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人员，开发新的诊断测试， 影响低资源人群的难以诊断的传染病。巴尔博士迄今为止的研究 强调新的分子技术和免疫诊断学来检测结核性脑膜炎。K23奖将 提供指导临床研究经验，教学法，并在生物统计学，免疫学，研究培训 设计，法规和新的诊断测试开发需要他建立自己作为一个 独立研究员。 研究：快速，准确的诊断测试是迫切需要的无数传染病， 影响低收入人群，死亡率高。全世界约有1%的结核病例 脑膜炎结核性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 不敏感的诊断。Bahr博士与GeneXpert MTB/Rif和重新设计的GeneXpert MTB/Rif的合作 Ultra提供的证据支持使用新的快速（约2小时）分子诊断工具， 精度然而，即使使用这些改进的检测方法，仍有多达三分之一的结核性脑膜炎病例被漏诊。附加语， 新的免疫学诊断方法可以提高结核性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，这种方法是不充分的，并且在世界上只有 可获得培养和/或组织病理学。亚急性/慢性肺动脉高压的诊断尤其困难。 组织胞浆菌病组织胞浆菌干扰素γ释放试验的建立 荚膜可以提高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足导致诊断延迟， 依赖经验疗法，结果不佳。针对宿主的替代诊断方法 免疫反应可以提供更好的结果。 本提案的目的是：1）确定GeneXpert MTB/Rif Ultra是否可以改善结核性脑膜炎 与Xpert MTB/Rif、培养和尸检检测相比的诊断，2）确定是否为新 免疫生物标记物，当添加到标准的微生物学/分子技术，可以改善结核病 脑膜炎诊断，与单独的常规技术相比，和3）为了确定是否有新的 与抗原相比，荚膜组织胞浆菌IGRA可提高肺组织胞浆菌病的诊断率 检测、培养和组织病理学。总之，这些目标有可能大大改善 结核性脑膜炎和肺组织胞浆菌病的诊断。这些拟议研究的结果和 建议在生物统计学、免疫学、研究设计和监管以及诊断测试开发方面进行培训 将告知R01提案，以进一步评估传染病的新型诊断测试。

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.