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

描述(申请人提供)：中枢神经系统(CNS)感染在撒哈拉以南非洲很常见，无论是否有艾滋病毒感染，所有年龄段都是如此。在艾滋病毒携带者中，隐球菌性脑膜炎(CM)是非洲第二常见的艾滋病定义疾病，现在有了艾滋病毒抗逆转录病毒疗法(ART)，长期存活应该是可能的。然而，艾滋病毒免疫重建炎症综合征(IRIS)的新挑战已经出现。虹膜是一种鲜为人知的免疫学现象，部分艾滋病患者(约30%)开始接受抗逆转录病毒治疗时，随着免疫系统的改善，病情反而恶化。虹膜事件的特点是在微生物治疗成功的背景下出现夸大的炎症反应。当IRIS的炎症在中枢神经系统发生失调时，死亡经常发生，但幸存者的神经学结果尚不清楚。我们提出了一项前瞻性队列研究，研究对象是撒哈拉以南非洲HIV感染者中的CNS感染者。我们将使用分子诊断学来确定中枢神经系统感染的病因。在人们开始抗逆转录病毒治疗后，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，以发现预测神经预后不良、未来IRIS和/或死亡的生物标志物。假设：我们假设晚期HIV患者的神经学结果更差，与那些没有经历过CNS-IRIS的人相比，随后发生与CNS相关的IRIS事件的人的神经系统结果更差。我们假设中枢神经系统的促炎性基线细胞因子谱可以预测未来的不良结果。具体目标1)我们将确定撒哈拉以南非洲感染艾滋病毒的青少年、成年人和老年人中中枢神经系统感染的病原学和神经学结果。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)后检测他们的神经预后，以确定出现免疫重建炎症综合征(IRIS)的患者是否比没有发生IRIS的患者预后更差。3)我们将确定特定的脑脊液细胞因子谱是否可以预测CNS感染患者的神经预后更差，或者预测CNS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)是撒哈拉以南非洲第二常见的艾滋病定义疾病，占非洲艾滋病可归因性死亡的30%。其他中枢神经系统感染也会发生，包括原因不明的无菌性脑膜炎。随着抗逆转录病毒治疗(ART)的出现，免疫重建炎症综合征(IRIS)出现了新的挑战，导致了矛盾的临床恶化和死亡率。IRIS对神经学结果的影响尚不清楚。预测IRIS的生物标志物是必要的。

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.