Renal And Neurological Outcomes In Chronically Infected West Nile Virus Patients

描述(申请人提供)：西尼罗河病毒(WNV)是一种重要的新兴黄病毒，可导致人类急性脑炎，有时甚至是致命脑炎。在动物模型中，西尼罗河病毒可持续感染中枢神经系统(CNS)和肾脏。当我们发现我们队列中的西尼罗河病毒患者的数量比预期的更多时，我们开始担心类似的持续感染可能发生在人类身上，他们正在经历进行性神经系统疾病和肾衰竭。申请者有一个庞大的、有充分记录的112名西尼罗河病毒患者队列，她自2002年以来一直跟踪调查这些患者。我们发现，77%的脑炎患者有异常的神经学检查，其中63%的患者串联步态受损，提示前庭-小脑和/或背柱功能障碍。此外，23%的患者发展为肾脏疾病，其中5人死于肾功能衰竭。我们的初步研究发现，症状的持续性、持续的可检测到的IgM抗体反应和细胞因子表达的变化之间存在关联，这加强了我们的假设，即一些患者可能患有持续性感染。最近，我们报告了25名队列参与者中有5名(20%)的尿液中含有西尼罗河病毒RNA，这是有史以来第一个有记录的证据表明人类持续感染西尼罗河病毒。这些人中有两人患有肾衰竭。对队列的进一步测试显示，总共有21/55名患者(38%)在尿液中排出西尼罗河病毒RNA；其中45%的患者报告在急性感染后发展为肾脏疾病。考虑到美国已有超过25,000名西尼罗河病毒患者被报告给疾控中心，我们的发现非常新颖和令人担忧。我们迫切需要进一步研究这些大体终点下的病理损害以及定义持续感染西尼罗河病毒的临床参数，这是本提案的目标。因此，这项拟议研究的目标是确定与持续感染西尼罗河病毒相关的肾脏和神经病理以及预后。我们计划通过肾活检的组织病理学检查、病毒分离株的基因分型和表型分析来确定可能与肾脏趋向性相关的突变，并进行神经认知检查、体积磁共振成像和电生理研究，以确定中枢神经系统的病理损害位置，从而确定肾功能衰竭的程度和病毒在尿液中的排泄模式。这是这一建议的假设，即持续感染与严重和进行性的肾脏和神经病理有关。这项研究将提供必要的信息，以评估患者的持续感染和制定治疗方案。

DESCRIPTION (provided by applicant): West Nile virus (WNV) is an important emerging flavivirus resulting in acute and sometimes fatal encephalitis in humans. In animal models, WNV can persistently infect the central nervous system (CNS) and the kidneys. We became concerned that a similar persistent infection could occur in humans when we discovered a larger than expected number of WNV patients in our cohort were experiencing progressive neurologic disease and kidney failure. The applicant has a large, well-documented cohort of 112 WNV patients who she has followed since 2002. We have found that 77% of patients who presented with encephalitis have abnormal neurologic exams, including 63% who have impaired tandem gait, suggestive of vestibular-cerebellar and/or dorsal column dysfunction. Additionally, 23% of patients developed renal disease, including 5 who died from renal failure. Our preliminary research found associations between persistence of symptoms, sustained detectable IgM antibody response, and altered cytokine expressions, which strengthened our hypothesis that some patients might have persistent infection. Recently, we reported 5 out of 25 (20%) cohort participants' urine contained WNV viral RNA, which is the first ever documented evidence of persistent WNV infection in humans. Two of these individuals are in renal failure. Further testing of the cohort has revealed a total of 21/55 (38%) patients shedding WNV RNA in the urine; 45% of these patients reported developing kidney disease after their acute infection. Our findings are very novel and worrisome considering more than 25,000 WNV patients across the US have been reported to CDC. We urgently need to further investigate the pathologic lesions underlying these gross endpoints and the clinical parameters that define persistent infection with WNV, which is the goal of this proposal. Thus, the objective of the proposed study is to determine the renal and neurological pathology and outcomes associated with persistent infection with WNV. We plan to identify the degree of renal failure and pattern of shedding of virus in the urine, identify the infected cell types through histopathologic examination of renal biopsies, genotypic and phenotypic analysis of virus isolates to determine mutations potentially related to renal tropism, and perform neurocognitive examinations, volumetric MRI, and electrophysiological studies to determine the location of pathologic lesions in the CNS. It is the hypothesis of this proposal that persistent infection is associated with severe and progressive renal and neurological pathology. This research will provide the information necessary to evaluate patients for persistent infection and develop treatment protocols.