Food Allergies

Food allergies are immunologically mediated adverse reactions to foods. Such allergies can result in disorders with an acute onset of symptoms following ingestion of the triggering food allergen (eg, anaphylaxis), as well as in chronic disorders (eg, atopic dermatitis, eosinophilic esophagitis). Symptoms observed in a food-induced anaphylactic reaction may involve the skin, gastrointestinal tract, and respiratory tract. (See Pathophysiology, Etiology, and Presentation.)[6]

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 (medically supervised, gradual test feedings) . Sesame appears to be an emerging allergen. (See Etiology and Workup.)

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. (See Workup.)[7]

Adverse reactions to food that are not immune mediated are not considered to be food allergies. An example is lactose intolerance, which is caused by a deficiency of lactase. Adverse reactions to foods can also occur from toxic (eg, bacterial food poisoning) or pharmacologic (eg, caffeine) effects.

Although anaphylaxis can occur without skin symptoms, cutaneous reactions are the most common clinical manifestations of an allergic reaction to a food or food additive. Symptoms range from acute urticaria (most common) to flushing to angioedema to exacerbations of atopic dermatitis. Food allergy is rarely the cause of chronic urticaria or angioedema.

Atopic dermatitis

Controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis.[8] Studies show that among patients with moderate chronic atopic dermatitis, 35-40% have IgE-mediated food allergy.[9, 10] Food-specific IgE-mediated and cellular mechanisms appear responsible for chronic eczematous inflammation.

Removal of a specific food allergen may lead to reduction or resolution of clinical symptoms in affected patients; reintroduction of the food may then exacerbate the atopic dermatitis if it is food-responsive.[11, 12] 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.[13]

In a study of 619 exclusively breastfed infants, those with atopic dermatitis were significantly more likely to be sensitized to foods.[14, 15] In addition, a strong association between the severity of the dermatitis and sensitization was observed, and positive associations between atopic dermatitis and specific foods (egg, cow’s milk, and peanut) were found.

In addition to skin-prick testing against cow's milk, egg, cod fish, wheat, sesame, and peanut, infants in the study were screened for filaggrin loss-of-function (FLG) gene mutations.[15] FLG mutations were significantly associated with incidence of atopic dermatitis and higher median transepidermal water loss relative to dermatitis severity. Although children with atopic dermatitis were significantly more likely to be sensitized to foods, this effect was not related to FLG mutation inheritance.

Celiac disease

Celiac disease is the result of an immune response to gluten proteins in grain.

Dermatitis herpetiformis

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. Elimination of gluten from the diet usually leads to resolution of skin symptoms.

IgE-mediated gastrointestinal food allergy

These food allergy reactions include immediate hypersensitivity reactions and the pollen-food allergy syndrome (oral allergy syndrome). Specific gastrointestinal symptoms include nausea, vomiting, abdominal pain, and cramping. Diarrhea is found less frequently.

Pollen-food allergy syndrome (oral allergy syndrome)

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.[16]

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)

Symptoms vary according to location of the 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. Children may experience weight loss or failure to thrive.[17]

A complete blood count (CBC) 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.

Eosinophilic esophagitis is characterized by symptoms related to esophageal dysfunction, such as dysphagia and pain, and histologically by eosinophil-predominant inflammation. Pathologically, 1 or more biopsy specimens must show a peak of 15 or more eosinophils per high power field. Alternative explanations (eg, reflux) for symptoms/histopathologic abnormalities should be excluded.

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.

In addition to diet therapy (or in place of diet therapy), treatment with anti-inflammatory medications (eg, corticosteroids) may be needed. Eosinophilic esophagitis appears to be a chronic disease and fibrosis and stricture formation could occur. Updated diagnostic and treatment approaches have been proposed.[18]

Non–IgE-mediated gastrointestinal food allergy

Food protein–induced enterocolitis syndrome (FPIES) typically manifests in the first few months of life with severe projectile vomiting, diarrhea, and failure to thrive.[19] Cow milk and soy protein formulas are usually responsible for these reactions. However, solid foods may also trigger these reactions, especially rice and oats.[20]

When the allergen is removed from the diet, symptoms resolve. Reexposure prior to resolution results in a delayed (2h) onset of vomiting, lethargy, increase in the peripheral blood polymorphonuclear leukocyte count, and, later, diarrhea. Hypotension and methemoglobinemia may occur.

Infants with FPIES 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.

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.[21] Additional causes of bleeding (eg, infection, fissures) should be considered.

Upper and lower respiratory tract reactions

Upper respiratory reactions typically include nasal congestion, sneezing, nasal pruritus, or rhinorrhea. They are usually observed in conjunction with ocular, skin, or gastrointestinal symptoms. IgE-mediated pulmonary symptoms may include laryngeal edema, cough, or bronchospasm.

Asthma

Although wheezing can occur during a food-allergic reaction, foods do not appear to be a common trigger for chronic asthma.[22, 23, 24]

Food-induced pulmonary hemosiderosis (Heiner syndrome)

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.

While the precise immunologic mechanism is unknown, it is thought to be secondary to a non-IgE hypersensitivity process.

Food allergies are primarily the result of immune responses to food proteins. (Allergic reactions to non-protein food additives are uncommon.[23] ) Normally, noninflammatory immune responses develop to ingested foods in a process called oral tolerance.[25, 26] 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.[27]

IgE antibody-mediated responses

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 in 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

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.[28] 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.[29] Celiac disease is the result of an immune response to gluten proteins in grains.

Characteristics of food allergens

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 cross-react immunologically (ie, lead to the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less frequently cross-react clinically.[2] Delayed allergic reactions to meat proteins have been attributed to reactions to carbohydrate moieties.[30]

Risk factors

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.[31, 7] Teenagers and young adults appear to be overrepresented in registries of food allergy fatalities and present a special risk group.

General surveys report that as many as 25–30% of households consider at least 1 family member to have a food allergy.[32, 33] However, this high rate is not supported by controlled studies in which oral food challenges are used to confirm patient histories.

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.[34]

In a meta-analysis 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.[35]

Sex- and age-related demographics

Among children, males appear to be more affected; among adults, females are more frequently affected.[36] The prevalence of food allergies has been estimated to be up to 8% in infants and children and 3.7 % in adults.[37]

However, variations in prevalence have been reported according to method used (self report, testing, physician evaluation), geographic region, and foods included in the assessment.[38]

In a population-based survey study of 40,443 US adults, an estimated 10.8% were food allergic at the time of the survey, whereas nearly 19% of adults believed that they were food allergic. Nearly half of food-allergic adults had at least 1 adult-onset food allergy, and 38% reported at least 1 food allergy–related ED visit in their lifetime.[39]

Studies in the United States and the United Kingdom indicate a rise in peanut allergy among young children in the past decade.[36, 40] One study showed an increase of peanut allergy in children from 0.4% in 1997 to 0.8% in 2002.[36] Studies from Canada and the United Kingdom indicate allergy rates to peanut of over 1% in children.[41, 42]

A report from the US Centers for Disease Control and Prevention (CDC) indicated that among children aged 0–17 years, the prevalence of food allergies increased from 3.4% in 1997–1999 to 5.1% in 2009–2011, a 50% rise.[43]

Based on available studies, estimations of the rate of food allergies in children have been summarized as follows for common food allergens:[37]

• Cow milk - 2.5%

• Eggs - 1.3%

• Peanuts - 0.8%

• Wheat - 0.4%

• Soy - 0.4%

In general, most infants and young children outgrow or become clinically tolerant of their food hypersensitivities. Specifically, most "outgrow" allergies to milk, egg, soy and wheat. Allergies to peanut, tree nuts, fish, and shellfish are more persistent.[44]

Population-based studies generally show that 85% of young children outgrow their allergy to milk or egg by age 3-5 years.[44] However, studies reported from a referral center showed more persistence of egg, milk, and soy allergies, with only about 50% of patients resolving these allergies by age 8-12 years.[45, 46, 47] Children continued to lose their allergy into adolescent years.

About 20% of infants and young children experience resolution of their peanut allergy by the time they reach school age.

Children with non-IgE–mediated food allergies, such as proctocolitis and enterocolitis, typically resolve their food allergy in the first years of life.[48] Allergic eosinophilic esophagitis appears to be a persistent disorder.[49]

Morbidity and mortality

Severe anaphylactic reactions, including death, can occur following the ingestion of food.[31, 7] 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 food-induced anaphylactic reactions, although anaphylactic reactions to a wide variety of foods have been reported. Fatalities caused by reactions to milk have increasingly been noted.[7]

Preparation

Patients should always carry a self-injectable device with epinephrine that has been properly stored and is current (ie, not expired). Ensure that the patient receives proper training regarding when and how to use the injection device. Patients should also have an H1-blocker medication (again, properly stored and not expired) in a syrup or chewable tablet form available. In addition, patients should be instructed to obtain immediate medical assistance (eg, call 911) in the event of anaphylaxis.

Caregivers of children should be instructed on identification and treatment of allergic and anaphylactic reactions.

Avoidance of allergens

Complete avoidance of the offending food allergen is the best strategic approach and the only proven therapy once the diagnosis of food hypersensitivity is established. Therefore, patients with food allergies should be taught to recognize relevant food allergens that must be eliminated from their diet.

Instruct the patient about the proper reading of food labels and the need to inquire about food ingredients when dining out. If the patient is in doubt about a food or food ingredient, suggest avoidance of the food in question. Educate patients about the potential for food allergens to be present in medications and cosmetics.

Support groups

Inform patients with food allergies how to identify and use support groups. One such organization is the Food Allergy Research and Education group.

Early detection and treatment

Educate patients regarding recognition of the early signs and symptoms of a food-induced allergic reaction, and provide them with a written management plan for successfully dealing with these reactions.

Write a specific list of clinical signs and symptoms to look for if a reaction may be occurring, and include a clear management plan. An excellent example of such a plan is available on the Food Allergy Research and Education Web site.

Demonstrate to the patient and family how to actually administer medications, especially injectable epinephrine, in the event of an allergic reaction. To accomplish this, use demonstration trainer devices in the clinic setting. Reinforce that if injectable epinephrine is administered, the patient must be immediately evaluated in a medical setting.

For patient education information, see the Allergies Center, as well as Food Allergy and Severe Allergic Reaction (Anaphylactic Shock).

Symptoms of food-induced anaphylaxis can include the following:

• Oropharyngeal pruritus

• Angioedema (eg, laryngeal edema)

• Stridor

• Dysphonia

• Cough

• Dyspnea

• Wheezing

• Nausea

• Vomiting

• Diarrhea

• Flushing

• Urticaria

• Angioedema

• Ocular injection, ocular pruritus, conjunctival edema, periocular swelling

• Nasal congestion, nasal pruritus, rhinorrhea, and sneezing

• Abdominal pain

• Feeling of impending doom

• Cardiovascular collapse

History

Necessary elements of a thorough medical history include the following:

• Develop a complete list of all foods suspected to cause symptoms

• Discuss the manner of preparation of the food (cooked, raw, added spices or other ingredients)

• Determine the minimum quantity of food exposure required to cause the symptoms

• Determine the reproducibility of symptoms upon exposure to the food

• Inquire about a personal or family history of other allergic disease

• Inquire about eliciting factors that can potentiate a food-allergic reaction (eg, exercise[1] , nonsteroidal anti-inflammatory drugs [NSAIDs], or alcohol)

In addition, 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 one’s severity

• The duration of the reaction

• The treatment provided and the clinical response to treatment

• The most recent reaction

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.[50]

Physical examination

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.

The approach to the diagnosis of food allergy requires consideration of the history, the epidemiology of food allergic disease, cross-reactivity, and the degree of positivity of tests; these must be evaluated to assist in diagnosis. Simple tests for food-specific IgE antibodies are available, but the clinician must appreciate that a positive test for food-specific IgE primarily denotes sensitization and may not confirm clinical allergy. A physician-supervised oral food challenge may be required for diagnosis.

When the history of an allergic reaction to a food suggests that the onset of symptoms is delayed by hours or days following ingestion, adjust the timing and monitoring of the challenge to correspond to these characteristics.

Because specific laboratory tests for some food hypersensitivities are not available, diagnosing non–IgE-mediated food allergies (eg, cow milk–induced and soy-induced enterocolitis syndromes or allergic eosinophilic gastroenteritis) is more difficult than diagnosing IgE-mediated food allergies.

In cases of allergic eosinophilic gastroenteritis, a biopsy may need to be performed. Elimination diets with gradual reintroduction of foods and supervised oral food challenges are often needed to help identify the causative foods.

For food protein–induced enterocolitis syndrome, the oral food challenge is typically performed with 0.15-0.30 g of protein per kilogram of body weight of the implicated protein and observe the patient for several hours. Positive reactions (eg, profuse vomiting, diarrhea) are typically accompanied by a rise in the absolute neutrophil count of more than 3500 cells/mm3 (see the Absolute Neutrophil Count calculator). Because of the potential for shock, these challenges are best performed in the hospital setting.

The successful administration of oral food challenges to young children requires a great deal of preparation, patience, and creativity. Young children may refuse to ingest the challenged food. Prior planning with the family is important to choose proper vehicles (eg, juice, cereal, solid food) for disguising the challenged substance.[51]

IgE antibody testing

Specific IgE antibodies to foods can be quantified by in vitro laboratory methods. The term RAST (radioallergosorbent test) is antiquated because modern methods do not use radiation.

The serum test may offer advantages over skin prick testing when skin testing is limited by dermatographism, generalized dermatitis, or a clinical history of severe anaphylactic reactions to a given food. However, although the serum test provides information similar to the skin prick test, it is more expensive and results are not immediate.

Studies have correlated the outcomes of physician-supervised oral food challenges with serum test results. While the studies have generally shown increasing risks of reaction with increasing concentrations of allergen, the specific correlations vary among studies.[52, 53] The concentration of food-specific IgE does not correlate very well with the severity of an allergy.

Studies (so far primarily using 1 brand of test system) have reported levels highly indicative of allergy (>95%).[52, 54] However, specific results have varied among studies, which is probably due to differences in patient selection, interpretation of positive outcomes, and other factors. Only a few foods have been analyzed in this manner (primarily peanuts, eggs, and milk), and predictive results are different for the different foods.

Test systems vary with regard to measurements, and similarly reported results may not be equivalent.[55] The clinician should also be aware of different reporting units that are not interchangeable with one another (eg, class vs units vs percentage).

An emerging serum test is component resolved diagnosis (CRD). Foods are composed of many proteins to which an IgE immune response may develop. IgE responses against labile proteins may carry little risk of significant allergy because these proteins presumably do not easily enter the circulation. In contrast, stable proteins are clinically relevant. With peanut, for example, the proteins Ara h 1, Ara h2, Ara h 3, and Ara h 9 are relatively stable, while Ara h 8 is a pollen related protein that is labile. In CRD, positive testing to Ara h 8 with negative results to Ara H 1-3 and 9 is typically not associated with any significant clinical allergy. These types of tests are being evaluated for improved diagnosis for many foods.[56, 57]

Peripheral serum measurements of eosinophils or total IgE concentrations

Abnormal results from these tests do not identify or confirm the diagnosis of food allergy. Likewise, normal values do not exclude diagnosis.

Basophil histamine-release assays

These tests are limited primarily to research settings and have not been shown conclusively to provide reproducible results useful for diagnostic testing in a clinical setting.

Other

Studies are underway to determine, for example, if analysis of IgE epitope binding provides additional diagnostic information.[58]

This consists of keeping a chronological record of all foods eaten and any associated adverse symptoms. It is an inexpensive endeavor that documents the frequency of symptoms and their occurrence in relationship to food ingestion. In addition, it encourages the patient to focus on his or her diet.

This record is occasionally helpful for identifying the food implicated in an adverse reaction; however, it is not usually diagnostic, especially when symptoms are delayed or infrequent.

Occasionally, review of the diet diary reveals that the patient is not experiencing a reaction when eating, as an ingredient in other foods, a significant amount of a food to which he or she was thought to be allergic.

This is used for diagnostic and treatment purposes. When used as a diagnostic tool, the elimination diet requires complete avoidance of suspected foods or groups of foods for a given time period (usually 7-14d) while the patient is monitored for an associated decrease in symptoms. The trial elimination diet may be most useful to evaluate chronic symptoms.

Success depends on identifying the correct food allergen and completely eliminating it from the diet. Limitations of this method include potential effects of patient or physician biases, variable patient compliance, and the time-consuming nature of the endeavor.

If symptoms improve, confirmation of the food as causal typically requires a medically supervised oral food challenge.

When the elimination diet is used as treatment, identified food allergens are removed from the diet indefinitely unless evidence exists that the food allergy has resolved.

Prick and puncture tests are the most common screening tests for food allergy and can even be performed on infants in the first few months of life. However, the reliability of the results depends on multiple factors, including use of the appropriate extracts and testing technique, accurate interpretation of the results, and avoidance of medications that might interfere with testing (eg, antihistamines).[59, 60]

When used in conjunction with a standard criterion of interpretation and appropriate controls (eg, histamine: positive; saline: negative), these tests provide useful and reproducible clinical information in a short period (ie, 15-20 min), with minimal expense and negligible risk to the patient.

This is a reliable method of excluding IgE-mediated food allergies. The negative predictive accuracy is generally greater than 90%; however, the positive predictive accuracy is generally less than 50%, which limits clinical interpretation of positive skin test results. Similar to in vitro testing, interpretation of the test results must consider the clinical history (to assess prior probability) and other factors, such as the likelihood, from epidemiologic observations, of the food being an allergy trigger.

The larger the skin test wheal size, the more likely that a clinical allergy exists.[61, 62] Positive skin test results, in addition to the suggestion of clinical reactivity based on the patient’s history, must often be confirmed by an oral food challenge unless the patient has a convincing history of significant food allergy.

A physician-supervised (medically supervised) oral food challenge involves gradually feeding the patient the food suspected to be causing an allergy, with careful assessment for any symptoms. If symptoms occur, the feeding is discontinued and medications are administered.[63]

Food challenges are typically preceded by a period of elimination of the suspected food. They are conducted when the patient is at a stable clinical baseline and not taking medications that could interfere with the observation of symptoms (eg, antihistamines).

Of these procedures, the double-blind, placebo-controlled food challenge (DBPCFC) is the most reliable method to help diagnose and confirm food allergy and other adverse food reactions, because it eliminates patient and observer bias. However, in a clinical setting where minimal bias is suspected, open food challenges may be preferable, because blinding of the food is often not required.

Conduct any food challenge in a clinic or hospital setting with the personnel and equipment necessary to treat a systemic allergic reaction available at all times. Patients undergoing a food challenge should not be taking beta-blocker medications or any medication that might interfere with the treatment of anaphylaxis. If indicated by risk assessment, obtaining intravenous access may be prudent.

Clinically indicated oral food challenges are not generally performed when the history and test results already support a current diagnosis of allergy to the target food.

The decision to proceed to an oral food challenge must consider many factors, including the likelihood of a reaction, the severity of a reaction if one were to occur, the need to obtain a definitive diagnosis, and social and nutritional factors, among others.

When performing oral food challenges, be prepared to recognize and treat adverse clinical symptoms immediately. Appropriately trained personnel and the necessary equipment for the treatment of anaphylactic shock must be available prior to and throughout the entire oral food challenge and observation period because of the risk of triggering an allergic reaction. Patients should never be instructed to perform a food challenge at home.

Confirm negative results from a double-blind, placebo-controlled food challenge (DBPCFC) using an open feeding (open food challenge) of the food in question in its usual form and quantity before giving final advice on dietary restrictions.

Open food challenge

This test involves the patient ingesting the suspected food, prepared in its customary fashion (ie, the challenge food is not disguised in any way). The patient and the observer (eg, physician, nurse) are aware of the food being ingested. The open food challenge is best used in clinical practice when the patient and physician bias is minimal.

Whenever the results are equivocal, perform a blinded challenge. Patients with a history of a previous reaction should never perform an open food challenge at home, even if the chance that they will develop severe symptoms is remote.

Single-blind food challenge

This challenge involves the patient ingesting the suspected food disguised in a challenge food so that the patient is unaware of the contents.

This type of challenge, which is suitable for clinical practice and some research investigations, is designed to reduce patient bias during the procedure. However, subjective attitudes regarding the outcome of the challenge cannot be completely eliminated.

Double-blind, placebo-controlled food challenge

DBPCFC involves supervised, gradual ingestion of the suspected food disguised in another food (or hidden in capsules). A food similar in taste and appearance, but without the allergen, is used as a placebo control. The feeding (potential allergen vs placebo) is randomized so that the patient and the observer are unaware of the contents of the challenge at the time of the feeding and observation. Feeding of the allergen and placebo may be separated by hours or days.[64]

This type of challenge is designed to reduce patient and observer bias and subjective attitudes during the procedure. DBPCFC is considered the criterion standard for diagnosing food allergies and is particularly used in research investigations. Currently, it is the only completely objective method for determining the validity of the history of an adverse reaction to a food.

Intradermal skin testing

The risk of inducing a systemic reaction with this type of testing is increased in comparison with the prick or puncture method; as a result, intradermal skin testing for food allergies should be avoided. In addition, the results obtained by using this method are less specific than are those obtained by using prick or puncture testing.

Patch tests

Patch tests are performed by exposing the skin to the food allergen for 24 hours under occlusion and then evaluating the area for erythema and papules in the subsequent 24-72 hours.

The test has been evaluated for diagnosis of food allergy in eosinophilic esophagitis,[65] enterocolitis,[66] and atopic dermatitis.[67] Some studies show promise for this technique, but additional studies are needed to better characterize the utility of the results.[68]

Peripheral serum measurements of eosinophils or total IgE concentrations

Results from these tests support but do not confirm the diagnosis of food allergy. Likewise, normal values do not exclude diagnosis.

Basophil histamine-release assays

These tests are limited primarily to research settings and have not been shown conclusively to provide reproducible results useful for diagnostic testing in a clinical setting.

Other

The diagnostic value of performing the following tests is not currently supported by objective scientific evidence:

• Food-specific IgG or IgG-subclass antibody concentration testing

• Testing for food antigen-antibody complexes

• Leukocyte cytotoxic tests

• Provocation and neutralization testing

• Kinesiology-based testing

The only proven medication therapy against a food allergy is strict elimination of the offending food allergen from the diet and avoidance of any contact with the food by ingestion, skin contact, inhalation, or injection.

In 2010, Guidelines for the Diagnosis and Management of Food Allergy in the United States were published. These provide evidenced-based, expert panel recommendations for the diagnosis and management of food allergies.[68] The guidelines do not cover issues for schools, which are of interest to pediatricians, but a 2010 Clinical Report reviews this topic area.[69]

Injectable epinephrine is the drug of choice for the initial management of a food-induced anaphylactic reaction. Ensure that the patient has self-injectable epinephrine readily available at all times. Advanced medical therapy of food allergen–induced anaphylaxis may include antihistamines, bronchodilators, histamine 2 (H2) blockers, corticosteroids, and administration of intravenous fluids, glucagon, and oxygen. In severe anaphylaxis, ventilatory and circulatory support may be needed.

A properly managed, well-balanced elimination diet (eg, allergen restriction) can lead to resolution of symptoms and help to avoid nutritional deficiencies.

Educate the patient and family about how to properly read food labels and identify common words used for indicating the presence of the food allergen of concern. US labeling laws now require major allergens (ie, egg, milk, wheat, soy, peanut, tree nuts, fish, crustacean shellfish) to be identified as ingredients on manufactured food products using plain English terms. Note that not all potential allergens are included and that some may be subsumed under terms such as spices or natural flavor. Advisory labels (eg, may contain) are not regulated, are voluntary, and may reflect variable risks.

Meal preparation must consider avoidance of cross contact (eg, through shared utensils or fryers) of allergens with otherwise safe foods.

With elimination diets, exclude only those foods confirmed to provoke allergic reactions. Review obvious and hidden sources of food allergens. Be aware of the potential for exposures by routes other than ingestion, such as skin contact, or inhalation. This concern is particularly problematic for foods while they are being cooked, because proteins are dispersed in the steam (eg, frying fish, boiling milk). Educate patients about the potential for food allergens to be present in medications and cosmetics.

Anticipate potential candidates for food allergen cross-reactivity, such as the following:[2]

• Eggs and chicken (< 5% of patients have both allergies)

• Cow milk and beef (10% of patients with milk allergy react to beef)

• Cow milk and goat milk (>90% allergic to cow milk also react to goat/sheep milk)

• Fish (>50% allergic to any finned fish are reactive to all types)

• Peanuts and other legumes (< 10% with a peanut allergy react to other legumes)

• Soy and other legumes (< 5% with a soy allergy react to other legumes)

• Wheat and other grains (25% with a wheat allergy react to rye and barley)

• Tree nuts and other nuts (>50% with an allergy to a tree nut react to others)

Encourage avoidance of high-risk situations (eg, buffets, picnics) where accidental or inadvertent ingestion of food allergens can occur. Instruct patients to discuss their food allergies with restaurant and food establishment personnel.

Despite following stringent avoidance measures for clinically relevant food allergens, accidental or inadvertent ingestions may occur. Therefore, patients must be instructed on actions to take in the event of a reaction. A concise written plan for the treatment of allergic reactions resulting from accidental exposure to a patient’s food allergen should be developed. Have copies of this plan available in appropriate places (eg, daycare, schools, work locations, college dormitory advisors). Examples of such a plan can be downloaded from www.foodallergy.org.

Patients with food allergies should be advised to obtain and wear medical identification jewelry indicating their food allergies.

Ensure that the patient has an emergency contact number available (eg, 911, their physician's office phone number, or a local emergency department) that can be used in the event of a major food-induced allergic reaction.

Anticipatory guidance measures cannot be overemphasized; for example, educate the patient about potential sources of accidental exposure to relevant food allergens (eg, daycare, school, travel, picnics, dining out).

Injectable epinephrine is the drug of choice for the initial management of a food-induced anaphylactic reaction. Ensure that the patient has self-injectable epinephrine readily available at all times. Also ensure that the patient receives proper training regarding when and how to use the injection device. An antihistamine should also be available. Patients with food allergies and asthma should always have access to a rapid-acting bronchodilator.

Self-injectable epinephrine is typically available by prescription (ie, EpiPen, EpiPen Jr, Adrenaclick 0.15 mg, Adrenaclick 0.3 mg, Auvi-Q 0.15 mg, Auvi-Q 0.3 mg). These devices should be stored properly (avoiding extremes of temperature) and replaced before the expiration date.

There are currently no curative therapies for food allergy. Injection immunotherapy is an accepted treatment for anaphylactic allergy to insect venoms and for environmental allergies, but it poses a high risk for food allergies (anaphylaxis to injected native food proteins).[70, 71]

Immunotherapy

The FDA approved the first immunotherapy for peanut allergy in early 2020. Peanut (Arachis hypogaea) allergen oral powder (Palforzia) mitigates allergic reactions that may occur with accidental exposure to peanuts. It is indicated for mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut in patients with a confirmed diagnosis of peanut allergy.

Approval was supported by a phase 3 trial of patients with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one-third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P< 0.001). Efficacy was not shown in the participants 18 years of age or older.[5]

Investigational treatments

Studies are under way to determine if oral, sublingual, or epicutaneous immunotherapy is safe and effective for food allergies, with some promising results.[4] Additional studies are needed to define the safety profile and side effects (short term and long term) and to determine whether treatment affects resolution of the allergy (tolerance without repeated dosing of the allergen) or desensitization (an increased threshold while undergoing dosing). A strategy using anti-IgE antibodies (omalizumab) in conjunction with oral immunotherapy is also under investigations as it may allow faster up-dosing with fewer side effects.

Studies are under way to determine whether therapies with modified food proteins are safe and effective. Promising results from a phase II study support Viaskin Milk as the first potential treatment for IgE-mediated cow's milk protein allergy (CMPA). The study, which evaluated the efficacy and safety of three dose regimens of Viaskin Milk (150 µg, 300 µg, 500 µg) in 198 milk-allergic patients, found a statistically significant desensitization to milk in children ages 2 to 11 years treated with Viaskin Milk 300 µg for 12 months.[72]  

Additional therapeutics may in the future be derived from investigations of cytokine and anticytokine therapies, as well as from the evaluation of traditional Chinese medicine.

Consultation with a board-certified allergist/immunologist should be considered when food allergy is suspected or confirmed.

Consultation with a nutritionist or nutrition service is invaluable in the overall management of food allergies. The elimination diet can be reviewed and appropriate substitutions can be recommended. Dietary deficiencies can be anticipated and prevented.

Consultation with a gastroenterologist is also useful in the evaluation of selected patients. For example, patients who present with possible anatomic gastrointestinal abnormalities, eosinophilic esophagitis or gastroenteritis, failure to thrive, and malabsorption syndromes may benefit from consultation with an allergist and a gastroenterologist.

Early introduction

The Learning Early about Peanut Allergy (LEAP) study addressed the possibility that early ingestion of peanut, rather than delay, may prevent peanut allergy.[73]

The UK study randomized 640 infants aged 4-11 months at high risk for developing peanut allergy, as defined by having severe eczema, egg allergy or both, to ingest or to avoid peanut to age 5 years. Infants were skin tested with peanut at screening and excluded if they had large test results (>4 mm) on the assumption they were already allergic. Two cohorts were identified: those with negative peanut skin tests (not sensitized) and those with skin test wheals 1-4 mm (sensitized). Infants were randomized 1:1 for avoidance or early consumption (6 g peanut protein/week); 542 were not sensitized to peanut at enrollment. Among the non-sensitized cohort, 13.7% in the avoidance group and 1.9% in the consumption group had peanut allergy at age 5 years (p< 0.001), an 86% reduction. In the sensitized group, the corresponding rates were 35.3% and 10.6%, respectively (p=0.004), a 70% reduction. Overall, those randomized to early ingestion experienced a relative risk reduction of 80%.

A follow-up study had the peanut-tolerant children avoid peanut for a year and undergo re-testing with results suggesting that the children had maintained the benefit even when not eating peanut so frequently.[74]

A Consensus report suggests that infants at high risk, like those in the LEAP study, be evaluated (by testing and possibly a medically supervised feeding) to determine if they can have peanut introduced into the diet early, as early as 4-6 months, to potentially prevent peanut allergy. The report substantially suggests following the LEAP study approach to testing and feeding, which includes using infant-safe forms of peanut protein.[75]

Another study randomized infants, who were not selected for high risk, to early feeding of a variety of allergens from 3 months of age. This study did not show a prevention effect in the intention-to-treat analysis.[76]

For patients with mild reactions, such as localized urticaria, oral itch, or mild abdominal pain, treatment may be limited to an oral antihistamine.

If the patient has systemic symptoms, the treatment of choice is self-injectable epinephrine administered by intramuscular injection in the lateral thigh.[77] Patients must be educated regarding when to use their self-injector and the proper technique. They should also be instructed to obtain immediate medical assistance (eg, call 911) in the event of anaphylaxis.

Epinephrine should likely be administered to any patient with a history of a severe allergic reaction as soon as ingestion of the food allergen is discovered and the first symptoms appear (and possibly even before symptoms appear).

Patients should not depend on bronchodilators or antihistamines to treat anaphylaxis. However, antihistamines can be used as additional therapy during an allergic reaction, and a bronchodilator may be used as adjunctive therapy for asthma.[77] Although corticosteroids are often given for anaphylaxis, they are not believed to alter the early symptoms; theoretically, they may reduce late symptoms.

The first immunotherapy for peanut allergy was approved by the FDA in 2020.[5]

Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

Diphenhydramine (Anti-Hist, Aler-Dryl, Benadryl)

This is a first-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and the body. It competitively blocks histamine from binding to H1 receptors. It is used for symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Cetirizine (Zyrtec)

Second-generation histamine H1-receptor antagonist. Competes with histamine on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract. Available in a variety of oral formulations (tablet, liquid, chewable, oral disintegrating) to allow ease of administration.

Class Summary

These are used in the emergency management of systemic allergic reactions or anaphylaxis (eg, urticaria, angioedema, bronchospasm, cardiovascular collapse). The effects are immediate and dramatic. The appropriate use of this class of medication can be lifesaving, especially in the emergency management of anaphylaxis.

Epinephrine (EpiPen, EpiPen Jr, Adrenaclick, Auvi-Q)

Epinephrine is the drug of choice for the treatment of anaphylaxis. It helps to decrease symptoms of anaphylaxis by increasing systemic vascular resistance, elevating diastolic pressure, producing bronchodilation, and increasing inotropic and chronotropic cardiac activity. In addition, epinephrine helps to reduce urticaria, angioedema, laryngeal edema, and other systemic manifestations of anaphylaxis. Products are available as autoinjectors to ease caregiver or self-administration. Auvi-Q also provides audible instructions and visual cues.

Class Summary

Immunotherapy implements gradual desensitization and maintenance to protect peanut allergic individuals in case of accidental exposure to an allergen.

Peanut oral allergen powder (Palforzia, Peanut Arachis hypogaea allergen powder-dnfp)

Indicated for mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut in patients with a confirmed diagnosis of peanut allergy. Treatment is administered in 3 sequential phases: Initial dose escalation, up-dosing, and maintenance. Administer initial dose escalation to patients aged 4-17 years; up-dosing and maintenance may be continued in patients aged 4 years or older. Use in conjunction with a peanut-avoidant diet. Efficacy was not shown in the clinical trial participants aged 18 years or older.