Food allergies are immunologically mediated adverse reactions to foods that are often but not exclusively IgE mediated. Any food protein, and sometimes carbohydrate moieties,[1, 2] 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 the majority of these reactions. In children, 90% of food allergies can be attributed to cow's milk, chicken egg, soybean, wheat, peanut, tree nuts, fish, and shellfish.[3, 4] In adults, shellfish, fish, peanuts, and tree nuts are the foods most often implicated. The most serious allergic reaction is anaphylaxis, but food-related allergic reactions can include other types of reactions such as limited IgE reactions (eg, urticaria, angioedema), oral allergy syndrome (OAS) also known as pollen food allergy syndrome (PFAS), food protein-induced enterocolitis (FPIES), milk protein-induced allergic proctocolitis, and eosinophilic esophagitis and eosinophilic gastroenteritis.
IgE-mediated reactions
Signs and symptoms of IgE-mediated reactions, including anaphylaxis, which is a rapidly progressive, life-threatening reaction, include:
OAS/PFAS
FPIES [8, 9]
Milk protein-induced proctocolitis (infants) [8, 9, 10]
Esinophilic gut disease [11]
Medical history
In addition, obtain a thorough description of each reaction, including the following:
Physical examination
Physical examination findings are most useful for the following:
See Clinical Presentation for more detail.
Specific laboratory tests for some hypersensitivities are not available; food protein-induced enterocoloitis and milk protein-induced proctocolitis cannot be identified by laboratory tests.
Laboratory studies that may be helpful in identifying IgE-induced food hypersensitivity include the following:
Skin testing
Biopsy
When eosinophilic gut disease is suspected, biopsy of the gut for evaluation of eosinophilic infiltrates is warranted.
Diet-related diagnostic measures
These may be helpful as follows for most forms of food allergy:
See Workup for more detail.
There are currently no curative therapies for food allergy. The only proven treatment is strict dietary elimination of the offending food allergen. A properly managed, well-balanced elimination diet includes the following elements:
Adherence to avoidance measures notwithstanding, accidental or inadvertent ingestions may occur and lead to a reaction. Strategies for dealing with such a reaction include the following:
Emergency medications include the following:
In severe anaphylaxis, ventilatory and circulatory support may be needed.
Preventive therapies include the following:
See Treatment and Medication for more detail.
Food allergies are immunologically mediated adverse reactions to foods that are often but not exclusively immunoglobulin E (IgE) mediated. Any food protein, and sometimes carbohydrate moieties, 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 the majority of these reactions. In children, 90% of food allergies can be attributed to cow's milk, chicken egg, soybean, wheat, peanut, tree nuts, fish, and shellfish.[3, 4] In adults, shellfish, fish, peanuts, and tree nuts are the foods most often implicated. Symptoms observed in a food-induced anaphylactic reaction most frequently involve the skin, gastrointestinal tract, and respiratory tract.[1]
The most serious allergic reaction is anaphylaxis, but food-related allergic reactions can include other types of reactions such as limited IgE reactions (eg, urticaria, angioedema), oral allergy syndrome (OAS) also known as pollen food allergy syndrome (PFAS), food protein-induced enterocolitis (FPIES), milk protein-induced allergic proctocolitis, and eosinophilic gut disease. While IgE-mediated reactions are immediate, some food allergies result in chronic disorders (eg, FPIES, eosinophilic esophagitis). 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.[35] (See Workup.)
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.
IgE antibody–mediated responses are the most widely recognized form of food allergy and account for most reactions. IgE-mediated reactions are generally acute, and most reactions occur within minutes of ingesting the offending food.
Patients with atopy produce IgE antibodies to specific epitopes (areas of the protein or carbohydrate moieties) 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.[4]
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 vasodilation, smooth muscle contraction, and mucus secretion, which, in turn, are responsible for the spectrum of clinical symptoms observed during acute allergic reactions to food.
T-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 production of the cytokine tumor necrosis factor (TNF)-alpha.[36] 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.[37] Celiac disease is the result of an immune response to gluten proteins in grains.
Eosinophilic esophagitis and gastrointestinal disease are eosinophilic mediated. Eosinophil granules release substances toxic to multiple tissues. These substances include major basic protein 1 and 2, eosinophilic cationic protein, eosinophilic-derived neurotoxin, and eosinophil peroxidase. Triggering of eosinophils leads to the generation of proinflammatory cytokines including Il-1, Il-3, Il-4, Il-5, and Il-13, and granulocyte-macrophage colony-stimulating factor.[11] Eosinophil degranulation is responsible for tissue damage in eosinophilic gut disease.
Food allergens that cause IgE-mediated reactions have been studied extensively. They 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.[22] Delayed allergic reactions to meat proteins have been attributed to reactions to carbohydrate moieties.[2]
Food allergies are primarily the result of immune responses to food proteins (allergic reactions to non-protein food additives are uncommon but do occur).[38] Normally, noninflammatory immune responses develop to ingested foods in a process called oral tolerance.[39, 40] 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 allergy 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, especially in patients with atopic dermatitis.[41]
Controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis.[14] Studies show that among patients with moderate chronic atopic dermatitis, 35–40% have IgE-mediated food allergy.[42, 43] Food-specific IgE-mediated and cellular mechanisms may be partially 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.[44, 45] 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.[46]
Because it is often difficult to isolate which food/foods are responsible for atopic dermatitis exacerbations, consideration must be given to false positive–specific IgE in the face of elevated total IgE. Nutritional concerns (especially for children) and practicality of multiple food elimination diets for atopic dermatitis must also be considered.
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.[47, 35] Teenagers and young adults appear to be overrepresented in registries of food allergy fatalities and present a special risk group.
Risk of atopy is more common in children of atopic parents.
General surveys report that as many as 25–30% of households consider at least 1 family member to have a food allergy.[48, 49] 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.[50]
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.[51]
Among children, males appear to be more affected; among adults, females are more frequently affected.[52] The prevalence of food allergies has been estimated to be up to 8% in infants and children and 3.7 % in adults.[53, 54]
However, variations in prevalence have been reported according to method used (self-report, testing, physician evaluation), geographic region, and foods included in the assessment.[55]
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.[56]
Studies in the United States and the United Kingdom indicate a rise in peanut allergy among young children in the past decade.[52, 57, 54] One study showed an increase of peanut allergy in children from 0.4% in 1997 to 0.8% in 2002.[52] Studies from Canada and the United Kingdom indicate allergy rates to peanut of over 1% in children.[58, 59]
A report from the US Centers for Disease Control and Prevention (CDC) indicated that 5.8% of children nationwide had a food allergy in 2021. The percentage of children with a food allergy increased with age, from 4.4% in children 0–5 years old to 5.8% in children 6–11 years old, and 7.1% in children 12–17 years old.[60]
Based on available studies, estimations of the rate of food allergies in children have been summarized as follows for common food allergens:[53]
Research indicates that racial and socioeconomic disparities play a crucial role in shaping the landscape of food allergy prevalence, access to care, and health outcomes.
According to a 2023 study, in the United States, Hispanic, Black, and Asian individuals experience higher rates of allergies across all age groups. Prevalence rate was 10.6% in Hispanic and Black individuals, 10.5% in Asian individuals, and 9.5% in White individuals. The study also found that prevalence of food allergies was lowest among households in the highest income bracket (> $150,000 annually).[61]
Another study found that people of color are less likely to have an allergy diagnosis but have higher rates of food-induced anaphylaxis.[62]
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.[63, 11]
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, one 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, and may also be the treatment.
In addition to diet therapy (or in place of diet therapy), anti-inflammatory medications (eg, corticosteroids) may be needed. Eosinophilic esophagitis appears to be a chronic disease, and fibrosis and stricture formation can occur. Updated diagnostic and treatment approaches have been proposed.[64]
Food protein–induced enterocolitis syndrome (FPIES) typically manifests in the first few months of life with severe projectile vomiting, diarrhea, and failure to thrive.[8] Cow milk and soy protein formulas are usually responsible for these reactions. However, solid foods may also trigger these reactions, especially rice and oats.[9]
When the allergen is removed from the diet, symptoms resolve. Re-exposure prior to resolution results in a delayed (about 2 hours) 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.
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 if the infant is breastfed, and elimination of the cow's milk formula will resolve symptoms in bottle-fed infants. The majority of infants will tolerate cow's milk protein by the first year of life. Eosinophilic inflammation of the rectum is noted if a biopsy is performed.[10] Additional causes of bleeding (eg, infection, fissures) should be considered.
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.
Patients with this syndrome are sensitized to pollen (allergic rhinitis and/or asthma) that cross-reacts with particular foods, most commonly raw fruits or vegetables. They 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.[7]
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 apple, raw carrots, celery, potato, peach or hazelnut.
This is a cross-reactivity syndrome in persons sensitized (IgE) to natural rubber. Of those patients sensitized to latex, 30%–50% also have reactions to avocado, banana, chestnut, kiwi, peach, tomato, potato, and bell pepper.[65, 4]
This is an IgE-mediated response to the glycan galactose-alpha-1,3-galactose (alpha-gal) primarily associated with hard-bodied tick bites with cross-reactivity to mammalian meats.[2]
This syndrome is IgE mediated, but anaphylaxis occurs only when the offending food ingestion is coupled with exercise. Symptoms are primarily angioedema and urticaria, wheezing and shortness of breath, abdominal pain, diarrhea, and vomiting. Symptoms generally occur within the first 30 min of exercise.
It can be a challenge to differentiate this syndrome from exercise induced anaphylaxis not associated with food allergy.
It is treated as any other anaphylaxis is treated, but precautions should include not exercising alone. Epinephrine injector should always be carried during exercise, and a medical alert bracelet is advised.
Although wheat was one of the first food allergens associated with this syndrome multiple foods and alcohol have been associated with this syndrome.[66]
Many infants and young children outgrow or become clinically tolerant of their early IgE food hypersensitivities, specifically allergies to milk, egg, soy, and wheat. However, allergies to peanut, tree nuts, fish, and shellfish are more persistent.[67]
Component testing for certain allergens such as peanut and egg can allow prediction of whether or not the IgE allergy to these foods will be permanent and severe or transitory and less severe.[18, 19]
Population-based studies generally show that 85% of young children outgrow their allergy to milk or egg by age 3–5 years.[67] 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.[68, 69, 70] 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.[71] Eosinophilic esophagitis and eosinophilic gastroenteritis are persistent disorders.[72]
Severe anaphylactic reactions from food can result in death.[47, 35] 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.[35]
Patients should always carry a self-injectable epinephrine device 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 and preferably 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.
School treatment plans and allergen avoidance plans should be provided to parents of school-age children.[27, 73, 74]
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.
Inform patients with food allergies how to identify and use support groups. One such organization is the Food Allergy Research and Education group.
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.
IgE-mediated reactions
Signs and symptoms of IgE-mediated reactions including anaphylaxis, which is a rapidly progressive, life-threatening reaction. Other signs and symptoms may include the following:
Oral allergy syndrome/pollen food allergy syndrome (OAS/PFAS)
Food protein-induced enterocolitis (FPIES) [8, 9]
Milk protein-induced proctocolitis (infants) [8, 9, 10]
Eosinophilic gut disease [11]
Food-induced anaphylaxis
Necessary elements of a thorough medical history include the following:
In addition, obtain a thorough description of each reaction, including the following:
Physical examination findings are most useful for the following:
Complications of food protein-induced enterocolitis syndrome (FPIES), milk-induced proctocolitis, and eosinophilic gut diseases include weight loss and failure to thrive.
Eosinophilic esophagitis can cause difficulty swallowing, food impaction, and strictures.
All food allergies can lead to anxiety and food avoidance issues, which may require counseling.
Anaphylaxis can lead to death.
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 and consider FPIES or eosinophilic gut disease as well as non-allergic etiologies.
Because specific laboratory tests for some food hypersensitivities are not available, diagnosing non-gE–mediated food allergies (eg, cow milk–induced and soy-induced enterocolitis syndromes or allergic eosinophilic gastroenteritis) is very reliant on history.
In cases of allergic eosinophilic gastroenteritis, a biopsy may needed to confirm the diagnosis, but it will not specifically identify the causative food. Elimination diets with gradual reintroduction of foods and supervised oral food challenges are often needed for identification of the causative food or 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 the patient is observed 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 a hospital setting.[4, 75]
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.[75]
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, recent use of antihistamines, 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 can be 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.[76, 77] The concentration of food-specific IgE does not correlate well with the severity of an allergy.
Some serum IgE studies have reported levels indicative/predictive of allergy.[76, 78] 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.[79] 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 multiple foods.[80, 81]
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 (BATs) have historically been limited to research settings but may be emerging as clinical tests for severe allergic reactions. BAT measures immediate histamine release from basophils. It may be a useful tool in evaluating IgE reactions from low-molecular-weight substances.[17, 20]
Studies are underway to determine if analysis of IgE epitope binding provides additional diagnostic information.[82]
The diagnostic value of performing the following tests is not currently supported by objective scientific evidence:
A diet diary involves 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 their 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 a significant amount of a food to which they were thought to be allergic.
An elimination diet 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 7–14 days) while the patient is monitored for an associated decrease in symptoms. The trial elimination diet may be most useful to evaluate chronic symptoms but is reliant on adherence of patient.
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.
Skin prick tests are the most common screening tests for IgE-mediated 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).[83, 84]
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.[85, 86] 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.
Patch tests evaluate for cell-mediated, delayed-type hypersensitivity.
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,[87] enterocolitis,[88] and atopic dermatitis.[89] Additional studies are needed to better characterize the utility of the results.[90]
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.[28, 91, 92]
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 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.
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.
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.
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.[93]
This type of challenge is designed to reduce patient and observer bias and subjective attitudes during the procedure. DBPCFC is considered the 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, but it is difficult to perform in clinical settings.
The primary preventive therapy against a recurrent 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.[90] The guidelines do not cover issues for schools, which are of interest to pediatricians, but a 2010 Clinical Report reviews this topic area.[94]
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 for 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 of food allergy and help to avoid nutritional deficiencies.
Educate the patient and family about how to properly read food labels and identify common words used to indicate 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. Inhalation of allergens may occur while some foods 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. Occupational allergy/asthma to food proteins that are inhaled is also reported.[95]
Anticipate potential candidates for food allergen cross-reactivity, such as the following:[22]
Less likely candidates for food allergen cross-reactivity include:
Encourage avoidance of high-risk situations (eg, buffets, picnics) where accidental or inadvertent ingestion of food allergens can occur. Advise 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).[96, 97]
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.[29, 31]
Studies are under way to determine if oral, sublingual, or epicutaneous immunotherapy is safe and effective for other food allergies, with some promising results.[30] 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).
Omalizumab
Omalizumab (Xolair) is the first medication approved by the FDA to reduce IgE-mediated food allergies that may occur due to accidental exposure in patients aged 1 year and older. It is used in conjunction with food allergen avoidance. Subcutaneous dose and frequency of omalizumab is determined by total IgE level and body weight.
Approval was based on the Phase 3 OUtMATCH study. Among 177 children and adolescents randomized, 67% (79/118) of those who received omalizumab were able to tolerate ≥ 600 mg peanut protein compared with 7% (4/59) of those who were taking placebo (P< 0.001). Similar results were observed with cashews, eggs, milk, walnuts, hazelnuts, and wheat.[28]
Studies are under way to determine whether therapies with modified food proteins are safe and effective. Promising results from a phase II study support a modified milk protein 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 a modified milk protein (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 modified milk protein 300 µg for 12 months.[98] The modified milk protein is not yet FDA-approved for treatment.
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 eosinophilic esophagitis or gastroenteritis, failure to thrive, and malabsorption syndromes may benefit from consultation with an allergist and a gastroenterologist.
The Learning Early about Peanut Allergy (LEAP) study addressed the possibility that early ingestion of peanut, rather than delay, may prevent peanut allergy.[99]
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.[100]
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.[101]
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.[102]
Early introduction of other foods is also now encouraged by extrapolation from the LEAP study.
The Allergy Immunology Joint Task Force on Practice Parameters (JTFPP) published a 2023 practice parameter update for anaphylaxis.[103, 104]
Diagnosis of anaphylaxis
The JTFPP recommends that clinicians obtain a baseline serum tryptase (bST) level in patients presenting with a history of recurrent, idiopathic, or severe anaphylaxis, particularly those presenting with hypotension.
The JTFPP suggests drawing an acute-phase tryptase level as early as possible during a suspected anaphylactic event (ideally within 2 hours after onset of symptoms). The JTFPP also suggests drawing a second tryptase measurement at a later time as a baseline for comparison to determine whether there was a significant acute elevation.
Clinicians should consider evaluating for hereditary alpha tyrptasemia, an autosomal dominant trait that is defined by an increased gene copy number encoding alpha (a)-tryptase. This genetic variant is characterized by elevated baseline serum tryptase and may predispose to allergic reactions.[105]
Anaphylaxis in infants and toddlers
Because there are no criteria specific to infants and toddlers, the JTFPP suggests that clinicians use current National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network (NIAID/FAAN) or World Allergy Organization (WAO) anaphylaxis criteria to assist in the diagnosis of anaphylaxis in infants/toddlers.[73, 74]
The JTFPP suggests that clinicians prescribe either the 0.1-mg or the 0.15-mg epinephrine autoinjector (EAI) dose for infants/toddlers weighing less than 15 kg.[104, 106]
For patients with mild reactions, such as localized urticaria, oral pruritis, or rhinorrhea, 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 preferably in the lateral thigh.[107] Patients must be educated regarding when to use their self-injector with proper technique. They should also be instructed to obtain immediate medical assistance (eg, call 911) in the event of anaphylaxis.
Epinephrine should 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.
Patients and providers 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 relief of respiratory symptoms.[107] 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.[31]
In 2024, the FDA approved the first medication (ie, omalizumab) to reduce IgE-mediated food allergies.[28] It is now approved for prophylaxis in a patients with multiple food allergies.
Clinical Context: 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.
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.
Clinical Context: 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 relief of symptoms caused by release of histamine in allergic reactions.
Clinical Context: 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.
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.
Clinical Context: Indicated for reduction of allergic reactions (Type I), including anaphylaxis, that may occur with accidental exposure to foods in adult and pediatric patients aged 1 year and older with IgE-mediated food allergy.
Recombinant humanized monoclonal antibody. Selectively binds to IgE and inhibits binding to IgE receptors on surface of mast cells and basophil.
Immunotherapy implements gradual desensitization and maintenance to protect peanut allergic individuals in case of accidental exposure to an allergen.
Clinical Context: 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.