Novel Diagnostic Development for TB Meningitis and Histoplasmosis

项目摘要： 巴尔博士的长期目标是成为一名独立的研究员，开发新的诊断测试 影响低资源人群的难以诊断的传染病。巴尔博士到目前为止的研究已经 强调了新的分子技术和免疫诊断技术来检测结核病脑膜炎。这个K23奖项将 提供有关生物统计学、免疫学、研究等方面的临床研究经验、教学和培训 他需要设计、规范和新的诊断测试开发来确立自己的地位 独立研究人员。 研究：迫切需要对各种传染病进行快速、准确的诊断测试 影响低收入人口，死亡率高。全球约1%的结核病病例 脑膜炎。结核病脑膜炎的死亡率高得令人无法接受(50%)，这在很大程度上是由于缓慢和 不敏感的诊断。巴尔博士与GeneXpert MTB/Rif和重新设计的GeneXpert MTB/Rif的工作 Ultra已提供证据支持使用新的快速(~2小时)分子诊断工具，改进后的工具 精确度。然而，即使有了这些改进的测试，多达三分之一的结核病脑膜炎病例也被漏掉了。辅助词， 新的免疫学诊断方法可能会提高结核病脑膜炎的诊断准确性。组织胞浆菌病是 在美国和拉丁美洲的大部分地区都很常见。在美国，诊断是由 抗原检测；然而，这种方法是不够的，在世界上许多地方是不可用的，因为只有 可提供培养和/或组织病理学检查。亚急性/慢性肺病的诊断尤其困难。 组织胞浆菌病。组织胞浆干扰素-γ释放试验(IGRA)的建立 包膜可以改善肺组织胞浆菌病的诊断，从而改善预后。 在这两种情况下，基于病原体检测的诊断测试不充分会导致延迟诊断， 依赖经验性治疗，结果不佳。以主机为中心的替代诊断方法 免疫反应可能会提供更好的结果。 这项建议的目的是：1)确定GeneXpert MTB/Rif Ultra是否可以改善结核脑膜炎 诊断与Xpert结核分枝杆菌/RIF、培养和尸检的比较，2)确定是否有新的 免疫生物标记物，当加入标准的微生物学/分子技术时，可以改善结核病 脑膜炎的诊断，与常规技术相比，以及3)确定是否有新的 与抗原相比，组织胞浆菌IGRA可提高对肺组织胞浆菌病的诊断 检测、培养和组织病理学。这些目标加在一起，有可能显著改善 肺结核脑膜炎和肺组织胞浆菌病的诊断。这些拟议研究的结果和 生物统计学、免疫学、研究设计和调节以及诊断测试开发方面的拟议培训 将为R01提案提供参考，以进一步评估新的传染病诊断测试。

Project Abstract: Dr. Bahr's long-term goal is to become an independent investigator developing novel diagnostic tests for difficult-to-diagnose infectious diseases affecting low-resource populations. Dr. Bahr's research to date has emphasized novel molecular technologies and immunodiagnostics to detect TB meningitis. This K23 award will provide the mentored clinical research experience, didactics, and training in biostatistics, immunology, study design, regulation, and novel diagnostic test development required for him to establish himself as an independent researcher. Research: Rapid, accurate diagnostic tests are urgently needed for a myriad of infectious diseases that affect low-income populations and carry high mortality rates. Approximately 1% of TB cases worldwide develop meningitis. TB meningitis has an unacceptably high mortality rate (>50%), in large part due to slow and insensitive diagnostics. Dr. Bahr's work with GeneXpert MTB/Rif and the re-engineered GeneXpert MTB/Rif Ultra has provided evidence to support the use of new, rapid (~2hrs) molecular diagnostic tools with improved accuracy. Yet, up to one third of TB meningitis cases are missed, even with these improved tests. Adjunctive, novel, immunologic diagnostics may provide improved diagnostic accuracy for TB meningitis. Histoplasmosis is common throughout much of the United States and Latin America. In the United States, diagnosis is made by antigen detection; however, this approach is inadequate and is unavailable in much of the world where only culture and/or histopathology are available. Diagnosis is particularly difficult for sub-acute/chronic pulmonary histoplasmosis. The development of an interferon gamma release assay (IGRA) directed at Histoplasma capsulatum may improve diagnosis of pulmonary histoplasmosis, leading to improved outcomes. In both conditions, inadequate diagnostic tests based on pathogen detection lead to delayed diagnosis, reliance on empiric therapy, and poor outcomes. Alternative diagnostic approaches focused on the host immune response may provide better results. The aims of this proposal are: 1) To determine if GeneXpert MTB/Rif Ultra can improve TB meningitis diagnosis in comparison to Xpert MTB/Rif, culture, and post-mortem testing, 2) To determine if novel immunologic biomarkers, when added to standard microbiologic/molecular techniques, can improve TB meningitis diagnosis, in comparison to conventional techniques alone, and 3) To determine if a novel Histoplasma capsulatum IGRA can improve diagnosis of pulmonary histoplasmosis, compared to antigen detection, culture, and histopathology. Together, these aims have the potential to significantly improve the diagnosis of TB meningitis and pulmonary histoplasmosis. The findings from these proposed studies and the proposed training in biostatistics, immunology, study design and regulation, and diagnostic test development will inform an R01 proposal to further evaluate novel diagnostic tests for infectious diseases.