Die Erstlinientherapie bei einer schweren systemischen allergischen Reaktion (Anaphylaxie) ist die Gabe von Adrenalin, die im Notfall durch Selbstanwendung mit einem Adrenalin-Autoinjektor (AAI) intramuskulär (i. m.) erfolgen kann. AAIs werden trotz bekannten Anaphylaxie-Risikos häufig nicht verordnet, nicht mitgeführt oder im Notfall gar nicht oder mit Verzögerung eingesetzt. Mögliche Motive, den AAI nicht mitzuführen oder einzusetzen, sind logistische Gründe (wie u. a. Größe und Handhabbarkeit des AAI), Schwierigkeiten, die Symptome zu erkennen, die den Einsatz erfordern, mangelnde Vertrautheit mit der Anwendung des AAI und generell die Angst vor Nadeln. Kürzlich wurde in Deutschland ein Nasenspray zur intranasalen Anwendung von Adrenalin zugelassen und in Verkehr gebracht. Die pharmakokinetischen Studien zur Entwicklung dieses Adrenalin-Nasensprays (ANS) im Vergleich zu der i. m. Injektion mit einem AAI oder manuell (Spritze mit Injektionskanüle) ergaben vergleichbare Profile. Die einfache Anwendung, geringe Größe des Nasensprays, die Nadelfreiheit und verbesserte Lagerungsbedingungen des ANS können dazu beitragen, die Barrieren der Adrenalinanwendung, wie sie sowohl für Patientinnen und Patienten und andere Anwendende bis heute bestehen, abzubauen und eine Anaphylaxie rechtzeitig adäquat zu behandeln. Zitierweise: Treudler R, Beyer K, Blümchen K, Gernert S, Gerstlauer M, Hamelmann E, Jakob T, Klimek L, Pfaar O, Ruëff F, Schnadt S, Schönherr M, Seurig S, Vogelberg C, Wieczorek D, Worm M, Wüstenberg E. Treatment of severe allergic reactions and anaphylaxis with an adrenaline nasal spray. Allergo J Int. 2026;35:38-44

The fire ant Solenopsis invicta is an aggressive invasive species whose venom frequently triggers hypersensitivity reactions, including severe anaphylaxis. In endemic regions, its stings represent a significant cause of Hymenoptera-related allergy. Four venom allergens have been identified - phospholipase A1 (Sol i 1), antigen 2 (Sol i 2), antigen 3 (Sol i 3), and antigen 4 (Sol i 4) - with Sol i 3 recognized as the predominant sensitizer. However, the molecular determinants that drive Sol i 3 allergenicity and its potential cross-reactivity with other Hymenoptera venoms remain insufficiently understood. This study identified the linear immunoglobulin E (IgE) epitopes of Sol i 3 and examined their recognition by sera from yellow jacket venom (YJV) - and Polistes wasp-allergic patients. Two linear epitopes were mapped: Sol i 3_e1 (ELRQRVASGKEMRG) and Sol i 3_e2 (WAKTTKIGCGRIMF). Although Sol i 3 exhibits limited sequence and structural similarity to other antigen 5 proteins, it contains a conserved immunoreactive core (WAKTTK), analogous to the WAKTKE motif described for the allergen Poly p 5 from Polybia paulista. This conserved region may represent a shared epitope contributing to cross-reactivity among Hymenoptera venoms. Consistently, sera from P. dominula-sensitized patients and YJV-sensitized patients recognized Sol i 3_e2. These findings define key B-cell epitopes of Sol i 3 and reveal a conserved motif that may underlie cross-reactivity, offering implications for improved diagnosis and immunotherapy.

Insect venoms can cause severe allergic reactions, including anaphylaxis, in sensitized individuals. In this study, we aim at preventing anaphylaxis mediated by the most abundant and dominant honeybee venom allergen phospholipase A2 (Api m 1) by blocking its interaction with allergic patient IgE. Therefore, we characterize selected Api m 1-specific nanobodies and identify two high-affinity binders with non-overlapping epitopes. Crystal structures of Api m 1/nanobody complexes reveal diametrically opposed epitopes, one of which involves the active site of Api m 1. Based on this background, we develop mono- and bispecific nanobody-human IgG1 Fc, which exhibits pronounced blocking of IgE binding and effector cell activation in blood samples from honeybee venom allergic patients and reduces systemic reactions in a mouse model of allergen-induced anaphylaxis. This work provides a rationale for using nanobody-based inhibitors to prevent Api m 1-mediated anaphylaxis in honeybee venom allergy.

Bei der Betreuung allergischer Patienten ist wegen der Komplexität der Beschwerden mit vielfältiger Symptomatik, der unterschiedlichen zugrunde liegenden Immunreaktionen und schließlich der individuellen Spezifität der Auslöser sehr viel mehr hinsichtlich Diagnostik und Therapie zu beachten als bei der üblichen Routineversorgung anderer Krankheiten. Diesem Thema widmet das neue „Weißbuch Allergie in Deutschland“ ein Kapitel, dessen erster Teil hier wiedergegeben wird.

BACKGROUND:Hymenoptera venom allergy (HVA) is a leading cause of anaphylaxis in adults and requires precise diagnostic work-up to guide venom immunotherapy (VIT). However, the high prevalence of asymptomatic sensitization and frequent double sensitization complicate the identification of clinically relevant allergens. MATERIALS AND METHODS:This narrative review summarizes current concepts and recent advances in in vitro diagnostics of HVA, including conventional IgE testing, component-resolved diagnostics (CRD), IgE ratio analysis, and cellular assays and biomarkers for risk stratification. Emphasis is placed on their diagnostic performance, limitations, and clinical applicability. RESULTS:Measurement of venom-specific IgE remains the cornerstone of HVA diagnosis, offering high sensitivity for clinically relevant HVA. CRD using recombinant, CCD-free allergens improves discrimination between primary sensitization and cross-reactivity, particularly in patients with double sensitization to honeybee and yellow jacket venoms. However, incomplete allergen panels, especially in honeybee venom allergy, limit sensitivity. IgE ratio analysis has emerged as a complementary tool to identify the most likely culprit venom, although it may be influenced by recent sting exposure. Cellular assays such as the basophil activation test provide functional information and may support diagnosis in complex cases but are restricted to specialized centers. In addition, biomarkers such as basal serum tryptase and KIT p.D816V mutation are important for risk stratification. CONCLUSION:Modern in vitro diagnostics substantially enhance the precision of HVA diagnosis but cannot replace clinical history. An integrated approach combining serology, molecular diagnostics, ratio analysis and, where appropriate, functional assays, is essential for accurate identification of the relevant venom and optimal patient management.

First-line therapy for a severe allergic reaction (anaphylaxis) is the administration of adrenaline, which, in an emergency, can be self-administered intramuscularly (i.m.) via an adrenaline autoinjector (AAI). Despite the known risk of anaphylaxis, AAIs are often not prescribed, not carried, not used, or used with delay in an emergency. Possible reasons for this include logistical issues (e.g., size and portability of the AAI), difficulties in recognizing symptoms that require the use of an AAI, lack of familiarity with the AAI application, and general fear of injections. Recently, an adrenaline nasal spray (ANS) for intranasal application of adrenaline has been authorized and introduced in Germany. Pharmacokinetic studies for ANS development in comparison with the i.m. injection using an AAI or manual injection (syringe and needle) resulted in comparable profiles. The simple use and small size of the ANS, the needle-free design, and the improved storage conditions can help reduce barriers to adrenaline administration for patients and other users. This may lead to an earlier administration of adrenaline in anaphylaxis treatment.

Hymenoptera venoms are prominent elicitors of systemic IgE-mediated allergic reactions and sometimes fatal anaphylaxis [1]. In Latin America, Hymenoptera stings are one of the major causes of hypersensitive reactions, along with drugs and foods [2]. Despite hosting a wide diversity of clinically relevant insects (bees, ants, and wasps), allergy diagnostics in Brazil is commonly based on non-standardised venom extracts [3]. The use of this type of raw material in clinical practice often compromises identification of the venom responsible for the primary sensitization [4] and the outcome of the immunotherapy. Currently, no venom allergens from Brazilian native species are available for the rational design of component-resolved diagnostics (CRD) [5]. In contrast to European wasps, no recombinant venom allergens from Brazilian Hymenoptera are commercially available as surrogates for venom extracts-based diagnostics, which is often affected by detection of clinically irrelevant cross-reactive IgE, in addition to low sensitivity. Apoica pallens (Hymenoptera, Vespidae) is a clinically relevant Neotropical social wasp commonly found in rural areas, occurring from Mexico to Argentina. Despite causing a high number of sting accidents and IgE-mediated anaphylaxis, A. pallens venom allergy is a neglected human health problem in most Latin American countries, including Brazil [6]. A. pallens nests were collected at São Paulo State University and in surrounding areas, in Rio Claro, São Paulo State, southeast Brazil (SISGEN protocol A0C2FB3). After collection, the insects were immediately frozen, dissected, and the crude venom was extracted. The venom was fractionated thorough a cation exchange chromatography, and the proteins were sequenced and identified by using proteomic shotgun approach, through digestion in solution with trypsin and chymotrypsin. This strategy permitted the unambiguous sequencing of PLA1 and antigen 5, which will appear in the UniProt Knowledgebase under accession codes C0HMC9 and C0HMD0, respectively. Multiple alignment analysis showed high to moderate levels of primary sequence similarity of the PLA1 and antigen 5 with homologous venom proteins from other clinically relevant social wasps. The specific IgE (sIgE) reactivities to these proteins were detected by immunoblotting, using a pool of sera from A. pallens venom allergic patients. The IgE immunoreactivities of purified native PLA1 and antigen 5 were assessed by ELISA. The allergens were incubated with individual sera from patients (n = 22) with a clinical history of allergic reaction to A. pallens venom and sensitization confirmed by UniCAP250 (cutoff i3, sIgE ≤ 0.35 kU/L). Only peptide epitope-based sIgE reactivity was detected, as previously reported for allergens of venoms from Neotropical wasps including A. pallens, which lack cross-reactive carbohydrate determinants (CCD) [7]. Both purified allergens were recognised by the sera of all the sensitised patients (n = 22). All the sera also presented reactivity to A. pallens crude venom (Figure 1A). PLA1 and antigen 5 are unique marker allergens with no homologues in HBV. As expected, there was no detected cross-reactivity of PLA1 and antigen 5 with sera from HBV mono-sensitised patients (Figure 1B), suggesting that they could be valuable novel diagnostic tools for distinguishing wasp venom from Apid sensitizations during routine diagnostics in Brazil [5]. These results strongly suggested that the combined use of the novel allergens would provide high diagnostic sensitivity. Finally, investigation was made of the peptide-based cross-reactivity among these allergens and their homologues in Polistes dominula, the European paper wasp. Consistent with results obtained previously for venom PLA1 of the Brazilian paper wasp P. paulista (Pol p 1) [8], extensive peptide-based cross-reactivity was detected in ELISA for PLA1 and antigen 5 with sera from Polistes sensitised patients (Figure 1C). Due to the features reported above, the WHO/IUIS Allergen Nomenclature Sub-Committee considered both proteins as novel allergens from the venom of the social wasp A. pallens. Hence, as allergens, PLA1 was officially named Apo p 1 (https://www.allergen.org/viewallergen.php?aid=1160), while antigen 5 was named Apo p 5 (https://www.allergen.org/viewallergen.php?aid=1161). Venom allergens from clinically relevant Brazilian native wasps remain largely unexplored. To date, only the major components from P. paulista wasp venom (Pol p 1, Pol p 2, and Pol p 5) have been officially annotated as wasp venom allergens [9]. Therefore, given the lack of data on A. pallens allergenic venom compounds, a comprehensive biochemical and immunological characterisation was performed for the Apo p 1 and Apo p 5 as novel venom allergens. To our knowledge, this represents the first conclusive evidence of extensive cross-reaction among homologous allergens from major elicitors of wasp venom allergy in Europe and Latin America. The high levels of similarity of the primary sequences and the 3-D structural models of Apo p 1 and Apo p 5 with their counterparts in PDV and P. paulista (Hymenoptera: Vespidae), suggest the common linear and conformational peptide epitopes as the structural basis for the cross-reactivity detected among members of the Polistinae subfamily. The high levels of diagnostic sensitivity of Pol d 1 and Pol d 5 for the detection of A. pallens sensitization indicates that they may potentially be used as surrogates for venom extracts in routine IgE testing. Hence, Apo p 1 and Apo p 5 are novel candidates for the development of molecular diagnostics of A. pallens venom allergy, which could enable better rationale for therapeutic decisions regarding Brazilian allergic patients. A detailed description of the methods and results is available at: https://osf.io/fmsyc/?view_only=3a1a76cf7b614e07b8dc1cf74dcb0f7d. Amilcar Perez-Riverol: Formal analysis, investigation, methodology, writing – review and editing. Gabriel Hideki Izuka Moraes: Investigation, methodology. José Roberto Aparecido dos Santos-Pinto: Supervision, validation, writing – review and editing. Luis Gustavo Romani Fernandes: Formal analysis, investigation, methodology, writing – review and editing. Alexis Musacchio Lasa: Investigation and Methodology. Brita Dorn: Formal analysis, investigation, methodology, writing – review and editing. Maria Beatrice Biló: Resources, validation, writing – review and editing. Ricardo de Lima Zollner: Resources, supervision, validation, writing – review and editing. Thilo Jakob: Resources, supervision, validation, writing – review and editing. Mario Sergio Palma: Resources, supervision, validation, writing – review and editing. The authors declare no conflicts of interest. The data that supports the findings of this study are available in the supporting information of this article.

Background: Venom immunotherapy (VIT) and natural exposure to Hymenoptera venom induce immune tolerance in allergic patients and beekeepers, respectively. Specific IgE (sIgE) and IgG4 (sIgG4) antibodies play crucial roles in allergic reactions and immune tolerance. Objective: To investigate the dynamics of sIgE and sIgG4 responses to Hymenoptera venom in patients undergoing VIT and in nonallergic beekeepers at a component-resolved level. Methods: Serum samples from patients allergic to honeybee venom (HBV) or yellow jacket venom (YJV) and from beekeepers were collected during the first year of VIT and before and after the beekeeping season, respectively. sIgE and sIgG4 levels to whole venom and molecular allergens were measured using the ImmunoCAP platform. Results: Pronounced sIgE and sIgG4 responses to Ves v 1 and 5 in YJV-allergic patients were accompanied by more frequent sensitization to Ves v 1 after up-dosing. While sIgE profiles in HBV-allergic patients were highly diverse, with a marked contribution of Api m 1 and Api m 10 sIgE, the sIgG4 response during VIT was strongly dominated by Api m 1. Different VIT preparations did not significantly affect the sIgG4 response to low-abundance HBV allergens. In beekeepers, induction of sIgG4 was dependent on sting frequency and was dominated by Api m 1. Conclusion: Robust induction of IgG4 during VIT and natural venom exposure occurs primarily to abundant allergens and is unaffected by the choice of VIT preparation. The effectiveness of VIT and beekeepers' tolerance to HBV indicate that strong sIgG4 responses to lowabundance allergens are not crucial for immune tolerance.