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BackgroundLong-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking.ObjectivesWe conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae.MethodsParticipants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method.ResultsFifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index

Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus‐based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug‐specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti‐inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory. [ABSTRACT FROM AUTHOR]

Background: In recent years, skin reactions secondary to the use of medical devices (MD), such as allergic contact dermatitis have increasingly been observed (e.g. to continuous blood sugar monitoring systems, insulin pumps, wound dressings, medical gloves, etc.): this is regarded as a developing epidemic. Lack of labelling of the composition of MD, as well as frequent lack of cooperation of manufacturers to disclose this relevant information, even when contacted by the clinician for the individual case of an established adverse reaction, significantly impede patient care. Objectives: To advocate for full ingredient labelling in the implementation of EU regulation for MD. Methods: This position paper reviews the scientific literature, the current regulatory framework adopted for MD to date, and the likely impact, including some costs data in case of the absence of such labelling. Results: Efforts made by several scientific teams, who are trying to identify the culprit of such adverse effects, either via asking for cooperation from companies, or using costly chemical analyses of MD, can only partly, and with considerable delay, compensate for the absence of meaningful information on the composition of MD; hence, patient management is compromised. Indeed, without knowing the chemical substances present, physicians are unable to inform patients about which substances they should avoid, and which alternative MD may be suitable/tolerated. Conclusion: There is an urgent need for full and accurate labelling of the chemical composition of MD in contact with the human body. [ABSTRACT FROM AUTHOR]

Background: Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects., Objectives: To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression., Methods: This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability., Results: Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R., Conclusions: This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU., Competing Interests: Conflicts of interest E.G. was an advisor for Novartis. M. Metz is or recently was a speaker and/or advisor for Amgen, AstraZeneca, argenx, Celldex, Escient, Jasper Therapeutics, Novartis, Pharvaris, Sanofi-Aventis and Third Harmonic Bio. S.A. is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Allakos, Biocryst, CSL Behring, Phavaris, Sanofi, Takeda, ThermoFisher, Moxie and Novartis. A.B. is or has recently been a speaker/advisor/investigator and/or received research funding from AbbVie, Almirall, Amgen, AstraZeneca, Biofrontera, Blueberry Therapeutics, Celldex, Centogene, Galderma, Genentech, Gilead, Incyte, LEO Pharma, Lilly, L’Oréal, Novartis, Sanofi, Regeneron and Shire/Takeda. L.L. has received consulting fees/medical writing/direction strategy fees from Regeneron, Celldex, Gossomer Bio, Kenjockety, Gamida Cell, Arvelle Therapeutics, Sun Pharma, Halozyme, UCARE and Noema Pharma. K.B. is or recently was a speaker and/or advisor for AstraZeneca, Novartis, Biomarin, Synlab, Blueprint, ThermoFisher, Bencard and ALK. G.H. declares grants from Deutsche Forschungsgemeinschaft (DFG) and personal fees from Allergopharma, Biotest, Eli Lilly, Sanofi, AbbVie and Leti outside the submitted work. K.K.S., T.H. and O.E.S. are employees of LEO Pharma. M. Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Alvotech, Amgen, Aquestive, Aralez, AstraZeneca, Astria, Bayer, BioCryst, Blueprint, Celldex, Celltrion, Centogene, CSL Behring, Evoemmune, GSK, Ipsen, Kalvista, Kyowa Kirin, LEO Pharma, Lilly, Menarini, Mitsubishi Tanabe Pharma, Moxie, Noucor, Novartis, Orion Biotechnoloy, Pharvaris, Resonance Medicine, Sanofi/Regeneron, Septerna, Takeda, Teva, Trial Form Support International AB, Third HarmonicBio, Valenza Bio, Yuhan Corporation and Zurabio., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: EU Commission Regulation 2017/1410 prohibits using atranol and chloroatranol, the main allergens in Evernia prunastri (oakmoss), and hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) in cosmetic products. Oakmoss absolute is contained in fragrance mix (FM) I and HICC in FM II which are patch tested as screening mixtures in the baseline series., Objective: To describe the time trends of reaction frequencies to both FMs as well as to their components in FM-positive patients., Methods: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2012-2021., Results: Positive reactions to FM I (FM II) declined from 9.1% (4.7%) in 2012 to 4.6% (3.0%) in 2021. Full breakdown tests were performed in 24% (FM I) and 31% (FM II), respectively, of the mix-positive patients. From this data, frequencies of sensitization to the 14 single fragrances of FM I and FM II were calculated. For the majority, a decline was noted from 2012/2013 to 2020/2021, for oakmoss absolute 1.9%-0.8% and for HICC 1.8%-0.9%., Conclusion: EU Commission Regulation 2017/1410 was an effective measure. However, our data have some limitations, possibly causing underestimation of sensitization frequencies to fragrances., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Flow cytometry-based basophil activation tests (BAT) have been performed with various modifications, differing in the use of distinct identification and activation markers. Established tests use liquid reagents while a new development involves the use of tubes with dried antibody reagents. The aim of this pilot study was to compare these two techniques in patients with insect venom allergy., Methods: Seventeen patients with an insect venom allergy were included in the study. The established "BAT 1" utilizes conventional antibody solutions of anti-CCR3 for basophil identification and anti-CD63 to assess basophil activation, whereas "BAT 2" uses dried anti-CD45, anti-CD3, anti-CRTH2, anti-203c and anti-CD63 for identification and activation measurement of basophils. Negative and positive controls as well as incubations with honey bee venom and yellow jacket venom at three concentrations were performed., Results: Seven patients had to be excluded due to low basophil counts, high values in negative controls or negative positive controls. For the remaining 10 patients the overall mean (± SD) difference in activated basophils between the two tests was 0.2 (± 12.2) %P. In a Bland-Altman plot, the limit of agreement (LoA) ranged from 24.0 to -23.7. In the qualitative evaluation (value below/above cut-off) Cohen's kappa was 0.77 indicating substantial agreement. BAT 2 took longer to perform than BAT 1 and was more expensive., Conclusion: The BAT 2 technique represents an interesting innovation, however, it was found to be less suitable compared to an established BAT for the routine diagnosis of insect venom allergies., (© 2024. The Author(s).)

Background: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry., Methods: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years)., Results: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up., Conclusions: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis (ECNM) and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells (GREM) were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase (AP), ß2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P<0.001). With regard to subvariants of AdvSM, an elevated LDH ≥260U/L was associated with multi-lineage expansion (leukocytosis, r=0.37, P<0.001; monocytosis, r=0.26, P<0.001) and the presence of an associated myeloid neoplasm (P<0.001), whereas tryptase levels were highest in mast cell leukemia (MCL vs. non-MCL, 308 µg/L vs. 146 µg/L, P=0.003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to lactate dehydrogenase (HR 2.1 [95% CI 1.1-4.0], P=0.018) and 1.5 points each to ß2-microglobulin (HR 2.7 [95% CI 1.4-5.4], P=0.004) and albumin (HR 3.3 [95% CI 1.7-6.5], P=0.001) delineated a highly predictive three-tier risk classification system (0 points, 8.1 years vs. 1 point, 2.5 years, ≥1.5 points, 1.7 years; P<0.001). Moreover, serum chemistry parameters enabled further stratification of IPSM-AdvSM1/2 risk-score classified patients (P=0.027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants., (Copyright © 2024 American Society of Hematology.)

Wheat allergy dependent on augmentation factors (WALDA) is the most common gluten allergy in adults. IgE-mediated sensitizations are directed towards ω5-gliadin but also to other wheat allergens. The value of the different in vitro cellular tests, namely the basophil activation test (BAT) and the active (aBHRA) and passive basophil histamine-release assays (pBHRA), in the detection of sensitization profiles beyond ω5-gliadin has not been compared. Therefore, 13 patients with challenge-confirmed, ω5-gliadin-positive WALDA and 11 healthy controls were enrolled. Specific IgE (sIgE), skin prick tests, BATs, aBHRA, and pBHRA were performed with allergen test solutions derived from wheat and other cereals, and results were analyzed and compared. This study reveals a distinct and highly individual reactivity of ω5-gliadin-positive WALDA patients to a range of wheat allergens beyond ω5-gliadin in cellular in vitro tests and SPT. In the BAT, for all tested allergens (gluten, high-molecular-weight glutenin subunits, α-amylase/trypsin inhibitors (ATIs), alcohol-free wheat beer, hydrolyzed wheat proteins (HWPs), rye gluten and secalins), basophil activation in patients was significantly higher than in controls ( p = 0.004- p < 0.001). Similarly, significant histamine release was detected in the aBHRA for all test substances, exceeding the cut-off of 10 ng/mL in all tested allergens in 50% of patients. The dependency of tests on sIgE levels against ω5-gliadin differed; in the pBHRA, histamine release to any test substances could only be detected in patients with sIgE against ω5-gliadin ≥ 7.7 kU/L, whereas aBHRA also showed high reactivity in less sensitized patients. In most patients, reactivity to HWPs, ATIs, and rye allergens was observed. Additionally, alcohol-free wheat beer was first described as a promising test substance in ω5-gliadin-positive WALDA. Thus, BAT and aBHRA are valuable tools for the identification of sensitization profiles in WALDA.

Immune checkpoint inhibition (ICI) improves outcomes in melanoma patients, but associated T-cell activation frequently leads to immune-related cutaneous adverse events (cutAEs). To dynamically identify T-cell subtypes and immune signatures associated with cutAEs, a pilot study was performed in stage III-IV melanoma patients using blood samples for flow cytometry and cytokine analysis. Blood samples were taken from patients before initiation of ICI (naive), at the onset of a cutAE, and after 6 months of ICI treatment. Overall, 30 patients were treated either with anti-PD1 monotherapy or with anti-PD-1/anti-CTLA-4 combination therapy. Flow cytometry analysis of PBMCs showed that ICI induced an overall shift from a Th2 towards a Th1 profile. Twelve patients (40%) developed cutAEs, which were associated with increased Th22 cells and Th17 cells, supported by a tendency to have elevated Th17/Th22-associated cytokines such as IL-17A, IL-22 and IL-23 levels in the plasma. Cytokine signatures specific for urticaria and T-cell-mediated cutAEs were identified in the plasma of patients by a bead-based assay. IL-10 was elevated in non-responders and, interestingly, during cutAEs. In conclusion, we identified distinct immune signatures based on the Th17/Th22 pathway in cutAEs, both in PBMCs and plasma. In addition, our finding of upregulated IL-10 during cutAEs supports the notion of treating these patients early and adequately to avoid implications for the overall outcome.

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low-risk patients. The task force suggests a strict definition of such low-risk patients in children and adults. Based on experience and evidence from studies of allergy to beta-lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non-steroidal anti-inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1%-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Mastocytosis is characterized by an accumulation of clonal mast cells (MCs) in tissues such as the skin. Skin lesions in mastocytosis may be clinically subtle or heterogeneous, and giving the correct diagnosis can be difficult., Methods: This study compiles personal experiences together with relevant literature, discussing possible obstacles encountered in diagnosing skin involvement in mastocytosis and cutaneous mastocytosis (CM)., Results: The nomenclature of the term "CM" is ambiguous. The WHO classification defines CM as mastocytosis solely present in the skin. However, the term is also used as a morphological description, e.g., in maculopapular cutaneous mastocytosis (MPCM). This is often seen in systemic, as well as cutaneous, mastocytosis. Typical CM manifestations (MPCM), including mastocytoma or diffuse cutaneous mastocytosis (DCM), all share a positive Darier's sign, and can thus be clinically recognized. Nevertheless, distinguishing monomorphic versus polymorphic MPCM may be challenging, even for experienced dermatologists. Less typical clinical presentations, such as MPCM with telangiectatic erythemas (formerly called telangiectasia macularis eruptiva perstans), confluent, nodular or xanthelasmoid variants may require a skin biopsy for histopathological confirmation. Because MC numbers in CM have a large overlap to those in healthy and inflamed skin, detailed histopathological criteria to diagnose mastocytosis in MPCM are needed and have been proposed. D816V KIT mutational analysis in tissue is helpful for confirming the diagnosis. Biomarkers allow the prediction of the course of CM into regression or evolution of the disease. Further diagnostic measures should screen for concomitant diseases, such as malignant melanoma, and for systemic involvement., Conclusions: Whereas in typical cases the diagnosis of CM may be uncomplicated, less typical manifestations may require specific investigations for making the diagnosis and predicting its course.

Background: Histamine intolerance (HIT) is frequently diagnosed in patients with polysymptomatic otherwise unexplained symptoms., Objectives: To exclude HIT by a single-blind placebo-controlled histamine challenge (SBPCHC), to study clinical features of patients with positive challenge, and to examine the predictability of HIT by biomarkers., Methods: SBPCHC was performed in 59 patients with suspected HIT. History and clinical data, including serum diamine oxidase (DAO) and histamine skin test wheal size of patients with positive versus negative SBPCHC, were compared., Results: Patients were predominantly middle-aged women (84.7%). Three-quarters reported improvement but never resolution of symptoms during a histamine-low diet. Histamine provocation was safe; only 1 patient was treated with antihistamines. Thirty-seven patients (62.7%) displayed symptoms to placebo. HIT was excluded in 50 patients (84.7%). Objective symptoms occurred in 4 of 59 cases (6.8%) after histamine but not after placebo challenge. These were diagnosed with "plausible HIT" because reactions occurring by chance could not be excluded. Another 5 patients (8.5%) were diagnosed with "possible HIT" after case-dependent detailed analysis. Patients with plausible/possible HIT had reported more gastrointestinal symptoms (P = .01), but comparable diet response and equal histamine skin prick test wheal sizes to those without HIT. Serum DAO activity tended to be lower in patients with HIT (P = .08), but was highly variable in those without, limiting its value as a biomarker., Conclusions: SBPCHC disproves HIT in the majority of patients. Placebo-controlled challenges are needed as placebo reactions were frequent. Gastrointestinal symptoms after food intake and reduced DAO levels are markers for HIT; however, specificity is not sufficient enough for making the diagnosis., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Food allergies including cofactor-dependent allergies such as cofactor-dependent wheat allergy (CDWA) decrease the quality of life (QOL) of patients., Objective: To define the health-related QOL and fears in patients with CDWA and to evaluate the impact of diagnosis confirmation by oral challenge test (OCT)., Methods: Patients with CDWA diagnosed by clinical history, sensitization, and OCT were invited to participate. Clinical characteristics, patients' fears, self-perceived overall QOL, the Food Allergy Quality of Life Questionnaire-Adult Form score, and the risks and benefits of OCT were evaluated after the final diagnosis., Results: A total of 22 adults with CDWA (13 male, 9 female; mean age 53.5 years; median 5 years until diagnosis) were included. Specific immunoglobulin E (IgE) levels for gluten proteins were inversely correlated with the reaction threshold (P < .05). Higher reaction severity in the patients' histories correlated with increased basal serum tryptase levels (P = .003) and gluten and gliadin specific IgE (P < .05), but not to QOL. After the first allergic reaction, patients reported a drop in QOL (P < .001). Challenge-confirmed diagnosis and medical consultation could restore the patients' QOL (P < .05) and reduce their fear of further reactions (P < .01). No severe reactions occurred during OCT, which was rated as not stressful and highly beneficial. Compared with patients with CDWA diagnosed without OCT in the literature, health-related QOL was less impaired (mean Food Allergy Quality of Life Questionnaire-Adult Form score 3.8), especially regarding the emotional impact (P < .001 vs existing literature)., Conclusion: Until final diagnosis, patients with CDWA have a severe physical and psychological burden. OCT is a safe method to confirm the diagnosis, restore the patients' severely affected QOL, and reduce their fear of further reactions., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is an IgE-mediated food allergy with allergic symptoms ranging from intermittent urticaria to severe anaphylaxis that occurs when wheat ingestion is combined with augmenting cofactors such as exercise, non-steroidal anti-inflammatory drugs, or alcohol. In most cases, patients are identified by sensitization to ω5-gliadins in the gluten fraction of wheat. ω5-gliadin-negative subtypes of WDEIA are often difficult to diagnose and may be caused by Tri a 14 (wheat lipid transfer protein), after percutaneous sensitization with hydrolyzed wheat proteins, or, in rare cases, by cross-reactivity to grass pollen. Diagnosis is established based on the patients' history in combination with serum IgE profile, skin testing, basophil activation tests, and challenge tests with cofactors. Individual dietary counselling remains the central pillar in the management of WDEIA patients. A completely wheat-free diet is a possible option. However, this appears to promote tolerance less than continued regular consumption of gluten-containing cereals in the absence of cofactors. All patients should have an emergency set for self-treatment including an adrenaline autoinjector and receive adequate instruction. More data are needed on sublingual immunotherapy for WDEIA, a potentially promising therapeutic prospect. This article provides an overview of current knowledge on the diagnosis and management of WDEIA including an optimized challenge protocol using wheat gluten and cofactors., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Not available., Competing Interests: The information on interests was collected using the AWMF form of 2018 and assessed by Prof. Dr. Monika Raulf for a thematic relation to the guideline. Guideline-relevant lecturing or consulting activities for manufacturers of devices for allergy diagnosis were categorized as a low conflict of interest, and direct financial secondary interests (e.g., share ownership, patent) as a moderate/high conflict of interest. Low conflicts of interest resulted in abstention from voting. Strong conflicts of interest were not present. Protective factors counteracting conflict of interest bias were the pluralistic composition of the guideline group, structured consensus building under neutral moderation, discussion on interests, and handling of conflicts of interest at the beginning of each consensus meeting, and a public consultation version. Abbreviations.Abbreviations. ADRAdverse drug reactionAGEPAcute generalized exanthematous pustulosisAWMFGerman Association of the Scientific Medical SocietiesCOPDChronic obstructive pulmonary diseaseDGAKIGerman Society for Allergology and Clinical ImmunologyDRESSDrug reaction with eosinophilia and systemic symptomsINNInternational non-proprietary nameMPEMaculopapular exanthemNSAIDNon-steroidal anti-inflammatory drugsSJSStevens-Johnson syndromeTENToxic epidermal necrolysis Table 1.Definitions.Adverse drug reaction (ADR): A noxious and unintended reaction that occurs in addition to the intended effect of a drug, for which a causal relationship between the use of the drug and the adverse effect is suspected. ADRs can be both type A (pharmacological/toxic) and type B (hypersensitivity).Type A (“augmented” = pharmacological/toxic (on-target) drug effects): Disease manifestations due to dose-dependent predictable pharmacological/toxic effects of a drug at the recommended dose (examples: sedative effect of older antihistamines, hair loss due to cytostatics) or increased dosage (intoxication).Type B (“bizarre” = hypersensitivity (off-target) reactions): Individual, unpredictable clinical reaction to a drug, i.e., symptoms occur only in specially predisposed patients. Two forms can be distinguished:   –Drug allergy: Hypersensitivity is based on an immunological reaction (types I – IV according to Coombs and Gell).   –Non-allergic drug hypersensitivity: An allergic mechanism is not detectable. Previously, this type of reaction was further divided into:      –Drug intolerance: Typical symptoms of pharmacological action (toxicity) develop even at low doses that are usually tolerated.      –Drug idiosyncrasy: The symptoms differ from the pharmacological substance effect. In cases where the symptomatology of this form of hypersensitivity looked similar to an allergic reaction, the term pseudoallergy has also been used. Table 2.Time interval, clinic, and pathomechanism – three levels for classifying a drug hypersensitivity reaction. 1) Time reaction intervalsa) For those already sensitized   –Immediate reaction (“immediate”) immediate up to 60 minutes (in rare exceptions up to 6 hours)   –Delayed reaction (“non-immediate”) > 6 hours to several weeksb) In case of new sensitization under therapy   –Typical sensitization latency 7 – 10 days2) Clinical manifestationsa) Immediate reaction: E.g., flush, urticaria, angioedema, bronchospasm, anaphylaxis.b) Late reaction: Maculopapular exanthem (MPE), acute generalized exanthematous pustulosis (AGEP). Severe cutaneous drug reactions: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).c) Others: E.g., hepatitis, cytopenia, autoimmune diseases (e.g., lupus erythematosus, drug-induced linear IgA dermatosis)3) Pathomechanisma) Allergic hypersensitivity: Immediate type (type I according to Coombs and Gell, IgE mediated): typical manifestation, immediate-type symptoms (reaction time: 0 – 6 hours)b) Non-allergic hypersensitivity: Typical manifestation immediate-type symptoms (reaction time: 0 – 6 hours, rarely up to 12 hours)c) Allergic hypersensitivity: Delayed-type (type IV according to Coombs and Gell, T-cell mediated): typical manifestation delayed-type (reaction time: 24 – 72 hours, begin rarely after 6 – 24 hours).d) Other forms of immunologically mediated hypersensitivity (type II, type III according to Coombs and Gell, IgG, IgA, or IgM mediated): Cytopenias, serum sickness, immune complex vasculitis (vasculitis allergica); (reaction time: 24 hours or more).e) In case of new sensitization under therapy: Typical immunologic sensitization latency 5 – 7 days for types I –IV, with reaction latency of 1 –3 days). Onset of MPE after 7 –10 days. However, the reaction in SJS/TEN, DRESS may occur after weeks, that in autoimmune diseases (e.g., lupus erythematosus) after months, probably due to sensitization only after prolonged exposure (e.g., sensitization or triggering favored by cofactors). Table 3.Typical time interval between start of drug intake and first occurrence of reactions. Reaction patternTime intervalUrticaria, asthma, anaphylaxis≤ 1 hour, rarely up to 6 hours after start of exposureFixed drug exanthem ≤ 48 hours, rarely later after start of exposureMaculopapular drug exanthem4 – 14 days after start of exposure*AGEP1 –12 days after start of exposure**SJS/TEN4 – 28 days after start of exposure***DRESS2 – 8 weeks after start of exposureAGEP = acute exanthematous generalized pustulosis; SJS = Stevens-Johnson Syndrome; TEN = toxic epidermal necrolysis; DRESS = drug reaction with eosinophilia and systemic symptoms. *In repeat reactions, time interval typically shortened compared to initial reaction. In maculopapular drug exanthem typically reaction after 1 – 4 days, in AGEP, SJS, TEN, DRESS typical time interval after repeat reactions not studied. **For antibiotics mostly 1 – 2 days, for other drugs often 7 – 12 days. ***Sometimes longer for allopurinol. Table 4.Important clinical and anamnestic information for the test plan. A) Clinical manifestation   – Documentation of clinical manifestations and/or organ systems involved: e.g., skin, airways, cardiovascular system, gastrointestinal tract, liver, kidney.   – Exact description of the clinical-morphological findings (especially in case of skin manifestations/mucosal reactions) additionally photo documentation   – General symptoms: Fever, reduced general condition   – Course of the reaction (onset of the reaction in temporal relation to the drug administration, duration of the reaction, morphological change of the reaction).   – Laboratory findings (e.g., blood count changes such as eosinophilia, thrombocytopenia; liver and kidney values; serum tryptase).   – If necessary, histological findings (especially in the case of blistering skin reactions)B) Other circumstances of the reaction   – Acute illness at the time of the reaction (e.g., concurrent infectious disease).   – Co-factors that may lower the threshold for an allergic or non-allergic reaction: stress, physical exertion, food intake, alcohol intake, UV exposure, menstruation.C) Documentation of drugs used in temporal relation to the reaction.   – Indication for drug use   – Trade name   – Mode of application   – Ingredients (active ingredients)   – Duration of application   – Dosage   – Tolerance after previous or during renewed applicationD) General history and findings   – Known hypersensitivity reactions (allergy passport)   – Similar reactions without drug application (e.g., natural latex allergy)   – Atopic diseases, food allergy   – Disposing diseases (e.g., asthma, nasal polyps, chronic urticaria, mastocytosis, infections, e.g., HIV, EBV)   – Other relevant past or current medical conditions (including somatoform or mental health conditions)   – Noxious agents: Nicotine, alcohol, drugs   – Current medication (long-term medication)E) Chronology of the hypersensitivity reaction   – Timing in relation to drug application   – First occurrence   – Course and resolution   – Therapeutic measures and responseF) Diagnosis and pathophysiological classification of the clinical reaction taking into account (see Table 1):   – Morphology and symptoms   – Time courseNote: In the case of multiple reactions, the information for each individual reaction is required. Table 5.Non-irritant skin test concentrations of commonly tested drugs [17]. Drug or classSkin prick testIntradermal test8Patch testBeta-lactam antibiotics   Benzylpenicilloyl-octa-L-lysine8.6 × 10-5 mol/L8.6 × 10-5 mol/LNA   Sodium benzylpenilloate1.5 × 10-3 mol/L1.5 × 10-3 mol/LNA   Benzylpenicillin10,000 UI/mL10,000 UI/mL5%   Amoxicillin20 mg/mL20 mg/mL5%   Ampicillin20 mg/mL20 mg/mL5%   Cephalosporins20 mg/mL1020 mg/mL105%Anticoagulants   Heparins1Undiluted81/10 dilutedUndiluted8   Heparinoids2Undiluted81/10 dilutedUndiluted8Platinum salts   Carboplatin10 mg/mL1 mg/mLNA   Oxaliplatin1 mg/mL0.1 mg/mLNA   Cisplatin1 mg/mL0.1 mg/mLNANSAID   Pyrazolone3Suspension90.1 – 1 mg/mL10%   Coxibe4Suspension910%   Other NSAIDs5Suspension90.1 – 1 mg/mL10%Biologics   Adalimumab50 mg/mL50 mg/mLUndiluted8   Etanercept25 mg/mL5 mg/mLNA   Infliximab10 mg/mL10 mg/mLNA   Omalizumab1.25 µg/mL1.25 µg/mLNAOther   Local anestheticsUndiluted81/10 dilutedUndiluted8   X-ray contrast agentUndiluted81/10 dilutedUndiluted8   Gadolinium chelatesUndiluted81/10 dilutedNA   Patent blueUndiluted1/10 dilutedNA   Methylene blueUndiluted1/100 dilutedNA   FluoresceinUndiluted81/10 dilutedUndiluted8   Proton pump inhibitors6Undiluted940 mg/mL10%   Anticonvulsants7NANA10%   Chlorhexidine digluconate5 mg/mL0.002 mg/mL1% 1Heparins: unfractionated heparin, nadroparin, dalteparin, enoxaparin; testing contraindicated in heparin-induced thrombocytopenia. 2Heparinoids: danaparoid, fondaparinux. 3Pyrazolones: metamizole, propyphenazone, aminopyrine, phenazone, phenylbutazone. 4Coxibs: celecoxib, etoricoxib, valdecoxib. 5Other nonsteroidal anti-inflammatory drugs: e.g., aspirin, ibuprofen, naproxen, indomethacin, diclofenac, fenoprofen, meloxicam, mefenamic acid, nimesulide. 6For lasoprazole and rabeprazole no intravenous solution for intradermal test (IDT), only skin prick test. 7For severe reactions, first test with 1%. 8Use of commercially available solution for intravenous infusion or subcutaneous injection. 9Crushing of the tablet and preparation of a suspension with physiological saline solution. 10Only for cefepime 2 mg/mL each. NA = not applicable or no concentration recommended. Table 6.Selection of commercial tests for the determination of specific IgE antibodies against drugs in serum*. – Ampicilloyl1– Amoxicylloyl1– Cefaclor2– Chlorhexidine2– Gelatin (bovine)1 Galactoseα−1,3-galactose (α-gal)1,3– Insulin (Human) 1– Morphine2– Penicilloyl G1– Penicilloyl V1– Pholcodin2– Suxamethonium (succinylcholine) 2*When determining sIgE for drugs, attention must be paid to the validation of the test methods. CE certification requires at least five, FDA registration at least 30 positive patient sera, as well as studies on stability and reproducibility. If these criteria are not met, test reagents may be offered for research purposes. Here, particular attention should be paid to the quality of the deposited literature. In routine diagnostics, no determinations of sIgE should be performed against substances for which no IgE-mediated allergic reactions have been described so far. 1CE-certified and FDA-registered; 2CE-certified,3 α-gal, this is an IgE-reactive sugar epitope which is held responsible for anaphylactic reactions to cetuximab and infusion solutions containing gelatine. Figure 1.Diagnostic algorithm for suspected drug hypersensitivity [2]., (© Dustri-Verlag Dr. K. Feistle.)

In 2002, the European Competence Network on Mastocytosis (ECNM) was launched as a multidisciplinary collaborative initiative to increase the awareness and to improve diagnosis and management of patients with mast cell (MC) disorders. The ECNM consists of a net of specialized centers, expert physicians, and scientists who dedicate their work to MC diseases. One essential aim of the ECNM is to timely distribute all available information about the disease to patients, doctors, and scientists. In the past 20 years, the ECNM has expanded substantially and contributed successfully to the development of new diagnostic concepts, and to the classification, prognostication, and treatments of patients with mastocytosis and MC activation disorders. The ECNM also organized annual meetings and several working conferences, thereby supporting the development of the World Health Organization classification between 2002 and 2022. In addition, the ECNM established a robust and rapidly expanding patient registry and supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their U.S. colleagues, various patient organizations, and other scientific networks. Finally, ECNM members have started several collaborations with industrial partners, leading to the preclinical development and clinical testing of KIT-targeting drugs in systemic mastocytosis, and some of these drugs received licensing approval in recent years. All these networking activities and collaborations have strengthened the ECNM and supported our efforts to increase awareness of MC disorders and to improve diagnosis, prognostication, and therapy in patients., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)