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Adverse food reactions can be broadly classified into 2 categories.1 The first category consists of immunologically-mediated adverse reactions to foods that are termed food allergies. Food allergies can result in disorders with an acute onset of symptoms following ingestion of the triggering food allergen (eg, anaphylaxis) and in chronic disorders (eg, atopic dermatitis). The second category is composed of adverse reactions that are not immune-mediated. An example is lactose intolerance caused by a deficiency of lactase. Adverse reactions to foods can also occur from toxic (eg, bacterial food poisoning) or pharmacologic (eg, caffeine) effects.

Food allergies are primarily the result of immune responses to food proteins.2 Normally, noninflammatory immune responses develop to ingested foods in a process called oral tolerance.3 For reasons that remain unclear, but likely include environmental and genetic factors, tolerance may be abrogated, leading to adverse immune responses. While sensitization (eg, development of an immunoglobulin E [IgE] immune response) to an allergen has been primarily assumed to occur from ingestion, this may not always be the case. For example, oral allergy syndrome (pollen-food related syndrome) describes an allergic response to specific raw fruits or vegetables that share homologous proteins with pollens; the initial route of sensitization is respiratory exposure to pollen proteins rather than oral exposure to food proteins. The skin may be another potential route of sensitization.4 IgE antibody mediated responses are the most widely recognized form of food allergy and account for acute reactions. Patients with atopy produce IgE antibodies to specific epitopes (areas of the protein) of one or more food allergens. These antibodies bind to high-affinity IgE receptors on circulating basophils and tissue mast cells present throughout the body, including the skin, gastrointestinal tract, and respiratory tract. Subsequent allergen exposure binds and cross links IgE antibodies on the cell surface, resulting in receptor activation and intracellular signaling that initiates the release of inflammatory mediators (eg, histamine) and synthesis of additional factors (eg, chemotactic factors, cytokines) that promote allergic inflammation. The effects of these mediators on surrounding tissues result in vasodilatation, smooth muscle contraction, and mucus secretion, which, in turn, are responsible for the spectrum of clinical symptoms observed during acute allergic reactions to food. Cell-mediated responses to food allergens may also mediate allergic responses, particularly in disorders with delayed or chronic symptoms. For example, food protein induced enterocolitis syndrome (FPIES), a gastrointestinal food allergy, appears to be mediated by T-cell elaboration of the cytokine tumor necrosis factor (TNF)-alpha.5 Persons with atopic dermatitis that flares with ingestion of milk have been noted to have T cells that, in vitro, express the homing receptor cutaneous lymphocyte antigen, which is thought to home the cell to the skin and mediate the

response.6 Celiac disease is the result of an immune response to gluten proteins in grains; this disorder is reviewed in the eMedicine Pediatrics article Celiac Disease. Food allergens are typically water-soluble glycoproteins resistant to heating and proteolysis with molecular weights of 10-70 kd. These characteristics facilitate the absorption of these allergens across mucosal surfaces. Numerous food allergens are purified and well-characterized, such as peanut Ara h1, Ara h2, and Ara h3; chicken egg white Gal d1, Gal d2, and Gal d3; soybean-Gly m1; fish-Gad c1; and shrimp-Pen a1. Closely related foods frequently contain allergens that crossreact immunologically (ie, lead to the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less frequently crossreact clinically.7 Recently, delayed allergic reactions to meat proteins have been attributed to reactions to carbohydrate moieties.8

General surveys report that as many as 25-30% of households consider at least 1 family member to have a food allergy.9,10 This high rate is not supported by controlled studies in which oral food challenges (a medically supervised, gradual test feeding) are used to confirm patient histories.11,12 The actual prevalence of food allergies is estimated to be 5-6% in infants and children and 3.7 % in adults.13 However, comprehensive studies that include oral food challenges are few in number. Considering allergy to milk, egg, peanut, and seafood in a meta-analysis of 6 international studies using oral food challenges, estimated rates of 1-10.8% were obtained.14 In a metaanalysis including allergy to fruits and vegetables (excluding peanut), only 6 international studies included oral food challenges, and estimates of allergy varied widely from 0.1-4.3% for fruits and tree nuts to 0.1-1.4% for vegetables to under 1% for wheat, soy, and sesame.15 Studies in the United States and the United Kingdom indicate a rise in peanut allergy among young children in the past decade.16,17 One study showed an increase of peanut allergy in children from 0.4% in 1997 to 0.8% in 2002.16 Recent studies from Canada and the United Kingdom indicate allergy rates to peanut of over 1% in children.18,19 Based upon available studies, estimations of the rate of food allergies in children have been summarized as follows for common food allergens: cow milk, 2.5%; eggs, 1.3%; peanuts, 0.8%; wheat, 0.4%; and soy, 0.4%.13 Allergic reactions to non-protein food additives are uncommon.20


Severe anaphylactic reactions, including death, can occur following the ingestion of food.21,22,23,24 Symptoms observed in a food-induced anaphylactic reaction may involve the skin, gastrointestinal tract, and respiratory tract. Frequently observed symptoms include oropharyngeal pruritus, angioedema (eg, laryngeal edema), stridor, dysphonia, cough, dyspnea, wheezing, nausea, vomiting, diarrhea, flushing, urticaria, and angioedema. Fatalities result from severe laryngeal edema, irreversible bronchospasm, refractory hypotension, or a combination thereof.

Peanuts, tree nuts, fish, and shellfish are the foods most often implicated in severe foodinduced anaphylactic reactions, though anaphylactic reactions have been reported to a wide variety of foods. Fatalities caused by reactions to milk are increasingly noted.22 Risk factors or associations for fatal food-induced anaphylaxis include: (1) the presence of asthma, especially in patients with poorly controlled disease; (2) previous episodes of anaphylaxis with the incriminated food; (3) a failure to recognize early symptoms of anaphylaxis; and (4) a delay or lack of immediate use of epinephrine to treat the allergic reaction.21,22,23,24 Teenagers and young adults appear to be overrepresented in registries of food allergy fatalities and present a special risk group.


No predilection is known.


Among children, males appear to be more affected; among adults, females are more frequently affected.16


In infants and children younger than 3 years, the prevalence of food allergy is approximately 5-6%.13 The estimated prevalence in adults is approximately 3.7%.13


Necessary elements of a thorough medical history o Develop a complete list of all foods suspected to cause symptoms. o Discuss the manner of preparation of the food (cooked, raw, added spices or other ingredients). o Determine the minimum quantity of food exposure required to cause the symptoms. o Determine the reproducibility of symptoms upon exposure to the food. o Obtain a thorough description of each reaction, including the following: The route of exposure (ingestion, skin contact, inhalation) and dose The timing of the onset of symptoms in relation to food exposure All observed symptoms and each ones severity The duration of the reaction The treatment provided and the clinical response to treatment The most recent reaction o Inquire about a personal or family history of other allergic disease.

Inquire about eliciting factors that can potentiate a food-allergic reaction (eg, exercise25 , nonsteroidal anti-inflammatory drugs [NSAIDs], alcohol)

Clinical manifestations and disorders26

Cutaneous reactions o These are the most common clinical manifestations of an allergic reaction to a food or food additive. o Symptoms range from acute urticaria (most common) to flushing to angioedema to exacerbations of atopic dermatitis. o Food allergy is rarely the cause of chronic urticaria or angioedema. Atopic dermatitis27 o Controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis. Studies show that of patients with moderate chronic atopic dermatitis, 35-40% have IgE-mediated food allergy.28,29 o Both food-specific IgE-mediated and cellular mechanisms appear responsible for chronic eczematous inflammation. o Removal of a specific food allergen leads to reduction or resolution of clinical symptoms in affected patients; reintroduction of the food exacerbates the atopic dermatitis.30,31 Reintroduction of a suspected food allergen should be performed under medical supervision because, in some instances, initial reintroduction of the food after a period of dietary elimination has resulted in more significant symptoms than were observed when the food was regularly ingested.32 o Prophylactic studies show that avoiding particular foods (eg, cow milk, eggs, peanuts) helps delay the onset of atopic dermatitis.33 Celiac disease: Celiac disease is the result of an immune response to gluten proteins in grain. This disorder is reviewed in the eMedicine Pediatrics article Celiac Disease. Dermatitis herpetiformis o This is a form of non-IgE cell-mediated hypersensitivity related to celiac disease. It is a blistering skin disorder that manifests clinically with a chronic and intensely pruritic rash with a symmetrical distribution. o Elimination of gluten from the diet usually leads to resolution of skin symptoms. IgE-mediated gastrointestinal food allergy o These food allergy reactions include immediate hypersensitivity reactions and the pollen-food allergy syndrome (oral allergy syndrome). o Specific gastrointestinal symptoms include nausea, vomiting, abdominal pain, and cramping. Diarrhea is found less frequently. Pollen-food allergy syndrome (oral allergy syndrome) o Patients with this syndrome develop itching or tingling of the lips, tongue, palate, and throat following the ingestion of certain foods. In addition, edema of the lips, tongue, and uvula and a sensation of tightness in the throat may be observed. In fewer than 3% of cases, symptoms progress to more systemic reactions, such as laryngeal edema or hypotension.34 o This syndrome is caused by cross-reactivity between certain pollen and food allergens. For example, individuals with ragweed allergy may experience oropharyngeal symptoms following the ingestion of bananas or melons, and

patients with birch pollen allergy may experience these symptoms following the ingestion of raw carrots, celery, potato, apple, peach or hazelnut. Mixed IgE/non-IgE gastrointestinal food allergy (eosinophilic esophagitis and gastroenteritis)35 o Symptoms vary according to location of eosinophilia. Typical symptoms include postprandial nausea, abdominal pain, and a sensation of early satiety. Eosinophilic esophagitis may manifest as reflux symptoms and dysphagia; food impaction can occur as well. o Children may experience weight loss or failure to thrive. o CBC count and differential findings may show eosinophilia in approximately 50% of patients; however, this is not diagnostic. Typically, endoscopy and biopsy must be performed in order to establish the presence of eosinophils in the affected segment of the gut. While a dense eosinophil infiltrate may be seen anywhere from the lower esophagus through the large bowel, involvement is patchy and variable. o An elemental (no potential allergens) or oligoantigenic diet (a diet that removes common allergenic foods) and trials of food elimination may be required to determine the role of foods in a patient's condition. Eosinophilic esophagitis does not respond to acid blockade therapy. o In addition to diet therapy (or in place of diet therapy), treatment with antiinflammatory medications (eg, corticosteroids) may be needed. NonIgE-mediated gastrointestinal food allergy o Food protein induced enterocolitis syndrome typically manifests in the first few months of life with severe projectile vomiting, diarrhea, and failure to thrive.36 o Cow milk and soy protein formulas are usually responsible for these reactions. However, solid foods may also trigger these reactions, especially rice and oats.37 o When the allergen is removed from the diet, symptoms resolve. Re-exposure prior to resolution results in a delayed (2 h) onset of vomiting, lethargy, increase in the peripheral blood polymorphonuclear leukocyte count, and, later, diarrhea. Hypotension and methemoglobinemia may occur. o Infants who are chronically ingesting the allergen typically appear lethargic, wasted, and dehydrated. The presentation may mimic sepsis. An oral food challenge may establish the diagnosis but is not always needed if the history is clear. No other definitive diagnostic tests are available. o Breastfed infants may have mucus and blood in their stool, attributed to food allergens ingested by the mother, primarily cow milk. This allergic proctocolitis does not typically lead to anemia and is not associated with vomiting or poor growth. Maternal exclusion of the allergen resolves the bleeding. Eosinophilic inflammation of the rectum is noted if a biopsy is performed.38,2 Additional causes of bleeding (eg, infection, fissures) should be considered. Upper and lower respiratory tract reactions o Upper respiratory reactions typically include nasal congestion, sneezing, nasal pruritus, or rhinorrhea. They are usually observed in conjunction with ocular, skin, or gastrointestinal symptoms. o IgE-mediated pulmonary symptoms may include laryngeal edema, cough, or bronchospasm.

Asthma39 o The role of food allergy in the pathogenesis of asthma is a controversial area of investigation. o At the National Jewish Center for Immunology and Respiratory Medicine, 67 (24%) of the 279 children with a history of food-induced asthma were documented to have a positive result after a blinded food challenge, which included wheezing. Interestingly, only 5 (2%) of these patients had wheezing as their only objective adverse symptom.40 o In a related report, 320 children with atopic dermatitis undergoing blinded food challenges at Johns Hopkins Hospital were monitored for respiratory reactions. Overall, 34 (17%) of 205 children with positive results from food challenges developed wheezing as part of their reaction. Therefore, a conservative estimate is that 5-10% of patients with asthma have food-induced allergy symptoms.41 o In a pediatric case-controlled study comparing 19 children who required ventilation for an exacerbation of asthma and 38 control subjects matched by sex, age, and ethnicity, coincident food allergy was found to be independently associated with life-threatening asthma.42 o Wheezing as the only manifestation of an allergic reaction to food is rare. Food-induced pulmonary hemosiderosis (Heiner syndrome) o This is a rare disorder characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates, hemosiderosis, gastrointestinal blood loss, iron deficiency anemia, and failure to thrive in infants. o While the precise immunologic mechanism is unknown, it is thought to be secondary to a non-IgE hypersensitivity process. Food-induced anaphylaxis o Following the ingestion of food, severe anaphylactic reactions (ie, systemic allergic reactions), including death, can occur. o Symptoms may include the following: Oropharyngeal pruritus Angioedema (eg, laryngeal edema) Urticaria Ocular injection, ocular pruritus, conjunctival edema, periocular swelling Nasal congestion, nasal pruritus, rhinorrhea, and sneezing Stridor Dysphonia Cough Dyspnea Wheezing, bronchospasm Nausea Emesis Abdominal pain Diarrhea A feeling of impending doom Cardiovascular collapse 24 o Anaphylaxis can occur without skin symptoms

Food-associated, exercise-induced anaphylaxis describes a disorder in which exercise is tolerated and a food or foods are tolerated, but when exercise follows ingestion of a specific food or foods, anaphylaxis results.43


The physical examination findings are most useful for assessing overall nutritional status, growth parameters, and signs of other allergic disease, such as atopic dermatitis, allergic rhinitis, or asthma. Findings from a comprehensive physical examination can help rule out other conditions that may mimic food allergy.


Any food protein can trigger an allergic response, and allergic reactions to a large number of foods have been documented; however, only a small group of foods account for most of these reactions. Eggs, milk, peanuts, soy, fish, shellfish, tree nuts, and wheat are the foods most often implicated in allergic reactions that have been confirmed in well-controlled blinded food challenges. Sesame appears to be an emerging allergen. Investigations of near-fatal or fatal anaphylactic reactions following food ingestion reveal that most are caused by peanuts, tree nuts, and shellfish, although milk has been increasingly reported.24,22