Lack of association between IFITM3 rs34481144 polymorphism and RSV disease severity in infants

Respiratory syncytial virus (RSV) is a leading cause of infant morbidity and mortality. Numerous factors can increase the risk of severe disease; however, the majority of severe cases occur in previously healthy children, and the specific predictors of life-threatening RSV disease remain unknown. The IFITM3 rs34481144 (C/T) polymorphism is a known loss-of-function variant associated with severe influenza. We investigated whether this SNP influences RSV severity in pediatric patients. We conducted a prospective cohort study in infants (<12 months) in Buenos Aires, Argentina. Severity was categorized as mild (no supplementary oxygen), severe (oxygen requirement), and life-threatening disease (LTD; ICU admission). Genotyping was performed using real-time PCR allelic discrimination. Eighty-eight RSV-positive patients were studied. No significant association was observed between the rs34481144 T-allele and disease severity. Specifically, no statistically significant association was observed when comparing the mild vs. the severe group (P = 0.14) or when comparing the mild vs. the LTD group (P = 0.11). Viral load and RSV subtypes did not correlate with clinical outcomes or genotype. Our findings suggest that IFITM3 rs34481144 is not a primary driver of RSV severity in previously healthy infants. This contrast with influenza studies highlights the virus-specific nature of host genetic susceptibility. These "negative" results are crucial for refining our understanding of RSV immunopathology and direct future research toward alternative pathways.IMPORTANCERespiratory syncytial virus (RSV) is a major threat to infant health, often causing severe lung infections. However, it remains unclear why some otherwise healthy babies develop critical illness, while others do not. This study examined a specific genetic variation in the IFITM3 gene, which has been associated with increased susceptibility to severe influenza. By studying a group of hospitalized infants, we found that this variant is not a major risk factor for severe RSV. These findings are important because they highlight that genetic factors influencing susceptibility may differ between viruses.