EAACI Guidelines on allergen immunotherapy: IgE‐mediated food allergy

Food allergy can result in considerable morbidity, impairment of quality of life, and healthcare expenditure. There is therefore interest in novel strategies for its treatment, particularly food allergen immunotherapy (FA‐AIT) through the oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. This Guideline, prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE‐mediated Food Allergy, aims to provide evidence‐based recommendations for active treatment of IgE‐mediated food allergy with FA‐AIT. Immunotherapy relies on the delivery of gradually increasing doses of specific allergen to increase the threshold of reaction while on therapy (also known as desensitization) and ultimately to achieve post‐discontinuation effectiveness (also known as tolerance or sustained unresponsiveness). Oral FA‐AIT has most frequently been assessed: here, the allergen is either immediately swallowed (OIT) or held under the tongue for a period of time (SLIT). Overall, trials have found substantial benefit for patients undergoing either OIT or SLIT with respect to efficacy during treatment, particularly for cow's milk, hen's egg, and peanut allergies. A benefit post‐discontinuation is also suggested, but not confirmed. Adverse events during FA‐AIT have been frequently reported, but few subjects discontinue FA‐AIT as a result of these. Taking into account the current evidence, FA‐AIT should only be performed in research centers or in clinical centers with an extensive experience in FA‐AIT. Patients and their families should be provided with information about the use of FA‐AIT for IgE‐mediated food allergy to allow them to make an informed decision about the therapy.     

Efficacy and safety of sublingual immunotherapy in children

Allergen immunotherapy (AIT) is currently the only available disease-modifying and aetiological treatment of IgE-mediated diseases. Sublingual allergen immunotherapy (SLIT) constitutes the preferred route of administration of AIT for respiratory allergies in Europe. Recently it has also been approved in the US. Further applications are currently under evaluation, such as IgE-mediated food allergy and IgE-mediated atopic dermatitis. The SLIT safety profile is overall favourable, although local adverse events, usually mild, are described. Most of the meta-analyses confirmed the efficacy of SLIT in reducing symptoms and medication intake in children with allergic diseases. AIT, as an immune-modulating treatment, can modify the natural history of the allergic diseases: reduction of the risk of development of asthma and bronchial hyperreactivity in patients with allergic rhinitis, and reduction of the onset of new sensitizations. A great interest is now devoted to the preventive effects of AIT and, consequently, to the optimal time of initiation.     

The Use of Biomarkers to Predict Aero-Allergen and Food Immunotherapy Responses

The incidence of allergic conditions has continued to rise over the past several decades, with a growing body of research dedicated toward the treatment of such conditions. By driving a complex range of changes in the underlying immune response, immunotherapy is the only therapy that modulates the immune system with long-term effects and is presently utilized for the treatment of several atopic conditions. Recent efforts have focused on identifying biomarkers associated with these changes that may be of use in predicting patients with the highest likelihood of positive clinical outcomes during allergen immunotherapy (AIT), providing guidance regarding AIT discontinuation, and predicting symptomatic relapse and the need for booster AIT after therapy. The identification of such biomarkers in food allergy has the additional benefit of replacing oral food challenges, which are presently the gold standard for diagnosing food allergies. While several markers have shown early promise, research has yet to identify a marker that can invariably predict clinical response to AIT. Skin prick testing (SPT) and specific IgE have commonly been used as inclusion criteria for the initiation of AIT and prediction of reactions during subsequent allergen challenge; however, existing data suggests that changes in these markers are not always associated with clinical improvement and can be widely variable, reducing their utility in predicting clinical response. Similar findings have been described for the use of allergen-specific functional IgG4 antibodies, basophil activation and histamine release, and type 2 innate lymphoid cells. There appears to be a promising association between changes in the expression of dendritic cell-associated markers, as well as the use of DNA promoter region methylation patterns in the prediction of allergy status following therapy. The cellular and molecular changes brought about by immunotherapy are still under investigation, but major strides in our understanding are being made.     

Allergen immunotherapy for food allergy from the Asian perspective: key challenges and opportunities

Introduction: Prevalence of food allergy is rising in different regions of the world. Asia has not been spared from this epidemic, but epidemiological data have revealed a different pattern of food allergens in this continent. Allergen-specific immunotherapy (AIT) for food allergy, which has been revolutionary as the main focus of research in recent years, needs to be adapted for the different populations in Asia.

Areas covered: Recent evidence shows increasing popularity and superiority of AIT over strict food avoidance as the cornerstone of food allergy management. Asia is a distinctive continent with specific food allergy triggers, in particular, seafood, and wheat. Peanut, on the contrary, is not a common food allergen in most parts of Asia. The common Asian food allergens, as well as the rapidly developing food-specific AIT in this region will be covered in this article.

Expert commentary: Evidence on oral immunotherapy for wheat allergy and preclinical data on shellfish AIT are promising. Further work should be done on resolving cross-sensitization between environmental allergens with wheat and shellfish allergens, and a modified AIT approach to enhance the safety and effectiveness of food-specific immunotherapy.     

Allergen Immunotherapy: Past,Present, and Future

Allergen-specific immunotherapy (AIT), although in clinical use for more than a century, is still the only causal treatment of allergic diseases. The safety and efficacy of AIT has been demonstrated in a large number of clinical trials. In addition to allergy symptom reduction AIT plays an essential role in preventing new allergies and asthma and shows long-term effects after discontinuation of treatment. Ideally, it is capable of curing allergy. However, AIT is not effective in all allergic individuals and is not equally effective in the treatment of various hypersensitivities to different allergens. For many years, the route of administration and the vaccine compositions have been evolving. Still there is a strong need for research in the field of new AIT modalities to increase its effectiveness and safety. Growing evidence on immunological effects of AIT, especially new T cell subsets involved in antigen/allergen tolerance, provides novel concepts for safer and more effective vaccination. Pharmacoeconomic studies have demonstrated a clear advantage of AIT over pharmacologic therapies.     

Novel Approaches to Food Allergy

Food allergies have increased in recent decades. However, they cannot be effectively treated by the current management, which is limited to the identification and avoidance of foods that induce allergies and to the use of medicines for symptoms relief. To meet the medical need of prevention and cure of food allergies, several therapeutic strategies are under investigation. Some newly developed biologics such as anti-IgE antibody and anti-interleukin (IL)-5 antibody directed against significant molecules in the allergic process have shown their potential for the treatment of food allergies. Allergen-specific immunotherapy is the therapy that induces immune tolerance and may reduce the need for conventional medication, severity of allergic symptoms and eliminate hypersensitivity. In this article, clinical studies of immunotherapy via subcutaneous, oral, sublingual, and epicutaneous routes are extensively reviewed for their safety and effectiveness on various food allergies. In addition, to reduce the risk of anaphylaxis and increase toleragenic immunity, many studies are focusing on the modification of traditional allergens used for immunotherapy. Moreover, a Chinese herbal formulation with potential anti-allergic effects is being evaluated for its efficacy in patients with peanut allergy. Although more studies are needed, accumulated data of current studies represent compelling evidence of curative effects of some strategies and give a hope that food allergies are likely to be successfully treated in the future.     

Tree nut allergies: Allergen homology,cross‐reactivity,and implications for therapy

Tree nut allergy is a potentially life‐threatening disease that is increasing in prevalence, now affecting 1% of the general population in the United States. While other food allergies often resolve spontaneously, tree nut allergies are outgrown in less than 10% of cases. Due to the likelihood of cross‐sensitization to multiple tree nut allergens, the current treatment guideline is strict avoidance of all nuts once one tree nut allergy has been diagnosed. For example, walnut and pecan are highly cross‐reactive, along with cashew and pistachio, but the extent of clinical, IgE‐mediated cross‐reactivity among other tree nuts remains unclear, therefore making avoidance of all tree nuts a safe approach. There have been recent advances in immunotherapy for food allergies. For instance, there are investigational immunotherapies for milk, egg and peanut allergies, specifically oral immunotherapy, sublingual immunotherapy and epicutaneous immunotherapy. However, there are no large randomized controlled clinical trials for tree nut allergies. Even though there has been less research into tree nut allergy immunotherapies, the evidence of T‐cell cross‐reactivity among tree nuts exists in animal models and in T cells from allergic patients indicates that immunotherapeutic interventions may be possible. Here, we review the literature regarding epidemiology, allergen homology and cross‐reactivity among tree nuts, and explore how current findings can be employed for effective therapy.     

Clinical trials in allergen immunotherapy: current concepts and future needs

Allergen immunotherapy (AIT) is a safe, effective treatment for allergic rhinoconjunctivitis and allergic asthma. However, AIT's clinical effect is still contested—primarily due to heterogeneity in clinical trial designs, study populations, therapeutic formulations, and efficacy criteria. After discussing current concepts and unmet needs, an international panel of experts made several recommendations: (i) explore and validate definitions for (clinical) responders in AIT trials; (ii) use of well‐documented, standardized provocation tests prior to inclusion of subjects with relevant diseases in AIT trials; (iii) monitoring neo‐sensitizations and occurrence of new allergy in extended AIT trials, and exclusion of polyallergic participants; (iv) validation of allergen exposure chambers with regard to natural exposure; (v) in studies of seasonal allergies, focus on peak exposure but also consider organizing two parallel, geographically distinct but otherwise identical trials; (vi) discuss adaptive trial designs with the regulatory authorities; (vii) use e‐health and m‐health technologies to capture more information on individual exposure to allergens; (viii) initiate research on potential psychological, biochemical, immune, neural, and even genomic markers of the placebo response; (ix) identify trial designs and primary endpoints that will give children with allergies easier, faster access to AIT formulations; and (x) promote and apply standardized methods for reporting systemic and local adverse events. The latest technologies and trial designs may provide novel, ethical ways of reducing bias and heterogeneity in AIT clinical trials. There is scope for physicians, patient organizations, companies, and regulators to improve clinical trials in AIT and, ultimately, to provide patients with better treatments.     

Novel approaches and perspectives in allergen immunotherapy

In this review, we report on relevant current topics in allergen immunotherapy (AIT) which were broadly discussed during the first Aarhus Immunotherapy Symposium (Aarhus, Denmark) in December 2015 by leading clinicians, scientists and industry representatives in the field. The aim of this symposium was to highlight AIT‐related aspects of public health, clinical efficacy evaluation, mechanisms, development of new biomarkers and an overview of novel therapeutic approaches. Allergy is a public health issue of high socioeconomic relevance, and development of evidence‐based action plans to address allergy as a public health issue ought to be on national and regional agendas. The underlying mechanisms are in the focus of current research that lays the ground for innovative therapies. Standardization and harmonization of clinical endpoints in AIT trials as well as current knowledge about potential biomarkers have substantiated proof of effectiveness of this disease‐modifying therapeutic option. Novel treatments such as peptide immunotherapy, intralymphatic immunotherapy and use of recombinant allergens herald a new age in which AIT may address treatment of allergy as a public health issue by reaching a large fraction of patients.     

Immunotherapy in allergic rhinitis and lower airway outcomes

Allergic rhinitis and asthma constitute two clinical expressions of a single‐condition, respiratory allergy. Allergen immunotherapy (AIT) is a form of treatment specifically aimed at modifying the response to sensitizing allergens. The inherent potential benefit of AIT is the simultaneous treatment of all clinical expressions of respiratory allergy. Current data support the effectiveness of subcutaneous and sublingual immunotherapy in rhinitis. Studies also provide proof for a beneficial effect in allergic asthma. Even more, substantial evidence points to the preventive effect on the progression from rhinitis to asthma. Despite the current knowledge on the basic mechanisms underlying the immunological effect of AIT is vast, the specific mechanisms for the preventive effect of primary sensitization or new sensitizations are poorly understood. This review aimed to provide a critical overview of the current knowledge on the effectiveness of AIT and its potential role in secondary prevention of respiratory allergy progression.     

Allergen immunotherapy for IgE‐mediated food allergy: a systematic review and meta‐analysis

Background

The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE‐mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost‐effectiveness of AIT in the management of food allergy.

Methods

We undertook a systematic review and meta‐analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT‐NRS tool for quasi‐RCTs. Random‐effects meta‐analyses were undertaken, with planned subgroup and sensitivity analyses.

Results

We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty‐five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty‐seven studies assessed desensitization, and eight studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta‐analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease‐specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta‐analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses.

Conclusions

AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE‐mediated food allergy whilst receiving (i.e. desensitization) and post‐discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost‐effectiveness of AIT.     

Can food allergy be cured? What are the future prospects?

Food allergies have become a significant heath burden as prevalence continues to rise, affecting 6%-13% of the global population. In the absence of drugs approved by regulatory agencies, the current standard of care remains avoidance of allergenic foods and management of acute allergic reactions with antihistamines and epinephrine autoinjectors. Allergen immunotherapy has been shown to increase the threshold of reactivity in the majority of food-allergic individuals. However, challenges include long treatment periods, high rates of adverse reactions, and lack of permanence of desensitization and established protocols. To address these limitations, adjunctive allergen-specific immunotherapy, vaccines, and non–allergen-specific therapies (eg, monoclonal antibodies) are being explored. The future of food allergy treatment is promising with a number of clinical trials in progress. Currently, although desensitization can be achieved for the majority of individuals with food allergy through immunotherapy, continued ingestion of allergen is needed for most individuals to maintain desensitization. Further understanding of the mechanisms of food allergy and identification of biomarkers to distinguish between temporary and permanent resolution of allergies is needed before a cure, where reactivity to the allergen is permanently lost enabling the individual to consume the allergen in any amount at any time, can be envisioned.     

The Changing Geoepidemiology of Food Allergies

The science of food allergy has been rapidly evolving before our eyes in the past half century. Like other allergic disorders, the prevalence of food allergies has dramatically increased, and coupled with the increased public awareness of anaphylaxis due to food allergy, this has driven an explosion in basic and clinical research in this extremely broad subject. Treatment of food allergies has evolved and practices such as food challenges have become an integral part of an allergy practice. The impact of the increase of food allergy has driven package labeling laws, legislation on emergency treatment availability in schools and other public places, and school policy. But to this day, our knowledge of the pathogenesis of food allergy is still incomplete. There are the most obvious IgE-mediated immediate hypersensitivity reactions, but then multiple previously unidentified conditions such as eosinophilic esophagitis, food protein-induced enterocolitis syndrome, milk protein allergy, food-induced atopic dermatitis, oral allergy syndrome, and others have complicated the diagnosis and management of many of our patients who are unable to tolerate certain foods. Many of these conditions are not IgE-mediated, but may be T cell-driven diseases. The role of T regulatory cells and immune tolerance and the newly discovered immunological role of vitamin D have shed light on the variable clinical presentation of food allergy and the development of new methods of immunotherapy in an example of bench-to-bedside research. Component-resolved diagnostic techniques have already begun to allow us to more precisely define the epitopes that are targeted in food allergic patients. The development of biological modulators, research on genomics and proteomics, and epigenetic techniques all offer promising avenues for new modes of therapy of food allergy in the twenty-first century.     

Molecular approaches to allergen‐specific immunotherapy: Are we so far from clinical implementation?

Conventional allergen‐specific immunotherapy (AIT), based on administrations of allergen extracts, represents up to now the unique protocol for the desensitization of allergic patients. Whereas the effectiveness of AIT was evidenced for the treatment of allergic rhinitis and allergic asthma, such strategy remains experimental for food allergies up to now. However, important issues are commonly associated with AIT as the quality of natural allergen extracts, the long duration and adverse side‐effects which negatively affect successful desensitization together with the patient compliance. The rapid progression of molecular allergology made possible the quest of safer, shorter and more effective immunotherapeutic approaches. The aim of this review was to provide an update on these different innovative recombinant derivatives including their efficacy but also their limitations. Despite promising preclinical and early clinical studies, the absence of convincing data in large phase III trials precludes so far the translation of these immunotherapeutic candidates into the clinic.     

Pioneering immunotherapy for food allergy: clinical outcomes and modulation of the immune response

There is no approved therapy for food allergies, which affect 12?million people in the United States and millions more worldwide. In the last few years, our research team at Duke has begun to develop protocols to treat peanut and other food allergies. Two distinct therapies are being developed. Oral immunotherapy (OIT), which relies on ingestion of increasing amounts of the allergenic food, has been used to successfully desensitize more than 50 peanut allergic subjects. Sublingual immunotherapy (SLIT) involves placing small quantities of peanut allergens under the tongue and has shown promise in our initial placebo-controlled clinical trial. Immunologic changes associated with OIT and SLIT include reduction in mast cell reactivity as determined by skin prick test size, decreased basophil responses, decreased specific-IgE, increased IgG4, and induction of regulatory T cells. Development of these immunotherapy strategies has generated much excitement in the food allergy community; however, further studies are needed before these approaches are ready for clinical use.     

The evolution of allergy immunotherapy

ObjectiveThe objective of this review is to trace the evolution of the art and science of allergy immunotherapy (AIT).Data SourcesOriginal reports relating to the evolution of the concept of respiratory allergy and its specific treatment were identified by following references in journal articles, review articles, and allergy textbooks from the mid-20th century to the present.Study SelectionsStudies highlighting substantial milestones in the evolution of the practice of allergy immunotherapy were included.ResultsThe story of AIT begins with the recognition of hay fever as a distinct entity and subsequent studies that established grass pollen as one of the causes. This knowledge led several investigators, most notable Leonard Noon and John Freeman who worked at St. Mary’s Hospital in London, to attempt to induce tolerance giving grass pollen extract by injection to their patients. After the publication of the work of Noon and Freeman in 1911, the practice of AIT spread rapidly and was applied to many other pollen allergens besides grass and for perennial rhinitis and asthma. The early studies were largely anecdotal, but over the past 60 to 70 years, studies of AIT have been conducted with increasingly sophisticated scientific methods. Nowadays, not only is the practice of AIT based on carefully conducted studies, but the underlying immunologic basis of allergy and the response to AIT have also been and still are being firmly established.ConclusionBoth the art and the science behind the practice of AIT have been established by a solid base of clinical and immunologic studies.     

IgE and non-IgE-mediated food allergy: treatment in 2007

PURPOSE OF REVIEW: Our understanding of the mechanism of food allergy has substantially increased over the past decade. Food allergies can be classified into those that are IgE mediated and those that are non-IgE mediated. RECENT FINDINGS: Various advances have been made in treating IgE-mediated food allergies. A phase II clinical trial of a second anti-IgE antibody, omalizumab, was recently initiated in subjects with peanut allergy, but was stopped as a result of safety concerns after severe reactions occurred during initial oral challenges. Oral immunotherapy is showing promise in various studies on patients with IgE-mediated food allergies. Gastrointestinal food allergic disorders involving non-IgE-mediated food allergies have recently received attention, particularly eosinophilic esophagitis. Although amino acid-based formula therapy remains the most successful in controlling inflammation and symptoms in these disorders, other therapeutic options including various dietary elimination protocols and swallowed fluticasone are showing success. Anti-IL-5 therapy may prove to be a promising future therapeutic option for refractory patients. SUMMARY: Although there are no specific therapeutic recommendations for many IgE-mediated and non-IgE-mediated food allergic disorders besides allergen avoidance, various novel approaches are currently being investigated and may influence treatment approaches in the future.     

Immunology in the Clinic Review Series; focus on allergies: immunotherapy for food allergy

There is no approved therapy for food allergy. The current standard of care is elimination of the triggering food from the diet and accessibility to epinephrine. Immunotherapy is a promising treatment approach. While desensitization to most foods seems feasible, it remains unclear if a permanent state of tolerance is achievable. The research team at Duke is pioneering immunotherapy for food allergies. Work here has evolved over time from small open-label pilot studies to larger randomized designs. Our data show that immunological changes associated with immunotherapy include reduction in mast cell reactivity, decreased basophil responses, decreased specific-immunoglobulin (Ig)E, increased IgG4 and induction of regulatory T cells. Immunotherapy has generated much excitement in the food allergy community; however, further studies are needed before it is ready for clinical use.