4.2 Interpretation
We confirmed that eczema presence represents a risk factor for FA, as shown previously.13-16 Further, we demonstrated associations between eczema presence and presence of asthma and hay fever, reflecting findings from other studies.13,17,18Associations between eczema phenotypes and FA, asthma and hay fever presence revealed, that all phenotypes, especially the persistent ones, had significantly higher risks of developing subsequent allergic disease when compared to the “Never eczema” group. Other studies also reported that persistent eczema was associated with the development of FA19 as well as asthma and hay fever.8,20 Further, our results suggest that, the age at eczema onset plays an important role in allergic multimorbidity. Earlier onset of eczema showed a stronger association with FA, asthma and hay fever presence, with “Very early onset” showing higher aOR’s (adjusted Odds Ratio) than “Early onset” and “Late onset”. These findings agree with similar reports, showing eczema onset before 2 years of age to be associated with development of FA, asthma and hay fever.20-22 Onset of eczema in the first 2 months has even been reported to have the strongest association with development of FA by age 3.23
Taken together, our findings suggest that individuals with disease onset before 6 months and persistent eczema are at highest risk for developing allergic multimorbidity during childhood and adolescence. This supports our hypothesis that this subpopulation might be at highest risk for sensitization against food or inhalant allergens before allergen tolerance developed. The higher likelihood of allergen sensitization and subsequent development of FA, asthma and hay fever in patients with eczema can be, at least partially, attributed to impairment of the skin’s barrier function 24,25. The dual allergen exposure hypothesis suggests that, regarding FA, the oral consumption of allergenic foods promotes immune tolerance, whereas exposure to food allergens on the skin (before oral tolerance could develop), is more likely to lead to epicutaneous sensitization through allergen penetration and cytokine dysregulation. This applies especially, but not exclusively, to eczematous skin.4,24,26For asthma and hay fever, evidence regarding epicutaneous sensitization with inhalant allergens is still limited.6,27Although, it has been reported that likelihood for inhalant allergen sensitization is higher in children with eczema, due to increased skin permeability, even when skin barrier parameters were measured on non-lesional skin. The same study described a correlation between allergy score (cumulative skin-prick-test results) and eczema duration.28 The dual allergen exposure hypothesis has gained traction throughout the last decade and resulted in a change in management from allergen avoidance strategies towards early dietary introduction of allergenic foods, aiming for tolerance induction.29 It is important to note, that the clinical manifestation of eczema is no driving factor for the development of FA, but rather represents a symptom indicating an underlying epithelial barrier dysfunction.30 Thus, restoring barrier function represents a promising preventative strategy for allergic multimorbidity in children with eczema.31,32 However, specific interventions for preventing allergic diseases, like the use of emollients, have not proven to be successful yet.33Still, those who experience the longest duration of skin barrier impairment, like our “Very early onset – persistent” phenotype, may benefit the most from early eczema prevention and treatment. It would be crucial to find a method or biomarker to identify this subpopulation as early as possible.
The atopic trajectories for eczema, asthma and hay fever, we presented in our cohort, closely resemble the typical trajectory of the atopic march across all FA presence groups.5 Early peaks of eczema prevalence around the age of 2 years, followed by peaks of asthma prevalence around 5.5 years and peaks of hay fever prevalence around 10 years of age. However, multiple findings have challenged the idea of the strict sequence suggested in the atopic march, which originally stems from epidemiological studies focusing on cumulative trajectories in large cohorts. When profiles of eczema, asthma (wheeze) and hay fever (rhinitis) are analyzed based on individuals, the developmental trajectories display greater heterogeneity.34,35 In one investigation the identified group closest to the atopic march only covered about 7 % of children who observed symptoms.34 Another study reported early-life eczema representing the largest risk factor for allergic multimorbidity, but it only led to multimorbidity in about 25 % of cases.35Thus, the paradigm of the strictly sequential atopic march needs to be reconsidered and focus should lie on identifying those at highest risk for multimorbidity in early life.