Development, Clinical Validation, and Readiness for Implementation of a Novel Mp1p D4 Poin Diagnosis of Talaromycosist of Care Test for Rapid

新型 Mp1p D4 点诊断踝部真菌护理测试的开发、临床验证和准备实施

基本信息

批准号：
10700281
负责人：
Ashutosh Chilkoti
金额：
$ 73.2万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-11 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700281
关键词：
Acquired Immunodeficiency Syndrome Affect Antifungal Therapy Asia Biological Markers Blood Body Fluids Caring Cells Cessation of life China Clinic Clinical Communities Complex Cost Analysis Costs and Benefits Country Cryptococcosis Data Detection Development Diagnosis Diagnostic Diagnostic Procedure Discipline Disease Dose Early Diagnosis Early treatment Engineering Enzyme Immunoassay Failure Goals Guidelines HIV Health system Histology Hospitalization Human Image Immunoassay Immunocompromised Host Implementation readiness Incubated Individual Infection International Laboratories Medical Microfluidics Microscopy Modeling Mycoses Organ Outpatients Patient-Focused Outcomes Patients Performance Persons Policies Policy Developments Policy Maker Policy Making Polymers Population Printing Proteins Provider Public Health Rapid diagnostics Reagent Reference Standards Risk Role Running Sampling Science Screening procedure Serum Southeastern Asia Specificity Speed Talaromyces Technology Testing Thailand Time Translating Translations Tuberculosis Urine Validation Vietnam acceptability and feasibility bench to bedside burden of illness cohort commercialization cost cost effective cost effectiveness detection limit detector diagnostic tool early screening forging fungus implementation facilitation improved individual patient mannoproteins mortality multidisciplinary novel point of care point of care testing polyclonal antibody pre-clinical prevent prognostic prospective rapid test response risk prediction screening screening program skin lesion stakeholder perspectives

项目摘要

ABSTRACT Talaromycosis caused by the dimorphic fungus Talaromyces marneffei (Tm) is an invasive mycosis endemic in Southeast Asia. Tm causes a multi-organ disseminated infection that kills one in three affected persons with an immunocompromised condition despite antifungal therapy. Persons with advanced HIV disease (AHD, CD4<200 cells/L) have the greatest risk and account for 90% of diagnosed cases globally. In highly-endemic countries of Vietnam, Thailand, and China, Tm accounts for 18% of HIV-related hospital admissions and surpasses tuberculosis and cryptococcosis as the leading cause of AIDS deaths. An impediment to reducing talaromycosis mortality is our reliance on century-old diagnostic methods of culture which lack sensitivity and can take up to 28 days, leading to treatment delay and higher mortality. The scientific premise of this proposal is that early diagnosis of talaromycosis (up to 16 weeks before culture diagnosis) using a novel point-of-care test (POCT) is achievable, thus would enable early treatment and improve patient outcomes. We will engage multidisciplinary team science to translate a first-in-kind POC technology from bench to bedside to policy, and we will pave a way for an active screen-and-treat strategy to reduce disease burden and HIV mortality in Southeast Asia. Our objective is to develop, optimize, and validate a novel POCT for early diagnosis and for screening of talaromycosis, and to gather inputs from stakeholders to inform the development of a talaromycosis screening program in people with AHD. Contact MPI Le and colleagues have developed a sensitive and specific enzyme immunoassay (EIA) targeting a Tm-specific mannoprotein Mp1p abundantly secreted in patient blood and urine during infection. She has shown that Mp1p is a more sensitive biomarker than blood culture for diagnosis and can be detected up to 16 weeks before blood culture turns positive. MPI Chilkoti has pioneered the D4 POCT— a self-contained immunoassay that can quantify Mp1p levels in <30 minutes. Herein, we propose the translation of the Mp1p EIA onto the Mp1p D4 POCT to provide a rapid, cheap, and ultra-sensitive test for talaromycosis. AIM 1: Develop and optimize a Mp1p D4 point-of-care test (POCT) for early diagnosis of talaromycosis in human blood, serum, and urine. AIM 2: Determine the clinical utility of the Mp1p D4 POCT as a rapid diagnostic tool for symptomatic talaromycosis and as a screening tool for pre-clinical disease in two cohorts of patients with AHD. AIM 3: Determine the cost-effectiveness, feasibility, and acceptability of implementing a public health talaromycosis screening program. Impact: This proposal will translate a novel POC technology from ‘bench to bedside to policy’, forging a paradigm shift from passive treatment to an active screen-and-treat approach that will improve the individual patient outcome and reduce disease burden at the population level. It will build important partnerships with the health system and community and facilitate the implementation of a talaromycosis screening program in Vietnam.

抽象的马尔尼菲踝节菌 (Talaromyces marneffii, Tm) 引起的两型性真菌病是一种侵袭性真菌病，在东南亚，Tm 会引起多器官播散性感染，导致三分之一的感染者死亡。尽管接受抗真菌治疗，但仍处于免疫功能低下的情况。患有晚期 HIV 疾病的人（AHD，CD4<200）。细胞/μL）的风险最大，占全球确诊病例的 90%。越南、泰国和中国，Tm 占 HIV 相关住院人数的 18%，并超过结核病和隐球菌病是艾滋病死亡的主要原因，是减少踝部真菌病的一个障碍。死亡率是我们对已有百年历史的培养诊断方法的依赖，这种方法缺乏敏感性，并且可能需要长达 28天，导致治疗延误和更高的死亡率，这一建议的科学前提是尽早。使用新型即时检测 (POCT) 诊断踝部真菌病（培养诊断前最多 16 周）可以实现，从而能够实现早期治疗并改善患者的治疗效果。团队科学将首创的 POC 技术从实验室转化为临床，再转化为政策，我们将为之铺平道路采取积极的筛查和治疗策略，以减少东南亚的疾病负担和艾滋病毒死亡率。我们的目标是开发、优化和验证一种新型 POCT，用于早期诊断和筛查踝关节菌病，并收集利益相关者的意见，为踝关节菌病筛查的制定提供信息 MPI Le 及其同事开发了一种敏感且特异的酶。针对患者血液和尿液中大量分泌的 Tm 特异性甘露糖蛋白 Mp1p 的免疫测定 (EIA) 她表明，Mp1p 是一种比血培养更敏感的生物标志物，可用于诊断和治疗。 MPI Chilkoti 率先推出了 D4 POCT，可在血培养呈阳性之前长达 16 周进行检测。一种独立的免疫测定法，可以在 30 分钟内量化 Mp1p 水平。在此，我们提出了翻译。将 Mp1p EIA 集成到 Mp1p D4 POCT 上，为踝部真菌病提供快速、廉价且超灵敏的检测。目标 1：开发并优化 Mp1p D4 即时检测 (POCT)，用于早期诊断踝部真菌病人类血液、血清和尿液。目标 2：确定 Mp1p D4 POCT 作为症状快速诊断工具的临床效用踝部真菌病并作为两组 AHD 患者临床前疾病的筛查工具。目标 3：确定实施公共卫生计划的成本效益、可行性和可接受性踝部真菌病筛查计划。影响：该提案将把新颖的 POC 技术从“实验室到床边再到政策”转化为典范从被动治疗转变为主动筛查和治疗方法，这将改善个体患者的情况它将与卫生部门建立重要的伙伴关系。系统和社区，并促进越南踝部真菌病筛查计划的实施。