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.     

One Child's Food Fight: A Case Study of Oral Immunotherapy Treatment for Food Allergies

The prevalence of food allergy has risen dramatically in the last two decades. Primary care providers encounter food-allergic children on a daily basis. Although the standard of care has traditionally been strict avoidance of the allergen and advisement to carry an epinephrine autoinjector in case of an accidental exposure resulting in a severe reaction, food allergy research has progressed in the past decade concerning various immunotherapies that may provide an alternate treatment strategy. Oral immunotherapy (OIT), performed under the supervision of an allergist, is the most widely studied of these therapies. In the past, OIT has been available in the realm of clinical trials, but it is now being offered by a small but increasing number of allergists in private practice throughout the United States. Pediatric primary care clinicians should be aware of both the risks and possible benefits of this treatment, because they are likely to encounter patients who may inquire about OIT in their practices. In this case report, use of OIT will be reviewed in the treatment of a food-allergic child.     

Pathogenesis of IgE-mediated food allergy and implications for future immunotherapeutics

Our understanding of the immune basis of food allergy has grown rapidly in parallel with the development of new immune-targeted interventions for the treatment of food allergy. Local tissue factors, including the composition of skin and gastrointestinal microbiota and production of Th2-inducing cytokines (TSLP, IL-33, and IL-25) from barrier sites, have been shown not only to contribute to the development of food allergy, but also to act as effective targets for treatment in mice. Ongoing clinical trials are testing the targeting of these factors in human disease. There is a growing understanding of the contribution of IL-13 to the induction of high-affinity IgE and the need for continual T-cell help in the maintenance of long-lived IgE. This provides a strong rationale to test biologics targeting both IL-4 and IL-13 in the treatment of established food allergy. Various forms of allergen immunotherapy for food allergy have clearly shown that low specific IgE and elevated specific IgG4 are predictive of sustained treatment effect. Treatments that mimic that immune response, for example, lowering IgE, with monoclonal antibodies such as omalizumab, or administering allergen-specific IgG, are in various stages of investigation. As we gain more opportunities to use immune-modifying treatments for the treatment of food allergy, studies of the immune and clinical response to those interventions will continue to rapidly advance our understanding of the immune basis of food allergy and tolerance.     

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.     

Oral immunotherapy and tolerance induction in childhood

Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food‐allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long‐term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy.     

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.     

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.     

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.     

Addressing risk management difficulties in children with food allergies

Risk is a concept inherent in every medical procedure. It can be defined as the probability of an adverse event in a defined population over a specified period of time. In the frame of food allergy management, it might be related to a diagnostic procedure, a treatment, or the consumption of foods. The risk of an adverse event can also be augmented by individual factors. This rostrum article discusses various aspects faced by children with food allergies in the light of risk, and their practical implications. Identifying personal risks for severe reaction, such as unstable asthma, and correcting them whenever possible also contribute to a reduction of the risk inherent to food allergy. Among the facets discussed, oral food challenges (OFC) are the most common diagnostic procedures implying an inherent risk. The risk of OFCs can be minimized by correct indication and timing of the test, a safe setting, as well as by ensuring that the patient is otherwise well without potential stressor potentially increasing the risk of a more severe reaction. Oral immunotherapy (OIT) has been studied as a potential treatment for increasing the threshold dose for reaction, and thus reducing the risk of accidental reaction. Nevertheless, the procedure is not devoid of risk as the patients may and do often react during the course of the procedure. Ingestion of trace amounts in processed foods, mainly in community settings such as restaurants, schools, or day care, represents a potential risk of reactions, although for a minority of patients. Precautionary allergen labeling (PAL) is a widespread strategy to reduce the potential risk of reactions due to traces. However, PAL is currently inefficient due to inconsistent labeling, also not indicating a clear maximum amount possibly present in the manufactured food. Finally, cost-effectiveness needs to be considered in risk management, as many risk reduction procedures are clearly not cost-effective.     

Safety and efficacy of epicutaneous immunotherapy for food allergy

Food allergy is increasingly common in children, affecting about 4%‐8%. The mainstays of management remain allergen avoidance and emergency preparedness to treat allergic reactions with emergency medications. Unfortunately, these approaches are unsatisfactory for many patients and their families as the restrictions, constant vigilance, and unpredictable severity of allergic reactions negatively impact quality of life. In recent decades, there has been significant interest in developing treatments for food allergy that lead to desensitization to increase thresholds for triggering allergic reactions and decrease the risk of reacting to allergen‐contaminated food products. Epicutaneous immunotherapy (EPIT) is a novel therapy that is currently under investigation, delivering allergen via repeated applications to the skin and targeting antigen‐presenting cells in the superficial skin layers. Murine models have demonstrated that allergen uptake is an active process by skin dendritic cells with subsequent migration to draining lymph nodes. Allergen exposure to the non‐vascularized epidermis limits systemic absorption, contributing to the high‐safety profile. Results from murine experiments showed that EPIT has comparable efficacy as subcutaneous immunotherapy in terms of challenge outcomes, airway hyper‐responsiveness, and immunologic parameters. Several clinical trials of EPIT have recently been completed or are ongoing. Results support the high safety and tolerability of this approach. Efficacy data suggest that the change in threshold eliciting dose following 1 year of therapy is less than that seen compared to high‐dose (2‐4 g peanut protein) oral immunotherapy, but more prolonged treatment with EPIT appears to lead to increasing desensitization. Additional data from larger‐scale studies should provide a more robust assessment of safety and efficacy of EPIT.     

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.     

Novel insights regarding anaphylaxis in children - With a focus on prevalence,diagnosis, and treatment

Anaphylaxis is a serious allergic reaction that occurs rapidly and causes a life-threatening response involving the whole body. This reaction often leads to difficulty in breathing and can result in death. The estimated prevalence of anaphylaxis is 0.05%–2%, which is reported to be increasing in children. Although drugs and venom are the most common causes of anaphylaxis in adults, food is the most common cause of anaphylaxis in children. An interesting association between food-dependent exercise-induced anaphylaxis (FDEIA) and oral immunotherapy (OIT) has recently been reported. A provocation test to determine the diagnostic and augmenting factors of FDEIA has been reported in recent years. Remarkably, several articles showed allergic symptoms without exercise in children with FDEIA and in those with FDEIA development after OIT. Regarding OIT, full-dose OIT poses a risk of adverse reactions, including anaphylaxis. Recent trials have shown the efficacy and safety of low-dose OIT in patients with food-induced anaphylaxis. In this review, we summarized the novel insights regarding anaphylaxis in the pediatric population.     

Bewährte Eckpfeiler in der Therapie von Nahrungsmittelallergien

To date there is no causal treatment option for food allergies. Currently, specific immunotherapy as a possible therapeutic approach should only be conducted within clinical trials. Thus, the first and most important “treatment” option for patients with food allergies remains the strict avoidance of the food responsible for the allergy. Therefore, detailed and individual recommendations of a dietician experienced in food allergy are of prime importance. Nonetheless, despite taking great care accidental ingestion of the offending allergen is common. Therefore, patients with a risk of anaphylactic reactions should receive medication for self-treatment including self-injectable epinephrine which represents the second essential part of medical recommendations. In addition to practical instructions on self-treatment, this group of patients and their caregivers should be given the possibility to participate in an educational program for anaphylaxis. An anaphylaxis pass should be issued.     

Hypoallergene Säuglingsnahrung zur Allergieprävention

The fact that more than 30% of children today suffer from at least one atopic manifestation represents a significant challenge for the pediatrician. Apart from certain environmental factors, genetic disposition and early allergen exposure play a major role in the development of allergic diseases. To reduce the allergen burden for the infant at risk during early infancy, hypoallergenic infant formulas are appropriate supplementations to breastfeeding for primary allergy prevention. The overview of studies using hydrolyzed infant formulas has shown a preventive effect of both extensively hydrolyzed formulas and partially hydrolyzed formulas, mainly on the incidence of atopic dermatitis and food allergy. This preventive potential seems not only dependent on the degree of hydrolyzation or the protein source but also on factors such as the processing itself. It is therefore recommended to use only hydrolysates that have been shown effective for primary prevention in prospective controlled trials.     

The role of dietary interventions in the prevention of IgE‐mediated food allergy in children

Over the last 30 years, the prevalence of food allergy has been on the rise and remains a disease that can have a significant impact on the quality of life of children and their families. There are several hypotheses that have been suggested to account for the increasing prevalence, but this review will focus on the impact that dietary factors have on food allergy development. In the past food allergy, prevalence has largely focused on allergen avoidance; however, there is increasing evidence from interventional studies that have shown that early introduction to potential food allergens may have a beneficial role in allergy prevention. This review aims to look at the evidence in support of early introduction of allergens into infant diets to prevent against the development of food allergy.     

Practical approach to nutrition and dietary intervention in pediatric food allergy

Although the need for nutritional and dietary intervention is a common thread in food allergy management, the type of food allergic disorder and the identified food allergen will influence the approach to dietary intervention. A comprehensive nutrition assessment with appropriate intervention is warranted in all children with food allergies to meet nutrient needs and optimize growth. However, dietary elimination in food allergy may also have undesirable consequences. Frequently, an elimination diet is absolutely necessary to prevent potentially life‐threatening food allergic reactions. Allergen elimination can also ease chronic symptoms, such as atopic dermatitis, when a food is proven to trigger symptoms. However, removing a food with proven sensitivity to treat chronic symptoms may increase the risk of an acute reaction upon reintroduction or accidental ingestion after long‐term avoidance, so it is not without risk. Additionally, it is not recommended to avoid foods in an attempt to control chronic symptoms such as AD and EoE when allergy to the specific food has not been demonstrated. Ultimately, allergen elimination goals are to prevent acute and chronic food allergic reactions in the least restrictive, but also the safest environment to supply a balanced diet that promotes health and growth and development in children.     

The prevention and management of anaphylaxis in children

The severity of allergic reactions covers a spectrum, from mild (e.g. facial urticaria) to severe (severe dyspnoea and/or hypotension). Anaphylaxis represents an extreme end of this spectrum and has unpredictable and life-threatening consequences. In the adult population it is most often caused by drugs, food and hymenoptera venom, but in young children food and drugs are usually responsible. The incidence has increased over recent years, a trend seen in all allergic disease. Treatment of acute anaphylaxis is described. Prevention of further episodes is vital and is most effectively achieved by early referral to a specialist allergy clinic. The cause of anaphylaxis may then be determined, detailed advice given on allergen avoidance and treatment of further reactions, with training of carer/school in allergen avoidance and self-administration of emergency medication. This approach has been shown to reduce the number and severity of subsequent allergic reactions and provides a model of good practice applicable to all causes of anaphylaxis.     

Food allergy: Is strict avoidance the only answer?

It is an immunological paradigm that avoidance of food allergen may reduce the risk or prevent immunological reactions and conversely that a greater exposure increases the magnitude of the immune response. Consequently, food allergen avoidance has been recommended to reduce the risk of sensitization in infants and to prevent clinical reactions in children with positive skin prick tests (SPT). In the latter setting, it is hoped that avoidance may either promote or at least not retard the development of tolerance. Animal studies, however, have demonstrated that tolerance to food allergens may be induced by either large (high zone tolerance) or small (low zone tolerance) doses, whereas doses in between may actually stimulate immune responses. In this review, we discuss whether strict allergen avoidance is always the most appropriate strategy for preventing or managing IgE-mediated food allergy.     

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.     

NIAID-sponsored 2010 guidelines for managing food allergy: applications in the pediatric population

Data from many studies have suggested a rise in the prevalence of food allergies during the past 10 to 20 years. Currently, no curative treatments for food allergy exist, and there are no effective means of preventing the disease. Management of food allergy involves strict avoidance of the allergen in the patient's diet and treatment of symptoms as they arise. Because diagnosis and management of the disease can vary between clinical practice settings, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored development of clinical guidelines for the diagnosis and management of food allergy. The guidelines establish consensus and consistency in definitions, diagnostic criteria, and management practices. They also provide concise recommendations on how to diagnose and manage food allergy and treat acute food allergy reactions. The original guidelines encompass practices relevant to patients of all ages, but food allergy presents unique and specific concerns for infants, children, and teenagers. To focus on those concerns, we describe here the guidelines most pertinent to the pediatric population.