In this study, we longitudinally assessed the developmental relationships between allergic sensitization and virus-induced wheezing from infancy to 6 years of age, reasoning that the time sequence of these events in early life would provide information about the direction of causality. We have demonstrated that sensitization to aeroallergens, beginning in the first year of life, consistently predisposes children to viral wheezing illnesses. The reverse was not true; we found no evidence that outpatient virus-induced wheezing illnesses increased the risk of sensitization to aeroallergens in subsequent years. Finally, there was evidence of virus specificity, in that allergic sensitization specifically increased the risk of wheezing with HRV but not RSV infections.
This relationship between allergic sensitization and HRV wheezing could be explained by a common underlying susceptibility to both conditions or by a causal relationship. In support of a common underlying predisposition, low IFN-γ responses during early life have been associated with greater risk of early childhood wheeze and allergy (12
). Furthermore, impaired innate immune responses have been associated with allergy and asthma (15
). However, our data regarding the directionality of the observed relationship between allergic sensitization and HRV-wheezing illness demonstrate that the former is significantly more likely to precede the development of the latter.
A number of underlying mechanisms by which allergic sensitization increases the risk of HRV-induced wheezing have been proposed. Recent work has suggested that interactions between innate and allergic inflammatory mechanisms may lead to more severe viral illnesses in allergic individuals (17
). In addition, ongoing allergic inflammation in the airways may directly lead to impairment of the epithelial cell barrier and antiviral response. For example, goblet cells, commonly found in the airways of individuals with allergic asthma, were recently reported to be particularly susceptible to HRV infection (18
). Finally, allergic inflammation may directly inhibit host antiviral responses. Gill and colleagues found that increased expression and cross-linking of the high-affinity IgE receptors on plasmacytoid dendritic cells impaired production of IFN-α to influenza infection in vitro
). This counterregulation between IgE and antiviral responses could lead to increased severity of viral illnesses in allergic individuals. In support of this potential mechanism, a recent clinical trial by Busse and colleagues demonstrated that omalizumab, a monoclonal anti-IgE antibody that down-regulates high-affinity IgE receptor expression on plasmacytoid dendritic cells and other cell types (20
), was effective in preventing virus-induced asthma exacerbations in a highly allergic inner-city population (21
Our findings that early life wheezing illnesses did not lead to subsequent aeroallergen sensitization differ from the Sigurs study, which showed that severe RSV bronchiolitis was associated with increased risk of sensitization at school age (6
). This may reflect differences in the population because the COAST children were nearly all outpatients, whereas Sigurs and colleagues studied children who were hospitalized with bronchiolitis. However, the rates of sensitization in the control group in the Sigurs study were low compared with the general population, and other groups have been unable to replicate these findings (22
The strengths of our study include the meticulous characterization of viral respiratory illnesses during the preschool years, with virus detection rates of 90% during wheezing illnesses (1
). In addition, annual assessment of allergen-specific IgE allowed comprehensive and repeated assessments of transitions in our four-state model. We specifically chose to focus on sensitization to aeroallergens, rather than foods, because this is a stronger risk factor than food sensitization for asthma inception (1
), and, from a physiologic perspective, responses to respiratory allergens would be expected to affect the risk of wheeze more than responses to food protein. A limitation of our study is that allergic sensitization was not assessed until 1 year of age, whereas wheezing episodes were assessed continuously from birth. However, only about 10% of the cohort developed allergic sensitization by 1 year of age, suggesting that assessment of sensitization earlier during infancy would not have provided much additional information. Another potential limitation of our study is that COAST is a high-risk cohort; however, about one half of the cohort did not develop allergic sensitization by 6 years of age, providing a large nonallergic population for comparison.
In summary, using a longitudinal model in a well characterized birth cohort, we have clearly demonstrated that allergic sensitization increases the risk for HRV wheezing and that the converse is not true. When considered together with plausible mechanisms for allergic sensitization to inhibit antiviral responses, this sequential relationship supports a causal role for allergic sensitization in this developmental pathway. To definitively prove causality, one would need to prevent or modify allergic sensitization in early life and demonstrate lower risk of subsequent HRV wheezing illnesses. Allergen avoidance strategies have not led to reductions in sensitization (24
); therefore, novel strategies aimed at the prevention of allergic sensitization are needed. This is an important goal given the close relationship between HRV wheezing illnesses in early life and the subsequent development of asthma (1