Egg allergy: Clinical features and diagnosis

INTRODUCTION — Hen's egg allergy is the second most common food allergy in infants and young children (cow's milk is the most common) [1]. Egg allergies are immunologic responses to proteins in foods and include immunoglobulin E (IgE) antibody-mediated allergy as well as other allergic syndromes such as atopic dermatitis and eosinophilic esophagitis (EoE) [2]. (See "Role of allergy in atopic dermatitis (eczema)" and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

The epidemiology, pathogenesis, clinical features, and diagnosis of egg allergy are presented in this topic review. Management of egg allergy is discussed separately. General discussions of food allergy are presented separately in appropriate topic reviews. The options for administration of the influenza vaccine in patients with egg allergy are also discussed separately. (See "Egg allergy: Management" and "Influenza vaccination in persons with egg allergy".)

EPIDEMIOLOGY — The prevalence of hen's egg allergy confirmed by oral challenge was 1.6 percent of children three years of age in an unselected population in Denmark [3]. A subsequent meta-analysis of the prevalence of food allergy estimated that egg allergy affects 0.5 to 2.5 percent of young children [1]. There were several limitations to the meta-analysis. There was significant variability in study design that made direct comparisons difficult. The majority of studies included in the meta-analysis were based upon self-reports of food allergy, which tend to overestimate the prevalence. Some studies used skin prick test and food-specific IgE levels to confirm sensitization to the allergen, but not all diagnoses were challenge proven. The form of egg used in challenges also contributes to the variability in egg allergy prevalence. An Australian population-based cohort study challenged children using raw egg white and reported an egg allergy prevalence of 9.5 percent (95% CI 8.7-10.3 percent) at one year and 1.2 percent (95% CI 0.9-1.6 percent) at four years [4]. Challenge-proven egg allergy in South African toddlers (12 to 36 months) was 1.9 percent (95% CI 1.1-2.7) for raw egg white and 0.8 percent (95% CI 0.3-2.3) for cooked egg [5]. New-onset egg allergy in adults is rare and is limited to case reports [6]. (See "Oral food challenges for diagnosis and management of food allergies".)

PATHOGENESIS — Five major allergenic proteins from the egg of the domestic chicken (Gallus domesticus) have been identified that are responsible for IgE-mediated reactions; these are designated Gal d 1 to 5 [7]. Most of the allergenic hen's egg proteins are found in egg white, including ovomucoid (Gal d 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3), lysozyme (Gal d 4), and ovomucin. Ovomucoid is the dominant allergen in egg (ie, is the allergen to which the most patients are sensitized), although ovalbumin is the most abundant protein comprising egg white. Two additional proteins, lipocalin-type prostaglandin D synthase and egg white cystatin, that have IgE reactivity in individuals with egg allergy have been identified [8]. Chicken serum albumin, or alpha-livetin (Gal d 5), is the major allergen in egg yolk and is involved in the bird-egg syndrome [9]. (See "Pathogenesis of food allergy" and "Molecular features of food allergens" and "Food allergens: Clinical aspects of cross-reactivity".)

Egg-specific IgE molecules that identify sequential or conformational epitopes can distinguish different clinical phenotypes of egg allergy. Sequential epitopes are determined by contiguous amino acids, whereas conformational epitopes contain amino acids from different regions of the protein that are in close proximity due to the folding of the protein. Conformational epitopes can be destroyed by heating or partial hydrolysis, which alter the tertiary structure of the protein.

Studies have found that the majority of egg-allergic individuals can tolerate extensively heated or baked egg [10-14]. Heating denatures proteins, thus eliminating conformational epitopes. In addition, results from a murine study suggest that heating may reduce allergenicity of ovalbumin and ovomucoid by altering digestion and absorption of these proteins in the gastrointestinal tract [15]. Ovalbumin epitopes are heat labile, but ovomucoid epitopes are not altered by extensive heating, suggesting that children who have specific IgE primarily to ovalbumin are likely to tolerate heated forms of egg [16]. (See "Molecular features of food allergens".)

Breakdown of proteins by gastric enzymes and the low pH of the stomach can alter the allergenicity of food proteins. Gastric digestion has been demonstrated to reduce the allergenicity of ovomucoid [17], which can explain why some patients have skin contact reactions to egg but not ingestion reactions [18].

The pathogenesis of non-IgE-mediated egg allergy is less clear. Egg allergy has been implicated as a trigger for atopic dermatitis and eosinophilic esophagitis (EoE). Egg is also a common trigger for food protein-induced enterocolitis syndrome (FPIES). Enteropathy induced by egg is rare. (See 'Mixed and non-IgE-mediated reactions' below and "Role of allergy in atopic dermatitis (eczema)" and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

CLINICAL FEATURES

IgE-mediated reactions — IgE-mediated allergic reactions are the most common type of allergic reactions to hen's egg. IgE-mediated reactions are rapid in onset (usually within minutes to two hours after ingestion), and symptoms such as urticaria, angioedema, respiratory symptoms, and laryngeal edema are common (table 1). The severity of symptoms can range from mild to life-threatening anaphylaxis. The clinical features of IgE-mediated reactions are discussed in more detail elsewhere. (See "Clinical manifestations of food allergy: An overview".)

Children can demonstrate symptoms of egg allergy starting in infancy, with most suffering from cutaneous symptoms. The development of sensitization in these patients is postulated to occur in utero [19] or via exposure to maternal breast milk [20]. For some children, the first known direct ingestion of egg can result in an allergic reaction [21], supporting the idea that sensitization can occur early through the mother. Mouse models suggest that sensitization may also occur via epicutaneous exposure (prior to gut mucosa exposure) and may play a role in the development of atopic dermatitis and asthma [22,23].

Although cutaneous symptoms are most common, gastrointestinal and respiratory symptoms are reported as well. The severity of reactions can be unpredictable and vary from episode to episode. Egg allergy is potentially life threatening. Anaphylaxis can occur with exposure to egg, and individuals with asthma, in particular, are at high risk for severe allergic reactions [24-26]. Egg accounted for 7 percent of severe anaphylactic reactions in infants and children in a German survey [27]. Fatal reactions to egg are rare but have been reported [28]. (See "Food-induced anaphylaxis" and "Anaphylaxis in infants".)

Egg allergy is associated with other IgE-mediated allergies:

●Occupational asthma is reported in bakery workers who are frequently exposed to aerosolized egg and in people who work in egg-processing factories [29-31]. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors" and "Respiratory manifestations of food allergy".)

●Bird-egg syndrome is a condition where the primary sensitization is to airborne bird allergens and there is secondary sensitization or crossreactivity with albumin in egg yolk (Gal d 5). These patients experience respiratory symptoms (rhinitis and/or asthma) with bird exposure and allergic symptoms with egg ingestion [9].

●Food-dependent, exercise-induced anaphylaxis with egg as the trigger has been reported. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

Mixed and non-IgE-mediated reactions — Egg can trigger non-IgE-mediated and mixed IgE and non-IgE-mediated reactions. Disorders that fall into these categories include atopic dermatitis and the eosinophilic gastroenteropathies.

Atopic dermatitis — Egg allergy can present as infantile atopic dermatitis (eczema). A close association was found between early-onset, moderate-to-severe eczema and egg sensitization in an international, multicenter study of children with atopic dermatitis [2]. In contrast, eczema onset after 12 months of age was not associated with food allergy. However, sensitization is not equivalent to clinical allergy. A small, randomized trial of egg avoidance in children with egg sensitization and atopic dermatitis demonstrated that egg elimination decreases the extent and severity of eczema, indicating that egg sensitization was clinically relevant in these patients [32]. (See "Role of allergy in atopic dermatitis (eczema)".)

The incidence of asthma was 80 percent in a small cohort of children with both egg allergy and atopic dermatitis [33]. If such patients develop asthma, they are at increased risk for more severe allergic reactions to foods.

Some children with atopic dermatitis experience delayed flares one to two days after ingesting egg. These delayed reactions are not IgE mediated but instead are likely due to T cell-mediated mechanisms [34]. Elimination of egg from the diet in these patients leads to improvement of skin symptoms.

Gastrointestinal reactions — Eosinophilic esophagitis (EoE) is an inflammatory disorder characterized by high numbers of intraepithelial eosinophils in the esophagus and is mediated by mixed IgE and non-IgE-mediated processes [35-37]. In a series of over 500 patients diagnosed with EoE, egg was found to be the second most common allergen triggering symptoms, confirmed on endoscopy after allergy testing (prick skin testing and patch testing) [38]. Elimination of food triggers has been found to be an effective treatment for EoE. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Future diagnostic tools for food allergy", section on 'Atopy patch testing'.)

Egg has also been implicated in food protein-induced enterocolitis syndrome (FPIES). FPIES is typically characterized by profuse, repetitive vomiting within one to four hours and diarrhea within two to ten hours of ingestion of a triggering food [39]. Additional common features include pallor and lethargy. In one US cohort, egg was identified to be the trigger in 11 percent of children with FPIES [40]. FPIES due to egg allergy was also reported in an adult [41]. FPIES is presented in greater detail separately. (See "Food protein-induced enterocolitis syndrome (FPIES)".)

Food protein-induced enteropathy due to egg has been reported [42]. A five-month-old boy developed protein-losing enteropathy and resultant hypogammaglobulinemia due to egg exposure through maternal breast milk. Maternal elimination of egg led to resolution of symptoms, and reintroduction of egg into the maternal diet caused recurrence of symptoms. (See "Food protein-induced allergic proctocolitis of infancy".)

Natural course — Tolerance is achieved by the majority of children with egg allergy. A multicenter, observational cohort study found that almost 50 percent of children with egg allergy had become tolerant to egg at six years of age [43]. However, another study suggested that egg allergy is more persistent, with children outgrowing egg allergy in adolescence (68 percent by 16 years of age) [44]. Whether these differing results are due to population differences or a change in the natural history of egg allergy is unclear. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

Several prognostic indicators for the development of tolerance to egg have been identified. These include lower baseline level of egg-specific IgE [43], lower levels of ovomucoid- and ovalbumin-specific IgE [45-47], faster rate of decline of egg-specific IgE level over time [48], earlier age at diagnosis [48], milder symptoms (isolated urticaria/angioedema) at initial presentation [43], smaller skin test wheal sizes [49], and tolerance to extensively heated egg [12,50,51].

DIAGNOSIS — A general discussion of the diagnosis of food allergy is presented elsewhere. A summary of this information, with a focus on those aspects that are most relevant to the diagnosis of hen's egg allergy, is provided below. (See "History and physical examination in the patient with possible food allergy" and "Diagnostic evaluation of IgE-mediated food allergy".)

With the exception of in vitro immunoassays for specific IgE, other diagnostic allergy procedures, including skin testing and food challenges, should be performed by allergy specialists with training in the management of serious allergic reactions. (See "Overview of skin testing for IgE-mediated allergic disease" and "Oral food challenges for diagnosis and management of food allergies".)

IgE-mediated reactions — The history of an immediate reaction consisting of typical allergic symptoms, supported by positive tests for specific immunoglobulin E (IgE) antibodies, is sufficient to establish the diagnosis for suspected IgE-mediated reactions. Either skin prick tests or in vitro tests for IgE are usually performed initially. (See "History and physical examination in the patient with possible food allergy" and "Overview of in vitro allergy tests" and "Diagnostic evaluation of IgE-mediated food allergy".)

Double-blind, placebo-controlled oral food challenges (DBPCFCs) are the gold standard for the diagnosis of food allergy. A clinician-supervised oral food challenge is required if the history and/or IgE test results do not clearly indicate an allergy. The use of challenges in the diagnosis of food allergy is presented separately. (See "Oral food challenges for diagnosis and management of food allergies".)

The skin prick test wheal size and level of specific IgE correlate with the likelihood of an allergic reaction.

●Studies using the ImmunoCAP have demonstrated that an IgE level of 7 kUA/L to egg has a 95 percent positive predictive value (PPV) for clinical reactivity to egg for children over two years of age; for children two years or under, a level of 2 kUA/L has a 95 percent PPV [52-55].

●Similar analyses have been performed for skin testing. A wheal size of 7 mm has a 95 percent PPV for children over two years of age. For children two years or under, a cohort study found that a 5 mm wheal has a 95 percent PPV for egg allergy, and a population-based study found that a wheal of 4 mm has 95 percent PPV for egg allergy [55,56].

Children with skin prick or IgE results above these levels have at least a 95 percent chance of experiencing an allergic reaction with ingestion of egg; therefore, they are presumed to be clinically reactive, and oral food challenges are avoided in these cases.

Skin test results may help guide the decision to challenge or continue avoidance in children with low serum egg-white-specific IgE. In one retrospective series, children who passed an egg challenge had a median skin prick test wheal of 3 mm compared with a median wheal of 5 mm in children who failed the challenge, although there was significant overlap between the two groups [57].

Both skin prick testing and measurement of specific IgE levels also have high negative predictive values [58]. Predictive values are much more dependent upon the population prevalence of the disease than sensitivity and specificity. Thus, these results may not apply to other populations, such as adults. (See "Glossary of common biostatistical and epidemiological terms", section on 'Predictive values'.)

Although these tests provide an indication of likelihood of clinical reactivity to egg, neither is able to predict the severity of allergic reactions that may occur with each individual nor the natural history of the allergy. However, the rate of decline of specific IgE levels over time is a prognostic indicator for the development of tolerance [48].

Asthma — The diagnosis of suspected occupational asthma due to egg allergy, which is also IgE mediated, involves skin prick testing, pulmonary function testing, and possible bronchoprovocation challenge. Occupational asthma is discussed in more detail separately. (See 'IgE-mediated reactions' above and "Occupational asthma: Clinical features, evaluation, and diagnosis".)

Other reactions — IgE tests are expected to be negative if the symptoms do not suggest an IgE-mediated reaction, such as some cases of atopic dermatitis or allergic gastrointestinal disorders. Atopy patch testing may provide additional information in these cases. (See 'Mixed and non-IgE-mediated reactions' above and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Role of allergy in atopic dermatitis (eczema)" and "Food protein-induced allergic proctocolitis of infancy" and "Future diagnostic tools for food allergy", section on 'Atopy patch testing'.)

Diagnostic pitfalls — The presence of undetectable IgE levels to egg (<0.35 kUA/L) does not exclude clinical reactivity to egg [53,59]. The rate of positive food challenges to egg in those with egg white-specific IgE levels <0.35 kUA/L ranges from approximately 10 to 33 percent.

DIFFERENTIAL DIAGNOSIS — Gastrointestinal symptoms, such as vomiting and diarrhea, occurring after ingestion of undercooked hen's egg can be due to food poisoning, such as Salmonella or Campylobacter infection, rather than allergy. Onset of symptoms is 8 to 72 hours after exposure, unlike food allergy reactions that usually occur within minutes to a few hours. (See "Causes of acute infectious diarrhea and other foodborne illnesses in resource-abundant settings".)

Allergies to foods other than egg should also be considered in the differential diagnosis. (See "History and physical examination in the patient with possible food allergy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Food allergy symptoms and diagnosis (Beyond the Basics)" and "Patient education: Food allergen avoidance (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Hen's egg is one of the most common food allergens in childhood. (See 'Introduction' above and 'Epidemiology' above.)

●Natural history – Most patients outgrow their egg allergy by adolescence. (See 'Natural course' above and "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

●Allergenic egg proteins – Five major allergenic proteins in egg are responsible for immunoglobulin E (IgE) mediated reactions. Ovomucoid (Gal d 1) is the dominant allergen in egg white. (See 'Pathogenesis' above.)

●Clinical features – Manifestations of IgE-mediated egg allergy include urticaria/angioedema/anaphylaxis, atopic dermatitis, and occupational asthma. IgE-mediated egg allergy can be severe, but most children tend to outgrow this allergy. There are also mixed or non-IgE-mediated forms of allergy that present with delayed skin or gastrointestinal reactions. (See 'Clinical features' above.)

●Diagnosis – Diagnosis of IgE-mediated egg allergy is based upon a careful history supported by skin prick tests and in vitro tests for egg-specific IgE. Diagnostic food-specific IgE levels and skin test wheal sizes have been defined from limited studies in children, above which there is a greater than 95 percent likelihood of clinical reactivity to egg. An oral food challenge is warranted if the diagnosis of egg allergy is uncertain. (See 'Diagnosis' above.)