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Evaluation and management of insect sting allergy are often not straightforward when there is uncertainty about the history of reaction, the significance of test results, and the risk of severe reaction to future stings. Patients encounter misinformation about the chance of reaction and may have strong beliefs about the need for treatment. Shared decision-making encourages the clinician to listen to the patients' concerns and beliefs, share relevant information and evidence, and partner with patients to incorporate their values and preferences. This review discusses some major decision points in diagnosis and treatment of insect-allergic patients, with attention to the potential burdens or harms that are important to patients and factors that relate to patients' values and preferences concerning the choices they must make. This is especially true in patients with no history of moderate to severe sting anaphylaxis in whom the risk may be overestimated, but it can also be important in patients who underestimate the risk associated with severe sting anaphylaxis. Clinicians should become more knowledgeable about patient-important beliefs and outcomes and engage in shared decision-making to help patients understand and be comfortable with the choices they must make., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Allergen Immunotherapy (AIT) is a well-established, efficient, and safe way to treat respiratory and insect-venom allergies. After determining the diagnosis of the clinically relevant culprit allergen, AIT can be prescribed. However, not all patients are eligible for AIT, since some diseases/conditions represent contraindications to AIT use, as described in several guidelines. Allergists are often preoccupied on whether an extensive workup should be ordered in apparently healthy AIT candidates in order to detect contra-indicated diseases and conditions. These preoccupations often arise from clinical, ethical and legal issues. The aim of this article is to suggest an approach to the workup and assessment of the presence of any underlying diseases/conditions in patients with no case history before the start of AIT. Notably, there is a lack of published studies on the appropriate evaluation of AIT candidates, with no globally accepted guidelines. It appears that Allergists are mostly deciding based on their AIT training, as well as their clinical experience. Guidance is based mainly on experts’ opinions; the suggested preliminary workup can be divided into mandatory and optional testing. The evaluation for possible underlying neoplastic, autoimmune, and cardiovascular diseases, primary and acquired immunodeficiencies and pregnancy, might be helpful but only in subjects for whom the history and clinical examination raise suspicion of these conditions. A workup without any reasonable correlation with potential contraindications is useless. In conclusion, the evaluation of each individual candidate for possible medical conditions should be determined on a case-by-case basis.

Wasp allergy with a diagnostic profile of double sensitizations to vespid venom is a frequent clinical problem in areas where different genera of wasps are present. Identification of the insect responsible for serious reactions poses a diagnostic challenge as the only effective treatment to date is immunotherapy based on the specific venom. In southern Europe, the double sensitization to Vespula and Polistes venoms is highly frequent. It has been shown that the major allergenic proteins (Phospholipase A1 and Antigen 5) share sequences across the different genera and species, which would be the cause of cross-reactivity. Additionally, the minor allergens (Dipeptidyl-peptidases, Vitellogenins) have been found to share partial sequence identity. Furthermore, venom contains other homologous proteins whose allergenic nature still remains to be clarified. The traditional diagnostic tools available are insufficient to discriminate between allergy to Vespula and Polistes in a high number of cases. IgE inhibition is the technique that best identifies the cross-reactivity. When a double sensitization has indeed been shown to exist or great uncertainty surrounds the primary sensitization, therapy with two venoms is advisable to guarantee the safety of the patient. In this case, a strategy involving alternate administration that combines effectiveness with efficiency is possible.

Objectives: Venom immunotherapy (VIT) is an effective treatment method and is addressed to patients with a history of an anaphylactic reaction to Hymenoptera stings. However, the immunological mechanisms of protection have not been explained yet. The objective of this study was to analyze neutrophils, interleukin 8 (IL-8) and interleukin 17 (IL-17) before and after the initial phase of the immunotherapy.Material and Methods: Overall, 40 individuals, including 20 wasp venom sensitized and 20 bee venom sensitized patients, were included in the study. The patients had had a history of severe allergic reactions type III and IV according to Mueller's classification. An ultra-rush VIT protocol was used in this study. The concentration of serum IL-8 and IL-17A was determined using the ELISA enzymatic method.Results: The authors demonstrated a significant rise in the IL-8 level after the immunotherapy, compared to baseline (14.9 vs. 24.7, p < 0.05). The rise in the neutrophils level was also noticeable but proved to be barely out of the range of statistical significance (4.3 vs. 5.0, p = 0.06). The shift in IL-17A was negligent and not statistically significant in the paired samples t-test (1.6 vs. 1.5, p = 0.34).Conclusions: Venom immunotherapy induces neutrophils and IL-8 activity after 2 days. After the desensitization, the level of IL-17A did not change. Int J Occup Med Environ Health. 2020;33(6):811-7. [ABSTRACT FROM AUTHOR]

Introduction: Venom immunotherapy (VIT) is highly effective and the treatment of choice for patients with a history of systemic anaphylactic reactions to a Hymenoptera sting. It has been assumed that VIT protocols with a rapid dose increase during the induction phase are associated with a higher frequency of systemic reactions (SR); however, study data addressing this issue are conflicting. Objective: The aim of this study was to compare the safety of 3 different Hymenoptera VIT protocols (half-day ultra-rush, 3-day rush, 3-week cluster). Methods: This retrospective 2-center study included 143 Hymenoptera venom-allergic patients, who underwent 147 VIT procedures during the years 2015–2018. Twenty cluster, 75 rush, and 52 ultra-rush VIT protocols were performed with honeybee (54 protocols) and wasp (93 protocols) venom. All documented side effects were classified into large local and SR (Ring and Messmer classification). Results: SR were observed during 11 (7.5%) VIT procedures and did not exceed severity grade II. SR occurred more frequently in cluster compared to accelerated protocols. This result was observed for both honeybee (cluster: 25%, rush: 8.7%, and ultra-rush: 15.8%) and wasp VIT (cluster: 12.5%, rush: 0%, and ultra-rush: 6.1%), though the differences were statistically significant only in the wasp VIT subgroup. Honeybee venom elicited more SR than wasp venom (14.8 and 3.2%, respectively, p = 0.01). The risk for SR did not depend on age, sex, concomitant antihypertensive medication, hypertryptasemia, or severity of the index sting reaction. Conclusion: Accelerated VIT protocols, namely, rush and ultra-rush protocols are safe therapeutic options for Hymenoptera venom-allergic patients and displayed fewer SR than cluster VIT protocols in our study. [ABSTRACT FROM AUTHOR]

Purpose of Review: In Hymenoptera venom allergy, the research focus has moved from whole venoms to individual allergenic molecules. Api m 10 (icarapin) has been described as a major allergen of honeybee venom (HBV) with potentially high relevance for diagnostics and therapy of venom allergy. Here, we review recent studies on Api m 10 characteristics as well as its role in component-resolved diagnostics and potential implications for venom-specific immunotherapy (VIT). Recent Findings: Api m 10 is a major allergen of low abundance in HBV. It is an obviously unstable protein of unknown function that exhibits homologs in other insect species. Despite its low abundance in HBV, 35 to 72% of HBV-allergic patients show relevant sensitization to this allergen. Api m 10 is a marker allergen for HBV sensitization, which in many cases can help to identify primary sensitization to HBV and, hence, to discriminate between genuine sensitization and cross-reactivity. Moreover, Api m 10 might support personalized risk stratification in VIT, as dominant sensitization to Api m 10 has been identified as risk factor for treatment failure. This might be of particular importance since Api m 10 is strongly underrepresented in some therapeutic preparations commonly used for VIT. Summary: Although the role of Api m 10 in HBV allergy and tolerance induction during VIT is not fully understood, it certainly is a useful tool to unravel primary sensitization and individual sensitization profiles in component-resolved diagnostics (CRD). Moreover, a potential of Api m 10 to contribute to personalized treatment strategies in HBV allergy is emerging. [ABSTRACT FROM AUTHOR]

Introduction: Venom immunotherapy (VIT) can protect against severe anaphylactic reactions (SR) in 80-100% of subjects allergic to Hymenoptera venom. The mechanisms of induction of immunological tolerance produced by VIT are still little known. It has been shown that VIT modulates Treg activity, Th2 or Th1 cells or both, increases production of IL-10, decreases secretion of IL-13, and causes an IgG4/IgE ratio shift. Aim: To investigate the blood eosinophil count, CCL5/RANTES and IL-17E/IL-25 concentrations before and after the initial phases of the rush protocol of VIT. Material and methods: Forty individuals (14 males, 26 females) of mean age 41.03 ±12.43 years were included in the study. The peripheral eosinophils and the concentration of serum interleukin IL-17E/IL-25 and RANTES were determined before and after the initial phase of VIT. Results: Paired sample t-test revealed that all patients after VIT had significantly higher eosinophil levels compared to the baseline (mean: 0.42 vs. 0.64, p < 0.05). Moreover, in subjects treated with bee venom, RANTES levels proved to rise significantly (51 × 103 vs. 62 × 103, p < 0.05) while IL-17E/IL-25 dropped with near-marginal significance (916 vs. 650, p = 0.069). Conclusions: Our immunological study on the early phase of venom immunotherapy suggested that eosinophils, cytokines such as CCL5/RANTES and IL-17E/IL-25 contribute to the immunological response. [ABSTRACT FROM AUTHOR]

Allergen-specific immunotherapy is the only curative treatment of honeybee venom (HBV) allergy, which is able to protect against further anaphylactic sting reactions. Recent analyses on a molecular level have demonstrated that HBV represents a complex allergen source that contains more relevant major allergens than formerly anticipated. Moreover, allergic patients show very diverse sensitization profiles with the different allergens. HBV-specific immunotherapy is conducted with HBV extracts which are derived from pure venom. The allergen content of these therapeutic extracts might differ due to natural variations of the source material or different down-stream processing strategies of the manufacturers. Since variations of the allergen content of therapeutic HBV extracts might be associated with therapeutic failure, we adressed the component-resolved allergen composition of different therapeutic grade HBV extracts which are approved for immunotherapy in numerous countries. The extracts were analyzed for their content of the major allergens Api m 1, Api m 2, Api m 3, Api m 5 and Api m 10. Using allergen-specific antibodies we were able to demonstrate the underrepresentation of relevant major allergens such as Api m 3, Api m 5 and Api m 10 in particular therapeutic extracts. Taken together, standardization of therapeutic extracts by determination of the total allergenic potency might imply the intrinsic pitfall of losing information about particular major allergens. Moreover, the variable allergen composition of different therapeutic HBV extracts might have an impact on therapy outcome and the clinical management of HBV-allergic patients with specific IgE to particular allergens.

Summary: Background. Bee venom allergy (BVA) can trigger local and systemic allergic reactions, including anaphylaxis. Recently, the molecular sensitization profile has gained importance in the reaction's stratification and venom immunotherapy (VIT). Methods. Retrospective analysis of patients with hypersensitivity to BVA, confirmed by specific sIgE to Apis mellifera ≥0.35 kU/L and/or positive skin tests to bee venom commercial extract, evaluated in specialized consultation. Demographic, clinical, and laboratory data (including molecular Api m 1, 4, and 10) were analyzed, looking for risk factors associated with the severity of the index reaction and reactions during VIT. Results. 93 patients were included (55.9% male; median age of 46 years), 57.3% with atopic comorbidities, and 23.4% with cardiovascular comorbidities. The median specific IgE to Apis mellifera was 6.7 kU/L (IQR 1.0-20.3) kU/L. Regarding the molecular profile, the median IgE to Api m 1 was 0.5 kU/L (57.5% positive out of all measurements); Api m 4 - 0.01 kU/L (11.9% positive), and Api m 10 - 0.3 kU/L (50.0% positive). No patient was monosensitized to Api m 4. The median age of the most severe sting reaction was 36 (IQR 26-48) years, with a median severity (Müeller scale) of 3 (IQR 2-3). Forty-seven patients (50.5%) underwent VIT, with 35.6% of reactions recorded. Allergic reactions during VIT were recorded in 35.6% of cases. The severity of the index reaction correlated positively with older ages (p=0.040; r=0.249), in contrast to monosensitization to Api m 1, which was an independent predictor of milder reactions (p=0.015). Sensitization to Api m 10 was associated with a higher likelihood of reactions during VIT (p=0.038) but potentially less systemic reactions at re-stings (p=0.097). Conclusions. Molecular sensitization profile appears to be relevant not only to the severity of index reactions but also during VIT. Studies of a large cohort of patients with molecular profiles are essential to validate these results and improve the clinical and therapeutic approach to BVA.

Background: Patients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD. Methods: A retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48 months), respectively. Results: During VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re‐stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient‐based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom‐specific IgG4 concentrations increased during VIT (P <.001) although tryptase and IgE were unaltered. Conclusion: Both safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re‐stings. [ABSTRACT FROM AUTHOR]

Introduction: Venom immunotherapy (VIT) is considered to be the gold-standard treatment for patients with Hymenoptera venom allergy. Data regarding VIT in bee venom (BV) allergic patients are scarce. Aim: The aim of this study was to evaluate the outcome of VIT in patients with exclusive BV allergy and to try to define risk factors for VIT-induced systemic reactions (VIT-ISR) and VIT failure. Methods: This is a retrospective study including data from all BV allergic patients that were treated by VIT in the Allergy Unit at the Meir Medical Center in the years 1995–2018. Results: Two hundred and forty-seven patients with exclusive BV allergy were included; 206 (83.4%) preferred to undergo rush buildup. Sixty-nine patients (27.9%) had at least 1 reaction during buildup, with the c-kit mutation being the only significant risk factor (100 vs. 28.9%, p = 0.02). Female gender (25.4 vs. 13.3%, p = 0.04), conventional buildup schedule (26.8 vs. 14.1%, p = 0.04), and c-kit mutation (100 vs. 16.8%, p < 0.01) but not tryptase level were found to be significantly more frequent in recurrent reactors. Females (20.3 vs. 9%, p = 0.03), patients with severe systemic reaction to the index sting (24.3 vs. 9.5%, p = 0.004), and c-kit mutation (66 vs. 12%, p = 0.05) but not tryptase level were found to be risk factors for severe systemic reactions. Conclusion: Despite the considerably high rate of VIT-ISR in patients with exclusive BV allergy, VIT can be performed safely and efficiently. C-kit mutation, and not basal serum tryptase level, seems to be a preferable biomarker for VIT-ISR in these patients. [ABSTRACT FROM AUTHOR]

MicroRNAs are small non-coding molecules playing a significant regulatory role in several allergic diseases. However their role in tolerance induction remains unclear. The aim of this study was to determine the expression of selected microRNAs during the first three months of wasp venom immunotherapy (VIT). 5 adult patients with a history of severe systemic reactions after stinging by wasps and confirmed sensitization were included. Venous blood samples were collected before VIT, 24 hours after completing its initial phase and after 3 months of the maintenance therapy. A control group was comprised of 5 healthy individuals with no history of allergy. In the blood samples expression of 96 microRNAs was determined with the use of microfluidic cards. In a statistical analysis the expression was compared between the study groups as well as between the pre- and post-VIT samples. Significant differences were found between the patients with wasp venom allergy and the healthy controls in the expression of miR-601 and miR-1201 upregulated in allergic patients at every time point (p = 0.04; p = 0.015, respectively). During VIT profile of microRNA was changing with lower expression of 6 microRNAs (including miR-182, miR-342, miR-375) and higher of 11 microRNAs (including let-7d, miR-34b, miR-143). To conclude, VIT has led to some changes in the expression of microRNA associated with Th2-type inflammation and tolerance induction. [ABSTRACT FROM AUTHOR]

• Current allergen immunotherapy approaches are limited by long treatment duration, cost and adverse reactions. • Immune adjuvants may improve efficacy, durability and cost of allergen immunotherapy. • Delta inulin (Advax™) is a well-tolerated and safe carbohydrate-based immune adjuvant. • Jack Jumper ant venom immunotherapy is compatible with Advax adjuvant. • Delta inulin enhances the immunogenicity of Jack Jumper ant venom immunotherapy. A major challenge in broader clinical application of Jack Jumper ant venom immunotherapy (JJA VIT) is the scarcity of ant venom which needs to be manually harvested from wild ants. Adjuvants are commonly used for antigen sparing in other vaccines, and thereby could potentially have major benefits to extend JJA supplies if they were to similarly enhance JJA VIT immunogenicity. The purpose of this study was to evaluate the physicochemical and microbiological stability and murine immunogenicity of low-dose JJA VIT formulated with a novel polysaccharide adjuvant referred to as delta inulin or Advax™. Jack Jumper ant venom (JJAV) protein stability was assessed by UPLC-UV, SDS-PAGE, SDS-PAGE immunoblot, and ELISA inhibition. Diffraction light scattering was used to assess particle size distribution of Advax; pH and benzyl alcohol quantification by UPLC-UV were used to assess the physicochemical stability of JJAV diluent, and endotoxin content and preservative efficacy test was used to investigate the microbiological properties of the adjuvanted VIT formulation. To assess the effect of adjuvant on JJA venom immunogenicity, mice were immunised four times with JJAV alone or formulated with Advax adjuvant. JJA VIT formulated with Advax was found to be physicochemically and microbiologically stable for at least 2 days when stored at 4 and 25 °C with a trend for an increase in allergenic potency observed beyond 2 days of storage. Low-dose JJAV formulated with Advax adjuvant induced significantly higher JJAV-specific IgG than a 5-fold higher dose of JJAV alone, consistent with a powerful allergen-sparing effect. The pharmaceutical data provides important guidance on the formulation, storage and use of JJA VIT formulated with Advax adjuvant, with the murine immunogenicity studies providing a strong rationale for a planned clinical trial to test the ability of Advax adjuvant to achieve 4-fold JJAV dose sparing in JJA-allergic human patients. [ABSTRACT FROM AUTHOR]

Venom allergy may be life-threatening allergic reaction. Systemic allergic reactions occur with a frequency of 7.5% in adults and 3.4% in children. Since the risk of systemic reactions is a constant risk, it is necessary to prevent the continuing availability of symptomatic medications - adrenaline, antihistamines and corticosteroid injectors, which greatly affects the quality of life of a patient. The only form of treatment that effectively reduces the risk of future systemic responses is venom immunotherapy. This paper presents the latest guidelines in the diagnosis and treatment of venom allergy and discusses the efficacy, safety and efficacy of venom immunotherapy. [ABSTRACT FROM AUTHOR]

Venom immunotherapy (VIT) is administered to allergic patients to reduce the risk of dangerous systemic reactions following an insect sting. To better understand the mechanism of this treatment and its impact on the human organism, we analysed serum proteomic patterns obtained at five time-points from Hymenoptera-venom-allergic patients undergoing VIT. For statistical analyses, patients were additionally divided into two groups (high responders and low responders) according to serum sIgG4 levels. VIT was found to be associated with changes in seven proteins: the fibrinogen alpha chain, complement C4-A, complement C3, filamin-B, kininogen-1, myosin-9 and inter-alpha-trypsin inhibitor heavy chain H1. The number of discriminative m/z (mass-to-charge ratio) features increased up to the 90th day of VIT, which may be associated with the development of immunity after the administration of increased venom doses. It may also suggest that during VIT, there may occur processes involved not only in protein synthesis but also in protein degradation (caused by proteolytic venom components). The results are consistent with measured serum sIgG4 levels, which increased from 2.04 mgA/I at baseline to 7.25 mgA/I at 90 days. Moreover, the major proteomic changes were detected separately in the high responder group. This may suggest that changes in protein–peptide profiles reflect the actual response to VIT.

Keywords: hymenoptera venom allergy; real-life stings; venom immunotherapy EN hymenoptera venom allergy real-life stings venom immunotherapy 209 211 3 02/24/21 20210201 NES 210201 To the Editor, It is known that a Hymenoptera sting cannot be avoided with absolute certainty in a patient affected by Hymenoptera venom allergy (HVA). Indeed, for example, it has been established for particular extracts of VIT for honeybees, that the content of the relevant allergens is mainly represented by Api m 1, and the other allergens make up only to 0.6-2% of their dry weight.12 On the other side, it has been shown that honeybee venom, in addition to Api m 1, contains multiple allergens such as Api m 2, Api m 3, Api m 4, Api m 5 and Api m 10. Component-resolved evaluation of the content of major allergens in therapeutic extracts for specific immunotherapy of honeybee venom allergy. [Extracted from the article]

Keywords: allergen extract; switch; tolerability; venom immunotherapy EN allergen extract switch tolerability venom immunotherapy 1800 1802 3 07/14/20 20200701 NES 200701 Throughout Europe, aqueous preparations are generally used for the rapid up-dosing phase of Hymenoptera venom allergen immunotherapy (VIT) and are often substituted with an aluminum adsorbed (so-called "depot") preparation during maintenance treatment. No systemic allergic reactions occurred in the four cohort patients who received both vespid and bee VIT in the up-dosing, when the switch occurred, nor during the maintenance phase. In a systematic literature review, a comparable rate of systemic allergic reactions was found during VIT in aqueous and depot venom allergen extracts in the overall patient population and among patients who underwent vespid VIT. [Extracted from the article]

Background and Objective: The safety profile of venom immunotherapy (VIT) is a relevant issue and considerable differences in safety and efficacy of VIT have been reported. The primary aim of this study was to evaluate the safety of ACE inhibitors and beta-blockers during VIT, which has already been published. For a second analysis, data concerning premedication and venom preparations in relation to systemic adverse events (AE) during the up-dosing phase and the first year of the maintenance phase were evaluated as well as the outcome of field stings and sting challenges., Methods: The study was conducted as an open, prospective, observational, multicenter study. In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients., Results: Premedication with oral antihistamines was taken by 52.1% of patients during the up-dosing and 19.7% of patients during the maintenance phase. Taking antihistamines had no effect on the frequency of systemic AE (p=0.11) but large local reactions (LLR) were less frequently seen (OR: 0.74; 95% CI: 0.58-0.96; p=0.02). Aqueous preparations were preferentially used for up-dosing (73.0%) and depot preparations for the maintenance phase (64.5%). The type of venom preparation neither had an influence on the frequency of systemic AE nor on the effectiveness of VIT (p=0.26 and p=0.80, respectively), while LLR were less frequently seen when depot preparations were used (p<0.001)., Conclusion: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLR but not systemic AE. All venom preparations used were equally effective and did not differ in the frequency of systemic AE.

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Abstract: Background: Currently available tests are unable to distinguish between asymptomatic sensitization and clinically relevant Hymenoptera venom allergy. A reliable serological marker to monitor venom immunotherapy (VIT) does also not exist. Our aim was to find reliable serological markers to predict tolerance to bee and vespid stings. Methods: We included 77 asymptomatically sensitized subjects, 85 allergic patients with acute systemic sting reactions, and 61 allergic patients currently treated with VIT. Levels of sIgE and sIgG4 to bee and vespid venom, rApi m 1, and rVes v 5 were measured immediately after allergic sting reactions or before sting challenges and 4 weeks later. All sting challenges were tolerated. The inhibitory activity was determined using BAT inhibition and ELIFAB assay. Results: Median sIgG4 levels were 96‐fold higher in VIT patients (P < .001) while sIgE/sIgG4 ratios were consistently lower (P < .001). The ELIFAB assay was paralleled by low sIgE/sIgG4 ratios in VIT patients, showing markedly higher allergen‐blocking capacity (P < .001). An almost complete inhibition of the basophil response was seen in all patients treated with vespid venom, but not in those treated with bee venom. Four weeks after the sting, sIgE and sIgG4 levels were increased in allergic and asymptomatically sensitized patients, but not in VIT patients. Conclusion: Immunological responses after stings varied in bee and vespid venom‐allergic patients. In patients under VIT, sIgE and sIgG4 remained completely stable after sting challenges. Monitoring VIT efficacy was only possible in vespid venom allergy, and the sIgG4 threshold for rVes v 5 had the highest sensitivity to confirm tolerance. The BAT inhibition test was the most reliable tool to confirm tolerance on an individual basis. [ABSTRACT FROM AUTHOR]

Abstract: Hymenoptera venom allergy is a potentially life‐threatening allergic reaction following a honeybee, vespid, or ant sting. Systemic‐allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate to severe with a risk of life‐threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H1‐antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence‐based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta‐analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom‐allergic children and adults to prevent further moderate‐to‐severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline autoinjector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence‐based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence. [ABSTRACT FROM AUTHOR]

Introduction: Allergy to Hymenoptera (Apis mellifera, Vespula species, Polistes species, Vespa crabro) venom can be safely and effectively treated by venom immunotherapy (VIT), which in the 40 years since its introduction has been able to prevent reactions to stings, and to treatment as well, though systemic reactions, occasionally severe, are possible. Areas covered: We reviewed the recent literature on VIT by searching in PubMed for the terms ‘venom immunotherapy’ and ‘Hymenoptera venom immunotherapy’ to highlight the current status of VIT and the likely development in the coming years. Expert commentary: VIT, provided the correct choice of the venom and adequate venom preparations and maintenance doses are used, is a treatment of great value in preventing systemic reactions to Hymenoptera stings. A 5-year duration ensures a prolonged tolerance to stings following VIT discontinuation, unless patients suffer from mastocytosis. In fact, due to reports of fatal reactions after stopping VIT, patients with mastocytosis, or with very severe reactions to stings, need an indefinite duration of treatment. [ABSTRACT FROM AUTHOR]

Background: Skin test reactivity to hymenoptera venom and venom-specific IgE are important for diagnosing venom allergy and deciding on the appropriate allergen for venom immunotherapy (VIT). Longitudinal data on skin test reactivity during VIT and their correlation with venom-specific immunoglobulin (Ig)E and IgG are scarce. Methods: We retrospectively analyzed shifts in skin test reactivity and serum levels of venom-specific IgE and IgG in patients allergic to hymenoptera venom before the initiation of VIT with ultrarush therapy and after ≥ 3 years of VIT. Results: Fifty-four patients received ultrarush desensitization and subsequent VIT with wasp venom, 26 with honeybee venom, and 8 with both wasp and honeybee venom. Hymenoptera-specific skin test reactivity decreased during VIT in most patients, and became negative in 8% of the wasp-allergic patients and in 25% of the honeybee-allergic patients. Serum levels of venom-specific IgE positively correlated to skin test reactivity before VIT, but did not change significantly during VIT. ]IgG serum levels and the IgG/IgE ratio increased during VIT in most patients. A high IgG/IgE ratio correlated with low skin test reactivity after ≥ 3 years of VIT. Conclusions: The correlation between a high venom-specific IgG/IgE ratio and low skin test reactivity after VIT may be interesting for future investigations that assess its role as a potential marker for VIT efficacy. [ABSTRACT FROM AUTHOR]

Background An omalizumab treatment and a high maintenance venom dose may both help to prevent recurrent systemic allergic reactions ( SAR) to venom immunotherapy ( VIT). The effectiveness of this combination therapy, however, is unclear. Objective We wanted to explore the possibility whether a temporary treatment with the anti-IgE antibody omalizumab combined with a VIT using an elevated maintenance dose of >100 μg venom may establish a permanent tolerance of maintenance VIT. Methods For this retrospective case series, we scoured our institutional data base for patients who had had an insect venom allergy, and in whom it had not been possible to continue VIT because of repeated unstoppable SAR during maintenance VIT. Patients were divided into those who had received the combination therapy (omalizumab group) and those who had not received omalizumab because its costs could not be covered (controls). Guided by the total IgE level and by body weight, omalizumab had been given subcutaneously 5, 3 and 1 weeks before VIT had been restarted. Three to 6 months after an elevated maintenance dose (200-300 μg venom) had been reached, omalizumab had been stopped. Results Between 2006 and 2011, 15 patients had qualified for an off-label use of omalizumab: 10 patients had received the combination therapy, and 5 patients had remained without such a therapy. The combination therapy leads to a durable tolerance of VIT in all patients even after omalizumab had been discontinued (median of follow-up time 5.8 years, IQR 2.7-8.6 years). Sting challenge tests were tolerated by all of the re-stung omalizumab patients (n = 8). In all controls, VIT had to be stopped permanently due to repeated SARs ( P < .001 vs omalizumab group). Conclusions and Clinical Relevance Combining a temporary omalizumab therapy with an elevated maintenance dose seems a promising approach to achieve a tolerance of treatment in patients with a recurrent SAR to VIT. [ABSTRACT FROM AUTHOR]

Background: Venom immunotherapy (VIT) is considered to be the gold standard treatment for patients with hymenoptera venom allergy. This treatment induces systemic reactions (SR) in a significant number of patients. Objective: To evaluate the outcome of VIT in patients with known risk factors for VIT-induced SR and to compare rush VIT (RVIT) and conventional VIT (CVIT). Methods: All of the patients who received VIT and had at least one of the following risk factors were included: current cardiovascular disease, uncontrolled asthma, high basal serum tryptase, current treatment with β-blockers or angiotensin-converting enzyme inhibitors, and age >70 or <5 years. Results: Sixty-four patients were included, and most of them (52; 81.5%) were allergic exclusively to bee venom. Thirty-five (54.7%) patients underwent RVIT and 29 CVIT. The incidence of patients who developed SR during the build-up phase was similar for RVIT and CVIT (25.7 and 27.5%, respectively; p = 1). However, the incidence of SR per injection was significantly higher in CVIT than in RVIT (5.6 and 2.75%, respectively; p = 0.01). Most reactions (79.1%) were mild, limited to the skin. Most of the patients (92.1%) reached the full maintenance dose of 100 μg. This dose was reached by a significantly larger number of patients receiving RVIT compared to CVIT (100 and 82.7%, respectively; p = 0.01). None of the patients experienced exacerbation of their concurrent chronic disease during VIT. Conclusion: VIT can be performed safely and efficiently in patients with risk factors for immunotherapy. In these patients RVIT appears to be safer and more efficient than CVIT. [ABSTRACT FROM AUTHOR]

Background: Data on the long-term outcome of children after specific venom immunotherapy (VIT) are limited. Therefore, we assessed sting recurrence and anaphylaxis relapse rates as well as adherence to anaphylaxis guidelines with regard to the availability of emergency equipment and education status. Methods: For this long-term survey, data of 311 children with a history of anaphylactic reactions to hymenoptera stings were collected by chart review. We included patients who were treated with a 3-year VIT between 1993 and 2009 and had completed a questionnaire. Results: Forty of the 311 patients were included. Mean VIT duration was 3.1 years. Of the 40 patients included, 29 children (72.5%) received VIT with vespid venom, 9 with bee venom, and 2 patients with both venoms. During a mean follow-up period of 13 years, 20/40 patients (50%) suffered re-stings. Six of the 20 (30%) patients developed again anaphylactic symptoms (grade 1 n = 5, grade 3 n = 1); 2 were allergic to vespid and 4 to bee venom. Of the entire cohort, only 5/40 (12.5%) had appropriate emergency kits according to the guidelines of the European Academy of Allergy and Clinical Immunology. Among the patients who had emergency kits available, one third (5/15) felt uncertain about the correct application of the medication. Less than two thirds of our population (25/40) affirmed that they have been educated in emergency management. The vast majority (95%; 38/40) of our patients did not have allergy follow-ups after VIT completion. Conclusions: Anaphylactic relapses are not uncommon, and there are considerable deficits in the emergency management of patients. Hence, comprehensive standardized anaphylaxis education programs as well as regular follow-ups of the allergy status are crucial. [ABSTRACT FROM AUTHOR]

Introduction: Venom immunotherapy (VIT) is recommended as the first-line treatment for patients allergic to Hymenoptera venom. Aim: To analyze the safety and efficacy of VIT in a real life setting. Material and methods: One hundred and eighty patients undergoing VIT were studied to evaluate the safety, efficacy, incidence and nature of symptoms after field stings and adverse reactions to VIT. Results: Significantly more patients were allergic to wasp than bee venom (146 vs. 34, p < 0.0001). Early and late side effects were more common during the maintenance (48 patients, 26.7%) than during the induction of VIT (32 patients, 17.8%), were more frequent in patients allergic to bees, and were not associated with angiotensin convertase inhibitors (ACEi) or β-adrenergic antagonists use. Systemic reactions were observed in 4 individuals on wasp VIT (2.7%) and in 6 patients allergic to bees (17.65%). The VIT was efficacious as most patients reported no reactions (50%) or reported only mild local reactions (43.75%) to field stings. The decrease in sIgE at completion of VIT correlated with the dose of vaccine received (r = 0.53, p = 0.004). Beekeeping (RR = 29.54, p < 0.0001) and female sex (RR = 1.27, p = 0.033) were associated with a higher risk of venom allergy. Conclusions: Venom immunotherapy is highly efficacious and safe as most of the adverse events during the induction and maintenance phase are mild and local. Side effects of VIT are more common in subjects on bee VIT. Beekeeping and female sex are associated with a higher risk of allergy to Hymenoptera venom. [ABSTRACT FROM AUTHOR]

Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of β-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT., Competing Interests: The conflicts of interest were recorded using the AWMF portal interessenerklaerungonline.de, evaluated by the conflict of interest officer of the DGAKI (for details see the guideline report) and tabulated in accordance with the AWMF. The guideline report and conflict of interest table are available at www.awmf.org/leitlinien/. AbbreviationsAbbreviations.AAIAdrenaline auto-injectorABDWorking Group for Occupational and Environmental Dermatology e.V.AeDAMedical Association of German AllergologistsAITAllergen immunotherapyAWMFAssociation of the Scientific Medical SocietiesbSTBaseline serum tryptase concentrationCCDCross-reactive carbohydrate determinantsDDGGerman Society of DermatologyDELBIGerman Guideline Assessment ToolDGAKIGerman Society for Allergology and Clinical ImmunologyDGHNO-KHCGerman Society of Oto-Rhino-Laryngology, Head and Neck SurgeryDGKJGerman Society of Pediatrics and Adolescent MedicineDGPGerman Respiratory SocietyEAACIEuropean Academy of Allergology and Clinical ImmunologyGPASociety for Pediatric Allergy and Environmental MedicineH1Histamine 1HBHoney beeHIVHuman immunodeficiency virusHVHymenoptera venomHVAHymenoptera venom allergyHVSHymenoptera venom sensitizationHV-sIgEHymenoptera venom-specific IgE antibodiesILInterleukinÖGAIAustrian Society for Allergy and ImmunologySARSystemic allergic reactionssIgESpecific IgE antibodiesVITVenom immunotherapyVVVespid venom Table 1.Participating organizations and delegated representatives. German Respiratory Society (DGP)Dr. Wolfgang Sieber Norbert K. MülleneisenGerman Society for Allergology and Clinical Immunology (DGAKI)Prof. Dr. Margitta Worm Prof. Dr. Knut Brockow Univ.-Prof. Dr. Thilo Jakob Prof. Dr. Bettina Wedi Prof. Dr. Franziska RuëffGerman Society of Dermatology (DDG)Prof. Dr. Ulf Darsow Prof. Dr. Regina Treudler Prof. Dr. Wolfgang Pfützner Dr. Jörg FischerAustrian Society for Allergy and Immunology (ÖGAI)Prof. Dr. Wolfram Hötzenecker Priv.-Doz. Mag. Dr. Stefan WöhrlMedical Association of German Allergists (AeDA)Prof. Dr. Randolf Brehler Prof. Dr. Thomas Fuchs Univ.-Prof. Dr. Hans Merk Prof. Dr. Ludger KlimekGerman Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC)Priv.-Doz. Dr. Adam Chaker Priv.-Doz. Dr. Sven BeckerSociety for Pediatric Allergy and Environmental Medicine (GPA)Dr. Sunhild Gernert Dr. Michael Gerstlauer Dr. Irena NeustädterArbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (Association for Occupational and Environmental Dermatology, ABD)Prof. Dr. Andrea Bauer Prof. Dr. Christoph SkudlikGerman Society for Pediatrics and Adolescent Medicine (DGKJ)Dr. Lars Lange Prof. Dr. Eckhard Hamelmann Table 2.Recommendation strengths. StrengthSyntaxStrong recommendationShallWeak recommendationShouldOpen recommendationCan Table 3.Severity scale for the classification of anaphylactic reactions (according to Ring and Messmer) [7]*. GradeSkin#AbdomenRespiratory tractCardiovascular systemIItch Flush Urticaria Angioedema–––IIItch Flush Urticaria AngioedemaNausea CrampsRhinorrhea Hoarseness DyspneaTachycardia (increase of heart rate ≥ 20/minutes) Hypotension (decrease of systolic blood pressure ≥ 20 mmHg) ArrhythmiaIIIItch Flush Urticaria AngioedemaVomiting DefecationLaryngeal Edema Bronchospasm CyanosisShock Loss of consciousnessIVItch Flush Urticaria AngioedemaVomiting DefecationRespiratory arrestCardiac arrest #Generalized skin symptoms apart from the sting area; *Classification is based on the most severe symptoms encountered (none of the symptoms is obligatory). Box 1.Recommendations on the indication of allergological testing (skin test, IgE detection). Strength of consensus1. If there is a history of a general allergic reaction after a Hymenoptera sting, allergy testing shall be performed.Strong2. Without evidence of a general allergic reaction after Hymenoptera sting(s) („exclusion of insect venom allergy“), no diagnostic procedures should be undertaken.Majority3. If therapeutic consequences are unlikely because of only a mild systemic reaction limited to the skin, allergy testing should be avoided.Majority Table 4.Questionnaire for taking medical history in case of a systemic insect sting reaction. Insect venom allergy questionnaireDatePatient:       female □       male □Weight:       kgHeight:       cmSeverity of reaction1st sting2nd sting3rd stingSymptoms1st sting2nd sting3rd stingSting date (day/month/year)Itching all over the bodyInsectBeeHeat sensationVespulaRash all over the bodyOtherTingling in hands/feetCertainFace swellingUncertainRunny noseLocalization of the stingRedness of the eye conjunctivaInterval until symptom onset (min/h)Lump/tightness in the throatSite and circumstances of the eventCough irritationPhysical effort?Shortness of breathMental stress when reacting?NauseaDid the sting remain in the skin?VomitingOccupation?Urinary (stool) urgency/dischargeOutdoor activities?DizzinessLater tolerated stings?       Yes □       No □Feeling of weakness (circulatory disorder)Beekeeper?       Yes □       No □HeadacheIs there a beekeeper in the neighborhood?       Yes □       No □Unconsciousness (duration)OtherOtherHay fever □       Asthma □       Atopic eczema □Treatment: self/doctorComorbiditiesAdrenalineGlucocorticoidAntihistaminesIntravenous fluidsHospital admissionMedication at reaction (R) or currently (C)Intensive Care UnitRecovery after (hour(s)/day(s)/week(s))Information sheet handed out       Yes □       No □Emergency kit available       Yes □       No □Adrenaline auto-injector (trade name)Other medications: Table 5.Clues about the kind of insect causing the reaction [44]. BeeVespidRather “peaceful” (except at the hive)Rather “aggressive”, sting can also occur in “passing flight”.Main flying season spring to late summer(even on warm winter days!)Main flying season summer until late autumnAfter a sting, the stinger usually remains in the skinSting usually does not remain in the skin (exceptions are possible due to shearing, if the insect was trapped, for example)Occurrence mainly in the vicinity of bee hives, flowers, and cloverOccurrence mainly in the vicinity of food or garbage Table 6.Variables increasing exposure risk. (Hobby) beekeepers, family members and neighbors of beekeepersProfessions such as fruit or bakery seller, forestry worker, gardener, firefighter, farmer, roofer, construction workerIntensive practice of outdoor activities Box 2.Recommendations on the recording of risk factors. Strength of consensus4. Risk factors for an increased sting risk shall be obtained when taking the medical history.Strong5. The medical history shall capture possible risk factors for more severe anaphylaxis.Strong6. If a systemic allergic reaction has not only affected the skin, basic diagnosis for the detection of mastocytosis shall involve a skin inspection to detect mastocytosis of the skin and a determination of basal serum tryptase concentration.Consensus Box 3.Recommendations on the in-vitro diagnostics of sIgE against Hymenoptera venoms and their components. Strength of consensus7. A determination of specific IgE antibodies against bee and/or Vespula venom/components shall be performed; in case of a suspected sting reaction caused by other Hymenoptera, this determination shall be also directed against the corresponding other venom.Strong8. In the case of negative test results obtained shortly (less than 2 weeks) after the sting reaction, the tests shall be repeated (no sooner than 4 – 6 weeks after the sting reaction).Strong9. In case of double sensitization against whole bee and Vespula venom extract, or if an implausible result is suspected, testing of sIgE against recombinant components shall be performed.Strong Box 5.Recommendations on the determination of bST. Strength of consensus12. All patients with anaphylaxis (severity grade ≥ II) after a Hymenoptera sting shall have a determination of bST.Strong13. In case of elevated serum tryptase measured within 24 hours after the acute sting event, a control measurement shall be performed in the symptom-free interval.Strong14. If the bST concentration is permanently elevated (> 20 µg/L), further diagnostic measures shall be performed to clarify mastocytosis.Consensus Box 6.Recommendations on skin tests with Hymenoptera venoms. Strength of consensus15. If an unequivocal diagnosis is obtained by in-vitro diagnostics, a skin test can be omitted.Consensus16. The skin test can be performed as a titrated prick and/or intradermal test.Strong Box 7.Recommendation on sting provocation in adults. Strength of consensus17. Diagnostic sting provocations (before the start of VIT) or sting provocations after completion of VIT shall not be performed.Consensus Box 8.Recommendations on large local sting reactions. Strength of consensus18. Acute treatment can be symptomatic using non-sedating antihistamines, cooling compresses, topical and/or systemic glucocorticoids.Consensus19. Antibiotic therapy for the treatment of non-infectious lymphangitis or lymphadenopathy shall not be performed.Consensus Box 9.Recommendations for long-term care in patients with a history of a large local reaction. Strength of consensus20. VIT shall not be performed for large local reactions.Strong Table 9.Emergency medication for self-treatment in children and adults [43]. Adrenaline auto-injector for intramuscular application, weight-adapted:7.5 – 25 kg BW or 15 – 30 kg BW150 μg*25 – 50 kg BW or 30 – 50 kg BW300 μg*> 50 kg BW300 – 500# – 600# μg– H1 receptor-blocking antihistamine, according to patient age and preference, orally as liquid or (melting) tablet – The dose of the respective antihistamine can be increased off-label up to four times the single dose – For dimetinden drops, a weight-adapted dosage of the IV formulation can be recommended as an oral dose (Table 8)Glucocorticoid, according to patient age and preference, rectally or orally (as liquid or tablet) with 50 – 100 mg prednisolone equivalentIn case of known bronchial asthma or previous reaction with bronchospasm additionally β2-adrenoceptor agonist 2 puffsIf there is a history of laryngeal edema, additionally: inhaled adrenaline preparation with spray head for drug vial (to be specifically requested from pharmacist)Note: An emergency first aid kit should include an anaphylaxis passport with written instructions for use of the components. *According to the respective approval status for the prescribed autoinjector; BW = body weight; #not available in Austria; IV = intravenous. Table 11.Recommendations for prescribing AAIs in patients with insect venom allergy. Absolute indication– Children and adults with mastocytosis and/or elevated basal serum tryptase levels: before, during, and after completion of immunotherapy– Untreated children and adults with more than cutaneous/mucosal SAR (i.e., grade I anaphylaxis) and at high risk of re-exposure– During VIT: in children and adults with more than cutaneous/mucosal SARs (i.e., grade I anaphylaxis) when there are additional risk factors* for non-response to immunotherapy– After completion of regular VIT in children and adults presenting with more than cutaneous/mucosal SAR (i.e., grade I anaphylaxis) and if there are additional risk factors* for non-response to VIT.Relative indication– Long distance to medical care and/or high risk of exposure and/or impaired quality of life– After completion of regular VIT in children and adults with cutaneous/mucosal reactions (grade I) who are at increased risk of exposure and/or have had a short duration of immunotherapy (< 3 years)– Individual patient request*Risk factors in this context are severe insect venom anaphylaxis (grade III or IV), high risk of exposure (e.g., beekeeper), (repeated) systemic reaction under immunotherapy, mastocytosis, or elevated baseline serum tryptase above 20 µg/L . For adults, bee venom allergy is also considered a risk factor. Table 10.Patient information sheet “How to behave in the event of a sting”. – Keep calm! If attacked by bees or wasps, protect the head with arms or clothing. The retreat must not be hectic, but very slow. Insects release pheromones when stinging, which also motivate other insects to sting. Therefore, the sting site should be covered with the hand in the event of a sting.– Try to selectively inform bystanders about the sting event and its possible consequences.– Immediately remove any stinger remaining in the skin. When doing so, do not squeeze the sting apparatus with your fingers, but scrape it away to the side.Emergency medication in case of mild reactions limited to the skin:– If venom-specific immunotherapy has not yet been administered, oral medication is taken immediately after the sting, even in the absence of symptoms, according to the doctor‘s instructions: – Antihistamines – Steroids– After a successful allergen-specific immunotherapy*, medication should only be taken if, contrary to expectations, systemic symptoms do occur. For symptoms limited to the skin, oral medications are used first, and for more extensive reactions, the adrenaline auto-injector is used.Emergency measures in case of shortness of breath, swelling in the mouth/throat region or of circulatory problems:– Inject adrenaline laterally into the lateral thigh– In case of asthma, inhale 2 puffs of the emergency spray– Correct positioning (shortness of breath→ raised upper body, circulatory problems head-down position, unconsciousness→ stable side position)– Take oral medications only if swallowing is possible without problems– Alert an emergency doctor immediately!*Your allergist has confirmed that success of an allergen-specific immunotherapy is highly likely based on a tolerated sting provocation or field sting. Box 10.Recommendations on the emergency kit. Strength of consensus21. In patients with a history of a severity grade I reaction, and in the absence of other risk factors, the prescription of an AAI is not required. However, the AAI can be prescribed in special situations (e.g., high risk of exposure, long distance to medical care, limitation of quality of life).Consensus22. In patients with a history of anaphylaxis (grade II – IV) or of a severity grade I reaction in combination with a high risk of re-exposure, an emergency kit including an AAI shall be prescribed until allergy diagnosis and assessment are complete.Consensus23. After successful initiation of VIT and reaching the maintenance dose at the maintenance interval, the prescription of an AAI can be waived in patients with a history of a systemic sting reaction (severity grade I – II) and in the absence of other risk factors for VIT failure.Consensus24. After successful completion of VIT, the prescription of an AAI can be waived in patients with a history of a systemic sting reaction (severity grade I – II) and in the absence of other risk factors for VIT failure.Consensus25. Patients with grade III or IV anaphylaxis or patients who present with other risk factors for VIT failure shall carry an emergency kit with an AAI during and after VIT. Risk factors include: high risk of exposure (e.g., beekeepers), repeated SAR on immunotherapy, mast cell disease, and/or elevated basal serum tryptase (> 20 µg/L). For adults, bee venom allergy is also considered a risk factor.Consensus Box 11.Recommendation on ACE inhibitors. Recommendation on ACE inhibitorsStrength of consensus26. If there is no firm need for the use of ACE inhibitors and if their switching is straightforward, the drug may be replaced by another medication.Consensus Box 12.Recommendations on the indication of Hymenoptera VIT. Strength of consensus27. VIT shall be performed in patients with a history of an anaphylactic reaction of severity grade ≥ II according to Ring and Messmer, and with evidence of IgE-mediated sensitization to the culprit venom.Strong28. If there is increased exposure, if there are relevant risk factors for a particularly severe anaphylaxis, and/or if quality of life would be significantly impaired without VIT, VIT shall be performed even if there is only a history of an exclusively cutaneous SAR.Strong Table 12.Contraindications of VIT. Uncontrolled asthmaActive malignant neoplastic diseasesSevere active systemic autoimmune diseases and severe immunodeficienciesInsufficient complianceUntreated, chronic infection (e.g., active HIV, viral hepatitis) Box 19.Recommendation on sting provocation. Strength of consensus43. Sting provocation can be performed on a case-by-case basis to verify the success of therapy. Provocation shall only be performed in patients who have reached the planned maintenance dose and tolerate VIT.Strong Table 16.Variables associated with treatment failure/success [59]. Risk factors or predictors of treatment failure– Bee venom > Vespula venom– Repeated systemic allergic reactions while being on VIT– Mastocytosis, increased bSTProtective factors– Higher treatment dose (also double VIT)– Extended treatment time Box 20.Recommendations on the management of systemic allergic sting reactions while being on maintenance therapy. Strength of consensus44. If treatment failure is evident during ACE inhibitor therapy, discontinuation of the ACE inhibitor should be considered.Strong45. If there is evidence of overt therapeutic failure, maintenance venom dose shall be increased in adults to up to 200 µg or above (maximum 400 µg), and in children to up to 200 µg.Strong46. If protection cannot be established by increasing the maintenance dose and if there are co-factors for severe anaphylaxis, co-medication with an IgE antibody (omalizumab; off-label use) should be considered during the relevant insect flight period.Strong Figure 1.Apis mellifera (honey bee).Figure 2.Vespula germanica on ivy.Figure 3.Vespula vulgaris on a plum.Figure 4.Dolichovespula media on the earth.Figure 5.Dolichovespula saxonica.Figure 6.Polistes dominulus while drinking.Figure 7.Vespa crabro (hornet) on a leaf.Figure 8.Bombus hortorum (bumblebee).Figure 9.Stepwise diagnosis using whole venoms (bee venom (BV) and Vespula venom (VV)) and allergen components of bee venom (Api m) and Vespula venom (Ves v).Figure 10.Algorithm for the diagnosis of suspected Hymenoptera venom allergy. Table 7.Allergologically significant components of bee and Vespula venom (http://www.allergome.org). Apis melliferaVespula speciesApi m 1Phospholipase A2a#Ves v 1Phospholipase A1a#Api m 2Hyaluronidasea,b#Ves v 2Hyaluronidasea,bApi m 3Acid phosphatasea#Ves v 3Dipeptidyl peptidasea,b#Api m 4Melittinc#Ves v 5Antigen 5aApi m 5Dipeptidyl peptidasea,b#Ves v 6VitellogeninbApi m 6Protease inhibitorApi m 7CUB Serine ProteaseApi m 8CarboxylesteraseApi m 9Serine carboxypeptidaseApi m 10Icarapinea#Api m 11Gellée royal proteinApi m 12VitellogeninbaMajor allergen: More than 50% of the patients tested show sensitization to the allergen in question; bcross-reacting venom allergens. The sIgE reactivity against bee venom hyaluronidase can be interpreted as a marker for bee venom-specific sensitization. In contrast, sIgE reactivity against Vespula venom hyaluronidase is mainly based on reactivity against cross-reactive carbohydrate determinants; cresearch purposes; #IgE detection kits for single detection are commercially available (singleplex). Table 8.Measures to prevent Hymenoptera stings. – Repellents (chemical insect repellents) do not provide protection.– When being outdoors, avoid eating or drinking food, picking fruits or flowers, staying near waste baskets, trash cans, animal enclosures, or fallen fruit, and using perfume or scented cosmetics. Wash hands and wipe mouth after eating.– Do not drink from bottles or beverage cans, cover drinking glasses, use straws.– Do not scare insects away from food sources, especially not with hectic movements.– Keep skin largely covered by clothing (at least when gardening). Do not walk barefoot, or use open foot wear. When riding a motorcycle, wear gloves and motorcycle clothing close to the skin. Open bicycle helmets are to be provided with a net.– Be especially careful on days with hot and humid weather, as insects are aggressive during such weather.– Avoid wearing loose-fitting, light garments, e.g., loose skirts or dresses with dark colors; try to wear dresses with light colors.– Keep apartment windows closed during the day or secure them with insect nets. No light in the evening when windows are open, as hornets are nocturnal and then prefer to fly towards light sources.– Watch for hidden insects (especially in bed or shoes).– Beehives must be avoided. Nests near a permanent residence must be removed (by beekeeper or fire department).– Wasp traps or repellent sprays can be helpful.– When approached by insects or being near the nest, avoid hectic or flapping movements, pull back slowly! Nests must not be shaken. Do not breathe into a flight hole. Box 4.Recommendations on IgE determination against Hymenoptera venoms and their components. Strength of consensus10. If HVA requiring absolutely necessary treatment is suspected, and if results from IgE detection methods for venom components and whole venom and from skin tests are not conclusive, cellular tests can be performed.Consensus11. Determination of specific IgG antibodies to Hymenoptera venom should not be used to assess the need for treatment of HVA.Consensus Table 13.Schemes* for updosing to 100 µg insect venom. PeriodHymenoptera venom dose in µgDayHourUltra-rushRush (3 days)Cluster100.010.020.020.50.10.04110.080.041.5100.22200.40.082.5400.838023.544.0820100822041004068030802100WeekHour100.210.4200.812404185106207408809100*There are numerous modifications to these updosing schemes in which the maintenance dose of 100 µg can be reached in a shorter or longer time, and which contain even more or fewer intermediate steps. Table 14.Updosing schemes with aqueous Hymenoptera venom [according to Ruëff (scheme 1) or Bauer (scheme 2)] to > 100 µg). Scheme 1Scheme 2DayMinutesDose (µg)Dose (µg)10100100+302040+30306020150100+3020100+30303200 Table 15.Management of repeated systemic allergic reactions to Hymenoptera VIT. 1. Identification (and, where possible, elimination) of risk factors for SARs in VIT.   Drugs    Concomitant inhalant or food allergy    Chronic infection, other general diseases    Physical exertion on the day of injection   Optimization of drug therapy at the reacting organ (for example, an anti-obstructive therapy for asthmatic reactions).2. Adjunctive therapy with H1-blocking antihistamine3. Continued administration of the highest tolerated dose of HV for 3 months, then starting updosing again4. Pretreatment with an anti-IgE antibody (300 mg omalizumab; off-label use): e.g., 5, 3, and 1 week before resuming updosing (> 100 µg maintenance dose if necessary) and subsequent continuation every 4 weeks for 4 – 6 months [134].SAR = systemic allergic reactions; VIT = venom immunotherapy; HV = hymenoptera venom Box 13.Recommendations on contraindications of Hymenoptera VIT. Strength of consensus29. The use of β-blockers and ACE inhibitors are no contraindication of VIT. Patients should be informed about possible interactions.Consensus30. The following contraindications to VIT shall be respected: uncontrolled bronchial asthma, active malignant neoplastic disease, severe active systemic autoimmune disease and severe immunodeficiency (terminal AIDS), inadequate compliance, untreated chronic infection (e.g., active HIV, hepatitis C), pregnancy (for re-initiation)Strong31. In individual cases, VIT may be applied despite the presence of contraindications. This concept shall include a thorough weighing of the benefits and risks. Autoimmune diseases, severe cardiovascular or pulmonary diseases, and malignant diseases shall be optimally treated, shall be in remission before initiation of VIT, and shall be closely monitored during the course of VIT.Strong Box 15.Recommendations on venom selection for Hymenoptera VIT. Strength of consensus34. For VIT, that venom shall be used, which was the culprit venom according patient history and to the results of the allergological work-up.Strong35. If there is double sensitization, if the history of the patient is uncertain with regard to the culprit venom, and if the culprit venom cannot be determined even by additional diagnostic procedures, VIT with both venoms shall be performed.Strong36. If allergy to the venoms of bumblebees or hornets is certain, VIT shall be performed with the related, partly cross-reacting venoms of bees or wasps.Consensus Box 14.Recommendations on the practical implementation of Hymenoptera VIT. Strength of consensus32. The standard maintenance dose of VIT shall be 100 µg of Hymenoptera venom.Strong33. In case of bee venom allergy and increased risk of sting or risk of particularly severe anaphylaxis, starting VIT with a maintenance dose of 200 µg may be considered.Consensus Box 16.Recommendation on the maintenance therapy of Hymenoptera VIT. Strength of consensus37. The maintenance dose should be administered at 4-week intervals in the 1st year and, taking into account the manufacturer’s information, can be administered every 5 – 6 weeks from the 2nd year onwards, depending on the preparation used, and every 8 weeks from the 3rd year onwards if a depot preparation is used.Consensus Box 17.Recommendation on the reduction of side effects in Hymenoptera VIT. Strength of consensus38. A non-sedating antihistamine can be administered as a preventive measure during updosing, which can be continued in the further treatment if required. In case of reactions in the area of the injection site, local cooling measures shall be used.Consensus Box 18.Recommendations on the management of repeated systemic allergic adverse events in Hymenoptera VIT. Strength of consensus39. Possible risk factors of systemic side effects of VIT shall be identified and eliminated as appropriate.Majority40. Concomitant therapy with an H1-blocking antihistamine should be performed. The last tolerated dose should be continued for 3 months and, subsequently, a new updosing should be attempted.Consensus41. If risk factors for systemic side effects are present and cannot be eliminated, and if concomitant therapy with an H1-blocking antihistamine is not effective, concomitant treatment with an anti-IgE antibody (omalizumab; off-label use) should be performed.Majority42. If side effects continue to occur, the last maximum dose that was tolerated should be administered every 4 weeks for 5 years.Consensus Box 21.Recommendations on the duration of Hymenoptera VIT. Strength of consensus47. In the absence of risk factors described below (recommendations 48 and 49), VIT can be discontinued after 3 – 5 years, provided that maintenance therapy has been tolerated without recurrent anaphylactic side effects.Consensus48. Permanent VIT can be considered in patients with, among others, – established mastocytosis, – cardiovascular or respiratory arrest due to Hymenoptera stings – other specific individual constellations indicating an increased individual risk (e.g., hereditary α-tryptasemia)Strong49. If insect exposure time is greatly increased and unavoidable (e.g., occupational), VIT can be given to adults until the end of intensive contact.Consensus, (© Dustri-Verlag Dr. K. Feistle.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: In Hymenoptera venom allergy serologically double-sensitized patients, it is often difficult to identify the culprit insect for venom immunotherapy (VIT)., Objectives: To evaluate if basophil activation tests (BATs) performed not only with venom extracts but additionally with single component-resolved diagnostics could differentiate between sensitized and allergic individuals and how the test results influenced the physicians' decision regarding VIT., Methods: BATs were performed with bee and wasp venom extracts and with single components (Api m 1, Api m 10, Ves v 1, and Ves v 5) in 31 serologically double-sensitized patients., Results: In 28 finally included individuals, 9 BATs were positive and 4 negative for both venoms. Fourteen of 28 BATs showed positive results for wasp venom alone. Two of 10 BATs positive for bee venom were only positive to Api m 1 and 1 of 28 BATs only to Api m 10, but not for whole bee venom extract. Five of 23 BATs positive for wasp venom were only positive for Ves v 5 but negative for wasp venom extract and Ves v 1. Finally, VIT with both insect venoms was recommended in 4 of 28 individuals, with wasp venom alone in 21 of 28 patients and with bee venom alone in 1 of 28. In 2 cases no VIT was recommended., Conclusions: BATs with Ves v 5, followed by Api m 1 and Api m 10, were helpful for the decision for VIT with the clinically relevant insect in 8 of 28 (28.6%) patients. A BAT with components should therefore be additionally carried out in cases with equivocal results., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Diagnosis of Hymenoptera venom allergy (HVA) 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 at risk for severe systemic sting reactions (SSR), and conversely, patients with weakly positive or even negative tests can experience severe SSR. Venom immunotherapy (VIT) is safe, highly effective, and recommended in patients with moderate to severe SSR and in patients with SSR confined to generalized skin symptoms if quality of life is impaired. [ABSTRACT FROM AUTHOR]