EAACI guidelines on allergen immunotherapy: Executive statement
Authors: A. Muraro, G. Roberts, S. Halken, I. Agache, E. Angier, M. Fernandez‐Rivas, R. Gerth van Wijk, M. Jutel, S. Lau, G. Pajno, O. Pfaar, D. Ryan, G. J. Sturm, R. van Ree, E.‐M. Varga, C. Bachert, M. Calderon, G. W. Canonica, S. R. Durham, H. J. Malling, U. Wahn, A. Sheikh
Journal: Allergy (2018)

The allergist's community has recently celebrated 100 years of allergen immunotherapy (AIT). Unfortunately, the implementation of this treatment is still impaired by some challenges. With the diversity of definitions, methodology, and different allergen products used, research studies have produced conflicting outcomes. This has resulted in confusion about the benefits and risks of AIT amongst policymakers and professionals, as well as in the variable availability of AIT products, regulation, and reimbursement policies globally. In 2015, EAACI initiated the AIT Guidelines Project as part of the Presidential Plan to settle the controversies. The result has been a rigorous process of guideline development1 to inform and facilitate high-quality clinical practice for AIT. The guidelines are based on some key pillars: an evidence-based approach, involvement of multidisciplinary and multiprofessional groups, recommendations centered on the patient, highlighting the benefits and harms of AIT. In the development process, accountability to evidence meant paying attention to transparency and independency of the process. Rigor of development was reflected in the provision of search strategy details, a description of the process for external review and a plan for future update of the guidelines. Although these guidelines were funded by EAACI, the funder did not have influence on the guideline production process, its contents, nor the decision to publish. Task Force members' conflict of interests were declared and taken into account. Final decisions about strength of evidence for recommendations were checked by the methodologists who had no conflict of interests in this area. The process of producing these guidelines has involved recognition of the importance of following a structured process,2 has created a valuable opportunity for clinicians, researchers, methodologists, and patient representatives to work together, and has allowed a shared appreciation of the need to also consider implementation considerations so the benefits of AIT can be safely realized by our patients. We have had to address some challenges, shared with other disciplines,3 that it would be useful to discuss. Firstly, the evidence-based approach is often seen as too demanding so we adopted a user-friendly approach to facilitate appraisal of the key evidence to generate recommendations.4 Secondly, guidelines are often seen as very narrow so we carefully considered and incorporated the views of other stakeholders in formulating recommendations. Thirdly, a criticism was raised as to whether the time, effort, and expense involved were worthwhile and whether it would make a difference to the ultimate recommendations. We suggest that a rigorous process and transparent process provide good value by adding confidence on the validity of the recommendations for practicing clinicians. The EAACI AIT Steering Group decided to employ the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach to generate the AIT guidelines,2 as this was considered to be the best approach to generate guidelines for clinicians. This framework ensures appropriate representation of the full range of stakeholders, a careful search for and critical appraisal of the relevant literature, a systematic approach to the formulation, and presentation of recommendations and steps to minimize the risk of bias at each step of the process. The initial full range of clinical questions that were considered important for the guidelines was rationalized into an overarching question for each guideline, namely the effectiveness, safety, and cost-effectiveness of allergen immunotherapy for allergy prevention, food allergy, allergic rhinitis, asthma, and venom allergy. These questions were then pursued through developing systematic reviews led by independent methodologists. We continued to track relevant evidence after our systematic review cutoff dates. We graded the strength and consistency of key findings from the systematic reviews and, where possible and appropriate, performed meta-analyses using random-effects models to take into account the heterogeneity of findings. This approach was the basis to formulate evidence-based recommendations for clinical care. The Oxford Centre for Evidence-based Medicine4 methodology was used as a practical approach that could be readily utilized by the EAACI Task Force members. This involved both formulating the recommendations and detailing the strength of evidence underpinning each recommendation. Although the systematic reviews did not cover the clinical area, we took a hierarchical approach to review other evidence until we could formulate a recommendation as follows: (i) other systematic reviews on the subject to see whether they provided any further clarity on the topic; (ii) randomized controlled trials (RCT) within these systematic reviews; (iii) other RCT known to Task Force members; and (iv) a consensus-based approach within the Task Force. This evidence was graded and clearly labeled in the recommendation tables. When there were insufficient pediatric data, we extrapolated from the adult recommendation where it was biologically likely that the intervention would also be effective in children, but in so doing, the recommendation was downgraded by at least 1 level. A draft of each guideline was externally peer-reviewed by invited experts from a range of organizations, countries, and professional backgrounds. Additionally, each draft guideline was made available on the public domain of the EAACI Web site for a 3-week period in May 2017 to allow a broader array of stakeholders to comment. All feedback was considered by Task Force members, and final revisions were made in light of the feedback received. These guidelines5-8 are aimed at healthcare professionals and should help them deliver better clinical care with more effective and safe use of AIT. Professionals still need to utilize their clinical training, experience, and judgment to deliver personalized health care. The guidelines provide answers to key clinical questions (see Box 1) summarizing the evidence for and against different therapies. Recommendations are clearly described but may not be appropriate for all people, patients, and situations. A key conclusion from the guidelines is the need to limit practice to the use of high-quality, standardized AIT products with good evidence of effectiveness—a product-specific approach—as many available products are not supported by sufficient evidence of efficacy. Grades A to D represents the strength of the recommendation with A being the strongest with recommendations being based on consistent, randomized, controlled trial data; B being based on 2 groups, nonrandomized studies (eg, cohort, case-control); C being based on 1 group, nonrandomized studies (eg, before and after); and D being based on expert opinion.4 The use of AIT is currently restricted by the limited availability of high-quality, standardized products with good evidence of effectiveness.9, 10 This could be improved with the widespread adoption by industry and specialists of the best regulatory framework (Box 2). Special consideration will however be required for rare allergens where it may not be possible to undertake large clinical trials. Another key limitation is access to AIT. Greater awareness of the need for and availability of AIT within primary care and partnership with specialists will be necessary to overcome this.11 Clinical care pathways and better quality standards of care are required to facilitate this. The guidelines highlight many gaps in the evidence base, particularly around the long-term effectiveness of AIT, the evidence for effectiveness of many commercial products, and a shortage of data in children and for health economic considerations. We hope that these guidelines will catalyze the commissioning of research to fill these evidence gaps. EAACI plans to update these guidelines with recommendations informed by evidence published over the 5 years 2017-2022. The AIT guidelines and underpinning systematic reviews can all be accessed at http://www.eaaci.org/resources/guidelines/ait-guidelines-part-2.html (last accessed January 17, 2018). The EAACI Guidelines Group thank Stefan Vieths and Andreas Bonertz for their advice; all the Task Force members, particularly the representatives from the patient organizations; the expert reviewers for their constructive appraisal of the draft guidelines; and members of EAACI who commented on the draft guidelines posted on the EAACI Web site. We also thank EAACI and the BM4SIT project (grant number 601763) in the European Union's Seventh Framework Programme FP7 for their funding of the project. The authors were Chairs of the EAACI Allergen Immunotherapy Guidelines or assisted in the finalization of the guideline documents. Antonella Muraro, Graham Roberts, Susanne Halken, Liz Angier, Montserrat Fernandez-Rivas, Roy Gerth van Wijk, Giovanni Pajno, Oliver Pfaar, Dermot Ryan, Gunter Sturm, Ronald van Ree, Eva-Maria Varga, Iona Agache, Marek Jutel, Susanne Lau, and Aziz Sheikh were the AIT Guidelines Chairs. Claus Bachert, Moises Calderon, G Walter Canonica, Stephen Durham, Hans-Jørgen Malling, and Ulrich Wahn assisted in the finalization of the guidelines after the public consultation. The EAACI Guidelines on AIT were chaired by Antonella Muraro and coordinated by Graham Roberts.