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.