Cholinergic Urticaria to Exercise-Induced Anaphylaxis: The Spectrum

Introduction Exercise-induced anaphylaxis (EIA) and cholinergic urticaria (CholU) are both exercise-induced type I hypersensitivity conditions that have distinct characteristics but often overlap on a clinical spectrum. Cholinergic urticaria is a subtype of chronic urticaria that occurs in response to aerobic exercise and also can be triggered by passive heat exposure (1). It is limited to dermatologic symptoms, with characteristic pinpoint (2–5 mm) hives rather than typical wheals (2). The pathogenesis of CholU is hypothesized to be sweat-induced immunoglobulin E (IgE) receptor activation, histamine release, and dermal mast cell degranulation. Acetylcholine secretion and sensitivity also may play a role (3). The reported prevalence of cholinergic urticaria was found to range from 0.23% to 11.2% in the general population (4). By contrast, EIA is a rare, potentially life-threatening allergic reaction provoked by physical exertion. One epidemiological study in Japanese students found the prevalence of EIA to be 0.031% and food-dependent exercise-induced anaphylaxis (FDEIA) to be 0.017% (5). Clinically, symptoms can include generalized pruritus, large urticarial lesions, angioedema, wheezing, gastrointestinal distress, airway obstruction, palpitations, or, in severe cases, cardiovascular collapse. EIA also is theorized to be an IgE-mediated process in which exercise triggers mast cell degranulation with the release of histamine and tryptase (6). This condition can demonstrate variable and inconsistent manifestations even within the same individual. A history of only mild symptoms does not exclude the possibility of a future anaphylactic reaction; therefore, identifying subtle systemic signs during exercise is critical for the timely diagnosis of EIA. FDEIA is a unique form of EIA that is triggered by physical exertion after exposure to specific foods (e.g., wheat, shellfish, nuts) or cofactors (such as nonsteroidal anti-inflammatory drugs) (7). Case Presentation A 31-year-old female with a history of irritable bowel syndrome and seasonal allergies presented to her primary care physician for evaluation of a rash occurring exclusively with high-intensity exercise such as running. She described diffuse, pruritic welts developing several minutes into running, accompanied by linear red marks at scratch sites (examples seen in Figs. 1 and 2). These symptoms resolved within an hour after exercise cessation. She did not experience similar symptoms with sweating or heat exposure unrelated to exercise. Additionally, she reported occasional lip and eyelid swelling, flushing, palpitations, shortness of breath, and nausea early in her runs, but denied symptoms during lighter activities. As a multisport athlete, she found these recent exercise-induced symptoms unusual and noted their onset only within the past few months. She denied any identifiable food triggers preceding symptom onset, childhood asthma, or cardiac ectopy. While she previously had hives associated with naproxen use, she did not experience recurrence upon subsequent exposures and had no other known allergies. Physical examination during clinic evaluation was unremarkable, without wheezing, tachycardia, arrhythmia, or visible urticarial lesions. Electrocardiogram and electrical heart monitoring demonstrated a normal sinus rhythm. Laboratory testing, which included tryptase, tissue transglutaminase immunoglobulin A antibody, IgE, thyroid-stimulating hormone, erythrocyte sedimentation rate, and complete blood count, returned within normal limits. The clinical suspicion was EIA. Referral to allergy and immunology resulted in clinical confirmation of the diagnosis. Treatment recommendations included initiating maximum-dose fexofenadine and carrying an epinephrine pen during exercise. The patient initially did well with maximum-dose antihistamines but had a recurrence of symptoms with exercise, prompting initiation of omalizumab and exercise modification to avoid high-intensity exercise (running and heavy weightlifting).Figure 1:: Multiple raised lesions consistent with wheals that can be seen in EIA.Figure 2:: Erythematous wheals on the lateral thigh, demonstrating a coalescing pattern with surrounding erythema and evidence of dermatographism.Discussion Athletes may present with overlapping features of cholinergic urticaria and EIA. Distinguishing between cholinergic urticaria and EIA is critical, as failure to correctly identify and treat EIA can lead to devastating outcomes. It also is important to evaluate for other concomitant allergic or respiratory conditions (e.g., atopic dermatitis, chronic urticaria unrelated to exercise, or exercise-induced bronchospasm) that might confound the clinical picture. Both CholU and EIA are ultimately diagnoses of exclusion. The clinical history and physical exam are paramount, and workup should rule out other potential causes of exercise-associated symptoms based on the unique clinical scenario (8). Recommended diagnostic evaluation could include: Cardiac evaluation: Ambulatory heart monitoring or echocardiography to assess for arrhythmia or structural heart disease. Pulmonary assessment: Spirometry or pulmonary function testing to rule out asthma or other underlying lung pathology. Laboratory testing: Thyroid-stimulating hormone and complete blood count to assess for thyroid dysfunction or anemia. For patients with suspected CholU or EIA, referral to an allergist for specialized assessment is often beneficial. Measuring baseline mast cell mediators (tryptase and/or histamine) provides a reference for comparison with postexercise levels (6). An elevated baseline tryptase may suggest an underlying mast cell disorder. If tryptase or histamine is elevated immediately following symptoms elicited by exercise, this may support a diagnosis of EIA but does not differentiate between FDEIA and EIA (2,9). Evaluation for specific food allergies (via serum IgE or skin-prick testing) can help confirm FDEIA by identifying a culprit food trigger (7). Skin or in vitro testing for IgE sensitization to environmental allergens also may exclude other allergic triggers encountered during exercise. In some cases, custom skin test solutions (e.g., prepared from sports drinks or supplements used by the athlete) are used to evaluate unique exercise-related exposures (8). Clinicians should carefully characterize the rash and associated symptoms to differentiate CholU from EIA. Additionally, clinicians can recommend that patients photograph their skin reactions during episodes to document lesion morphology. Any systemic symptoms beyond the skin should raise a strong suspicion for EIA (Table 1). An exercise treadmill challenge may aid in diagnosis; however, because these reactions are inconsistent, a negative exercise challenge does not rule out either condition (2,6). Furthermore, there is no established protocol for exercise challenge testing in EIA. Table 1. - Differences between cholinergic urticaria and exercise-induced anaphylaxis. Feature Cholinergic Urticaria (CholU) Exercise-Induced Anaphylaxis (EIA) Triggers Heat, exercise, passive heating Exercise alone or combined with food Symptoms Pinpoint hives, localized flushing Urticaria, angioedema, airway distress First-line management High-dose antihistamines Epinephrine autoinjector Provocation tests Treadmill test Treadmill test Prevention strategies Premedication with antihistamines Avoid triggers, do not exercise alone, emergency plan in place Treatment differs for cholinergic urticaria versus EIA (Table 2). For cholinergic urticaria, the mainstay of treatment is nonsedating H1 antihistamines, which can be titrated up to four times the recommended daily dose. Additionally, simultaneous use of H2 antihistamines with H1 antihistamines can be considered for further symptom control (10). There is also data supporting the use of omalizumab, an anti-IgE monoclonal antibody, for refractory cases of CholU, although not approved by Food and Drug Administration for this indication (11). In EIA, antihistamines may be used prophylactically, and there are case reports of successful treatment with omalizumab (12). However, to avoid catastrophic outcomes, an epinephrine autoinjector and overall exercise modification are key components of the treatment plan. Patients should not exercise alone and should have an emergency action plan in place. Providing a personalized exercise prescription with specific intensity limits, safety precautions, and risk/benefit counseling is advised. Addressing overlapping or contributing conditions can further reduce symptom burden. For example, if exercise-induced bronchospasm is present, a preexercise albuterol inhaler may help. If FDEIA is noted, the patient must avoid the implicated food before exercising. Table 2. - Cholinergic urticaria and exercise-induced anaphylaxis management. Treatment/Strategy Drug Class Typical Dose Range/Administration Notes General treatments for exercise-induced allergic conditions Fexofenadine 2nd-generation antihistamine 180 mg orally daily or twice a dayUp to 360 mg twice a day Mainstay of treatment Cetirizine 2nd-generation antihistamine 10 mg orally dailyUp to 20 mg twice a day Mainstay of treatment Loratadine 2nd-generation antihistamine 10 mg orally dailyUp to 20 mg twice a day Mainstay of treatment Albuterol inhaler Adrenergic bronchodilator 2 puffs (90 mcg/puff) before exercise or as needed As needed — may alleviate respiratory symptoms in EIA Omalizumab Monoclonal antibody SC injection every 2–4 wk (75–600 mg)(based on serum IgE levels) Reduces frequency/severity in refractory cases Exercise-induced anaphylaxis specific treatments Epinephrine autoinjector Sympathomimetic catecholamine Adult: 0.3 mg IMChild: 0.15 mg IM Emergency treatment for acute anaphylaxis Avoid known food triggers Lifestyle modification Identify and avoid food triggers Critical in FDEIA cases Exercise safety Lifestyle modification Provide specific exercise prescription Run with a partner and near help IM, intramuscular; SC, subcutaneous. Conclusion This case illustrates the importance of differentiating EIA from other allergic conditions, including exercise-induced urticaria. In a patient presenting with exercise-induced hives, clinicians should maintain a high index of suspicion for EIA by identifying any systemic symptoms. Providing an epinephrine autoinjector, outlining safety measures for return to play, and treating underlying allergic components are mainstays of treatment. Ultimately, early recognition and appropriate management of EIA, as opposed to assuming a harmless urticaria, can be lifesaving. The authors declare no conflict of interest and do not have any financial disclosures.