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    EAACI guidelines on allergen immunotherapy: IgE mediated Food Allergy 1

    Draft 0.14; 12th May 2017 2


    Authors: Xxxxx, xxxxxxx, xxxxxxxxx, xxxxxxx, on behalf of EAACI Immunotherapy 4

    Guidelines Group 5


    Affiliations: 7

    1. xxxxxx 8





    External expert panel: 13

    XXXXX 14


    Address for correspondence: 16

    XXX 17


    Short title: EAACI Food Allergy Immunotherapy Guidelines 19


    Key words: adolescent, adult, allergen immunotherapy, allergy, food, paediatric 21


    Words: 4831 23


    Abbreviations: AGREE II, Appraisal of Guidelines for Research & Evaluation; AIT, Allergen 25

    immunotherapy; BAT, basophil activation test; CCT, controlled clinical trial; CI, confidence 26

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    interval; CM, cow’s milk; CRD, component-resolved diagnosis; DBPCFC, double-blind, 1

    placebo-controlled food challenge; EAACI, European Academy of Allergy and Clinical 2

    Immunology; EMA, European Medicines Agency; EPIT, Epicutaneous immunotherapy; 3

    EoE, eosinophilic esophagitis; FA, food allergy; GRADE, Grading of Recommendations 4

    Assessment, Development and Evaluation; HE, hen’s egg; IgE, immunoglobulin E; IgG, 5

    immunoglobulin G; IgG4, immunoglobulin G4; OFC, oral food challenge; OIT, oral 6

    immunotherapy; QoL, quality of life; RCT, randomized controlled trial; RR, risk ratio; sIgE, 7

    specific IgE; SCIT subcutaneous immunotherapy; SLIT, sublingual immunotherapy; SPT, 8

    skin prick test; SR, systematic review; WAO, World Allergy Organization. 9


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    Food allergy can have significant effects on morbidity and quality of life and can be costly in 3

    terms of medical visits and treatments. There is therefore considerable interest in generating 4

    efficient and new active therapeutic approaches that represent a novel strategy for the 5

    treatment of food allergies. In this field, current clinical research focuses on food allergen-6

    specific immunotherapy through oral (OIT), sublingual (SLIT) or epicutaneous (EPIT) routes. 7

    These Guidelines have been prepared by the European Academy of Allergy and Clinical 8

    Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE mediated food allergy 9

    and are part of the EAACI Guidelines for Allergen Immunotherapy – AIT guidelines for 10

    clinical practice. They aim to provide evidence based recommendations for active treatment 11

    of IgE mediated food allergy with food allergen immunotherapy (AIT). 12

    Immunotherapy relies on the delivery of gradually increasing doses of specific allergen to 13

    increase threshold of reaction while on therapy (e.g. desensitization) in patients with 14

    persistent food allergy and ultimately, to achieve post-discontinuation effectiveness (e.g. 15

    tolerance). The most frequent route of administration for AIT for food allergy is the oral route, 16

    where the allergen is either immediately swallowed (OIT) or held under the tongue for an 17

    interval (SLIT). Epicutaneous (EPIT) route is also under investigation, it consists of the 18

    application of patches containing food allergen onto the skin. Overall, the studies revealed 19

    a substantial benefit for the patients undergoing either OIT or SLIT with respect to efficacy 20

    during treatment. Regarding post-discontinuation effectiveness a benefit for the patient 21

    trough allergen immunotherapy was suggested but could not be confirmed. Adverse events 22

    during AIT had been frequently reported. However, few subjects had to discontinue 23

    immunotherapy. Based on this evidence, patients and their families can be provided with 24

    evidence based advice about AIT for IgE mediated food allergy. The advice includes that 25

    there is more evidence of efficacy of AIT in children in comparison with adults, and for cow’s 26

    milk, hen’s egg and peanut allergies than for other food allergies. Taking into account both 27

    currently issues and gaps, AIT could be performed in research centers or in specialized 28

    clinical centers for food allergy immunotherapy. 29



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    §1. Introduction 1

    Food allergy (FA) has emerged as a significant medical problem in recent decades. With FA 2

    affecting up to 8% of children and 5% of adults in westernized countries, development of 3

    therapies for this potentially life-threatening condition has become a public health priority (1-4

    3).The key terms and clinical presentation of food allergy are summarized in Boxes 1 and 5

    2A. 6


    The current approach to managing FA focuses on avoidance of the trigger foods and 8

    availability and training in the use of rescue medication in the event of an allergic reaction 9

    developing. Allergen immunotherapy (AIT) is potentially a curative therapy. AIT has the 10

    potential to increase the amount of food that the patient can tolerate, preventing allergic 11

    symptoms and reducing the risk of potentially life-threatening allergic reactions. The first 12

    case of AIT was described in 1908 to hen’s egg (4) and the principles underlying the therapy 13

    have remained the same i.e. therapy consists of the administration of gradually increasing 14

    doses of food allergens via an oral (OIT), sublingual (SLIT), subcutaneous (SCIT) route (2). 15

    A fixed dose of allergen can be administered through an epicutaneous route (EPIT) (2). 16


    The ultimate goal of AIT for FA is to achieve post-discontinuation effectiveness so ideally a 18

    patient can eat a normal serving of the trigger food without symptoms. This is also known 19

    as “tolerance” or “sustained unresponsiveness”. These all imply that the food allergen can 20

    be ingested without the appearance of allergic symptoms despite a period of absence of 21

    exposure. The time period required to establish true post-discontinuation effectiveness is 22

    not yet defined. Based on current evidence, a more attainable target is effectiveness during 23

    treatment (typically referred to as “desensitization”) which concerns a reversible or partially 24

    reversible clinical response that is dependent on ongoing allergen exposure. If the 25

    administration of the allergen is discontinued, the previous level of clinical reactivity 26

    frequently returns (5). 27


    The primary outcome of efficacy of AIT for FA is a change in the threshold of reactivity, which 29

    is ideally determined by an oral food challenge (OFC) and where possible, a double-blind, 30

    placebo-controlled food challenge (DBPCFC). There is great variability described in the 31

    change in threshold between different studies and for different food (6,7). Additional 32

    parameters have been included in the monitoring of AIT for FA: SPTs (8), sIgE, IgG and 33

    IgG4 levels in serum (9). Few studies looked at basophil activation test (BAT) (10), cytokines 34

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    (e.g. IL-10, IL- 5 and IFN-ү) (11-12), or regulatory T-cells (13). 1


    The most frequent route of administration of AIT for FA is the oral route, where the allergen 3

    is either immediately swallowed (oral immunotherapy, OIT) or held under the tongue for an 4

    interval (sublingual immunotherapy (SLIT)) (3). There are currently ongoing studies with the 5

    subcutaneous route (SCIT) for peanut and fish allergies (14-16). Epicutaneous 6

    immunotherapy (EPIT) is also under investigation for peanut and milk; it involves application 7

    of patches containing food allergen onto the skin (17). There is no consistent formulation of 8

    the food used for FA-AIT in studies conducted to date (18). Dilution of unprocessed 9

    products, crude extracts and flours have been used (18). In addition, some studies have 10

    been carried out with powered or lyophilized products, prepared by pharmaceutical 11

    companies or hospital pharmacies (19). 12


    These guidelines have been prepared by the European Academy of Allergy and Clinical 14

    Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE-mediated Food Allergy 15

    and are part of the EAACI allergen specific immunotherapy (AIT) guidelines for clinical 16

    practice. The guidelines aim to provide evidence based recommendations for the use of AIT 17

    in patients with diagnosed IgE-mediated FA. The primary audience is hospital-based clinical 18

    allergists or pediatric allergists. However, these guidelines are also likely to be of relevance 19

    to other healthcare professionals (e.g. doctors, nurses, dieticians, psychologists and 20

    paramedics) who are involved in the management of allergic patients and their families in 21

    any setting. The development of these Guidelines has been informed by the systematic 22

    review (SR) and meta-analysis on AIT for FA (18). 23


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    Box 1. Key terms



    Repeated allergen exposure at regular intervals to modulate immune

    response to reduce symptoms and the need for m


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