Post-COVID-19 Patterns of Respiratory Viruses in South African Children With Acute Respiratory Illness

BACKGROUND: The COVID-19 pandemic disrupted respiratory virus epidemiology. We describe the postpandemic prevalence, seasonality and clinical presentation of viral respiratory tract infections (RTIs) among hospitalized South African children. METHODS: Children 0-<13 years of age with acute RTIs were prospectively enrolled between October 2024 and October 2025. Nasopharyngeal aspirates were collected on admission and tested for 7 common respiratory viruses using a multiplex real-time polymerase chain reaction. Clinical, demographic and outcome data were recorded. Disease severity was classified as mild, moderate or severe based on the need for hospitalization, respiratory support, intensive care or major complications. Cluster analysis identified distinct clinical phenotypes. RESULTS: We enrolled 315 children, median age 9.3 months [interquartile range 3.6-24.7, 132/315 (41.9%) female, 7/315 (2.2%) living with HIV and 53/315 (16.8%) HIV-exposed but uninfected. Disease severity was mild in 55 (17.5%), moderate in 184 (58.4%) and severe in 76 (24.1%) children. Respiratory viruses were detected in 276/315 (87.6%); most commonly human rhinovirus (167/276; 60.5%), respiratory syncytial virus (94/276; 34%) and adenovirus (59/315; 18.7%). Respiratory syncytial virus showed strong winter seasonality (P < 0.001), human rhinovirus circulated year-round (P < 0.001) and seasonal Severe acute respiratory syndrome coronavirus-2 activity was low at 10%. HIV exposure (adjusted odds ratio: 3.08)] and viral co-detection (43.5%; P = 0.015) were independently associated with disease severity. Cluster analysis revealed 3 distinct clinical phenotypes of RTIs, with unique symptom profiles, trajectories and virological patterns. CONCLUSION: Respiratory viruses remained common in young South African children hospitalized with RTIs, with most returning to pre-COVID seasonal patterns and limited Severe acute respiratory syndrome coronavirus-2 activity. Distinct clinical phenotypes identify vulnerable subgroups and underscore the need for improved tools to distinguish severe disease from self-limiting illness.