Food allergy

Food allergy is extremely common and affects approximately 8% of US children.¹ Prevalence rates for the most common food allergies are estimated to be 2.5% for milk, 1.3% for egg, 1% for peanut, and 0.5% for tree nuts. The overall prevalence of food allergy appears to be rising in all developed countries.²

Because food allergies appear to be such a common problem, pediatricians are likely to regularly encounter children with true allergy and to entertain questions about allergies from families on a daily basis.

Because most reported adverse food reactions are in fact not true food allergy, and the diagnostic tests for food allergy are not terribly accurate, answers may be ambiguous.

What are real food allergies?

To begin, it is important to recognize that not all adverse food reactions are really food allergies but rather food intolerances or other more benign conditions. It is therefore very important that we work with a common definition for food allergy, which is, a specific immune response that occurs reproducibly on exposure to a given food, almost always the protein component of the food.³

Although more than 170 foods have been recognized as food allergens, for day-to-day practice, it is important to remember that just 8 foods (or food groups) account for more than 90% of all food reactions.^3,4 The most important allergens are milk, egg, and peanut, followed by tree nuts, wheat, soy, fish, and shellfish.

The immune mechanisms leading to food allergy most often involve production of immunoglobulin E (IgE) antibodies, but the mechanisms can also be non-IgE mediated (cell mediated) or mixed (with both IgE and non-IgE elements).

The antibody class that causes type 1 hypersensitivity reactions, IgE can be detected by the skin and blood tests commonly used in the diagnosis of food allergy. It is important to remember that IgE cannot be detected or used to diagnose non-IgE-mediated food allergies such as food protein-induced enterocolitis syndrome or allergic proctocolitis.⁵

Diagnosis of food allergy

Diagnosis of food allergy should be guided by a comprehensive medical history and physical exam. Although food allergy should of course be considered in all patients who report symptoms of an acute allergic reaction or anaphylaxis, it is important to consider food allergy in certain chronic conditions without obvious relationship to food ingestion. These include infants and children with moderate to severe atopic dermatitis and patients with eosinophilic esophagitis, gastroenteropathy, or proctocolitis.³

For example, a prospective study of children with moderate to severe atopic dermatitis found that 37% had IgE-mediated food allergy.⁶ Another study of children with eosinophilic esophagitis found that 14.8% had confirmed IgE-mediated food allergy, most commonly to peanut, egg, and milk.⁷

A thorough medical history, including questions regarding the foods that were ingested, the amount, and in what form (cooked, raw, etc) can help focus subsequent testing. IgE-mediated reactions typically occur within a few minutes to hours after ingestion of the culprit food, so details of the reaction experienced, including timing of onset, resolution, treatment, and reproducibility, should be assessed (Table).³

Factors surrounding the event, including exercise, alcohol consumption, and aspirin or nonsteroidal anti-inflammatory use, should also be identified because these can provoke or exacerbate a food allergy-associated reaction. Outside of acute reactions, physical exam findings are typically not helpful in diagnosing food allergy.

History

In acute reactions, the history may be virtually diagnostic (eg, hives immediately after the first egg ingestion). Unfortunately, however, the food allergy history is not very accurate. Most people reporting food allergy do not turn out to have true food allergy on further testing.

For example, a 2007 meta-analysis found that 12% of children and 13% of adults had self-reported food allergy, but the prevalence fell to only 3% when skin testing, IgE testing, and food-challenge results were taken into consideration.⁸ Findings from the medical history should therefore be confirmed with objective measures, although it is important to recognize that many of these are far from perfect.

Testing

Skin prick testing and serologic testing for allergen-specific IgE are most commonly used to help identify causative foods. However, the presence of a positive reaction or a specific IgE found via either method only signifies sensitization and does not necessarily predict clinical reactivity. So although negative tests rule out an allergy at least 90% of the time, a positive test only indicates a true allergy about 50% of the time.

The positive predictive value of these tests falls even lower if they are used indiscriminately, because it is common to find positive tests to foods that a child is eating without difficulty.

As an example of how peanut allergy might be erroneously diagnosed, although 8% of people test positive to peanut, we know that only about 1% are truly allergic.^9,10 Therefore, testing should only be done when it is clinically indicated, and results should always be interpreted in the context of a carefully acquired history.

Serologic testing is currently under development to analyze allergen-specific IgE binding to food allergen components instead of whole allergen extracts. These assays may provide better specificity in diagnosis and identify tests that may be positive because of cross-reactivity with other allergens. It is reasonable to either refer patients with suspected food allergy to an allergy specialist or for the primary care provider to obtain screening serologic tests and then refer patients with positive results for further evaluation.

Food challenge

The gold standard for the diagnosis of food allergy continues to be an oral food challenge.¹¹ In a food challenge, the patient is given gradually increasing doses of the food in question under close medical supervision. Challenges are also used to determine whether a known allergy has been outgrown. When indicated, the medical history and serum specific-IgE testing can guide the timing of a challenge. Although it is the most definitive means of diagnosis, food challenges may not be practical in a busy office setting given their time commitment, expense, and inherent risk.

Non-IgE-mediated food allergies

The diagnosis of a non-IgE-mediated food allergy can be especially difficult given the lack of available objective measures.³ As with IgE-mediated food allergy, a thorough medical history should be the first step in diagnosis.

For some conditions that involve acute symptoms, such as food protein-induced enterocolitis syndrome (FPIES), the history may be very helpful. For conditions with more chronic manifestations, such as eosinophilic gastroenteritis, the history is less likely to be informative.

The next step in the evaluation most often includes an elimination diet, which may vary depending on the history, the age of the patient, and the specific condition that is suspected.³

For example, in FPIES, only 1 or 2 foods that were associated with reactions may need to be avoided, whereas in eosinophilic gastroenteritis, multiple foods may need to be avoided, and some sicker patients may even need to be placed on an elemental diet. In some instances, such as in patients with eosinophilic esophagitis, the success or failure of an avoidance diet can only be determined through follow-up endoscopy
with biopsy.

Management of food allergy

Once the diagnosis of food allergy is made and the culprit food has been identified, strict avoidance of those food allergens is recommended for both IgE-mediated and non-IgE-mediated disease.³ Families must be educated on reading food labels and ingredient lists to help recognize food allergens.

The Food Allergen Labeling and Consumer Protection Act (FALCPA), passed in 2004, requires manufacturers to identify any product containing milk, egg, soy, wheat, peanut, tree nut, fish, and shellfish on the package ingredient label.¹² This does not include precautionary labels that are used at the discretion of the manufacturer and include wording such as “may contain,” “processed on shared equipment,” or “processed in a facility.” Foods with these warning labels also should be avoided for most patients.

Food avoidance, especially for young patients on extensive elimination diets, could have effects on their nutritional status.¹³ The guidelines recommend that children with food allergy should have nutritional counseling and ongoing growth evaluations. Particular attention should be given to following total daily calorie, protein, calcium, and vitamin D intake.

Natural history of food allergy

Studies on the natural history of food allergy have shown that approximately 70% to 80% of patients outgrow milk and egg, 60% to 70% outgrow soy and wheat, and 10% to 20% outgrow peanut and tree nut allergy.^14-18 Therefore, follow-up reassessment is indicated to update reaction history, and repeat serum-specific-IgE testing is necessary.

Serum-specific-IgE testing may provide additional information regarding the likelihood of clinical reactivity based on predictive values for passing oral food challenges.¹⁹ For milk, egg, and peanut, a specific IgE level of less than 2 kUA/L predicts a 50% likelihood of passing an oral food challenge. Reliable levels for wheat and soy have not been identified. Yearly reevaluation is recommended for patients with milk, egg, wheat, and soy allergy, but less frequent testing is usually sufficient for those with peanut, tree nut, fish, and shellfish allergy, especially in those who clearly have persistent disease.³

Management of reactions

Despite food avoidance, reactions to accidental exposures are common. For example, in a study of children with peanut allergy, the rate of yearly peanut ingestion was 4.7%, with 1.6% of exposures causing severe reactions; epinephrine was used at a rate of 1.1% per year.²⁰

For children, food allergy is the leading cause of anaphylaxis requiring medical attention.²¹ Ingestion of peanut and tree nuts, age (adolescents and young adults), asthma, and delay of epinephrine treatment are all risk factors for mortality from food-induced anaphylaxis.

For acute IgE-mediated food allergy, intramuscular epinephrine is the recommended treatment for anaphylaxis, and self-injectable epinephrine should be available to the patient at all times.³ Dosing of the epinephrine auto-injector is based on weight, with patients weighing 10 kg to 25 kg receiving 0.15 mg, and patients weighing more than 25 kg requiring a 0.3 mg dose.

If symptoms do not improve after the initial dose, epinephrine injections should be administered every 5 to 15 minutes. A recent study found that 19% of food-induced anaphylactic reactions required more than 1 dose of epinephrine.²¹ All patients should be observed for at least 4 to
6 hours in a medical facility after a severe
allergic reaction.³

In addition to epinephrine, other interventions and medications can be used as adjunctive treatment of anaphylactic reactions.

Bronchodilators are indicated for bronchospasm that has not responded to epinephrine treatment. First- and second-generation H₁ antihistamines can be used to treat pruritis and urticaria for minor reactions and anaphylaxis. Although there are very few studies to support their use, H₂ antihistamines are often also prescribed.

Other therapeutic interventions include placing the patient in the recumbent position with feet elevated or administering intravenous fluids, oxygen, vasopressors, glucagon (for patients taking ß-adrenergic receptor-blocking medications),
and atropine.

After the initial anaphylactic reaction, some patients will experience a biphasic reaction, and a few will have protracted reactions.³ Most biphasic reactions will occur within 4 hours but can occur up to 72 hours after the initial reaction and are experienced in up to 20% of episodes.²²

Although evidence is actually limited to support their use, corticosteroids are typically administered to prevent biphasic reactions and treat protracted symptoms. However, in most instances, only a single dose of corticosteroid needs to be administered.³

Future directions

Although strict avoidance is still the mainstay of therapy for most food allergy, there are exciting new studies documenting that many children with milk and egg allergy may tolerate these foods in an extensively heated (eg, baked) form, even though they are still allergic to the uncooked forms of
the food.^23,24

In addition to improving quality of life by allowing these children to eat many of their favorite foods (eg, birthday cake), studies have shown that this exposure may help to build tolerance and potentially help to outgrow the allergy
more quickly.

Immunotherapy for treatment of IgE-mediated food allergy is currently under investigation.³ The goal of immunotherapy is to effectively induce long-term tolerance to the culprit food with the least amount of systemic adverse effects.

Many different modalities of delivery have been or are currently being studied, including subcutaneous injection, oral ingestion, sublingual absorption, epicutaneous, and rectal.

The optimum route of administration, product formulation, dosing protocol, length of treatment, and safely profile are yet to be determined. Therefore, immunotherapy is not currently US Food and Drug Administration approved and is not recommended for the treatment of food allergy, pending further study.

For non-IgE-mediated food allergy, avoidance of the culprit food is indicated. In cases of eosinophilic esophagitis unrelated to food allergy, topical corticosteroid treatment with budesonide or fluticasone propionate can help improve symptoms and histologic findings.⁵

Patients with food protein-induced enterocolitis and allergic proctocolitis usually outgrow the allergy within a few years of diagnosis, so oral food challenges are indicated at appropriate intervals.³

Another common issue in pediatric practice relates to immunizations in children with egg allergy. Current guidelines say that the measles, mumps, and rubella vaccine contains negligible levels of egg allergen and is safe for all children with egg allergy to receive.³

Influenza vaccines do contain measurable levels of egg protein, and although levels may vary among manufacturers, they have become more consistently low in recent years.

Numerous studies have also documented that reactions to influenza vaccines are very uncommon, even in children with significant egg allergy.²⁵ It is therefore recommended that patients with a history of mild allergic reactions to egg, including hives, may receive the inactivated (not intranasal) vaccine in their primary care physician’s office with a 30-minute observation, and those with a history of more severe reactions should be referred to an allergist for management. Older measures such as skin testing with the vaccine and dividing doses are no
longer recommended.²⁶

Facing the challenges

The diagnosis and management of the food allergic patient can be challenging given the paucity of evidence-based data, together with diagnostic tests that leave much to be desired. Optimal care of patients with food allergy can be best provided as a partnership between the pediatrician, the allergist, and the family, all working to keep the child or adolescent safe and yet maximize their quality of life in spite of the dietary restrictions and constant fear of a reaction. New studies provide hope that food allergy will someday be a treatable condition, and all pediatricians anxiously wait for that day to come.

References

• Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9-e17.

• Sicherer SH. Epidemiology of food allergy. J Allergy Clin Immunol. 2011;127(3):594-602.

• NIAID-Sponsored Expert Panel, Boyce J, Assa’ad A, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 suppl):S1-S58.

• Branum AM, Lukacs SL. Food Allergy Among US Children: Trends in Prevalence and Hospitalizations. NCHS Data Brief No. 10. Hyattsville, MD: National Center for Health Statistics; 2008.

• Furuta GT, Liacouras CA, Collins MH, et al; First International Gastrointestinal Eosinophil Research Symposium (FIGERS) Subcommittees. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342-1363.

• Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics. 1998;101(3):E8.

• Spergel JM, Brown-Whitehorn TF, Cianferoni A, et al. Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet. J Allergy Clin Immunol. 2012;130(2):461-467.e5.

• Rona RJ, Keil T, Summers C, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. 2007;120(3):638-646.

• Liu AH, Jaramillo R, Sicherer SH, et al. National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol. 2010;126(4):798-806.e13.

• Sicherer SH, Wood RA; American Academy of Pediatrics Section on Allergy and Immunology. Allergy testing in childhood: using allergen-specific IgE tests. Pediatrics. 2012;129(1):193-197.

• Nowak-Wegrzyn A, Assa’ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS; Adverse Reactions to Food Committee of American Academy of Allergy, Asthma, and Immunology. Work Group report: oral food challenge testing. J Allergy Clin Immunol. 2009;123(6 suppl):S365-S383.

• US Food and Drug Administration. Food Allergen Labeling and Consumer Protection Act of 2004 (Public Law 108-282, Title II). Silver Springs, MD: US Food and Drug Administration; 2006.

• Christie L, Hine RJ, Parker JG, Burks W. Food allergies in children affect nutrient intake and growth. J Am Diet Assoc. 2002;102(11):1648-1651.

• Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history of egg allergy. J Allergy Clin Immunol. 2007;120(6):1413-1417.

• Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow’s milk allergy. J Allergy Clin Immunol. 2007;120(5):1172-1177.

• Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA. The natural history of peanut allergy. J Allergy Clin Immunol. 2001;107(2):367-374.

• Keet CA, Matsui EC, Dhillon G, Lenehan P, Paterakis M, Wood RA. The natural history of wheat allergy. Ann Allergy Asthma Immunol. 2009;102(5):410-415.

• Savage JH, Kaeding AJ, Matsui EC, Wood RA. The natural history of soy allergy. J Allergy Clin Immunol. 2010;125(3):683-686.

• Perry TT, Matsui EC, Kay Conover-Walker M, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol. 2004;114(1):144-149.

• Neuman-Sunshine DL, Eckman JA, Keet CA, et al. The natural history of persistent peanut allergy. Ann Allergy Asthma Immunol. 2012;108(5):326-331.e3.

• Järvinen KM, Sicherer SH, Sampson HA, Nowak-Wegrzyn A. Use of multiple doses of epinephrine in food-induced anaphylaxis in children. J Allergy Clin Immunol. 2008;122(1):133-138.

• Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol. 2005;95(3):217-226.

• Nowak-Wegrzyn A, Bloom KA, Sicherer SH, et al. Tolerance to extensively heated milk in children with cow’s milk allergy. J Allergy Clin Immunol. 2008;122(2):342-347.e1-2.

• Lemon-Mulé H, Sampson HA, Sicherer SH, Shreffler WG, Noone S, Nowak-Wegrzyn A. Immunologic changes in children with egg allergy ingesting extensively heated egg. J Allergy Clin Immunol. 2008;122(5):977-983.e1.

• Chung EY, Huang L, Schneider L. Safety of influenza vaccine administration in egg-allergic patients. Pediatrics. 2010;125(5):e1024-e1030.

• Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60(33):1128-1132.