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

马尔尼菲塔拉霉菌(Talarmyces marneffei，TM)是人类七种二型性真菌病原体之一，可引起大量 全球免疫能力和免疫受损个体的发病率和死亡率。TM是 在东南亚流行，是主要的死亡原因和治疗中的死亡 30%的人患有晚期艾滋病毒。降低死亡率的一个关键障碍是我们无法 做出早期诊断。这种疾病是潜伏的，早期症状是非特异性的。诊断学 依赖于从只有在晚期才呈阳性的临床标本中培养出微生物 并且需要长达14天的时间才能确认。因此，许多患者在培养之前就去世了。 已经做出了诊断。该项目旨在通过引入一种新的敏感抗原来降低TM的死亡率 检测方法和测试一种创新的概念，将使早期疾病筛查和 治疗。我们有初步数据表明，一种新的酶免疫分析(EIA)检测TM特异性 大量释放的细胞壁蛋白Mp1p具有高度的特异性，比血液培养更敏感 用于TM检测。该项目将推动这项新技术转化为改善患者 护理，测试其作为快速诊断测试的临床实用性，并建立感染的概念证明 可以在临床前阶段早期发现。这将为疾病创造新的机会 筛查和预防策略。为了做到这一点，我们将建立一个发热艾滋病患者队列，用于 评估诊断效用，并将建立一个无症状艾滋病患者队列 评价HIV治疗对疾病早期发现的影响。我们将检验以下假设：1) Mp1p EIA的敏感性至少比传统培养高20%，并减少了诊断时间；2) 在无症状的患者中，Mp1p抗原先于距菌病的发生，并与 发病率和全因死亡率；3)Mp1p EIA在尿中具有类似的敏感性和特异性 与患者的血浆/血清样本进行比较。我们已经建立了一支杜克大学的调查小组 香港大学、牛津大学临床研究部及其合作伙伴 在开发和临床评估方面具有专业知识和经验的越南医院 诊断。项目完成后，我们预计将提供强大的数据来支持整合 将Mp1p EIA转换为常规TM诊断算法。这些研究产生的数据具有 将当前的治疗模式从治疗晚期疾病转变为预防疾病的潜力 通过筛选和处理的方法进行开发。我们预计我们的战略将产生重大影响 疾病负担。

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.