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Background: It is mandatory to label food products with the 14 main allergens in the EU. Reasonable allergen labeling requires knowledge of population-based thresholds derived from food challenges. The aim of this study was to evaluate the threshold-distribution in clinically verified food allergic patients for allergens mandatory for labeling., Methods: All positive open oral food challenges and double-blind placebo-controlled food challenges (DBPCFC) performed at the Allergy Center, Odense University Hospital, Denmark (2000-2022) were included. For each included challenge, the cumulative threshold (LOAEL) was obtained and NOAEL estimated. Data were modelled as an interval censored log-normal distribution., Results: Overall, 38 of all 2612 challenges (1.5%) in 1229 patients (717 male, 986 children) reacted to <5 mg protein. The majority of the most sensitive patients reacted with a Sampson severity score of 2-3. Using interval censored log-normal models only five groups (hens´ egg, fish, peanut, milk, tree-nuts) elicited reactions after ingestion of 0.5 mg protein and in low frequencies of the population. Hen's egg was the most potent allergen, with reactivity to <0.5 mg protein in 0.24% [0.13-0.44%] of egg allergic patients while the estimated fraction of allergic patients reacting to a eliciting dose on 0.5 mg protein for most other allergens were below 0.04%., Conclusion: Our data demonstrates that the majority of food allergic patients as expected tolerating traces of allergenic foods without developing severe allergic symptoms and signs. Hen's egg appears to be the food most likely to elicit reactions in the most sensitive individuals at very low doses., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Diagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high-quality diagnostic allergens for in vivo diagnosis of IgE-mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies. With the need to ensure the availability of high-quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens. Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Allergic contact dermatitis is a widespread health disorder and occupational skin disease. Hence, screening for contact-sensitizing chemicals is highly relevant to toxicology, dermatology, and occupational medicine. The use of animal tests for this purpose is constrained by ethical considerations, need for high-throughput screening, and legislation (e.g., for cosmetics in the European Union). T cell activation is the final and most specific key event of the "adverse outcome pathway" for skin sensitization and therefore a promising target for the development of in vitro sensitization assays. We present a novel in vitro sensitization assay with a lymphocyte endpoint as an add-on to the loose-fit coculture-based sensitization assay (LCSA): the LCSA-ly. While the LCSA measures dendritic cell activation, the LCSA-ly offers the option for an additional lymphocyte endpoint which can be measured concurrently. We incorporated lymphocytes in our previously established coculture of primary human keratinocytes and monocyte-derived dendritic cells and tested nine substances: five sensitizers [2,4-dinitrochlorobenzene (DNCB) 1.25-15 µmol/l, p-phenylenediamine (PPD) 15.6-125 µmol/l, 2-mercaptobenzothiazole (MBT) 50-1000 µmol/l, coumarin, and resorcinol (both: 250-1500 µmol/l)] and four non-sensitizers (monochlorobenzene, caprylic acid, glycerol, and salicylic acid (all: 125-1000 µmol/l)]. DNCB and MBT increased a subset of IL-23 receptor + /IFN-γ receptor 1 (CD119) + lymphocytes. DNCB, PPD, and MBT enhanced a subunit of the IL-4 receptor (CD124) and a memory marker (CD44) on lymphocytes. Remarkably, DNCB, PPD, and MBT raised IL-4 concentrations in coculture supernatants while IFN-γ levels decreased, which might point to Th2 activation in vitro. Coumarin, resorcinol, and non-sensitizers did not alter any of the tested surface markers or cytokines. IL-17 was not affected by any of the substances. Relative strength of sensitizers according to lymphocyte markers was DNCB > PPD > MBT, which corresponds to earlier results from the LCSA without lymphocyte endpoint, the murine local lymph node assay, and human data. This study is the first to prove the suitability of lymphocyte surface markers for sensitization testing and potency assessment.

Background: Allergen exposure chambers (AECs) are clinical facilities allowing for controlled exposure of subjects to allergens in an enclosed environment. AECs have contributed towards characterizing the pathophysiology of respiratory allergic diseases and the pharmacological properties of new therapies. In addition, they are complementary to and offer some advantages over traditional multicentre field trials for evaluation of novel therapeutics. To date, AEC studies conducted have been monocentric and have followed protocols unique to each centre. Because there are technical differences among AECs, it may be necessary to define parameters to standardize the AECs so that studies may be extrapolated for driving basic immunological research and for marketing authorization purposes by regulatory authorities., Methods: For this task force initiative of the European Academy of Allergy and Clinical Immunology (EAACI), experts from academia and regulatory agencies met with chamber operators to list technical, clinical and regulatory unmet needs as well as the prerequisites for clinical validation., Results: The latter covered the validation process, standardization of challenges and outcomes, intra- and interchamber variability and reproducibility, in addition to comparability with field trials and specifics of paediatric trials and regulatory issues., Conclusion: This EAACI Position Paper aims to harmonize current concepts in AECs and to project unmet needs with the intent to enhance progress towards use of these facilities in determining safety and efficacy of new therapeutics in the future., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Field clinical trials of pollen allergy are affected by the impossibility of predicting and determining individual allergen exposure because of many factors (eg, pollen season, atmospheric variations, pollutants, and lifestyles). Environmental exposure chambers, delivering a fixed amount of allergen in a controlled environmental setting, can overcome these limitations. Environmental exposure chambers are currently already used in phase 2, 3, and even 4 trials. Unfortunately, few chambers exist in the world, and this makes it difficult to perform large, multicenter clinical trials. The new Global Allergy and Asthma European Network (GA 2 LEN) mobile exposure chamber is a step forward because the mobility of the chamber makes it convenient for patients to participate in clinical testing., Objective: This study was made to validate the reproducibility, sensitivity, and specificity of the results obtained in the new GA 2 LEN chamber., Methods: Seventy-two adult patients (19-61 years old) with allergic rhinitis with or without asthma caused by grass pollen were included in different clinical validation tests. Total symptom scores and total nasal symptom scores were recorded at time zero (0) and every 10 minutes during exposures, along with nasal and respiratory parameters., Results: Exposure tests confirmed the reproducibility between subsequent runs and the sensitivity (P < .00001 vs patients exposed to placebo) and specificity (very low score in nonallergic subjects) in the GA 2 LEN chamber. No adverse reactions were recorded during the tests., Conclusions: The mobility of the GA 2 LEN chamber provides a new, potentially effective, and safe way of generating reliable data in allergy multicenter clinical trials., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

For nearly a decade, the majority of the world's population has been living in cities, including a considerable percentage of people suffering from pollen allergy. The increasing concentration of people in cities results in larger populations being exposed to allergenic pollen at the same time. There is almost no information about spatial distribution of pollen within cities as well as a lack of information about the possible impact to human health. To obtain this increasing need for pollen exposure studies on an intra-urban scale, a novelty screening network of 14 weekly changed pollen traps was established within a large metropolitan area-Berlin, Germany. Gravimetric pollen traps were placed at a uniform street-level height from March until October 2014. Three important allergenic pollen types for Central Europe-birch (Betula), grasses (Poaceae), and mugwort (Artemisia)-were monitored. Remarkable spatial and temporal variations of pollen sedimentation within the city and the influences by urban local sources are shown. The observed differences between the trap with the overall highest and the trap with the overall lowest amount of pollen sedimentation were in the case of birch pollen 245%, grass pollen 306%, and mugwort pollen 1962%. Differences of this magnitude can probably lead to different health impacts on allergy sufferers in one city. Therefore, pollen should be monitored preferably in two or more appropriate locations within large cities and as a part of natural air quality regulations.

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non-IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The in vitro sensitization assay LCSA (Loose-fit Coculture-based Sensitization Assay) has proved reliable for the detection of contact sensitizers in the past. However, the coculture of human monocyte-derived dendritic cells (DCs) with primary human keratinocytes (KCs) in serum-free medium is relatively complex compared to other sensitization assays which use continuous cell lines. To facilitate high-throughput screening of chemicals, we replaced KCs with the HaCaT cell line under various culture conditions. Coculture of HaCaT with peripheral blood mononuclear cells in serum-supplemented medium leads to generation of CD1a + /CD1c + DCs after addition of GM-CSF, IL-4, and TGF-β1 (as opposed to CD1a - /CD1c - DCs which arise in the "classic" LCSA coculture). These cells resemble monocyte-derived DCs generated in monoculture, but, unlike those, they show a marked upregulation CD86 after treatment with contact allergens. All of the nine sensitizers in this study were correctly identified by CD1a + /CD1c + DCs in coculture with HaCaT. Among the substances were weak contact allergens such as propylparaben (which is false negative in the local lymph node assay in mice) and resorcinol (which was not detected by CD1a - /CD1c - DCs in the "classic" LCSA). The level of CD86 upregulation on CD1a + /CD1c + DCs was higher for most allergens compared to CD1a - /CD1c - DCs, thus improving the assay's discriminatory power. Three out of four non-sensitizers were also correctly assessed by the coculture assay. A false-positive reaction to caprylic (octanoic) acid confirms earlier results that some fatty acids are able to induce CD86 on DC in vitro. In conclusion, change of the LCSA protocol led to reduction of time and cost while even increasing the assay's sensitivity and discriminatory power.

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings., Objective: To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points., Methods: The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated., Results: Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen., Conclusion: These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use., (© 2013 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Aims of the Monaco Charter: (1) to present the current evidence on the efficacy and safety of allergen-specific immunotherapy (SIT) and to address the reasons for its underuse in clinical practice; (2) to develop strategies to increase the awareness about the benefits and the hazards of SIT in allergic patients, lay public and healthcare professionals not trained in allergy, and (3) to make SIT accessible and affordable to eligible patients., (Copyright © 2012 S. Karger AG, Basel.)

Immunotherapy was introduced 100 years ago and still is the only treatment that modifies the course of allergic diseases. The success of its use depends on correct indications, use of standardized extracts and monitoring the therapeutic response., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Specific immunotherapy (SIT) is one of the treatments for allergic rhinitis. However, for allergists, nonspecialists, regulators, payers, and patients, there remain gaps in understanding the evaluation of randomized controlled trials (RCTs). Although treating the same diseases, RCTs in SIT and pharmacotherapy should be considered separately for several reasons, as developed in this study. These include the severity and persistence of allergic rhinitis in the patients enrolled in the study, the problem of the placebo, allergen exposure (in particular pollen and mite), the analysis and reporting of the study, the level of symptoms of placebo-treated patients, the clinical relevance of the efficacy of SIT, the need for a validated combined symptom-medication score, the differences between children and adults and pharmacoeconomic analyses. This statement reviews issues raised by the interpretation of RCTs in sublingual immunotherapy. It is not possible to directly extrapolate the rules or parameters used in medication RCTs to SIT. It also provides some suggestions for the research that will be needed. Interestingly, some of the research questions can be approached with the available data obtained from large RCTs., (© 2011 John Wiley & Sons A/S.)

Background: The diagnosis of cattle-related sensitization is complicated by the variability and complexity of cattle allergen extracts., Objective: To evaluate a modified diagnostic procedure leading to more accurate results especially in the early phase of sensitization., Methods: We tested 27 claw trimmers with and 65 without cattle-related symptoms using two commercially available cattle allergen extracts. We also used a self-prepared cattle allergen mix designed to represent the full spectrum of cattle allergens from a typical agricultural workplace., Results: More than 50% of symptomatic claw trimmers showed negative test results with commercial extracts and a sensitization cutoff point of 0.35 kU/l. In contrast, with the self-prepared cattle allergen mix, positive results were observed for almost all of them. Evaluating the results of the commercial test kits at different cutoff levels, we found an ideal cutoff point to improve the sensitivity at 0.2 kU/l., Conclusion: Additional tests with self-made cattle hair extracts can help to bridge the diagnostic gap seen in patients showing cattle-related symptoms, but negative results in commercially available tests. For early-stage sensitization screening, we propose to lower the cutoff level indicating sensitization to 0.2 kU/l.

Background: Randomized trials provide evidence to inform treatment decisions. The Consolidated Standards of Reporting Trials (CONSORT) Statement is a set of recommendations for the reporting of trials., Objective: We sought to assess the quality of reporting allergen-specific immunotherapy trials according to CONSORT criteria., Methods: The reporting of the procedure, randomization, dropouts, strict conduct of intention-to-treat (ITT) analysis, and sample size calculation according to CONSORT were assessed in the 46 subcutaneous and 48 sublingual immunotherapy (SLIT) blind, placebo-controlled randomized trials published between 1996 and 2009 in English., Results: One subcutaneous immunotherapy (2.2%) and 3 SLIT (6.6%) trials met CONSORT Statement criteria. These were used for the registration of sublingual tablets to the European Medicines Agency. In subcutaneous immunotherapy, 16 (35%) studies reported a CONSORT flow chart, and 12 (26%) provided a description of dropouts. Adequate randomization was reported in 9 (35%) studies, and incomplete randomization was reported in 15 (33%). Power analysis was reported in 15 (33%) studies. In SLIT, 20 (42%) studies reported a CONSORT flow chart, and 16 (32%) a description of dropouts. ITT analysis was carried out in 1 (2.2%) SLIT study, and a modified ITT analysis was used in 1 (2.2%) subcutaneous immunotherapy study and 2 (4.4%) SLIT studies. Adequate randomization was reported in 6 (12%) studies, and incomplete randomization was reported in 16 (32%). Power analysis was reported in 15 (27%) studies., Conclusion: As in other areas of medicine, the quality of reporting of most immunotherapy trials is low, and only 4.2% of SLIT randomized controlled trials met all of the criteria of the CONSORT Statement. Use of the CONSORT criteria should be encouraged., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

We have developed a coculture system which in parallel indicates the sensitizing and irritative potential of xenobiotics. The assay is named loose-fit coculture-based sensitization assay (LCSA) and may be performed within 5 days. The system is composed of human monocytes that differentiate to a kind of dendritic cells by 2-day culturing in the presence of allogenic keratinocytes. The culture medium is enriched by a cocktail of recombinant cytokines. On day 3, concentration series of probes are added. On day 5, cells are harvested and analyzed for expression range of CD86 as a marker of sensitizing potential and for uptake of the viability stain 7-AAD as a marker of irritative potential. Estimation of the concentration required to cause a half-maximal increase in CD86 expression allowed quantification of sensitizing potential, and estimation of the concentration required to reduce viability to 50% allowed quantification of irritative potential. Examination of substances with known potential resulted in categorization of test scores. To evaluate our data, we have compared results with those of the validated animal-based sensitization test, the murine local lymph node assay (LLNA, OECD TG 429). To a large extent, results from LCSA and from LLNA achieved analogous grouping of allergens into categories like weak-moderate-strong. However, the new assay showed an improved capacity to distinguish sensitizers from non-sensitizers and irritants. In conclusion, the LCSA contains potential to fulfil the requirements of the EU's programme for the safety of chemicals "Registration, Evaluation, Authorization and Restriction of chemical substances" (REACH, 2006) to replace animal models., ((c) 2010 Elsevier Inc. All rights reserved.)

Background: Sodium cromoglicate (SCG) has long been used in the management of allergic diseases, including as an ointment for atopic dermatitis. Although mast cell stabilization was initially considered as its mechanism of action, anti-inflammatory actions and modulation of sensory nerve function have also been suggested., Objectives: To investigate the mechanism(s) by which SCG relieves allergen- and histamine-induced dermal inflammation by assessing its effects on pruritus, flare, skin temperature and weal volume., Methods: Aqueous cream containing 0.2%, 1% or 4% SCG or no SCG (placebo) was applied in a randomized single-blind manner to four areas on each forearm (two sites per arm) and covered with an occlusive dressing. One hour later, skin-prick tests were performed in 20 allergic subjects with allergens to which they had previously shown sensitization, and in 40 nonallergic subjects with codeine (9 mg mL(-1), 20 subjects) and histamine (10 mg mL(-1), 20 subjects). Weal volume, skin temperature increase, erythema area and pruritus intensity were assessed at 0, 5, 10 and 15 min., Results: SCG significantly (P < 0.05 to P < 0.001) reduced pruritus induced by all stimuli, with 4% SCG being most effective. Significant (P < 0.05 to P < 0.01) reductions of erythema area were also seen but there was no inhibition of weal volume or temperature increase., Conclusions: SCG is effective in reducing pruritus but has no effect on weals, supporting the proposition that, in the skin, SCG inhibits sensory C-fibre nerve activation rather than preventing mast cell degranulation. We suggest that topical SCG treatment, delivered in an appropriate vehicle, may be beneficial for symptomatic relief of pruritus in patients with cutaneous mastocytosis and other pruritic dermatoses.

Background: Mean diameter or longest diameter are the 2 most frequently used parameters for wheal response assessment after skin prick testing (SPT). We aimed to compare these 2 parameters taking as gold standard the surface of the wheal skin response., Patients and Methods: Patients suspected of having an allergic reaction against inhalant allergens have been skin prick tested using the Pan-European GA(2)LEN SPT panel. Fifteen minutes later, macroscopically evident wheal and flare reactions were marked with a pen and transferred to paper with a transparent scotch tape. Each paper-transferred wheal was scanned with an ordinary scanner, and its surface-corresponding maximum perpendicular diameters and longest diameters were measured using a computer software application for image recognition, developed for this purpose. Correlation coefficients (Spearman's rho) between surfaces and respective mean (rho(mean)) or longest (rho(longest)) diameters were calculated and subsequently compared., Results: 1,554 SPTs were performed in 74 patients. In 264, a macroscopically evident wheal and flare response was observed. Both mean and longest diameters correlated significantly with the wheal surfaces. However, rho(longest) was statistically significantly larger than rho(mean) when the surface of the wheal was >17 mm(2) (rho(longest) > 0.860 vs. rho(mean) < 0.660; p < 0.05).Such a surface corresponds to a maximum diameter of approximately 7 mm and a mean diameter of approximately 6 mm. Thus, the larger the surface of the wheal, the more appropriate the usage of the longest diameter., Conclusions: The longest wheal diameter alone seems to be a better surrogate marker of the wheal surface in comparison with the mean diameter. In addition, it is easier and faster to measure. Therefore, we propose this as the optimal methodology to evaluate SPTs., (2009 S. Karger AG, Basel.)

The methodology of randomized clinical trials is essential for the critical assessment and registration of therapeutic interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement was developed to alleviate the problems arising from the inadequate reporting of randomized controlled trials. The present article reflects on the items that we believe should be included in the CONSORT checklist in the context of conducting and reporting trials in allergen-specific immunotherapy. Only randomized, blinded (in particular blinding of patients, health care providers, and outcome assessors), placebo-controlled Phase III studies in this article. Our analysis focuses on the definition of patients' inclusion and exclusion criteria, allergen standardization, primary, secondary and exploratory outcomes, reporting of adverse events and analysis.

Background: The number of allergens to be tested in order to identify sensitized patients is important in order to have the most cost-effective approach in epidemiological studies., Objective: To define the minimal number and the type of skin prick test (SPT) allergens required to identify a patient as sensitized using results of the new Pan-European GA(2)LEN skin prick test study., Method: In a large Pan-European multicenter (17 centers in 14 countries) patient based study, a standardized panel of 18 allergens has been prick tested using a standardized procedure. Conditional approach allowed to determine the allergens selection., Result: Among the 3034 patients involved, 1996 (68.2%) were sensitized to at least one allergen. Overall, eight allergens (grass pollen, Dermatophagoides pteronyssinus, birch pollen, cat dander, Artemisia, olive pollen, Blatella and Alternaria) allowed to identified more than 95% of sensitized subjects. However, differences were observed between countries, two allergens being sufficient for Switzerland (grass pollen and cat dander) as opposed to nine for France (grass pollen, Dermatophagoides pteronyssinus, olive pollen, cat dander, Blatella, cypress, dog dander, alder and [Artemisia or Alternaria]). According to country, up to 13 allergens were needed to identify all sensitized subjects., Conclusion: Eight to ten allergens allowed the identification of the majority of sensitized subjects. For clinical care of individual patients, the whole battery of 18 allergens is needed to appropriately assess sensitization across Europe.

Background: Skin prick testing is the standard for diagnosing IgE-mediated allergies. However, different allergen extracts and different testing procedures have been applied by European allergy centres. Thus, it has been difficult to compare results from different centres or studies across Europe. It was, therefore, crucial to standardize and harmonize procedures in allergy diagnosis and treatment within Europe., Aims: The Global Asthma and Allergy European Network (GA(2)LEN), with partners and collaborating centres across Europe, was in a unique position to take on this task. The current study is the first approach to implement a standardized procedure for skin prick testing in allergies against inhalant allergens with a standardized pan-European allergen panel., Methods: The study population consisted of patients who were referred to one of the 17 participating centres in 14 European countries (n = 3034, median age = 33 years). Skin prick testing and evaluation was performed with the same 18 allergens in a standardized procedure across all centres., Results: The study clearly shows that many allergens previously regarded as untypical for some regions in Europe have been underestimated. This could partly be related to changes in mobility of patients, vegetation or climate in Europe., Conclusion: The results of this large pan-European study demonstrate for the first time sensitization patterns for different inhalant allergens in patients across Europe. The standardized skin prick test with the standardized allergen battery should be recommended for clinical use and research. Further EU-wide monitoring of sensitization patterns is urgently needed.

Background: Skin prick testing is the standard for diagnosing IgE-mediated allergies. A positive skin prick reaction, however, does not always correlate with clinical symptoms. A large database from a Global Asthma and Allergy European Network (GA(2)LEN) study with data on clinical relevance was used to determine the clinical relevance of sensitizations against the 18 most frequent inhalant allergens in Europe. The study population consisted of patients referred to one of the 17 allergy centres in 14 European countries (n = 3034, median age = 33 years). The aim of the study was to assess the clinical relevance of positive skin prick test reactions against inhalant allergens considering the predominating type of symptoms in a pan-European population of patients presenting with suspected allergic disease., Methods: Clinical relevance of skin prick tests was recorded with regard to patient history and optional additional tests. A putative correlation between sensitization and allergic disease was assessed using logistic regression analysis., Results: While an overall rate of >or=60% clinically relevant sensitizations was observed in all countries, a differential distribution of clinically relevant sensitizations was demonstrated depending on type of allergen and country where the prick test was performed. Furthermore, a significant correlation between the presence of allergic disease and the number of sensitizations was demonstrated., Conclusion: This study strongly emphasizes the importance of evaluating the clinical relevance of positive skin prick tests and calls for further studies, which may, ultimately, help increase the positive predictive value of allergy testing.

Background: Elevated specific IgE antibody levels are common in atopic individuals, caused by T-helper type 2-dominated B cell activation. The induction of antigen-specific IL-10 secreting T cells is discussed as an important mechanism during specific immunotherapy. By contrast the presence and function of B cell-derived IL-10 is not well defined yet., Objective: We investigated whether type-I allergen extracts induce IL-10 expression in human B cells and analysed its functional role on IgE production., Methods: Human peripheral B cells were stimulated with grass pollen, house dust mite (HDM) (Dermatophagoides pteronyssimus; Der p) and dog allergen extract. Expression of IL-10 by activated human B cells was determined by flow cytometric analysis and ELISA. Functional analysis considering immunoglobulin production was assayed by ELISA., Results: The allergen extracts studied induced IL-10 expression in B cells. However, the ability to induce IL-10 differed between the allergen extracts. The most potent allergen extract was dog (169+/-28 pg/mL), followed by grass pollen (141+/-10 pg/mL) and HDM allergen (125+/-11 pg/mL). Upon allergen extract stimulation only CD27 expressing memory B cells produced IL-10 and co-expressed the very early activation antigen CD69. The addition of allergen extracts to B cells activated by anti-CD40 and IL-4 selectively inhibited IgE which was dependent on allergen extract-induced IL-10. By contrast the other immunoglobulin subclasses like IgA, IgG or IgM were not altered upon allergen extract challenge., Conclusion: Our data indicate that allergen-activated memory B cells can modulate IgE production through secretion of IL-10.

Background: Pollen-associated food allergy is common. However, systemic reactions or even life-threatening anaphylaxis are rare., Objective: The aim of this study was to investigate the clinical impact of native, heat-processed and encapsulated hazelnuts (HN) in patients with proven HN allergy., Methods: One hundred and thirty-two patients with a positive history of HN allergy were recruited. Sensitization was confirmed by a skin prick test (SPT) and sIgE against HN. After an HN-free diet, double-blind placebo-controlled challenges were performed with increasing amounts of native and roasted HN. A subset of patients were given HN capsules to circumvent the oral mucosa. Basophil activation was measured by flow cytometry before and after provocation but also ex vivo using native and roasted HN extracts., Results: Three groups of HN-allergic patients were identified depending on their clinical reaction pattern. The dosages by which allergic reactions were elicitated varied for native HN from 0.01 to 2.0 g, with a median of 0.1 g, for roasted HN from 0.01 to 10.0 g, with a median of 0.23 g, and for encapsulated HN from 0.1 to 3.0 g, with a median of 0.3 g. Accordingly, the SPT was more frequently positive and resulted in greater weal reactions if native HN was used. This finding was confirmed by ex vivo basophil activation showing that significantly higher allergen extract concentrations (roasted>native) were necessary to induce 50% basophil activation., Conclusion: Our data show that heat processing of HN reduces its allergenicity. SPT but also the basophil activation test can be used to determine the reactivity of an allergen extract.

Skin testing has a central role in the diagnosis of food allergy. Prick testing is well- established as a routine diagnostic tool. Nonetheless, unstable allergens and the lack of standardized extracts create difficulties in the identification of sensitization to foods in patients with suspected food allergy. Therefore prick-to-prick tests with native (raw, fresh) foods are still recommended. The indications and contraindications are the same as those of routine skin testing in clinical allergology. We recommend a careful and restricted application of skin tests in patients with a history of severe anaphylaxis to foods.

Establishing of alternatives to animal tests is ethically desirable and gains in importance in context of new European Union regulations such as REACH. We have refined our new in vitro assay for prediction of the sensitizing potency of xenobiotics. Monocytes cocultured with primary human keratinocytes develop to a novel class of in vitro generated dendritic cells after treatment with transforming growth factor beta and Interleukin-4 in serum-free medium. These dendritic cell-related cells (DCrc) are the key players in the loose-fit coculture-based sensitization assay (LCSA). Assay duration and cytokine consumption could be cut down without impairing the assay's functionality. DCrc showed a dose-dependent upregulation of CD86 after treatment with the contact allergens 2,4,6-trinitrobenzenesulfonic acid, the prohapten isoeugenol, and alpha-hexyl cinnamic aldehyde. The metal allergens nickel and cobalt could be detected by measuring Interleukin-6 and macrophage inflammatory protein 1-beta (MIP-1beta, CCL-4) in coculture supernatants. The irritant zinc elicited no reaction. Lipopolysaccharide produced upregulation of CD86, IL-6 and MIP-1beta. Determination of tolerable concentrations of an allergen in consumer products requires a widely accepted sharp quantitative assay. Animal-based assays do not meet this requirement. The LCSA provides dose-response information, thereby allowing prediction of the relative ability of a substance to induce sensitization.

Protection against contact allergy begins with the collection of reliable data about the sensitizing potential of chemicals. Today, the local lymph node assay (LLNA) in mice is widely used to identify sensitizing substances. For several reasons, an in vitro assay could be preferable to animal experiments. We propose an in vitro test for the detection of a sensitizing potential of a chemical composed of a single layer of human nondifferentiating keratinocytes and of allogenic floating monocytes which are cocultured in serum-free medium in the presence of a cytokine cocktail. Within days, the coculture develops to an allergen- sensitive system consisting of activated keratinocytes and of mobile dendritic cell-related cells (DC-related cell). The sensitizing potential can be determined by analyzing the expression of the dendritic cell maturation marker CD86. For the model contact allergens tested so far [trinitrobenzenesulfonic acid (TNBS), phenylendiamine, and 4-aminoacetanilide], the strength of the reaction was in concordance with results from the LLNA. Sensitivity of the assay allowed testing at concentrations without general cytotoxicity. Thus, a differentiation between allergens and irritants was possible. Regarding cytokine secretion, the assay distinguished between the allergen TNBS and the Toll-like receptor ligand lipopolysaccharide. The coculture can be set up from cryopreserved cells. The assay is easy to perform and reproducible. Donor-variance is negligible. This in vitro assay based on a loose-fit coculture is a reasonable approach to screen for the sensitizing potential of xenobiotics and might partially replace the LLNA and other animal tests.

Background: House dust mites (HDMs) represent significant indoor allergen sources for patients with atopic dermatitis (AD). Subcutaneous allergen-specific immunotherapy (SCIT) has been shown to be successful in patients with allergic rhinitis and mild asthma and might represent an attractive therapeutic option for the long-term treatment of HDM sensitizations in AD patients. However, only a few studies have been conducted on the effectiveness of HDM SCIT in AD, resulting in controversial clinical results. Data on immunological changes induced by SCIT in AD patients are rare., Objectives: We performed an open pilot study to assess clinical changes and objective laboratory parameters and evaluate the benefit of HDM SCIT in 25 AD patients with IgE-mediated sensitization against HDM., Methods: The severity of AD was evaluated by the severity scoring of atopic dermatitis system (SCORAD). Specific IgE and IgG4 against HDM and serum levels of TARC/CCL17, MDC/CCL22, IL-16, IL-4, IFN-gamma, IL-10 and TGF-beta1 were measured during SCIT., Results: Subjective and objective SCORAD improved significantly within only 4 weeks of treatment. The level of the tolerogenic cytokine IL-10 increased, whereas CCL17 and IL-16 decreased in the sera of the patients during SCIT. Allergen specific IgE decreased, while IgG4 increased during SCIT., Conclusion: In this open-label pilot study, SCIT with an HDM extract in patients with AD led to a significant improvement of AD mirrored by a reduction of SCORAD as well as serological and immunological changes, which might serve as valuable parameters to estimate the therapeutic effect of SCIT.

Skin prick testing (SPT) is the standard method for diagnosing allergic sensitization but is to some extent performed differently in clinical centres across Europe. There would be advantages in harmonizing the standard panels of allergens used in different European countries, both for clinical purposes and for research, especially with increasing mobility within Europe and current trends in botany and agriculture. As well as improving diagnostic accuracy, this would allow better comparison of research findings in European allergy centres. We have compared the different SPT procedures operating in 29 allergy centres within the Global Allergy and Asthma European Network (GA(2)LEN). Standard SPT is performed similarly in all centres, e.g. using commercial extracts, evaluation after 15-20 min exposure with positive results defined as a wheal >3 mm diameter. The perennial allergens included in the standard SPT panel of inhalant allergens are largely similar (e.g. cat: pricked in all centres; dog: 26 of 29 centres and Dermatophagoides pteronyssinus: 28 of 29 centres) but the choice of pollen allergens vary considerably, reflecting different exposure and sensitization rates for regional inhalant allergens. This overview may serve as reference for the practising doctor and suggests a GA(2)LEN Pan-European core SPT panel.

Background: Previous studies have shown a 10-fold discrepancy of self-reported food-induced symptoms and physician-diagnosed food hypersensitivity. Little information is available on the prevalence of food hypersensitivity in unselected paediatric populations. No data were available for German children., Objective: To study the perception of food-induced symptoms in the paediatric population, to investigate the allergens accused, to objectify patients' reports, and to identify subgroups at risk of having food-induced allergy (FA) or non-allergic food hypersensitivity (NAFH) reactions., Methods: This paper presents the data of the paediatric group (0-17 years) of a representative, randomly sampled, cross-sectional population-based survey studying 13 300 inhabitants of the German capital city Berlin regarding food-related symptoms. Instruments included mailed questionnaires, structured telephone interviews, physical examination, skin-prick tests, specific serum IgE and standardized, controlled and blinded oral food challenges., Results: Two thousand three hundred and fifty-four individuals were contacted by mailed questionnaire, 739 (31.4%) responses could be fully evaluated. Four hundred and fifty-five (61.5%) participants reported symptoms related to food ingestion, 284 (38.4%) affirmed reproducible symptoms in the standardized telephone interview. One hundred and eighty-four (24.8%) individuals were fully examined. Reproducible symptoms to food were found in 31 (4.2%) children and adolescents: 26 (3.5%) showed symptoms of FA and five (0.7%) of NAFH. The oral allergy syndrome was most often observed. Foods most commonly identified by oral challenges were apple, hazelnut, soy, kiwi, carrot and wheat., Conclusion: The perception of food-related symptoms is common among children and adolescents from the general population. Self-reports could be confirmed in around one out of 10 individuals, still resulting in 4.2% of proven clinical symptoms. However, most reactions were mild and mainly because of pollen-associated FA, while NAFH reactions were less common. Severe IgE-mediated FA was observed in individuals with pre-existing atopic disease, who should be fully investigated for clinically relevant FA.

Background: CD23 plays an important role in IgE regulation. The modulation of CD23 expression during specific immunotherapy (SIT) has been described previously. In the present study, we investigated in detail the effects of complete birch pollen allergen extract (BPA) on CD23 expression of peripheral blood mononuclear cells (PBMCs) in vitro., Methods: PBMCs from 14 birch pollen-allergic (bp-allergic) patients and eight non-bp-allergic controls were stimulated with IL-4 and increasing doses of BPA. CD23 expression on monocytes and B cells was measured by flow cytometry; sCD23 release and the levels of IFN-gamma and IL-10 secretion were determined by ELISA. To analyse the mechanisms on CD23 expression in more detail, neutralizing anti-IFN-gamma and anti-IL-10 antibodies were added to IL-4 and BPA-stimulated cultures., Results: IL-4 induced CD23 expression on B cells and on monocytes and sCD23 release in the bp-allergic and non-bp-allergic groups. The addition of BPA to IL-4-stimulated PBMC decreased CD23 expression significantly and dose-dependently on B cells in both groups. CD23 expression on monocytes was also decreased in both groups after the addition of BPA, but higher doses were required in the non-bp-allergic population. IL-4-induced sCD23 release was also significantly decreased after the addition of BPA. IFN-gamma and IL-10 were induced by BPA in both the bp-allergic and non-bp-allergic groups. The addition of neutralizing anti-IFN-gamma antibodies increased CD23 expression on B cells, which were stimulated with IL-4 and BPA, but had no effect on monocytes, whereas the addition of anti-IL-10 antibodies increased CD23 expression on monocytes but not on B cells., Conclusion: These data indicate that early immunological effects like down-regulation of CD23 on B cells and monocytes, which are observed during SIT are dose dependent, mediated by IFN-gamma and IL-10 and seem not to depend per se on the sensitization state of an individual.

Background: Adverse reactions after ingestion of alcoholic beverages are common. Metabolic differences in individuals and also the histamine content in alcoholic beverages have been implicated. By contrast pure ethanol has rarely been reported as a cause of hypersensitivity reactions and its mechanism has not been clarified yet., Objective: To determine whether ethanol itself accounts for alcohol hypersensitivity in patients with anaphylactic reactions after alcohol intake. In search of possible pathomechanisms all patients were analysed by skin prick testing and sulfidoleukotriene production of peripheral leucocytes using ethanol and its metabolites., Methods: Double-blind, placebo-controlled food challenges with a cumulated amount of 30 mL ethanol were performed in 12 adult patients with a positive history of adverse reactions after consumption of different alcoholic beverages. Skin prick tests and measurement of sulfidoleukotriene production were performed using different concentrations of ethanol and acetaldehyde from 50 to 1000 mm., Results: Oral challenges with pure ethanol were positive in six out of eleven patients. All challenge-positive patients, but also four out of five challenge-negative patients, showed an increased sulfidoleukotriene production in-vitro compared with healthy controls. Skin prick tests using alcoholic beverages, ethanol, acetaldehyde and acetic acid were negative in all patients (12/12)., Conclusion: Our study shows that ethanol itself is a common causative factor in hypersensitivity reactions to alcoholic beverages. These reactions occur dose-dependent and a non-IgE-mediated pathomechanism is likely, because skin prick tests were negative in all cases. Increased sulfidoleukotriene production was determined in some patients, but is no reliable predictor. Therefore oral provocation tests remain indispensable in making the diagnosis of ethanol hypersensitivity.

Background: Pseudoallergic reactions (PARs) against both additives and natural foods have been reported to elicit chronic urticaria, but in natural food the responsible ingredients are largely unknown., Objective: The study was aimed at identifying novel pseudoallergens in food and focused on evaluating tomatoes, white wine, and herbs as frequently reported food items eliciting wheal responses in urticaria., Methods: In 33 patients with chronic urticaria and PARs to food (proved by means of elimination diet and subsequent re-exposure with provocation meals), oral provocation tests were performed with field-grown tomatoes, organically grown white wine (whole food, steam distillates, and residues), oily extracts from herbs, and food additives. In addition, skin biopsy specimens from patients were studied for in vitro mast-cell histamine release with tomato distillate alone or on subsequent stimulation with anti-IgE, substance P, and C5a., Results: Seventy-six percent of patients reacted to whole tomato (steam distillate, 45%; residue, 15%), 50% to food additives, 47% to herbs, and 44% to whole wine (extract, 27%; residue, 0%). Histamine, protein, and high levels of salicylate were only found in residues. The tomato distillate was further analyzed by means of mass spectroscopy, identifying low molecular-weight aldehydes, ketones, and alcohol as major ingredients. In vitro histamine release was not caused by tomato extract itself but was enhanced by means of subsequent stimulation with substance P and C5a but not by anti-IgE., Conclusion: Aromatic volatile ingredients in food are novel agents eliciting PARs in chronic urticaria. Histamine, salicylate, and a direct mast-cell histamine release are not involved in this reactivity to naturally occurring pseudoallergens.

Adverse reactions to food are a frequently discussed cause of urticaria. In acute urticaria 63% of patients suspect food as the eliciting factor; however, this cannot be confirmed in prospective studies. In adults the rate of type I allergic reactions is below 1%, although in children the percentage appears to be higher. Also in chronic urticaria type I allergic reactions play only a minor role as an eliciting factor. The same holds for the physical urticarias. The role of pseudoallergic reactions has not been investigated for all types of urticaria, but apparently they are not important in physical urticarias; however, in acute urticaria pseudoallergic reactions against NSAID are responsible for approximately 9% of cases, and in a subset of patients with chronic urticaria a diet low in pseudoallergens has been proven to be beneficial in several studies, with response rates observed in more than 55% of patients. Double-blind, placebo-controlled challenge tests have shown that artificial food additives are not only to blame, with the majority of reactions being traced back to naturally occuring pseudoallergens in food.

Background: Adverse reactions to food play an important role in the pathogenesis of atopic dermatitis (AD). In infancy and childhood, food allergies are observed in up to 30%, whereas nonallergic hypersensitivity reactions (pseudoallergic reactions) towards food additives have been reported to occur between 2 and 7%. By contrast, sensitizations towards food allergens are rarely of clinical relevance in adults and little data is available on nonallergic hypersensitivity reactions. To date the role of pseudoallergic reactions as an aggravating factor in AD of adult patients remains controversial. However, many adult patients report on food-related aggravation of the disease and nonallergic hypersensitivity reactions have been incriminated repeatedly., Objective: To elucidate the relevance of food additives in adult patients suffering from AD., Methods: Fifty patients were monitored over 4 weeks under regular diet followed by 6 weeks of a diet omitting known pseudoallergens. Skin status of patients was assessed every 2 weeks by a standardized scoring, and serum eosinophilic cationic protein (ECP) was determined before and after diet., Results: Nine of fifty patients dropped out, 26 showed a significant improvement of the Costa-score by 57%. In 23/26 patients a corresponding reduction of serum ECP level by 52% on average was determined. Responder patients (24/26) were orally challenged with food rich in pseudoallergens followed by double-blind exposure to food additives (n = 15). A worsening of the eczema was seen in 19/24 patients after intake of pseudoallergen-rich food and in 6/15 patients after exposure to food additives., Conclusion: These results indicate that a subgroup of adult patients with AD clinically improve on low-pseudoallergen diet but only a small subgroup respond to oral provocation with food additives.

The rates of sensitization and allergy to four birch pollen related plant foods were investigated in a group of 167 patients who were sensitive to at least one kind of pollen and one particular food. Sensitivity was concluded from a positive skin prick test or the determination of specific IgE, whereas allergy was based on anamnestic data. The positivity rates for sensitization and allergy, respectively, were: apple, 93 and 84%; hazelnut, 90 and 78%; celery, 70 and 14%; carrot, 60 and 37%. Comparative testing by skin prick test and enzyme allergosorbent test (EAST) with extract from native and microwaved (750 W, 30 min, 100 degrees C) celery root was performed on 46 of these patients. At least one positive test result (either prick test or EAST) was obtained for native celery in 36/46 (78%) and for heated celery in 20/46 (43%) of these patients. Although the concordance between the EAST and the skin test was very low, extended control experiments of both test procedures revealed no evidence for nonspecificity. Immunoblot analyses of extract from native celery and sera of 60 patients with a positive EAST (class > or = 2, > or = 0.7 U/ml) for celery resulted in the following rates of IgE binding to known cross-reactive celery allergens: Api g 1:33%, celery profilin: 17%; multiple bands most probably due to carbohydrate epitopes: 32%. The rate of binding to other allergens was below 10%. Since these three important structures are also present in birch pollen, no allergen could be identified as a candidate to mediate an exclusive celery/mugwort association. Investigation of extract from native and heated celery by immunoblotting pointed to a high lability of Api g 1, whereas profilin and carbohydrate epitopes appeared to be more resistant to heat. It has been concluded that sensitization to celery in German patients is without clinical significance in the majority of cases, in contrast to other birch-pollen-related plant foods such as apple and hazelnut. For the particular kind of extract used, neither the EAST nor the skin test alone represents an appropriate diagnostic method for testing sensitization to celery.

Skin prick test reactivity to a battery of common allergens was examined in 26 adults with atopic eczema, in 9 patients with allergic rhinitis and in 10 nonatopic controls. In both patient groups, reactivity was most frequent for grass pollen, followed by rye, house dust mite, tree and herb, with no reactions to food allergens. Repeated tests at weekly intervals were less reproducible in weak reactions and in severely affected eczema patients compared to those lightly affected. Skin prick tests are therefore reliable and reproducible in atopics and provide means to counsel patients on avoidance of eliciting agents of their disease.

Phenoxyethanol, or 2‐phenoxyethanol, has a large spectrum of antimicrobial activity and has been widely used as a preservative in cosmetic products for decades. It is effective against various Gram‐negative and Gram‐positive bacteria, as well as against yeasts, and has only a weak inhibitory effect on resident skin flora. According to the European Scientific Committee on Consumer Safety, phenoxyethanol is safe for all consumers – including children of all ages – when used as a preservative in cosmetic products at a maximum concentration of 1%. Adverse systemic effects have been observed in toxicological studies on animals but only when the levels of exposure were many magnitudes higher (around 200‐fold higher) than those to which consumers are exposed when using phenoxyethanol‐containing cosmetic products. Despite its widespread use in cosmetic products, phenoxyethanol is a rare sensitizer. It can be considered as one of the most well‐tolerated preservatives used in cosmetic products. [ABSTRACT FROM AUTHOR]

While allergic mast cell ( MC) degranulation occurs by Fcε RI aggregation and varies in strength among subjects, the analogous pseudo-allergic route was recently uncovered to proceed via MRGPRX2. Here, we examine interindividual variability in skin MC responses to Fcε RI triggering vs those evoked by MRGPRX2. While population-based variability is comparable between the routes, Fcε RI- and MRGPRX2-stimulated pathways are completely independent from each other, and responsiveness to one has therefore no predictive value for the other. Conversely, degranulation triggered by compound 48/80 is highly correlated to the process elicited by substance P. MRGPRX2 mRNA shows pronounced population-based variability (coefficient of variation 102.9%). Surprisingly, stem cell factor ( SCF) as the MC-supportive mediator par excellence potently inhibits pseudo-allergic degranulation, while it simultaneously promotes allergic stimulation via Fcε RI . We conclude that SCF can have selective MC-dampening functions. Clinically, the data imply that subjects highly reactive in one pathway are not automatically hyper-responsive in terms of the alternative route. [ABSTRACT FROM AUTHOR]

The Future of the Allergists and Specific Immunotherapy ( FASIT) workshop provides a regular platform for global experts from academia, allergy clinics, regulatory authorities and industry to review developments in the field of allergen immunotherapy ( AIT). The most recent meeting, held in February 2017, had two main themes: advances in AIT and hot topics in AIT from the regulatory point of view. The first theme covered opportunities for personalized AIT, advances in adjuvants and delivery systems, and the development of new molecules and future vaccines for AIT. Key topics in the second part of the meeting were the effects of the enactment of European Directive 2001/83 on the availability of allergens for therapy and diagnosis across the EU, the challenges of conducting Phase 3 studies in the field, the future role of allergen exposure chambers in AIT studies and specific considerations in performing AIT studies in the paediatric population. Finally, the group highlighted the forthcoming EAACI guidelines and their particular importance for the standardization of practice in the treatment of allergies. This review presents a comprehensive insight into those panel discussions and highlights unmet needs and also possible solutions to them for the future. [ABSTRACT FROM AUTHOR]