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

 描述（由申请人提供）：背景：结核病（TB）是全球范围内细菌死亡的主要原因，婴儿和幼儿受到不成比例的影响。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生物体，对儿童不敏感。生物标志物，如淋巴细胞上清液中的抗体（ALS）检测和经肾结核DNA检测，可用于成人，并有望用于儿童。ALS使用血液（而不是血清）来测量结核特异性抗体，这些抗体是从患有结核病的儿童循环中发现的未成熟浆细胞中积极分泌的。同时，免疫介导的来自肺TB的结核分枝杆菌（Mtb）的分解导致小的无细胞核酸释放到血浆中，所述小的无细胞核酸通过肾脏过滤，并且可以在尿液中检测到Mtb DNA的片段。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和跨肾TB DNA检测作为疾病活动性的诊断生物标志物。每月ALS测量值的变化也将作为反应预测生物标志物进行评价。研究方法：这是一项前瞻性研究，纳入了408名来自孟加拉国达卡的幼儿（<5岁），他们因肺炎体征和症状住院，疑似患有肺结核。儿童将被跟踪6个月以上。我们将确定每种生物标志物与GeneXpert和/或TB培养阳性疾病的“金标准”参考相比的诊断准确性。二次分析将使用NIH共识的临床病例定义来评估每种生物标志物的诊断性能，因为许多儿童没有微生物学证实的TB。将使用逻辑回归模型来确定在存在临床预测因子和确证性实验室检查的情况下，任一生物标志物是否为预测TB提供额外信息。最后，每月ALS值的动力学将与临床反应和TB治疗结果相关。影响：这些目标的成功实现将为疑似结核病儿童提供急需的微创诊断和监测策略，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.