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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. [ABSTRACT FROM AUTHOR]

Background: Peanuts (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy and can lead to life-threatening reactions. The current advice for allergic patients is to strictly avoid the offending food independently of their individual threshold level, whereas sensitized patients without allergic symptoms should frequently consume the food to avoid (re-)development of food allergy. The aim of this trial is to investigate (I) whether the consumption of low allergen amounts below the individual threshold may support natural tolerance development and (II) to what extent regular allergen consumption in sensitized but tolerant subjects prevents the (re-)development of PN or TN allergy.Methods: The TINA trial consisting of (part I) a randomized, controlled, open, parallel group, single-center, superiority trial (RCT), and (part II) a prospective observational exploratory cohort study. Children and adults (age 1-67 years) with suspected or known primary PN and/or TN allergy will undergo an oral food challenge (OFC) to determine their clinical reactivity and individual threshold. In the RCT, 120 PN or TN allergic patients who tolerate ≥100 mg of food protein will be randomized (1:1 ratio) to consumption of products with low amounts of PN or TN on a regular basis or strict avoidance for 1 year. The consumption group will start with 1/100 of their individual threshold, increasing the protein amount to 1/50 and 1/10 after 4 and 8 months, respectively. The primary endpoint is the clinical tolerance to PN or TN after 1 year assessed by OFC. In the cohort study, 120 subjects sensitized to PN and/or TN but tolerant are advised to regularly consume the food and observed for 1 year. The primary endpoint is the maintenance of clinical tolerance to PN and/or TN after 1 year assessed by challenging with the former tolerated cumulative dose.Discussion: This clinical trial will help to determine the impact of allergen consumption versus avoidance on natural tolerance development and whether the current dietary advice for PN or TN allergic patients with higher threshold levels is still valid.Trial Registration: German Clinical Trials Register; ID: DRKS00016764 (RCT), DRKS00020467 (cohort study). Registered on 15 January 2020, http://www.drks.de . [ABSTRACT FROM AUTHOR]

Background: Peanut allergy has a rising prevalence in high‐income countries, affecting 0.5%–1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods: Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in‐depth review of food‐induced anaphylaxis cases in a tertiary paediatric allergy centre. Results: 3514 cases of food anaphylaxis were reported between July 2007 ‐ March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p =.001), asthma comorbidity (47% vs. 35%; p <.001), relevant cofactors (29% vs. 22%; p =.004) and biphasic reactions (10% vs. 4%; p =.001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p =.001). Self‐administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non‐peanut food anaphylaxis (34% vs. 26%; p =.003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p =.004). Conclusions: The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life‐threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first‐line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition. [ABSTRACT FROM AUTHOR]

Background: Worldwide, guidelines recommend the use of adrenaline autoinjectors (AAIs) for self-medication in patients who experience severe allergic reaction. The European Medical Agency recommends the prescription of two AAIs, which should be carried by patients at all times. The European Academy of Allergy and Clinical Immunology guidelines propose to prescribe a second AAI under some defined conditions. In the present study, we aimed to examine the adherence to these guidelines and prescription behavior of allergy experts regarding the number of AAIs prescribed for a given patient. Methods: A standardized questionnaire was applied to the participants of the 5th International Conference of the Network of Online Registration for Anaphylaxis (NORA e. V.). Twenty-six experts (medical doctors with at least 2 years of experience in the field of anaphylaxis) answered the questions regarding the number of autoinjectors prescribed and the reasons influencing their decisions. Results: Sixty-eight percent of the experts usually prescribed one AAI, while 32% prescribed two. The pediatricians and physicians with less experience tended to prescribe two autoinjectors more frequently. The experts were more likely to prescribe two adrenaline autoinjectors if the patient was a child, had a previous severe reaction, had mastocytosis, asthma, cardiovascular disease, or high body weight, or lived far from the emergency department. Conclusion: Our data confirm the lack of consensus regarding the number of AAIs to prescribe. Despite the European Medical Agency recommendation, the majority of allergy experts prescribed one autoinjector per patient. However, under distinct circumstances (e.g. mastocytosis, asthma, excess body weight, a history of severe anaphylaxis, or restricted access to immediate emergency), experts tended to prescribe more AAIs, which is in accordance with the European Academy of Allergy and Clinical Immunology guidelines. [ABSTRACT FROM AUTHOR]

Background: Contact urticaria (CU) is an infrequent, mostly occupational disease that may be life‐threatening (CU syndrome stage 4). Objectives: To identify the current frequency, elicitors and cofactors of CU. Patients: Three cohorts were retrospectively analysed for CU: (a) patients from the Information Network of Departments of Dermatology (IVDK) database (2000‐2014; n = 159 947); (b) patients from an allergy unit (Department of Dermatology, University Hospital Erlangen, 2000‐2015; n = 4741); and (c) patients from the Anaphylaxis Registry (2007‐2015: 6365 reported cases, including 2473 patients with Ring and Messmer grade III‐IV reactions) for severe cases with skin/mucosal manifestations occurring at the workplace vs cases not occurring at the workplace (n = 68 vs n = 1821). Results: Four hundred and forty‐eight CU patients (0.28%) were diagnosed in the IVDK cohort, and 16 (0.34%) (10 of immunological aetiology, and 6 of non‐immunological aetiology) in the Erlangen cohort. The most frequent elicitors in the IVDK cohort were cosmetics, creams, sun protection agents (although these were less frequent in CU patients than in controls without CU; 26.8% vs 35.6%, P < .0001), and gloves (significantly more frequent in CU patients than in controls; 18.1% vs 6.5%, P < .0001). The most frequent elicitors in the Erlangen cohort were natural rubber latex and sorbic acid. Among the MOAHLFA index characteristics, in both cohorts occupational disease was more common in CU patients than in patients without CU. CU was significantly associated with allergic rhinitis and allergic asthma. Wet work was a relevant cofactor. In the Anaphylaxis Registry, 19 cases (0.3%) were identified with severe reactions including skin symptoms at the workplace linked to common occupational elicitors. Conclusions: CU is a rare occupational skin manifestation with a frequency of <0.4% in the examined patients; it may, however, progress to anaphylaxis. Preventive measures are important, and should take into account the identified elicitors and cofactors. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic data on occupational anaphylaxis is scarce, and there is a need of more knowledge about work‐related anaphylactic episodes. Methods: Based on the data of the Anaphylaxis Registry, we identified cases related to occupational exposure and analyzed the elicitors, demographics, severity of clinical reaction and management. Results: Since 2017, 5851 cases with an information about the occupational relation of the anaphylactic episode were registered whereby 225 (3.8%) were assigned to be caused by an occupational allergen. The vast majority of these occupational anaphylaxis cases were caused by insects (n = 186, 82.7%) followed by food (n = 27, 12.0%) and drugs (n = 8, 3.6%). Latex elicited occupational anaphylaxis in only two cases. Beekeepers, gardeners, farmers, and individuals working in professions associated with food handling, for example, employees in restaurants, bakery, pastry, and cooks were most frequently affected. The comparison of the occupational insect venom‐induced anaphylaxis to a group of non‐occupational insect anaphylaxis in adults (n = 1842) revealed a significant younger age in occupational anaphylaxis (46 vs. 53 years), a predominance of bee‐induced cases (38% vs. 17%), and a higher rate of venom immunotherapy in a primary care setting (3.3% vs. 1.3%, p =.044). In the occupational‐ versus non‐occupational adults with food‐induced anaphylaxis atopic dermatitis as concomitant atopic disease was observed more frequently (n = 486; 20% vs. 10%), although this was not significant. Conclusion: Our data demonstrate the impact of venom allergy in work‐related anaphylaxis. Foods and drugs are less frequently elicitors, and latex‐induced occupational anaphylaxis was rare. More data are needed to determine risk factors associated with occupational anaphylaxis. [ABSTRACT FROM AUTHOR]

Background: Drugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment. Methods: Data from the European Anaphylaxis Registry (2007–2019) with 1815 reported cases of drug‐induced anaphylaxis were studied accordingly. Results: Drugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use. Conclusion: The study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines. [ABSTRACT FROM AUTHOR]

The impact on health‐related quality of life (HRQL) plays a key role for patients suffering from allergies and anaphylaxis. In this narrative review we review the HRQL in allergic patients suffering from food and venom allergy, both being the most frequent elicitors of severe allergic, potential life‐threatening reactions and provide an overview on the current knowledge and identified gaps. The data show that for food and venom allergy standardized assessment tools to measure HRQL are available and have been successfully applied. Our analysis shows that multiple factors can modulate HRQL in these patient groups. These include sociodemographic data like patients' age and sex, fear of accidental reactions but also external factors like the social environment and the appreciation of the seriousness of the condition by others. External factors may have a significant impact on HRQL and should be considered in patient‐related outcome assessments to avoid biased measurements possibly affecting the results. The assessment of the quality of life in the context of specific immunotherapy should consider lifestyle factors and ideally, the individual change in HRQL should be measured. Although there are many data indicating a negative impact on HRQL in food allergic children and their caregivers, limited data are existing from adults with food allergy and venom allergic patients from all age groups. Also, the use of standardized questionnaires should be extended to allow for a better comparability of results between studies. Therefore, translation to additional languages is necessary. Taken together, the eliciting allergen, the severity of the allergic disease but moreover multiple external factors impact the outcome in HRQL and should be considered in HRQL assessment. [ABSTRACT FROM AUTHOR]

Background: Food allergy is a growing health concern with a prevalence of 2%–3% in the adult population in Europe. Non‐immune‐mediated food hypersensitivities, which include reactions after ingestion of food additives, affect 1% of adults and may resemble IgE‐induced allergic reactions without identifiable immunologic sensitization. A double‐blind placebo‐controlled food challenge (DBPCFC) is the gold standard for the diagnosis of any food hypersensitivity. Objective: We analysed a large group of adult patients with suspected food hypersensitivity, who had undergone DBPCFC, to better understand IgE‐mediated food allergy and non‐immune‐dependent food hypersensitivity to food additives in adults regarding elicitors, symptoms and positivity rates of oral challenges. Methods: Data from 541 patients with suspected food hypersensitivity were analysed, who underwent an oral food challenge between 2010 and 2019. Results: IgE‐dependent food allergy was confirmed in 114 of 329 adult patients (34.6%). The confirmation rate was lower in the group of patients with suspected non‐immune‐mediated reactions to food additives (65 of 286, 22.7%). Urticaria and angioedema appeared more frequently in patients with IgE‐mediated food allergies. By contrast, flush and diarrhoea were the most frequent symptoms after a challenge in the group with the non‐immune‐mediated reactions to food additives. Wheat and celery were the most frequently identified food allergens in adults, whereas colourings and preservatives were the most frequent elicitors of non‐immune‐mediated food hypersensitivity. Conclusion: The importance of oral food challenges for the diagnosis of food hypersensitivity is confirmed. IgE‐dependent food allergy is more frequently proven, reaching a positivity rate of one‐third and only about 20% for non‐immune‐mediated hypersensitivity. Future studies should elaborate on the mechanisms of non‐immune‐mediated food hypersensitivity and the clinical impact of cofactors in this setting. [ABSTRACT FROM AUTHOR]

Anaphylaxis, anaphylaxis severity, artificial intelligence, artificial neuronal network, machine learning AI trained with cases, evaluated in consensus by several experts, could be applied in the future as an universal tool to evaluate anaphylaxis caused by different elicitors in different age groups and thereby improve quality of anaphylaxis research. Keywords: anaphylaxis; anaphylaxis severity; artificial intelligence; artificial neuronal network; machine learning EN anaphylaxis anaphylaxis severity artificial intelligence artificial neuronal network machine learning 1244 1246 3 04/14/21 20210401 NES 210401 To the Editor, Anaphylaxis is an acute systemic allergic reaction, the clinical course of which may vary between some mild symptoms and life-threatening cardiovascular or respiratory involvement. [Extracted from the article]

Background: IgE‐mediated food allergy is the result of an aberrant immune response involving the interaction of a food allergen with its specific IgE bound to FcɛRI, the high affinity IgE receptor, on mast cells. Allergen‐specific IgE also binds to soluble binding factors, but, their expression and role in food allergy is not well characterized. Here, we assess the prevalence and relevance of soluble IgE binding factors in food allergy and tolerance. Methods: We measured serum levels of four IgE binding factors, that is, galectin‐3, galectin‐9, soluble FcɛRI (sFcεRI) and soluble CD23 (sCD23) in 67 adults sensitized to peanut or hazelnut and sFcɛRI in 29 children sensitized to hen's egg. Adults without food allergen sensitization (n = 17) served as healthy controls. We compared serum levels of patients and controls and assessed them, in the former, for links to clinical features including allergy and tolerance. Results: Serum levels of sFcɛRI and sCD23, but not galectin‐3 and galectin‐9, significantly differ in food‐sensitized patients as compared to healthy controls. A subgroup (28%) of peanut and hazelnut allergic patients had elevated sFcεRI levels, that were associated with higher total and specific IgE levels. Furthermore, sFcεRI levels were significantly higher in tolerant subjects compared to allergics. Among hazelnut allergic patients, those with high sFcεRI levels tolerated the highest protein amounts in the oral food challenge. Conclusion: sFcɛRI but not sCD23, galectin‐3 and galectin‐9 might play a role in the pathophysiology of food allergy. Its functional role or use as biomarker should be assessed in further studies. [ABSTRACT FROM AUTHOR]

Background: Peanut allergy is a frequent cause of food allergy and potentially life‐threatening. Within this interdisciplinary research approach, we aim to unravel the complex mechanisms of peanut allergy. As a first step were applied in an exploratory manner the analysis of peanut allergic versus non‐allergic controls. Methods: Biosamples were studied regarding DNA methylation signatures, gut microbiome, adaptive and innate immune cell populations, soluble signaling molecules and allergen‐reactive antibody specificities. We applied a scalable systems medicine computational workflow to the assembled data. Results: We identified combined cellular and soluble biomarker signatures that stratify donors into peanut‐allergic and non‐allergic with high specificity. DNA methylation profiling revealed various genes of interest and stool microbiota differences in bacteria abundances. Conclusion: By extending our findings to a larger set of patients (e.g., children vs. adults), we will establish predictors for food allergy and tolerance and translate these as for example, indicators for interventional studies. [ABSTRACT FROM AUTHOR]

Background: The heterogeneity and lack of validation of existing severity scores for food allergic reactions limit standardization of case management and research advances. We aimed to develop and validate a severity score for food allergic reactions. Methods: Following a multidisciplinary experts consensus, it was decided to develop a food allergy severity score (FASS) with ordinal (oFASS) and numerical (nFASS) formats. oFASS with 3 and 5 grades were generated through expert consensus, and nFASS by mathematical modeling. Evaluation was performed in the EuroPrevall outpatient clinic cohort (8232 food reactions) by logistic regression with request of emergency care and medications used as outcomes. Discrimination, classification, and calibration were calculated. Bootstrapping internal validation was followed by external validation (logistic regression) in 5 cohorts (3622 food reactions). Correlation of nFASS with the severity classification done by expert allergy clinicians by Best‐Worst Scaling of 32 food reactions was calculated. Results: oFASS and nFASS map consistently, with nFASS having greater granularity. With the outcomes emergency care, adrenaline and critical medical treatment, oFASS and nFASS had a good discrimination (receiver operating characteristic area under the curve [ROC‐AUC]>0.80), classification (sensitivity 0.87–0.92, specificity 0.73–0.78), and calibration. Bootstrapping over ROC‐AUC showed negligible biases (1.0 × 10−6–1.23 × 10−3). In external validation, nFASS performed best with higher ROC‐AUC. nFASS was strongly correlated (R 0.89) to best‐worst scoring of 334 expert clinicians. Conclusion: FASS is a validated and reliable method to measure severity of food allergic reactions. The ordinal and numerical versions that map onto each other are suitable for use by different stakeholders in different settings. [ABSTRACT FROM AUTHOR]

Background: Up to 8% of all children in industrialized countries suffer from food allergies, whereas children with atopic eczema are affected considerably more frequently. In addition, the type and starting time of weaning foods seem to influence the development of food allergies. However, data from interventional studies on weaning are controversial. The aim of this randomized-controlled clinical trial is to investigate, whether an early introduction of hen's egg (HE), cow's milk (CM), peanut (PN), and hazelnut (HN) in children with atopic eczema can reduce the risk for developing food allergies in the first year of life.Methods: This is a protocol for a randomized, placebo controlled, double blind, single-center clinical trial. One hundred fifty infants with atopic eczema at 4-8 months of age will be randomized in a 2:1 manner into an active group that will receive rusk-like biscuit powder with HE, CM, PN, and HN (initially approximately 2 mg of each food protein) for 6-8 months or a placebo group, whose participants will receive the same rusk-like biscuit powder without HE, CM, PN, and HN on a daily basis. During the interventional period, the amount of allergens in the study product will be increased three times, each after 6 weeks. All study participants who are sensitized to HE, CM, PN, or HN at the end of the interventional period will undergo an oral food challenge to the respective food in a further visit. Primary endpoint is IgE-mediated food allergy to at least one of the four foods (HE, CM, PN or HN) after 6-8 months of intervention (i.e., at around 1 year of age). Secondary endpoints include multiple food allergies, severity of eczema, wheezing, and sensitization levels against food allergens.Discussion: This clinical trial will assess whether an early introduction of allergenic foods into the diet of children with atopic eczema can prevent the development of food allergies. This trial will contribute to update food allergy prevention guidelines.Trial Registration: German Clinical Trials Register DRKS00016770 . Registered on 09 January 2020. [ABSTRACT FROM AUTHOR]