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Background: Anaphylaxis is a systemic allergic reaction that is potentially life-threatening. Occupational anaphylaxis is an anaphylaxis that occurs in an occupational context. In this position paper, we propose diagnostic criteria for occupational anaphylaxis and provide an overview of the current state of knowledge in terms of prevalence, triggers, prevention, and management., Results: The most common triggers of occupational anaphylaxis include Hymenoptera venoms, followed by food and drugs. Chemicals, bites or contact with animals (mammals/snakes/insects) and natural rubber latex are far less common. Occupations at risk for occupational anaphylaxis are therefore beekeepers, outdoor workers, or those who handle food as well as healthcare workers. The route of contact, intensity, and frequency of exposure, type of allergen, and the simultaneous occurrence of co-factors determine the clinical manifestation. A detailed medical history is required to confirm the diagnosis of anaphylaxis and to identify the trigger. Both skin tests and the determination of specific IgE are recommended, but only very few commercially available and quality-tested allergens are available that can be examined using both test methods. Preventive measures are based on avoiding further exposure or, if necessary, replacing a working substance. A written emergency plan and the prescription of an adrenaline autoinjector as well as instructions for its use are mandatory. Allergen immunotherapy is recommended for systemic Hymenoptera venom allergy. Depending on the national healthcare systems, patients with occupational anaphylaxis must be reported to the accident insurance., Conclusion: Occupational anaphylaxis is very rare. We recommend educational measures and generally standardized recording of occupational anaphylaxis for occupations with an increased risk of anaphylaxis., Competing Interests: RT received research support from Sanofi-Genzyme and the Hautnetz Leipzig/Westsachsen e.V. as well as fees for lectures and consultations from AbbVie, Allmirall, ALK-Abello, LeoPharma, Novartis, Pfizer, Sanofi-Genzyme, Viatris and support for congress visit from CSL-Behring; all outside this paper. She is head of working group “Anaphylaxis” of the German Society for Allergy and Clinical Immunology (DGAKI). MW reports support for consultancies, lectures, and other scientific activities from ALK-Abelló Arzneimittel GmbH, Abbvie, Eli Lilly, Mylan Germany GmbH, Bencard Allergie GmbH, Novartis AG, Biotest AG, Sanofi-Aventis Deutschland GmbH, HAL Allergie GmbH, DBV Technologies S.A, Aimmune Therapeutics UK Limited, Regeneron Pharmaceuticals, Inc, Stallergenes GmbH. AB reports support for lectures, consultancies, and project funding by Abbvie, Almirall, Amgen, AstraZeneca, Biofrontera, Blueberry Therapeutics, Celldex, Centogene, Escient, Galderma, Genentec, Incyte, Jasper, Leo, Lilly, Phavaris, L’Oreal, Novartis, Regeneron, Sanofi, Shire, Takeda. HD reports support for consultancies, lectures, and other scientific activities from LEO Pharma GmbH, Novartis Pharma GmbH, and Stallergenes GmbH, not concerning the contents of the manuscript. GH reports personal fees for consultancies or lectures from Abbvie, Allergopharma, ALK-Abelló, Biotest, Eli Lilly, Leti, Novartis, Sanofi, all outside of this work. UJ has received hotel accommodation and meals for a lecture and for leading a workshop organized by ALK Abello. The fee went to the organization, the RCB. In addition, another hotel night and dinner were recently provided by ALK Abello. Her research on molecular allergology is funded by the Federal Ministry of Education and Science, the Federal Ministry of Food and Agriculture (BMEL), the German Research Foundation, and the Kanert Foundation, all outside the topic of this article. The Federal Ministry of Technology, Economics and Technology has funded their research on assays for the detection of anti-drug antibodies via the AiF-ZIM program. LK reports grants and/or personal fees from Allergopharma, MEDA / Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk, and Cassela med outside the submitted work; and memberships: AeDA, DGHNO, German Academy of Allergology and Clinical Immunology, HNO-BV, GPA, EAACI. MR received fees for lectures from Alk-Abelló Arzneimittel GmbH, Berufsverband Deutscher Baubiologen VDB e.V, Haus der Technik, LetiPharma, ThermoFisher Scientific (Phadia). With regard to the content of this article, there are no conflicts of interest that could arise from an employment relationship, benefits for lectures, or other activities. BW reports support for one-day advisory boards and/or lectures and/or other scientific acitivities by ALK-Scherax, Bencard, Biocryst, CSL Behring, Kalvista, Novartis, Sanofi, Takeda, all outside the submitted work. OP reports grants and/or personal fees from ALK-Abelló, Almirall S.A., Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, ASIT Biotech Tools S.A., Laboratorios LETI/LETI Pharma, GlaxoSmithKline, ROXALL Medizin, Novartis, Sanofi-Aventis and Sanofi-Genzyme, Med Update Europe GmbH, streamedup! GmbH, Pohl-Boskamp, Inmunotek S.L., John Wiley and Sons, AS, Paul-Martini-Stiftung (PMS), Regeneron Pharmaceuticals Inc., RG Aerztefortbildung, Institut für Disease Management, Springer GmbH, AstraZeneca, IQVIA Commercial, Ingress Health, Wort&Bild Verlag, Verlag ME, Procter&Gamble, ALTAMIRA, Meinhardt Congress GmbH, Deutsche Forschungsgemeinschaft, Thieme, Deutsche AllergieLiga e.V., AeDA, Alfried-Krupp Krankenhaus, Red Maple Trials Inc., Königlich Dänisches Generalkonsulat, Medizinische Hochschule Hannover, ECM Expro&Conference Management, Technische Universität Dresden, Lilly, Paul Ehrlich Institut (PEI), Japanese Society of Allergy, Forum für Medizinische Fortbildung, Dustri Verlag, all outside the submitted work and within the last 36 months; and he is Vice President of EAACI and member of EAACI Excom, member of external board of directors DGAKI; coordinator, main or co-author of different position papers and guidelines in rhinology, allergology, and allergen-immunotherapy and Associate Editor of the journal(s) Allergy and Clinical Translational Allergy (CTA). JR has received honoraria for consulting and lectures from Sanofi, Viatris, Allergika, AbbVie, Pfizer. SS reports support for consultancy and lectures from Mylan Germany, DBV Technologies S.A., Aimmune Therapeutics, all outside this paper. TW reports support for consultancy, lectures, and other scientific activities from AbbVie, ALK Abello, Almirall, Astellas, Bencard, Galderma, Janssen/JNJ, Leo Pharma, Leti, Lilly, Novartis, Pfizer, Regeneron/Sanofi, Stallergenes. TZ reports support for consultations, lectures and other scientific activities by AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Henkel, Kryolan, Leti, Lofarma, L’Oreal, Meda, Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Sanoflore, Stallergenes, Takeda, Teva, UCB as well as responsible participation in the following organizations: Committee member, WHO initiative ‘Allergic Rhinitis and its Impact on Asthma’ (ARIA), Member of the Board, German Society for Allergy and Clinical Immunology (DGAKI), Head, European Centre for Allergy Research Foundation (ECARF), Secretary General, Global Allergy and Asthma European Network (GA2LEN), Member, Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO). KB reports support for consultancies, lectures, and other scientific activities from ALK-Abelló Arzneimittel GmbH, Bencard Allergie GmbH, Novartis AG, HAL Allergie GmbH, DBV Technologies S.A, ThermoFisher, all outside of this paper. DW, WF, TJ, FR, GW, JZ have no conflict of interest. Table 1.Criteria for the diagnosis of anaphylaxis according to Sampson et al. [4]. Anaphylaxis is highly likely when any one of three criteria are fulfilled:1.Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus, or flushing, swollen lips-tongue-uvula)and at least one of the following   a.Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow (PEF), hypoxemia)   b.Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g., hypotension (collapse), syncope, incontinence)2.Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):   a.Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-uvula)   b.Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)   c.Reduced BP or associated symptoms (e.g., hypotension (collapse), syncope, incontinence)   d.Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)3.Reduced BP after exposure to known allergen for that patient (minutes to several hours):   a.Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP*   b.Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that person’s baseline*Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 1 year, less than (70 mmHg + [2 × age]) from 1 to 10 years, and less than 90 mmHg from 11 to 17 years. Table 2.Diagnostic criteria for classification of occupational anaphylaxis. Sensitization at workplace probableAnaphylaxis at workplaceClassification as occupational anaphylaxisExampleYesYesYesInsect allergy in beekeepers Food allergy in cooks or in workers in food service sector and in food industryYesNoYesDrug allergy in healthcare workers (e.g., reaction when receiving antibiotic)No/unknownYesYes, if allergen source belongs to typical work materialFood allergy in cooks or in workers in food service sector and in food industryNo/unknownYesYes, if sensitization at workplace is probable even if allergen source does not belong to typical work materialInsect allergy in forest workersNo/unknownYesNo, if allergen contact is attributable to private activitiesFood consumption at work during break time Table 3.Selected workplaces with possible elicitors of occupational anaphylaxis. Workplace/OccupationPossible elicitorsHealthcare workerDrugs, natural rubber latex, chemicalsBeekeeper, gardener, green house worker, sales assistant in bakeries and confectioneriesInsect venomFood production and processingAnimal and vegetable food (inhalation, ingestion/skin contact)Hunter, rangerAlpha-GAL in meat, insect venomLaboratory workerChemicals, animal bites/contact Table 4.Important aspects for history taking in occupational allergy [10, 11]. Allergen exposureExposure at the workplace or outsideRoute of exposureFrequency of exposureType of allergenPotential cofactorsPhysical activity, exerciseAlcoholStressAcute infectionsConcurrent medications (i.e., beta-blocker, angiotensin-converting enzyme inhibitors)Predisposing individual risk factorsOlder ageIncreased levels of basal tryptase, mastocytosisUncontrolled AsthmaCardiovascular diseaseSex Table 5.Animal- and plant-derived elicitors of occupational anaphylaxis. AllergenOccupation/WorkplaceReferenceAnimal-derived food allergens   SushiCook Truck driver[24, 25]   SeafoodCook[22]   AnisakisFish monger, supermarket#[26]   Cow’s milkDairy industry[27]   Donkey’s milkFood laboratory[28]   Quail eggPoultry worker[29]   OysterOyster mushroom farmer[30]   Red meat/alpha-GALForest service employee, hunter§, cattle worker, cook[18, 20, 31]Plant-derived food allergens   Avocado, banana, chestnut, manioc, and othersHealthcare worker with sensitization to natural rubber latex as cross reaction[21, 32]   BuckwheatCook[33]   BroccoliCook[24]   ChicoryCook[34]   CorianderSpice grinder[35, 36]   PaprikaSpice and condiment seller[37]   SunflowerSunflower processing worker[38]   TamarilloCarpenter with sensitization to obeche wood as cross reaction[39]Wheat flourCook #[24] #Generalized urticaria; §no clinical reactions given in detail) [20]. Table 6.Drugs as elicitors in occupational anaphylaxis. Group of allergen/elicitorAllergenOccupation/workplaceReferenceAntibioticsPencillin Cefotiam Piperacillin-tazobactam Isoniazid RifapentinHealthcare workers[40, 41, 42, 43, 44, 45, 46, 47, 48, 49]DisinfectantsChlorhexidine Povidone Iodine Polyhexanide Chloramine Chlorocresol/chloroxylenolHealthcare workers Butchery Carer[52, 53, 54, 55, 56, 57, 58, 72]LaxativePsylliumHealthcare workers[59]Allergen immunotherapeuticTimothy grassHealthcare worker[60]Coronavirus vaccinesIn question; direct complement activation?Healthcare workers[63, 64, 66]Narcotic agentsSuccinylcholine Neuromuscular blocking agents (several)Healthcare worker Hair dresser Cleaner[61, 62] Table 7.Chemicals as elicitors of occupational anaphylaxis. Elicitor/AllergenApplicationWorkplace/occupationReferenceChlorothalonilFungicideGreenhouse[74]Iridium chlorideChemicalElectrochemistry[75]Cobalt chloridePaintCeramic decorator[76]Polyethylene glycolsExcipients, solventsPainter[79]Chromium vaporChemicalWelder[80]BenzonitrileIntermediate for chemicalsChemical industry[81]HexafluorophosphatesCoupling reagentsLaboratory worker[82]Methyl methacrylateAdhesiveHealthcare worker[84]PerfumesCosmeticsHealthcare worker[85, 86]PersulfatesBleachingsHair dresser[87, 88, 89]Hair/textile dyes (2,4-toluylenediamine/Lanasol Yellow 4G)ColoringsHair dresser, textile industry[90, 91] Table 8.Animals (bites/contact) as elicitors of occupational anaphylaxis. Elicitor/allergenContactWorkplace/occupationReferenceRodents   RatBiteLaboratory[106]   MouseBiteLaboratory[107]   Rat, mouseBites (N = 2)Laboratory[108]   RabbitNeedle injury after contact to rabbit tissueResearch physician[109]Snakes   Different snake venomsBites (n = 3)Outdoor worker[110]   ViperBiteResearch laboratory[111]     Atractaspis corpulentaDeath after bite, anaphylaxis suspected (reaction to antivenom was not ruled out)Mechanical foreman[112]     Bothrops spp.BiteHerpetologist1[113]     Bothrops moojeniBiteViper farm[114]Insects     Rhiphicephalus spp.Tick biteGoatherd[115]     Bruchus pisorumInhalation of dust of peas infested by B. pisorumFarmer[116]     Thaumetopoea pityocampa2Skin contactPine/oak or resin collectors/ woodcutters Farmers/Stockbreeders Farmers/stockbreeders[117]     Thaumetopoea pityocampa2Skin contactPine-resin worker[118]     Thaumetopoea pityocampa2Skin contactForest[119]     Glossina morsitans3BiteLaboratory[120] 1Experts working with amphibians and reptiles; 2processionary caterpillar; 3tsetse fly. Table 9.Summarized recommendations for management of occupational anaphylaxis 1.Improved diagnostic criteria for classification of occupational anaphylaxis have to consider that   a.sensitization may take place at the workplace or outside the workplace (e.g., Hymenoptera allergy)   b.clinical reaction may not only manifest at the workplace but also outside the workplace (e.g., drug allergy in healthcare workers).2.The acute management of an anaphylactic reaction at the workplace should follow general guidelines on anaphylaxis.3.In Germany, urgent medical suspicion of occupational anaphylaxis must be reported to the Social accident insurance in Germany (Unfallversicherungsträger).4.Prevention measures in patients with a history of occupational anaphylaxis should include training in allergen avoidance and eliminating the allergen as completely as possible.5.Every measure to prevent further exposure should be carried out, this includes (according to STOP principle): Substitution of elicitors, Technical measures, Organizational measures for elicitor avoidance, and Personal safety precautions.6.Patients with history of occupational anaphylaxis should be equipped with emergency medications including adrenaline autoinjectors and a written emergency management plan. They should receive safety education and training.7.In any occupational setting where there is an employee with a history of previous anaphylaxis, the availability of adrenaline and a person trained in its administration are mandatory.8.In patients with venom anaphylaxis, an occupational factor should always be considered.9.In occupational Hymenoptera allergy, venom immunotherapy should be started.10.Workers with compromised skin and especially atopic individuals should not wear gloves containing natural rubber latex (NRL) – to primarily prevent sensitization. In secondary prevention a “NRL-free” strategy should be followed.11.In occupations at greater risk for occupational anaphylaxis, surveillance and awareness campaigns are recommended.12.We call for awareness, documentation, and registration of occupational anaphylaxis in registries., (© Dustri-Verlag Dr. K. Feistle.)

Staphylococcus aureus acts both as a colonizing commensal bacterium and invasive pathogen. Nasal colonization is associated with an increased risk of infection caused by the identical strain. In patients with atopic dermatitis (AD), the degree of S. aureus colonization is associated with the severity of the disease. Here, we comparatively analyzed the in vivo transcriptional profile of S. aureus colonizing the nose and non-diseased skin (non-lesional skin) as opposed to the diseased skin (lesional skin-defined here as infection) of 12 patients with AD. The transcriptional profile during the asymptomatic colonization of the nose closely resembled that of the lesional skin samples for many of the genes studied, with an elevated expression of the genes encoding adhesion-related proteins and proteases. In addition, the genes that modify and remodel the cell wall and encode proteins that facilitate immune evasion showed increased transcriptional activity. Notably, in a subgroup of patients, the global virulence regulator Agr (accessory gene regulator) and downstream target genes were inactive during nasal colonization but upregulated in the lesional and non-lesional skin samples. Taken together, our results demonstrate a colonization-like transcriptional profile on diseased skin and suggest a role for the peptide quorum sensing system Agr during the transition from asymptomatic nasal colonization to skin colonization/infection.

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.)

Background: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited., Objective: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology., Methods: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE., Results: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort., Conclusions: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-sedating H 1 -antihistamines (nsAH) are the most commonly used treatment for chronic spontaneous urticaria (CSU). Many patients use them as on-demand (OD) therapy rather than a maintenance treatment. Here, we compared OD versus daily maintenance treatment with the nsAH rupatadine, assessed the efficacy of rupatadine updosing, and investigated potential long-term disease-modifying effects., Methods: This multicenter, randomized study consisted of 2 weeks of screening, 8 weeks of double-blind treatment, and 6 weeks of treatment-free follow-up (OD allowed). Adult patients were randomized to 10 mg rupatadine OD or 10 mg rupatadine daily. At Week 4, if patients did not have a complete response, they switched from 10 to 20 mg rupatadine daily or underwent sham updosing (patients on 10 mg rupatadine OD). The primary aim was to compare CSU disease activity at the end of follow-up between daily versus OD. Additionally, we assessed the efficacy of rupatadine updosing. Major outcomes were disease activity, CSU-related quality of life (QoL), and disease control., Results: At Week 4, disease activity and QoL significantly improved in daily versus OD-treated patients. Updosing of rupatadine did not improve the mean disease activity, but the number of complete responders increased during updosing from 5% to 22%. At the end of follow-up, the disease activity of patients treated OD versus daily was not significantly different., Conclusions: Daily rupatadine treatment significantly improved CSU disease activity and QoL during treatment versus OD treatment but not after discontinuation of rupatadine, indicating the benefits of a daily maintenance nsAH schedule., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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: The lymphocyte transformation test (LTT) is used for the in vitro detection of a drug sensitization in assumed drug allergic patients. It is based on the detection of antigen (drug)-specific activation of T cells indicated by e.g. proliferation or cytokine secretion. However, occasional stimulatory effects of the drug unrelated to specific drug-allergic mechanisms can only be detected if a larger number of non-drug allergic control persons are tested with this specific drug. In this respect, the overall specificity of the LTT with ELISA read-out is summarized in several review articles, but the impact of a specific drug on the specificity has not yet been analyzed in a larger set of control persons., Objective: Do amoxicillin, cefuroxime and clindamycin induce an interferon (IFN)-y or interleukin (IL)-5 secretion of PBMC from control persons using the LTT with ELISA read-out?, Methods: We performed LTTs with amoxicillin, cefuroxime and clindamycin and determined drug-specific IFN-γ and IL-5 secretion measured by ELISA read-out. We included PBMC from 60 non-drug allergic control persons, who were unexposed to the tested drug at the time of blood donation., Results: PBMC from 12 out of 23 control persons tested with amoxicillin gave a positive stimulation index (SI > 3.0) for IFN-γ resulting in a specificity of 47.8%. The corresponding specificity was 75% for cefuroxime (5/20 if SI > 3.0) and 58.8% for clindamycin (7/17, if SI > 2.0), respectively. In a next step, we calculated the Δ IFN-γ concentration by subtracting the background IFN-γ concentration in the unstimulated sample from the stimulated sample. After stimulation with amoxicillin, a mean concentration of 21.0 pg/mL IFN-γ was secreted. The less outlier prone median concentration was 7.4 pg/mL and much higher than for cefuroxime (1.7 pg/mL) and clindamycin (1.0 pg/mL). Remarkably, IL-5 concentrations were below the detection limit (< 1 pg/mL) for all drugs in all control persons who responded to TT., Conclusion: Consideration of these observations may be helpful since a positive LTT result in a control patient may challenge the validity of a positive LTT result in the same experiment for a patient with assumed drug allergy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Systemic allergic reactions to vaccines are very rare. In this study we assessed the management and outcome of suspected SARS-CoV-2 vaccine hypersensitivity., Methods: Totally, 334 individuals underwent an allergy work up regarding SARS-CoV-2 vaccination (group A: 115 individuals suspected to be at increased risk for vaccine-related reactions before vaccination and group B: 219 patients with reactions after COVID vaccination). The large majority of the SPT/IDT with the vaccines were negative; however, we identified in 14.1% (n = 47) a possible sensitization to the SARS-CoV-2 vaccine and/or its ingredients defined as one positive skin test. Of the 219 individuals (group B) who experienced symptoms suspicious for a hypersensitivity reaction after vaccination, 214 were reported after the first vaccination with a mRNA vaccine (157 mRNA (Comirnaty®, 38 Spikevax®) and 18 with a vector vaccine (Vaxzevria®), 5 cases were after the second vaccination., Results: The symptom profile in group B was as follows: skin symptoms occurred in 115 cases (n = 59 angioedema, n = 50 generalized urticaria and n = 23 erythema/flush. Seventy individuals had cardiovascular, 53 respiratory and 17 gastrointestinal symptoms. Of the overall 334 individuals, 78 patients tolerated (re)-vaccination (out of skin test positive/negative 7/19 from group A and 17/35 from group B)., Conclusion: Proven IgE-mediated hypersensitivity to SARS-CoV-2 vaccines is extremely rare and not increased in comparison with reported hypersensitivity to other vaccines. The value of skin tests is unclear and nonspecific reactions, in particular when intradermal testing is applied, should be considered., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes ( SERPING1 , F12 , PLG , ANGPT1 , and KNG1 ) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p -value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p .adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mathey, Maj, Scheer, Fazaal, Wedi, Wieczorek, Amann, Löffler, Koch, Schöffl, Dickel, Ganjuur, Hornung, Forkel, Greve, Wurpts, Hallberg, Bygum, Von Buchwald, Karawajczyk, Steffens, Stingl, Hoffmann, Heilmann-Heimbach, Mangold, Ludwig, Rasmussen, Wadelius, Sachs, Nöthen and Forstner.)

Acute or chronic redness of the lower leg is a frequent reason for visits to clinics and practices. The differential diagnosis is often challenging. The aim of this guideline is to define criteria and procedures for the differential diagnosis of acute or chronic, unilateral or bilateral redness of the lower leg. Finding the correct diagnosis is essential for selecting an appropriate treatment and can help to reduce the inappropriate use of antibiotics. The guideline committee identified the most relevant differential diagnoses: 1. erysipelas, 2. stasis dermatitis, 3. hyperergic ictus reaction, 4. superficial and deep vein thrombosis, 5. gout, 6. chronic allergic contact dermatitis, and 7. acute toxic or allergic contact dermatitis. Algorithms/diagnostic pathways, each of which can be broken down into anamnesis, clinical examination, and diagnostics, have been developed for these seven diagnoses. In addition, the guideline group identified over 40 other relevant diagnoses and summarized their characteristics in a table to facilitate further differential diagnoses., (© 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Patch test (PT) readings are recommended after 48 h and 72 h (D3). An additional day 7 (D7) reading has been suggested by some, although data on efficient patient selection are scarce. We investigated positive D7 reactions regarding (i) allergens in the baseline series and additional PT series of the German Contact Dermatitis Research Group (DKG) and (ii) characteristics of the patients tested., Methods: Retrospective, multicentre analysis of 190 allergens derived from 17 DKG test series in 4687 patients with an additional D7 reading. Patients were patch tested with the baseline series and additional series, if required. Occurrence of novel D7 reactions as well as increasing skin reactions from D3 to D7 was analysed separately., Results: Depending on the allergen tested, waiving D7 readings would have missed 4.4-26.8% of positive PT results. Patch test series with the highest number of novel D7 reactions were baseline series, metal series, and leather/shoe series. New positive reactions on D7 were associated with age over 50 years and with a negative irritant control containing sodium lauryl sulphate. Of note, application of the PT allergens for 48 h instead of 24 h was positively associated with late PT reactions., Conclusion: Within the most frequently tested allergens, without late readings, on average 11.7% of sensitizations would have been missed. Novel late reacting allergens were identified. This study comprehensively dissects patient-, allergen- and test-dependent parameters in support for D7 readings. We propose to always consider late readings individually based on effort-benefit considerations., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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.)