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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., (© 2023 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

One hundred and ten years after Noon's first clinical report of the subcutaneous application of allergen extracts, allergen immunotherapy (AIT) has evolved as the most important pillar of the treatment of allergic patients. It is the only disease-modifying treatment option available and the evidence for its clinical efficacy and safety is broad and undisputed. Throughout recent decades, more insights into the underlying mechanisms, in particular the modulation of innate and adaptive immune responses, have been described. AIT is acknowledged by worldwide regulatory authorities, and following the regulatory guidelines for product development, AIT products are subject to a rigorous evaluation before obtaining market authorization. Knowledge and practice are anchored in international guidelines, such as the recently published series of the European Academy of Allergy and Clinical Immunology (EAACI). Innovative approaches continue to be further developed with the focus on clinical improvement by, for example, the usage of adjuvants, peptides, recombinants, modification of allergens, new routes of administration, and the concomitant use of biologicals. In addition, real-life data provide complementary and valuable information on the effectiveness and tolerability of this treatment option in the clinical routine. New mobile health technologies and big-data approaches will improve daily treatment convenience, adherence, and efficacy of AIT. However, the current coronavirus disease 2019 (COVID-19) pandemic has also had some implications for the feasibility and practicability of AIT. Taken together, AIT as the only disease-modifying therapy in allergic diseases has been broadly investigated over the past 110 years laying the path for innovations and further improvement., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component-resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decisions., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Since its discovery in 1967, IgE antibody detection in skin and blood has identified a state of allergic sensitization and served as a necessary but not sufficient risk factor that requires objective symptoms to make the definitive diagnosis of human allergic disease. More recently, quantitative IgE antibody levels in serum against allergenic extracts, molecules, and epitopes have pushed its application into more accurately identifying the specificity of the allergic response for targeting immunotherapy, predicting allergic symptom severity after allergen exposure, and attempting to distinguish tolerance from food allergy. This review examines new in vivo and in vitro developments in the design, performance, interference, and application of the methods used to identify allergic sensitization. The increasing accepted applications of molecular allergen and allergen epitope-based IgE antibody measurements, especially as applied to food allergy diagnosis and management, are highlighted as state-of-the-art advances. Despite these major advances in allergic sensitization documentation, their ultimate value requires integration by the clinician with the patient's history and pretest probability of disease., (Copyright © 2020. Published by Elsevier Inc.)

Pollen from various Fagales tree species prolongs the season and makes tree pollen allergy a major health problem. Despite involving the same causative allergens, allergy immunotherapy (AIT) treatment habits differ significantly across different geographical regions. Diagnosis and treatment with AIT in patients allergic to tree pollen were discussed by a group of German medical experts who give practical recommendations based on the available data. Regulatory perspective: According to current guidelines on allergen products, birch pollen are the representative allergen source of the birch homologous group including several Fagales trees based on sequence and structural similarity of their allergen proteins. Immunological perspective: A high level of IgE cross-reactivity towards allergens from the birch homologous group has been observed in basic research and clinical trials. Clinical perspective: Clinical trial data show that the efficacy of birch pollen AIT is not only related to birch pollen allergy but extends to pollen from other trees, especially alder, hazel and oak. In order to optimize diagnosis and treatment of tree pollen allergy, the experts recommend to focus diagnosis and respective treatment with AIT primarily to birch as the representative allergen of the Fagales tree homologous group, but further diagnostics may be needed for some patients to determine adequate treatment., (© 2019 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.)

Guidelines on the treatment of asthma, allergic rhinitis (AR), and allergen immunotherapy (AIT) lack recommendations for house dust mite (HDM) allergy. An expert panel reviewed current guidelines in the light of new data to assess whether guidelines could be improved. Most guidelines and key position papers did not provide specific recommendations on treatment of allergic asthma (AA) caused by HDM allergy, although some included AIT as a treatment option for AA in general. Around half of the guidelines stated that AIT with HDM extract was an effective treatment for AR, with several indicating sublingual immunotherapy as an option. This heterogeneity is caused by quality issues affecting studies of AIT with perennial allergens in patients with AA and AR, including use of different diagnosis and severity criteria, lack of consistent scoring or grading systems for primary and safety outcomes, and lack of consensus on treatment parameters. There is a need for well-designed clinical trials to serve as a basis for guideline recommendations. Although results from recent studies strengthen the evidence base for the efficacy and safety of sublingual immunotherapy in patients with HDM-induced AA and AR, their effect on subsequent guideline updates will depend on the methodology and evidence model used by each guideline., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: After the re-introduction of ImmunoCAP® ISAC sIgE 112 on the market, we undertook a study to evaluate the performance of this multiplex-based immunoassay for IgE measurements to allergen components., Methods: The study was carried out at 22 European and one South African site. Microarrays from different batches, eight specific IgE (sIgE) positive, three sIgE negative serum samples and a calibration sample were sent to participating laboratories where assays were performed according to the manufacturer's instructions., Results: For both the negative and positive samples results were consistent between sites, with a very low frequency of false positive results (0.014%). A similar pattern of results for each of the samples was observed across the 23 sites. Homogeneity analysis of all measurements for each sample were well clustered, indicating good reproducibility; unsupervised hierarchical clustering and classification via random forests, showed clustering of identical samples independent of the assay site. Analysis of raw continuous data confirmed the good accuracy across the study sites; averaged standardized, site-specific ISU-E values fell close to the center of the distribution of measurements from all sites. After outlier filtering, variability across the whole study was estimated at 25.5%, with values of 22%, 27.1% and 22.4% for the 'Low', 'Moderate to High' and 'Very High' concentration categories, respectively., Conclusions: The study shows a robust performance of the ImmunoCAP® ISAC 112 immunoassay at different sites. Essentially the same results were obtained irrespective of assay site, laboratory-specific conditions and instruments, operator, or the use of microarrays from different batches.

Background: There is a need to establish the effectiveness, cost-effectiveness, and safety of allergen immunotherapy (AIT) for the prevention of allergic disease., Methods: Two reviewers independently screened nine international biomedical databases. Studies were quantitatively synthesized using random-effects meta-analyses., Results: A total of 32 studies satisfied the inclusion criteria. Overall, meta-analysis found no conclusive evidence that AIT reduced the risk of developing a first allergic disease over the short term (RR = 0.30; 95% CI: 0.04-2.09) and no randomized controlled evidence was found in relation to its longer-term effects for this outcome. There was, however, a reduction in the short-term risk of those with allergic rhinitis developing asthma (RR = 0.40; 95% CI: 0.30-0.54), with this finding being robust to a pre-specified sensitivity analysis. We found inconclusive evidence that this benefit was maintained over the longer term: RR = 0.62; 95% CI: 0.31-1.23. There was evidence that the risk of new sensitization was reduced over the short term, but this was not confirmed in the sensitivity analysis: RR = 0.72; 95% CI: 0.24-2.18. There was no clear evidence of any longer-term reduction in the risk of sensitization: RR = 0.47; 95% CI: 0.08-2.77. AIT appeared to have an acceptable side effect profile., Conclusions: AIT did not result in a statistically significant reduction in the risk of developing a first allergic disease. There was, however, evidence of a reduced short-term risk of developing asthma in those with allergic rhinitis, but it is unclear whether this benefit was maintained over the longer term. We are unable to comment on the cost-effectiveness of AIT., (© 2016 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 the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Prevention of Allergic Disease. We seek to critically assess the effectiveness, cost-effectiveness, and safety of AIT in the prevention of allergic disease., 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 synthesized., Discussion: The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Symptoms are recorded by obtaining a clinical history. Allergen sensitization is demonstrated by skin prick test or allergen-specific IgE serology. IgE sensitizations to allergen sources can be identified knowing the relationship between major aeroallergens and homologous allergen families. Some develop allergic sensitization to pan-allergens. Allergen extracts do not allow definitive separation of the sources. IgE antibody analysis of the major allergenic molecules facilitates differentiation of sensitizing allergen sources. IgE sensitizations to inhalant allergens are only relevant in the case of corresponding symptoms. In questionable cases, conjunctival or nasal provocation tests help induce confirmatory symptoms and identify relevant allergens for immunotherapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal. The conclusions below focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Although house dust mite (HDM) allergy is a major cause of respiratory allergic disease, specific diagnosis and effective treatment both present unresolved challenges. Guidelines for the treatment of allergic rhinitis and asthma are well supported in the literature, but specific evidence on the efficacy of pharmacotherapy treatment for known HDM-allergic patients is weaker. The standard diagnostic techniques--skin prick test and specific IgE testing--can be confounded by cross-reactivity. However, component-resolved diagnosis using purified and recombinant allergens can improve the accuracy of specific IgE testing, but availability is limited. Treatment options for HDM allergy are limited and include HDM avoidance, which is widely recommended as a strategy, although evidence for its efficacy is variable. Clinical efficacy of pharmacotherapy is well documented; however, symptom relief does not extend beyond the end of treatment. Finally, allergen immunotherapy has a poor but improving evidence base (notably on sublingual tablets) and its benefits last after treatment ends. This review identifies needs for deeper physician knowledge on the extent and impact of HDM allergy in respiratory disease, as well as further development and improved access to molecular allergy diagnosis. Furthermore, there is a need for the development of better-designed clinical trials to explore the utility of allergen-specific approaches, and uptake of data into guidance for physicians on more effective diagnosis and therapy of HDM respiratory allergy in practice., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The prevalence of allergy to furry animals has been increasing, and allergy to cats, dogs, or both is considered a major risk factor for the development of asthma and rhinitis. An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics. A workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases. In this review research results discussed at the workshop are presented, including the effect of concomitant exposures from other allergens or microorganisms, the significance of the community prevalence of furry animals, molecular-based allergy diagnostics, and a detailed discussion of cat and dog components., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Allergic sensitization to cat allergens is common and represents a major risk factor for asthma. Specific immunotherapy (SIT) is effective but cumbersome and associated with IgE-dependent adverse events. Immunotherapy targeting allergen-specific T cells, with synthetic peptides representing T-cell epitopes, might improve safety and reduce the duration of treatment., Objective: We sought to define major T-cell epitopes of Fel d 1 for peptide immunotherapy, generate a peptide vaccine, and evaluate its safety and tolerability in subjects with cat allergy., Methods: We determined the binding affinities of Fel d 1 peptides for 10 commonly expressed HLA-DR molecules. Functionally immunodominant peptides were identified by means of proliferation and cytokine secretion. Histamine-releasing activity was assessed, and a peptide vaccine was formulated. Safety and tolerability were evaluated in a dose-ranging phase IIa clinical trial., Results: MHC-binding sequences were identified throughout Fel d 1. Some regions contained multiple overlapping T-cell epitopes that bound multiple MHC molecules. Immunodominant sequences were identified on the basis of proliferative and cytokine (IFN-γ, IL-10, and IL-13) responses. Cat allergen extract, but not peptides, induced histamine release in blood basophils. A single administration of peptide vaccine was safe and well tolerated. The dose of vaccine resulting in the greatest inhibition of the late-phase skin response to intradermal whole allergen challenge was 3 nmol., Conclusions: Fel d 1 contains multiple overlapping MHC-binding motifs. A peptide vaccine comprising the immunodominant regions of the allergen was safe and well tolerated when given to subjects with cat allergy as a single dose. The dose of vaccine resulting in the greatest reduction in late-phase skin response was defined for future clinical development., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)