Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design
Authors: Gross Rachel S. , Thaweethai Tanayott , Rosenzweig Erika B. , Chan James , Chibnik Lori B. , Cicek Mine S. , Elliott Amy J. , Flaherman Valerie J. , Foulkes Andrea S. , Gage Witvliet Margot , Gallagher Richard , Gennaro Maria Laura , Jernigan Terry L. , Karlson Elizabeth W. , Katz Stuart D. , Kinser Patricia A. , Kleinman Lawrence C. , Lamendola-Essel Michelle F. , Milner Joshua D. , Mohandas Sindhu , Mudumbi Praveen C. , Newburger Jane W. , Rhee Kyung E. , Salisbury Amy L. , Snowden Jessica N. , Stein Cheryl R. , Stockwell Melissa S. , Tantisira Kelan G. , Thomason Moriah E. , Truong Dongngan T. , Warburton David , Wood John C. , Ahmed Shifa , Akerlundh Almary , Alshawabkeh Akram N. , Anderson Brett R. , Aschner Judy L. , Atz Andrew M. , Aupperle Robin L. , Baker Fiona C. , Balaraman Venkataraman , Banerjee Dithi , Barch Deanna M. , Baskin-Sommers Arielle , Bhuiyan Sultana , Bind Marie-Abele C. , Bogie Amanda L. , Bradford Tamara , Buchbinder Natalie C. , Bueler Elliott , Bükülmez Hülya , Casey B. J. , Chang Linda , Chrisant Maryanne , Clark Duncan B. , Clifton Rebecca G. , Clouser Katharine N. , Cottrell Lesley , Cowan Kelly , D’Sa Viren , Dapretto Mirella , Dasgupta Soham , Dehority Walter , Dionne Audrey , Dummer Kirsten B. , Elias Matthew D. , Esquenazi-Karonika Shari , Evans Danielle N. , Faustino E. Vincent S. , Fiks Alexander G. , Forsha Daniel , Foxe John J. , Friedman Naomi P. , Fry Greta , Gaur Sunanda , Gee Dylan G. , Gray Kevin M. , Handler Stephanie , Harahsheh Ashraf S. , Hasbani Keren , Heath Andrew C. , Hebson Camden , Heitzeg Mary M. , Hester Christina M. , Hill Sophia , Hobart-Porter Laura , Hong Travis K. F. , Horowitz Carol R. , Hsia Daniel S. , Huentelman Matthew , Hummel Kathy D. , Irby Katherine , Jacobus Joanna , Jacoby Vanessa L. , Jone Pei-Ni , Kaelber David C. , Kasmarcak Tyler J. , Kluko Matthew J. , Kosut Jessica S. , Laird Angela R. , Landeo-Gutierrez Jeremy , Lang Sean M. , Larson Christine L. , Lim Peter Paul C. , Lisdahl Krista M. , McCrindle Brian W. , McCulloh Russell J. , McHugh Kimberly , Mendelsohn Alan L. , Metz Torri D. , Miller Julie , Mitchell Elizabeth C. , Morgan Lerraughn M. , Müller-Oehring Eva M. , Nahin Erica R. , Neale Michael C. , Ness-Cochinwala Manette , Nolan Sheila M. , Oliveira Carlos R. , Osakwe Onyekachukwu , Oster Matthew E. , Payne R. Mark , Portman Michael A. , Raissy Hengameh , Randall Isabelle G. , Rao Suchitra , Reeder Harrison T. , Rosas Johana M. , Russell Mark W. , Sabati Arash A. , Sanil Yamuna , Sato Alice I. , Schechter Michael S. , Selvarangan Rangaraj , Sexson Tejtel S. Kristen , Shakti Divya , Sharma Kavita , Squeglia Lindsay M. , Srivastava Shubika , Stevenson Michelle D. , Szmuszkovicz Jacqueline , Talavera-Barber Maria M. , Teufel Ronald J. , Thacker Deepika , Trachtenberg Felicia , Udosen Mmekom M. , Warner Megan R. , Watson Sara E. , Werzberger Alan , Weyer Jordan C. , Wood Marion J. , Yin H. Shonna , Zempsky William T. , Zimmerman Emily , Dreyer Benard P. ,   on behalf of the RECOVER-Pediatric Consortium
Published: May 2024

Importance
The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or “Long COVID”) in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults.

Observations
We describe the protocol for the Pediatric Observational Cohort Study of the NIH’s REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science.

Conclusions and relevance
RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions.

Clinical trials.gov identifier
Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.