Early life RSV infection as a preventable risk factor for asthma

Abstract Allergic asthma is increasingly common and strongly influenced by genes and environment1,2. Human respiratory syncytial virus (hRSV) bronchiolitis is a common cause of early life wheezing but it is less clear if and how it is a risk factor for allergy, recurrent wheezing in early childhood, and persistent asthma3,4. Here, we studied the Danish National Patient and Prescription Registries and found that children admitted to hospital for RSV bronchiolitis in the first 6 months of life had a 3-fold higher risk of hospital-diagnosed asthma until the age of 24 years compared with uninfected children. The risk for asthma was highest when either or both of the parents also had an asthma diagnosis, but particularly children born to an asthmatic mother and hospitalized with hRSV had a 5.4-fold increased asthma risk compared to non-infected children born to non-asthmatic parents. To model this, we infected mice in the first week of life with pneumonia virus of mice5, the murine counterpart of human RSV. When exposed to allergen in the perinatal period, infected mice developed more severe asthma features in adulthood, and this effect was strongly enhanced by maternal allergy. Mechanistically, virus infection in the pups induced the expression of activating antibody Fc receptors on dendritic cells. Neonatal dendritic cells used antibodies transferred from allergic dams to recognize allergen, explaining enhanced Th2 polarization in allergen-reactive T cells in offspring of allergic mothers. Given the recent recommendations of maternal RSV vaccination in pregnancy6 or RSV immunoprophylaxis of all newborns using long-acting RSV-neutralizing antibodies7-9, we administered cross-protective neutralizing RSV antibodies to lactating dams, and this abolished the enhancing effects of PVM infection on Th2 priming and asthma risk in the offspring. Combined, these epidemiological and mechanistic data show that early life RSV infection is a preventable risk factor for asthma, influenced by parental asthma history. Since 15% of childhood asthma is attributable to RSV irrespective of severity10, universal immunoprophylaxis in the perinatal period could have profound effects on asthma incidence and healthcare needs.