Reviews and feature article
International consensus on allergy immunotherapy

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Allergen immunotherapy (AIT) has been used to treat allergic disease since the early 1900s. Despite numerous clinical trials and meta-analyses proving AIT efficacious, it remains underused and is estimated to be used in less than 10% of patients with allergic rhinitis or asthma worldwide. In addition, there are large differences between regions, which are not only due to socioeconomic status. There is practically no controversy about the use of AIT in the treatment of allergic rhinitis and allergic asthma, but for atopic dermatitis or food allergy, the indications for AIT are not well defined. The elaboration of a wider consensus is of utmost importance because AIT is the only treatment that can change the course of allergic disease by preventing the development of asthma and new allergen sensitizations and by inducing allergen-specific immune tolerance. Safer and more effective AIT strategies are being continuously developed both through elaboration of new allergen preparations and adjuvants and alternate routes of administration. A number of guidelines, consensus documents, or both are available on both the international and national levels. The international community of allergy specialists recognizes the need to develop a comprehensive consensus report to harmonize, disseminate, and implement the best AIT practice. Consequently, the International Collaboration in Asthma, Allergy and Immunology, formed by the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the World Allergy Organization, has decided to issue an international consensus on AIT.

Introduction

The international consensus statement on allergen immunotherapy (AIT) is a concise document authored by a multinational group of experts reviewing the pertinent literature and summarizing the key statements for AIT. The document combines the best scientific evidence with expert opinion consensus and was developed to serve as the resource for health care professionals managing patients with allergic diseases. The document also provides a rationale for providing better access to AIT based on the public health and pharmacoeconomic analyses that can be used by policymakers. It is adaptable for all countries worldwide, allowing for modifications based on the regional availability of diagnostic and therapeutic interventions.

The current board of the International Collaboration in Asthma, Allergy and Immunology and the participating organizations formed the working committee on the basis of regional representation, expertise in the field, and previous participation in the creation of AIT guidelines. The members of the committee proposed the most relevant areas and selected the documents for critical review; the major documents are listed in Table I.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 Many task force reports and consensus documents of the European Academy of Allergy and Clinical Immunology (EAACI) AIT Interest Group, as well as key scientific papers, were also considered. Each member was responsible for the preparation of text. A draft was subsequently compiled and circulated (in January 2015) among the authors for comments and corrections. The governing boards of the participating organizations then approved the final draft. The nomenclature and terms used are summarized in Box 1.

AIT was introduced by Leonard Noon 103 years ago and is the only potential disease-modifying treatment for allergic subjects. Significant progress has been made in terms of proving its efficacy and safety both for respiratory allergy and venom hypersensitivity, and recent data look promising also for AIT as a disease-modifying treatment for food allergy and atopic dermatitis (AD). However, AIT remains underused mainly because of: (1) a lack of agreement in documented efficacy; (2) insufficient data on its cost-effectiveness; (3) differing proportion and educational level of physicians taking care of allergic subjects; (4) lack of awareness of AIT in the general population and non–allergy/immunology-trained population; (5) scattered availability of regimens, products for application, or both; and (6) varying selection of potential responders.31

Historically, AIT was administered by means of subcutaneous immunotherapy (SCIT), but in the past 25 years, there has been a substantial increase in the use of sublingual immunotherapy (SLIT). In part, this has been driven by issues concerning the safety of SCIT: in the 1980s, a number of fatal adverse reactions were reported,32 which led to restrictions on the use of SCIT in some parts of Europe and stimulated the exploration of safer routes of administration. Practical and logistic considerations have also favored the introduction of SLIT because many patients cannot easily commit time to for an injection regimen. Standardization of allergen extracts has also improved significantly. Several novel approaches are under investigation. They use either recombinant antigen technology to produce modified proteins and peptides or intradermal or epicutaneous application of immunodominant peptides or approaches to enhance the desirable immune response to allergens with decreased side effects by using adjuvants or by stimulating the innate immune system. Such approaches are under development, aiming to reduce the risk of anaphylaxis and hence allow more rapid updosing. Although this is a desirable objective, most of these approaches are still in the early phases of clinical trials. Assessment of cost-effectiveness has been difficult, mainly because of problems in assessing efficacy.

Increasingly, health care payers and regulators are asking for greater detail about the clinical benefit that can be achieved, and to that end, we need better systems for defining benefit not only in statistical terms but also in terms of what is relevant to individual patients. Harmonization of scoring systems is desirable, but it is more important to validate these in terms of patient-relevant outcomes. A World Allergy Organization (WAO) Task Force proposed a 20% effect over placebo as a reasonable cutoff of clinical efficacy for clinical trials.33 Recently, an EAACI Task Force recommended a homogeneous combined symptom and medication score as the primary outcome for AIT effectiveness, which provides a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner.34 On the other hand, reliable systems of allergen exposure are needed to assess AIT-induced allergen-specific tolerance. In this context environmental exposure chambers provide a very promising approach.35

Section snippets

Routes of administration

Subcutaneous injection has been the predominant method of administration. Over the last 2 decades, sublingual application of the extracts has increased and is now the dominant approach in several European countries.36 Additional approaches to AIT under active investigation include epicutaneous and intralymphatic administration.37, 38

Administration regimens

The conventional schedule for SCIT with unmodified allergen extracts consists of a dose build up by means of one-weekly injections, followed by maintenance dose

Indications and efficacy

According to the Allergic Rhinitis and its Impact on Asthma guidelines,25, 49 AIT is indicated for the treatment of moderate-to-severe intermittent or persistent symptoms of AR, especially in those who do not respond well to pharmacotherapy. Allergen extracts are available for grass, tree, and weed (ie, ragweed) pollens; HDMs; mold; and animal dander. Standardized extracts should be used in clinical practice because the efficacy and safety of AIT depends strictly on extract quality.

Recent

Safety of AIT

Adverse reactions associated with AIT can be local or systemic. Local reactions (LRs) are fairly common with both SCIT (erythema, pruritus, and swelling at the injection site) and SLIT (oropharyngeal pruritus, swelling, or both), affecting up to 82% of patients receiving SCIT13 and 75% of patients receiving SLIT.98 Gastrointestinal symptoms associated with SLIT can be classified as LRs (if only associated with oromucosal symptoms) or SRs (if occurring with other systemic symptoms).

Most

Conclusions and unmet needs

The key messages of this position statement are summarized in Box 2. AIT is effective in reducing symptoms of allergic asthma and rhinitis and potentially modifies the underlying course of disease. Studies on AIT in the treatment of AD and food allergy could broaden the indications. However, AIT remains underused because of a lack of awareness, limited access to specialist care, the reimbursement policy, long duration, and concerns regarding safety and effectiveness (Fig 1). The major barrier

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    Disclosure of potential conflict of interest: M. Jutel has received research support from the Polish National Science Centre and lecture fees from Allergopharma and Stallergenes. S. Bonini has provided expert testimony for the European Medicines Agency. A. W. Burks is on the FARE and World Allergy Organization boards; is on the Murdoch Children's Research Institute advisory board; has received consultancy fees from Gerson Lehrman Group, ActoGeniX, Genentech, Sanofi US, Valeant Pharmaceuticals North America; has provided unpaid consultation for Dynavax Technologies, Perrigo Company (PBN Nutritionals), and Perosphere; is employed by the University of North Carolina; has patents (US5558869, US55973121, US6441142, US6486311, US6835824, US7485708, and US7879977); has received payment for developing educational presentations from Current Views 2012; and has stock/stock options in Allertein and Mastcell Pharmaceuticals. M. Calderon has received consultancy fees from ALK-Abelló, STG, and Hal Allergy; has received lecture fees from ALK-Abelló STG, and Allergopharma; and has received travel support from ALK-Abelló, STG, Allergopharma, and Hal Allergy. W. Canonica has received consulting fees from ALK-Abelló, Allergy Therapeutics, Lofarma, and Stallergenes. L. Cox has received consulting fees from Greer, has received fees for participation in review activities from Circassia and Biomay, is on the American Board of Allergy and Immunology and American Academy of Allergy, Asthma & Immunology Boards, and has received lecture fees from Southeastern Allergy Asthma Immunology Association. P. Demoly has received consultancy fees from ALK-Abelló, Circassia, Stallergenes, Allergopharma, Thermo Fisher Scientific, DBV, Chiesi, and Pierre Febre Medicaments and has received lecture fees from Menarini, MSD, AstraZeneca, and GlaxoSmithKline. J. Kleine-Tebbe is on the ALK-Abelló, Novartis, Leti, and Bencard advisory boards; has received consultancy fees from Merck and Circassia; has received research support from Circassia; and has received lecture fees from Allergopharma, ALK-Abelló, Bencard, HAL Allergy, LETI, Lofarma, Novartis, and Stallergenes. A. Muraro has received consultancy fees from Meda, Nutricia, Allergopharma, and Novartis. G. Lack has stock/stock options in DBV Technologies. D. Larenas is on the CMICA board; has received consultancy fees from Meda, Pfizer, MIT, Boehringer Ingelheim, Novartis, and Glenmark; has received research support from Novartis, Pfizer, Meda, UCB, GlaxoSmithKline, AstraZeneca, Sunovion, Sanofi, MSD, Teva, and Commet; has received lecture fees from AstraZeneca, Glenmark, MSD, UCB, Meda, and Pfizer; has received payment for developing educational presentations from Glenmark; and has received travel support from MSD, UCB, AstraZeneca, Pfizer, Meda, Senosiain, Glenmark, ALK-Abelló, Novartis, and Chiesi. H. Nelson is on the advisory board for Merck and Circassia, is on the data monitoring board for AstraZeneca and Pearl Therapeutics, and has received research support from Circassia. O. Pfaar has received consultancy fees from Bencard (Germany), HAL-Allergy (The Netherlands), Novartis/LETI (Germany), MEDA (Germany), ALK-Abelló (Germany/Denmark), Allergopharma (Germany), Biotech Tools s.a. (Belgium), GfK Bridgehead (United Kingdom), NAVIGANT-consulting (United States), Sanofi (United States), Guidepoint Global Advisors (United States), Stallergenes (Germany/France), and Mobile Chamber Experts (MCX), a GA2LEN Partner (Germany); is employed by Universitätsmedizin Mannheim, Heidelberg University; has received research support from ALK-Abelló (Germany/Denmark), Allergopharma (Germany), Stallergenes (Germany/France), HAL-Allergy (Germany/The Netherlands), Artu Biologicals (The Netherlands), Allergy Therapeutics/Bencard (UK/Germany), Hartington (Spain), Lofarma (Italy), Novartis/Leti (Germany/Spain), GlaxoSmithKline (United Kingdom/Germany), Essex-Pharma (Germany), Cytos (Switzerland), Curalogic (Denmark), Roxall (Germany), Biomay (Austria), Thermo Fisher (Germany), Circassia (UK), E.U (FP-7-Health-2013-Innovation 1), Biotech Tools s.a. (Belgium), and MEDA-Pharma GmbH (Germany); has received lecture fees from ALK-Abelló (Germany/Denmark), Allergopharma (Germany), Stallergenes (Germany/France), HAL-Allergy (Germany/The Netherlands), Allergy Therapeutics/Bencard (United Kingdom/Germany), Hartington (Spain), Lofarma (Italy), Novartis/Leti (Germany/Spain), GlaxoSmithKline (United Kingdom/Germany), Roxall (Germany), Thermo Fisher (Germany), and MEDA-Pharma GmbH (Germany); is coeditor and author of textbook “Allergien bei Kindern und Jugendlichen” (Schattauer, Germany), author of different chapters of “Allergologie-Handbuch” (Schattauer, Germany), and author of 1 chapter in “Allergologie” (Springer, Germany); has received payment for developing educational presentations from GlaxoSmithKline (Germany), Bencard (Germany), and Novartis (Germany); has received travel support from HAL-Allergy (Netherlands/Germany) and Allergopharma (Germany); and is current chairman of IT IG of European Academy of Allergy and Clinical Immunology (EAACI), and current secretary of ENT-section of DGAKI. R. van Ree is on the EAACI board, has received consultancy fees from HAL Allergy BV, has received research support from the European Union, and has received lecture fees from Thermo Fisher Scientific. H. Sampson is an unpaid consultant on the DBV Scientific Advisory Board. G. Du Toit has received lecture fees from Thermo Fisher, owns 2% equity of the FoodMaestro app, and has received travel support from the EAACI as secretary of the paediatric section. R. Gerth van Wijk has received consultancy fees from MSD, HAL, Crucell, ALK-Abelló, and Novartis; has received research support from NWO, STW, Novartis, Biomay, and DBV; has received lecture fees from Allergopharma and Thermo Fisher; has received payment for manuscript preparation from Chiesi; and receives royalties from de Tijdstroom and Bohn, Stafleu, van Loghum. C. A. Akdis has received consultancy fees from Actellion, Aventis, Stallergenes, Allergopharma, and Circacia; is employed by the Swiss Institute of Allergy and Asthma Research, University of Zuurich; has received research support from Novartis, PREDICTA, Swiss National Science Foundation, MeDALL (Programme no. 261357), and the Christine-Kuhne Center for Allergy Research and Education. The rest of the authors declare that they have no relevant conflicts of interest.

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