Upper Airway and Neurological Manifestations of Pediatric Omicron Infection: From Novel Pathogen to Endemic Respiratory Virus — A Natural Experiment in Immuno-naive versus Primed Children

Abstract Background The Omicron variant of SARS-CoV-2 has been associated with altered clinical phenotypes in children, including upper airway involvement and neurological complications. However, the magnitude of these manifestations relative to established pediatric respiratory viruses remains incompletely quantified, and the extent to which immune priming attenuates severity is unknown. We aimed to characterize upper airway obstruction (UAO) and neurological events in hospitalized children with Omicron infection, to compare outcomes with respiratory syncytial virus (RSV) and human rhinovirus (HRV) using propensity score-matched analyzes, and to leverage a unique natural experiment to assess the impact of first versus second immune exposure on disease severity. Methods In this retrospective cohort study, we identified 2,085 hospitalized children (0–18 years) with laboratory-confirmed infection: 211 with Omicron (temporal proxy), 424 with RSV, 824 with HRV, and 957 with other viruses. Primary outcomes were UAO and neurological events. Propensity score matching (1:2) compared Omicron with RSV and HRV, adjusting for age, sex, comorbidities, and admission severity. A natural-experiment analysis compared first exposure (Wave 1, December 2022–February 2023, n = 82) versus second exposure (Wave 2+, March–December 2023, n = 51) among children ≥ 6 months of age. Age-stratified and wave-period analyzes were prespecified. Results UAO occurred in 20 of 211 children with Omicron (9.5%, 95% CI 5.9–14.2%) versus 1 of 424 with RSV (0.2%) and 1 of 824 with HRV (0.2%). Any neurological event was observed in 44 of 211 with Omicron (20.9%, 95% CI 15.7–26.9%) versus 20 of 424 with RSV (4.7%) and 26 of 824 with HRV (3.2%). After matching, Omicron was associated with increased risks of MODS score ≥ 2 (vs. RSV: RR 3.80, 95% CI 1.84–7.86; vs. HRV: RR 4.50, 95% CI 2.32–8.72), non-febrile neurological events (vs. RSV: RR 5.2, 95% CI 2.8–9.6; vs. HRV: RR 6.8, 95% CI 3.9–11.8), and severe adverse outcomes (vs. RSV: RR 3.08, 95% CI 1.52–6.24; vs. HRV: RR 3.85, 95% CI 1.98–7.49). In the immune exposure analysis, severe outcomes were markedly lower after second exposure (13.7%) than after first exposure (45.1%; p < 0.001), representing a 71% relative reduction. UAO decreased from 18.3% to 2.0% (p = 0.005), while LRTI rates were unchanged (45.1% vs. 56.9%; p = 0.214), indicating immune “taming” of severity without prevention of infection. Conclusions Pediatric Omicron infection was associated with substantially higher rates of UAO and neurological events than RSV or HRV, with risks extending beyond infancy. Immune priming dramatically attenuated severe outcomes and upper airway toxicity, though lower respiratory involvement persisted. These findings document the transition of Omicron from a novel, severe pediatric pathogen toward an established respiratory virus, and highlight the need for age-specific clinical vigilance and ongoing surveillance.