In allergic diseases, immune responses are induced by normally well-tolerated allergens, which result in chronic inflammation characterized by antibody secretion and T cell activation. For almost 100 years, allergen-specific immunotherapy (allergen-SIT) has been the potentially curative and antigen-specific method for the treatment of allergic diseases. Allergen-SIT alters the course of allergic diseases and can reduce allergic symptoms and medication use. The key mechanism behind allergen-SIT is the induction of peripheral T cell tolerance by altering the balance between Th cells and regulatory T cells. Both naturally occurring thymus-derived FOXP3(+)CD4(+)CD25(+) regulatory T cells and inducible type 1 regulatory T cells suppress the development of allergic diseases via several mechanisms including suppression of dendritic cells, Th cells, mast cells, eosinophils and basophils; suppression of inflammatory cell migration to tissues; and decrease of the ratio between allergen-specific IgE and IgG4 antibodies. These effects are mainly mediated by the suppressive cytokines IL-10 and TGF-β. Knowledge of this molecular basis is crucial to understanding the regulation of the immune response and their possible therapeutic applications for allergic diseases.
Eosinophilic oesophagitis (EoE) is an antigen-driven pan-oesophagitis that is defined by the presence of at least 15 eosinophils per high power field on oesophageal histology in conjunction with upper gastrointestinal symptoms. EoE is closely associated with atopic disorders, in particular with food allergy, and as for other atopic diseases in childhood, there is a strong preponderance of male patients who have this disorder. The mechanisms leading to EoE have been characterised at the molecular level. Eotaxin-3, interleukin-5 and interleukin-13 are the key effector molecules in EoE pathogenesis. EoE presents with a diverse range of gastrointestinal symptoms, including regurgitation, vomiting, feeding difficulties or feeding refusal in infancy, as well as heartburn, dysphagia and food bolus impaction in older children and adults. The diagnosis may also be ascertained as an incidental finding in patients undergoing gastroscopy for other suspected conditions, including coeliac disease. EoE is different from gastro-oesophageal reflux disease and does not improve in response to proton pump inhibitors. Therefore, EoE needs to be distinguished from so-called PPI-responsive oesophageal eosinophilia. The long-term prognosis of EoE remains poorly defined, and complications mainly relate to subepithelial remodelling and fibrosis that may result in dysmotility, dysphagia and oesophageal strictures. The treatment of EoE involves elimination diets and topical swallowed aerosolised corticosteroids, while biological therapies targeting molecular mechanisms have so far been unsuccessful. In children, elemental diets have proved highly effective, but multiple food elimination diets are more sustainable in the long term. Further randomised, controlled trials on dietary or pharmacological interventions are needed to inform the optimal long-term management of EoE.
Food allergy is a known trigger of anaphylaxis. Although the awareness of food allergies has improved, food-related allergic reactions and anaphylaxis still commonly occur. The recognition of anaphylaxis, its prompt treatment, and patient education are important for the prevention of future food reactions. Patients and health care providers should also recognize the importance of epinephrine as the primary treatment of anaphylaxis. When food-related anaphylaxis occurs, patients should receive education regarding their food allergies, an epinephrine auto-injector, and follow-up with a food allergy specialist to reduce the risk of future food-related reactions.
Dietary intervention is a crucial component of food allergy management but can negatively impact nutrient intake. A comprehensive nutrition assessment with appropriate intervention is warranted in all children with food allergies to meet nutrient needs and optimize growth. Nutrition assessment may also be indicated in adults with food allergy. Frequently, an elimination diet is absolutely necessary to prevent potentially life-threatening anaphylaxis. Allergen elimination can also improve chronic symptoms, such as atopic dermatitis, when a food is proven to trigger symptoms. Allergen elimination goals are to prevent acute and chronic food-allergic reactions in the safest and least restrictive environment to supply a balanced diet that promotes health in children and adults.
Among grains and legumes, wheat and soybean are the most frequent and well-characterized allergenic foods. Wheat proteins are divided into water/salt-soluble and water/salt-insoluble (gluten) fractions. The most dominant allergen in the former is α-amylase/trypsin inhibitor, which acts as an inhaled allergen causing baker's asthma. Gluten allergens, including ω-5 gliadin and high- and low-molecular-weight glutenins, contribute to wheat-dependent exercise-induced anaphylaxis in adults and immediate-type wheat allergies, including anaphylaxis, in children. Recently, wheat allergies exclusively caused by hydrolyzed wheat proteins or deamidated glutens have been reported, and the presence of unique IgE-binding epitopes has been suggested. Soybean allergens contributing to immediate-type allergic reactions in children are present in seed storage proteins, namely Gly m 5, Gly m 6 and Gly m 8. However, pollen-related soybean allergy in adults is caused by the Bet v 1 homolog of soybeans, Gly m 4. Taken together, the varying clinical manifestations of wheat and soybean allergies are predominantly caused by their different allergen components.
There is currently no well-established disease-modifying treatment for food allergy, so management relies upon strict avoidance of food allergen(s), implementation of risk minimisation strategies to avoid inadvertent exposure and allergic reactions, and prompt management of acute allergic reactions, should they occur. The pharmacological management of acute food-induced allergic reactions is dependent on the underlying pathophysiology of the allergic reaction and the severity of clinical symptoms and signs. Mild to moderate symptoms of an immunoglobulin E-mediated acute allergic reaction may be treated effectively with an oral anti-histamine. In patients exhibiting the clinical features of anaphylaxis, adrenaline is the only first-line therapy recommended by expert consensus. Adjunctive therapies, including anti-histamines, beta-agonists and glucocorticoids, may be used in the subsequent management of immunoglobulin E-mediated anaphylaxis. Here, we present the current recommendations for the pharmacological management of acute food-induced allergic reactions, together with a summary of the evidence supporting these recommendations.
Fruit and vegetable allergies are the most prevalent food allergies in adolescents and adults. The identification of the allergens involved and the elucidation of their intrinsic properties and cross-reactivity patterns has helped in the understanding of the mechanisms of sensitisation and how the allergen profiles determine the different phenotypes. The most frequent yet contrasting fruit and vegetable allergies are pollen-food syndrome (PFS) and lipid transfer protein (LTP) syndrome. In PFS, fruit and vegetable allergies result from a primary sensitisation to labile pollen allergens, such as Bet v 1 or profilin, and the resulting phenotype is mainly mild, consisting of local oropharyngeal reactions. In contrast, LTP syndrome results from a primary sensitisation to LTPs, which are stable plant food allergens, inducing frequent systemic reactions and even anaphylaxis. Although much less prevalent, severe fruit allergies may be associated with latex (latex-fruit syndrome). Molecular diagnosis is essential in guiding the management and risk assessment of these patients. Current management strategies comprise avoidance and rescue medication, including adrenaline, for severe LTP allergies. Specific immunotherapy with pollen is not indicated to treat pollen-food syndrome, but sublingual immunotherapy with LTPs seems to be a promising therapy for LTP syndrome.
Approximately one-third of children with severe atopic eczema suffer from a food allergy, whereas in adult patients, food allergies are rare. In child patients, three different clinical reaction patterns can be differentiated as follows: (1) immediate-type reactions, (2) isolated late eczematous reactions, and (3) combined immediate-type and late eczematous reactions. In childhood food allergies, food allergens, such as cow's milk or hen's egg, are primarily responsible for allergic reactions, while in adolescents and adults, food allergies often develop consecutively after primary sensitization to pollen allergens. Dysfunctions in the epidermal barrier seem to be vitally important in the development of food allergies in patients with atopic eczema by facilitating sensitization after epicutaneous allergen exposure. Further investigation is required to determine the role of intestinal epithelial barrier defects in the pathogenesis of these allergies as well as the genetic characteristics associated with an increased risk of food allergy. The diagnosis of eczematous reactions to food requires a careful diagnostic procedure, taking into account a patient's history and sensitization patterns. The clinical relevance of sensitization often has to be proven by an oral food challenge, with the rating of the skin condition by validated scores after 24 h and the later evaluation of the eczematous reaction.
Although most food allergy patients have immediate-type reactions, some have delayed-type reactions. Unlike for the detection of food-specific IgE antibody in immediate-type (IgE-mediated) food allergies, only a few tests are currently available to aid in the diagnosis of delayed-type (non-IgE-mediated) food allergies. This chapter summarizes our current understanding of one in vitro test and one in vivo test for non-IgE-mediated food allergies: the lymphocyte stimulation test (LST) and the atopy patch test (APT). Although the LST is not yet standardized, a food protein-specific LST might be a useful tool for diagnosing delayed-type food allergies, and especially those manifesting with gastrointestinal symptoms but not skin symptoms. Various remaining issues - including basophil contamination of the peripheral blood mononuclear cell fraction and lipopolysaccharide contamination of food antigen preparations - are also discussed. The APT uses an epicutaneous patch technique to occlusively apply food antigens to the skin to induce inflammatory reactions at the patch application site. Because the APT shows modest sensitivity and specificity, the clinical benefit of the APT in the diagnosis of food allergies in patients with atopic dermatitis is limited. A position paper on the APT issued by the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network in 2006 is briefly summarized, and several recent APT-related topics, including APT use for the diagnosis of food protein-induced enterocolitis syndrome, are discussed.
Fish and shellfish consumption has increased worldwide, and there are increasing reports of adverse reactions to fish and shellfish, with an approximate prevalence of 0.5-5%. Fish allergy often develops early in life, whilst shellfish allergy tends to develop later, from adolescence onwards. Little is known about the natural history of these allergies, but both are thought to be persistent. The clinical manifestations of shellfish allergy, in particular, may vary from local to life-threatening 'anaphylactic' reactions within an individual and between individuals. Parvalbumin and tropomyosin are the two major allergens, but several other allergens have been cloned and described. These allergens are highly heat and biochemically stable, and this may in part explain the persistence of these allergies. Diagnosis requires a thorough history, skin prick and in-vitro-specific IgE tests, and oral challenges may be needed for diagnostic confirmation. Strict avoidance of these allergens is the current standard of clinical care for allergic patients, and when indicated, an anaphylactic plan with an adrenaline auto-injector is prescribed. There are no published clinical trials evaluating specific oral immunotherapy for fish or shellfish allergy.
The majority of research on food allergy has been bio-medical in orientation, focusing on issues such as the molecular structure of allergens, or aimed at methods of diagnosis. In the last decade, there has been a growing interest in the development of questionnaires that measure the impact of food allergy on health-related quality of life (HRQL). These studies have provided insight into the everyday burden of living with food allergy and have suggested ways that HRQL can be improved. The EuroPrevall project (europrevall@bbsrc.ac.uk) has given great impetus to research in the area of HRQL. In addition to clinical research on the prevalence, mechanisms and causes of food allergy, research output in the area of psycho-social impact has included HRQL measures for all age groups and examination of the socio-economic impact of food allergy. In this chapter, we review the literature on the impact of food allergy on children, teens and their parents; the majority of this data was generated over the life of the EuroPrevall project. We then examine both quantitative and qualitative research findings to provide an in-depth picture of the impact of food allergy on the concerns and everyday lives of children, teens, adults and parents. Research on factors that are related to and impact HRQL is also discussed. There is a strong emphasis throughout the chapter on developmental considerations of food allergy, spanning from infants to adults. We conclude by discussing methodological issues in relation to the measurement of HRQL in relation to food allergy. We offer some recommendations for future research and practice on HRQL so that HRQL measures can reach their full potential in research, practice and policy, with the help of the findings in this review. Overall, the findings suggest that food allergy has a strong impact on HRQL in terms of social, dietary, and psychological factors. 'Rules' and restrictions ostensibly apply to food, but because food is such an integral part of everyday life, these restrictions extend far beyond 'mealtimes'. Therefore, social events are experienced differently and have a different meaning for those living with food allergy, giving rise to feelings of exclusion and difference when compared to those without allergy. Children, teens, and parents need to cope with normal developmental changes as well as with the food allergy, placing them under increased psycho-social stress and leading to adverse effects on HRQL and coping. To address and attempt to alleviate such stressors, both quantitative and qualitative research suggests that targeting uncertainty should be a major goal for health professionals working with children, teens and families with a food allergy. Remarkable similarities in response to food allergy across countries suggest that policies and programmes that address quality of life issues may be relevant to many different populations. An in-depth understanding of the relationship between a diagnosis of food allergy and HRQL, as well as the factors that impact it, will ultimately lead to the promotion of earlier, more effective preventive strategies and interventions that are focused on maximising optimal health development and quality of life.
About 17% of German children and adolescents suffer from at least one of the following atopic illnesses: allergic rhinoconjunctivitis, atopic eczema or asthma. Consistent professional therapy is necessary to limit the health-related risks and improve these medical conditions. The consequences of a diagnosis often mean an additional task for the parents of diseased children, where they have to act simultaneously as an educator and therapist for their children. Structured educational programmes were developed for a few diseases such as asthma and atopic eczema in order to prepare parents and affected children to accept this important responsibility. Moreover, a structured programme for anaphylaxis is being developed. These proposals aim not only to transfer knowledge about the disease but also to effectively support self-reliant treatment and emotional coping with the disease as well as its collateral strain.
Accurately diagnosing patients with suspected food allergy is obviously critically important. The patient's health may be compromised if problem foods are left in the diet, while nutrition and quality of life may be negatively affected if foods are unnecessarily removed from the diet. In some patients, the diagnosis is very straightforward, such as with anaphylaxis with the first known exposure to peanut, but in many cases, the diagnosis will not be clear based on the history, skin tests, and serologic tests, especially because these tests often yield falsely positive results. In these instances, further testing will be needed, typically including diagnostic elimination diets and/or oral food challenges, which are the gold standard for the diagnosis of food allergy.
Molecular allergology is a breakthrough science that enables the quantification of IgE antibodies against individual allergen protein components at the molecular level. The diagnosis of IgE-mediated allergic disorders is based on the clinical history and on sensitization demonstrated through an allergy test. Identifying whether the sensitization is primary (species specific) or due to cross-reactivity with proteins with similar protein structures helps the clinician to judge the risk of allergic reaction. This is possible today because allergen component tests for food allergy are now available for clinicians to use in everyday practice.
The labeling of allergenic foods is an important public health measure to assist food-allergic consumers in avoiding foods that can cause allergic reactions. The regulatory framework for such labeling depends upon the selection of priority allergenic foods, which vary among countries. Most countries include milk, eggs, fish, crustacean shellfish, peanuts, tree nuts, soybeans, and cereal sources of gluten on the priority allergenic foods list, as recommended by the Codex Alimentarius Commission. However, a variety of other foods appear on the priority lists of some countries but not on others. Sesame seeds, molluscan shellfish, buckwheat, and mustard are identified in two or more countries. In most countries, all ingredients derived from these priority allergen sources must also be declared on labels by source. However, exemptions exist for some ingredients in some countries but not in others. Detection methods are critical for the enforcement of allergen labeling regulations and for the investigation of allergic reactions in the community by public health officials. The development of detection methods has advanced considerably over the past several decades and will be briefly reviewed in this chapter. Because of the emphasis on labeling and the development of detection methods, the ingredient statement on packaged food labels now contains more information than ever before to assist food-allergic consumers.
Despite a trend towards delayed weaning, food allergies (FAs) have increased in the past few decades and are now considered a public health concern, resulting in significant morbidity as well as occasional mortality. Whilst genetic factors are clearly important in the development of FA, a rise in FAs has occurred over a short period of time and is therefore unlikely to be due to germ-line genetic changes alone. Thus, it seems plausible that one or more environmental exposures may, via epigenetic changes, result in the interruption of the 'default immunologic state' of tolerance to foods. Strategies are therefore required for the prevention of FA: primary prevention seeks to prevent the onset of IgE-sensitisation; secondary prevention seeks to interrupt the development of FA in IgE-sensitised children; and tertiary prevention seeks to reduce the expression of 'end-organ' allergic disease in children with established FA. This chapter will outline the major findings in this field, with the aim of equipping the clinician with an evidence-based approach to a burgeoning yet poorly understood clinical problem. We also highlight the methodological challenges hindering the interpretation of existing FA studies. Fortunately, there are now robust studies underway, the results of which are expected to guide public health recommendations with respect to how and when to introduce major allergenic foods to children, regardless of allergic risk.
The currently known food allergens are assigned to a relatively small number of protein families. Food allergens grouped into protein families share common functional and structural features that can be attributed to the allergenic potency and potential cross-reactivity of certain proteins. Molecular data, in terms of structural information, biochemical characteristics and clinical relevance for each known allergen, including isoforms and variants, are mainly compiled into four open-access databases. Allergens are designated according to defined criteria by the World Health Organization and the International Union of Immunological Societies Allergen Nomenclature Sub-committee. Food allergies are caused by primary sensitisation to the disease-eliciting food allergens (class I food allergen), or they can be elicited as a consequence of a primary sensitisation to inhalant allergens and subsequent IgE cross-reaction to homologous proteins in food (class II food allergens). Class I and class II allergens display different clinical significance in children and adults and are characterised by different molecular features. In line with this, high stability when exposed to gastrointestinal digestion and heat treatment is attributed to many class I food allergens that frequently induce severe reactions. The stability of a food allergen is determined by its molecular characteristics and can be influenced by structural (chemical) modifications due to thermal processing. Moreover, the immunogenicity and allergenicity of food allergens further depends on specific T cell and B cell epitopes. Although the T cell epitope pattern can be highly diverse for individual patients, several immuno-prominent T cell epitopes have been identified. Such conserved T cell epitopes and IgE cross-reactive B cell epitopes contribute to cross-reactivity between food allergens of the same family and to clinical cross-reactivity, similar to the birch pollen-food syndrome.
Given its increasing prevalence and potential severity, food allergy not only negatively impacts the health and quality of life of affected individuals but also carries a significant economic burden. To address these problems, a community approach including efforts to increase awareness of food allergy among the general public and the implementation of appropriate public policies to keep affected individuals safe is required. This chapter reviews the general public's knowledge and perceptions of food allergy, the disease's psychosocial impact on affected individuals, and the current state and future directions of food allergy public policy.
Egg allergy is one of the most frequent food allergies in infants and young children. The prevalence of egg allergy is estimated to be between 1.8 and 2% in children younger than 5 years of age. The reactions are mainly mediated by IgE and partially by non-IgE or are a mix of both types. Egg white contains more than 20 different proteins and glycoproteins. Ovomucoid (Gal d 1), ovalbumin (Gal d 2), conalbumin (ovotransferrin) (Gal d 3) and lysozyme (Gal d 4) have been identified as major allergens in hen's egg. Alpha-livetin (Gal d 5) is thought to be a main egg yolk allergen responsible for bird-egg syndrome. The diagnosis of egg allergy is based on history taking, antigen-specific IgE measurements, such as the skin prick test, in vitro antigen-specific blood IgE tests and histamine release tests, and oral food challenges. The measurements of specific IgE to ovomucoid and its linear epitopes are more useful in the diagnosis of heated egg allergy and in the prediction of prognosis. Currently, the management of egg allergy is essentially minimal elimination based on the correct identification of the causative allergen. Although oral immunotherapy is promising as a tolerance induction protocol, several questions and concerns still remain, predominantly regarding safety.
The diagnosis of food allergy requires responses to two important questions: Does the patient have a food allergy? If so, which foods will elicit allergic symptoms? The first question will most often have to be answered following a physical examination and an interview with the patient and/or caretakers. Based on this, a provisional decision to pursue a food allergy diagnosis may be made after carefully considering other possible reasons for an adverse reaction to a food: aversion, infection, intoxication, or an underlying metabolic disease. To respond to the next question, the anamnesis is highly important in selecting which tests and, ultimately, oral food challenges the patient should undergo to reach the final diagnosis. For the diagnosing doctor, it is important to know and consider the regional pattern of inhalation and food allergies, the food consumption patterns in the local community, and the selection of patients--in terms of both age groups and symptoms--visiting the center.
