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A practical focus on egg oral immunotherapy

Authors:
  • Texas Children's Hospital & Baylor College of Medicine

Abstract

Egg allergy usually develops in the first year of life, with an estimated prevalence of 2.6%‐9%. Rates of resolution and timing vary, with approximately one-third of patients outgrowing their egg allergy by age 6 years. Persistent egg allergy has been associated with high egg white specific immunoglobulin E levels and sensitization to the egg allergen component Gal d 1, which is resistant to heat and digestion. These individuals seem to have a more severe and persistent phenotype of egg allergy. Recently, an active approach has emerged for patients with food allergy, including those with egg allergy, in the form of oral immunotherapy. Egg oral immunotherapy consists of the administration of gradually increasing doses of egg, with the aim to enable patients to consume small amounts of egg without having allergic reactions, which thus provides protection from accidental exposures to egg-containing foods. This article aims to discuss published evidence on egg oral immunotherapy, provide practical information on dosing protocols, and address special challenges associated with this intervention.
A practical focus on egg oral immunotherapy
Aikaterini Anagnostou, M.D., Ph.D.
1,2
ABSTRACT
Egg allergy usually develops in the rst year of life, with an estimated prevalence of 2.6%9%. Rates of resolution and timing
vary, with approximately one-third of patients outgrowing their egg allergy by age 6 years. Persistent egg allergy has been
associated with high egg white specic immunoglobulin E levels and sensitization to the egg allergen component Gal d 1,
which is resistant to heat and digestion. These individuals seem to have a more severe and persistent phenotype of egg allergy.
Recently, an active approach has emerged for patients with food allergy, including those with egg allergy, in the form of oral
immunotherapy. Egg oral immunotherapy consists of the administration of gradually increasing doses of egg, with the aim to
enable patients to consume small amounts of egg without having allergic reactions, which thus provides protection from acci-
dental exposures to egg-containing foods. This article aims to discuss published evidence on egg oral immunotherapy, provide
practical information on dosing protocols, and address special challenges associated with this intervention.
(J Food Allergy 4:132135, 2022; doi: 10.2500/jfa.2022.4.220013)
Arecent active approach, in the form of oral immu-
notherapy (OIT), has emerged for patients with
egg allergy. Egg OIT consists of the administration of
gradually increasing doses of egg with the aim to ena-
ble patients to consume small-to-medium amounts of
egg without having allergic reactions,
1
which thus pro-
vides protection from accidental exposures to egg-con-
taining foods. Egg OIT research has been conducted in
the United States and in Europe, including pilot studies
2,3
and randomized clinical trials.
46
In addition, both daily
ingestion of full servings of baked egg and egg ladder are
approaches that have been described in the literature for
management of certain phenotypes of egg allergy, but
those approaches are beyond the scope of this article.
7
EFFICACY AND SAFETY
In an early, pilot (proof of concept), open-label study
of seven children with egg allergy and who were
nonanaphylactic (7 months to 7 years old) Buchanan et
al.
3
administered treatment in the form of 300 mg of
egg white powder daily for 24 months. The interven-
tion was successful in 57% of the participants, who
were able to tolerate 10 g of egg powder (equivalent to
8 g of egg protein) in oral food challenge after therapy.
A seminal multicenter randomized OIT study was con-
ducted in the United States and included 55 children
with immunoglobulin E (IgE) mediated egg allergy
who received immunotherapy for a period of 10
months, with a maintenance dose of 2 g of egg white
powder (equivalent to one-third of egg).
4
The trial showed a 55% rate of successful desensitiza-
tion in the active arm compared with 0% in the placebo
arm, which supported the efcacy of this intervention,
4
with an additional year of egg OIT (total of 22 months of
therapy), which increased the desensitization rate up to
75%.
4
Adverse events were reported to be highest during
the rst 10 months of treatment, and most were mild
oropharyngeal associated with 25% of the doses in
78% of children who received egg OIT.
4
After the rst
10 months, the rate of adverse events decreased to
8.3% of the OIT doses.
4
No severe adverse events as a
result of the therapy were recorded. Approximately
15%ofthechildrenwereunabletocompleteOIT,
mostly due to recurrent and/or persistent allergic
reactions (nonresponders).
4
A high-dose OIT protocol was used in Spain in 32
children (518 years old) with persistent egg allergy.
8
The protocol involved a 5-day rush updosing phase,
followed by 5 months of maintenance dosing every 48
hours. After 5 months of treatment, 93.8% of the partic-
ipants were able to eat one egg (fried, scrambled, or
omelet).
8
Adverse events were noted in 31% of the
doses during the buildup phase, with 85.4% being clas-
sied as mild, 12.9% as moderate, and 1.7% as severe.
Epinephrine was administered in two participants for
From the
1
Division of Immunology, Allergy and Retrovirology, Department of Pediatrics,
Texas Childrens Hospital, Houston, Texas; and
2
Division of Immunology, Allergy and
Retrovirology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
A. Anagnostou has received honorariums from Aimmune Therapeutics, DBV
Technologies, Alk and Food Allergy Research and Education
No external funding sources reported
Address correspondence to Aikaterini Anagnostou, M.D., Ph.D., Division of
Immunology, Allergy and Retrovirology, Baylor college of Medicine, 1102 Bates
Ave., Ste 330, Houston, TX 77030
E-mail address: Aikaterini.Anagnostou@bcm.edu
This manuscript is part of the Journal of Food Allergy collection of published works
referred to as the Oral Immunotherapy Manual.The contents of this work reflects
the opinion(s) of the author(s) and is not intended to replace published guidelines or
the clinicians medical advice in the doctor-patient relationship
This article is distributed under the terms of the Creative Commons Attribution License-
NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license (https://
creativecommons.org/licenses/by-nc-nd/4.0/), which permits reproduction and redistribu-
tion in any medium or format according to the license terms, provided the work is not
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Copyright ©2022, The Author(s). Published by OceanSide Publications, Inc., U.S.A.
132 J Food Allergy (USA) 4:2 JFoodAllergy.com 2022
anaphylaxis.
8
No episodes of anaphylaxis occurred
during maintenance.
A separate U.S. trial examined 50 children ages 316
years, all reactive to unbaked egg, who received 2
years of treatment with either baked egg or egg OIT.
9
A comparison group of children who were reactive to
baked egg were also included and received egg OIT.
After 2 years of treatment, the OIT was discontinued
for 810 weeks to evaluate sustained unresponsive-
ness.
9
It was reported that 11.1% of the children who
consumed baked egg compared with 43.5% of the chil-
dren who received egg OIT achieved sustained unre-
sponsiveness to egg.
9
In the baked eggreactive group,
17.9% achieved this outcome.
9
The investigators con-
cluded that the participants who received egg OIT had
a higher likelihood to achieve sustained unresponsive-
ness compared with those who consumed baked egg
alone (without OIT).
9
Adverse events were described
in 3.9% of the doses per participant, with most of these
being oropharyngeal, followed by gastrointestinal and
respiratory, and successfully treated with oral antihist-
amines.
9
No epinephrine-treated reactions were
recorded.
9
Although sustained unresponsiveness has
been explored by a variety of studies, it is important to
note that egg is a common element of many diets and
that it is likely that, after successful egg OIT, most
patients may be exposed to variable amounts of egg
protein at least once, if not several times a week.
Early egg OIT is an important consideration. Most
individuals will outgrow egg allergy during childhood,
but rates of resolution and timing vary, with approxi-
mately one-third outgrowing their egg allergy by age 6
years in a U.K. study
10
; in the United States, 4% were
reported as outgrowing their egg allergy by age 4 years,
12% by age 6 years, 37% by age 10 years, and 68% by age
16 years.
11
Generally, persistent egg allergy has been
associated with high egg white specic IgE levels and
sensitization to the egg allergen component Gal d 1,
which is resistant to heat and digestion.
12
These children
seem to have a more severe and persistent phenotype of
egg allergy. Although it may not be possible to predict if
a 4-year-old will ever outgrow his or her egg allergy, it is
reasonable to assume that, if the egg specic IgE level is
high at 1 year and keeps increasing yearly by age four,
thepatient is unlikely to outgrow egg allergy within the
next several years and may be considered a candidate
for OIT. This is an important part of the discussion
with some families.
After publication of multiple studies that evaluated
egg OIT as an alternative management option for indi-
viduals with egg allergy, a systematic review was per-
formed to investigate the efcacy and safety of this
intervention.
13
A total of 10 randomized controlled tri-
als were included (439 participants between ages 1 and
18 years overall).
13
The review showed that most chil-
dren who received egg OIT were able to consume a
partial serving of egg (17.5 g) compared with only 10%
in those who avoided egg completely.
13
A full portion of
egg was successfully consumed by almost 50% in the
OIT group compared with 10% in children after an egg
elimination diet.
13
The investigators concluded that OIT
induces tolerance in almost 50% of subjects compared
with only 1 in 10 subjects who followed egg avoid-
ance.
13
However, it was noted that adverse events are
likely to be more frequent in participants on OIT and
that some children (;1 in 12 from the pooled data) may
have severe allergic reactions and/or anaphylaxis that
requires epinephrine administration.
13
As shown, from the multiple trials described above,
many OIT protocols allow for escalation to a target
and a maintenance egg dose that permits incorporation
into the diet, either as egg-containing products or as a
whole egg. Generally, one large whole egg contains ;6
g of egg protein (the exact amount depends on the size
of the egg). For comparison, a baked egg mufn con-
tains approximately one-third of an egg (usually two
eggs are used to prepare six baked egg mufns).
PUBLISHED DOSING SCHEDULES
A variety of egg OIT dosing schedules have been
published by different research groups. Some of these
are described in detail here. Staden et al.
6
report a 67-
day specic oral tolerance induction schedule that uses
hens egg powder. The initial dose is 5 mg of powder
(0.006 mg of egg protein), increasing gradually to 0.9
mg of egg protein by day 20, 148 mg of egg protein by
day 40, and 2.8 g of egg protein by day 67. The powder
is diluted in water, with increasing concentrations as
the protein doses increase.
Buchanan et al.
3
used an initial rush phase that con-
sisted of the following doses of powdered egg white
(which contained 80% egg protein): 0.1, 0.2, 0.4, 0.8,
1.5, 3, 6, 12, 25, 50, 100, and 200 mg, every 30 minutes
(200 mg of egg white powder are approximately equiv-
alent to 160 mg of egg protein). The highest tolerated
dose from the rush phase was given as the rst dose in
the buildup phase that followed. During the buildup
phase, doses were increased by 25 mg every 2 weeks
until reaching 150 mg and then increased by 50 mg at
each visit until reaching the maintenance dose of 300
mg, which would be taken daily for the length of the
study (24 months). This dose aimed to protect from ac-
cidental exposures to egg-containing products.
Burks et al.
4
initially performed a rush-day escalation
that started at 0.1 mg to a maximum of 50 mg of egg
white powder (;40 mg of egg protein), followed by
every 2 weeks increases to 75, 100, 156, 195, 245, 306,
383, 479, 599, 749, 936, 1170, 1463, 1829, and 2000 mg of
egg white powder (2 g of egg white powder is the ap-
proximate equivalent of 1.6 g of egg protein or one-
third of an egg).
J Food Allergy (USA) 4:2 JFoodAllergy.com 2022 133
Pérez-Rangel et al.
8
offered a 5-day rush buildup
phase, which started from 0.04 mg of egg white pow-
der (0.03 mg of egg protein), followed by 0.08, 0.16,
0.32, and 0.64 mg of egg white powder at hourly inter-
vals on day 1. Day 2 consisted of 0.4, 0.8, 1.6, 4, 20 mg
of egg white powder at hourly intervals.
8
On day 3,
ve doses were administered: 20, 50, 100, 225, 450 mg
of egg white powder, and, on day 4, a further three
doses were given: 450, 900, 1800 mg of egg white pow-
der.
8
On the nal day, day 5, two doses were adminis-
tered: 1800 and 3600 mg of egg white powder, the nal
equivalent to 2808 mg of egg protein or one whole
egg.
8
Maintenance dosing started after completion of
the updosing schedule in the form of one whole egg
(fried, omelet, or scrambled) every 48 hours, for the
length of the study (5 months).
8
When comparing different trial escalation regimes, a
few observations stand out. First, the rush buildup
phase aims to increase the egg protein dose rapidly
and, therefore, decrease the time to reach maintenance
and the overall study duration. The disadvantage of
such an approach is that the subjects may not tolerate
such a fast increase in dosing and may have signicant
allergic reactions. Second, the target maintenance dose
varies from tolerance to egg-containing products (esti-
mated as containing 75150 mg of egg protein) up to
one whole egg. The advantage of a lower maintenance
dose is that more patients are likely to tolerate it. The
disadvantage is that patients are unlikely to tolerate
ingestion to large amounts of egg protein, such as a
whole egg. However, it is important to note that inges-
tion of a whole egg equivalent may not be necessary or
practical for some patients, especially in the long term.
Analysis of data from Japan suggests that continuous
intake of low-dose OIT (1/32 of a volume of one egg)
may improve egg allergy and even be as effective as
the consumption of larger quantities,
14
although this
has not been replicated in other studies.
DOSE PREPARATION AND MASKING
All OIT doses should be prepared in a clean area,
free from contamination with any potential food aller-
gens. For egg OIT, hens egg powder (whole egg or
egg white powder) is most frequently used in research
studies (powder has been noted to sometimes be dif-
cult to dissolve). Pasteurized liquid egg has also been
used for egg OIT. Egg-free vehicles may be used for
dose mixing and disguising taste. Apple juice, apple-
sauce, yogurt, pudding, smoothies, or other age-appro-
priate food have all been used in research trials.
SPECIFIC CHALLENGES AND
CONSIDERATIONS
Similar to other food allergies with a favorable natu-
ral history (likely resolution), the timing of egg OIT is
a key consideration. It is important to allow time for
natural egg allergy resolution and, if possible, to iden-
tify the phenotype for persistent egg allergy, which
may be more in need of active intervention. Families
will require time to understand the process, risks and
benets, and commitment for egg OIT. Their preferen-
ces and goals for treatment should be discussed, and
all their related questions should be addressed before
initiating this intervention to ensure the best patient
outcome. Young children may also be involved in
the decision-making process in an age-appropriate
way.
15,16
Long-term management of patients with egg
allergy who were successfully desensitized will gen-
erally depend on both the immunotherapy response
and the patientstreatment goals. Some individuals
may prefer protection to egg-containing products
and have no interest in regular consumption of
larger amounts of egg. In this case, oral food chal-
lenges to assess for higher dose tolerance are
unlikely to be useful. For other patients, who wish to
incorporate large amounts of egg into the diet or free
eating, follow-up oral challenges to assess the extent
of desensitization and a discussion about which cu-
mulative dose should be aimed for may be useful to
patients and families. Shared decision-making will
allow for the best plan to be made based on individ-
ual preferences.
17
CLINICAL PEARLS
OIT for egg allergy is effective but not without risk.
The risk-benet ratio should be clearly outlined and
discussed in detail with patients and families so
they can make the decision that best ts their expect-
ations and preferences.
Multiple protocols exist for egg OIT that use a vari-
ety of dosing schedules and buildup intervals. There
is no standardized approach for egg OIT.
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This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the clinical effectiveness and safety of egg oral and sublingual immunotherapy in children and adults with IgE-mediated egg allergy.
Article
Background: Egg oral immunotherapy is effective but time consuming. Objective: To assess the efficacy and safety of egg rush oral immunotherapy (ROIT) with a targeted dose equivalent to a raw egg white. Methods: Thirty-three persistent egg allergic children confirmed by double-blind, placebo-controlled food challenge (DBPCFC) were randomized to receive egg ROIT immediately after randomization (ROIT1 group), or to continue an egg avoidance diet for 5 months after randomization (control group [CG]). A 5-day build-up phase starting with the highest single tolerated dose at baseline DBPCFC was scheduled and several doses administered daily until achieving a dose of approximately 2,808 mg of egg white protein. In the maintenance phase, patients ate an undercooked egg every 48 hours for 5 months. The CG participants who failed the DBPCFC at 5 months began active treatment. Children from the ROIT1 group plus children from the CG who failed a second DBPCFC at 5 months and then received egg ROIT were randomized to the ROIT2 group. Adverse events (AEs) and immune marker evolution were recorded. Results: A total of 17 (89%) of 19 children in the ROIT1 group and no CG patients were desensitized at 5 months (P < .001). A total of 31 (97%) of the 32 children in the ROIT2 group completed the build-up phase in a median of 3 days (range, 1-14 days), and 30 (94%) of 32 maintained desensitization at 5 months. From baseline to 5 months of treatment, skin prick test, specific IgE, and specific IgE/IgG4 ratio to egg fractions significantly decreased, whereas specific IgG4 increased. During the build-up phase, AEs occurred in 69% of patients (50% had ≤2 AEs) and 31% of doses (2% severe, 55% gastrointestinal). Lower threshold dose in the DBPCFC and higher egg white and ovalbumin specific IgE levels at baseline revealed an association with a higher rate of AEs. Conclusion: The proposed 5-day egg ROIT desensitized 94% of the allergic patients, with most AEs being mild or moderate.
Article
Background: The minimal dose for oral immunotherapy (OIT) tolerance is unknown. We investigated the efficacy and safety of low-dose OIT with 1/32 of the volume of a whole egg. Methods: Thirty-three children (aged ≥5 years) with egg allergies confirmed by oral food challenge against 1/32 of a heated whole egg (194 mg of egg protein) were enrolled. The OIT group ingested a scrambled egg once a day. The volume was gradually increased up to a maximum of 1/32 of a heated whole egg. Egg consumption was completely absent in the control group. Results: There were no significant differences in background between the OIT and control groups. Respectively, 71% (15/21) and 0% (0/12) of the patients in the OIT and control groups exhibited sustained unresponsiveness to 1/32 of a whole egg 2 weeks after stopping OIT after 12 months (p < 0.001); 33% (7/21) and 0% (0/12; p = 0.032), respectively, showed sustained unresponsiveness to 1/2 of a whole egg. Egg white- or ovomucoid-specific IgE levels in the OIT group were significantly lower than at baseline after 12 months. Egg white- or ovomucoid-specific IgG as well as IgG4 levels in the OIT group were significantly higher than baseline levels after 1, 3, 6, and 12 months. Adverse allergic reactions were rare, and most symptoms were mild. Conclusions: Low-dose OIT induced sustained unresponsiveness to 1/32 and 1/2 of a whole egg, with no severe symptoms. To improve food allergies, continuous intake of small amounts of these foods may be as effective as the consumption of larger quantities.