Novel and Optimized Diagnostics for Pediatric TB

针对儿童结核病的新颖且优化的诊断

• 批准号: 10673360
• 负责人: David Alland
• 金额: $ 22万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-07 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673360
• 关键词: 5 year old; Address; Adult; Age-Years; Bacteria; Bacteriology; Biological Assay; Biological Markers; Body Fluids; Boston; C-reactive protein; Case Fatality Rates; Centers for Disease Control and Prevention (U.S.); Child; Childhood; Clinical; Clinical Trials; Collection; Country; Diagnosis; Diagnostic; Drug resistance; Feces; Foundations; Gene Expression Profile; Genomics; Goals; Gold; HIV; HIV Infections; Immune response; Kenya; Medical Research; Microbiology; Mycobacterium tuberculosis; Nature; Observational Study; Plasma; Plasma Cells; Probability; Prospective Studies; Public Health; Reference Standards; Research Institute; Research Personnel; Risk; Sampling; Science; Signal Transduction; Specificity; Specimen; Stratification; Symptoms; T-Cell Activation; Testing; Translations; Tuberculosis; Tuberculosis diagnosis; Uganda; Universities; Validation; Whole Blood; base; biobank; biomedical referral center; cell free DNA; cohort; cytokine; deep sequencing; diagnostic accuracy; frontier; genome sequencing; innovation; laboratory facility; lateral flow assay; lipoarabinomannan; mortality; nano-string; next generation; noninvasive diagnosis; novel; novel diagnostics; novel strategies; oropharyngeal swab; point of care; point of care testing; rapid diagnosis; respiratory; response; stool sample; study population; tuberculosis treatment; whole genome

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.

为了回应RFA AI-19-036 创新的新诊断（发现），麦吉尔大学，波士顿边境科学，美国疾病中心 控制与预防，肯尼亚医学研究所和牛津大学建议研究小说 在一项针对良好的儿童的前瞻性研究中，小儿结核病的诊断（点头） <乌干达5岁，并通过肯尼亚的一项小儿诊断研究获得生物验证。这 研究人群富含人类免疫缺陷病毒（HIV）感染的艾滋病毒和未感染的HIV （HEU）孩子。成人结核病诊断（TB）的主要进步尚未扩展到小儿 TB。这样做的原因有几个。大多数在症状兼容症状的高负担国家中的大多数儿童 结核病的诊断所需的临床和实验室设施的通道有限。即使在推荐中心 在诊断可行的地方，由于小儿结核的贫血性质 具有兼容临床表现的儿童可以在细菌学上得到证实。当前的细菌学 结核病诊断的参考标准需要难以获得呼吸样本，并且灵敏度有限。 尚不确定HIV感染和HIV暴露对诊断准确性的影响。低诊断和误诊 小儿结核病的高病态率率在<5岁的儿童中最高 艾滋病毒感染。我们提出的地址的新颖的儿童结核病诊断方法 当前需求：a）避免收集呼吸标本的护理点（POC）测试； b）增加 具有更敏感诊断的细菌学病例的比例；并且，c）儿童分层 由于结核病的可能性未经证实，他们有TB。我们假设当前的新型诊断 基于整个基因组测序（WGS），可用或进一步优化和新的诊断方法 可以解决这些需求中的每一个。我们将在3个具体目标中实现这些目标：1。评估和开发 通过检测非量表中的分枝杆菌（MTB）细菌产物来诊断结核病的新颖测定 体液与微生物学确认的结核病与儿童相比，比较了高度特征的儿童 怀疑但被认为不太可能患有结核病（不太可能结核病）。 2。评估和开发诊断的新颖测定 结核病通过检测非量表体液中的宿主生物标志物，将儿童与确认的结核病与不太可能的儿童进行比较 TB。 3。确定可以使用共同应用的测定的组合可以用来诊断儿童中的结核病 怀疑有结核病，但培养为阴性（未经证实的结核病）。我们将提出一个新的参考 可能包含宿主和基于细菌的测定法的结核病的标准。一旦被大量验证 观察性研究和临床试验，它可以允许针对目前归类为归类为的儿童的结核病治疗 未经证实。