A Longitudinal Study of COVID-19 Sequelae and Immunity

2019冠状病毒病于二零二零年初被发现，而这一新发现的病毒性疾病继而成为全球性大流行。急性COVID-19的临床特征和疾病严重程度谱正在界定中，相当一部分感染者出现严重的疾病表现，包括肺炎、急性呼吸窘迫综合征伴呼吸衰竭，在某些情况下甚至死亡。关于急性感染消退后可能持续存在的临床后遗症知之甚少。此外，对SARS-CoV-2（引起COVID-19的病毒）的初始细胞免疫和抗体反应的特征正在确定中，目前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，以建立一个从COVID-19中康复的患者的纵向队列，以描述从COVID-19中康复后的医学后遗症和持续症状;估计COVID-19后医学后遗症的发生率和风险因素;并描述疾病幸存者对SARS-CoV-2的抗体和细胞介导的免疫应答以及这些应答随时间的变化。 研究的参与者是自我推荐的患有实验室记录的SARS-CoV-2感染的成年人，他们从症状发作开始至少6周，无论是否存在症状或急性疾病的严重程度如何。对照组包括没有COVID-19病史或SARS-CoV-2感染血清学证据的人，无论他们目前的健康状况如何，他们都被招募。无论是否存在症状，所有参与者都会进行相同的评估，包括体格检查、实验室检查和问卷调查、认知功能测试和心肺评估。从所有参与者中采集外周血单核细胞、血清和血浆样本。 该研究的基线结果于2022年7月发表在《内科学年鉴》上。其中包括在研究第一年登记的309名参与者的结果。这是189名COVID-19患者（其中12%在急性疾病期间住院）和120名对照。在入组时，55%的COVID-19队列和13%的对照参与者报告了与SARS-CoV-2感染急性后后遗症（PASC）一致的症状。在女性和有焦虑症病史的人群中，PASC的风险增加。结果符合PASC定义的参与者在标准化测试中报告生活质量较低。体格检查和诊断试验的异常结果不常见。在未接种COVID-19疫苗的队列中，27%的人对刺突蛋白的中和抗体水平为阴性，接种COVID-19疫苗的队列中无一人为阴性。探索性研究未发现PASC患者存在持续性病毒感染、自身免疫或异常免疫激活的证据。局限性包括PASC患者可能更有动力入组（导致高估PASC患病率）以及研究中未采集入组前消退的PASC（导致低估PASC患病率）。该研究表明，COVID-19后患者的持续症状负担很高，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.