Blood RNA biomarkers for tuberculosis screening in people living with HIV prior to anti-retroviral therapy initiation: A diagnostic accuracy study.
Blood RNA biomarkers for tuberculosis screening in people living with HIV prior to anti-retroviral therapy initiation: A diagnostic accuracy study.
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在开始抗逆转录病毒治疗之前，用于艾滋病毒感染者结核病筛查的血液 RNA 生物标志物：一项诊断准确性研究。
DOI：
10.1101/2023.06.01.23290783
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发表时间：
2023
期刊：
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通讯作者：
Noursadeghi,Mahdad
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作者：
Mann,Tiffeney;Gupta,RishiK;Reeve,ByronWp;Ndlangalavu,Gcobisa;Chandran,Aneesh;Krishna,AmirthaP;Calderwood,ClaireJ;Tshivhula,Happy;Palmer,Zaida;Naidoo,Selisha;Mbu,DesireeL;Theron,Grant;Noursadeghi,Mahdad
背景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已显示出诊断结核病的希望。我们试图评估其诊断准确性和系统性抗逆转录病毒治疗前 (ART) 结核病筛查的临床实用性。方法我们连续招募了在南非开普敦社区卫生中心开始 ART 的成年人（年龄≥18 岁），无论症状如何。获得两种液体培养物的痰（如果需要的话使用诱导）。使用定制的 Nanostring 基因组对全血 RNA 样本进行转录分析。我们使用受试者工作特征曲线下面积 (AUROC) 分析，以及预设阈值（高于健康对照平均值的两个标准分数；Z2）测量了七种候选 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）的诊断准确性，作为结核分枝杆菌培养状态的参考标准。通过计算决策曲线分析中的净效益来评估临床效用。我们将性能与 C 反应蛋白（CRP；阈值 ≥5 mg/L）、WHO 四症状筛查 (W4SS) 和 WHO 结核病分类测试目标产品概况进行了比较。 结果共纳入 707 名 HIV 感染者（407 [58%] 女性和 300 [42%] 男性），CD4 计数中位数为 306 个细胞/mm3 (IQR 184-486)。在 676 名有痰培养结果的参与者中，89 名 (13%) 经培养证实患有结核病。七个 RNA 特征具有中度至高度相关性（Spearman 等级系数 0·42–0·93），并具有相似的 AUROC（0·73–0·80）来区分结核培养阳性，但没有一个在统计学上优于 CRP（AUROC 0·78，95% CI 0·72–0·83）。 CD4 计数各层的诊断准确性相似，但与阳性 (AUROC 0·75–0·84) 相比，W4SS 阴性参与者 (AUROC 0·56–0·65) 的诊断准确性较低。 AUROC 点估计值最高的 RNA 生物标志物是四基因特征（Suliman4；AUROC 0·80，95% CI 0·75–0·86），Z2 阈值的敏感性为 83%（95% CI 74–90），特异性为 59%（55–63）。在决策曲线分析中，Suliman4 和 CRP 在指导结核病确诊检测方面具有相似的临床效用，但两者的净效益均高于 W4SS。在探索性分析中，结合 CRP (≥5 mg/L) 和 Suliman4 (≥Z2) 的方法的敏感性为 80% (70-87)，特异性为 70% (66-74)，并且比单独使用任一生物标志物更高的净效益。未达到世卫组织建议的目标。可能需要采用独立于干扰素的方法来提高宿主反应生物标志物的准确性，以支持在开始 ART 之前进行结核病筛查。资助南非医学研究理事会、欧洲和发展中国家临床试验合作伙伴 2、美国国立卫生研究院、国家过敏和传染病研究所、威康信托基金、国家健康与护理研究所、伦敦皇家内科医学院。
BackgroundUndiagnosed 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.MethodsWe 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 ofMycobacterium tuberculosisculture 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.FindingsA total of 707 people living with HIV (407 [58%] female and 300 [42%] male) were included, with median CD4 count 306 cells per mm3(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.InterpretationRNA 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.FundingSouth 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.