How Did the Clinical Presentation of COVID-19 in Children Change Across SARS-CoV-2 Variants? A Systematic Review

(1) Background: SARS-CoV-2 variants clinical presentation and severity may differ in children. This systematic review evaluated changes that occurred in pediatric COVID-19 across successive viral variants. (2) Methods: PubMed/MEDLINE, Embase, and Web of Science were searched through 26 September 2026 for comparative studies of SARS-CoV-2 variants in patients aged 18 years or younger. We assessed their methodological quality with the Newcastle–Ottawa Scale (NOS) and their clinical manifestations and severity outcomes were synthesized narratively. (3) Results: Twenty-nine studies were included. Delta was generally associated with a greater symptomatic burden than Alpha, even though the differences in severe outcomes were inconsistent. Omicron was associated with a distinct clinical phenotype, more frequent croup and seizures, some of which were reported as febrile seizure, while gastrointestinal findings varied across studies. Population-based studies generally indicated lower risks of hospitalization or severe disease with Omicron than Delta, but findings among hospitalized children were less consistent. Studies of Omicron subvariants identified differences in individual symptoms without a consistent trend in disease severity. (4) Conclusions: The clinical phenotype of pediatric COVID-19 evolved across SARS-CoV-2 variants. Omicron was particularly associated with increased upper-airway, particularly croup, while several studies also reported increased seizure frequency, including febrile seizures. Population-based studies generally suggesting less severe disease than Delta infections. Differences in age, study setting, variant ascertainment, and outcome definitions should be considered when interpreting these findings.