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

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很常见，所有年龄段都有或没有hiv感染。在艾滋病毒感染者中，隐球菌性脑膜炎（CM）是非洲第二大最常见的艾滋病定义疾病，现在随着艾滋病毒抗逆转录病毒治疗（ART）的可用性，长期生存应该是可能的。然而，HIV免疫重构炎症综合征（IRIS）的新挑战已经出现。IRIS是一种鲜为人知的免疫现象，即部分艾滋病患者（约30%）开始抗逆转录病毒治疗时，免疫系统却在改善，但情况反而恶化。IRIS事件的特点是在微生物治疗成功的情况下出现夸大的炎症。当中枢神经系统发生IRIS炎症失调时，经常发生死亡，但幸存者的神经系统预后尚不清楚。我们建议对撒哈拉以南非洲伴有hiv感染的中枢神经系统感染患者进行前瞻性队列研究。我们将使用分子诊断来确定中枢神经系统感染的病因。在患者开始抗逆转录病毒治疗后，我们将前瞻性地对IRIS进行监测，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，以发现预测神经系统预后不良、未来IRIS和/或死亡的生物标志物。假设：我们假设晚期HIV （CD4 <100）患者的神经系统预后较差，并且随后发生cns相关IRIS事件的患者的神经系统预后比未经历CNS-IRIS的患者更差。我们假设中枢神经系统的促炎基线细胞因子谱可以预测未来的不良结果。1)我们将确定撒哈拉以南非洲青少年、成人和老年人hiv感染的中枢神经系统感染的病因学和神经系统预后。2)对于患有IRIS相关中枢神经系统感染的艾滋病患者，我们将确定他们在开始抗逆转录病毒治疗（ART）后的神经系统预后，以确定发生免疫重建炎症综合征（IRIS）的患者是否比未发生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中枢神经系统感染患者更差的神经预后，或预测中枢神经系统感染和艾滋病患者的IRIS。

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.