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After national recommendations, palivizumab is administered in Germany to high-risk infants to prevent hospitalizations related to respiratory syncytial virus (RSV) infection. Limited data are available to characterize those children who receive palivizumab in 2 consecutive RSV seasons.This was a comparative analysis of data from a postmarketing observational study (German SYNAGIS Registry, AbbVie Germany GmbH & Co.KG, Wiesbaden) detailing RSV-related risk factors and main indications for palivizumab in 920 children who received at ≥1 palivizumab injection in a second season between 2010 and 2016 [second season population (SSP)].Median birth weight and gestational age at birth as well as the proportion of children with hemodynamically significant congenital heart disease, with any form of chronic lung disease of prematurity or with any form of neuromuscular impairment, were significantly higher in the SSP. Accordingly, hemodynamically significant congenital heart disease, chronic lung disease and other reasons (including neuromuscular impairment) and not prematurity were the main indications for palivizumab in the SSP. The RSV-related hospitalization rate confirmed by viral testing in the SSP (receiving palivizumab prophylaxis) was 0.9%. No deaths due to RSV were reported.Second season recipients of palivizumab differ from one season recipients of palivizumab in terms of risk factors and main indications for prophylaxis. Keeping in mind the limitations of an uncontrolled prospective observational study, these results support the effectiveness of palivizumab (concerning the RSV rehospitalization rate) and do not reveal new safety alerts in a large SSP.