Unveiling the Risk Period for Death After Respiratory Syncytial Virus Illness in Young Children Using a Self-Controlled Case Series Design

BACKGROUND: Respiratory syncytial virus (RSV)-related acute lower respiratory infection is an important cause of death in infants and young children. However, little is known about the risk period for RSV-related deaths after presentation to health services with an RSV illness. METHODS: Using the Scottish national mortality database, we identified deaths from respiratory/circulatory causes (hereafter "respiratory/circulatory deaths") in young children aged <5 years during 2009-2016, whose medical history and records of laboratory-confirmed RSV infections were obtained by linking the mortality database to the national surveillance data set and the Scottish Morbidity Record. We used a self-controlled case series (SCCS) design to evaluate the relative incidence of deaths with respiratory/circulatory deaths in the first year after an RSV episode. We defined the risk interval as the first year after the RSV episode, and the control interval as the period before and after the risk interval until 5 years after birth. Age-adjusted incidence ratio and attributable fraction were generated using the R software package SCCS. RESULTS: We included 162 respiratory/circulatory deaths, of which 36 occurred in children with a history of laboratory-confirmed RSV infection. We found that the mortality risk decreased with time after the RSV episode and that the risk was statistically significant for the month after RSV illness. More than 90% of respiratory/circulatory deaths occurring within 1 week after the RSV episode were attributable to RSV (attributable fraction, 93.9%; 95% confidence interval, 77.6%-98.4%), compared with about 80% of those occurring 1 week to 1 month after RSV illness (80.3%; 28.5%-94.6%). CONCLUSIONS: We found an increased risk of death in the first month after an RSV illness episode leading to healthcare attendance. This provides a practical cutoff time window for community-based surveillance studies estimating RSV-related mortality risk. Further studies are warranted to assess the mortality risk beyond the first month after RSV illness episode.