Peanut allergy (part 2)

Peanut Allergy
Part 2
• Topic Review
• May 29th, 2020
• Rapisa Nantanee, M.D.
• Pediatric Allergy and Immunology Unit
• King Chulalongkorn Memorial Hospital
This Photo by Unknown Author is licensed under CC BY-NC

Preformed
mediators
Gilda Varricchi, et al. Immunological Reviews. 2018;282:8–34.

W. Yu, et al. Nat Rev Immunol 16, 751–765 (2016).

Hugh A. Sampson, et al. J Allergy Clin Immunol 2018;141:11-9.

Treatment
• Subcutaneous immunotherapy (SCIT)
• Demonstrated the potential for desensitization but concerns for side
effects and the safety of the treatment led to it being mostly
abandoned.
• Oral immunotherapy (OIT)
• Sublingual immunotherapy (SLIT)
• Epicutaneous immunotherapy (EPIT)
EH. Kim, AW. Burks. Allergy. 2020;00:1–10.

Treatment
• Ideal goal of treatment: permanent tolerance
• The lack of accepted biomarkers designating tolerance and the
arbitrary nature of prescribed treatment avoidance has typically
precluded the use of the term tolerance.
• Sustained unresponsiveness (SU)
• Persistence of a nonreactive state on DBPCFC for a short time off of
therapy
• Remission
• Describe the ability of an allergic individual to reincorporate the food
allergen(s) into the diet after treatment.

MD. Kulis, et al. J Allergy Clin Immunol 2018;141:491-8.

OIT
Initial dose escalation
Multiple increasing doses of
food allergen are ingested
over a period of several hours
in an observed setting.
- The starting OIT dose is ingested in clinic
under observation after which the dose is
repeated daily at home for 1-2 weeks.
- The OIT dose is then increased per the
protocol and ingested under observation,
and the pattern is repeated until the
maintenance dose is achieved. Home OIT dosing
continues daily with
interval follow-up clinic
visits for safety.
OFC
OFC OFC
Establish the diagnosis of food
allergy and to determine the
baseline reaction threshold.
Assessed for desensitization
which is defined as an
increase in reaction threshold
while actively on therapy.
Assess for a
lasting
treatment
effect

J. Andrew Bird, et al. J Allergy Clin Immunol Pract 2020;8:75-90.

OIT
• Significant variability has existed across studied protocols.
• Target cumulative doses during IDEs have been prescribed up to 500
mg but today have more commonly been capped at 6-12 mg.
• Dose escalations have ranged from 25% to 100% increases occurring at
weekly to biweekly intervals.
• Maintenance doses have ranged from a few hundred mg up to several
thousand mg with treatment lasting several weeks up to 5 years.
• SU has been investigated from 2 weeks up to 3 months of avoidance.

Peanut OIT

FDA-approved peanut OIT
• Indication:
• Mitigation of allergic reactions, including
anaphylaxis, that may occur with accidental
exposure to peanut.
• Contraindication:
• Uncontrolled asthma,
• History of eosinophilic esophagitis or other
eosinophilic gastrointestinal disease
• Approved for use in patients with a
confirmed diagnosis of peanut allergy.
• Initial Dose Escalation may be
administered to patients aged 4 through 17
years.
• Up-Dosing and Maintenance may be
continued in patients 4 years of age and
older.
• Use in conjunction with a peanut-avoidant
diet.
• Open capsule(s) or sachet and empty the
entire dose of PALFORZIA powder onto
refrigerated or room temperature semisolid
food.
• Cost $4,200/yearPalforzia® prescribing information.
ICER June 2019.

EPIT
The allergen content of the patch remains
constant and peanut exposure is instead
varied by duration of application.
Increases in the duration of patch application are
usually accomplished over just a few weeks up to
the 24-hour maintenance application.
OFC
OFC OFC
Establish the diagnosis of food
allergy and to determine the
baseline reaction threshold.
Assessed for desensitization
which is defined as an
increase in reaction threshold
while actively on therapy.
Assess for a lasting
treatment effect

Peanut EPIT
• Epicutaneous immunotherapy (EPIT) as a
treatment for allergic disease has been a recent
consideration with one of the earliest reports
published in 2009 by Senti, et al describing
improvements in nasal provocation testing to grass
pollen after EPIT.
• The Viaskin® peanut patch was developed by DBV
Technologies.
• The premise of this platform was the application of the
patch onto intact skin with peanut protein electrostatically
adhered to the inner portion of the patch.
• Solubilization of the peanut by sweat concurrently with the
opening of skin pores would then allow for the passive
transfer of peanut to skin-based Langerhans cells with
minimal risk of systemic absorption.
https://www.dbv-technologies.com/viaskin-platform/

Peanut EPIT

Peanut EPIT
CoFAR 6 study
VIPES study
• Parallel phase 2 studies
• In the CoFAR 6 study, a statistical difference was seen with both the 250 and 100 mcg patch;
however, the efficacy appeared stronger with the 250 mcg patch. As in the VIPES study, the
treatment effect was seen in the 4- to 11-year-old cohort.
• In the VIPES study, a statistical difference in responder rate was seen with the 250 mcg patch
but not with the other doses. When stratified for age, the statistical difference remained for
the 6- to 11-year-old cohort.
• Immunologic data demonstrated initial increases followed by steady decreases in pn-sIgE,
increases in pn-sIgG4, and decreases in peanut SPT in both studies suggesting immune
modulation with this novel delivery method.

Peanut EPIT
• Local mild-to-moderate skin reactions were common; however,
only 2 (0.9%) subjects in the VIPES study and 1 (3.4%) subject
in the CoFAR 6 study withdrew due to local skin reactions.
CoFAR 6 study
VIPES study

Peanut EPIT
• Multi-national phase 3 “Peanut EPIT Efficacy and Safety Study” (PEPITES) trial
• 356 subjects across 5 countries
• Children aged 4 to 11 years using the Viaskin® 250 mcg peanut patch
• Response to EPIT was stratified by baseline ED
• Subjects reactive to an ED ≤ 10 mg considered responders with a post-treatment ED ≥ 300 mg
• Subjects reactive to 10-300 mg considered responders with a post-treatment ED ≥ 1000 mg
• After a 12-month treatment period, a responder rate of 35.3% was seen with the peanut EPIT
group vs 13.6% in the placebo group.
• While the response rates were statistically different, the confidence interval around the 21.7%
difference in responder rates did not meet prespecified cutoffs, and thus, the study did not meet its
primary efficacy outcome.

Peanut EPIT
• The safety profile for peanut EPIT remained reassuring with
mostly mild-to-moderate local site reactions reported.
• 22 subjects (9.2%) reported AEs treated with epinephrine and 8
subjects developed anaphylaxis (3.4%).
• Four subjects withdrew prematurely due to AEs, and 3 due to
anaphylaxis.

Comparison of OIT and EPIT
• Peanut OIT has
repeatedly
demonstrated strong
desensitization;
however, concerns for
tolerability have
persisted.
• A recent comprehensive
systematic review by
Nurmatov, et al as well
as the PACE meta-
analysis suggested a
higher risk on OIT
treatment than with
peanut avoidance.
• EPIT has provided simple
administration, minimal
lifestyle restrictions due
to treatment, and a low
rate of withdrawals due to
side effects.
• However, its desensitization
effect has not been as clear
as its pivotal phase 3 study
did not meet its primary
outcome.
• Increasing responder
rates after 2 and 3 years
of treatment in the 2-year
extension of the VIPES
study has suggested that
improved success with
peanut EPIT may still be
possible, but further study
is needed
OIT and EPIT in its current iterations may not be
appropriate for everyone and that peanut
avoidance may still be the right choice for some
patients.
OIT EPIT

Future directions for food therapy
• Further optimizations of allergen-specific treatments have been under
investigation.
• Examples: protocol modifications (dose, duration, patient selection), the use of
biologics with immunotherapy, probiotics with immunotherapy, and the concurrent
treatment of multiple allergens with OIT simultaneously
• Alternative modalities
• Sublingual immunotherapy (SLIT)
• Subcutaneous injections (SCIT)
• Modified proteins and DNA vaccines
• Allergen nonspecific treatments with the potential to treat multiple allergens
simultaneously are also under investigation including biologics targeting aspects of
the allergic immune response and continued work on an anti-anaphylaxis Chinese
herbal formulation.

Prevention
• The Learning Early about Peanut Allergy (LEAP) trial
• The Enquiring about Tolerance (EAT) trial
• Addendum guidelines for the prevention of peanut allergy in the
United States: Report of the National Institute of Allergy and
Infectious Diseases–sponsored expert panel
• Early introduction of allergenic foods for the prevention of food
allergy from an Asian perspective—An Asia Pacific Association
of Pediatric Allergy, Respirology & Immunology (APAPARI)
consensus statement

Randomized Trial of Peanut Consumption
in Infants at Risk for Peanut Allergy
• The Learning Early about Peanut Allergy (LEAP) trial
• Whether the early introduction of dietary peanut could serve
as an effective primary and secondary strategy for the
prevention of peanut allergy.
• A randomized, open-label, controlled trial conducted at a single
site in the United Kingdom.
• Study enrollment took place from December 2006 to May 6,
2009.
G. Du Toit, et al. N Engl J Med 2015;372:803-13.

To be eligible for enrollment, infants
had to be least 4 months and less
than 11 months of age and had to
have severe eczema, egg allergy,
or both.
No measurable
wheal after testing
A wheal
measuring 1 to 4
mm in diameter
Baseline
open-label
food challenge
Baseline
open-label
food challenge
LEAP Trial
Participants
randomly assigned
to consumption
were fed at least 6 g
of peanut protein per
week, distributed in
three or more meals
per week, until they
reached 60 months
of age.
Participants
assigned to
avoidance were
to avoid the
consumption of
peanut protein
until they reached
60 months of age.
The primary
outcome was the
proportion of
participants with
peanut allergy at
60 months of age
by oral food
challenge.

• Results
• The group with a negative result on the initial skin-prick
test
• At 60 months of age, 13.7% of the avoidance group and 1.9% of the
consumption group were allergic to peanuts;
• This absolute difference in risk of 11.8 percentage points (95%
confidence interval [CI], 3.4 to 20.3; P<0.001) represents an 86.1%
relative reduction in the prevalence of peanut allergy.
• The group with positive results on the initial skin-prick
test
• At 60 months of age, 35.3% of the avoidance group and 10.6% of the
consumption group were allergic to peanuts;
• The absolute difference in risk of 24.7 percentage points (95% CI,
4.9 to 43.3; P = 0.004) represents a 70.0% relative reduction in the
prevalence of peanut allergy.
• The results in the per-protocol population and worst-case
imputation analysis in the intention-to-treat population were
consistent with the results of the main intention-to-treat
analysis.

• At 60 months
• The mean diameter of wheals
and the number of participants
with markedly elevated levels of
peanut-specific IgE titers were
higher in the peanut-avoidance
group than in the consumption
group.
• In contrast, the peanut-
consumption group showed a
significantly greater and earlier
increase in levels of peanut-
specific IgG and IgG4.

Randomized Trial of Peanut Consumption
in Infants at Risk for Peanut Allergy
• Among infants with high-risk atopic disease, sustained peanut consumption beginning in the
first 11 months of life, as compared with peanut avoidance, resulted in a significantly smaller
proportion of children with peanut allergy at the age of 60 months.
• Peanut consumption may not be possible in some children who meet the LEAP eligibility criteria.
• The LEAP study design excluded 9.1% of the infants who were screened (76 of 834) because large wheals
(greater than 4 mm in diameter) developed after the skin-prick test that were probably associated with peanut
allergy; the safety and effectiveness of early peanut consumption in that population remain unknown.
• IgG4 is associated with a protective role against the development of allergy.
• The main weakness of the study
• lack of a placebo regimen
• The study did not include low-risk infants and those who had large wheals (>4 mm in diameter).

The prevalence of peanut allergy at 60
months of age among only the
participants in the primary trial who
enrolled in the follow-up study.
LEAP-On
Study
months of age among participants in the
follow-up study who were included in the
intention-to-treat analysis (i.e., all
enrolled participants in the follow-up study
who had a peanut-allergy outcome that
could be evaluated).
months of age among participants who
met the per-protocol criteria in both the
primary trial and the follow-up study.
The reduction in
the prevalence of
peanut allergy that
was associated with
the early
introduction and
consumption of
peanuts until 60
months of age
persisted at 72
months of age after
12 months of not
eating peanuts.

Randomized Trial of Introduction of
Allergenic Foods in Breast-Fed Infants
• The Enquiring about Tolerance (EAT) trial
• Whether the early introduction of common dietary allergens
(peanut, cooked hen’s egg, cow’s milk, sesame, whitefish, and
wheat) from 3 months of age in exclusively breast-fed infants
in the general population would prevent food allergies, as
compared with infants who were exclusively breastfed for
approximately 6 months.
• Randomized, controlled trial at a single site in the United
Kingdom
MR. Perkin, et al. N Engl J Med 2016;374:1733-43.

- Exclusively breast-fed to
approximately 6 months of
age.
- After 6 months of age, the
consumption of allergenic
foods was allowed
according to parental
discretion.
- Skin-prick testing in duplicate
at baseline
- Six allergenic foods
introduced: cow’s milk (yogurt)
first, followed (in random order)
by peanut, cooked (boiled) hen’s
egg, sesame, and whitefish;
wheat was introduced last.
- 2 g of the allergen protein
twice weekly
Infants in the early-
introduction group who
had a wheal of any
size on skin-prick
testing at baseline
underwent an open-
label incremental food
challenge totaling 2 g
of protein of that food.
Singleton infants who
were 3 months of age and
exclusively breast-fed
The primary outcome was
challenge-proven food
allergy to one or more of
the six early-introduction
foods between 1 year and 3
years of age.

Randomized Trial of Introduction of
Allergenic Foods in Breast-Fed Infants
• The per-protocol population
• In each group, breast-feeding was continued to at least 5 months of age.
• The standard-introduction group
• No consumption of peanut, egg, sesame, fish, or wheat before 5 months of age and
• Consumption of less than 300 ml per day of formula milk between 3 and 6 months of
age.
• The early-introduction group
• Consumption of at least five of the early-introduction foods, for at least 5 weeks
between 3 and 6 months of age, of at least 75% of the recommended dose (i.e., 3 g
per week of allergenic protein).

The prevalence of IgE-
mediated food allergy
To one or more of the six
early-intervention foods
(peanut, cooked egg,
cow’s milk, sesame,
whitefish, and wheat)
To peanut
To egg
Intention to treat Per protocol
Adjusted
per protocol
In the per-protocol analysis, the rate of the
primary outcome was significantly lower in
the early-introduction group than in the
standard-introduction group (2.4% [5 of 208
participants] vs. 7.3% [38 of 524]).
In the per-protocol analysis of peanut
consumption, there were no cases of
peanut allergy among the 310 participants
in the early-introduction group, as
compared with 13 cases among 525
participants (2.5%) in the standard-
introduction group (P = 0.003).
The prevalence of egg allergy among
participants who adhered to the protocol with
respect to egg consumption was 1.4% in the
early-introduction group versus 5.5% in the
standard-introduction group, representing a
75% lower relative risk (P = 0.009).

Addendum guidelines for the prevention of peanut
allergy in the United States: Report of the NIAID–
sponsored expert panel
A. Togias, et al. J Allergy Clin Immunol 2017;139:29-44.
Severe eczema is defined as persistent or
frequently recurring eczema with typical
morphology and distribution assessed as severe by
a health care provider and requiring frequent need
for prescription-strength topical corticosteroids,
calcineurin inhibitors, or other anti-inflammatory
agents despite appropriate use of emollients.
Egg allergy is defined as a history of an allergic
reaction to egg and a skin prick test (SPT) wheal
diameter of 3 mm or greater with egg white extract,
or a positive oral egg food challenge result.

A. Togias, et al. J Allergy Clin Immunol 2017;139:29-44.
Addendum guidelines for the
prevention of peanut allergy in the
United States: Report of the
NIAID–sponsored expert panel

A. Togias, et al. J Allergy Clin
Immunol 2017;139:29-44.

EH. Tham, et al. Pediatr Allergy Immunol. 2018;29:18–27.
APAPARI
consensus
statement
Undiagnosed food allergies may
exist in this group of infants even
before introduction of allergenic food.

Prevention
• The dual-allergen exposure hypothesis
• Early environmental exposure (through the skin) to peanut may
account for early sensitization, whereas early oral exposure may lead
to immune tolerance.
• A trend toward Th2 skewing in skin-homing CLA+ cells of peanut-
allergic subjects, suggesting that allergic sensitization occurs through
the skin, whereas Th1 skewing in gastrointestinal (GI)-homing
α4β7+ cells of peanut-tolerant subjects suggested that allergen
exposure through the GI tract promotes tolerance.
S. M. H. Chan, et al. Allergy 67 (2012) 336–342.

Conclusion
• Peanut allergy is a common cause of food allergy in Western
countries, and also one of the most frequent food allergens
involved in lethal anaphylaxis.
• Various diagnostic test, other than food challenge, has been
studied to confirm peanut allergy.
• Potential treatment for peanut allergy are developed, ex. OIT,
EPIT.
• Early introduction of peanut in high-risk infants is beneficial.

Peanut allergy (part 2)

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