Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; DSI-NRF Centre of Excellence for Biomedical TB Research, South African MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Department of Pulmonary Medicine, Oslo University Hospital, Oslo, Norway.
J Infect. 2021 Oct;83(4):433-443. doi: 10.1016/j.jinf.2021.07.036. Epub 2021 Jul 29.
To evaluate the performance of selected host immunological biomarkers in differentiating tuberculosis (TB) disease from latent TB infection (LTBI) in HIV uninfected and infected individuals enrolled in TB low-burden countries.
Participants with TB disease (N = 85) and LTBI (N = 150) were recruited from prospective cohorts at hospitals in Norway and Denmark. Plasma concentrations of 54 host markers were assessed by Luminex multiplex immunoassays. Using receiver operator characteristic curves and general discriminant analysis, we determined the abilities of individual and combined biomarkers to discriminate between TB disease and LTBI including when patients were stratified according to HIV infection status.
Regardless of the groups compared, CCL1 and IL-2Ra were the most accurate single biomarkers in differentiating TB disease from LTBI. Regardless of HIV status, a 4-marker signature (CCL1+RANTES+CRP+MIP-1α) derived from a training set (n = 155) differentiated TB disease from LTBI in the test set (n = 67) with a sensitivity of 56.0% (95% CI, 34.9-75.6) and a specificity of 85.7% (95% CI, 71.5-94.6). A 5-marker signature derived from the HIV uninfected group (CCL1+RANTES+MIP-1α+procalcitonin+IP-10) performed in HIV-infected individuals with a sensitivity of 75.0% and a specificity of 96.7% after leave-one-out cross validation. A 2-marker signature (CCL1+TNF-α) identified in HIV-infected persons performed in HIV-uninfected with a sensitivity and specificity of 66.7% and 100% respectively in the test set.
Plasma CCL1 and IL-2Ra have potential as biomarkers for differentiating TB disease from LTBI in low TB burden settings unaffected by HIV infection. Combinations between these and other biomarkers in bio-signatures for global use warrant further exploration.
评估在结核病（TB）低负担国家中，选定的宿主免疫生物标志物在区分HIV 未感染者和感染者中的 TB 疾病与潜伏性 TB 感染（LTBI）方面的性能。
从挪威和丹麦医院的前瞻性队列中招募了 TB 疾病（N=85）和 LTBI（N=150）患者。通过 Luminex 多重免疫分析评估了 54 种宿主标志物的血浆浓度。使用接受者操作特征曲线和广义判别分析，我们确定了单个和组合生物标志物区分 TB 疾病与 LTBI 的能力，包括当根据 HIV 感染状态对患者进行分层时。
无论比较的组别如何，CCL1 和 IL-2Ra 都是区分 TB 疾病与 LTBI 最准确的单一生物标志物。无论 HIV 状态如何，一个源自训练集（n=155）的 4 标志物特征（CCL1+RANTES+CRP+MIP-1α）在测试集（n=67）中区分 TB 疾病与 LTBI 的敏感性为 56.0%（95%CI，34.9-75.6），特异性为 85.7%（95%CI，71.5-94.6）。源自 HIV 未感染组的 5 标志物特征（CCL1+RANTES+MIP-1α+降钙素原+IP-10）在经过留一法交叉验证后，在 HIV 感染个体中具有 75.0%的敏感性和 96.7%的特异性。在 HIV 未感染个体中，源自 HIV 感染者的 2 标志物特征（CCL1+TNF-α）的敏感性和特异性分别为 66.7%和 100%。
在未受 HIV 感染影响的 TB 负担较低的环境中，血浆 CCL1 和 IL-2Ra 有可能成为区分 TB 疾病与 LTBI 的生物标志物。这些标志物与其他生物标志物的组合在生物标志物的全球应用中具有进一步探索的潜力。
