An algorithm for the diagnosis and treatment of Hymenoptera venom allergy, 2024 update

Hymenoptera venom allergy (HVA) exhibits a wide range of symptoms, which can be mild, such as skin symptoms, and extend to life-threatening reactions like unconsciousness and cardiac arrest. Diagnosis is straightforward in the majority of patients, but can be challenging in double positive and test negative patients. Test results sometimes can be confusing as patients with high skin test reactivity and high specific IgE (sIgE) levels are not necessarily at risk for severe systemic sting reactions (SSR), and conversely, patients with weakly positive or even negative tests can experience severe SSR. Patients should be trained to properly use the emergency kit in case of another sting reaction. However, all patients with moderate to severe reactions should receive venom immunotherapy (VIT) as it is safe and highly effective. VIT can also be considered for patients with generalized skin symptoms if their quality of life is significantly impaired. HVA is the most common cause of anaphylaxis in adults in Europe.1 The main clinical presentations are large local reactions (LLR) at the sting site and SSR. A large local reaction has been defined as a swelling exceeding a diameter of 10 cm that lasts for longer than 24 h.2 SSR can range in severity. Mild reactions include generalized skin symptoms such as urticaria, angioedema, or flushing. Examples of moderate SSRs include laryngeal dyspnea, nausea, dizziness, and a drop in blood pressure. Anaphylactic shock, loss of consciousness, and/or cardiac or respiratory arrest all define a severe SSR. The clinical history of the reaction(s), skin testing, and detection of sIgE to venom preparations are still the mainstays of the diagnostic procedure in cases of HVA. Molecular allergy diagnosis in HVA is still evolving and currently of limited use. Some relevant cross-reactive bee and vespid allergens such as Api m 12 as well as Ves v 3 and 6 are still unavailable for routine diagnosis. Moreover, sensitivity of the available bee venom allergen panel (Api m 1, 2, 3, 5, and 10), and particularly of Api m 1 is low with 72%3 and 57%–62%,4, 5 respectively. The basophil activation test (BAT) has been shown to be a useful test in double positive6, 7 or negative patients.8 However, the BAT should be performed within 2 days after blood collection and requires special technical skills because the assay is not automated. Therefore, it is still not widely used. IgE inhibition assays are easier to perform and can be helpful to distinguish between cross-reactivity and true double sensitization,9, 10 even though CAP inhibition presents pitfalls in terms of technical procedure and expenditure.11 To identify patients at high risk for severe SSR, usually the basal serum tryptase is assessed. Recent data indicate that elevated tryptase levels predominantly arise from the presence of KIT p.D816 mutation and α-tryptasemia.12 Importantly, 196 of 285 (69%) patients with the KIT p.D816 mutation had normal tryptase levels.13 These data suggest that in addition to tryptase determination, patients should be examined for KIT p.D816V, using a highly sensitive allele-specific PCR test to diagnose clonal mast cell disorders. Available tests and approaches to solving diagnostic problems are provided in Figure 1. The only treatment that can potentially prevent further SSR is VIT, which is reported to be effective in 77%–84% of patients treated with honeybee venom, and in 91%–96% of patients receiving vespid venom.14 The EAACI guidelines on VIT were published in 2018.14 It aimed to provide evidence-based recommendations for the use of VIT. In brief, VIT is indicated in children and adults with detectable sensitization and SSR that exceeds generalized skin symptoms. VIT is also recommended in adult patients with SSR confined to generalized skin symptoms if quality of life is impaired. In patients with recurrent, troublesome LLR it can be considered to reduce the duration and size of future LLR. Since the publication of the guidelines, there has been an influx of data that aids in facilitating VIT procedures: After decades of debate, it has been conclusively demonstrated in an European multicenter study that the use of β-blockers or ACE inhibitors neither escalates the occurrence of systemic adverse events during VIT nor exacerbates SSR. Furthermore, these medications do not compromise the effectiveness of VIT.15 In the context of dual VIT with bee and vespid venom, simultaneous injection of both venoms has also been proven to be safe in a large case series.16 The treatment algorithm in Figure 2 is based on the recommendations of the guidelines. Adapted treatment algorithm based on EAACI guidelines on venom immunotherapy14. *Consider special conditions: Cardiovascular and organ specific autoimmune diseases must be stable; ACE inhibitor and/or beta- blocker therapy can be continued;15 VIT contraindications: acute malignant disease, multisystem autoimmune disease, children <5 years, pregnancy, VIT can also be performed in high risk venom- allergic patients with remission of a malignant disease and children <5 years, when child is likely to be cooperative. In children, treatment over 3–5 years may be sufficient. #Reasons for lifelong VIT (major risk factors for relapse):14 highly exposed patients with bee venom allergy, patients with very severe initial sting reactions, patients with systemic side- effects during VIT LLR, large local reaction; QoL, Quality of life; SSR, systemic sting reaction; VIT, venom immunotherapy. Dr. Arzt-Gradwohl has nothing to disclose. Dr. Sturm reports grants from ALK-Abelló, personal fees from ALK-Abelló, personal fees from Allergopharma, personal fees from Novartis, and personal fees from Stallergenes-Greer, outside the submitted work.