INTRODUCTION — Exercise-induced anaphylaxis (EIAn) is a disorder in which anaphylaxis occurs in association with physical exertion. The clinical manifestations, theories of pathogenesis, evaluation, and diagnosis of EIAn and food-dependent, exercise-induced anaphylaxis (FDEIAn) will be reviewed here. The management and prognosis of EIAn and FDEIAn are discussed separately. (See "Exercise-induced anaphylaxis: Management and prognosis" and "Food-induced anaphylaxis".)

TERMINOLOGY — Anaphylaxis, from any cause, is defined as a serious allergic or hypersensitivity reaction that is rapid in onset and may cause death [1,2]. The diagnostic criteria for anaphylaxis are reviewed in detail separately. (See "Anaphylaxis: Acute diagnosis", section on 'Diagnostic criteria'.)

The following terms are used in this topic review:

●Exercise-induced anaphylaxis (EIAn) – EIAn is a disorder in which anaphylaxis occurs only in association with physical exertion.

●Food-dependent, exercise-induced anaphylaxis (FDEIAn) – FDEIAn is a disorder in which symptoms develop only if exercise takes place within a few hours of eating and, in most cases, only if a specific food to which the patient is sensitized is eaten in the pre-exercise period. This definition has been used for several decades, although work in the pathophysiology of FDEIAn has raised the question of whether exercise is absolutely necessary for the development of symptoms. (See 'Theories of pathogenesis' below.)

●Augmentation factor-triggered food allergy – Augmentation factor-triggered food allergy is a more general term that refers to a food allergy in which reactions are dependent upon the presence of one or more augmenting factors, including exercise, alcohol, and nonsteroidal anti-inflammatory drugs [3]. (See 'Other cofactors' below.)

CLINICAL MANIFESTATIONS

Signs and symptoms — EIAn (food dependent or independent) is characterized by signs and symptoms of anaphylaxis in the setting of physical exertion. Symptoms may begin at any stage of exercise and occasionally occur just after exercise [4]. Early signs and symptoms typically include the following [5,6]:

●Diffuse warmth and/or flushing

●Generalized pruritus

●Urticaria (hives are usually 10 to 15 mm in diameter or larger, rather than the "punctate" hives normally seen in cholinergic/heat-induced urticaria)

●Sudden fatigue

If exercise continues, there is a progression to more severe symptoms, including one or more of the following:

●Angioedema of the face and/or extremities (often the hands)

●Gastrointestinal symptoms, including nausea, abdominal cramping, and diarrhea

●Laryngeal edema

●Hypotension and/or collapse

Bronchospasm is reported in some patients, although it may be less common in EIAn than in anaphylaxis from other causes [6]. Some patients experience headache that can persist for hours to days after the attack [6,7]. The diagnostic criteria for anaphylaxis (from any cause) are reviewed in detail separately. (See "Anaphylaxis: Emergency treatment".)

Cessation of exercise usually results in improvement or resolution of symptoms. Perhaps for this reason, reports of fatality are limited to a few cases [8-11]. However, it is possible that fatal episodes may be underdiagnosed or mistaken for other causes of sudden death during exercise.

Although stopping activity usually prevents progression of the attack, patients often do not instinctively stop exertion when they first experience symptoms. Instead, many try to run for help, which typically precipitates a dramatic worsening of symptoms. Patients should be educated about the importance of immediate cessation of activity. (See "Exercise-induced anaphylaxis: Management and prognosis".)

Frequency of attacks — The frequency and predictability with which symptoms occur vary among patients with EIAn and food-dependent, exercise-induced anaphylaxis (FDEIAn). Most patients exercise regularly but experience attacks only occasionally. A minority of individuals experience symptoms with most attempts at exercise. Still other patients have one or two attacks over a span of several years, although such infrequent attacks should prompt a careful evaluation for undetected cotriggers and cofactors. (See 'Other cofactors' below.)

Triggering activities — Vigorous forms of exercise, such as jogging, racquet sports, dancing, and aerobics, are most often implicated, although lower levels of exertion (eg, brisk walking or yard work) are capable of triggering attacks in some patients [7]. As an example, the exertion of crossing the street was sufficient to trigger symptoms in some older patients [12].

Implicated foods — The foods most commonly implicated in FDEIAn are wheat, other grains, and nuts in Western populations and wheat and shellfish in Asian populations; however, an array of culprit foods has been reported, including fruits, vegetables, seeds, legumes, and, less often, various meats, cow's milk, and egg [4,13-23]. The amount of food ingested is important in some patients [3,24].

Most patients develop symptoms only after eating a specific food, although a few have attacks if any food (usually solids rather than liquids) has been ingested [25]. Rare patients have been described in whom symptoms only occurred if two foods were eaten together before exercise [26].

The processing of the food may be critical in some cases. In one report, a patient developed FDEIAn with tofu but could tolerate soy milk [27]. Immunoblotting identified beta-conglycinin as the main allergen. Pepsin digestion readily degraded the beta-conglycinin in soy milk, but the same allergen in tofu was resistant to pepsin digestion, suggesting that this difference in allergen stability was fundamental to the patient's presentation.

Other cofactors — Many patients develop symptoms more readily in the presence of one or more additional cofactors, although exercise remains the immediate inciting factor. These include the following:

●Nonsteroidal anti-inflammatory drugs (NSAIDs) [3,28-32]

●Alcoholic beverages [3,7]

●Premenstrual or ovulatory phases of the menstrual cycle in women [18,28,33]

●Extremes of temperature (either high heat and humidity or cold exposure) [7]

●Seasonal pollen exposure in pollen-sensitized patients [7]

●Infections or illness [34]

Temporal association between exercise and co-factors — In FDEIAn, symptoms occur when the person exercises within minutes to a few hours after eating. In rare cases, symptoms occur when the food is eaten shortly after exercise (ie, within one hour). It is the combination of the food and exercise that precipitates attacks. Affected patients can eat the food in question without symptoms if there is no associated exercise, and they can exercise without symptoms if they have not eaten the culprit food.

Exposure to the cofactor typically occurs first, and then exercise precipitates symptoms.

●In most cases of FDEIAn, symptoms occur when the food is ingested within minutes to two hours before exercise [35]. However, food ingestion may occur up to six hours before exercise, and there are rare cases of FDEIAn in which the food was ingested shortly AFTER exercise [5,7,25,36].

●The temporal association between ingestion of alcoholic beverages is poorly reported, although the critical time period before exertion seems to be minutes to a few hours, similar to that of food.

●Ingestion of NSAIDs may precede exercise by hours to a day.

EPIDEMIOLOGY — Both EIAn and food-dependent, exercise-induced anaphylaxis (FDEIAn) have been reported around the world [4,16,37-42]. Adolescents and young adults account for most reported cases. Both EIAn and FDEIAn have occasionally been described in preadolescent children and older adults [38,43,44]. The female-to-male ratio is approximately 2:2.5 [19]. Patients report fewer symptoms over time, probably due to better avoidance of triggering factors, since the disorder has not been reported to resolve. (See "Exercise-induced anaphylaxis: Management and prognosis", section on 'Prognosis'.)

EIAn and FDEIAn appear to be rare, but there have been few attempts to systematically establish prevalence. The best study surveyed all school nurses in Yokohama, Japan to identify possible cases of EIAn or FDEIAn among Japanese adolescents [37,45]. Each case was investigated and confirmed. In this population, the prevalences of EIAn and FDEIAn were 0.03 and 0.017 percent, respectively. There was no apparent gender predilection in EIAn, whereas FDEIAn was more often identified in boys, contrary to the gender ratio noted above. EIAn and FDEIAn are usually sporadic, although familial cases have been reported [46,47].

THEORIES OF PATHOGENESIS — Cutaneous mast cell degranulation [48] and transient elevations in plasma histamine [49,50] and serum tryptase [51-53] have been documented in patients with EIAn and food-dependent, exercise-induced anaphylaxis (FDEIAn). Thus, mast cell activation and release of vasoactive mediators is believed to be responsible for the associated clinical manifestations, as in other forms of anaphylaxis [54]. Basophil function has not been specifically studied. (See "Pathophysiology of anaphylaxis".)

Exercise-induced anaphylaxis unrelated to food — The specific physiologic changes and/or cellular events that occur during exercise to trigger mast cell activation are not fully understood. A 2015 expert panel concluded that none of the current theories was adequate and recommended that a global research network be established to advance the field [55]. The leading theories are reviewed briefly here.

Food-dependent forms — Because patients with FDEIAn are sensitized to the culprit food but tolerate ingestion in the absence of exertion, theories of pathogenesis have focused on changes that occur during exercise that could overcome or reverse this tolerance:

●Gastric permeability can increase during exercise, which may permit increased entry of intact or incompletely digested allergens into the circulation during exercise but not during rest [30,56]. Nonsteroidal anti-inflammatory drugs (NSAIDs) and alcohol, which are recognized cofactors in FDEIAn reactions, also increase gastric permeability [57,58].

●Aspirin and other NSAIDs can also lead to mast cell degranulation through effects on arachidonic acid metabolism [59]. Premedication with aspirin increases the likelihood that a food/exercise challenge will elicit symptoms and is sometimes used in diagnosis. (See 'Exercise challenge testing' below.)

However, a study of 12 healthy volunteers failed to detect increased absorption of gliadin after the ingestion of wheat with various combinations of exercise, aspirin, alcohol, or pantoprazole [60]. Thus, either increased allergen absorption is not the simple explanation for the disorder, or patients with FDEIAn have unique sensitivities to the effects of cofactors.

Another theory posits that the shifts in blood flow that normally occur with exercise, ie, away from the stomach, intestines, and other intra-abdominal organs and towards the heart, skeletal muscles, and skin allow food allergens to reach a different population of mast cells that may be more reactive to the food in question than mast cells residing in the gut.

Wheat-dependent FDEIAn — Wheat-dependent food-dependent, exercise-induced anaphylaxis (FDEIAn) is the best-studied form of FDEIAn. Omega-5 gliadin, a protein in gluten, has been identified as an important allergen in this disorder [61], as well as in wheat allergy causing anaphylaxis independent of exercise [62]. However, omega-5 gliadin is not the only wheat allergen implicated in FDEIAn [22,63,64] and not all patients with omega-5 gliadin allergy have FDEIAn [62]. In addition, many patients who initially present with FDEIAn will develop symptoms at rest if enough wheat is ingested [3,53].

●The necessity of exercise was brought into question in a 2014 study of patients with wheat-dependent FDEIAn. In this study, 16 patients who tolerated wheat ingestion at rest and had positive in vitro tests for immunoglobulin E (IgE) to omega-5 gliadin were challenged with increasing amounts of gluten-rich bread, alone or combined with aspirin, alcohol, and exercise [3]. In 14 of 16, objective reactions (most commonly urticaria) could be elicited with some combination of larger amounts of gluten-rich bread, aspirin, and alcohol, even in the absence of exercise. These findings suggest that exercise is simply another cofactor for the clinical expression of an underlying food allergy and not an absolute requirement for symptoms. The authors suggested the term "augmentation factor-triggered food allergy" instead of FDEIAn. Another interesting finding in this study was that gastric and intestinal permeability in patients with FDEIAn, as measured by absorption of nondigestible sugars, did not appear to differ from that in normal controls, either at baseline or during exercise.

A 2018 study by the same group confirmed the earlier study and demonstrated that exercise increased the severity of wheat-induced anaphylaxis and lowered the threshold for developing symptoms but was not an absolute requirement in many cases [53]. However, symptoms could not be elicited in approximately one-half of patients, even after ingestion of the equivalent of 55 slices of bread. This study also developed a protocol for the diagnosis of wheat-dependent FDEIAn.

●A subset of patients (mostly Japanese women) with wheat-dependent EIAn may become sensitized through cutaneous exposure to hydrolyzed wheat protein in personal products (eg, facial soap) [63,64]. Omega-5 gliadin is not the main allergen in this syndrome. The relevance of these findings to other populations is not known.

EVALUATION AND DIAGNOSIS — The diagnosis of EIAn or food-dependent, exercise-induced anaphylaxis (FDEIAn) is made clinically in the majority of cases based largely upon a meticulous history of the events surrounding the episodes. Typically, patients present with episodes of warmth/flushing and urticaria during exertion, which progress to involve more severe symptoms if the exertion continues. Symptoms immediately begin to improve when exertion is stopped.

The diagnosis also requires exclusion of other disorders that could present similarly. (See 'Differential diagnosis' below.)

Diagnosis of EIAn — The diagnosis of EIAn is appropriate in a patient with the following:

●Signs and symptoms consistent with anaphylaxis that occurred during (or occasionally shortly after) exercise

●No other diagnosis that explains the clinical presentation (see 'Clinical history' below and 'Differential diagnosis' below)

A positive exercise challenge confirms the diagnosis, but a negative challenge does not reliably exclude the diagnosis. Thus, until a validated protocol for exercise challenge is established, challenge is not required for diagnosis.

Diagnosis of FDEIAn — The diagnosis of food-dependent, exercise-induced anaphylaxis (FDEIAn) is appropriate in a patient with the following:

●Signs and symptoms consistent with anaphylaxis that occurred during (or shortly after) exercise but only when exercise was preceded (typically by no more than two to three hours) by food ingestion (see 'Questions about food' below)

●No other diagnosis that explains the clinical presentation (see 'Clinical history' below and 'Differential diagnosis' below)

If a specific food is implicated, then there should also be:

●Evidence of specific immunoglobulin E (IgE) to the implicated food, either by skin testing or food-specific IgE immunoassays (see 'Skin testing or in vitro testing' below)

●No symptoms upon ingestion of that food in the absence of exertion and no symptoms if exercise occurs without ingestion of that food (see 'Questions about food' below)

A positive food/exercise challenge confirms the diagnosis, but a negative challenge does not reliably exclude the diagnosis. Thus, until a validated protocol for exercise challenge is established, challenge is not required for diagnosis. (See 'Exercise challenge testing' below.)

If testing for food sensitization is negative but the history is strongly suggestive of FDEIAn, we suggest repeat testing in six months to one year. We have encountered patients in whom sensitization was not demonstrable at presentation but became so within a period of months.

Clinical history — The clinician should carefully review the details of each episode and attempt to discern the following information:

●Was exercise or some type of exertion associated with each of the attacks? If not, then the patient with food-associated symptoms may have a primary food allergy with symptoms that are exacerbated by exercise.

●Does it seem that a certain level of exertion must be reached before symptoms appear, or can attacks occur at different levels of exertion? This information is useful in determining which activities the patient can safely resume in the future.

●Do symptoms begin to subside when the patient stops all physical activity? This is an important clinical feature of both EIAn and FDEIAn.

●Do other activities that involve passively heating the body induce symptoms, such as hot baths, showers, or saunas? Symptoms triggered by changes in core body temperature are suggestive of cholinergic urticaria, which can include systemic symptoms. (See 'Differential diagnosis' below.)

●Were any medications (over the counter or prescription) or alcohol ingested in the 24 hours preceding the attack? As with all forms of anaphylaxis, these are known cofactors that increase the likelihood of a reaction or lead to more severe reactions. (See 'Other cofactors' above and "Anaphylaxis: Confirming the diagnosis and determining the cause(s)", section on 'Concurrent medications and other substances'.)

●Do symptoms occur in specific environments (eg, indoors or outdoors)? Were there any common ambient outdoor conditions on days of attacks (eg, high humidity, peak pollen season)? Is there any seasonal variation? (See 'Other cofactors' above.)

●Does the patient have a history of other allergic diseases, such as allergic rhinitis (consider pollens as a possible cofactor) or chronic urticaria (could the patient have a physical urticaria with systemic symptoms)? (See 'Differential diagnosis' below.)

Questions about food — For patients suspected of having FDEIAn, additional questions should be directed at determining if a primary food allergy is present and if the reaction could have represented a primary food allergy that was exacerbated by exercise. (See 'Differential diagnosis' below.)

●Since the last attack, has the patient ingested portion-sized amounts of the food in question in the absence of exercise, and, if so, did any symptoms result? In FDEIAn, the food only causes symptoms if there is associated exercise.

●Does the patient have symptoms of oral allergy syndrome? Oral allergy syndrome presents with itching and/or mild swelling of the mouth and throat immediately following ingestion of certain uncooked fruits or vegetables. Were any pollen-related foods ingested before the attack? (See "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food allergy syndrome)".)

●Does the patient ingest any health drinks, protein bars, or other supplements? These commonly contain grains, fruits, nuts, soy, and other potential food allergens (eg, gelling agents) and are routinely overlooked by patients who may forget to report snacks.

Physical examination — There are no physical findings that are unique to patients with EIAn or FDEIAn. There may be signs of allergic diseases, such as eczematous skin changes or allergic "shiners" (dark circles under the eyes from longstanding nasal congestion), a transverse nasal crease (suggesting frequent nose rubbing), and/or pale, boggy mucosa on nasal speculum examination suggesting allergic rhinitis.

A careful skin examination should be performed to ensure that urticaria pigmentosa, the characteristic skin finding in mastocytosis, is not present. Mastocytosis can present with anaphylaxis upon exertion, as well as in response to a variety of other triggers. (See "Physical (inducible) forms of urticaria" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Cardiac examination should be performed to exclude abnormal heart sounds or rhythms as exercise-induced cardiac conditions are in the differential diagnosis. (See 'Differential diagnosis' below.)

Laboratory studies — A baseline serum tryptase level should be measured in all patients. The blood sample should be obtained a few days or more after resolution of an episode. Serum tryptase is normal at baseline in both EIAn and FDEIAn. Elevated values at baseline are suggestive of mastocytosis. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

As with anaphylaxis from any cause, elevations in mast cell mediators (ie, serum tryptase or serum or plasma histamine) can support the clinical impression of anaphylaxis but are not necessary for making the diagnosis of anaphylaxis and do not provide information about the cause [65]. There are very limited data about how often elevations in these mediators are present after episodes of EIAn and FDEIAn. Normal mediator levels obtained shortly after the onset of anaphylaxis symptoms do not rule out anaphylaxis because elevations during anaphylaxis are highly variable. These tests are reviewed separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Skin testing or in vitro testing — In patients with FDEIAn, skin testing and/or in vitro testing for food-specific IgE is essential to the evaluation because sensitization to the precipitating food(s) is usually demonstrable, with rare exceptions [66].

Patients may not be aware of the relationship to food, because they normally eat the food without reaction, and, thus, an argument can be made for testing for food-specific IgE to foods commonly involved in FDEIAn even if the patient is not suspicious of this association [67]. However, the clinical history can usually limit the list of possible causative foods.

If skin testing with a commercial extract yields negative results, epicutaneous (ie, prick) skin testing with fresh food should be performed. The prick-by-prick method is used, in which the food is pricked with a testing lancet, then the cleaned skin of the volar forearm is pricked.

Specific tests for wheat allergy — In patients with suspected wheat-dependent FDEIAn, it is also possible to perform skin testing with a high-gluten flour, mixed into saline to form a paste.

The utility of testing with different types of wheat flour has been evaluated in patients with wheat-dependent FDEIAn:

●In a study of 17 patients with wheat-dependent FDEIAn, 29 percent were skin-test positive when a commercial wheat extract was used, while 80 percent tested positive to a paste of wheat flour [68].

●If testing to wheat using wheat flour is negative, testing with a paste of high-gluten flour may reveal the allergy. In a study of 16 patients with wheat-dependent FDEIAn, all 16 subjects reacted to skin testing with high-gluten flour, while 15 reacted to regular wheat flour, and 8 (50 percent) reacted to commercial wheat extract [3].

If skin testing with high-gluten flour is not possible or is negative and wheat-dependent EIAn is strongly suspected based upon the history, an ImmunoCAP commercial assay for IgE to recombinant omega-5 gliadin is available. The sensitivity of this assay was found to be 80 percent in a study of 50 Japanese patients with positive wheat/exercise challenges, making this immunoassay more clinically useful than those for wheat, gluten, or other wheat allergens [69]. IgE to omega-5 gliadin may be positive even when IgE to wheat is negative [70]. In the study of 17 German patients with wheat-dependent FDEIAn mentioned previously, 82 percent had IgE to omega-5 gliadin, although other gliadins (alpha, beta, and gamma) were also important, as demonstrated with experimental ImmunoCAP assays [68]. The extent to which different populations of patients with wheat-dependent EIAn are sensitized to different wheat allergens has not been systematically evaluated.

Skin testing or in vitro testing for IgE sensitization to environmental allergens is useful in the evaluation of EIAn if specific cofactors are suspected, such as high pollen counts in a patient with concomitant allergic respiratory disease. However, it is not a routine component of the evaluation.

Basophil activation testing — Basophil activation testing (BAT), where available (uncommonly used in the United States outside of research protocols), appears useful in the diagnosis of wheat-dependent exercise-induced anaphylaxis (WDEIAn). In a study of 12 patients with challenge-proven WDEIAn and 10 controls, gluten and specific gluten proteins resulted in robust basophil activation in a dose-dependent manner in patients, but not in controls [71].

Exercise challenge testing — There is no established protocol for exercise challenge, with or without food, to evaluate patients for EIAn or FDEIAn. A validated exercise challenge protocol would be useful in confirming the diagnosis of EIAn. It would also exclude EIAn in a patient whose reactions are believed to be dependent upon food (FDEIAn), thereby allowing them to resume exercise safely in the fasting state.

Most studies have reported variable rates of success in eliciting symptoms with exercise challenge (with or without food) [3,4,24,32,37,50,72]. The Standard Bruce protocol for stress testing, with added spirometry before and periodically during the procedure, has been used by several groups [32,37]. In a literature review of 234 cases of FDEIAn, food/exercise challenges were performed in 81 and failed to reproduce symptoms in 29 (36 percent) [24]. Thus, a negative test does not exclude FDEIAn. The amount of food, the interval between food ingestion and exercise, and the intensity of the exercise may all be important factors [3,4,24,65]. In some patients with negative food/exercise challenges, premedication with aspirin (500 or 1000 mg orally before food ingestion) increased the likelihood that symptoms were elicited with repeat challenge [3,69].

The measures that may be required to elicit a reaction were illustrated in the study of 16 patients with wheat-dependent FDEIAn described previously [3]. Each of these patients gave the history of reacting only to the combination of wheat and exercise. Because the intent of this study was to determine if exercise was absolutely required for reactions, patients were challenged sequentially with and without cofactors and exercise. Patients ingested between 10 and 80 grams of gluten-enriched bread, in response to which four developed symptoms. Another 10 subjects required wheat ingestion plus premedication with 500 to 1000 mg of aspirin and 10 to 30 mL of 95 percent alcohol to develop symptoms. The remaining two subjects required all of these measures, plus exercise, to develop symptoms. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'Exercise test procedure'.)

It remains to be determined why such measures are necessary to elicit symptoms in a laboratory challenge but apparently not in the patient's routine life. It is possible that other cofactors must also be present for symptoms to develop and that these have not all been identified.

If pursued, exercise challenge procedures should be performed by allergy specialists with the expertise, staff, and equipment available to treat anaphylaxis. Informed consent should be obtained.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of EIAn includes cholinergic urticaria, mastocytosis, cardiovascular events, exercise-induced asthma, exercise-associated gastroesophageal reflux, and postural orthostatic tachycardia syndrome (POTS). In addition, the differential diagnosis of food-dependent, exercise-induced anaphylaxis (FDEIAn) includes primary food allergy exacerbated by exercise.

Cholinergic urticaria — Cholinergic urticaria is a form of physical urticaria characterized by small punctate wheals (1 to 3 mm in diameter) with surrounding erythema of the affected skin (picture 1). Urticaria is elicited by raising the core body temperature. Patients may experience symptoms with exercise but also upon exposure to factors that passively increase body temperature, such as hot showers or saunas, very strong emotion, or very spicy food. Symptoms of cholinergic urticaria are usually limited to the skin, although generalized symptoms can occur if cutaneous mast cell mediators are released in sufficient amounts and diffuse into the systemic circulation [73-75]. (See "Physical (inducible) forms of urticaria", section on 'Cholinergic urticaria'.)

The wheals of EIAn are usually large (10 to 15 mm in diameter), whereas those of cholinergic urticaria are typically small and punctate. This distinction is not true in all cases, and the punctate wheals of cholinergic urticaria may enlarge and coalesce as symptoms progress.

Primary food allergy exacerbated by exercise — Patients with food allergy may have reactions that are more severe because of concomitant exertion. Thus, it must be determined that a patient with suspected FDEIAn does indeed tolerate the food in the absence of exercise. A formal food challenge should be performed to determine tolerance if the patient cannot report tolerating portion-sized amounts of the food in question in the absence of exercise SINCE the last episode of anaphylaxis. In light of new developments in the pathogenesis of FDEIAn, it is possible that FDEIAn is actually a subclinical form food allergy that only results in symptoms in the presence of additional cofactors (exercise, nonsteroidal anti-inflammatory drugs [NSAIDs], alcohol, physical or emotional stress). (See "Oral food challenges for diagnosis and management of food allergies".)

Cold-induced urticaria/anaphylaxis — Cold-induced urticaria can cause sufficient systemic mediator release to precipitate anaphylaxis. Patients with this disorder who experience symptoms from exercising in cold weather may be mistakenly diagnosed with EIAn. However, cold ambient conditions may be a cofactor in some patients with EIAn [7,76,77]. Questioning about passive cold exposure should reveal other circumstances in which the patient has experienced symptoms separate from exercise. An ice cube challenge is useful in diagnosing some cold-induced urticarial syndromes [78].

Mastocytosis — Mastocytosis describes a group of disorders of pathologic mast cell accumulation in tissues. These diseases can be limited to the skin (cutaneous mastocytosis) or involve extracutaneous tissues (systemic mastocytosis). Patients with either form are susceptible to anaphylaxis from a variety of triggers, including exercise [79].

Patients with systemic mastocytosis often have persistent elevations in serum mature tryptase, whereas patients with anaphylaxis (from various other causes) may demonstrate elevations of serum tryptase during and immediately after an episode of anaphylaxis, but the serum tryptase level returns to normal once the symptoms have fully resolved. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Cardiovascular events — Arrhythmias and other cardiovascular events can cause sudden fatigue, dyspnea, and collapse during exercise but do not cause pruritus, urticaria, angioedema, or laryngeal edema. Cardiovascular disorders that may be precipitated by exercise are reviewed elsewhere. (See "Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation" and "Athletes: Overview of sudden cardiac death risk and sport participation".)

Exercise-induced bronchoconstriction — Exercise-induced bronchoconstriction presents with symptoms that are limited to the airways and often occurs in patients with known asthma. (See "Exercise-induced bronchoconstriction".)

Exercise-associated reflux — Laryngopharyngeal reflux during exercise can mimic mild symptoms of EIAn, including flushing, throat discomfort, and chest tightness/cough. However, pruritus, urticaria, and angioedema are not observed, and the symptoms do not escalate as they can in EIAn. (See "Laryngopharyngeal reflux".)

Postural orthostatic tachycardia syndrome — POTS is a disorder of unknown etiology that may be defined as an excessive increase in heart rate (>30 beats per minute) when changing from a supine to upright posture in a patient with accompanying symptoms [80]. Symptoms include tachycardia, headache, abdominal discomfort, nausea, dizziness, presyncope, and fatigue and should develop within 10 minutes of the change in posture. However, patients do not usually become frankly hypotensive or experience syncope. POTS often develops in adolescents, following a period of inactivity or illness, after which they are unable to return to their previous activities because of these symptoms [81]. It can be distinguished from EIAn by the absence of urticaria, angioedema, or bronchospasm. However, there are rare reports of POTS occurring in association with mast cell disorders [82]. (See "Postural tachycardia syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anaphylaxis".)

SUMMARY

●Exercise-induced anaphylaxis (EIAn) is a disorder in which anaphylaxis occurs in response to physical exertion. A subset of patients has a food-dependent form (FDEIAn) in which symptoms occur only if exercise takes place within a few hours of eating and, in most cases, only if a specific food is eaten. (See 'Introduction' above.)

●Typical symptoms include extreme fatigue, warmth, flushing, pruritus, and urticaria, progressing to angioedema, wheezing, upper airway obstruction, and collapse. Symptoms usually begin to improve immediately upon cessation of exercise. (See 'Clinical manifestations' above.)

●Some patients experience symptoms only if cotriggers or cofactors are present in association with exercise. In addition to food (FDEIAn), these may include nonsteroidal anti-inflammatory drugs (NSAIDs), alcoholic beverages, infections, high pollen levels, extremes of heat and humidity, and menstrual status in some women. (See 'Other cofactors' above.)

●The pathogenesis of EIAn and FDEIAn is not fully understood. It is possible that FDEIAn may be a form of food-induced anaphylaxis in which exercise is simply an augmenting co-factor. (See 'Theories of pathogenesis' above.)

●The diagnosis of EIAn/FDEIAn is usually based upon the clinical history and exclusion of other disorders. Exercise challenge is not required for the diagnosis, but a positive challenge can be useful in confirming the diagnosis. A negative challenge does not reliably exclude the diagnosis. Testing for allergen-specific immunoglobulin E (IgE) should be performed if indicated by the clinical history (eg, testing for foods in patients with suspected FDEIAn). (See 'Evaluation and diagnosis' above.)

●The differential diagnosis of EIAn includes cholinergic urticaria, systemic mastocytosis, cardiovascular events, exercise-induced asthma, and exercise-associated laryngopharyngeal reflux. The differential diagnosis of FDEIAn includes primary food allergy exacerbated by exercise. (See 'Differential diagnosis' above.)