Innovative Steroid Treatment to Reduce Asthma Development in Children After First-time Rhinovirus Induced Wheezing

Overview

The overall objective of the study is to determine the efficacy of corticosteroids in preventing recurrent wheezing and asthma in high-risk, first-time severe wheezing children with rhinovirus infection, stratified by rhinovirus genome load. The secondary objectives are to determine duration and severity of each acute episode with acute expiratory breathing difficulty, the number of episodes with acute expiratory breathing difficulty, degree of pulmonary hyperreactivity and quality of life within 24 months after study entry.

Asthma is a major and growing public health problem in Norway and beyond. The reason for the increased occurrence of asthma is still poorly understood. However, the disease is a result of a complex interplay between genetic and environmental factors. The current view of asthma pathogenesis is that an abnormal immune response to environmental agents, such as allergens or respiratory viruses, is responsible for initiation and perpetuation of chronic inflammation in genetically susceptible individuals. It is also increasingly evident that asthma originates early in life. However, intervention measures introduced before birth and during the first year of life that reduced or eliminated exposure to house dust, pets, and tobacco smoke together with encouragement of breast-feeding and delayed introduction of solid foods, only had minor effects in preventing asthma development. Thus, there is an urgent need to develop new approaches to asthma prevention in young children. Recent evidence suggests that rhinovirus infection is a main and independent trigger of acute wheezing and asthma exacerbations in children. Rhinovirus may cause 20-40% of acute wheezing episodes (bronchiolitis) in children during the first 2 years of life, and up to 90% of asthma exacerbations in older children. Rhinovirus etiology of early wheezing is particularly interesting because it has been strongly associated with recurrent wheezing and doctor-diagnosed asthma up to 13 years of age. The strength of this effect has been reported with odds ratios ranging from 3 to 10 during early life. Previously, personal objective markers for increased asthma risk have mainly been related to the presence of atopy development, but atopic disease with eczema generally manifests later, at age 2-3 years. This understanding of early-life rhinovirus associated wheezing as an early marker for asthma has opened a novel opportunity for effective secondary prevention of asthma by identifying children with increased risk of asthma. Recognizing the role of rhinovirus as an early risk factor for asthma development, has made it essential to control viral effects. Unfortunately, no feasible rhinovirus antivirals are available for children yet. Rhinovirus infection may lead to broken epithelial barriers facilitating development of inflammation, and asthma is a chronic inflammatory disease of the airways. It is becoming increasingly clear that control of early virus induced inflammation that may develop into chronic inflammation is crucial to intervene with the asthma disease development. Most cases with bronchiolitis are caused by respiratory syncytial virus (RSV) and rhinovirus. Recent data have shown that RSV is associated with a more severe short-term outcome than rhinovirus, whereas rhinovirus more often than RSV is associated with a more severe long-term outcome related to atopic predisposition and with increased risk of developing asthma. In line with this, several randomized clinical trials (RCT) have failed to show any corticosteroid effect in preventing asthma after early-life infection with RSV. In contrast, and as a major finding that in fact have led to this project, researchers in Turku, Finland have previously reported a post hoc analysis of RCT data showing that a short treatment with oral prednisolone during the first wheezing episode caused by rhinovirus, reduced the risk of recurrent wheezing over the next 1 - 7 years. Moreover, in a prospective single-center RCT, the same researchers confirmed that children with high rhinovirus genome load did benefit from systemic corticosteroids by having fewer recurrences during a 12-month follow-up period and 25% less asthma diagnoses during a 1- and 4-year follow-up.16;17 Hence, asthma after RSV may not be prevented by corticosteroids because RSV infected children less often are atopic and less often develop chronic inflammation, whereas early rhinovirus induced wheezing often occur in genetic predisposed and/or atopic children, and therefore asthma development may be prevented by early corticosteroid intervention. These highly clinically relevant findings must be confirmed in an adequately powered multicenter RCT to fully address the clinical significance of corticosteroid intervention. We expect that this trial will be a landmark in demonstrating long-term disease modifying effects of recurrent wheezing and asthma inception.