Outcomes of Cryptococcal Meningitis in Uganda

乌干达隐球菌性脑膜炎的结果

• 批准号: 8511559
• 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
• 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/8511559
• 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; Cells; 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; 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

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）：隐球菌脑膜炎（CM）是与艾滋病相关的机会感染，导致全球死亡人数最多。疾病预防控制中心估计，每年约有一百万个新的CM病例发生，其中70％的新病例发生在撒哈拉以南非洲。目前，60％的CM患者在3-6个月内死亡。尽管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），许多开始艺术的CM患者的临床状况表现出矛盾的恶化。由于夸张的炎症反应对新隐孢子虫的炎症反应，这些患者导致这些患者的临床恶化。在CM患者中，虹膜表现包括复发性脑膜炎，颅内压升高，新的局灶性神经系统症状，淋巴结肿大的发育，颅内加密癌，肺炎，肺炎或加密环球脓肿。我们来自乌干达AIDS患者的初步数据表明，启动ART后约50％的CM患者发生IRIS，导致大约25％的CM患者死亡。该赠款建议将我与乌干达CM有关的合作研究计划扩展，并将该研究计划用作向美国和乌干达的医师学员的学者提供指导的场所。研究计划的具体目的是1）在撒哈拉以下非洲500人中进行多站点随机试验，以比较早期的艺术启动（CM诊断后的2周内）与标准的艺术启动（CM诊断后4-5周）（在CM诊断后4-5周）相对于26周的26周死亡率（主要的结果），CM IRIS，HIV IRIS，HIV IRIS，HIV，HIV，HIV，HIV抑制。耐受性，2）评估CM幸存者之间的长期神经学结局，以确定与不发展IRIS的人相比，在艺术启动后发展IRIS的人是否会出现较差的结果，3）确定CM患者血液或CSF中炎症性生物标志物是否可以预测远离现象，IRIS，IRIS，或长期的神经系统疾病。指导计划包括1）初级教师和传染病的主要指导者，他们将在该项目上工作，2）明尼苏达大学的初级教师和感染性疾病研究员的指导计划领导。