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The ALEX2-test (MacroArray Diagnostics, Vienna, Austria) is a diagnostic multiplex IgE-test for the simultaneous detection of IgE to 178 allergens and 117 extracts, in addition to total IgE. Test results from more than 90 countries are stored on a GDPR-compliant cloud server for backup, customer support, and continuous postmarket surveillance. To improve the coverage of exposomes on a global scale and to further increase the sensitivity of the test, the allergen panel was updated from ALEX2 to ALEX3. By mid-2023, when ALEX3 was designed, almost 400,000 real-world ALEX2 test results were available. Analysing prevalences and average sIgE-levels of individual allergen preparations, coverage of extracts by components, and co-reactivity of members of the same allergen family provided a rationale for updating the array. In parallel, based on the scientific literature and clinical studies, new allergens were selected. On ALEX3, 218 allergens and 82 extracts will be represented, including 52 new allergens. Allergen preparations with low prevalence and clinical relevance, as well as redundant allergens and extracts, were discontinued. New allergens encompass, e.g., cyclophilins, alpha-gal, and additional markers from respiratory and food allergen sources. Using a large dataset of ALEX2 test results exemplifies the targeted, data-driven improvement of a diagnostic IgE-macroarray.

Allergic reactions to stings of Hymenoptera species may be severe and are potentially fatal deviations of the immunological response observed in healthy individuals. However, venom-specific immunotherapy (VIT) is an immunomodulatory approach able to cure venom allergy in the majority of affected patients. An appropriate therapeutic intervention and the efficacy of VIT not only depend on a conclusive diagnosis, but might also be influenced by the patient-specific manifestation of the disease. As with other diseases, it should be borne in mind that there are different endotypes and phenotypes of venom allergy, each of which require a patient-tailored disease management and treatment scheme. Reviewed here are different endotypes of sting reactions such as IgE-mediated allergy, asymptomatic sensitization or a simultaneous presence of venom allergy and mast cell disorders including particular considerations for diagnosis and therapy. Additionally, phenotypical manifestations of venom allergy, as e.g. differences in age of onset and disease severity, multiple sensitization or patients unsusceptible to therapy, are described. Moreover, biomarkers and diagnostic strategies that might reflect the immunological status of the patient and their value for therapeutic guidance are discussed. Taken together, the increasing knowledge of different disease manifestations in venom hypersensitivity and the growing availability of diagnostic tools open new options for the classification of venom allergy and, hence, for personalized medical approaches and precision medicine in Hymenoptera venom allergy.

The objective of this analysis was to compare the multiplex ImmunoCAP ISAC (Thermo Fisher Scientific, Sweden) and the multiplex Alex Allergy Explorer (Macro Array Diagnostics GmbH, Austria) platform on specific IgE to grass pollen (Phl p 1, Phl p 5), tree pollen (Bet v 1), house dust mites (Der p 1, Der p 2) and cat (Fel d 1) allergens in allergic patients. Our findings demonstrate a good correlation of presently used methods to detect serum sIgE. Multiplex testing of allergen-specific IgE can be the method of choice for a prospective component-resolved diagnosis of type I allergy, and the basis for the design and monitoring of a patient-tailored specific therapy.

Purpose of ReviewThe aim of this article is to discuss how allergen-specific immunotherapy (AIT) can be improved through molecular approaches. We provide a summary of next-generation molecular AIT approaches and of their clinical evaluation. Furthermore, we discuss the potential of next generation molecular AIT forms for the treatment of severe manifestations of allergy and mention possible future molecular strategies for the secondary and primary prevention of allergy.Recent FindingsAIT has important advantages over symptomatic forms of allergy treatment but its further development is limited by the quality of the therapeutic antigen preparations which are derived from natural allergen sources. The field of allergy diagnosis is currently undergoing a dramatic improvement through the use of molecular testing with defined, mainly recombinant allergens which allows high-resolution diagnosis. Several studies demonstrate that molecular testing in early childhood can predict the development of symptomatic allergy later on in life.SummaryClinical studies indicate that molecular AIT approaches have the potential to improve therapy of allergic diseases and may be used as allergen-specific forms of secondary and eventually primary prevention for allergy.

The prevalence of food allergy continues to rise, posing a significant burden on health and quality of life. Research on antigenic epitope identification and hypoallergenic agent design is advancing allergen-specific immunotherapy (AIT). This review focuses on food allergens from the perspective of molecular allergology, provides an overview of integration of bioinformatics and experimental validation for epitope identification, highlights hypoallergenic agents designed based on epitope information, and offers a valuable guidance to the application of hypoallergenic agents in AIT. With the development of molecular allergology, the characterization of the amino acid sequence and structure of the allergen at the molecular level facilitates T-/B-cell epitope identification. Alignment of the identified epitopes in food allergens revealed that the amino acid sequence of T-/B-cell epitopes barely overlapped, providing crucial data to design allergen molecules as a promising form for treating (FA) food allergy. Manipulating antigenic epitopes can reduce the allergenicity of allergens to obtain hypoallergenic agents, thereby minimizing the severe side effects associated with AIT. Currently, hypoallergenic agents are mainly developed through synthetic epitope peptides, genetic engineering, or food processing methods based on the identified epitope. New strategies such as DNA vaccines, signaling molecules coupling, and nanoparticles are emerging to improve efficiency. Although significant progress has been made in designing hypoallergenic agents for AIT, the challenge in clinical translation is to determine the appropriate dose and duration of treatment to induce long-term immune tolerance. Graphical Abstract

Background As extract‐based skin testing as well as in vitro tests for major allergens have their own advantages, both procedures are usually performed in routine settings. In times of shortages in medical staff and supplies, we asked ourselves, how many patients would be underdiagnosed, if only one test could be used. Methods In a retrospective analysis, we investigated a cohort of 2646 patients seen by a single physician in a large Austrian outpatient allergy clinic in 2018. Only patients with an allergen source‐specific history and pairs of extract‐based skin prick (SPT) and in vitro molecular allergy tests to major allergens were included. Results For all tested allergen sources, sensitivity was higher for SPT than for sIgE‐based molecular allergy testing. Concerning 1006 birch pollen‐allergic patients, 791 (78.6%) had positive results with both tests, while 153 (15.2%) only with the SPT and 62 (6.2%) only with the sIgE to Bet v1. The other allergen sources showed similar results: For house dust mite 816/1120 (72.9%), grass pollen 1077/1416 (76.1%) and cat 433/622 (69.6%) remained test‐positive with both procedures, whereas in 276 (24.6%), 224 (15.8%) and 173 (27.8%) times only the SPT and 28 (2.5%), 115 (8.1%) and 16 (2.6%) times only the sIgE to Der p1/2/23, Phl p1/5 and Fel d1 showed a positive result. Each comparison was statistically significant (each p < 0.0001, Chi‐squared test). Conclusions Screening for allergy with major molecular allergens has lower sensitivity when compared with extract‐based skin tests. A combination of both is required for an optimal sensitivity.

The term allergy was coined in 1906 by the Austrian scientist and pediatrician Clemens Freiherr von Pirquet. In 1976, Dietrich Kraft became the head of the Allergy and Immunology Research Group at the Department of General and Experimental Pathology of the University of Vienna. In 1983, Kraft proposed to replace natural extracts used in allergy diagnostic tests and vaccines with recombinant allergen molecules and persuaded Michael Breitenbach to contribute his expertise in molecular cloning as one of the mentors of this project. Thus, the foundation for the Vienna School of Molecular Allergology was laid. With the recruitment of Heimo Breiteneder as a young molecular biology researcher, the work began in earnest, resulting in the publication of the cloning of the first plant allergen Bet v 1 in 1989. Bet v 1 has become the subject of a very large number of basic scientific as well as clinical studies. Bet v 1 is also the founding member of the large Bet v 1-like superfamily of proteins with members—based on the ancient conserved Bet v 1 fold—being present in all three domains of life, i.e., archaea, bacteria and eukaryotes. This suggests that the Bet v 1 fold most likely already existed in the last universal common ancestor. The biological function of this protein was probably related to lipid binding. However, during evolution, a functional diversity within the Bet v 1-like superfamily was established. The superfamily comprises 25 families, one of which is the Bet v 1 family, which in turn is composed of 11 subfamilies. One of these, the PR-10-like subfamily of proteins, contains almost all of the Bet v 1 homologous allergens from pollen and plant foods. Structural and functional comparisons of Bet v 1 and its non-allergenic homologs of the superfamily will pave the way for a deeper understanding of the allergic sensitization process.

Cow’s milk allergy (CMA) is an increasingly common problem among children and adults that requires the use of appropriate diagnostics to eliminate allergic reactions and prevent unnec-essary dietary regimes. The current diagnostics methods are imperfect hence new, more effective methods are still being sought. Component-resolved diagnostics (CRD) is one of them. CRD assesses sensitivity to individual allergen molecules using purified native or recombinant allergens. The present paper reviews the role of CRD in diagnosing CMA, as well as the benefits and limitations of its use, especially in predicting allergy development or acquiring immunotolerance. It examines the possibility of replacing the current gold diagnostic standard with component tests directed against specific milk proteins. In addition, CRD could be helpful in the evaluation of prognosis. However, CRD allows for improvement in clinical management, particularly of polysensitized subjects, there is still no cogent evidence that it offers more efficient CMA diagnostics than existing tests.

Atopic dermatitis (AD) represents a widespread chronic skin disease associated with different atopic disorders and allergies. These associations, similar to overall AD pathophysiology, are entangled, multifactorial and they are yet to be clarified. IgE and non IgE mediated pathomechanisms appear to be implicated in AD. Allergens constitute key aspects in AD pathogenesis, as they may serve as trigger factors. This review emphasizes mainly house dust mites (HDM), as they are likely the most relevant airborne allergen for AD. Here we review in a concise form the mite allergens, the role of molecular diagnosis and the treatment strategies for HDM. Strategies of avoiding allergens, with a few exceptions, are not enough to control children's AD; recent studies show HDM avoidance procedures in diagnosed AD are insufficient. Regardless, some guidelines acknowledge the benefit of mattress and pillow covers in patients with dust mite sensitization that are unresponsive to optimal AD management. Most clinical trials investigating allergen-specific immunotherapy (AIT) as a potential treatment for AD were done with adult patients; a scarce number of studies looked into the efficacy of AIT as a treatment option in children suffering from AD, with conflicting data among them. One of the most feasible of these studies showed significant improvement of AD outcomes only in the mild/moderate group, but not in the severe group. Uncontrolled studies are hard to interpret, considering the natural history of remitting and relapsing of AD, in many of the patients, without clinical interventions. More AIT studies, especially pediatric studies, are required in order to either prove the reproducibility of positive results or to deny its effectiveness.

Purpose of Review Allergenic molecules of the house dust mite (HDM) are crucially important indoor allergens, contributing to allergic rhinitis and asthma around the globe. In the past years, recombinant molecules for diagnostics opened new pathways to investigate individual sensitization profiles and new chances for the prevention and treatment of HDM allergy. This review summarizes the latest findings on the evolution of IgE responses towards mite allergens. Recent Findings Several cross-sectional and longitudinal studies confirmed the role of Der p 1 and Der p 2 as major allergenic proteins of the HDM. A newly identified player is the major allergen Der p 23. Apart from identifying the early sensitization towards this molecule as a risk factor for asthma in school age, a recent longitudinal study described sensitization patterns showing that the production of IgE usually starts towards a group of initiator proteins and may stay monomolecular or expand to an oligo- or even polymolecular stage. This phenomenon also correlates to clinical symptoms. A relation between a broad sensitization pattern and symptom severity has also been shown cross-sectionally. Summary Individual sensitization profiles towards HDM allergens provide important information to evaluate a patient’s current stage and risk for clinical symptoms. This knowledge paves the way for an early and adequate prevention and/or treatment.