Food-dependent exercise-induced anaphylaxis

Food-dependent
exercise-induced anaphylaxis
Puttatida Chetwong
16-Jul-2021

Outline
• Introduction
• Clinical features
• Pathophysiology
• Differential diagnosis
• Diagnosis
• Management
• Prophylactic medication
• Prognosis

Introduction
• The first case of this condition was reported in 1979, who described a
patient who developed anaphylaxis after eating shellfish before
exercise.
• Can occur following the ingestion of a food allergen either pre or post
exercise
• Can occur at any point during the time frame of exercise (i.e., from
the warm-up to the cooling-down period)
• Other cofactors: NSAIDs, alcohol, environmental temperature,
infection, stress, menstruation
Curr Opin Allergy Clin Immunol. 2019 Jun;19(3):224-228.

J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.

• A 31-year-old vigorous male long-distance runner (50 to 130 km/wk)
• 10 bouts over 3 yr of transient facial flushing and edema, diffuse urticaria, and
intense pruritus occurring immediately following exercise.
• Two bouts of the postexercise urticaria within 4 days with almost complete upper
airway closure, requiring epinephrine and antihistamines
• Atopic history with an allergy to penicillin and a history of seasonal hay fever.
• Shellfish were a staple of his diet and routinely caused no systemic allergic reaction.
J Allergy Clin Immunol. 1979 Jun;63(6):433-4.

• A detailed epidemiologic history including dietary intake revealed shellfish
intake 5 and 24 hr prior to the two exercise-related events.
• Eight boiled shrimp with ketchup preceded the first bout of urticaria and 1 can
(100 gm) of smoked oysters was eaten prior to the second reaction.
• Similar data were not available for previous episodes.
• Two runs of 10 k on intervening days between the bouts of urticaria were not
preceded by shellfish and did not result in allergic reaction.

• The patient initially avoided shellfish due to strong suspicion generated
• At least 30 separate runs from 10 to 15k in distance over the 30-day
period did not induce an allergic episode.
• However, an inadvertent self-challenge with shellfish (100 gm smoked
oysters) 20 hr prior to running 1 month later resulted in the described
reaction immediately following exercise.
• He now assiduously avoids shellfish and has had no further reactions.
• Cutaneous allergy testing showed positive prick tests to clams, oysters,
shrimp, crabs (all 1/20 w/v), peanuts (1/20 w/v), trees, grass, and weeds
(all 20,000 protein nitrogen units)

Clinical features
• Symptoms of anaphylaxis
• Maybe severe and fatal
• Symptoms may occur anywhere from 10 min or up to 4 h after food
allergen intake
• The prevalence of anaphylactic biphasic reactions in FDEIA is not known
• Most patients are able to tolerate the culprit allergen and exercise
independently as long as the ingestion of the allergen occurs 4–5 h
apart from exercising

Clinical features
• This disorder appears to be more common in females than
males and most prevalent in the late teens to mid-30s.
• Patients usually have
• asthma and other atopic disorders
• positive skin-prick test results for the food that provokes their
symptoms
• occasionally a history of reacting to the food when they were
younger
Nowak-Węgrzyn A, Burks AW, Sampson HA. Reactions to foods. In Middleton’s Allergy (9th ed). Elsevier.

Pathophysiology
• The exact mechanism that causes FDEIA is not fully understood
• Proposed mechanism
1. Increased gastric/intestinal permeability during exercise
leads to abnormal entry of allergens into the circulation only
during exercise.
Concomitant intake of NSAIDs, which increase gastric
permeability, increases the likelihood of symptoms in patients
with FDEIA and supports this mechanism
Immunol Allergy Clin North Am. 2015 May;35(2):261-75.

• Rhamnose will cross the small intestinal epithelia via a
transcellular route
• Lactulose molecule will transverse the epithelia via a
paracellular route through tight junctions
• An increase in the urinary lactulose-to-rhamnose ratio
expressed as percent recovery of the ingested dose is
interpreted as an increase in small intestinal
permeability
J Appl Physiol (1985). 1997 Feb;82(2):571-6.

J Appl Physiol (1985). 1997 Feb;82(2):571-6.
Running at 80% VO2peak increased small
intestinal permeability compared with rest
and running at 40 and 60% VO2peak.

Pathophysiology
2. Exercise mobilizes or activates immune cells from gut-
associated depots, stimulating proinflammatory responses that
are normally countered by anti-inflammatory responses when
patient is at rest

Pathophysiology
3. Exercise results in alterations in blood flow, redirecting blood
from away from the viscera to the skin and musculature. This
could carry food allergens to tissues containing mast cells that
are not tolerant to those allergens, resulting in an allergic
reaction during exercise but not at rest.

Pathophysiology
4. Patients with FDEIA may have dysregulation of the autonomic
nervous system
5. Exercise may result in changes in serum osmolality within
mucosal tissues, similar to a mechanism that has been
implicated in exercise-induced asthma. Hyperosmolality
increases basophil histamine release in response to allergens.

Differential diagnosis
• Exercise-induced anaphylaxis
• Cholinergic urticaria
• Cold urticaria
• Mast cell disorders
• Cardiovascular events
• Postural orthostatic tachycardia syndrome
• Exercise-induced bronchoconstriction
• Exercise-associated reflux
• Allergic reactions associated with exercise

Exercise-induced anaphylaxis
• Affected individuals typically experience a sensation of warmth,
flushing, generalized itching and the development of urticaria or hives
during vigorous exercise
• EIA tends to affect females around the time of menstruation, or with
aspirin or NSAIDs use.
• There is a positive family history but no association with food.
Pediatr Allergy Immunol 2006: 17: 157–160.

Cholinergic urticaria
• Cholinergic urticaria (CU) is associated with an elevation in the core
body temperature and can therefore also occur during exercise
• The urticaria of CU are punctate and small in size (1–3 mm), whilst
those of FDEIA are typically larger (10–15 mm) and more diﬀuse.
• The airway symptoms of FDEIA may include choking, stridor
secondary to obstruction and bronchospasm whilst CU patients may
experience wheezing from spasm of the smaller airways but no life-
threatening angioedema or vascular collapse.

Cold urticaria
• Cold urticaria is a physical urticaria where exposure to cold
temperature can rapidly induce the onset of hives on the face, neck
or hands.
• Common cold triggers include swimming, cold water bathing and
environmental cold exposure.
• The low temperature induces a massive histamine release which may
even result in low blood pressure, fainting and shock
• It is important to question the environment in which symptoms
began.

Mast cell disorders
• Symptoms triggered by a variety of situations and not limited to
exercise.
• These include exposure to medications (eg, NSAIDS, narcotics),
physical factors other than exercise (massage, extremes of
temperature), ingestion of spicy food or alcohol, surgical
instrumentation, emotional stress, infections, Hymenoptera stings
and other toxic exposures.
• Urticaria pigmentosa may be present on skin
• Elevated serum tryptase when patient in baseline state

Cardiovascular events
• Patient may present with flushing, lightheadedness, syncope,
tachycardia.
• Urticaria, angioedema, throat tightness, and asthmatic symptoms
should not be present.

Postural orthostatic tachycardia syndrome
• Such as arrhythmia, myocardial infarction
• Patients may report palpitations, lightheadedness, headache,
abdominal discomfort or nausea, fatigue, inappropriate sweating or
flushing.
• Urticaria, throat tightness, asthmatic symptoms should not be
present.

Exercise-induced bronchoconstriction
• Exercise-induced bronchoconstriction develops when vigorous
physical activity triggers airway narrowing in people who have
heightened bronchial reactivity, resulting in cough, wheezing,
dyspnea, and/or chest tightness.
• Symptoms of exercise-induced bronchoconstriction often peak 10–15
min after the completion of exercise
• If there is absence of rash or anaphylaxis  diﬀerentiate this
condition from FDEIA.
• Response to prophylactic albuterol taken before exercise

Exercise-associated reflux
• Patients may have throat symptoms, flushing, and chest symptoms.
• Urticaria and angioedema should not be present.
• Careful history may reveal that patient also has some symptoms of
GERD unrelated to exercise.
• Response to H2 antihistamines or proton pump inhibitors.

Allergic reactions associated with exercise
• For example, pollen and pet dander exposure during exercise
• The relationship between exercise and allergic symptoms is not
causal
• Exercise may be a cofactor for anaphylaxis

Diagnosis
an unequivocal history of food ingestion followed by
exercise, the rapid onset (within 1 to 2 hours) of classic
IgE-mediated symptoms
demonstration of food-specific IgE antibodies by
skin-prick testing or in vitro tests for IgE
Nowak-Węgrzyn A, Burks AW, Sampson HA. Reactions to foods. In Middleton’s Allergy (9th ed). Elsevier.

A serum tryptase level should be measured in all
patients and should be normal in individuals with FDEIA
when the patients are in their usual state of health.

Symptoms compatible with anaphylaxis during exercise
Allergy testing (SPT, IgE ect.)
Co-factors (NSAID/ASA,
alcohol, stress, PPI ect.)
Co-morbidity (Asthma,
urticaria, mastocytosis ect.)
Positive Negative
Food
challenge
Exercise
challenge
Positive Positive
Negative Negative
Food allergy Exercise induced anaphylaxis
Exercise induced asthma
Cholinergic urticaria
Expert Rev Clin Immunol. 2019 Mar;15(3):265-273.

Negative
food challenge
Negative
exercise challenge
Exercise
challenge + food
Negative
Positive
FDEIA
Exercise challenge
+ food
+ cofactor
Positive Negative
Idiopathic anaphylaxis
Exercise challenge
+ elicitor
Negative
Positive
Cold/heat/aqua urticaria
Co-factors (NSAID/ASA,
alcohol, stress, PPI ect.)
Expert Rev Clin Immunol. 2019 Mar;15(3):265-273.

Asian Pac J Allergy Immunol. 2021 Jan 2.
• To evaluate the positivity rate of
exercise-food challenge test to confirm
the diagnosis
• During 2014-2018
• 17 patients aged 5-60 years old with a
convincing history of WDEIA

Either
- skin prick test (SPT) result to wheat ≥3 mm using wheat
extracts (1:10 w/v) in Coca’s solution and 10% alcohol and/or
- level of sIgE to wheat and/or
- ω5-gliadin >0.35 kUA/L using the ImmunoCAP System
A diagnosis of WDEIA was made based on
Convincing history of having an immediate allergic reaction
after wheat ingestion followed by exercise within 4 hours or
vice versa

4-day challenge protocol
ASA graded challenge
- 10 mg/kg/dose (maximum 300 mg) for children
- 300-381 mg for adults
Day 1
Day 2
Day 3
Open OFC to wheat
- 4 slices of bread (60 gm of wheat or 7.6 gm of wheat protein) in children
- 5 slices of bread (75 gm of wheat or 9.5 gm of wheat protein) in adults
Exercise challenge test
Using a motor-driven treadmill to achieve 80% of maximum heart rate during the first 2-5
minutes with subsequent maintenance at this targeted heart rate
- for at least 4 minutes in children
- for at least 15 minutes in adults, or for as long as could be tolerated
Day 4 Combination provocation test
- Administration of ASA as a cofactor (to increase the sensitivity of the test) 
administration of 4-5 slices of bread  exercise challenge test
- With a 30-60 minute period between each of the 3 tests

Positive
10/14
= 71.4%

Management
• The management of FDEIA is centered on avoidance of the culprit
food before exercise and identification of other augmenting factors
that are important for that individual.

Clinical recommendations for patients with FDEIA
• Have epinephrine autoinjector and mobile phone available in
all exercise settings.
• Stop exertion immediately if any symptoms occur (never
“push through”).
• Avoid the causative food for 4-6 h before exercise*, at least
initially. Time may be reduced going forward, although most
patients must avoid the food for a minimum of 2 h.
Avoid any potential trigger foods at least 4–6 h
before exercise and 1 h after exercise

Clinical recommendations for patients with FDEIA
• Avoid possible augmenting factors and pay close attention to
circumstances surrounding symptoms to detect other factors that might
be important.
• Exercise with other informed individuals, at least initially until it is clear
to the patient and the clinician that the situations that induce symptoms
can be avoided successfully.
• As with prevention of anaphylaxis of any etiology, adult patients should
be informed about the risks of certain long-term medications, such as
beta-blockers and angiotensin-converting enzyme inhibitors, and discuss
with allergist if another clinician prescribes

Prophylactic medication
• No randomized trials of medications to prevent episodes of FDEIA,
• Recommendations are based on small series, case reports, and
clinical experience
• Not needed in cases in which behavior can be modified and triggering
foods and augmenting factors identified and avoided
• Should not replace food avoidance

• 14-year-old girl
• U/D allergic rhinitis, allergic conjunctivitis
• First presentation of FDEIA at age 12 after
playing a chasing game 2 hours after lunch
• Prescribed 100 mg of sodium cromoglycate
orally 20 minutes before lunch
• Developed symptoms when forgot to take
medication
Clin Pediatr (Phila). 2009 Nov;48(9):945-50.
Cromolyn sodium

Measurement of intestinal permeability to mannitol and
lactulose as a means of diagnosing food allergy and evaluating
therapeutic effectiveness of disodium cromoglycate.
• 90 fasting healthy subjects and 60 patients with food allergy
• oral administration to both groups of
• 5 g of mannitol, a marker of absorption of small molecules, and
• 5 g of lactulose, a marker of abnormal absorption of large molecules
mean 5-hour urinary
excretion
Mannitol Lactulose
Healthy subjects 14.11% 0.26%
Patients, fasting 13.22% 0.55%
Patients, food allergen 11.57% 1.04%
Patients, food allergen +
disodium cromoglycate
13.53% 0.62%
Ann Allergy. 1987 Nov;59(5 Pt 2):127-30.

H1 antihistamine
• May mask early symptoms
• However, if needed to control concomitant allergic disease, such as
severe allergic rhinitis, standard doses of newer antihistamines do
not appear to interfere with recognition of early symptoms.

• A 20-year-old woman
• She was admitted to the hospital for
treatment of anaphylaxis while walking
after ingesting a hamburger.
• She experienced the symptoms specifically
while walking or running after ingesting
pork, beef, and wheat-based foods, such as
breads, noodles, and instant noodles
• Skin prick test and sIgE to likely allergen:
negative
• Oral food challenge with pork, beef, and
wheat (200 mg of each): all negative
• Ingestion 30 minutes before running for
20 minutes
• Beef, pork: negative
• Wheat: positive
• Prescribed 2 mg of ketotifen po ac bid
(decrease to 1 mg due to drowsiness)
• Symptom-free for 6 months
Ann Dermatol 2009;21:203-5.

Benefits in case reports
• Omalizumab
• Misoprostol (a synthetic analogue of the gastro-protective
prostaglandin, prostaglandin E1)
No clear benefits
• Oral glucocorticoid
• Leukotriene receptor antagonist
Prophylactic medication

Prognosis
• A small number of case reports describe fatalities attributed to FDEIA.
• FDEIA appears to be a persistent disorder
• Most patients report fewer attacks over time.
• Improvement may be attributable to recognition of early symptoms,
modifications in exercise habits, and improved avoidance of triggering
food and augmenting factors.

Food-dependent exercise-induced anaphylaxis

Food-dependent exercise-induced anaphylaxis

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