Reinfection with SARS-CoV-2 in the Omicron Era is Associated with Increased Risk of Post-Acute Sequelae of SARS-CoV-2 Infection: A RECOVER-EHR Cohort Study

IMPORTANCE Post-acute sequelae of SARS-CoV-2 infection (PASC) remains a major public health challenge. While previous studies have focused on characterizing PASC and identifying its subphenotypes in children and adolescents following an initial SARS-CoV-2 infection, the risks of PASC with Omicron-variant reinfections remain unclear. Using a real-world data approach, this study investigates the risks of PASC following reinfections during the Omicron phase in the pediatric population. OBJECTIVE To investigate the risks of PASC diagnosis and 24 PASC symptoms and conditions after reinfection of SARS-CoV-2 during Omicron period in the pediatric population. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used data from the RECOVER consortium comprising 40 children's hospitals and health institutions in U.S. between January 2022 and October 2023. EXPOSURES A second SARS-CoV-2 infection, confirmed by a positive polymerase-chain-reaction (PCR) or antigen tests, or a diagnose of COVID-19, occurring at least 60 days after the initial infection, compared to the initial infection. MAIN OUTCOMES AND MEASURES PASC was identified using two approaches: (1) the ICD-10-CM diagnosis code U09.9 and (2) a symptom-based definition including 24 physician-identified symptoms and conditions. Absolute risks of incident PASC were reported, and relative risks (RRs) were calculated by comparing the second infection episode with the first infection episode groups using a modified Poisson regression model, adjusting for demographic, clinical, and healthcare utilization factors through exact matching and propensity scoring matching. RESULTS A total of 465,717 individuals under 21 years old (mean [SD] age 8.17 [6.58] years; 52% male) were included. Compared to the first infection, a second infection was associated with significantly increased risk of an overall PASC diagnosis (RR, 2.08; 95% confidence interval [CI], 1.68-2.59), and with many specific conditions including: myocarditis (RR, 3.60; 95% CI, 1.46-8.86); changes in taste and smell (RR, 2.83; 95% CI, 1.41-5.67); thrombophlebitis and thromboembolism (RR, 2.28; 95% CI, 1.71-3.04); heart disease (RR, 1.96; 95% CI, 1.69 to 2.28); acute kidney injury (RR, 1.90; 95% CI, 1.38 to 2.61); fluid and electrolyte (RR, 1.89; 95% CI, 1.62 to 2.20); generalized pain (RR, 1.70; 95% CI, 1.48 to 1.95); arrhythmias (RR, 1.59; 95% CI, 1.45-1.74); abnormal liver enzyme (RR, 1.56; 95% CI, 1.24 to 1.96); fatigue and malaise (RR, 1.50; 95% CI, 1.38 to 1.64); musculoskeletal pain (RR, 1.45; 95% CI, 1.37 to 1.54); abdominal pain (RR, 1.42; 95% CI, 1.34 to 1.50); postural orthostatic tachycardia syndromes (POTS)/dysautonomia (RR, 1.35; 95% CI, 1.20 to 1.51); cognitive functions (RR, 1.32; 95% CI, 1.15 to 1.50); and respiratory signs and symptoms (RR, 1.29; 95% CI, 1.25 to 1.33). The risks were consistent across various organ systems, including cardiovascular, respiratory, gastrointestinal, neurological, and musculoskeletal systems. CONCLUSIONS AND RELEVANCE Children and adolescents face significantly higher risk of various PASC outcomes after reinfection with SARS-CoV-2. These findings suggest a cumulative risk of PASC and highlight the urgent need for targeted prevention strategies to reduce reinfections, which includes an increased emphasis on initial or re-vaccination of children.