A Longitudinal Study of COVID-19 Sequelae and Immunity

新冠肺炎于2020年初被发现，这种新发现的病毒性疾病后来成为一种全球大流行。正在确定急性新冠肺炎的临床特征和疾病严重程度谱，很大一部分感染者出现严重疾病表现，包括肺炎、伴有呼吸衰竭的急性呼吸窘迫综合征，在某些情况下甚至死亡。对于急性感染缓解后可能存在的临床后遗症，人们知之甚少。此外，对SARS-CoV-2(导致新冠肺炎的病毒)的初始细胞免疫和抗体反应的特征正在确定，尚不清楚感染产生的免疫反应是否提供长期保护性免疫。 我们迅速动员起来研究这种新的感染，并设计了一项研究，以建立新冠肺炎康复患者的纵向队列，以表征新冠肺炎康复后的医学后遗症和持续症状；估计新冠肺炎后医学后遗症的发生率和危险因素；以及表征疾病幸存者中对SARS-CoV-2的抗体和细胞介导的免疫应答以及这些应答。 这项研究的参与者是有实验室记录的SARS-CoV-2感染的自我转介成年人，他们在症状出现至少6周后登记参加研究，无论是否存在症状或急性疾病的严重程度。对照组包括没有新冠肺炎病史或血清学证据的SARS-CoV-2感染者，无论他们目前的健康状况如何，都会被招募。所有参与者都有相同的评估，无论是否存在症状，包括体检、实验室测试和问卷调查、认知功能测试和心肺评估。所有参与者的外周血单核细胞、血清和血浆样本都已收集。 这项研究的基线结果于2022年7月发表在《内科医学年鉴》上。其中包括309名参与者的结果，他们在研究的第一年登记。这些患者是189名新冠肺炎患者(其中12%是在急性疾病期间住院)和120名对照组。在注册时，55%的新冠肺炎队列参与者和13%的对照组参与者报告了与SARS-CoV-2感染(PASC)急性后遗症一致的症状。女性和有焦虑症病史的人患PASC的风险增加。符合PASC定义的参与者报告标准化测试的生活质量较低。体检和诊断测试的异常发现并不常见。在未接种新冠肺炎的队列中，27%的人对S蛋白的中和抗体水平为阴性，而在接种新冠肺炎的队列中，无一例中和抗体水平为阴性。探索性研究没有发现PASC参与者持续病毒感染、自身免疫或异常免疫激活的证据。局限性包括患有PASC的人可能更有动力参加(导致高估PASC患病率)，以及在登记前解决的PASC没有被纳入研究(导致低估PASC患病率)。研究表明，新冠肺炎后患者有很高的持续性症状负担，但广泛的诊断评估显示，在大多数情况下，报告的症状没有具体原因。

COVID-19 was identified in early 2020, and this newly recognized viral disease went on to become a worldwide pandemic. The clinical characteristics and spectrum of disease severity of acute COVID-19 were being defined, with a significant portion of those infected developing severe disease manifestations including pneumonia, acute respiratory distress syndrome with respiratory failure, and, in some cases, death. Very little was known about possible clinical sequelae that could persist after resolution of the acute infection. In addition, the characteristics of the initial cellular immune and antibody response to SARS-CoV-2 (the virus that causes COVID-19) were being defined and it was not known if the immune responses generated by infection provides long-term protective immunity. We mobilized quickly to study this new infection and designed a study to establish a longitudinal cohort of patients who recovered from COVID-19 to characterize the medical sequalae and persistent symptoms following recovery from COVID-19; estimate the incidence and risk factors for post-COVID-19 medical sequalae; and characterize antibody and cell-mediated immune responses to SARS-CoV-2 in disease survivors and these responses over time. Participants in the study are self-referred adults with laboratory-documented SARS-CoV-2 infection who were at least 6 weeks from symptom onset were enrolled regardless of presence of symptoms or severity of the acute illness. The control group includes persons with no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, who are recruited regardless of their current health status. All participants have the same evaluations regardless of presence of symptoms, including physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation. Samples of peripheral blood mononuclear cells, serum, and plasma has been collected from all participants. The baseline findings of the study were published in July 2022 at the Annals of Internal Medicine. These include the results from 309 participants who enrolled during the first year of the study. These are 189 patients with COVID-19 (12% of whom were hospitalized during acute illness) and 120 controls. At enrollment, symptoms consistent with postacute sequelae of SARS-CoV-2 infection (PASC) were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC. Limitations include the possibilities that persons with PASC may have been more motivated to enroll (leading to overestimation of PASC prevalence) and that PASC that resolved before enrollment was not captured in the study (leading to underestimation of PASC prevalence). The study showed that there is a high burden of persistent symptoms in persons after COVID-19, but extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases.