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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.

摘要由二型真菌马尔尼菲Talaromyces marneffei（Tm）引起的Talaromycosis是一种侵袭性真菌病，在中国流行东南亚TM引起多器官播散性感染，免疫功能低下的情况下，尽管抗真菌治疗。晚期艾滋病毒感染者（AHD，CD 4 <200 细胞/mL）的风险最大，占全球诊断病例的90%。在高度流行的国家，越南、泰国、中国，Tm占艾滋病相关住院人数的18%，超过结核病和隐球菌病是艾滋病死亡的主要原因。减少足癣的障碍死亡率是我们依赖于几个世纪前的文化诊断方法，这些方法缺乏敏感性， 28天，导致治疗延迟和死亡率升高。这一提议的科学前提是，使用新的床旁检测（POCT）诊断距骨真菌病（培养诊断前长达16周），因此，这将使早期治疗和改善患者的结果成为可能。我们将开展多学科合作，团队科学将第一种POC技术从实验室转化为床边政策，我们将铺平道路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、优化和验证一种新的POCT，用于早期诊断和筛查。并收集利益相关者的意见，为制定Talaromycosis筛查提供信息在患有AHD的人身上进行治疗。MPI Le及其同事开发了一种敏感且特异的酶靶向患者血液和尿液中大量分泌的Tm特异性甘露糖蛋白Mp 1 p的免疫测定（EIA）在感染期间。她已经证明，Mp 1 p是一种比血培养更敏感的诊断生物标志物，可以在血培养呈阳性前16周检测到。MPI Chilkoti开创了D4 POCT- 一种独立的免疫测定法，可以在30分钟内定量Mp 1 p水平。在此，我们建议翻译将Mp 1 p EIA转移到Mp 1 p D4 POCT上，为足菌病提供快速、廉价和超灵敏的检测。目的1：开发和优化Mp 1 p D4床旁检测（POCT），用于早期诊断足癣，人血、血清和尿液。目的2：确定Mp 1 p D4 POCT作为症状性胰腺炎快速诊断工具的临床效用在两个AHD患者队列中，作为临床前疾病的筛查工具。目标3：确定实施公共卫生政策的成本效益、可行性和可接受性。踝真菌病筛查计划。影响：该提案将把一种新的POC技术从“长凳到床边再到政策”，形成一种范式。从被动治疗转变为主动筛查和治疗方法，这将改善个体患者在人口水平上减少疾病负担。它将与卫生部建立重要的伙伴关系，在越南，我们的目标是促进系统和社区的健康，并促进踝真菌病筛查计划的实施。