Food allergy

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".[18] In April of 2021, President Joe Biden signed the FASTER Act into law. This landmark food allergy law recognizes sesame as the ninth mandatory food label allergen. It also encourages research that will improve the quality of life for food allergy families, and that could potentially lower the rates of future food allergies.[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]

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.[42][43] An estimated 28.5 million people worldwide are engaged in the seafood industry, which includes fishing, aquaculture, processing and industrial cooking.[44] In these occupational settings, individuals with fish and shellfish allergies are at high risk of exposure to allergenic proteins via aerosolization.[45][44] 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.[46][44] Another occupational food allergy that involves respiratory symptoms is "baker's asthma," which commonly develops in food service workers who work with baked goods.[47] Previous studies detected 40 allergens from wheat, some cross-reacted with rye proteins and a few cross-reacted with grass pollens.[48]

Allergic sensitization can occur via skin antigen exposure, which usually manifests as hives.[49] The skin has been suggested to be a critical sensitization route for peanut-allergic individuals.[50][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.[42] Environmental factors, such as exposure to food, microorganisms, creams, and detergents, may lead to skin barrier dysfunction.[51] Several studies reveal that children exposed to skin creams containing peanut oil are reported to have a higher risk of peanut allergy,[51] suggesting that impaired skin may be a risk factor for sensitization.[42][43]

Food allergies develop more easily in people with the atopic syndrome, a very common combination of diseases: allergic rhinitis and conjunctivitis, eczema, and asthma.[52] The syndrome has a strong inherited component; a family history of allergic diseases can be indicative of the atopic syndrome.

Some children who are allergic to cow's milk protein also show a cross-sensitivity to soy-based products.[53] 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. [54]

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.[55]

People with latex allergy often also develop allergies to bananas, kiwifruit, avocados, and some other foods.[56]

Degranulation process in allergy:
1 — antigen
2 — IgE antibody
3 — FcεRI receptor
4 — preformed mediators (histamine, proteases, chemokines, heparin)
5 — granules
6 — mast 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 T_H2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These T_H2 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.[61]

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.[61]

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.[62] Cytokines from mast cells may also play a role in the persistence of long-term effects.[63]

Important differential diagnoses are:

• Lactose intolerance generally develops later in life, but can present in young patients in severe cases. It is not an immune reaction and is due to an enzyme deficiency (lactase). It is more common in many non-Western people.
• Celiac disease. While it is caused by a permanent intolerance to gluten (present in wheat, rye, barley and oats), is not an allergy nor simply an intolerance, but a chronic, multiple-organ autoimmune disorder primarily affecting the small intestine.[76][77][78]
• Irritable bowel syndrome
• C1 Esterase inhibitor deficiency (hereditary angioedema), a rare disease, generally causes attacks of angioedema, but can present solely with abdominal pain and occasional diarrhea, and thus may be confused with allergy-triggered angioedema.

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.[84][85] The most frequent reported cases of reactions by inhalation of allergenic foods were due to peanut, seafood, legumes, tree nut, and cow's milk.[84] Steam rising from cooking of lentils, green beans, chickpeas and fish has been well documented as triggering reactions, including anaphylactic reactions.[84][86] 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.[84]

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.[88]

Antihistamines can alleviate some of the milder symptoms of an allergic reaction, but do not treat all symptoms of anaphylaxis.[89] 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.

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.[90]

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.[97] 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.[98]

In the United States, food allergy affects as many as 5% of infants less than three years of age[99] and 3% to 4% of adults.[100][101] The prevalence of food allergies is rising.[102][103][104] Food allergies cause roughly 30,000 emergency room visits and 150 deaths per year.[105]

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.

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.[118][119][120][121][122][123][124][125]

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.[119] The eight-ingredient is list originated in 1999 from the World Health Organisation Codex Alimentarius Commission.[124] 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).[119][121] The European Union requires listing for those eight major allergens plus molluscs, celery, mustard, lupin, sesame and sulfites.[120]

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.[126] 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)."[127]

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.[128]

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.[125] 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.[122][123] The act also does not apply to food prepared in restaurants.[129][130] 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.[131]

In the United States, there is no federal mandate to address the presence of allergens in drug products, medicines, or cosmetics.[132]

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.).[124][125] 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.[133][134]

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.[124][135] Precautionary allergen labeling can be confusing to consumers, especially as there can be many variations on the wording of the warning.[135][136] Precautionary allergen labeling is optional in the United States.[137] 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-contamination through a documented risk assessment and despite adherence to Good Manufacturing Practice.[124] 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."[138][139] VITAL 2.0 was developed by the Allergen Bureau, a food industry sponsored, non-government organization.[140] The European Union has initiated a process to create labeling regulations for unintentional contamination but is not expected to publish such before 2024.[141]

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.[118]

Although there is a scientific consensus that available food derived from genetically modified crops poses no greater risk to human health than conventional food,[142][143][144] 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,[145] 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.[146][145][147]

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.[147] Of the food currently 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.[145] 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.[146]

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?[145] 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 a FDA mandated recall.[148] 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).[146]

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.[149]

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.[150]