Genetic and Immuno-inflammatory Drivers of Post-acute Pulmonary Sequelae of SARS-CoV-2

摘要 这项建议的目标将是研究SARS急性后遗症的频率、慢性和病因。 CoV-2，其方案旨在表征影响后遗症的遗传和免疫炎症因素 冠状病毒并发症。我们将建立1200个或更多深表型SARS CoV-2的队列 以确定新冠肺炎感染在不同的PASC队列中的长期影响。病人 将根据肺部症状的存在与否进行分类。我们将重点关注肺脏的变化 3、6、12个月的肺功能(DLCO和FVC，TLC)和6分钟步行试验(6MWT)。 此后5年内每年一次。为了评估进行性肺纤维化，我们将包括x光和 肺部的计算机断层扫描(CT)。为了探索致病机制，我们将：1)确定 特定细胞因子水平与PASC相关疾病的严重程度或进展相关；以及，2) 确定在PASC中是否存在特征性自身抗体谱，包括抗细胞因子抗体 患者；3)对1200名患者进行全球多样性阵列(GDA)芯片分析，开发无偏基因 PASC的风险评分；4)确定特定的基因类型：a)影响PASC的严重性或慢性化， 包括特发性肺纤维化的发生或b)有助于持续性免疫学 PASC患者的反应。最后，我们将确定是否存在与PASC的遗传关联 症状因自我认同的种族/民族而异(父系)。总而言之，这些新颖的研究是 旨在更好地了解疾病的致病机制，这可以导致识别 急性后遗症患者的治疗目标和策略。

ABSTRACT The goal of this proposal will be to study the frequency, chronicity and etiology of post-acute sequelae of SARS CoV-2 with protocols designed to characterize genetic and immuno-inflammatory factors that influence post- COVID complications. We will establish a cohort of 1200 or more deeply phenotyped SARS CoV-2 patients in order to determine the long-term effects of COVID-19 infection in distinct PASC cohorts. Patients will be categorized by the presence or absence of pulmonary symptoms. We will focus on changes in pulmonary lung function (DLCO and FVC, TLC) and 6-minute walk test (6MWT) distance at 3, 6, and 12 months and bi- annually thereafter for 5 years. To assess for progressive pulmonary fibrosis we will include x-rays and computerized tomography (CT) of the lung. To explore pathogenic mechanisms we will: 1) determine whether specific cytokine levels associate with the severity or progression of PASC-associated disease; and, 2) determine whether there is a characteristic autoantibody profile, including anti-cytokine antibodies, in PASC patients; 3) perform Global Diversity Array (GDA) chip analysis on 1200 patients to develop an unbiased genetic risk score for PASC; 4) determine whether specific genotypes: a) influence the severity or chronicity of PASC, including the development of Idiopathic Pulmonary Fibrosis or b) contribute to the sustained immunological responses in PASC patients. Finally, we will determine whether there is a genetic association with PASC syndromes that varies across self-identified race/ethnicity (SIRE). Taken together, these novel studies are intended to better understand pathogenetic mechanisms of disease, which can lead to the identification of therapeutic targets and strategies for patients with post-acute sequelae.