Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design

Leora I. Horwitz, Department of Population Health, NYU Grossman School of Medicine, New York, New York, United States of America.
Tanayott Thaweethai, Department of Biostatistics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Shari B. Brosnahan, Division of Pulmonary Critical Care and Sleep Medicine, NYU Langone Health, New York, New York, United States of America.
Mine S. Cicek, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
Megan L. Fitzgerald, Patient Led Research Collaboration on COVID-19, Washington, DC, United States of America.
Jason D. Goldman, Division of Infectious Diseases, Providence Swedish Medical Center, Seattle, Washington, United States of America.
Rachel Hess, Department of Population Health Sciences and Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.


IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.