Eosinophilic gastrointestinal disorders and allergen immunotherapy: Lights and shadows

Allergic diseases, such as IgE-mediated food allergy, asthma, and allergic rhinitis, are relevant health problems worldwide and show an increasing prevalence. Therapies for food allergies are food avoidance and the prompt administration of intramuscular epinephrine in anaphylaxis occurring after accidental exposure. However, allergen immunotherapy (AIT) is being investigated as a new potential tool for treating severe food allergies. Effective oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) induce desensitization and restore immune tolerance to the causal allergen. While immediate side effects are well known, the long-term effects of food AIT are still underestimated. In this regard, eosinophilic gastrointestinal disorders (EGIDs), mainly eosinophilic esophagitis, have been reported as putative complications of OIT for food allergy and sublingual immunotherapy (SLIT) for allergic asthma and rhinitis. Fortunately, these complications are usually reversible and the patient recovers after AIT discontinuation. This review summarizes current knowledge on the possible causative link between eosinophilic gastrointestinal disorders and AIT, highlighting recent evidence and controversies.     

Oral immunotherapy in food allergies: A practical update for pediatricians

Food oral immunotherapy (OIT) is a promising treatment for persistent and severe food allergies (FAs) in children, but also for accelerating tolerance to cow's milk and cooked egg in young children. In the near future, pediatricians will increasingly encounter severely allergic children undergoing FA-OIT. FA-OIT consists in daily ingestion of increasing doses of the allergen during the up-dosing phase, and ingestion of a constant dose during the maintenance phase. The global aim is to increase the reactive threshold of allergic patients, and finally enable them to ingest a target quantity of allergen without any reaction throughout the treatment (desensitization). Many studies showed the efficacy of FA-OIT in desensitization, and some of them in sustained unresponsiveness. This corresponds to tolerance after FA-OIT discontinuation, especially for cow's milk and hen's egg allergy. However, there is an ongoing debate about the safety of the treatment. Side effects are frequent, notably aversion to the allergen and oral syndromes as well as systemic allergic symptoms. These reactions occur mainly during the up-dosing phase and become less frequent with time, but they are common causes of FA-OIT discontinuation. Patients and their families must be trained to manage these reactions at home. Long-term side effects can also occur, such as eosinophilic esophagitis. Pediatricians play an important role in maintaining patient motivation; they also provide knowledge on possible allergic reactions and the reactogenic cofactors (mainly fever and viral infection, anti-inflammatory intake, physical activity), and refer the patient to the relevant specialists in the case of long-term care. Other routes of administration for food immunotherapy (epicutaneous and sublingual) and different adjuvant treatments (probiotics, anti-IgE molecule) are currently under study. This will allow us to improve the efficacy of immunotherapy and reduce the risk of any side effects, in order to provide a more favorable risk–benefit ratio.     

Immunotherapy – risk/benefit in food allergy

Food allergy is a growing health concern in the westernized world with approx. 6% of children suffering from it. A lack of approved treatment has led to strict avoidance of the culprit food proteins being the only standard of care. Nowadays in‐depth research is conducted to evaluate the possible use of allergen‐specific immunotherapy (SIT) as an active therapeutic option for food allergy. Various routes of administration for the immunotherapy are investigated, including subcutaneous, oral, sublingual, and epicutaneous, and some appear to be successful in inducing a temporary tolerant state. Most research has been conducted with oral immunotherapy due to its efficacious and relatively safe profile. Increasing interest is dedicated to safer and more convenient approaches, such as sublingual and epicutaneous SIT; however, doubts exist about their possible capacity to induce temporary tolerant state and permanent oral tolerance. The high frequency of allergic adverse reactions of the various approaches and the inability to achieve permanent oral tolerance have highlighted the need of refinements in the strategies. A promising strategy for preventing IgE cross‐linking and thus enhancing safety of SIT, while still activating T cells, is the use of tolerogenic peptides. The implementation of such an immunotherapy approach has the potential of not only increasing the chance of achieving a permanent state of tolerance, but also improving the safety and tolerability of the therapy. Immunotherapy for food allergy is still not ready for the clinic, but current and upcoming studies are dedicated to collect enough evidence for the possible implementation of allergen‐SIT as a standard treatment for food allergy.     

Combining anti‐IgE with oral immunotherapy

Food allergy is a significant medical problem that affects up to 8% of children in developed countries. At present, there are no curative therapies available in routine practice and management of food allergy involves strict allergen avoidance, education, and prompt treatment upon accidental exposure. Oral immunotherapy (OIT) is an efficacious experimental approach to food allergy and has been shown to provide a substantial benefit in terms of allergen desensitization. However, OIT is associated with high rates of allergic reactions, and the period of protection offered by OIT appears to be limited and highly variable. Recurrence of allergen sensitivity after a period of treatment discontinuation is commonly observed. With the aim of overcoming these limitations of OIT, several trials have studied omalizumab (anti‐IgE monoclonal antibody) as an adjuvant treatment for patients undergoing OIT. Results from these trials have shown that the addition of omalizumab to OIT leads to a significant decrease in the frequency and severity of reactions, which allows for an increase in the threshold of tolerance to food allergens. This review provides a summary of the current literature and addresses some of the key questions that remain regarding the use of omalizumab in conjunction with OIT.     

Improving the safety of oral immunotherapy for food allergy

Food allergy is a major public health problem in children, impacting upon the affected individual, their families and others charged with their care, for example educational establishments, and the food industry. In contrast to most other paediatric diseases, there is no established cure: current management is based upon dietary avoidance and the provision of rescue medication in the event of accidental reactions, which are common. This strategy has significant limitations and impacts adversely on health‐related quality of life. In the last decade, research into disease‐modifying treatments for food allergy has emerged, predominantly for peanut, egg and cow's milk. Most studies have used the oral route (oral immunotherapy, OIT), in which increasing amounts of allergen are given over weeks–months. OIT has proven effective to induce immune modulation and ‘desensitization’ – that is, an increase in the amount of food allergen that can be consumed, so long as regular (typically daily) doses are continued. However, its ability to induce permanent tolerance once ongoing exposure has stopped seems limited. Additionally, the short‐ and long‐term safety of OIT is often poorly reported, raising concerns about its implementation in routine practice. Most patients experience allergic reactions and, although generally mild, severe reactions have occurred. Long‐term adherence is unclear, which rises concerns given the low rates of long‐term tolerance induction. Current research focuses on improving current limitations, especially safety. Strategies include alternative routes (sublingual, epicutaneous), modified hypoallergenic products and adjuvants (anti‐IgE, pre‐/probiotics). Biomarkers of safe/successful OIT are also under investigation.     

儿童过敏性疾病免疫治疗新进展

变应原特异性免疫治疗（AIT）属主动免疫疗法,能调节固有免疫和适应性免疫。变应性鼻结膜炎、哮喘的AIT新途径为淋巴结内免疫治疗和表皮内免疫治疗,但有效性及标准方案仍需进一步研究。低变应原性的重组变应原衍生物和具有免疫原性的肽段,联合新佐剂均是新的AIT研究方向。食物过敏口服免疫治疗具有一定疗效,但不良反应尤其是严重过敏反应的风险仍是需要解决的问题。近年来,被动免疫疗法应用于过敏领域的进展迅速,多种单克隆抗体生物制剂在传统治疗控制不佳的哮喘、特应性皮炎中有着较好效果,AIT联合生物制剂治疗提供了新的治疗选择。     

Specific oral tolerance induction in childhood

Food allergy continues to be a significant public health concern for which there are no approved treatments and management strategies primarily include allergen avoidance and pharmacological measures for accidental exposures. Food allergy is thought to result from either a failure to establish oral tolerance or the breakdown of existing oral tolerance, and therefore, experimental preventative and treatment strategies are now aimed at inducing specific oral tolerance. This may occur in infancy prior to the development of food allergy through the optimal timing of dietary exposure (primary oral tolerance induction) or as a treatment for established food allergy through oral immunotherapy (secondary oral tolerance induction). Trials examining the effectiveness of early dietary allergen exposure to prevent food allergy have yielded promising results for peanut allergy but not so for other allergens, although the results of several trials are yet to be published. Although infant feeding guidelines no longer advise to avoid allergenic foods and exposure to food allergens orally is an important step in inducing food tolerance by the immune system, evidence regarding the optimal timing, dose and form of these foods into the infant's diet is lacking. Likewise, oral immunotherapy trials appear promising for inducing desensitization; however, the long‐term efficacy in achieving sustained desensitization and optimal protocols to achieve this is unknown. More research is needed in this emerging field.     

Orale Immuntherapie bei Nahrungsmittelallergien

Specific immunotherapy (SIT) has been successfully used for many years as an effective therapeutic option for allergic diseases, such as allergic rhinoconjunctivitis or insect venom allergy. In recent years much research has been conducted on SIT as a causal treatment option for food allergies. Currently, many studies have focused on oral immunotherapy (OIT). Many OIT studies could demonstrate the efficacy of this treatment in terms of desensitization but long-term efficacy with regard to tolerance development is not yet proven. It seems that OIT has an immunomodulatory effect on T-cells and B-cells; however, safety remains a major issue in OIT studies due to side effects in many patients. Therefore, at the moment this treatment option cannot be recommended outside of clinical trials. Hence, the only option for food allergy patients remains the strict elimination of the offending food.     

Anaphylactoid reaction to high‐dose methotrexate and successful desensitization

Anaphylactic/anaphylactoid reaction to methotrexate (MTX) is uncommon. It may occur with the first dose (non‐allergic reactions) or after a previous exposure to the drug (allergic or specific reactions). Desensitization has been shown effective in children with allergic‐type reactions permitting the continuation of high‐dose methotrexate (HDMTX) therapy. We report the case of a child with localized osteosarcoma who developed an anaphylactoid reaction after a first HDMTX course. A desensitization protocol was successfully applied allowing the administration of four additional courses. In our experience, desensitization can be a safe and effective procedure in children with anaphylactoid reactions to HDMTX. Pediatr Blood Cancer. 2010;55:557–559. © 2010 Wiley‐Liss, Inc.     

儿童食物过敏的口服免疫治疗

到目前为止,食物过敏治疗尚没有确切的有效治疗方法,主要采用回避过敏原和针对严重过敏反应急诊处理等方法,口服免疫治疗(oral immunotherapy,OIT)作为一种新的食物过敏治疗方法,它能诱导IgE介导的儿童食物过敏的脱敏,但仍不了解诱导耐受的状况能否持续.虽然OIT治疗过程中发生严重过敏反应并不多见,但不良反应是共同存在的.今后需在严格设计的多中心随机、双盲、对照研究基础上,进一步了解OIT治疗后过敏原耐受状况能否维持,并明确耐受的特异性实验室指标.

Abstract：

At present there is no definitive therapy for food allergy and the mainstays of treatment are allergen avoidance and ready access to emergency medications. Significant progress toward an novel oral immunotherapy (OIT)for food allergy has been made. These preliminary data on OIT are encouraging, OIT can be effective in desensitizing at least a subset of children with IgE-mediated food allergy, however, it remains uncertain whether OIT can induce long-term tolerance. During OIT, allergic reactions are common, although severe reactions are less common. Additional studies are needed to realize whether tolerance would be maintained, and to determine the specific laboratory indicators in rigorous multicenter randomized and placebo-controlled trials.     

变应原特异性免疫治疗在儿童变应性疾病中的应用

变应原特异性免疫治疗是一种应用于IgE介导的变应性疾病的脱敏疗法,其主要和药物治疗联合使用,治疗过敏原无法避免的变应性哮喘、变应性鼻炎及特发性皮炎患者,也是可能改变变应性疾病自然病程的治疗方法.但是免疫治疗在儿童过敏性疾病中的应用尚存在争议,研究较少.现就变应原特异性免疫治疗的作用机制及其在儿童变应性疾病中的临床疗效和安全性进行综述.     

Local allergic rhinitis: A critical reappraisal from a paediatric perspective

The so‐called local allergic rhinitis (LAR) has been proposed as a phenotype of rhinitis with Th2‐driven prominent local allergic inflammation, nasal synthesis of specific IgE and a positive response to a nasal allergen provocation test, in the absence of ‘systemic’ atopy (negative skin prick test and serum allergen‐specific IgE antibodies). To date, available data on LAR are mostly focused on adults. The purpose of this ‘Rostrum’ was to critically discuss data and implications of the ‘LAR concept’ in paediatrics. In the natural history of rhinitis due to IgE‐mediated reactions triggered by exposure to allergens, a ‘LAR’ can be either the initial, transient stage of classical allergic rhinitis or a stable phenotype never evolving to ‘systemic’ IgE sensitization. Given the present difficulties in performing routinely nasal allergen provocation test in children, the development of sensitive and specific tests to detect IgE in the child's nasal secretions is a research priority. We suggest also the hypothetical role of allergen immunoprophylaxis or immunotherapy in LAR. Last, the term ‘local allergic rhinitis’ may be inappropriate, as rhinitis is always ‘local’, while IgE sensitization can be either ‘local’ or ‘systemic’.     

Allergen immunotherapy in children

Specific allergen immunotherapy is the only potentially curative allergy treatment currently available. It is used in Europe and North America in the treatment of allergic rhinitis, venom allergy and asthma in children. However, following a series of deaths in the 1980s, the use of immunotherapy in the UK is limited to a small number of specialist allergy clinics. This article reviews the route of administration, safety, efficacy and indications for specific allergen immunotherapy in children. New developments in immunotherapy are discussed.     

Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy

Mösges R, Graute V, Christ H, Sieber H‐Jochen, Wahn U, Niggemann B. Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy.
Pediatr Allergy Immunol 2010: 21: 1135–1138.
© 2010 John Wiley & Sons A/S The recommendation to use sublingual‐swallow immunotherapy (SLIT) in children and adults with allergic rhinitis has been established over the past decade. Recently, ultra‐rush titration of SLIT has become more and more common, raising concerns about its safety in children with asthma. Fifty‐four children with asthma and adolescents aged 6–14 with documented allergic disease because of tree pollen (birch and possibly alder and/or hazel) from 14 study centers in Germany participated in a randomized, double‐blind, and placebo‐controlled study. Twenty‐seven were randomized to receive SLIT with standardized birch pollen allergen extract and the other 27 to receive placebo. An ultra‐rush high‐dose SLIT titration regimen reaching the maintenance dose of 300 index of reactivity (IR) within 90 min (30–90–150–300 IR) was used. The difference in mean PFR changes during ultra‐rush titration between SLIT and placebo was not significant (p = 0.056). A 95% probability that SLIT does not decrease PFR during ultra‐rush titration was demonstrated. Neither anaphylactic shock nor else serious systemic reactions to the study drug occurred. No serious adverse event assessed by the investigator as related to study drug treatment was reported.     

Immunotherapy in children and adolescents with allergic rhinoconjunctivitis: a systematic review

Allergen‐specific immunotherapy is one of the cornerstones of allergic rhinoconjunctivitis treatment. Since the development of non‐invasive administration forms with better safety profiles, there is an increasing tendency to prescribe immunotherapy in youngsters. However, no overview is available on the efficacy of immunotherapy in all its different administration forms in youngsters. Therefore, we systematically reviewed randomized controlled trials (RCTs) to evaluate the effect of immunotherapy with inhalant allergens on symptoms and medication use in children and adolescents with allergic rhinoconjunctivitis. Medline, EMBASE, the Cochrane Controlled Clinical Trials Register and reference lists of recent reviews and published trials were searched. RCTs including youngsters aged 0–18 yr with allergic rhinoconjunctivitis and comparing immunotherapy with placebo, symptomatic treatment or a different administration form of immunotherapy were included. Primary outcome measures were rhinoconjunctivitis symptom and/or medication scores. Methodological quality was assessed using the validated Delphi list. A method of best evidence synthesis, a rating system with levels of evidence based on the overall quality and the outcome of the trials, was used to assess efficacy. Six subcutaneous (SCIT), four nasal (LNIT), seven oral (OIT) and 11 sublingual (SLIT) immunotherapy trials, comprising 1619 youngsters, were included. Only 39% of the trials were of high methodological quality. For the SCIT and OIT subgroups the level of evidence for efficacy was conflicting. Moderate evidence of effect was found for LNIT. Analysis of the SLIT subgroup showed no evidence of effect. The evidence for the perennial and seasonal allergen trials within the subgroups varied from moderate evidence of effect to no evidence of effect. In conclusion, there is at present insufficient evidence that immunotherapy in any administration form has a positive effect on symptoms and/or medication use in children and adolescents with allergic rhinoconjunctivitis.     

Allergenspezifische Immuntherapie/Hyposensibilisierung

Immunologic desensitization

Hyposensitization/allergen-specific immunotherapy represents the only disease-modifying treatment of IgE-mediated allergic disorders. According to test results relevant allergens are administered in increasing doses by subcutaneous or sublingual route. The most promising results in allergen immunotherapy are obtained in subcutaneous hyposensitization in insect venom allergy, allergic rhinoconjunctivitis and mild persistent bronchial asthma.

Possible adverse effects and their treatment

To prevent adverse effects of allergen-specific immunotherapy it is important to identify patient-related risk factors having a negative impact on the tolerance to treatment; these risk factors include acute infectious diseases, current allergic symptoms and individually excessive dose of allergen. Monitoring the patient by trained personnel during the first 30 min after subcutaneous allergen administration is mandatory. Systemic allergic reactions are treated immediately according to the prevailing symptoms, including prompt administration of epinephrine for anaphylaxis.

Conclusion

Hyposensitization treatment provided by allergy-experienced medical staff is a safe and sustainable therapy.     

Spezifische Immuntherapie (SIT, Hyposensibilisierung) im Kindesalter

Allergen-specific immunotherapy

Allergen-specific immunotherapy (SIT: specific immunotherapy, hyposensizitation) represents at present the single therapeutic entity for allergic disease, which reduces symptom burden and demonstrates disease-modifying effects.

Indications

In children with allergic rhinitis/rhinoconjunctivitis, allergic asthma, and systemic reactions to hymenoptera stings, SIT has proven efficacy. The use of SIT in children with atopic dermatitis and oral allergy syndrome is under discussion. Prerequisites for the initiation of SIT are the detection of IgE (immunoglobulin E) antibodies or evidence of sensitization with the skin prick test to clinically relevant allergens, the availability of allergen extracts with proven efficacy for the underlying allergic disease, and the impossibility of allergen avoidance.

Contraindications

Contraindications for SIT are partially or fully uncontrolled asthma [FEV₁ <?70?% (FEV₁: forced expiratory volume in 1 s)], severe acute autoimmune disorders, severe immunodeficencies, acute inflammatory syndromes, malignancies, treatment with β-blockers and ACE (angiotensin-converting enzyme) inhibitors and cardiovascular diseases with increased risk of adverse events during administration of epinephrine.     

Oral immunotherapy for the treatment of food allergy

In the absence of a curative treatment, patients with food allergy continue to live with the risk of accidental exposure to food allergens and the possibility of severe allergic reactions. Over the last 5 years, research in the area of immunotherapy for food allergy has intensified. Although this novel therapeutic option has not reached routine clinical practice, results from immunotherapy studies have yielded encouraging results. In this review article, we will discuss the immunological mechanisms involved in tolerance induction and the clinical efficacy and safety of oral and sublingual immunotherapy for food allergy.     

Marche allergique chez l’enfant,de la rhinite à l’asthme : prise en charge,place de la désensibilisation

Allergic rhinitis (AR) is a common IgE dependent disorder. AR is maybe one of the steps of the allergic march, which starts with atopic dermatitis and food allergy and includes atopic asthma. AR and asthma are frequently associated. AR is frequently under-diagnosed and undertreated although it affects quality of life and school performance. Management of AR depends on its severity and will associate environmental control (best guided by environmental investigation and skin testing of specific IgE antibodies), pharmacotherapy (with antihistamines and intranasal corticosteroids as first line drugs). At present allergen immunotherapy is considered in patients with severe AR, insufficiently controlled by pharmacotherapy and who demonstrate specific IgE antibodies to relevant allergens. Sublingual immunotherapy is well tolerated. Only immunotherapy with the right allergens has the potential to alter the natural history of the allergic march, by preventing the development of new allergen sensitizations and reducing the risk for the subsequent development of asthma. This fact might extend the indications of specific allergen immunotherapy. Patients (and parents) education is of utmost importance in the management of allergic disorders.     

特异性免疫治疗新进展

特异性免疫治疗(SIT)作为目前唯一可能根治变应性疾病的治疗方法,不仅可以减轻过敏症状,减少用药,还可阻止自然病程的进展,预防新变应原的产生.近年来舌下SIT因其良好的安全性、有效性和易操作性已在欧洲各国广泛开展.标准化的变应原制剂在国内外逐步应用,已取代非标准化制剂.然而无论是皮下注射还是舌下含服方法,其具体有效剂量、治疗方案、治疗疗程尚待规范统一.随着对其作用机制的不断深入研究,以及以重组变应原为主的新制剂的研发,SIT的应用范围将会进一步扩大,更好地用于变应性疾病的治疗.