Renal And Neurological Outcomes In Chronically Infected West Nile Virus Patients

描述（由申请人提供）：西尼罗病毒（WNV）是一种重要的新兴黄病毒，可导致人类急性和有时致命的脑炎。在动物模型中，西尼罗河病毒可以持续感染中枢神经系统（CNS）和肾脏。当我们发现我们的队列中出现进行性神经系统疾病和肾衰竭的西尼罗河病毒患者数量大于预期时，我们开始担心类似的持续性感染可能发生在人类中。申请人自2002年以来对112名西尼罗河病毒患者进行了跟踪调查。我们发现，77%的脑炎患者有异常的神经系统检查，包括63%的串联步态受损，提示前庭-小脑和/或背柱功能障碍。此外，23%的患者出现肾脏疾病，其中5人死于肾衰竭。我们的初步研究发现症状持续、持续可检测到的IgM抗体反应和细胞因子表达改变之间存在关联，这加强了我们的假设，即一些患者可能存在持续感染。最近，我们报道了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记录的人类持续西尼罗河病毒感染的证据。其中两个人患有肾衰竭。该队列的进一步检测显示，共有21/55（38%）患者在尿液中排出西尼罗河病毒RNA；这些患者中有45%报告急性感染后出现肾脏疾病。我们的发现是非常新颖和令人担忧的，因为美国已经向疾病预防控制中心报告了超过25,000名西尼罗河病毒患者。我们迫切需要进一步研究这些总体终点的病理病变和定义西尼罗河病毒持续感染的临床参数，这是本提案的目标。因此，拟议研究的目的是确定与西尼罗河病毒持续感染相关的肾脏和神经病理学和预后。我们计划确定肾功能衰竭的程度和尿中病毒脱落的模式，通过肾活检的组织病理学检查，病毒分离物的基因型和表型分析来确定感染细胞类型，以确定可能与肾向性相关的突变，并进行神经认知检查，体积MRI和电生理研究来确定中枢神经系统病理病变的位置。这一建议的假设是，持续感染与严重和进行性肾脏和神经病理有关。这项研究将为评估持续感染患者和制定治疗方案提供必要的信息。

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.