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Alergia; Anafilaxia; Asma Allergy; Anaphylaxis; Asthma Al·lèrgia; Anafilaxi; Asma Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the “EAACI Molecular Allergology User's Guide” (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

Sensitization to lipid transfer protein (LTP), the most frequent cause of food allergy in southern Europe, still shows several controversial, but also intriguing, aspects. Some of these include the degree of cross-reactivity between LTPs from botanically distant sources, the definition of risk factors, the role of some cofactors, clinical outcomes, geographical differences and the identification of the primary sensitizer in different areas. This review article tries to analyse and comment on these aspects point by point suggesting some explanatory hypotheses with the final scope to stimulate critical thoughts and elicit the scientific discussion about this issue in the readership.

BACKGROUND Clinically complex phenotypes require more and more sophisticated and comprehensive diagnostic approaches, able to discriminate genuine sensitizations from cross-reactivity. Interpretative complexity of multiplex diagnostic arrays has somewhat limited their diffusion. This study compares two currently available methods, namely ISAC® test and ALEX2® test. METHODS In total, 140 allergic individuals, with a history of atopic dermatitis, adverse food reactions, allergic rhinitis and/or bronchial asthma were studied by Allergy Explorer-ALEX2® macroarray and ImmunoCAP ISAC112® . Lin's concordance correlation coefficient, intraclass correlation coefficient and Bland-Altman plots were used to verify the agreement between continuous values. Cohen's kappa coefficient (k) was assessed for the molecules available in both tests. The degree of relationship was analysed using Spearman's correlation (quantitative variables) and Pearson's χ2 or Fisher's exact test (categorical variables). RESULTS A substantial agreement (κ = 0.795) was observed between the two methods with 94,3% concordant results when results were dichotomized as negative or positive, but if double-negative results were discarded, the agreement dropped to 71%. Conversely, little or no concordance was observed comparing raw data. Considering the 102 molecules shared by both systems, 28/102 (27%) showed an almost perfect agreement (k > 0.81), and concordance was good (k > 0.61) in a further 32 (31%) cases. A perfect to substantial agreement was observed by comparing species-specific aeroallergens. Heterogeneous results emerged comparing panallergens (co-recognition ranging from 30% for tropomyosin/serum albumins to 70% for PR-10/profilin). The correlation among LTP, profilin and PR-10 assayed with ISAC® was better than ALEX2® , but the latter identified more positive cases due to the wider number of molecules available. The CCD blocker provided by ALEX® test abolishes the carbohydrate determinants signal in 60% of the 33 cases reactive to MUXF3 on the ISAC® test. CONCLUSION Despite the excellent concordance of the species-specific markers, the analysis of the panallergens provided in both methods suggests a better performance of the ISAC® test on those components, while the ALEX2® test, which includes a larger number of allergens, allowing a broader molecular detection.

Chronic spontaneous urticaria (CSU) is characterized by the recurrent occurrence of short-lived wheals with or without angioedema for more than 6 weeks. Although its pathogenesis is not completely defined, several mechanisms seem involved, including autoimmunity and autoallergy with complement and coagulation activation. Various biologics are currently available or under investigation to counteract different CSU pathomechanisms.The recent literature dealing with biologics in the treatment of CSU was screened and analyzed; the different treatments were divided into anti-IgE and other than anti-IgE biologics. The latter were subdivided according to their target mechanisms.Biologic drugs exert their effects in a very precise and specific manner. A majority of patients (arguably those with type I disease) respond to anti-IgE treatment. Others, possibly with type IIa disease, show a slow response to anti-IgE drugs. Things are much more complicated in anti-IgE-refractory patients. Some respond well to nonspecific immune suppressors, such as corticosteroids and cyclosporin suggesting that an immune-mediated pathogenic mechanism, not involving the high-affinity IgE receptor, is probably active. Several ongoing studies are evaluating biologics and small molecules counteracting other pathomechanisms, including anti-receptor biologics, Bruton tyrosine kinase (BTK) inhibitors, mast cell targets, and specific cytokines.

Introduction: Chronic spontaneous urticaria (CSU) is a frequent disorder in which activation of effector cells and histamine release can be induced via several distinct pathogenetic mechanisms. Much work has been carried out to identify biomarkers useful for classifying CSU patients, and to predict their response to currently available treatments.Areas covered: The recent literature dealing with CSU biomarkers was screened in PubMed and Google Scholar using 'chronic spontaneous urticaria', 'biomarker', 'diagnosis', 'therapy' and 'treatment response' as key words. The characteristics found in relevant papers were divided into clinical and serological biomarkers of (a) clinical severity/disease activity, and (b) response to treatments.Expert opinion: A diagnostic biomarker for CSU is still missing. Most biomarkers described so far do not seem to possess sufficient specificity for this disease. Basopenia and the activation of the coagulation cascade might be biomarkers of disease activity and severity, but information available so far is insufficient to consider their routine use. Markers suggesting IgG-mediated autoimmunity (autologous serum skin test, basophil activation/histamine release assays, low total IgE) seem to identify patients less prone to respond to omalizumab but responsive to cyclosporine. In contrast, 'autoallergy' (i.e. the presence of IgE to autoallergens), which is often associated with elevated IgE levels seems to identify patients who will respond to omalizumab.

Background: The so-called “thunderstorm asthma” (TA) is an uncommon but dramatic outbreak of asthma attacks occurring during a thunderstorm in the pollen and moulds season. Mechanisms which make the pollen able to enter the deeper airways and provoke severe asthma symptoms are still unclear. Objective: To test the hypothesis that sub-pollen particles (SPPs) originated from the rupture by an osmotic shock of pollen associated with TA contain allergens. Methods: After hydration, SPPs released from pollen grains of grass, pellitory, olive, cypress, ragweed and birch were isolated and determined by microscopy. Allergens were determined by in vitro ELISA inhibition tests indirectly using the sera from 10 polyreactive patients. An inhibition 75% complete. Results: The inhibition experiments showed that the SPPs from birch and cypress were unable to inhibit serum IgE reactivity to Bet v 1 and Cup a 1, respectively. Ragweed SPPs inhibited ragweed pollen extract and Amb a 1 by 75.8±0.11% and 81.2±0.15%, respectively. Olive and pellitory SPPs retained almost the whole IgE-binding capability in all cases tested. Grass SPPs inhibited 32±0.06% of Lolium perenne Lol p 1 and 65% of Phleum pratense extracts, but results were highly variable for individual allergens (97.5%-0.03% for Phl p 2, 45.3±0.12% for Phl p 5, 24.7±0.22% for Phl p 6, and 38.3±0.2% for Phl p 1). Conclusions: Inhibition experiments confirm the hypothesis that SSPs obtained after the osmotic shock of pollen involved in TA, namely grass, pellitory and olive tree pollen, contain allergens and therefore they can induce severe asthma attacks during thunderstorms.

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GALEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast-cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic urticaria, i.e. chronic spontaneous urticaria and chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This article is protected by copyright. All rights reserved.

Shrimp and other crustaceans and molluscs are one of the most frequent causes of food allergy and anaphylaxis at all ages. Molecular biology has paved the way to a better understanding of the allergen profile of invertebrates that is much more complex than thought only one decade ago. While tropomyosin has been traditionally considered as the dominating major allergen in crustaceans and other invertebrates, recent research demonstrated that IgE to this allergen can be detected in about 50% of shrimp-allergic patients only. Many of these allergens are conserved ones and, hence, potentially cross-reacting across different invertebrates, including house dust mites. Patients not sensitized to tropomyosin frequently experience anaphylactic reactions, suggesting that also the so-called minor allergens may have an extreme clinical relevance. This review focuses on the clinical features of shrimp allergy and highlights the recent findings on shrimp allergens. The use of epinephrine, which remains a cornerstone of the treatment of anaphylaxis, is reviewed as well.

Omalizumab has become the mainstay of the treatment of severe CSU, but a subset of patients seems completely unresponsive to the drug. This review tried to understand the reasons for this different behavior. Growing evidence shows that IgE-mediated autoimmunity to an array of autoallergens is common in CSU, while IgG-mediated autoimmunity to IgE or to the high-affinity IgE receptor, which has been known for many years, seems to be involved in a minority of patients. This may explain the different responsiveness to anti-IgE therapy. CSU is probably an autoimmune disease in most cases. Patients with an IgE-mediated disease (autoallergy) seem those who respond to omalizumab, whereas those with an IgG-mediated autoimmune disease appear to respond slowly or are unresponsive to the drug and are candidates to the immunosuppressive treatments, like cyclosporine.

Background: Management of hundreds of analytes obtained from the molecular multiplex techniques currently available may represent a challenge for clinicians in daily clinical practice. Objectives: The aim of the study was to describe a comprehensive and simple approach to assess such complex molecular results, to display relevant disease-specific signatures at a glance, and to facilitate their interpretation. Method: A total of 6,332 consecutive allergic patients, categorized based on clinical symptoms reported at the time of the first visit before IgE testing, were evaluated through ImmunoCAP ISAC112®. Results and Conclusions: The occurrence of bronchial asthma is associated with polcalcin, serum albumin, or lipocalin reactivity. Higher risk of severe reaction to food is linked to tropomyosin or nonspecific lipid transfer protein reactivity (in the absence of plant pathogenesis-related proteins [PR-10] or profilin sensitization). We used radar graphic display to highlight, at a glance, the molecular reactivity profiles associated with relevant disease-specific patterns.

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.

Chronic spontaneous urticaria (CSU) is a debilitating mast cell-driven disease characterized by recurrent wheals and/or angioedema. Substantial progress has been made in dissecting the 2 main autoimmune mechanisms that drive the pathogenesis of CSU. Type I autoimmune (autoallergic) CSU is associated with IgE antibodies against autoantigens, for example, thyroid peroxidase and IL-24. Type IIb autoimmune CSU is mediated by autoantibodies that activate mast cells, for example, via IgE and FcεRI, and is present in less than 10% of patients with CSU when strict criteria are used, that is, triple positivity of autologous serum skin test, immunoassays for IgG autoantibodies, and basophil activation tests. A subpopulation of patients with CSU has both types. Type IIb autoimmune CSU is characterized by higher disease severity, concomitant autoimmune diseases, low levels of total IgE, elevated levels of IgG-anti-thyroid peroxidase, basopenia, eosinopenia, poor response to antihistamines and to omalizumab, and a good response to cyclosporine. Novel targeted therapies for CSU are under development such as ligelizumab, an anti-IgE, fenebrutinib and remibrutinib, Bruton's tyrosine kinase inhibitors, and dupilumab, an anti-IL-4Rα. Further studies should investigate the overlap between autoallergic and type IIb autoimmune CSU, optimize the diagnosis of both autoimmune endotypes using easy-to-perform, noninvasive, and inexpensive markers, and assess differences in response to therapy.

13 Pág., Diagnosis of food allergies is challenging, as combining information from specific IgE (sIgE)-sensitization pattern and skin prick tests (SPTs) with clinical history is necessary for a personalized management of allergic patients. The aim of this study was to compare two molecular tests, the ImmunoCAP ISAC (ISAC) and the Allergy Explorer, version 2 (ALEX2 ) in the context of pollen food syndrome (PFS) diagnosis in a real-life scenario, to assess the benefit of multiplex testing in PFS patients., This work was financially supported by the H2020 EU project “AllerScreening” (H2020-NMBP-X-KET-2017-768641). EJJ was supported by the Danube Allergy Research Cluster, #08, Vienna and Krems, Austria

Shellfish allergy is an important cause of food allergies worldwide. BothTo investigate the features of shrimp-allergic patients either reactive or tolerant to mollusks, with the currently available diagnostic methods.Nineteen centers, scattered throughout Italy, participated in the real-life study, enrolling patients allergic to shrimp with or without associated reactions to mollusks. Patients underwent skin tests using commercial extracts or fresh raw and cooked shrimp and mollusks, and IgE reactivity to currently available allergenic extracts and molecules was measuredTwo hundred and forty-seven individuals with a self reported adverse reactions to shrimp participated in the study; of these 47.8% reported an adverse reaction to mollusks ingestion (cephalopod and/or bivalve). Neither of the tests used,The current diagnostic methods are inadequate to predict the cross-reactivity between crustaceans and mollusks. The detection of mollusks hypersensitivity should still rely on skin tests with fresh material. The exclusion of mollusks from shrimp allergic patients' diets should occur when clinical history, available diagnostic instruments, and/or tolerance tests support such a decision.

Hymenoptera stings mostly cause acute urticaria but we describe a case of CU after wasp stings which remitted during venom immunotherapy. IgE‐mechanisms have not been fully clarified in CU, except for isolated circumstances. In our case immunotherapy has played a positive role reducing immune cells reactivity and improving urticaria symptoms.

Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based), its cost-effectiveness and long-term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.

Sensitization to one or more non-specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non-steroidal anti-inflammatory drugs, Cannabis sativa) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy-focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.

Background:It is not well-understood why symptom severity varies between patients with peanut allergy (PA).Objective:To gain insight into the clinical profile of subjects with mild-to-moderate and severe PA, and investigate individual and collective predictive accuracy of clinical background and IgE to peanut extract and components for PA severity.Methods:Data on demographics, patient history and sensitization at extract and component level of 393 patients with probable PA (symptoms ≤ 2 h + IgE sensitization) from 12 EuroPrevall centers were analyzed. Univariable and penalized multivariable regression analyses were used to evaluate risk factors and biomarkers for severity.Results:Female sex, age at onset of PA, symptoms elicited by skin contact with peanut, family atopy, atopic dermatitis, house dust mite and latex allergy were independently associated with severe PA; birch pollen allergy with mild-to-moderate PA. The cross-validated AUC of all clinical background determinants combined (0.74) was significantly larger than the AUC of tests for sensitization to extract (0.63) or peanut components (0.54–0.64). Although larger skin prick test wheal size, and higher IgE to peanut extract, Ara h 1 and Ara h 2/6, were associated with severe PA, and higher IgE to Ara h 8 with mild-to-moderate PA, addition of these measurements of sensitization to the clinical background model did not significantly improve the AUC.Conclusions:Models combining clinical characteristics and IgE sensitization patterns can help establish the risk of severe reactions for peanut allergic patients, but clinical background determinants are most valuable for predicting severity of probable PA in an individual patient.

BACKGROUND: It is crucial to identify patients at highest risk for opioid use disorder (OUD) and to address challenges in reducing opioid use. Reported nonsteroidal anti-inflammatory drug (NSAID) allergies may predispose to use of stronger pain medications and potentially to OUD. OBJECTIVE: We sought to investigate the clinical impact of reported NSAID allergy on OUD in patients with chronic back pain. METHODS: We conducted a retrospective study of adults receiving care at a tertiary health care system from January 1, 2013, to December 31, 2018. Back pain and OUD were identified using administrative data algorithms. We used propensity score matching and logistic regression to estimate the impact of self-reported NSAID adverse drug reactions (ADRs) on risk of OUD, adjusting for other relevant clinical information. RESULTS: Of 47,114 patients with chronic back pain, 3,620 (7.7%) had a reported NSAID ADR. In an adjusted propensity score–matched analysis, patients with NSAID ADRs had higher odds (odds ratio, 1.34; 95% CI, 1.07–1.67) of developing OUD as compared with those without NSAID ADRs. Additional risk factors for OUD included younger age, male sex, Medicaid insurance, Medicare insurance, higher number of inpatient and outpatient visits in the previous year, and comorbid anxiety and depression. Patients with listed NSAID ADRs also had higher odds of a documented opioid prescription during the study period (odds ratio, 1.22; 95% CI, 1.11–1.34). CONCLUSIONS: Adults with chronic back pain and reported NSAID ADRs are at a higher risk of developing OUD and receiving opioid analgesics, even after accounting for comorbidities and health care utilization. Allergy evaluation is critical for potential delabeling of patients with reported NSAID allergies and chronic pain.

Chronic spontaneous urticaria is characterized by a perivascular non-necrotizing cellular infiltrate around small venules of the skin. It consists primarily of CD4(+) lymphocytes, a prominence of the T helper (Th)2 subtype but also Th1 cells, with Th17 cell–derived cytokines elevated in plasma. There are also neutrophils, eosinophils, basophils, and monocytes. Chemokines derived from mast cells and activated endothelial cells drive the process. Although the role of the cellular infiltrate has not previously been addressed, each constituent can contribute to the overall pathogenesis. It is of interest that CSU responds to corticosteroid, yet, short-term steroids do not affect autoimmunity or degranulation of mast cells, and act on margination of cells along the endothelium and chemotaxis to enter the surrounding dermis. In this review, we address each cell's contribution to the overall inflammatory response, as it is currently understood, with a view toward development of therapeutic options that impede the function of critical cells and/or their secretory products.

BACKGROUND Heat-and-pepsin-sensitive plant food allergens (PR-10 and profilin) sometimes cause systemic reaction. OBJECTIVE To detect the risk factors for systemic reactions induced by labile food allergens. METHODS A retrospective multicenter study was performed on patients with a documented history of systemic allergic reaction to labile plant food allergens and on age-matched controls with a history of oral allergy syndrome (OAS) induced by the same foods. Offending foods, their amount, and state (solid or liquid), and potential cofactors (nonsteroidal anti-inflammatory drugs, protonic pump inhibitors, exercise, alcohol, and fasting) were considered. RESULTS We studied 89 patients and 81 controls. Sensitization to PR-10 or profilin, IgE to Bet v 1 and/or Bet v 2, and foods causing OAS were similar in the two groups. Twenty patients experienced >1 systemic allergic reaction. Tree nuts, Rosaceae, Apiaceae, and soymilk were the main offending foods. Seventeen (19%) patients were taking a PPI when the systemic reaction occurred (vs 5% in controls; P

BACKGROUND: Severe Covid-19 is associated with a cytokine storm leading to the hyper-expression of cytokines such as IFN-gamma, TNF-alpha, and IL-6, which may be responsible for most severe symptoms and signs of the disease. The immune response of the atopic patient is mostly Th2-oriented, associated with the expression of cytokines such as IL-4, IL-5, and IL-13, and atopic patients express fewer ACE-2 receptors than non-atopic individuals do. We assessed whether atopic status may protect from the most severe consequences of Covid-19. METHODS: Atopic status along with co-factors such as diabetes, hypertension, coronary heart disease, and thrombosis was investigated in severe Covid-19 patients admitted to different Italian hospitals. Patients were classified as having a mild, severe, or very severe disease based on the need of respiratory assistance; severity was plotted against the different co-factors and underwent multivariate analysis. RESULTS: 531 adults aged 25 - 100 years were studied; 57 (11.7%) were atopic. Atopic status showed a significant association with a milder disease irrespective of all other co-factors considered (p

In the recent years, it was recognized that type-2 inflammation links many forms of nasal polyposis with severe asthma. Thus, some biological drugs developed for severe asthma appeared to exert an effect on nasal polyposis. So far, there are several trials supporting this concept; therefore, some monoclonal antibodies for severe asthma were assessed also in polyposis, with promising results. Since different specialists are involved in the management of nasal polyposis (eg, pulmonologists, ENT, allergists), it was felt that an educational and informative document was needed to better identify the indications of biologicals in nasal polyposis. We collected the main Italian Scientific Societies, and prepared (under the Allergic Rhinitis and its Impact on Asthma, ARIA) a document endorsed by all Societies, to provide a provisional statement for the future use of monoclonal antibodies as a medical treatment for polyposis. It is the first nationwide endorsed document on this aspect. The current pathogenic knowledge and the experimental evidence are herein reviewed, and some suggestions for a correct prescription and follow-up are provided.

This document summarizes the aims of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence (ACAREs) and elaborates the requirements that ACAREs must fulfill to become certified. It also provides (see Appendix S1) background information on GA2LEN and HAEi, including HAEi member organizations and regional patient advocates, on why we need an Angioedema Center of Reference and Excellence (ACARE) program and network, and on the accreditation and certification process, governance and funding, and on the interaction with other GA2LEN networks of centers of reference and excellence. The protocols, aims, requirements, and provisions related to becoming a certified CARE are based on (a) the experience of the GA2LEN UCARE network and (b) input from angioedema patients, general practitioners, and angioedema specialists.

Summary Chronic spontaneous urticaria (CSU) pathogenesis shows a complex and still unclear interplay between immunoglobulin (Ig)G- and IgE-mediated autoimmunity, leading to mast cell and basophil degranulation and wheal formation. The objective of this study was to evaluate at the same time IgE- and IgG-reactivity to well recognized and recently reported autoantigens in CSU patients, and to assess the effects of such reactivity on response to the anti-IgE monoclonal antibody omalizumab. Twenty CSU patients underwent omalizumab treatment. Urticaria activity score 7 (UAS7) was recorded at baseline and at different drug administration time-points for categorizing early-, late- or non-responders. At baseline, sera from the 20 patients and from 20 controls were tested for IgE and IgG autoantibodies to high- and low-affinity IgE receptors (FcεRI and FcεRII), tissue factor (TF) and thyroglobulin (TG) by immunoenzymatic methods. Antibody levels were compared with those of controls and analysed according to response. Eighteen patients were omalizumab responders (11 early and seven late), while two were non-responders. More than 50% of patients had contemporary IgE and IgG to at least to one of the four different autoantigens. Late responders showed higher levels of both anti-TF IgE and IgG than early responders (P= 0·011 and P= 0·035, respectively). Twenty-five per cent of patients had levels of anti-FcεRI IgE, exceeding the upper normal limit, suggesting that it could be a novel auto-allergen in CSU. In CSU, there is an autoimmune milieu characterized by the co-existence of IgE and IgG autoantibodies to the same antigen/allergen, particularly in late responders to omalizumab, possibly explaining the slower response.

Focusing on the strict relationship between house dust mites and crustaceans from the allergenic point of view. The well-known tropomyosin was considered for years as the cross-reacting allergen between shrimp and house dust mites. In the last few years, several allergens not only in shrimps but also in house dust mite have been identified and other molecules other than tropomyosin have been shown to cross-react between crustaceans and mites. The present review investigates the very complex allergen sources in shrimp and mites, giving a satisfactorily complete picture of the interrelationships between common allergens. Several minor HDM allergens are homologous to major and minor shrimp allergens; tropomyosin is not the only cross-reactive allergen between shrimp and mites.

BACKGROUND: Walnut allergy is common across the globe, but data on the involvement of individual walnut components are scarce.OBJECTIVES: To identify geographical differences in walnut component sensitization across Europe, explore cosensitization and cross-reactivity, and assess associations of clinical and serological determinants with severity of walnut allergy.METHODS: As part of the EuroPrevall outpatient surveys in 12 European cities, standardized clinical evaluation was conducted in 531 individuals reporting symptoms to walnut, with sensitization to all known walnut components assessed in 202 subjects. Multivariable Lasso regression was applied to investigate predictors for walnut allergy severity.RESULTS: Birch-pollen-related walnut sensitization (Jug r 5) dominated in Northern and Central Europe and lipid transfer protein sensitization (Jug r 3) in Southern Europe. Profilin sensitization (Jug r 7) was prominent throughout Europe. Sensitization to storage proteins (Jug r 1, 2, 4, and 6) was detected in up to 10% of subjects. The walnut components that showed strong correlations with pollen and other foods differed between centers. The combination of determinants best predicting walnut allergy severity were symptoms upon skin contact with walnut, atopic dermatitis (ever), family history of atopic disease, mugwort pollen allergy, sensitization to cat or dog, positive skin prick test result to walnut, and IgE to Jug r 1, 5, 7, or carbohydrate determinants (area under the curve = 0.81; 95% CI, 0.73-0.89).CONCLUSIONS: Walnut-allergic subjects across Europe show clear geographical differences in walnut component sensitization and cosensitization patterns. A predictive model combining results from component-based serology testing with results from extract-based testing and information on clinical background allows for good discrimination between mild to moderate and severe walnut allergy.

Seed storage proteins are extremely stable allergens in nuts, seeds, and legumes and are responsible for the most severe allergic reactions to these foods. The cross-reactivity between seed storage proteins from different sources has not been studied at a molecular level so far. This study aimed to ascertain the cross-reactivity between walnut and hazelnut seed storage proteins using recombinant allergens. Sera from 13 consecutive patients with severe primary walnut and/or hazelnut allergy and hypersensitive to both nuts were studied. IgE specific for rCor a 9, rCor a 14, and rJug r 1 was measured, and inhibition experiments were carried out by measuring IgE reactivity after absorption of patients’ sera with freshly prepared walnut extract. All 13 sera showed strong IgE reactivity against walnut 2S albumin, Jug r 1, 12 reacted to hazelnut 2S albumin, Cor a 14, and 8 to the hazelnut legumin, Cor a 9. In inhibition experiments, absorption of sera with whole walnut extract led to the complete disappearance of IgE reactivity to Jug r 1 in 12/13 cases, as expected, but also to the complete disappearance of specific IgE to Cor a 14 in 9/12 sera, and of IgE reactivity to Cor a 9 in 7/8. In the remaining cases a dramatic drop in IgE reactivity was observed. The study shows that patients primarily allergic to either walnut or hazelnut showing a skin or serological reactivity to the other nut also are potentially at risk of severe allergic reactions caused by cross-reactivity between 2S albumins and legumins.

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Mosquito bite is usually followed by a local reaction, but severe or systemic reaction may, in rare cases, occur. Allergic reactions to Aedes communis (Ac) may be underestimated due to the lack of reliable diagnostic tools. In this multicenter study, 205 individuals reporting large local reactions to Ac were enrolled and studied for cutaneous or IgE reactivity to Ac, Blattella germanica, Penaeus monodon, and Dermatophagoides pteronyssinus. Extract and molecular IgE reactivity to bees, wasps, hornets, and yellow jacket venoms were also studied in 119 patients with a clinical history of adverse reaction to Hymenoptera. Immunoblot (IB) analysis and immunoCAP IgE inhibition experiments were carried out in selected sera. Ac sensitization was recorded in 96 (46.8%) patients on SPT. Strict relationship between Ac and D. pteronyssinus, B. germanica, P. monodon, or Apis mellifera reactivity on SPT was observed. Ac IgE recognition was seen in 60/131 (45.8%) patients, 49 (81.6%) of them SPT positive, and 5/14 IB reactors. Ac IgE sensitization was associated with Tabanus spp, A. mellifera, Vespula vulgaris, and Polistes dominula reactivity. A strict relationship between Ac IgE reactivity and Api m 1, Api m 2, Api m 3, Api m 5, and Api m 10 was recorded. IgE reactivity to AC was inhibited in 9/15 cases after serum absorption with the A. mellifera extract. Both SPT and IgE Ac reactivity is observed in about half of patients with a history of large local reactions to mosquito bites. The significant relationship between Ac sensitization and either extract or single bee venom components is suggestive of a “bee-mosquito syndrome” occurrence.

The humanized anti-IgE antibody omalizumab has been available for patients with chronic spontaneous urticaria (CSU) in Italy since 2015. This review summarizes the unresolved issues and unmet therapeutic needs associated with omalizumab and discusses practical recommendations for its use in the management of CSU.Although modern second-generation H1-antihistamines are the standard of care for patients with CSU, adjunctive treatments (including omalizumab) may be required for effective control of symptoms in many patients. Evidence from clinical trials and experience from daily clinical practice suggest that the use of omalizumab in patients with CSU who have inadequate response to H1-antihistamines remains challenging.Based on current international guidelines, omalizumab labelling information and our experience in clinical practice, we provide treatment recommendations regarding the use of omalizumab in patients with CSU. These include: optimal treatment duration, the use of concomitant antihistamine therapy, the definition and management of disease relapse after treatment, and the management of patients with late or no response to treatment.

Nine hundred and thirty-nine rPla a 1, nPla a 2, and rPla a 3 ImmunoCAP ISAC reactors were studied. nPla a 2pos MUXF3pos but Pla a 1/2neg subjects were excluded from the study because they were cross-reactive carbohydrate determinant reactors. Among the 764 remaining participants, 71.9% were Pla a 3pos, 54.1% Pla a 2pos, and 10.9% Pla a 1pos. Among Pla a 3 reactors, 89.6% were Pru p 3pos and 86.8% Jug 3pos, but the strongest IgE recognition relationship was observed between Pla a 3 and Jug r 3. Distinctive clinical subsets could be documented among plane tree-allergic patients. Pla a 3 reactors had both local and systemic food-induced reactions, but lower past respiratory symptoms occurrence. Pla a 2 reactivity was associated with respiratory symptoms but inversely related to systemic reactions to food. Cosensitization to Pla a 2 and Pla a 3 was associated with a lower past incidence of severe food-induced reactions.

BACKGROUND Atopic dermatitis (AD) represents a chronic skin disorder seriously affecting patients' QoL and is often associated with immunological imbalance, disorders of the skin barrier function and environmental factors. OBJECTIVE We extensively studied the proteomic IgE sensitization profile in a large AD Mediterranean cohort. METHODS A total of 588 individuals with moderate-severe (70.6%) or mild and/or history of (29.4%) AD were evaluated in comparison to 1285 unselected atopic controls (AC) with a history of adverse reactions to foods, allergic rhinitis and/or bronchial asthma by means of ImmunoCAP ISAC112 ® and Allergy Explorer-ALEX® microarray analysis. RESULTS The olive tree pollen β-1,3-glucanase rOle e 9 and the manganese superoxide dismutase from Aspergillus rAsp f 6 were the molecules most significantly associated with AD occurrence and allowed to discriminate among the moderate and severe forms of disease. An IgE hyper-reactivity to cypress, grasses, olive tree, house dust mites (including rDer p 11), and to all cross-reactive components except profilin and polcalcin was observed. About 60% of adults with severe AD were sensitized to nsLTPs. Cross-reactive carbohydrate determinants (CCDs) IgE was found in about one-third of AD participants. Hen eggs nGal d 1 IgE sensitization was more prevalent in the paediatric population, whilst rAsp f 6 and rOle e 9 reactivity was found particularly in older patients. Despite the status of widespread IgE sensitization to both environmental and food allergens, a reduced frequency of patient-reported severe reactions to food or of asthma was observed in AD patients compared to AC, particularly in case of concomitant Ole e 9 reactivity. CONCLUSION AND CLINICAL RELEVANCE Testing IgE reactivity to a large panel of molecular components unveils important associations between IgE reactivity profiles and AD clinical presentation, highlights the allergens useful for a precise AD signature and allows the detection of interesting sensitisations patterns.

Background: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. Methods: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). Results: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P

Clinical relevance of Der p23 in a multicenter Italian study

Table of contents A1 Characterization of the immunoallergic profile towards the proteins of the wheat flour in Cuban population Raúl Lázaro Castro Almarales, Mary Carmen Reyes Zamora, Beatriz Tamargo, Damaris Torralba Averoff, Raysa Cruz, Yunia Oliva Diaz, Mirta Alvarez Castello, Alexander Ciria, Alexis Labrada, Maytee Mateo A2 Are peanuts causing food allergy in Cuba? Maytee Mateo, Damaris Torralba Averoff, Raysa Cruz, Yunia Oliva Diaz, Mirta Alvarez Castello, Alexander Ciria, Mary Carmen Reyes Zamora, Beatriz Tamargo, Alexis Labrada A3 Prick test and immunoallergic profile to soy allergens in Cuban population Omar Herrera, Maytee Mateo, Raysa Cruz, Mirta Alvarez Castello, Alexander Ciria, Raúl Lázaro Castro Almarales, Mary Carmen Reyes Zamora, Alexis Labrada A4 Skin sensitization and immunoallergic profile to hen's egg in Cuban population José Severino Rodríguez Canosa, Raysa Cruz, Maytee Mateo, Mirta Alvarez Castello, Alexander Ciria, Raúl Lázaro Castro Almarales, Mary Carmen Reyes Zamora, Alexis Labrada A5 Sensitization to three domestic mites in patients with adverse food events to shellfish Mirta Alvarez Castello, Raúl Lázaro Castro Almarales, Alexis Labrada, Biocen A6 Diagnostic efficacy by skin prick test with allergenic extracts of legumes in Cuban patients Yamilet Ibizate Novales, Ilonka Estruch Fajardo, Alexis Labrada, Maytee Mateo, Armando Ginard A7 Baked egg goods without wheat flour carry an increased risk of reaction Bruce Lanser, Anna Faino, Erwin Gelfand, Pia Hauk A8 Prevalence, incidence and associated risk factors of adverse reaction to food in Cuban infants - a population-based prospective study Silvia Venero Fernández, Julia Urbina, Mirta Alvarez Castello, Raúl Lázaro Castro Almarales, Ramón Suárez Medina, Hermes Fundora Hernández, John Britton, Andrew William Fogarty A9 Microbiome in ice machines and assessing the plasma nanotechnology in breaking the biofilm and improving air quality Nabarun Ghosh, Clinton Ross Bell, Chandini Revanna, Constantine Saadeh, Jeff Bennert, Danius Bouyi, Mitsy Veloz, Nelofar Sherali A10 Characteristics of patients with food allergy in health public service Magna Coelho A11 Allergic rhinitis and asthma index increased in Texas panhandle and AHPCO and plasma nanotechnology as solutions Nabarun Ghosh, Jeff Bennert, Danius Bouyi, Constantine Saadeh, Clinton Ross Bell, Mitsy Veloz, Chandini Revanna, Nelofar Sherali A12 Antigen-specific T follicular helper cells mediate peanut allergy in mice Joseph J. Dolence, Takao Kobayashi, Koji Iijima, Hirohito Kita, Hirohito Kita, Ashli Moore, James Krempski A13 Production of recombinant Mal d 3, a major apple allergen, in Pichia Pastoris, to investigate the impact of the food matrix and post-translational modifications on Mal d 3 immuno-reactivity Roberta Aina, Riccardo Asero, Sabine Pfeifer, Pawel Dubiela, Merima Bublin, Christian Radauer, Piotr Humeniuk, Karin Hoffmann-Sommergruber A14 Reaction to sports drink: no whey! Whey allergy in absence of clinical cow’s milk allergy Frank Eidelman, Ves Dimov, Charl Khalil A15 Food allergy on Tumblr: focus on teenage audience may increase educational impact Ves Dimov, Frank Eidelman, Charl Khalil A16 Changes in IgE levels following one-year immunizations in two children with food allergy Alice E. W. Hoyt, Peter Heymann, Alexander Schuyler, Scott Commins, Thomas Platts-Mills A17 IgE and IgG4 antibodies to cow's milk components in children with eosinophilic esophagitis: higher specific IgG4 antibodies and IgG4:IgE ratios compared with subjects with IgE-mediated food allergy Alexander Schuyler, Patrice Kruszewski, John Russo, Lisa Workman, Thomas Platts-Mills, Elizabeth Erwin, Anubha Tripathi A18 Frequency of Sensitization to Food Allergens in Patients with Rhinitis and Asthma in the National Medical Center La Raza “Dr. Antonio Fraga Mouret”, Mexico City Gabriela Yvette Castellanos, Elizabeth Mendieta, Martín Becerril-Angeles

Allergen immunotherapy (AIT) is presently the only treatment able to modify the natural history of respiratory allergic disease. The essential condition for AIT to be effective is that the right allergen(s) is/are administered. The proportion of allergic patients showing multiple sensitizations to distinct airborne allergen sources has dramatically increased during the last decades, and this fact, along with the frequent co-recognition of highly cross-reacting pollen panallergens (i.e., profilin and polcalcin), may make a correct diagnosis virtually impossible by using the traditional allergen extracts for diagnosis. Many purified recombinant or natural allergens are currently available for the in vitro diagnosis of respiratory allergy. These represent an invaluable tool to prevent the inclusion of inappropriate allergens in AIT extracts, and the present article provides some suggestions for their rational use in everyday clinical practice.

Precision allergy molecular diagnostic applications (PAMD@) is increasingly entering routine care. Currently, more than 130 allergenic molecules from more than 50 allergy sources are commercially available for in vitro specific immunoglobulin E (sIgE) testing. Since the last publication of this consensus document, a great deal of new information has become available regarding this topic, with over 100 publications in the last year alone. It thus seems quite reasonable to publish an update. It is imperative that clinicians and immunologists specifically trained in allergology keep abreast of the new and rapidly evolving evidence available for PAMD@.PAMD@ may initially appear complex to interpret; however, with increasing experience, the information gained provides relevant information for the allergist. This is especially true for food allergy, Hymenoptera allergy, and for the selection of allergen immunotherapy. Nevertheless, all sIgE tests, including PAMD@, should be evaluated within the framework of a patient's clinical history, because allergen sensitization does not necessarily imply clinical relevant allergies. Keywords: Diagnosis, Molecular allergy, Cross reactivity, Panallergen, Specific IgE, PAMD@

Background Grass pollen–related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. Methods We examined 1120 children (age 4–18y) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight Phleum pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. Results The analysis of IgE responses against eight Phleum pratense molecules showed 87profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SAR, and complex profiles were associated with longer disease duration. Conclusions In a large pediatric population, the complexity of IgE sensitization profiles against Phleum pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7 and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response. This article is protected by copyright. All rights reserved.

BACKGROUND: Component-resolved diagnosis (CRD) has revealed significant associations between IgE against individual allergens and severity of hazelnut allergy. Less attention has been given to combining them with clinical factors in predicting severity. AIM: To analyze associations between severity and sensitization patterns, patient characteristics and clinical history, and to develop models to improve predictive accuracy. METHODS: Patients reporting hazelnut allergy (n = 423) from 12 European cities were tested for IgE against individual hazelnut allergens. Symptoms (reported and during Double-blind placebo-controlled food challenge [DBPCFC]) were categorized in mild, moderate, and severe. Multiple regression models to predict severity were generated from clinical factors and sensitization patterns (CRD- and extract-based). Odds ratios (ORs) and areas under receiver-operating characteristic (ROC) curves (AUCs) were used to evaluate their predictive value. RESULTS: Cor a 9 and 14 were positively (OR 10.5 and 10.1, respectively), and Cor a 1 negatively (OR 0.14) associated with severe symptoms during DBPCFC, with AUCs of 0.70-073. Combining Cor a 1 and 9 improved this to 0.76. A model using a combination of atopic dermatitis (risk), pollen allergy (protection), IgE against Cor a 14 (risk) and walnut (risk) increased the AUC to 0.91. At 92% sensitivity, the specificity was 76.3%, and the positive and negative predictive values 62.2% and 95.7%, respectively. For reported symptoms, associations and generated models proved to be almost identical but weaker. CONCLUSION: A model combining CRD with clinical background and extract-based serology is superior to CRD alone in assessing the risk of severe reactions to hazelnut, particular in ruling out severe reactions.

There is increasing evidence that the coagulation cascade may play a role in the pathophysiology of chronic urticaria, particularly in severely active forms. Although anticoagulant therapy is presently not included among the standard treatments of severe chronic urticaria, based on the limited, but encouraging, literature presently available either warfarin or heparin could be considered as an add-on therapy in severely affected patients that do not respond to either antihistamines, omalizumab or ciclosporin, showing elevated plasma levels of D-dimer.

Chronic spontaneous urticaria (CSU) is characterized by the recurrence of itchy wheals for at least 6 weeks, affects up to 1% of the general population and may severely impair quality of life. H1-antihistamines are the cornerstones of treatment, but in about 10% of cases they fail to control the disease even at higher than licensed doses. In these patients, short courses of oral steroids may induce a remission in about 50% of cases. Omalizumab, a monoclonal anti-IgE, is effective in antihistamine-unresponsive patients although optimal treatment duration needs to be defined. Immunosuppressive treatment with cyclosporine is also effective in the majority of antihistamine-resistant chronic spontaneous urticaria (CSU) patients, but its use is limited by potential side effects. In refractory patients, other approaches include intravenous immunoglobulin, rituximab, dapsone and anticoagulants. The present review looks with particular interest at the prevalence of treatment failures with the main third-level treatments (corticosteroids, omalizumab and cyclosporine) and discusses them in light of the possible different pathogenic mechanisms underlying chronic spontaneous urticaria.

Allergen-specific immunotherapy is the only treatment able to change the natural history of either respiratory or hymenoptera venom allergy. From an immunological point of view, there is no reason to believe that its clinical effects should be different in food allergies. However, due to the high prevalence of adverse events that accompanied the first attempts of injection immunotherapy with food extracts some 20 years ago, such treatment is presently non-available although a thoroughly standardized food extract for injection immunotherapy should theoretically not expose the patients to higher risks than airborne allergen extracts or venoms. Allergen-specific immunotherapy with birch pollen extract is an interesting model to investigate the effects of the treatment on plant-food allergies that occur as a consequence of cross-reactivity with the major allergen, Bet v 1. Although the interest for this field has partly settled during the last years, the available data suggest that an adequate dose of the birch pollen major allergen, Bet v 1, particularly if administered subcutaneously, is able reduce secondary plant food allergy also, although doses needed to exert such effect are probably higher than those required to reduce respiratory symptoms. The administration of higher doses of the major allergen without an increase of the risk of adverse reactions should be possible if modified hypoallergenic molecules obtained either by genetic engineering or chemical treatments are used.