Food allergy is also distinct from adverse reactions that do not involve an immune response. These adverse reactions may result from a metabolic disorder (such as lactose or alcohol intolerance), a pharmacologic reaction (such as sensitivity to caffeine), a structural abnormality (such as hiatal hernia), or another, undefined response [2,18,19]. Headache, heartburn, vomiting, irritability or nervousness, and gas or bloating are symptoms related to food intolerance, whereas the hallmark symptoms of food allergy are rash or hives, itchy skin, cramping stomach pain, diarrhea, and in severe cases, shortness of breath, wheezing, and chest pain [2,18,20].

The percentage of children in whom a food allergy is lost varies according to the allergen and increases with age (Table 4) [2,5,7,8,44,45]. Most children who have allergy to milk, egg, soy, or wheat lose the sensitivity over time, with the time varying according to food [2]. In contrast, allergy to peanut, tree nuts, and shellfish usually persists into adulthood [2]. Allergy to peanut or tree nuts is lost in about 20% of children after the age of 5 years [45]. The level of allergen-specific IgE is often an indicator of persistence; high initial levels of allergen-specific IgE have been associated with lower rates of resolution, and decreases in IgE levels over time often indicate the onset of tolerance [2].

Several strategies have been proposed as measures to prevent the development of food allergy, including maternal dietary restrictions, the use of soy-based formula, exclusive breastfeeding, and delayed introduction of solid foods and of allergenic foods. Maternal dietary restrictions have not been shown to be effective prevention strategies; in fact, the results of one study suggested that maternal intake of peanuts and tree nuts during pregnancy may even decrease the risk of the development of food allergy in a child [46,189]. With regard to soy-based formulas, a systematic review demonstrated that using such formulas could not be recommended to prevent allergy or food intolerance in infants at high risk [47,189]. The expert panel that developed the NIAID-sponsored guidelines on food allergy notes that maternal restrictions and use of soy-based formula are not recommended as preventive strategies [2,189]. Data are insufficient to support the benefit of exclusive breastfeeding until the age of 4 to 6 months for the prevention of food allergies, but this practice is still recommended because of the nutritional value and the effect of breast milk on the infant's immune system [2,48,49,189].

Recommendations regarding the timing of the introduction of solid foods have changed since 2000. The Committee on Nutrition of the American Academy of Pediatrics (AAP) initially recommended feeding an infant only breast milk for the first six months because of its decreased potential for causing an allergic reaction compared with cow's milk (in addition to the other, aforementioned, benefits) [48]. The Committee also recommended delaying solid foods until after 4 to 6 months of age, with longer delays for dairy products and wheat (12 months), hen's egg (24 months), and nuts and fish (36 months). Six years later, the ACAAI published a consensus statement in which it supported this prevention strategy [50]. However, these organizations subsequently modified their statements on the basis of continued research. In their jointly developed 2006 practice parameter, the AAAAI, ACAAI, and JCAAI stated that the effectiveness of delaying the introduction of solid foods had not been established (reaffirmed in 2014) [9,167]. In 2008, the AAP stated that little evidence supported the benefit of delaying the introduction of solid foods, including potential allergens such as peanuts, eggs, and fish, beyond 4 to 6 months of age to prevent food allergy or atopic disease in general, and this stance was reaffirmed in the updated 2019 guidelines [49,189]. The NIAID-sponsored guidelines were revised in 2017 to recommend introducing peanut-containing foods as early as 4 to 6 months of age as a strategy to prevent peanut allergy in high-risk infants, and this strategy was also affirmed in the 2019 AAP guidelines [176,189].

Food allergy manifests itself primarily through the skin, gastrointestinal tract, and respiratory system, and symptoms are categorized as acute or delayed (Table 5) [2]. Cutaneous symptoms are typically the most common.

Oral allergy syndrome, also known as pollen-associated food allergy syndrome, is most common among children and adults with pollen allergy [63]. This syndrome is primarily a localized IgE-mediated reaction, with mild symptoms that include itching, irritation, or swelling occurring around the mouth after eating raw fresh fruits and vegetables, and other symptoms, such as rash, hives, watering of the eyes, nasal congestion, or tingling of the lips or tongue, may also develop [2,63]. Symptoms usually resolve within a few minutes after ingestion and rarely progress to a systemic reaction [63]. Often, no allergic reaction occurs after ingestion of fruits and vegetables that have been cooked, as heating destroys the foods' proteins [63]. Due to cross-reactivity, allergic reactions can be more common when levels of ragweed pollen are high.

Like food allergy, asthma is an atopic disease, and, as noted previously, there is a strong association between the two conditions [41]. Food-induced wheezing and bronchospasms occur in up to 24% of children during acute allergic reactions to food [71]. Food-induced asthma also occurs in 17% to 27% of children with atopic dermatitis and in 29% of infants with cow's milk allergy [71]. Nearly half of children with allergy to peanut or tree nuts have asthma symptoms during allergic reactions. Studies have failed to demonstrate a link between respiratory symptoms and either milk (and other dairy products) or food additives, such as monosodium glutamate [71]. It has been recommended that any child with asthma be evaluated for food allergy, especially when acute episodes are unexplained or when asthmatic symptoms are accompanied by other manifestations of food allergy [71,72]. Similarly, children with food allergy, especially those who have allergy to more than one food or who have severe allergy, should be evaluated for asthma [41].

In obtaining a detailed history, several questions are crucial, and healthcare professionals should ask the following [2,78]:

It may be helpful to request emergency department records or information from another physician who has evaluated the patient; details about the most recent reaction are of the most benefit [78]. If the history includes an anaphylactic episode, the physician should gain as much information as possible about the reaction to help predict future reactions and develop an appropriate emergency plan [78]. In addition, the history should elicit information about personal or family history of atopy or other allergies. A history of asthma or sensitivity to latex, for example, should prompt further diagnostic testing. When the patient and/or parents cannot suggest a causal food, they should be asked to keep a food diary and note any symptoms that correlate with dietary intake.

Even the most detailed history can lack the details sufficient for an accurate diagnosis. For example, it is difficult to isolate a single food that caused a reaction after a meal, especially when it may not be known how the suspected food was manufactured or prepared or if there was cross contamination [79]. Symptoms that are thought to be related to a food allergy (such as urticaria or symptoms of anaphylaxis) may be associated with another cause. Also, symptoms of non-IgE-mediated reactions are difficult to relate to a food due to the long interval of time between ingestion and symptoms.

The skin prick test is performed with a lancet containing a 1 mm point. A drop of the selected allergen is introduced into the skin, usually on the volar or inner aspect of the forearm. A pen is commonly used to mark a grid on the arm, and the allergens are instilled at intervals of at least 2 cm [82]. The reaction is usually obvious after 10 to 15 minutes. In general, a wheal with a diameter of 3 mm or more is considered positive, and the larger the wheal, the more likely an allergy is present [2]. However, the size of the wheal does not predict the severity of a reaction, and there are no standards for interpreting the results of skin prick tests [2,22].

Negative findings on a skin prick test are of the most value, as the test has an excellent negative predictive value (95% or more), especially when testing for allergy to egg, milk, wheat, peanut, tree nuts, fish, and shellfish [78]. Negative skin prick test results rarely occur in an individual who has an IgE-mediated reaction to one of these foods; nevertheless, if the history is strong, a food allergy should not be ruled out on the basis of negative results on a skin prick test alone. The combination of a positive test result and an inconclusive history should prompt an oral food challenge [25].

Some issues to consider with skin prick testing include [82,83]:

The rising prevalence of food allergy and the associated public concern has heightened awareness of the problem in restaurants, schools, day care settings, camps, airplanes, and other community-based institutions. Still, vigilance and precaution are required. In a study of food-induced allergic reactions among infants (3 to 15 months of age), half of the reactions were caused by food given to them by someone other than a parent [57]. Precaution is needed with older children and teenagers, as well, whose behaviors are often guided by a need to be accepted by peers. Practitioners should emphasize the importance of asking about ingredients when eating at a restaurant or away from home and of accurate interpretation of food labels. Issues with eating at restaurants include cross contamination (the most common cause of allergic reactions related to meals in a restaurant), knowledge gaps among restaurant staff, and nondisclosure of an allergy to restaurant staff [97,98].

The most commonly used self-injectable epinephrine in the United States is EpiPen, although other brands are available. The disposable drug-delivery system comes in two doses: 0.3 mg in 0.3 mL (EpiPen) and 0.15 mg in 0.3 mL (EpiPen Jr) autoinjectors, designed to be given intramuscularly. The manufacturer's labeling recommends one initial 0.15-mg dose for children weighing 15 to <30 kg or one 0.3-mg initial dose for children and adults who weigh ≥30 kg [193]. Another brand available in the United States, Auvi-Q, is a 0.1-mg autoinjector approved for use in children who weigh 7.5 to <15 kg [193].

The accurate interpretation of food labels is essential for minimizing risk among people with food allergy. The Food Allergen Labeling and Consumer Protection Act, which became effective January 1, 2006, requires that labels clearly indicate ingredients and note the presence of major food allergens [108]. The law applies only to nine major allergens (including sesame, added in 2023) and does not apply to certain egg products, fruits and vegetables, and noncrustacean shellfish [196]. The law also does not regulate the use of advisory labeling, and one study of more than 20,000 labels showed that 25 different advisory labels were used, with many labels containing nonspecific language and ambiguities [109]. Phrases that are used to indicate possible cross-contact with allergens include "may contain," "processed in a facility with," and "manufactured on shared equipment with" [61]. But the distinction between these phrases is unclear, and the phrases do not accurately indicate different levels of risk. In fact, studies have shown that 2% to 42% of products with an advisory label contain detectable amounts of the allergen protein [110,111,112]. Differences in phrases lead to differences in adherence to advisory labels. Hefle et al. found that nearly 90% of consumers avoided a product labeled with "may contain," but only 58% avoided a product labeled with "packaged in a facility that also packages products containing [allergen]" [110]. Young people are especially apt to misinterpret or disregard advisory labels, with 42% of teenagers and young adults at risk for anaphylaxis saying that they would eat a food that was labeled with "may contain" an allergen [106]. Misinterpretation of labels has been associated with consequences. In a Canadian study, nearly half (47%) of people who had accidental exposure to an allergen attributed the exposure to inappropriate labeling, while 29% and 8% said the cause was failure to read a food label and disregard of a precautionary statement, respectively [113].

Another challenge in understanding food labels is that terminology is often not directed at lay readers. One study of parents of children who have food allergy showed that 7% could correctly identify the labels of 14 products that contained milk, and 22% could correctly identify soy protein in seven products [114]. Most parents could identify wheat and egg as ingredients, and slightly more than half of parents could correctly identify peanut in five products. The parents who were able to identify the most ingredients had received previous instruction from a dietician, emphasizing the important contribution of this healthcare professional as part of the treatment team.

The interpretation of food labels is a complex process, involving general food knowledge, literacy, and other factors. When reading labels, people with food allergy and caregivers draw on factors in addition to precautionary labels, such as trust of a particular brand or manufacturer, previous experience with a product, and images and product names (not intended to denote risk) [115]. The NIAID expert panel suggests that healthcare professionals provide education and training to patients with food allergies and their caregivers about how to best interpret ingredient lists on food labels and how to recognize incomplete labeling of ingredients [2]. The expert panel also suggests that individuals with food allergy avoid products with precautionary labeling, such as "this product may contain trace amounts of [allergen]" [2].

Another challenge in understanding food labels is that terminology is often not directed at lay readers. One study of parents of children who have food allergy showed that 7% could correctly identify the labels of 14 products that contained milk, and 22% could correctly identify soy protein in seven products [114]. Most parents could identify wheat and egg as ingredients, and slightly more than half of parents could correctly identify peanut in five products. The parents who were able to identify the most ingredients had received previous instruction from a dietician, emphasizing the important contribution of this healthcare professional as part of the treatment team.

The NIAID-sponsored guidelines do not recommend allergen-specific immunotherapy or immunotherapy with cross-reactive allergens as treatment of IgE-mediated food allergy [2]. However, the results of more recent studies have shown promise. Several types of immunotherapy have been evaluated, including subcutaneous, epicutaneous, heated food, sublingual, and oral immunotherapy [126,127,128,171,188]. Subcutaneous immunotherapy is no longer used because of severe systemic reactions, and although epicutaneous immunotherapy uses the lowest maintenance dose of the immunotherapies and also has an improved safety profile, it is, thus far, less efficacious, and additional research is needed [188].

Immunotherapy with heated food proteins has been evaluated in children with generally transient allergies, such as to egg or milk. Heating egg and milk proteins at high temperature denatures allergenic proteins, making them less allergenic. Approximately 70% to 75% of children with egg or milk allergy have tolerated baked egg or milk, and introducing baked egg into the diet of children with egg allergy has accelerated the development of tolerance to regular egg, compared with strict avoidance of the food [126,129,130,131]. This treatment approach may not be effective for children with severe food allergy or for those with a high milk-specific IgE [126].

Sublingual immunotherapy has been evaluated in children with allergies to nuts or milk, and this strategy has led to an increase in the amount of food that can be tolerated on an oral food challenge and generally mild reactions [126,132,133,188]. However, the maximum amount of food that can be tolerated is limited by the amount of food that can be given sublingually [126]. In 2013, sublingual immunotherapy for peanut allergy was evaluated in 40 individuals, 12 to 37 years old, in a randomized, double-blind, placebo-controlled multicenter trial, one of the first of its kind [134]. After 44 weeks of daily therapy, 70% of the individuals were able to consume at least 10 times more peanut powder than they could at the beginning of the study (compared with 15% of individuals given placebo) [134]. Longer therapy (65 weeks) led to the ability to consume significantly more peanut powder without an allergic reaction. The treatment appeared safe, with side effects being minor (itching in the mouth) [134]. A three-year follow-up to this trial showed that 50% of patients discontinued therapy, and 10.8% of patients were desensitized to 10 g of peanut powder and achieved sustained unresponsiveness eight weeks after therapy concluded [188]. While sublingual immunotherapy has an improved safety profile and promising results, it appears to be less efficacious than oral immunotherapy [188].

Questions have arisen about the safety of some vaccinations for individuals with food allergy, specifically the measles-mumps-rubella (MMR) vaccine and certain types of influenza vaccine, both of which are cultured in egg embryos. Studies have demonstrated that the MMR vaccine is safe for children with egg allergy, and the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the NIAID-sponsored guidelines all support MMR vaccination for children with egg allergy, even children who have a history of severe reactions [2].

The 2010 NIAID-sponsored guidelines note that there is insufficient evidence to recommend administering either trivalent inactivated or live-attenuated influenza vaccines to children with egg allergy who have a history of hives, angioedema, allergic asthma, or systemic anaphylaxis to egg proteins [2]. However, since that time, the results of several studies have shown that the influenza vaccine is safe for most people with a history of egg allergy, without the need to divide and administer the vaccine by a two-step approach or for skin testing with vaccine [142,143,144,145]. Based on these findings, the ACIP has changed its recommendations, now stating that mild (hives only) or more severe symptoms (angioedema, respiratory distress, lightheadedness, recurrent emesis, administration of epinephrine or another emergency medical intervention) after exposure to egg are no longer contradictions for any influenza vaccine in adults or children. These individuals should receive any licensed, recommended, age-appropriate influenza vaccine [145,146]. The vaccine should be administered by a healthcare provider who is familiar with identifying and managing the potential manifestations of egg allergy if any symptoms are previously known. A previous severe allergic reaction to influenza vaccine, regardless of the component suspected of causing the reaction, is a contraindication to future receipt of the vaccine [145,146]. The AAP and a joint AAAAI and ACAAI task force support these recommendations, noting that the risks of not vaccinating outweigh the risks of vaccinating [143,144].

Early recognition of the clinical signs and symptoms of anaphylaxis is necessary to ensure immediate, appropriate treatment. In most cases, these signs and symptoms will occur within one hour after the accidental ingestion (ranging from within less than one minute to a few hours) and will vary in terms of presence, sequence, and severity [100]. In 1% to 20% of anaphylaxis cases, there will be a biphasic response, with recurrence of symptoms 8 to 12 hours later, after the individual had seemed to recover [100]. The interval between the initial reaction and the recurrence has ranged from 1 to 72 hours [154,155]. A biphasic reaction occurs in approximately 6% to 11% of children; such reactions typically occur within 8 hours after the first reaction but may occur as long as 72 hours later [3].

As with less severe food-induced allergic reactions, cutaneous manifestations are the most common, followed by respiratory and gastrointestinal symptoms [2,147,153,154]. In one study of more than 600 children, cutaneous manifestations were documented in 87% to 98% of children; respiratory manifestations, in 59% to 81%; and gastrointestinal manifestations, in 50% to 59% [153]. The cardiovascular system is less frequently involved, and is more often involved in adolescents [3,153]. Still, cutaneous manifestations may be absent in about 10% to 20% of cases of anaphylaxis, which may contribute to under-recognition [2].