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Whole Allergen

f1 Egg white

f1 Egg white Scientific Information

Type:

Whole Allergen

Display Name:

Egg white

Route of Exposure:

Ingestion

Family:

Phasianidae

Species:

Gallus gallus

Latin Name:

Gallus spp.

Other Names:

Egg white

Summary

Hen’s egg (Gallus gallus domesticus) is a protein-rich food source and is usually consumed as raw, cooked, or processed. Egg white is rich in proteins and is regarded as highly allergenic. The egg has been considered one of the most common food allergy sources, particularly in infants and children. Around 0.5 – 2.5 % of young children within a normal population have been found to be allergic to eggs. However, the prevalence of egg allergy in adults is less than 0.25 %. Egg sensitization, having IgE antibodies to egg, is a prerequisite for egg allergy. Egg sensitization is more prevalent than egg allergy, and the prevalence rate has been reported to be up to 6 % depending on age. The specific IgE (sIgE) test for egg white is commonly used when investigating a patient with a suspicion of egg allergy. Most egg-allergic children can develop tolerance to egg proteins over time. A patient's highest recorded egg white sIgE is significantly related to the persistence of egg allergy. A higher egg white sIgE value denotes a more extended period to develop tolerance. Egg IgE is predictive of allergy outcome and should be used in counseling patients on prognosis.

Egg white consumption may lead to allergic symptoms, such as gastrointestinal reactions, respiratory symptoms, cutaneous reactions, and anaphylaxis among egg white allergic patients. Therefore, egg-allergic individuals are usually recommended to avoid egg and egg-based food products strictly.

Moreover, egg allergy children are often falsely denied influenza or MMR vaccination as the vaccine might contain a small amount of egg protein. However, several studies and guidelines have claimed these vaccines to be safe for children with egg allergies.

An oral food challenge is considered to be the gold standard for diagnosing egg allergy. Egg sIgE testing can aid in diagnosing egg allergy, indicate when an egg challenge is safe to perform, and is predictive of egg allergy outcome. This means that the egg white test could be utilized in counseling patients on prognosis. Furthermore, egg allergy or egg white sensitization has been found to elevate the risk of developing sensitization to aeroallergens (such as grass pollens, house dust mites, cats, and dogs).

Early introduction of egg into the infants’ diet has been found to be beneficial in developing tolerance to the egg; it is presently studied as a means of primary prevention of egg allergy. Additionally, oral immunotherapy (for egg) is also performed in some countries on egg-allergic patients who fail to develop natural tolerance to the egg.

 

 

Allergens

Nature

Egg (Gallus gallus) is a food product with substantial nutritional content, suitable for all ages. Egg white is rich in proteins, mainly composed of water and lacks lipids (1). The egg is reported to contain both macro and micronutrients required for embryonic development (1).

Egg white of chicken (Gallus domesticus) constitutes the albumin portion present in the egg (2). It primarily contains water (approximately 88%) and more than 20 glycoproteins (like ovalbumin), fibrous structural proteins (ovomucins), antibacterial proteins (lysozyme), and peptides (1, 3). Egg white is regarded as the principal source of allergen; the egg white proteins are potentially more allergenic compared to protein derived from egg yolk (4-6). The major allergens found in egg white include ovomucoid (Gal d 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3), and lysozyme (Gal d 4) (4, 7). Globally, eggs have been extensively utilized in food products like bread, egg noodles, pancakes, waffles, cakes, French toast, tea-boiled egg, and others (8).

Nature

 

Hen’s eggs are regarded as fresh up to 28 days post laying. Room temperature or preferably refrigeration is considered ideal for the storage of shelled eggs. Variation in egg storage condition and duration can induce physiochemical changes and further protein denaturation. These changes are manifested due to the exchange of water between egg white and yolk and the loss of carbon dioxide and water through eggshells' pores. This further results in the rise of air cells between the two membranes of the eggshell. Moreover, with storage duration, the albumen height reduces, whereas the whipping volume and pH of albumen surge. (1).

Taxonomy

Gallus domesticus (hen’s egg) belongs to the family Phasianidae (chicken) (9). A study confirmed high cross-reactivity between hen’s egg white with egg white from turkey, duck, and goose belonging to the order Anseriformes (10). 

Taxonomic tree of Hen’s Egg (9)
Domain Eukaryota
Kingdom Animalia
Phylum Chordata
Subphylum Vertebtata
Class Aves
Order Galliformes
Family Phasianidae
Subfamily Phasianinae
Genus Gallus
Species Gallus gallus
Sub-species Gallus gallus domesticus
Taxonomic tree of Hen’s Egg (9)

Tissue

The average protein concentration of a whole egg is found to be 12.5g/100g of a raw fresh egg, while the average protein concentration of egg white (including vitelline membrane) might be 10.9g/100g of a raw fresh egg. The mean egg white volume has been estimated to be around 30ml (egg of 60-gram weight, including eggshell) (1). Egg white is primarily composed of protein (11%), water (88%), trace amounts of carbohydrates, ash, and lipids (1% in total). Further, the proteins present in egg white are categorized as major and minor proteins (11). The major protein comprises of ovalbumin (54%), ovotransferrin (12%),  ovomucoid (11%), and lysozyme (3.4%) (2, 12) .While, the minor proteins include ovoinhibitor (1.5%), ovoglycoprotein (1%), ovoflavoprotein (0.8%), ovomacroglobulin (0.5%), cystatin (0.05%) and avidin (0.05%) (11).

During the cooking process, the proteins in egg white have been found to usually lose their allergenicity due to conformational modifications (epitope destruction or epitope blocking) leading to protein denaturation (3, 13). This process of protein denaturation may lead to the inactivation of antinutritional factors like antiprotease from egg-white and other highly resistant proteins in eggs (1). 

Epidemiology

Worldwide distribution

The egg has been reported as one of the common inducers of food allergy prevalent in industrialized countries (14). According to a study, around 0.5-2.5% of young children have been observed to be affected with egg allergy (15, 16). A high prevalence of childhood egg allergy has been reported in Japan and France (4). According to a study conducted in Japan among 24 egg white allergic patients, 92% showed reactivity towards the egg white allergen (Gal d 1, ovomucoid) (17). An Italy-based study involving 104 suspected egg-allergic patients (0.7-15.1 years) reported 43.5% (20/46), 52.1% (24/46), and 36.9% (17/46) of patients to exhibit allergenicity towards Gal d 1, Gal d 2, and Gal d 4, respectively (18). Furthermore, a US-based cohort study also detected the prevalence of egg allergy to be approximately <0.25% (from graphical representation) in 4425 adults (20-60+ years) (19).

Sensitization to the egg white means that IgE antibodies are produced towards the egg white and is a prerequisite for an IgE-mediated egg allergy. Egg white sensitization is more prevalent than egg allergy, and IgE antibodies have been detected already in very young age groups. Tedner et al. found in a Nordic population-based birth-cohort study the prevalence of egg white sensitization among 3-month old infants to be 3.7% (41/1102)  (20). A German-based population study conducted on 14,836 children and adolescents (3-17 years) found the overall sensitization rate towards egg white was 5% (21). Moreover, a Japan-based cohort study found 0.8% of the children (at 9 years) to be sensitized towards egg white protein (Gal d 1) (22). A Taiwanese study on 2256 allergic children (0.1-17.6 years) detected the positive sensitization rate for egg white was highest  (53.5%) among children of age 2-4 years (12). Besides, egg white sensitization among the adult population has been reported in few studies. A European cohort study found an overall prevalence of egg white sensitization to be 0.4% among the adult (20-39 years) population (23). Furthermore, a US-based cohort study reported the prevalence of egg white sensitization in the adult population ranging between 2.1% to 3.9% among 4425 adults (20-60+ years) (19).

The natural history of egg white allergy

Food allergy during childhood could be a transitory condition, although it can be a persistent one in some cases. Hen’s egg has been reported to be one of the frequent food allergens affecting children during the first 10 years of life  (24). Egg allergy has been claimed to get resolved naturally with aging (2-6 years)  (5, 25). A study conducted on 226 egg allergic children (<6 years) reported tolerance development in 30% (66/226) of children by the age of 3 years, while in 73% (164/226) of children by 6 years (26). Savage et al. examined the relationship between the peak egg white IgE level and the development of tolerance while studying the natural history of egg allergy. The tolerance development rate was found to be inversely proportional to the peak level of egg IgE (P < 0.0001). The fastest rate of tolerance development was found in children with a peak egg IgE <2 kU/L, whereas tolerance development rate was slower in children with peak IgE between 2 and 49.9. Nonetheless, the majority of the children with the peak IgE ranging between 2 to 49.9 kU/L developed tolerance towards egg subsequently. The tolerance rate was slowest among children with peak egg IgE ≥50 kU/L. These children mostly developed tolerance, not before 18 years (the end of the study period). For instance, the tolerance development among the study population was found to be 46% (peak egg IgE <2 kU/L), 32% (peak IgE 2 to.4.9 kU/L), 17% (IgE peak level between 5 to 9.9 kU/L), 16% (peak level of 10 to 19.9 kU/L), 14% (peak IgE 20 to 49.9 kU/L), and 11% (peak sIgE level ≥50 kU/L) by 8 years of age. The authors concluded egg IgE to be a predictor of the outcome of allergy and, therefore, should be utilized in patients’ counselling on prognosis(27).

Moreover, according to some studies, the majority of the egg-allergic children showing reactions to lightly cooked regular egg preparations (scrambled eggs or French toast) were found to be tolerant towards baked egg products (muffin, waffle, cakes, etc.) (28-30). This tolerance towards baked egg products was indicative of the immunological shift towards the development of tolerance for regular eggs (28).  

Risk factors

Egg allergy is associated with atopic dermatitis (AD), asthma, rhinitis, and other food allergies (such as peanut) (2, 4, 12, 15). Clinical allergy towards eggs has been found to be associated with risk factors like male gender, young age, ethnicity/race (19), and family history (31). Moreover, the presence of specific IgE (sIgE) towards all four egg allergens (Gal d 1, 2, 3, or 5) has been reported to elevate the risk of developing persistent raw egg allergy (32).

Children with egg allergy are often denied influenza vaccination because the vaccine contains a small amount of egg protein. However, recent studies have demonstrated that children with even severe egg allergy can safely receive the vaccine. Therefore, based on this outcome, the current guidelines recommend routine immunization (influenza vaccination) of such egg-allergic patients without undergoing any testing or special considerations  (33). Moreover, as per the recommendations of vaccination-specific guidelines, the influenza vaccine can be received under usual clinical settings (34). A study conducted on egg-allergic patients immunized with live attenuated influenza vaccine reported no systemic reactions (allergic) or anaphylaxis among these patients post-immunization (35).

National Advisory Committee on Immunization (NACI) has deemed patients with egg allergy suitable for receiving the Measles Mumps Rubella (MMR) vaccination. According to this guideline, the immunization may be administered without prior testing but under proper guidance and adequate facility (36).

Pediatric issues

A significant correlation exists between sensitization towards outdoor/indoor aeroallergens (like grass pollens, house dust mites, cat, dog) and egg allergy during infancy (6, 37). Additionally, the coexistence of egg allergy and eczema at infancy has also been reported as a predictive indicator of aeroallergen sensitization and respiratory allergies among children (4 years) (37).

Environmental Characteristics

Worldwide distribution

Hen’s egg is consumed globally in various forms like raw, semi-cooked (poached or soft-boiled eggs) (1), completely cooked (hard-boiled, scrambled, baked, or fried) (38) or as an additive in products like bread, waffles, cakes and others (8). Additionally, eggs are also utilized in the cosmetic, pharmaceutical (especially vaccine preparation), and beverage refining (wine and beer) industry (38).

Route of Exposure

Main

The route of exposure is through consumption of egg-white(39). 

Clinical Relevance

Egg allergy has been claimed as one of the most frequent food allergies prevalent in children (6). Egg white consumption may lead to allergic symptoms, such as gastrointestinal (GI) reactions, respiratory symptoms, cutaneous reactions, and anaphylaxis in individuals allergic to egg white (40-42).

Anaphylaxis

An elevated egg white sIgE level has been reported to be correlated with anaphylaxis (43). As per a study, serum sIgE level towards egg white has been found to be higher (84.8%; 28/33) in patients with a history of anaphylaxis post-consumption of egg or egg derivatives (44). An OFC study on 374 egg white-allergic patients reported anaphylaxis among 2% (8/374) of the patients (40). Moreover, a Japanese study reported anaphylaxis in 8% (3/38) of the patients allergic to both heated and raw egg white (42).

Gastrointestinal (GI) reactions 

GI symptoms are mostly seen as immediate hypersensitivity reactions in egg-allergic individuals (6). As per an OFC study, 9% (34 out of 374) of egg white-allergic children exhibited GI reactions (40). In another OFC study, 84% (104/124) of patients (egg-sensitized; 1-19 years) showing positive response towards heated egg white challenge reported GI symptoms (41).

Skin reactions and Atopic dermatitis

Cutaneous reactions due to egg white allergy usually include urticaria, erythema, angioedema, and oral allergy syndrome (OAS). In an OFC study (with cooked and raw egg white), 95% (37/39) of children with positive challenge showed cutaneous reactions such as urticaria (28/37), erythema (4/37), OAS (4/37), and angioedema (2/37) (45). Another OFC study (with egg white) found cutaneous reactions in 98% (368/374) of egg-white allergic patients (40). Additionally, as per an OFC study, 41% (51/124) and 48% (59/124) of patients (egg-sensitized; 1-19 years) showing positive response towards heated egg white challenge reported skin symptoms and OAS, respectively (41).

Children with AD have been commonly found to show sensitization towards hen’s egg (41). A study reported AD in 87% (33/38) of the patients allergic to both heated and raw egg white (42).

Diagnostics Sensitization

Challenge test

Oral food challenge is considered the gold standard for diagnosing egg allergy. However, this diagnosis mode is often regarded as time extensive, resource-consuming, and potentially risky (5, 18, 44). 

In-vitro diagnostics

Egg white sIgE testing is used as an aid in diagnosing egg allergy and to monitor the disease development. The sIgE diagnostic values have been reported to be beneficial for physicians in deciding the necessity of an egg challenge while estimating its potential risk on the patients’ health. Furthermore, an age-specific correlation has been observed between egg sIgE levels and OFC outcome; younger children usually exhibit reactivity to even at low egg sIgE levels in contrast to the older children (40). Therefore, periodic monitoring of the absolute values of egg specific-IgE antibody level combined with a clinical history of egg allergy and physical examination can accurately help diagnose egg allergy as well as indicate when an egg challenge should be performed (2, 5, 13, 47). A prospective study conducted on 81 children (<2years; suspected of egg allergy) diagnosed (utilizing cooked and raw egg white) egg allergy among 79% (56/81) of these children, and egg white sIgE testing has been reported to show high diagnostic efficacy (45).   

Prevention and Therapy

Prevention strategies

Complete avoidance of egg and egg-based products from the diet is the recommended treatment for egg allergy (2, 39, 48); however, this could be challenging as egg is a common ingredient of many food and accidental intake of egg or egg-based products are usually quite common (5, 48).  

Patients allergic to heat-labile egg protein (like ovalbumin) might be tolerant towards cooked, boiled, or fried form of eggs (39). Hence, differential avoidance is typically recommended for egg-allergic patients based on their reactivity towards raw or cooked eggs.  Here, component resolved diagnosis (CRD) with egg components can be helpful in giving personalized avoidance advice. Moreover, reactivity towards raw or slightly cooked eggs has been found to be more prevalent compared to extensively processed egg-based food (42).

Early introduction of eggs into the diet has been found to be potentially beneficial in the prevention of egg allergy (14).  In a study conducted on 231 infants allergic to egg, early introduction of egg (4-6 months age) was found to be correlated with a reduced risk of egg allergy. In contrast, late introduction of an egg-based diet (at 10 months) might increase the risk of developing egg allergy (49). In general, guidelines recommend the necessity of more studies before early introduction of egg into the diet of an infant.

Allergen immunotherapy

Currently, allergen immunotherapy has been attempted to treat egg-allergic patients in addition to induction of oral tolerance (48). A study was conducted on 30 egg-allergic children (≥4 years) to estimate the efficacy of oral immunotherapy (OIT)-egg desensitization and evaluate the maintenance of tolerance. All the patients (n=16) attained desensitization towards egg after 4 months of therapy, while 31% were reported to retain tolerance towards egg even after 3 months of avoiding egg consumption  (50). 

Molecular Aspects

Allergenic molecules

Egg white possesses 23 distinct proteins and is considered a vital allergen source from egg (4, 7, 51).

However, only four allergenic proteins (listed below in the table) from egg-white of G. domesticus (i.e., Hen’s egg) have been officially recognized in the IUIS database (52). 

Allergen 

Biochemical Name 

Molecular Weight 

Allergenicity 

Gal d 1

Ovomucoid

28 kDa

·        Gal d 1 is a strongly allergenic, heat-resistant protein (53) [p169] and contributes 11% of protein content in egg white (54).

·       According to an OFC study, 43.5% (20/46) of the patients (0.7-15.1 years) exhibited sIgE reactivity towards Gal d 1 (18)

Gal d 2

Ovalbumin

44 kDa

·       Gal d 2 is heat-unstable and therefore bears the risk of manifesting clinical reactivity towards the raw or slightly heated egg (53) [p169]; it contributes 54% of protein content in egg white (54).

·       According to an OFC study, 52.1% (24/46) of the patients (0.7-15.1 years) exhibited sIgE reactivity towards Gal d 2 (18).

Gal d 3

Ovotransferrin

78 kDa

·       • Gal d 3 is thermo-labile and can manifest the risk of clinical reactivity towards raw or slightly heated egg (53)[p169]; it contributes 12% of the protein content in egg white (54).

·       According to an OFC study, 13.0% (6/46) of the patients (0.7-15.1 years) exhibited sIgE reactivity towards Gal d 3 (18).

Gal d 4

Lysozyme C

14 kDa

·       Gal d 4 contributes 3% of protein content in egg white (54).

·       According to an OFC study, 36.9% (17/46) of the patients (0.7-15.1 years) exhibited sIgE reactivity towards Gal d 4 (18).

Allergen 

Biochemical Name 

Molecular Weight 

Allergenicity 

IgE: Immunoglobulin E, kDa: kilodaltons, EA: Egg Allergy, ES: Egg-sensitized

Apart from the above-mentioned egg-white allergens, ovomucin (165 kDa; containing a trypsin inhibitor-like domain), a heavily glycosylated protein with strong antiviral activity (53) [p169] and ovoinhibitor (belonging to Kazal protease inhibitor family) are also reported to be present in egg white (55). 

Biomarkers of severity

As per a study, the best diagnostic biomarkers for raw and cooked egg allergy are distinct. Studies have found ovomucoid (Gal d 1) sIgE as a superior biomarker for cooked egg allergy  (51, 56-59). Additionally, ovalbumin (Gal d 2) is considered the best marker for diagnosing raw and cooked egg allergy (56). 

Cross-reactivity

A study reported cross-reactivity of the majority of allergens found in hen’s egg white with egg white proteins from turkey, duck, goose, and seagull (10). Moreover, egg white protein (Gal d 1) has been found to exhibit cross-reactivity with proteins present in egg yolk (Gal d 5 and Gal d 6) (57).

Furthermore, an immunoreactive allergen (66 kDa) isolated from the bird’s nest is claimed to be homologous with ovoinhibitor protein found in hen’s egg white, resulting in cross-reactivity between the two allergenic proteins (60). Additionally, livetin (allergenic protein) mediated cross-reactivity between hen’s egg proteins and bird dander has also been reported (61).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr Magnus Borres

 

Last reviewed: November  2021

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