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

项目摘要 脑膜炎（TBM）是撒哈拉以南非洲地区第二大常见的脑膜炎原因。 神经功能障碍和死亡是常见的，艾滋病毒感染者的死亡率至少为50%。TBM诊断 仍然很困难，诊断延迟/漏诊是不良结局的主要原因。抗酸 脑脊液（CSF）的细菌涂片便宜且快速，但在大多数情况下灵敏度仅为~10%。 CSF培养提高了敏感性（约50-60%），但速度较慢，最长可达6周。我们对GeneXpert的研究 MTB/Rif和重新设计的GeneXpert MTB/Rif Ultra在这些条件下的灵敏度提高（50-80%）， 快速（约2小时）测试。然而，这些测试不足以排除TBM的阴性预测值，需要 昂贵的仪器和墨盒，而且在TB最高的地区，它们的可用性不一致 发病率。因此，TBM的替代或额外测试仍然是改善结果的关键需求。 既往脂阿拉伯甘露聚糖（LAM）抗原检测（Alere）在CSF中的灵敏度仅为~20%。我们研究 CSF中的SILVAMP TB LAM（FujiLAM）检测发现，与 Xpert Ultra为55%，但该研究规模较小，需要确认。在58例确定或可能的病例中， TBM，FujiLAM检测6例阳性，但Xpert Ultra检测结果不阳性。8例经Xpert Ultra检测呈阳性，但FujiLAM检测不呈阳性。这 研究无法系统和彻底地解决FujiLAM可能虚假的病例。此外，本发明还 对这次试验和其他重要的隧道掘进机试验还没有进行正式的成本效益分析。鉴于这一成本 尽管结核病仍然是获得结核病诊断测试的主要限制因素，但缺乏这方面的研究是个问题。 我们的总体目标是通过提高诊断准确性， 速度和成本效益。为了实现这些目标，本提案的目的是：1）确定 脑脊液中SILVAMP TB LAM（FujiLAM）诊断TBM准确性与均匀TBM病例的比较 定义; 2）确定是否阳性SILVAMP TB LAM（FujiLAM）测试，而无需其他 使用尸检和宏基因组学下一代测序，TBM测试是假阳性或真阳性;以及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。 前两个目标的重点是更好地定义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。第三个目标侧重于成本效益， 这个测试和其他常用的测试。这些研究将通过更好地告知我们的 了解TBM的诊断工具。这一提议有可能改变隧道掘进机的模式 两种快速检测试剂盒（FujiLAM和Xpert Ultra）的诊断影响了国际世卫组织指南，同时提供了 为利益攸关方和卫生部考虑投资和实施提供宝贵的成本计算数据。

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.