Commentary: why are young healthy term infants protected against respiratory syncytial virus bronchiolitis?

In this month’s edition of the journal, Simões et al report on the incidence of respiratory syncytial virus (RSV) lower respiratory illness (LRI) in children less than 5 years of age in a large rural and suburban population in Indonesia. The authors prospectively followed more than 2000 children for 28 months. They performed physical examinations during each LRI episode. Nasal washes were obtained for RSV testing by enzyme immunoassay or polymerase chain reaction. The authors characterized 802 episodes of LRI in 479 children. RSV LRI was observed in 149 children. In children 12 months of age, 42% of RSV LRI cases fulfilled WHO criteria of severe pneumonia, whereas among older children, this was only 18%. Hospitalization was required in 12% of cases with RSV LRI. The most remarkable finding in the study by Simões et al is the age distribution of patients with RSV LRI. The highest incidence of RSV LRI was found at the age of 6 to 24 months. The incidence of RSV LRI in children 6 months was low and virtually absent in children 3 months of age. This finding was in sharp contrast with existent literature suggesting that RSV LRI is most commonly observed during the first 3 to 6 months of life. However, most of these data are derived from cohorts of children hospitalized for RSV LRI. The results of the study by Simões et al resemble data from other population-based studies in which it becomes clear that RSV LRI is a relatively rare event in children 3 to 6 months of age. For example, the age distribution of RSV LRI cases in the study by Simões et al is remarkably similar to our recent healthy birth cohort study in the Netherlands. In this study, RSV LRI incidence was also low during the first 3 to 6 months of life. Age distribution of RSV LRI cases in the general community (Fig. 1A) was clearly different from other cohorts of RSV patients previously described by our group (Fig. 1B–D). We conclude that RSV LRI during the first 3 to 6 months of life is rare, but has a severe course of disease when it occurs. The explanation for the remarkable absence of RSV LRI during the first months of life in healthy term children is not obvious. The first and most likely explanation is protection by maternal antibodies. Indeed, high titers of RSV-neutralizing antibodies in cord blood are associated with reduced incidence of RSV bronchiolitis. Nevertheless, this explanation is not completely satisfactory, because protection provided by maternal antibodies is only partial. Second breast-feeding is associated with reduced risk of RSV LRI. Simões does not show detailed breast-feeding data. However, previous studies have only shown modest effects of breast-feeding on the incidence of RSV LRI. Third, low viral exposure during early infancy may explain low incidence of RSV LRI in children 3 to 6 months of age. Children 3 to 6 months of age often do not yet attend day care. However, the article by Simões et al clearly shows that low incidence of RSV LRI is also observed in families with large number of preschool and school-aged children. Could there be alternative explanations for the low incidence of RSV LRI during the first months of life? It appears unlikely, that a robust innate immune system protects against RSV infection. Instead, children are born with weak innate immune responses. In particular, they produce less cytokines required for antiviral immunity, such as type I interferons and interleukin-12 on Toll-like receptor activation. Could the airway epithelium of young infants be resistant to RSV infection? And if so, what would be the underlying mechanism? Information is required on age-specific functions of infant airway epithelium, such as expression of surface immune receptors and production of antiviral molecules. Taken together, RSV LRI is a rare disease during the first 3 to 6 months of life and we need new explanations to fully understand this phenomenon. Can we use the results of the study by Simões et al to prevent hospitalization for RSV LRI in healthy term infants? Although the highest incidence of hospitalization for RSV LRI is observed at 3 to 6 months of life, Simões shows that the highest incidence in the community is typically observed at a later age. We need to identify children at the highest risk of developing RSV LRI during the first months of life. Host factors, such as genetic polymorphisms, immunologic maturation, neonatal lung function, and also socioeconomic factors contribute to the risk of viral bronchiolitis. We now need to use this information to identify individual healthy term infants with the highest risk of RSV LRI before the age of 3 to 6 months.