Phase I Open-Label Study of Omalizumab (Xolair) in Peanut

Kari C. Nadeau, MD, PhD
Division of Allergy , Immunology, and
Rheumatology
at Stanford
Describe the pathophysiology, initial evaluation &
management of patients with food allergy including
gastrointestinal food allergy, oral allergy syndrome
and type I food allergy
 Identify recent advances in the field of food allergy
and have some familiarity with published guidelines
for managing food allergy
 Outline current and emerging treatment modalities
for food allergic patients
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Nothing to disclose
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ID: 9.5 y.o. male with a history of severe food
allergies, eczema, and asthma
CC: Presents to PICU with hypoxic brain
injury due to anaphylaxis from cow’s milk
ingestion
Transferred to PICU from outside hospital
after multiple failed resuscitations over a 3 hr
period
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On the evening of 8-11-04, patient accidentally drank from
his sister’s cup of cow’s milk on the way to bed.
He immediately developed emesis and became SOB; parents
gave Epipen jr. to his thigh and called 911
Paramedics arrived in 10-15 minutes
On the scene, intubation was attempted but difficult
Duration of code=1 hr.
CT scan showed hypoxic injury and right uncal herniation.
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In 2001, he presented to LPCH AAI clinic and had severe
eczema and asthma. RAST tests were performed at 2001 and
showed IgE > 2000, Milk> 100, Peanut>100, Egg 40.3, Soy
17.9, Wheat 20.2, Corn 26.3, Oat 12.3. No known allergies to
beef.
He had had one prior visit to the ER for milk ingestion in
2001. He presented with hyperventilation and emesis. He
was given benadryl and his symptoms improved.
He was hospitalized three times in the first year of life for
asthma; no intubations but did need steroids
Patient and family were prescribed an Epipen jr. and
taught about anaphylaxis precautions
 Patient then began to receive care at private AI
facility and was recommended 9 months prior to
event to repeat RAST testing. This was not done.
 Over the past couple of months prior to event,
parents decided to allow him to eat wheat, corn,
oat, and egg products since he did not seem to have
any symptoms from these foods.
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Background
Definition
Clinical signs and symptoms
Natural History
 Cow’s milk, hen’s egg, soy, peanut, tree nuts
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Diagnostic work-up
Treatment
Research studies and FAQs
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Prevalence ~4%
- Peanuts – 3 million allergic in U.S. (~1.1%)
Branum 2009 Pediatrics 124:1549-55
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Most common cause of visits for pediatric
anaphylaxis treated in U.S. Emergency Rooms
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> 15% of patients/year have accidental reactions
Yu 2006 J Allergy Clinical Immunology 118: 466-472
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100-150 deaths/year reported from food
allergies
- Bock SA J Allergy Clinical Immunology 2001: 107 (1): 191-193
Food culprits (n=79)
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Peanut
Tree nut
Fish/shellfish
Milk
Wheat
Unknown
56%
24%
8%
9%
1%
3%
Mixed nuts, baked goods, cookies, candies, Ethnic
food, buffets, sauces, cross-contamination
Bock S.A. AAAAI meeting 2009
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Adolescents
Nut Allergy
Known food allergy
History of Anaphylaxis
Asthma, especially those with poor control
Lack of skin symptoms
Denial of symptoms
Concomitant intake of alcohol (which may increase absorption of
food)
Belief that antihistamines alone were sufficient to treat symptoms
Delay or lack of administration of epinephrine
However even timely injections of epinephrine do not necessarily
prevent death (4 of 32 cases)
Bock SA J Allergy Clinical Immunology 2001: 107 (1): 191-193
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Can occur in 30-60 minutes
Due to upper or lower respiratory
compromise or cardiovascular collapse
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Pumphrey et al. Clin Exp Allergy 30 (2000): 1144–1150.
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Adverse health effect arising from a
specific immune response that occurs
reproducibly on exposure to a given food.
National Institute of Allergy and Infectious Diseases (NIAID )
Guidelines for the Diagnosis and Management of Food Allergy 2010
National Institute of Allergy and Infectious Diseases (NIAID )
Guidelines for the Diagnosis and Management of Food Allergy 2010
Signs and symptoms
Cutaneous
Urticaria and angioedema
Flush
Pruritus without rash
Respiratory
Dyspnea, wheeze
Upper airway angioedema
Rhinitis
Dizziness, syncope,
hypotension
Abdominal
Nausea, vomiting,
diarrhea, cramping pain
Miscellaneous
Headache
Substernal pain
Seizure
Percentage of cases
>90
85–90
45–55
2–5
40–60
45–50
50–60
15–20
30–35
25–30
5–8
4–6
1–2
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Over 170 foods have been reported to cause
IgE-mediated reactions
However over 90% of food allergies are
caused by the following foods
 Milk
 Hen’s egg
 Soy
 Wheat
 Peanut
 Tree Nuts
 Shellfish
 Fish
National Institute of Allergy and Infectious Diseases (NIAID )
Guidelines for the Diagnosis and Management of Food Allergy 2010
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Children with food allergy*:
 35-71% atopic dermatitis
▪ Possible that peanut sensitization is associated with
atopic dermatitis, use of peanut oil containing skin
preparations, and household consumption of peanut**
 33-40% allergic rhinitis
 34-39% asthma
* Sicherer et al. J of Allergy and Clin Immunology 2001: 108: 128-32
** Fox et al. J of Allergy and Clin Immunology 2009: 123 (2): 417-23.
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Oral pruritus, rapid onset, IgE-mediated,
rarely progressive
Usually fresh fruits and vegetables
Heat labile: cooked forms, no reaction
Cause: cross reactive proteins pollen/food
Birch
Ragweed
Grass
Pollen
Apple, apricot, carrot, cherry, kiwi, plum
Banana, cucumber, melon, watermelon
Cherry, peach, potato, tomato
Foods
Age Onset:
Duration:
Characteristics:
Enterocolitis
Enteropathy
Proctitis
Infant
Infant/Toddler
Newborn
12-24 mo
12-24 mo
Failure to thrive
Shock
Lethargy
Diarrhea
Vomiting
9 mo-12 mo
Malabsorption Bloody stools
Villous atrophy
Eosinophilic
Self limited
Non-IgE-mediated, typically milk and soy induced
 Spectrum may include colic, constipation and occult GI
blood loss
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Celiac Disease (Gluten-sensitive enteropathy)
 Anti-gliadin IgG, anti-endomysial IgG, IgA
 Villus atrophy, malabsorption, pain, associated CA
Eosinophilic esophagitis, gastritis, gastroenteritis
 Eosinophilic infiltration
 Poor growth, pain, vomit, diarrhea, reflux
 Multiple food allergy, IgE and non-IgE-mediated
 May affect varying regions of gut
Gastrointestinal Anaphylaxis
 Acute vomit/diarrhea, IgE-mediated
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Migraines
Behavioral / Developmental
disorders
Arthritis
Seizures
Inflammatory bowel disease
Condition
What is not a food allergy?
Symptoms
Mechanism
Lactose intolerance
Bloating, abdominal pain, diarrhea
(dose-dependent)
Lactase deficiency
Fructose intolerance
Bloating, abdominal pain, diarrhea
(dose-dependent)
Fructase deficiency
Pancreatic
insufficiency
Malabsorption
Deficiency of pancreatic enzymes
Gallbladder/liver
disease
Malabsorption
Deficiency of liver enzymes
Food poisoning
Pain, fever, nausea, emesis,
diarrhea
Bacterial toxins in food
Scombroid fish
poisoning
Flushing, angioedema, hives,
abdominal pain
In spoiled fish histidine is metabolized to
histamine
Caffeine
Tremors, cramps, diarrhea
Pharmacologic effects of caffeine in susceptible
individuals
Tyramine
Migraine
Pharmacologic effects of tyramine in susceptible
individuals
Auriculotemporal
syndrome (Frey
syndrome)
Facial flush in trigeminal nerve
distribution associated with
spicy foods
Neurogenic reflex, frequently associated with
birth trauma to trigeminal nerve (forceps
delivery)
Gustatory rhinitis
Profuse watery rhinorrhea
associated with spicy foods
Neurogenic reflex
Panic disorder
Subjective reactions, fainting upon
smelling or seeing the food
Psychologic
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Most children will outgrow cow’s milk, egg, and wheat
allergy
Far fewer will outgrow peanut and tree nut allergy
A high initial specific IgE against the food is associated with a
lower rate of resolution of clinical allergy over time
Atopic dermatitis resolution is a useful marker for onset of
tolerance to food allergens
Skin tests to a food can remain positive long after tolerance
to a food has developed.
Nevertheless, reduction in the size of the skin test wheal
may be a marker for the onset of tolerance to the food
allergen.
National Institute of Allergy and Infectious Diseases (NIAID )
Guidelines for the Diagnosis and Management of Food Allergy 2010
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First foreign protein introduced into infant’s diet
Most common food allergy in young children
 2.5% of children in first two years of life
 1.1% is IgE-mediated
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Minimal threshold dose to cause allergic reaction
as low as 0.02 mL of milk (e.g. drops)
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Cross-reactivity with cows, goat, and sheep milk
secondary to homology between these proteins
 90% children allergic to cow’s milk will be reactive to
goat’s milk on oral food challenge
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75% of cow’s milk allergic children will
tolerate extensively heated cow’s milk (e.g.
baked goods)
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1-2% children
Yolk considered less allergenic than white
Egg white has 23 glycoproteins
70% egg allergic children may be able to
ingest small amounts of egg protein in
extensively heated (baked) products
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0.4% children
Belongs to legume family with peanut
 88% have concomitant peanut allergy
 1.1%
 Most common food allergy in
pediatric population beyond 4 years
of age
 Most likely to cause fatalities
 21.5% chance of outgrowing peanut
allergy
 8% risk of recurrence
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0.6% population allergic
Walnuts – 34%
Cashews – 20%
Almonds – 15%
Pecan – 9%
Pistachio – 7%
Hazelnut, Brazil nut, Pine Nut, Macadamia
nut < 5%
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In recent study, 12% patients allergic to more than 1 tree nut
Approximately 30-50% of peanut allergic patients have at
least one tree nut allergy
Approximately 9% outgrow tree nut allergy
 Note 14/19 patients who never ingested tree nuts but had elevated
specific IgE passed the oral food challenge
 Of these 14 patients, 58% with specific IgE ≤ 5 passed the oral food
challenge while 63% with specific IgE ≤ 2 passed the oral food
challenge
Fleischer DM. J Allergy Clin Immunol. 2005;116(5):1087-93
The severity of a reaction cannot be accurately
predicted by the degree of severity of past reactions
and depends on:
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Amount ingested
Food form (cooked, raw, or processed)
Co-ingestion of other foods
The severity also may be influenced by
 The age of the patient
 The degree of sensitization at the time of ingestion
 The rapidity of absorption, based on whether
The food is taken on an empty stomach
 The ingestion is associated with exercise
 The patient has other co-morbid conditions (e.g., asthma or AD )
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1% to 20%
Typically occur 8 hours after initial reaction, but up
to 72 hours later
Up to 25% of fatal or near-fatal food reactions
There is no consensus on optimal observation time
following the initial reaction; recommendations
range from 4 to 24 h
Minimum 4 hour observation
Studies suggest that delayed administration,
inadequate dosing, or a need for large doses of
epinephrine are risk factors for biphasic reactions
Also failure to administer corticosteroids also seems
to predispose towards biphasic reaction
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ImmunoCAP – Allergy blood tests*
 Generally felt to be less sensitive than SPT
Allergen
kUA/L
PPV[+]
Egg
7
98
Infants ≤2 yr[∗]
2
95
Milk
15
95
Infants ≤1[∗∗]
5
95
Peanut
15
99
Fish
20
95
Soybean
30
73
Wheat
26
74
Tree nuts[∗∗∗]
≈15
≈95
*Results from ImmunoCAP testing are not comparable to IgE levels from other assay systems such as Immunolite and Turbo-MP. Must
know assay lab using.
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Airway, Breathing, Circulation
Vital signs
EpiPen
Concurrently, call 911
Supine position with legs elevated (unless
respiratory compromise or vomiting)
Supplemental O2
 Optimize organ perfusion and bronchodilates
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IVF
Weight estimation for dosing of medications
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What are the indications to give Epinephrine?
 Severe reaction
 Respiratory distress
 Swollen throat
 Loss of Consciousness
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Seconds but is rapidly metabolized
Effect often short-lived and repeat doses may
be necessary for severe or protracted
anaphylaxis (within 1-2 minutes if first one is
not working)
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10-20% of anaphylactic cases required 2nd
Epipen injection
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Jarvinen et al. J Allergy Clin Immunology 2008; 122:133-138
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Second line treatment only
Not life-saving
Only relieve itching and urticaria
Do not relieve stridor, shortness of breath,
wheezing, GI symptoms, or shock
Onset of action 20-60 minutes
H1 and H2 antagonism superior to H1 alone
National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management
of Food Allergy 2010
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Prolonged observation is mandated
At least 8-24 hours after symptoms have
resolved
 Moderate to severe reaction
 Asthmatic wheezing
 Ingested antigen with risk of systemic absorption
 Previous history of biphasic response
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Strict Avoidance of Allergenic Foods
 Regular growth monitoring
 Nutritionist
▪ Possibly decreases risk of malnutrition (e.g. Ca, Vit D)
▪ Christie et al. J Am Diet Assoc 2002; 102(11): 1648-51.
▪ Education on how to read labels
 Only 7%, 22%, and 54% of parents correctly identified labeled
products containing milk, egg, and peanut respectively
 Joshi et al . J Allergy Clin Immunol 109(6): 920-2.
▪ Food Allergen Labeling and Consumer Protection Act (FALCA) effective
2006 mandates manufacturer disclosure of the most common allergens
(milk, egg, wheat, soy, peanut, tree nuts, fish, and crustacean shellfish) in
plain English in the ingredient list or in a separate “contains” statement
▪ 17% of 20,214 products contain advisory labels
 Pieretti, J Allergy Clin Immunol 2009;124:337-41
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Strict Avoidance of Allergenic Foods
 Nutritionist
▪ Education on how to read labels
▪ Food allergic patients assume incorrectly that terms such as
‘‘shared equipment,’’ ‘‘shared facility,’’ or ‘‘may contain’’ indicate
different levels of risk.
▪ Avoid products that state “may contain” or “manufactured on
equipment”
▪ 5-17% risk of significant amount of allergen in food
▪ 1.9% without declaration of allergen contained allergen
- Remington et al. J Allergy Clin Immunol 2010;125 (2): AB218
- Ford et al. J Allergy Clin Immunol 2009; 123 (2): S176
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Even when patients ask about ingredient
information they may receive inaccurate
information
If symptoms start assume allergic reaction,
call for help
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Bock S.A. Academy of Allergy Asthma and Immunology Annual meeting 2009
 Food Allergy and Anaphylaxis Network
(www.foodallergy.org)
▪ Newsletter
▪ Website with patient handouts, educational
videos and children’s books
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Epinephrine
 1st line treatment
 Life-saving
 Majority of patients who have prescription do not carry
Epinephrine
 Even those who carry the Epinephrine do not administer
the medication when clinically indicated
▪ Only 3% of patients who died of food anaphylaxis had Epineprhine
▪ Bock et al. J Allergy Clin Immunol 2001;107:191-3
 Only 21% of families demonstrate proper use
▪ Sicherer, et al. Pediatrics 105 (2000), pp. 359–362
 Must demonstrate how to use it
 Have families practice
 Watch Training Video (EpiPen or TwinJect)
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While administering epinephrine, call 911
Delayed administration of epinephrine has
contributed to fatalities
 Give Epinephrine immediately, but at least within 30
minutes, of food allergic reaction
▪ Sampson et al. Engl J Med. 1992. 327(6):380-4.
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All other medications, including antihistamines and
corticosteroids considered adjunctive
 Antihistamine use most common reason cited for not
using Epinephrine and may significantly increase risk of
life-threatening reaction
▪ Simons et al. J Allergy Clin Immunol 2009;124:301-6
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Liquid Zyrtec or Benadryl at all times
 Prefilled teaspoons are easy to transport and
readily available over the counter
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Medicalert.org
laurenshope.com
Inscription example: “Patient’s name. Allergic to peanuts,
tree nuts + Asthma. Give EpiPen and call 911. Mother or
father: cell phone number.”
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MMR and Varicella and influenza grown in
chicken-embryo fibroblast culture and
contains minimal amounts of egg protein
Can be administered safely in egg-allergic
patients, even those with a severe h/o allergic
reaction if skin test is negative
National Institute of Allergy and Infectious Diseases (NIAID )
Guidelines for the Diagnosis and Management of Food Allergy 2010
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History: symptoms, timing, reproducibility
 Acute reactions vs chronic disease
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Diet details / symptom diary
 Specific causal food(s)
 “Hidden” ingredient(s)
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Physical examination: evaluate disease
severity
Identify general mechanism
 Allergy vs intolerance
 IgE versus non-IgE mediated
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Suspect IgE-mediated
 Prick skin tests (fresh extract if oral allergy)
 RAST
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Suspect non-IgE-mediated
 Consider biopsy of gut, skin
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Suspect non-allergic, consider:
 Breath hydrogen
 Sweat test
 Endoscopy
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Positive prick test or RAST
 Indicates presence of IgE antibody NOT clinical
reactivity
Negative prick test or RAST
 Essentially excludes IgE antibody (>95%)
ID skin test with food
 Risk of systemic reaction & not predictive
 Contraindicated
Unproven/experimental tests
 Provocation/neutralization, cytotoxic tests,
applied kinesiology, hair analysis, IgG4
Recommended Interpretation of Food Allergen-Specific IgE levels (kU/L)
Reactive if >
Egg
Milk
Peanut
Fish
Soy
Wheat
7
15
14
20
65
80
30
26
0.35
0.35
Possibly
reactive
(physician
challenge)
Unlikely
reactive if <
(home
challenge)
0.35 0.35 0.35
0.35
* Sampson, H. Utility of food specific IgE in predicting symptomatic food allergy. JACI. 2001.
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Elimination diets (1 to 6 weeks)
 Eliminate suspected food(s), or
 Prescribe limited “eat only” diet, or
 Elemental diet
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Oral challenge testing (MD
supervised, ER meds available)
 Open
 Single-blind
 Double-blind, placebo-controlled
(DBPCFC)
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Test for specific-IgE antibody
 Negative: reintroduce food*
 Positive: start elimination diet
Elimination diet
 No resolution: reintroduce food*
 Resolution
▪ Open / single-blind challenges to “screen”
▪ DBPCFC for equivocal open challenges
* Unless convincing history warrants supervised challenge
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Includes disease with unknown mechanisms
 Food additive allergy
Elimination diets (may need elemental diet)
Oral Challenges
 Timing/dose/approach individualized for disorder
▪ Enterocolitis syndrome can elicit shock
▪ Enteropathy / eosinophilic gastroenteritis may need
prolonged feedings to develop symptoms
 DBPCFCs preferred
 May require ancillary testing
(endoscopy / biopsy)
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If Specific IgE to a food > 25 kU/L., low likelihood of losing allergy
Component Diagnostic Testing and Epitope Arrays are moving
forward to further our knowledge and diagnostics capabilities
There are no reliable predictors to determine whose food allergy
will persist
There are no reliable predictors to determine whose food allergy
will lead to severe anaphylaxis (predicted in 50% of cases of food
allergy)
The gold standard to identify an offending food allergen is a
double blind, placebo-controlled in vivo challenge which requires
hospitalization, is costly, lengthy and can result in an
anaphylactic shock
Once the tests occur, there are many false positives that can
lead to elimination diets in children associated with malnutrition
(NY Times.2009)
Epitope Arrays : Development of a novel peptide microarray
for large-scale epitope mapping of food allergens
Serum dilution experiment (A) and
peptide inhibition assay (B). Areas
showing non-specific binding are
indicated with black arrows.
Targeted peptides, which are the
peptides pre-incubated with the
serum pool are indicated with red
arrows for each inhibition group.
Areas with possible crossinhibition based on sequence
alignment are indicated with blue
arrows.
J Allergy Clin Immunol. 2009 Aug;124(2):315-22.
Lin J, et al.
New Diagnostic Allergy Test
based on rapid assessment of blood basophil activation
Stimulated by
Antigen
Unstimulated
Expression of molecules on the
cell surface (expressed by
cytoplasmic compartments) for
example CD203c or CD63
New Diagnostic Allergy Test
Based on rapid assessment of blood basophil activation
Non Activated-diluent
Activated-allergen
20 minutes incubation
Spin 300 x g
0 Breaks
Plasma
Leukocytes
Gradient
Antibodies
1. Anti-CD203c
2. Anti-CD63
3. Anti-CD123
4. HLA-DR
Abs
Staining
RBC
TIME To RESULT: ~ 1 HOUR
Abs diluted in
1% BSA
0.05% NaN3
in PBS
Wash,
and
Flow
Cytometry
•Responses to multiple allergens can be tested at the same time (to assess
which are most important in that patient)
•Results available within 1 hour
•Use the finger stick test to determine who can tolerate their next dose of food
oral immunotherapy
Our Diagnostic Allergy Test Can Detect
Allergic vs. Non-allergic Patients
1000
CD203c (MFI)
Non Activated
basophils
750
500
250
0
Modified Bock's Reaction Grade
Controls
A
4
3
2
r2=0.81
1
0
0
100
200
300
CD203c MFI
400
500
Modified Bock's Reaction Grade
Peanut allergic
Activated basophils
B
4
3
2
1
r2=0.81
0
0
100
200
CD63 MFI
300
400
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Hidden ingredients (peanut in sauces or egg
rolls)
Labeling issues (“spices”, changes, errors)
Cross contamination (shared equipment)
“Code words” (“Natural flavor” may be CMP)
Seeking assistance
 Registered dietitian: (www.eatright.org)
 Food Allergy Network (www.foodallergy.org; 800-
929-4040)
Artificial butter flavor, butter, butter fat, buttermilk, casein,
caseinates (sodium, calcium, etc.), cheese, cream, cottage
cheese, curds, custard, Half&Half®, hydrolysates (casein, milk,
whey), lactalbumin, lactose, milk (derivatives, protein, solids,
malted, condensed, evaporated, dry, whole, low-fat, non-fat,
skim), nougat, pudding, rennet casein, sour cream, sour cream
solids, sour milk solids, whey (delactosed, demineralized,
protein concentrate), yogurt. MAY contain milk: brown sugar
flavoring, natural flavoring, chocolate, caramel flavoring, high
protein flour, margarine.
* It is common to have a reaction to a hidden ingredient to rather
than to have an allergic reaction to a previously tolerated food.
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Soy (confirm soy IgE negative)
 <15% soy allergy among IgE-CMA
 ~50% soy allergy among non-IgE CMA
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Cow’s milk protein hydrolysates
 >90% tolerance in IgE-CMA
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Partial hydrolysates
 Not hypoallergenic! (ex/ Nutramigen)
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Elemental amino acid-based formulas
 Lack allergenicity (ex/ Neocate)
* CMA=cow’s milk allergy
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Epinephrine: drug of choice for reactions
 Self-administered epinephrine readily available
 Train patients: indications/technique
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Antihistamines: secondary therapy
Emergency plan in writing
 Schools, spouses, caregivers, mature sibs / friends
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Emergency identification bracelet
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Re-evaluate for tolerance periodically
Interval and decision to re-challenge:
 Type of food allergy
 Severity of previous symptoms
 Allergen
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Ancillary testing
 Skin prick test/RAST may remain positive
 Reduced concentration food specific-IgE
encouraging
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Aimed at “high risk” newborn
 Positive family history: biparental or parent / sib
Breast feeding generally protective of allergy
Wean / supplement with extensively hydrolyzed
hypoallergenic protein hydrolysate
Delay introduction of solid foods > 6 mo
 Cow milk/dairy: 6-12 months
 Egg: 12-24 months
 Peanut, tree nut, seafood > 24-48 mo
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Identification of causative food
Institution of elimination diet
Education on food avoidance
Development of action plan
Prevention of other allergies
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History and physical paramount
IgE & non-IgE mediated conditions exist
Diagnosis by elimination and challenge
Avoidance/education/preparation for
emergencies are current therapies
Periodic re-challenge to monitor tolerance as
indicated by history, allergen, and level of
food specific-IgE



Review several new forms of allergen
immunotherapy
Discuss positive and negative findings of their
use in clinical trials and argument if they
might become available in the future
Discuss the usefulness of immunotherapy in
food allergy and the current status of these
investigations

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
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Recombinant anti-IgE antibody (Stanford)
Gene (naked DNA) immunization with CPG
repeats (Johns Hopkins)
Sublingual Immunotherapy (Stanford)
Oral Immunotherapy (Stanford)
Hypo-allergenic formulas (Stanford)
Probiotics (UCSF)
Background
BACKGROUND

There is no effective, FDA-approved treatment for food
allergy, except to avoid the offending foods and to have
ready access to self-injectable epinephrine.

Recently, oral desensitization has been used to treat patients
with food allergy; the process is slow and associated with
frequent allergic reactions.

OIT (multi or single)---4-55 yrs
 Milk, Wheat, Egg, Peanut, Tree Nut, Sesame Seed, and/or Soy





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Recombinant anti-IgE antibody + OIT---4-55 yrs
Sublingual Immunotherapy (peanut only)---5-21 yrs
Skin patch (peanut only)---5-21 yrs
Chinese Herbal Medicine---5-21 yrs
Recombinant/Engineered protein allergens
Peanut OIT- 12 mo to 48 mo
Lactobacillus (genetically modified)---Phase I
Denatured/baked milk vs non baked milk---5-21 yrs
Highly cooked egg vs less cooked egg---5-21 yrs
Oral Immunotherapy Study Design
Provided by Dr. Wesley Burks of Duke University
*
Inclusion Criteria:
 Age >4 yrs age
 Symptomatic food
allergy sensitivity include positive skin prick testing (greater tha
n 8 mm) and specific IgE > 7 kU/L.
 Medically documented history of near fatal reaction to food ingestion
 Positive DBPCFC
 Allowed to take antihistamines, asthma meds, and nasal steroid
s as indicated for symptomatic control of atopic conditions
Exclusion Criteria:
 No significant organ system disease
 Failure to comply with training for allergy reactions
 FEV1 or PEF is <80% predicted with or without meds
 Subjects taking oral, IM,IV steroids, beta blockers.
* Similar to Duke and Arkansas
Screening period is very important
Preliminary Dosing Visit: Incremental escalating doses of
fod flour given orally as tolerated to a max of the top dose
of allergen of 6 mg (as per Duke and Arkansas protocol).
 Up dosing visits weekly to MTD (awareness of symptoms)
 Treatment Course: Top dose (“ maintenance dose”)
self administered daily for minimum of 12 months
 Blood samples minimally should be
collected at baseline, 6 months, 12 months, continuing


Role of Adjunctive therapy in OIT:
Use of Anti IgE in reported studies as example

AAAAI, 2011 Savage, et al. Omalizumab In Peanut Allergy: Effects On The Basophil, Mast Cell, And Food
Challenge Response
 N=10 Peanut-allergic adults with 6 mos of omalizumab. At a median of 5 weeks, a DBPCPC was
performed in 9 subjects. Results: “There was a significant increase in the mean dose of peanut
protein tolerated (DPP, 212 mg to 6,010 mg,p<0.01)”

AAAAI, 2011 Pena-Peloche, et al. Treatment Of Severe And Persistent Food Allergy With Omalizumab
 Milk and egg allergic children underwent 16 weeks of omalizumab. Out of seven patients, 2 patients
showed improvement on food challenge, 3 patients went forward with OIT.

JACI, 2011 Sampson, et al. A phase II, randomized, double-blind, parallel-group, placebo-controlled oral
food challenge trial of Xolair (omalizumab) in peanut allergy.
- 14 subjects reached primary endpoint (n=9 Xolair and n=5 placebo) and comparing change from
baseline in maximum tolerable peanut dose after 24 wks of treatment, there appeared to be a greater
shift in peanut tolerability in subjects treated with omalizumab (44%) vs placebo (20%).

NEJM, 2003 Leung, D. et al. Effect of anti-IgE therapy in patients with peanut allergy
 A double-blind, randomized, dose-ranging trial in 84 patients. A 450-mg dose of TNX-901 increased
the threshold of sensitivity to peanut on oral food challenge from 0.5 to 9 peanuts.

Allergy Asthma Proc. 2010 Rafi, et al. Effects of omalizumab in patients with food allergy.
 Assessed the efficacy of omalizumab in 22 patients with persistent asthma and concomitant IgEmediated food allergy with improvement on reexposure to sensitized foods.
CURRENTLY ONGOING ANTI – IGE AND
FOOD ORAL IMMUNOTHERAPY STUDIES
- Milk OIT + omalizumab in milk allergic subjects (7-35 yrs)




▪ PI, Dr. Hugh Sampson
Peanut OIT + omalizumab study in peanut allergic patients (>12 yrs)
▪ PI, Dr. Wesley Burks
Peanut OIT + anti IgE in peanut allergic subjects (>18 yrs)
▪ Novartis
Peanut OIT + omalizumab in peanut allergic subjects (7-25 yrs)
▪ PI, Dr. Dale T. Umetsu
Multi OIT + omalizumab in tree nut, milk, egg, and/or peanut allergic subjects
(4-55 yrs)
▪ PI, Dr. Kari Nadeau
Source: clinicaltrials.gov
Mechanisms of Anti IgE Therapy
IgE
Anti-IgE
Anti-IgE
FcεRI receptor
Mast cell
Monoclonal anti-IgE antibodies, like omalizumab, selectively bind to the Cɛ3
domain of IgE with high affinity. Each IgE molecule has two antigenic sites
for anti-IgE, and so can be bound by two drug molecules simultaneously.
These form small, soluble, biologically inert IgE/anti-IgE complexes that are
easily cleared from the circulation.
Possible historical comparisons: Cow’s milk OIT with no omalizumab
Anti IgE Studies in Food Allergy at Stanford (example)
Study
Patient Population
Methods
Results
Yu et al. (2009)
5 pts (5- 25 yrs) with
peanut allergy;
positive peanut SPT (≥
8mm wheal) or serumspecific IgE (peanut
IgE ≥15kUa/L)
Pilot study using
omalizumab every 2-4
wks (dosing based on
wgt/IgE level per
product insert); no
placebo
Free IgE anti-peanut decreased (from mean of
119.4 kUa/L to 5.9 kUa/L) within 4-12 wks of
treatment. One pt developed a negative peanut
SPT at 4 wks and was able to tolerate 5 gms of
peanut in DBPCFC.
Iyengar et al.
(2008)
8 patients (4-22 yrs)
with food allergy and
severe refractory AD
Pilot phase I study
using higher dosing
frequency of
omalizumab for
higher IgE levels
(<3,000 IU/ml;
mean=1,068 IU/ml)
and 1:1 placebo
Clinical effect not markedly different (likely due
to very high serum total IgE); TARC, TSLP, and
OX40 ligand reduced (60-80% in 3/4 pts; 50-75%
and 70-80% in 4/4 pts, respectively) and IL-10
levels increased 80-100% in treatment group
Nadeau et al
(2011)
11 children (7-17 years)
with cow’s milk allergy;
milk-specific IgE
(median 50; range
41.6-342 kUA/L),
positive milk SPT
(median 20/50 mm;
range, 11-45/20-52
mm),
Pilot phase I study
using omalizumab
(starting 9 wks before)
rapid oral milk
desensitization to
1000-mg; wkly dose
increase over next 712 wks
9/10 patients reached 1000-mg dose during oneday desensitization period; 9/10 patients
reached the max 2000 mg daily dose by wk 16;
All 9 pts passed DBPCFC 8 wks after last dose
(wk 24) during which cumulative dose of 7250
mg (or 220 mL milk) given. All 9 pts continued
daily milk >8000 mg/day after DBPCFC;
reactions (mostly local and GI) occurred at
approx. 1%
I single center study using AntiIgE
StudyPhase
design:
Schematic
of Clinical
Study:
with milk
oral
immunotherapy
Baseline visit
Start omalizumab (wk 0)
Desensitization
(1000 mg milk powder dose,
2000 mg cumulative)
Weekly up dosing and continued
omalizumab
Maintain daily milk dose at home
Off omalizumab
Maintenance dose was 2000 mg
Week 0-9
Week 9
Week 9-16,
escalation
phase
Week 16-24
DBPCFC*
Home daily milk ≥ 8 oz
Week 24-27
Week 24-52
*DBPCFC=double blind placebo
controlled food challenge
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011
Summary of Demographics
Subject Characteristics

11 patients with histories of acute reactions to
uncooked and cooked milk (recruited at 2 study sites).
◦ Subjects with prior history of eosinophilic GI diseases, immunotherapy,
severe asthma, and/or history of intubation were excluded.




Mean age: 10 years (median 8 years).
Mean skin test to milk: 22 mm wheal (median 20
mm).
Mean milk specific IgE: 98 kU/L (median 50 kU/L).
Mean total IgE: 701 kU/L (median 349 kU/L).
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011
Results
Efficacy Results

One-day desensitization to 1,000 mg (cumulative dose=2,000 mg of milk)
• 7 out of 11 patients passed.
• One drop out after first day of desensitization.

After up to 7-11 additional wks, 9 out of 10 subjects reached an oral daily
dose of 2,000 mg (primary endpoint)

At 24-27 wks, DBPCFC to 3,000 mg (cumulative dose 7,200 mg)
• 9 out of 10 patients passed.

After passing DBPCFC, 9 patients began tolerating 8-12 oz milk/day
(including ice cream, pizza, yogurt) the next day.
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011
Results:
Overall Safety Data
Total number of subjects=11
Safety Results
Milk doses per child, mean (range)
209 (36-334)
Total doses
2301
No. (%) of total doses
No. of reactions per child, mean
(range)
Total reactions
41 (1.8%)
3.7 (1-7)
Grade 1 (Mild) symptoms
29 (1.3%)
2.6 (1-5)
Symptom/treatment
On rush desensitization day
14
During weekly dose
escalation phase
10
During maintenance dosing
5
Grade 2 (Moderate) symptoms
8 (0.3%)
On rush desensitization day
5
During weekly dose
escalation phase
1
During maintenance dosing
2
Grade 3 (Severe) symptoms
4* (0.1%)
On rush desensitization day
2
During weekly dose
escalation phase
1
During maintenance dosing
1
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011
0.7 (0-2)
0.3 (0-1)
Summary CLINICAL CONCLUSIONS




This study is the first published study to use
omalizumab in combination with oral desensitization.
9 of 11 patients with milk allergy treated with
omalizumab and oral milk desensitization achieved the
primary objective, and tolerated desensitization to a
dose of 2,000 mg/day within 7-10 wks.
The 9 patients then passed a DBPCFC, and began
tolerating >240 ml (>8 oz) of milk/day in their diet.
These results suggest a potential value for using
omalizumab during rapid oral desensitization for food
allergy.
Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011
SummarySAFETY OIT: CONCLUSIONS
There is no cure at the current time.
 Drop out rates during clinical OIT studies are 15-25%
 Although most reactions are mild, up to 4% have been
reported to be severe (requiring epinephrine).
 Most allergic reactions occur during home dosing
 Patients and families must be frequently educated
 Random allergic reactions can occur 3-4 years after
OIT was begun.
 Viral infections, temperature, other allergies, exercise,
menstruation—all can modulate the threshold for an
allergic reaction during ingestion of food therapy
 Reaction medications must still be available at all times

Possible mechanisms of Oral Immunotherapy
Incorvaia, et al. 2008,
Antunez, et al. 2008, Aslam, et al 2010,
Frew, 2010, Jutel, et al. 2006,
Jones, et al. 2009, Adkis and Adkis, 2009
Nadeau and Umetsu, 2011
Why study mechanisms of OIT?



Provides our field with new targets for
 Therapy (ie. peptide vaccine based in recognized epitopes
in T cells)
 Diagnostics (ie. basophil activation)
 Prognostics (ie. following epitope arrays and inhibitory
assays)
Identifies predictive biomarkers in samples for successful and
safe clinical outcomes (ie. Treg epigenetics? Basophil
threshold studies?)
Defines biological parameters for improved, customized,
patient-focused therapy (dose amount, dose frequency,
initiation and termination of therapy, adverse event
frequency)
OIT Study Summary Results
• OIT could be promising HOWEVER
• It must be considered experimental and in its early phases
• There is still much to learn as to dosing and frequency and
length of time on therapy
• SAFETY is paramount
• Work with appropriate regulatory agencies
and institutional boards
• Trained staff should perform DBPCFCs and DEs in
a hospital setting
• Patients and their families must be trained and frequently
retrained
• Constant (i.e. 24/7) availability of trained staff,
short term and long term follow up are important.
• OIT IS NOT READY FOR CLINIC USE





Identification of causative food
Institution of elimination diet
Education on food avoidance
Development of action plan
Prevention of other allergies





History and physical paramount
IgE & non-IgE mediated conditions exist
Diagnosis by elimination and challenge
Avoidance/education/preparation for
emergencies are current therapies
Periodic re-challenge to monitor tolerance as
indicated by history, allergen, and level of
food specific-IgE
Stanford Alliance For Food Allergy Research
Funded By:
Seeking Clinical Trials and Mechanistic
Assays of Immune Tolerance in Allergy and
Asthma
The ITN provides:
• Funding for innovative research
• Collaborative scientific exchange
• Public education and involvement
Submit your proposal:
• Partnership opportunities
www.immunetolerance.org
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