Host blood biomarkers for the diagnosis prognosis and treatment response of childhood TB

项目摘要 儿童结核病（TB）的发病率和死亡率高于成人疾病，但 在成人中发现的诊断和预后测试在儿童中不太准确。存在一个临界 需要对儿童结核病进行更敏感的诊断测试，而不需要呼吸道样本 收集;用于对卡介苗（BCG）接种更具特异性的预后检测 儿童;以及改进监测治疗的工具。两种新方法，宿主血液RNA 特征和T细胞抗原特异性活化测定，靶向免疫应答的互补方面。 免疫应答，并有望作为诊断、预后和治疗应答生物标志物， 儿童肺结核结核病风险的预后RNA特征也显示出出色的诊断灵敏度 和对活动性结核病的特异性，以及对反映疾病进展的治疗的反应， 在成年人中发现。已通过qRT-PCR进行验证;简约的11个基因和6个基因 已经开发了具有相同性能的版本;签名显示有希望 应用于已发表的儿科微阵列数据时的诊断灵敏度和特异性。宿主的血 测量结核分枝杆菌特异性T细胞活化的生物标志物也可以产生极好的诊断结果。 性能我们验证并将这种T细胞生物标志物转化为简化的全血检测 适用于儿科使用的基本流式细胞仪广泛用于艾滋病毒筛查计划。我们将 评价这两种生物标志物用于儿童结核病诊断和预后的性能， 探索对治疗的反应我们将招募一组家庭暴露于成人的儿童， 结核病患者;使用严格病例，通过标准化调查算法评估其结核病 定义;并在基线时收集血液用于生物标志物测定。没有流行结核病的儿童将 转介接受预防性治疗，并随后对结核病事件进行长达3年的随访。 被诊断患有结核病的儿童将在治疗期间进行血液采样。我们将 评价这些宿主血液生物标志物与Xpert MTB/RIF Ultra相比的诊断性能 与干扰素-γ释放试验（IGRA）相比， 先天免疫遗传变异与生物标志物表达相关; 儿童结核病生物标志物靶向筛查策略的影响和成本效益。宿主的血 在儿科TB的发病机理谱中显示特征性反应的生物标志物， 从结核分枝杆菌感染增加到疾病进展和治疗期间消退， 将是朝着更好的诊断、预后和治疗监测工具的重大进步， 儿童肺结核

Project Summary Childhood tuberculosis (TB) has greater risk of morbidity and mortality than adult disease, yet diagnostic and prognostic tests discovered in adults are less accurate in children. There is a critical need for more sensitive diagnostic tests for childhood TB that do not need respiratory sample collection; for prognostic tests that are more specific in Bacille Calmette Guerin (BCG)-vaccinated children; and for improved tools to monitor treatment. Two novel approaches, host blood RNA signatures and the T cell Antigen-Specific Activation assay, target complementary aspects of the immune response and offer promise as diagnostic, prognostic and treatment-response biomarkers of childhood TB. A prognostic RNA signature of TB risk that also shows excellent diagnostic sensitivity and specificity for active TB, and response to treatment that mirrors disease progression, has been discovered in adults. Validation by qRT-PCR has been achieved; parsimonious 11-gene and 6-gene versions have been developed with identical performance; and the signature shows promising diagnostic sensitivity and specificity when applied to published pediatric microarray data. A host blood biomarker that measures activation of M.tb-specific T cells also yields excellent diagnostic performance. We validated and translated this T cell biomarker to a simplified whole blood assay suitable for pediatric use on basic flow cytometers widely available to HIV screening programs. We will evaluate performance of these two biomarkers for diagnosis and prognosis of pediatric TB disease and explore response to treatment. We will enroll a cohort of children with household exposure to an adult TB patient; evaluate them for TB disease by standardized investigation algorithm using a rigorous case definition; and collect blood for biomarker assays at baseline. Children without prevalent TB disease will be referred for preventive therapy and thereafter followed for incident TB disease for up to 3 years. Children diagnosed with TB disease will have blood sampled during curative treatment. We will evaluate diagnostic performance of these host blood biomarkers compared with Xpert MTB/RIF Ultra and prognostic performance compared with interferon-gamma release assay (IGRA); discover whether innate immune genetic variants are associated with biomarker expression; and project public health impact and cost-effectiveness of biomarker-targeted screening strategies for pediatric TB. A host blood biomarker that displays a characteristic response through the spectrum of pathogenesis of pediatric TB, increasing from M.tuberculosis infection through progression to disease and resolving during treatment, would be a major advance towards better diagnostic, prognostic and treatment monitoring tools for childhood TB.