Division of Infection and Immunity, University College London, London, UK.
Institute of Health Informatics, University College London, London, UK.
Lancet Glob Health. 2024 May;12(5):e783-e792. doi: 10.1016/S2214-109X(24)00029-9. Epub 2024 Apr 4.
Undiagnosed tuberculosis remains a major threat for people living with HIV. Multiple blood transcriptomic biomarkers have shown promise for tuberculosis diagnosis. We sought to evaluate their diagnostic accuracy and clinical utility for systematic pre-antiretroviral therapy (ART) tuberculosis screening.
We enrolled consecutive adults (age ≥18 years) referred to start ART at a community health centre in Cape Town, South Africa, irrespective of symptoms. Sputa were obtained (using induction if required) for two liquid cultures. Whole-blood RNA samples underwent transcriptional profiling using a custom Nanostring gene panel. We measured the diagnostic accuracy of seven candidate RNA signatures (one single gene biomarker [BATF2] and six multigene biomarkers) for the reference standard of Mycobacterium tuberculosis culture status, using area under the receiver-operating characteristic curve (AUROC) analysis, and sensitivity and specificity at prespecified thresholds (two standard scores above the mean of healthy controls; Z2). Clinical utility was assessed by calculating net benefit in decision curve analysis. We compared performance with C-reactive protein (CRP; threshold ≥5 mg/L), WHO four-symptom screen (W4SS), and the WHO target product profile for tuberculosis triage tests.
A total of 707 people living with HIV (407 [58%] female and 300 [42%] male) were included, with median CD4 count 306 cells per mm (IQR 184-486). Of 676 participants with available sputum culture results, 89 (13%) had culture-confirmed tuberculosis. The seven RNA signatures were moderately to highly correlated (Spearman rank coefficients 0·42-0·93) and discriminated tuberculosis culture positivity with similar AUROCs (0·73-0·80), but none statistically better than CRP (AUROC 0·78, 95% CI 0·72-0·83). Diagnostic accuracy was similar across CD4 count strata, but lower among participants with negative W4SS (AUROCs 0·56-0·65) compared with positive (AUROCs 0·75-0·84). The RNA biomarker with the highest AUROC point estimate was a four-gene signature (Suliman4; AUROC 0·80, 95% CI 0·75-0·86), with sensitivity 83% (95% CI 74-90) and specificity 59% (55-63) at the Z2 threshold. In decision curve analysis, Suliman4 and CRP had similar clinical utility to guide confirmatory tuberculosis testing, but both had higher net benefit than W4SS. In exploratory analyses, an approach combining CRP (≥5 mg/L) and Suliman4 (≥Z2) had sensitivity of 80% (70-87), specificity of 70% (66-74), and higher net benefit than either biomarker alone.
RNA biomarkers showed better clinical utility to guide confirmatory tuberculosis testing for people living with HIV before ART initiation than symptom-based screening, but their performance did not exceed that of CRP and fell short of WHO recommended targets. Interferon-independent approaches might be required to improve accuracy of host-response biomarkers to support tuberculosis screening before ART initiation.
South African Medical Research Council, European and Developing Countries Clinical Trials Partnership 2, National Institutes of Health National Institute of Allergy and Infectious Diseases, The Wellcome Trust, National Institute for Health and Care Research, Royal College of Physicians London.
未确诊的结核病仍然是艾滋病毒感染者的主要威胁。多种血液转录组生物标志物在结核病诊断方面显示出良好的前景。我们旨在评估其诊断准确性和临床实用性，以进行系统的抗逆转录病毒治疗（ART）前结核病筛查。
我们连续招募了南非开普敦社区卫生中心准备开始 ART 的成年患者（年龄≥18 岁），无论症状如何。使用诱导法（如果需要）获得痰液进行两种液体培养。使用定制的 Nanostring 基因面板对全血 RNA 样本进行转录谱分析。我们使用接收者操作特征曲线（AUROC）分析评估了七种候选 RNA 特征（一种单基因生物标志物 [BATF2] 和六种多基因生物标志物）对于分枝杆菌培养状态参考标准的诊断准确性，并使用特定阈值（健康对照均值以上两个标准分数；Z2）计算了灵敏度和特异性。通过计算决策曲线分析中的净效益来评估临床实用性。我们比较了性能与 C 反应蛋白（CRP；阈值≥5mg/L）、世界卫生组织四项症状筛查（W4SS）和世界卫生组织结核病分诊测试的目标产品特征。
共纳入了 707 名艾滋病毒感染者（407[58%]名女性和 300[42%]名男性），中位数 CD4 计数为 306 个细胞/mm（IQR 184-486）。在 676 名有可用痰培养结果的参与者中，89（13%）例培养确诊为结核病。这七种 RNA 特征具有中度至高度相关性（Spearman 秩系数 0.42-0.93），并且具有相似的 AUROC（0.73-0.80）来区分分枝杆菌培养阳性，但没有一种在统计学上优于 CRP（AUROC 0.78，95%CI 0.72-0.83）。在 CD4 计数分层中，诊断准确性相似，但在 W4SS 阴性的参与者中（AUROC 0.56-0.65），与阳性（AUROC 0.75-0.84）相比，诊断准确性较低。AUROC 点估计值最高的 RNA 生物标志物是一个由四个基因组成的特征（Suliman4；AUROC 0.80，95%CI 0.75-0.86），其灵敏度为 83%（95%CI 74-90），特异性为 59%（55-63），在 Z2 阈值。在决策曲线分析中，Suliman4 和 CRP 与 W4SS 相比，在指导确认性结核病检测方面具有相似的临床实用性，但两者的净效益均高于 W4SS。在探索性分析中，一种结合 CRP（≥5mg/L）和 Suliman4（≥Z2）的方法具有 80%（70-87）的敏感性、70%（66-74）的特异性和高于任一生物标志物的净效益。
RNA 生物标志物在开始 ART 前指导艾滋病毒感染者进行确认性结核病检测方面，比基于症状的筛查具有更好的临床实用性，但它们的性能没有超过 CRP，也没有达到世界卫生组织推荐的目标。可能需要使用干扰素独立的方法来提高宿主反应生物标志物的准确性，以支持开始 ART 前的结核病筛查。
南非医学研究理事会、欧洲和发展中国家临床试验伙伴关系 2、美国国立卫生研究院过敏和传染病研究所、惠康信托基金会、英国国家卫生与保健研究所、皇家内科医师学院伦敦分校。
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