Exercise-Induced Anaphylaxis Differential Diagnoses

Updated: Jan 04, 2022
  • Author: Peter N Huynh, MD; Chief Editor: Harumi Jyonouchi, MD  more...
  • Print

Diagnostic Considerations

Diagnostic considerations for pediatric exercise-induced anaphylaxis include cholinergic urticaria, idiopathic cold urticaria, mastocytosis, cardiovascular disorders, food allergy exacerbated by exercise, and angioedema.

Cholinergic urticaria

Cholinergic urticaria is a form of physical urticaria that can be precipitated by exercise. The skin lesions are distinctive and appear as 2-4 mm pruritic wheals surrounded by extensive areas of macular erythema. Rare reports describe patients with cholinergic urticaria who develop recurrent episodes of hypotension, which may mimic exercise-induced anaphylaxis (EIA).

Key distinguishing features include the size of the skin lesions and the underlying pathophysiologic features. Cholinergic urticaria usually produces pinpoint hives, which may coalesce to larger lesions. Exercise-induced anaphylaxis produces giant hives.

Passive heat challenges are valuable in differentiating between cholinergic urticaria and exercise-induced anaphylaxis. [31] In cholinergic urticaria, passive heating (eg, from hot baths or saunas) with an increase in core body temperature of more than 0.7° C causes histamine release, urticaria, and anaphylactic symptoms. In contrast, patients with exercise-induced anaphylaxis do not react with passive heating.

Idiopathic cold urticaria

Idiopathic cold urticaria is a form of physical urticaria characterized by the development of urticaria and/or angioedema after cold exposure. Other organ systems may become involved, which may progress to frank anaphylaxis. Anaphylaxis has resulted in deaths either directly from the anaphylactic reaction or by drowning when swimming in cold water. [32]

Patients with idiopathic cold urticaria who experience symptoms from exercising in cold weather may be misdiagnosed with exercise-induced anaphylaxis. Ascertaining whether passive cold exposure in the absence of exercise can elicit symptoms is important.

An ice cube challenge test is useful in differentiating between cold-induced urticaria and exercise-induced anaphylaxis. This test entails the application of an ice cube for a nonstandardized time interval followed by a period of rewarming. Patients with idiopathic cold urticaria develop a wheal at the ice cube site after the skin is rewarmed.


Mastocytosis is a disorder characterized by mast cell proliferation and accumulation within various organs, most commonly the skin. [33] Patients with mastocytosis are susceptible to anaphylaxis from various triggers, including exercise.

A useful distinguishing feature between exercise-induced anaphylaxis and mastocytosis is the serum tryptase level. Patients with mastocytosis have persistent elevation in serum tryptase levels, whereas patients with anaphylaxis from other causes (exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis) demonstrate elevation of tryptase only during acute attacks.

In addition, patients with mastocytosis may have characteristic cutaneous findings of urticaria pigmentosa, characterized by oval or round red-brown macules, papules, or plaques. Gently stroking normal skin may produce raised wheals and a burning or itching sensation (Darier sign).

Cardiovascular disorders

Cardiac events such as myocardial infarction and arrhythmias can cause sudden fatigue, dyspnea, and vascular collapse during exercise. However, cardiovascular disorders do not cause pruritus, urticaria, angioedema, and laryngeal edema.

Food allergy exacerbated by exercise

Patients with food allergy may have more severe and frequent reactions with concomitant exercise. Exercise increases GI permeability, which may allow increased entry of intact or incompletely digested allergens into the circulation. In the case of food-dependent exercise-induced anaphylaxis, demonstrating that patients can tolerate the offending food in the absence of physical activity is essential. A formal food challenge may be helpful in this regard.


Hereditary angioedema is an inherited disease resulting from a deficiency or dysfunction of the C1 inhibitor enzyme (C1-INH). [34] Acquired angioedema is caused by autoimmune interference with C1-INH function. [35]

Both hereditary and acquired forms are characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affect the skin or the mucosal tissues of the upper respiratory and GI tracts. Angioedema attacks may be precipitated by exercise, stress, and cold exposure. A key distinction between hereditary or acquired angioedema and exercise-induced anaphylaxis is the absence of urticaria and pruritus in hereditary and acquired angioedema.

Differential Diagnoses

  • Cardiovascular disorders

  • Cholinergic urticaria

  • Food allergy

  • Idiopathic cold urticaria

  • Mastocytosis

  • Pediatric Angioedema