Long-term multi-systemic complications following SARS-CoV-2 Omicron and Delta infection in children: a retrospective cohort study

Objectives: Most studies on long-term sequelae of SARS-CoV-2-infection in children were conducted pre-Omicron and pre-dated vaccination rollout. We examined long-term risk of new-incident multi-systemic sequelae after SARS-CoV-2 Delta/Omicron infection in a multi-ethnic Asian pediatric population.

Methods: Retrospective cohort study of Singaporean children aged 1- 17 years infected during Delta/Omicron BA.1/2 transmission, and contemporaneous test-negative groups. Cox-regression was utilized to estimate risks of new-incident sequelae at 31-300 days post-infection.

Results: 267,952 SARS-CoV-2-infected children were included, together with 273,517 test-negatives. ≥95% were infected during Omicron. During Delta, 23.6% of infected cases were fully-vaccinated; during Omicron, 60.4% were fully-vaccinated. ≥98% had mild infection not requiring hospitalisation. Overall, there was modestly increased risk of long-term respiratory sequelae (adjusted-hazard-ratio,aHR=1.09[95%CI=1.01-1.18]) and specifically bronchitis (aHR=1.17[95%CI=1.06-1.29]) in the SARS-CoV-2-infected group versus test-negatives. During Delta, increased risk of endocrine conditions (eg. diabetes) was observed (aHR=3.63[95%CI=1.25-10.50]); while during Omicron, increased risk of bronchitis (aHR=1.09[95%CI=1.02-1.20]) was observed in COVID-19 cases versus test-negatives. Elevated risk of bronchitis was observed amongst unvaccinated COVID-19 cases (aHR=1.17[95%CI=1.06-1.29]) versus test-negatives, but not in individuals who had received ≥1 vaccine dose. Risks of chronic sequelae following COVID-19 hospitalisation were comparable to those following historical influenza hospitalisation; albeit reduced when compared to respiratory sequelae following historical hospitalisations for respiratory-syncytial-virus (RSV).

Conclusion: Evidence of chronic sequelae in organ systems other than the respiratory system was limited in a pediatric cohort predominantly infected with mild SARS-CoV-2 Omicron infection. Risks of chronic sequelae in hospitalized COVID-19 cases did not substantially differ from historical influenza hospitalisations. Elevated risk of bronchitis was observed following SARS-CoV-2 infection in children, versus test-negatives; similarly, increased risk of respiratory sequelae was documented post-RSV hospitalisation, including children under-5.