT 对活动性肺结核的检测效果，而不论参与者是否有结核病症状、HIV 状态、CD4 细胞计数或研究环境如何。我们排除了招募不连续、系统或随机的研究；提供痰液或尿液是纳入标准的研究；诊断结核病的参与者少于 30 人的研究；未明确界定截止值的早期研究检测；以及未研究人类的研究。我们提取了研究水平的数据，并邀请了合格研究的作者提供匿名的个体参与者数据。主要结果是尿液脂阿拉伯甘露聚糖检测、痰液 NAAT 和 SSM 的结核病诊断效果。使用贝叶斯随机效应和混合效应荟萃分析预测诊断效果。本研究在 PROSPERO 注册，CRD42021230337。
我们从 844 条记录中筛选出 20 个数据集和 10202 名参与者（4561 名男性参与者和 5641 名女性参与者）纳入荟萃分析。所有研究均评估了 HIV 感染者 15 岁及以上人群的 Xpert（MTB/RIF 或 Ultra，Cepheid，Sunnyvale，CA，USA）和尿液 Alere Determine TB LAM（AlereLAM，Abbott，Chicago，IL，USA）。几乎所有（10202 名参与者中的 9957 名）参与者都提供了尿液，并且 82%（10202 名参与者中的 8360 名）在 2 天内提供了痰液。在招募无症状住院患者的研究中，只有 54%（1993 名参与者中的 1084 名）提供了痰液，而 99%（1993 名参与者中的 1966 名）提供了尿液。AlereLAM 的诊断效果为 41%（95%可信区间[CrI] 15-66），Xpert 的诊断效果为 61%（95%CrI 25-88），SSM 的诊断效果为 32%（95%CrI 10-55）。研究之间的诊断效果存在异质性，受 CD4 细胞计数、结核病症状和临床环境的影响。在预设的亚组分析中，所有检测方法在有症状的参与者中的效果更高，而在 CD4 计数较低和住院患者中，AlereLAM 的效果更高。在纳入未选择症状的参与者的研究中，住院患者中 AlereLAM 和 Xpert 的效果相似（51%比 47%）。在未选择的住院患者中，AlereLAM 和 Xpert 的联合检测效果为 71%，支持实施联合检测策略。
具有快速周转时间和简单性的 AlereLAM 应该优先考虑用于告知 HIV 阳性住院患者的结核病治疗，无论症状或 CD4 细胞计数如何。基于痰液的结核病检测的效果受到无法产生痰液的 HIV 感染者的影响，而几乎所有参与者都能够提供尿液。荟萃分析的优势在于其规模大、精心协调的分母、使用贝叶斯随机效应和混合效应模型预测效果；然而，数据在地理上受到限制，未将临床诊断的结核病纳入分母，并且关于获取痰液样本的策略信息很少。
FIND，全球诊断联盟。
