Impact of HIV and HIV therapy on the Etiology and Outcome of Meningitis in Uganda

乌干达艾滋病毒和艾滋病毒治疗对脑膜炎病因和结果的影响

• 批准号: 7920491
• 负责人: Paul R Bohjanen
• 金额: $ 14.55万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920491
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Adolescent; Adult; Africa; Africa South of the Sahara; Age; Algorithms; Aseptic Meningitis; Biological Markers; CD4 Lymphocyte Count; CXCL10 gene; Caring; Cell Count; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Cessation of life; Clinical; Clinical Research; Cognitive; Cohort Studies; Cryptococcal Meningitis; Data; Deterioration; Development; Diagnosis; Diagnostic; Elderly; Enrollment; Etiology; Event; Future; Goals; HIV; HIV Infections; HIV therapy; Hospital Mortality; Hospitals; Immune; Immune system; Immunologic Surveillance; Immunologics; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interferons; Interleukin-6; Laboratories; Meningitis; Molecular; Neuraxis; Neurologic; Neurological outcome; Newly Diagnosed; Opportunistic Infections; Outcome; Patients; Persons; Pilot Projects; Proteins; Public Health; Research; Risk; Serologic tests; Severities; Survivors; Syndrome; Techniques; Testing; Tuberculosis; Uganda; X-Ray Computed Tomography; adverse outcome; antiretroviral therapy; attributable mortality; base; cognitive function; cohort; cytokine; disability; experience; functional status; gamma-Chemokines; improved; mortality; prospective; public health relevance; reconstitution; scale up; success

DESCRIPTION (provided by applicant): Central nervous system (CNS) infections are common in Sub-Saharan Africa, either with or without HIV-infection across all ages. In persons with HIV, cryptococcal meningitis (CM) is the second most common AIDS defining illness in Africa, and now with the availability of HIV antiretroviral therapy (ART), long term survival should be possible. However, the new challenge of HIV immune reconstitution inflammatory syndrome (IRIS) has emerged. IRIS is a poorly understood immunologic phenomenon whereby a portion of persons (~30%) with AIDS starting ART paradoxically worsen as their immune systems improve. IRIS events are characterized by exaggerated inflammation in the setting of microbiologic treatment success. When the dysregulated inflammation of IRIS occurs in the CNS, death frequently occurs, yet the neurologic outcome among survivors is unknown. We propose a prospective cohort study of persons presenting with CNS infections in Sub- Saharan Africa with HIV-infection. We will use molecular diagnostics to determine the etiologies of CNS infections. After persons initiate ART, we will prospectively conduct surveillance for IRIS and assess neurological, functional, and neuro-cognitive status. We will profile cytokines in the cerebrospinal fluid (CSF) to discover biomarkers predictive of poor neurologic outcome, future IRIS, and/or death. Hypothesis: We hypothesize that persons with advanced HIV (CD4 <100) have worse neurologic outcomes, and persons with subsequent CNS-related IRIS events have worse neurologic outcomes than those who do not experience CNS-IRIS. We hypothesize that pro-inflammatory baseline cytokine profiles of the CNS will be predictive of future adverse outcomes. Specific Aims 1) We will determine the etiology and neurologic outcomes of CNS infections in Sub-Saharan Africa among adolescents, adults, and elderly with HIV-infection. 2) For AIDS patients who have IRIS-related CNS infections, we will determine their neurologic outcomes after they initiate antiretroviral therapy (ART) in order to determine if patients who develop Immune Reconstitution Inflammatory Syndrome (IRIS) have worse outcomes compared to those who do not develop IRIS. 3) We will determine whether specific CSF cytokine profiles can predict worse neurological outcomes in patients with CNS infections or predict IRIS in patients with CNS infections and AIDS. PUBLIC HEALTH RELEVANCE: Cryptococcal meningitis (CM) is the second most common AIDS defining illness in Sub- Saharan Africa causing 30% of the AIDS-attributable mortality in Africa. Other CNS infections also occur, including aseptic meningitis of unknown etiology. With the availability of antiretroviral therapy (ART), the new challenge of Immune Reconstitution Inflammatory Syndrome (IRIS) occurs resulting in paradoxical clinical deterioration and mortality. The impact of IRIS on neurologic outcomes is unknown. Biomarkers to predict IRIS are needed.

描述（由申请人提供）：中枢神经系统（CNS）感染在撒哈拉以南非洲地区很常见，无论是否在所有年龄段的艾滋病毒感染中都有或没有HIV感染。在患有艾滋病毒的人中，隐球菌脑膜炎（CM）是定义非洲疾病的第二大艾滋病，现在有了HIV抗逆转录病毒疗法（ART），应该可以长期生存。但是，艾滋病毒免疫重构炎症综合症（IRIS）的新挑战已经出现。艾里斯（Iris）是一种鲜为人知的免疫学现象，因此，一部分人（约30％），随着免疫系统的改善，艾滋病的一部分（约30％）开始狂欢。虹膜事件的特征是在微生物治疗成功的情况下夸张的炎症。当CNS发生虹膜炎症失调时，死亡经常发生，但幸存者的神经系统效果尚不清楚。 我们提出了一项前瞻性队列研究，该研究对撒哈拉以南非洲的中枢神经系统感染的人进行HIV感染。我们将使用分子诊断来确定中枢神经系统感染的病因。人类发起艺术后，我们将对虹膜进行监视，并评估神经，功能和神经认知状况。我们将在脑脊液（CSF）中介绍细胞因子，以发现可预测神经系统差，未来虹膜和/或死亡的生物标志物。 假设：我们假设患有晚期HIV的人（CD4 <100）的神经系统效果较差，并且随后与CNS相关的IRIS事件的人的神经系统效果差于那些没有CNS-IRI的人。我们假设中枢神经系统的促炎基线细胞因子谱将预测未来的不良结果。具体目的1）我们将确定撒哈拉以南非洲中枢神经系统感染的病因和神经系统感染的患有HIV感染的青少年，成人和老年人。 2）对于患有IRIS相关的中枢神经系统感染的AIDS患者，我们将在启动抗逆转录病毒疗法（ART）后确定他们的神经系统结局，以确定与不发育IRIS相比，患有免疫重建炎症综合征（IRIS）的患者是否患有较差的结果。 3）我们将确定特定的CSF细胞因子谱是否可以预测中枢神经系统感染患者的神经系统效果较差，或者预测CNS感染和艾滋病患者的虹膜。 公共卫生相关性：隐球菌脑膜炎（CM）是定义撒哈拉以南非洲疾病的第二大最常见的艾滋病，在非洲造成了30％的艾滋病可归因于死亡率。还会发生其他中枢神经系统感染，包括病因未知的无菌脑膜炎。随着抗逆转录病毒疗法（ART）的可用性，免疫重建炎症综合征（IRIS）的新挑战发生导致矛盾的临床恶化和死亡率。虹膜对神经系统结局的影响尚不清楚。需要预测虹膜的生物标志物。