egg oral immunotherapy

Egg oral immunotherapy

Suparat Sirivimonpan, MD

25/1/2013

Egg allergy

Introduction

Oral immunotherapy RCT

Rush protocol

Baked egg protocol

Individualized protocol

Introduction• Hen’s egg allergy is the second most common

food allergy in infants and young children

• Closely associated with atopic dermatitis • Increase risks of sensitization to aeroallergens and

asthma in children with egg allergy• Estimated prevalence : varies depending on method of

data collection or definition (1.7-7%)

Julie Wang et al.Pediatr Clin N Am 2011;58:427–443

Treatment

• Standard therapy for egg allergy is strict avoidance

Egg allergy• Currently, there are no treatments that can cure or provide

long-term remission from food allergy

• several treatment strategies are being investigated : allergen-specific or aimed at modulating overall allergic response

• Much recent research has focused on the safety, efficacy, and mechanism of oral immunotherapy (OIT) as a disease-modifying treatment

A. Wesley Burks et al.N Engl J Med 2012;367:233-43

• multicenter, double-blind, randomized, placebo-controlled study

• Primary end point – induction of sustained unresponsiveness after 22 months

of oral immunotherapy with egg• Secondary end points

– Desensitization : ability to pass an oral food challenge with 5 g of egg-white powder at 10 months and with 10 g at 22 months, while still receiving daily OIT

– safety of oral immunotherapy


Eligible participants • 5 - 18 years of age• Convincing clinical history of egg allergy (allergic symptoms within minutes to 2 hours after ingesting egg)

• Serum egg-specific IgE antibody level ≥ 5 kU/L for children ≥ 6 years of age or

≥ 12 kU /L for those 5 years old– These levels were chosen to exclude children who were likely to outgrow the

allergy during the course of the study

• Children with a history of severe anaphylaxis (i.e., previous hypotension) after egg consumption were excluded


• Skin-prick testing with egg extract (Greer Laboratories)

– saline and histamine controls was performed – at enrollment and at 10 months and 22 months

• Basophil activation – CD63 up-regulation on flow cytometry

• Serum egg-specific IgE and IgG4 antibody levels – use of the Immuno-CAP 100 (Thermo Fisher Scientific)



Randomly (computer algorithm) in a ratio of 8:3 at 5 clinical sites

The study was blinded

Raw egg-white powder cornstarch

History+elevated sIgE (egg)No OFC was performed at baseline


10 mo : OFC 5 g EW powder Desensitized

22 mo : OFC 10 g EW powder

blinded

unblinded

24 mo : OFC 10 g EW powder and whole cooked egg assess “sustained unresponsiveness”add egg to diet ad libitum Report adverse events 30,36 mo

children who passed OFC at 22 months discontinued OIT and avoided egg consumption for 4-6 wks

2 g EW powder ≈ 1.6 g EW protein1 whole egg ≈ 6-7 gm egg protein ≈ 3.6-4 gm EW protein

4 g EW protein ≈ 1 whole egg

• 3 phases: an initial-day dose escalation, a build-up phase, and a maintenance phase ingested up to 2 g of EW powder/day,(1/3 of egg)

• children should avoid egg consumption other than oral immunotherapy

• severity of allergic reactions was reported with the use of a customized grading system (1-5)– 1 (transient or mild) , 2 (moderate), 3 (severe), 4 (life threatening), 5 (death)

• After 10 months – placebo was stopped, followed through 24 months– treatment was continued in the oral-immunotherapy group on an open-label basis


Egg OITInitial day escalation : in clinical research setting

• 0.1 mg raw egg white powder, doubling every 30 minutes, up to 50 mg• maximum tolerated single dose = starting dose for the build-up phase• minimum dose of 3 mg of egg white powder was required to continue

dosing

Build-up : ingested a daily dose of egg white powder at home • For subjects whose maximal day 1 dose was less than 50 mg, doses were

doubled every 2 weeks up to 50 mg• After 50 mg, dosing was increased to 75 mg, and then dosing increased by

25% until 2 gm of egg white powder was reached• maximum time for the build-up phase = 10 months• dose achieved at 10 months = maintenance dose• Subjects who did not reach 306 mg by 10 months were discontinued from

dosing but were included in the endpoint analysis

Egg OIT

Maintenance• After reaching their highest build-up dose (maximum 2 gm), subjects

continued this dose daily for at least 2 months before the month 10 OFC• egg OIT subjects continued maintenance dosing through 22 months• Per protocol, subjects not reaching a maintenance dose of 2 gm by 10

months were allowed to escalate to 2 gm after the 10 month OFC

2 gm/day egg white powder ≈ 1.6 gm/day egg white protein1 whole egg ≈ 6-7 gm egg protein ≈ 3.6-4 gm egg white protein




blinded

unblinded

24 mo : OFC 10 g EW powder and whole cooked egg assess “sustained unresponsiveness”add egg to diet ad libitum Report adverse events 30,36 mo

children who passed OFC at 22 months discontinued OIT and avoided egg consumption for 4 to 6 weeks.

Build up phase ( max 2 g)

Maintenance phase

desensitized

The children who passed OFC at 22 months discontinued OIT and avoided any egg consumption for 4 to 6 weeks.


unblinded

blinded

egg-sIgE > 2 kU/L

P <0.001

P <0.001


add egg to their diet ad libitum and to report any adverse events

Egg consumption and adverse events were ascertained by telephone or at clinic visits at 30 months and 36 months

1 also underwent a challenge with a wholeegg (protocol deviation) and did not pass


desensitized Sustained unresponsivenessdesensitized

Egg-specific Ig4


• Logistic regression analysis confirmed these correlations egg-specific IgG4 antibody levels at 10 months correlated with desensitization at 10 months and also predicted desensitization at 22 months and sustained unresponsiveness at 24 months

• Logistic regression analysis confirmed that a reduced wheal size at 22 months, as compared with baseline,

• correlated with sustained unresponsiveness at 24 months.


SPT : wheal size


After 10 months, the rate of symptoms in the oral-immunotherapy group decreased to 8.3% of 15,815 doses

All serious adverse events (3 respiratory infections and 1 allergic reaction to peanuts) were considered to be unrelated to dosing

• Advantage – Substantial number of children at multiple sites – Double blind, randomized, controlled study design – long-term follow-up during ad libitum consumption (30,36 months)

• Sustained unresponsiveness (28% (11/40)) appears to be therapeutically more desirable than desensitization

• Suppression of mast cells (decreased wheal size on SPT, and basophil activation) and elevation of egg-specific IgG4 were noted in children receiving oral immunotherapy immune tolerance ??


• OIT provides protection in a majority of children with egg allergy by raising the reaction threshold and represents a highly promising therapeutic intervention for food allergy

• The approach is relatively safe – reactions to dosing were mild (grade 1)– less than 1% of reactions scored as moderate (grade 2)

• However, some allergic reactions were of sufficient clinical significance 15% of children who received OIT did not complete the therapy

• The mechanisms underlying the success of OIT and their relationship to natural immune tolerance are unknown


For oral immunotherapy to be recommended as a standard of care,

• important to better define the risks of OIT versus allergen avoidance

• determine the dosing regimens with the most favorable outcomes

• identify patients who are most likely to benefit from OIT• develop post desensitization strategies that promote long-

term immune tolerance


R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 (41) 1289–1296

• prospective, open, uncontrolled study

Inclusion criteria1.Children over 5 years of age

2. history suggestive of immediate allergy to egg (2 hr after eating)

3. IgE-mediated egg allergy demonstrated by at least one of the following tests:(a) Positive SPT to egg or its proteins

(b) Detection of sIgE to egg white or any of its proteins (ovalbumin, ovomucoid, lysozyme and conalbumin)

(c) Positive oral challenge test to egg or an unequivocal history of a reaction to egg in the previous 3 months

• Exclusion criteria– Patients who were unstable from a respiratory point of view or who

presented intercurrent disease at the time of starting desensitization were excluded


• Desensitization was performed using pasteurized raw egg white mixed with a food product well tolerated by the patient (yoghurt, milkshake)


one egg = 30mL of egg white

Desensitization = 1 whole cooked egg+ raw egg white 8 ml

not admitted, but under observation for 7 h/day

• desensitization lasted > 5 days last tolerated dose at home each day over the weekend

• A slow regimen : repeated moderate reactions or any severe reaction – weekly increase of 0.5mL in the dose from the last tolerated

• patients who achieved tolerance to a whole egg continued with daily ingestion of a cooked egg for the first 3 months

• At 3 months space out exposure to every 48 h • At 6 months : every72 h

• allowed to eat any food containing egg in lesser quantities


mean, 8.1 yrs (5-17) 14 AD15 asthma

oral challenge test 12/23



20/23 (86.9%) tolerance to a whole cooked egg (omelette) with protocol (rush)14 /20 within the programmed 5 days and 6/20 in <10 days

Slow protocol

18/23 (78.3%) : at least one allergic reaction35 mild reactions , 20 moderate, no severe reactions5 pts : no reaction

7 patients reacted to omelette after tolerated 8mL of raw egg white, but mild

mean ±SD dose was 1.17 mL (155 mg) ± 2.01mL

0.65mg


Desensitize in 5 days (n =14)

Desensitize > 5 days (n=8)

P value

SPT EW 2.6 mm 11.2 mm P = 0.037

mean sIgE to egg white

4.35 kU/L 18.6 kU/L P = 0.005

mean sIgE to ovomucoid

2.15 kU/L 11.6 kU/L P = 0.009

- 5-day regimen appears to be more successful in patients with smaller SPT reactions and lower levels of sIgE to egg proteins

- More patients should be included to confirm that very high levels of sIgE would be a relative contraindication for this rush regimen

• One patient became symptomatic again on egg exposure owing to poor adherence– This is the only patient who initially refused the regular egg

intake

• the other patients showed no problem regarding the introduction of egg into their diets



differences compared with baseline were only significant at 6 months for SPT ,sIgEsIgG levels were significantly different from baseline at 3-week follow-up

• This regimen achieved desensitization in 86.9% of patients– similar to the results obtained with other slower egg desensitization regimens

and better than those reported by some authors

• All the doses were given under medical supervision, in controlled circumstances rather than at home

• All the reactions in our study were mild or moderate, none was severe

• There were no reactions with the first dose of the proposed regimen, all of which would indicate a significant safety margin

• No prophylactic treatment with antihistamines numerous mild reactions


• Almost no incidents during follow-up and none of the patients suffered a recurrence of symptoms on ingestion of egg

(except for the patient who did not comply with the regular intake of egg)

• The children tolerated not only one cooked egg but also other foods that contain raw egg, such as mayonnaise and ice cream

• Limitation : lack of a control group– short period of desensitization impossible to acquire tolerance

naturally in that time – difficult to justify the performance of a new challenge test in the control

group only a week after a positive one– it would be interesting to evaluate the long-term immunological

response to egg in both desensitized patients and a control group


Conclusion• Tolerance to egg can be achieved within a matter of days in

symptomatic allergic patients, even in patients with anaphylaxis

• The proposed protocol is relatively safe, although not risk free– carried out in specialized centres with staff experienced in the

treatment of this type of reaction – with sufficient means to perform close clinical monitoring of the

patients


Extensively heated/Baked Egg

• Food processing alters protein structure and affects allergenicity• Extensively heated egg is tolerated by most patients with egg

allergy• A diet containing baked egg may be a safer and perhaps more

natural approach to oral immunomodulation

• incorporation of extensively heated egg in the diet • improving quality of life and accelerating the resolution of their

allergy


Faith Huang and Anna Nowak-We˛grzyn.Curr Opin Allergy Clin Immunol 2012, 12:283–292

J Allergy Clin Immunol 2012;130:473-80

Objective : • To characterize immunologic changes associated with

ingestion of baked egg • evaluate the role that baked egg diets play in the

development of tolerance to regular egg


Inclusion criteria• 0.5 and 25 years of age with documented IgE-mediated egg allergy • Documented IgE-mediated egg allergy was defined by

– a positive EW SPT result and/or – detectable (>0.35 kUA/L) serum EW-specific IgE level, and – a recent history (within the past 6 months) of a type I hypersensitivity

reaction to egg or a positive physician-supervised oral food challenge (OFC) to egg; or,

– if no history of recent reaction, a serum EW-specific IgE level ≥ 2 kUA/L in children younger than 2 years or ≥7 kUA/L in children older than 2 years


Design• OFC baked egg (muffin and waffle)• Subjects tolerant to baked egg challenge with regular egg

• Regular egg-tolerant subjects all forms of egg into diet, at least twice a week

• Baked egg–tolerant subjects baked egg products into diets– Consume 1 to 3 servings of baked egg per day and avoid regular egg – reevaluated every 3 -12 months– after 6 months or more were offered challenges to regular egg

• Subjects reactive to baked egg repeat challenges to baked egg after 12 months or more

• Baked egg–reactive subjects were instructed to strictly avoid all forms of egg


OFCeach containing 1/3 of an egg (2.2 g of egg proteins (open) : muffin or waffle)


intent-to-treat group : 79 subjects71% malesmedian age of 5.8 years (range, 1.6-15.8) Median initial serum EW-specific IgE level of 2.5 (range, 0.2-101) followed for a median of 37.8 months (range, 7.6-69.7)

Tolerate RE 36/56 (64%)

14/23 (61%)

Tolerate RE 6/14 (42%)

The comparison : 47 subjects 66% malesmedian age of 4.6 years (range, 1.7-20.9 years) median initial serum EW-specific IgE level of 4.8 (range, 0.2-58followed for a median of 67.3 months (range, 40.5-81.8)

-70/79 (89%) subjects in the intent-to-treat group tolerated baked egg over length of the study-42/79 (53%) now tolerate regular egg with a median time to tolerance of 52.4 months (range, 7.6-67.5 months) - 9 (11%) continued to avoid egg strictly

once initially baked egg–reactive subjects became baked egg tolerant, they were just as likely as the initially baked egg–tolerant subjects to develop tolerance to regular egg



subjects in the intent-to-treat group who initially tolerated baked egg were 3.3 times more likely to develop regular egg tolerance than subjects initially reactive to baked egg over the follow-up period (hazard ratio, 3.3; 95% CI, 1.2-8.9; P 0.017)

Initially baked egg–tolerant subjects developed regular egg tolerance significantly earlier than initially baked egg– reactive subjects(median time 41.7 months VS 57.5 months,P 0 .004)

• Baked egg–tolerant subjects had lower baseline EW-specific IgE levels than baked egg–reactive subjects– median 1.9 kUA/L (interquartile range [IQR], 0.6-6.1; range, 0.0-101)

versus 13.5 kUA/L (IQR, 5.9-18.9; range, 2.8-58.9) (P 0 .002)

• Baked egg–tolerant subjects also had smaller baseline EW-induced SPT wheal diameters than baked egg–reactive subjects– median 6 mm (IQR, 5-8; range, 0-19) versus 8 mm (IQR, 8-9;

range, 7-15) (P 0 .005)



decreased significantly from baseline insubjects ingesting baked egg

increased significantly


subjects in the per-protocol group were 14.6 times more likely to develop regular egg tolerance than subjects in the comparison group over the follow-up period (hazard ratio, 14.6; 95% CI, 5.8-36.4; P < .0001)

Tolerability of baked egg diet• Baked egg was well tolerated without reports of acute allergic

reactions to baked egg at home or worsening of eczema or asthma

• 1 subject initially reactive to baked egg passed a baked egg rechallenge, then subsequently developed vomiting and diarrhea hours after accidental exposures to regular egg (in icing and cookie dough ice cream)– consistent with atypical food protein–induced enterocolitis syndrome, and this

child reverted to complete egg avoidance

• None of the subjects developed EoE


• a majority of subjects initially reactive to baked egg subsequently developed tolerance to baked egg over the follow-up period and some of them now tolerate regular egg

• Higher baseline EW-specific IgE levels are associated with baked and regular egg reactivity, while initial baked egg reactivity is not

• long-term ingestion of baked egg associated with immunologic changes– decreasing serum whole and component egg-specific IgE levels – sustained changes in SPT wheal diameter and serum component IgG4 levels


• ingestion of baked egg in the diet of egg-allergic children was well tolerated (F/U 6 years) and accelerates the development of tolerance to regular egg

• 1 subject with atypical FPIES• It is unknown whether a baked egg diet may have predisposed this subject to

developing FPIES–like symptoms

• ingestion of baked egg products is a safer, more convenient, less costly, and less labor-intensive form of oral immunomodulation


• oral challenges to baked egg must be undertaken under physician supervision with all precautions

• Egg allergy phenotypes and markers of baked egg tolerance have not been fully defined

• safety of home introduction of baked egg has not been validated• anaphylaxis to baked egg occurs and is not easily predicted

• Further studies are required to more clearly define which egg-allergic patients can safely tolerate and benefit from the inclusion of baked egg in their diets



Our proposed guidelines for the introduction of baked egg into the diets of egg-allergic children

Conclusion

• Oral immunotherapy (OIT) is the most extensively studied approach toward a treatment for food allergy esp. for egg allergy

• Benefit– Immunomodulatory benefit– make a significant contribution to helping improve the prognosis– possibly provide an effective strategy to shorten the time to achieve

tolerance– improve the quality of life, vastly increasing the variety of food

products– fulfillment of nutritional requirements– reduce parental anxiety, lessen the child’s discomfort in social

situations

Conclusion

extensively heated egg : • associated immunologic changes with continued ingestion of

extensively heated egg seem favorable, • incorporation of extensively heated egg in the diet may present a

more natural form of immunotherapy

Conclusion• Early pilot trials suggest efficacy• But definitive conclusions are prevented by study design flaws including

small sample sizes, soft outcome measurements, lack of controls, and absence of randomization– high probability of spontaneous tolerance development unclear

• Desensitization VS Tolerance with recurrence of symptoms after discontinuation of therapy

• Risk of adverse event– approached with caution and should be done under physician supervision

• Current routine laboratory diagnostic tests do not reliably predict tolerance to egg

• Critical questions remain unanswered, such as the appropriate dose and length of treatment

Egg allergy

• OIT is still considered investigational, therefore is not recommended in routine clinical practice


Large, high-quality studies with well defined endpoints are needed assesses the long-term efficacy, safety and cost-effectiveness of SOTI analyze the precise mechanisms

egg oral immunotherapy

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