A 16-Year-Old Girl With Full-Body Rash, Dyspnea, and Swelling

Peter Huynh, MD


January 19, 2022

The differential diagnosis for EIA includes cholinergic urticaria, idiopathic cold urticaria, mastocytosis, cardiovascular disorders, food allergy exacerbated by exercise, and angioedema.

Cholinergic urticaria is a form of physical urticaria that can be precipitated by exercise. The skin lesions are distinctive and appear as 2- to 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 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; in contrast, EIA produces giant hives.

Passive heat challenges are valuable in differentiating between cholinergic urticaria and EIA.[11] In cholinergic urticaria, passive heating (eg, hot baths, saunas) with an increase in core body temperature of more than 1.26°F (0.7°C) causes histamine release, urticaria, and anaphylactic symptoms. In contrast, patients with EIA do not react with passive heating.

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.[12] Patients with idiopathic cold urticaria who experience symptoms from exercising in cold weather may be misdiagnosed with EIA. 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 EIA. This test entails the application of an ice cube for a certain period (usually 10 minutes), 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.[13] Patients with mastocytosis are susceptible to anaphylaxis from various triggers, including exercise.

A useful distinguishing feature between EIA and mastocytosis is the serum tryptase level. Patients with mastocytosis have persistent elevation in serum tryptase levels, whereas patients with anaphylaxis from other causes (EIA and FDEIA) 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).

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.

Patients with food allergy may have more severe and frequent reactions with concomitant exercise. Exercise increases gastrointestinal permeability, which may allow increased entry of intact or incompletely digested allergens into the circulation. In the case of FDEIA, 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.[14] Acquired angioedema is caused by autoimmune interference with C1 inhibitor enzyme function.[15] Both the 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 gastrointestinal tracts. Angioedema attacks may be precipitated by exercise, stress, and cold exposure. A key distinction between hereditary or acquired angioedema and EIA is the absence of urticaria and pruritus in hereditary and acquired angioedema.


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