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

摘要 这项建议的目的是研究严重急性呼吸系统综合症后遗症的发生率、慢性程度和病因 CoV-2与旨在表征影响后炎症的遗传和免疫炎症因子的方案 新冠并发症。我们将建立一个1200人或更多人的队列， 患者，以确定COVID-19感染在不同PASC队列中的长期影响。患者 将根据是否存在肺部症状进行分类。我们将重点关注肺部的变化， 在3、6和12个月时以及两个月时的肺功能（DLCO和FVC，TLC）和6分钟步行试验（6 MWT）距离。 此后每年5年。为了评估进行性肺纤维化，我们将包括X射线和 肺部计算机断层扫描（CT）。为了探索致病机制，我们将：1）确定是否 与PSC相关疾病的严重性或进展相关的特定细胞因子水平;和，2） 确定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，以开发无偏倚的遗传分析。 PASC的风险评分; 4）确定特定基因型是否：a）影响PASC的严重性或慢性性， 包括特发性肺纤维化的发展，或B）有助于持续的免疫性 PASC患者的反应。最后，我们将确定PASC是否存在遗传关联 在自我认定的种族/民族（SIRE）之间变化的综合征。综合起来，这些新的研究是 目的是更好地了解疾病的发病机制，这可以导致确定 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.