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）：隐球菌性脑膜炎（CM）是艾滋病相关的机会性感染，在全球范围内导致死亡人数最多。CDC估计，每年约有100万新的CM病例，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。虽然使用抗逆转录病毒治疗（ART）改善了结果，但许多开始ART的CM患者由于HIV免疫重建炎症综合征（IRIS）而表现出其临床状态的矛盾恶化。由于对新型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、淋巴结病、颅内隐球菌瘤、肺炎或隐球菌感染。我们从乌干达艾滋病患者的初步数据表明，IRIS发生在大约50%的CM患者开始ART后，导致死亡的CM患者约25%。这笔赠款提议扩大我在乌干达与CM相关的合作研究计划，并利用该研究计划作为一个场所，为来自美国和乌干达的医生-科学家学员提供国际以患者为导向的研究指导。研究计划的具体目标是：1）在撒哈拉以南非洲的500名CM患者中进行多中心随机试验，比较早期ART启动（CM诊断后2周内）至标准ART启动（CM诊断后4-5周）关于26周死亡率（主要结局）、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局，以确定在开始ART后发生IRIS的人与未发生IRIS的人相比是否具有更差的结局，和3）确定CM患者血液或CSF中的炎性生物标志物是否可以预测诸如死亡率、IRIS或长期神经功能缺损的结果。导师计划包括1）初级导师初级教师和传染病研究员学员谁将在这个项目上工作，2）在以病人为导向的研究在明尼苏达大学的初级教师和传染病研究员的导师计划的领导。