Food allergies are increasing in prevalence. In order for pediatric clinicians to appropriately diagnose and manage food allergies, the characteristic signs and symptoms of these potentially severe reactions must be recognized. Unlike nonimmunologic adverse food reactions (such as lactose intolerance and food poisoning), food allergies by definition are immune-mediated responses that occur reproducibly on food ingestion. The varying clinical presentations of food allergy include IgE-mediated disorders, mixed IgE- and cell-mediated disorders, and cell-mediated food allergies. This review describes the clinical manifestations of each of these categories of food allergy, with special emphasis on recognition of food-induced anaphylaxis.
Key points
- •
Unlike nonimmunologic adverse food reactions (such as lactose intolerance and food poisoning), food allergies (FAs) by definition are immune-mediated responses that occur reproducibly on food ingestion.
- •
There are varying clinical presentations of FA, owing to different underlying immunologic mechanisms (IgE-mediated, mixed IgE- and cell-mediated, and cell-mediated disorders).
- •
IgE-mediated FA may result in food-induced anaphylaxis, a potentially life-threatening severe systemic reaction, requiring prompt recognition and treatment.
Introduction
The prevalence of FAs is widespread and rising rapidly, affecting up to 8% of children in the United States. FAs may result in significant morbidity. Among patients treated for anaphylaxis in the emergency department (ED), FA is the most common cause, accounting for one-third to half of cases. Given this increasing prevalence and potential severity, pediatric clinicians must be able to quickly recognize the signs and symptoms of FA. The range of clinical manifestations of FAs is wide and varies based on the underlying immunopathology. Symptoms may affect the cutaneous, respiratory, gastrointestinal (GI), or cardiovascular systems. The most severe presentation of FAs is anaphylaxis, an acute systemic allergic reaction that can ultimately lead to death if untreated. This review starts by defining FAs and then discusses the range of clinical presentations of various types of FAs based on underlying immune mechanisms. Important questions in the history of a patient with a suspected FA are also discussed.
Defining food allergies
The term adverse food reaction is used to describe any untoward health effect that occurs after food ingestion. It can be divided into FAs, which are due to a specific immune response and occur reproducibly on food ingestion, and all other reactions, which, in contrast to true FAs, are nonimmunologic in nature. It is important that the pediatric clinician distinguish these nonimmunologic adverse food reactions (summarized in Table 1 ) from FA to guide appropriate treatment.
| Host-specific metabolic disorders |
|
| Response to pharmacologically active food component | Scombroid poisoning (fish: tuna, mackerel, mahi mahi, sardines, anchovies) Histamine-like compounds (wine, sauerkraut) Caffeine Tyramine (aged cheeses, pickled fish) Theobromine (tea, chocolate) Tryptamine (tomato, plum) Serotonin (banana, tomato) |
| Toxic reactions (food poisoning) | Fish: ciguatera poisoning (grouper, snapper) Shellfish: saxitoxin Fungal toxins: aflatoxins, trichothecanes, ergot Other food poisoning ( Clostridium botulinum , Staphylococcus aureus ) |
| Gastrointestinal disorders | Structural abnormalities (hiatal hernia, pyloric stenosis, tracheoesophageal fistula, Hirschsprung disease) Gastroesophageal reflux Peptic ulcer disease |
| Psychological reactions | Food aversions Food phobias |
| Neurologic reactions | Auriculotemporal syndrome (facial redness or sweating after eating tart foods) Gustatory rhinitis (rhinorrhea after eating hot or spicy foods) |
Nonimmunologic adverse food reactions can result from metabolic disorders such as lactose intolerance, galactosemia, and alcohol intolerance. Lactose intolerance manifests as a result of an inability to digest the carbohydrate lactose in milk and dairy products, owing to deficiency of the lactase enzyme. Symptoms might include abdominal pain, bloating, gas, diarrhea, and nausea. Pharmacologically active components in foods, such as caffeine and food-borne toxins, may also cause nonimmune adverse food reactions. For example, scombroid fish poisoning is a toxic adverse food reaction caused by histaminic chemicals found in spoiled dark-meat fish such as tuna, mackerel, and sardines. Exposure to these chemicals can result in cutaneous and systemic symptoms such as flushing, urticaria, angioedema, nausea, abdominal cramping, and diarrhea that closely mimic a food-allergic reaction. However, the underlying mechanism of scombroid poisoning is nonimmunologic, and thus it is not an FA.
Nonimmune adverse food reactions can also be the result of GI disorders such as gastroesophageal reflux, psychological disorders such as food aversions and food phobias, or neurologic disorders such as auriculotemporal syndrome and gustatory rhinitis. Key questions in the history (discussed later) can help distinguish FA from nonimmune adverse food reactions, but referral to an allergist should be considered if uncertainty remains.
Because FAs are immune-mediated responses, an understanding of their underlying immunologic mechanisms allows food-allergic reactions to be classified into 1 of 3 groups: (1) IgE-mediated reactions, (2) non-IgE-mediated reactions, and (3) mixed IgE-mediated and non-IgE-mediated reactions.
Defining food allergies
The term adverse food reaction is used to describe any untoward health effect that occurs after food ingestion. It can be divided into FAs, which are due to a specific immune response and occur reproducibly on food ingestion, and all other reactions, which, in contrast to true FAs, are nonimmunologic in nature. It is important that the pediatric clinician distinguish these nonimmunologic adverse food reactions (summarized in Table 1 ) from FA to guide appropriate treatment.
| Host-specific metabolic disorders |
|
| Response to pharmacologically active food component | Scombroid poisoning (fish: tuna, mackerel, mahi mahi, sardines, anchovies) Histamine-like compounds (wine, sauerkraut) Caffeine Tyramine (aged cheeses, pickled fish) Theobromine (tea, chocolate) Tryptamine (tomato, plum) Serotonin (banana, tomato) |
| Toxic reactions (food poisoning) | Fish: ciguatera poisoning (grouper, snapper) Shellfish: saxitoxin Fungal toxins: aflatoxins, trichothecanes, ergot Other food poisoning ( Clostridium botulinum , Staphylococcus aureus ) |
| Gastrointestinal disorders | Structural abnormalities (hiatal hernia, pyloric stenosis, tracheoesophageal fistula, Hirschsprung disease) Gastroesophageal reflux Peptic ulcer disease |
| Psychological reactions | Food aversions Food phobias |
| Neurologic reactions | Auriculotemporal syndrome (facial redness or sweating after eating tart foods) Gustatory rhinitis (rhinorrhea after eating hot or spicy foods) |
Nonimmunologic adverse food reactions can result from metabolic disorders such as lactose intolerance, galactosemia, and alcohol intolerance. Lactose intolerance manifests as a result of an inability to digest the carbohydrate lactose in milk and dairy products, owing to deficiency of the lactase enzyme. Symptoms might include abdominal pain, bloating, gas, diarrhea, and nausea. Pharmacologically active components in foods, such as caffeine and food-borne toxins, may also cause nonimmune adverse food reactions. For example, scombroid fish poisoning is a toxic adverse food reaction caused by histaminic chemicals found in spoiled dark-meat fish such as tuna, mackerel, and sardines. Exposure to these chemicals can result in cutaneous and systemic symptoms such as flushing, urticaria, angioedema, nausea, abdominal cramping, and diarrhea that closely mimic a food-allergic reaction. However, the underlying mechanism of scombroid poisoning is nonimmunologic, and thus it is not an FA.
Nonimmune adverse food reactions can also be the result of GI disorders such as gastroesophageal reflux, psychological disorders such as food aversions and food phobias, or neurologic disorders such as auriculotemporal syndrome and gustatory rhinitis. Key questions in the history (discussed later) can help distinguish FA from nonimmune adverse food reactions, but referral to an allergist should be considered if uncertainty remains.
Because FAs are immune-mediated responses, an understanding of their underlying immunologic mechanisms allows food-allergic reactions to be classified into 1 of 3 groups: (1) IgE-mediated reactions, (2) non-IgE-mediated reactions, and (3) mixed IgE-mediated and non-IgE-mediated reactions.
IgE-mediated food allergies
IgE-mediated food-allergic reactions are mediated by surface IgE on tissue mast cells and circulating basophils, which develop during initial sensitization to a food. On reexposure to the food antigen, IgE cross-linking on the surface of mast cells and basophils results in the acute release of preformed allergic mediators that cause signs and symptoms to develop rapidly. Thus, IgE-mediated FA should be considered in a patient who develops signs and symptoms minutes to 2 hours after ingesting the culprit food. Newly synthesized mediators may also be released, causing a delayed phase of symptoms several hours after the initial response.
There is one known form of IgE-mediated FA in which characteristic symptoms do not develop rapidly. Allergic reactions to mammalian meats (particularly beef, pork, and lamb) containing a carbohydrate antigen called galactose-α-1,3-galactose (alpha-gal) are typically delayed 4 to 6 hours after ingestion, likely because of the time it takes for antigen digestion and/or processing. Allergic reactions to the alpha-gal antigen are the only IgE-mediated FA identified to date in which the food antigen is a carbohydrate, and not a protein. Sensitization to alpha-gal has been described following bites of Ixodes ticks.
Patients with IgE-mediated FA can present with a variety of symptoms that involve several organ systems, including urticaria and angioedema, rhinoconjunctivitis, respiratory distress, GI disturbances, and cardiovascular compromise. Key features of each are summarized in Table 2 .
| Symptom Complex/Disorder | Key Points/Clinical Features | Most Common Causal Foods |
|---|---|---|
| Urticaria/angioedema | 20% of acute urticaria (<6 wk duration) is due to FA. Chronic urticaria is unlikely related to FA Contact urticaria can occur in which hives are localized only to areas of food contact 20% of anaphylaxis, and 80% of fatal food-induced anaphylaxis, involves no hives | Cow’s milk, egg, peanut, tree nuts, soy, wheat, fish, and shellfish Contact urticaria is triggered by these foods as well as raw meats and raw fruits and vegetables |
| Oral allergy syndrome | Pruritus, mild edema confined to oral cavity Uncommonly progresses beyond mouth (<10%) or anaphylaxis (1%–2%) Occurs in half of pollen-allergic patients | Raw fruit/vegetables (cooked forms tolerated) |
| Rhinoconjunctivitis and bronchospasm | Accompanies food-induced allergic reaction, but rarely isolated symptom except in occupational asthma | Major allergens (Occupational: wheat, egg, seafood) |
| Anaphylaxis | Rapidly progressive, multiple organ system reaction that is life threatening Respiratory symptoms: Present in up to 70% of episodes; primary cause of death in FA-induced anaphylaxis. Risk of death is higher in asthmatics GI symptoms: Present in up to 45% of episodes; upper GI symptoms are within minutes, whereas lower GI symptoms can be delayed Cardiovascular symptoms: Present in up to 45% of episodes; massive fluid shifts can cause shock within minutes | Any allergens, but more commonly peanut, tree nuts, shellfish, fish, milk, egg, and sesame |
| Food-dependent, exercise-induced anaphylaxis | Food triggers anaphylaxis only if ingestion followed 2–4 h by exercise | Most common: wheat, shellfish, celery |
Urticaria and Angioedema
Both urticaria and angioedema develop because of cross-linking of food-specific IgE on cutaneous mast cells. In the former, mast cells in the superficial dermis are involved, whereas in the latter, those in the deep dermis and subcutaneous tissues are implicated. Although urticaria can be the result of various processes including infection, reactions to medications, and insect bites, it is estimated that at least 20% of acute urticaria is due to FA.
Urticaria or hives appear as raised erythematous wheals that are pruritic. They are usually well circumscribed or coalescing and often migrate around the body. IgE-mediated FA should be considered in patients with acute urticaria whose symptoms were preceded by a recent food exposure. If urticaria persists for greater than 6 weeks, they are classified as chronic, and FA is unlikely the cause. It is important to recognize that, although the route of food exposure causing acute urticaria is often ingestion, direct contact may also cause contact urticaria, in which hives are localized only to the areas of food contact. For example, a child with IgE-mediated peanut allergy may develop hives after rubbing peanut butter on his/her face without actually ingesting the food.
Angioedema is characterized by asymmetric, nonpitting edema involving nongravitationally dependent areas. It may affect the face, extremities, or upper airway. Although any food allergen may cause acute urticaria and angioedema, the most common foods to do so are cow’s milk, egg, peanut, tree nuts, soy, wheat, fish, and shellfish. Contact urticaria may be triggered by these foods, as well as by raw meats, raw fruits and vegetables, and rice.
Although hives and swelling are common signs of food allergic reactions, their absence does not preclude a FA diagnosis. Skin symptoms may be absent in up to 10% to 20% of anaphylaxis. About 80% of fatal food-induced anaphylaxis is not associated with skin findings, which suggests that the lack of cutaneous signs may result in delayed recognition and treatment of an allergic reaction and thereby increased risk of fatality. Pediatric clinicians should be vigilant for the noncutaneous signs of IgE-mediated FA discussed later.
Oropharyngeal Symptoms: Oral Allergy Syndrome
Oropharyngeal symptoms may occur as part of a more systemic food allergic reaction or in isolation, for example, when the dose of allergen ingested is small or when the allergen is unstable or labile, as in oral allergy syndrome (OAS).
OAS, also referred to as pollen-associated FA syndrome, is a form of IgE-mediated FA in which the ingestion of raw fruits or vegetables causes oropharyngeal pruritus, tingling, and/or mild swelling of the lips, tongue, palate, and throat. The reaction is most often limited to the oropharynx and subsides within minutes of ingestion. Less than 10% of patients progress to systemic involvement of symptoms, and only 1% to 2% progress to anaphylaxis. The antigen causing OAS is a heat-labile food protein of plant origin, which is structurally similar and thereby cross-reactive with pollen allergens. OAS occurs in up to half of pollen-allergic patients, and symptoms may be more prominent during the relevant pollen season. Because the antigens are heat labile, patients are usually able to tolerate cooked forms of the causative fruits and vegetables.
Respiratory Tract Symptoms: Rhinoconjunctivitis and Bronchospasm
IgE-mediated FA may manifest with ocular and nasal symptoms after food exposure, such as periocular pruritis, edema, conjunctival erythema, and lacrimation, as well as sneezing, nasal itching, congestion, and rhinorrhea. Upper airway findings (hoarseness, stridor, sensation of throat tightness) and lower airway symptoms (dyspnea, tachypnea, wheezing, cough) may also be observed. Symptoms of rhinoconjunctivitis and bronchospasm are frequently observed as part of systemic IgE-mediated FA reactions (see Anaphylaxis section), but rarely as isolated findings. In a study of 480 children who underwent oral ingestion double-blind placebo-controlled food challenges, 39% of the 185 children with positive reactions experienced ocular and respiratory symptoms. Only 5% had symptoms confined to the respiratory tract alone.
An exception in which isolated respiratory symptoms are observed after food exposure is occupational asthma/rhinitis among workers in the food preparation and packaging industry. These individuals may develop isolated upper and/or lower respiratory symptoms after inhalation of the culprit food allergen, such as wheat in baker’s asthma. The food is often tolerated on ingestion.
Gastrointestinal Symptoms
In patients with IgE-mediated FA, GI symptoms may be divided into those derived from involvement of the upper GI tract (nausea, vomiting, and/or abdominal pain typically occurring minutes to 2 hours after ingestion) versus the lower GI tract (cramping and diarrhea delayed 2–6 hours). GI symptoms commonly occur as part of systemic FA reactions (see Anaphylaxis section). When GI symptoms occur in isolation after food allergen ingestion, this is referred to as GI anaphylaxis.
Food-Induced Anaphylaxis
The most serious clinical implication of IgE-mediated FA is anaphylaxis, a systemic allergic reaction that is rapid in onset and may cause death. Anaphylaxis affects up to 2% of the population, and FAs are responsible for up to 50% of all cases. In children and young adults who develop anaphylaxis outside of the hospital setting, FA is the leading cause among identified triggers. Several risk factors, including adolescence or young adult age, coexistent asthma, reactions due to peanut or tree nuts, and delayed administration of epinephrine, increase the risk of a fatal reaction from food-induced anaphylaxis. Most cases of fatal FA reactions are preceded by prior reactions, but those were rarely severe. This finding underscores the unpredictable nature of FA in that the severity of prior reactions cannot predict future reaction severity.
Although any food may cause anaphylaxis, in the United States (and some European countries), the most commonly implicated foods are peanut and tree nuts, followed by shellfish and fish. Based on small series, the foods most commonly implicated in fatal food-induced anaphylaxis are peanut, tree nuts, and cow’s milk. A variety of other foods, including soy, egg, wheat, sesame, food additives, and spices, have also been associated with anaphylactic reactions.
Rapid and massive release of allergic mediators and cytokines, including histamine, tryptase, chymase, platelet-activating factor, prostaglandin D2, cysteinyl leukotrienes, interleukin 6, and tumor necrosis factor alpha, into the systemic circulation contributes to the multiorgan compromise seen in anaphylaxis. As a systemic reaction, anaphylaxis may present with a wide array of potential symptoms and signs ( Box 1 ). To assist in accurate diagnosis of anaphylaxis, formal diagnostic criteria have been developed by the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network ( Box 2 ). In general terms, these criteria help to confirm a diagnosis of anaphylaxis after the acute development (within minutes to hours from exposure) of symptoms affecting at least 2 organ systems (or hypotension alone). These criteria have been prospectively validated in an ED population. Findings suggested that the criteria are likely to be useful in the ED for the diagnosis of anaphylaxis.
