Egg Allergy

Etiology

Egg allergy is IgE-mediated and healthy individuals are capable of generating antigen-specific IgE upon exposure to egg allergens.  It is believed that there may be a genetic component to the development of egg allergy as the progeny of atopic individuals are more likely to suffer from allergies themselves.  The consensus is that IgE responses are genetically controlled by MHC-linked genes that are found on chromosome six. Other components that may be associated with atopy and allergy include the IgE Fc receptor located on chromosome eleven.

Epidemiology

Estimating the prevalence of food allergies is challenging for several reasons.  Determining true IgE-mediated egg allergy is limited in patients who undergo appropriate diagnostic workups such as skin allergen testing, egg specific allergen serum IgE, or oral food challenge (addressed below under “Diagnostics”).  Individuals with a real egg allergy may not be aware of their condition if there is inadequate exposure to egg allergen, particularly in populations where egg consumption is minimal. On the other hand, patients who become symptomatic to exposure to egg proteins may attribute their condition to a supposed egg allergy when there might be no true allergy.  In these cases, there could be the presence of another allergen responsible or the patient’s symptomatology may have other plausible, non-allergy explanations (i.e., asthma, gastrointestinal distress, etc.). Another challenge is determining the true prevalence of egg allergy versus egg intolerance and an egg allergy.  Patients or their parents can easily confuse simple food intolerance with a true IgE-mediated allergic response [2].  The failure to distinguish between the two may lead to a significant number of false-positives.Hen egg allergies often present within a year of age with no distinction between either gender.  In a significant portion of patients, tolerance to hen egg allergens develops by school-age although some may only develop this tolerance only by adolescence.  As opposed to other food allergies such as tree nut, peanut, or fish, egg allergy typically resolves or improves relatively earlier in life.

Pathophysiology

The Gel-Coombs classification of hypersensitivity reactions is based on specific mediators of the allergic response. Egg allergy is IgE mediated, and so it is classified (like all food allergies) as a type one hypersensitivity reaction.

An allergic response is typically mediated by the presence of immunoglobulin E (IgE) and the process of binding of IgE to human mast cells and basophils is termed sensitization.  The IgE-immune cell binding is via the fragment crystallizable (Fc) region of the IgE immunoglobulin (Fc-epsilon-RI), composed of an alpha chain, a beta chain, and two gamma chains.  The process of sensitization prepares mast cells and basophils cells for antigen-specific activation. In the activation phase, reexposure to egg protein allergens initiates degranulation of mast cells and basophils with subsequent release of pharmacoactive mediators.  As addressed earlier, these mediators include heparin, histamine, leukocyte chemotactic factors, and leukotrienes; these mediators are responsible for the clinical manifestations of egg allergy. The degranulation process is not apoptotic; on the contrary, degranulated mast cells or basophils regenerate and are able to resume their normal cellular function once their granular contents are synthesized.  In the case of egg allergy, the cross-linking of egg protein-specific IgE on mast cells in response to egg allergen occurs in mast cells in the upper and lower GI tract. The release of chemical mediators causes smooth muscle contraction and vasodilation, leading to emesis and diarrhea. The egg protein allergens can also be absorbed into the bloodstream due to increased vascular permeability due to histamine release.  The egg proteins can interact with skin mast cells, causing atopic urticaria.

IgE is the immunoglobulin responsible for egg allergy, and the IgE responses have a TH2 dependency.  While TH2-derived cytokines promote IgE response, it is balanced by TH1-derived cytokine downregulation of IgE.  Egg allergy can result from a failure of this balance, leading to an overproduction of IL-4 by TH2 cells.

A majority of the immunogenic proteins are found in the egg white with five major allergenic components of egg white: ovomucoid (Gal d 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3), egg white lysozyme (Gal d 4), and ovomucin [3].  Although these are the major allergenic proteins, lipocalin-type prostaglandin D synthase and egg white cystatin have also been associated with IgE reactivity.  Hen egg yolk also contains allergens, the major allergen being alpha-livetin (Gal d 5). Although Gal d 2 ovalbumin is the most abundant protein in egg white, Gal d 1 ovomucoid is the considered the dominant allergen in hen egg white.Egg specific IgE molecules can be classified as either sequential epitopes or conformational epitopes, the primary difference being the spatial relation between amino acids.  Sequential epitopes have contiguous amino acid sequences while conformational epitopes contain amino acids in different regions of the protein structure. Individuals with egg allergies can tolerate cooked products containing eggs, suggesting that the allergic response is dependent on epitope configuration.  Heat-labile allergenic proteins alter their arrangement with the cooking process, thus blunting or minimizing their immunogenic potential. In particular, ovalbumin proteins are heat-labile while ovomucoid epitopes are generally not affected by extensive heating.

History and Physical

Hen egg allergy often presents in infancy and most symptoms are typically cutaneous in nature, often presenting with diffuse urticaria and angioedema.  However, gastrointestinal symptoms such as vomiting, and/or respiratory symptoms can also occur. Symptoms often present within minutes post-exposure but can sometimes be delayed to 2 hours after ingestion.  In severe cases, life-threatening anaphylaxis can occur with hen egg exposure, often requiring epinephrine administration.

Egg allergy can also present with two related disorders: eosinophilic esophagitis and food protein-induced enterocolitis syndrome (FPIES).  Eosinophilic esophagitis is an inflammatory disorder associated with the accumulation of intraepithelial eosinophils, and it is mediated by both IgE and non-IgE processes.   Egg protein is one of the more common triggering factors for the development of eosinophilic esophagitis [4].  As with other forms of esophagitis, eosinophilic esophagitis can present with dysphagia and nonspecific symptoms such as chest discomfort.  

FPIES is also an inflammatory disorder characterized by vomiting, lethargy, and diarrhea.  Typically symptomatic presentation in FPIES occurs 2 - 6 hours after ingestion of egg protein.  

As previously mentioned, dermatitis can be a presenting symptom of an allergic reaction to egg protein exposure.  This finding, however, is typically found in children less than one year of age. Atopic dermatitis onset after one year of age is not usually associated with egg allergy, and any workup should include other differentials beyond egg allergy.

Asthma has often been associated with food allergies due to the association with IgE mediated reactions.  A small cohort study involving 1218 children indicated an incidence of asthma in 80% of the children with egg allergy with a calculated odds ratio of 5.0 [5].

Evaluation

Any evaluation of suspected egg allergy should always begin with a detailed history and physical examination.  History should include dietary intake of an egg (amount, frequency per day, form.), reactions (i.e., diarrhea, rash, etc.) and the time of onset of symptoms after ingestion of egg or egg-containing product.  Family history may also provide important clues, especially if there is documented or suspected egg allergy in a parent or sibling.

Diagnostic evaluation for suspected hen egg allergy includes skin testing (in which small quantities of allergenic egg proteins are introduced subcutaneously and monitored for reaction), egg-specific serum IgE levels, and oral food challenges.  Although food diaries (a written log of everything the patient consumes) are non-diagnostic, they can be useful in identifying egg as a potential allergen. Among the diagnostics evaluations for egg allergy, the double-blinded, placebo-controlled oral food challenge is considered the gold standard for assessment and diagnosis of suspected egg allergy.  Unlike egg-specific serum IgE levels, the oral food challenge should be done under the close supervision of a trained professional for the significant possibility of anaphylaxis.

Skin testing involves the introduction of an allergen into the subcutaneous tissue.  The allergen introduction prompts the cross-linking of antigen-specific IgE to mast cells, resulting in degranulation and subsequent urticaria. The food allergens are applied with respective positive (histamine) and negative (saline) controls.  Upon introduction of the egg allergen to the skin, a reaction is observed. Mast cell degranulation occurs in the presence of egg protein IgE antibody, leading to the release of histamine. It is generally accepted that a weal of 3 mm or greater in diameter is considered a positive result. Skin testing, however, can have a higher rate of false negatives, mainly if the patient used antihistamines or Benadryl within a week before skin allergen testing. Also, skin testing should not be performed for several weeks after an episode of anaphylaxis since anaphylaxis can lead to a temporary nonreactivity of the skin, thus increasing the false-negative rates.  

Immunoassay diagnostics include radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassay (FEIA).  They are less sensitive than skin testing but are not affected by prior antihistamine use. If there is a concern for significant anaphylaxis, immunoassays can be used safely.  Test results for egg allergen serum IgE levels are measured in kUA/L units and provide important predictive levels of experiencing an allergic response to an oral food challenge.  According to [6], an egg allergen IgE levels seven kUA/L (or 2 kUA/L if children are less than two years of age) is associated with a 95 percent predictive value.  The clinical interpretation is as follows: A patient (greater than two years of age) with a concerning history of egg allergy has 95% likelihood of experiencing an allergic reaction to egg upon challenge if their egg-specific IgE levels exceed 7 kUA/L.  If a patient’s egg-specific IgE serum level exceeds this threshold, an oral food challenge may not be warranted.

Oral food challenges (especially double-blinded, placebo-controlled) are the gold standard for the diagnosis of egg allergy.  The utility of an oral food challenge depends on several factors. If an egg is not a component of a patient’s daily diet and can just be avoided, an oral food challenge may not be warranted.  In addition, if the patient has a clinical history suspicious of egg allergy coupled with elevated egg-specific IgE serum levels, the oral food challenge may be deemed unnecessary.

Open oral food challenges involve the gradual oral introduction of an egg to a patient.  Both the patient and observer are both aware of that egg is being introduced, leading to increased susceptibility to bias (especially if symptoms present).  The open oral food challenge, however, is easy to perform as it requires no special preparation. Single-blinded oral food challenges involve the oral introduction of egg in a vehicle (I.e., in another food source in opaque capsules) to blind the patient to what intervention is performed.  It eliminates patient bias but is still prone to observer bias.

Oral food challenges require adequate preparation for accurate results.  All antihistamines, beta-agonists, and beta-blockers (including eye drops) should be discontinued for a specified amount of time before an oral food challenge.  The oral food challenge should be done under the clinical supervision of a trained physician trained in treating anaphylaxis should it occur.

Treatment / Management

Avoidance of egg exposure is the most effective form of egg allergy management but is not equivalent to cure and may not always be feasible.  Unfortunately, efforts of avoiding exposure can pose a significant psychosocial stressor on both the child and the parents. Instead of being engaged in their child’s day-to-day routine, parents may find themselves more focused on scrutinizing any potential exposures.  “Egg-free” food items may be more expensive compared to their egg-containing counterparts. Children, wanting to socialize with their peers, may feel more isolated and withdrawn. Also, avoidance of eggs (or any food allergen) can place children at higher risk for nutritional deficiencies [7].  For instance, in a study comprised of two hundred and forty two children (mean age of four) in which subjects were to abstain from particular food items completely, the participants less than two years of age with the dietary restriction had lower body mass index profiles compared to their control counterparts of similar age [8].  Oral immunotherapy (OIT) involves oral administration of allergenic egg white with an edible vehicle in gradually increasing dosages.  OIT has demonstrated the success of desensitization in patients with egg allergy [9], [10]. However, it remains relatively time-consuming and often requires long term maintenance therapy.(A1)

Differential Diagnosis

Egg allergy presents with non-specific symptoms and can often be confused for general food intolerance, gastrointestinal upset, or another associated food allergy.If a patient is lactose intolerant and consumes a milk product that can contain egg product (i.e., custard, ice cream), the gastrointestinal symptoms can be falsely attributed to egg allergy although there is no exact IgE-mediated allergic reaction.  Skin manifestations (such as atopic dermatitis) can be due to contact allergies.

Prognosis

A significant majority of patients with hen egg allergy will develop tolerance to hen egg allergens by the time they reach school age.  Some, however, build tolerance only in adolescence. Prognostic factors for the development of tolerance include baseline levels of egg-specific IgE, early age of diagnosis, the severity of symptoms, skin test weal size on skin prick testing, and tolerance of extensively heated egg.  Egg specific serum IgE to IgG4 ratios may be useful for predicting tolerance [11] although it is not routinely used.  Regarding weal size, a 2013 cohort study demonstrated that a weal size of approximately 5 mm correlated to a 95% PPV for egg allergy [12].  The meta-analysis that evaluated this study indicated the benefits of performing skin allergen testing before an oral food challenge.  Although relatively nonspecific, weal size correlation with PPV could prevent children from undergoing more time consuming oral food challenges.    

Complications

An allergic response to egg allergens can range from dermatological manifestation (i.e. rashes, hives), gastrointestinal symptoms (i.e., diarrhea, nausea, vomiting) to potentially life-threatening anaphylaxis.