Food Allergies

A food allergy is an “adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.” IgE-mediated food allergy is a life-threatening systemic allergic reaction to antigens in food. 

The incidence of fatal food anaphylaxis is approximately 0.03 to 0.3 million people per year. Most deaths in the United States are caused by peanut allergy.

The common causes of food-related anaphylaxis in young children are

• Cow’s milk
• Eggs
• Peanuts
• Tree nuts (eg, almond, hazelnut, cashew, pistachio, pecan, walnut, Brazil nut, pine nuts)
• Fish
• Shellfish (eg, shrimp, crab, lobster, scallops)
• Wheat
• Soy
• Sesame seeds

Milk, eggs, peanuts, soy, and wheat collectively cause 90% of hypersensitivity reactions in young children. Peanut, tree nuts, fish, and crustacean shellfish cause approximately 85% of reactions in teenagers and adults.

In the United States in 2018, a large population survey revealed that among children with food allergies:

• 19.0% of parents reported at least 1 food allergy–related emergency department visit in the previous year.
• 40.7% of patients had a current epinephrine autoinjector prescription.

IgE-mediated food allergies are more frequent in children with certain atopic disorders, such as atopic dermatitis.

• Approximately 35% of children with moderate to severe atopic dermatitis have a food allergy. 
• The younger the child and the more severe the atopic dermatitis, the greater the likelihood that the child has a food allergy. 

Up to 8% of US children have a food allergy. 

• Prevalence rates of food allergy are higher among Black children and children with atopic comorbidities.
• Evidence points to increasing prevalence in developing countries, with rates of challenge-diagnosed food allergy in China and Africa reported to be similar to that in Western countries. (

Self-reported food allergy rates tend to be higher than rates confirmed by oral food challenge.

• Australia reports 10% prevalence by oral food challenge in infants aged 12 months (mostly to egg) and 4% at 4 years.
• One randomized control trial in the United Kingdom demonstrated a confirmed prevalence for food allergy of 7.1% at age 3 years in breastfed infants. Another UK study showed that challenge-proven food allergy was 4% for children younger than 5 years.
• In China, the prevalence varies between 2.5% and 5.5%, depending on geographic location.
• In children younger than 5 years, the prevalence of challenge-proven food allergy has been reported to be
  • 3.6% in Denmark
  • 6.8% in Norway

Immune recognition of dietary antigens is a normal feature of mucosal immune development and generally leads to oral tolerance rather than allergy. This tolerogenic process forms the basis for early introduction of foods such as peanut as a means of preventing food allergy. 

The pathogenesis of IgE-mediated food allergy involves 3 phases: sensitization, challenge, and the appearance of clinical findings.

1. Sensitization begins when a genetically predisposed child ingests, inhales, or touches an allergen.
   • Activation of helper T cell type 2 (TH2) cells and the release of cytokines eventually lead to specific IgE production.
   • Priming of basophils and mast cells occur when allergen-specific IgE binds to receptors on their surfaces.
   • A deficiency in immunoregulatory Treg cells are thought to play a major role in sensitization.
2.  The challenge phase occurs when the same allergen or one that is closely related cross-links receptors on the surface of basophils and mast cells. Cross-linking leads the primed cells to degranulate and release immune modulators.
3. The final phase of food allergy involves the production of the classic clinical manifestations. Typically, these are rapid-onset acute symptoms that can be life-threatening.

IgE-mediated food allergies manifest in various ways, depending on the organ system that is affected and the length of time after exposure.

Although rare, reactions may follow a biphasic course, with initial symptoms waning and severe symptoms occurring 1 to 2 hours later (or longer).

Symptoms of Food Allergy by Body System

Death appears to be more common in teenagers and young adults, possibly because of risk-taking behaviors.

• Fatalities occur typically in those with a diagnosed food allergy and asthma and delayed treatment with epinephrine, despite having clinically significant symptoms.
• Life-threatening symptoms include laryngeal edema, respiratory distress, and cardiovascular compromise.

The newborn gastrointestinal tract and gut-associated lymphoid tissue is responsible for the tasks of processing ingested food, developing immunity, and remaining unresponsive to large quantities of nutrient antigens. In the mature gut, about 2% of ingested food antigens are absorbed and transported through the body in an immunologically intact form. These proteins do not typically cause adverse reactions because tolerance develops in most individuals.

The development of an IgE-mediated response to an allergen is the result of a series of molecular and cellular interactions involving antigen-presenting cells (APCs), intestinal epithelial cells, T cells, and B cells.

• After antigen presentation and T-cell proliferation, B cells are stimulated and isotype switching occurs, leading to the formation of antigen-specific IgE.
• Specific IgE binds to surface receptors of mast cells, basophils, macrophages, and other APCs, priming the immune system for a reaction to the next encounter of the specific antigen.

Intestinal epithelial cells determine the rate and pattern of uptake of ingested antigens. Animal studies indicate that intestinal antigen transport proceeds in 2 phases.

Phase 1: Transepithelial Transport

• Occurs through endosomes
• Is antigen specific and mast cell independent
• Occurs 10 times faster in sensitized animals than in non-sensitized control animals

Phase 2: Transport

• Paracellular
• Mast cell dependent
• Not antigen specific
• Markedly increased by antigen challenge in sensitized animals compared to non-sensitized control animals

Thus, during IgE-mediated responses in sensitized individuals, both the rate and amount of antigen absorbed in the gastrointestinal (GI) tract increases. Although the response involves a specific antibody, cytokines likely play a role. Intestinal epithelial cells have multiple cytokine receptors and are altered by cytokine exposure.

Typically, serum-specific IgE (sIgE) antibodies to foods appear within the first 2 years after birth. A decrease over time in specific IgE may be associated with the development of tolerance to the food. Similarly, a reduction in the size of the skin prick test wheal may be a marker for the onset of tolerance. However, each food has unique characteristics with respect to whether most children do or do not outgrow that particular food allergy.

Most children with a food allergy to milk, egg, soy, and wheat eventually become tolerant. Far fewer eventually tolerate tree nuts and peanuts. Shellfish allergies tend to develop (and persist) later in childhood and/or in adulthood. 

The course of food allergy in children varies by food. Following are some common food allergens and their natural history in children.

Egg Allergy

Egg allergy affects 1.3% of children younger than 5 years and 0.9% of all children, according to a US national cross-sectional study of more than 38,400 children and parents. 

• 64% reported baked egg tolerance.
• 60% had allergy to other foods, with 29% having peanut allergy.
• Asthma was more prevalent in children with an egg allergy (47%) than in children with the other top 8 food allergies (33%).

Most infants with egg allergy become tolerant to egg at a young age. An estimated 66% of children become tolerant by age 7 years.

In a large retrospective study of children with an egg allergy, tolerance to egg was reported as follows:

• 4% by age 4 years
• 12% by age 6 years
• 37% by age 10 years
• 68% by age 16 years

In that study, tolerance was defined as passing an egg challenge or having an egg sIgE level less than 2 kUA/L and no symptoms in 12 months.

Persistence of egg allergy was associated with

• A high initial level of egg sIgE
• The presence of other atopic disease
• The presence of an allergy to another food

Milk Allergy

Studies from several countries show that cow’s milk allergy is present in approximately 2.5% of infants. Infants and children who develop a milk allergy tend to do so before 12 months of age. 

• Tolerance to milk eventually develops in most children. One study (ref) showed the percentage of milk tolerization over time to be
  • 19% by age 4 years
  • 42% by age 8 years
  • 64% by age 12 years
  • 79% by age 16 years
• The rate of decline of sIgE levels over time may be used to predict the development of tolerance to milk in children. 

Soy Allergy

Soy is a common allergy, occurring in approximately 0.4% of children.

In a retrospective review of 133 US children with soy allergy, the predicted resolution of soy allergy was

• 25% by age 4 years
• 45% by age 6 years
• 69% by age 10 years

Tolerance to soy was more common in children with lower sIgE levels, such that tolerance occurred in

• 59% of children with a peak soy sIgE level less than 5 kUA/L
• 18% of children with a peak soy sIgE level higher than 50 kUA/L

Wheat Allergy

Wheat allergy is one of the most common allergies.

In a US study of 103 patients with IgE-mediated wheat allergy (not celiac disease), rates of resolution were

• 29% by age 4 years
• 56% by age 8 years
• 65% by age 12 years

Although peak sIgE predicts persistence of wheat allergy, many children with even the highest levels of wheat sIgE outgrow their allergy.

Peanut Allergy

Between 1999 and 2010, the estimated prevalence of peanut allergy in US children increased from 0.4% to 2%. Peanut allergy is the leading cause of death related to food-induced anaphylaxis in the United States. Typically, peanut allergy begins soon after birth and persists as a lifelong problem.

• Peanut allergy is outgrown in approximately 22% of patients.
• Children who outgrow peanut allergy are at risk for recurrence.
  • Recurrence is significantly higher for those who avoid peanut after resolution of their allergy.
  • For this reason, peanut allergy is not considered resolved unless an individual has demonstrated ongoing peanut tolerance.

Tree Nut Allergy

The worldwide prevalence of tree nut allergy varies between 0.05% and 4.9%. 

• More than 2% of the pediatric population is affected by allergies to tree nuts, and many will carry these allergies into adulthood.
• Tree nut allergies with high prevalence in the United States include almond, walnut, and cashew allergies.
• Hazelnut appears to be the most common tree nut allergy in Europe, largely owing to its cross-reactivity with birch pollen, while pistachio allergy is the least commonly reported.
• Brazil nut allergy is particularly prevalent in the United Kingdom and in Australia, where 3% of children younger than 6 years have clinically confirmed allergy.
• Tree nut allergy is not as common in Asian countries as in Western countries.

On the basis of a US study of 278 patients with sIgE to tree nuts

• 9% (of 101 patients) with a history of reactions to tree nuts outgrew the allergy, including some with severe reactions.
• Patients aged 4 years and older with all sIgE levels of 5 kUA/L or less could be considered for an oral food challenge.
• The presence of asthma or rhinitis does not appear to be associated with the likelihood of tolerance. 

Children with ongoing allergies to other foods, including other tree nuts and peanuts, as well as those with atopic dermatitis and increased IgE levels, are less likely to outgrow tree nut allergies.

Shellfish Allergy

The prevalence of allergy to crustacean shellfish likely ranges according to region and is reported to be 0.5% to 2% in the United States.

In Spain, shellfish are the third most common type of food allergy, and in Australia, shellfish are responsible for 87% of anaphylactic reactions to food.

Shellfish allergy is far more common in adults than in children.

Sesame Allergy

Sesame is the most common seed allergy and is now considered one of the “top 9” most common food allergens. In the United States, sesame allergy ranges from 0.1% to 0.24% of the population. 

A sesame allergy usually begins between 6 months and 3.5 years of age, although adult onset is not unusual. Approximately 20% to 30% of individuals outgrow their sesame allergy.

FDEIA is a rare, life-threatening condition that occurs when exercise follows ingestion of a food that is otherwise tolerated.

In exercise-induced anaphylaxis exercise results in anaphylaxis, irrespective of food intake. Food-dependent, exercise-induced anaphylaxis (FDEIA) is a subtype of this condition.

• The first known cases were associated with wheat.
• Prevalence data are limited and are likely inaccurate.
• The reported prevalence in Japanese population studies (reference 1, reference 2) has ranged from less than 0.017% to 0.23%.
• FDEIA appears to be twice as common in the female population as in the male population, with the highest prevalence between the teenage years and 35 years of age; it occurs at a lower rate in children, although this may be because of unreported cases.

In FDEIA, ingestion of causative food usually precedes exercise by several minutes or even hours. FDEIA may also occur if the food is ingested soon after the completion of exercise. This suggests that the temporal overlap of these triggering factors, rather than either factor alone, is critical in precipitating symptoms. Although the mechanisms behind FDEIA are not fully understood, exercise increases gut permeability, allowing greater systemic absorption of food allergens and an increased amount of food allergen presented to mast cells and basophils. The immune systems of patients with FDEIA may also have a lower threshold for histamine release.

Signs and Symptoms

FDEIA resembles the typical presentation of anaphylaxis. Symptoms vary depending on the amount of ingested culprit food, intensity of exercise, and sensitivity of the immune system.

FDEIA generally progresses from skin manifestations to loss of consciousness or dyspnea.

• Skin symptoms may include generalized urticaria, angioedema, and erythema.
• Respiratory symptoms include dyspnea, coughing, and/or wheezing.

Other symptoms include:

• Abdominal pain
• Fatigue
• Hypotension

Prevention and Treatment

Swift anaphylaxis treatment is necessary. Prevention involves

• Avoiding exercise 1 to 4 hours after eating the putative food trigger
  • The amount of exercise associated with anaphylaxis varies according to the individual.
• Avoiding eating the food trigger 1 to 2 hours after exercise
• Establishing an emergency treatment plan and carrying an epinephrine autoinjector

PFAS is an allergic reaction to food that occurs in individuals who have been sensitized to similar protein antigens in pollen. 

In children with PFAS, food ingestion after sensitization results in a type 1 allergic reaction.

• PFAS prevalence appears to be increasing, (reference 1)(reference 2) and a warming climate may contribute to this phenomenon.
• Rarely, PFAS can result in anaphylaxis, particularly when the antigen is concentrated in smoothies, plant-based foods, and supplements. 

The term PFAS is often used interchangeably with oral allergy syndrome (OAS), although the 2 conditions are not identical.

• PFAS more broadly includes food allergy that develops after pollen sensitization and results in oral and/or systemic symptoms.
• OAS refers to symptoms of IgE-mediated immediate-type allergy after sensitization and is localized to the oral mucosa (includes latex cross-reactivity).

Common examples of cross-reacting homologous proteins found in food and pollen appear in the following table:

The Immunology of PFAS

PFAS is mediated by pan-allergens that are commonly present in many different foods and pollens. Pan-allergens are basic proteins important for plant survival, and their genes are conserved across plant species, triggering cross-reactivity. Pan-allergens are classified into antigen families.

• The pollens, fruits, and legumes that cause PFAS often contain multiple allergens of each family of antigens.
  • For example, birch pollen contains antigens from the antigen families PR-10 and profilin.
• Some antigen families (eg, PR-10) that lead to PFAS are sensitive to heat; thus, cooking fruit and vegetables may reduce allergic responses.
• Some pan-allergen families are resistant to heat, such as gibberellin-regulated proteins (GRPs) and lipid transfer proteins (LTPs).
  • GRPs derived from peaches and other fruits cross-react with cypress and cedar pollen and can cause severe PFAS.
  • LTPs and GRPs are both heat- and digestive-enzyme–resistant, and sensitized individuals are more prone to anaphylaxis.
  • Eventually, LTPs and GRPs may become markers to predict PFAS severity.

Symptoms and Diagnosis

The diagnosis of PFAS relies on a medical history of hypersensitivity symptoms in the oral and pharyngeal mucosa after ingestion of certain foods, followed by specific testing.

PFAS symptoms typically appear after raw food ingestion and include

• Type 1 allergic symptoms localized to the oral mucosa
  • Itching and swelling of the lips, tongue, oral mucosa, and pharyngeal mucosa immediately after or within 1 hour of consuming the causative food

Less common symptoms include:

• Nasal (nasal obstruction, rhinorrhea, sneezing)
• Ocular (tearing, conjunctival hyperemia, itching)
• Skin (facial swelling, itching, generalized rash)
• Digestive (abdominal pain, vomiting, diarrhea)
• Respiratory (hoarseness, wheezing, dyspnea)
• Anaphylaxis (rarely)

Diagnosis begins with a thorough medical history focused on suspected foods and symptom patterns. Key questions include the type of symptoms, the specific food trigger and reproducibility, amount ingested, form of the food (baked versus raw), timing of symptom onset, ability to tolerate the food at other times, occurrence of symptoms without exposure, duration, and response to treatment.

Testing

Testing should be guided by clinical history. Indiscriminate food panels are not recommended. Many patients have positive test results to cross-reactive foods that are clinically tolerated.

• Skin prick and/or serum IgE testing to relevant pollens (eg, birch, ragweed, grass) can be performed to document sensitization.
• Skin prick and/or serum IgE testing to foods is generally not indicated, as sensitization to pollens is the primary cause of PFAS. An exception is when patients have a history of anaphylactic (systemic) reaction.
• A positive result indicates sensitization, not clinical reactivity.

Treatment and Prevention of PFAS

For treatment of PFAS:

• If symptoms are confined to the oral mucosa, they generally resolve without treatment or with antihistamines.
• Intramuscular epinephrine is not universally prescribed for patients with PFAS. It is only prescribed if there is history of systemic reactions.
• If skin, respiratory, or gastrointestinal symptoms are present in addition to oral symptoms, anaphylaxis treatment with epinephrine is necessary, as discussed previously.

For prevention of PFAS:

• Cook offending foods to deactivate heat labile allergen proteins and avoid them in their raw form.
• Peel raw fruits and vegetables because antigens often are found in the skin.
• Avoid the specific triggering foods, particularly during allergy season when the syndrome worsens.
  • Elimination diets are a mainstay but should not be maintained in the absence of a convincing previous history of a reaction or a positive supervised oral food challenge.

Referral Considerations

• Allergy evaluation should be performed in consultation with a board-certified allergist/immunologist because test limitations often warrant specialized evaluation to confirm the role of specific allergens.
• A therapy plan, which may include allergen avoidance and/or medical treatment(s), should be discussed with an allergist/immunologist.

Diagnosis of food allergy should begin with a careful review of the reaction history, including timing, symptoms, and suspected trigger(s). When food allergy is suspected, referral to an allergist/immunologist is often appropriate for further evaluation. When assessing a possible food allergy, clinicians should consider both IgE-mediated and non-IgE–mediated food allergies.

Testing (eg, skin prick, serum-specific IgE measurement) is used to evaluate suspected IgE-mediated food allergies. However, not all food allergies are IgE mediated. Some children experience non-IgE–mediated food allergic disorders, which typically present with non-immediate symptoms.

Infants with moderate-to-severe early atopic dermatitis (especially onset in the first 3 months after birth) represent a group at high risk for developing a coexisting IgE-mediated food allergy.

Additional considerations include:

• Up to 35% of individuals who report a reaction to food believe they have a food allergy; however, oral food challenges suggest a much lower prevalence of about 3.5%.
• Many causes of reactions to foods are not allergic in origin.

Testing may be performed to aid in the diagnosis of IgE-mediated food allergy, including skin prick and/or serum tests. These tests are typically conducted under the guidance of an allergist.

• These tests perform similarly. They are generally very sensitive (approximately 75%–95%) and modestly specific (approximately 30%–60%).
• Care in selecting and interpreting test results is paramount, and consideration of the epidemiology and pathophysiology of food allergies aids in test selection and interpretation.

Skin Prick Tests

Skin prick testing is commonly used by allergists to assess for IgE-mediated sensitization to foods. Results are available during the same clinical visit and must be interpreted in the context of the clinical reaction history. These tests are performed on rash-free skin when the patient has not taken antihistamines.

Additional notes

• Commercial extracts are available for performing skin prick tests for many foods.
  • Fresh extracts, particularly when testing fruits and vegetables in which proteins are prone to degradation, may be more sensitive.
• If IgE antibody specific for the food protein is present, a wheal and flare will occur that is compared with positive (histamine) and negative (saline) controls.
• The skin prick test is low cost, provides immediate results, and is available to allergists.
• Intradermal skin tests should not be used.

A positive skin prick test result indicates that sensitization is present; it does not indicate the presence of a clinical allergy.

• Larger-wheal diameters are associated with a higher probability of clinical allergy.
• The size of the wheal does not reflect severity of the allergic reaction.
• Testing large panels of allergens without consideration of the history, geographic relevance, and disease characteristics is not recommended, as it may
  • Result in many clinically irrelevant positive results.
  • Lead to unnecessary allergen avoidance that can be costly and detrimental to the social, emotional, and nutritional well-being of a child.
• Children with atopic dermatitis have a high likelihood of sensitization, although this is most often not associated with food allergy. As such, preemptive food allergy testing in children with atopic dermatitis who do not have a food reaction history is generally discouraged.
  • In a 2025 study in Turkey, food sensitivity versus food allergy was determined in 257 infants and children with moderate-to-severe atopic dermatitis. The infants were stratified according to age of onset of atopic dermatitis.
  • 0 to 3 months of age at onset: 60.3% had food sensitivity versus 32.5% with food allergy
  • 4 to 11 months at onset: 59.6% had food sensitivity versus 17.2% with food allergy
  • Older than 12 months at onset: 39.3% had food sensitivity versus 0% with food allergy
• The development of tolerance with complementary feeding likely explains an age-related reduction in food allergy.
• These data highlight the importance of careful diagnosis of food allergy to avoid needless dietary restriction.

Food-Specific Serum IgE Testing

As an alternative or complementary testing strategy to skin prick testing, causative allergens may be identified through directed, specific IgE testing. Specific IgE tests are selected and interpreted in the context of a clinical presentation. Testing for sIgE can be used to identify or confirm triggers, However, they are not considered diagnostic in and of themselves.

• A higher concentration of IgE at serum testing generally correlates with an increased risk of clinical allergy.
• Test relevance may vary according to the patient’s age, allergen exposure, and performance characteristics of the test.
• A positive serum IgE test result indicates that sensitization is present; it does not indicate the presence of a clinical allergy.
• Tests for specific IgE may be influenced by cross-reactive proteins that may or may not have clinical relevance to disease.

Other tests for the diagnosis of food allergy that are not recommended and have not been found useful in blinded studies include

• Measurement of immunoglobulin G (IgG) antibody
• Provocation-neutralization (diluted liquid extracts of foods placed under the tongue or injected to enable diagnosis and treatment of various symptoms)
• Applied kinesiology (muscle strength testing)

Dietary Avoidance

Once food allergy is diagnosed, strict elimination of the offending food trigger(s) is the mainstay of preventing anaphylaxis.

Infants

• Formula-fed infants who are allergic to cow’s milk–derived standard formulas may tolerate an extensively hydrolyzed, casein-based formula.
• If the extensively hydrolyzed formula (eHF) is not tolerated, the infant may need to be transitioned to an amino acid–based formula.
• For IgE-mediated food allergy, maternal food elimination is typically not required. However, this may be required for other types of food allergies, such as FPIAP.

Children

Toddlers, children, and adolescents with restricted diets require nutritional counseling and growth monitoring. A large systematic review showed:

• Children with multiple food allergies may be at increased risk for growth impairments and nutritional inadequacies.
  • Growth impairment (including short stature) appears to be more pronounced in children with at least 3 food allergies.
• A reduced intake of essential nutrients, with proteins being the most frequently reported deficiency.
• Commonly inadequate nutrients included calcium and vitamin D; other deficiencies included zinc, iodine, vitamin B12, and folate.

Avoiding ingestion, rather than skin or air exposure, is the primary goal for dietary elimination. However:

• Avoiding fumes of allergens (eg, boiling milk, steaming shellfish) may be necessary.
• Adolescents and young adults should avoid passionate kissing when a partner recently consumed the allergen.

In select cases, an allergist may recommend that a child with cow’s milk or egg allergy consume baked food product but continue to avoid non-baked forms. This is because:

• Approximately 70% of children with allergic reactions to milk or egg products can tolerate these foods when they are heated (eg, baked into muffins or breads).
• Further, immune responses to the consumption of these foods are similar to those seen during successful active immunotherapy (eg, an increase in food-specific IgG antibodies, some suppression of IgE, and some indication of accelerated tolerance).
• Care must be taken in deciding which children should adhere to a strict elimination diet because some children experience anaphylaxis to heated products.

To avoid unnecessary food avoidance, care should be taken not to overinterpret the presence of positive skin prick test results to multiple foods that are related to a food that elicits a serious reaction. The clinical evidence of cross-reactivity is not as common as test results might indicate.

The rate of clinically relevant cross-reactivity varies by food. For example, most people with a peanut allergy have IgE antibodies to other legumes (eg, peas and string beans). However, 95% of children with peanut allergy tolerate most other beans. 

Some tree nuts have homologous proteins, such as walnut with pecan, cashew with pistachio, and hazel with almond.

In general, foods that are already tolerated in the diet without reactions should be continued, even if food allergy testing results are positive. Any uncertain food allergy testing should be discussed with an allergist for further guidance.

Oral Immunotherapy

Peanut allergen powder (Palforzia) was approved after a multicenter, double-blind placebo-controlled phase III trial in which 551 participants with confirmed allergy to peanut (100 mg) received increasing amounts of peanut protein in 3 stages. The end point was safe tolerance of an oral food challenge of 600 mg of peanut protein.

• 4% of participants (aged 4–17 years) in the control group achieved sufficient tolerance at the food challenge.
• Approximately 67% of participants (aged 4–17 years) in the treatment group achieved tolerance.
• Palforzia was not effective in inducing tolerance in those older than 18 years.

Certain allergy practices offer oral immunotherapy to children who have been diagnosed with IgE-mediated food allergy. The treatment requires extensive time commitment for both the patient and family. There is a risk of potentially severe allergic reactions to the immunotherapy.

Injectable Biological Therapy

Omalizumab is a monoclonal anti-IgE antibody that was recently approved for subcutaneous use as a means of preventing IgE-mediated food allergic reactions. Its efficacy was demonstrated in a randomized placebo-controlled trial of 180 participants aged 1 to 55 years who were allergic to peanut and at least 2 other foods.

Omalizumab was provided to the treatment group for 16 weeks. The primary end point was safe ingestion of peanut protein in a single dose of 600 mg or more. Three secondary end points were the safe consumption of cashew, milk, and egg in single doses of at least 1,000 mg each.

Compared to placebo, 67% of patients taking omalizumab were able to tolerate a single dose of 600 mg of peanut, versus 7% taking a placebo.

Omalizumab is now approved for subcutaneous use every 2 to 4 weeks to treat IgE-mediated food allergy in people 1 year and older to reduce allergic reactions to food.

Omalizumab is also approved for other indications, including moderate-to-severe persistent asthma and chronic urticaria.

Omalizumab is not for the emergency treatment of any allergic reactions, including anaphylaxis.

Other monoclonal antibody therapies (eg, ligelizumab, LP003, RPT904) are in development, but none have completed phase 3 trial as of January 2026.

Treatment

An allergic reaction that consists of only itching and rash that is not widespread can be treated with antihistamines, such as cetirizine.

However, if there is 2-system involvement and the patient meets criteria for anaphylaxis, epinephrine is the primary treatment.

• In the health care setting, the dosing is 0.01 mg per kilogram of body weight (injected intramuscularly) to a maximum of 0.3 mg in a prepubertal child and up to 0.5 mg in a teenager.
  • Epinephrine, 0.3 mg administered intramuscularly, is 10 times safer than epinephrine administered as an intravenous bolus.
  • Serious adverse effects of intramuscular epinephrine are rare in children.
• Fixed-dose epinephrine autoinjectors can be used either before transport or in a health care setting. They are available in 0.1-, 0.15-, and 0.3-mg doses in the United States (and 0.5-mg doses outside the United States). Nasal epinephrine devices are also available, which come in 1-mg and 2-mg dosing.
  • 6% to 19% of children need a second dose of epinephrine.
• If reactions do not fully respond to a single treatment with epinephrine and/or if the patient continues to have symptoms, they should be transported to an emergency facility for treatment and observation, because recurrence of severe symptoms is possible.
• Individuals with shock should remain prone to avoid the potentially fatal “empty ventricle syndrome.”
• Patients should have updated epinephrine injectors and may benefit from medical jewelry identifying their allergen(s).
• Teenagers are at special risk of fatal reactions. Therefore, education of the affected teenager, school staff, and friends about the allergy and when to treat with epinephrine is encouraged.
• Asthma is an important risk factor for death from anaphylaxis, especially in adolescents and young adults. 

Physicians should educate patients and parents about the symptoms of anaphylaxis. Resources include allergy and anaphylaxis emergency plans.

Other resources include this patient education brochure and this video for parents.

Several non-IgE–mediated allergic disorders of the gastrointestinal (GI) tract that primarily occur in infants are associated with atopic disease.

• Eosinophilic esophagitis
• Food-protein–induced enterocolitis syndrome (FPIES)
• Food-protein–induced allergic proctolitis (FPIAP)

Comorbid atopic diseases are common in patients with these GI conditions.

• 40% to 60% of children with FPIES have an atopic comorbidity.
  • The presence of FPIES does not affect atopic disease development but indicates a shared etiologic origin.
• 40% to 50% of children with food protein–induced enteropathy and FPIAP have an atopic comorbidity.

Further highlighting the atopic nature of these GI allergic conditions, a family history of atopy is present in

• 60% of infants with FPIAP
• 80% of infants with FPIES

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE–mediated gastrointestinal food allergy that predominantly affects infants and young children. Unlike IgE-mediated food allergies, FPIES is characterized by a delayed onset of severe vomiting and potential hemodynamic collapse. Because it lacks the “classic” allergic markers (ie, hives, wheezing, or positive skin prick results), it is frequently misdiagnosed as acute gastroenteritis or sepsis.

The prevalence is higher than previously recognized, affecting 0.15% to 0.70% of infants during the first year after birth. Most infants experience their first reaction within the first 6 months after birth, with 51% having a reaction with their first known exposure to the trigger food.

Clinical Presentation

FPIES typically presents in infancy, often on the introduction of first solid foods. FPIES presents in 2 forms: acute (most common) and chronic (less common).

For acute FPIES, the hallmark presentation is delayed onset of symptoms 1 to 4 hours after ingestion of the trigger food.

• Repetitive, profuse vomiting: This is the cardinal symptom and is typically projectile.
• Lethargy and pallor: Often profound.
• Diarrhea: Occurs in 25% to 40% of cases, typically 4 to 6 hours after ingestion (may occur up to 24 hours later).
• Severe reactions: Up to 15% of patients develop hypotension and hypovolemic shock.
• Laboratory findings: Neutrophilia (3,500 cells/μL), thrombocytosis, blood in stool.

Key distinguishing features of FPIES from sepsis/gastroenteritis include

• Rapid resolution of symptoms within hours
• Absence of fever
• Lack of significant C-reactive protein elevation

Chronic FPIES is uncommon, occurring primarily in infants younger than 3 months who are fed cow’s milk or soy formula. Chronic FPIES

• Occurs with daily ingestion of the trigger (often cow’s milk or soy formula).
• Presents with chronic diarrhea, intermittent vomiting, and failure to thrive.
• Typically resolves within 3 to 10 days of removing the offending protein.

Common Food Triggers

The most common triggers of FPIES vary by geographic region. In the United States and Australia, the most common triggers are:

• Rice (22%–45% of cases)
• Oat (16%–22% of cases)
• Cow’s milk (26%–44% of cases)

In Europe and the Mediterranean, the most common triggers are:

• Fish (25% of cases)
• Cow’s milk

In Japan, the most common triggers are

• Hen’s egg
• Cow’s milk

Other triggers include soy, chicken, beef, vegetables, fruits, and peanut (emerging in the United States).

Most children with FPIES (65%–85%) react to a single food. Multiple food triggers occur in 15% to 35% and are associated with younger age at onset, FPIES reactions to fruits/vegetables, and atopic disease.

Diagnosis

FPIES is a clinical diagnosis based on characteristic symptoms. There are currently no validated skin or blood tests to confirm the diagnosis.

Important considerations include

• A subset of patients (4%–24%) may have detectable food-specific IgE (“atypical FPIES”); these patients tend to have a more prolonged course and may transition to IgE-mediated reactions.
• Endoscopy is not required for diagnosis.

Management

For acute management of FPIES reactions, treatment is tailored to severity of the FPIES reaction. For mild-to-moderate reactions, treatment with ondansetron and oral rehydration with close monitoring may be sufficient. For more severe reactions, patients may need to seek emergency care and require rehydration via intravenous fluids.

There is no role for the routine use of epinephrine in the treatment of an FPIES reaction.

Long-term dietary management for breastfed infants includes continued breastfeeding (most FPIES does not occur during exclusive breastfeeding). FPIES reactions that occur from ingesting breastmilk are very rare, and maternal elimination of a child’s FPIES trigger is generally not necessary.

For long-term dietary management in formula-fed infants

• Switch to eHF for cow’s milk or soy FPIES. Amino acid–based formula may be required in some cases.
• Avoid soy formula in cow’s milk FPIES due to potential cross-reactivity.

For multiple food triggers:

• Avoid only confirmed trigger foods.
• Introduce new foods cautiously, starting with foods from already-tolerated and low-risk groups.
• Consultation with a dietitian is recommended.
• Monitor feeding patterns, as patients with at least 3 food triggers are at risk for food aversion.

Reintroduction and Assessment of Tolerance

The timing of reintroducing foods is as follows:

• Traditional approach: Reintroduce foods 12 to 18 months after the most recent acute reaction.
• Earlier challenges may be appropriate in uncomplicated cases, as a result of shared decision-making with the family and their specialists, including pediatric allergists and gastroenterologists.

Prognosis

FPIES has a favorable prognosis. Most children outgrow the condition by age 3 to 5 years. FPIES typically resolves by school age. No fatalities have been reported, and there should not be any long-term gastrointestinal sequelae.

Factors associated with delayed tolerance include:

• Multiple food triggers
• IgE sensitization to trigger foods

There can be a risk of phenotype switch, as well.

• · 6% to 24% of patients may develop IgE sensitization to their FPIES trigger over time.
• Among children with cow’s milk–specific IgE, 41% may transition to an IgE-mediated phenotype.
• Patients with “atypical FPIES” tend to have a more protracted course.

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Milk and soy protein intolerance, also referred to as food protein-induced allergic proctocolitis (FPIAP), is a non-IgE–mediated inflammatory response allergy that represents one of the most common causes of rectal bleeding in otherwise healthy infants. The condition is benign and self-limited, typically presenting in the first months after birth and resolving by 12 months of age in most patients.

Reported prevalence varies widely from 0.18% to 17.0%, depending on diagnostic criteria and study methodology. This variation reflects differences in diagnostic stringency, particularly whether confirmatory oral food challenges are performed. Notably, up to 60% of cases occur in infants who are exclusively breastfed.

Clinical Presentation

FPIAP typically manifests as blood-streaked, mucoid stools in an otherwise healthy, thriving infant. The median age of symptom onset is approximately 2 months. Key features include

• Visible blood in stool: Blood-streaked or blood-flecked stools, often mixed with mucus.
• General appearance: Infants appear well, feed normally, and maintain normal growth.
• Associated symptoms: Most infants are asymptomatic, aside from bloody stools; some may have diarrhea or irritability.

Common Food Triggers

The most common triggers are:

• Cow’s milk protein (94.5% of patients): This is the predominant trigger.
• Egg (37.4% of patients).
• Soy: There is a high rate of cross-reactivity between cow’s milk protein and soy protein, owing to their similar molecular structures. Approximately 30% to 60% of infants who are intolerant to cow’s milk protein will also react to soy. For this reason, clinicians generally recommend a simultaneous elimination of both proteins to achieve faster symptom resolution.

Diagnosis

FPIAP is a clinical diagnosis based on:

1. Supportive history: Blood-streaked stools in an otherwise healthy infant. Sometimes, other symptoms such as mucus in stools, fussiness, and reflux can be seen in FPIAP, but these symptoms are nonspecific.
2. Response to dietary elimination: Resolution of symptoms typically occurs within 3 days to 2 weeks after eliminating the suspected food.
3. Recurrence with reintroduction: Symptoms recur when the trigger food is reintroduced.

The diagnostic approach includes:

• Obtaining a detailed dietary history for the infant and the breastfeeding mother.
• Performing a physical examination to assess growth and rule out other causes.
• Laboratory testing (complete blood cell count, albumin levels) may provide supportive evidence but is not recommended.
• Skin prick tests and serum sIgE levels (eg, ImmunoCAP) are not useful, as the mechanism is cell-mediated and not IgE-mediated.
• Endoscopy is not required for typical presentations.

The standard of reference for FPIAP is the resolution of symptoms when following a strict elimination diet, followed by a “repeat challenge” after several months to confirm the infant has outgrown the intolerance.

Management

The cornerstone of management is strict avoidance of the trigger food protein. For breastfed infants, maternal dietary restriction is the first line of treatment. Strict elimination is necessary; the mother must remove all dairy and soy from her diet (including “hidden” ingredients such as whey, casein, and soybean solids). It can take 72 hours to 2 weeks for maternal proteins to clear the system and for the infant’s gut inflammation to subside.

For supplementation, ensure the mother takes a calcium (1,000 mg/day) and vitamin D supplement while on the restricted diet.

For formula-fed infants

• Switch to an extensively hydrolyzed formula (eHF).
• If symptoms persist, use amino acid–based formula (required in 10%–15% of cases).
• Soy formula is not recommended, owing to high cross-reactivity rates.

When monitoring the infant’s response, visible blood should resolve within 3 days to 2 weeks. If no improvement in symptoms occurs after 2 to 4 weeks, reconsider the diagnosis or evaluate the child for additional triggers.

Reintroduction and Assessment of Tolerance

Regular reassessment for tolerance development is essential to avoid unnecessary prolonged dietary restrictions. For the timing of reintroduction, the newest literature suggests reintroduction after 4 weeks of symptom improvement.

Prognosis

FPIAP has an excellent prognosis and is typically considered a benign, self-limited condition as the gut mucosa matures.

References for this section: (ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref)

• Management of Food Allergy in Schools: Clinical Report
• Epinephrine for First-aid Management of Anaphylaxis
• Guidelines for the Diagnosis and Management of Food Allergy in the United States: Report of the NIAID-Sponsored Expert Panel
• Addendum Guidelines for the Prevention of Peanut Allergy in the United States: Report of the NIAID-Sponsored Expert Panel
• Guidelines for Clinicians and Patients for Diagnosis and Management of Food Allergy in the United States
• EAACI Guidelines on the Diagnosis of IgE-Mediated Food Allergy
• EAACI Guidelines on the Management of IgE-Mediated Food Allergy
• EAACI Guideline: Preventing the Development of Foo Allergy in Infants and Young Children (2020 Update)
• Food Allergy Research & Education