Search

Allergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence-based recommendations for the use of house dust mites (HDM) AIT as add-on treatment for HDM-driven allergic asthma. This guideline was developed by a multi-disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AIT with HDM SLIT-tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add-on to regular asthma therapy for adults with controlled or partially controlled HDM-driven allergic asthma (conditional recommendation, moderate-quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM-driven allergic asthma as the add-on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low-quality evidence)., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Adequate quality is essential for any medicinal product to be eligible for marketing. Quality includes verification of the identity, content and purity of a medicinal product in combination with a specified production process and its control. Allergen products derived from natural sources require particular considerations to ensure adequate quality. Here, we describe key aspects of the documentation on manufacturing and quality aspects for allergen immunotherapy products in the European Union and the United States. In some key parts, requirements in these areas are harmonized while other fields are regulated separately between both regions. Essential differences are found in the use of Reference Preparations, or the requirement to apply standardized assays for potency determination. As the types of products available are different in specific regions, regulatory guidance for such products may also be available in one specific region only, such as for allergoids in the European Union. Region-specific issues and priorities are a result of this. As allergen products derived from natural sources are inherently variable in their qualitative and quantitative composition, these products present special challenges to balance the variability and ensuring batch-to-batch consistency. Advancements in scientific knowledge on specific allergens and their role in allergic disease will consequentially find representation in future regulatory guidelines., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Purpose: The European Academy of Allergy and Clinical Immunology (EAACI) has produced Guidelines on Allergen Immunotherapy (AIT). We sought to gauge the preparedness of primary care to participate in the delivery of AIT in Europe., Methods: We undertook a mixed-methods, situational analysis. This involved a purposeful literature search and two surveys: one to primary care clinicians and the other to a wider group of stakeholders across Europe., Results: The 10 papers identified all pointed out gaps or deficiencies in allergy care provision in primary care. The surveys also highlighted similar concerns, particularly in relation to concerns about lack of knowledge, skills, infrastructural weaknesses, reimbursement policies and communication with specialists as barriers to evidence-based care. Almost all countries (92%) reported the availability of AIT. In spite of that, only 28% and 44% of the countries reported the availability of guidelines for primary care physicians and specialists, respectively. Agreed pathways between specialists and primary care physicians were reported as existing in 32%-48% of countries. Reimbursement appeared to be an important barrier as AIT was only fully reimbursed in 32% of countries. Additionally, 44% of respondents considered accessibility to AIT and 36% stating patient costs were barriers., Conclusions: Successful working with primary care providers is essential to scaling-up AIT provision in Europe, but to achieve this, the identified barriers must be overcome. Development of primary care interpretation of guidelines to aid patient selection, establishment of disease management pathways and collaboration with specialist groups are required as a matter of urgency., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Food allergy can result in considerable morbidity, impairment of quality of life, and healthcare expenditure. There is therefore interest in novel strategies for its treatment, particularly food allergen immunotherapy (FA-AIT) through the oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. This Guideline, prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE-mediated Food Allergy, aims to provide evidence-based recommendations for active treatment of IgE-mediated food allergy with FA-AIT. Immunotherapy relies on the delivery of gradually increasing doses of specific allergen to increase the threshold of reaction while on therapy (also known as desensitization) and ultimately to achieve post-discontinuation effectiveness (also known as tolerance or sustained unresponsiveness). Oral FA-AIT has most frequently been assessed: here, the allergen is either immediately swallowed (OIT) or held under the tongue for a period of time (SLIT). Overall, trials have found substantial benefit for patients undergoing either OIT or SLIT with respect to efficacy during treatment, particularly for cow's milk, hen's egg, and peanut allergies. A benefit post-discontinuation is also suggested, but not confirmed. Adverse events during FA-AIT have been frequently reported, but few subjects discontinue FA-AIT as a result of these. Taking into account the current evidence, FA-AIT should only be performed in research centers or in clinical centers with an extensive experience in FA-AIT. Patients and their families should be provided with information about the use of FA-AIT for IgE-mediated food allergy to allow them to make an informed decision about the therapy., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Hymenoptera venom allergy is a potentially life-threatening allergic reaction following a honeybee, vespid, or ant sting. Systemic-allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate to severe with a risk of life-threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H 1 -antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence-based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta-analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom-allergic children and adults to prevent further moderate-to-severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline autoinjector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence-based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high-quality AIT products are inherently linked to each other. While allergen products are available in many countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved, is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products. While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly either by obtaining a marketing authorization or by being distributed as named patient products. Exemptions from marketing authorizations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Allergic diseases are common and frequently coexist. Allergen immunotherapy (AIT) is a disease-modifying treatment for IgE-mediated allergic disease with effects beyond cessation of AIT that may include important preventive effects. The European Academy of Allergy and Clinical Immunology (EAACI) has developed a clinical practice guideline to provide evidence-based recommendations for AIT for the prevention of (i) development of allergic comorbidities in those with established allergic diseases, (ii) development of first allergic condition, and (iii) allergic sensitization. This guideline has been developed using the Appraisal of Guidelines for Research & Evaluation (AGREE II) framework, which involved a multidisciplinary expert working group, a systematic review of the underpinning evidence, and external peer-review of draft recommendations. Our key recommendation is that a 3-year course of subcutaneous or sublingual AIT can be recommended for children and adolescents with moderate-to-severe allergic rhinitis (AR) triggered by grass/birch pollen allergy to prevent asthma for up to 2 years post-AIT in addition to its sustained effect on AR symptoms and medication. Some trial data even suggest a preventive effect on asthma symptoms and medication more than 2 years post-AIT. We need more evidence concerning AIT for prevention in individuals with AR triggered by house dust mites or other allergens and for the prevention of allergic sensitization, the first allergic disease, or for the prevention of allergic comorbidities in those with other allergic conditions. Evidence for the preventive potential of AIT as disease-modifying treatment exists but there is an urgent need for more high-quality clinical trials., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Type 1 diabetes mellitus (T1D) as well as allergies in childhood have increased worldwide during the last 2 decades. The reasons for this increase are still unknown but early life origins are being discussed, such as dietary and hygiene factors that may play a role in the development of both diseases. The aim of this study was to compare the prevalence of allergies in children with and without T1D and to define potential influencing factors., Materials and Methods: Data were collected from 104 patients with T1D (n = 104; mean age 11.4 ± 4.4 years; m/f: 77/27) and 104 healthy controls (CG) (n = 104; mean age 11.4 ± 4.3 years; m/f: 77/27). A questionnaire on allergic symptoms was obtained from each individual. In parallel, ImmunoCAP tests to detect specific allergen sensitization were performed., Results: Allergen sensitization rates were not significantly different between both groups (T1D: 42% vs CG 38%; P = 0.625). In both groups, a comparable number of patients reported allergic symptoms in the questionnaire (T1D: 20% vs CG 26%; P = 0.43). Allergen sensitization and allergic symptoms were independent of breastfeeding, pets at home or diabetes duration. However, in T1D, fewer family members smoked (T1D: 10% vs CG 56%; P < 0.001)., Conclusions: The present cohort study shows the same prevalence of allergy and atopy in a pediatric diabetes population compared to healthy controls. Diabetes per se does not seem to influence the development of allergies., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost-effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis., Methods: We searched nine international biomedical databases for published, in-progress, and unpublished evidence. Studies were independently screened by two reviewers against predefined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication, and combined symptom and medication scores. Secondary outcomes of interest included cost-effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random-effects meta-analyses., Results: We identified 5960 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD -0.53, 95% CI -0.63, -0.42), medication (SMD -0.37, 95% CI -0.49, -0.26), and combined symptom and medication (SMD -0.49, 95% CI -0.69, -0.30) scores while on treatment that were robust to prespecified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post-discontinuation of AIT, suggesting a benefit in relation to symptom scores., Conclusions: AIT is effective in improving symptom, medication, and combined symptom and medication scores in patients with allergic rhinoconjunctivitis while on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis (ARC). To inform the development of recommendations, we sought to critically assess the systematic review evidence on the effectiveness, safety and cost-effectiveness of AIT for ARC., Methods: We undertook a systematic overview, which involved searching nine international biomedical databases from inception to October 31, 2015. Studies were independently screened by two reviewers against pre-defined eligibility criteria and critically appraised using the Critical Appraisal Skills Programme (CASP) Systematic Review Checklist for systematic reviews. Data were descriptively synthesized., Results: Our searches yielded a total of 5932 potentially eligible studies, from which 17 systematic reviews met our inclusion criteria. Eight of these were judged to be of high, five moderate and three low quality. These reviews suggested that, in carefully selected patients, subcutaneous (SCIT) and sublingual (SLIT) immunotherapy resulted in significant reductions in symptom scores and medication requirements. Serious adverse outcomes were rare for both SCIT and SLIT. Two systematic reviews reported some evidence of potential cost savings associated with use of SCIT and SLIT., Conclusions: We found moderate-to-strong evidence that SCIT and SLIT can, in appropriately selected patients, reduce symptoms and medication requirements in patients with ARC with reassuring safety data. This evidence does however need to be interpreted with caution, particularly given the heterogeneity in the populations, allergens and protocols studied. There is a lack of data on the relative effectiveness, cost-effectiveness and safety of SCIT and SLIT. We are now systematically reviewing all the primary studies, including recent evidence that has not been incorporated into the published systematic reviews.

Peanut allergy is an IgE-mediated severe hypersensitivity disorder. The lack of a treatment of this potentially fatal allergy has led to intensive research on vaccine development. Here, we describe the design and initial characterization of a carrier-bound peptide derived from the most potent peanut allergen, Ara h 2, as a candidate vaccine. Based on the adjuvant capability of bacterial surface (S-) layers, a fusion protein of the S-layer protein SlpB from Lactobacillus buchneri CD034 and the Ara h 2-derived peptide AH3a42 was produced. This peptide comprised immunodominant B-cell epitopes as well as one T cell epitope. The fusion protein SlpB-AH3a42 was expressed in E. coli, purified, and tested for its IgE binding capacity as well as for its ability to activate sensitized rat basophil leukemia (RBL) cells. The capacity of Ara h 2-specific IgG rabbit-antibodies raised against SlpB-AH3a42 or Ara h 2 to inhibit IgE-binding was determined by ELISA inhibition assays using sera of peanut allergic patients sensitized to Ara h 2. IgE specific to the SlpB-AH3a42 fusion protein was detected in 69% (25 of 36) of the sera. Despite the recognition by IgE, the SlpB-AH3a42 fusion protein was unable to induce β-hexosaminidase release from sensitized RBL cells at concentrations up to 100ng per ml. The inhibition of IgE-binding to the natural allergen observed after pre-incubation of the 20 sera with rabbit anti-SlpB-AH3a42 IgG was more than 30% for four sera, more than 20% for eight sera, and below 10% for eight sera. In comparison, anti-Ara h 2 rabbit IgG antibodies inhibited binding to Ara h 2 by 48% ±13.5%. Our data provide evidence for the feasibility of this novel approach towards the development of a peanut allergen peptide-based carrier-bound vaccine. Our experiments further indicate that more than one allergen-peptide will be needed to induce a broader protection of patients allergic to Ara h 2., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines on Allergen Immunotherapy (AIT) for the management of insect venom allergy. To inform this process, we sought to assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy., Methods: We undertook a systematic review, which involved searching 15 international biomedical databases for published and unpublished evidence. Studies were independently screened and critically appraised using established instruments. Data were descriptively summarized and, where possible, meta-analysed., Results: Our searches identified a total of 16 950 potentially eligible studies; of which, 17 satisfied our inclusion criteria. The available evidence was limited both in volume and in quality, but suggested that venom immunotherapy (VIT) could substantially reduce the risk of subsequent severe systemic sting reactions (OR = 0.08, 95% CI 0.03-0.26); meta-analysis showed that it also improved disease-specific quality of life (risk difference = 1.41, 95% CI 1.04-1.79). Adverse effects were experienced in both the build-up and maintenance phases, but most were mild with no fatalities being reported. The very limited evidence found on modelling cost-effectiveness suggested that VIT was likely to be cost-effective in those at high risk of repeated systemic sting reactions and/or impaired quality of life., Conclusions: The limited available evidence suggested that VIT is effective in reducing severe subsequent systemic sting reactions and in improving disease-specific quality of life. VIT proved to be safe and no fatalities were recorded in the studies included in this review. The cost-effectiveness of VIT needs to be established., (© 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Allergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a working group of AIRWAYS integrated care pathways for airways diseases, the model of chronic respiratory diseases of the European Innovation Partnership on active and healthy ageing (DG CONNECT and DG Santé). It considered (1) the political background, (2) the rationale for allergen immunotherapy across the life cycle, (3) the unmet needs for the treatment, in particular in preschool children and old age adults, (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunotherapy, its mechanisms and the concept of active and healthy ageing.

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Management of Allergic Rhinoconjunctivitis. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in the management of allergic rhinoconjunctivitis., Methods: We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised., Conclusion: The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT.

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Management of Insect Venom Allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy., Methods: We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised., Discussion: The findings from this review will be used to inform the development of recomendations for EAACI's Guidelines on AIT.

Background: Peanut allergy develops after primary sensitization to peanut allergens and/or IgE cross-sensitization with homologous allergens from various plants. Therefore, heterogeneous patterns of sensitization to individual peanut allergens are observed in different countries. The aim of this study was to examine the IgE sensitization patterns of Austrian peanut-allergic patients., Methods: Sera from 65 peanut-allergic patients and 20 peanut-tolerant atopics were obtained in four Austrian allergy clinics. Sensitization patterns against peanut allergens Ara h 1-3, 6, 8 and 9 were identified by ImmunoCAP and ImmunoCAP ISAC., Results: Austrian peanut-allergic patients were sensitized to Ara h 2 and 6 (71%), followed by Ara h 1 (62%), Ara h 8 (45%), Ara h 3 (35%) and Ara h 9 (11%). All sera containing Ara h 2-specific IgE were also positive for Ara h 6, with Ara h 6-specific IgE levels significantly (p < 0.05) higher compared with Ara h 2. Twelve percent displayed IgE reactivity exclusively to Ara h 8. Peanut extract and Ara h 8 showed low diagnostic specificities of 25 and 10%, respectively. The other peanut allergens showed 100% specificity. Diagnostic sensitivities determined by ImmunoCAP ISAC and ImmunoCAP were highly similar for Ara h 2, 3 and 8., Conclusions: The majority of symptomatic peanut-allergic patients are sensitized to Ara h 2 and Ara h 6. In peanut-symptomatic patients with additional birch pollen allergy, other peanut allergens, especially Ara h 8, should be tested when IgE reactivity to Ara h 2 is absent., (© 2015 S. Karger AG, Basel)

Background: Ara h 1, a vicilin; Ara h 2, a 2S albumin; and Ara h 3, a legumin, are major peanut allergens. Ara h 2 is an important predictor of clinical reactivity to peanut, but cosensitization to all 3 allergens is correlated with the severity of patients' symptoms., Objective: We investigated whether cosensitization to these 3 allergens is caused by IgE cross-reactivity, despite the fact that they do not display obvious structural or sequence similarities., Methods: IgE cross-inhibitions were performed with purified Ara h 1, Ara h 2, and Ara h 3 and IgG-depleted sera from 10 patients with peanut allergy. After an in silico search for similar peptides, IgE ELISA inhibition assays with synthetic peptides were performed., Results: Ara h 2 inhibited IgE binding to Ara h 1 (average, 86% ± 13%) and Ara h 3 (average, 96% ± 6%). IgE binding to Ara h 2 was inhibited by Ara h 1 by 78% ± 15% and by Ara h 3 by 80% ± 6%. A subsequent sequence comparison showed that these nonhomologous allergens contained several similar surface-exposed peptides. IgE binding to Ara h 2-derived peptides was completely inhibited by Ara h 1 and Ara h 3. A mixture of these peptides reduced IgE binding to Ara h 1 and Ara h 3 by 20% to 60% and to Ara h 2 by 49% to 89%., Conclusion: Occurrence of similar sequences in the 3 major peanut allergens accounts for the high extent of cross-reactivity among them., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe's policy-makers to coordinate actions and improve individual and public health in allergy by:Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.

This article is the result of consensus reached by a working group of clinical experts in paediatric allergology as well as representatives from an ethical committee and the European Medicine Agency (EMA). The manuscript covers clinical, scientific, regulatory and ethical perspectives on allergen-specific immunotherapy in childhood. Unmet needs are identified. To fill the gaps and to bridge the different points of view, recommendations are made to researchers, to scientific and patient organizations and to regulators and ethical committees. Working together for the benefit of the community is essential. The European Academy of Allergy and Clinical Immunology (EAACI) serves as the platform of such cooperation., (© 2012 John Wiley & Sons A/S.)

Background: For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects., Methods: This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies., Results: Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made., Conclusion: Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies., (© 2011 John Wiley & Sons A/S.)

Background: Allergic rhinoconjunctivitis is a risk factor for asthma development. Treating the underlying allergy may represent an attractive method of asthma prevention. No regulatory guidance exists in this area, and, to our knowledge, no clinical investigations meeting modern regulatory standards have been published., Objective: The objective of this publication is to describe the rationale behind the design of and report on the recruitment for the ongoing pediatric Grazax Asthma Prevention (GAP) trial., Methods: The trial was designed for assessment of the preventive effect of an SQ-standardized grass allergy immunotherapy tablet (AIT) on asthma development, both during treatment and after the end of treatment. (The standardized quality [SQ] procedure is a standardization procedure comprising 3 components: total potency, major allergen content, and assessment of extract complexity.) The trial design was discussed with several European Competent Authorities., Results: The GAP trial is a multinational, parallel-group, double-blind, placebo-controlled randomized trial. Main eligibility criteria were age of 5 to 12 years, grass pollen-induced allergic rhinoconjunctivitis, no asthma, and no overlapping symptomatic allergies. The children have been randomized 1:1 to receive the grass AIT or placebo once daily for 3 years, followed by a blinded observational period of 2 years. Asthma is assessed by the investigators according to specific diagnostic criteria, used at screening visits before randomization to exclude children with existing asthma, and evaluated at least half-yearly during the trial. Seven months of screening resulted in 812 randomized children at 101 centers in 11 countries., Conclusions: To our knowledge, the GAP trial represents the first double-blind, placebo-controlled randomized trial to assess the preventive effect of allergen-specific immunotherapy on asthma development. A total of 812 children were successfully recruited into the trial. EudraCT number: 2009-011235-12., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Common buckwheat (Fagopyrum esculentum) is known to cause severe anaphylactic reactions in adult individuals. However, type I allergy to buckwheat is rarely seen in children. We report on a 7-year-old boy who developed a grade III anaphylactic reaction after consumption of a cake containing buckwheat flour. Prior to this incident, the boy had developed severe allergic reactions to hazelnuts and suffered from an oral allergy syndrome to poppy seed. Analysis of the patient's IgE reactivity by immunoblotting experiments revealed that he was sensitized to members of the 2S albumin and 11S globulin protein families in buckwheat. Additionally, cross-reactivity was found between the 11S globulins in buckwheat, poppy and hazelnut. IgE inhibition experiments indicated that the 11S globulin in buckwheat was the initial sensitizing protein. We conclude that 11S globulins in buckwheat have the potential to induce IgE antibodies cross-reactive with 11S globulins in other, botanically unrelated foods and may induce anaphylactic reactions., (Copyright © 2011 S. Karger AG, Basel.)

Background: Immunotherapy for bee venom allergy is effective and provides long-term protection. Venom-specific IgG4 levels are increased but with no correlation with clinical improvement. Following grass pollen immunotherapy, elevation of antigen-specific IgG4 is accompanied by increases in IgG-dependent serum inhibitory activity for IgE-facilitated binding of allergen-IgE complexes to B cells. As this 'functional' assay of inhibitory antibodies may be more predictive of clinical efficacy, we investigated the time course of serum inhibitory activity for IgE-facilitated antigen binding during venom immunotherapy (VIT) in children and following 2 years of VIT withdrawal., Methods: Ten bee venom-allergic children (mean age: 9.3 years; m/f, 7/3) with moderate to severe allergic reactions to bee stings received VIT. A separate group of seven children (mean age: 14 years; m/f, 5/2) were investigated 2 years after VIT withdrawal. Ten age- and gender-matched children served as non-allergic controls. Allergen-specific serum IgG4 and IgE levels were measured by ELISA at baseline, after 2 years of VIT and 2 years after VIT withdrawal. Serum inhibitory activity was assessed using the facilitated-allergen binding (FAB) assay., Results: Sera obtained during VIT significantly inhibited allergen-IgE binding to B-cells (pre-treatment=104+/-23%; 2 years=46+/-15%; P<0.001) when compared with sera obtained after treatment withdrawal and sera from normal controls. In parallel to FAB inhibition during VIT, significantly higher IgG4 levels were noted after immunotherapy (pre-treatment=8.6+/-2.3 AU; 2 years=26.7+/-3.5 AU; P<0.001) compared with those observed after withdrawal and in the controls. In contrast, progressively lower IgE concentrations were observed compared with pre-treatment (44+/-7 AU) in sera obtained after 2 years of VIT (25+/-5 AU; P<0.01) and 2 years following the withdrawal of VIT (10+/-3 AU; P<0.05)., Conclusions: In contrast to grass pollen immunotherapy, the persistent decline in venom-specific IgE levels, rather than serum inhibitory activity for FAB, may be more relevant for long-term clinical efficacy of VIT.

A pediatric consensus report on allergen-specific immunotherapy for children and adolescents is presented for Austria. Products on the market in Austria are presented and categorised according to studies performed on the target population of children and adolescents, their effectiveness and indication. In general, more clinical studies on children and adolescents are mandatory for most of the available allergen-specific immunotherapeutics. In addition, the use of allergen-specific immunotherapy in general should be promoted as the exclusive treatment with long-lasting effects in type I allergies in particular in children.

Background: Current diagnosis of allergy and asthma to cat is confirmed using cat dander extract (CDE). We have previously engineered a recombinant major cat allergen, rFel d 1, with properties identical to the natural molecule., Objective: The aim of the study was to evaluate IgE and IgG4 antibodies to rFel d 1 among sera from cat-allergic children and adults suffering from asthma and/or rhinoconjunctivitis (RC) in populations from Sweden and Austria., Methods: Cat-allergic children and adults from Sweden (n=27 and 31, respectively) and Austria (n=41 and 41) with RC and/or asthma were selected. Sera were tested for IgE and IgG4 antibodies to CDE and rFel d 1 by CAP, and IgE to rFel d 1 by ELISA. Healthy subjects and non-cat-allergic patients (n=75) were included as controls., Results: There was a high correlation between IgE responses to rFel d 1 and CDE among the 140 patients (r(s)=0.85, P<0.001); however, measured levels to rFel d 1 were on average 30% higher (P<0.0001). Ninety-eight percent of patients and none of the controls showed IgE to rFel d 1 and there was a threefold increased risk of asthma for half of the children with the highest IgE levels [odds ratio 3.23; 95% confidence interval (CI), 1.19-8.79] by ELISA. IgE responses to rFel d 1 among children with asthma were higher (median 19.4 kU/L) compared with children with RC (median 6.6 kU/L, P<0.05) and adults with asthma (median 3.0 kU/L, P<0.01). Furthermore, children with asthma displayed higher IgG4 levels than the asthmatic adults., Conclusion: A single recombinant molecule, rFel d 1, is at least as sensitive for in vitro diagnostics of cat allergy as the current extract-based test. Elevated IgE antibody levels to Fel d 1 are suggested to be a risk factor for asthma in cat-allergic children.

Background: A considerable proportion of animal-allergic patients are sensitized to both cat and dog allergens but knowledge about cross-reactive allergens in cat and dog dander is limited., Objective: To investigate whether dog dander contains an allergen that cross-reacts with the major cat allergen, Fel d 1., Methods: Recombinant Fel d 1 with the same immunological properties as natural Fel d 1 was used for quantitative (CAP) IgE competition experiments performed with sera obtained from cat-allergic patients (n=36). A Fel d 1 cross-reactive dog allergen was characterized by one- and two-dimensional immunoblotting using rFel d 1 for IgE inhibition experiments and with monospecific, polyclonal rabbit anti-recombinant Fel d 1 antibodies., Results: In 25% of Fel d 1-reactive cat-allergic patients, more than 50% inhibition of IgE reactivity to dog allergens was achieved with recombinant Fel d 1. An Fel d 1 cross-reactive 20 kDa allergen with a pI of approximately 3.4 was detected in dander extracts of several different dog breeds., Conclusion: This is the first report demonstrating the presence of an Fel d 1-like allergen in dog dander extracts, which may be responsible for double positivity to cat and dog in serology. However, the clinical relevance of this cross-sensitization needs to be confirmed. These results are important for the diagnostic and therapeutic use of dog dander allergen extracts.

Background: Unlike other chemokines, fractalkine is expressed as a membrane-bound form, mainly on endothelial and epithelial cells, and can be shed as a soluble chemotactic form. Fractalkine can capture leukocytes expressing its receptor (CX(3)CR(1)), including T lymphocytes, rapidly and firmly in an integrin-independent manner. Because of its dual activity, fractalkine plays a major role in the transendothelial and transepithelial migration of leukocytes during inflammation., Objective: We sought to study the fractalkine-CX(3)CR(1) axis in patients with allergic airways diseases., Methods: Plasma fractalkine levels were measured by means of ELISA in 19 control subjects and 55 patients with symptomatic allergic rhinitis, asthma, or both, and CX(3)CR(1) function was studied by using triple-color flow cytometry in circulating T-lymphocyte subpopulations. Segmental allergen challenge was performed in 16 allergic asthmatic patients to analyze fractalkine expression and inflammatory cell recruitment in bronchoalveolar lavage fluid and bronchial biopsy specimens., Results: Compared with control subjects, patients with symptomatic allergic rhinitis and asthmatic patients had increased circulating fractalkine levels, and CX(3)CR(1) function was upregulated in circulating CD4(+) T lymphocytes. Twenty-four hours after segmental allergen challenge, bronchoalveolar lavage fluid soluble fractalkine concentrations increased and correlated with the total number of recruited cells. Bronchial epithelial and endothelial cells expressed high levels of the membrane-bound form of fractalkine before and after challenge., Conclusion: Allergic asthma and rhinitis are associated with systemic and bronchial upregulation of the chemotactic axis fractalkine-CX(3)CR(1). This might contribute to the rapid recruitment of circulating CD4(+) T lymphocytes in the airways after allergen stimulation.

Over the last decades the prevalence of allergic disorders, such as hayfever and asthma has increased worldwide, mostly in westernised countries where up to 20 % of the population are affected. The "hygiene hypothesis" suggests that modernised lifestyles such as improved housing conditions, altered dietary habits and smaller family sizes may be responsible for the decrease in infectious and the increase in allergic diseases. Childhood atopic diseases, like eczema, food allergies and recurrent wheezy bronchitis represent a considerable health problem and a major socioeconomic burden due to the chronicity of these disorders. In recent years, a better understanding of the immunopathogenesis of allergic diseases has evolved, which has contributed to the development of novel more targeted forms of therapy. Allergen injection immunotherapy is the only treatment in current use with the potential for modifying the course of allergic disease. In order to better target mucosal allergies, new approaches of administering allergen, via the sublingual or intranasal route, are being developed. The use of modified allergens, allergen peptides, DNA immunization and the use of novel adjuvants represent alternatives to conventional immunotherapy with potential for improved efficacy with less side effects. For atopic asthma, novel treatment strategies aim at locally targeting inflamed airways. Nebulized monoclonal blocking antibodies and soluble interleukin receptors against "Th(2)-type" cytokines have been designed. An alternative approach has been the administration of "Th(1) -type" cytokines. Although, immunomodulatory strategies provide a promising outlook for the treatment of allergic patients, more studies are needed in the future to address issues of efficacy, safety and long-term effects of altered immune responses.

We studied the regulation of CCR4 expression in peripheral blood and in human models of cutaneous and pulmonary allergen challenge. CCR4 expression was detectable on freshly isolated CD4+ lymphocytes and in CD4+ and CD8+ T cell lines derived from blood of atopic donors. Numbers of CCR4+ cells were up-regulated in T cell lines expanded in the presence of IL-4. CCR4 mRNA was absent at baseline in normal subjects in lung and skin, but present at baseline in the lung of some atopics. Baseline expression of CCR4 mRNA and protein was higher in lung vs. skin, but allergen-induced increases in CCR4 mRNA+ cells were observed in both organs. CCR4 protein+ cells were present at higher levels after allergen challenge in atopics compared to normal subjects. CCR4 may be important in the recruitment of T lymphocytes at sites of allergic inflammation, in a non-organ-specific manner.

IgE is important in both early and late allergic responses. Increases in the numbers of RNA transcripts coding for IgE have been observed in the bronchial mucosa of asthmatics and in the nasal mucosa of hay fever patients both during natural allergen exposure and after nasal allergen challenge, suggesting that IgE may be synthesized locally in the mucosa. In this study we have examined bronchoalveolar lavage (BAL) taken before and 24 h after bronchoscopic segmental allergen challenge from 18 atopic asthmatic patients, looking for evidence of increases in IgE protein. Allergen-specific IgG and total and allergen-specific IgE were measured in BAL using a fluoroenzyme immunoassay. There was a significant increase in allergen-specific IgE (Ku/L) in the BAL after allergen challenge [before [median (interquartile range)] 0 (0, 0); after 0.35 (0, 1.87): p = 0.009] which was not observed for allergen-specific IgG (p = 1.0) or for IgE specific to an allergen to which the subject was sensitized but was not used for provocation (p = 1.0). Correction for corresponding increases in total IgE, albumin, and urea in BAL did not affect the observed changes in allergen-specific IgE. These data indicate that allergen provocation results in a selective local accumulation of isotype-specific and allergen-specific IgE antibody within the bronchi, independent of alterations in circulating IgE.

Background: Basophils represent an important source of inflammatory mediators and cytokines after IgE-dependent activation in human beings., Objective: To assess the role of basophils in allergic asthma, we measured the number of basophils in the bronchial mucosa and their capacity to express IL-4 mRNA and protein during allergen-induced late asthmatic responses., Methods: Fiberoptic bronchoscopic bronchial biopsies were obtained at 24 hours from sites of segmental bronchial allergen challenge and control sites in 19 patients with atopic asthma and 6 nonatopic healthy volunteers. Basophil numbers were assessed by immunohistochemistry through use of mAb 2D7. IL-4 mRNA--positive cells were detected through use of in situ hybridization and colocalized to basophils through use of sequential immunohistochemistry/in situ hybridization. IL-4 protein was detected and colocalized to basophils through use of dual immunohistochemistry., Results: After allergen challenge, there was an increase in the median number of 2D7-positive basophils per square millimeter in the bronchial mucosa in patients with asthma (0.9 cells/mm(2) at baseline to 8.8 cells/mm(2) after challenge; P =.002), which also was significantly higher than what was seen in nonasthmatic controls (P =.01). Similarly, IL-4 mRNA--positive cells were increased at 24 hours in patients with asthma (1.4 to 14) in comparison with controls (0 to 0; P =.02). Colocalization studies revealed that 15% and 41% of the basophil population in patients with asthma after allergen-challenge expressed, respectively, IL-4 mRNA and protein. Conversely, 19% of IL-4 mRNA-positive cells and 72% of IL-4 protein--positive cells were accounted for by basophils., Conclusion: After allergen provocation in sensitive patients with atopic asthma, basophils are recruited to the bronchial mucosa and express IL-4 mRNA and protein, which might contribute to local IgE synthesis and/or tissue eosinophilia or other aspects of allergic inflammation during late responses and ongoing asthma.

Unlabelled: We report on two Turkish children who presented with progressive airway obstruction. Open lung biopsy revealed follicular bronchiolitis. The children were treated with systemic steroids and various topical medications. Whereas the respiratory situation of patient 1 required immunosuppressive therapy, the condition of patient 2 stabilised without systemic medication., Conclusion: Diagnosis of follicular bronchiolitis should be considered when children present with recurrent respiratory tract infections, progressive dyspnoea, and chronic bronchial obstruction. Children in whom follicular bronchiolitis is suspected should undergo open lung biopsy for confirmation of diagnosis.