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

评估 SARS-CoV-2 神经系统急性后后遗症的流行病学和决定因素

• 批准号: 10507640
• 负责人: Lawrence James Purpura
• 金额: $ 19.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507640
• 关键词: 2019-nCoV; ACE2; Acute; Acute Disease; Affect; Antibiotics; Antibodies; Antigens; Autoantibodies; Autoimmunity; Biometry; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; COVID-19 survivors; COVID-19 vaccine; Centers for Disease Control and Prevention (U.S.); Chronic; Chronic Fatigue Syndrome; Clinical; Clinical Management; Clinical Research; Clinical Treatment; Communicable Diseases; Complication; Data; Diagnostic; Disease Outbreaks; Dysautonomias; Ebola; Environment; Epidemic; Epidemiology; Etiology; Fatigue; Feces; Functional disorder; Funding; G-Protein-Coupled Receptors; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Heat shock proteins; Human Herpesvirus 4; IL2 gene; Immune; Immunology; Impaired cognition; Individual; Infection; Inflammation; Integration Host Factors; Intelligence; Interferon Type II; Interferons; Intestinal permeability; Knowledge; Liberia; Link; Longitudinal cohort; Medical center; Medicine; Memory; Mentored Patient-Oriented Research Career Development Award; Mentors; Natural Killer Cells; Neurologic; Neurologic Symptoms; Nucleocapsid; Outcome; Participant; Peripheral; Phase; Phenotype; Physicians; Positioning Attribute; Post-Acute Sequelae of SARS-CoV-2 Infection; Postural Orthostatic Tachycardia Syndrome; Predisposing Factor; Public Health; Relapse; Reporting; Role; Scientist; Services; Severe Acute Respiratory Syndrome; Severities; Severity of illness; Signal Transduction; Specimen; Surveys; Survivors; Syndrome; Testing; Time; Training; Translational Research; United States; Universities; Vaccination; Variant; Viral; Virus; Virus Diseases; activin B; acute infection; biobank; career; cohort; comorbidity; cytokine; demographics; design; dysbiosis; experience; extracellular; gastrointestinal; gut microbiota; immune activation; innovation; insight; longitudinal design; microbial; microbiome; microbiome analysis; microbiota; multidisciplinary; neurologic sequelae of COVID-19; novel; pathogen; prospective; skills; transcriptome sequencing; trend

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.

项目摘要/摘要：理由：COVID-19 大流行已影响了超过 4200 万人 在美国，长期并发症经常被报道，称为急性后并发症。 SARS-CoV-2 (PASC) 的后遗症。即使在患有轻度急性疾病的幸存者中，神经系统症状如 慢性疲劳、自主神经功能障碍和认知障碍经常被报道。迄今为止，病因学和 神经系统 PASC 的病理生理学仍不清楚；然而，潜在的自身抗体和免疫 怀疑有激活。在我们前瞻性的 COVID-19 ID 持续队列 (C-PIC) 中，超过一半的人 COVID-19 幸存者一年后报告神经系统 PASC。我们已经确定了之间的关联 具有 SARS-CoV-2 特异性抗体和 ANA 的神经 PASC。具体来说，核衣壳（NP） 与神经系统疾病参与者的尖峰三聚体 (ST) 抗体水平相比，抗体水平升高 帕斯卡。此外，我们的初步数据已经确定了连接神经 PASC 和 胃肠道微生物群多样性下降。在这个指导性职业项目中，我们假设 自身免疫、免疫激活和微生物群失调与神经系统 PASC 相关。候选人： 作为一名拥有公共卫生和应用流行病学和疫情硕士学位的传染病医生 通过疾病预防控制中心流行病情报服务的培训，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。我的毕业后学习经历 利比里亚的埃博拉综合症为我提供了先见之明，以贡献病毒的持久性和后遗症的目的 C-PIC 研究，包括纵向 PASC 调查数据和生物样本库样本。通过 在我杰出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，以及（2）桥接转化研究 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还拥有 在帮助年轻医师科学家在以下领域发展独立和成功的职业生涯方面有着长期的记录 学术医学。方法：我们假设慢性疲劳、自主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 PASC 流行病学特征， 使用纵向神经学 PASC 调查来确定轨迹和亚表型。在目标 2 中，我们将确定 神经 PASC 与 SARS-CoV-2 特异性抗体和自身抗体之间的关联。在目标 3 中，我们 将确定神经 PASC 和免疫激活之间的关联，并探索肠道的作用 微生物群。该提案提供了一种研究神经 PASC 决定因素的创新方法，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科学家。