Novel and Optimized Diagnostics for Pediatric TB

作为对RFA AI-19-036的回应，来自罗格斯大学、马凯雷雷大学、 创新新诊断（FIND），麦吉尔大学，前沿科学波士顿，美国疾病中心 控制和预防，肯尼亚医学研究所和牛津大学提议研究小说 和优化诊断（NOD）用于儿童结核病的前瞻性研究， 在乌干达，5岁以下的儿童，以及从肯尼亚的儿科诊断研究中获得生物储存库。的 研究人群富集了人类免疫缺陷病毒（HIV）感染者和HIV暴露者、未感染者 (HEU)孩子成人结核病（TB）诊断的主要进展尚未扩展到儿科 TB.这有几个原因。高负担国家的大多数儿童的症状与 结核病患者获得诊断所需的临床和实验室设施的机会有限。即使在转诊中心 在诊断可行的情况下，由于儿童结核病的少菌性， 具有相容临床表现的儿童可以进行细菌学确认。目前细菌 用于TB诊断的参考标准需要难以获得的呼吸样品并且具有有限的灵敏度。 HIV感染和HIV暴露对诊断准确性的影响尚不确定。诊断不足和误诊 儿童结核病的高发病率导致5岁以下儿童和 艾滋病病毒感染。我们提出的5岁以下儿童结核病诊断的新方法 当前的需求：a）避免收集呼吸道标本的护理点（POC）检测; B）增加 诊断更敏感的细菌学确诊病例的比例;以及，c）儿童分层 与未确诊的结核病患者进行比较。我们假设目前流行的新诊断方法 基于无细胞DNA的全基因组测序（WGS）的可用或进一步优化的新诊断 可以满足每一种需求。我们将通过三个具体目标来实现这些目标：1。评估和开发 通过检测非痰中结核分枝杆菌（MTB）细菌产物诊断TB的新测定法 将高度特征化的经微生物学证实的结核病儿童与 怀疑但被认为不太可能患有结核病（不太可能患有结核病）。2.评估和开发新的检测方法， 通过检测非痰体液中的宿主生物标志物来比较确诊为结核病的儿童与不太可能确诊的儿童 TB. 3.确定可用于诊断儿童结核病的检测组合 怀疑患有结核病，但培养阴性（未经证实的结核病）。我们将提出一个新的参考 结核病诊断标准，可能包含宿主和细菌检测。一旦大规模验证 观察性研究和临床试验，它可以使结核病治疗的儿童目前分类为 未经证实

In response to RFA AI-19-036, investigators from Rutgers University, Makerere University, the Foundation for Innovative New Diagnostics (FIND), McGill University, Frontier Sciences Boston, the US Centers for Disease Control and Prevention, the Kenyan Medical Research Institute and Oxford University propose to study Novel and Optimized Diagnostics (NOD) for Pediatric TB in a prospective study of well-characterized cohorts of children <5 years of age in Uganda and by accessing the biorepository from a pediatric diagnostic study in Kenya. The study populations are enriched for human immunodeficiency virus (HIV)-infected and HIV-exposed, uninfected (HEU) children. The major advances in the diagnosis of adult tuberculosis (TB) have not extended to pediatric TB. There are several reasons for this. Most children in high burden countries with symptoms compatible with TB have limited access to clinical and laboratory facilities necessary for the diagnosis. Even at referral centers where diagnosis is feasible, because of the paucibacillary nature of pediatric TB only a small proportion of children that have a compatible clinical presentation can be bacteriologically confirmed. The current bacteriologic reference standard for TB diagnosis requires difficult to obtain respiratory samples and has limited sensitivity. The impact of HIV infection of and HIV-exposure on diagnostic accuracy is uncertain. Under- and misdiagnosis of pediatric TB contributes to the high case-fatality rates that are highest in children <5 years of age and in those with HIV infection. The novel approaches for TB diagnosis in children < 5 year of age that we propose address the current needs: a) Point-of-care (POC) tests that avoid collections of respiratory specimens; b) increasing the proportion of bacteriologically-confirmed cases with more sensitive diagnostics; and, c) stratification of children with unconfirmed TB by their likelihood of having TB. We hypothesize that novel diagnostics that are currently available or further optimized and new diagnostics based on whole genome sequencing (WGS) of cell free DNA can address each of these needs. We will accomplish these goals in 3 specific aims: 1. Evaluate and develop novel assays that diagnose TB by detecting Mycobacterium tuberculosis (MTB) bacterial products in non-sputum body fluids comparing highly characterized children with microbiologically confirmed TB versus children suspected but deemed unlikely to have TB (unlikely TB). 2. Evaluate and develop novel assays that diagnose TB by detecting host biomarkers in non-sputum body fluids comparing children with confirmed TB versus unlikely TB. 3. Identify combinations of assays that applied together could be used to diagnose TB among children suspected of having TB but that are culture negative (unconfirmed TB). We will propose a new reference standard for the diagnosis of TB that might contain host and bacteria-based assays. Once validated in large observational studies and clinical trials, it could allow targeting of TB treatment in children currently classified as unconfirmed.