Egg oral immunotherapy Presented by Suparat Sirivimonpan, MD. on Jan25, 2013

1. Egg oral
immunotherapy
25/1/2013
Suparat Sirivimonpan, MD

2. Egg allergy
Introduction
Oral immunotherapy
RCT
Rush protocol
Baked egg protocol
Individualized protocol

3. 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

4. Treatment
• Standard therapy for egg allergy is strict
avoidance

5. 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

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

7. • 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
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

8. 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
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

9. • 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)
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

10. History+elevated sIgE (egg)
No OFC was performed at baseline
Randomly (computer algorithm) in a
ratio of 8:3 at 5 clinical sites
cornstarch Raw egg-white powder
The study was blinded
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

11. blinded
4 g EW protein ≈ 1 whole egg
10 mo : OFC 5 g EW powder
 Desensitized
22 mo : OFC 10 g EW powder
children who passed OFC at
22 months discontinued OIT
and avoided egg consumption
24 mo : OFC 10 g EW powder and
for 4-6 wks
whole cooked egg  assess
“sustained unresponsiveness”
add egg to diet ad libitum
Report adverse events 30,36 mo
2 g EW powder ≈ 1.6 g EW protein
unblinded 1 whole egg ≈ 6-7 gm egg proteinal.N Engl J Medgm EW protein
A. Wesley Burks et ≈ 3.6-4 2012;367:233-43

12. • 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
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

13. Egg OIT
Initial 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

14. 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 protein
1 whole egg ≈ 6-7 gm egg protein ≈ 3.6-4 gm egg white protein

15. blinded
Build up phase
( max 2 g)
10 mo : OFC 5 g EW powder
Maintenance phase
22 mo : OFC 10 g EW powder
children who passed OFC at 22
months discontinued OIT and
avoided egg consumption for 4
24 mo : OFC 10 g EW powder and
to 6 weeks.
whole cooked egg  assess
“sustained unresponsiveness”
add egg to diet ad libitum
Report adverse events 30,36 mo
unblinded A. Wesley Burks et al.N Engl J Med 2012;367:233-43

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

17. blinded
P <0.001 desensitized
unblinded
egg-sIgE > 2 kU/L
P <0.001
The children who passed OFC at 22 months discontinued OIT and avoided any egg
consumption for 4 to 6 weeks.
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

18. 1 also underwent a challenge with a whole
egg (protocol deviation) and did not pass
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
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

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

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

21. 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
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

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

23. SPT : wheal size
• Logistic regression analysis
confirmed that a reduced wheal
size at 22 months, as compared
with baseline,
• correlated with sustained
unresponsiveness at 24 months.
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

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

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

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

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

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

29. All serious adverse events (3 respiratory infections and 1 allergic reaction to
peanuts) were considered to be unrelated to dosing
After 10 months, the rate of symptoms in the oral-immunotherapy group
decreased to 8.3% of 15,815 doses
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

30. • 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 ??
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

31. • 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
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

32. 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
A. Wesley Burks et al.N Engl J Med 2012;367:233-43

33. R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

34. • prospective, open, uncontrolled study
Inclusion criteria
1.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
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

35. • Desensitization was performed using pasteurized raw egg white mixed
with a food product well tolerated by the patient (yoghurt, milkshake)
not admitted, but under observation for 7 h/day
one egg = 30mL of egg white
Desensitization
= 1 whole cooked egg+ raw egg white 8 ml
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

36. • 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
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

37. mean, 8.1 yrs (5-17) 14 AD oral challenge test 12/23
15 asthma
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

38. 18/23 (78.3%) : at least one allergic reaction
35 mild reactions , 20 moderate, no severe reactions
5 pts : no reaction
Slow protocol
7 patients reacted to omelette after
tolerated 8mL of raw egg white, but mild
0.65mg
mean ±SD dose was 1.17 20/23 (86.9%) tolerance to a whole cooked egg (omelette)
mL (155 mg) ± 2.01mL with protocol (rush)
14 /20 within the programmed 5 days and 6/20 in <10 days
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

39. Desensitize in 5 days Desensitize > 5 P value
(n =14) days (n=8)
SPT EW 2.6 mm 11.2 mm P = 0.037
mean sIgE to 4.35 kU/L 18.6 kU/L P = 0.005
egg white
mean sIgE to 2.15 kU/L 11.6 kU/L P = 0.009
ovomucoid
-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
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

40. • 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
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

41. differences compared with baseline were only significant at 6 months for SPT ,sIgE
sIgG levels were significantly different from baseline at 3-week follow-up
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

42. • 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
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

43. • 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
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

44. 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
R. Garcia Rodriguez et al, Clinical & Experimental Allergy, 2011 ( ) –

45. 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
Julie Wang et al.Pediatr Clin N Am 2011;58:427–443
Faith Huang and Anna Nowak-We˛grzyn.Curr Opin Allergy Clin Immunol 2012, 12:283–292

46. J Allergy Clin Immunol -

47. 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
J Allergy Clin Immunol -

48. 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
J Allergy Clin Immunol -

49. Design
OFCeach containing 1/3 of an egg (2.2 g of egg
• OFC baked egg (muffin and waffle) proteins (open) : muffin or 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
J Allergy Clin Immunol -

50. intent-to-treat group : subjects
71% males
median age of 5.8 years (range, 1.6-15.8) Tolerate RE
Median initial serum EW-specific IgE level of 2.5 (range, 0.2-101) 36/56 (64%)
followed for a median of 37.8 months (range, 7.6-69.7)
Tolerate RE
6/14 (42%)
14/23 (61%)
The comparison : 47 subjects
66% males
median age of 4.6 years (range, 1.7-20.9 years)
median initial serum EW-specific IgE level of 4.8 (range, 0.2-58
followed for a median of 67.3 months (range, -
-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
J Allergy Clin Immunol -

51. 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
J Allergy Clin Immunol -

52. 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)
J Allergy Clin Immunol -

53. • 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)
J Allergy Clin Immunol -

54. decreased significantly from baseline in
subjects ingesting baked egg
increased significantly
J Allergy Clin Immunol -

55. J Allergy Clin Immunol -

56. J Allergy Clin Immunol -

57. 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)
J Allergy Clin Immunol -

58. 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
J Allergy Clin Immunol -

59. • 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
J Allergy Clin Immunol -

60. • 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
J Allergy Clin Immunol -

61. • 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
J Allergy Clin Immunol -

62. Our proposed guidelines for the introduction of baked egg into the diets of egg-
allergic children
J Allergy Clin Immunol -

63. 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

64. 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

65. 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

66. 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
Julie Wang et al.Pediatr Clin N Am 2011;58:427–443