Non-respiratory biomarkers to diagnose and monitor response in pediatric TB

 描述(申请人提供)：背景：结核病(TB)是世界范围内一种细菌导致的主要死亡原因，婴幼儿受到的影响不成比例。然而，目前还没有一种准确的测试来诊断或监测患有结核病的儿童。传统的诊断方法依赖于从痰中检测实际的分枝杆菌微生物，对儿童不敏感。生物标志物，如淋巴细胞上清液抗体(ALS)检测和经肾结核DNA检测，在成人中可用，并有望在儿童中使用。ALS使用血液(而不是血清)来测量结核病特异性抗体，这些抗体是从患有结核病的儿童体内循环中发现的未成熟浆细胞中主动分泌的。与此同时，结核分枝杆菌(Mtb)在免疫介导下从肺结核病中分解，导致小的、无细胞的核酸释放到血浆中，这些核酸通过肾脏过滤，并在尿中作为Mtb DNA片段被检测到。目的：我们的总体目标是使用非呼吸道标本来评估儿童肺结核的生物标志物。我们建议评估ALS和经肾结核DNA检测作为疾病活动性的诊断生物标志物。每月肌萎缩侧索硬化症测量的变化也将被评估为反应预测生物标记物。方法：这是一项前瞻性研究，研究对象为来自孟加拉国达卡的408名5岁儿童，他们有肺炎的症状和体征住院，疑似患有肺结核病。儿童将接受6个月以上的跟踪调查。我们将确定每个生物标志物的诊断准确性，并将其与基因Xpert和/或结核培养阳性疾病的“金标准”参考进行比较。二次分析将使用NIH-Consensus临床病例定义来评估每个生物标记物的诊断性能，因为许多儿童没有微生物确诊的结核病。Logistic回归模型将被用来确定在存在临床预测因素和验证性实验室测试的情况下，这两个生物标记物是否对预测结核病贡献了额外的信息。最后，每月ALS值的动态变化将与临床反应和结核病治疗结果相关。影响：成功完成这些目标将为疑似患有结核病的儿童提供急需的微创诊断和监测战略，从而减少误诊。

 DESCRIPTION (provided by applicant): Background: Tuberculosis (TB) is the leading cause of death from a bacteria worldwide and infants and young children are disproportionately affected. However, there is currently no single accurate test to diagnose or monitor children with TB disease. Traditional diagnostic methods that rely upon detecting the actual mycobacterial organisms from sputum are insensitive in children. Biomarkers, like the Antibodies in Lymphocyte Supernatant (ALS) assay and the trans-renal TB DNA assay, are available in adults and hold promise for use in children. ALS uses blood (and not serum) to measure TB-specific antibodies which are actively being secreted from immature plasma cells found in circulation among children who are suffering from TB. Concurrently, the immune-mediated breakdown of Mycobacterium tuberculosis (Mtb) from pulmonary TB results in the release of small, cell-free nucleic acids into the plasma which are filtered through the kidney and can be detected as fragments of Mtb DNA in urine. Objectives: Our overall goal is to use non-respiratory specimens to evaluate biomarkers for pulmonary TB in children. We propose to evaluate the ALS and trans-renal TB DNA assays as diagnostic biomarkers of disease activity. The changes in monthly ALS measurements will also be evaluated as a response-predictive biomarker. Methods: This will be a prospective study among 408 young children (<5 years) from Dhaka, Bangladesh who are hospitalized with signs and symptoms of pneumonia are suspected of having pulmonary TB. Children will be followed over 6 months. We will determine the diagnostic accuracy of each biomarker in comparison to a "gold standard" reference of GeneXpert and/or TB culture-positive disease. Secondary analysis will evaluate the diagnostic performance of each biomarker using an NIH-consensus clinical case definition, since many children do not have microbiologically confirmed TB. Logistic regression models will be used to determine whether or not either biomarker contributes additional information to predicting TB in the presence of clinical predictors and confirmatory laboratory tests. Lastly, the kinetics of monthly ALS values will be correlated with clinical response and TB treatment outcome. Impact: Successful completion of these aims will provide much-needed minimally-invasive diagnostic and monitoring strategies for children suspected of having TB, thereby limiting misdiagnosis.