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

项目摘要 结核性脑膜炎(TBM)是撒哈拉以南非洲地区第二常见的脑膜炎原因。 神经系统残疾和死亡很常见，艾滋病毒携带者的死亡率至少为50%。TBM诊断 仍然很困难，诊断延迟/漏诊是导致预后不佳的主要原因。抗酸性 脑脊液细菌涂片廉价、快速，但在大多数情况下灵敏度仅为10%。 脑脊液培养提高了敏感性(~50-60%)，但速度很慢，长达六周。我们对基因Xpert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(~2小时)测试。然而，这些测试没有足够的阴性预测价值来排除TBM，需要 昂贵的仪器和墨盒，在结核病最高的地区，它们的可用性不一致 发病率。因此，替代或额外的TBM测试仍然是改善结果的关键需要。 以往的脂肪阿拉伯甘露聚糖(LAM)抗原试验(ALERE)在脑脊液中的敏感性仅为~20%。我们的研究 脑脊液中SILVAMP TB LAM(FujiLAM)检测发现，与 55%的Xpert Ultra，但这项研究规模很小，需要证实。在确定或可能发生的58起案件中 TBM，6例富士LAM阳性，Xpert Ultra不阳性。Xpert Ultra有8人呈阳性，但FujiLAM不呈阳性。这 这项研究无法系统和彻底地解决FujiLAM可能虚假的案件。此外， 这项试验和其他重要试验的正式成本效益分析尚未完成。考虑到这一成本 仍然是获得结核病诊断检测的一大限制，但这一领域缺乏研究是有问题的。 我们的总体目标是通过提高诊断准确率来降低由TBM引起的死亡率和发病率。 速度快，成本效益高。为了实现这些目标，本提案的目的是：1)确定 脑脊液中SILVAMP TB LAM(FujiLAM)与常规TBM诊断的准确性比较 定义；2)确定SILVAMP TB LAM(FujiLAM)阳性检测是否未经其他人的证实 使用尸检和元基因组学下一代测序，TBM检测是假阳性或真阳性；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、快速测试、 这需要有限的技术基础设施或专业知识。第三个目标集中在成本效益上 这项测试和其他常用的测试。这些研究将通过更好地向我们的 了解TBM的诊断工具。这一提议有可能改变全面预算管理的范式 对两种快速检测的诊断，FujiLAM和Xpert Ultra，影响国际世卫组织指南，同时提供 有价值的成本计算数据，供利益相关者和卫生部考虑投资和实施。

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.