NIH RECOVER: A Multi-Site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults

The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal, observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients with and without known SARS-CoV-2 infection will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC.

The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows:
1. Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection. 1. Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection.1. Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection.
The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs:

1) **NIH RECOVER**: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (**this study**)

The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization.

A summary of information available by request in the RECOVER Adult Cohort (this study) can be reviewed via the "[Adult Cohort Dataset Release Notes](javascript:getPage(this,'document.cgi', 8757);return true;)" and the "[REDCap Codebook for the Adult Cohort](javascript:getPage(this,'document.cgi', 8758);return true;)" documents.

2) **The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study**: A Multi-Center Observational Study (data not yet released)<br>

The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization.

3) **NIH RECOVER**: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection (data not yet released)

The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

美国国立卫生研究院（National Institutes of Health, NIH）新冠康复研究计划（RECOVER, Researching COVID to Enhance Recovery）由三项结合回顾性与前瞻性的纵向观察性元队列研究组成，配套嵌套病例对照研究，旨在在美国具有广泛代表性的普通新冠感染人群中，明确并表征严重急性呼吸综合征冠状病毒2（Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2）感染急性后后遗症（PASC，即新冠后综合征（Post-COVID syndrome））的流行病学特征、自然病程、临床谱及潜在发病机制。该研究将对已知感染与未感染SARS-CoV-2的入组患者进行随访，监测其PASC相关临床体征与症状，并评估与PASC严重程度及进展相关的风险因素、恢复弹性因素及潜在中介因素。

本计划的核心目标是加深对SARS-CoV-2感染后康复过程的认知，以支持新型诊断与治疗干预手段的开发。整体科学目标如下：
1. 明确SARS-CoV-2感染后遗症的发病率与患病率；
2. 表征SARS-CoV-2感染后遗症的临床症状谱、亚临床器官功能障碍、自然病程及明确的后遗症表型；
3. 阐明SARS-CoV-2感染后遗症发病的生物学机制。

RECOVER观察性研究包含覆盖全生命周期的三个队列（成人队列、儿科队列及组织病理学（尸检）队列）。各队列的数据收集与分析方案已尽可能统一，采用通用数据元素。各队列简要介绍如下：

1) **NIH RECOVER成人队列：SARS-CoV-2感染急性后后遗症多中心观察性研究（本研究）**
RECOVER成人队列研究为结合回顾性与前瞻性的纵向观察性元队列，入组对象包括曾感染与未感染SARS-CoV-2的个体，且入组时处于感染前后的不同阶段。研究将对感染与未感染SARS-CoV-2、伴或不伴PASC症状的个体进行随访，以识别PASC的风险因素与发病情况。本研究在美国开展，招募对象来自住院、门诊及社区场景。研究数据包括年龄、人口学特征、健康社会决定因素、病史、疫苗接种史、急性SARS-CoV-2感染详情、整体健康与躯体功能状况及PASC症状筛查结果，将由受试者自行报告，或通过病例报告表从电子健康档案中按指定间隔采集。生物标本将按指定间隔采集，部分检测在本地临床实验室完成，其余检测由集中式研究中心完成或存入生物标本库。高级临床检查与影像学检查将在各本地研究站点开展，并实现跨站点标准化。
如需查阅本成人队列研究的可用信息概要，可通过《成人队列数据集发布说明》([Adult Cohort Dataset Release Notes](javascript:getPage(this,'document.cgi', 8757);return true;))及《成人队列REDCap编码手册》([REDCap Codebook for the Adult Cohort](javascript:getPage(this,'document.cgi', 8758);return true;))文档进行查看。

2) **RECOVER SARS-CoV-2感染急性后后遗症（PASC）儿科队列研究：多中心观察性研究（数据尚未发布）**
RECOVER儿科队列研究为结合回顾性与前瞻性的纵向观察性元队列，入组对象为年龄从新生儿至25岁的个体，入组时包括曾感染与未感染SARS-CoV-2的个体，且处于感染前后的不同阶段。研究将对感染与未感染SARS-CoV-2、伴或不伴PASC症状的个体进行随访，以识别PASC的风险因素与发病情况。本研究在美国的住院、门诊及社区场景招募参与者。研究数据包括年龄、人口学特征、健康社会决定因素、病史、疫苗接种史、急性SARS-CoV-2感染详情、整体健康与躯体功能状况及PASC症状，将由参与者自行报告，或通过病例报告表从电子健康档案中按指定间隔采集。生物标本将按指定间隔采集，部分检测在本地临床实验室完成，其余检测由集中式研究中心完成或存入生物标本库。高级临床与影像学检查将在各本地研究站点开展，并实现跨站点标准化。

3) **NIH RECOVER组织病理学研究：SARS-CoV-2感染急性后后遗症多中心病理学研究（数据尚未发布）**
RECOVER组织病理学研究为横断面研究，旨在在美国具有广泛代表性的普通新冠感染人群中，明确并表征SARS-CoV-2感染急性后后遗症的流行病学特征、自然病程、临床谱及潜在发病机制。本尸检研究将对两类人群的PASC病理学特征进行表征：（i）新冠症状出现后30天及以上死亡的非住院患者；（ii）因新冠住院且出院后30天及以上死亡的住院患者。研究对象包括此前已完全康复的SARS-CoV-2感染者（即非住院患者发病后≥30天，或住院患者出院后≥30天），以及符合世界卫生组织近期发布的PASC临床诊断标准的死者（详见下文5.4章节）。本尸检研究还将对一小部分在症状出现后15-30天内死亡的患者的急性SARS-CoV-2感染病理学特征进行探索。本方案定义了通用临床数据元素、组织采集尸检流程、核心检测指标、病理学研究方案、共享病理学组织样本及数据元素与研究方法。各研究站点需对死者进行尸检，以探究SARS-CoV-2感染潜在长期效应对人类健康的病理生理学机制。联盟分析计划将通过以下方式解答研究问题：1）从各II期参与者所在站点获取的尸检组织样本；2）从联盟内其他病理学研究人员/尸检站点获取的可用组织样本。