Multimorbidity
The term multimorbidity is used to indicate the clustering and
co-occurrence of different diseases in an individual, where,
conceptually, a “primary” disease in not obvious [42].
Epidemiological data suggest that rhinitis/rhinoconjunctivitis, asthma
and dermatitis form a multimorbidity cluster, attributed to shared
genetic polymorphisms and pathogenetic mechanisms [43]. The MeDALL
(Mechanisms of the Development of ALLergy) project, including more than
12.000 children from 12 ongoing longitudinal cohort studies, clearly
showed that co-existence of asthma, rhinitis and eczema in the same
child is more prevalent than expected by chance [44]. IgE (poly)
sensitization was acknowledged as a fundamental component of a specific
phenotypical presentation, although not the sole one, significantly
associated with disease severity and multimorbidity risk [45].
Moreover, prospective studies indicate that either sensitization per se,
or early polysensitization and co-sensitization to both perennial and
seasonal allergens, or to furry animals and molds, in case of sole
perennial sensitization, are associated with enhanced likelihood of AR
patients to present other allergy-associated diseases [46, 47];
however, it is well accepted that a significant proportion of children
with IgE sensitization do not develop any allergy-associated disease
[48]. In line, molecular studies identified eosinophilic-mediated
pathways, including IL-4 and GATA3-related signals, with their
respective induced proteins as prominent mediators in allergic
multimorbidity [49]; nevertheless, more recently other cell types
and pathways have also been implicated in the AR-multimorbidity such as
TLR and IL-1 mediated responses [50]. In respect to the implicated
genes, several independent risk variants are identified with allergic
diseases specific effects have been identified, potentially by
dysregulating the expression of lymphocyte-mediated immunity [51]. A
recent meta-analysis of worldwide asthma-genome associations studies,
verified two loci (8q21.13 and 16p13.13) implicated in the comorbidity
of asthma and AR [52].
In respect to allergy-associated disease progression, the MAS study
showed that parental history of allergy and broad polymolecular IgE
sensitization is a risk factor for presenting allergic multimorbidity
later in life [53]. From another perspective, AR combined with
ocular and skin allergic diseases is strongly associated with asthma
occurrence in adulthood, although this association wanes with age
[54]. Sex and puberty-related mechanisms are thought to be related
in the “sex shift” prevalence, from male to female predominance after
puberty, of allergic multimorbidity, as shown from individual
participant data (IPD) meta-analyses in the MeDALL and other cohorts
[55]. Of importance, patients with allergic multimorbidity present
increased disease burden, drug and healthcare use and costs in all age
groups [56].