South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lancet Glob Health. 2021 Jun;9(6):e841-e853. doi: 10.1016/S2214-109X(21)00045-0. Epub 2021 Apr 13.
A rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disease (prognosis) in people with HIV in a community setting.
In this prospective diagnostic and prognostic accuracy study, adults (aged 18-59 years) with HIV were recruited from five communities in South Africa. Individuals with a history of tuberculosis or household exposure to multidrug-resistant tuberculosis within the past 3 years, comorbid risk factors for tuberculosis, or any condition that would interfere with the study were excluded. RISK11 status was assessed at baseline by real-time PCR; participants and study staff were masked to the result. Participants underwent active surveillance for microbiologically confirmed tuberculosis by providing spontaneously expectorated sputum samples at baseline, if symptomatic during 15 months of follow-up, and at 15 months (the end of the study). The coprimary outcomes were the prevalence and cumulative incidence of tuberculosis disease confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or Mycobacteria Growth Indicator Tube culture, or a combination of such, on at least two separate sputum samples collected within any 30-day period.
Between March 22, 2017, and May 15, 2018, 963 participants were assessed for eligibility and 861 were enrolled. Among 820 participants with valid RISK11 results, eight (1%) had prevalent tuberculosis at baseline: seven (2·5%; 95% CI 1·2-5·0) of 285 RISK11-positive participants and one (0·2%; 0·0-1·1) of 535 RISK11-negative participants. The relative risk (RR) of prevalent tuberculosis was 13·1 times (95% CI 2·1-81·6) greater in RISK11-positive participants than in RISK11-negative participants. RISK11 had a diagnostic area under the receiver operating characteristic curve (AUC) of 88·2% (95% CI 77·6-96·7), and a sensitivity of 87·5% (58·3-100·0) and specificity of 65·8% (62·5-69·0) at a predefined score threshold (60%). Of those with RISK11 results, eight had primary endpoint incident tuberculosis during 15 months of follow-up. Tuberculosis incidence was 2·5 per 100 person-years (95% CI 0·7-4·4) in the RISK11-positive group and 0·2 per 100 person-years (0·0-0·5) in the RISK11-negative group. The probability of primary endpoint incident tuberculosis was greater in the RISK11-positive group than in the RISK11-negative group (cumulative incidence ratio 16·0 [95% CI 2·0-129·5]). RISK11 had a prognostic AUC of 80·0% (95% CI 70·6-86·9), and a sensitivity of 88·6% (43·5-98·7) and a specificity of 68·9% (65·3-72·3) for incident tuberculosis at the 60% threshold.
RISK11 identified prevalent tuberculosis and predicted risk of progression to incident tuberculosis within 15 months in ambulant people living with HIV. RISK11's performance approached, but did not meet, WHO's target product profile benchmarks for screening and prognostic tests for tuberculosis.
Bill & Melinda Gates Foundation and the South African Medical Research Council.
一种快速的、基于血液的分诊测试，可以在护理点针对结核病进行靶向调查，这可能会缩短结核病治疗时间并降低死亡率。我们旨在测试宿主血液转录组特征（RISK11）在诊断结核病和预测艾滋病毒感染者发生活动性肺部疾病（预后）方面的性能，这些患者来自南非的五个社区。
在这项前瞻性诊断和预后准确性研究中，从南非的五个社区招募了 18-59 岁的成年艾滋病毒感染者。有结核病病史或在过去 3 年内家中接触过耐多药结核病、合并结核病的风险因素或任何会干扰研究的条件的个体被排除在外。基线时通过实时 PCR 评估 RISK11 状态；参与者和研究人员对结果进行了屏蔽。参与者接受了通过在基线时提供自发性咳出的痰样、在 15 个月的随访期间如果出现症状以及在 15 个月（研究结束时）进行微生物学确诊结核病的主动监测。主要结局是通过至少两次在任何 30 天内收集的单独痰样中阳性 Xpert MTB/RIF、Xpert Ultra 或分枝杆菌生长指示剂管培养的结果，或其组合，确定的结核病疾病的患病率和累积发病率。
在 2017 年 3 月 22 日至 2018 年 5 月 15 日期间，对 963 名符合条件的参与者进行了评估，其中 861 名参与者被纳入。在 820 名具有有效 RISK11 结果的参与者中，8 人（1%）在基线时患有活动性结核病：285 名 RISK11 阳性参与者中有 7 人（2.5%；95%CI 1.2-5.0）和 535 名 RISK11 阴性参与者中有 1 人（0.2%；0.0-1.1）。RISK11 阳性参与者的患病率是 RISK11 阴性参与者的 13.1 倍（95%CI 2.1-81.6）。RISK11 的接收者操作特征曲线（AUC）下的诊断面积为 88.2%（95%CI 77.6-96.7），在预定评分阈值（60%）下的敏感性为 87.5%（58.3-100.0）和特异性为 65.8%（62.5-69.0）。在有 RISK11 结果的参与者中，有 8 人在 15 个月的随访期间发生了原发性结核病事件。在 RISK11 阳性组中，结核病发病率为每 100 人年 2.5 例（95%CI 0.7-4.4），在 RISK11 阴性组中为每 100 人年 0.2 例（0.0-0.5）。在 RISK11 阳性组中，原发性结核病事件的发生概率大于 RISK11 阴性组（累积发病率比 16.0 [95%CI 2.0-129.5]）。RISK11 的预后 AUC 为 80.0%（95%CI 70.6-86.9），在 60%的阈值下，对结核病事件的敏感性为 88.6%（43.5-98.7）和特异性为 68.9%（65.3-72.3）。
RISK11 鉴定了活动性结核病，并预测了在 15 个月内发生活动性结核病的风险。RISK11 的性能接近，但未达到世卫组织针对结核病筛查和预后检测的目标产品概况基准。
比尔及梅琳达·盖茨基金会和南非医学研究理事会。
