Rhinoviruses have been implicated in the development of wheeze that evokes childhood asthma. Johnston et al. [
13] identified RVs induce two thirds of upper respiratory viral infections in children (ages 9–11) with cough/wheeze through a community based longitudinal study. Similarly, RVs were detected in 33% of nasopharyngeal aspirates in children hospitalized for wheezing. In the same study, RV-positive cases were associated with development of asthma (OR = 4.14) while RV-negative cases were not [
80]. Notably, it was reported that ~ 90% of children with RV wheezing illness in the third year had developed asthma by the sixth year [
64]. The COAST birth cohort study revealed a significant role of RVs in pediatric wheezing illness and development of asthma [
81‐
84]. RV was associated with asthma at 13 years as well as significantly reduced lung function measures compared to measures observed with exposure to other respiratory viruses. In another high-risk cohort study, a statistically significant association between wheezy lower respiratory infection by RV and current asthma, persistent wheeze, and current wheeze was reported [
85]. Recently, findings from a meta-analysis confirmed a possible association between RV-induced wheeze in the first 3 years and development of wheeze or asthma [
86]. Other factors may co-influence the association between RV and the inception of asthma. Lukkarinen and colleagues studied 127 steroid-naive children with a first episode of wheeze [
87]. Subjects were enrolled around 11 months of age and re-evaluated for asthma at age 7 years. The authors found that 37 of these children maintained an asthma diagnosis and were atopic at the follow-up. The risk factors discovered at study enrollment for future atopic asthma included allergic sensitization (OR 12;
p < 0.001), eczema (OR 4.8;
p = 0.014), and wheezing with rhinovirus (OR 5.0;
p = 0.035). Although the above studies provide strong evidence for a relationship between RV and the development of wheeze/asthma, it was not possible to determine whether RV-induced wheezing precipitates asthma. While the causation relationship is a possibility, another plausible hypothesis is that RV-induced wheeze in infancy is only a sign of predisposition to development of asthma.
Atopy, RV, and wheezing
Atopy is a risk factor that has been implicated in the development of RV-induced exacerbations of asthma. A positive association between IgE sensitization and RV wheezing illness in hospitalized wheezing children was found [
88]. In another study, RV-infected children sensitized to allergens exhibited higher odds of wheezing compared to controls [
20]. A genetic predisposition toward developing wheeze leading to asthma has also been impugned. A susceptibility locus on the 17q21 chromosome in COAST and COPSAC cohorts was discovered [
89]. The 17q21 genotypes were found to have significant association with children with RV wheezing illness but not with those without RV wheezing illness. Interestingly, previous studies (genome-wide association studies in particular) have identified the locus in the 17q21 chromosome to be linked to the development of asthma [
90,
91]. However, since the birth cohort study encompassed subjects of primarily European descent, the findings may not be applicable to the general population. Bochkov et al. [
47] similarly identified an asthma susceptibility gene product in CDHR3 and proposed that the Tyr
529 variant at rs6967330 (rs6967330-A) in the
CDHR3 gene is a potential risk factor for RV-C wheezing illness. The COPSAC
2010 and COAST birth cohorts confirmed the association of the rs6967330-A variant with respiratory episodes with RV-C detection [
92]. The 1000 Genomes Projects found rs6967330-A to be most predominant in African populations [
92], which report high asthma incidence and morbidity [
93].