Respiratory Pathogen Co-Detection in Hospitalized Infants with Bronchiolitis and Implementation of Universal Nirsevimab Immunoprophylaxis: A Six-Year Observational Study

Background: Bronchiolitis is a leading cause of hospitalization in infants, with respiratory syncytial virus (RSV) as the main etiological agent. The clinical relevance of respiratory pathogen co-infections and the role of emerging preventive strategies, including nirsevimab immunoprophylaxis, remain under investigation. Methods: We conducted two complementary observational analyses within the pediatric healthcare network of Western Sicily. The first was a retrospective study including 580 children younger than 24 months hospitalized for bronchiolitis between 2019 and 2025 at the “Giovanni Di Cristina” Hospital in Palermo, Italy, to investigate respiratory pathogen detection patterns and their clinical correlates. Patients were classified according to microbiological findings as single-virus infections or viral–viral/viral–bacterial co-detections. The second was a separate observational cohort of 458 newborns from two birth centers inWestern Sicily during the 2024–2025 RSV season, established to evaluate the implementation, safety, and respiratory outcomes associated with nirsevimab prophylaxis. Results: Viral–viral and/or viral–bacterial codetections were identified in 45.5% of hospitalized infants and were associated with longer hospital stay (8.86 vs. 6.35 days, p < 0.001) and a higher frequency of complications (18.6% vs. 8.5%, p < 0.001), without differences in age, sex, or respiratory support requirements. RSV remained the predominant pathogen throughout the study period. In the complementary observational subgroup analysis, the observed safety findings were reassuring, with only mild and self-limiting events reported during follow-up; however, the sample size and observational design limit the ability to assess rare or delayed adverse events. Among infants undergoing clinically indicated respiratory testing, RSV was detected in 7/9 (77.8%) non-prophylaxed infants and 5/24 (20.8%) prophylaxed infants. Among hospitalized infants, complications were less frequently observed among those who had received nirsevimab (3.5% vs. 26.9%, p < 0.001), although substantial baseline differences between groups precluded causal interpretation of this finding. Conclusions: Viral–viral and viral–bacterial co-detections are frequent in hospitalized bronchiolitis and are associated with increased clinical complexity, mainly through prolonged hospitalization and higher occurrence of complications. The observational nirsevimab analysis showed a favorable safety profile and a lower proportion of RSV detection among clinically tested prophylaxed infants. However, because respiratory testing was performed according to clinical indication and differed substantially between groups, these findings cannot be interpreted as estimates of RSV incidence or as definitive evidence of nirsevimab effectiveness. The observed difference in complications should also be interpreted cautiously because of substantial baseline differences between prophylaxed and non-prophylaxed infants. Prospective studies with systematic respiratory testing are warranted.