Food-dependent, exercise-induced anaphylaxis

Food Dependent Exercise
Induced Anaphylaxis
Topic: 20th October 2023
Tanatchabhorn Soponkanabhorn, MD.
Division of Allergy, Immunology and Rheumatology Unit
Department of Pediatrics, King Chulalongkorn Memorial Hospital

Outline
• Definition
• Pathogenesis
• Clinical manifestation
• Differential Diagnosis
• Investigation
• Management
• Prognosis

Definition
• Food-dependent exercise induced allergic reactions:
• Reaction manifest when exercise or other cofactors coincide with the
consumption of specific trigger foods
• The most severe manifestation being anaphylaxis
Exercise Food
Allergic Reaction
Srisuwatchari W, et al. Foods. 2023; 12(20):3768.

Exercise-induced anaphylaxis (EIA)
• Exercise-induced anaphylaxis (EIA)
• A disorder in which anaphylaxis occurs
exclusively in association with physical
exertion of significant intensity
• Can begin at any stage of exercise
• Triggered by moderate intensity exercise
• Not fully repeatable/not fully predictable
(in same exercise)
• Prevalence: 3% of all cases of anaphylaxis
Giannetti MP. Curr Allergy Asthma Rep. 2018 Oct 26;18(12):72.
• Symptoms:
• Flushing, increased warmth, malaise,
diffuse itching, urticaria, angioedema
• Bronchospasm, laryngeal edema
• GI symptoms

Sheffer AL, et al. J Allergy Clin Immunol. 1980 Aug;66(2):106-11.
Exercise-induced anaphylaxis (EIA)
• EIA has 4 symptoms stages: Prodromal, early, fully
delveloped, and late symptoms
• ‘Although the reactions begin with a sensation of cutaneous warmth and
pruritus and proceed to the development of cutaneous erythema and
urticaria. It was the dramatic occurrence of collapse in 12 and upper
respiratory distress in 10 of the original 16 patients’ – Sheffer AL

Food Dependent Exercise Induced Anaphylaxis (FDEIA)
• The first case was reported by Maulitz et al. in 1979
• A-31-year old male, long distance
runner, with history of facial flushing
and edema, diffuse urticaria, and
intense pruritus immediately after
exercise
• He had shellfish intake (boiled shrimp
and smoked oysters) 5 and 24 hr prior
the two exercise-related events
• SPT positive to calms, oysters, shrimp,
crabs
• Stastical association between ingestion
of shellfish and reaction was very
strong (P < 0.01)
Maulitz RM, et al. J Allergy Clin Immunol. 1979 Jun;63(6):433-4.

• Epidemiology:
• Uncommon but reported around the world (30-50% of EIA patients)
• Prevalence: 0.02% among junior high school students in Japan
• Most commonly affects young adults, female > male
• An episode of anaphylaxis develops during exercise within 4 to 6 hours of ingesting a
specific food
• May begin at any stage of exercise and occasionally occur just after exercise
• Early symptoms: sudden fatigue, diffuse warmth, flushing, itching, and/or urticaria
• If the patients stops and rests, symptoms usually resolve
• Late symptoms: angioedema, GI symptoms, laryngeal edema, brochospasm, hypotension, or
collapse
Feldweg AM. J Allergy Clin Immunol Pract. 2017 Mar-Apr;5(2):283-288.

• Forms of exercise:
• Jogging or aerobic exercises
• Minimal exertion; crossing the street,
ironing had been reported in older
patients
• Common culprit foods
• Western populations: wheat, other
grains, and nuts
• Asian populations : wheat and shellfish
• Solid foods > liquid foods
• Food processing may have a role in
some patients
Du Toit G. Pediatr Allergy Immunol. 2007 Aug;18(5):455-63.

Pathogenesis
• Published proposed pathophysiological
mechanisms of EIA
• Exercise induced increases in
gastrointestinal permeability
• Increased activity of tissue
transglutaminase in gut mucosa
• Redistribution of blood during exercise and
mast cell heterogeneity: no experimental
evidence to support
• Exercise induced increases in plasma
osmolarity inducing basophil histamine
release: low evidence
• Exercise-induced acidosis and mast cell
degranulation: weak evidence
Ansley L, et al. Allergy. 2015 Oct;70(10):1212-21.

Pathogenesis
Kulthanan K, et al. J Allergy Clin Immunol Pract. 2022 Sep;10(9):2280-2296.
Exercise induced
increases in
gastrointestinal
permeability
Increased activity
of tissue
transglutaminase
in gut mucosa

Pathogenesis
• Increased in gastrointestinal permeability
• Exercise -> decreased acid production
• Increased gastric permeability and modify
tight junction
• Absorption of only partially digestes allergenic
proteins
• Intact structural allergens induce mast cells
activation
• Eg. WDEIA, ASA and NSAID ingestion
Foong RX, et al. Curr Opin Allergy Clin Immunol. 2019 Jun;19(3):224-228.

Pathogenesis
• Increased activity of tissue transglutaminase
in gut mucosa
• Exercise -> IL-6 release
• Increase level of transglutaminase (tTG)
activity
• Omega-5-gliadin-derived peptide
crosslinking
• Peptide aggregation and specific IgE
binding -> anaphylaxis
• Eg. WDEIA

Culprit foods (Triggers)
• Others:
• Cow’s milk
• Grains/cereals (barley, oat, rye, buckwheat, rice)
• Seafood (mollusks, shellfish, finfish)
• Vegetables and fruit (orange, onion, celery, tomato,
grape)
• Meat (pork, wild boar meat, beef)
• Food contaminated aeroallergen (penicillium mold,
house-dust mite)
• Potential food allergen
associated with sport practice
• Energy drinks that contain
animal derived gelatin or
soya
• Energy boosting
carbohydrate meals
(omega-5-gliadin, maize,
rice, or concentrated fruit
puree)
• Can be related to both plant and animals proteins
• Most common: Wheat (omega-5-gliadin), shellfish, and nuts

Cotriggers (Augmenting factor)
• Drugs
• Alcohol
• Infection
• Menstruation
• Stress
• Weather

Wheat Dependent Exercise Induced Anaphylaxis (WDEIA)
• Most common form of FDEIA
• Wheat protein categories:
• Water soluble albumin
• Salt soluble globulins
• Alcohol soluble gliadins
• Insoluble glutenins
• Hydrolyzed wheat proteint
• Omega-5-gliadin (Tri a 19): protein component of gluten
• Major allergen in WDIEA
Chinuki Y, Morita E. Allergol Int. 2012 Dec;61(4):529-37.

• The first study using gluten in the diagnosis of WDEIA
• 16 patients with WDEIA and omega-5-gliadin sensitization were challenged with gluten-enriched
bread + alone or combined with aspirin, alcohol, and exercise
• Augmentation cofactor-triggered food allergy’
• Augmentation cofactor: Exercise, ASA, alcohol
Brockow K, et al. J Allergy Clin Immunol. 2015 Apr;135(4):977-984.e4.

Results:
• Higher gluten doses or ASA plus alcohol were cofactors
• Exercise was not absolutely necessary to induce
symptoms in all patients with WDEIA
• No correlation between gastrointestinal permeability
(measured by absorption of nondigestible sugars)
• Clinical history, IgE gliadin, and baseline gastrointestinal
level were not predictive of challenge outcome
• SPT to gluten: sensitivity 100%, specificity 96%
Brockow K, et al. J Allergy Clin Immunol. 2015 Apr;135(4):977-984.e4.

• WDEIA Variant (HWP-WDEIA)
• Japanese women have been sensitized hydrolyzed wheat protein (HWP) through cutaneous
exposure from water-soluble foaming agent (facial soap)
Cha no Shizuku
Glupearl 19S-supplemented soap

• History of of using HWP-supplemented
soap (same brand)
• Symptoms: facial edemia, urticaria,
anaphylaxis (after ingesting natural wheat
proteins)
• SPT:
• Almost all patients had tested
positive to 0.1% soap solution and
0.01% Glupearl 19S solution
• None of CO-WDEIA reacted with
these allergen

• Specific IgE (CAP-FEIA):
• Wheat and gluten specific IgE
were detected in almost of HWP-
WDEIA patients
• HWP-WDEIA patients had
significant lower level of omega-5-
gliadin specific IgE

• SDS-PAGE and Western
blotting:
• All of HWP-WDEIA patients
reacted to Glupearl 19S with a
smear pattern, whereas they
did not reacted to omega-5-
gliadin
• CO-WDEIA reacted with water
soluble and water insoluble
wheat proteins, and omega-5-
gliadin
3: Glupearl 19S
4: Purified omega-5-gliadin

• Basophil activation test
using Glupearl 19S:
• Glupearl 19S enhanced
CD203c expression of
basophils in HWP-WDEIA
patients
• No significant enhancement of
CD203c with purified omega-
5-gliadin in in HWP-WDEIA
patients

• Omega-5-gliadin is not the main allergen in this syndrome
(HWP-WDEIA)
• Avoidance of hydrolyzed wheat protein contaning products may
lead to allergic resolution (different from WDIEA)

Onset
• Duration from exercising to the onset of symptoms ranged from 5
minutes to 5 hours (median 30 minutes)
• Symptoms occurred within the first 30 minutes in 69% of patients
• Symptoms occurred within 1 hours in 98.8% of patients

Type of food (Culprit food)
• 91.3% were reported to
react only 1 culprit food
• 2 culprit foods (5%), 3 culprit
foods (2.5%)
• Wheat was the most
commonly reported culprit
food
• Vegetables (9.4%)
• Seafood (8.7%)
• Legumes (7.3%)
• Fruits (6.3%)

Augmenting factors
• Aspirin and wheat-based
products are the most common
augmenting factors in patients
with FDEIA

Type of exercise
• Many different types of
physical exercise
triggered FDEIA
• Running (17.7%)
• Walking (10.7%)
• Playing football
and/or soccer (8.6%)

Personal history/Comorbidities
• History of atopy (50%)
• Allergic rhinitis (80.4%)
• Asthma (31.6%)
• Allergic conjunctivitis (22%)
• Atopic dermatitis (19.6%)
• Family history of atopy (48.1%)
• History of urticaria (37.2%)

Clinical manifestation
• Anaphylaxis:
• RS problems (64%), CVS (56.6%) and GI
problems (23.6%)
• Single organ involvement:
• RS problems (23.8%), CVS (18.4%) and
GI problems (2.3%)

Clinical manifestation: Phenotype
• Phenotype in Food
dependent exercise
induce allergic reaction
• FDEIA with wheal and/or
angioedema (FDEIA-A+/WvA+)
• FDEIA without wheal or
angioedema (FDEIA-A+/WvA-)
• Patients had stand-alone
wheals and/or
angioedema with no
anaphylaxis (FDEIA-A-/WvA+)
Kulthanan K, et al. J Allergy Clin Immunol Pract. 2023 Jun;11(6):1926-1933.

• Patients with wheals,
angioedema, or both
together with
anaphylaxis had a history
of urticaria more often
and had less often of
history of atopy
• Wheat was the most
common culprit food in
all phenotype
• Frequent types of
exercise that induced
food dependent allergic
reactions were similar

• Almost all patients with
anaphylaxis with
wheals/angioedema
reported augmenting
factors compared to
those without
wheal/angioedema

Differential diagnosis
• Food allergy
• Exercise induced asthma
• Dust mite ingestion associated EIA
• Cholinergic urticaria
• Cold urticaria
• Mastocytosis
• Benign flushing conditions
• Hereditary angioedema
• Neoplastic disorders

• Mimic anaphylaxis, associated with exercise

• Mimic anaphylaxis, not associated with exercise

Exercise-Induced Anaphylaxis
Geller M. J Allergy Clin Immunol Pract. 2020 Jul-Aug;8(7):2209-2214.
• EIA is a disorder in which anaphylaxis occurs exclusively in association with physical
exertion of significant intensity
• Clinical presentation:
• Flusing, urticaria, angioedema, GI symptoms, bronchospasm
• Wheals are large and may coverage
• Anaphylaxis quite often
• Type of exercise: requiring running, biking, vigourous dancing
• Exercise may modify enzyme and cytokine expression
• Management:
• Prophylaxis
• Acute treatment
• Prognosis: 50% of patients improve with 10-year follow up

Cholinergic urticaria
• Prevalence: 5% of CSU, 30% of CIndU
• Clinical presentation:
• Typical small, punctate wheals with surrounding flare
reaction, involving mainly trunk and extremities
• Angioedema frequently occurs in ChoIU
• Precipitated by exercise and passive warming with core
temperature rising
• Diagnosis:
• Methacholine chloride intradermal provocation test
(positive 30%)
• Management:
• 2nd generation H1 antihistamine
• Omalizumab

Dust mite ingestion associated EIA
• Case report
• A 16-year-old girl who experienced upper limb and later generalized
itching accompanied by facial (eyelid) edema and breathlessness while
playing soccer at school.
• Approximately 30 minutes before playing soccer, she had taken
homemade pancakes made from a commercial pancake mixture that had
been stored in a previously opened container
• Suidasia medanensis in a concentration of 4814.8 mites per gram of flour
was found
• Her SPT were positive for D pteronyssinus, B tropicalis, and pancake mix
extract and negative for other inhalant and food extracts, including
wheat.
• Management:
• Epipen autoinjector
• Preserve the flour in freezer to avoid contaminate Sánchez-Borges M, et al. J Allergy Clin Immunol. 2007 Sep;120(3):714-6.

Cold urticaria
Barg W, et al. Curr Allergy Asthma Rep. 2011 Feb;11(1):45-51.
• Triggers:
• Exposed to cold (usually on the hands, face, and neck) and promptly take up
the whole body
• Intensive exposure to cold may induce a robust histamine release -> CVS
collapse -> shock
• Symptoms:
• Skin lesion similar to EIA
• Cold urticaria can result from exercise with exposure to cold
• Swimming/outdoor activity in winter

Exercise induced asthma
• Symptoms:
• Manifested with typical symptoms of asthma exacerbations
• Symptoms are limited to lower airways (except in life threatening asthma)
• Management:
• Prevention: Inhaled, rapid acting beta agonist (prior exercise)
Barg W, et al. Curr Allergy Asthma Rep. 2011 Feb;11(1):45-51.

Diagnosis
• Clinical diagnosis

Evaluation
• Initial evaluation
• Type of activity, Intensity of activity
• Onset of symptoms
• Food consumption
• Medication use
• Additional details
• Substance use/known allergen
• Known cofactors
• NSAIDs, alcohol, pollen, temperature changes, menstruation

Evaluation
• History taking

Evaluation
• Serum tryptase levels
• Skin prick testing and specific IgE on possible food triggers
• May include less common allergens such as food additives and spices
• WDEIA:
• Specific IgE to omega-5-gliadin (sensivitity 80%)
• SPT to purified gluten (sensitivity 100%)
• Food exercise challenge test (gold standard)
• Double blinded placebo-controlled food exercise challenge test
(DBPCFEC)
• Using an age-appropriate portion of suspected trigger food to
demonstrate an association
Food
Food exercise
challenge test

Provocation Test Protocol

• Japanese Pediatric Guideline for food allergy (1/2)
• The use of antihistamine and leukotriene antagonists was stopped 3 days before the test
• ASA (10mg/kg) and the suspected foods were administered 90 and 60 min before exercise
• The patients were given large amounts of foods
• Udon noodle 200-400 g (5.2-10.4 g wheat protein)
• Shrimp 40-100 g
• One whole apple
• Exercise was performed using an ergometer according to the exercise stress test for bronchial
asthma
• Exercise was started at 2.1 W/kg and increased up to 3 or 4 W/kg, conducted for 6 min or
more according to patient’s abilities
• Target heart rate was > 160 beats/min
• Stop exercise when the patient was unable to continue
Asaumi T, et al. Pediatr Allergy Immunol. 2016 Feb;27(1):44-9.

• Japanese Pediatric Guideline for food allergy (2/2)
• When the exercise was insufficient, patient was required to run additionally
• Lung function was measured before and at 0, 5, 15, and 30 min after exercise
• Decreased lung function:
• a 15% decrease in the FEV in 1 s
• Or a 20% decrease in the peak expiratory flow
• Follow the progress of the test at least 2 hr, when symtoms appeared, treat
them accordingly to their severities
• When one or more allergic symptoms (hive, wheezing, erythema, or icth)
appeared, the provocation test was judged as positive
Asaumi T, et al. Pediatr Allergy Immunol. 2016 Feb;27(1):44-9.

Provocation and allergy test
• Provocation and allergy test are positive
in most tested patients
• 61.8% of patients had positive both
standard food and exercise
provocation test
• Baseline serum tryptase were
elevated during reaction 37.5%

Management
• Acute treatment:
• Adrenaline administration
• Antihistamine: relief symptoms in
milder cases
• Longterm treatment:
• Idenfication of culprit foods and
augmenting factors
• Carry autoinjectable adrenaline with
written personalized emergency plan
• Preplanned interval:
• Avoid any potential trigger foods
at least 4-6 hr before exercise and
1 hr after exercise
• All patients should exercise with
partner
• Patients should always stop
exertion at the first sign of
symptoms

Management

Prophylactic medication
• Prophylactic medication are not needed in cases in which
behavior can be modified and triggering foods and
augmenting factors identified and avoid
• Cromolyn sodium
• Children: 100 mg orally, 20 minutes before meals
• Adults: 200 mg orally, 20 minutes before meals
• H1 antihistamines
• Omalizumab
• Omalizumab 300 mg SC q 2 weeks
• Negative exercise challenge after 17 weeks of OMA
• Misoprostol
• Desensitization of causative food: absent of current
recomendations
Christensen MJ. J Allergy Clin Immunol Pract. 2017 Jan-Feb;5(1):204-206.

Treatment and prognosis
• On-demand antihistamine,
corticosteroids, and epinephrine
effectuate high rates of marked
response
• Prophylactic treatment
• AH and cromoglycate were most
commonly prescribed prophylactic
treatments
• Patients who no longer eat
culprit foods before exercise
cease to develop FDEIA

Reference
• Asaumi T, Yanagida N, Sato S, Shukuya A, Nishino M, Ebisawa M. Provocation tests for the diagnosis of food-dependent exercise-induced
anaphylaxis. Pediatr Allergy Immunol. 2016 Feb;27(1):44-9.
• Ansley L, Bonini M, Delgado L, Del Giacco S, Du Toit G, Khaitov M, Kurowski M, Hull JH, Moreira A, Robson-Ansley PJ. Pathophysiological
mechanisms of exercise-induced anaphylaxis: an EAACI position statement. Allergy. 2015 Oct;70(10):1212-21.
• Barg W, Medrala W, Wolanczyk-Medrala A. Exercise-induced anaphylaxis: an update on diagnosis and treatment. Curr Allergy Asthma Rep.
2011 Feb;11(1):45-51.
• Brockow K, Kneissl D, Valentini L, Zelger O, Grosber M, Kugler C, Werich M, Darsow U, Matsuo H, Morita E, Ring J. Using a gluten oral food
challenge protocol to improve diagnosis of wheat-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol. 2015 Apr;135(4):977-
984.e4.
• Chinuki Y, Morita E. Wheat-dependent exercise-induced anaphylaxis sensitized with hydrolyzed wheat protein in soap. Allergol Int. 2012
Dec;61(4):529-37.
• Du Toit G. Food-dependent exercise-induced anaphylaxis in childhood. Pediatr Allergy Immunol. 2007 Aug;18(5):455-63.
• Fukutomi Y, Itagaki Y, Taniguchi M, Saito A, Yasueda H, Nakazawa T, Hasegawa M, Nakamura H, Akiyama K. Rhinoconjunctival sensitization to
hydrolyzed wheat protein in facial soap can induce wheat-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol. 2011
Feb;127(2):531-533.e1-3.
• Kulthanan K, Ungprasert P, Jirapongsananuruk O, Rujitharanawong C, Munprom K, Trakanwittayarak S, Pochanapan O, Panjapakkul W,
Maurer M. Food-Dependent Exercise-Induced Wheals, Angioedema, and Anaphylaxis: A Systematic Review. J Allergy Clin Immunol Pract.
2022 Sep;10(9):2280-2296.
• Kulthanan K, Ungprasert P, Jirapongsananuruk O, Rujitharanawong C, Munprom K, Trakanwittayarak S, Pochanapan O, Panjapakkul W,
Maurer M. Food-Dependent Exercise-Induced Wheals/Angioedema, Anaphylaxis, or Both: A Systematic Review of Phenotypes. J Allergy Clin
Immunol Pract. 2023 Jun;11(6):1926-1933.
• Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol. 1979 Jun;63(6):433-4.

Reference
• Geller M. Clinical Management of Exercise-Induced Anaphylaxis and Cholinergic Urticaria. J Allergy Clin Immunol Pract.
2020 Jul-Aug;8(7):2209-2214. doi: 10.1016/j.jaip.2020.01.025.
• Giannetti MP. Exercise-Induced Anaphylaxis: Literature Review and Recent Updates. Curr Allergy Asthma Rep. 2018 Oct
26;18(12):72.
• Feldweg AM. Food-Dependent, Exercise-Induced Anaphylaxis: Diagnosis and Management in the Outpatient Setting. J
Allergy Clin Immunol Pract. 2017 Mar-Apr;5(2):283-288.
• Foong RX, Giovannini M, du Toit G. Food-dependent exercise-induced anaphylaxis. Curr Opin Allergy Clin Immunol. 2019
Jun;19(3):224-228.
• Sánchez-Borges M, Iraola V, Fernández-Caldas E, Capriles-Hulett A, Caballero-Fonseca F. Dust mite ingestion-associated,
exercise-induced anaphylaxis. J Allergy Clin Immunol. 2007 Sep;120(3):714-6.
• Sheffer AL, Austen KF. Exercise-induced anaphylaxis. J Allergy Clin Immunol. 1984 May;73(5 Pt 2):699-703.
• Sheffer AL, Austen KF. Exercise-induced anaphylaxis. J Allergy Clin Immunol. 1980 Aug;66(2):106-11.
• Srisuwatchari W, Kanchanaphoomi K, Nawiboonwong J, Thongngarm T, Sompornrattanaphan M. Food-Dependent
Exercise-Induced Anaphylaxis: A Distinct Form of Food Allergy—An Updated Review of Diagnostic Approaches and
Treatments. Foods. 2023; 12(20):3768.

Food-dependent, exercise-induced anaphylaxis

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