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： 巴尔博士的长期目标是成为一名独立研究者 难以诊断的传染病影响低农源型人群。迄今为止，巴尔博士的研究已有 强调了新的分子技术和免疫诊断，以检测TB脑膜炎。这个K23奖将 提供指导的临床研究经验，教学法和生物统计学，免疫学，研究的培训 设计，监管和新颖的诊断测试开发需要他确定自己 独立研究员。 研究：迫切需要快速，准确的诊断测试，用于多种传染病 影响低收入人群并具有高死亡率。全球大约有1％的结核病病例 脑膜炎。 TB脑膜炎的死亡率高（> 50％），这在很大程度上是由于缓慢和 不敏感的诊断。 Bahr博士与GenExpert MTB/RIF和重新设计的GenExpert MTB/RIF的工作 Ultra提供了证据，以支持使用新的，快速（约2小时）的分子诊断工具的使用 准确性。然而，即使进行了这些改进的测试，也错过了多达三分之一的结核病脑膜炎病例。辅助性， 新型免疫学诊断可能可以提高TB脑膜炎的诊断准确性。组织质症是 在美国和拉丁美洲的大部分地区很常见。在美国，诊断是由 抗原检测；但是，这种方法是不足的，在世界上大部分地区都无法使用 可以使用培养和/或组织病理学。诊断对于亚急性/慢性肺部特别困难 组织质症。针对组织肿瘤的干扰素伽马释放分析（IGRA）的开发 囊膜可以改善肺部肿瘤病的诊断，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导致诊断延迟， 依赖经验疗法和结果不佳。专注于主机的替代诊断方法 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TB脑膜炎 与XPERT MTB/RIF相比 免疫学生物标志物将添加到标准微生物/分子技术中时，可以改善TB 与单独的传统技术相比，脑膜炎诊断，3）确定是否是新颖的 与抗原相比 检测，文化和组织病理学。这些目标共同有可能显着改善 TB脑膜炎和肺部肿瘤病的诊断。这些提出的研究和 提议的生物统计学，免疫学，研究设计和调节以及诊断测试开发的培训 将为R01提案提供通知，以进一步评估传染病的新诊断测试。