Outcomes of Cryptococcal Meningitis in Uganda

描述(申请人提供)：隐球菌性脑膜炎(CM)是一种与艾滋病相关的机会性感染，导致全球最多的死亡病例。美国疾病控制与预防中心估计，每年约有100万新发CM病例，其中70%发生在撒哈拉以南非洲地区。目前，60%的CM患者在3-6个月内死亡。虽然使用抗逆转录病毒疗法(ART)可以改善预后，但由于HIV免疫重建炎症综合征(IRIS)，许多开始抗逆转录病毒治疗的CM患者的临床状况出现了矛盾的恶化。由于对新生隐球菌的过度炎症反应，虹膜导致这些患者的临床恶化。在CM患者中，IRIS的表现包括复发的脑膜炎、颅内压升高、新的局灶性神经体征、淋巴结病、颅内隐球菌病、肺炎或隐球菌脓肿。我们来自乌干达艾滋病患者的初步数据表明，在开始抗逆转录病毒治疗后，大约50%的CM患者会发生IRIS，导致大约25%的CM患者死亡。这笔赠款建议扩展我在乌干达与CM相关的合作研究计划，并将该研究计划作为一个场所，为来自美国和乌干达的医生-科学家实习生提供面向患者的国际研究方面的指导。该研究计划的具体目标是1)在撒哈拉以南非洲的500名CM患者中进行一项多点随机试验，以比较早期ART启动(在CM诊断后2周内)和标准ART启动(CM诊断后4-5周)关于26周死亡率(主要结果)、CM IRIS的发生率和严重性、HIV病毒抑制、隐球菌的微生物清除和ART耐受性，2)评估CM幸存者的长期神经学结果，以确定启动ART后出现IRIS的人是否比那些没有发展IRIS的人预后更差。3)确定CM患者血液或脑脊液中的炎性生物标志物是否可以预测死亡率、IRIS或长期神经功能缺失等预后。导师计划包括1)对将参与该项目的初级教员和传染病研究员进行主要指导，以及2)领导明尼苏达大学初级教员和传染病研究员以患者为导向的研究指导计划。 项目简介：隐球菌性脑膜炎(CM)是一种与艾滋病相关的机会性感染，导致全球最多的死亡病例。美国疾病控制与预防中心估计，每年约有100万新发CM病例，其中70%发生在撒哈拉以南非洲地区。虽然艾滋病治疗对于CM患者的生存是必要的，但许多开始治疗艾滋病的CM患者由于HIV免疫重建炎症综合征(IRIS)而病情加重或死亡，IRIS是一种炎症反应，在开始艾滋病治疗后随着免疫系统的改善而发生。这项研究的目标是1)确定在确诊CM后不久开始艾滋病治疗是否会通过提高免疫系统对抗隐球菌感染或导致更多因IRIS而死亡的能力来提高存活率；2)确定有或没有IRIS的CM幸存者是否有神经功能障碍；以及3)开发可用于诊断IRIS并预测哪些患者有风险的实验室测试，以便他们在生病之前得到治疗。通过参与这项研究，来自美国和乌干达的医生-科学家实习生将了解国际艾滋病研究并获得经验，这些经验将帮助他们成为下一代国际艾滋病研究领导者。

DESCRIPTION (provided by applicant): Cryptococcal meningitis (CM) is the AIDS-associated opportunistic infection that causes the largest number of deaths worldwide. The CDC estimates that approximately one million new cases of CM occur each year, with 70% of these new cases occurring in sub-Saharan Africa. Currently, 60% of patients with CM die within 3-6 months. Although use of antiretroviral therapy (ART) improves outcomes, many CM patients who start ART exhibit paradoxical deterioration in their clinical status because of HIV immune reconstitution inflammatory syndrome (IRIS). IRIS causes clinical worsening in these patients due to exaggerated inflammatory responses to Cryptococcus neoformans. In patients with CM, IRIS manifestations include relapsing meningitis, increased intracranial pressure, new focal neurological signs, development of lymphadenopathy, intracranial cryptococcomas, pneumonitis, or cryptococcal abscesses. Our preliminary data from Ugandan AIDS patients suggest that IRIS occurs in approximately 50% of patients with CM after initiation of ART, causing death in approximately 25% of patients with CM. This grant proposes to extend my collaborative research program related to CM in Uganda and to use this research program as a venue to provide mentorship in international patient-oriented research to physician-scientist trainees from the United States and Uganda. The specific aims of the research plan are 1) to conduct a multi-site randomized trial among 500 persons with CM in sub- Saharan Africa to compare early ART initiation (within 2 weeks of CM diagnosis) to standard ART initiation (4-5 weeks after CM diagnosis) with respect to 26 week mortality (primary outcome), incidence and severity of CM IRIS, HIV virological suppression, microbiological clearance of cryptococcus, and ART tolerability, 2) to assess long-term neurological outcomes among survivors of CM to determine if persons who develop IRIS after initiation of ART have worse outcomes compared to those who do not develop IRIS, and 3) to determine if inflammatory biomarkers in blood or CSF of patients with CM can predict outcomes such as mortality, IRIS, or long-term neurological deficits. The mentorship plan includes 1) primary mentorship to junior faculty and infectious diseases fellow trainees who will work on this project and 2) leadership of mentorship programs in patient- oriented research for junior faculty and infectious diseases fellows at the University of Minnesota. Project Narrative: Cryptococcal meningitis (CM) is the AIDS-associated opportunistic infection that causes the largest number of deaths worldwide. The CDC estimates that approximately one million new cases of CM occur each year, with 70% of these new cases occurring in sub-Saharan Africa. Although AIDS treatment is necessary for patients with CM to survive, many CM patients who start AIDS treatment become sicker or die due to HIV immune reconstitution inflammatory syndrome (IRIS), an inflammatory reaction that occurs as the immune system improves after starting AIDS therapy. The goals of this study are 1) determine if starting AIDS therapy shortly after the diagnosis of CM will improve survival by improving the ability of the immune system to fight the cryptococcal infection or cause more deaths due to IRIS, 2) determine if survivors of CM with or without IRIS have neurological impairment, and 3) develop laboratory tests that could be used to diagnose IRIS and predict which patients are at risk so they can be treated before they become ill. By participating in this research, physician-scientist trainees from the United States and Uganda will learn about international AIDS research and gain experience that will help them become the next generation of international AIDS research leaders.