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: 8073433
• 负责人: Paul R Bohjanen
• 金额: $ 13.01万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073433
• 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; 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 outcomes; 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，所有年龄段的人都感染或未感染艾滋病毒。对于艾滋病毒感染者来说，隐球菌性脑膜炎 (CM) 是非洲第二常见的艾滋病定义疾病，现在随着艾滋病毒抗逆转录病毒疗法 (ART) 的出现，长期生存应该是可能的。然而，HIV免疫重建炎症综合征（IRIS）的新挑战已经出现。 IRIS 是一种人们知之甚少的免疫学现象，部分艾滋病患者（约 30%）在开始 ART 后，随着免疫系统的改善，病情反而恶化。 IRIS 事件的特点是在微生物治疗成功的情况下过度炎症。当中枢神经系统中发生 IRIS 炎症失调时，经常会发生死亡，但幸存者的神经系统结果尚不清楚。 我们建议对撒哈拉以南非洲地区的 HIV 感染者进行一项前瞻性队列研究。我们将使用分子诊断来确定中枢神经系统感染的病因。在人们开始 ART 后，我们将前瞻性地进行 IRIS 监测并评估神经、功能和神经认知状态。我们将分析脑脊液 (CSF) 中的细胞因子，以发现预测不良神经系统结果、未来 IRIS 和/或死亡的生物标志物。 假设：我们假设晚期 HIV 患者（CD4 <100）的神经系统结果更差，而随后发生 CNS-IRIS 事件的人比没有经历 CNS-IRIS 的人神经系统结果更差。我们假设中枢神经系统促炎基线细胞因子谱将预测未来的不良后果。具体目标 1) 我们将确定撒哈拉以南非洲地区 HIV 感染青少年、成人和老年人中枢神经系统感染的病因和神经系统结果。 2) 对于患有 IRIS 相关中枢神经系统感染的艾滋病患者，我们将在他们开始抗逆转录病毒治疗 (ART) 后确定他们的神经系统结局，以确定发生免疫重建炎症综合征 (IRIS) 的患者是否比未患有免疫重建炎症综合征 (IRIS) 的患者有更差的结局不发展IRIS。 3) 我们将确定特定的脑脊液细胞因子谱是否可以预测中枢神经系统感染患者的较差神经学结果或预测中枢神经系统感染和艾滋病患者的 IRIS。 公共卫生相关性：隐球菌性脑膜炎 (CM) 是撒哈拉以南非洲地区第二常见的艾滋病定义疾病，占非洲艾滋病死​​亡率的 30%。还发生其他中枢神经系统感染，包括病因不明的无菌性脑膜炎。随着抗逆转录病毒疗法（ART）的出现，免疫重建炎症综合征（IRIS）的新挑战出现，导致矛盾的临床恶化和死亡。 IRIS 对神经系统结果的影响尚不清楚。需要预测 IRIS 的生物标志物。