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.

项目概要 结核性脑膜炎（TBM）是撒哈拉以南非洲地区脑膜炎的第二常见原因。 神经系统残疾和死亡很常见，HIV 感染者的死亡率至少为 50%。 TBM诊断 仍然很困难，诊断延迟/漏诊是导致不良结果的主要原因。抗酸 脑脊液 (CSF) 杆菌涂片既便宜又快速，但在大多数情况下灵敏度仅为 10% 左右。 脑脊液培养的敏感性有所提高（约 50-60%），但速度较慢，最长可达六周。我们在 GeneXpert 上的研究 MTB/Rif 和重新设计的 GeneXpert MTB/Rif Ultra 显示出更高的灵敏度 (50-80%) 快速（约 2 小时）测试。然而，这些测试的阴性预测价值不足以排除 TBM，需要 昂贵的仪器和试剂盒，并且在结核病最高的地区其可用性不一致 发生率。因此，TBM 的替代或额外测试仍然是改善结果的关键需求。 之前的阿拉伯脂甘露聚糖 (LAM) 抗原测试 (Alere) 在脑脊液中的敏感性仅为约 20%。我们的研究 脑脊液中的 SILVAMP TB LAM (FujiLAM) 检测发现，与传统的 TBM 相比，确定或可能的 TBM 的敏感性为 52% Xpert Ultra 为 55%，但这项研究规模较小，需要确认。在 58 例确定或可能的病例中 TBM 中，FujiLAM 检测结果为 6 例，但 Xpert Ultra 检测结果为阳性。 Xpert Ultra 检测结果显示 8 例呈阳性，但 FujiLAM 未检测到阳性。这 研究无法系统、彻底地解决FujiLAM可能造假的案例。更远， 该测试以及 TBM 的其他重要测试尚未进行正式的成本效益分析。考虑到这个成本 仍然是获得结核病诊断测试的主要限制，该领域缺乏研究是个问题。 我们的总体目标是通过提高诊断准确性来降低 TBM 导致的死亡率和发病率， 速度快、成本效益高。为了实现这些目标，本提案的目标是： 1) 确定 与统一的 TBM 病例相比，脑脊液中的 SILVAMP TB LAM (FujiLAM) 诊断 TBM 的准确性 定义； 2) 确定 SILVAMP TB LAM (FujiLAM) 测试是否呈阳性且未经其他证实 TBM 测试是假阳性或真阳性，使用尸检和宏基因组下一代测序；和 3) 确定 TBM 诊断测试策略的成本和成本效益，包括 FujiLAM 和 GeneXpert MTB/Rif Ultra。 前两个目标侧重于更好地定义 FujiLAM 的诊断准确性，FujiLAM 是一种易于使用、快速的测试， 这需要有限的技术基础设施或专业知识。第三个目标侧重于成本效益 该测试和其他常用测试。这些研究将通过更好地为我们提供信息来影响临床实践 了解 TBM 诊断工具。该提案有可能改变 TBM 的范式 FujiLAM 和 Xpert Ultra 两种快速检测方法的诊断影响了国际 WHO 指南，同时提供 为利益相关者和卫生部考虑投资和实施提供宝贵的成本计算数据。