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Copyright of Journal of Laboratory Medicine / Laboratoriums Medizin is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The basis of allergen immunotherapy (AIT) is the diagnosis of the eliciting allergen sources, which is a challenge, especially in the case of multiple sensitizations. Molecular allergy diagnostics can be of special help, since detection of "marker allergens", usually important major allergens, allows to distinguish between primary sensitization and cross-reactions. Thus, the indication and extract selection for AIT can be facilitated. While molecular diagnosis is particularly useful for double-sensitized hymenoptera venom and polysensitized pollen allergic patients, the benefit is probably lower in case of house dust mite allergy., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Allergen immunotherapy (AIT) is the only causally effective, disease-modifying form of therapy that, in addition to alleviating allergic symptoms, counteracts disease progression.This article provides an up-to-date overview of immunological, regulatory and practical aspects of AIT. Current literature was included and recent conceptual regulatory developments from the Division of Allergology at the higher federal authority (Paul-Ehrlich-Institut) are presented.The 62 AIT products currently approved in Germany and further 61 AIT products under the development program of the Therapy Allergen Ordinance (TAO) include 95 products for subcutaneous (SCIT) and 28 for sublingual (SLIT) treatment of birch/alder/hazel pollen, grass pollen, weed pollen, house dust mite and insect venom allergies. Native and chemically modified allergen extracts (allergoids) adsorbed to aluminium, tyrosine (partly monophosphoryl lipid A-adjuvanted) or lactose or based on lyophilisates are used as active ingredients.These 123 AIT products are subject to official state batch release testing. This does not apply to named patient products (NPPs) available for the treatment of less prevalent allergies (e.g. to olive pollen, animal hair, storage mites or moulds). There is a particular need for development of AIT products for children.As a new class of active ingredients, food allergens are in clinical phase II and III studies. A first food preparation for oral AIT of peanut allergy in children is currently undergoing a central European marketing authorization (MA) procedure. MA can only be granted if the benefit-risk balance is positive. Science and regulation are in continuous exchange on the development of AIT products that correspond to the current state of clinical research and regulation in the EU and enable early causal treatment of widespread allergies.

Competing Interests: Jörg Kleine-Tebbe bezieht neben Einnahmen aus selbständiger Praxis- und klinischer Forschungstätigkeit Autorenhonorare (Allergopharma, Dustri-Verlag, Springer International, Springer Medizin, Thieme Verlag), Vortragshonorare (Allergopharma, Allergy Therapeutics, ALK-Abelló, AstraZeneca, Bencard, Dr. Pfleger, HAL Allergy, InfectoPharm, Leti, Lofarma, Novartis, Roxall, Sanofi, Stallergenes-Greer, ThermoFisher), institutionelle Forschungsmittel (Allergopharma, ALK-Abelló, HAL Allergy, Glaxo, LETI, Novartis, Paraxel International, Stallergenes-Greer) und Beratungshonorare (Allergen Online – Allergen-Datenbank, Allergy Therapeutics, Bencard, ALK-Abelló, Circassia, LETI, Lofarma, Merck (US), Novartis, Sanofi, Stallergenes-Greer, ThermoFisher

Competing Interests: R. Buhl gibt Folgendes an: Vorträge und/oder Beratungen für AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Novartis, Roche, Sanofi und Teva; Forschungsunterstützung der Universitätsmedizin Mainz: Boehringer Ingelheim, GlaxoSmithKline, Novartis und Roche – außerhalb der vorliegenden Arbeit.R. Brehler gibt Folgendes an: Vortragstätigkeit für ALK, Allergopharma, Almirall, AstraZeneca, Bencard, Gesellschaft zur Förderung der Dermatologischen Forschung und Fortbildung, Gesellschaft für Information und Organisation, GSK, Dr. Pfleger, HAL, Leti, Merck, Novartis, Oto-Rhino-Laryngologischer Verein, Pierre Fabre, Pohl Boskamp, Stallergenes, Thermo-Fischer; Beratertätigkeit für Allergopharma, Bencard, HAL, Leti, Novartis; klinische Studien fürAllergopharma, Bencard, Biotech Tools, Genentech, Leti, Novartis, Circassia – außerhalb der vorliegenden Arbeit.U. Darsow war Referent, Prüfarzt und Berater für ALK Abello, Bencard and Novartis Pharma – außerhalb der vorliegenden Arbeit.T. Jakob hat Zuschüsse, Honorare oder nichtfinanzielle Unterstützung von Novartis, ALK-Abelló, Bencard/Allergy Therapeutics, Allergopharma, Thermo Fisher Scientific und Celgene erhalten – außerhalb der vorliegenden Arbeit.M. Jutel gibt an, Honorare von ALK Abello, Allergopharma, Stallergenes, Anergis, Allergy Therapeutics, Circassia, Leti, Biomay und HAL erhalten zu haben – während der Durchführung der Studie. Außerdem gibt er an, Honorare von AstraZeneka, nGSK, Novartis, Teva, Vectura, UCB, Takeda, Roche, Janssen, Medimmune und Chiesi erhalten zu haben – außerhalb der vorliegenden Arbeit.L. Klimek gibt an, Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, Leti, Stallergenes, Quintiles, Sanofi, ASIT bio tech, Lofarma, Allergy Therapeut., Astra- Zeneca, GSK, Inmunotk erhalten zu haben – außerhalb der vorliegenden Arbeit. Außerdem ist er Mitglied bei folgenden Organisationen: AeDA, DGHNO, Deutsche Akademie für Allergologie und Klinische Immunologie, HNO-BV GPA, EAACI.S. Lau war beratend für Allergopharma tätig.P. Matricardi gibt an, Zuschüsse und/oder Honorare von DFG, Hycor, Omron, Stallergens, Euroimmun, Novartis, TPS, Stallergenes- Greer erhalten zu haben – außerhalb der vorliegenden Arbeit. Außerdem hat er nichtfinanzielle Unterstützung von Thermo Fisher Scientific erhalten – ebenfalls außerhalb der vorliegenden Arbeit.O. Pfaar gibt an, für die letzten 36 Monate Forschungsmittel und/oder Honorare von ALK-Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding B. V./HAL Allergie GmbH, Bencard Allergie GmbH/ Allergy Therapeutics, Lofarma, Biomay, Circassia, ASIT Biotech Tools S. A., Laboratorios LETI/LETI Pharma, MEDA Pharma/MYLAN, Anergis S. A., Mobile Chamber Experts (a GA2LEN Partner), Indoor Biotechnologies, Glaxo Smith Kline, Astellas Pharma Global, EUFOREA, Roxall, Novartis, Sanofi Aventis, Med Update Europe GmbH und streamedup! GmbH erhalten zu haben – alle außerhalb der vorliegenden Arbeit.P. Schmid-Grendelmeier gibt Honorare für Teilnahme an Adboards von Allergopharma, ALK-Abello, Bencard u. Stallergenes an.R. Valenta hat Forschungsgelder von Viravaxx, Vienna, Austria und HVD Life Sciences, Vienna, Austria erhalten. Außerdem war er als Berater für Viravaxx tätig.M. Worm erklärt den Erhalt von Honoraren und/oder Beratungsgebühren von folgenden Unternehmen: ALK Abelló Arzneimittel GmbH, Mylan Deutschland GmbH, Leo Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Regeneron Pharmaceuticals, DBV Technologies SA, Stallergenes GmbH, HAL Allergie GmbH, Allergopharma GmbH & Co.KG, Bencard Allergie GmbH, Aimmune Therapeutics UK Limited, Actelion Pharmaceuticals Deutschland GmbH, Novarits AG und Biotest AG.M. Wagenmann gibt an, Forschungsmittel und/oder Honorare von folgenden Firmen erhalten zu haben: ALKAbelló, Allergopharma, AstraZeneca, Bencard, Genzyme, GlaxoSmithKline,HAL Allergie, LETI Pharma, MEDA Pharma, Novartis, Sanofi Aventis, Stallergenes und Teva.T. Werfel gibt Folgendes an: Adboards, honorierte Vorträge für ALK Scherax, Bencard, Leti und Stallergens.T. Zuberbier war als Berater tätig für Bayer Health Care, FAES, Novartis und Henkel; er hat Forschungsgelder erhalten von Novartis und Henkel. Außerdem hat er Vortragshonorare erhalten von AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Leti, Meda, Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Stallergenes, Takeda, Teva, UCB, Henkel, Kryolan und L’Oréal – außerhalb der vorliegenden Arbeit.S. Wöhrl gibt Advisory boards bei Bencard und ALK-Abelló und bezahlte Vorträge für Bencard, ALK-Abelló und Allergopharma an.W. Aberer, C. Akdis, M. Akdis, S. Becker, K.-C. Bergmann, T. Bieber, T. Biedermann, J. Bousquet, J. Buters, A. Chaker, W. Czech, A. Fink-Wagner, T. Fuchs, M. Gerstlauer, E. Hamelmann, K. Hoffmann-Sommergruber, F. Horak, K. Jung, T. Keil, N. Khaltaev, J. Kleine-Tebbe, M. Maurer, H. Merk, J.-P. Michel, R. Mösges, N. Mülleneisen, K. Nemat, L. Nicod, V. Niederberger- Leppin, I. Pali- Schöll, W. Pohl, K. Rabe, U. Rabe, J. Ring,R. Roller-Wirnsberger, J. Saloga, W. Schlenter, F. Spertini, O. Spranger, P. Staubach, P. Stute, C. Taube, P.- V. Tomazic, C. Vogelberg, C. Vogelmeier, W. Wehrmann und H. Wrede erklären, dass keine Interessenkonflikte bestehen.

Immunologically mediated hypersensitivity to foods is defined as food allergy, mainly due to immunglobulins of class E (IgE) triggering immediate reactions (type I hypersensitivity) with possible involvement of mucosa, skin, airways, intestinal tract, and the vascular system. Primary food allergy is based on (early) IgE sensitization against animal (e. g., cow's milk, hen's eggs) or plant proteins (e. g. peanut, hazelnut or wheat). In the case of secondary food allergies, IgE against pollen proteins (e. g., birch) reacts to structurally related food proteins (with cross-reactions to stone and pit fruits). Non-immunological food intolerance reactions are mostly based on carbohydrate malassimilation (e. g., lactose intolerance, fructose malabsorption) and are rarely due to pseudo-allergies (e. g., flavors, dyes, preservatives) primarily in patients with chronic urticaria. Common intestinal symptoms are mainly due to functional disorders (e. g., irritable bowel disease), rarely because of inflammatory intestinal diseases (e. g., celiac disease). Histamine intolerance, gluten hypersensitivity, and so-called food type III hypersensitivities are controversial diagnoses. The aforementioned disease entities/models are of variable importance for the affected individuals, the public health system, and society in general.

Allergen-specific immunotherapy (SIT, desensitization) is applied monthly with subcutaneous injections (SCIT) or sublingually (SLIT) with droplets or tablets on a daily basis. Numerous immunological changes during SIT induce long-lasting tolerance. Efficacy has been demonstrated by a number of controlled studies for insect venom hypersensitivity (SCIT), allergic rhinoconjunctivitis (SCIT, SLIT particularly in grass pollen allergy), and allergic asthma (SCIT > SLIT). SIT is indicated in children and adults with severe allergic reactions from insect venoms (e.g., bee, wasp) or cumbersome symptoms from pollen, house dust mites or mold allergens and proven immediated-type allergy. Contraindications must be considered individually. SIT is performed for 3 years, in case of venom allergy 3-5 years. Severe systemic reactions are rare after SCIT. After SLIT rather local allergic symptoms of short duration occur in the mouth and throat. At present, the number prescriptions for SIT has decreased due to inadequate reimbursement of allergy-related services (diagnostics, therapies, monitoring). In the future, inferior medical care of allergic patients in Germany is expected, who until now have benefited from the preventive effects of SIT (reduced risk of developing asthma and new allergic sensitizations).

Inappropriate test methods are increasingly utilized to diagnose allergy. They fall into two categories: I. Tests with obscure theoretical basis, missing validity and lacking reproducibility, such as bioresonance, electroacupuncture, applied kinesiology and the ALCAT-test. These methods lack both the technical and clinical validation needed to justify their use. II. Tests with real data, but misleading interpretation: Detection of IgG or IgG4-antibodies or lymphocyte proliferation tests to foods do not allow to separate healthy from diseased subjects, neither in case of food intolerance, allergy or other diagnoses. The absence of diagnostic specificity induces many false positive findings in healthy subjects. As a result unjustified diets might limit quality of life and lead to malnutrition. Proliferation of lymphocytes in response to foods can show elevated rates in patients with allergies. These values do not allow individual diagnosis of hypersensitivity due to their broad variation. Successful internet marketing, infiltration of academic programs and superficial reporting by the media promote the popularity of unqualified diagnostic tests; also in allergy. Therefore, critical observation and quick analysis of and clear comments to unqualified methods by the scientific medical societies are more important than ever.

The following guideline of the "Arbeitsgruppe Nahrungsmittelallergie der DGAKI" (Task Force on Food Allergy of the German Society of Allergology and Clinical Immunology) and the ADA ("Arzteverband Deutscher Allergologen", Medical Association of German Allergologists) and the GPA (German Society of Pediatric Allergology) summarizes the approach to be taken when food allergy is suspected in patients with atopic dermatitis (neurodermatitis, atopic eczema). The problem is clinically relevant because many patients assume that allergic reactions against foods are responsible for triggering or worsening their eczema. It is important to identify those patients who will benefit from an elimination diet but also to avoid unnecessary diets. Elimination diets (especially in early childhood) are associated with the risk of malnutrition and additional emotional stress for the patients. The gold standard for the diagnosis of food-dependent reactions is to perform placebo-controlled, double-blind oral food challenges because specific IgE, prick tests and history often do not correlate with clinical reactivity. This is particularly true in the case of delayed eczematous skin reactions. Diagnostic elimination diets should be used before an oral provocation test. If multiple sensitizations against foods are discovered in a patient, an oligoallergenic diet and a subsequent stepwise supplementation of the nutrition should be performed. If a specific food is suspected of triggering food allergy, oral provocation should be performed after a diagnostic elimination diet. As eczema-tous skin reactions may develop slowly (i. e. within one or two day), the skin be inspected the day after the provocation test and that a repetitive test be performed if the patient has not reacted to a given food on the first day of oral provocation. The guideline discusses various clinical situations for patients with atopic dermatitis to facilitate differentiated diagnostic procedures.

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

Allergen specific immunotherapy (SIT) is the only potentially curative treatment of IgE mediated allergic diseases. To ensure its effective use, many requirements must be met before and during therapy. Before starting immunotherapy, informed consent should be obtained, along with the consideration of the indications and contraindications. SIT should be prescribed and administered only by physicians with experience in allergic disease who are qualified to manage severe anaphylactic reactions. The clinical symptoms and the age of the patients determine the route of application, choice of allergen extracts and the duration of treatment. Numerous products and protocols facilitate an individualised therapy.

Immediate symptoms caused by allergens without previous primary sensitization are commonly based on cross-reactive IgE antibodies. They are responsible for pollen-associated food allergies, i.e., fruit allergy in cases of birch pollen allergy or allergy to celery and spices in cases of mugwort pollen allergy. Similar structures between the major allergen of birch pollen (Bet v 1) and a variety of pathogenesis-related proteins from the same family (PR-10), abundant in hazelnuts, fruits, and vegetables, have been well established. Other candidates are profilins, ubiquitous panallergens with little clinical relevance, and stable lipid transfer proteins, responsible for systemic reactions predominantly in Mediterranean countries. Depending on stability, dose, and resorption of these proteins, clinical symptoms are limited to the oro-pharyngeal cavity or develop systemically far from the site of allergen exposure. Clinical diagnosis is based on a positive case history with corresponding allergic sensitization to pollen allergens. Targeted skin testing with native products (i.e., prick to prick test with fresh fruits) appears to be superior for unstable allergens compared to commercial extracts. Individuals should be familiar with cross-reactive patterns; however, allergen avoidance is only recommended in cases of clinical symptoms.

Mechanisms of allergen immunotherapy (AIT) are complex inducing numerous immunological effects. Successful AIT is most likely based on a functional switch of and tolerance induction in specific T cells downregulating allergic hypersensitivity and inflammation. Subcutaneous AIT for allergic rhinoconjunctivitis and allergic asthma has been successfully assessed in controlled studies with several clinically important allergens (i. e. birch-, grass- and mugwortpollen, dust mites, animal dander) and has shown convincing clinical efficacy. Considered as the only causal treatment besides allergen avoidance at present, AIT can alter the natural course of allergic diseases. Hymenopteravenom hypersensitivity (to bee- and wasp venom) treated with AIT gives the best results compared to AIT with other allergens. AIT is indicated in patients with IgE-mediated sensitizations and corresponding clinical symptoms to allergens, which do not or hardly permit allergen avoidance and which are available as suitable extracts. Decisions about indication and allergen selection should only be made by a physician with certified training or qualified knowledge and skills in allergology. AIT is administered by physicians experienced in this therapy. After addressing tolerability and present status of health the recommended or individually adjusted does is injected and precisely documented, followed by a mandatory waiting period of 30 minutes. Indication for and application of AIT in children are quite similar compared to the treatment of adults. Children tolerate AIT very well and benefit especially from its immunomodulatory effects. Risk factors for and results of unwanted systemic effects can effectively be minimized by training of the staff members involved, adhering to safety standards and immediate emergency treatment. Modified allergens, recombinant proteins and immunomodulatory adjuvants created by basic research are promises for an improved efficacy of AIT with reduced unwanted effects in the future.