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Food-dependent exercise-induced anaphylaxis

  1. 1. Food-dependent exercise-induced anaphylaxis Puttatida Chetwong 16-Jul-2021
  2. 2. Outline • Introduction • Clinical features • Pathophysiology • Differential diagnosis • Diagnosis • Management • Prophylactic medication • Prognosis
  3. 3. 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.
  4. 4. J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.
  5. 5. • 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.
  6. 6. • 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. J Allergy Clin Immunol. 1979 Jun;63(6):433-4.
  7. 7. • 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) J Allergy Clin Immunol. 1979 Jun;63(6):433-4.
  8. 8. 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 Curr Opin Allergy Clin Immunol. 2019 Jun;19(3):224-228.
  9. 9. 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.
  10. 10. 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.
  11. 11. • 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.
  12. 12. 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.
  13. 13. Pathophysiology • Proposed mechanism 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 Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  14. 14. Pathophysiology • Proposed mechanism 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. Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  15. 15. Pathophysiology • Proposed mechanism 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. Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  16. 16. 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
  17. 17. 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.
  18. 18. 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. Pediatr Allergy Immunol 2006: 17: 157–160.
  19. 19. 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. Pediatr Allergy Immunol 2006: 17: 157–160.
  20. 20. 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 Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  21. 21. Cardiovascular events • Patient may present with flushing, lightheadedness, syncope, tachycardia. • Urticaria, angioedema, throat tightness, and asthmatic symptoms should not be present. Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  22. 22. 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. Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  23. 23. 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 Pediatr Allergy Immunol 2006: 17: 157–160. Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  24. 24. 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. Immunol Allergy Clin North Am. 2015 May;35(2):261-75.
  25. 25. 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 Pediatr Allergy Immunol 2006: 17: 157–160.
  26. 26. 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.
  27. 27. J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.
  28. 28. J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288. 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.
  29. 29. 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.
  30. 30. 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.
  31. 31. 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
  32. 32. 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 Asian Pac J Allergy Immunol. 2021 Jan 2.
  33. 33. 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 Asian Pac J Allergy Immunol. 2021 Jan 2.
  34. 34. Asian Pac J Allergy Immunol. 2021 Jan 2.
  35. 35. Asian Pac J Allergy Immunol. 2021 Jan 2.
  36. 36. Positive 10/14 = 71.4% Asian Pac J Allergy Immunol. 2021 Jan 2.
  37. 37. 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. J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.
  38. 38. 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. J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288. Avoid any potential trigger foods at least 4–6 h before exercise and 1 h after exercise Curr Opin Allergy Clin Immunol. 2019 Jun;19(3):224-228.
  39. 39. 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 J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.
  40. 40. 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 J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.
  41. 41. • 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
  42. 42. 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.
  43. 43. 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.
  44. 44. • 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.
  45. 45. 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 J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.
  46. 46. 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. J Allergy Clin Immunol Pract. Mar-Apr 2017;5(2):283-288.

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