Risk factors for severe outcomes of respiratory syncytial virus infection in children: a nationwide cohort study in Sweden.

Background: While risk factors for respiratory syncytial virus (RSV) hospitalization are well established, few studies have assessed severe disease outcomes. We investigated risk factors for RSV-associated severe disease outcomes in children 0-18 years. Methods: A register-based cohort study including all children born in Sweden between 2001 and 2022 was performed. Data on RSV related ICD-10 diagnoses, sociodemographic factors and comorbidities were retrieved from national registers. The outcomes were RSV-associated death, Intensive Care Unit (ICU) admission, and prolonged hospitalization (≥7 days). Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were calculated using multivariable Cox regression both in the full cohort and in the subpopulation of children with an RSV diagnosis. Findings: Among 2,354,302 children, 38,919 (1·7%) had an RSV diagnosis. Of these, 4621 (11·9%) had severe disease outcomes. The median age of children admitted to ICU were 1·9 months and 500 (41·3%) had an underlying comorbidity. Birth in winter (HR 2·96, 95% CI: 2·53-3·46), small for gestational age (aHR 3·91, 95% CI: 3·08-4·97), multiple birth (aHR 3·43, 95% CI: 2·80-4·21), having siblings 0-3 years (aHR 2·92, 95% CI: 2·57-3·31), and comorbidities (aHRs > 4) were the factors most strongly associated with ICU admission or death in the full cohort. Similar, but attenuated, associations were seen among children with an RSV diagnosis. Comorbidities were less common in severe cases under 3 months of age than in older children (40·3% vs 71·6%, p < 0·0001). Interpretation: Severe RSV cases often affect healthy, full-term infants under 3 months, beyond those with severe comorbidities. Risk factors such as small for gestational age, multiple births, and young siblings are not currently included in RSV immunization strategies, but should be considered to better target vulnerable infants. Funding: Financial support was provided by KID funding from Karolinska Institutet, the Swedish Research Council, the Swedish Heart Lung Foundation, the Swedish Asthma and Allergy Association Research Fund, grants from Region Stockholm, the Strategic Research Program in Epidemiology at Karolinska Institutet, The Society for Child Welfare, Åke Wiberg Foundation, Martin Rind Foundation, Karolinska Institutet Research Foundation Grants, and the Foundation Freemason Children's Home in Stockholm.