The prevalence of food allergies has been on the increase over the last 2 decades. Diagnosing food allergies can be complicated, as there are multiple types that have distinct clinical and immunologic features. Food allergies are broadly classified into immunoglobulin E (IgE)-mediated, non-IgE–mediated, or mixed food allergic reactions. This review focuses on the clinical manifestations of the different categories of food allergies and the different tests available to guide the clinician toward an accurate diagnosis.
Key points
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Food allergies consist of a group of diseases that result from immunologic, adverse reactions to foods.
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Clinical history is paramount in the diagnosis of food allergy.
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Skin tests and specific immunoglobulin E (IgE) can indicate sensitization that may not be clinically relevant.
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It is important to recognize and distinguish IgE-mediated reactions, as these can be life threatening and require significant patient education.
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Specialists, such as allergists/immunologists and gastroenterologists, play an important role in the diagnosis and management of food allergies.
Introduction
The prevalence of food allergies in children and adults has been increasing over the last few decades. Food allergies are due to abnormal immunologic responses following ingestion of the offending food. Multiple food allergy entities can be characterized based on the immunologic response. For the purposes of this review, the diagnosis of food allergies is divided into immunoglobulin E (IgE)-mediated reactions, non–IgE-mediated reactions, and mixed allergic reactions ( Table 1 ). The most important diagnostic tool is the clinical history, which is aided by diagnostic testing such as skin and blood tests to assess for food-specific IgE. When necessary, the diagnosis is confirmed with oral food challenges and elimination diets to assess for clinical symptoms related to the ingestion of an implicated food.
| IgE-Mediated Reactions | Mixed Allergic Reactions | Non–IgE-Mediated Reactions |
|---|---|---|
| Food ingestion reactions within 2 h of ingestion | Atopic dermatitis | Food protein–induced enteropathy |
| “Alpha Gal” allergy | Eosinophilic esophagitis | Food protein–induced enterocolitis |
| Oral allergy syndrome | Eosinophilic gastritis | Food protein–induced proctitis |
| Food-dependent exercise-induced anaphylaxis | –– | Celiac disease |
Diagnosing Immunoglobulin E–mediated food allergies
Clinical History
When the clinician suspects an IgE-mediated food allergy, the medical history and physical examination can provide a good pretest probability of an IgE-mediated allergy. It is important for the clinician to note the dietary history, foods involved at the time of the allergic event, timing of exposure to the onset of symptoms, route of exposure, nature and duration of symptoms, and treatments received ( Table 2 ). Supplemental factors, such as concomitant medication use or alcohol ingestion, may play a role in the reaction severity. Symptoms during an IgE-mediated allergic reaction can range from mild to severe, involving one or multiple organ systems ( Table 3 ). A history consistent with anaphylaxis, an immediate, severe, allergic reaction involving multiple organ systems, after the ingestion of a food is highly suggestive of an IgE-mediated food allergy. The timing and events during an allergic episode, such as the timing of exercise in food-dependent, exercise-induced anaphylaxis (FDEIAn), and the type (cooked vs raw) and amount of the suspected offending food ingested, are important parts of the history to be elicited. Comorbid conditions such as asthma, allergic rhinitis, or atopic dermatitis might indicate an increased risk of IgE-mediated food allergy.
| Offending food | Cow’s milk, egg, wheat, soy, peanut, tree nut, fish, shellfish (these 8 foods account for 90% of reactions) |
| Timing of exposure to onset of symptoms | Minutes to hours (usually within the first 2 h); however, late reactions can occur with normal foods and within 3–6 h after ingestion of red meat, such as beef, pork, and lamb in “Alpha Gal” allergy |
| Route of exposure | Oral ingestions tend to have more severe reactions; mild skin reactions occur with cutaneous exposure |
| Type of food | Oral pruritus with raw forms of fruits or vegetables, but tolerance of cooked forms, would suggest oral allergy syndrome |
| Nature of symptoms | Cutaneous, gastrointestinal, and respiratory symptoms predominate |
| Duration of symptoms | Less than 1 h to several hours; however, late reactions and biphasic reactions can occur |
| Treatment of symptoms | Responsive to antihistamines and/or epinephrine |
| Dietary history | Foods eaten before and after an allergic episode without reaction are typically not the culprit of an IgE-mediated food allergy (exception is exercise-induced anaphylaxis); note avoidance patterns |
| Supplemental factors | Alcohol consumption, NSAID use, exercise, concurrent illness |
| Cutaneous | Gastrointestinal | Respiratory |
|---|---|---|
| Erythema Pruritus Urticaria Morbilliform rash Angioedema Eczematous rash (typical of late reactions) | Nausea Abdominal pain Reflux Vomiting Diarrhea | Nasal congestion Rhinorrhea Sneezing Hoarseness Laryngeal edema Cough Chest tightness Dyspnea Wheezing Increased work of breathing |
It is important to consider and rule out, if necessary, other diseases, triggers, and syndromes that may be mistaken for IgE-mediated food allergies, which may include allergic reactions caused by:
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Medications or insect stings (possibly around the same time of food ingestion)
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Metabolic disorders: gluten and lactose intolerances and sensitivities
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Toxic reactions: food poisoning caused by toxins, such as histamine in scombroid poisoning
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Chemical exposures, such as chlorine or fragrant perfumes, which may cause rhinitis, skin irritation, or exacerbation of asthma
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Viral syndromes that may cause rhinorrhea and/or urticaria
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Reactions and sensitivities to food additives such as sulfites, nitrites, and monosodium glutamate
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Most cases of new-onset urticaria in children are infectious in origin and do not involve IgE-mediated mechanisms. In addition, most cases of chronic idiopathic urticaria are related to physical factors (cold, pressure, sun exposure, and so forth) rather than food ingestion
Food-Dependent Exercise-Induced Anaphylaxis
FDEIAn is a disorder whereby allergic symptoms occur if exercise takes place within several hours after consumption of the causative food allergen, as identified by clinical history and allergy testing. Omega-5 gliadin, a protein component of gluten, is a major protein involved in wheat allergy that causes exercise-induced anaphylaxis, although other foods have also been implicated, including egg, nuts, crustaceans, meats, fruits, and vegetables. The diagnosis of FDEIAn can be made when a patient has signs and symptoms consistent with recurrent anaphylaxis upon or soon after physical exertion, and if the food allergen was consumed within 2 to 4 hours before the allergic event. There should also be an absence of symptoms during vigorous physical activities or food allergen ingestion alone. The patient should demonstrate evidence of sensitization to the food allergen by skin-prick or in vitro (specific IgE [sIgE]) testing. When no allergen is found, a repeat test after 6 to 12 months may increase the sensitivity of identifying the culprit food allergen.
Oral Allergy Syndrome
Almost all patients with pollen-food allergy syndrome, more commonly known as oral allergy syndrome (OAS), have underlying allergic rhinoconjunctivitis caused by respiratory sensitization to airborne pollens. OAS results from IgE sensitization to aeroallergens and cross-reactive antibodies recognizing homologous epitopes in fruits (ie, Pru p 1 in peach), vegetables (ie, Api g 1 in celery), or other plant-derived, heat-labile food proteins (ie, Ara h 8 in peanut). A local IgE-mediated response leads to an immediate sensation of oropharyngeal pruritus after food contact or ingestion, which is sometimes accompanied by angioedema of the oral mucosa and abdominal discomfort. Cooking or factory processing of the food can denature the conformational integrity of the culprit proteins, resulting in significant reductions in IgE-binding avidity, which generally renders the food harmless when consumed. More severe symptoms such as vomiting, diarrhea, and anaphylaxis rarely develop, and thus would be less consistent with OAS but more concerning for systemic reactions associated with heat-stable proteins.
Skin-Prick Tests and Serum Tests
Diagnostic testing in suspected IgE-mediated food allergy should be guided by the clinical history. A positive skin-prick test (SPT) or positive sIgE test denotes sensitization and not necessarily clinically relevant allergy. Careful patient selection for testing is advised because of the potential for false-positive results, possibly resulting in unnecessary dietary restrictions. In general, the larger the SPT or sIgE, the more likely that the allergen is clinically relevant, although these tests correlate less with the severity of reactions. Although SPTs have varying positive predictive values (PPVs), they generally have a relatively high negative predictive value. Threshold values for SPTs and sIgE have been identified for some allergens to define the 95% PPV, the point at which patients are likely to react to a food challenge ( Table 4 ).
| >95% Positive Predictive Value in Children | ||
|---|---|---|
| Food | SPT (mm) | sIgE (kUA/L) |
| Egg white | ≥7 or ≥13 | ≥7 (≥2 in infants <2 y old) |
| Cow’s milk | ≥8 or ≥12.5 | ≥15 (≥5 in infants <2 y old) |
| Peanut | ≥8 | ≥14 |
| Fish | Undetermined | ≥20 |
Skin and in vitro testing with commercially available, heat-labile, and easily degradable fruit and vegetable extracts often leads to false-negative results. However, the prick-prick skin test, whereby the fruit or vegetable is pricked and then the patient’s skin is pricked, is a reliable method for confirming OAS, described in the previous section.
The ratio of sIgE to total IgE has also been examined. Some have found that it does not add additional value compared with sIgE alone, whereas others have found the ratio to be higher for those who failed their food challenge when compared with those who passed. This finding is particularly true for allergens that are less likely to be outgrown, such as peanuts, shellfish, tree nuts, and seeds.
Component-resolved diagnosis (CRD) is now more widely available to investigate IgE against smaller, relevant peptides of the larger parent protein. This approach allows for distinction between peptides that are similar to pollens and may be heat labile. Proteins that are degraded by digestion or heat are less likely to cause systemic reactions and are often implicated in OAS. In addition, nonspecific lipid transfer proteins have been implicated in allergic reactions associated with supplemental factors. Using components may aid in understanding which patients might tolerate baked egg or milk food challenges. Some clinical pearls using component testing are listed in Table 5 . Of importance is that severe reactions can still occur despite negative component testing results, as all relevant peptides have not been identified.
| Food | Components | Clinical Pearls |
|---|---|---|
| Peanut | Heat-stable: Ara h 1, 2, 3 | Higher risk of systemic reactions |
| Heat-labile: Ara h 8 (Bet v 1 homologue) | Low risk of systemic reactions | |
| Hazelnut | Heat-stable: Cor a 8, 9, 14 | Higher risk of systemic reactions |
| Heat-labile: Cor a 1 (Bet v 1 homologue) | Low risk of systemic reactions | |
| Wheat | Omega-5 gliadin Tri a 14 | Associated with wheat-dependent exercise-induced anaphylaxis |
| Meat | Galactose a 1,3 galactose “Alpha Gal” | Delayed anaphylaxis, 3–6 h after ingestion of red meat |
| Peach | Pru p 3 | Associated with food-dependent exercise-induced anaphylaxis |
| Pru p 1 (Bet v 1 homologue) | Low risk of systemic reactions | |
| Apple | Mal d 3 | Higher risk of systemic reactions |
| Mal d 1 (Bet v 1 homologue) | Low risk of systemic reactions | |
| Cow’s milk | Caseins: Bos d 8 | Casein-specific IgE <0.7 kUA/L is a very favorable prognostic factor for tolerance of baked milk |
| Whey proteins: Bos d 4 α-lactalbumin Bos d 5 β-lactoglobulin Bos d 6 serum albumin Lactoferrin | For those exclusively allergic to whey proteins, many tolerate baked milk and yogurt Bos d 6; can also be allergic to beef | |
| Egg white | Heat-stable: Gal d 1 (ovomucoid) | Higher sIgE levels to ovomucoid associated with persistent egg allergy |
| Heat-labile: Gal d 2: ovalbumin Gal d 3: ovotransferrin Gal d 4: lysozyme | Gal d 2: most abundant protein in egg white; heating may reduce allergenicity; lower ovalbumin sIgE/IgG4 ratio is associated with tolerance to heated egg Gal d 4: might be important in occupational asthma |
Oral Food Challenge
The gold standard of diagnosing an IgE-mediated food allergy is the double-blind, placebo-controlled food challenge. If this is not feasible or realistic, open challenges or single-blind challenges, whereby a placebo dose is introduced into the succession of true allergen doses, may be considered. The challenge is typically done in the office of a specialist well trained in treating allergic reactions, and consists of ingesting multiple doses of a food spaced out over time to minimize the risk of severe reactions. Patients are then observed for clinical reactions, with medications to treat allergic reactions readily available in the clinic. Oral food challenges are necessary because of the poor sensitivity and specificity of SPT and sIgE; 89% of children diagnosed with food allergy based on sIgEs were able to reintroduce foods into their diet following a challenge.
Diagnosing mixed Immunoglobulin E and non–Immunoglobulin E food reactions
Some food allergy disorders can have both IgE-mediated and cellular-mediated pathology (delayed Th2 responses). Mixed disorders typically manifest in the gastrointestinal (GI) tract and the skin. The relationship between food allergies and atopic dermatitis has been reviewed comprehensively elsewhere. This review addresses mixed food allergic GI disorders. Eosinophilic GI disorders (EGIDs) are a group of inflammatory disorders primarily classified by the presence of a high density of infiltrating eosinophils within the GI mucosal epithelium, muscularis, and serosal layers. EGIDs include eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC). EoE is one of the most studied of the EGIDs, while less is known about EC because of its rare occurrence. Healthy esophageal tissue is normally free of eosinophils, and the rest of the GI tract contains a low density of these cells. Characteristic findings for the EGIDs are outlined in Table 6 .
| Disease | Location Affected | Symptoms | Endoscopic Findings | Histology/Lab Tests |
|---|---|---|---|---|
| Eosinophilic esophagitis | Esophagus | Adults: Dysphagia, food impaction Children: Irritability, feeding difficulties, vomiting, abdominal pain, malnutrition | Ringed esophagus, strictures, linear furrows, narrow esophagus, vesicles on mucosal surface | ≥15 eosinophils per high-powered field (eos/hpf) in middle esophagus, peripheral eosinophilia |
| Eosinophilic gastritis | Stomach and duodenum, but can affect esophagus to colon | Abdominal pain, nausea, vomiting, diarrhea, weight loss, anemia, malabsorption, motility issues (affecting muscle layer), ascites (serosal layer) | Nodular gastric mucosa, erythema, erosions | ≥30 eos/hpf (no consensus), abnormal d -xylose, and increased fecal fat (in malabsorption) |
| Eosinophilic colitis | Large Intestine | Abdominal pain, bloody stools, diarrhea | Edema, patchy granularity | Eosinophilic infiltration on biopsy |
Clinical History
Eosinophilic infiltration of the GI tract can be induced by drug hypersensitivities, parasitic infections, Helicobacter pylori infections, and cancer, and it is important to rule out these conditions. In addition, gastroesophageal reflux disease (GERD) and inflammatory bowel disease can present with symptoms similar to EGIDs. Individuals who have unexplained dysphagia or food impaction, a history of atopy, peripheral eosinophilia, and a family history of EGIDs should be considered for EGID. The most characteristic symptoms seen in EoE in children is failure to thrive and malnutrition, whereas adults present with dysphagia, food impaction, and heartburn. The prevalence of EoE is approximately 50 of 100,000 inhabitants in select regions of the United States and Europe, and the condition is more common in males than females, at a ratio of 3:1. Several studies show that at least half of both children and adult populations with EoE and EG often suffer from other atopic conditions. In one study, more than 40% of 381 children with EoE had first-degree family members with atopic or food allergies.
Serum Testing
The pathogenesis of these diseases is not well understood, but epidemiologic and clinical features suggest allergic components. IgE-mediated food sensitizations and elevated total and food-specific IgEs are common among patients with EoE, although they are often not correlative with the culprit food. A cross-sectional study of 53 children with EoE showed that 80% had IgE sensitization to multiple food allergens and aeroallergens, and 32% had elevated total IgE levels. Younger EoE patients had more sensitizations to foods, whereas older patients had more sensitizations to aeroallergens. In another study, 62% of 107 patients with EGIDs (EoE or EG) had sensitizations to an average of 10.5 food allergens. However, food sensitizations detected by SPTs and atopy patch tests generally do not correlate with clinical episodes of EoE. This finding indicates that food sensitizations and elevations in IgE levels detected by conventional tests may not necessarily be able to link those foods to the pathophysiology of EGID.
Endoscopic Evaluation
Along with gross endoscopic observation, histologic studies of GI biopsies are an integral part of the diagnostic process. Four to 5 biopsies should be taken from each site, including normal and grossly abnormal appearing mucosa, as either can demonstrate eosinophilic inflammation. Classic endoscopic and histologic findings are presented in Table 6 . In the case of eosinophilic esophageal findings, one must rule out GERD (a common finding includes eosinophils in the middle and distal portions of the esophagus). A trial of a proton-pump inhibitor (PPI) is given for 6 to 8 weeks. EoE is considered if eosinophils remain in the middle esophagus, which is distinguished from PPI-responsive EoE (PPI-REE) if eosinophils remit from the mid-esophagus. It is unclear whether PPI-REE is a disease distinct from EoE. Repeat endoscopies are often necessary to assess the effectiveness of appropriate management of EoE, whether a patient is treated with topical steroids or elimination diets.
Elimination Diets
Food elimination diets have been highly effective at reversing the clinical severity of all types of EGIDs, and are thus a part of the diagnostic algorithm. A meta-analysis and systematic review of numerous studies published between 1995 and 2013 compared the efficacy of the various elimination diets in both pediatric and adult EoE patient populations. Most studies removed specific foods from the diet for a minimum of 6 weeks, followed by clinical, endoscopic, and histologic analyses. Efficacy of the diets was defined as histologic remission, denoted by a peak eosinophil count of ≤15 eosinophils per high-powered field. The summary findings of the elimination diets from this meta-analysis are presented in Table 7 .
