Respiratory Syncytial Virus, Rhinoviruses, and Recurrent Wheezing Unraveling the Riddle Opens New Opportunities for Targeted Interventions

Abstract

The development of recurrent wheezing after viral bronchiolitis in early life has attracted the attention of clinicians and intrigued investigators for several decades. Because respiratory syncytial virus (RSV) is the most frequent etiologic agent responsible for severe bronchiolitis and it was easily identified with traditional diagnostic methods, most of the original studies describing the link between bronchiolitis and recurrent wheezing were focused on this virus.^1,2 These observations stimulated early investigations on the role of the host immune response, the possible associations with allergic sensitization, and the importance of the airway anatomy.^3,4 The introduction of molecular diagnostic assays allowed a much better identification of the different respiratory viruses responsible for bronchiolitis. Shortly afterwards, it became obvious that rhinoviruses were also frequent etiologic agents of bronchiolitis, especially in the milder forms of the disease, and that rhinovirus infections were significantly associated with an increased risk for recurrent wheezing.⁵ These observations inspired further research into the immune mechanisms and the role of allergic sensitization in the origins of asthma and how rhinoviruses facilitate these dysregulated immune responses that lead to recurrent wheezing. A significant advance occurred with the discovery of rhinovirus C.⁶ Studies showed that this particular rhinovirus species was associated with severe bronchiolitis and more frequent asthma exacerbations than other rhinovirus types.⁷ The discovery of the cadherin-related family member 3 (CDHR3) protein (encoded by the CDHR3 gene that is associated with increased asthma susceptibility) as a receptor for rhinovirus C provided a molecular basis for the epidemiologic association of rhinoviruses and recurrent wheezing and further suggested that this association could be specifically relevant for rhinovirus C.^6,8