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Food allergy
Food allergy
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Food allergy
Hives on the back are a common allergy symptom.
SpecialtyEmergency medicine, allergy and immunology
SymptomsItchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, low blood pressure[1]
Usual onsetMinutes to several hours of exposure[1]
DurationLong term, some may resolve[2]
CausesImmune response to food[1]
Risk factorsFamily history, vitamin D deficiency, obesity, high levels of cleanliness[1][2]
Diagnostic methodBased on a medical history, elimination diet, skin prick test, oral food challenge[1][2]
Differential diagnosisFood intolerance, celiac disease, food poisoning[1]
PreventionEarly exposure to potential allergens,[2][3] omalizumab
TreatmentAvoiding the food in question, having a plan if exposure occurs, medical alert jewelry[1][2]
MedicationAdrenaline (epinephrine)[1]
Frequency~6% (developed world)[1][2]

A food allergy is an abnormal immune response to food. The symptoms of the allergic reaction may range from mild to severe. They may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. This typically occurs within minutes to several hours of exposure. When the symptoms are severe, it is known as anaphylaxis.[1] A food intolerance and food poisoning are separate conditions, not due to an immune response.[1][4]

Common foods involved include cow's milk, peanuts, eggs, shellfish, fish, tree nuts, soy, wheat, and sesame.[1][5][2][6] The common allergies vary depending on the country.[1] Risk factors include a family history of allergies, vitamin D deficiency, obesity, and high levels of cleanliness.[1][2] Allergies occur when immunoglobulin E (IgE), part of the body's immune system, binds to food molecules.[1] A protein in the food is usually the problem.[2] This triggers the release of inflammatory chemicals such as histamine.[1] Diagnosis is usually based on a medical history, elimination diet, skin prick test, blood tests for food-specific IgE antibodies, or oral food challenge.[1][2]

Management involves avoiding the food in question and having a plan if exposure occurs.[2] This plan may include giving adrenaline (epinephrine) and wearing medical alert jewelry.[1] Early childhood exposure to potential allergens may be protective against later development of a food allergy.[2][3] The benefits of allergen immunotherapy for treating food allergies are not proven, thus not recommended as of 2015.[7] Some types of food allergies among children resolve with age, including those to milk, eggs, and soy; while others such as to nuts and shellfish typically do not.[2]

In the developed world, about 4% to 8% of people have at least one food allergy.[1][2] They are more common in children than adults and appear to be increasing in frequency.[2] Male children appear to be more commonly affected than females.[2] Some allergies more commonly develop early in life, while others typically develop in later life.[1] In developed countries, more people believe they have food allergies when they actually do not have them.[8][9][10]

Signs and symptoms

[edit]
Signs and symptoms of anaphylaxis
Signs and symptoms of anaphylaxis

Food allergy symptoms occur within minutes to hours after exposure and may include:[11]

  • Rash
  • Hives[11]
  • Itching of mouth, lips, tongue, throat, eyes, skin, or other areas[11]
  • Swelling (angioedema) of lips, tongue, eyelids, or the whole face[11]
  • Difficulty swallowing[11]
  • Runny or congested nose[11]
  • Hoarse voice[11]
  • Wheezing and/or shortness of breath[11]
  • Diarrhea, abdominal pain, and/or stomach cramps[11]
  • Lightheadedness[11]
  • Fainting[11]
  • Nausea[11]
  • Vomiting[11]

In some cases, however, onset of symptoms may be delayed for hours.[11]

Symptoms can vary. The amount of food needed to trigger a reaction also varies.[12]

Serious danger regarding allergies can begin when the respiratory tract or blood circulation is affected. The former can be indicated through wheezing and cyanosis. Poor blood circulation leads to a weak pulse, pale skin and fainting.[13]

A severe case of an allergic reaction, caused by symptoms affecting the respiratory tract and blood circulation, is called anaphylaxis. When symptoms are related to a drop in blood pressure, the person is said to be in anaphylactic shock. Anaphylaxis occurs when IgE antibodies are involved, and areas of the body that are not in direct contact with the food become affected and show symptoms.[14] Those with asthma or an allergy to peanuts, tree nuts, or seafood are at greater risk for anaphylaxis.

Causes

[edit]

Common food allergies

[edit]

Allergic reactions are abnormal immune responses that develop after exposure to a given food allergen.[15] Food allergens account for about 90% of all allergic reactions.[16] The most common food allergens include milk, eggs, peanuts, tree nuts, fish, shellfish, soy, and wheat,[17] which are referred to as "the big eight", and are required by US law to be on labels of foods that contain those foods.[18] In April 2021, President Biden signed the FASTER Act into law. This recognized sesame as the ninth US mandatory food label allergen.[19][20]

Peanuts, a member of the legume family, are one of the most common food allergens that induce reactions in both children and adults.[21] Affecting about 2% of the Western population, peanut allergies tend to cause more severe reactions and anaphylaxis than other food allergies.[22] Tree nuts, including almonds, brazil nuts, cashews, coconuts, hazelnuts, macadamia nuts, pecans, pistachios, pine nuts, and walnuts, are also common allergens. Affected individuals may be sensitive to one particular tree nut or many different ones.[23] Peanuts and seeds, including sesame seeds and poppy seeds, can be processed to extract oils, but trace amounts of protein may also elicit an allergic reaction.[23] Peanut and tree nut allergies are lifelong conditions for the majority of those affected, although evidence shows that ~20% of those with peanut allergies and 9% of those with tree nut allergies may outgrow them.[24]

Egg allergies affect about one in 50 children but are frequently outgrown when children reach age five.[25] Affected individuals can be sensitive to proteins both in the egg white and egg yolk, but most children are allergic to those in the white while most adults are allergic to those in the yolk.[26]

Cow's milk is the most common food allergen in infants and young children, yet many adults are also sensitized to cow's milk.[27] Many affected individuals cannot tolerate dairy products such as cheese and yogurt.[28] A small portion of children with milk allergy, roughly 10%, have a reaction to beef because it contains small amounts of protein that are also present in cow's milk.[29]

Shellfish, which are divided into crustaceans (shrimp, crab, lobster, etc.) and mollusks (mussel, oyster, scallop, squid, octopus, snail, etc.), are the most common food allergy in adults.[30] People may be allergic to other types of seafood, such as fish.[31] Fish allergies were found to be more common in countries that have high fish consumption compared to those with lower consumption.[32]

Other common food allergens include soy and wheat.[33] Those allergic to wheat may be sensitized to any protein in the wheat kernel.[34] To a lesser frequency, people may be mildly allergic to raw fruits and vegetables, a disease known as oral allergy syndrome.[33] Less common allergens include maize, spices, synthetic and natural colors,[35] and chemical additives.[36]

Balsam of Peru, which is in various foods, is in the "top five" allergens most commonly causing patch test reactions in people referred to dermatology clinics.[37]

Routes of exposure

[edit]

Exposure to certain food proteins triggers the production of antigen-specific immunoglobulin E (IgE) antibodies, which, if unaccompanied by allergic symptoms, is known as allergic sensitization.[38] Oral ingestion is the main sensitization route for most food allergy cases, yet other routes of exposure include inhalation and skin contact.[39][34]

For example, inhaling airborne particles in a farm-scale or factory-scale peanut shelling/crushing environment, or from cooking, can induce respiratory effects in allergic individuals.[40] Furthermore, peanut allergies are much more common in adults who had oozing and crusted skin rashes as infants,[41] suggesting that impaired skin may be a risk factor for sensitization.[34][42] An estimated 28.5 million people worldwide are engaged in the seafood industry, which includes fishing, aquaculture, processing and industrial cooking.[43] In these occupational settings, individuals with fish and shellfish allergies are at high risk of exposure to allergenic proteins via aerosolization.[44][43] Respiratory symptoms may be induced by inhalation of wet aerosols from fresh fish handling, inhalation of dry aerosols from fishmeal processing, and dermal contact through skin breaks and cuts.[45][43] Another occupational food allergy that involves respiratory symptoms is "baker's asthma," which commonly develops in food service workers who work with baked goods.[46] Previous studies detected 40 allergens from wheat, some cross-reacted with rye proteins and a few cross-reacted with grass pollens.[47]

Allergic sensitization can occur via skin antigen exposure, which usually manifests as hives.[48] The skin has been suggested to be a critical sensitization route for peanut-allergic individuals.[49][40] Peanut allergies are much more common in adults who had oozing and crusted skin rashes as infants,[41] reinforcing that those with disrupted epithelial barriers, notably the skin barrier, are more prone to skin sensitization.[34] Environmental factors, such as exposure to food, microorganisms, creams, and detergents, may lead to skin barrier dysfunction.[50] Several studies reveal that children exposed to skin creams containing peanut oil are reported to have a higher risk of peanut allergy,[50] suggesting that impaired skin may be a risk factor for sensitization.[34][42]

Cross-contact

[edit]

Cross-contact of food occurs when allergens are unintentionally transferred from one food item to another, often through shared cooking equipment, not properly cleaned surfaces, or utensils. This can lead to severe allergic reactions in individuals with food allergies, even if the allergen is present in trace amounts.[51] To mitigate risks, food labeling regulations such as in the United States, require manufacturers to clearly indicate potential allergens on packaging, often with statements like "may contain" or "processed in a facility that handles." Proper handling practices, such as thorough cleaning and separation of allergen-free foods, are essential in both commercial and home kitchens to prevent cross-contact and ensure safety for those with food allergies. Although the term cross-contamination is often used interchangeably with cross-contact, the FDA specifies that cross contamination is associated with the spread of biological, physical, and chemical contaminants in food while cross-contact is associated with food allergens.[52]

Atopy

[edit]

Food allergies develop more easily in people with the atopic syndrome, a very common combination of diseases: allergic rhinitis and conjunctivitis, eczema, and asthma.[53] The syndrome has a strong inherited component; a family history of allergic diseases can be indicative of the atopic syndrome.[medical citation needed]

Cross-reactivity

[edit]

Some children who are allergic to cow's milk protein also show a cross-sensitivity to soy-based products.[54] Some infant formulas have their milk and soy proteins hydrolyzed, so when taken by infants, their immune systems do not recognize the allergen and they can safely consume the product. Hypoallergenic infant formulas can be based on proteins partially predigested to a less antigenic form. Other formulas, based on free amino acids, are the least antigenic and provide complete nutritional support in severe forms of milk allergy.[55]

Crustaceans (shrimp, crab, lobster, etc.) and molluscs (mussel, oyster, scallop, squid, octopus, snail, etc.) are different invertebrate classes, but the allergenic protein tropomyosin is present and responsible for cross-reactivity.[56]

People with latex allergy often also develop allergies to bananas, kiwifruit, avocados, and some other foods.[57] In some cases, allergic symptoms may occur upon first ingestion of a particular food due to IgE cross-reactivity: prior sensitization to structurally similar proteins from other sources leads the immune system to recognize homologous proteins in the newly consumed food as allergens.[58]

Pathophysiology

[edit]
Histamine, the structure shown, causes a person to feel itchy during an allergic reaction.

Conditions caused by food allergies are classified into three groups according to the mechanism of the allergic response:[59]

  1. IgE-mediated (classic) – the most common type, occurs shortly after eating and may involve anaphylaxis.
  2. Non-IgE mediated – characterized by an immune response not involving immunoglobulin E; may occur some hours after eating, complicating diagnosis
  3. IgE and/or non-IgE-mediated – a hybrid of the above two types

Allergic reactions are abnormal immune responses to certain substances that are normally harmless. When immune cells encounter the allergenic protein, IgE antibodies are produced; this is similar to the immune system's reaction to foreign pathogens. The IgE antibodies identify the allergenic proteins as harmful and initiate the allergic reaction. The harmful proteins are those that do not break down due to the strong bonds of the protein. IgE antibodies bind to a receptor on the surface of the protein, creating a tag, just as a virus or parasite becomes tagged. Why some proteins do not denature and subsequently trigger allergic reactions and hypersensitivity while others do is not entirely clear.[60]

Hypersensitivities are categorized according to the parts of the immune system that are attacked and the amount of time it takes for the response to occur. The four types of hypersensitivity reaction are: type 1, immediate IgE-mediated; type 2, cytotoxic; type 3, immune complex-mediated; and type 4, delayed cell-mediated.[61] The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a "late-phase reaction" which can substantially prolong the symptoms of a response, and result in tissue damage.[62]

Many food allergies are caused by hypersensitivities to particular proteins in different foods. Proteins have unique properties that allow them to become allergens, such as stabilizing forces in their tertiary and quaternary structures which prevent degradation during digestion. Many theoretically allergenic proteins cannot survive the destructive environment of the digestive tract, thus do not trigger hypersensitive reactions.[63]

Acute response

[edit]
Degranulation process in allergy:
1 — antigen
2 — IgE antibody
3 — FcεRI receptor
4 — preformed mediators (histamine, proteases, chemokines, heparin)
5granules
6mast cell
7 — newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)

In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is the production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage, are sensitized to the allergen.[64]

If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation, and smooth-muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, the allergen, and the mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems.[64]

Late-phase response

[edit]

After the chemical mediators of the acute response subside, late-phase responses can often occur due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial site. The reaction is usually seen 2–24 hours after the original reaction.[65] Cytokines from mast cells may also play a role in the persistence of long-term effects.[66]

Diagnosis

[edit]
Skin testing on the arm is a common way for detecting an allergy, but it is not as effective as other tests.
Patch test

Diagnosis is usually based on a medical history, elimination diet, skin prick test, blood tests for food-specific IgE antibodies, or oral food challenge.[1][2]

  • For skin-prick tests, a tiny board with protruding needles is used. The allergens are placed either on the board or directly on the skin. The board is then placed on the skin, to puncture the skin and for the allergens to enter the body. If a hive appears, the person is considered positive for the allergy. This test only works for IgE antibodies. Allergic reactions caused by other antibodies cannot be detected through skin-prick tests.[67]

Skin-prick testing is easy to do and results are available in minutes. Different allergists may use different devices for testing. Some use a "bifurcated needle", which looks like a fork with two prongs. Others use a "multitest", which may look like a small board with several pins sticking out of it. In these tests, a tiny amount of the suspected allergen is put onto the skin or into a testing device, and the device is placed on the skin to prick, or break through, the top layer of skin. This puts a small amount of the allergen under the skin. A hive will form at any spot where the person is allergic. This test generally yields a positive or negative result. It is good for quickly learning if a person is allergic to a particular food or not because it detects IgE. Skin tests cannot predict if a reaction would occur or what kind of reaction might occur if a person ingests that particular allergen. They can, however, confirm an allergy in light of a patient's history of reactions to a particular food. Non-IgE-mediated allergies cannot be detected by this method.

  • Patch testing is used to determine if a specific substance causes allergic inflammation of the skin. It tests for delayed food reactions.[68][69][70]
  • Blood testing is another way to test for allergies; however, it poses the same disadvantage and only detects IgE allergens and does not work for every possible allergen. Radioallergosorbent testing (RAST) is used to detect IgE antibodies present to a certain allergen. The score taken from the RAST is compared to predictive values, taken from a specific type of RAST. If the score is higher than the predictive values, a great chance the allergy is present in the person exists. One advantage of this test is that it can test many allergens at one time.[71]

A CAP-RAST has greater specificity than RAST; it can show the amount of IgE present to each allergen.[72] Researchers have been able to determine "predictive values" for certain foods, which can be compared to the RAST results. If a person's RAST score is higher than the predictive value for that food, over a 95% chance exists that patients will have an allergic reaction (limited to rash and anaphylaxis reactions) if they ingest that food. [citation needed] Currently,[when?] predictive values are available for milk, egg, peanut, fish, soy, and wheat.[73][74][75] Blood tests allow for hundreds of allergens to be screened from a single sample, and cover food allergies as well as inhalants. However, non-IgE-mediated allergies cannot be detected by this method. Other widely promoted tests such as the antigen leukocyte cellular antibody test and the food allergy profile are considered unproven methods, the use of which is not advised.[76]

  • Food challenges test for allergens other than those caused by IgE allergens. The allergen is given to the person in the form of a pill, so the person can ingest the allergen directly. The person is watched for signs and symptoms. The problem with food challenges is that they must be performed in the hospital under careful watch, due to the possibility of anaphylaxis.[77]

Food challenges, especially double-blind, placebo-controlled food challenges, are the gold standard for diagnosis of food allergies, including most non-IgE-mediated reactions, but is rarely done.[78] Blind food challenges involve packaging the suspected allergen into a capsule, giving it to the patient, and observing the patient for signs or symptoms of an allergic reaction.[medical citation needed]

The recommended method for diagnosing food allergy is to be assessed by an allergist. The allergist will review the patient's history and the symptoms or reactions that have been noted after food ingestion. If the allergist feels the symptoms or reactions are consistent with food allergy, he/she will perform allergy tests. Additional diagnostic tools for evaluation of eosinophilic or non-IgE mediated reactions include endoscopy, colonoscopy, and biopsy.[medical citation needed]

Differential diagnosis

[edit]

Important differential diagnoses are:

Prevention

[edit]

Breastfeeding for more than four months may prevent atopic dermatitis, cow's milk allergy, and wheezing in early childhood.[82] Early exposure to potential allergens may be protective.[2] Specifically, early exposure to eggs and peanuts reduces the risk of allergies to these.[3] Guidelines suggest introducing peanuts as early as 4–6 months and include precautionary measures for high-risk infants.[83] The former guidelines, advising delaying the introduction of peanuts, are now[when?] thought to have contributed to the increase in peanut allergy seen recently.[84][better source needed]

To avoid an allergic reaction, a strict diet can be followed. It is difficult to determine the amount of allergenic food required to elicit a reaction, so complete avoidance should be attempted. In some cases, hypersensitive reactions can be triggered by exposures to allergens through skin contact, inhalation, kissing, participation in sports, blood transfusions, cosmetics, and alcohol.[85]

Early introduction of peanut and egg alongside other solids, or by one year of age, may help prevent development of food allergy. Introduction of these allergenic foods within the first year of life appears to be safe. A window of opportunity for the introduction of different food allergens may exist, such as egg introduction ahead of peanut.[86]

Inhalation exposure

[edit]

Allergic reactions to airborne particles or vapors of known food allergens have been reported as an occupational consequence of people working in the food industry, but can also take place in home situations, restaurants, or confined spaces such as airplanes. According to two reviews, respiratory symptoms are common, but in some cases there has been progression to anaphylaxis.[87][88] The most frequent reported cases of reactions by inhalation of allergenic foods were due to peanut, seafood, legumes, tree nut, and cow's milk.[87] Steam rising from cooking of lentils, green beans, chickpeas and fish has been well documented as triggering reactions, including anaphylactic reactions.[87][89] One review mentioned case study examples of allergic responses to inhalation of other foods, including examples in which oral consumption of the food is tolerated.[87]

Treatment

[edit]

The mainstay of treatment for food allergy is total avoidance of the foods identified as allergens. An allergen can enter the body by consuming a portion of food containing the allergen, and can also be ingested by touching any surfaces that may have come into contact with the allergen, then touching the eyes or nose. For people who are extremely sensitive, avoidance includes avoiding touching or inhaling problematic food. Total avoidance is complicated because the declaration of the presence of trace amounts of allergens in foods is not mandatory (see regulation of labelling).

If the food is accidentally ingested and a systemic reaction (anaphylaxis) occurs, then epinephrine should be used. A second dose of epinephrine may be required for severe reactions. The person should then be transported to the emergency room, where additional treatment can be given. Other treatments include antihistamines and steroids.[90]

Epinephrine

[edit]
Epinephrine autoinjectors are portable single-dose epinephrine-dispensing devices used to treat anaphylaxis.

Epinephrine (adrenaline) is the first-line treatment for severe allergic reactions (anaphylaxis). If administered in a timely manner, epinephrine can reverse its effects. Epinephrine relieves airway swelling and obstruction, and improves blood circulation; blood vessels are tightened and heart rate is increased, improving circulation to body organs. Epinephrine is available by prescription in an autoinjector.[91]

Antihistamines

[edit]

Antihistamines can alleviate some of the milder symptoms of an allergic reaction, but do not treat all symptoms of anaphylaxis.[92] Antihistamines block the action of histamine, which causes blood vessels to dilate and become leaky to plasma proteins. Histamine also causes itchiness by acting on sensory nerve terminals. The most common antihistamine given for food allergies is diphenhydramine.

Steroids

[edit]

Glucocorticoid steroids are used to calm down the immune system cells that are attacked by the chemicals released during an allergic reaction. This treatment in the form of a nasal spray should not be used to treat anaphylaxis, for it only relieves symptoms in the area in which the steroid is in contact. Another reason steroids should not be used is the delay in reducing inflammation. Steroids can also be taken orally or through injection, by which every part of the body can be reached and treated, but a long time is usually needed for these to take effect.[93]

Immunotherapy

[edit]

Immunotherapies seek to condition the immune system to elicit or suppress a specific immune response. In the treatment of allergies, common immunotherapies seek to desensitize the immune system by gradually exposing the body to allergens in increasing amounts. These forms of immunotherapy have had varying and limited success and have generally been used to treat peanut and environmental allergies.[94]

Omalizumab

[edit]

Omalizumab, an injectable asthma treatment drug sold under the brand name Xolair, was approved in the United States in February 2024 to reduce severe reactions to accidental exposure to food allergens.[95] It is a genetically engineered monoclonal antibody which specifically binds to immunoglobulin E (IgE) to reduce the severity of an immune response. Successful results were reported for wheat, eggs, milk and baked products containing wheat and milk.[96]

Epidemiology

[edit]

Food allergies affect up to 10% of the worldwide population, and they are currently more prevalent in children (~8%) than adults (~5) in western nations.[34] In several industrialized countries, food allergies affect up to 10% of children.[97] Children are most commonly allergic to cow's milk, chicken eggs, peanuts, and tree nuts.[21] While studies on adults with food allergy are not as abundant, surveys suggest that the most common food allergens for adults include fish, shellfish, peanuts, and tree nuts.[97]

Food allergies have become increasingly prevalent in industrialized/westernized nations over the last 2–3 decades.[98] An estimated 15 million people currently have food allergies in the United States.[99] In 1997, 0.4% children in the United States were reported to have peanut allergy, yet this number markedly rose to 1.4% in 2008.[100] In Australia, hospital admission rates for food-induced anaphylaxis increased by an average of 13.2% from 1994–2005.[97] One possible explanation for the rise in food allergy is the "old friends" hypothesis, which suggests that non-disease-causing organisms, such as helminths, could protect against allergy. Therefore, reduced exposure to these organisms, particularly in developed countries, could have contributed towards the increase.[citation needed]

Children of East Asian or African descent who live in westernized countries were reported to be at significantly higher risk of food allergy compared to Caucasian children.[15] Several studies predict that Asia and Africa may experience a growth in food allergy prevalence as the lifestyles there become more westernized.[97]

The prevalence of certain food allergies is suggested to depend partly on the geographical area and country. For instance, allergy to buckwheat flour, used for soba noodles, is more common in Japan than peanuts, tree nuts or foods made from soy beans.[101] Also, shellfish allergy is the most common cause of anaphylaxis in adults and adolescents particularly in East Asian countries like Hong Kong, Taiwan, Singapore, and Thailand.[97] Individuals in East Asia have further developed an allergy to rice, which forms a large part of their diet.[102] Another example is that, out of nine European countries, egg allergy was found[by whom?] to be most prevalent in the UK and least prevalent in Greece.[citation needed]

Special population: children

[edit]

About 75% of children who have allergies to milk protein are able to tolerate baked-in milk products, i.e., muffins, cookies, cake, and hydrolyzed formulas.[103] About 50% of children with allergies to milk, egg, soy, peanuts, tree nuts, and wheat will outgrow their allergy by the age of 6. Those who are still allergic by the age of 12 or so have less than an 8% chance of outgrowing the allergy.[104]

United States

[edit]

In the United States, food allergy affects as many as 5% of infants less than three years of age[105] and 3% to 4% of adults.[106][107] The prevalence of food allergies is rising.[108][109][110] Food allergies cause roughly 30,000 emergency room visits and 150 deaths per year.[111]

Regulation

[edit]

Whether rates of food allergy are increasing or not, food allergy awareness has definitely increased, with impacts on the quality of life for children, their parents and their caregivers.[112][113][114][115] In the United States, the Food Allergen Labeling and Consumer Protection Act of 2004 causes people to be reminded of allergy problems every time they handle a food package, and restaurants have added allergen warnings to menus. The Culinary Institute of America, a premier school for chef training, has courses in allergen-free cooking and a separate teaching kitchen.[116] School systems have protocols about what foods can be brought into the school. Despite all these precautions, people with serious allergies are aware that accidental exposure can easily occur at other peoples' houses, at school or in restaurants.[117]

Regulation of labelling

[edit]
An example of a list of allergens in a food item

In response to the risk that certain foods pose to those with food allergies, some countries have responded by instituting labeling laws that require food products to clearly inform consumers if their products contain priority allergens or byproducts of major allergens among the ingredients intentionally added to foods.

The priority allergens vary by country.

Food allergens prioritized in labeling laws by country
Food US[118] Canada[119] UK[120] Australia & New Zealand[121] EU[122]
peanuts Yes Yes Yes Yes Yes
tree nuts Yes Yes Yes Almonds, Brazil nuts, cashews, hazelnuts, macadamias, pecans, pistachios, pine nuts, and walnuts Yes
milk Yes Yes Yes Yes Yes
eggs Yes Yes Yes Yes Yes
fish Yes Yes Yes Yes Yes
shellfish Crustaceans only Crustaceans and molluscs Crustaceans and molluscs Crustaceans and molluscs Crustaceans and molluscs
soy Yes Yes Yes Yes Yes
gluten No Yes Yes Yes Yes
wheat Yes Includes triticale Included under gluten Yes Included under gluten
sesame seeds Yes as of 2023[123] Yes Yes Yes Yes
mustard No Yes Yes No Yes
sulphites (not a true allergy) No Yes Yes Yes, if >10 mg/kg Yes, if >10 mg/kg
celery No No Yes No Yes
lupin No No Yes Yes Yes

There are no labeling laws mandating declaration of the presence of trace amounts in the final product as a consequence of cross-contamination, except in Brazil.[124][125][126][127][128][129][130][131]

Ingredients intentionally added

[edit]

In the United States, the Food Allergen Labeling and Consumer Protection Act of 2004 requires companies to disclose on the label whether a packaged food product contains any of these eight major food allergens, added intentionally: cow's milk, peanuts, eggs, shellfish, fish, tree nuts, soy and wheat.[125] The eight-ingredient list originated in 1999 from the World Health Organisation Codex Alimentarius Commission.[130] To meet labeling requirements, if an ingredient is derived from one of the required-label allergens, then it must either have its "food sourced name" in parentheses, for example, "Casein (milk)," or as an alternative, there must be a statement separate but adjacent to the ingredients list: "Contains milk" (and any other of the allergens with mandatory labeling).[125][127] The European Union requires listing for those eight major allergens plus molluscs, celery, mustard, lupin, sesame and sulfites.[126]

In 2018, the US FDA issued a request for information for the consideration of labeling for sesame to help protect people who have sesame allergies.[132] A decision was reached in November 2020 that food manufacturers voluntarily declare that when powdered sesame seeds are used as a previously unspecified spice or flavor, the label be changed to "spice (sesame)" or "flavor (sesame)."[133]

Congress and the President passed a law in April 2021, the "FASTER Act", stipulating that labeling be mandatory, to be effect January 1, 2023, making it the ninth required food ingredient label.[134]

The Food Allergen Labeling and Consumer Protection Act of 2004 applies to packaged foods regulated by the FDA, which does not include poultry, most meats, certain egg products, and most alcoholic beverages.[131] However, some meat, poultry, and egg processed products may contain allergenic ingredients. These products are regulated by the Food Safety and Inspection Service, which requires that any ingredient be declared in the labeling only by its common or usual name. Neither the identification of the source of a specific ingredient in a parenthetical statement nor the use of statements to alert for the presence of specific ingredients, like "Contains: milk", are mandatory.[128][129] The act also does not apply to food prepared in restaurants.[135][136] The EU Food Information for Consumers Regulation 1169/2011 – requires food businesses to provide allergy information on food sold unpackaged, for example, in catering outlets, deli counters, bakeries and sandwich bars.[137]

In the United States, there is no federal mandate to address the presence of allergens in drug products, medicines, or cosmetics.[138]

Trace amounts as a result of cross-contamination

[edit]

The value of allergen labeling other than for intentional ingredients is controversial. This concerns labeling for ingredients present unintentionally as a consequence of cross-contact or cross-contamination at any point along the food chain (during raw material transportation, storage or handling, due to shared equipment for processing and packaging, etc.).[130][131] Experts in this field propose that if allergen labeling is to be useful to consumers, and healthcare professionals who advise and treat those consumers, ideally there should be agreement on which foods require labeling, threshold quantities below which labeling may be of no purpose, and validation of allergen detection methods to test and potentially recall foods that were deliberately or inadvertently contaminated.[139][140]

Labeling regulations have been modified to provide for mandatory labeling of ingredients plus voluntary labeling, termed precautionary allergen labeling, also known as "may contain" statements, for possible, inadvertent, trace amount, cross-contamination during production.[130][141] Precautionary allergen labeling can be confusing to consumers, especially as there can be many variations on the wording of the warning.[141][142] Precautionary allergen labeling is optional in the United States.[143] As of 2014, precautionary allergen labeling is regulated only in Switzerland, Japan, Argentina, and South Africa. Argentina decided to prohibit precautionary allergen labeling since 2010 and instead puts the onus on the manufacturer to control the manufacturing process and label only those allergenic ingredients known to be in the products. South Africa does not permit the use of precautionary allergen labeling, except when manufacturers demonstrate the potential presence of allergen due to cross-contact through a documented risk assessment and despite adherence to good manufacturing practice.[130] In Australia and New Zealand there is a recommendation that precautionary allergen labeling be replaced by guidance from VITAL 2.0 (Vital Incidental Trace Allergen Labeling). A review identified "the eliciting dose for an allergic reaction in 1% of the population" as the threshold reference dose for certain foods (such as cow's milk, egg, peanut and other proteins) to provide food manufacturers with guidance for developing precautionary labeling and give consumers a better idea of what might be accidentally in a food product beyond "may contain."[144][145] VITAL 2.0 was developed by the Allergen Bureau, a food industry sponsored, non-government organization.[146] The European Union has initiated a process to create labeling regulations for unintentional contamination but is not expected to publish such before 2024.[147]

In Brazil, since April 2016, the declaration of the possibility of cross-contamination is mandatory when the product does not intentionally add any allergenic food or its derivatives, but the good manufacturing practices and allergen control measures adopted are not sufficient to prevent the presence of accidental trace amounts. These allergens include wheat, rye, barley, oats and their hybrids, crustaceans, eggs, fish, peanuts, soybean, milk of all species of mammalians, almonds, hazelnuts, cashew nuts, Brazil nuts, macadamia nuts, walnuts, pecan nuts, pistachios, pine nuts, and chestnuts.[124]

Genetically modified food

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There is a scientific consensus that available food derived from genetically modified crops poses no greater risk to human health than conventional food,[148][149][150] and a 2016 U.S. National Academy of Sciences report concluded that there is no relationship between consumption of genetically modified foods and the increase in prevalence of food allergies.[151] However, there are concerns that genetically modified foods, also described as foods sourced from genetically modified organisms, could be responsible for allergic reactions, and that the widespread acceptance of these types of foods may be responsible for what is a real or perceived increase in the percentage of people with allergies.[152][151][153]

One concern is that genetic engineering could make an allergy-provoking food more allergic, meaning that smaller portions would suffice to set off a reaction.[153] Of the food currently[when?] in widespread use of genetically modified organisms, only soybeans are identified as a common allergen. However, for the soybean proteins known to trigger allergic reactions, there is more variation from strain to strain than between those and the genetically modified varieties.[151] Another concern is that genes transferred from one species to another could introduce an allergen in a food not thought of as particularly allergenic. Research on an attempt to enhance the quality of soybean protein by adding genes from Brazil nuts was terminated when human volunteers known to have tree nut allergy reacted to the modified soybeans.[152]

Prior to a new genetically modified food receiving government approval, certain criteria need to be met. These include: Is the donor species known to be allergenic? Does the amino acid sequence of the transferred proteins resemble the sequence of known allergenic proteins? Are the transferred proteins resistant to digestion – a trait shared by many allergenic proteins?[151] Genes approved for animal use can be restricted from human consumption due to potential for allergic reactions. In 1998 StarLink brand corn restricted to animals was detected in the human food supply, leading to first a voluntary and then an FDA-mandated recall.[154] There are requirements in some countries and recommendations in others that all foods containing genetically modified ingredients be so labeled, and that there be a post-launch monitoring system to report adverse effects (similar to the requirements in some countries for drug and dietary supplement reporting).[152]

Restaurants

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In the US, the FDA Food Code states that the person in charge in restaurants should have knowledge about major food allergens, cross-contacts, and symptoms of food allergy reactions. Restaurant staff, including wait staff and kitchen staff, may not be adequately informed about allergenic ingredients, or the risk of cross-contact when kitchen utensils used to prepare food may have been in previous contact with an allergenic food. The problem may be compounded when customers have a hard time describing their food allergies or when wait staff have a hard time understanding those with food allergies when taking an order.[155]

Diagnosing issues

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There exists both over-reporting and under-reporting of the prevalence of food allergies. Self-diagnosed perceptions of food allergy are greater than the rates of true food allergy because people confuse non-allergic intolerance with allergy, and also attribute non-allergy symptoms to an allergic response. Conversely, healthcare professionals treating allergic reactions on an out-patient or even hospitalized basis may not report all cases. Recent increases in reported cases may reflect a real change in incidence or an increased awareness on the part of healthcare professionals.[156]

Social impact

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Food fear has a significant impact on quality of life.[114][115] For children with allergies, their quality of life is also affected by the actions of their peers. An increased occurrence of bullying has been observed, which can include threats or deliberate acts of forcing allergic children to contact foods that they must avoid or intentional contamination of allergen-free food.[157] The social impacts of food allergies can carry over into adulthood.[158]

Portrayal in media

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Media portrayals of food allergy in television and film are not accurate, often used for comedic effect or underplaying the potential severity of an allergic reaction.[159] These tropes misinform the public and also contribute to how entertainment media will continue to wrongly portray food allergies in the future. Types of tropes: 1) characters have food allergies, providing a weakness that can be used to sabotage them. In the movie Parasite a housekeeper is displaced by taking advantage of her peach allergy.[160] In the animated film Peter Rabbit, the farm owner is attacked by being pelted with blackberries, causing an anaphylactic reaction requiring emergency treatment with epinephrine. After many public protests, Sony Pictures and the Peter Rabbit director apologized for making light of food allergies.[161] 2) Food allergy is used for comedic effect, such as in the movies Hitch and in television, Kelso's egg allergy in That '70s Show. 3) Food allergies may be incorporated into characters who are also portrayed as annoying, weak and oversensitive, which can be taken as implying that their allergies are either not real or not potentially severe. In season 1, episode 16 of The Big Bang Theory Howard Wolowitz deliberately consumes a peanut-containing food bar (and has a serious reaction) just to delay Leonard from returning to his apartment where a surprise birthday party is being arranged. 4) Any of these portrayals may underplay the potential severity of food allergy, some showing that Benadryl treatment is sufficient.[160] Viewing of humorous portrayals of food allergies has been shown to have a negative effect on related health policy support due to low perceived seriousness.[159]

Research

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Several theories have been suggested to explain why certain individuals develop allergic sensitization instead of oral tolerance to food allergens. One such theory is the dual allergen hypothesis, which states that ingesting food allergens early on promotes oral tolerance while skin exposure leads to sensitization.[99] Instead of oral ingestion, skin barrier disruption in conditions like eczema, for instance, was suggested to cause allergic sensitization in animal and human infants.[48] Inhalation was recently proposed to be an additional sensitization route in the dual allergen hypothesis.[42] Another theory is the barrier regulation hypothesis, describing the role of commensal bacteria in preventing the development of food allergy by maintaining integrity of the intestinal epithelial barrier.[99] Environmental and lifestyle factors, such as early life nutrition and antibiotic treatment, may contribute to food allergy prevalence by affecting gut microbial composition, and thus, intestinal immune homeostasis in infants and young children.[162]

A number of desensitization techniques are being studied.[163] Areas of research include specific oral tolerance induction (also known as oral immunotherapy), and sublingual immunotherapy. The benefits of allergen immunotherapy for food allergies is unclear, thus is not recommended as of 2015.[7]

There is research on the effects of increasing intake of polyunsaturated fatty acids during pregnancy, lactation, via infant formula and in early childhood on the subsequent risk of developing food allergies during infancy and childhood. From two reviews, maternal intake of omega-3, long-chain fatty acids during pregnancy appeared to reduce the risks of medically diagnosed IgE-mediated allergy, eczema and food allergy per parental reporting in the first 12 months of life,[164][165] but the effects were not all sustained past 12 months.[165] The reviews characterized the literature's evidence as inconsistent and limited.[164][165] Results when breastfeeding mothers were consuming a diet high in polyunsaturated fatty acids were inconclusive.[166] For infants, supplementing their diet with oils high in polyunsaturated fatty acids did not affect the risks of food allergies, eczema or asthma either as infants or into childhood.[167]

There is research on probiotics, prebiotics and the combination of the two (synbiotics) as a means of treating or preventing infant and child allergies. From reviews, there appears to be a treatment benefit for eczema,[168][169][170] but not asthma, wheezing or rhinoconjunctivitis.[171] The evidence was not consistent for preventing food allergies and this approach cannot yet be recommended.[169][170][172][173]

The Food Standards Agency, in the United Kingdom, are in charge of funding research into food allergies and intolerance.[156] Since their founding in 1994 they have funded over 45 studies.[156] In 2005 Europe created EuroPrevall, a multi-country project dedicated to research involving allergies.[156] 

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia
from Grokipedia
Food allergy is an adverse to specific dietary proteins, most commonly mediated by (IgE) antibodies that bind to allergens and trigger degranulation, releasing and other mediators to produce symptoms ranging from localized and gastrointestinal upset to systemic involving , airway obstruction, and potential fatality. The condition differs from food intolerances, which lack immune involvement and do not risk life-threatening reactions. IgE-mediated food allergies predominate in rapid-onset cases, with the "big eight" allergens—cow's , eggs, , nuts, soy, , , and —accounting for over 90% of reactions in affected populations, particularly children who often outgrow milk and egg allergies but retain peanut and tree nut sensitivities into adulthood. Prevalence has risen markedly over recent decades, impacting roughly 8% of children and 10% of adults globally based on confirmed cases, though self-reported figures inflate estimates due to misattribution of non-allergic symptoms; U.S. data indicate 6.2% of adults with diagnosed food allergy as of 2021. Symptoms typically emerge within minutes to hours of exposure, encompassing skin manifestations like urticaria or , oral itching, vomiting, wheezing, and in —defined by multi-organ involvement—potentially cardiovascular collapse requiring immediate epinephrine administration via auto-injector. Diagnosis relies on clinical history corroborated by prick testing, serum IgE levels, and oral food challenges, while management emphasizes avoidance, education on cross-contamination risks, and preparedness with epinephrine; emerging oral immunotherapies, including recent adult trials like the GUPI study for peanut allergy, show promise for desensitization in both children and adults but carry risks of adverse reactions. The involves genetic predispositions interacting with environmental factors like delayed introduction in infancy, with supporting early exposure guidelines to mitigate risk, though causes of the observed surge remain incompletely elucidated beyond hygiene and alterations.

Definition and Classification

IgE-Mediated Allergies

IgE-mediated food allergies constitute reactions triggered by specific food proteins, distinguished by the involvement of (IgE) antibodies. In the sensitization phase, antigen-presenting cells process the , activating Th2 lymphocytes that stimulate B cells to produce allergen-specific IgE, which binds to high-affinity FcεRI receptors on mast cells and . Re-exposure to the cross-links these IgE molecules, inducing immediate and release of mediators such as , , leukotrienes, and prostaglandins, which drive the inflammatory response. This mechanism contrasts with subjective self-reports of food sensitivity, as true IgE-mediated allergy requires demonstrable allergen-specific IgE via tests like skin prick or serum assays, with oral food challenges providing confirmatory evidence of clinical reactivity. Symptoms manifest rapidly, typically within minutes to two hours of ingestion, encompassing cutaneous effects like urticaria and ; gastrointestinal disturbances including , , and crampy ; and respiratory symptoms such as wheezing or laryngeal edema, potentially progressing to in severe instances. These acute responses arise from localized mediator effects in target organs, with systemic dissemination possible via bloodstream absorption of the . Prevalence data from challenge-confirmed studies indicate IgE-mediated food allergies affect about 6% of young children, declining somewhat with age but persisting for certain allergens. Peanut allergy shows a challenge-proven rate of approximately 3% in Australian infants and 1.4% in U.S. children as of 2008, while ranges from 1-3% globally, with these eliciting the majority of severe and persistent cases due to low tolerance thresholds and high risk.00135-7/fulltext) Self-reported figures often exceed these by 2-3 fold, underscoring the need for objective verification to avoid overestimation.

Non-IgE-Mediated Reactions

Non-IgE-mediated reactions to food proteins encompass a spectrum of gastrointestinal disorders driven by cell-mediated immune responses, distinct from the immediate of IgE-mediated allergies. These reactions typically manifest hours to days after , involving T-cell activation and release rather than degranulation, often classified under mechanisms or mixed innate-adaptive pathways. Unlike IgE-mediated processes, they lack detectable allergen-specific IgE and do not trigger systemic , though severe can occur in acute episodes. The prototypical condition is (FPIES), primarily affecting under 6 months, with symptoms including profuse, repetitive onset 1-4 hours post-ingestion, , , and occasionally hypotonicity or bloody in chronic exposures. Common triggers include cow's milk (50-65% of cases), soy, , and oats, with linked to gut mucosal inflammation, elevated tumor necrosis factor-alpha (TNF-α), and IL-9 from peripheral blood mononuclear cells upon challenge. Cohort studies report FPIES incidence at approximately 0.015-0.34% in high-risk infant populations, rarer than IgE-mediated allergies (which affect 6-8% of children), and with spontaneous resolution by age 3-5 years in 90% of cases. Other entities include food protein-induced allergic proctocolitis (FPIAP), seen in breastfed or formula-fed infants, featuring and in stools 1-3 weeks after trigger introduction, without systemic involvement. Predominantly triggered by cow's milk or soy via maternal diet, FPIAP reflects localized or lymphocytic infiltration in the colonic mucosa, resolving upon elimination and rarely persisting beyond infancy. Food protein-induced enteropathy (FPE) presents with , , and villous atrophy resembling celiac disease, but tied to non-IgE cow's milk or soy exposure, with histological confirmation via small bowel showing intraepithelial . These reactions collectively pose minimal anaphylactic risk due to absent IgE cross-linking, though acute FPIES can mimic , necessitating differentiation via timed symptom reproducibility in controlled challenges.

Distinction from Food Intolerances

Food allergies involve an aberrant to food proteins, typically mediated by (IgE) antibodies that trigger degranulation and release of and other mediators, leading to potential systemic effects. In contrast, food intolerances arise from non-immune mechanisms, such as enzymatic deficiencies or metabolic disturbances, without activation of the or detectable IgE sensitization. For instance, results from insufficient enzyme activity in the , causing undigested to reach the colon where bacterial produces gas and osmotic , confined primarily to gastrointestinal effects. Diagnostic tests for allergies, including skin prick or serum IgE assays, remain negative in intolerances, underscoring the absence of immunological . Empirical studies using double-blind, placebo-controlled challenges (DBPCFC), the standard for confirming adverse reactions, reveal frequent misattribution of intolerances as in self-reports. Up to 35% of individuals self-diagnose food hypersensitivity, yet blinded challenges often fail to reproduce symptoms attributable to true , instead identifying non-immune triggers like carbohydrate . A population-based analysis found substantial discrepancies between perceived intolerance and objective DBPCFC outcomes, with many reported cases resolving as effects or unrelated digestive issues upon rigorous testing. Causally, allergies propagate via antigen-specific T-cell and B-cell memory leading to rapid or delayed inflammatory cascades, whereas intolerances stem from direct physicochemical interactions, such as substrate-enzyme mismatches, yielding localized osmotic or fermentative disturbances without storms or changes. Although both can manifest rapidly—allergic reactions typically within minutes via immune mechanisms, while non-allergic indigestion or epigastric discomfort may start around 10 minutes after eating but lacks immune involvement and life-threatening potential—intolerances do not elicit recruitment or activation observed in allergic responses, preventing escalation to . Mislabeling risks unnecessary avoidance, potentially exacerbating nutritional deficits without addressing the underlying metabolic .

Historical Development

Early Observations and Recognition

The earliest documented observations of adverse food reactions trace to , where (c. 460–377 BC) described how certain foods like cheese provoked distress or death in susceptible individuals, while others consumed them harmlessly, attributing this to individual differences in bodily humors. These accounts, echoed in texts by later figures such as , represented anecdotal idiosyncrasies rather than systematic inquiry, with no empirical framework to distinguish allergic responses from digestive upset or poisoning. Isolated reports persisted through medieval and early modern periods, including Ibn Sina's notes on food-triggered swellings and Sir John Floyer's 1698 mention of fatal shellfish reactions, yet they elicited minimal medical scrutiny amid prevailing humoral theories. By the , European cataloged more precise instances of immediate skin eruptions post-ingestion, as Robert Willan detailed in his 1808 dermatology treatise cases of urticaria from almonds, mushrooms, , , and mussels, sometimes escalating to fatal "urticaria febralis."00043-7/fulltext) Such descriptions aligned with emerging clinical observation but faced interpretive challenges, often conflated with infections or toxins, as as a distinct entity remained undefined until Charles Richet's 1902 Nobel-recognized work on in animals, which indirectly highlighted risks without direct application to cases. Systematic study lagged, constrained by absent diagnostic standards and a focus on infectious etiologies over immune idiosyncrasies. In 1912, pediatrician Oscar M. Schloss advanced recognition through the inaugural use of scratch testing on to confirm food-specific sensitivities, reporting a case where extracts of , , and elicited reactions correlating with clinical symptoms in a . Published in the American Journal of Diseases of Children, this method introduced extract-based provocation for objectivity, diverging from reliance on dietary histories alone and signaling a pivot toward testable hypotheses, though adoption was gradual amid variable reproducibility. Skepticism dominated pre-1960s discourse, with many physicians dismissing food allergies as rare psychosomatic or intolerance phenomena due to diagnostic imprecision and failure to replicate reactions under controlled conditions, leading to underreporting and therapeutic neglect. This doubt persisted even as case series accumulated, exemplified by the American Academy of Allergy's reluctance to prioritize food reactions until mechanistic validation; the 1967 identification of IgE by Kimishige and Teruko Ishizaka as the carrier of reaginic activity in allergic sera furnished the empirical cornerstone for IgE-mediated pathways, catalyzing acceptance of food allergy's immunological legitimacy.30165-8/fulltext)

Advances in Immunology and Diagnosis

The elucidation of mechanisms in the 1950s, involving release triggered by , laid groundwork for understanding immediate allergic responses, though full integration with mediation awaited later discoveries. In 1967, Kimishige and Teruko Ishizaka identified (IgE) as the key in reaginic , demonstrating its role in binding to FcεRI receptors on and , which upon cross-linking initiate and mediator release central to IgE-mediated food allergies. This breakthrough enabled targeted models of , distinguishing IgE-dependent pathways from other immune responses and facilitating the development of IgE-specific diagnostics like serum-specific IgE assays. Diagnostic advancements in the and emphasized reducing reliance on skin prick tests (SPT) and radioallergosorbent tests (RAST), which exhibited high sensitivity but low specificity, often resulting in of food allergies. The double-blind, placebo-controlled oral (DBPCOFC), refined during this period, became the reference standard, involving blinded administration of escalating doses under medical supervision to provoke and confirm clinical reactions, thereby validating or refuting suspected allergies with direct causal evidence. By the , standardized protocols for DBPCOFC minimized risks and improved reproducibility, addressing prior inconsistencies in open challenges and enhancing diagnostic precision beyond correlative tests alone. The 2015 Learning Early About Peanut Allergy (LEAP) study marked a in preventive , showing via that introducing protein at 4-11 months in high-risk infants (those with severe eczema or ) reduced development by 81% at age 5 compared to avoidance. This evidence from 640 participants challenged the avoidance-centric approach, rooted in observational data, and supported early exposure as a causal preventive strategy, influencing guidelines to prioritize introduction over delay based on interventional outcomes rather than associative risks. Subsequent analyses confirmed sustained benefits, underscoring empirical validation over precautionary narratives.

Pathophysiology

Immune Mechanisms

Food allergies primarily involve IgE-mediated reactions, where initial occurs through the processing of food by antigen-presenting cells (APCs), such as dendritic cells in the gastrointestinal mucosa. In genetically predisposed atopic individuals, these APCs present allergen peptides via to naive CD4+ T cells, promoting differentiation into Th2 cells that secrete cytokines including IL-4, IL-13, and IL-5. IL-4 drives class-switch recombination to produce allergen-specific IgE antibodies, which bind to the high-affinity FcεRI receptors on mast cells, , and other effector cells. This phase establishes immunological memory, distinguishing food allergy from transient intolerances. Upon subsequent exposure to the , the effector phase is triggered when multivalent food allergens cross-link IgE molecules bound to FcεRI on sensitized effector cells, initiating intracellular signaling cascades such as Lyn and Syk . This leads to rapid , releasing preformed mediators like from granules, alongside de novo synthesis of lipid mediators including leukotrienes (e.g., LTC4) and prostaglandins, and cytokines such as TNF-α and IL-4. These mediators cause immediate effects through , smooth muscle contraction, and increased , while late-phase responses involve recruitment driven by IL-5. Epithelial barrier dysfunction plays a causal role in facilitating sensitization by allowing intact or partially digested proteins to penetrate the gut mucosa, evading normal digestive degradation and tolerance induction. Studies in filaggrin-deficient mouse models and human cohorts with early-life demonstrate increased transepithelial flux correlating with higher IgE rates. Human data reveal reduced proteins like in food-allergic infants, supporting "leaky gut" as an entry point for Th2-skewing antigens, particularly when combined with dysbiotic that impair function.30376-4/fulltext) Animal models further confirm that barrier disruption via detergents or genetic mutations precedes allergic priming, underscoring over mere .

Acute and Late-Phase Responses

In IgE-mediated food allergies, the acute phase response initiates within minutes of allergen exposure upon cross-linking of allergen-specific IgE antibodies bound to FcεRI receptors on sensitized and , prompting rapid . This process releases preformed mediators, including , , and proteoglycans, alongside newly synthesized mediators such as and cysteinyl leukotrienes. promotes and endothelial permeability, contributing to urticaria and , while leukotrienes induce contraction in the respiratory and gastrointestinal tracts, manifesting as or abdominal cramping. The late-phase response emerges 6 to 12 hours after the initial exposure, characterized by the recruitment of , , and T lymphocytes to the site of challenge, driven by like eotaxin and cytokines such as IL-5 produced during the acute phase. , in particular, degranulate to release toxic granule proteins (e.g., major basic protein) and additional mediators, perpetuating tissue and potentially prolonging symptoms. Studies of cutaneous challenges demonstrate this phase through persistent wheal-and-flare reactions and histological evidence of infiltration, underscoring its role in sustained allergic . Biphasic reactions, reflecting the interplay of acute and late-phase mechanisms, occur in 1% to 20% of food allergy-induced cases, with the secondary phase typically arising within hours to a day after apparent resolution of the initial symptoms. This risk, observed in clinical models of , necessitates extended monitoring protocols post-exposure to mitigate recurrence, as late-phase eosinophil-mediated effects can escalate severity independently of ongoing presence.

Clinical Manifestations

Common Signs and Symptoms

Cutaneous manifestations predominate as initial signs in IgE-mediated food allergic reactions, with and occurring in approximately 80-90% of acute episodes. These symptoms typically involve itchy, raised welts on the skin or deeper swelling, respectively, and may appear rapidly following exposure. Gastrointestinal symptoms are also common, encompassing , , , and , which can occur alone or alongside skin reactions. Respiratory involvement, such as wheezing or , arises less frequently in non-severe cases but signals potential escalation. Symptom onset generally occurs within minutes to two hours after in IgE-mediated cases, though variability exists by reaction type and ; for instance, reactions manifest swiftly, often within minutes to one hour. In non-IgE-mediated reactions, particularly to cow's protein, gastrointestinal symptoms like and may be delayed, emerging 2 to 48 hours post-exposure.

Anaphylaxis and Severity

Anaphylaxis represents the most severe manifestation of food allergy, defined as an acute-onset, life-threatening systemic reaction involving the skin or mucosa plus either respiratory compromise (e.g., dyspnea, , ) or reduced /end-organ dysfunction, per the National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy & Anaphylaxis Network (FAAN) consensus criteria. These criteria, validated prospectively with 97% sensitivity for emergency department anaphylaxis diagnosis, emphasize multi-system involvement to distinguish from milder reactions. In food-induced cases, symptoms often progress rapidly after , with as a hallmark of severity indicating cardiovascular collapse. Severity escalates with factors such as comorbid , which elevates the of by 2.07-3.29 compared to non-asthmatic individuals, particularly in severe asthma where hazard ratios reach 8.23. Peanut and tree nut allergies demonstrate higher propensity for anaphylactic reactions than milk or egg allergies, with nuts implicated in a disproportionate share of severe pediatric cases due to potent IgE cross-linking and rapid absorption. Biphasic reactions, involving symptom recurrence without re-exposure (typically within 72 hours), occur in up to 20% of cases and predict poorer outcomes; predictors include initial , unknown triggers, and delayed epinephrine administration beyond 60 minutes. Fatal outcomes from food anaphylaxis remain rare, with an incidence of 0.03-0.3 deaths per million person-years, though untreated severe episodes carry substantial mortality risk due to airway obstruction or shock. In analyzed cohorts, severe food (grade 3-4) comprises about 28% of reactions, with 27.9% classified as high-grade including fatalities, underscoring the need for rapid intervention despite overall low lethality in treated settings. High doses further amplify severity by overwhelming compensatory mechanisms, as evidenced in challenge studies.

Epidemiology

Food allergy affects approximately 8% of children and 10% of adults worldwide based on self-reported data from recent reviews, though confirmed rates via diagnostic challenges, such as oral food challenges for IgE-mediated reactions, are typically lower at around 5-6% in population studies conducted between 2019 and 2025. , diagnosed food allergy stands at 5.8% among children aged 0-17 years and 6.2% among adults as of 2021, per Interview Survey data, reflecting physician-diagnosed cases rather than self-reports. These figures underscore a distinction between perceived and verified allergies, with self-reported estimates often exceeding challenge-confirmed IgE-mediated cases due to inclusion of intolerances or unverified symptoms. Prevalence varies markedly by region, with higher rates in Western countries compared to and other developing areas. In , self-reported food allergy affects about 10% of children, positioning it among the highest globally. In contrast, rates in Asian populations are substantially lower, often 1-2% for confirmed cases, as evidenced by comparative studies and International Study of Asthma and Allergies in Childhood (ISAAC) data showing symptom-based food allergy reports under 3% in many Asian centers. ISAAC Phase 1 surveys across multiple countries reported self-reported food-related symptoms in 2-8% of children aged 6-7 and 13-14 years, with elevated figures in affluent Western settings and lower in , highlighting geographic disparities beyond diagnostic access. Trends indicate a genuine rise in prevalence, independent of improved diagnostics alone. In the , food allergy among children increased by 50% from 3.4% in 1997-1999 to 5.1% in 2009-2011, followed by another approximate 50% rise through 2021, based on serial Interview Surveys tracking parent- or physician-reported cases. Global epidemiological reviews corroborate this pattern, noting sustained increases across high-income regions since the , with meta-analyses of studies up to 2023 showing overall prevalence climbing from earlier baselines of 3% to current estimates exceeding 6% in affected populations.

Demographic Risk Factors

Food allergies demonstrate higher prevalence in children compared to adults, with estimates of approximately 4% in children and 1% in adults based on global surveys. Children represent a high-risk demographic group, though a substantial proportion outgrow specific allergies; for , up to 75% of affected children eventually resolve it, often by school age. Sex differences vary by age, with boys comprising about 64% of children diagnosed with food allergy (male-to-female ratio of 1.8:1), while in adulthood the distribution equalizes or shifts toward females (approximately 65% female). A family history of atopic elevates the of food allergy in , with odds ratios of 1.8 (95% CI 1.5-2.3) for children with two or more allergic family members in population-based studies. Co-occurrence of other atopic conditions, such as eczema or , further triples the risk in affected children according to cohort analyses. Food allergies in the elderly remain understudied, with limited cohort data available on prevalence or demographic patterns in this group.

Increases in Incidence

Hospitalizations for food-induced anaphylaxis among US children under 18 years old increased substantially from the late 1990s to the mid-2000s, with pediatric food allergy hospitalizations tripling during this period according to data from the National Hospital Ambulatory Medical Care Survey. Similar trends were observed in state-level registries, such as New York, where anaphylaxis hospitalizations in individuals under 20 years rose markedly from 1990 to 2006, with food allergens implicated in a growing proportion of cases following the adoption of specific ICD-9 codes in 1994. These rises reflect real immunological shifts rather than solely coding changes, as food anaphylaxis overtook other triggers in hospitalization dominance post-1994. Post-2010 analyses confirm the persistence of these upward trends. Self-reported food allergy among children increased by 50% from 2007 to 2021, building on a prior 50% rise between 1997 and 2011, per surveys. Meta-analyses and epidemiological reviews indicate sustained incidence growth, with global and data showing continued elevation in confirmed cases through the , independent of diagnostic advancements alone. Explanations attributing increases solely to improved recognition are challenged by evidence of genuine rises in immunologically verified allergies. Rates of food allergies confirmed via double-blind placebo-controlled oral food challenges, the gold standard for diagnosis, have demonstrated multi-fold increases in select cohorts from the late 1990s to early 2000s, paralleling hospitalization data.00562-4/abstract) Migration studies further support environmental contributions to these shifts, with first-generation immigrants from low-prevalence regions (e.g., Asia) to high-prevalence countries (e.g., Australia, US) exhibiting intermediate risks that converge toward host-country rates in subsequent generations, underscoring non-genetic factors in incidence escalation.

Etiology and Risk Factors

Genetic Contributions

Twin studies demonstrate substantial for food allergies, with monozygotic twins showing markedly higher concordance rates than dizygotic twins, indicating a dominant genetic component. For specifically, pairwise concordance was 64.3% among 14 monozygotic twin pairs compared to 6.8% among 44 dizygotic pairs. Overall estimates from twin studies place food allergy at approximately 80%. These findings underscore that genetic factors play a primary role, though the trait manifests through complex polygenic inheritance rather than monogenic , involving multiple loci of modest effect sizes. Loss-of-function mutations in the gene (FLG), which encodes a key epidermal barrier protein, confer increased risk for food allergies as part of the atopic march, where early skin barrier defects predispose to subsequent allergic sensitization. Children carrying FLG mutations exhibit odds ratios for food allergy ranging from 2.0 to 2.9, independent of eczema in some cohorts.01032-X/abstract) FLG variants have been consistently replicated across studies, highlighting their role in epithelial integrity and penetration. Human leukocyte antigen (HLA) genes in the also show associations with specific food allergies, influencing and specificity. For instance, certain HLA class II alleles correlate with risk and severity across populations, with polymorphisms in HLA binding grooves potentially tagging recognition differences. Genome-wide association studies (GWAS) have identified additional loci beyond FLG and HLA, including SERPINB (involved in inhibition and ), C11orf30/EMSY, and MALT1 (with the largest reported , 10.99), supporting a polygenic where no single variant dominates.31574-9/fulltext) These genetic signals are modulated by non-genetic factors, as evidenced by epigenetic marks on loci like FLG, but the core predispositions remain heritable.

Environmental and Lifestyle Factors

The posits that reduced early-life exposure to diverse microbes in sanitized modern environments disrupts , increasing susceptibility to allergic diseases including food allergies. supports this through the protective "farm effect," where children raised on with animal contact and diverse microbial environments exhibit halved risk of allergic sensitization (odds ratio approximately 0.5). Similarly, farm residency correlates with lower odds of (OR 0.31, 95% CI 0.13-0.78), extending to broader via enhanced regulatory T-cell responses from endotoxin-rich exposures. These associations hold after adjusting for confounders like family history, underscoring causal roles for microbial diversity over mere rural isolation. Urbanization amplifies these risks by limiting microbial contacts and correlating with higher food allergy prevalence; U.S. studies report 9.8% in urban children versus 6.2% in rural ones, a 3.5% differential attributed to diminished environmental . Vitamin D deficiency, prevalent in urban settings due to indoor lifestyles and limited , shows inconsistent but suggestive links to elevated food allergy odds; persistently low levels yield OR 2.04 for food (95% CI 1.02-4.10), while insufficiency in sensitized infants raises allergy likelihood sixfold in select cohorts. However, systematic reviews highlight null overall associations, indicating potential by sunlight exposure's independent immunomodulatory effects rather than as sole mediator. Lifestyle practices influencing allergen timing further modulate risk; pre-2000 guidelines promoted delayed complementary feeding to avert , yet randomized controlled trials refute this, demonstrating early introduction (4-11 months) slashes incidence by 81% in high-risk infants. The LEAP trial's causal evidence prompted reversals in recommendations, with sustained protection into , implying avoidance historically exacerbated epidemics by forgoing oral tolerance windows. Such interventions align with causal realism, prioritizing empirical prevention over unverified delay benefits.

Specific Allergens and Sensitization Routes

The major food allergens responsible for the majority of reactions worldwide include cow's milk, , , nuts (such as , , and ), , soy, , and crustacean , collectively known as the "Big 8," with recognized as a ninth major allergen in recent regulatory updates. These account for approximately 90% of confirmed food allergy cases. In pediatric populations, cow's milk and allergies are the most prevalent, affecting 2-3% and 1-2% of infants, respectively, but are often outgrown by age or in 80-90% of cases. In contrast, allergies to , nuts, , and are more persistent, with resolution rates below 20% for and nuts, and adult prevalence remaining stable at 1-2% for these groups. Sensitization to food allergens primarily occurs through oral exposure, which typically promotes tolerance in healthy individuals but can lead to IgE-mediated under certain conditions, such as early-life disruptions in gut or microbial . However, cutaneous exposure via disrupted skin barriers, as in , serves as a key alternative route, driving Th2-skewed immune responses and systemic without prior oral tolerance, per the dual allergen exposure hypothesis supported by murine and human cohort studies. Inhalational is less common for initial development but can provoke reactions in already sensitized individuals, particularly in occupational settings like where aerosolized proteins (e.g., from or ) are inhaled. Cross-contact during preparation amplifies risks across routes, as trace amounts via skin or air can trigger responses in hypersensitive cases. Empirical evidence indicates significant within allergen groups, particularly tree nuts (up to 50% co-sensitization between species like and due to shared storage proteins), (high homology leading to 75% cross-reactivity among , , and ), and (parvalbumin conservation causing frequent overlap). (OAS), affecting up to 70% of pollen-allergic individuals, exemplifies pollen-food cross-reactivity, where heat-labile profilins or lipid transfer proteins in raw fruits and (e.g., pollen with apple or ) elicit localized IgE responses that denature upon cooking. This cross-reactivity is clinically milder and confined to mucosal sites, distinguishing it from primary food allergies.

Diagnosis

Diagnostic Tests and Criteria

The diagnosis of IgE-mediated food allergy relies on a history of immediate-type symptoms following ingestion of a suspected food, supported by and tests to detect allergen-specific IgE , with confirmation via controlled challenge procedures. Skin prick testing (SPT) involves applying extracts to the skin and pricking to assess wheal formation, offering high sensitivity (typically 85-95%) for detecting but variable specificity (often 30-60%) for predicting clinical reactions, as positive results indicate IgE presence without confirming symptomatic allergy. For common allergens like , SPT wheal sizes ≥8 mm correlate with higher positive predictive values (PPV) for allergy, though false positives remain common due to asymptomatic . Serum-specific IgE (sIgE) testing quantifies IgE antibodies to food extracts, with thresholds like >0.35 kUA/L indicating sensitization but low specificity (around 38%) for clinical ; higher cutoffs, such as sIgE ≥15 kUA/L for , yield PPVs exceeding 95% in selected populations, aiding in avoiding unnecessary challenges. Component-resolved diagnostics (CRD) enhance precision by measuring IgE to individual components; for , sIgE to Ara h 2 (a major ) outperforms whole extract testing, with levels ≥0.35 kUA/L predicting with PPV up to 92% and sensitivity around 80%, reducing reliance on challenges in high-risk cases. The double-blind, placebo-controlled food challenge (DBPCFC) serves as the gold standard for definitive , administering escalating doses of disguised versus on separate days to confirm objective symptoms at the eliciting dose while minimizing bias. Diagnostic criteria per EAACI guidelines require reproduction of typical symptoms during challenge, graded by severity (e.g., mild cutaneous to severe ), with open challenges acceptable for low-risk scenarios but DBPCFC preferred for objectivity in ambiguous cases. Negative challenges rule out allergy, while surrogates like SPT or sIgE guide but do not supplant this confirmatory step due to their imperfect predictive values.

Differential Diagnosis and Challenges

Food allergies must be differentiated from non-allergic food intolerances, such as or , which produce gastrointestinal symptoms like bloating or diarrhea without involving IgE-mediated immune responses. Unlike true allergies, intolerances lack systemic reactions like urticaria or and can be confirmed through specific enzyme assays or elimination-rechallenge protocols excluding immunologic markers. Non-IgE-mediated conditions, including (FPIES), present with profuse vomiting and lethargy 1-4 hours post-ingestion, often misdiagnosed initially as acute , whereas (EoE) features chronic and food impaction due to esophageal eosinophilic infiltration, distinguishable via and rather than skin prick or serum IgE tests. Oral food challenges remain the gold standard for confirmation, as they replicate symptoms under controlled conditions to rule out psychogenic reactions or behavioral aversions mimicking . Overdiagnosis arises frequently from reliance on parent-reported symptoms or unverified tests, with a 2024 UK study finding 16.1% of children with parent-reported cow's milk hypersensitivity, compared to only 3-5% confirmed in population-based oral challenge validations. This discrepancy stems from subjective interpretations of symptoms like or eczema, which may resolve spontaneously or stem from unrelated causes, leading to unnecessary avoidance diets that risk nutritional deficits. Diagnostic challenges include pitfalls in testing, such as commercial IgG panels, which the American Academy of Allergy, Asthma & Immunology deems invalid for identifying allergies, as elevated IgG reflects normal exposure and tolerance rather than adverse reactions. Skin prick and specific IgE tests yield false positives in up to 50-90% of cases without clinical correlation, necessitating confirmatory challenges. Cofactors like exercise exacerbate symptoms in food-dependent exercise-induced anaphylaxis, where ingestion of triggers such as wheat precedes exertion by 1-4 hours, complicating history-taking and requiring cofactor-inclusive challenges for accurate diagnosis, as reactions occur irregularly without them. These factors contribute to diagnostic delays, with FDEIA often taking years to identify due to inconsistent triggers.

Management

Acute Emergency Treatment

The primary intervention for acute triggered by food allergens is immediate intramuscular administration of epinephrine, which reverses , , and other life-threatening effects by activating alpha- and beta-adrenergic receptors. Guidelines recommend a dose of 0.01 mg/kg (maximum 0.5 mg for adults, 0.3 mg for children) injected into the anterolateral , with repeat doses every 5 to as necessary until response occurs. Epinephrine auto-injectors, such as EpiPen, facilitate rapid delivery outside medical settings, and patients at risk should carry them with prescribed training. Following epinephrine, supportive measures include calling emergency services, placing the patient in a with legs elevated unless respiratory distress predominates, and administering supplemental oxygen, intravenous fluids for , and such as if obstruction develops. Adjunctive therapies like H1-antihistamines (e.g., diphenhydramine 1 mg/kg IV/IM) and systemic corticosteroids (e.g., 1-2 mg/kg IV) may mitigate symptoms but do not replace epinephrine and lack evidence for reducing mortality. Bronchodilators like albuterol are indicated for wheezing unresponsive to epinephrine. Due to the risk of biphasic reactions, where symptoms recur after initial resolution, observation for at least 4 to 6 hours in a medical facility is standard, with studies indicating that over 95% of secondary reactions occur within this window if they happen at all. Case fatality rates for range from 0.65% to 2%, predominantly in untreated or delayed-treatment cases, underscoring epinephrine's role in reducing mortality to near negligible levels when administered promptly. Observational data confirm that lack of early epinephrine correlates with fatal outcomes, emphasizing its causal necessity over other interventions.

Long-Term Avoidance and Monitoring

Long-term management of food allergies primarily involves strict avoidance of the implicated to prevent reactions, as even trace exposures can trigger symptoms in sensitized individuals. Elimination diets require complete removal of the allergen from the diet, including hidden sources in processed foods, with patients advised to scrutinize ingredient lists and warnings for cross-contamination risks. For instance, guidelines emphasize avoiding foods processed on shared , as residual proteins can persist despite cleaning. Nutritional adequacy must be monitored through consultation with dietitians to mitigate deficiencies from prolonged restriction, particularly in children eliminating staples like or . Threshold eliciting doses underscore the need for vigilance, with empirical data showing that minute quantities suffice to provoke reactions in a subset of allergic persons. The eliciting dose affecting 5% of milk-allergic children (ED05) is approximately 2.4 mg of protein, while for egg it is 2.3 mg; similarly, peanut exposures below 30 mg protein can elicit responses across allergens in dose-response studies. These low thresholds, derived from oral food challenges, justify zero-tolerance approaches over probabilistic risk assessments, as individual variability precludes safe partial exposures without testing. Periodic reassessment for tolerance is essential, especially for common pediatric allergies like and , which many children outgrow. Approximately 60-80% of young children with or allergy achieve tolerance by , prompting annual evaluations via prick tests, serum IgE levels, or supervised oral challenges to confirm resolution. Such re-challenges, conducted in clinical settings, allow empirical verification of outgrowing rather than reliance on waning IgE alone, enabling dietary liberalization when safe. Preventing cross-contact demands proactive on environmental controls, including dedicated utensils, color-coded storage, and thorough surface sanitization with allergen-specific cleaners, as inadvertent transfer during or dining heightens reaction . Patients and caregivers should be trained to recognize and mitigate these hazards in homes, schools, and eateries. Concomitantly, epinephrine auto-injectors must be carried at all times by those with history, with guidelines mandating two doses for adults and appropriate weights for children to address potential biphasic reactions. Regular device checks and retraining ensure readiness, as carriage rates below 60% correlate with adverse outcomes in surveys.

Pharmacologic Options

Pharmacologic interventions for food allergy primarily target symptom modulation and reduction in reaction severity following accidental exposure, without addressing the underlying IgE-mediated or providing a . Meta-analyses of clinical trials confirm that these agents offer only palliative benefits, with no evidence of disease modification or long-term tolerance induction. Second-generation H1-antihistamines, such as or loratadine, are recommended for mild symptoms like urticaria, pruritus, or minor gastrointestinal upset in non-anaphylactic reactions. Randomized controlled trials (RCTs) demonstrate modest in reducing histamine-mediated effects, though limitations include incomplete blockade of severe responses and reliance on evidence from broader allergic conditions rather than food-specific challenges. Mast cell stabilizers, notably oral cromolyn sodium, serve a prophylactic role by inhibiting degranulation in some patients, particularly for gastrointestinal symptoms. However, RCTs yield mixed results, with four trials showing inconsistent symptom reduction and no robust prevention of systemic reactions, restricting use to off-label application in select cases. Omalizumab, a monoclonal anti-IgE , mitigates reaction thresholds to multiple foods via subcutaneous injection every 2-4 weeks. The FDA approved it on February 16, 2024, for IgE-mediated food allergy in individuals aged 1 year and older, based on phase 3 RCTs where 16 weeks of treatment increased tolerance to and other allergens compared to placebo, reducing risk from accidental ingestion. Systemic corticosteroids, such as or , are employed adjunctively for protracted or biphasic to curb and shorten reaction duration. Systematic reviews indicate potential in preventing prolonged symptoms, though RCTs highlight variable efficacy and risks like delayed adverse effects, with no impact on initial reaction severity.

Prevention Strategies

Early Allergen Introduction

The recommendation to delay introduction of allergenic foods in infancy, once prevalent based on observational data suggesting avoidance might prevent , has been overturned by randomized controlled trials demonstrating that proactive early exposure promotes tolerance and substantially lowers allergy risk. The Learning Early About (LEAP) study, a 2015 multicenter trial involving 640 high-risk infants aged 4 to 11 months with severe eczema or , randomized participants to either consume products regularly or avoid them until age 5. Those introduced to peanuts early experienced an 81% relative reduction in prevalence (3.2% vs. 17.2% in the avoidance group), with sustained protection confirmed into adolescence in follow-up analyses. Complementing LEAP, the Enquiring About Tolerance (EAT) study, published in 2016, examined early introduction (from 3 months) of six allergenic foods—including , , and cow's —in 1,303 infants, with per-protocol analysis showing a 67% reduction in food allergy overall among adherers, particularly pronounced for (relative 0.25) and in high-risk subgroups. For specifically, trials like the Prevention of Egg Allergy with Tiny Amount Intake (PETIT) in 2017 demonstrated that daily heated consumption from 6 months in atopic dermatitis infants halved allergy rates at 12 months compared to controls (adjusted 0.47). These findings underpin updated guidelines from bodies like the National Institute of Allergy and Infectious Diseases (NIAID) and , which since 2017—and reaffirmed in 2023–2024—advocate introducing and other top allergens (e.g., , ) around 4–6 months in all infants once developmentally ready, without prior skin testing except in select high-risk cases, extending benefits beyond peanuts to multiple allergens. Mechanistically, early oral exposure drives oral tolerance by inducing allergen-specific regulatory T cells (Tregs), which suppress Th2-driven IgE responses and promote IgG4 blocking antibodies, as evidenced in murine models and human cohorts where Treg depletion abolishes tolerance. This causal pathway contrasts with delayed exposure, which permits unchecked via skin or other routes, highlighting a first-principles shift toward leveraging the gut's tolerogenic environment in early infancy.

Dietary and Hygiene Considerations

The posits that diminished early-life exposure to diverse microorganisms contributes to the rising prevalence of allergic diseases, including food allergies, by impairing the development of . This framework, evolved into the "old friends" hypothesis, emphasizes that coevolved organisms such as , helminths, and environmental microbes—termed "old friends"—modulate immune responses to prevent . Epidemiological evidence supports an inverse correlation between farm environments and allergic , with meta-analyses indicating that exposure to farm life before age one year significantly reduces the odds of through mechanisms involving microbial diversity and endotoxin exposure. Similarly, helminth parasite exposure has been linked to lower rates of allergic diseases in observational studies, reflecting evolutionary adaptations where such interactions promote regulatory T-cell activity and suppress Th2-driven responses. Early dietary diversity fosters gut microbiome maturation, which empirical data associate with enhanced oral tolerance and reduced food allergy risk. Studies demonstrate that higher diversity in complementary foods, particularly fruits and at 6-9 months, correlates with a 10% lower odds of food allergy by age 10, likely via increased short-chain production and microbial taxa like that support anti-inflammatory pathways. Gut analyses in the first 1000 days reveal that enriched diversity and specific compositions—such as higher —predict lower childhood food allergy incidence, underscoring causal links between dietary antigens, microbial ecology, and immune programming. supplementation, however, yields mixed results for prevention; systematic reviews indicate limited efficacy in reducing food allergy onset, with benefits confined to symptom alleviation in established cases rather than primary prophylaxis, due to strain-specific and heterogeneous trial outcomes. Breastfeeding shows a neutral association with food allergy risk in meta-analyses of cohort studies, with no significant protective effect observed across feeding patterns in infants. In low-risk populations, durations exceeding six months may confer modest benefits against related atopic conditions like but do not consistently prevent food allergies and could theoretically elevate risk in subsets via delayed exposure. Strict maternal dietary restrictions during lack empirical support for allergy prevention and are not recommended, as they fail to alter sensitization rates while potentially compromising al adequacy.

Controversies and Debates

Overdiagnosis and Misattribution

Self-reported food rates often exceed those confirmed by objective criteria, such as oral food challenges, by a factor of approximately 2 to 3, reflecting widespread diagnostic inflation. For example, a review of studies found that confirmed food was present in only about 44% of cases with a reported history consistent with , indicating that self-reports overestimate true prevalence. This discrepancy arises from misattribution of non-allergic symptoms, such as gastrointestinal discomfort or irritations, to IgE-mediated reactions without rigorous verification. A prominent case is cow's milk allergy (CMA) in infants, where overdiagnosis is prevalent in primary care settings. In a 2024 cohort study from the BEEP trial, parent-reported cow's milk hypersensitivity affected 16.1% of infants, while primary care records indicated 11.3%, with confirmed CMA rates substantially lower, underscoring overdiagnosis driven by symptom-based attributions without challenge confirmation. Risk factors included high prescribing of low-allergy formulas in practices and maternal reports of reactions, amplifying unnecessary labels. Contributing to misattribution are unvalidated diagnostic tools, notably IgG antibody tests for food sensitivities, which lack scientific validation for identifying allergies and have been refuted by professional bodies. These tests measure normal immune exposure rather than pathological responses, and expert guidelines deem them irrelevant, as randomized evidence shows no diagnostic utility and potential for harm through false positives. Incentives such as parental anxiety over vague symptoms and promotion by providers further propel reliance on such tests over gold-standard challenges. Unnecessary avoidance diets resulting from impose nutritional risks, particularly in children, including deficiencies, faltering growth, and impaired development. For instance, unwarranted CMA elimination can lead to inadequate calcium and protein intake, exacerbating vulnerabilities in growing infants without allergic benefit. Rigorous challenge testing is essential to mitigate these outcomes and prevent iatrogenic harm from unsubstantiated restrictions.

Explanations for Rising Prevalence

The prevalence of food allergies has risen markedly, with challenge-proven cases in infants increasing from approximately 3% in cohorts born in the 1980s-1990s to over 10% in those born after 2000 in population-based studies from and elsewhere. This trend is corroborated by a tripling of pediatric hospitalizations for food allergy between the late and mid-2000s, a period predating major refinements in diagnostic criteria like standardized oral food challenges. Explanations emphasizing improved reporting or awareness alone fail to account for the observed escalation in objective measures of severity, such as admissions, which parallel shifts across generations. Migration studies provide stronger evidence for environmental causation: foreign-born children in high-prevalence nations like the initially show rates akin to their countries of origin (often under 5%), but these rise toward host-country levels after 10 years of residence, independent of genetic heritage. Similarly, Australian children of Asian immigrant mothers born locally exhibit nut rates 2-3 times higher than Asian-born migrants, highlighting modifiable exposures over inherited risk. The , linking diminished early microbial diversity to immune dysregulation, garners empirical support through microbiome analyses revealing odds ratios of 2-4 for food allergy in infants with or low-diversity gut compared to peers. Reduced exposure to diverse pathogens—via , , and fewer siblings—correlates with this , fostering Th2-skewed responses that promote IgE-mediated . Correlational factors like cesarean section deliveries (odds ratio ~1.2-1.5 in large cohorts) and insufficiency (linked to sensitization in ) show modest associations but lack robust causal validation, as prospective trials and adjusted analyses often attenuate effects after controlling for confounders such as maternal or . These do not independently explain the temporal surge, unlike microbial and exposure dynamics.

Common Myths and Empirical Critiques

A persistent holds that food allergic reactions progressively worsen in severity with each subsequent exposure, implying a trajectory toward inevitable . Empirical data refute this, demonstrating that reaction severity remains unpredictable and is not predetermined to escalate over time. No longitudinal studies support consistent worsening; instead, individual episodes vary based on dose, individual , and external modulators. Cofactors such as exercise, alcohol ingestion, use of nonsteroidal anti-inflammatory drugs, and can lower the reaction threshold or amplify symptoms in specific instances, explaining episodic variability without indicating overall progression. These elements influence activation and thresholds, but their presence is sporadic, underscoring the absence of a linear severity increase. Clinical guidelines emphasize for any reaction level rather than of escalation. Self-diagnosis frequently conflates immunoglobulin E-mediated allergies with non-allergic intolerances or irritant responses, prompting excessive avoidance that risks nutritional deficits without addressing true . Among adults reporting food allergies, self-reported reaches 9.1%, yet physician-diagnosed cases comprise only 5.3%, with confirmatory testing (e.g., oral food challenges) validating an even smaller subset. Meta-analyses of adverse food reactions reveal that while 35% of reporters perceive allergy, formal confirms it in just 3.5%, highlighting diagnostic overreach driven by symptom misattribution rather than immunological evidence. Public discourse often exaggerates the scope of food allergens, citing over 170 implicated foods, yet eight principal ones—, , , tree nuts, wheat, soy, , and crustacean shellfish—account for at least 90% of reactions . This concentration reflects epidemiological patterns from challenge-confirmed cases, not anecdotal reports, countering narratives of ubiquitous novelty allergens. Recent additions like to regulatory lists (effective 2023) represent exceptions, not a broadening beyond the core group.

Societal and Regulatory Frameworks

Food Labeling and Trace Contaminants

The Food Allergen Labeling and Consumer Protection Act (FALCPA) of 2004 mandates that packaged foods in the United States declare the presence of any of the major food allergens—initially defined as , eggs, , tree nuts, , , soybeans, and —in plain language either within the ingredients list or via a separate "Contains" statement. was added as the ninth major allergen effective January 1, 2023, following the FASTER Act of 2021, accounting for approximately 90% of food allergy reactions. The U.S. (FDA) enforces these requirements through inspections and recall monitoring, though specific compliance rates for allergen labeling remain variably reported, with undeclared s frequently cited in product recalls due to cross-contact rather than labeling failures. In the , Regulation (EC) No 1169/2011 requires labeling of 14 priority allergens—including cereals containing , crustaceans, eggs, , , soybeans, , nuts, , mustard, , sulphur dioxide, lupin, and molluscs—regardless of quantity, but without mandatory quantitative thresholds for declaration. Precautionary allergen labeling (PAL), such as "may contain traces," is voluntary and unregulated, leading to inconsistent application across products and manufacturers, which complicates risk assessment for consumers. Oral food challenge studies indicate that eliciting doses—the minimum amounts triggering reactions in sensitive individuals—can be as low as 1 mg of protein or 2-3 mg for , corresponding to parts per million (ppm) levels in contaminated products, underscoring the potential risks from trace cross-contamination even below advisory label thresholds. Regulatory frameworks do not address genetically modified (GM) foods differently for allergen labeling, as empirical data spanning over 25 years of widespread GM crop consumption show no associated increase in food allergy prevalence or novel allergenicity compared to conventional counterparts. Despite early concerns about potential allergen transfer in GM development, rigorous pre-market assessments and post-market surveillance have confirmed that approved GM varieties do not elevate endogenous allergen levels or introduce new risks, with allergy rates rising concurrently across non-GM and organic food systems due to other environmental factors. Limitations persist in current labeling, as trace contaminants from shared facilities evade mandatory declaration, relying instead on variable PAL efficacy, which challenge studies suggest may not reliably correlate with actual contamination levels, prompting calls for threshold-based standards to balance and food availability.

Public Accommodations and Policy

Policies in schools and restaurants regarding food allergies, particularly and nut restrictions, have proliferated despite limited evidence of risks. Airborne exposure to allergens does not typically provoke severe reactions, as confirmed by studies showing no significant allergen dispersion through ventilation systems or casual contact in shared spaces. Nut-free zones, such as dedicated tables or entire bans, aim to mitigate risks but have demonstrated mixed or negligible impacts on reaction rates; one analysis found higher epinephrine administrations for nut reactions in schools enforcing such policies compared to those without. These measures impose operational costs, including nutritional limitations and heightened anxiety among students, while empirical data indicate that most school reactions (79%) stem from ingestion rather than environmental exposure. Airline policies address food allergy risks through allowances for personal epinephrine auto-injectors and, increasingly, onboard supplies, reflecting the rarity of in-flight incidents. Allergic medical emergencies occur at a rate of approximately 0.7 per million passengers, 10-100 times lower than ground-level rates, with severe even scarcer—about one per 3,600 food-allergic passengers annually. U.S. enacted in 2024 mandates epinephrine auto-injectors in airline emergency kits, addressing prior reliance on vials that require medical expertise for administration, though passengers must still carry their own devices. Claims for blanket prohibitions, like nut-free flights, lack substantiation given the predominance of over triggers and minimal documented public exposures. International regulatory approaches vary, with the enforcing stricter declarations for 14 versus the U.S. focus on nine major ones, yet no causal link exists between such precautionary frameworks and reduced . Self-reported food rates in range from under 1% to over 10% by region and , mirroring rises in the U.S. without correlating to policy stringency; both areas report increasing incidences over decades. These disparities highlight that accommodation mandates, while promoting perceived equity, often exceed evidence-based necessities, as transmission risks remain low and trends persist independently of regulatory intensity.

Economic and Quality-of-Life Impacts

Food allergies impose substantial economic burdens on individuals, families, and , with estimates placing the annual cost in the United States at approximately $25 billion as of recent analyses, encompassing direct medical expenses such as emergency care and diagnostics, alongside like lost and special dietary needs. This figure derives from prevalence-based modeling of physician-diagnosed cases, highlighting components like $6.8 billion in direct medical costs and the remainder in indirect societal impacts, though updated models suggest potentially higher totals exceeding $370 billion when factoring broader opportunity losses. Avoidance strategies, including specialized allergen-free products, elevate household grocery expenditures, with studies indicating gluten-free alternatives alone can cost up to 159% more than standard options, contributing to out-of-pocket family expenses averaging thousands annually per affected child. Quality-of-life impairments manifest prominently in psychological domains, with surveys of families reporting that food allergies disrupt social activities for nearly half of affected households, fostering anxiety over accidental exposure and limiting participation in communal eating events. Children experience heightened psychosocial stressors, including peer differences and fear of reactions, which correlate with elevated anxiety levels and reduced health-related quality of life compared to non-allergic peers, as evidenced by validated instruments like the Food Allergy Quality of Life Questionnaire. Caregiver productivity suffers through absenteeism for medical appointments, allergen vigilance, and reaction management, with annual lost labor costs per child estimated at over $2,800, primarily from missed workdays or reduced . These burdens are amplified by potential , where non-IgE-mediated intolerances or misattributed symptoms prompt unnecessary avoidance regimens and interventions, inflating costs without corresponding clinical benefits and underscoring the need for rigorous diagnostic confirmation to mitigate avoidable economic strain.

Research Directions

Emerging Therapies and Trials

In February 2024, the U.S. Food and Drug Administration approved (Xolair), an anti-IgE , as the first medication to reduce allergic reactions, including , following accidental exposure to multiple foods in individuals aged 1 year and older with IgE-mediated food allergies. This approval stemmed from the phase 3 OUtMATCH , which demonstrated that subcutaneous administered every 2-4 weeks for 16-20 weeks increased the cumulative tolerated dose of allergens like , , , and by at least 10-fold compared to in 67% of treated participants versus 7% in the group. A 2025 multicenter study further indicated 's superiority over oral in achieving higher desensitization thresholds with fewer gastrointestinal side effects, though long-term data on sustained tolerance remain limited. Oral immunotherapy (OIT) protocols for have shown sustained unresponsiveness rates of 50-70% in recent trials, defined as tolerating challenge doses after discontinuation, though adherence challenges persist due to frequent adverse reactions like and requiring epinephrine. A 2025 phase 2 trial in children with high-threshold reported 68.4% achieving sustained unresponsiveness to 9,043 mg protein after treatment, outperforming avoidance controls. The Grown Up Peanut Immunotherapy (GUPI) phase 2 trial, published in 2025, evaluated OIT in 21 adults with peanut allergy using gradually increasing doses of peanut protein starting at 0.8-3 mg and increasing every two weeks to a 1000 mg maintenance dose. The trial demonstrated desensitization with the median tolerated dose increasing 100-fold from 30 mg (equivalent to 1/8 peanut) to 3000 mg (12 peanuts) peanut protein; 67% of participants tolerated at least 1.4 g peanut protein (equivalent to five peanuts), with improvements in quality of life and mostly mild adverse reactions. Sublingual immunotherapy (SLIT), involving lower doses under the tongue, has emerged as a safer alternative with post-2020 trials in toddlers showing modest desensitization, such as increased tolerated doses by 10-fold in 67% of participants after 12 months, with fewer systemic reactions than OIT but lower efficacy in achieving full tolerance. Ongoing SLIT studies emphasize real-food formulations to improve practicality, yet sustained unresponsiveness rates remain below 50% in most cohorts. Epicutaneous immunotherapy (EPIT) via patches like Viaskin Peanut targets delivery to induce tolerance with minimal systemic exposure. The phase 3 PEPITES trial, reported in 2023, found 12 months of daily Viaskin Peanut 250 μg patching desensitized 35.3% of peanut-allergic children aged 4-11 years to 1,000 mg protein, compared to 13.1% on , with benefits persisting in open-label extensions. A 2025 three-year extension analysis confirmed progressive efficacy, with responders showing doubled tolerated doses and high adherence (over 90%), though occurred in under 1% of applications; regulatory approval is pending further data on sustained effects post-discontinuation. These modalities highlight a shift toward biologics and non-oral routes to mitigate OIT's safety limitations, with combination trials underway to enhance remission rates.

Preventive Interventions and Biomarkers

Primary prevention strategies for food allergies emphasize interventions administered before allergy onset, such as early allergen introduction and microbiome-targeted approaches. Randomized controlled trials (RCTs) have extended early introduction protocols beyond to include and in high-risk infants, with ongoing studies evaluating their efficacy in reducing rates. For instance, a 2022 indicated that early exposure before 6-12 months may lower risk, though evidence for direct food allergy prevention remains limited and under investigation in prospective cohorts. Probiotics and prebiotics are in clinical pipelines for primary prevention, often tested via maternal or neonatal supplementation to modulate and promote . A 2025 review highlighted ' role in altering Th2-skewed responses, with trials showing reduced IgE-mediated sensitization in infants when administered alongside breastfeeding or formula. Emerging vaccine-like constructs, including - and nucleic acid-based immunotherapies, are being adapted for prophylactic use in at-risk populations, aiming to induce regulatory T-cell responses pre-allergen exposure. Microbiome modulation features prominently in 2025 research roadmaps, prioritizing scalable, low-cost interventions like synbiotics to restore dysbiotic profiles linked to risk. The Food Allergy Research Roadmap outlines microbiota-targeted therapies as a priority for equitable prevention, focusing on universal applicability without socioeconomic barriers. Biomarkers for predicting allergy persistence include trajectories of allergen-specific IgE (sIgE) levels, where rising or persistently high sIgE correlates with poor and sustained reactivity. Longitudinal studies demonstrate that children with declining sIgE over time achieve resolution in up to 80% of cases for allergens like and , whereas elevated trajectories predict chronicity into . Additional markers, such as total IgE and IgG4 ratios, complement sIgE in risk stratification, enabling targeted monitoring in preventive cohorts.

References

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