Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis

描述(申请人提供)：中枢神经系统(CNS)感染在撒哈拉以南非洲所有年龄段的人中都很常见，无论是否感染艾滋病毒。在艾滋病毒携带者中，隐球菌性脑膜炎特别常见，是非洲定义疾病的第二种最常见的艾滋病，也是整个撒哈拉以南非洲成年人脑膜炎的最常见原因。随着HIV抗逆转录病毒治疗(ART)的广泛应用，合并中枢神经系统感染的艾滋病患者的长期生存应该是可能的，但延迟或不准确的诊断会导致较差的急性结局，包括较高的急性死亡率。我们建议对乌干达坎帕拉1000名疑似中枢神经系统感染的艾滋病毒感染者进行前瞻性队列研究。我们将使用护理点和分子诊断学来快速确定中枢神经系统感染的病因，特别是结核病(TB)脑膜炎的新诊断测试。在隐球菌性脑膜炎患者中，我们将在一项随机临床试验中前瞻性地评估神经、功能和神经认知状况，以确定辅助剂舍曲林是否具有抗真菌活性和神经认知益处。在他的试验中，我们还将评估隐球菌病患者不良神经认知结果的风险因素。假设：1.我们假设，与标准的脑脊液分析相比，新的脑膜炎诊断算法的实施将提高诊断的速度和准确性，并降低成本。2.我们假设舍曲林对HIV感染者的隐球菌性脑膜炎具有抗真菌活性，辅助治疗将提高脑脊液灭菌率和改善神经学预后。3.我们假设根据早期参数可以预测更差的神经认知结果，包括：1)脑脊液干扰素-γ降低；2)脑脊液IL-7升高；3)脑脊液两性霉素水平升高；4)免疫重建炎症综合征(IRIS)的发展。具体目标1)通过实施一种新的诊断算法来确定撒哈拉以南非洲艾滋病毒感染者中中枢神经系统感染的病原学，我们将降低成本并改善结果。2)我们将确定辅助性舍曲林是否能改善患有隐球菌性脑膜炎的HIV感染者的抗真菌和神经认知结果。3)我们将确定隐球菌病患者神经认知功能不良的危险因素。

DESCRIPTION (provided by applicant): Central nervous system (CNS) infections are common across all ages in Sub-Saharan Africa in people with or without HIV-infection. In persons with HIV, cryptococcal meningitis is particularly common, being the second most common AIDS defining illness in Africa and the most common cause of meningitis in adults in Sub-Saharan Africa overall. With the widespread availability of HIV antiretroviral therapy (ART), long term survival in AIDS patients with CNS infections should be possible, but delayed or inaccurate diagnoses contributes to poor acute outcomes, including high acute mortality. We propose a prospective cohort study of 1000 HIV-infected persons presenting with suspected CNS infection in Kampala, Uganda. We will use point-of-care and molecular diagnostics to rapidly determine the etiologies of CNS infections, with a specific focus on new diagnostic tests for Tuberculosis (TB) meningitis. Among persons with cryptococcal meningitis, we will prospectively assess neurological, functional, and neurocognitive status in a randomized clinical trial to determine if adjunctive sertraline has antifungal activity and neurocognitive benefit. In his trial, we will also assess for risk factors for adverse neurocognitive outcomes in persons with cryptococcosis. Hypotheses: 1. We hypothesize that implementation of a new meningitis diagnostic algorithm will improve the rapidity and accuracy of diagnoses and lower costs compared to a standard CSF analysis. 2. We hypothesize that sertraline has an antifungal activity in HIV-infected persons with cryptococcal meningitis, and adjunctive sertraline therapy will improve the rate of CSF sterilization and improve neurologic outcomes. 3. We hypothesize that worse neurocognitive outcomes can be predicted based on early parameters, including: i) decreased CSF IFN-y; ii) increased CSF IL-7; iii) higher CSF amphotericin levels; iv) development of immune reconstitution inflammatory syndrome (IRIS). Specific Aims 1) By implementing a novel diagnostic algorithm to determine the etiology of CNS infections in Sub- Saharan Africa among HIV-infected adults, we will decrease costs and improve outcomes. 2) We will determine if adjunctive sertraline improves anti-fungal and neurocognitive outcomes among HIV-infected persons with cryptococcal meningitis. 3) We will determine risk factors for poor neurocognitive outcomes in persons with cryptococcosis.