Role of interferon gamma release assays in tuberculosis
Role of interferon gamma release assays in tuberculosis
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干扰素γ释放测定在结核病中的作用
DOI：
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
K. Chang
中科院分区：
文献类型：
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作者：
C. Leung;K. Chang
结核病是一种古老的疾病，但它仍然是世界许多地区的主要杀手。尽管进行了一个世纪的专门研究，但结核病感染和疾病的诊断仍然存在问题，特别是在儿童和免疫功能受损的人群中。免疫学测试在许多病毒感染的诊断中做出了显著贡献，即使在分离病原体有困难的时候也是如此。对于结核病来说，情况要复杂得多。人体主要依靠细胞免疫反应来防御结核杆菌。体液反应是不同的和不一致的，没有任何血清学测试被确凿地发现对结核病感染或疾病的诊断有用。多年来，结核菌素皮肤试验(TST)一直是诊断潜伏性结核病感染的黄金试验，它测量了体内对皮内注射的人类结核杆菌纯化蛋白衍生物(PPD)的细胞免疫反应。然而，由于TST对卡介苗(卡介苗)和非结核分枝杆菌有交叉反应，因此往往可以获得相对较高的特异性，但往往以牺牲敏感性为代价，无论婴儿、幼儿、老年人、严重营养不良者和免疫功能减退者的临界值如何，TST的特异性也是次要的。需要单独进行一次测试阅读访问以及可能增加对系列测试的反应也影响到其现场应用，特别是在边缘化人口群体或保健环境中。随着免疫学和基因组学的发展，在致病结核分枝杆菌复合体中发现了一些相对特异的抗原。它们包括早期分泌抗原靶标6(ESAT-6)和培养滤液蛋白10(CFP10)，它们由位于细菌基因组差异区(RD-1)的基因编码，在所有卡介苗菌株和大多数环境分枝杆菌中都不存在(除了szulgai分枝杆菌、海洋分枝杆菌、黄色分枝杆菌和堪萨斯分枝杆菌)。新推出的干扰素-g释放分析(IGRA)、量子结核金标(QFT-G)、量子结核金试管(QFT-G-IT)(澳大利亚维多利亚州卡内基的Cellestis Limited)和T-SPOT.TB测试(牛津免疫技术公司，英国牛津)测量在这些特定抗原刺激下单核细胞释放干扰素-g的情况。与TST相比，IGRA具有操作上的优势，如一次检查即可完成测试，24小时即可得到结果，不存在观察者间和观察者内的分歧，可检测到潜在的免疫抑制，避免了助推现象。然而，它们目前的成本和运送新鲜血液的需要可能会限制在大多数结核病流行地区大规模应用的可行性。在没有潜在结核病感染的金标准的情况下，大多数现有的评估TST和IGRA性能的研究都使用了替代指标，如培养确认的结核病中的阳性率(敏感性)和结核病感染低风险受试者的阴性率(特异性)。在最近一项涉及38项研究的荟萃分析中，Quantiferon-TB Gold的合并敏感度为78%(95%CI：73-82%)，Quantiferon-TB Gold In-Tube的敏感度为70%(95%CI：63-78%)，T-SPOT.TB的敏感度为90%(95%CI：86-93%)。与TST一样，IGRA的敏感度明显低于理想水平。在未接种卡介苗的参与者中，两种Quantiferon检测的混合特异度为99%(95%可信区间：98-100%)，在接种卡介苗的参与者中，合并特异度为96%(95%可信区间：94-98%)，而T-SPOT.TB(包括其商品化前的ELISpot版本)的合并特异度为93%(95%可信区间：86-100%)。通过使用特异性抗原预测，卡介苗接种不影响IGRA的特异性。在未接种卡介苗的参与者中，TST的特异性一直很高(97%(95%CI：95-99%))，但在接种卡介苗的人群中，TST的特异性很低且可变。婴儿期或复种期接种卡介苗效果更明显。梁志超博士
Tuberculosis (TB) is an ancient disease, but it is still a major killer in many parts of the world. Despite a century of dedicated research, the diagnoses of both TB infection and disease still remain problematic, especially among children and the immunocompromised. Immunological tests have contributed remarkably in the diagnosis of many viral infections, even when there is difficulty in isolating the causative organism. For TB, the situation is much more complex. The human body relies mainly on cellular immune response to defend against the tubercle bacillus. Humoral responses are variable and inconsistent, and no serological test has been conclusively found to be useful for the diagnosis of either TB infection or disease. The tuberculin skin test (TST), which measures the in vivo cellular immune response to intradermally injected purified protein derivatives (PPD) of the human tubercle bacillus, has been the golden test for diagnosis of latent TB infection for many years. However, as TST is cross-reactive to BCG (bacille Calmette-Guérin) and non-tuberculous mycobacteria, a relatively high specificity is attainable often at the expense of sensitivity, which is also suboptimal regardless of the cut-off value among infants, young children, the elderly, the severely malnourished and the immunocompromised. The need for a separate test-reading visit and potential boosting of response on serial testing also affect its field application, especially in marginized population segments or health-care settings. With advances in immunology and genomics, a number of relatively specific antigens have been discovered in the pathogenic Mycobacterium tuberculosis complex. These include the early secretory antigen target 6 (ESAT-6) and culture filtrate protein 10 (CFP10), which are encoded by genes located in the Region of Difference (RD-1) of the bacillary genome, and are absent in all BCG strains and most environmental mycobacteria (with the exception of Mycobacterium szulgai, M. marinum, M. flavescens and M. kansasii). The newly introduced interferon-g release assays (IGRA), QuantiFERON-TB Gold (QFT-G), QuantiFERON-TB Gold in-Tube (QFT-G-IT) (Cellestis Limited, Carnegie, Victoria, Australia) and the T-SPOT.TB test (Oxford Immunotec, Oxford, UK) measure the release of interferon-g by blood monocytes upon stimulation by these specific antigens. IGRA have operational advantages over TST, such as completion of test in one visit, results available in 24 h, absence of interand intra-observer divergence, detection of potential immuno-depression and avoidance of the booster phenomenon. However, their current costs and the need for delivery of fresh blood may limit the feasibility of large-scale application in most TB-endemic areas. In the absence of a gold standard for latent TB infection, surrogate measures like positive rate among culture-confirmed TB (for sensitivity) and negative rate among subjects with low risk for TB infection (for specificity) were used in most of the available studies evaluating the performance of TST and IGRA. In a recent meta-analysis involving 38 studies, the pooled sensitivity was 78% (95% CI: 73–82%) for QuantiFERON-TB Gold, 70% (95% CI: 63–78%) for QuantiFERON-TB Gold In-Tube, and 90% (95% CI: 86–93%) for T-SPOT.TB. Like TST, the sensitivity of IGRA was considerably less than ideal. The pooled specificity for both QuantiFERON tests was 99% among non-BCG-vaccinated participants (95% CI: 98–100%) and 96% (95% CI: 94–98%) among BCG-vaccinated participants, while the pooled specificity of T-SPOT.TB (including its pre-commercial ELISpot version) was 93% (95% CI: 86–100%). As predicted from the use of specific antigens, the specificity of IGRA was not affected by BCG vaccination. The specificity of TST was consistently high (97% (95% CI: 95–99%) ) in non-BCG-vaccinated participants, but low and variable in BCG-vaccinated populations. More marked effects were observed for BCG vaccination after infancy or revaccination. Dr Chi Chiu Leung