"Delabeling" by direct provocation testing in children and adolescents with a suspected history of a delayed reaction to ß-lactam antibiotics: Consensus paper of Gesellschaft für pädiatrische Allergologie und Umweltmedizin (GPAU), Deutsche Gesellschaft für Allergologie und klinische Immunologie (DGAKI), and Ärzteverband deutscher Allergologen (ÄDA).

BACKGROUND: Approximately 10% of European children are classified as allergic to drugs. In the majority of these children, no allergy to ß-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.

Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

Efficacy and safety of peanut epicutaneous immunotherapy in patients with atopic comorbidities.

Background: Co-occurring atopic conditions are common in children with peanut allergy. As such, it is important to examine the safety and efficacy of epicutaneous immunotherapy with Viaskin Peanut 250 µg patch (VP250) in peanut-allergic children with these conditions. Objective: We sought to compare efficacy and safety of VP250 versus placebo in peanut-allergic children with/without ongoing atopic conditions at baseline, including asthma, atopic dermatitis/eczema, or concomitant food allergy. Methods: A subgroup analysis of peanut-allergic children aged 4 to 11 years enrolled in PEPITES (12 months) and REALISE (6 months) randomized, placebo-controlled, phase 3 trials was conducted. The efficacy outcome measure was the difference in prespecified responder rate between placebo and VP250 groups at month 12 based on eliciting dose of peanut protein using double-blind, placebo-controlled food challenge in PEPITES. Safety profiles were evaluated by baseline concomitant disease subgroup in all randomized subjects who received 1 or more dose of the study drug in PEPITES and REALISE pooled data. Results: Responder rates were significantly (P < .05, all comparisons) greater with VP250 compared with placebo treatment regardless of whether subjects had other atopic conditions. Safety and tolerability profiles were generally similar across subgroups, with no new safety concerns detected. A trend for both higher responder rates and rates of local reactions was observed in subjects with baseline atopic dermatitis versus those without. In subjects with concomitant food allergy at baseline, higher rates of treatment-emergent adverse events, but not study discontinuations or overall rates of anaphylaxis, were observed. Conclusions: The results support the safety and efficacy of VP250 for treating peanut-allergic children with or without concomitant atopic conditions.

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

Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of ß-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT.

Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (ÄDA), the German Society for Pediatric Allergology (GPA), the German Contact Dermatitis Research Group (DKG), the German Society for Pneumology (DGP), the German Society of Otorhinolaryngology, Head and Neck Surgery, the Austrian Society of Allergology and Immunology (ÖGAI), the Austrian Society of Dermatology and Venereology (ÖGDV), the German Academy of Allergology and Environmental Medicine (DAAU), and the German Documentation Center for Severe Skin Reactions (dZh).

Not available.

The role of online symptom questionnaires to support the diagnosis of cow's milk allergy in children for healthcare professionals - A Delphi consensus study.

BACKGROUND: Cow's milk allergy (CMA) is one of the most common food allergies world-wide. The emergence of online CMA symptom questionnaires, aimed at parents and/or healthcare professionals (HCP), may raise awareness about the possible diagnosis of CMA, but also increases the risk for overdiagnosis leading to unnecessary dietary restriction impacting on growth and nutrition. This publication sets out to establish the availability of these CMA symptom questionnaires and critically assesses the development and validity. METHODS: Thirteen HCP working in the field of CMA, from different countries, were recruited to participate. A combination of a Pubmed and CINAHL literature and online review using the Google search engine in English language was used. Symptoms in the questionnaires were assessed, using the European Academy for Allergy and Clinical Immunology guidelines for food allergy. Following the assessment of both the questionnaires and literature, the authors followed the modified Delphi approach to generate consensus statements. RESULTS: Six hundred and fifty-one publications were identified, of which 29 were suitable for inclusion, with 26 being associated with the Cow's Milk-Related Symptoms Score. The online search yielded 10 available questionnaires: 7/10 were sponsored by formula milk companies and 7/10 were aimed at parents and three at HCP. Following the assessment of data, 19 statements were generated in two rounds of anonymous voting reaching 100% agreement. CONCLUSIONS: Online CMA questionnaires, available to parents and HCP's, are varied in symptoms, and most were not validated. The overarching consensus generated from authors is that these questionnaires should not be used without the involvement of HCP.

Food-Induced Anaphylaxis: Data From the European Anaphylaxis Registry.

BACKGROUND: Food is one of the most common elicitors of anaphylaxis, with an increasing incidence over recent years. OBJECTIVES: To characterize elicitor-specific phenotypes and identify factors enhancing the risk or severity of food-induced anaphylaxis (FIA). METHODS: We analyzed data from the European Anaphylaxis Registry applying an age- and sex-matched analysis of associations (Cramer's V) for single food triggers and calculated odds ratios (ORs) for severe FIA. RESULTS: We identified 3,427 cases of confirmed FIA showing an age-dependent elicitor ranking (for children: peanut, cow's milk, cashew, and hen's egg; and for adults: wheat flour, shellfish, hazelnut, and soy). The age- and sex-matched analysis revealed defined symptom patterns for wheat and cashew. Wheat-induced anaphylaxis was more frequently associated with cardiovascular symptoms (75.7%; Cramer's V = 0.28) and cashew-induced anaphylaxis with gastrointestinal symptoms (73.9%; Cramer's V = 0.20). Furthermore, concomitant atopic dermatitis was slightly associated with anaphylaxis to hen's egg (Cramer's V = 0.19) and exercise was strongly associated with anaphylaxis to wheat (Cramer's V = 0.56). Additional factors influencing the severity were alcohol intake in wheat anaphylaxis (OR = 3.23; CI, 1.31-8.83) and exercise in peanut anaphylaxis (OR = 1.78; CI, 1.09-2.95). CONCLUSIONS: Our data show that FIA is age-dependent. In adults, the range of elicitors inducing FIA is broader. For some elicitors, the severity of FIA seems to be related to the elicitor. These data require confirmation in future studies considering a clear differentiation between augmentation and risk factors in FIA.

Cow's milk and hen's egg anaphylaxis: A comprehensive data analysis from the European Anaphylaxis Registry.

BACKGROUND: Cow's milk (CM) and hen's egg (HE) are leading triggers of anaphylaxis in early childhood. The aim of this study was to identify clinical phenotypes and therapeutic measures for CM anaphylaxis (CMA) compared to HE anaphylaxis (HEA) in children up to 12 years of age, based on a large pan-European dataset from the European Anaphylaxis Registry. METHODS: Data from 2007 to 2020 on clinical phenotypes and treatment from 10 European countries, as well as Brazil, were analysed. The two-step cluster analysis was used to identify the most frequent phenotypes. For each trigger, three clusters were extracted based on sex, age, and existence of symptoms in four vitally important systems. RESULTS: Altogether 284 children with CMA and 200 children with HEA were identified. They were characterised as male (69% vs. 64%), infants (65% vs. 61%), with a most frequent grade III of Ring&Messmer classification (62% vs. 64%), in CMA versus HEA, respectively. Respiratory symptoms occurred more often in CMA (91% vs. 83%, p = 0.010), especially in infants (89% vs. 79%, p = 0.008). Cardiovascular symptoms were less frequent in CMA (30% vs. 44%, p = 0.002), in both infants (33% vs. 46%, p = 0.027), and older children (25% vs. 42%, p = 0.021). The clusters extracted in the CMA group were characterised as: (1) mild dermal infants with severe GI (40%), 2. severe dermal (35%), 3. respiratory (25%). While in HEA group: 1. infants with severe GI and/or reduction of alertness (40%), (2) conjunctival (16%), (3) mild GI without conjunctivitis (44%). The severity of the reaction was independent from the amount of ingested allergen protein, regardless of trigger. The first-line adrenaline application differed between the countries (0%-92%, as well as the reasons for not administering adrenaline, p < 0.001). CONCLUSIONS: Despite the similarity of their age, sex, and severity grade, the clinical profiles differed between the CMA and HEA children. Adrenaline was underused, and its administration was country dependent. Further studies are needed to assess to what extent the differences in the clinical profiles are related to matrix and/or absorption effects, and/or the allergen itself.

FPIES: Data for Germany in international comparison.

Food protein-induced enterocolitis syndrome (FPIES) is a rare, non-IgE-mediated food allergy. The triggering foods differ significantly from the typical triggers of an IgE-mediated food allergy. Until recently, there were no data on triggers of FPIES in Germany. In order to create an advisory basis for the care of German patients, a large multicenter study was initiated and published at the end of 2021. This revealed clear differences in international comparisons. The most frequent triggers for FPIES in Germany are cow's milk, fish, vegetables, and meat. Most children (84%) react to only one food. The prognosis is usually good, depending on the trigger. Regional data should be used for counseling patients with FPIES. Specific recommendations for this are given in this article.

Ana o 3 sIgE and diagnostic algorithms reduce cost of cashew allergy diagnosis in children compared with skin prick test: A cost comparison analysis.

BACKGROUND: In the absence of a clear clinical history of reaction, diagnosis of cashew allergy using skin prick tests (SPT) or cashew-specific IgE requires a high number of oral food challenges (OFC). By using Ana o 3 sIgE alone, or a two-step diagnostic algorithm using cashew sIgE followed by Ana o 3 sIgE, there is a reduced need for OFC. We aimed to perform a cost comparison for both of these approaches compared with cashew SPT alone. METHODS: Pooled individual-level data from 6 studies were used to determine diagnostic accuracy and OFC rate. Two studies used cashew SPT (n = 567, 198 allergic), with 95% positive and negative predictive values of ≥12 mm and <3 mm. Four studies were included in the pathways for Ana o 3 sIgE alone or a 2-step algorithm incorporating cashew and Ana o 3 sIgE (n = 271, 156 allergic). Cut-offs used were ≥8.5kUA/L and ≤0.1kUA/L for cashew sIgE and ≥0.35kUA/L and ≤0.1kUA/L for Ana o 3 sIgE. Costs were constructed based on unit prices from hospital inpatient admissions, expenses incurred by families, individual patient data on allergic reaction types and rates, and adrenaline autoinjector carriage, applying a health system perspective. RESULTS: Modeled data through the Ana o 3 pathway resulted in a 46.43% cost reduction (€307,406/1000 patients) compared with using cashew SPT alone (€573,854/1000 patients). The 2-step algorithm resulted in a 44.94% cost reduction compared with SPT alone (€315,952.82/1000 patients). Both the Ana o 3 pathway and 2-step algorithm resulted in a 79%-80% reduction in OFCs compared with SPT. CONCLUSIONS: Using Ana o 3 as a standalone test for cashew allergy diagnosis or a 2-step algorithm incorporating cashew sIgE and Ana o 3 sIgE is accurate and results in a large reduction in both OFCs and health system costs compared with cashew SPT alone.

Organ-specific symptom patterns during oral food challenge in children with peanut and tree nut allergy.

BACKGROUND: Peanut and tree nut allergies are common in childhood and often severe in nature. The clinical picture shows a wide variety of symptoms. OBJECTIVE: To analyze the distribution of clinical symptoms and severity during oral food challenges (OFC) in children. METHODS: Analysis of 1.013 prospectively recorded, positive OFCs with peanut (n = 607), hazelnut (n = 266), walnut (n = 97), and cashew (n = 43). Symptoms were categorized as immediate-type skin, gastrointestinal, upper and lower respiratory, cardiovascular symptoms, and eczema exacerbation. Symptom severity and treatment were recorded. RESULTS: Skin symptoms presented in 78%, followed by gastrointestinal (47%), upper (42%), and lower respiratory symptoms (32%). Cardiovascular symptoms presented in 6%. In three-quarter of the reactions, more than one organ was involved. Importantly, severe reactions occurred at every dose level. Peanut- and cashew-allergic patients had a higher relative risk of gastrointestinal symptoms compared with hazelnut- and walnut-allergic patients. Patients without vomiting had a 1.7 times higher risk developing immediate-type skin and/or lower respiratory symptoms. Three-quarter of the patients ever had eczema but worsening presented in only 10.5% of the OFCs. In patients with multiple food allergies, organs involved, eliciting dose and severity differed between allergens. CONCLUSION: Although comparisons between allergen groups with different clinical history, severity, comorbidities and laboratory data are difficult and might contain bias, our data confirm the high allergenic potential of peanut and tree nuts. The rare occurrence of eczema worsening emphasizes that avoidance diets of peanuts and tree nuts to cure eczema seem to be unnecessary and may hamper tolerance maintenance.

Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.

BACKGROUND: Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE: This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS: Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS: At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS: After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

Different Patterns of Foods Triggering FPIES in Germany.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food allergy mainly affecting infants and young children. Allergic FPIES reactions differ from IgE-mediated food allergies, for example, regarding elicitors and clinical course. OBJECTIVE: The aim of our study was to describe causative agents and development of tolerance in German children with FPIES. METHODS: We conducted a retrospective survey on children with FPIES from 14 centers in Germany assessing a 6-year period. RESULTS: We analyzed 142 patients with 190 FPIES reactions, 130 of which met acute FPIES criteria and 60 were defined as chronic FPIES. The most frequent eliciting food for acute FPIES was cow's milk, followed by fish, vegetables (eg, potato, pumpkin), meats (eg, beef), and grains. A total of 119 children reacted to 1 food only, 16 children to 2 or 3 foods, and 7 children to ≥4 foods. In chronic FPIES, all but 4 exclusively breastfed infants reacted to cow's milk feeding. IgE sensitization to the triggering food was found in 21 of 152 (14%) cases. Two children developed additional IgE-mediated symptoms upon a food challenge. Time to proof of tolerance was shortest in cow's milk-induced FPIES, and it was shorter in chronic than in acute FPIES. CONCLUSION: In our national survey, we identified triggers for acute FPIES that partially differ from those reported internationally. Mainly foods introduced early in infant nutrition triggered acute reactions. Time to proven tolerance was shown to be contingent on FPIES symptomatology and on the triggering food. These data should be considered regarding nutritional advice for infants with FPIES.

White paper on peanut allergy - part 1: Epidemiology, burden of disease, health economic aspects.

Peanuts are Leguminosae, commonly known as the legume or pea family, and peanut allergy is among the most common food allergies and the most common cause of fatal food reactions and anaphylaxis. The prevalence of peanut allergy increased 3.5-fold over the past two decades reaching 1.4-2% in Europe and the United States. The reasons for this increase in prevalence are likely multifaceted. Sensitization via the skin appears to be associated with the development of peanut allergy and atopic eczema in infancy is associated with a high risk of developing peanut allergy. Until recently, the only possible management strategy for peanut allergy was strict allergen avoidance and emergency treatment including adrenaline auto-injector in cases of accidental exposure and reaction. This paper discusses the various factors that impact the risks of peanut allergy and the burden of self-management on peanut-allergic children and their caregivers.

Update of the S2k guideline on the management of IgE-mediated food allergies.

Not available.