CRD and AIT safety:
There are different heterogeneous evidence showing an association of risk factors for adverse events during AIT associated to particular IgE sensitization profiles. The most studied model is grass pollen allergy. Adverse reactions with subcutaneous immunotherapy, both local and systemic, correlate with sensitization progression (Phl p 1+5+12 >Phl p 1+5 > Phl p 1/5)117. In sublingual AIT, adverse events were also related with highest levels of Phl p 5 or Phl p 1 2727 and with allergen sensitivity 118. Under extreme exposure to grass pollen, patients are frequently sensitized to profilin and present severe adverse reactions to foods caused by profilin. Interestingly, this type of these reactions to profilin-containing foods are similar to the infrequent reactions observed during SLIT. This rare phenotype constitutes therefore a unique model to understand disease severity and limits for AIT. Profilin severe reactors undergo extensive oral mucosa damage and present a unique systemic metabolic status that points to T cell proliferation, sustained inflammation and altered repair function. The fact that profilin-sensitized patients in Spain present an enhanced T cell proliferation compared with similar patients from Denmark suggests that progression to severe phenotypes might be linked to an uncontrolled inflammation and T cell proliferation. Interestingly, in the other severity models previously mentioned systemic barrier damage, uncontrolled effector cell response, and altered repair-associated biomarkers have been described. In all cases, might be explained by T cell cross-reactive allergens: Profilin, Ole e 7 (a nsLTP from pollen) and Lep d 2 (a frequent food contaminant inducing reactions in patients with storage mite sensitization).