Evaluation of novel tuberculosis LAM assays among people living with HIV and sepsis

HIV 感染者和败血症患者中新型结核病 LAM 检测的评估

• 批准号: 10669787
• 负责人: Tania A Thomas
• 金额: $ 18.71万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-21 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669787
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Affinity; Africa South of the Sahara; Antigens; Antitubercular Agents; Biological; Biological Assay; Blood; CD4 Lymphocyte Count; Case Fatality Rates; Cause of Death; Cell Wall; Cessation of life; Characteristics; Clinical; Coupled; Critical Illness; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dose; Epidemiology; Etiology; Evaluation; Functional disorder; Genus Mycobacterium; Goals; HIV; HIV/AIDS; HIV/TB; Hospitalization; Immunologic Deficiency Syndromes; Infrastructure; Intervention; Intervention Trial; Life; Lipopolysaccharides; Lung; Methods; Monoclonal Antibodies; Mycobacterium tuberculosis; Nanotrap; Organ; Outcome; Parents; Patients; Performance; Persons; Pharmaceutical Preparations; Population; Process; Protocols documentation; Randomized; Randomized, Controlled Trials; Recommendation; Reference Standards; Reporting; Research; Sensitivity and Specificity; Sepsis; Silver; Site; Specificity; Specimen; Specimen Handling; Sputum; Symptoms; Syndrome; Tanzania; Technology; Testing; Tuberculosis; Tuberculosis diagnosis; Uganda; Undifferentiated; United States National Institutes of Health; Urine; Vulnerable Populations; Work; World Health Organization; accurate diagnosis; clinical implementation; clinical practice; clinically relevant; comparative; design; detection method; diagnostic accuracy; early phase clinical trial; improved; insight; lateral flow assay; lipoarabinomannan; mortality; multiplex assay; novel; particle; pathogen; performance tests; point of care; prospective; randomized trial; randomized, clinical trials; rapid test; standard of care; survival outcome; treatment arm; trial design; tuberculosis diagnostics; tuberculosis treatment; uptake; urinary

PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis is a leading cause of sepsis and the leading killer among people living with HIV (PLWH) in sub-Saharan Africa. The diagnosis of tuberculosis (TB) is challenging to confirm in this population due to the paucibacillary and disseminated disease state, coupled with a frequent inability to produce sputum even among those with a pulmonary focus of TB. There is a pressing need for improved TB diagnostics, particularly those that rely on readily-available specimens such as urine. One example of this is the AlereLAM assay, which detects a TB cell-wall fragment (lipoarabinomannan, or “LAM”) from urine. The AlereLAM has been endorsed by the World Health Organization (WHO) since 2015 and performs relatively well among people with advanced HIV/AIDS, however the sensitivity is still modest at 56%. The Fujifilm SILVAMP is a newer urinary LAM assay that uses high affinity monoclonal antibodies and a silver amplification step to aid interpretation. Early studies have demonstrated improved sensitivity at 71% among PLWH, but the assay has not yet been tested among a subset of PLWH who present with undifferentiated sepsis. There is room for improvement in the accuracy of these assays. Therefore, we will evaluate the ability for a ~30 minute urine processing step, using the Ceres Nanotrap, to augment the yield of these rapid urinary LAM assays. This project serves as a substudy of the ATLAS Trial, a randomized controlled trial using a 2x2 factorial design of immediate empiric anti-TB therapy initiation and sepsis-specific doses of anti-TB therapy along with standard of care among people living with HIV who present with sepsis to our collaborative sites in Tanzania and Uganda. We will compare the performance between the AlereLAM and SILVAMP assays before and after processing the urine with the Ceres Nanotrap which concentrates urinary LAM and removes interfering substances within the urine. We will also evaluate the diagnostic accuracy and incremental yield of rapid assays to detect urinary LAM as compared to robust diagnostic reference standards (including blood/sputum culture for TB, sputum smear and TB-PCR testing, bacterial culture of blood/sputum/urine, as well as a novel multiplex PCR assay to identify the etiology of sepsis from blood and TB-PCR testing of urine) that are designed to identify TB and non-TB etiologies of sepsis, as well as a clinical reference standard that is partly informed by the ATLAS Trial interventions and outcomes. We will leverage the interventional ATLAS trial design and pursue exploratory analyses to understand the epidemiologic impact of a more accurate, rapid, TB diagnostic as well as the clinical impact of timelier initiation of anti-TB treatment on mortality. Our work within this unique trial infrastructure can inherently hasten the implementation of improved urinary TB diagnostics into clinical practice in settings with high TB/HIV burden for critically ill people.

项目摘要/摘要 结核分枝杆菌是败血症的主要原因，也是艾滋病毒携带者的头号杀手。 (PLWH)在撒哈拉以南非洲。结核病(TB)的诊断在该人群中的确认具有挑战性。 由于少杆菌和播散性疾病状态，加上经常无法产生痰 即使是那些有肺结核肺部病灶的人也是如此。迫切需要改进结核病诊断， 尤其是那些依赖于尿液等现成样本的疾病。AlereLAM就是一个这样的例子 从尿液中检测结核细胞壁碎片(脂阿拉伯甘露聚糖，或“LAM”)的方法。AlereLAM一直是 自2015年以来得到世界卫生组织(WHO)的认可，在患有 晚期艾滋病毒/艾滋病，但敏感度仍然较低，为56%。富士SILVAMP是一种较新的尿液 LAM检测使用高亲和力的单抗和银扩增步骤来辅助解释。早些时候 研究表明，PLWH的敏感度提高了71%，但该检测方法尚未进行测试。 在出现未分化脓毒症的PLWH亚群中。这方面还有改进的余地。 这些化验的准确性。因此，我们将评估~30分钟尿液处理步骤的能力，使用 CERES纳米捕捉器，以增加这些快速尿液LAM分析的产量。本项目作为一项子研究 ATLAS试验的一项随机对照试验，采用立即经验性抗结核的2x2析因设计 抗结核治疗的启动和脓毒症的特定剂量以及生活在人群中的护理标准 我们在坦桑尼亚和乌干达的合作网站提供了感染败血症的艾滋病毒感染者。我们将比较 CERES处理尿液前后AlereLAM和SILVAMP检测结果的比较 纳米捕捉器，浓缩尿液中的LAM，去除尿液中的干扰物质。我们还将 评价尿液LAM快速检测方法的诊断准确性和增量收益 可靠的诊断参考标准(包括结核病的血液/痰培养、痰涂片和结核-聚合酶链式反应 检测，血/痰/尿的细菌培养，以及一种新的多重聚合酶链式反应分析，以确定病因 来自血液的脓毒症和尿液的结核-聚合酶链式反应检测)，旨在识别败血症的结核和非结核病因， 以及部分由ATLAS试验干预和结果提供信息的临床参考标准。 我们将利用介入的ATLAS试验设计并进行探索性分析，以了解 更准确、更快速的结核病诊断的流行病学影响以及更及时的启动对临床的影响 抗结核治疗对死亡率的影响。我们在这个独特的试验基础设施中的工作可以内在地加速 在结核病/艾滋病毒负担较高的环境中将改进的尿结核病诊断方法应用于临床实践 病危的人。