Reinfection Raises Long COVID Risk in Children and Adolescents 

Children and adolescents who are reinfected with SARS-CoV-2 face a significantly higher risk of developing long COVID, according to a large, multi-institutional study published in The Lancet Infectious Diseases. 

The study, which analyzed electronic health record data from 40 children’s hospitals and health systems across the United States, found that young patients who experienced a second confirmed SARS-CoV-2 infection during the omicron period were more than twice as likely to receive a clinician-documented diagnosis of post-acute sequelae of COVID-19 (PASC) as those in the same calendar period after a first infection. 

“This work comes out of the NIH-funded RECOVER Initiative, which was established to understand the long-term consequences of SARS-CoV-2 infection,” said David Liebovitz, MD, professor of Medicine in the Division of General Internal Medicine, and a co-author of the study. “Earlier work helped define long COVID in children after a first infection, but once omicron became dominant and reinfections became routine, a pressing clinical question emerged: does getting COVID a second time carry its own distinct risk of long COVID, or does prior infection confer meaningful protection? Existing pediatric evidence was thin, mostly based on small survey-based studies with self-reported outcomes and limited ability to control for confounders.” 

The cohort included more than 465,000 patients younger than 21 years with at least one documented SARS-CoV-2 infection after January 1, 2022. Within this cohort, roughly 407,300 patients were analyzed after a first infection and 58,417 were analyzed after a second infection occurring at least 60 days after the first. 

Over a six-month follow-up period, the incidence of clinician-documented PASC was roughly 1,884 cases per million children after a second infection, compared with about 904 cases per million after a first infection. After adjusting for demographic characteristics, underlying health conditions, vaccination status, and healthcare utilization, reinfection remained associated with a more than twofold increase in PASC risk. 

“The results of this study further support one of the strongest reasons I give patients, families and physicians about getting vaccinated: More vaccines should lead to fewer infections, which should lead to less long COVID,” said Ravi Jhaveri, MD, division chief and the Virginia H. Rogers Professor of Infectious Disease in the Department of Pediatrics, who was a co-author of the study. 

“The findings directly contradict the common assumption that because acute omicron illness is usually mild in children, reinfection is clinically inconsequential,” said Liebovitz, who is also associate vice chair for clinical informatics in the Department of Medicine. “Instead, the risk appears cumulative, meaning each successive infection adds to a child’s long-term health burden rather than being neutralized by prior immunity.” 

Beyond formal PASC diagnoses, children and adolescents who experienced reinfection had an elevated risk of a wide range of symptoms and conditions previously associated with long COVID. These outcomes spanned multiple organ systems, including cardiovascular complications such as myocarditis, arrhythmias, heart disease and chest pain; neurologic and cognitive effects such as headaches, cognitive impairment, postural orthostatic tachycardia syndrome (POTS) and other forms of dysautonomia; kidney injury; thrombotic events; and more common symptom clusters including fatigue, abdominal pain and musculoskeletal pain. Myocarditis risk was more than three times higher after a second infection, and the risk of thrombotic events more than doubled. 

The elevated risk of PASC after reinfection was evident across subgroups defined by vaccination status and by the severity of the acute infection. 

The study authors noted that prior pediatric long COVID studies have relied largely on surveys and self-reported symptoms, often with limited ability to control for confounding factors. In contrast, the harmonized electronic health record infrastructure used in this study made it possible to analyze clinician-documented diagnoses and symptoms at scale. 

“Because the analysis used medically documented diagnoses from electronic health records with propensity score matching across hundreds of covariates, the findings carry more methodological weight than the self-reported survey data that has dominated the pediatric long COVID literature to date,” Liebovitz said. 

The findings challenge the common perception that reinfection with newer SARS-CoV-2 variants is clinically inconsequential for children, particularly given that acute omicron infections are often mild. 

“The practical message for families and clinicians is that preventing reinfection still matters, even when acute illness looks mild,” Liebovitz said. “Pediatric COVID-19 vaccination rates have dropped substantially, driven by a combination of pandemic fatigue, the perception that omicron is benign in kids, and delayed vaccine availability for the youngest children. This study is a reminder that the acute phase is not the whole story. A mild cold-like illness in a child can still be followed weeks or months later by new cardiac, cognitive, or autonomic symptoms, and the probability of that outcome rises with each subsequent infection.” 

Moving forward, Liebovitz and Jhaveri said there is still a need for continued investigation into whether updated COVID-19 vaccines reduce the risk of long COVID, as well as mechanistic studies to better understand why repeated infections appear to compound risk. Longer-term follow-up will also be critical to determine how these conditions evolve over time. 

“This is the kind of question that can only be answered when dozens of children’s hospitals agree to harmonize and share data, and it is a good example of what multi-institutional learning health systems can accomplish,” Liebovitz said. 

The study was supported by the National Institutes of Health as part of the Researching COVID to Enhance Recovery (RECOVER) Initiative.