Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food and is distinct from food intolerance. Clinical manifestations of food allergy are varied and involve many systems including respiratory, cutaneous, and gastrointestinal. The double-blinded placebo-controlled oral food challenge remains the gold standard for the diagnosis of IgE-mediated food allergy. Areas of ongoing research include improved understanding of determinants for the development of tolerance versus sensitization for foods, the role of diagnostic testing for specific epitopes for food allergens, and the use of oral immunotherapy for IgE-mediated food allergy.
Food allergies are immunologically mediated phenomena that may involve immediate or delayed symptoms and result in both acute and chronic disease. Food allergies not only affect quality of life, but can be potentially fatal. Diagnosis currently relies on a careful history and an appreciation of epidemiologic aspects of the disorder; the role and limitation of simple diagnostic tests; and if needed, the use of an oral food challenge to confirm allergy or tolerance.
Although an understanding of food allergies has increased in the past decade, knowledge about the epidemiology and causes of food allergy remains limited. In general, it is recognized that food allergy represents an abnormal response of the mucosal immune system to antigens delivered through the oral route. The mucosal immune system regularly encounters enormous quantities of antigen and must suppress immune reactivity to food and harmless foreign organisms. Even though intact foreign food antigens routinely penetrate the gastrointestinal (GI) tract, they infrequently induce clinical symptoms because tolerance develops in most individuals.
To help differentiate food allergies from adverse food reactions, the recently published Guidelines for the Diagnosis and Management of Food Allergy by the National Institutes of Health (NIH) have recommended that the term “food allergy” be used to describe an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. The guidelines further define a “food” as any substance that is intended for human consumption including chewing gum, drinks, food additives, and dietary supplements. Substances used only as drugs, tobacco products, and cosmetics that may be ingested are not included.
“Food allergens” are defined as those specific components of food or ingredients within food (typically proteins, but sometimes also chemical haptens) that are recognized by allergen-specific immune cells and elicit specific immunologic reactions resulting in characteristic symptoms. Foods or food components that elicit reproducible adverse reactions but do not have established immunologic mechanisms are not considered food allergens.
It is conceptually helpful to categorize food-induced allergic disorders based on immunopathology among those that are IgE-mediated, non–IgE-mediated, mixed IgE- and non–IgE-mediated, and cell-mediated. IgE-mediated reactions are characterized by immediate allergic reactions, which can involve the skin; respiratory tract; GI tract; or generalized reactions, such as anaphylaxis. In most of these patients, serum food-specific IgE antibodies can be measured that, in conjunction with specific signs and symptoms on exposure to the specific food, confirm the IgE-mediated pattern of the reaction. Symptoms of IgE-mediated food allergy typically occur within minutes to hours of the ingested food.
Non–IgE-mediated GI diseases are often classified as dietary protein enteropathies. Dietary protein enterocolitis and celiac disease are the most common forms. Celiac disease is characterized by villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytes, and a mixed inflammatory infiltrate. Dietary protein enterocolitis and enteropathy are typically caused by cow’s milk or soy protein and cause variable small or large bowel injury associated with nonspecific villous atrophy and inflammation.
Mixed IgE and non-IgE mediated disorders include the eosinophilic gastroenteropathies of eosinophilic protocolitis, eosinophilic gastroenteritis, and eosinophilic esophagitis. These diseases are characterized by infiltration of the GI tract with eosinophils with an absence of other inflammatory cells. The eosinophils may infiltrate the mucosa, the muscular layer, and the serosa.
Cell-mediated skin reactions to foods include contact dermatitis and dermatitis herpetiforme. Atopic dermatitis is considered a mixed IgE and cell-mediated reaction that can be triggered by ingestion of foods to which the patient is sensitized. Several studies involving standardized exposure to food by double-blind, placebo-controlled food challenges (DBPCFC) have carefully characterized these manifestations of food allergy occurring in up to 40% of children with moderate to severe atopic dermatitis.
An understanding of these categories of food-induced allergic disorders is important for the otolaryngologist because many patients with upper airway inflammatory disease are atopic and at increased risk for having concomitant food allergy. Food allergy seems to be increasing and the otolaryngologist is likely to encounter an increasing number of patients with various manifestations of food allergy. Thus, an awareness of basic definitions, categories of food allergy and clinical manifestations, and familiarity with diagnostic testing and treatment strategies for food allergy, will engender quality comprehensive patient care. This article provides a review of the epidemiology, pathophysiology, clinical manifestations, diagnosis, and treatment of food allergy focusing primarily on IgE-mediated disease.
Epidemiology
Knowledge of the epidemiology of food allergy is essential in directing the otolaryngologist’s evaluation of a patient with possible food allergy. Interestingly, the prevalence of food allergies is greatest in the first few years of life, affecting about 6% of infants less than 3 years of age and decreasing over the first two decades. Although genetic risk factors are not solely responsible for the incidence of food allergy, there are genetic predisposing factors for its development, just as there are genetic factors that predispose toward other atopic diseases.
In the case of peanut allergy, a child has a seven-fold increase in the risk of peanut allergy if he or she has a parent or sibling with peanut allergy. It has been shown that in monozygotic twins, a child has a 64% likelihood of peanut allergy if his or her twin sibling has peanut allergy. This indicates a strong genetic contribution to peanut allergy.
The expression of genetic predisposition seems to be influenced by environmental factors, such as molecular characteristics of the food antigen and the timing and route of exposure. Evidence supporting the hypothesis that the timing of exposure to foods is important includes a recent study showing Israeli Jewish children of school age (consumption of peanut at ages 8–14 months was 7.1 g) had peanut allergy rates of 0.17%, compared with Jewish children in the United Kingdom (consumption of peanut at ages 8–14 months was 0 g) where the rate of peanut allergy was 10-fold higher (1.85%). This study supports the theory that early oral exposure to peanut might promote tolerance, and that perhaps in the absence of oral tolerance sensitization occurs.
There is a well-documented association between food allergy and other atopic diseases. Highlighting the importance of food allergy to the otolaryngologist, there is a strong association between food allergy and allergic rhinitis noted in the literature. Bozkurt and coworkers showed that food allergy was the most common coexisting atopic condition in adult rhinitis patients. In a recent study by Sahin-Yilmaz and colleagues aimed at evaluating the prevalence of IgE-mediated food allergy among adults with allergic rhinitis, a 23.4% prevalence of peanut sensitization was observed.
There is also a well-documented link between the presence of early eczema in childhood and the development of food allergy. About 33% of children with infantile eczema have IgE-mediated food allergy. Eczema severity in the first year of life is associated with the development of egg, milk, and peanut allergies. The presence of eczema in the first 6 months of life was associated with an increased risk of peanut allergy, and this risk increased with more severe eczema. More recently, a study of 2184 infants showed that the risk of egg, milk, or peanut allergy was approximately twice as high if eczema was present in the first 6 months of life compared with the second 6 months of life.
Food allergy rates vary by age, local diet, and many other factors. The prevalence of food allergy is difficult to establish because of the lack of studies applying reliable diagnostic methodologies, inconsistencies in reporting, and variations in the definition of food allergy. Despite these challenges to accurate epidemiology, most studies suggest individual food allergies have increased over the last decade, and there clearly is the impression that new food allergies are increasing in prevalence, particularly kiwi allergy and sesame seed allergy.
A 2008 Centers for Disease Control and Prevention report indicated an 18% increase in childhood food allergy from 1997 to 2007, with an estimated 3.9% of children currently affected. Recent studies focusing on peanut indicate that the prevalence rates in children have increased, essentially doubling, and exceed 1% of school-aged children.
Although an allergy could be triggered by virtually any food, a small number of foods account for most food allergies. In young children the most common causal foods are cow’s milk (2.5%); egg (1.3%); peanut (0.8%); wheat (0.4%); soy (0.4%); tree nuts (0.2%); fish (0.1%); and shellfish (0.1%). Historically, studies indicated that childhood food allergies typically resolve by age 5 years, but more recent studies reveal that rates of resolution may be significantly slower. Although this may be affected by selection bias (because of the referral patterns to academic centers, which may draw patients with more severe and persistent disease), recent studies show resolution for cow’s milk allergy at 79% by age 16 years and for egg allergy at 68% by 16 years. In contrast to milk and egg allergy, only 20% of children develop tolerance to peanut and less than 10% outgrow allergy to tree nuts.
Accordingly, adults are more likely to have allergies to shellfish (2%); peanut (0.6%); tree nuts (0.5%); and fish (0.4%). The clinician must also consider a variety of adverse reactions to foods that are not food allergies. Although up to 25% of adults report symptoms that may be related to certain foods, the prevalence of food allergies among adults is less than 3%, making self-reporting of food allergy highly inaccurate. It is estimated that more than 20% of adults and children alter their diets based on these perceptions.
Adverse food reactions that are not classified as food allergies include host-specific metabolic disorders, such as lactose intolerance, galactosemia, and alcohol intolerance. Individuals may also experience a response to a pharmacologically active component in food, such as caffeine. Other examples include tyramine in aged cheeses triggering migraine headaches and histaminic chemicals in the spoiled dark meat of certain fish resulting in scombroid poisoning. Toxin-mediated reactions (food poisoning) also cause food-induced symptoms.
Another challenge in determining the existence of food allergy relates to the diagnostic tools available. Simply establishing the presence of allergen-specific IgE (sensitization), whether measured in vivo (skin testing) or in vitro (IgE testing), does not independently indicate clinically relevant disease. Because sensitization may be symptomatic (as in food allergy) or asymptomatic, the latest food allergy guidelines recommend that both the presence of sensitization and the development of specific signs and symptoms on exposure to that food be present for a diagnosis of IgE-mediated food allergy.
Immunology and pathophysiology
In considering food allergy, the clinician must first determine whether the adverse reaction to food is immunologic in nature. There exist many adverse reactions to foods that are not classified as food allergies because they lack an immunologic basis. For the purposes of this review of food allergy immunology and pathophysiology, the definition of food allergy outlined by the expert panel in the NIH 2010 Guidelines for the Diagnosis and Management of Food Allergy is used. Again, the panel defines as food allergy an “adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”
Host factors, including both innate and adaptive immunity, are thought to contribute to the development of food allergy. Nonhost factors, such as dosing and frequency of exposure, may also play a role in the pathophysiology of food allergy.
Food allergy represents an abrogation of normal oral tolerance. The GI mucosa encounters large quantities of non–self antigen. While processing and absorbing nutrients, the GI immune system is also determining which non–self antigens are harmful. GI innate immune factors include the physical barrier of the gut, intestinal enzymes, and pH maintenance, and natural killer cells, macrophages, and toll-like receptors. Adaptive factors include lymphocytes, Peyer patches, specific IgA, and cytokines that drive a specific response to antigen. Developmental immaturity of these various components, particularly altered intestinal permeability, poorly maintained gut pH, and immature secretory IgA, have all been highlighted as possible factors in the development of sensitization and food allergy in early childhood.
Several cell types have been identified as playing an important role in developing oral tolerance. Suppressor CD8 + cells and natural killer cells have been shown to be mediators of tolerance. Additionally, several groupings of regulatory CD4 + T cells, including TH3 cells, TR1 cells, and CD4 + and CD25 + cells, seem to play an important role in intestinal immunity.
Nonhost factors, or antigen-related factors, including the dose, frequency, and form of the antigen, may affect the balance of antigen sensitization or tolerance. It has been theorized that high-dose antigen challenges result in a state of lymphocyte anergy, promoting tolerance. Investigation of low-dose antigen challenges suggests a role for regulatory T cells inducing a state of tolerance. The properties of the antigen also seem to play a role in tolerance induction. Antigen qualities that may affect sensitization include solubility, cross reactivity with pollen, and extraintestinal exposure.
Murine studies and evidence from human epidemiologic studies indicate that such allergens as egg and peanut might evade oral tolerance by initial sensitizing exposure through the skin. Interestingly, symptoms of peanut allergy have been noted to occur on the first known peanut exposure in an estimated 75% of patients, supporting the theory that the initial sensitizing exposure may actually bypass the gut. The argument that epicutaneous exposure contributes to the development of allergy, particularly peanut allergy, has been supported by the correlation of peanut allergy with exposure to topical application of oils containing peanut protein. These investigations into alternate routes of sensitization remain ongoing areas of research. Defects of the skin barrier, as seen in atopic dermatitis, have been suggested to allow easier extraintestinal sensitization, which bypasses oral tolerance.
Additional host-related factors include genetics, age, and host flora. Murine models have demonstrated support for genetic influence on the development of food allergy. Studies in human subjects have been more elusive, partially because of difficulties in experimental design. Age has also been identified as a factor that may contribute to oral tolerance. Eastham and coworkers showed stronger immunologic reactions to dietary antigens in infants 3 months and younger and attributed this phenomena to immature gut permeability. Host flora also seem to contribute to oral tolerance development. The importance of commensal flora has been supported by the finding that administering lactobacillus to cow’s milk–allergic children with atopic dermatitis improved their eczema.
With an understanding of the basic immunology and pathophysiology of food allergy, the clinician must next focus attention on the variable manifestations of food allergy. There are several frameworks for categorizing the clinical manifestations of food allergy. Food allergy can be categorized based on pathophysiologic mechanisms, specifically IgE-mediated and non–IgE-mediated disorders. Food allergies may also be categorized by severity. Finally, an alternate means of conceptualizing food allergy focuses attention on the primary system involved. Although these groupings are commonly used in the literature, there is no agreed on uniform classification. Despite limitations, a systems-based approach is used for the purposes of this article.
Immunology and pathophysiology
In considering food allergy, the clinician must first determine whether the adverse reaction to food is immunologic in nature. There exist many adverse reactions to foods that are not classified as food allergies because they lack an immunologic basis. For the purposes of this review of food allergy immunology and pathophysiology, the definition of food allergy outlined by the expert panel in the NIH 2010 Guidelines for the Diagnosis and Management of Food Allergy is used. Again, the panel defines as food allergy an “adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”
Host factors, including both innate and adaptive immunity, are thought to contribute to the development of food allergy. Nonhost factors, such as dosing and frequency of exposure, may also play a role in the pathophysiology of food allergy.
Food allergy represents an abrogation of normal oral tolerance. The GI mucosa encounters large quantities of non–self antigen. While processing and absorbing nutrients, the GI immune system is also determining which non–self antigens are harmful. GI innate immune factors include the physical barrier of the gut, intestinal enzymes, and pH maintenance, and natural killer cells, macrophages, and toll-like receptors. Adaptive factors include lymphocytes, Peyer patches, specific IgA, and cytokines that drive a specific response to antigen. Developmental immaturity of these various components, particularly altered intestinal permeability, poorly maintained gut pH, and immature secretory IgA, have all been highlighted as possible factors in the development of sensitization and food allergy in early childhood.
Several cell types have been identified as playing an important role in developing oral tolerance. Suppressor CD8 + cells and natural killer cells have been shown to be mediators of tolerance. Additionally, several groupings of regulatory CD4 + T cells, including TH3 cells, TR1 cells, and CD4 + and CD25 + cells, seem to play an important role in intestinal immunity.
Nonhost factors, or antigen-related factors, including the dose, frequency, and form of the antigen, may affect the balance of antigen sensitization or tolerance. It has been theorized that high-dose antigen challenges result in a state of lymphocyte anergy, promoting tolerance. Investigation of low-dose antigen challenges suggests a role for regulatory T cells inducing a state of tolerance. The properties of the antigen also seem to play a role in tolerance induction. Antigen qualities that may affect sensitization include solubility, cross reactivity with pollen, and extraintestinal exposure.
Murine studies and evidence from human epidemiologic studies indicate that such allergens as egg and peanut might evade oral tolerance by initial sensitizing exposure through the skin. Interestingly, symptoms of peanut allergy have been noted to occur on the first known peanut exposure in an estimated 75% of patients, supporting the theory that the initial sensitizing exposure may actually bypass the gut. The argument that epicutaneous exposure contributes to the development of allergy, particularly peanut allergy, has been supported by the correlation of peanut allergy with exposure to topical application of oils containing peanut protein. These investigations into alternate routes of sensitization remain ongoing areas of research. Defects of the skin barrier, as seen in atopic dermatitis, have been suggested to allow easier extraintestinal sensitization, which bypasses oral tolerance.
Additional host-related factors include genetics, age, and host flora. Murine models have demonstrated support for genetic influence on the development of food allergy. Studies in human subjects have been more elusive, partially because of difficulties in experimental design. Age has also been identified as a factor that may contribute to oral tolerance. Eastham and coworkers showed stronger immunologic reactions to dietary antigens in infants 3 months and younger and attributed this phenomena to immature gut permeability. Host flora also seem to contribute to oral tolerance development. The importance of commensal flora has been supported by the finding that administering lactobacillus to cow’s milk–allergic children with atopic dermatitis improved their eczema.
With an understanding of the basic immunology and pathophysiology of food allergy, the clinician must next focus attention on the variable manifestations of food allergy. There are several frameworks for categorizing the clinical manifestations of food allergy. Food allergy can be categorized based on pathophysiologic mechanisms, specifically IgE-mediated and non–IgE-mediated disorders. Food allergies may also be categorized by severity. Finally, an alternate means of conceptualizing food allergy focuses attention on the primary system involved. Although these groupings are commonly used in the literature, there is no agreed on uniform classification. Despite limitations, a systems-based approach is used for the purposes of this article.
Clinical manifestations
The clinical picture of food allergy can be quite varied making the diagnosis of food allergy challenging. The clinician must exclude adverse reactions to food that are not true food allergies. Examples of these include lactose intolerance; scombroid poisoning; and pharmacologic reactions to components in food, such as tyramine or caffeine. Once such adverse reactions are considered and excluded, the diagnosis of food allergy continues to be challenging because the clinical manifestations can be so varied.
Food-induced Anaphylaxis
Perhaps most familiar for the otolaryngologist is the IgE-mediated clinical presentation of anaphylaxis, which can be associated with food ingestion. Consideration of food allergy in the evaluation of any anaphylactic event is important because food allergy has been recognized as the leading cause of outpatient anaphylaxis in most surveys. Failure to recognize a food as an anaphylactic trigger may result in serious morbidity and mortality.
Typically occurring in close temporal proximity to a food ingestion, food-induced anaphylaxis is IgE-mediated and affects multiple organ systems. There are no universally accepted diagnostic criteria or reliable biomarkers to facilitate the diagnosis of anaphylaxis. Cutaneous manifestations are common, occurring in 80% of individuals with anaphylaxis, and may include acute-onset urticaria or angioedema. Respiratory compromise with dyspnea or wheezing and cardiovascular manifestations including hypotension and tachycardia may also occur. There are rare reports of isolated hypotension as the primary manifestation of anaphylaxis, yet cardiovascular symptoms occur less frequently in food-induced anaphylaxis.
Familiarity with the manifestations of anaphylaxis and recognition of the appropriate trigger are essential in caring for the food-allergic patient. Food-induced anaphylaxis can be life-threatening; however, it is a treatable and largely preventable manifestation of allergic disease. Most patients with food-induced anaphylaxis are aware of their food allergies, which highlights the importance of patient education and avoidance once the diagnosis is established.
Cutaneous Food Hypersensitivities
Reactions involving the skin or mucus membranes are among some of the most common manifestations of food allergy. Acute urticaria and angioedema can be IgE mediated and are sometimes related to food allergy. Atopic dermatitis is also associated with food allergy, and its pathophysiology is more complex. A mixed reaction including both cellular and IgE-mediated responses to foods induces atopic dermatitis. The role of food allergy in the pathophysiology of atopic dermatitis continues to be controversial ; however, there does seem to be induction of urticarial lesions and itching associated with ingestion of specific food allergens, particularly in infants and young children.
GI Food Hypersensitivities
A broad spectrum of GI food hypersensitivities has been described and there is some overlap between these various conditions. Oral allergy syndrome most commonly affects patients who are allergic to cross reactive inhalant allergens. An IgE-mediated allergic reaction, oral allergy syndrome is characterized by itching or swelling of the mucus membranes of the oral cavity and is usually associated with ingestion of plant proteins, which cross react with inhalant allergens. Common examples include patients with birch allergy may have symptoms after ingesting apples, pears, or hazelnuts; similarly, patients with ragweed allergy may have oral allergy symptoms after ingestion of fresh melon.
Immediate GI hypersensitivity, or GI anaphylaxis, is also IgE-mediated and presents with symptoms of nausea, vomiting, and abdominal pain. Most commonly, acute vomiting occurs rapidly with exposure to the food trigger.
Eosinophilic esophagitis seems to be mediated by both IgE and non-IgE mechanisms and is characterized by eosinophilic inflammation of the esophagus. In infants and young children, the clinical presentation can be quite varied and may include weight loss, vomiting, reflux symptoms, or failure to thrive. Adults tend to present with such symptoms as esophageal food impaction and dysphagia. Diagnosis is made by biopsy and the exact role of food allergy in its pathogenesis remains unclear.
Eosinophilic gastroenteritis is also mediated by both IgE and non-IgE mechanisms and is characterized by eosinophilic infiltration of localized or widespread lengths of the GI tract. Clinical manifestations correlate with the location and extent of eosinophilic infiltration but range from abdominal pain, vomiting, diarrhea, and blood in the stool. Presentation in infants may actually be pyloric outlet obstruction with projectile vomiting. Although commonly associated with food allergy, the true role of food allergy in its pathogenesis remains unclear as is also the case in eosinophilic esophagitis.
Food protein-induced proctocolitis typically appears in early infancy and is characterized by gross or microscopic blood in the stool. Unique from other disorders, infants are otherwise healthy and asymptomatic. This clinical entity seems to be associated with non-IgE mechanisms because IgE to specific foods is most typically absent. A causal relationship is inferred from a typical history related to specific exposures. It is thought to be related to ingestion of milk or soy proteins transmitted either via formula or maternal breast milk. Unfortunately, there are no specific diagnostic tests for this clinical entity.
Food protein-induced enterocolitis syndrome is similarly a non–IgE-mediated food hypersensitivity reaction characterized most typically by vomiting and diarrhea leading to dehydration in infants. The pathophysiology is believed to be a cell-mediated reaction to cow’s milk or soy proteins. A similar syndrome is described in adults, which is most commonly associated with shellfish ingestion.
Respiratory Food Hypersensitivities
Although food allergy can induce acute respiratory symptoms associated with anaphylaxis, isolated respiratory manifestations of food allergy are uncommon. Both allergic rhinitis (upper airway) and asthma (lower airway) can be exacerbated by food allergy. It has been well documented that worsening of chronic asthma can occur after the ingestion of particular foods in sensitized subjects and food allergy has been noted to be an independent risk factor for severe life-threatening asthma.
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