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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., Competing Interests: BE reports non-financial support from Bühlmann Laboratories outside the submitted work. KB received lecture fees from ALK, Bencard and ThermoFisher and reports non-financial support from Bühlmann Laboratories outside the submitted work. SB reports grants and personal fees from Bencard, Thermo Fisher Scientific and Allergy Therapeutics, grants from Leti Pharma, and non-financial support from Siemens Healthineers, outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. Table 1. Overview of possible current applications of basophil activation test for Hymenoptera venom allergy. Field of applicationGroup of patientsAllergens to be used in the BATDiagnosis of Hymenoptera venom allergyPatients with negative results in routine testingWhole venom extracts, allergen componentsPatients with double sensitizationWhole venom extracts, allergen components Efficacy and tolerance of VITPatients with adverse events during VITSubmaximal concentrations of whole venom extracts in the course of VITPatients with systemic reactions after a field sting or sting challenge during VITSubmaximal concentrations of whole venom extracts in the course of VIT Characterization of allergen componentsPatients with a history or sensitization profile relevant to the scientific issueAllergen components BAT = basophil activation test; VIT = venom-specific immunotherapy., (© Dustri-Verlag Dr. K. Feistle.)

Background: Approximately 10% of European children are classified as allergic to drugs. In the majority of these children, no allergy to β-lactam antibiotics (BLA) can be found. In most cases, the exanthema is caused by the infection., Materials and Methods: The objective of this paper is to describe the causes and consequences of a misdiagnosis of drug allergy. We propose a method for establishing a correct diagnosis in the case of a history of a delayed reaction during treatment with a BLA. For this purpose, a proposal was discussed via e-mail communication, and consensus was reached among the members of the drug allergy working groups of the participating medical societies., Results: The suspicion of a BLA allergy based on the medical history alone can have a negative impact on future antibiotic treatment. Exanthema associated with febrile infections not related to drug administration is a frequent finding in children. This makes it all the more important to be able to recommend a standardized procedure for clarification in children and adolescents with suspected hypersensitivity reactions. The medical history should be the basis on which to diagnose either a drug allergy or another possible differential diagnosis. A mild maculopapular exanthema (MPE) can be an expression of a drug allergy or a nonspecific viral exanthema. Uncomplicated MPE is not associated with significant systemic involvement, and there is no involvement of the mucous membranes or cutaneous blistering. Only a small number of children with uncomplicated MPE show positive skin tests and only ~ 7 - 16% of suspected BLA diagnoses can be confirmed by provocation tests. Thus, in children with uncomplicated MPE, drug provocation can be performed in an outpatient setting even without prior skin testing. This paper presents a 3-day outpatient direct provocation scheme for BLA delabeling in children with uncomplicated MPE., Conclusion: Many children and adolescents are unnecessarily denied treatment with BLA after an uncomplicated MPE while being treated with a BLA., Competing Interests: The author declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. Table 1.Warning signs of β-lactam allergy, modified according to [1, 12]. Immediate reactionDelayed reactionConjunctival erythemaPronounced facial edemaShock symptoms (arterial hypotension/dizziness)Atypical target lesions, bullous lesionsCoughing, sneezing, wheezing ErythrodermaDyspneaHemorrhagic and necrotic lesionsHoarsenessPainful skin, mucous membrane involvementDysphagiaGeneralized lymphadenopathyPathological laboratory findings (e.g., liver enzyme elevation, impaired renal function) Table 2.Provocation regime [6, 8, 15]. Day 1 (practice/clinic)Day 2 (at home)Day 3 (at home)1 single doseDaily dose distributed in 2 – 3 doses (depending on the antibiotic)Daily dose distributed in 2 – 3 doses (depending on the antibiotic)Monitoring for 1 hourStart ~ 24 hours after the first dose day 1**Wash-out period should be ~ 24 hours so that delayed reactions can be recorded after the 1st dose during the time interval between reaching the therapeutic dose and the subsequent dose. Figure 1Estimates on the likelihood of allergic cross-reactions between the various β-lactam antibiotics ([14])., (© Dustri-Verlag Dr. K. Feistle.)

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.)

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.)

Background: Coronavirus disease-2019 (COVID-19) has significantly hampered the regular workflow for allergists and allergy departments., Materials and Methods: The purpose of this review is to highlight our own experiences on SARS-CoV-2 and allergy as well as to discuss findings from the literature., Results: Vaccination against SARS-CoV-2 is needed for protection against severe infection. Skin reactions may arise with SARS-CoV-2 infections. Short-term general immune reactions and skin reactions are also possible upon SARS-CoV-2 vaccination; however, they recur in only a proportion of patients during follow-up vaccinations. Initial reports of anaphylaxis after vaccination fueled public fear. On the other hand, more recent epidemiologic data do not show a substantially increased anaphylaxis risk compared with other vaccines. Fear-related reactions may be essential for many "anaphylaxis" reports. In Germany, the flow chart developed by Paul-Ehrlich-Institut (PEI) and Robert-Koch-Institut (RKI) together with the allergological societies helps to care for patients with suspected "allergy history" safely and effectively. Through this, patients with increased risk of anaphylaxis to SARS-CoV-2 vaccines and their ingredients (e.g., polyethylene glycol (PEG), polysorbate 80) are identified. However, since only small amounts of these excipients are contained in mRNA vaccines, even some PEG-allergic patients can tolerate the vaccination. In Germany, an allergy test-guided procedure is recommended for high-risk patients, including an allergy history, prick tests, intradermal and basophil activation tests, and, if necessary, provocation tests. This also appears effective for anxiety reduction in patients with vaccination skepticism. To date, all of our patients have been able to be vaccinated with SARS-CoV-2 vaccines without the occurrence of significant reactions., Conclusion: Many initial concerns about unexpected side effects of SARS-CoV-2 vaccination have not been confirmed. The flowchart and, in the case of suspicion of hypersensitivity, an allergy test-guided risk assessment helps to reduce patients' fear of vaccination and enables safe vaccination., Competing Interests: The authors declare no conflict of interest. Table 1.Lessons on SARS-CoV-2 and allergy in recent years. Skin reactions associated with SARS-CoV-2 infectionCommon maculopapular exanthema, papulovesicular exanthema, acute urticaria, and vascular reactionsHypersensitivity reactions to drugs used to control SARS-CoV-2 infectionRare, no typical triggers of hypersensitivity reactionsSide effect rate of SARS-CoV-2 vaccinationLow and overall comparable to other vaccinesCommon general adverse reactions to SARS-CoV-2 vaccination As with other vaccines, predominantly flu-like symptomsSkin reactions after SARS-CoV-2 vaccinationIn particular, local reactions, urticaria and morbilliform exanthema, also worsening of chronic inflammatory skin diseases, pityriasis rosea and zoster. Recurrence with follow-up vaccination < 50%.Severe complications after SARS-CoV-2 vaccination mRNA vaccinesIncreased risk of myocarditis and pericarditis, mostly mild and no contraindication for follow-up vaccination after healing. Vector vaccines: thrombosis at atypical sites especially in younger patients, and questionable Guillain-Barré syndrome, both contraindications for these vaccinesRisk of anaphylaxis to vaccinationInitially many individual cases of anaphylaxis reported, significantly increased risk of anaphylaxis feared, incidence now equal to or not substantially above that of other vaccines. Frequently women, allergies often reported, previous anaphylaxisVaccination in “allergic” patientsProcedure according to flow chart (Figure 2)Vaccination in patients with contact sensitization to PEGNo evidence of PEG immediate type allergy; we have advised patients to vaccinate and have several reports of good tolerabilityAllergy testing prior to vaccinationIn Germany/Europe if there is evidence of vaccine hypersensitivity or PEG allergy. In the U.S., increasingly vaccination without prior allergy testing on an emergency standby basisAllergy testing methodsDepending on availability and experience, skin prick test, intradermal test if necessary, basophil activation test and provocation tests with vaccine residues and adjuvants.Vaccination of PEG-allergic patientsPossible after allergy diagnostics, after appropriate documented information and consent of the patient under appropriate monitoring and emergency preparedness. Figure 1.Adverse reactions frequently reported to the Paul Ehrlich Institute after vaccination with Spikevax (Moderna), Vaxzevria (AstraZeneca), Comirnaty (BioNTech/Pfizer), and the COVID-19 vaccine Janssen. Percent frequencies are given (percentage of the number of adverse reactions reported in each case out of the total number of adverse reactions reported after administration of each COVID-19 vaccine). Source: https://www.pei.de/DE/newsroom/dossier/coronavirus/coronavirus-inhalt.html, Safety-Report-27-12-to-31-07-21.Figure 2.Updated flowchart on the procedure in patients with positive allergy history before COVID-19 vaccination., (© Dustri-Verlag Dr. K. Feistle.)

Background: In Europe, North America, and Australia, 5% to 10% of the population are now classified as penicillin (β-lactam) allergic. Only ~ 10% of these questionable diagnoses, mostly made in childhood, can be confirmed by allergy diagnostics., Materials and Methods: The aim of this review is to show causes and consequences as well as recommendations for dealing with the often questionable diagnosis of penicillin (β-lactam) allergy (BLA)., Results: An incorrect BLA diagnosis may negatively impact antibiotic treatment needed in the future, by using a less effective antibiotic or using a broad-spectrum antibiotic, for example, further exacerbating the problem of increasing antibiotic resistance. Accordingly, there is growing pressure from antibiotic stewardship programs to critically challenge the BLA diagnosis. Conservatively, a suspected BLA is reviewed by an allergist using medical history, skin testing, laboratory testing, and provocation. This clarification is costly and is not remunerated in the German health care system; that is the reason why this testing is only offered in a few specialized clinics and practically not at all in general practice. In view of thousands of affected patients, additional strategies are needed to treat patients with a low risk of hypersensitivity reaction despite suspected allergy with a β-lactam antibiotic. In recent years, various methods have been proposed to eliminate suspected allergy as promptly as possible and directly before necessary treatment with a β-lactam antibiotic, including standardized history (also in the form of an algorithm), skin test with immediate reading after 15 minutes, or administration of a small test dose. Investigations of small case series and also multi-center studies to date have yielded promising results in terms of feasibility and safety., Conclusion: Of the large number of patients with (questionable) BLA, most have never been tested and - if antibiotic treatment becomes necessary - simply receive an alternative antibiotic. The diagnosis of BLA therefore requires new approaches besides classical allergy testing to critically question BLA., (© Dustri-Verlag Dr. K. Feistle.)

Not available., (© Dustri-Verlag Dr. K. Feistle.)

Not available., (© Dustri-Verlag Dr. K. Feistle.)

Severe allergic reactions to vaccines are very rare. Single severe reactions have occurred worldwide after vaccination with the new mRNA-based COVID-19 vaccines. PEG2000 is discussed as a possible trigger. We provide guidance on risk assessment regarding COVID-19 vaccination in patients with allergic diseases and suggest a standardized, resource-oriented diagnostic and therapeutic procedure. Reports of severe allergic reactions in the context of COVID-19 vaccination can be made via www.anaphylaxie.net using an online questionnaire., (© Dustri-Verlag Dr. K. Feistle.)

This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach - even in cases where the need to administer a BLA is acute - is guided by patient history and risk - benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole., (© Dustri-Verlag Dr. K. Feistle.)

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.