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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double‐blind, placebo‐controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for Allergic Asthma. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in the management of allergic asthma. 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 recommendations for EAACI's Guidelines on AIT. [ABSTRACT FROM AUTHOR]

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 ÄDA (“Ärzteverband 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. [ABSTRACT FROM AUTHOR]

Chronic urticaria, recurrent angioedema and non-allergic asthma have all been associated with pseudoallergic reactions to food ingredients. For atopic dermatitis and diseases of the gastrointestinal tract, this association is controversial. Pseudoallergic reactions can be elicited by additives as well as by natural food ingredients. An altered histamine metabolism may be associated with pseudoallergy. Acute urticaria or a short episode of angioedema is not an indication for exhaustive evaluation. If basic diagnostic screening is negative in chronic urticaria, a low-pseudoallergen diet can be considered. Skin and serological tests are not objective diagnostic parameters for pseudoallergic reactions. The severity of symptoms should be documented while the patient is on a low-pseudoaller-gen diet. Oral provocation with additives leads to reproducible symptoms only in a few cases. Therefore, if a low-pseudoallergen diet brings improvement, the patient is then exposed to a pseudoallergen-rich "super meal". After a positive reaction to the "super meal" the challenge with additives takes place in the form of collective group exposition. When the patient has asthma or a history of anaphylac-toid reactions, testing with individual substances in carefully increasing dosages is required. The suspicion of adverse reactions against histamine can be confirmed by a challenge with histamine dihydrochloride. In the case of respiratory symptoms, provocation by inhalation should be considered. Objectifying symptoms especially in gastrointestinal diseases is mandatory and should include double-blind placebo-controlled food challenge, if possible. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)