Long COVID associated with SARS-CoV-2 reinfection among children and adolescents in the omicron era (RECOVER-EHR): a retrospective cohort study - 01/10/25

Doi : 10.1016/S1473-3099(25)00476-1

Bingyu Zhang, MS ^a,^b, Qiong Wu, PhD ^a,^c,^d, Ravi Jhaveri, ProfMD ^f, Ting Zhou, MD PhD ^a,^c, Michael J Becich, ProfMD PhD ^e, Yuriy Bisyuk, MD PhD ^g, Frank Blanceró, BA ^h, Elizabeth A Chrischilles, ProfPhD ⁱ, Cynthia H Chuang, ProfMD MSc ^j, Lindsay G Cowell, ProfMS PhD ^k, Daniel Fort, PhD MPH ^l, Carol R Horowitz, ProfMD MPH ^m, Susan Kim, MD MMSc ⁿ, Nathalia Ladino, MS ^o, David M Liebovitz, MD ^p, Mei Liu, PhD ^q, Abu S M Mosa, PhD ^r,^s, Hayden T Schwenk, MD MPH ^t, Srinivasan Suresh, ProfMD MBA ^u, Bradley W Taylor, MBA FAMIA ^v, David A Williams, ProfPhD ^w, Jeffrey S Morris, ProfPhD ^c, Christopher B Forrest, ProfMD PhD ^x,^y, Yong Chen, ProfPhD ^a,^b,^c,^y,^z,^aa,⁎
on behalf of the
RECOVER Consortium^{^†}
Collaborators listed in the Supplementary Material)
^a Center for Health AI and Synthesis of Evidence, University of Pennsylvania, Philadelphia, PA, USA
^b Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
^c Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
^d Department of Biostatistics and Health Data Science, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
^e Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
^f Division of Pediatric Infectious Diseases, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
^g University Medical Center New Orleans, New Orleans, LA, USA
^h RECOVER Patient, Caregiver, or Community Advocate Representative, New York, NY, USA
ⁱ Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA
^j Penn State College of Medicine, Hershey, PA, USA
^k O’Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA
^l Center for Outcomes Research, Ochsner Health, New Orleans, LA, USA
^m Institute for Health Equity Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA
ⁿ Department of Pediatrics, Division of Pediatric Rheumatology, Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, USA
^o NYU Langone Health, New York, NY, USA
^p Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
^q Department of Health Outcomes and Biomedical Informatics, University of Florida, College of Medicine, FL, USA
^r Department of Biomedical Informatics, Biostatistics, and Medical Epidemiology, University of Missouri School of Medicine, Columbia, MO, USA
^s Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, USA
^t Stanford School of Medicine, Division of Pediatric Infectious Diseases, Stanford, CA, USA
^u Department of Pediatrics, University of Pittsburgh, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
^v Clinical and Translational Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA
^w Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
^x Applied Clinical Research Center, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
^y Leonard Davis Institute of Health Economics, Philadelphia, PA, USA
^z Penn Medicine Center for Evidence-based Practice, Philadelphia, PA, USA
^aa Penn Institute for Biomedical Informatics, Philadelphia, PA, USA

^*Correspondence to: Prof Yong Chen, Center for Health AI and Synthesis of Evidence, University of Pennsylvania, Philadelphia, PA 19104, USACenter for Health AI and Synthesis of EvidenceUniversity of PennsylvaniaPhiladelphiaPA19104USA

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Summary

Background

Post-acute sequelae of SARS-CoV-2 infection (PASC) remain a major public health challenge. Although previous studies have focused on characterising PASC in children and adolescents after an initial infection, the risks of PASC after reinfection with the omicron variant remain unclear. We aimed to assess the risk of PASC diagnosis (U09.9) and symptoms and conditions potentially related to PASC in children and adolescents after a SARS-CoV-2 reinfection during the omicron period.

Methods

This retrospective cohort study used data from 40 children’s hospitals and health institutions in the USA participating in the Researching COVID to Enhance Recovery (RECOVER) Initiative. We included patients younger than 21 years at the time of cohort entry; with documented SARS-CoV-2 infection after Jan 1, 2022; and who had at least one health-care visit within 24 months to 7 days before the first infection. The second SARS-CoV-2 infection was confirmed by positive PCR, antigen tests, or a diagnosis of COVID-19 that occurred at least 60 days after the first infection. The primary endpoint was a clinician-documented diagnosis of PASC (U09.9). Secondary endpoints were 24 symptoms and conditions previously identified as being potentially related to PASC. We used the modified Poisson regression model to estimate the relative risk (RR) between the second and first infection episodes, adjusted for demographic, clinical, and health-care utilisation factors using exact and propensity-score matching.

Findings

We identified 407 300 (87·5%) of 465 717 eligible children and adolescents with a first infection episode and 58 417 (12·5%) with a second infection episode from Jan 1, 2022, to Oct 13, 2023, in the RECOVER database. 233 842 (50·2%) patients were male and 231 875 (49·8%) were female. The mean age was 8·17 years (SD 6·58). The incident rate of PASC diagnosis (U09.9) per million people per 6 months was 903·7 (95% CI 780·9–1026·5) in the first infection group and 1883·7 (1565·1–2202·3) in the second infection group. Reinfection was associated with a significantly increased risk of an overall PASC diagnosis (U09.9) (RR 2·08 [1·68–2·59]) and a range of symptoms and conditions potentially related to PASC (RR range 1·15–3·60), including myocarditis, changes in taste and smell, thrombophlebitis and thromboembolism, heart disease, acute kidney injury, fluid and electrolyte disturbance, generalised pain, arrhythmias, abnormal liver enzymes, chest pain, fatigue and malaise, headache, musculoskeletal pain, abdominal pain, mental ill health, POTS or dysautonomia, cognitive impairment, skin conditions, fever and chills, respiratory signs and symptoms, and cardiovascular signs and symptoms.

Interpretation

Children and adolescents face a significantly higher risk of various PASC outcomes after reinfection with SARS-CoV-2. These findings add to previous evidence linking paediatric long COVID to multisystem effects and highlight the need to promote vaccination in younger populations and support ongoing research to better understand PASC, identify high-risk subgroups, and improve prevention and care strategies.