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Food Allergy: Common Causes, Diagnosis, and Treatment

      Abstract

      Food allergy is a growing concern, and recognition of symptoms, knowledge of common food allergens, and management of reactions are important for patients and practitioners. Symptoms of a classic IgE-mediated food allergy vary in severity and can include any combination of laryngeal edema, wheezing, nausea, vomiting, diarrhea, urticaria, angioedema, and hypotension. Many foods can induce an allergic reaction, but the most commonly implicated foods include cow's milk, egg, peanut, tree nut, soy, wheat, fish, and shellfish. Milk and egg allergy generally develop and are outgrown in childhood. Peanut and tree nut allergy can occur during childhood or adulthood, are less likely to be outgrown, and tend to cause more fatal reactions. Given the possibility of life-threatening reactions, it is important to recognize the potential for cross-reactivity among food groups. Diagnosis of food allergy includes skin prick testing, specific serum IgE testing, and oral food challenges. Management is centered on avoidance of allergenic and cross-reacting foods and early recognition and immediate treatment of reactions. Treatment protocols to desensitize patients to food are currently under investigation.

      Abbreviations and Acronyms:

      alpha-gal (galactose-α-1,3-galactose), CRD (component-resolved diagnostics), NHANES (National Health and Nutrition Examination Survey), OIT (oral immunotherapy), sIgE (allergen-specific IgE), SLIT (sublingual immunotherapy), SPT (skin prick test), WDEIA (wheat-dependent exercise-induced anaphylaxis)
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      Learning Objectives: On completion of this article, you should be able to (1) recognize the foods most commonly associated with IgE-mediated allergic reactions, (2) identify the clinical implications of cross-reactive food allergens, and (3) appreciate the epidemiology, evaluation, and management of food allergy.
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      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
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      General Overview

      Epidemiology

      Food allergy is a public health concern that can impair quality of life and has the potential to induce life-threatening reactions. The prevalence of food allergy is increasing,
      • Burks A.W.
      • Tang M.
      • Sicherer S.
      • et al.
      ICON: food allergy.
      although an accurate prediction of prevalence is difficult given the imprecise diagnoses of food allergy.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      A systematic review reported that food allergy affects between 2% and 10% of the population.
      • Chafen J.J.
      • Newberry S.J.
      • Riedl M.A.
      • et al.
      Diagnosing and managing common food allergies: a systematic review.
      According to the National Health and Nutrition Examination Survey (NHANES) self-reported food allergy data from 2007-2010, the prevalence of food allergy was 8.96%, with a prevalence of 6.53% in children and 9.72% in adults.
      • McGowan E.C.
      • Keet C.A.
      Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007-2010.

      Risk Factors

      Atopic dermatitis, a family history of atopy, and asthma are the primary risk factors for development of a food allergy.
      • Boyce J.A.
      • Assa'a A.
      • Burks A.W.
      • et al.
      NIAID-sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored Expert Panel Report.
      These risk factors have been corroborated by studies suggesting that breakdown of the skin barrier in atopic dermatitis can result in epicutaneous sensitization to foods resulting in food allergy. Numerous other factors including vitamin D deficiency and obesity have been associated with food allergy, although these factors need further exploration.

      Early Exposure Can Be Preventive—Lessons From a Peanut Allergy Population

      In the past, it had been generally recommended that children avoid allergenic foods to reduce the likelihood of development of allergies. However, in a recent study, high-risk infants (those with atopic dermatitis, egg allergy, or both) were randomized to ingest or avoid peanut products from 4 to 11 months of age (depending on age at enrollment) until 5 years of age. The investigators found that high-risk children who regularly consumed peanut protein (in the form of peanut butter or peanut-flavored snacks) were far less likely (70%-86% reduction) to have development of a peanut allergy.
      • Du Toit G.
      • Roberts G.
      • Sayre P.H.
      • et al.
      LEAP Study Team
      Randomized trial of peanut consumption in infants at risk for peanut allergy.
      This marked reduction in development of allergy may impact new food allergy guidelines in the near future.

      Common Food Allergens and Natural History

      Although 170 foods have been identified as allergenic, only a small number of these foods are responsible for a majority of reactions.
      • Burks A.W.
      • Tang M.
      • Sicherer S.
      • et al.
      ICON: food allergy.
      Cow's milk, egg, peanut, tree nut, soy, wheat, fish, and shellfish are the most commonly allergenic foods. Allergy to egg, milk, soy, and wheat tends to occur most commonly during childhood (before 1-2 years of age),
      • Savage J.
      • Johns C.B.
      Food allergy: epidemiology and natural history.
      while fish, peanut, and tree nut allergies can occur during any phase of life. In general, children are more likely to outgrow a wheat, soy, milk, and egg allergy and are less likely to outgrow peanut, tree nut, fish, or shellfish allergy.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.
      Certain foods are more likely to produce a more severe reaction than others. In studies of food allergy fatalities, over 90% of fatal reactions were attributed to either peanuts or tree nuts.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Fatalities due to anaphylactic reactions to foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.

      Classic Symptoms of Food Allergy and Intolerance

      A food allergy is an IgE-mediated reaction. Symptoms may involve the respiratory tract, gastrointestinal tract, skin, and/or cardiovascular system. Respiratory symptoms include sneezing, congestion, rhinorrhea, wheezing, and laryngeal edema. Gastrointestinal symptoms include nausea, vomiting, abdominal pain, and diarrhea. Cutaneous findings include urticaria, angioedema, flushing, or pruritus. Cardiovascular findings include tachycardia, hypotension, or syncope. Symptoms are usually seen within minutes of ingesting a food but may not appear for up to 2 hours and can vary in severity from pruritus alone to anaphylactic shock.
      • Burks A.W.
      • Tang M.
      • Sicherer S.
      • et al.
      ICON: food allergy.
      Food allergy and food intolerances are different diagnoses and are commonly confused by patients. In childhood, intolerance syndromes, such as food protein–induced enterocolitis syndrome, can be severe and cause hypotension due to third spacing. Food protein–induced enterocolitis syndrome is triggered by milk, soy, oat, rice, and rarely meat and manifests with emesis, diarrhea, and lethargy.
      • Burks A.W.
      • Tang M.
      • Sicherer S.
      • et al.
      ICON: food allergy.
      Food protein–induced enteropathy presents as a milder reaction with diarrhea and less commonly with vomiting.
      • Nowak-Wegrzyn A.
      Food protein-induced enterocolitis syndrome and allergic proctocolitis.
      Food protein–induced allergic proctocolitis is a benign condition manifesting as bloody stools in well-appearing infants and is usually caused by milk or soy passed through breast milk or contained in formula.
      • Nowak-Wegrzyn A.
      Food protein-induced enterocolitis syndrome and allergic proctocolitis.
      In adults, food intolerance usually presents with gastrointestinal symptoms including bloating, flatulence, diarrhea, abdominal pain, or nausea and generally does not cause life-threatening reactions. Symptoms of a food allergy occur reliably and reproducibly with exposure to a specific food, which is not always the case with food intolerances in adults. Food intolerances can include lactose intolerance, fructose intolerance, or irritable bowel syndrome that may or may not be associated with certain foods.
      Other nonimmunologic conditions include histamine intolerance, which can be seen with high histamine containing and releasing foods (including alcoholic beverages, ripe cheese, tomato, and smoked or processed meats), and scombroid poisoning, which manifests as flushing, urticaria, diarrhea, or headache and occasionally with bronchospasm and hypotension due to excess histamine in fish as a result of improper storage.
      Food intolerances cannot be detected by traditional allergy testing, which includes in vitro IgE testing or skin prick testing (SPT). However, this testing is often pursued in patients with eosinophilic esophagitis to identify a subset of patients who have concurrent IgE-mediated food allergy.
      • Liacouras C.A.
      • Furuta G.T.
      • Hirano I.
      • et al.
      Eosinophilic esophagitis: updated consensus recommendations for children and adults.
      This article focuses on classic food allergy. Other immunologic and nonimmunologic reactions to food (many discussed in the preceding sections) are summarized in the Table.
      TableSpecific food-induced allergic conditions
      Adapted from J Allergy Clin Immunol,
      • Burks A.W.
      • Tang M.
      • Sicherer S.
      • et al.
      ICON: food allergy.
      with permission.
      PathologyDisorderKey featuresMost common causal foods
      IgE mediated (acute onset)Acute urticaria/angioedemaFood commonly causes acute (20%) but rarely chronic urticaria.Primarily “major allergens” (see text)
      Contact urticariaDirect skin contact results in lesions. Rarely this is due to direct histamine release (nonimmunologic).Multiple
      AnaphylaxisRapidly progressive, multiple organ system reaction can include cardiovascular collapse.Any but more commonly peanut, tree nuts, shellfish, fish, milk, and egg
      Food-associated, exercise-induced anaphylaxisFood triggers anaphylaxis only if ingestion is followed temporally by exercise.Wheat, shellfish, and celery most often described
      Oral allergy syndrome (pollen-associated food allergy syndrome)Pruritus and mild edema are confined to oral cavity and uncommonly progress beyond the mouth (∼7%) and rarely to anaphylaxis (1% to 2%). Might increase after pollen season.Raw fruit/vegetables; cooked forms tolerated; examples of relationships: birch (apple, peach, pear, carrot), ragweed (melons)
      Immediate gastrointestinal hypersensitivityImmediate vomiting, painMajor allergens
      Combined IgE and cell mediated (delayed onset/chronic)Atopic dermatitisAssociated with food allergy in ∼35% of children with moderate-to-severe rashMajor allergens, particularly egg, milk
      Eosinophilic esophagitisSymptoms might include feeding disorders, reflux symptoms, vomiting, dysphagia, and food impaction.Multiple
      Eosinophilic gastroenteritisVary on site(s)/degree of eosinophilic inflammation; might include ascites, weight loss, edema, obstructionMultiple
      Cell mediated (delayed onset/chronic)Food protein–induced enterocolitis syndromePrimarily affects infants; chronic exposure: emesis, diarrhea, poor growth, lethargy; re-exposure after restriction: emesis, diarrhea, hypotension (15%) 2 hours after ingestionCow's milk, soy, rice, oat, meat
      Food protein–induced allergic proctocolitisMucus-laden, bloody stools in infantsMilk (through breast-feeding)
      Allergic contact dermatitisOften occupational because of chemical moieties, oleoresins. Systemic contact dermatitis is a rare variant because of ingestionSpices, fruits, vegetables
      Heiner syndromePulmonary infiltrates, failure to thrive, iron deficiency anemiaCow's milk

      Common Allergens

      Cow's Milk

      Cow's milk allergy is the most common food allergy. Its prevalence is higher in children (prevalence of 2.64% in the NHANES population) than in adults (prevalence of 1.94%).
      • McGowan E.C.
      • Keet C.A.
      Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007-2010.
      Milk allergy usually develops in childhood and is outgrown by school age in most children.
      • Wood R.A.
      • Sicherer S.H.
      • Vickery B.P.
      • et al.
      The natural history of milk allergy in an observational cohort.
      Predictors of outgrowing a milk allergy include a lower milk-specific IgE level, a smaller wheal size on milk SPT, and milder atopic dermatitis.
      • Wood R.A.
      • Sicherer S.H.
      • Vickery B.P.
      • et al.
      The natural history of milk allergy in an observational cohort.
      In a study by Wood et al,
      • Wood R.A.
      • Sicherer S.H.
      • Vickery B.P.
      • et al.
      The natural history of milk allergy in an observational cohort.
      children with milk allergy with an IgE level of less than 2 kU/L had a 5.74-fold higher likelihood of tolerating milk at 66 months compared with children with a level of 10 kU/L. Clinical reactivity between cow's milk and goat's milk is 92%,
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      and therefore, patients with reactions to cow's milk should also avoid goat's milk and sheep's milk.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.
      Clinical cross-reactivity between cow's milk and beef is 10%, and cooking beef further decreases its allergenicity; therefore, avoiding beef is generally not recommended in patients with a milk allergy
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      (Figure).
      Figure thumbnail gr1
      FigureApproximate rate of clinical reactivity to at least one other related food. The probability of reacting to related foods varies, depending on numerous factors. Data derived from studies with double blind, placebo-controlled food challenges.
      From J Allergy Clin Immunol,
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      with permission.

      Egg

      Egg allergy also tends to occur in childhood, and most children outgrow egg allergy by late childhood.
      • Savage J.H.
      • Matsui E.C.
      • Skripak J.M.
      • Wood R.A.
      The natural history of egg allergy.
      The prevalence of egg allergy in the NHANES population was 0.65% in children and 0.51% in adults.
      • McGowan E.C.
      • Keet C.A.
      Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007-2010.
      A retrospective study found resolution of egg allergy in 4% of children by age 4 years, 12% by 6 years, 37% by 10 years, and 68% by 16 years. Patients who did not have resolution of their allergy had higher egg-specific IgE levels.
      • Savage J.H.
      • Matsui E.C.
      • Skripak J.M.
      • Wood R.A.
      The natural history of egg allergy.

      Influenza Vaccination and Egg Allergy

      Egg allergy has generated considerable interest because of concern regarding the safety of the influenza vaccine in patients with this allergy. The inactivated influenza vaccine and the live attenuated vaccines are produced by growing the influenza virus in chicken eggs, and therefore, these vaccines contain small quantities of ovalbumin. Many studies have found that these vaccines can be safely given to egg-allergic individuals including those with severe allergic reactions such as anaphylaxis.
      • Greenhawt M.J.
      • Spergel J.M.
      • Rank M.A.
      • et al.
      Safe administration of the seasonal trivalent influenza vaccine to children with severe egg allergy.
      Egg-allergic patients may receive the vaccine as a single dose or a 2-step challenge (10% of the dose followed by 90% of the dose), but these individuals should be monitored for 30 minutes after vaccination.
      • Greenhawt M.J.
      • Li J.T.
      • Bernstein D.I.
      • et al.
      Administering influenza vaccine to egg allergic recipients: a focused practice parameter update.
      Therefore, egg allergy, even in those with egg-induced anaphylaxis, may not be a contraindication to receiving the influenza vaccine. Alternatively, the recombinant influenza vaccine Flublok (Protein Sciences Corporation), which was first approved by the US Food and Drug Administration in January 2013, does not contain any egg protein and is also an option for patients with egg allergy.

      Baked Egg and Milk

      High-temperature cooking and processing of food can increase or decrease food allergenicity, depending on the particular food. For example, dry roasting of peanuts can increase the allergenicity of peanuts by strengthening bonds and forming new epitopes.
      • Nowak-Wegrzyn A.
      • Fiocchi A.
      Rare, medium, or well done? the effect of heating and food matrix on food protein allergenicity.
      However, with extensive heating of some foods, conformational epitopes can be denatured and combine with other food components forming a matrix, thereby making them unrecognizable to the immune system. Some proteins in egg and milk lose their allergenicity when cooked.
      • Nowak-Wegrzyn A.
      • Fiocchi A.
      Rare, medium, or well done? the effect of heating and food matrix on food protein allergenicity.
      Most patients with egg and milk allergy will tolerate the baked forms of these foods. In one study, 75% of milk-allergic children tolerated products with heated milk.
      • Nowak-Wegrzyn A.
      • Bloom K.A.
      • Sicherer S.H.
      • et al.
      Tolerance to extensively heated milk in children with cow's milk allergy.
      In another study performed in Australia, 80% of egg-allergic patients tolerated baked egg.
      • Osborne N.J.
      • Koplin J.J.
      • Martin P.E.
      • et al.
      HealthNuts Investigators
      Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants.
      Baked egg and milk may tolerize the immune system to these foods and can have an effect comparable to immunotherapy. In one study, children eating baked egg products regularly were 14.6 times more likely to be tolerant to regular egg and achieved tolerance sooner (50 months vs 78.7 months) than patients not ingesting baked egg.
      • Leonard S.A.
      • Sampson H.A.
      • Sicherer S.H.
      • et al.
      Dietary baked egg accelerates resolution of egg allergy in children.
      Similarly, in a study evaluating baked cow's milk, patients who regularly ingested baked milk were 16 times more likely to become tolerant to unheated milk than patients who were not consuming baked milk.
      • Kim J.S.
      • Nowak-Wegrzyn A.
      • Sicherer S.H.
      • Noone S.
      • Moshier E.L.
      • Sampson H.A.
      Dietary baked milk accelerates the resolution of cow's milk allergy in children.
      If patients have already incorporated baked egg and milk products into their diets, they should continue to ingest these foods regularly. If not, an oral food challenge with the baked food should be performed before consumption of the unbaked product.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.
      Incorporation of baked products not only hastens tolerance to regular milk and egg but also improves quality of life in these patients and therefore should be considered for egg- and milk-allergic patients.

      Peanut (Legumes)

      Peanut allergy is of particular concern given that it leads to fatal reactions more commonly than other foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Fatalities due to anaphylactic reactions to foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.
      In a study evaluating fatal food reactions, 62.5% of fatalities were thought to be due to peanut.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Fatalities due to anaphylactic reactions to foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.
      Peanut allergy can develop in adulthood or childhood and is not as likely to be outgrown. A recent prospective study found that a lower peanut-specific IgE level and a smaller wheal size on peanut SPT predicted a higher rate of resolution of peanut allergy.
      • Peters R.L.
      • Allen K.J.
      • Dharmage S.C.
      • et al.
      Natural history of peanut allergy and predictors of resolution in the first 4 years of life: a population-based assessment.
      In this study, an SPT threshold of 8 mm or a peanut-specific IgE level of 2.1 kU/L or greater at age 4 years had a 95% positive predictive value for persistent peanut allergy.
      • Peters R.L.
      • Allen K.J.
      • Dharmage S.C.
      • et al.
      Natural history of peanut allergy and predictors of resolution in the first 4 years of life: a population-based assessment.
      Only 22% of children with a peanut allergy diagnosed at age 1 year had resolution of their allergy by age 4 years.
      • Peters R.L.
      • Allen K.J.
      • Dharmage S.C.
      • et al.
      Natural history of peanut allergy and predictors of resolution in the first 4 years of life: a population-based assessment.
      Legumes (which include peanut and soy) have a high rate of cross-sensitization on testing, but clinical cross-reactions between foods in the legume family occur infrequently.
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      From limited data from double-blind, placebo-controlled trials, the rate of clinical reactivity to another food within the legume family is 5% (Figure).

      Tree Nuts

      Tree nuts include but are not limited to walnut, almond, hazelnut, cashew, pecan, pistachio, and Brazil nut. Tree nut allergy may develop in adulthood or childhood. The prevalence in childhood is 0.52%, and the prevalence in adulthood is 0.87%.
      • McGowan E.C.
      • Keet C.A.
      Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007-2010.
      As with peanuts, tree nuts can also lead to fatal reactions. In a study assessing food allergy fatalities, 31% of fatal reactions were attributed to tree nuts.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Fatalities due to anaphylactic reactions to foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.
      Another important point with tree nuts is the potential for cross-reactivity. Cross-reactivity between tree nuts has been reported at 37%, although comprehensive studies have not been performed given the potentially fatal and relatively frequent reactions to tree nuts.
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.

      Peanut and Tree Nut Cross-Reactivity

      The rate of clinical reactivity between peanuts and tree nuts is unknown but is reported to be between 23% and 50% in atopic patients and is likely lower in the general population.
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      Given the severity of reactions that can occur with tree nuts and peanuts and misidentification between these foods, avoidance of all tree nuts and peanuts should be considered in allergic patients, especially children.

      Shellfish

      Shellfish allergy has a prevalence of 0.87% in children and 2.04% in adults. Shellfish allergy commonly develops during adulthood. There is no established relationship between iodine allergy or radiocontrast reactions with shellfish or fish allergy.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.
      Clinical cross-reactivity between shellfish is 75%.
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      Tropomyosin is the identified allergen and has a high rate of conserving its sequence among different crustaceans including shrimp, crab, and lobster; mollusks including oyster, scallop, and squid; and insects such as cockroach, grasshopper, and dust mite.
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      Given the severity of shellfish reactions and cross-reactivity between shellfish, all shellfish should be avoided unless a challenge can prove tolerance.

      Fish

      As with shellfish, fish allergy can develop in adulthood. Clinical cross-reactivity between fish is 50%
      • Sampson H.A.
      • Gerth van Wijk R.
      • Bindslev-Jensen C.
      • et al.
      Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report.
      ; therefore, all fish should be avoided unless an oral challenge confirms tolerance to specific fish. Most patients with fish allergy are able to tolerate shellfish and vice versa.

      Wheat

      Wheat allergy most commonly develops in childhood and is usually outgrown before adulthood.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.
      Cross-reactivity between grains is 20%.
      • Sicherer S.H.
      Clinical implications of cross-reactive food allergens.
      Elimination of all grains in a patient with wheat allergy may be nutritionally harmful and therefore is not recommended.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.
      If there is concern about allergies to other grains, an oral challenge may be performed.
      Celiac disease is a non–IgE-mediated small-bowel immunologic reaction to gluten in genetically susceptible individuals. Patients present with symptoms of malabsorption including diarrhea, bloating, weight loss, and growth failure in children. Laboratory testing can reveal anemia and vitamin deficiencies. Testing for celiac disease should take into account whether a patient is consuming a gluten-free diet and the probability of disease. Testing may include small-bowel biopsy and serum anti–tissue transglutaminase antibody measurement (both of which should be done while the patient consumes a gluten-rich diet) and/or HLA-DQ2/DQ8 testing. Treatment is gluten avoidance.

      Other Forms of Food Allergy

      Oral Allergy Syndrome

      Oral allergy syndrome (also known as pollen food allergy syndrome) is caused by allergen proteins that share homology between environmental pollens and fruits, vegetables, and tree nuts. Patients are usually sensitized to the environmental allergen and then experience reactions when ingesting a food that contains the closely related protein. For example, the Bet v 1 protein in birch pollen shares homology with the Mal d 1 protein in apple and the Ara h 8 protein in peanut, resulting in clinical cross-reactivity in oral allergy syndrome. Symptoms are usually localized to the oropharynx and consist of itching, tingling, and mild swelling of the lips, tongue, oral mucosa, or throat. Systemic symptoms such as urticaria, asthma, or anaphylaxis are rare but can occur. In one study, 8.7% of patients with oral allergy syndrome had systemic symptoms.
      • Ortolani C.
      • Pastorello E.A.
      • Farioli L.
      • et al.
      IgE-mediated allergy from vegetable allergens.
      These cross-reactive proteins are generally heat labile, and therefore, symptoms seen with ingestion of the raw food do not occur when the food has been cooked or processed.

      Delayed Anaphylaxis Due to Red Meat and Association With Cetuximab Reactions

      Recently, a delayed reaction of 3 to 6 hours after ingestion of mammalian red meat has been identified. Identification of this phenomenon occurred after hypersensitivity reactions were reported to cetuximab, predominantly in patients in Southern states. Further investigations noted that these patients had an IgE antibody to galactose-α-1,3-galactose (alpha-gal), a carbohydrate moiety in cetuximab that is also present in mammalian red meat.
      • Arnold D.F.
      • Misbah S.A.
      Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose.
      It was later noted that the distribution of cetuximab reactions and delayed red meat reactions overlapped with the geographic distribution of Amblyomma americanum (the Lone Star tick). When questioned, patients who presented with delayed meat reactions and IgE antibodies to alpha-gal recalled recent tick bites.
      An IgE reaction to alpha-gal should be suspected in patients who may have been exposed to the Lone Star tick and present with repeated episodes of urticaria, angioedema, or anaphylaxis without a known trigger. The association with red meat may not be readily apparent given the delayed nature of these reactions. Patients often report reactions in the middle of the night after consuming mammalian red meat for dinner. Implicated meats include beef, lamb, pork, venison, goat, and bison. The diagnosis is made through history and detection of elevated serum IgE antibodies to alpha-gal on a commercially available test. Skin prick testing has variable utility in diagnosis.
      • Commins S.P.
      • Satinover S.M.
      • Hosen J.
      • et al.
      Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose.
      Affected patients should avoid all mammalian meat.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.

      Cofactors in Food-Induced Anaphylaxis

      Some patients experience allergic reactions to food only in the presence of a cofactor. Exercise, nonsteroidal anti-inflammatory drugs, asthma, infections, and alcohol are well-known cofactors that induce food-related reactions.
      • Hompes S.
      • Dölle S.
      • Grünhagen J.
      • Grabenhenrich L.
      • Worm M.
      Elicitors and co-factors in food-induced anaphylaxis in adults.
      Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a well-identified phenomenon. In a study of adult patients with anaphylaxis, over half of those with anaphylaxis due to wheat had WDEIA
      • Hompes S.
      • Dölle S.
      • Grünhagen J.
      • Grabenhenrich L.
      • Worm M.
      Elicitors and co-factors in food-induced anaphylaxis in adults.
      .Wheat-dependent exercise-induced anaphylaxis can manifest as urticarial or gastrointestinal, respiratory, or cardiovascular symptoms 1 to 4 hours after ingestion of wheat, although cases with symptoms occurring 10 or more hours after ingestion have been reported.
      • Rongfei Z.
      • Wenjing L.
      • Nan H.
      • Guanghui L.
      Wheat-dependent exercise-induced anaphylaxis occurred with a delayed onset of 10 to 24 hours after wheat ingestion: a case report.
      Patients with WDEIA should avoid exercise for at least 6 hours after wheat ingestion. Several case reports of anaphylaxis after celery ingestion and exercise have also been published.
      • Baek C.H.
      • Bae Y.J.
      • Cho Y.S.
      • Moon H.B.
      • Kim T.B.
      Food-dependent exercise-induced anaphylaxis in the celery-mugwort-birch-spice syndrome.
      Other foods such as nuts and shellfish can also be implicated in food-dependent exercise anaphylaxis. Identifying this association is important in advising against exercise after ingestion of these foods.

      Diagnosis

      Diagnosis of food allergy is based on a suggestive history, allergen-specific IgE (sIgE), SPT, and/or a food challenge. A positive SPT or sIgE result suggests sensitization, and therefore, a history of a reaction or a positive food challenge result is additionally needed to make a diagnosis of a clinical allergy.
      Skin prick testing has a high sensitivity and a negative predictive value of more than 90%,
      • Sicherer S.H.
      Food allergy.
      although specificity is lower. The accuracy of SPT depends on the commercial food extract used because such extracts are not standardized. In some instances, an SPT with fresh fruits and vegetables may be more accurate than using commercial extracts given the lability of allergenic proteins. A reaction 3 mm greater than the negative control is generally considered positive, although this standard can vary among facilities.
      Wheal size on SPT and sIgE levels correlate with the likelihood of a reaction and in some foods the probability of outgrowing an allergy, and therefore patients can be followed up over time to evaluate for tolerance.
      • Burks A.W.
      • Tang M.
      • Sicherer S.
      • et al.
      ICON: food allergy.
      For example, an sIgE for egg of 2 kU/L predicts a 95% probability of reaction to egg in children younger than 2 years of age. However, for children older than 2 years of age, an sIgE of 7 kU/L has a 95% probability of reaction to egg.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: epidemiology, pathogenesis, diagnosis, and treatment.
      An open oral food challenge is commonly used to confirm tolerance to a food after SPT and/or sIgE testing is negative for allergy in the setting of a questionable history and to confirm the development of tolerance in a previously allergic patient. An oral challenge should only be performed in a setting that is equipped to handle severe allergic reactions.
      Component-resolved diagnostics (CRD) is a relatively new testing option, and its utility has been studied principally in peanut allergy. Whereas traditionally used sIgE tests evaluate for IgE associated with the whole food, component testing can identify IgE for specific components of the food, differentiating between components that are clinically important in allergy and those that are not. Studies of component testing for Ara h 2 (a component of peanut) have reported greater diagnostic accuracy with this method than with evaluating IgE for whole peanut.
      • Dang T.D.
      • Tang M.
      • Choo S.
      • et al.
      HealthNuts Study
      Increasing the accuracy of peanut allergy diagnosis by using Ara h 2.
      The utility of CRD testing for other foods is variable, and increased specificity results in decreased sensitivity. Although CRD is promising, it should be studied further before it is widely used.
      Intradermal testing and patch testing should not be performed for diagnosis of food allergy.
      • Boyce J.A.
      • Assa'a A.
      • Burks A.W.
      • et al.
      NIAID-sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored Expert Panel Report.
      IgG testing is available commercially but is not recommended for diagnosis of food allergy.

      Treatment

      Diet and Education

      Unfortunately, there are no Food and Drug Administration–approved treatment options for food allergy. Management at this time is centered on strict avoidance of foods and immediate management of a reaction. Patients should be prescribed a targeted allergen avoidance diet including relevant cross-reactive foods. It is crucial that patients and parents of children with food allergy are educated on reading food labels and are aware of the potential for cross-contamination of foods at restaurants, parties, and other locations. Avoidance of foods that contain the labels “this product may contain trace amounts of allergen” or “manufactured on equipment with” may be prudent.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update-2014.
      The Food Allergy Research and Education website provides valuable and practical information for patients, including common products containing allergens and information on reading food labels. An epinephrine autoinjector should be provided to patients with food allergy, as well as a written emergency action plan for reactions. Patients should be followed up regularly by a physician to discuss accidental exposures or reactions and to evaluate for tolerance. Repeated SPT, sIgE testing, and oral challenges may be performed periodically depending on the natural history of the allergenic food.
      • Burks A.W.
      • Tang M.
      • Sicherer S.
      • et al.
      ICON: food allergy.
      A question that is occasionally raised is whether patients with food allergy can donate blood products. Although case reports have documented the transfer of a specific allergy via transfusions,
      • Arnold D.M.
      • Blajchman M.A.
      • Ditomasso J.
      • Kulczycki M.
      • Keith P.K.
      Passive transfer of peanut hypersensitivity by fresh frozen plasma.
      such transmission is extremely rare. At this time, the presence of a food allergy does not automatically exclude an individual from donating blood products.

      Oral Immunotherapy and Sublingual Immunotherapy for Food Allergy

      Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are methods of inducing tolerance to an allergenic food by gradually increasing the dose of the allergen extract. Oral immunotherapy is ingested, whereas allergen extract is placed under the tongue with SLIT. The effectiveness of OIT for peanut, egg, and milk allergy has been investigated in randomized double-blind, placebo-controlled studies, which have reported that patients receiving OIT were more tolerant of the allergenic food in oral food challenges than patients receiving placebo.
      • Varshney P.
      • Jones S.M.
      • Scurlock A.M.
      • et al.
      A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.
      • Burks A.W.
      • Jones S.M.
      • Wood R.A.
      • et al.
      Consortium of Food Allergy Research (CoFAR). Oral immunotherapy for treatment of egg allergy in children.
      • Skripak J.M.
      • Nash S.D.
      • Rowley H.
      • et al.
      A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy.
      However, local gastrointestinal reactions and systemic reactions requiring epinephrine have been reported with OIT, and further study is needed.
      • Jones S.M.
      • Burks A.W.
      • Dupont C.
      State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous.
      Studies on SLIT have also documented effectiveness with foods including peanut,
      • Burks A.W.
      • Wood R.A.
      • Jones S.M.
      • et al.
      Sublingual immunotherapy for peanut allergy: long-term follow-up of a randomized multicenter trial.
      hazelnut,
      • Enrique E.
      • Pineda F.
      • Malek T.
      • et al.
      Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract.
      and milk.
      • de Boissieu D.
      • Dupont C.
      Sublingual immunotherapy for cow's milk protein allergy: a preliminary report.
      In general, limited data suggest that OIT is more effective than SLIT in developing tolerance to an allergenic food, although SLIT has an improved safety profile.
      • Narisety S.D.
      • Frischmeyer-Guerrerio P.A.
      • Keet C.A.
      • et al.
      A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy.
      Oral immunotherapy and SLIT hold promise as future treatment options for food allergy, but additional studies confirming safety and efficacy should be performed before these therapies can be widely implemented.

      Conclusion

      A classic food allergy is an IgE-mediated reaction manifesting as any combination of respiratory, cutaneous, gastrointestinal, cardiovascular, or pulmonary symptoms. The most commonly implicated foods include cow's milk, egg, peanut, tree nut, soy, wheat, shellfish, and fish. Factors that should be considered in a patient presenting with food allergy include the possibility of food cross-contamination and cross-reactivity, cofactors contributing to a reaction such as exercise or the use of nonsteroidal anti-inflammatory agents, and food preparation, which can either increase or decrease the allergenicity of a food. Food allergy can be diagnosed by blood or skin IgE testing or an oral challenge. At this time, treatment of a food allergy is centered on education, avoidance of allergenic foods, and management of acute reactions.

      Supplemental Online Material

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