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.

马尔尼菲踝节菌 (Talaromyces marneffii, Tm) 是七种二态性人类真菌病原体之一，可导致大量 免疫功能正常和免疫功能低下个体的全球发病率和死亡率。温度为 该病在整个东南亚流行，是导致治疗死亡率的主要原因 晚期艾滋病毒患者中的 30%。降低死亡率的一个关键障碍是我们无法 做出早期诊断。该病发病隐匿，早期症状不明显。诊断 依赖于从临床标本中培养生物体，仅在晚期阶段呈阳性 疾病，最多需要 14 天才能识别。因此，许多患者在培养之前就死亡了 做出诊断。该项目旨在通过引入新型敏感抗原来降低 Tm 死亡率 检测方法并通过测试创新概念，使早期疾病筛查和 治疗。我们有初步数据表明，一种新型酶免疫分析 (EIA) 可以检测 Tm 特异性 大量释放的细胞壁蛋白 Mp1p 具有高度特异性，比血培养更敏感 用于 Tm 检测。该项目将推动这项新技术转化为改善患者状况 护理，测试其作为快速诊断测试的临床实用性，并建立感染感染的概念证明 可以在临床前阶段及早识别。这将为疾病创造新的机会 筛查和预防策略。为此，我们将建立一个发热性艾滋病患者队列 评估诊断效用，并将建立一个无症状艾滋病患者队列 用于评估早期疾病检测的 HIV 治疗。我们将测试以下假设：1） Mp1p EIA 比传统培养物的灵敏度至少高 20%，并可缩短诊断时间； 2） Mp1p 抗原先于无症状患者发生踝部真菌病，并与 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/血清样本进行比较。我们已经建立了一个由杜克大学的研究人员组成的团队 大学、香港大学及牛津大学临床研究中心及其合作伙伴 越南的医院在开发和临床评估方面拥有专业知识和经验 诊断。项目完成后，我们希望提供可靠的数据来支持集成 将 Mp1p EIA 纳入常规 Tm 诊断算法。这些研究产生的数据具有 有可能将当前的治疗模式从治疗晚期疾病转变为预防疾病 通过筛选和治疗方法进行开发。我们预计我们的战略将产生重大影响 疾病负担。