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Abstract In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century. The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients’ organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels. Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.

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

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Background: Oral food challenge using gluten and cofactors is the gold standard to diagnose wheat-dependent exercise-induced anaphylaxis (WDEIA), but this procedure puts patients at risk of an anaphylactic reaction. Specific IgE to ω5-gliadins as major allergens and skin prick tests to wheat may yield negative results. Thus, we designed a proof-of-principle study to investigate the utility of the basophil activation test (BAT) for WDEIA diagnosis., Methods: Different gluten protein types (GPT; α-, γ-, ω1,2- and ω5-gliadins, high-molecular-weight glutenin subunits [HMW-GS] and low-molecular-weight glutenin subunits [LMW-GS]) and gluten were used in different concentrations to measure basophil activation in 12 challenge-confirmed WDEIA patients and 10 control subjects. The results were compared to routine allergy diagnostics. Parameters analyzed include the percentage of CD63 + basophils, the ratio of %CD63 + basophils induced by GPT/gluten to %CD63 + basophils induced by anti-FcεRI antibody, area under the dose-response curve and test sensitivity and specificity., Results: GPT and gluten induced strong basophil activation for %CD63 + basophils and for %CD63 + /anti-FcɛRI ratio in a dose-dependent manner in patients, but not in controls ( p  < 0.001, respectively). BAT performance differed from acceptable (0.73 for LMW-GS) to excellent (0.91 for ω5-gliadins) depending on the specific GPT as evaluated by the area under the receiver operating characteristic curve. Patients showed individual sensitization profiles. After determination of the best cut-off points, ω5-gliadins and HMW-GS showed the best discrimination between patients and controls with a sensitivity/specificity of 100/70 and 75/100, respectively., Conclusion: This study shows the alternative role of BAT in better defining WDEIA and the causative wheat allergens. The best BAT parameters to distinguish WDEIA patients from controls were %CD63 + basophil values for ω5-gliadins and HMW-GS., Competing Interests: B. Eberlein received methodological and technical support from Buehlmann Laboratories AG (Schönenbuch, Switzerland). The other authors declare no competing interests., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

The clinical threshold in wheat-dependent, exercise-induced anaphylaxis seems to be lowered in patients on wheat free diet, whereas the opposite is seen in patients on regular wheat intake. Therefore, a recommendation of wheat consumption, if considered safe to the patient based on case-history and challenge results, could be advised., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: In wheat-dependent exercise-induced anaphylaxis (WDEIA), cofactors such as exercise, acetylsalicylic acid (ASA), alcohol or unfavorable climatic conditions are required to elicit a reaction to wheat products. The mechanism of action of these cofactors is unknown, but an increase of gliadin absorption has been speculated. Our objectives were to study gliadin absorption with and without cofactors and to correlate plasma gliadin levels with factors influencing protein absorption in healthy volunteers., Methods: Twelve healthy probands (six males, six females; aged 20-56 years) ingested 32 g of gluten without any cofactor or in combination with cofactors aerobic and anaerobic exercise, ASA, alcohol and pantoprazole. Gliadin serum levels were measured up to 120 min afterwards and the intestinal barrier function protein zonulin in stool was collected before and after the procedure; both were measured by ELISA. Stool microbiota profile was obtained by 16S gene sequencing., Results: Within 15 min after gluten intake, gliadin concentrations in blood serum increased from baseline in all subjects reaching highly variable peak levels after 15-90 min. Addition of cofactors did not lead to substantially higher gliadin levels, although variability of levels was higher with differences between individuals (p < 0.001) and increased levels at later time points. Zonulin levels in stool were associated neither with addition of cofactors nor with peak gliadin concentrations. There were no differences in gut microbiota between the different interventions, although the composition of microbiota (p < 0.001) and the redundancy discriminant analysis (p < 0.007) differed in probands with low versus high stool zonulin levels., Conclusion: The adsorption of gliadin in the gut in healthy volunteers is less dependent on cofactors than has been hypothesized. Patients with WDEIA may have a predisposition needed for the additional effect of cofactors, e.g., hyperresponsive or damaged intestinal epithelium. Alternatively, other mechanisms, such as cofactor-induced blood flow redistribution, increased activity of tissue transglutaminase, or increases in plasma osmolality and acidosis inducing basophil and mast cell histamine release may play the major role in WDEIA., Competing Interests: The authors declare that they have no competing interests.

Anaphylaxis is the maximal variant of an acute allergic reaction involving several organ systems. The phenomenon itself is old, but it was recognized and named at the beginning of the 20th century by Richet and Portier. The clinical symptoms of anaphylaxis affect various organs, most commonly starting in the skin and proceeding to the respiratory tract, to gastrointestinal involvement and to cardiovascular symptoms, and finally to cardiac and/or respiratory arrest. Anaphylaxis stricto sensu is an immunological reaction, mostly mediated by IgE antibodies, but also by IgG or IgM antibodies (immune complex anaphylaxis). There are cases with similar clinical symptomatology without detectable immunological sensitization which are called pseudo-allergic or anaphylactoid reactions. In the newer nomenclature, some authors tend to include these under the heading of 'anaphylaxis' which has then to be defined as an acute systemic hypersensitivity reaction. The most common elicitors of anaphylaxis include drugs, foods, additives, but also other allergens as well as physical factors (cold, heat, UV radiation). The clinical outcome--the intensity of the reaction--is not only influenced by the degree of sensitization, but also by concomitant other factors: sometimes, individuals only develop anaphylaxis after simultaneous exposure to the allergen and an infection, physical exercise, psychological stress or concomitant medication (e.g. beta blockers). The term 'summation anaphylaxis' has been proposed for this phenomenon which probably underlies many cases of so-called idiopathic anaphylaxis. In patients with insect venom anaphylaxis, decreased levels of plasma angiotensin have been measured in inverse correlation to the severity of the reaction. Certain differential diagnoses have to be distinguished from anaphylaxis. Every patient with a history of anaphylaxis should undergo allergy diagnosis with the aim to detect the eliciting agent, characterize the relevant pathomechanism (e.g. IgE-mediated reaction) and to offer a tolerable alternative (in food or drug allergy). In clear-cut IgE-mediated anaphylaxis, allergen-specific immunotherapy (hyposensitization) is the effective causal treatment, with success rates of 90% in insect venom anaphylaxis.

A 12-year-old girl developed acanthosis nigricans due to increased levels of serum insulin. Hyperinsulinemia has been recognized as the underlying cause in most cases of acanthosis nigricans. In this paper we outline a typical clinical case with special regard to the proposed pathogenesis.