Update on oral immunotherapy for egg allergy

ABSTRACT

Oral immunotherapy (OIT) is an emerging treatment of IgE-mediated egg allergy. In the past decade, a multitude of studies have assessed the potential for egg OIT to induce clinical desensitization. The following review will evaluate the efficacy and safety of this therapy as determined by randomized controlled, non-randomized controlled and uncontrolled trials. Recent studies using reduced allergenic egg products and anti-IgE assisted therapy to improve egg OIT safety will also be discussed. Recent advances in the mechanisms underlying food OIT suggest that certain immune parameters may be helpful in monitoring response to therapy, including egg OIT. Although, egg OIT is consistently shown to be effective with regards to clinical desensitization, fewer studies have looked at persistent tolerance or sustained unresponsiveness. Limited results of long-term follow-up trials suggest that this therapy may have disease-modifying effects. In general, the comparison of studies is complicated by major differences in study designs, OIT protocols and endpoints.

KEYWORDS:

• desensitization
• egg allergy
• food allergy
• OIT
• oral immunotherapy
• ovalbumin
• tolerance
• treatment

Introduction

Egg allergy represents one of the most common food allergies encountered in pediatric practice, with an estimated prevalence of 0.5 to 2% in infants and young children. ¹ Egg allergy is a particularly debilitating allergy, which has an important impact on quality of life. ² Patients and family have to avoid many types of foods and live with the fear of accidental reactions. Egg allergy is also an indicator of future development of asthma ³ and sensitization to aeroallergens. ⁴

The persistence of egg allergy directly correlates with baseline levels of specific IgE, ^5,6 with some cohorts reporting long-term resolution rates as low as 12% by age 6. ⁷ Children with egg specific IgE levels of more than 50 kU/L (ImmunoCAP ®) have a very low probability of egg allergy resolution before the age of 18. ⁷

Oral immunotherapy (OIT) to egg was first reported in 1908 in the Lancet by Dr. Schofield, who successfully desensitized a 13-year-old boy with egg allergy. However, literature on OIT was very limited during the rest of the 20th century until the OIT studies performed by Patriarca et al. in the 80s, ⁸ who reported successful desensitization to multiple foods including egg. Multiple OIT studies with different foods have been published since then with desensitization success rates generally above 70%. ⁹ This review will focus on egg OIT.

In this review, clinical desensitization is defined as a state in which the patient is able to tolerate egg as long as it is regularly ingested. It is considered as a temporary state as the patient may become allergic if he stops treatment for a prolonged period, of time. The time required for reactivity to return varies from patient to patient. Sustained unresponsiveness is defined as a state in which the patient who is desensitized can stop eating the food for a prolonged period and remain non reactive when the food is reingested. This period of avoidance varies from 4 weeks ¹⁰ to 6 months (NCT01867671) depending on studies.

Literature search strategy

We performed a search on pubmed using the following search terms: egg oral immunotherapy, egg OIT, egg desensitization, egg sustained unresponsiveness, egg specific tolerance induction, egg SOTI. We found a total of 312 articles. We excluded 289 studies based on non-relevant data. Out of the remaining 23 studies, we excluded 2 randomized controlled trials (RCTs) (Staden et al. ¹¹ Morisset et al. ¹² ), which reported combined data on multiple foods. We included 21 studies, including 9 RCTs, 2 non-randomized controlled trials and 10 uncontrolled trials.

State of randomized controlled trials

Results from the 9 RCTs and 2 non-randomized controlled studies are summarized in Table 1, which also includes target maintenance dose schedule, sustained unresponsiveness testing and adverse events (AEs). Table 2 describes in detail egg equivalences used in different OIT studies. Despite using different protocols, symptom grading systems and study endpoints, overall results are comparable.

Table 1. Prospective controlled trials on egg OIT.

	Study population				Efficacy				SU			Safety
															AE severity
Study	Age (y) median [range]	Median EW sIgE (kU/L) in T group	DBPCFC	Form	DSS endpoint (amount tolerated)	DSS rate (ITT)	Maintenance	Time to maintenace	Time tested	Avoid time	ITT rate	AE rate per dose (%)	AE rate per pt (%)	Total epi injections	Grading system	1	2	3	4
Randomized (n=9)
Burks (2012) n=55	7 [5–11]	10.3	✓	DEW	10g	22/40 (55%)	2 g qd	10m	24m	4–6w	11/40 (28%)	25%	NA	0	C	95%	5%	0	0
Dello-Iacono (2013) n=20	7^¥ [4–11]	23.3	✓	RHE	10mL	9/10	NA	6m	NA	NA	NA	NA	NA	0	S	6%	19%	66%	9%
					40mL	0/10
Fuentes Aparicio (2013) n=72	9^†¥ [4–15]	9.0		DPE	10g	37/40 (92.5%)	2 eggs qw	2.5m	NA	NA	NA	NA	21/40 (53%)	5	W	38%	38%	24%	0
Meglio (2013) n=20	8^§ [4–14]	11.3	✓	RHE	25mL	8/10 (80%)	3 HE qw	7m	NA	NA	NA	NA	7/10 (70%)	0	W	57%	43%	0	0
Escudero (2015) n=61	8 [5–17]	6.4	✓	DEW	2.8g protein	28/30 (93%)	1 egg q 48h	3m	4m	4w	11/30 (37%)	6%	21/30 (70%)	1	Cl	98%	2%	0	0
Caminiti (2015) n=31	6 [4–11]	36.6	✓	DEW	4g	16/17 (94%)	2–3 eggs qw	4m	13m	12w	5/16 (31%)	NA	5/17 (29%)	1	W	20%	60%	20%	0
Akashi (2016) n=36	6^† [4–11]	19.5	✓	DPE	4g	8/18 (44%)	4g qd	6m	NA	NA	NA	NA	17/18 (94%)	0	NA	NA	NA	NA	NA
Giavi (2016) n=29	2 [1–5]	18.7		HydE	9g	4/15 (27%)	9g	6m	NA	NA	NA	NA	14/15 (93%)	0	NA	NA	NA	NA	NA
Perez-Rangel (2017) n=33	10^† [5–18]	5.4	✓	DEW	3.6g	30/35 (86%)	1 egg q 48h	5d	NA	NA	NA	31%	22/32 (69%)	2	E	85%	13%	2%	0
Non-randomized (n=2)
Vazquez-Ortiz (2013) n=82	8[ 5–18]	5.5	✓	LEW	1 egg	40/50 (80%)	1 egg 2/w	4.5m	NA	NA	NA	7.5%	NA	18	S	30%	31%	16%	23%
Yanagida (2016) n=33	9^¥ [6–19]	50.3	✓	SE	1/32 egg	16/21 (76%)	1/32 egg qd	5d	12m	2w	15/21 (71%)	6.5%	NA	0	E	87%	12%	0	0

Legend:

† Mean age

¥ Treatment group

§ Based on raw data

* Mean specific IgE

** During build-up and maintenance phase

AE = Adverse event;

C= Cofar grade;

Cl = Clark's grade (34);

DEW = Dehydrated Egg White;

DBPCFC = Double Blind Placebo Controlled Food Challenge;

DPE = Dry powdered egg;

DSS = Desensitization;

E = EAACI grade (35);

epi = epinephrine;

EW = Egg White;

EWsIgE = Egg White specific IgE;

HydE = Hydrolysed Egg;

ITT = Intention to Treat;

HE = Hen's egg;

LEW liquid egg white;

m = months;

NA = Not Applicable;

qd = Once a day;

qw = Once a week;

RHE = raw hen's egg;

S = Sampson's grade (33);

SE= scrambled egg;

sIgE = specific IgE;

SU = sustained unresponsiveness;

T = Treatment;

W = WAO grade;

w = weeks.

For studies that did not include a grading system (16–18), symptoms were converted to a grade based on WAO immunotherapy criteria (37).

Table 2. Equivalence of egg products in egg OIT studies.

			DSS endpoint			Maintenance dose
							Egg preparation
Egg Product	USDA Nutrient Conversions Egg product (g): Egg protein (g)	Authors	Tolerated dose	Egg Protein (g)	Equivalence to natural whole egg (Size: S, M, L, XL, J)	Per protocol	Undercooked	Cooked	Egg protein (g per week)	Equivalence to natural whole egg (Eggs per week)
DEW	100 = 81	Burks (2012)	10 g	8	1 J	2g qd	NA	NA	11.2	2 ⅓ (S)
		Escudero (2015)	NS	2.8	½ M	1 egg q 48h	✓		14.4–19.2	3–4
		Caminiti (2015)	4 g	3.2	½ L	2–3eggs q w		✓	9.6–14.4	2–3
		Perez-Rangel (2017)	3.6 g	2.8	½ M	1 egg q 48h	✓		14.4–19.2	3–4
DPE	100 = 48	Fuentes-Aparicio (2013)	10 g	4.8	1 S	2 eggs q w	✓	✓	9.6	2
		Akashi (2016)	4 g	1.9	⅖ S	4g qd	NA	NA	13.3	2–3 (S)
RHE	100 = 13	Dello-Iacono (2013)	10ml/40ml	1.2 / 4.8	¼ S / 1 S	NA	NA	NA	NA	NA
		Meglio (2013)	25ml	3.1	½ L	3 eggs qw	✓	✓	14.4	3
LEW	100 = 11	Vazquez-Oritz (2013)	1 egg (60g)	7.5	1 XL/J	1 egg 2x/w	✓		9.6	2
SE	100 = 10	Yanagida (2016)	1/32 eg g	0.2	1/32 L	1/32 L egg qd	✓		1.4	⅕ (L)
HydE	NA	Giavi (2016)	9 ± 1 g	NS	NS	9 ± 1 g	NA	NA	NS	NS

† Equivalences determined according to information provided by authors and USDA National Nutrient Database for Standard Reference Release 28, Revised May 2016.

* Size of eggs not specified: To be conservative, a small egg was used for equivalence calculation.

1 Small egg = 38g ≈ 4.8g protein

1 Medium egg = 44g ≈ 5.5g protein

1 Large egg = 50g ≈ 6.3g protein

1 Extra-large egg = 56g ≈ 7.0g protein

1 Jumbo egg = 63g ≈ 7.9g protein

^§ There is discordance between results of protein content reported and calculation using USDA National Nutrient Database. Results reported are those using USDA Nutrient conversions.

Source: Adapted from United States Department of Agriculture (USDA) National Nutrient Database for Standard Reference Release 28 (Revised May 2016).

DEW = Dehydrated Egg White;

DPE = Dry Powdered Egg;

DSS = Desensitization;

EW = Egg White;

HydE = Hydrolysed Egg;

HE = Hen's egg;

J = Jumbo sized egg;

L = Large sized egg;

LEW = liquid egg white;

M = Medium sized egg;

NA = Not Applicable;

NS = Not Specified;

qd = Once a day;

qw = Once a week;

RHE = Raw hen's egg;

SE = Scrambled egg;

S = Small sized egg;

XL = Extra-large sized egg.

Burks et al. published the first RCT on egg OIT in the NEJM (2012). ¹³ This study is remarkable because it is one of the rare placebo-controlled multi-center studies with a thorough evaluation of immunologic changes and sustained unresponsiveness (SU) tested at 2 y. ¹³ They observed an intention-to-treat (ITT) SU rate of 28% (11/40) at 24 months. Of note, all of the 18 participants that reacted on the post avoidance challenge did so at a greater threshold than upon inclusion (5 consumed a dose of 7.5 g of dehydrated egg white (DEW), which is the equivalent of one egg), showing a sustained effect even in those other participants. A follow-up study performed at 4 y by Jones et al. ¹⁴ found an increased SU rate of 20/40 (50%), which shows that enhanced SU occurs with longer duration of therapy.

Three RCTs were subsequently published in 2013. Iacono et al. performed an open-label randomized controlled trial of raw-egg emulsion OIT involving 20 children aged 5 to 11 y. ¹⁵ At 6 months no patient had achieved maximum tolerance, defined as being able to tolerate 40mL of raw hen's egg emulsion in one dose (a small egg). Partial tolerance, defined as being able to tolerate between 10 mL and 40 mL in one dose, was achieved in 90% (9/10). One patient in the treatment group only tolerated 5 mL. In contrast, the highest dose achieved in the placebo group was 1.8 mL, with 90% (9/10) tolerating less than 1 mL.

Fuentes-Aparicio et al. reported a randomized control trial with 72 children aged 4 to 15 y. ¹⁶ Forty children were assigned to egg OIT using powdered pasteurized egg. Thirty-seven children (92.5%) achieved a maintenance dose of 2 eggs per week in 4 to 28 weeks. After at least 6 months on this maintenance, 54% could tolerate an unspecified amount of raw egg white.

Meglio et al. performed a randomized controlled open study of raw egg OIT involving 20 patients 4 to 14 y of age. ¹⁷ The maintenance dose of 25 mL of raw egg 3 times a week was achieved in 80% (8/10) at a mean of 215 d. Only 20% (2/10) of children in the control group could tolerate this amount on a double blind placebo controlled food challenge (DBPCFC.)

Two years later in 2015, Escudero et al. performed an open-label randomized controlled study of dehydrated egg white (DEW) OIT with 61 egg-allergic children aged 5 to 17 years. ¹⁰ In the treatment group, 93% (28/30) were fully desensitized and put on a maintenance dose of one undercooked egg every 48 hours. Twenty-five (83%) were fully desensitized by 3 months and were put on an avoidance diet for the fourth month. After DBPCFC, 11 (37% ITT, 44% per-protocol population(PPP)) were found to achieve SU compared with 3% (1/31) of control subjects on avoidance for 4 months.

The same year, Caminiti et al. performed a randomized, double blind, placebo-controlled study of DEW OIT with 31 egg allergic children aged 4 to 11 y. ¹⁸ Sixteen of 17 patients (94%) in the OIT group achieved desensitization after 4 months including one dropout. At 10 months, after 3 months of egg avoidance, 5/16 (31%) achieved SU. No patient in the placebo group was desensitized after 4 months but 1 reached spontaneous tolerance at 13 months.

In 2016, Akashi et al. performed a randomized controlled trial of dry powdered egg OIT in 36 egg-allergic Japanese patients aged 3 to 15 years. ¹⁹ Eighteen patients were randomly assigned to the OIT group and 18 to an egg elimination group. Interestingly, OIT was performed at home with dose increases at 3 to 4 day intervals. Forty-four percent of participants (8/18) were desensitized to 4 g of DEW by 6 months compared with none in the control group (0/18).

Even more recently, Perez-Rangel et al. performed an open-label controlled, randomized crossover study of DEW OIT involving 33 children aged 5 to 18 y old. ²⁰ The protocol involved a consecutive 5-day build-up phase on an outpatient basis starting at the highest tolerated dose based on the baseline egg DBPCFC. Doses were increased every hour with a target dose of 3600 mg of dehydrated egg white (DEW) (2808 mg of egg white protein) and a cumulative dose of 5400 mg (4212 mg of protein). Patients in the maintenance phase were advised to eat 1 undercooked egg (undercooked fried egg, scrambled egg, or omelet) every 48 hours for 5 months. Ninety percent (17/19) completed build-up and maintenance phase at 5 months. No patients in the control group (n = 13) passed the DBPCFC at 5 months. Of these, 13/13 (100%) patients crossing over to treatment were successfully desensitized for a total of 30/32 (94%). The advantage of such a rush (accelerated) protocol is the reduced time to reach maintenance dose and potentially fewer resources required. Despite this particularly high success rate, one should note that this was the study with the lowest baseline median egg specific IgE (5.4 kU/L).

Non-randomized controlled studies

In 2014, Vazquez-Ortiz et al. performed a non-randomized controlled trial in 82 patients 5 to 18 y. ²¹ Egg allergy was confirmed at entry by DBPCFC. A 2-day initial escalation phase was performed at the hospital with weekly dose increases in the outpatient clinic. The target maintenance dose of one raw egg was achieved in 40/50 (80%) in a median time of 4.5 months. Patients were then asked to ingest one raw egg twice a week for a median of 11 months. Of the 40 patients, 18 discontinued treatment and 4 required dose reductions. Thus, only 28 of the initial 50 patients (56%) achieved complete desensitization at the end of this study. This protocol was remarkable for the high amount of severe reactions and epinephrine use, despite low baseline egg specific IgE levels (5.5 kU/L).

In 2016, Yanagida et al. performed a single center nonrandomized open-label controlled study of low-dose OIT in 33 children aged 5 to 18 y. ²² Egg specific IgE (kU/L) were greater than other studies with medians of 50.2 and 66.4 in the treatment and placebo group, respectively. The study involved a 5-day build up phase at the hospital. Participants were then instructed to eat 62 to 194 mg of egg protein in a scrambled form once daily at home. After 12 months, daily intake was stopped for 2 weeks and OFC performed with 194 mg. Of the 16 participants that achieved desensitization at the end of the trial, 15 (71.4%) tolerated the final OFC and 7 (33%) could tolerate half of a whole heated egg.

Uncontrolled studies

Since 2007, there have been 10 uncontrolled studies for egg (OIT) (Table 3). In 2007, Patriarca et al. ²³ reported 14 cases of whole egg OIT in a cohort of 42 children desensitized to various foods with a desensitization rate of 10/14 (71.4%). The same year, Buchanan et al. ²⁴ reported low-dose egg OIT for 7 patients aged 14–84 months with a target maintenance of 300mg DEW. After 24 months, 4 of the 7 patients could tolerate a cumulative dose of 14.7 g of egg protein. All patients had a higher threshold to eggs than at the start of the study. Those who passed the challenge were instructed to avoid eggs for 3 months, and only 2/7 (28.6%) had sustained unresponsiveness (ITT analysis).

Table 3. Uncontrolled studies on egg OIT.

Studies	n	Age (years) Median [Range]	EW sIgE	Type of egg	DSS definition	DSS rate (ITT)
Patriarca 2007	14	7 [4–16]	21 (Mean)	Raw Egg	Whole egg	71%
Bucchanan 2007	7	4 [1.2–7]	23.75 (Mean)	DEW	10 g + scrambled egg	57%
Vickery 2010	8	5 [3–13]	12.5 (Median)	DEW	10 g	75%
Itoh 2010	6	10 [7–12]	17.5 (Median)	DEW	Whole egg (60g)	100%
Garcia Rodriguez 2011	23	7 [5–17]	9.87 (Median)	PEW	Whole cooked egg	87%
Ruiz Garcia 2012	17	7 [6–38]	3.6 (Median)	DEW	3.6g	74%
Ojeda 2012	34	9 [6–15]	5.215 (Median)	LPE	50mL	80%
Sudo 2014	30	6 [5–12]	17.95 (Median)	Omelet	32g	57%
Perezabad 2015	20	11 [5–15]	70 (Mean)	PEW	32mL	60%
Bravin 2016	15	11 [6–17]	NA	Baked egg	6.25g EP in biscuit	53%

* Estimated from graph

** Ovomucoid specific IgE

DEW = Dehydrated egg white;

DSS = Desensitization;

EP = Egg Protein;

EW = Egg White;

ITT = Intention to Treat;

LPE = Liquid pasteurized egg;

PEW = Pasteurized Egg White;

NA = Not Applicable;

sIgE = specific IgE.

In 2010, Vickery et al. ²⁵ reported reaching a target dose of 300mg of DEW in 6/8 patients (75%) aged 3–13 y in a median of 174 d using egg-specific IgE levels to guide therapeutic decisions. All of these patients passed a 10 g DBPCFC after a median length of treatment of 33 months. The same year, Itoh et al. ²⁶ published a study involving 6 patients aged 7–12 y undergoing rush egg OIT. All 6 patients were able to tolerate one whole egg in a median of 12 d. The median reaction threshold on baseline DBPCFC was 152 mg.

Similarly, in 2011 Garcia-Rodriguez et al. ²⁷ performed a 5-day rush OIT study in 5–17 y olds using pasteurized raw egg white mixed with foods tolerated by the patients. Twenty of the 23 participants (86.9%) were able to tolerate a whole cooked egg in less than 10 d.

In 2012, Ojeda et al. ²⁸ performed a home-based liquid pasteurized egg OIT study with 31 children aged 6 to 15. Twenty-five (81%) achieved complete tolerance (6037.50 mg of egg protein) in a median time of 43 d. Twenty-three of these (74%) passed a challenge with one raw egg. Three additional patients refused treatment but no further data are provided on these subjects for comparison.

The same year, Ruiz-Garcia et al. ²⁹ reported DEW OIT in 19 participants, including 3 adults. Of note, 2 of the adults dropped out for non-OIT related reasons. The target maintenance dose of 3600 mg was reached at a mean of 7 weeks in 14/19 patients (74%).

In 2014, Sudo et al. ³⁰ reported home based OIT with steamed omelet in 43 children 5–12 y of age. Patients were instructed to eat at least twice a week the dose at home and they were doubled every 2 months at the allergy clinic. After 1 year, 9/30 (30%) of patients in the OIT group were able to tolerate 32 g of cooked egg. After 2 y this number went up to 17/30 (56.6%). They reported very low rates of adverse events (45 out of 10380 doses; 0.45%).

In 2015, Perezabad et al. ³¹ reported on 20 children 5 to 15 y undergoing pasteurized egg white OIT. Twelve participants (60%) were able to tolerate 32mL of pasteurized egg white at a median of 11.75 months.

Finally, in 2016, Bravin et al. ³² described a series of 15 patients aged 6–17 y who underwent home-based baked egg OIT. Eight (53%) were able to tolerate 6.25 g of baked egg protein at the end of the build-up period over 60 d.

Sustained unresponsiveness and long-term outcomes of egg OIT

Studies evaluating long-term outcomes of egg OIT are scarce. To investigate the effects of long-term OIT in patients with egg allergy, Jones et al. (2016) administered egg OIT to children with egg allergy (n = 40, 5–18 years) for up to 4 y or placebo (n = 15) for 1 y or less. Of 40 egg OIT-treated subjects, 20/40 (50%) demonstrated SU by year 4. ¹⁴ In a previous study by the same authors, ¹³ SU was achieved in 28% of subjects by 24 months with all reporting consumption of egg 1 y later. The results from these trials suggest that OIT may have long-term disease modifying effects and that longer duration of therapy may increase the proportion of subjects developing SU. The smaller cohort from Buchanan et al. reported an identical ITT rate of 28% (2/7) at 24 months. ²⁴ In another study, Escudero et al. demonstrated an ITT SU rate of 37% (11/30) after only 3 months of treatment. ¹⁰ Caminiti et al. found a SU rate of 29% (5/17) after 10 months and an avoidance of 3 months. ¹⁸

The reasons for persistence of tolerance that occurs after an egg OIT trial are currently unknown. The minimal duration of therapy needed to achieve an end point of SU and the immune mechanisms underlying a change from the desensitized to tolerant state need to be better understood and warrant further research.

Although the studies use very different protocols and egg forms, there is clearly a favorable response to desensitization, with most studies having an ITT desensitization rate above 70%.

Safety of egg OIT

Grading of adverse events during OIT is not standardized, which makes comparison of studies difficult. The most frequent criteria used are Sampson's criteria, ³³ Clark's criteria ³⁴ and the EAACI anaphylaxis guidelines. ³⁵ Some authors report the number of reactions per doses and/or per patient whereas other studies give a direct description of symptoms experienced by patients.

The range of allergic reactions per dose varies from 0.43% ³⁰ to 31%. ²⁰ In the 9 RCTs reviewed, this range is between 5.9% ¹⁰ and 31%. ²⁰ This variability may depend on multiple factors, including the rapidity of the buildup phase, type of egg used, definition used for adverse events, use of pre-medication with doses, and differences in baseline characteristics. Dropout rates due to adverse reactions in RCTs vary from 0 ¹⁵ to 27%. ³⁶

Higher baseline levels of egg specific IgE during OIT have been associated with a higher frequency of adverse reactions. ^10,21 Vazquez Ortiz et al. ²¹ associated a baseline cutoff ovomucoid specific IgE of less than 8.85 kU/L with less severe dose related reactions. They also reported asthma and low threshold reactions at entry DBPCFC as being factors associated with early OIT discontinuation.

Antihistamines are sometimes used to prevent mild reactions during doses. Out of the 9 RCTs reviewed, only Meglio et al. ¹⁷ systematically used premedication with antihistamines. Although the number of reactions per dose is not specified in their study, only 7/10 patients experienced mild symptoms (WAO grade ³⁷ 1 or 2). Perez-Rangel et al. ²⁰ used premedication with cetirizine during build-up phase and the 1st half-week of maintenance phase. The authors reported 116 AE out of 374 doses (31%), which is the highest rate out of the reviewed RCTs. In the non-RCTs Ojeda et al. ²⁸ systematically used cetirizine as premedication. Their mean rate of reaction per patient was 5.8 but no severe reactions requiring epinephrine were reported. No serious adverse events were reported in the studies reviewed.

Many studies specifically advised patients to avoid cofactors, which could lead to worsening of reactions. ^17,20,21 These cofactors include exercise, fasting, non-steroid inflammatory drugs, respiratory tract infections. Caminiti et al. ¹⁸ described a patient who experienced abdominal pain with urticaria after exercise during maintenance phase (1 cooked egg). Perez-Rangel ²⁰ et al. described stress, exercise and respiratory tract infections as being aggravating factors for some reported AEs.

All in all, although the majority of studies reported reactions with doses, most were mild to moderate. In the 9 reviewed RCTs, only 4 mentioned the use of epinephrine during buildup phase: Fuentes Aparicio et al. ¹⁶ (3 uses), Escudero et al. ¹⁰ (1 use), Caminiti et al. ¹⁸ (1 use), Perez-Rangel et al. (2 uses). ²⁰ One non-randomized controlled trial reported 18 uses of epinephrine in 13 of 50 children. ²¹ This represents a rate of 0.13% epinephrine per dose, which is comparable to the rate of severe systemic reactions with subcutaneous immunotherapy to environmental allergens (0.2%). ³⁸ Also, as mentioned by Ibanez et al., ³⁹ using the number of epinephrine to infer the severity of reactions may be misleading as there is no correlation between the number of severe reactions and the number of epinephrine used in OIT studies.

A recent meta-analysis has shown the prevalence of eosinophilic esophagitis (EoE) to be 2.7% after food OIT. ⁴⁰ In the reviewed egg OIT studies, Fuentes-Aparicio et al. ¹⁶ mentioned one case of EoE (1/40), which was a cause of OIT failure. Escudero et al. ¹⁰ suspected 2 cases of EoE during OIT but parents refused endoscopy; however, all symptoms resolved after stopping OIT. Perez-Rangel et al. ²⁰ reported one case of suspected EoE but once again parents refused endoscopy. Symptoms also resolved after withdrawal of egg. Ridolo et al. reported a case of EoE confirmed by endoscopy after egg OIT. ⁴¹ Follow up endoscopy 1 y later showed a complete resolution after an egg free diet. Overall, the risk of EoE seems low during egg OIT.

Improvement of egg OIT safety

Adverse reactions and their management are a potential obstacle to the widespread use of egg OIT in routine clinical practice. Safer egg products and protocols with reduced allergenic potential are thus an active area of interest.

Baked egg as OIT

Regular exposure of heat-modified egg protein is well tolerated in up to 70% of egg allergic patients and may be clinically beneficial. ^42-44 Immune changes seen in OIT trials, such as decreases in skin test wheal diameters and ovalbumin specific IgE levels and increases in ovalbumin and ovomucoid specific IgG4 levels, are also seen in subjects regularly consuming baked egg. ⁴²

Ovalbumin and ovomucoid, the predominant proteins in egg, undergo various changes in their chemical structures following baking. Heating may cause a destruction of conformational epitopes that leads to reduced IgE binding and clinical reactivity. ⁴⁵ Additionally, the presence of wheat flour (gluten matrix) can reduce the antigenic activity of ovomucoid when mixed with egg white before baking. ⁴⁶ Applying this concept, the use of baked egg as OIT product may be a simple and affordable approach to improving the safety of induction of tolerance. The clinical trials in egg OIT completed to date have focused on a variety of egg forms including raw egg, ^15,17,23 liquid pasteurized egg, ²⁸ dehydrated egg white ^{10,13,18,20,24-26,29} , pasteurized egg white ^21,27,31 dehydrated whole egg, ^16,19 and lyophilized whole egg. ¹¹

In one proof of concept study, the authors developed a 5-stage recipe for an egg-containing biscuit to be used in a home-based OIT protocol. ³² The material prepared consisted of baked square biscuits with each square containing a calculated amount of egg protein, allowing for a gradual increase in the amount of egg ingested with each dose. Fifteen egg allergic children (aged 6–17 years) were given an initial biscuit in hospital containing 125 μg of baked egg protein. Subsequent up-dosing over 60 d was performed at home to a target dose of 6.25 g of baked egg protein. Once the maximum dose was achieved, the subjects underwent an open challenge with boiled egg, which was tolerated in 8 of 15 subjects (53%). All adverse reactions were mild and could be controlled with antihistamines.

No study compared baked egg to other forms directly. Thus it is unclear if the clinical efficacy for developing tolerance to more allergenic forms is comparable to previous studies. Advantages of using baked egg for OIT could include a reduction in the risk of adverse reactions, increased palatability and compliance.

Hydrolysed egg as OIT

This egg product is prepared by combining various heat treatment steps and enzymatic hydrolysis. ^47,48 Reduced reactivity to hydrolysed egg was shown in a clinical study where 22 of 24 patients with a confirmed egg allergy remained asymptomatic after undergoing a DBPCFC to this product. ⁴⁹ Despite this reduced reactivity, hydrolysed egg was shown to modulate the immune response in vivo and to induce oral tolerance in mice. ⁴⁸ Recently, a randomized double blind placebo-controlled pilot study ³⁶ of 29 egg allergic subjects (aged 1 to 5.5 years) was undertaken. Subjects were administered 9 g of hydrolysed egg or placebo daily for 6 months. Despite a trend in favor of the hydrolysed egg, no statistical differences in tolerance to whole egg were observed at the end of the study (36% vs 21% negative OFC, p = 0.66). However, a significant increase in specific IgG4 levels and a decrease in basophil activation were observed in the treatment group. Potential advantages of this formulation of egg are the reduction in adverse reactions during therapy, the standardization of the product and the reduced number of hospital visits required.

Recombinant egg proteins

Using recombinant technology, Dhanapala et al. (2017) ⁵⁰ have successfully produced a hypoallergenic variant of the major egg white allergen Gal d 1 (ovomucoid). This mutant protein expressed in E.Coli was created by disrupting 2 cysteine bridges in the molecular structure of Gal d 1 and showed reduced IgE reactivity against a pool of egg-allergic patient's sera when compared with its wild-type counterpart. ⁵⁰ These reduced allergenic proteins could theoretically decrease the adverse reactions associated with immunotherapy, but have not entered clinical phase yet. Animal models are required before their use in clinical trials. Furthermore, egg allergic patients may react to more than one allergen in egg, necessitating the development of hypoallergenic variants of other egg proteins.

Anti-IgE assisted therapy for egg OIT

Omalizumab, a humanized anti-IgE monoclonal antibody, is currently approved for use in patients with moderate to severe allergic asthma ⁵¹ and chronic urticaria. ⁵² It has also shown to be beneficial in allergic rhinitis and atopic dermatitis, ^53,54 and to increase reaction threshold rates to foods. ⁵⁵ Its mechanism of action involves the reduction of free circulating IgE and the decreased expression of the high affinity IgE receptor on effector cells. ^56,57 Recently, light has been shed on its potential to improve the safety and efficiency of food oral immunotherapy. As observed in clinical trials, a particular subgroup of patients is refractory to conventional food OIT and is particularly at risk of severe allergic reactions. Clinical studies have shown that concomitant omalizumab therapy can be effective in reducing these reactions in children undergoing OIT to peanut, ⁵⁸ milk, ^{59, 60} and multiple food allergens including egg. ⁶¹ Martorell-Calatayud et al. reported a case series of 9 egg-allergic patients refractory to conventional egg OIT who had a repeat desensitization performed 9 weeks after starting anti-IgE treatment. ⁶² At the end of the induction phase, all patients had achieved complete desensitization and passed an oral food challenge with 33ml of raw egg white. However, 1/3 of patients with egg white OIT relapsed after 2 to 4 months of omalizumab cessation. Similarly, Lafuente et al. reported 3 cases of children refractory to egg OIT who were successfully desensitized to egg with anti-IgE therapy but who experienced reactions 3 to 4 months after discontinuing omalizumab. ⁶³

Both these case series suggest that omalizumab might be especially helpful in high-risk egg allergic patients refractory to conventional egg OIT but that a longer duration of anti-IgE therapy may be necessary in such refractory patients given potentially higher likelihood of relapse with omalizumab weaning. However, these results need to be interpreted with caution given the very small number of patients. Larger studies with control groups need to be performed to determine the optimal use of omalizumab in various subgroups of egg OIT.

Role of biomarkers in egg OIT trials

Understanding the immune mechanisms responsible for the beneficial effects of egg OIT can be useful in identifying patients who will respond favorably to therapy and in monitoring the development of tolerance. Notably, several studies have shown that increases in specific IgG4 levels are associated with successful immunotherapy and loss of clinical reactivity to egg. ^{13,17–20,22,26,31,36} Mixed results have been found with regards to egg specific IgE levels, with certain studies showing a significant decrease, ^{15,17,20,22,25–27,31} and others reporting no significant changes in egg-specific IgE levels during OIT. ^16,19,24 Decreases in skin prick test results and basophil activation have also been observed with egg OIT. ^{13,15,17,20,25,27,64}

With regards to cellular changes, Perezabad et al. ³¹ have suggested a skewing from a Th2 to T regulatory predominant response following egg OIT. Significant increases in IL-10 production by OVA-stimulated peripheral blood mononuclear cells (PBMCs) with a trend toward lower IL-5 and Il-13 levels and higher tumor necrosis factor-α and interferon-γ were found in patients that could ingest 32 ml of pasteurized egg white (complete desensitization) without developing symptoms.

Limited data has been published with regards to biomarkers of sustained unresponsiveness (SU) for egg. Burks et al. found that SU at 24 months correlated with increased egg-specific IgG4 levels and decreased SPT at 10 months, but not egg-specific IgE. ¹³ In a long-term follow-up to this study, longitudinal blood samples were collected over a 4-year period to identify possible predictors of SU. ^14,65 The authors report that egg-specific and egg component-specific IgA and IgA2 levels increase during egg OIT and that relative increases in IgG4, IgA, and IgA2 to egg white and ovomucoid (p = 0.024, p = 0.024 and 0.029, respectively) are observed with SU.

Baseline specific IgE levels can be used as predictors of response to egg OIT. Jones et al. reported that baseline IgE to ovomucoid was lower in their 19 subjects achieving SU after 4 y (median 3.97 kU/l) compared with the 18 that did not (10.9 kU/l; p = 0.010). In general, lower baseline antigen-specific IgE levels appear to be related to successful egg OIT therapy ³¹ and elevated levels associated with a high probability of early protocol discontinuation. ²¹

Biomarkers for predicting the changes in the immune response that occur with egg OIT merit further investigation. These markers may help select patients who would benefit the most from this therapy. The discovery of biomarkers that can be used to stratify patients according to risk of adverse events, monitor their response to treatment and predict their ability to achieve sustained unresponsive would be of great benefit.

Quality of life with egg OIT

Quality of life (QOL) studies that focus on patients undergoing egg OIT are limited. Studies from other foods show an improvement of quality of life with desensitization but this benefit can be limited by the occurrence of adverse reactions. ^{66,67,68,69,70}

Investigating the impact of egg OIT on patient and family well being, especially in the context of long-term studies may improve our understanding of the risks and benefits associated with this type of treatment. Collecting this information in future trials is not only important in determining the psychological impact of treatment but can also provide clues on patient compliance, and justify the investment in resources required for this treatment.

Conclusion

Egg OIT has become a promising treatment approach with several prominent studies demonstrating the successful desensitization of most of its participants with an acceptable safety profile. Its potential as a disease-modifying treatment of egg allergy is becoming more and more evident. Nevertheless, several aspects of egg OIT may benefit from additional investigation, notably with regards to improved safety, sustained tolerance, direct head-to-head comparison of products and protocols, impact on quality-of-life, efficacy in adults and optimal biomarkers for prediction and monitoring of response to treatment. Given the extensive methodological differences between studies, standardization of protocols and of adverse event reporting from research and eventual clinical registries would improve assessment of egg OIT data.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Contribution of authors

Dr. François Graham contributed to the analysis and interpretation of studies, writing and revision of manuscript, and final approval of manuscript.

Dr. Natacha Tardio contributed to the analysis and interpretation of studies, writing and revision of manuscript, and final approval of manuscript.

Dr. Louis Paradis contributed to the revision of manuscript.

Dr. Anne Des Roches contributed to the revision of manuscript.

Dr. Philippe Bégin contributed to the analysis and interpretation of studies, preparation of manuscript, revision of manuscript, and approval of final manuscript.