Risk factors for severe sting reactions and side effects during venom immunotherapy.

Understanding the risk factors leading to severe systemic sting reactions (SSR) is crucial for initiating venom immunotherapy (VIT) and for educating affected individuals and their families. Some of these risk factors are well-established, some are no longer considered risk factors, and some remain controversial. Well-established risk factors for severe SSR include clonal mast cell disease, high baseline serum tryptase, and advanced age. The absence of skin symptoms and the rapid onset of symptoms are indicators of severe SSR. Recent publications indicate that antihypertensive treatment and stings in the head and neck area are not risk factors for severe SSR. VIT is the only available treatment that can potentially prevent further anaphylactic reactions. Although rare and generally manageable, individuals undergoing VIT may experience systemic adverse events (sAE). More sAE are expected in patients undergoing bee VIT compared to vespid VIT. The role of elevated baseline serum tryptase as a risk factor for sAE remains debated, but if it is a factor, the risk is increased by only about 1.5-fold. Rapid up-dosing protocols, depending on the specific regimen, can also be associated with more sAE. Severe initial SSR, antihypertensive medication, high skin test reactivity, and high specific IgE levels are not risk factors for sAE.

Diagnostic measures in patients with severe insect sting reactions and elevated baseline serum tryptase levels.

Mastocytosis or an elevated basal serum tryptase (bST) level are known risk factors for patients with insect venom allergy. We report on 3 patients with a history of severe anaphylactic insect sting reactions who underwent a detailed workup for insect venom allergy before starting venom immunotherapy. In addition to insect venom sensitization, an elevated concentration of bST (15.5, 20.8, and 23.2 µg/L) was found in all cases. There was no evidence of mastocytosis in the skin (MIS). Further testing revealed hereditary α-hypertryptasemia (HαT) in 2 patients and a D816V mutation by liquid biopsy in 1 patient, which is a minor diagnostic criterion for indolent systemic mastocytosis. Even without iliac crest puncture, causes of elevated bST can be narrowed down with minimally invasive diagnostic measures. As this has practical implications, patients with elevated bST should always undergo further work-up to determine the cause of this abnormal finding.

Basophil activation test in Hymenoptera venom allergy.

Before starting venom-specific immunotherapy (VIT), systemic sting reactions to Hymenoptera venoms require allergological workup in order to prove an IgE-mediated reaction and to identify the culprit insect venom. In addition to skin tests and the determination of specific IgE antibodies, the basophil activation test (BAT) using flow cytometry has emerged as a powerful tool and sensitive marker for this purpose in recent years. BAT seems to have a better informative value in terms of clinical relevance compared to the other tests. In Hymenoptera venom allergies, BAT is particularly useful for the diagnosis of cases with unclear or contradictory history and sensitization profile. Its results are associated with adverse reactions during VIT and efficacy of VIT and therefore have a certain predictive value for side effects and treatment failure of VIT. In research, it is mainly used to characterize the allergenic components of Hymenoptera venoms. This review article focuses on these topics.

Stinging Ant Anaphylaxis: Advances in Diagnosis and Treatment.

Stinging ants represent a wide range of over 200 different species across the world, of which Solenopsis, Myrmecia, Pogonomyrmex, and Brachyponera genera account for a substantial economic and healthcare burden. S. invicta (red imported fire ant [IFA]) and M. pilosula (jack jumper ant [JJA]) are 2 species of high clinical importance, known to cause anaphylaxis in humans, with numerous reported fatalities. Diagnostic testing should be performed in patients with a history of a systemic reaction with skin testing and/or in vitro specific immunoglobulin E (IgE) testing. In vitro testing is commercially available for IFA through whole-body extract specific IgE and JJA venom-specific IgE, but not widely available for other stinging ant species. Commercial venom component testing for IFA and JJA is currently not available. Patients with a clinical history and positive specific IgE testing should undergo treatment with specific immunotherapy, which is currently available for IFA and JJA. Buildup may be performed using conventional, semi-rush, rush, or ultra-rush schedules with similar risk profiles for IFA. Optimal duration for whole=body extract immunotherapy for IFA and specific JJA venom immunotherapy is not well studied, but generally recommended for at least 3 to 5 years. Sting challenges are used in research settings, primarily to assess treatment efficacy of immunotherapy.

The role of basophil activation test in venom immunotherapy: comparative evaluation with specific IgE and skin prick tests, innovative approaches.

Summary: Background. In diagnosing insect venom allergy and making immunotherapy decisions, clinical history, skin tests, and specific serum IgE levels are commonly utilized. This study aims to emphasize the clinical significance of using the basophil activation test in accurately identifying sensitivities in individuals with insect venom allergy and to compare its effectiveness with other testing methods. Methods. This study included a total of 43 patients, who experienced at least one systemic allergic reaction following insect stings and were deemed suitable for immunotherapy.Basophil activation test, specific serum IgE levels, and skin prick test results utilized in making immunotherapy treatment decisions were recorded. Results. Our study determined that the overall clinical sensitivities of the basophil activation test (BAT), specific serum IgE (spIgE), and skin prick test (SPT) for apis mellifera were 95.5%, 95.7%, and 48.4% respectively, while for vespula vulgaris, they were 83.3%, 100%, and 33.3%. Based on these results, the prediction of systemic reactions to bee stings is ordered as spIgE > BAT > SPT. Additionally, early-stage skin prick tests showed a sensitivity of 67% and specificity of 50% at a cut-off value of 1.5 mm, and 33% sensitivity and 83% specificity at 2.5 mm. Conclusions. This study demonstrates that the basophil activation test (BAT) can provide a high positive predictive value in immunotherapy treatment decisions and offer significant insights in clinical practices.

Should Patients With a Large Local Reaction be Offered Venom Immunotherapy? A Pro-Con Debate.

Insect stings can cause large local reactions (LLRs) that are IgE-mediated and associated with considerable morbidity. A risk for systemic reactions including anaphylaxis to subsequent stings has been reported and is often noted by patients and health care providers. Guidelines do not recommend venom immunotherapy (VIT) for LLRs based on the relatively low risk of anaphylaxis, but this is debated in this review. On the pro side: the risk of anaphylaxis may be higher than reported in the limited literature, especially in patients who had only 1 LLR; new species with more potent stings are spreading into new areas; the quality of life can be markedly impaired by LLRs; and VIT is generally safe and highly effective. On the con side: LLRs are benign, stings occur infrequently, VIT has significant cost, systemic reactions occur more often to VIT than to stings in patients with LLRs, and Food and Drug Administration approval and published guidelines do not recommend VIT for LLRs. In practice, shared decision-making is appropriate to incorporate knowledge of the natural history and known high-risk factors in the context of the patient's personal values and preferences.

Anaphylaxis in Practice: A Guide to the 2023 Practice Parameter Update.

This review summarizes new research developments and clinical practice recommendations for the diagnosis and management of anaphylaxis presented in the Joint Task Force on Practice Parameters 2023 Anaphylaxis practice parameter Update. It is intended to serve as a high-level summary of the 2023 practice parameter, which makes clinically impactful recommendations based on evidence that has emerged since the 2015 practice parameter. We invite clinicians to explore the full 2023 practice parameter to understand the research methods and underlying evidence that have informed the recommendations summarized here. There are new and evolving diagnostic criteria for anaphylaxis, rules for defining elevated tryptase levels, and recognition of signs and symptoms particular to infants and toddlers. The administration of epinephrine should not be used as a surrogate to diagnose anaphylaxis. Risk factors for anaphylaxis should be assessed on a case-by-case basis. Patient counseling and shared decision-making are essential to support patients' treatment decisions and capacity to manage the risk of anaphylaxis at home and in other community settings. Activation of emergency medical services after home epinephrine administration may not be required in all cases, and patients should be engaged in shared decision-making to determine when home management may be appropriate.

Shared Decision-Making in Insect Sting Allergy: To Bee or Not to Bee?

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.

Venom Immunotherapy Does Not Affect Survival of Patients with Malignant Tumor in Poland.

Background: Allergen immunotherapy (AIT) is a well-established and efficient method of causative treatment for allergic rhinitis, asthma and insect venom allergy. Traditionally, a recent history of malignant neoplasm is regarded as a contraindication to AIT due to concerns that AIT might stimulate tumor growth. However, there are no data confirming that the silencing of the Th2 response affects prognosis in cancer. Objectives: The aim of this study was to investigate frequency of malignant tumors in patients undergoing AIT and the association between AIT and cancer-related mortality. Patients and Methods: A group of 2577 patients with insect venom allergy undergoing AIT in 10 Polish allergology centers was screened in the Polish National Cancer Registry. Data on cancer type, diagnosis time and patients' survival were collected and compared with the general population. Results: In the study group, 86 cases of malignancies were found in 85 patients (3.3% of the group). The most common were breast (19 cases), lung (9 cases), skin (8 cases), colon and prostate cancers (5 cases each). There were 21 cases diagnosed before AIT, 38 during and 27 after completing AIT. Laplace's crude incidence rate was 159.5/100,000/year (general population rate: 260/100,000/year). During follow-up, 13 deaths related to cancer were revealed (15% of patients with cancer). Laplace's cancer mortality rate was 37.3/100,000/year (general population rate: 136.8/100,000/year). Conclusions: Malignancy was found in patients undergoing immunotherapy less often than in the general population. Patients with cancer diagnosed during or after AIT did not show a lower survival rate, which suggests that AIT does not affect the prognosis.

Safety and Efficacy of VIT against Wasp Venom in Ultra-Rush Protocols in Patients Older Than 60 Years.

BACKGROUND: Allergen immunotherapy remains a widely recognized and widely used method for the treatment of selected allergic diseases. Currently, according to the European Academy Of Allergy and Clinical Immunology (EAACI) guidelines, venom immunotherapy (VIT) may be considered for patients over 60. Nevertheless, no separate studies have confirmed the efficacy and safety of this therapy. This study aimed to evaluate the short-term effectiveness of VIT against wasp allergens in an ultra-rush protocol for older patients compared to young patients. METHODS: Among the 113 patients included in this study, 51 were older than 60 years (Group A), and 62 formed the control "young group" (age range: 18-35 years). All patients were desensitized to wasp venom using the ultra-rush protocol according to Muller and aqueous solutions of vaccines containing wasp venom. A basophil activation test (Basotest, Orpegen Pharma, Germany) and intracutaneous tests with dilutions of wasp allergen and specific IgE to extract wasp venom were performed at the start and after six months of VIT. The safety of VIT was assessed on the basis of the international Mueller scale. RESULTS: One hundred and eleven patients with confirmed wasp allergies completed six months of VIT: 51 participants over 60 years of age (Group A) and 60 young people (Group B). No systemic adverse reactions were observed during the VIT induction phase. However, large local reactions were noted in 17% of older patients and 20% of young patients at a similar level (p > 0.05). During maintenance VIT, two mild grade I systemic reactions were confirmed in young patients. These symptoms resolved spontaneously. There were no such reactions in older patients. The effectiveness of VIT was tested using BAT. There was a statistically significant reduction in CD63 reactivity in 86% of patients in Group A, and a comparable and substantial decrease in 84% of young patients in Group B. According to the BAT test, the mean reductions in the area under the curve (AUC) after six months of VIT were significant (p < 0.05) and comparable between Groups A and B: -6.52 vs. 7.21. CONCLUSIONS: VIT against wasp venom is safe and effective in short-term observation, and is comparable to that used for young patients.

Venom Hypersensitivity.

Stinging insects are a frequent cause of local and systemic hypersensitivity reactions, including anaphylaxis. For those with a history of life-threatening anaphylaxis, venom immunotherapy is effective, safe, and can be life-saving. Arachnids are a much less common source of envenomation through bites or stings and are less likely to cause a hypersensitivity reaction. However, recognizing the clinical manifestations when they do present is important for accurate diagnosis and treatment, and, when indicated, consideration of other diagnoses.

Hymenoptera Venom Immunotherapy Meets Factitious Disorder.

Factitious disorder on self is a psychiatric disorder in which individuals fabricate or induce signs or symptoms of a disease. Factitious anaphylaxis, with symptoms suggestive of a life-threatening allergic reaction, is extremely rare. Several cases of factitious disorder reactions during allergen immunotherapy for airborne allergens have been reported. We report the case of a young female patient who presented factitious anaphylaxis during venom immunotherapy to vespid venom extract. Symptoms of stridor, dyspnea, coughing and loss of consciousness were observed during the built-up phase of venom immunotherapy, mimicking allergic reactions to the venom extracts. Diagnosis of factitious disorder prompted the discontinuation of venom immunotherapy.

Blood Transcriptomics Identifies Multiple Gene Expression Pathways Associated with the Clinical Efficacy of Hymenoptera Venom Immunotherapy.

Allergen-specific venom immunotherapy (VIT) is a well-established therapy for Hymenoptera venom allergy (HVA). However, the precise mechanism underlying its clinical effect remains uncertain. Our study aimed to identify the molecular mechanisms associated with VIT efficiency. We prospectively included 19 patients with HVA undergoing VIT (sampled before the beginning of VIT, after reaching the maintenance dose, one year after finishing VIT, and after a sting challenge) and 9 healthy controls. RNA sequencing of whole blood was performed on an Illumina sequencing platform. Longitudinal transcriptomic profiling revealed the importance of the inhibition of the NFκB pathway and the downregulation of DUX4 transcripts for the early protection and induction of tolerance after finishing VIT. Furthermore, successful treatment was associated with inhibiting Th2, Th17, and macrophage alternative signalling pathways in synergy with the inhibition of the PPAR pathway and further silencing of the Th2 response. The immune system became activated when reaching the maintenance dose and was suppressed after finishing VIT. Finally, successful VIT restores the immune system's balance to a state similar to that of healthy individuals. Our results underline the important role of the inhibition of four pathways in the clinical effect of VIT: Th2, Th17, NFκB, and macrophage signalling. Two biomarkers specific for successful VIT, regardless of the time of sampling, were C4BPA and RPS10-NUDT3 and should be further tested as potential biomarkers.

Evaluation of the Cytokine Response Induced by Specific Allergen Immunotherapy in Patients with Vespa velutina Anaphylaxis.

INTRODUCTION: Changes in the cytokine profile from type 2 to type 1 together with the induction of regulatory cells are expected during hymenoptera venom immunotherapy (VIT). The present study was aimed to investigate the changes in type 1, type 2, and regulatory cytokines induced by a Vespula spp. VIT in patients with anaphylaxis to Vespa velutina. METHODS: Twenty consecutive patients with anaphylaxis due to Vespa velutina were treated with Vespula spp. VIT. Serum cytokines (IL-4, IL-5, IL-10, IL-13, and IFN-É£) were measured at baseline, 6, and 12 months after starting VIT. RESULTS: A significant increase in serum IFN-y was detected after 6 and 12 months of VIT. An increase in serum IL-10 and a decrease in IL-5 were observed after 12 months. IL-4 was undetectable all along the study, and an unexpected increase of IL-13 was present at 12 months of treatment. CONCLUSION: Vespula spp. VIT seems to be able to induce a shift to type 1 cytokine production measured through IFN-y levels and IL-10 production after, at least, 6 and 12 months of VIT, respectively.

Molecular profiling in bee venom allergy: clinical and therapeutic characterization in a Portuguese cohort.

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.

Real-Life Adherence to Venom Immunotherapy and Adrenaline Autoinjector.

INTRODUCTION: Venom immunotherapy (VIT) and adrenaline autoinjector (AAI) are important therapies in venom anaphylaxis. Adherence to VIT and AAI in patients with venom allergy has been evaluated in a few studies; however, solid data are lacking. This study aimed to evaluate VIT and AAI retrieval rates in patients with venom allergy with a special focus on adherence to treatment. Adherence was compared to subcutaneous immunotherapy (SCIT) with inhalant allergens. METHODS: This was a retrospective study among patients registered for allergen immunotherapy at the Allergy Center, Odense University Hospital, Denmark, from January 1, 2010, to December 31, 2014. Data on purchased immunotherapy and AAI were obtained from the Danish National Health Service Prescription Database. Multivariable logistic regression was used to analyze if allergen, age, sex, mastocytosis, and treatment site affected adherence. RESULTS: The 3-year adherence to VIT was 92.4% (244/264) compared to 87.4% (215/246) in SCIT with inhalant allergens, and the 5-year adherence to VIT was 84.1% (222/264) compared to 74.8% (184/246) in SCIT with inhalant allergens (p = 0.045). Females treated with VIT were more adherent than males (p = 0.45 [3-year], p = 0.008 [5-year]), whereas allergen, age, mastocytosis, or treatment site did not significantly affect adherence. Only 28.6% of patients (12/42) purchased an AAI after premature termination of VIT. CONCLUSION: In this register-based study, we found that the 3- and 5-year adherences to VIT and SCIT with inhalant allergens are at the upper end of the spectrum hitherto reported. Patients' 5-year adherence to VIT was higher than patients' 5-year adherence to SCIT with inhalant allergens. If VIT was prematurely terminated, less than 1/3 would have purchased an AAI.

Influencing factors on the safety and effectiveness of venom immunotherapy.

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.

Fatal Hymenoptera Venom-Triggered Anaphylaxis in Patients with Unrecognized Clonal Mast Cell Disorder-Is Mastocytosis to Blame?

Hymenoptera venom-triggered anaphylaxis (HVA) affects up to 8.9% of the general population and is the most frequent cause of anaphylaxis in adults, accounting for approximately 20% of all fatal anaphylaxis cases. Quite often, a fatal reaction is a victim's first manifestation of HVA. Mastocytosis represents one of the most important risk factors for severe HVA. We analyzed patients with documented fatal HVA for the presence of underlying clonal mast cell disorder (cMCD). Here, we report three cases of fatal HVA, with undiagnosed underlying cMCD identified by the presence of the peripheral blood and/or bone marrow KIT p.D816V missense variant postmortem. In the first case, anaphylaxis was the initial episode and was fatal. In the other two cases, both patients were treated with specific venom immunotherapy (VIT), nevertheless, one died of HVA after VIT discontinuation, and the other during VIT; both patients had cardiovascular comorbidities and were taking beta-blockers and/or ACE inhibitors. Our results point to the importance of screening all high-risk individuals for underlying cMCD using highly sensitive molecular methods for peripheral blood KIT p.D816V variant detection, including severe HVA and possibly beekeepers, for proper management and the need for lifelong VIT to prevent unnecessary deaths. Patients at the highest risk of fatal HVA, with concomitant cardiovascular and cMCD comorbidities, might not be protected from field stings even during regular VIT. Therefore, two adrenaline autoinjectors and lifelong VIT, and possibly cotreatment with omalizumab, should be considered for high-risk patients to prevent fatal HVA episodes.

Hymenoptera Venom Immunotherapy in Dogs: Safety and Clinical Efficacy.

Hymenoptera allergens are the main triggers for anaphylaxis in susceptible dogs and humans. Hymenoptera venom specific immunotherapy (VIT), the only disease-modifying treatment, has the potential to prevent future life-threatening reactions in human patients. Prospective clinical data on VIT efficacy in dogs are currently lacking. Therefore, the aim of this study was to show that VIT is not only safe but also efficacious in preventing anaphylaxis in dogs allergic to Hymenoptera. This uncontrolled prospective clinical trial included 10 client-owned dogs with a history of anaphylaxis following repeated Hymenoptera stings. The sensitization to bee and wasp allergens was demonstrated by intradermal testing (IDT) and allergen-specific IgE serology. For VIT induction (induction phase), dogs received a shortened rush immunotherapy protocol with aqueous allergens, which was then followed by monthly injections of 100 µg of alum-precipitated allergen (maintenance phase). VIT efficacy was determined by observing patients' clinical reactions to re-stings. No systemic adverse events were seen during the induction and maintenance phases. From the seven re-stung dogs, only one developed a mild angioedema at the site of the sting; the remaining dogs were asymptomatic. These results show that VIT represents a safe and effective treatment option for Hymenoptera-allergic dogs.

Diagnosis and treatment of Hymenoptera venom allergy: S2k Guideline of the German Society of Allergology and Clinical Immunology (DGAKI) in collaboration with the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (ABD), the Medical Association of German Allergologists (AeDA), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNOKC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Allergy and Environmental Medicine (GPA), German Respiratory Society (DGP), and the Austrian Society for Allergy and Immunology (ÖGAI).

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 ß-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.