Evaluating the Epidemiology and Determinants of Neurologic Post-acute Sequelae of SARS-CoV-2

项目概要/摘要：理由：COVID-19大流行影响了4200多万人 在美国的个体和长期并发症经常报告，称为急性后 SARS-CoV-2后遗症（PASC）。即使在患有轻微急性疾病的幸存者中， 因为经常报告慢性疲劳、自主神经功能障碍和认知障碍。到目前为止，病因和 神经系统PASC的病理生理学尚不清楚，然而，潜在的自身抗体和免疫 激活被怀疑。在我们的前瞻性COVID-19 ID持续队列（C-PIC）中，超过一半的 COVID-19幸存者在一年时报告神经系统PASC。我们已经发现了 神经系统PASC与SARS-CoV-2特异性抗体和ANA。核衣壳（NP） 与患有神经系统疾病的参与者中的刺突三聚体（ST）抗体水平相比， PASC。此外，我们的初步数据已经确定了一个潜在的信号连接神经PASC和 减少胃肠道微生物群多样性。在这个职业指导项目中，我们假设， 自身免疫、免疫激活和微生物菌群失调与神经系统PASC相关。候选人： 作为一名传染病医生，拥有公共卫生和应用流行病学和疫情硕士学位 通过疾病控制和预防中心的流行病情报服务培训，我是独一无二的 定位于研究神经系统PASC的流行病学和决定因素。我的学习经历- 利比里亚的埃博拉综合征为我提供了远见，有助于病毒的持久性和后遗症， C-PIC研究，其中包括PASC纵向调查数据和生物保藏标本。通过 在我优秀的多学科导师团队的指导下，我计划实现我的培训目标（1） 发展调查数据的高级生物统计分析方面的专业知识;（2）衔接转化研究 和描述性队列数据。环境：我在哥伦比亚大学欧文医学中心的导师团队 （CUIMC）是流行病学，生物统计学，免疫学和微生物组分析方面的专家。CUIMC也有一个 长期的跟踪记录，使年轻的医生，科学家发展独立和成功的职业生涯， 学术医学方法：我们假设慢性疲劳、植物神经功能障碍和认知障碍 神经系统PASC的亚表型具有不同的潜在病理生理学，包括自身免疫， 免疫激活和微生物群失调。在目标1中，我们将描述神经系统PASC流行病学， 轨迹和亚表型使用纵向神经PASC调查。在目标2中，我们将确定 神经系统PASC与SARS-CoV-2特异性抗体和自身抗体之间的相关性。在目标3中， 将确定神经PASC和免疫激活之间的关联，并探讨肠道的作用， 微生物群这一建议提供了一个创新的方法来研究神经系统PASC的决定因素， 拟议的培训将有助于我过渡到一个独立资助的临床科学家。

PROJECT SUMMARY/ABSTRACT: Rationale: The COVID-19 pandemic has affected over 42 million individuals in the United States and long-term complications are frequently reported, referred to as post-acute sequelae of SARS-CoV-2 (PASC). Even among survivors with mild acute illness, neurologic symptoms such as chronic fatigue, dysautonomia, and cognitive impairment are frequently reported. To date, the etiology and pathophysiology of neurologic PASC remain unclear; however, underlying autoantibodies and immune activation are suspected. In our prospective COVID-19 ID Persistence Cohort (C-PIC), more than half of COVID-19 survivors are reporting neurologic PASC at one year. We have identified an association between neurologic PASC with both SARS-CoV-2 specific antibodies and ANA. Specifically, nucleocapsid (NP) antibody levels are elevated compared to spike trimer (ST) antibody levels in participants with neurologic PASC. Furthermore, our preliminary data has identified a potential signal linking neurologic PASC and decreased gastrointestinal microbiota diversity. In this mentored career project, we hypothesize that autoimmunity, immune activation, and microbiome dysbiosis are associated with neurologic PASC. Candidate: As an Infectious Diseases physician with a master’s in public health and applied epidemiology and outbreak training through the Center for Disease Control and Prevention’s Epidemic Intelligence Service, I am uniquely positioned to study the epidemiology and determinants for neurologic PASC. My experience studying post- Ebola syndrome in Liberia provided me with the foresight to contribute viral persistence and sequelae aims to the C-PIC study, which includes longitudinal PASC survey data and biorepository specimens. Through the guidance of my outstanding multidisciplinary team of mentors, I plan to fulfill my training objectives of (1) developing expertise in advanced biostatistical analysis of survey data and (2) bridging translational research and descriptive cohort data. Environment: My team of mentors at Columbia University Irving Medical Center (CUIMC) are experts in epidemiology, biostatistics, immunology, and microbiome analysis. CUIMC also has a long track record of enabling young physician-scientists to develop independent and successful careers in academic medicine. Approach: We hypothesize that chronic fatigue, dysautonomia, and cognitive impairment sub-phenotypes of neurologic PASC have different underlying pathophysiology, including autoimmunity, immune activation, and microbiome dysbiosis. In Aim 1, we will characterize neurologic PASC epidemiology, trajectory, and sub-phenotypes using longitudinal neurologic PASC surveys. In Aim 2, we will identify associations between neurologic PASC with SARS-CoV-2 specific antibodies and autoantibodies. In Aim 3, we will identify associations between neurologic PASC and immune activation and explore the role of gut microbiota. This proposal provides an innovative approach to studying determinants for neurologic PASC, and the proposed training will facilitate my transition into an independently funded clinician-scientist.