Determining the performance and accuracy of SILVAMP TB LAM and cost-effectiveness of diagnostic testing for TB meningitis.

确定 SILVAMP TB LAM 的性能和准确性以及结核性脑膜炎诊断测试的成本效益。

• 批准号: 10548027
• 负责人: Nathan Bahr
• 金额: $ 66.35万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548027
• 关键词: Acid Fast Bacillae Staining Method; Address; Africa South of the Sahara; Area; Autopsy; Bacillus; Biological Assay; Cause of Death; Cerebrospinal Fluid; Cessation of life; Cost Analysis; Cost effectiveness research; Cost-Benefit Analysis; Data; Diagnosis; Diagnostic; Diagnostic tests; Engineering; Guidelines; HIV; Health; Hospital Costs; Hour; Incidence; Infrastructure; International; Investments; Japan; Meningeal Tuberculosis; Meningitis; Metagenomics; Morbidity - disease rate; Neurologic; Outcome; Patients; Performance; Persons; Pilot Projects; Predictive Value; Prospective cohort; Reference Standards; Research; Resources; Sampling; Specificity; Speed; Survivors; Techniques; Testing; Time; Tokyo; Tuberculosis; antigen test; clinical decision-making; clinical practice; cohort; cost; cost effective; cost effectiveness; diagnostic accuracy; diagnostic strategy; diagnostic tool; diagnostic value; disability; effectiveness testing; improved; improved outcome; instrument; lipoarabinomannan; mortality; mycobacterial; next generation sequencing; novel; performance tests; point of care; rapid test; rural setting; standard of care; study population; tuberculosis diagnostics

Project Summary Tuberculous meningitis (TBM) is the second most common cause of meningitis in Sub-Saharan Africa. Neurologic disability and mortality are common, mortality is at least 50% in people with HIV. TBM diagnosis remains difficult and diagnostic delay/missed diagnosis are major contributors to poor outcomes. Acid fast bacilli smear of cerebrospinal fluid (CSF) is cheap and fast but with sensitivity of only ~10% in most settings. CSF culture has improved sensitivity (~50-60%) but is slow, up to six weeks. Our studies on GeneXpert MTB/Rif and the re-engineered GeneXpert MTB/Rif Ultra showed improved sensitivity (50-80%) with these rapid (~2hrs) tests. Yet, these tests have inadequate negative predictive value to rule-out TBM, require expensive instruments and cartridges, and their availability is inconsistent across the areas with the highest TB incidence. Thus, alternative or additional tests for TBM remain crucial needs to improve outcomes. A previous lipoarabinomannan (LAM) antigen test (Alere) had only ~20% sensitivity in CSF. Our study of the SILVAMP TB LAM (FujiLAM) assay in CSF found 52% sensitivity in definite or probable TBM compared to 55% for Xpert Ultra yet this study was small and requires confirmation. Of the 58 cases of definite or probable TBM, six were positive by FujiLAM but not Xpert Ultra. Eight were positive by Xpert Ultra but not FujiLAM. This study was unable to systematically and thoroughly address cases that were possibly false by FujiLAM. Further, formal cost-benefit analysis for this test, and other important tests for TBM has not been done. Given that cost remains a major limitation in accessing TB diagnostic tests, the lack of research in this area is problematic. Our overall objective is to reduce mortality and morbidity due to TBM by improving diagnostic accuracy, rapidity, and cost-effectiveness. To accomplish these objectives, the aims of this proposal are to: 1) Determine the accuracy of SILVAMP TB LAM (FujiLAM) in CSF to diagnose TBM in comparison to uniform TBM case definitions; 2) Determine whether positive SILVAMP TB LAM (FujiLAM) tests without corroboration by other TBM tests are false or true positives, using autopsy and metagenomics next generation sequencing; and 3) Determine the cost and cost-effectiveness of TBM diagnostic testing strategies, including FujiLAM and GeneXpert MTB/Rif Ultra. The first two aims focus on better defining the diagnostic accuracy of FujiLAM, an easy to use, rapid test, that requires limited technological infrastructure or expertise. The third aim focuses on cost-effectiveness of this test and other commonly used tests. These studies will impact clinical practice by better informing our understanding of the diagnostic tools for TBM. This proposal has the potential to shift the paradigm of TBM diagnosis to two rapid tests, FujiLAM and Xpert Ultra, influencing international WHO guidelines while providing valuable costing data for stake holders and ministries of health to consider investment and implementation.

项目摘要 结核性脑膜炎（TBM）是撒哈拉以南非洲脑膜炎的第二大最常见原因。 神经系统残疾和死亡率很普遍，艾滋病毒患者的死亡率至少为50％。 TBM诊断 仍然很困难，诊断延迟/诊断是不良预后的主要因素。酸快 脑脊液（CSF）的杆菌涂片便宜且快速，但在大多数情况下仅敏感性约为10％。 CSF培养具有提高的灵敏度（〜50-60％），但较慢，长达六个星期。我们对GenExpert的研究 MTB/RIF和重新设计的GenExpert MTB/RIF Ultra具有提高的灵敏度（50-80％） 快速（〜2小时）测试。但是，这些测试对排除TBM的负预测值不足，需要 昂贵的仪器和墨盒，其可用性在TB最高的地区不一致 发病率。因此，对TBM的替代或其他测试仍然是改善预后的重要需求。 先前的脂肪脂瘤（LAM）抗原试验（ALERE）在CSF中仅具有约20％的敏感性。我们的研究 CSF中的Silvamp TB LAM（Fujilam）测定法发现了52％的敏感性，以确定或可能的TBM相比 XPERT ULTRA的55％却很小，需要确认。在58例明确或可能的案例中 TBM，六个是fujilam阳性的，但不是Xpert Ultra。 XPERT ULTRA阳性，但不为Fujilam阳性。这 研究无法系统地彻底解决Fujilam可能错误的案件。更远， 该测试的正式成本效益分析以及TBM的其他重要测试尚未进行。考虑到这一费用 在访问结核病诊断测试方面仍然是一个主要局限性，该领域缺乏研究是有问题的。 我们的总体目的是通过提高诊断准确性来降低由于TBM的死亡率和发病率， 速度和成本效益。为了实现这些目标，该建议的目的是：1）确定 与统一的TBM情况相比 定义； 2）确定阳性Silvamp TB LAM（Fujilam）是否在没有其他佐证的情况下进行测试 TBM测试是错误的或真实的阳性，使用尸检和宏基因组学下一代测序； 3） 确定包括Fujilam和包括Fujilam和 GenExpert MTB/RIF Ultra。 前两个目的是更好地定义Fujilam的诊断准确性，这是一种易于使用的快速测试， 这需要有限的技术基础设施或专业知识。第三个目标重点是成本效益 该测试和其他常用测试。这些研究将通过更好地告知我们的临床实践 了解TBM的诊断工具。该提议有可能改变TBM的范式 诊断为两个快速测试，即富吉兰和Xpert Ultra，影响了国际方面的指导方针。 利益持有人和卫生部的有价值的成本核算数据，以考虑投资和实施。