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].