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What Is Food Allergy?

Food allergy is an immunoglobulin (Ig)E- or non-IgE-mediated immune response to food protein. This column will focus on IgE-mediated food allergy represented by immediate hypersensitivity (Gell-Coombs Type I), which can include anaphylaxis and can be life-threatening. Non-IgE-mediated reactions are thought to be cell mediated (allergic eosinophilic esophagitis/gastroenteritis, food protein-induced proctocolitis, food protein-induced enterocolitis syndrome, food protein-induced enteropathy [including celiac disease], and food-induced pulmonary hemosiderosis).

Adverse reactions to foods are sometimes confused with food allergies, but these reactions are nonimmunologic. Nonimmunologic food reactions can be metabolic (lactose intolerance), pharmacologic (chemical migraine triggers such as tyramine, aspartame, monosodium glutamate, nitrates/nitrites, alcohol, coffee, and chocolate), or toxic (scombroid poisoning or food poisoning) in origin. Lactose intolerance can be managed with replacement of the enzyme lactase. Symptoms of scombroid poisoning, associated with bacterial histamine build-up in contaminated fish such as tuna or mackerel, can appear similar to an allergic reaction; affected patients respond well to antihistamines.^[1] In contrast to food allergy, food poisoning often occurs in clusters and is not reproducible.

The High and Increasing Prevalence of Food Allergy

Demographics. Food allergies affect up to 8% of children and 3%-4% of adults.^[2,3] Food allergies account for 29%-50% of all cases of anaphylaxis, ^[4,5] which in turn cause 150-200 deaths annually^[6](6-7 times more than deaths from insect stings).^[7] No gender or racial disparities have been noted in food allergy, except for Hispanic children, who have a lower rate of food allergy than white or black children.^[8]

Prevalence. Food allergy is growing. From 1997 to 2007, the prevalence of reported food allergy increased 18% in children under the age of 18 years.^[8] Peanut allergy has tripled in children under the age of 18 years in a similar time frame, from 0.4% in 1997 to 1.4% in 2008.^[9] Peanut allergy now affects 0.6% of the population and is the most common cause of fatal food-induced anaphylaxis.^[9,10] Adverse reactions to food additives, such as coloring or preservatives, are rare and estimated to affect be between 0.01% and 0.23% of the general population.^[11-13]

Virtually any food can cause an allergic reaction. The most common allergens in childhood are cow's milk (2.5%), egg (1.6%), peanut, soy, wheat, tree nuts, fish, and shellfish.^[2,14] In adults, the most common allergens are peanut, tree nuts, fish, and shellfish.

Associated conditions. About 80% of children outgrow their milk and egg allergies; however, recent studies suggest that children now require more time to outgrow these allergies than in the past.^[15-18] Only 20% of peanut-allergic children eventually outgrow this allergy and are able to tolerate peanut in their diets.^[19] Children who have a food allergy are more likely to have other atopic conditions such as atopic dermatitis, allergic rhinitis, and asthma compared with children who do not have a food allergy.^[8] Most children with atopic dermatitis are sensitized (have a positive skin test or elevated specific IgE) to food or aeroallergens.^[20,21]

In children with moderate-severe atopic dermatitis, 40% have clinical food allergy,^[22,23] most commonly egg.^[24]Food allergies have also been found to be a risk factor for life-threatening asthma.^[25]

The Pathophysiology of Food Allergy

A Type I immediate hypersensitivity reaction is precipitated by the presentation of antigen (in this case, food peptides), by antigen-presenting cells (APCs) to T cells, which direct B cells to produce IgE.^[26] The IgE antibodies then bind to tissue mast cells and basophils, the effector cells in an allergic reaction. Upon re-exposure, the antigen binds to and crosslinks IgE on mast cells and basophils, triggering degranulation and the release of preformed contents, such as histamine, tryptase, and proteoglycans. Activated mast cells and basophils also produce prostaglandins, leukotrienes, platelet-activating factor, and cytokines. These mediators act directly on tissue and recruit inflammatory cells. Histamine, the primary mediator, induces vascular permeability, mucus production, vasodilation, and airway and intestinal smooth muscle contraction; and affects cardiac function.^[27,28] These actions result in the flushing, hives, edema, bronchoconstriction, abdominal cramping, vomiting, hypotension, and dysrhythmias typically seen in acute allergic reactions and anaphylaxis. It is possible to react on first known exposure. Some speculate that exposure in the environment, through breastfeeding, or in utero might be the priming event.^[29]

Food allergy is viewed as a Th2-mediated condition.^[30] Th2 CD4+ T cells produce cytokines interleukin (IL)-4, IL-5, and IL-13 and generate a humoral immune response that is classically used to fight off parasites but also inappropriately causes allergies. In contrast, Th1 CD4+ T cells produce IL-2 and IFN-gamma and generate cell-mediated immune responses.

Proposed Explanations for the Rise in Allergic Disease

Why IgE antibody is inappropriately formed against benign food protein is not fully understood. One well-known hypothesis for the apparent Th2 shift and increase in allergic diseases in westernized countries is the hygiene hypothesis. This hypothesis postulates that because of our improved hygiene and vaccinations, our immune systems are not overburdened with disease or parasites, so instead we develop immunity against benign antigens that we are commonly exposed to, such as food.^[31] Other hypotheses for the increase in food allergies involve how we grow and process our food, how and when we introduce foods to infants and toddlers, dietary fat content, reduction in dietary antioxidants, vitamin D insufficiency, and environmental exposures to allergens, such as peanut oil in skin moisturizers, which may favor sensitivity as opposed to tolerance.^[32-37]

Clinical Manifestations of Food Allergy

Reactions to food can occur with very small amounts of exposure and develop in minutes or up to 2 hours after ingestion. Symptoms can be cutaneous, gastrointestinal, respiratory, circulatory, neurologic, and/or atypical, such as a metallic taste in the mouth (Table 1).

Table 1. Symptoms of an Allergic Reaction

About 90% of reactions present with cutaneous, 70% with respiratory, 30%-45% with gastrointestinal, and 10%-45% with circulatory symptoms ranging from palpitations to collapse.^[4] Severe reactions are predominantly respiratory in children and circulatory in adults.^[38,39]

Anaphylaxis

Anaphylaxis, by definition, is a severe multiorgan system allergic reaction that can be fatal.^[40] Anaphylaxis can progress rapidly without cutaneous symptoms. Although anaphylaxis is usually uniphasic, biphasic reactions can occur in up to 20% of cases, and protracted reactions have been reported.^[41] In a biphasic reaction, symptoms typically recur within 1-4 hours after apparent resolution of the initial event, although recurrence as late as 72 hours after exposure has been reported. Biphasic reactions occur more frequently when the initial administration of epinephrine is delayed and are rare after mild initial reactions. Rarely, protracted anaphylaxis can persist for several days, with multiple recurrences interrupted by asymptomatic periods lasting hours.^[42]

Contrary to a commonly held belief, allergic reactions do not automatically get worse each time. However, previous food-induced anaphylaxis does put a patient at risk for future anaphylactic reactions.^[42] A number of factors influence reaction severity such as the amount of allergen ingested, how the food was prepared (raw vs heated), the amount and type of other food ingested, the presence of acute viral illness, the status of an underlying chronic disease, alcohol consumption, and exercise.^[43,44]

Risk factors for fatal anaphylaxis include adolescence, a history of asthma, a history of anaphylaxis, delayed or no epinephrine received, cardiopulmonary disease, an upright posture during the reaction (mostly in adults, leading to empty ventricle syndrome), adrenal insufficiency, beta blockade, angiotensin-converting enzyme therapy, and initial misdiagnosis.^[44]

Other Reactions

Although contact reactions can occur after touching a food allergen, severe reactions are uncommon unless the antigen is ingested or absorbed through the mucosa.^[10] Local pruritus, redness, or urticaria can occur in contact reactions. Isolated respiratory symptoms are uncommon during a food-induced allergic reaction, but wheezing can be part of the larger reaction.^[10] Chronic asthma symptoms are unlikely to be caused by food allergy. Inhalation reactions can occur particularly if the food protein is airborne; for example, during the process of roasting nuts, steaming fish/shellfish, or boiling milk.^[45,46] The smell of food alone, even a strong smell like peanut butter, is comprised of aromatic chemicals that are not proteins and would not be expected to cause an allergic reaction.^[47]

Diagnosis of Food Allergy

Clinical history is vital in the diagnosis of food allergy.^[10] A double-blind placebo-controlled food challenge is the gold standard in food allergy diagnosis but is used mostly in research. Open oral food challenges are used in the clinical setting, usually when it is believed that the individual is not allergic or has become tolerant.^[10]Skin tests and allergen-specific IgE levels have high sensitivity but moderate specificity.

Skin Testing

The positive predictive value (PPV) for skin testing is ≤ 50%, whereas the negative predictive value (NPV) is ≥ 95%.^[10] Because of a high rate of false positives, a positive skin test should be correlated with clinical history, whereas a negative skin test can be used to rule out an IgE-mediated allergy. The larger the diameter of a wheal in a positive skin test, the greater the probability of clinical reactivity; however, the size cannot predict the type or severity of a potential reaction.^[48-50] In one study, a median wheal size of ≥ 8 mm for milk, egg, or peanut in children younger than 2 years was found to be 95% predictive of food allergy.^[51]

Food-Specific IgE Testing

Food-specific IgE testing has similar specificity (~ 50%) but slightly lower sensitivity (> 90%) than skin testing.^[10] In vitro testing is useful when skin testing is not possible; for instance, if the patient is taking antihistamines, the patient has dermatographism, a large number of allergens need to be tested, the patient is acutely ill, or the patient has active atopic dermatitis and no skin is free of inflammation. Monitoring food-specific IgE levels over time is also useful, because falling levels could indicate that the patient is outgrowing the allergy. Like the size of skin tests, the concentration of food-specific IgE does not predict the type or severity of reaction, only the probability of clinical reactivity.^[48-50]

Using the ImmunoCAP system to measure food-specific IgE levels, studies have established PPV and NPV for common food allergens. These are frequently used to confirm an allergy diagnosis and to assess the risks and benefits of doing an oral food challenge. For example, an IgE level of 14 kU/L for peanut is > 95% predictive of clinical reactivity, and on the basis of this level, it would be unlikely that a patient would pass an oral food challenge.^[48] An undetectable IgE level (< 0.35 kU/L) for peanut is still associated with a 20% chance of reactivity.^[48]

The diagnostic levels of food-specific IgE for common allergens and associated PPVs for clinical reactivity are^[15,52-54]:

• Egg: In children > 2 years of age, IgE level 7 kU/L (98% PPV); in infants ≤ 2 years, IgE level 2 kU/L (95% PPV)
• Milk: IgE level 15 kU/L (95% PPV)
• Peanut:IgE level 14 kU/L (95% PPV)
• Fish: IgE level 20 kU/L (95% PPV)
• Tree nuts: IgE level 15 kU/L (95% PPV)
• Soy: IgE level 30 kU/L (73% PPV)
• Wheat: IgE level 26 kU/L (74% PPV)

The probability of clinical reactivity on the basis of IgE levels depends on the particular food, and these levels are not comparable between foods. Therefore, the "classes" assigned to food-specific IgE levels by many laboratories are often confusing and may not be useful in predicting reactivity.

Overdiagnosis of Food Allergy

The high rate of false positives combined with the wide commercial availability of food-specific IgE testing (particularly the food allergy panels) has led to overdiagnosis and unnecessarily restrictive diets.^[10] Not only could this have a significant effect on quality of life, but it may be detrimental in children if dietary restriction affects nutrition and results in poor growth or development.

Food allergies can develop at any time; however, people uncommonly develop allergies to foods that are being regularly ingested. Cases of individuals who developed systemic reactions to food allergens that they previously tolerated after a period of strict avoidance because of atopic dermatitis have been reported.^[55-57] On the basis of these observations, it is not recommended that a food be taken out of a patient's diet as a result of a positive or even high IgE level, if the patient is tolerating the food on a regular basis. Evaluation by an allergist is recommended for patients who have atopic dermatitis but the causative food is not evident. Trial elimination diets can also be useful in certain situations but should not be continued if improvement is not seen.

Tests Not Recommended for Food Allergy Diagnosis

The following tests have not been supported by scientific data from controlled studies and are therefore not recommended by the American Academy of Allergy, Asthma, and Immunology to diagnose food allergies^[58]:

• Applied kinesiology testing and Nambudripad's allergy elimination test;
• Body chemical analysis;
• Cytotoxic testing;
• ELISA/ACT;
• Electrodermal diagnosis;
• IgG testing;
• Provocation and neutralization; and
• Pulse testing.

Some of these tests require ingestion or injection of the suspect allergen, which puts the patient at risk for a reaction. The European Academy of Allergy and Clinical Immunology (EAACI) published a strong statement against IgG and IgG4 testing for diagnosing food allergies.^[59] Several studies have presented evidence that food-specific IgG4 simply indicates repeated exposure to specific foods, and that IgG4 in conjunction with regulatory T cells seems to be an indicator of tolerance rather than hypersensitivity.^[59,60]

Management of Food Allergy

Currently, no cure for food allergy exists. Management consists of education, prevention, and treatment of acute reactions. The mainstays of treatment of acute food-induced allergic reaction are antihistamines and intramuscular epinephrine.^[10]

Treatment of Acute Reactions

Antihistamines can be given if symptoms develop or when a known allergen is ingested and symptoms have not yet developed. Evidence shows that oral cetirizine (0.25 mg/kg, maximum of 10 mg) works as fast as diphenhydramine (1.5 mg/kg, maximum of 50 mg); therefore, either can be used, and cetirizine has the added benefit of longer lasting effects.^[61]

Epinephrine is used when respiratory or circulatory symptoms are present, or if the reaction is progressing and involves 2 or more organ systems. Epinephrine is appropriate, for example, if a patient has generalized hives and protracted vomiting, even without respiratory or circulatory symptoms.

Every patient diagnosed with a food allergy is advised to carry 2 epinephrine self-injectors because the severity of each reaction cannot be predicted, and in some cases, 2 doses might be needed. The dose of epinephrine is 0.01 mg/kg; using prepackaged epinephrine, adults receive 0.3 mg epinephrine per dose, and children under 25 kg (55 lbs) receive 0.15 mg epinephrine per dose.

Proper administration technique involves intramuscular injection of epinephrine into the thigh muscle. Studies have shown that injection of epinephrine into the thigh muscle achieves higher peak plasma concentrations than injection into the deltoid muscle, and absorption occurs faster with intramuscular vs subcutaneous administration.^[62] Epinephrine can be injected through clothes if necessary; however, injecting directly against the skin avoids unseen buttons, seams, or zippers.

Patients are instructed to use their epinephrine when in doubt because a delay could allow the reaction to worsen. Patients are instructed to dial 911 or obtain immediate medical attention if the reaction is severe enough to use epinephrine. Not only might additional medication and monitoring be necessary, but the individual should be observed for 4-6 hours in the emergency department for a possible biphasic reaction.

Other components to emergency management include high-flow oxygen, inhaled beta-2 agonists for bronchospasm, and steroids.^[10] Steroids (prednisone 1 mg/kg, maximum 50 mg; or methylprednisone 1-2 mg/kg) are not intended for acute management because their onset of action is slow; however, these agents could prevent biphasic or protracted reactions.^[4] Dosing should be intravenous every 6 hours for severe reactions, whereas a single oral dose might suffice for milder reactions.^[40]

In cases involving hypotension, H2-blockers (which not only improve cutaneous symptoms but also counteract vasodilation), fluid resuscitation, and a supine position could be useful.^[10] Higher doses and intravenous administration of antihistamines can be given in a monitored setting. In refractory hypotension, vasopressors can be used. If a patient is taking beta-blockers, the effect of epinephrine could be diminished, and administration of glucagon might be necessary to reverse this blockade.

Avoidance of Exposure

Patients who have food allergies (and their caretakers) must be aware of the risks for hidden allergens or cross-contact at every meal, and frequently special provisions must be made for these individuals. Food allergies have a profound effect on quality of life,^[63] and support groups and food allergy organizations (such as the Food Allergy and Anaphylaxis Network, or FAAN) might be useful. School, camp, restaurants, entertainment events, birthday parties, air travel, and vacationing can be stressful situations for food-allergic individuals. General nutritional health should be assessed periodically, and patients should be monitored for psychological issues such as anxiety and depression as well as food phobias and eating disorders.^[64,65]

Conditions Associated With Food Allergy

Oral Allergy Syndrome

Oral allergy syndrome (OAS) is caused by proteins in fresh fruits, vegetables, and nuts that are homologous with proteins in pollen.^[66]Up to 50%-75% of individuals who suffer from pollen allergies are estimated to be affected.^[67,68] Classic examples of pollen-food associations include birch with apple, peach with hazelnut, and ragweed with banana and melon.^[69]

Symptoms are typically limited to oral pruritus and mild angioedema, with occasional rhinitis and facial rash. Because these homologous proteins are heat and acid labile, they are broken down easily by stomach acid and destroyed in cooking; therefore, symptoms are rarely systemic.^[70,71] Many patients continue to eat these foods in their fresh states despite the oral discomfort, and most patients report being able to tolerate the same foods when cooked or processed. One study showed that symptoms of OAS can become systemic in 8.7% of cases, and 1.7% experience anaphylaxis.^[72]

Treatment of OAS involves avoidance and treatment of symptoms with antihistamines and/or epinephrine if the reaction is systemic or severe.

Food-Dependent Exercise-Induced Anaphylaxis

Food-dependent exercise-induced anaphylaxis (FDEIA) is a rare condition in which symptoms develop if food (or a specific food) is eaten within 2 hours prior to exercising.^[73]

The most common food implicated in FDEIA is wheat, but celery, shellfish, tomatoes, grapes, chicken, dairy products, and mushrooms have also been reported, and theoretically any food can be associated with FDEIA.^[10,74] These same foods are otherwise tolerated in the diet when exercise is not involved.

Factors that can be associated with triggering FDEIA include menstrual cycle, amount of food ingested, alcohol, aspirin or NSAIDs, and weather.^[10] The immune mechanism for FDEIA is poorly understood, but proposed theories include altered splanchnic blood flow, stress-increased proinflammatory mediators, autonomic dysregulation, and increased intestinal permeability leading to absorption of larger peptides.^[75-80]

Management of FDEIA involves avoidance of trigger foods prior to exercise, not exercising alone, wearing a medic alert bracelet, and carrying self-injectable epinephrine in case of anaphylaxis.^[10]

Prognosis for Food Allergy

In the past, it was anticipated that avoidance might increase the chances of outgrowing the food allergy and possibly contribute to the development of tolerance.^[81,82] The American Academy of Pediatrics' 2000 dietary guidelines recommended that children avoid highly allergenic foods in infancy and early childhood.^[83] This has not been shown to be beneficial; in fact, the incidence of food allergy has continued to rise despite these guidelines, which were revised in 2008.^[8,84] One study in Jewish children noted a higher prevalence of peanut allergy in those born in the United Kingdom compared with those born and raised in Israel, where infants ingest peanut at an early age.^[85] This suggests that some early oral exposure of allergen might be protective, but the timing, amount, and form of exposure necessary are not yet known.

State of the Science: Research in Food Allergy

Subcutaneous immunotherapy (SCIT) has been used successfully for other allergic diseases, such as seasonal allergies, venom allergy, and asthma; however, unacceptable rates of systemic reactions have put SCIT trials for food allergy on hold.^[86,87]

Results have been favorable in oral immunotherapy (OIT) clinical trials for food allergy, in which patients have tolerated increased amounts of egg, milk or peanut with fewer and more minor side effects.^[88-91] When OIT was discontinued, however, clinical reactivity returned in a subset of patients, indicating desensitization, and not permanent tolerance, occurred.^[88,92]

Food processing alters protein structure and affects allergenicity.^[93]For example, heating or incorporating egg or milk into a wheat matrix can reduce allergenicity by destroying or blocking IgE-recognized peptides. Extensively heated protein represents an alternative and possibly safer method to OIT. In 2 recent studies, 70% of egg- and cow's milk-allergic children were able to tolerate extensively heated egg or milk.^[14,94] Decreasing skin test wheal size and increasing egg- or milk-specific IgG4 were seen with continued incorporation of extensively heated egg or milk in the diet, findings that are often seen as allergies resolve. Both OIT and introducing extensively heated egg and milk, however, remain investigational and are not currently the standard of care.

Sublingual immunotherapy, oral immunotherapy given in conjunction with omalizumab, recombinant vaccines, and Chinese herbal medicine are other methods that are currently in clinical trials.^[95]

Food allergy clinical trials may be viewed at ClinicalTrials.gov. Research in peptide immunotherapy, adjuvant-associated protein immunotherapy, and plasmid DNA immunotherapy are still in the laboratory at this time.^[95]

Final Perspective and Clinical Recommendations

Food allergies are on the rise in westernized countries for reasons that we do not completely understand. The rise in food allergies parallels the increase in other atopic diseases. No cure currently exists for food allergy. Management consists of education, avoidance of allergens, and appropriate response to acute reactions.

The most common food allergies in childhood are milk, egg, and peanut. Most children outgrow their milk and egg allergies, whereas peanut allergy is more likely to be lifelong. The most common food allergies in adulthood are peanut, tree nuts, fish, and shellfish. Although peanut is the allergen most often associated with severe or fatal reactions, any food has the potential to cause anaphylaxis.

Patient history is the most important diagnostic tool in the evaluation of food allergies. Skin testing and specific IgE testing provide additional information and can be used to monitor the status of food allergies over time or determine if an oral food challenge is appropriate. An oral food challenge is the gold standard for diagnosis of food allergy; however, this test is typically only used when the diagnosis is in question or if it is believed that the food allergy has been outgrown.

Food-allergic individuals and their caretakers must be aware of hidden allergens and cross-contact at every meal and be prepared to treat if an allergen is accidentally ingested. The amount of food required to trigger a reaction or the severity of a reaction cannot be predicted. Intramuscular epinephrine and antihistamines are the mainstays of treating acute allergic reactions. Research into curative or mitigating food allergy therapies is ongoing.

Recommendations for Practitioners

1. Delaying of potentially allergenic foods until 1, 2, or 3 years of age has not been shown to prevent food allergies. In 2008, the American Academy of Pediatrics amended their earlier position and no longer recommends avoidance of such foods as a preventive measure.
2. Food allergic patients, especially those with a new diagnosis, should be seen by an allergist for complete work-up, education, and management. Children can outgrow their food allergies, and yearly monitoring is warranted.
3. Specific food IgE levels can be measured after careful history-taking identifies potential allergens. The focus should be on foods ingested within 2 hours leading up to an acute reaction or foods that appear to consistently exacerbate eczema.
4. Specific food IgE testing panels are not recommended because of the occurrence of false positives and the potential for foods that an individual has been tolerating to be unnecessarily removed from their diet.
5. Removing a previously tolerated food from a patient's diet solely on the basis of an elevated specific IgE can put the patient at risk for developing an actual clinical allergy to that food.
6. An undetectable specific food IgE level is not a guarantee that an individual is not allergic. If the history is suggestive, skin testing should be performed (and possibly an oral food challenge as well) before the food is ingested again.
7. Specific food IgE levels help to predict the likelihood of reactivity but not the type or severity of reaction. The significance of the levels varies among foods, so they are not comparable.
8. Food allergic individuals should carry 2 self-injectable epinephrine devices and antihistamine at all times in case of emergency. Self-injectable epinephrine devices should be renewed once a year.
9. Epinephrine given for an allergic reaction is most effective when administered intramuscularly into the thigh muscle.
10. Biphasic reactions can occur in up to 20% of anaphylactic cases, and monitoring patients for 4-6 hours after a food allergy reaction is recommended.
11. Corticosteroids are not useful in the acute management of an allergic reaction because of slow onset, but they might prevent biphasic or protracted reactions.
12. Adolescents and patients with a history of asthma are at higher risk for fatal anaphylaxis and require additional education. Delay of epinephrine is also a risk factor for fatal anaphylaxis.
13. Food allergies have a profound effect on quality of life, and support groups and Websites of food allergy organizations (such as the Food Allergy and Anaphylaxis Network, or FAAN) can be useful.