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

项目摘要/摘要：理由：新冠肺炎大流行已影响4200多万人 在美国个人和长期并发症是经常报告的，称为急性后 SARS-CoV-2后遗症(PASC)。即使在患有轻度急性疾病的幸存者中， 由于慢性疲劳、自主神经功能障碍和认知障碍经常被报道。到目前为止，病因和 神经性PASC的病理生理学仍不清楚；然而，潜在的自身抗体和免疫 有激活的嫌疑。在我们预期的新冠肺炎ID持续队列(C-PIC)中，超过一半的人 新冠肺炎的幸存者在一年内报告了神经性PASC。我们已经确定了两者之间的联系 神经系统PASC同时具有SARS-CoV-2特异性抗体和ANA。具体地说，核衣壳(NP) 神经病学参与者的抗体水平高于尖峰三聚体(ST)抗体水平 PASC。此外，我们的初步数据已经确定了一个潜在的信号，将神经性PASC和 胃肠道微生物区系多样性降低。在这个有指导的职业项目中，我们假设 自身免疫、免疫激活和微生物组失调与神经性PASC相关。候选人： 作为一名传染病内科医生，拥有公共卫生和应用流行病学与疫情的硕士学位 通过疾病预防控制中心的流行病情报服务进行培训，我是独一无二的 定位于研究神经性PASC的流行病学和决定因素。我研究邮政的经验-- 利比里亚的埃博拉综合症为我提供了远见卓识，有助于病毒的持久性和后遗症 C-PIC研究，包括纵向PASC调查数据和生物库标本。通过 在我优秀的多学科导师团队的指导下，我计划完成我的培训目标(1) 发展调查数据高级生物统计分析方面的专门知识和(2)衔接翻译研究 和描述性队列数据。环境：我在哥伦比亚大学欧文医疗中心的导师团队 (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还拥有 使年轻的内科科学家能够在以下领域发展独立和成功的职业生涯的长期记录 学术医学。方法：我们假设慢性疲劳、自主神经障碍和认知障碍 神经PASC的亚型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，我们将描述神经性PASC流行病学， 轨迹，以及使用纵向神经学PASC调查的亚型。在目标2中，我们将确定 神经性PASC与SARS-CoV-2特异性抗体和自身抗体的关系在目标3中，我们 将确定神经性PASC和免疫激活之间的联系，并探索肠道的作用 微生物区系。这一建议为研究神经PASC的决定因素提供了一种创新的方法，并且 拟议的培训将有助于我转变为一名独立资助的临床医生兼科学家。

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.