Novel Diagnostic Development for TB Meningitis and Histoplasmosis

结核性脑膜炎和组织胞浆菌病的新诊断开发

• 批准号: 10651791
• 负责人: Nathan Bahr
• 金额: $ 4.48万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651791
• 关键词: Affect; Africa South of the Sahara; African; Americas; Autopsy; Biological; Biological Assay; Biological Testing; Biometry; CXCL10 gene; Case Fatality Rates; Cerebrospinal Fluid; Chronic; Clinical Research; Communicable Diseases; Cryopreservation; Cryptococcal Meningitis; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early treatment; Engineering; Goals; Histopathology; Histoplasma; Histoplasma capsulatum; Histoplasmosis; Immune response; Immunocompetent; Immunocompromised Host; Immunodiagnostics; Immunologic Markers; Immunology; Infection; Infrastructure; Interferon Type II; Kansas; Latin America; Lead; Low Income Population; Lung; Meningeal Tuberculosis; Meningitis; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Molecular; Mycobacterium tuberculosis; Neurologic; Outcome; Outcome Assessment; Pathogen detection; Patients; Persons; Population; Predictive Value; Process; Prospective Studies; Proteins; Rapid diagnostics; Recommendation; Regulation; Research; Research Design; Research Personnel; Resource-limited setting; Resources; Serum; Techniques; Technology; Test Result; Testing; Training; Treatment Protocols; Treatment outcome; Tuberculosis; Tuberculosis diagnosis; Uganda; United States; Urine; Validation; Work; accurate diagnostics; antigen detection; antigen test; communicable disease diagnosis; diagnostic accuracy; diagnostic biomarker; diagnostic strategy; diagnostic tool; experience; improved; improved outcome; low and middle-income countries; molecular diagnostics; mortality; mycobacterial; novel; novel diagnostics; prospective; tuberculosis treatment; unnecessary treatment

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.

项目摘要： Bahr 博士的长期目标是成为一名独立研究者，为以下疾病开发新型诊断测试： 影响资源匮乏人群的难以诊断的传染病。 Bahr 博士迄今为止的研究已经 强调新的分子技术和免疫诊断来检测结核性脑膜炎。这个K23奖将 提供指导性临床研究经验、教学法以及生物统计学、免疫学、研究方面的培训 设计、监管和新颖的诊断测试开发是他确立自己作为一个 独立研究员。 研究：迫切需要对多种传染病进行快速、准确的诊断测试 影响低收入人群并带来高死亡率。全球约 1% 的结核病病例发展为结核病 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缓慢且 不敏感的诊断。 Bahr 博士与 GeneXpert MTB/Rif 以及重新设计的 GeneXpert MTB/Rif 的合作 Ultra 提供了证据支持使用新型快速（约 2 小时）分子诊断工具，并改进了 准确性。然而，即使有了这些改进的检测方法，仍有高达三分之一的结核性脑膜炎病例被漏诊。辅助， 新颖的免疫学诊断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，诊断是通过 抗原检测；然而，这种方法是不够的，并且在世界上许多地方是不可行的，因为这些地方只有 可以获得培养和/或组织病理学。亚急性/慢性肺结核的诊断尤其困难 组织胞浆菌病。针对组织胞浆菌的干扰素γ释放测定（IGRA）的开发 capsulatum 可以改善肺组织胞浆菌病的诊断，从而改善结果。 在这两种情况下，基于病原体检测的诊断测试不足会导致诊断延迟， 依赖经验治疗，结果不佳。专注于宿主的替代诊断方法 免疫反应可能会提供更好的结果。 该提案的目的是： 1) 确定 GeneXpert MTB/Rif Ultra 是否可以改善结核性脑膜炎 与 Xpert MTB/Rif、培养和尸检测试进行比较的诊断，2) 确定是否新颖 当将免疫生物标志物添加到标准微生物/分子技术中时，可以改善结核病 脑膜炎诊断，与单独的传统技术相比，以及 3) 确定是否有一种新颖的方法 与抗原相比，荚膜组织胞浆菌 IGRA 可以改善肺组织胞浆菌病的诊断 检测、培养和组织病理学。总之，这些目标有可能显着改善 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以及 拟议的生物统计学、免疫学、研究设计和监管以及诊断测试开发方面的培训 将告知 R01 提案，以进一步评估传染病的新型诊断测试。