1 Department of Paediatrics and.
2 Infectious Diseases Unit and.
Am J Respir Crit Care Med. 2015 Aug 15;192(4):485-99. doi: 10.1164/rccm.201501-0059OC.
Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management.
To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB.
A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays.
IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively.
We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.
目前的结核病（TB）免疫诊断检测方法，包括结核菌素皮肤试验和 IFN-γ 释放试验（IGRA），存在着显著的局限性，包括无法区分潜伏性 TB 感染（LTBI）和活动性 TB，这一区分对于临床管理至关重要。
确定能够区分 LTBI 和活动性 TB 的 TB 感染特异性细胞因子生物标志物，确定其诊断性能特征，并评估这些生物标志物是否可用于区分 LTBI 和活动性 TB。
共招募了 149 名疑似 TB 感染的儿童进行研究；所有参与者均接受了结核菌素皮肤试验和 QuantiFERON-TB Gold 检测。同时，采用早期分泌抗原靶-6、培养滤液蛋白-10 和 PPD 作为刺激物进行全血检测，并通过 xMAP 多重分析测定细胞因子反应。
无论刺激物如何，LTBI 和活动性 TB 病例的 IFN-γ、干扰素诱导蛋白-10（IP-10）、肿瘤坏死因子（TNF）-α、IL-1ra、IL-2、IL-13 和巨噬细胞炎症蛋白-1β（MIP-1β）反应均显著高于未感染 TB 的个体。受试者工作特征分析显示，IP-10、TNF-α 和 IL-2 反应在区分未感染 TB 和感染 TB 的个体方面具有较高的敏感性和特异性。TNF-α、IL-1ra 和 IL-10 反应在区分 LTBI 和活动性 TB 病例方面具有最大的能力；TNF-α/IL-1ra 和 TNF-α/IL-10 的组合分别实现了 95.5%和 100%的正确分类。
我们发现了几种具有潜在应用于免疫诊断的 TB 特异性细胞因子生物标志物。将这些生物标志物纳入未来的 TB 免疫诊断检测中，可能会显著提高检测的敏感性，并可单独通过血液检测来区分 LTBI 和活动性 TB。
