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ALLERGIES. Food allergy has been recognized since the time of Hippocrates. People with adverse reactions to food can be difficult to evaluate because overlap exists between true food allergy and toxic and other reactions to chemicals or other food ingredients. The incidence of food allergy is increasing in the industrialized world, raising questions about the interactive effects between environmental and genetic factors. There is a considerable burden on society in terms of cost of treatment, death from anaphylactic reactions, and the anxiety produced by real or perceived food allergy. Avoidance of the food is the current treatment, but new strategies are being developed.

Definitions

Adverse reactions to the ingestion of food that can be reproduced is termed intolerance or hypersensitivity. Since this does not imply an underlying cause, it may encompass immune or nonimmune mechanisms. For example, chemicals such as caffeine may cause reproducible symptoms, but this is not mediated by the immune system. True food allergy or food hypersensitivity is defined as a reproducible adverse reaction to food caused by the immune system creating antibodies or cellular inflammation.

Type I IgE-mediated food allergy. The classic example is immediate anaphylactic reaction to food. In susceptible individuals after exposure to the food, the immune system creates specific IgE antibodies to that food. IgE is produced by the immune system's B-lymphocytes, and is bound to receptors on the surface of mast cells. Mast cells reside in tissues at body surfaces such as the skin, eyes, nose, throat, lung, and gastrointestinal tract. Mast cells are made up of granules containing chemicals including histamine. When the food protein contacts and binds to adjacent specific IgE molecules at the mast cell surface, a cascade of events occurs leading to degranulation of mast cells and release of chemicals that cause the allergic reaction. This may include skin hives, airway swelling, wheezing, abdominal pain, vomiting and/or diarrhea. This may progress to anaphylaxis, shock, and even death. This reactivity to food can be demonstrated by skin-prick tests, which have been used to diagnose allergy since the 1870s. Food protein is placed on the skin, the skin is scratched or pricked, and a hive will develop in the presence of skin mast cells with IgE directed against the food. In the 1920s Prausnitz and Kustner showed that a substance circulating in the blood of the allergic individual was responsible for a positive skin test, because blood serum could be transferred to the skin of a nonallergic individual resulting in a positive skin test. IgE is that substance, and food-specific IgE can be measured directly in the blood, by means of the IgE RAST (radioallergosorbent) test. Diagnosis of this immediate type of food allergy rests on the history of rapid onset of symptoms, demonstration of positive skin-prick test or specific IgE RAST. Challenging an individual with the food is the ultimate way to prove a food allergy.

Non-IgE-mediated food allergy. Other immune mechanisms can be responsible for allergic reactions to foods. The classic example is celiac disease (celiac sprue or gluten-induced enteropathy). This is an immune system reaction to wheat (gluten). Patients do not have IgE antibody directed against wheat, but exposure to gluten over a period of time causes inflammation of the intestine and a characteristic atrophy or flattening of the normal intestinal villous folds. The diagnosis rests on the characteristic biopsy of the small intestine coupled with another type of antibody (IgA) against wheat protein. Any food may also cause similar intestinal inflammation, leading to varying symptoms and signs depending on the area of the intestine affected. Unlike IgE-mediated allergy or celiac disease, there are no readily available confirmatory tests for these other food allergies.

Prevalence

Food allergy is perceived as being common; however, large studies support the idea that true food allergy is less common than people think. A study of 480 infants from birth to age three revealed 28 percent were suspected by their parents as having food allergy; however, this was confirmed in only 8 percent of this group. The prevalence then decreases with age. Twenty percent of adults suspect food allergy, though allergy is confirmed in only 1 to 2 percent of adults. Although food allergies in adults tend to persist with age, many infants and children out-grow them with time.

Recently, interest has grown over the apparent increase in the prevalence and severity of food allergy. This has paralleled an increase in other atopic disorders such as asthma in industrialized nations compared with children of similar genetic background in developing countries (atopic refers to a tendency to develop allergic conditions such as hay fever, asthma, or food allergies). The "hygiene hypothesis" contends that through evolution, the human immune system has developed with a specific microbial environment, and reduced exposure to microbes in the developed world may lead to increased allergic response. Further study is needed.

Type I Immediate (IgE-Mediated) Hypersensitivity Reactions to Food

Immediate hypersensitivity reactions to foods are most common in young children, with 50 percent of these reactions occurring in the first year of life. The majority is from cow's milk and soy protein from infant formulas. Other foods begin to predominate in older children, including eggs, fish, peanuts, and wheat, and along with milk and soy account for over 90 percent of food allergy in children. Peanut, tree nut, and shellfish allergy predominate in adults. Exposures may occur inadvertently due to improper labeling, changes in product composition with time, and contamination of foods during processing. Symptoms from multiple organ systems may occur, beginning within minutes. Unfortunately, fatal anaphylactic reactions (shock) to food occur despite strict dietary avoidance and treatment of reactions. Families, caregivers, and individuals with a history of anaphylaxis to food require education in diet and in the use of self-administered epinephrine. Individuals should be observed in a hospital setting after a significant reaction. Exercise-induced anaphylaxis to food occurs when the combination of ingesting the food followed by exercise leads to anaphylaxis. Oral allergy syndrome describes symptoms of itching of the mouth and throat often attributable to eating fruits, and typically does not progress. Chronic hives or urticaria can be caused by foods, but it is a common misconception that these conditions are usually food-related; only in 1 to 2 percent of cases is urticaria or chronic hives a reaction to food. Atopic dermatitis (AD) or eczema is a chronic skin condition found in atopic individuals. Patients with AD have a 30 to 40 percent prevalence of food allergy.

Investigation and treatment of type I immediate reactions to food. The rapid onset of symptoms after ingestion correlates highly with positive skin-prick or IgE RAST tests to the offending food, making confirmation of immediate hypersensitivity straightforward. Consultation with an allergist and dietitian is recommended. Groups such as the Food Allergy and Anaphylaxis Network can provide support and educational materials.

Non-IgE-Mediated Food Allergy

The spectrum of non-IgE food allergy is quite varied, and the symptoms often parallel the area of inflammation in the gastrointestinal tract (see sidebar). Avoidance of the food will resolve symptoms and intestinal inflammation; rechallenge with the food will reproduce the injury. However, unlike IgE food allergy, symptoms may take days or weeks to resolve or reappear with elimination or exposure respectively, making evaluation even more difficult.

Celiac disease or gluten-induced enteropathy (see sidebar) is a chronic intestinal condition caused by non-IgE mediated allergy to gluten, a protein in wheat and other grains. Chronic exposure to gluten causes inflammation and atrophy of small intestinal folds, leading to symptoms of malabsorption of food. Typically, patients have diarrhea, weight loss, and abdominal bloating. There is a genetic predisposition to celiac disease, but onset may occur at any age, suggesting an environmental factor such as infection may be needed in some individuals to trigger the inflammatory process. The disease has a higher prevalence (up to 1 in 400–500) in individuals of eastern European descent. Celiac disease is associated with a skin condition (dermatitis herpetiformis), thyroid disease, diabetes, and Down syndrome.

Allergic or eosinophilic colitis in infants is a common manifestation of non-IgE food protein allergy. It is characterized by diarrhea with blood and mucus. It is caused by milk or soy formula and may occur in breast-fed infants from dietary antigens transmitted through breast milk. Colon biopsy shows allergic inflammation.

Food protein-induced enterocolitis is a severe reaction to food, often delayed four to six hours, without evidence of IgE. Patients present with lethargy, vomiting, and diarrhea. Recovery is within six to eight hours after fluid resuscitation. A careful history usually reveals the offending food, although this may not be appreciated unless multiple episodes occur.

Chronic enteropathy from food allergy can also lead to inflammation with villous atrophy similar to celiac disease. Most patients have diarrhea, in addition to weight loss, anemia, and low albumin from protein loss from the intestine.

Allergic gastritis is inflammation of the stomach with pain and vomiting. As with other non-IgE food allergy, biopsies of the stomach demonstrate allergic (eosinophilic) inflammation.

Allergic esophagitis is characterized by intense eosinophilia of the esophagus on biopsy. Patients complain of pain and problems with swallowing, even to the point of having food impactions in the esophagus. Treatment with hypoallergenic formula has been shown to improve esophagitis in infants; however, older children and adults may require corticosteroid medication.

Infantile colic and excessive irritability can be symptoms related to allergy in a subgroup of infants. By definition, colic is a condition with increased crying behavior in infants, for which no cause can be found. However, since allergy can potentially lead to inflammation and pain, formula allergy is often considered.

Attempts have been made to associate a variety of other problems with food allergy including joint disease, migraine, and behavioral and developmental disorders such as autism. Causal relationship between food allergy and these disorders remains unproven.

Investigation and treatment of non-IgE-mediated food allergy. The diagnosis rests on the resolution of symptoms and/or biopsy findings on an elimination diet, with a return of symptoms on rechallenge. Unlike the rapid response characteristic of IgE-mediated disease, a prolonged challenge may identify delayed reactions with predominantly gastrointestinal symptoms up to six days after exposure. Elemental diets can be used to eliminate dietary protein antigens completely, then systematic rechallenge of the patient with suspected offending foods. As with IgE food allergies, avoidance of the specific food remains the mainstay of therapy.

New Frontiers

There are a number of exciting areas of research into the prevention and treatment of food allergies. Recent reports suggest that the allergic response can be altered by promoting beneficial gut flora ("probiotic therapy"). It has also been discovered that only a few sites (epitopes) on food protein molecules interact with the immune system to create an allergic reaction. Genetic engineering of foods makes it possible to alter these epitopes, creating crops that are "nonallergic." More study is needed to ensure that altering food proteins does not lead to other health concerns or different types of allergy. Other studies are under way to assess the effectiveness of promising new drug therapies for patients with food allergy.

See also Aversion to Food; Baby Food; Health and Disease; Immune System Regulation and Nutrients; Milk, Human; Proteins and Amino Acids.

Christopher J. Justinich