Outcomes of Cryptococcal Meningitis in Uganda

乌干达隐球菌性脑膜炎的结果

基本信息

批准号：
8701228
负责人：
Paul R Bohjanen
金额：
$ 20.35万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701228
关键词：
AIDS therapy AIDS-Related Opportunistic Infections Abscess Acquired Immunodeficiency Syndrome Africa Africa South of the Sahara Anti-Retroviral Agents Award Biological Markers Blood CD4 Lymphocyte Count Cause of Death Centers for Disease Control and Prevention (U.S.)Central Nervous System Infections Cerebrospinal Fluid Cessation of life Clinical Clinical Research Cohort Studies Communicable Diseases Complication Cryptococcal Meningitis Cryptococcus Cryptococcus neoformans Data Deterioration Development Diagnosis Enrollment Evaluation Exhibits Faculty Flow Cytometry Foundations Functional disorder Funding Gene Chips Goals Grant HIV Health Immune Immune system Impairment Incidence Infection Inflammatory Inflammatory Response International International AIDS Intracranial Hypertension L Cells Laboratories Leadership Learning Lymphatic Diseases Measures Medical Meningitis Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Minnesota Morbidity - disease rate Multi-Institutional Clinical Trial National Institute of Allergy and Infectious Disease National Institute of Neurological Disorders and Stroke Neurologic Neurological outcome Outcome Pathogenesis Pathologic Patients Persons Physicians Pilot Projects Pneumonia Reaction Relapse Research Research Infrastructure Research Project Grants Risk Sampling Scientist Severities Site South Africa Specimen Staging Survivors Syndrome Testing Time Treatment Protocols U-Series Cooperative Agreements Uganda United States United States National Institutes of Health Universities Work antiretroviral therapy cohort cytokine experience fighting immune activation improved mortality multidisciplinary next generation patient oriented research primary outcome programs randomized trial reconstitution treatment strategy

项目摘要

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.

描述（由申请人提供）：隐球菌性脑膜炎 (CM) 是与艾滋病相关的机会性感染，导致全世界死亡人数最多。 CDC 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 患者会在 3-6 个月内死亡。尽管使用抗逆转录病毒治疗 (ART) 可以改善预后，但许多开始 ART 的 CM 患者由于 HIV 免疫重建炎症综合征 (IRIS) 而表现出临床状态的矛盾恶化。由于对新生隐球菌的过度炎症反应，IRIS 导致这些患者的临床恶化。在 CM 患者中，IRIS 表现包括复发性脑膜炎、颅内压升高、新的局灶性神经系统体征、淋巴结肿大、颅内隐球菌瘤、肺炎或隐球菌脓肿。我们对乌干达艾滋病患者的初步数据表明，大约 50% 的 CM 患者在开始 ART 后出现 IRIS，导致大约 25% 的 CM 患者死亡。这笔赠款旨在扩展我在乌干达与 CM 相关的合作研究项目，并利用该研究项目为来自美国和乌干达的医师科学家实习生提供国际患者导向研究的指导。该研究计划的具体目标是 1) 在撒哈拉以南非洲地区 500 名 CM 患者中进行多中心随机试验，以比较早期 ART 开始（CM 诊断后 2 周内）与标准 ART 开始（4-5 周） CM 诊断后）关于 26 周死亡率（主要结果）、CM IRIS 的发生率和严重程度、HIV 病毒学抑制、隐球菌的微生物清除率和 ART 耐受性，2)评估 CM 幸存者的长期神经学结果，以确定开始 ART 后出现 IRIS 的患者是否比未出现 IRIS 的患者有更差的结果，以及 3) 确定 CM 患者血液或脑脊液中的炎症生物标志物是否可以预测死亡率、IRIS 或长期神经功能缺损等结果。指导计划包括 1) 对参与该项目的初级教师和传染病研究员提供主要指导，以及 2) 领导明尼苏达大学初级教师和传染病研究员以患者为导向的研究指导项目。