Precision Medicine in Hymenoptera Venom Allergy: Diagnostics, Biomarkers, and Therapy of Different Endotypes and Phenotypes

Abstract

Allergic reactions to stings of Hymenoptera species may be severe and are potentially fatal deviations of the immunological response observed in healthy individuals. However, venom-specific immunotherapy (VIT) is an immunomodulatory approach able to cure venom allergy in the majority of affected patients. An appropriate therapeutic intervention and the efficacy of VIT not only depend on a conclusive diagnosis, but might also be influenced by the patient-specific manifestation of the disease. As with other diseases, it should be borne in mind that there are different endotypes and phenotypes of venom allergy, each of which require a patient-tailored disease management and treatment scheme. Reviewed here are different endotypes of sting reactions such as IgE-mediated allergy, asymptomatic sensitization or a simultaneous presence of venom allergy and mast cell disorders including particular considerations for diagnosis and therapy. Additionally, phenotypical manifestations of venom allergy, as e.g. differences in age of onset and disease severity, multiple sensitization or patients unsusceptible to therapy, are described. Moreover, biomarkers and diagnostic strategies that might reflect the immunological status of the patient and their value for therapeutic guidance are discussed. Taken together, the increasing knowledge of different disease manifestations in venom hypersensitivity and the growing availability of diagnostic tools open new options for the classification of venom allergy and, hence, for personalized medical approaches and precision medicine in Hymenoptera venom allergy.

Keywords: Hymenoptera venom allergy; allergy diagnosis; biomarkers; immune tolerance; molecular allergology; precision medicine; venom allergen; venom-specific immunotherapy.

Figure 1

Taxonomy of allergy-relevant Hymenoptera. As the taxonomy of the order Hymenoptera is highly complex, only a selection of allergy-relevant taxa is shown. Displayed are exemplary species with particular relevance for Hymenoptera venom allergy.

Figure 2

Endotypes und Phenotypes of reactions to Hymenoptera stings. Depicted are proposed endotypes of reactions to Hymenoptera venoms as well as of proposed phenotypes of IgE-mediated systemic allergic reactions. Additionally, available diagnostic tools and biomarkers for the assessment of the reaction are shown. SRs, systemic reactions.

Figure 3

Diagnostic algorithms for the discrimination of (A) HBV and YJV allergy and (B) YJV and PDV allergy. The diagnostic algorithm presented in (A) can also be used to discriminate between HBV and PDV allergy using the Polistes dominula homologues of Ves v 1 and Ves v 5, Pol d 1 and Pol d 5, respectively. A plus indicates a positive and a minus a negative test result. ¹In the majority of cases, positive PCR results proving the presence of the c-kit D816V mutation in peripheral blood mononuclear cells can confirm systemic mastocytosis (121). ²These allergens are only available for selected multiplex sIgE platforms. ³The HBV allergens Api m 2 and Api m 5 show potential cross-reactivity to not commercially available homologous allergens of YJV and PDV so that a positive test result does not necessarily preclude YJV or PDV allergy. ⁴BAT proved to be an effective tool for the assessment of double-positivity in HBV and YJV allergy (122). However, currently, no studies have analyzed its usefulness for the discrimination of PDV and YJV allergy. BAT, basophil activation test; HBV, honeybee venom; PDV, Polistes dominula venom; REMA score, score of the Spanish Network on Mastocytosis for predicting mast cell clonality and systemic mastocytosis in patients who experience anaphylaxis without cutaneous mastocytosis; VIT, venom-specific immunotherapy; YJV, yellow jacket venom.