Interpretation
We show that children with more severe, early-onset AD before age 1 year have an increased risk for developing sensitization to aeroallergens and allergic rhinitis compared to children with onset of AD after age 1 year. This is in agreement with some previous studies23–26 as most studies found higher frequencies of allergy outcomes in early-onset vs. late-onset AD27,28, whereas one study found no difference29 and two other studies only found a higher risk if children with early-onset also had persistent AD30,31. Further, the latter study found an increased risk of sensitization to aeroallergens at 18 years among children with late-onset AD31.
The varying findings in these previous studies can be due to several factors. Importantly, the severity of AD in early life seems to be the most important factor according to our study but was not assessed in previous studies. Also, the diagnosis of AD and allergic rhinitis was mostly based on questionnaires, and the evaluation of allergy outcomes was done at different time-points across the studies ranging from 4 to 18 years. Only one other study diagnosed sensitization and allergic rhinitis at several time points31, but with low complete follow-up rates of 52% at 7 years, 40% at 12 years and 39% at 18 years, in contrast to a follow-up rate of 71% at 7 years and 86% at 12 years in our study. None of the previous studies assessed AD severity, which showed significantly different effects in early-onset vs. late-onset in relation to both aeroallergen sensitization and allergic rhinitis.
The possible mechanisms driving the association between AD and respiratory allergy have previously been explained by an underlying Th2-skewed immune system10,32, which leads to an increased risk of both AD, asthma and allergic rhinitis. An inherent genetic susceptibility may also influence the risk of developing all three diseases. Thus, a GWAS study identified shared AD, asthma, and allergic rhinitis immune-related genetic variants, suggesting that these disorders may co-exist because they share genetic risk loci that result in dysregulation of immune-related genes33. However, this does not explain the mechanism behind age at onset and severity of AD and development of aeroallergen sensitization and allergic rhinitis.
More recently, the hypothesis explaining the association between AD and allergy has shifted to include a primary defect in the epidermal barrier in AD34. The epidermis provides an essential barrier to the external environment, preventing both water loss from the body and intrusion of infectious agents and allergens. When allergens are captured and pro­cessed by antigen-presenting Langerhans cells of the epidermis, they migrate to the draining lymph nodes and if not down-regulated, they can inter­act with naïve T cells to promote Th2 immunity leading to allergies35. This epicutaneous sensitization has also been proposed to cause migration of Th2 memory cells from the skin to the bronchial lymphoid tissue, where subsequent inhalation of the sensitizing allergen causes a cellular and humoral response in the airways, resulting in symptoms of allergic rhinitis and asthma10. Finally, it has been proposed that chronic AD lesions may express thymic stromal lymphopoietin and other proinflammatory mediators, which increase the risk of developing allergic inflammation and sensitization in the lungs36.
Our study also showed a trend of higher risk of developing allergic rhinitis with increasing SCORAD among children with a FLGmutation compared to children without a mutation. Indeed, FLGmutation is known to lead to an impaired skin barrier, which is a plausible mechanistic explanation of the observed associations. To our knowledge no previous studies have investigated the role of FLGmutations in the relationship between AD age at onset, severity, and development of respiratory allergy. Our results should be interpreted with caution due to low numbers, and it would be interesting to investigate this association in a larger-scale study.
To ensure that early-onset AD was not present with concomitant allergic sensitization, and that reverse causation is not driving our results, we investigated early allergic sensitization at age 6 months. However, only 2 children were sensitized to an aeroallergen at this point - one from the early-onset AD group and one who never developed AD, so that is not likely to alter our results.
Our study suggests programming in early life and that appropriate early interventions may hamper the progression of AD to aeroallergen sensitization and allergic rhinitis, especially in children with early-onset, more severe disease and FLG mutation. Following such thoughts, early strengthening of the epidermal barrier in high-risk infants using emollients before the onset of AD has been hypothesized to prevent development of AD and subsequent respiratory allergy, but this could not be demonstrated in two recent randomized controlled trials37,38.
To prevent development of aeroallergen sensitization and allergic rhinitis in children with early-onset, severe AD, an alternative possible effective intervention may reside in modulating the immune response through manipulation of the route of earliest encounter with the allergen, along the same lines as has been shown with food allergens. Thus, early environmental exposure through the skin may lead to sensitization whereas early oral exposure may led to tolerance6–8 by stimulating regulatory T-cells induction and function in the gut39. A murine study has supported this hypothesis40, and two human studies have tested this hypothesis in children using a sublingual immunotherapy mixture of house dust mite, cat and grass41 or house dust mite alone42,43. The studies failed to show any effect on development of allergic sensitization, which was also less influenced by early-onset and severity of AD in our study compared to allergic rhinitis, i.e., clinically relevant sensitization. Further, they had some weaknesses including high drop-out rates, lack of compliance, the children being too old at the beginning of the study, difficulty taking the sublingual immunotherapy correctly, and difficulty identifying children at high risk for developing AD. To establish whether early sublingual exposure to aeroallergens can prevent development of sensitization and allergic rhinitis in children with early-onset, severe AD, randomized controlled trials taking all these factors into account are needed.