#98793: Food Allergies

With an IgE-mediated response, food-specific IgE antibodies are produced after exposure to certain proteins that bind to tissue mast cells and basophils, leading to the release of mediators such as histamines and leukotrienes [19]. The resultant reaction typically manifests in symptoms or disorders related to the skin, gastrointestinal tract, and respiratory system [19]. Symptoms occur within minutes to 1 to 2 hours after the causal food has been ingested and vary from mild (oral or cutaneous symptoms only) to a life-threatening systemic reaction [2,19]. Sensitization without clinical symptoms is common; for example, approximately 1% of the population has a true allergy to peanut (sensitization plus symptoms), whereas approximately 8% will have sensitization to peanut (a positive test result) but no symptoms [21,22].

In general, eight allergens account for approximately 85% to 90% of IgE-mediated food allergies: cow's milk, hen's egg, peanut, tree nuts (walnuts, cashews, etc.), fish (fin fish), shellfish, soy, and wheat [2,103]. With shellfish, allergy to crustaceans (shrimp, crab, and lobster) is more common than allergy to mollusks (clams, oysters).

Allergy to fresh fruits and vegetables is less common and is primarily attributed to oral allergy syndrome, a mild IgE-mediated reaction discussed later in this course [18]. However, allergic reaction to fruits and vegetables can be more serious. In one study, researchers evaluated 346 allergic reactions to fruit and found that 52% consisted of only oral symptoms; 37% consisted of oral symptoms and a systemic reaction; and 11% consisted of a systemic reaction only [23]. Melon, kiwifruit, and avocado were the most frequent causes of isolated oral symptoms, whereas peach, banana, and kiwifruit were most often associated with a systemic reaction. Of the 38 solely systemic reactions, 13 were severe and five were life-threatening [23].

Fruits and vegetables are also implicated in cross-reactivity, or an allergy to foods that have proteins similar to those in other allergens (Table 2). For example, the Bet v1 and Bet v2 (profilin) proteins are found in birch pollen as well as several fruits, vegetables, and nuts, and approximately 70% of patients who are allergic to birch pollen may have symptoms after eating foods in this group [18,24]. Latex-fruit allergy is another example; an allergy to fruit will develop in more than 50% of individuals who are allergic to latex [25]. The most common food allergens associated with latex allergy are avocado, banana, chestnut, and kiwifruit [18]. Cross-reactivity also refers to an allergy to more than one food in a particular food group; it is estimated that 70% to 90% of individuals with seafood allergy have had reactions to multiple types of fish [181].

One of the fastest growing new allergies is to sesame, with both IgE-mediated hypersensitivity and cell-mediated reactions occurring [27,103]. At the other end of the spectrum is a rare allergy that developed in an Inupiat boy; allergy was confirmed to bearded seal and bowhead whale, staples in the diet of residents of coastal Alaska [28]. This case is thought to be the first documentation of an IgE-mediated reaction to these species and is a reminder that all foods in a patient's diet should be considered as potential allergens.

The understanding of non-IgE-mediated reactions is not as clear as that of IgE-mediated reactions [18]. Most adverse food reactions have no immunologic basis. However, for many adverse reactions that affect primarily the gastrointestinal tract, a cell-mediated response is involved [18]. Several mechanisms have been suggested to play a role in these reactions, including an abnormal mucosal immune response and responses involving mast cells, eosinophils, macrophages, and T-cells [18,29]. In contrast to IgE-mediated reactions, the symptoms associated with non-IgE-mediated reactions are delayed, often not occurring for hours or days after the suspected food was ingested [18].

The true prevalence of food allergy has been difficult to determine for many reasons, including lack of uniform diagnostic criteria, misclassification of adverse reactions, the use of self-reports, and the potential for allergy resolution [30,31,180]. In general, the prevalence has been higher when food allergies are self-reported than when the food allergy has been documented after diagnostic testing. A meta-analysis of 51 studies and a later analysis of a national survey both demonstrated a range in the prevalence of self-reported food allergy (to any food) of up to 35% for all ages, much higher than the approximate prevalence of 3.5% when food allergy was defined by the results of an oral food challenge [32,178]. The authors of a later meta-analysis estimated the prevalence among the overall population as being higher than 1% to 2% but lower than 10% [33]. Food allergy in children has been studied much more extensively than in adults.

According to 2015–2016 data on nearly 53,600 children, the prevalence of food allergy is as high as 9.3%, a rate significantly greater than that reported in the past and an increase of 8% in 2009–2010; however, national survey data from 2018 indicated a food allergy prevalence of 6.5% in children [1,103,182]. CDC data showed a 50% increase from 1997 to 2011, and compared with 2009–2010 data, there was an increase of 21% in peanut allergy, 18% in tree nuts, and 7% in shellfish [165,179]. The prevalence of food allergy among children in one estimate varied according to age, with the highest rate (10.7%) among children 1 to 2 years of age and the lowest rate (3.6%) among infants 0 to 1 year of age [1]. More than 5.6 million children in the United States have food allergy, with the most common allergens being peanut, milk, and shellfish; nearly 40% of children with food allergies have allergies to more than one food (Table 3) [1,34,35,178,179]. The prevalence of individual allergens varies, however, according to age. For example, among children 0 to 2 years old, milk is the most common allergen (32% of all children), followed by peanut (22%) and egg (16%); among children 14 years and older, shellfish is most common (24%), followed by peanut (20%) and milk (18%) [1,179].

Although less information is available regarding the number of adults with food allergy, it is estimated that approximately 1% to 3% of adults overall have allergy to one or more foods, with peanut, tree nuts, fish, and shellfish the most common allergens [2,5]. However, a 2015–2016 study with more than 40,000 participants showed a self-reported, reaction-based food allergy rate of 10.8%, with a ranking of most common allergens as shellfish (2.9%), milk (1.9%), peanut (1.8%), tree nut (1.2%), and fin fish (0.9%) [181]. From this self-reported survey, 47.5% had a physician diagnosis of food allergy, with peanut being the most commonly diagnosed (72.5%). In addition, 48% of adults indicated adult-onset of at least one food allergy; 26.9% developed an allergy only as an adult, and 52% developed an allergy only before 18 years of age [181].

Data from the 2018 National Health Interview Survey (NHIS) provide information on children and adolescents with food allergy according to gender and race/ethnicity. In 2018, the prevalence was essentially the same in girls and boys (6.5% vs. 6.4%). The prevalence was lowest among Asian children (5.0%) and was 6.6% for non-Hispanic White (single race) and 6.0% for non-Hispanic Black children (single race) [182]. Among children of Hispanic ancestry, the prevalence was 6.0%, with a rate of 6.6% noted for Mexican or Mexican American children. The rate was highest (12.7%) for children of two or more races. Income may also indicate prevalence, with 2018 NHIS data showing the highest prevalence in households with incomes greater than $100,000 (7.3%) compared with households with incomes $50,000–$74,999 (5.2%) [182]. Geographic area is also a factor in the prevalence of food allergy, with the highest prevalence in the West (7.4%), followed by the South (6.5%), Northeast (6.4%), and Midwest (5.4%).

In a large 2015–2016 study of adults with food allergy, it was found that 7.5% of men and 13.8% of women have food allergy, and 3.0% and 7.2% were adult-onset, respectively [181]. Prevalence of food allergy according to race and ethnicity among adults were different in some ways to those of children, with the lowest rate seen in non-Hispanic White adults (10.1%) and higher rates among non-Hispanic Black adults (11.2%), Asian adults (11.4%), and Hispanic adults (11.6%); this survey also included adults with multiple or other races, who had the highest rate (15.9%) [181]. Household income of adults with food allergy also differs from that of children; prevalence appears to be highest when household income is $50,000–$99,999, and there is a decreased prevalence for incomes greater than and less than that range [181]. Geographic distribution of adult food allergy was also slightly different than that described for children, with the West accounting for the greatest prevalence (11.5%), followed by the Northeast (11.2%), South (10.4%), and Midwest (10.3%) [181].

There are few known risk factors for food allergy. The strongest factor appears to be a family history of atopy or the presence of atopic dermatitis [2,9]. The findings of one study indicate that the rate of food allergy is approximately four times higher among children who have either one or two parents with atopy or asthma [166].

The prevalence of IgE-mediated food allergy appears to increase with the severity of atopic dermatitis [38,181]. In an early study, 25% to 33% of children (younger than 5 years) with moderate-to-severe atopic dermatitis had IgE-mediated food allergy, and in another study, 85% of children with a peanut allergy had atopic dermatitis [39,40]. Among children with infantile eczema, 33% to 81% had food allergy, with early eczema most often associated with allergy to peanut, egg, or milk [6].

Data have shown that rates of asthma, eczema or skin allergy, and respiratory allergy are substantially higher among children with food allergy than among children without food allergy (Figure 1) [34]. In a study of more than 500 children, symptomatic food allergy was strongly associated with asthma in younger (less than 6 years) and older (more than 6 years) children [41]. The association between the two conditions was stronger for children, especially older children, who had multiple or severe food allergies [41]. Despite the high rates of respiratory allergy and asthma among children with food allergy and the significant association between asthma and food allergy, no causal links have been identified to date [2,41].

RATES OF ALLERGY SYMPTOMS AMONG CHILDREN YOUNGER THAN 18 YEARS OF AGE WITH AND WITHOUT FOOD ALLERGY

Figure 1

Source: Reprinted from Branum AM, Lukacs SL. Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS Data Brief. 2008;10.

Another risk factor appears to be food allergy itself. Among children who have an IgE-mediated reaction to one food allergen, the likelihood is high that reaction will occur to another food allergen, as well as to aeroallergens, such as pollens [5]. As noted, 40% of children with food allergy have multiple food allergies [1,178,179].

Among adults, the most common comorbid conditions with food allergy include latex allergy (28.8%), urticaria or chronic hives (27.8%), insect sting allergy (22.9%), asthma (20.9%), atopic dermatitis (19.2%), medication allergy (18.5%), and environmental allergies (17.2%) [181].

Food allergy is thought to be the result of immaturity of both the immune system and the mucosal barrier in the gastrointestinal tract. Early exposure to food proteins leads to allergic sensitization against a specific food [42]. Thus, most food allergies develop before the age of 2 years, with the prevalence peaking at 1 year of age and then gradually decreasing until late childhood [5]. The typical age at onset is 6 to 24 months for most food allergies, including allergy to milk, egg, wheat, soy, and peanut [7,8,32,43,44]. Limited research on the onset of food allergy in adulthood has led to a general understanding that it is uncommon; however, studies have shown that adult-onset food allergies are becoming more common and have been increasing over the past two decades [36,180,181]. A large-scale survey conducted in 2015–2016 showed that, among the 10.8% of adults who indicated that they had a food allergy, adult-onset allergy occurred most commonly with wheat (52.6%), shellfish (48.2%), soy (45.4%), fin fish (39.9%), tree nuts (34.6%), eggs (29%), sesame (25.7%), milk (22.7%), and peanut (17.5%) [181].

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].

The most common cutaneous conditions associated with food allergy are urticaria (hives) and angioedema. These skin conditions occur in approximately 15% to 28% of the general population with food allergy and are more common in younger patients and patients with atopy [62,181]. Urticaria is characterized by transient erythematous raised, well-demarcated plaques that are often intensely pruritic. The plaques frequently have central pallor and blanch when pressure is applied; they are usually the result of an inflammatory reaction [62,63]. Approximately 20% of cases of acute urticaria (duration of less than 6 weeks) are caused by IgE-mediated reactions [63]. Clinicians should take care in interpreting the cause of urticaria, as only a small fraction of people who believe the skin condition is associated with food actually have this manifestation in placebo-controlled studies [63].

Angioedema is considered a more severe form of the same pathologic process as urticaria. Whereas urticaria is limited to the superficial dermis, angioedema affects vessels in the deep dermis and subcutaneous tissue. Angioedema is characterized by edema of distensible tissue, including the face, genitals, extremities, lips, tongue, and uvula. If angioedema occurs in the respiratory tract, it can result in dysphagia, respiratory distress, or complete airway obstruction.

The gastrointestinal tract is a common target organ for cell-mediated reactions to foods [63]. Gastrointestinal disorders can be difficult to identify and diagnose, particularly because symptoms are not always easily associated with ingestion of causal foods. The American Gastroenterological Association (AGA) notes several elements that may suggest food allergy as a cause of gastrointestinal disease (Table 6) [64].

The respiratory system is not as commonly affected as the skin and gastrointestinal tract; its involvement usually indicates a systemic effect. The food allergens most commonly associated with respiratory system manifestations are egg, milk, peanut, fish, shellfish, and tree nuts [71]. Manifestations range from mild (rhinitis) to severe (asthma and anaphylaxis). Anaphylaxis is discussed in detail later in this course, but a rare entity—food-associated, exercise-induced anaphylaxis—is discussed in this section.

Given the increasing rate of food allergies over time, practitioners should ask all parents of infants and young children specific questions about reactions after eating or drinking. According to the NIAID guidelines, a food allergy should be considered for the following [2]:

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

The European Academy of Allergy and Clinical Immunology asserts that a detailed clinical history is essential for the diagnosis of food allergy. When taking a clinical history eliciting allergens, timing and chronicity, symptoms, severity and signs, reproducibility, known risk (co)factors, family history, and coexisting medical problems (including other allergic diseases) should be addressed

(https://medialibrary.eaaci.org/mediatheque/media.aspx?mediaId=60224&channel=8518 Last Accessed: April 15, 2022)

Level of Evidence: VD (Expert Opinion)

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.

Unless the patient is being examined within a short time after an adverse reaction to food, the findings on physical examination may be unremarkable. Symptoms related to the skin, gastrointestinal tract, and respiratory system should be evaluated for their potential association with a food allergy, as previously discussed.

Although such symptoms may suggest the likelihood of food allergy, chronic conditions are rarely indicators. Urticaria, diarrhea, rhinitis, and cough are related to food allergy only if they occur within minutes to hours after ingestion of the offending food and last only a few hours [78]. The presence of severe atopic dermatitis should raise suspicion of food allergy [78].

When food allergy is suspected on the basis of the history and/or physical examination, diagnostic testing should be done to confirm the identity of the causal food. Allergy testing can provide information on the likelihood of a reaction but it cannot predict the severity of clinical reaction [80]. The NIAID-sponsored guidelines include recommendations for tests that should and should not be used to diagnose food allergy (Table 7) [2]. The three primary methods used to diagnose food allergy are skin prick testing, determination of allergen-specific IgE levels, and oral food challenges. A systematic review showed that each of these tests has advantages and drawbacks, and no one test is superior in terms of sensitivity and specificity [33]. These recommendations are emphasized as part of the Choosing Wisely campaign, an initiative of the American Board of Internal Medicine Foundation. In that campaign, the AAAAI notes that "unproven diagnostic tests, such as immunoglobulin G (IgG) testing or an indiscriminate battery of immunoglobulin E (IgE) tests" should not be used to evaluate allergy [81]. Instead, the AAAAI recommends that the appropriate diagnosis (and treatment) of allergies requires specific IgE testing on either skin or blood. The 2020 joint practice parameter on the diagnosis of peanut allergy recommends skin prick testing or whole peanut serum-specific IgE (sIgE) (or component-specific peanut sIgE) testing for individuals with physician-judged high pretest probability of peanut allergy or a moderate pretest probability before an oral food challenge [191].

Better adherence to these recommendations is needed, especially for nonallergists [12]. In one survey of children with physician-diagnosed food allergy, 47% of children had skin prick testing, 40% had allergen-specific IgE testing, and 20% had an oral food challenge [77].

Although referrals from primary care physicians to board-certified allergists are common, primary care physicians have expressed a desire for referral guidelines [15]. Referrals are not discussed in the NIAID-sponsored guidelines, but are addressed in the AAAAI guidelines. The AAAAI recommends referrals for the following [89]:

The care of patients with food allergy requires a partnership, involving not only the primary care physician and an allergist/immunologist but also a gastroenterologist, a dermatologist, and a nutritionist, as appropriate [90]. When the results of allergen-specific IgE testing are positive, an allergist/immunologist can provide special expertise in the following areas [15,78]:

The results of studies have shown that both children and adults may underestimate the severity of a food allergy, which means that education on the consequences of risk-taking behaviors is essential. Many individuals with food allergy or their parents fear that a severe reaction will occur in a setting where immediate help will not be available. However, according to a survey, most severe reactions occur in a setting that is considered to be "safe," such as home, work, or school [3,95]. Although this fact should be reassuring, it does suggest that better education is needed to help individuals with food allergy and/or their parents be better able to avoid causal foods.

Patients and their families need help in identifying so-called hidden sources of food allergens to avoid inadvertent ingestion of a food allergen by cross contamination. For example, some deli meats may have trace amounts of dairy product if the meat was cut on a slicer also used to cut cheese. Particular emphasis should be placed on nonfood items as potential sources of allergens; for example, many cosmetics may contain milk, tree nut oils, wheat, or soy; modeling dough may contain wheat; and beanbag stuffing often includes nut shells (Table 9) [61,96].

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].

Parents and children should also be cautioned about the risks of exposure through means other than eating. For example, they should understand the risks of kissing and sharing utensils with people who have ingested an individual's food allergen. After eating peanut, preventive measures, such as brushing the teeth, rinsing the mouth and chewing gum, can reduce salivary Ara h1 (a peanut protein marker), but the allergen has remained detectable in about 40% of instances after such measures [99]. People who have ingested peanut should wait several hours before kissing a person with peanut allergy [99].

Individuals who are at risk for food-induced anaphylaxis should have medication on hand in case of inadvertent ingestion of a food allergen. Self-injectable epinephrine should be provided in a preloaded syringe to facilitate its use in an emergency situation, and the patient, as well as caregivers and all members of the family, should be instructed in how to administer the injection.

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].

Most allergists prescribe EpiPen Jr for children who weigh 22 to 44 pounds and the EpiPen for children who weigh 62 pounds or more [100]. The dose for children who weigh 44 to 61 pounds primarily depends on the physician's assessment of the child's risk for a severe anaphylactic reaction. Expert consensus and a pharmacokinetic study recommend switching children to the 0.3-mg dose when a child weighs 55 to 66 pounds [194]. The conventional approach, that children who weigh less than 22 pounds should receive a 0.01-mg/kg dose of epinephrine drawn up in a syringe from an ampule, has been challenged because several factors (e.g., caregivers' inability to draw and administer a correct dose in a reasonable amount of time) that ultimately leads to a delay in dosing, incorrect dosing, or no dose at all [194]. The 2017 AAP clinical report for management of anaphylaxis and the 2020 AAAAI anaphylaxis practice parameter, among other sources, recommend using the 0.15-mg (EpiPen Jr) or 0.1-mg (Auvi-Q) autoinjector for infants and children weighing less than 22 pounds, stating that the benefit-to-risk ratio is favorable [154,194]. Patients and caregivers should be instructed that the autoinjector should be administered at the middle thigh in average BMI individuals; for obese or severely obese individuals, the dose should be administered in the lower thigh or the calf muscle, respectively. The autoinjector will deliver the full dose in less than three seconds, and it should be removed promptly. If additional doses are required, they should be administered at an alternate site (e.g., the other thigh) [193].

Barriers to using self-injectable epinephrine have increased, with the rising cost of the self-injectable epinephrine pens, an underutilization of the pens when needed, and a supply shortage of injectable medications [193]. Reports have shown a 545% increase in price of an EpiPen between 2007 and 2016. The high cost of epinephrine auto-injectors (increasing from an average of $60 to more than $600 over the past 15 years) has been identified as a barrier to the initial filling and refilling of prescriptions [170]. Manufacturers have worked to make generic injectable pens more affordable, but cost and insurance/prescription coverage remain barriers to many [185]. As such, healthcare professionals have an ethical duty to advocate for lower drug costs for their patients.

Researchers also found that there is a need for more physicians to prescribe self-injectable epinephrine for their patients and to emphasize the importance of immediate treatment for food-induced anaphylaxis. Surveys of primary care physicians and of individuals with nut allergies have shown that approximately 50% to 75% of individuals with nut allergies have not been prescribed self-injectable epinephrine [13,15,101,188]. In addition, a study of children in three Massachusetts school districts showed that white children were nearly five times more likely than nonwhite children to be given injectable epinephrine for peanut or tree nut allergy [102].

Surveys of parents and physicians have indicated a need for improved education on emergency preparedness and the use of epinephrine. Studies vary with regard to individuals who use epinephrine for anaphylactic reaction before receiving emergency care, with rates varying between 65% and 85% of children presenting to the emergency department with anaphylaxis [13,14,15,184]. Among the reasons given for not administering epinephrine are lack of recognition of the severity of the reaction, unavailability of epinephrine, and fear of administering the drug [2,57,184]. A majority of parents, emergency medical personnel, and even physicians are reluctant to administer epinephrine due to a lack of knowledge of the necessity in anaphylaxis and of the drug's inherent safety (i.e., it is a chemical already present in the body, potentially in high levels, such as during exercise); other reasons for failing to administer epinephrine include lack of training and fear of worsening the patient's condition [168,169]. These findings suggest that practitioners should evaluate all patients carefully, use and follow treatment guidelines, talk to parents about identifying reactions and the need to act, prescribe self-injectable epinephrine, and instruct families in its use and safety. Studies have shown that up to 25% of children with previously unknown food allergy will experience their first allergic reaction while at school. As such, some states have created legislation to require or allow kindergarten–12th grade schools to stock undesignated epinephrine auto-injectors for use on students who do not have a prescription, due to unknown allergy or unprescribed allergy, who cannot afford the device, or who are not currently carrying an epinephrine pen. Law regarding schools carrying epinephrine varies by state, and parents and physicians should check the status of their local legislation and guidelines [186].

As the child grows older, parents and physicians should decide when it is appropriate for the child to assume increasing responsibility for management of his or her food allergy. Many parents have anxiety about their child assuming this increasing responsibility, especially with regard to selecting foods, but 85% agreed that their child should carry injectable epinephrine with them to school [10]. Most pediatric allergists believe that children should recognize the signs and symptoms of anaphylaxis and be able to use epinephrine by the time they are 12 to 14 years of age, with consideration given to developmental level [104,105]. Teenagers especially need reminders about the importance of having epinephrine available. In a survey undertaken to evaluate risk-taking behaviors in teenagers (median age: 16 years), 82% of the respondents had a history of food-induced anaphylaxis, yet many did not always carry epinephrine, especially when participating in sports (57%), wearing tight clothing (47%), attending a school dance (39%), or going to a friend's home (33%) [106]. Cultural and ethnic differences may influence the types of behaviors in which teenagers will engage. Any possible cultural barriers to the proper use of the medication should be addressed. Older children and teenagers should also be cautioned that the availability of epinephrine does not mean that they can relax avoidance of the food allergen [107].

Practitioners should encourage the patient and parents to make the allergy known to all family and friends and to ensure that family and close friends know what to do in case of accidental ingestion and when to seek emergency medical care. An emergency call should be made as soon as an anaphylactic reaction begins, and the patient should be taken to an emergency department in an ambulance. Other points of discussion include documenting the allergy with a medical emergency tag or bracelet and providing an emergency care plan for day care providers, schools, and camps and when traveling. Parents of children who have been prescribed self-injectable epinephrine should inform school personnel about the allergy and the availability of the medication.

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].

Children with food allergy, especially those with allergy to multiple foods, are at risk for nutrient deficiency during either diagnostic elimination diets or long-term allergen avoidance [116,117]. A nutritionist or dietician plays a key role by helping parents to [116,117,118]:

In addition, the nutritionist or dietician is the best equipped to conduct an annual nutrition assessment to prevent growth problems and to monitor the overall health effects.

The interval for follow-up diagnostic testing depends on the food in question, the age of the child, and the intervening medical history [2]. Decreases in food-specific IgE levels over time may indicate that the child will become tolerant of the food; thus, lower IgE levels may prompt repeat oral food challenges to determine resolution [2,119]. For example, an oral challenge can be offered to patients who have a low peanut-specific IgE and have not had an allergic reaction within the past year [45]. IgE levels may also remain elevated for some time, and an oral food challenge can determine if clinical reactivity still exists. The resolution of atopic dermatitis may also be associated with the onset of tolerance to food allergens [2]. A skin prick test is not helpful in determining resolution of allergy, as the results can remain positive even after tolerance has developed; however, a reduction in wheal size may indicate tolerance [2].

A food allergy can have a tremendous impact on quality of life, and attention should be given to the psychosocial needs of children and their parents. Children with food allergy have had substantially poorer scores related to general quality of life; physical health-related quality of life; quality of life within school; and emotional, psychologic, and social quality of life [120,121]. Approximately 45% of children with food allergy have said they were bullied or harassed (for any reason), and 31% said the bullying was specifically related to the food allergy [122,187]. This bullying is also associated with lower quality of life and increased distress, for both the child and the parents [122]. In addition, more than 25% of parents say that the child's friends treat him or her differently because of the allergy [10].

Social limitations are primary concerns of parents. In one survey, about half of caregivers said the food allergy affected the family's social activities, and 10% opted to home-school the child because of the food allergy [123]. More than half of parents have reported that some family relatives do not accommodate the child's food allergy, and 40% report hostility from other parents [10].

Food allergy affects anxiety and stress levels, and parents, especially mothers, have reported high scores for stress and anxiety [120,124]. Parents have also noted that the food allergy causes a strain on their marriage/relationship and that their career has suffered because of the allergy [10]. In one survey, 70% of caregivers said that mental health support would have been helpful, but 23% sought such help, even when it was available [124].

These negative effects of food allergy call for practitioners' heightened awareness of the psychosocial health of people with food allergy and their families, and greater encouragement of the use of mental health support. Practitioners should also encourage parents to discuss issues such as bullying with school administrators and suggest ways to better empower children. Education has been shown to enhance coping, and prescription of injectable epinephrine has decreased anxiety among mothers and children with food allergy [121,125]. In addition, 68% of young adults have said that educating their friends about the allergy would make it easier to cope [106].

Oral antihistamines and corticosteroids are commonly used to provide relief of symptoms associated with mild-to-moderate allergies, and bronchodilators should be prescribed for patients with asthma [13,25]. Physicians must emphasize that antihistamines or bronchodilators should not be used as a preventive measure before ingesting a possible food allergen, as oral food challenges have elicited positive results even in children who have taken such medication before the test [78].

According to the American Academy of Allergy, Asthma, and Immunology, the safety and efficacy of oral and sublingual immunotherapy for food hypersensitivity are currently investigational.

(https://www.aaaai.org/Aaaai/media/Media-Library-PDFs/Allergist%20Resources/Statements%20and%20Practice%20Parameters/Allergen-immunotherapy-Jan-2011.pdf Last Accessed: April 15, 2022)

Strength of Recommendation: NR (Not Rated)

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].

The number of studies of oral immunotherapy for egg, milk, and peanut allergy has increased substantially since the early 2000s. Overall, these studies have shown that oral immunotherapy is effective, with approximately 50% to 75% of people treated being able to tolerate an increasing amount of the food allergen and about 10% to 33% becoming partially desensitized [57,126,135,136,137,138,172,188]. This treatment approach also appears to be safe, with most adverse events being local and mild; no life-threatening events or deaths have occurred in any oral immunotherapy study to date [126,172]. The results show promise for reducing the severity of reactions to accidental ingestion of a food allergen and for developing a potential cure, and one study has shown improvement in quality of life [126]. However, many issues remain unresolved (Table 11) [126,139]. In 2020, the FDA approved peanut allergen powder (Palforzia) for the treatment of peanut allergy in individuals 4 to 17 years of age with a confirmed diagnosis [190]. The powder is packaged in pull-apart capsules, allowing the allergen to be added to a small amount of semisolid food and consumed.

Most adverse events in oral immunotherapy studies have occurred during the initial phase of increasing the dose of allergen, and new studies are focusing on ways to address this problem by pretreatment with an anti-IgE monoclonal antibody (such as omalizumab) or initial use of sublingual doses, with gradual increases in oral doses [126,139,140]. Omalizumab is currently U.S. Food and Drug Administration (FDA)-approved for allergic asthma, and its use as an adjunct to oral immunotherapy in trials has allowed more rapid and higher doses of immunotherapy [141,193]. In one study, 79% of participants in the omalizumab group (who were started on 250 mg of peanut protein, versus 22.5 mg for the placebo group) were able to tolerate 2,000 mg of peanut protein six weeks after stopping omalizumab, compared with only 12% in the placebo group [195].

The cost of oral immunotherapy protocols is expensive because of the time and monitoring needed to complete them; FDA approval and health insurance coverage are needed.

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].

Until 2006, there was no universal agreement on the definition of anaphylaxis or the criteria for its diagnosis. The NIAID and the Food Allergy and Anaphylaxis Network (FAAN) held two symposia to collaborate with representatives from 16 organizations and government bodies to develop a universally accepted definition of anaphylaxis as well as criteria for its diagnosis. They defined anaphylaxis as, "a serious allergic reaction that is rapid in onset and may cause death" [155]. The collaborative effort also led to the establishment of clinical criteria for diagnosis (Table 12) [155,156]. In a validation study of 86 emergency department patients who met these criteria, the criteria demonstrated a sensitivity of 96.7%, a specificity of 82.4%, a positive predictive value of 68.6%, and a negative predictive value of 98.4%, indicating that the criteria are likely to be useful in an emergency department setting [164].

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].

Appropriate treatment of anaphylaxis must be immediate, as death can occur within 30 to 60 minutes [2]. Guidelines for the treatment of anaphylaxis have been developed jointly by the AAAAI and the ACAAI as well as by the NIAID and by the World Allergy Organization [2,154,155,156,175]. The drug of choice for the treatment of anaphylaxis is epinephrine, and several studies have shown that the lack of early epinephrine is associated with an increase in biphasic reactions as well as greater morbidity and mortality [2,3,185]. Yet, healthcare professionals often fail to use epinephrine, with geographic variations in practice patterns [149,157,158,159,169,185]. Antihistamines (H1 and H2 blockers) and corticosteroids have been used to treat anaphylaxis, and the use of antihistamines is the most common reason given for not administering epinephrine [2,185]. However, three systematic reviews have demonstrated that there are few or no data to support the effectiveness of antihistamines or corticosteroids and that epinephrine is the only first-line treatment for anaphylaxis [160,161,162]. The recommended dose of epinephrine is 0.01 mg/kg (maximum dose: 0.3 mg for children and 0.5 mg for adults), given intramuscularly every 5 to 15 minutes as necessary to control symptoms and maintain blood pressure [2,3,154,155,174]. Peak plasma concentrations are highest and achieved fastest when epinephrine is administered intramuscularly in the thigh (versus the arm) [174].

Treatment of anaphylaxis must begin before the individual is transported to an emergency care facility. The NIAID expert panel recommends that the following steps be carried out concurrently as soon as an anaphylactic reaction has started [2]:

When the patient arrives at the emergency care facility, the first action is to assess the airway, breathing, and circulation. In the emergency care setting, additional injections of epinephrine may be necessary. There are multiple other components to treatment that vary according to many factors, most notably the individual's symptoms, the type of reactions that have occurred in the past, and the response to epinephrine (Figure 2) [100,155,174]. According to evidence-based guidelines for the treatment of anaphylaxis, adjunctive treatment may include [2,154,155,174]:

EMERGENCY ANAPHYLAXIS MANAGEMENT ALGORITHM

NIAID/FAAN = National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network, SIE = self-injectable epinephrine.

Figure 2

Source: Reprinted from Campbell RL, Li JT, Nicklas RA, Sadosty AT; Members of the Joint Task Force; Practice Parameter Workgroup. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(6):599-608, with permission from Elsevier.

The American Academy of Allergy, Asthma, and Immunology suggests that a clinician incorporate severity of anaphylaxis presentation and/or the administration of more than one dose of epinephrine for the treatment of initial anaphylaxis as a guide to determining a patient's risk for developing biphasic anaphylaxis.

(https://www.aaaai.org/Aaaai/media/Media-Library-PDFs/Allergist%20Resources/Statements%20and%20Practice%20Parameters/Anaphylaxis-2020-grade-document.pdf Last Accessed: April 15, 2022)

Level of Evidence: Very low

Due to the potential for a biphasic response, the individual should remain in the emergency department for observation for four to six hours [2]. In some instances, such as a history of severe reaction, it may be reasonable to admit the individual for longer observation. When discharged, the individual should be given self-injectable epinephrine, as well as a prescription for at least two doses, provided with educational resources on the symptoms of anaphylaxis and the use of epinephrine, and advised to make a prompt appointment with an allergist and to notify his or her primary care clinician [2,3].

Despite the availability of guidelines, anaphylaxis is often not appropriately treated. A review of randomly selected charts of individuals treated for food-induced anaphylaxis at 21 emergency departments in North America indicated the following [14,185]:

The establishment of treatment protocols and the availability of necessary supplies and equipment have been shown to significantly improve the management of anaphylaxis, with higher rates of epinephrine use and prescription, greater rates of admission to an observation area in the emergency department and a longer time in such an area, and lower rates of corticosteroid use (as monotherapy) and discharges without follow-up instructions [163]. In its guidelines on anaphylaxis, the World Allergy Organization provides examples of protocols and supply lists [156].

Patient J is a man, 35 years of age, who presents to the emergency room with acute dysphagia, vomiting, and abdominal pain. The symptoms began when he was having lunch at work, and they have persisted for a long period of time. The patient has a history of indigestion, asthma, and atopic dermatitis. The symptoms appear to be indicative of gastroesophageal reflux disease, and lansoprazole, 30 mg daily is prescribed. However, because the patient has a history of atopy and the onset of symptoms was acute, he is referred to a gastroenterologist for additional work-up.

The gastroenterologist performs an upper endoscopy with biopsy to determine if the symptoms are the result of an allergic response. Endoscopic examination shows the esophagus to be pink with linear furrows. Analysis of the biopsy samples demonstrates increased levels of eosinophils, approximately 26 per high-power field, in samples taken from the esophagus but not in those taken from the stomach or duodenum. Given the history of atopy, the results of the endoscopy and analysis indicate eosinophilic esophagitis.

The patient is referred to an allergist for testing to determine the allergen responsible for the response. Results of the skin prick tests demonstrate a response to bananas and honey. Patient J has eliminated these food items from his diet, and symptoms have resolved without recurrence.

A woman brings her son, Patient M, 1 year of age, to the pediatrician because of a persistent rash on the child's face, arms, and legs. The history regarding dietary intake indicates that cow's milk was newly introduced into Patient M's diet. Furthermore, the child's mother has a history of asthma and remembers that she drank soy milk as a child because she was allergic to cow's milk. On examination, Patient M's rash is limited to his cheeks and the extensor surface of his arms and legs. The rash is raised and intensely pruritic, with some small erythematous patches. The child has no respiratory or gastrointestinal symptoms and is afebrile. It is suspected that the patient is having an IgE-mediated response to cow's milk manifesting as atopic dermatitis. An immediate referral to an allergist is made, and the mother is advised to remove milk from the child's diet.

After reviewing Patient M's history and to confirm the initial diagnosis of IgE-mediated atopic dermatitis, the allergist performs a skin prick test. There is a positive response to cow's milk, with a wheal 6.5 mm in diameter. No reactions to other substances are noted. The positive reaction on the skin test and the family history of milk allergy negate the need for additional tests to confirm the diagnosis. Management includes removal of milk from Patient M's diet and treatment of pruritus with children's strength diphenhydramine (Benadryl) and a topical steroid cream. A follow-up appointment is made to monitor Patient M's allergy status.

Patient A is a woman, 21 years of age, with a known allergy to peanuts. She was having dinner at a Chinese restaurant with friends when she began to experience trouble breathing, which progressed to wheezing within a few minutes. She also showed signs of confusion and had slurred speech. Emergency response personnel were summoned to the scene.

On arrival, emergency personnel note diffuse and severe urticaria on Patient A's arms, legs, and face, particularly around the eyes and mouth. The patient also appears to have angioedema of the throat and/or tongue. Examination reveals pulmonary edema and a pulse of 140 beats per minute. The woman's friends tell the emergency response personnel that she has a peanut allergy. During transportation of the patient to the local hospital, an endotracheal tube is placed to create a patent airway, and 0.3 mg of epinephrine is administered intramuscularly in the thigh. After the epinephrine is administered, Patient A's symptoms begin to clear.

When the patient arrives at the hospital, she has a pulse of 100 beats per minute and her breathing is substantially improved. Intravenous corticosteroid is given in order to minimize lingering allergic response. It is determined that, although the patient did not intentionally consume peanuts, there had been some cross contamination at the restaurant, which does serve several dishes containing peanuts or peanut butter. Because Patient A has a known allergy, she has a prescription for self-injectable epinephrine. However, she states that she usually leaves the medication at home because she avoids peanuts and, therefore, has had no need for it. The patient is advised to always keep the self-injectable epinephrine with her and to tell friends and companions where the medication is and when to use it. It is also recommended that she wear a necklace or bracelet identifying her severe peanut allergy in order to assist emergency personnel in the future.