Making an early diagnosis of talaromycosis - an approach to reduce morbidity and mortality in advanced HIV disease in Southeast Asia

对踝部真菌病进行早期诊断——一种降低东南亚晚期艾滋病毒发病率和死亡率的方法

• 批准号: 10190805
• 负责人: Thuy Le
• 金额: $ 59.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190805
• 关键词: Acquired Immunodeficiency Syndrome; Admission activity; Algorithms; Amphotericin; Amphotericin B; Antigens; Asia; Blood; CD4 Lymphocyte Count; Caring; Cause of Death; Cell Wall; Cells; Cessation of life; China; Clinic; Clinical; Clinical Research; Country; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Early treatment; Enrollment; Enzyme Immunoassay; Epidemiology; Fever; Goals; Gold; Grant; HIV; HIV therapy; Hong Kong; Hospitals; Human; Immunoassay; Immunocompetent; Immunocompromised Host; Individual; Infection; International AIDS; Interruption; Itraconazole; Life; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mycoses; Organism; Outcome; Outpatients; Patient Care; Patient Recruitments; Patient-Focused Outcomes; Patients; Penicillium; Plasma; Positioning Attribute; Prevalence; Prevention; Prevention strategy; Prospective Studies; Proteins; Rapid diagnostics; Reference Standards; Reporting; Research; Research Personnel; Risk Factors; Sampling; Sensitivity and Specificity; Site; Southeastern Asia; Specificity; Specimen; Sterility; Symptoms; Talaromyces; Test Result; Testing; Therapy Evaluation; Time; Translating; Translations; United States National Institutes of Health; Universities; Urine; Vietnam; World Health Organization; advanced disease; antigen detection; base; biobank; burden of illness; cohort; detection method; detection test; diagnosis evaluation; disorder risk; early screening; experience; falls; fungus; high risk; improved; innovation; mannoproteins; mortality; new technology; novel; novel diagnostics; pathogenic fungus; pre-clinical; prevent; prognostic performance; research clinical testing; screening; tool; treatment trial; working group

Talaromyces marneffei (Tm) is one of seven dimorphic human fungal pathogens that cause substantial global morbidity and mortality in immunocompetent and immunocompromised individuals. Tm is endemic throughout Southeast Asia where it is a leading cause of death with an on-treatment mortality of 30% in people with advanced HIV disease. A critical barrier to reducing mortality is our inability to make an early diagnosis. The disease is insidious, and early symptoms are non-specific. Diagnosis relies on culturing the organism from clinical specimens which is only positive during advanced stage of disease and takes up to 14 days to identify. Consequently many patients die before a culture diagnosis is made. This project aims to reduce Tm mortality by introducing a novel sensitive antigen detection method and by testing an innovative concept that will enable early disease screening and treatment. We have preliminary data that a novel enzyme immunoassay (EIA) detecting a Tm-specific abundantly-released cell wall protein Mp1p is highly specific and is more sensitive than blood culture for Tm detection. This project will drive the translation of this new technology into improving patient care, testing its clinical utility as a rapid diagnostic test, and establishing a proof of concept that infection can be identified early during pre-clinical stage. This would create new opportunities for disease screening and prevention strategies. To do this, we will establish a cohort of febrile AIDS patients for the evaluation of diagnosis utility and will establish a cohort of asymptomatic AIDS patients starting HIV therapy for evaluation of early disease detection. We will test the following hypotheses: 1) the Mp1p EIA is at least 20% more sensitive than conventional cultures and reduces time to diagnosis; 2) Mp1p antigen precedes development of talaromycosis in asymptomatic patients and is associated with morbidity and all-cause mortality; 3) the Mp1p EIA has similar sensitivity and specificity in the urine compared to plasma/sera samples of patients. We have established a team of investigators from Duke University, University of Hong Kong, and Oxford University Clinical Research Unit and its partner hospitals in Vietnam with expertise and experience in the development and clinical evaluation of diagnostics. Upon completion of the project, we expect to provide robust data to support the integration of the Mp1p EIA into routine Tm diagnostic algorithm. Data generated from these studies have the potential to shift the current treatment paradigm from treating advanced disease to preventing disease development through a screen-and-treat approach. We expect our strategy will substantially impact disease burden.

Talaromyces Marneffei（TM）是七种二态人类真菌病原体之一，导致大量 免疫能力和免疫功能低下的个体中的全球发病率和死亡率。 TM是 在整个东南亚的地方病，这是死亡的主要原因，治疗死亡率 患有晚期艾滋病毒疾病的患者的30％。降低死亡率的关键障碍是我们无法 做早期诊断。该疾病是阴险的，早期症状是非特异性的。诊断 依靠临床标本培养生物，该标本仅在高级阶段阳性 疾病，最多需要14天才能识别。因此，许多患者在文化之前死亡 进行诊断。该项目旨在通过引入一种新型敏感抗原来降低TM死亡率 检测方法以及通过测试一种创新概念，该概念将实现早期疾病筛查和 治疗。我们有一个新型酶免疫测定（EIA）检测到TM特异性的初步数据 大量发行的细胞壁蛋白MP1P高度特异性，比血液培养更敏感 用于TM检测。该项目将推动这种新技术的翻译来改善患者 护理，测试其临床实用性作为快速诊断测试，并确定感染的概念证明 可以在临床前阶段早期确定。这将为疾病创造新的机会 筛查和预防策略。为此，我们将建立一群高热艾滋病患者 诊断实用程序的评估，并将建立一个无症状艾滋病患者的队列 HIV疗法评估早期疾病检测。我们将测试以下假设：1） MP1P EIA至少比常规培养物高20％，并减少了诊断时间。 2） MP1P抗原先于无症状患者的tal瘤性发展，并且与 发病率和全因死亡率； 3）MP1P EIA在尿液中具有相似的敏感性和特异性 与患者的血浆/血清样品相比。我们已经建立了杜克大学的调查员团队 大学，香港大学和牛津大学临床研究部门及其合作伙伴 具有专业知识和经验在开发和临床评估方面具有专业知识和经验的医院 诊断。项目完成后，我们希望提供强大的数据以支持集成 MP1P EIA的常规TM诊断算法。这些研究产生的数据具有 将当前治疗范式从治疗晚期疾病转移到预防疾病的潜力 通过屏幕和治疗方法开发。我们预计我们的策略将大大影响 疾病负担。