EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy

1 INTRODUCTION

Food allergy (FA) has emerged as a significant medical problem in recent decades. With FA now affecting up to 8% of children and 5% of adults in Westernized countries, development of therapies for this potentially life-threatening condition has become a public health priority.1-3 The key terms and clinical presentation of FA are summarized in Boxes 1 and 2.

The current approach in managing FA focuses on avoidance of trigger foods and the availability of and training in the use of rescue medication in the event of an allergic reaction. Allergen immunotherapy (AIT) is potentially a curative therapy. AIT may increase the amount of food that the patient can tolerate, preventing allergic symptoms and reducing the risk of potentially life-threatening allergic reactions. The first case of immunotherapy for food allergy (FA-AIT) was described in 1908 to hen's egg (HE)4; the principles underlying the therapy have remained the same; that is, therapy consists of the administration of gradually increasing doses of food allergens via the oral, sublingual, or subcutaneous routes.2 A fixed dose of allergen can be administered through the epicutaneous route.2

The ultimate goal of FA-AIT was to achieve post-discontinuation effectiveness so that a patient can eat a normal serving of the trigger food without symptoms. This is also known as “tolerance” or “sustained unresponsiveness.” These terms all imply that the food allergen can be ingested without the appearance of allergic symptoms despite a period of absence of exposure. The time period required to establish true post-discontinuation effectiveness is not yet defined. Based on current evidence, a more attainable target is effectiveness during treatment (typically referred to as “desensitization”) which refers to a reversible or partially reversible clinical response that is dependent on ongoing allergen exposure. If the administration of the allergen is discontinued, the previous level of clinical reactivity may return.5

The primary outcome of FA-AIT is a change in the threshold of allergen required to trigger an allergic reaction determined by an oral food challenge (OFC)—where possible, this is preferably a double-blind, placebo-controlled, food challenge (DBPCFC). There is great variability in the threshold of exposure between different studies and for different foods.6, 7 Additional parameters have been studied in the monitoring of FA-AIT, including skin prick tests (SPT),8 specific IgE (sIgE), IgG and IgG₄ levels in serum.9 Some studies have also looked at basophil activation tests (BAT),10 cytokines (e.g. IL-10, IL-5, and IFN-ү),11, 12 and regulatory T cells.13

The most frequent route of administration of FA-AIT is the oral route where the allergen is either immediately swallowed (oral immunotherapy, OIT) or held under the tongue for a period of time (sublingual immunotherapy, SLIT). There are currently ongoing studies using the subcutaneous route (subcutaneous immunotherapy, SCIT) for peanut and fish allergies.14-16 Epicutaneous immunotherapy (EPIT) is also under investigation for peanut and cow's milk (CM); it involves application of patches containing food allergen onto the skin.17 In general, there has been no consistent formulation of food in FA-AIT studies conducted to date.18 Dilutions of unprocessed products, crude extracts, and flours have been used. Some studies have been carried out with powdered or lyophilized products. Only a few have used food extracts with a quantification of major allergens prepared by pharmaceutical companies or hospital pharmacies.11, 19

This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE-mediated Food Allergy. It is part of the EAACI Guidelines on Allergen Immunotherapy. This Guideline aims to provide evidence-based recommendations for the use of AIT in patients with diagnosed IgE-mediated FA. The primary audience are clinical allergists. This Guideline is also likely to be of relevance to other healthcare professionals (e.g. other doctors, nurses, dieticians, psychologists, and paramedics) who are involved in the management of patients with food allergy and their families in any setting.

The development of this Guideline has been informed by a formal systematic review (SR) and meta-analysis on FA-AIT that included 31 trials studying 1259 patients. There were 25 randomized clinical trials (RCT) and 6 non-randomized controlled clinical trials (CCT). OIT was covered by 25 studies, SLIT was used in 5, and EPIT in 1. The food allergies most frequently studied were CM (16 studies), HE (11 studies), and peanut (7 studies).18

2 METHODOLOGY

This Guideline was produced using the Appraisal of Guidelines for Research & Evaluation (AGREE II) framework,20, 21 which is a structured approach to guideline production. This is designed to ensure 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 ensure that the risk of bias is minimized at each step of the process. The process started in April 2015 beginning with detailed face-to-face discussions agreeing on the process and the key clinical areas to address, followed by face-to-face meetings and web-conferences in which professional and lay representatives participated.

3 GENERAL CONSIDERATIONS BEFORE INITIATING AIT FOR IgE-MEDIATED FOOD ALLERGY

AIT is potentially indicated for patients with evidence of an IgE-mediated FA and in whom avoidance measures are ineffective, undesirable, or cause severe limitations to a patient's QoL. Prior to initiating AIT, confirming the diagnosis of IgE-mediated FA is mandatory. This requires a recent, clear clinical history of an acute reaction(s) after consumption of the triggering food. The presence of IgE to the triggering food should be established with SPT and/or sIgE. Where the diagnosis is unclear, an OFC is required. The baseline reaction threshold may be used to establish the efficacy of AIT in individual patients (Box 5).

Studies to date have enrolled patients with heterogeneous ages and clinical presentations.18 Studies have included infants and pre-school children who have tolerated FA-AIT safely.23, 24 However, the limited ability of young children to report early symptoms of allergic reactions should be considered. Furthermore, young children have a high likelihood of developing spontaneous tolerance, particularly to CM, HE, wheat, and soy.25-31 Therefore, it might be more appropriate to wait for the natural acquisition of spontaneous tolerance before commencing AIT for these allergens.25-31 The right time to start may be around 4-5 years of age, but this should be decided on an individual basis.

FA-AIT is logistically demanding, time-consuming, and most patients are affected by side effects. These are usually mild, but systemic reactions—including life-threatening anaphylaxis—may occur. AIT for FA should therefore only be undertaken in centers with professional training in FA care with the expertise, competencies, and full resuscitation facilities to safely deliver this therapy and manage any complications, including anaphylaxis (Box 6). Only patients and families who understand the aim of the intervention and its risks and are motivated and adherent should be considered for FA-AIT (Boxes S1 and S2). There are therefore many issues to be considered and discussed with the patient and family before commencing FA-AIT (Box 7).

4 GENERAL CONTRAINDICATIONS

Given the long-treatment duration and common adverse reactions, any medical or social condition that might prevent patients attending frequent clinical visits, being aware of side effects, or adhering to treatment represents an absolute contraindication. Uncontrolled asthma is also an absolute contraindication as it is associated with an increased risk of life-threatening systemic reactions.32 Well-controlled asthma is, however, not a contraindication for FA-AIT. Although a history of moderate-to-severe anaphylaxis to a food may be associated with more side-effects, it is not a contraindication; these patients require appropriate evaluation before starting FA-AIT and close supervision particularly during the build-up phase. Uncontrolled, severe atopic dermatitis/eczema and chronic urticaria are relative contraindications given the risk of acute exacerbation while on AIT and because they can confound safety assessment of AIT. Therefore, both disorders should be controlled before AIT is initiated. The presence of eosinophilic esophagitis (EoE) or any other eosinophilic gastrointestinal disease is a contraindication for FA-AIT because of the risk these worsen while on FA-AIT.33, 34

There is a lack of available data on the risks associated with FA-AIT in autoimmune disorders, severe medical conditions such as cardiovascular diseases, mastocytosis, or with the concomitant use of medications such as beta-blockers or angiotensin-converting enzyme (ACE) inhibitors. However, the risk in other types of AIT has been assessed35-39: these conditions can be considered relative contraindications, and FA-AIT should only be used with caution when likely benefits outweigh risks (Box 8). The final decision about starting AIT should be established on an individual basis in discussion with the patient and/or family.

5 EFFECTIVENESS OF DIFFERENT APPROACHES TO AIT FOR IGE-MEDIATED FOOD ALLERGY

The effectiveness of FA-AIT has to be assessed in relation to the culprit food and route of administration.

6 SAFETY OF AIT

Alongside efficacy, safety is pivotal to any treatment. In AIT, safety is particularly important, as potential adverse events are mostly immediate onset, food-induced IgE-mediated reactions, which can lead to anaphylaxis. Events related to safety have been highlighted in the studies addressed by the SR.18 The heterogeneity in the reporting formats reduced the number of studies that could be pooled in the meta-analysis. Despite this, it was shown that patients receiving the active preparation experienced significantly more reactions, both systemic and local, than those who received placebo.18 Recommendations on safety of AIT are shown in Box 11.

7 ALLERGEN FACTORS THAT AFFECT THE EFFECTIVENESS AND SAFETY OF AIT

In the SR on FA-AIT, the majority of trials were on CM (n = 16), HE (n = 11), and peanut (n = 7), with only 1-3 studies for each of the other foods.18 AIT for CM, HE, and peanut had similar efficacies in terms of desensitization with RR of 0.12 (95%CI 0.06, 0.25), 0.22 (0.11, 0.45), and 0.11 (0.04, 0.31), respectively. Of note, in these pooled analyses, the majority of studies were OIT with just a few SLIT ones and the products differed (e.g. peanut flour for OIT versus a peanut extract for SLIT).

Seven trials on different foods (3 CM, 1 HE, 1 peanut, 1 peach, and 1 hazelnut: the latter two dealing with SLIT and the remaining 5 with OIT) could be pooled for analysis regarding occurrence of systemic reactions. An increased risk of systemic reactions was observed with OIT, but a comparative subgroup analysis on the type of allergen could not be undertaken.18 For local reactions, milk seems more prone to cause side-effects than egg although no statistically significant differences were found between them (milk 2.70, 1.33, 5.47; egg 1.55, 1.09, 2.22).18 In conclusion, there is no evidence that the efficacy and safety are affected by the type and nature of the food allergen used in AIT.

8 PATIENT FACTORS THAT AFFECT THE EFFICACY AND SAFETY OF AIT

Different patient factors have been suspected to affect the outcomes of FA-AIT, in terms of both efficacy and safety. Concerning patient age, the SR and meta-analysis found that FA-AIT is effective in reducing FA in children and a population of mixed ages with IgE-mediated FA to a range of foods. It is still unclear whether AIT is effective for adults. There are no studies of OIT performed exclusively in adults and in those performed with mixed (i.e. children and adult) populations, efficacy could not be analyzed separately according to age.18 The only studies focused on adults used SLIT with hazelnut and peach and showed an increase in threshold of reaction while on therapy.11, 53

In the SR and meta-analysis on FA-AIT, there were insufficient data to analyze the role of other patient factors such as the number of culprit foods of clinical relevance, co-existence of asthma, or other severe allergic disorders, on FA-AIT outcomes.18 Some studies have shown that patients with greater IgE sensitization, lower threshold/higher severity, and associated asthma are those with a higher frequency of adverse events.57, 58, 62 In a similar vein, some studies found that smaller SPT wheal size and lower sIgE levels have been associated with an increased likelihood of achieving desensitization and tolerance.67, 68 However, other studies did not find a significant correlation between pre-FA-AIT SPT/sIgE results and treatment success,45, 52 and some FA-AIT studies have included children with severe FAs or anaphylaxis with elevated sIgE who were successfully treated with FA-AIT.7, 9 Two studies performed in children allergic to CM have shown that IgE recognitions of peptides of CM proteins are biomarkers that predict safety and efficacy of CM-AIT.54, 61

9 ADHERENCE TO AIT

Adherence to treatment is a crucial consideration to ensure both efficacy and safety of FA-AIT. Given that FA-AIT is time-consuming and burdened by potential side-effects, patients and their families must be extremely adherent, reliable and committed to a treatment regimen that may cover a long period of time. Given these premises, poor adherence to the treatment is an absolute contraindication (Box 8). A clear and detailed explanation about the FA-AIT procedure (i.e. up-dosing schedules, setting), the related outcomes, and risk of side effects, together with getting information on patients’ and/or families’ opinions and expectations are pre-requisites to the inclusion in the treatment protocol. Patients and their families need to be supported during the entire treatment. Informed consent should be signed by patients (where appropriate) and their parents.

10 SUMMARY, GAPS IN THE EVIDENCE AND FUTURE PERSPECTIVES

FA-AIT represents the active treatment of IgE-mediated FA instead of avoidance and rescue drug management. The usual management of FA demands changes in eating habits with serious repercussions on QoL, potential risk of nutritional deficiencies, especially in young children, and severe adverse reaction in case of accidental exposure to the culprit food.

The recent SR and meta-analysis on FA-AIT18 clearly demonstrated that FA-AIT is effective in reducing the likelihood of reacting to foods while receiving the therapy. In pediatric patients with FA to CM and peanut, data suggest that OIT is more effective than SLIT.45, 55 There is an increased risk of local (the most frequent) reactions with both OIT and SLIT but only OIT showed a significantly higher risk of systemic reactions. Due to the length of the protocol and safety issues, patients and their families must be extremely adherent, reliable, and committed to the treatment. FA-AIT may improve QoL scores, particularly with regard to social limitations, accidental exposure, and anxiety, although further studies are needed.5

Many children with CM allergy or HE allergy develop tolerance spontaneously. For this reason, for many patients and families, allergen avoidance while awaiting spontaneous resolution may represent a better option than FA-AIT. Therefore, FA-AIT cannot be recommended as routine practice, but must be limited only to carefully selected patients managed in specialized clinical settings, by trained personnel (Boxes 12 and 13).

There are still many gaps that need to be addressed (Box 14). The duration of FA-AIT may be burdensome for patients and their families. After completion of therapy, patients frequently need to continue to consume the allergen to maintain tolerance. It may be easier to achieve post-discontinuation effectiveness (e.g. tolerance or sustained unresponsiveness) for allergens that are typically outgrown in childhood (e.g. CM and HE) compared to other allergens (such as peanut), where probably lifelong ingestion may be required after therapy. In addition, efficacy during the treatment with CM can be maintained with a twice-weekly regimen. We await maintenance follow-up studies to assess whether more flexible regimens are possible with other foods.69

The quality of allergen preparations is critical for both diagnosis and treatment. Standardized allergen preparations of known potency and shelf life should be used. Currently, the allergens containing food protein and those prepared by pharmaceutical companies or hospital pharmacies are not available as standardized products. The allergens in such products should be well characterized as it is known that different formulations of a product may have significant variations in allergen load. Both the bacteriological load and biological activity of these products are still undetermined. Therefore, the use of fresh material or native foods for FA-AIT is advisable to achieve the goal of desensitization. Different disciplinary and clinical backgrounds including medical care, patient groups, allergen manufacturers, and regulators should be involved in the process of producing new data on standardized allergen preparations for the active treatment of FA.

Novel therapeutic approaches are being developed to improve FA-AIT, most of them in preclinical or early clinical trials. In particular, co-administration of humanized monoclonal anti-IgE (omalizumab) seems to markedly reduce adverse reactions due to OIT compared to placebo.70-72 Furthermore, as bacteria are potent stimulants of Th1 immune responses, modified bacterial products are under investigation as adjuvants for FA-AIT.46

Clinical studies carried out with FA-AIT have some limitations, a key one is the heterogeneity in protocols between centers. It is yet unclear which duration and frequency of ingestion of the allergic food(s) is required to maintain desensitization. Furthermore, we are lacking criteria with which to evaluate and diagnose permanent tolerance. In AIT trials and in clinical practice, safety is of the paramount importance: Strategies for improving safety during either up-dosing protocol or maintenance regimen need to be standardized. Managing these pivotal issues is mandatory for use of OIT/SLIT outside research settings or specialized clinical centers for FA-AIT.

FA-AIT should be utilized for patients with persistent food allergy (Box 15). In many patients, the downside of the adverse events associated with treatment is outweighed by both the achievement of desensitization and the reduced risk of a serious allergic reaction by accidental exposure at home or in the community. Considering the current evidence, there are still considerable knowledge gaps about how best to perform FA-AIT and more well-designed AIT trials are required.

CONFLICTS OF INTEREST

Dr. Bindslev-Jensen reports grants and personal fees from HAL Allergy, grants from Aimmune, grants from Anergis, outside the submitted work; Dr. Ebisawa reports and DBV technologies; Dr. Santos reports grants from Medical Research Council, grants from Immune Tolerance Network/NIAID, personal fees from Thermo Fisher Scientific, Nutricia, Infomed, outside the submitted work; Dr. Du Toit reports income from grants from National Institute of Allergy and Infectious Diseases (NIAID, NIH), Food Allergy & Research Education (FARE), MRC & Asthma UK Centre, UK Dept of Health through NIHR, National Peanut Board (NPB), and grants from UK Food Standards Agency (FSA); these grants part funded salary over period of this submitted work. Dr. Papadopoulos reports grants from Menarini, personal fees from Novartis, Faes Farma, BIOMAY, HAL, Nutricia Research, MEDA, Abbvie, MSD, Omega Pharma, Danone, outside the submitted work; Dr. Halken reports, personal fees from different companies e.g. MEDA, Stallergenes, Allergopharma and ALK-Abelló, outside the submitted work; Dr. Varga reports personal fees from Lecture fees, ALK-Abello, Stallergenes, Bencard, Allergopharma, MEDA, Nutricia, personal fees GAP-Trial Steering Committee Member, outside the submitted work; The other authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS

GB Pajno and M. Fernandez-Rivas jointly chaired the EAACI Guideline: AIT for IgE-mediated Food Allergy Taskforce. S Arasi, C Akdis, M Alvaro-Lozano, K Beyer, C Bindslev-Jensen, W Burks, M Ebisawa, P Eigenmann, EF Knol, KC Nadeau, A Muraro, LK Poulsen, R van Ree, G Roberts, A Santos, G du Toit were members of the Taskforce involved in conceptualizing the guidelines and writing and critical revision of drafts. S Arasi, S Dhami, U Nurmatov, and A Sheikh provided methodological support to the Taskforce. Y Boloh was the patients’ group representative. I Agache, E Angier, S Halken, M Jutel, S Lau, O Pfaar, R van Ree, D Ryan, G Sturm, E-M Varga, R Gerth van Wijk were members of the EAACI Guidelines Steering Committee and contributed in conceptualizing the guidelines and critically reviewed draft versions. All the authors satisfied the international authorship criteria with further details in the online supplement. This guideline is part of the EAACI Guidelines on Allergen Immunotherapy, chaired by A Muraro, and coordinated by G Roberts.