Version May 2024
INTRODUCTION — Exercise-induced anaphylaxis (EIA) is a rare disorder in which anaphylaxis occurs in association with physical exertion. In most patients, symptoms only develop if a certain food is eaten in close approximation to physical exertion or other cofactors are present, which is commonly called food-dependent, exercise-induced anaphylaxis (FDEIA). The clinical manifestations, epidemiology, pathogenesis, and diagnosis of EIA and FDEIA are discussed in this topic review. Management and prognosis are presented elsewhere. (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 'NIAID/FAAN diagnostic criteria'.)
The following terms are used in this topic review:
●Exercise-induced anaphylaxis (EIA) – EIA is a disorder in which anaphylaxis occurs only in association with physical exertion without relation to food intake.
●Food-dependent, exercise-induced anaphylaxis (FDEIA) – FDEIA 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. It is the combination of the food (allergy) and exercise (cofactor) that precipitates attacks. Patients tolerate the culprit food in the absence of exercise, and they tolerate exercise in the absence of the culprit food. One of the most common food allergies to present as FDEIA is wheat allergy, or wheat-dependent EIA (WDEIA).
Evolving terminology for FDEIA — The term FDEIA, although familiar to allergy specialists, is problematic for at least three reasons:
●Research in the pathophysiology of FDEIA has shown that, although exercise is the most common and consistent cofactor in FDEIA, symptoms can also be elicited by other cofactors, particularly alcohol and nonsteroidal anti-inflammatory drugs, even at rest [3-7]. Thus, symptoms are not strictly dependent on exercise.
●Some patients do not develop full anaphylaxis but experience only urticaria and/or angioedema from the combination of the culprit food and other cofactors. Therefore, anaphylaxis is not the only presentation.
●The disorder is primarily a form of food allergy, but one in which signs and symptoms only develop when certain other exposures are present. The term FDEIA does not capture the essential nature of the underlying food allergy.
Therefore, the term cofactor-dependent food allergy would be a more accurate and descriptive term. Although we prefer this term, we use FDEIA in this topic review because it is the better-recognized term at present.
CLINICAL MANIFESTATIONS
Signs and symptoms — EIA (food dependent or independent) is characterized by signs and symptoms of anaphylaxis in the setting of physical exertion (table 1). Symptoms may begin at any stage of exercise and occasionally occur just after exercise [8]. Patients may experience milder symptoms in association with exercise for several years before a first episode of anaphylaxis. Typical early signs and symptoms include the following [9,10]:
●Diffuse warmth and/or flushing
●Generalized pruritus
●Urticaria (the wheal component of the hives is usually 10 to 15 mm in diameter or larger, rather than the 1 to 3 mm wheal also referred to as "punctate" hives normally seen in cholinergic/heat-induced urticaria)
●Angioedema of the face and/or extremities (often the hands)
●Sudden fatigue
These same symptoms are often the initial ones in an episode that progresses to full anaphylaxis. More severe symptoms may include one or more of the following [3,4,11,12]:
●Gastrointestinal symptoms, including nausea, abdominal cramping, and diarrhea
●Dyspnea due to bronchospasm or laryngeal edema
●Hypotension and/or collapse
Allergic acute coronary syndrome has been described [13,14]. Some patients experience headache that can persist for hours to days after the attack [10,15].
Although stopping activity counteracts the progression of the attack, patients often do not instinctively stop exertion when they first develop the disorder. Instead, many try to run for help or "push through" early symptoms, which typically precipitates a dramatic worsening of symptoms. Patients should be educated about the importance of immediate cessation of activity as soon as the diagnosis is suspected. (See "Exercise-induced anaphylaxis: Management and prognosis".)
Range of severity — A 2022 systematic review identified 722 patients with food-dependent exercise-induced allergic reactions, in which 83 percent experienced anaphylaxis and 17 percent developed only urticaria and/or angioedema [16]. Systemic manifestations of anaphylaxis were respiratory (64 percent), followed by cardiovascular (57 percent), and gastrointestinal (24 percent).
Reports of fatality are limited to a few cases [17-20]. However, it is possible that fatal episodes may be underdiagnosed or mistaken for other causes of sudden death during exercise.
Frequency of attacks — The frequency and predictability with which symptoms occur vary among patients with EIA and FDEIA. 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 cofactors. (See 'Other cofactors' below.)
Triggering activities — Vigorous forms of exercise, such as jogging, racquet sports, playing football or soccer, 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 [3,4,15,16]. As an example, the exertion of crossing the street or gardening was sufficient to trigger symptoms in some older patients [21].
Implicated foods in FDEIA — The foods most commonly implicated in FDEIA 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 [8,22-35]. Wheat (66 percent), vegetables (9 percent), seafood (9 percent), legumes (7 percent), and fruits (6 percent) accounted for the most common culprit foods in a systematic review [16]. For some foods, the responsible component allergens or epitopes have been reported [22,36-43].
The amount of food ingested is important, and clinical threshold levels for gluten have been determined for use in designing challenge protocols [3,5,11,44].
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 [45]. Rare patients have been described in whom symptoms only occurred if two or more foods were eaten together before exercise [7,16,46].
The processing of the food may be critical in some cases. In one report, a patient developed FDEIA with tofu but could tolerate soy milk [47]. 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. In another study, nine patients were described who developed anaphylaxis only to the hydrolyzed wheat protein Meripro 711 in a cake mix [48]. Skin prick tests and serum levels of Meripro 711-specific immunoglobulin (Ig)E were positive in all patients. However, they tolerated ingestion of regular nonhydrolyzed wheat products (eg, bread or pasta) on a regular basis.
Other cofactors — Many patients develop symptoms more readily in the presence of one or more additional cofactors, although exercise remains the immediate inciting trigger in most instances. The cofactors that are relevant for any given patient may vary. Possible cofactors include the following:
●Nonsteroidal anti-inflammatory drugs (NSAIDs) [3,49-53]
●Alcoholic beverages [3,15,51]
●Premenstrual or ovulatory phases of the menstrual cycle in women [27,49,54]
●Extremes of temperature (either high heat and humidity or cold exposure) [15]
●Seasonal pollen exposure in pollen-sensitized patients [15]
●Infections or illness [55]
Temporal association between eating and cofactors — In FDEIA, symptoms most characteristically occur when the person exercises (or encounters other cofactors) within minutes to a few hours after eating.
Common patterns include the following:
●In most cases of FDEIA, symptoms occur when the food is ingested within minutes to two hours before exercise [3,53]. However, food ingestion may occur up to four hours before exercise, and 2 out of 722 patients described in the systematic review experienced symptoms even six hours after eating [16]. There are uncommon cases of FDEIA in which the food was ingested shortly after exercise [9,15,33,45]. Another unusual pattern is the appearance of symptoms a few minutes after stopping exercise, rather than during exercise.
●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. Alcohol given 30 minutes before each dose of gluten led to a reduction of the threshold dose for objective reaction by 36 percent in a study using a challenge protocol [5].
●Ingestion of NSAIDs may be a cofactor if it precedes exercise by hours to a day.
EPIDEMIOLOGY — Both EIA and food-dependent, exercise-induced anaphylaxis (FDEIA) have been reported around the world [8,25,56-61]. The vast majority of publications in the last decades describe cases of FDEIA, with EIA unrelated to food reported much less commonly. The association between EIA and food intake was not recognized in the first decades after the disorder was identified, and it is possible that many of these early cases of EIA were actually FDEIA. In addition, recognition of FDEIA is increasing. In a Hong Kong series of patients referred for the diagnosis of "idiopathic anaphylaxis," 16 of 29 cases had FDEIA [62]. In an Irish center, the number of patients diagnosed with FDEIA or related reactions per year increased from 1 in 2001 to 18 in 2016 [63].
Adolescents and young adults account for most reported cases, and the mean age at onset was 21 years in a systematic review, although both EIA and FDEIA have occasionally been described in preadolescent children and older adults [57,64,65]. The female-to-male ratio is approximately even [3,11,16,28,66-68]. EIA and FDEIA are usually sporadic, although familial cases have been reported [69,70]. Most patients (60 percent) had a history of atopy (eg, allergic rhinitis, asthma, and/or atopic dermatitis), and 37 percent of patients reported a previous history of urticaria [16].
There have been few systematic attempts to establish prevalence. The best study surveyed all school nurses in Yokohama, Japan, to identify possible cases of EIA or FDEIA among Japanese adolescents [56,71]. Each case was investigated and confirmed. In this population, the prevalences of EIA and FDEIA were 0.03 and 0.017 percent, respectively.
Other studies providing some information about prevalence relative to anaphylaxis or food allergy in general include the following:
●In a Korean anaphylaxis registry, FDEIA was the trigger in 2 percent and EIA in 0.4 percent of cases overall [62,72]; cofactors were reported to be important in 16.8 percent of all patients with anaphylaxis.
●In an immunology clinic in Sri Lanka, FDEIA was present in 29 of 238 (12.2 percent) of patients with anaphylaxis [12].
●In a Korean single-center study, 20 of 415 patients with food allergy (4.8 percent) had FDEIA to wheat.
●In a European anaphylaxis registry, FDEIA to wheat was the most common form of wheat anaphylaxis in adults (83 percent of 250 cases) and was more common in central than southern Europe [68].
THEORIES OF PATHOGENESIS — Cutaneous mast cell degranulation [66] and transient elevations in plasma histamine [67,73] and serum tryptase [11,74,75] have been documented in patients with EIA and food-dependent, exercise-induced anaphylaxis (FDEIA). Thus, mast cell activation and release of vasoactive mediators are believed to be responsible for the associated clinical manifestations, as in other forms of anaphylaxis [76]. For FDEIA, food allergens have been identified [36,37] (see 'Wheat-dependent EIA' below). In addition, basophils of patients with FDEIA can be activated by the culprit food [77-79].
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 [80]. The leading theories are reviewed briefly here. Of note, the vast majority of publications in the last decades describe cases of FDEIA, with EIA unrelated to food reported much less commonly. Thus, it is probable that many of the early cases of EIA were actually FDEIA, in which the association with food intake was not recognized. Failure to recognize the association with food may also partly explain the commonly made observation that identical episodes of exercise trigger symptoms on one occasion and not on others [67].
Food-dependent forms — In patients with FDEIA, anaphylaxis may be triggered even at rest by ingestion of much higher amounts of the specific food allergen than normally ingested in daily life [3,5,11]. Thus, the distinction between food allergy and FDEIA may primarily be an increased reaction threshold in FDEIA as compared with simple food allergy, rather than invoking a different pathogenesis. Because patients with FDEIA are sensitized to the culprit food but tolerate ingestion in the absence of cofactors, theories of pathogenesis have focused on changes that occur during exercise or upon exposure to other cofactors, which 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 [3,51,81,82]. Nonsteroidal anti-inflammatory drugs (NSAIDs) and alcohol, which are recognized cofactors in FDEIA reactions, also increase gastric permeability [3,83,84]. Consistent with this, aspirin and exercise increased levels of circulating gliadin peptides in patients with wheat-dependent EIA (WDEIA) [51]. However, in a study of 12 healthy volunteers, various combinations of exercise, aspirin, alcohol, or pantoprazole did not result in increased absorption of gliadin after the ingestion of wheat [85]. Thus, patients with FDEIA may have unique sensitivities to the effects of cofactors.
●Aspirin and other NSAIDs can also promote mast cell degranulation through effects on arachidonic acid metabolism [86].
●The possibility that an altered gut microbiome could lead to abnormally increased food absorption was raised by a study reporting alterations in intestinal microbiota in fecal samples from 25 patients with WDEIA, compared with 25 controls [87].
●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 toward 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 [80].
●Possible genomic risk factors for WDEIA were reported in four association studies from Japan and China. Each study reported one factor: the HLA-DPB1*02:01:02 allele, the G-allele in rs1946518 at the interleukin (IL-)18 locus, IL-4-C590T, and presence of an 287-base-pair intron at the angiotensin-converting enzyme (ACE) for patients with allergy to hydrolyzed wheat protein [88-91]. However, these data require confirmation.
FDEIA may also develop during the course of oral immunotherapy (OIT) as responsiveness is reduced but not eliminated. In patients undergoing OIT to foods such as wheat, egg, or milk, the presence of various cofactors (eg, exercise or illness) can lead to breakthrough symptoms [92]. These patients have developed short-term unresponsiveness, but the presence of cofactors appears to unmask residual allergy. Exercise was a more common contributor to moderate or severe symptoms than to mild symptoms. In another study of patients allergic to wheat and receiving wheat OIT, exercise-induced allergic reactions were reported in 14 out of 21 patients (67 percent) who eventually achieved desensitization. Eleven patients (52 percent) reported exercise-induced allergic reactions even five years or longer after stopping OIT [93,94] despite reduction of specific IgE levels to all gliadin and glutenin components as a result of OIT.
Wheat-dependent EIA — Wheat-dependent, exercise-induced anaphylaxis (WDEIA) is the best-studied form of FDEIA and a relatively severe form of food allergy. In a European anaphylaxis registry, wheat anaphylaxis was associated with more severe symptoms (odds ratio 4.3) and with a higher number of severe cardiovascular symptoms (87 percent) in comparison with other food allergies [68].
Omega-5 gliadin, a protein in gluten, has been identified as an important allergen in WDEIA [36] as well as in wheat allergy causing anaphylaxis independent of exercise [4,68]. However, omega-5 gliadin is not the only wheat allergen implicated in WDEIA [4,31,95,96]. Low and high molecular weight glutenins, the lipid transfer protein Tri a14, and alpha-beta-gamma gliadins have also been implicated [31,37,77,97]. Hydrolyzed wheat proteins may be relevant allergens for some patients [48,95,96,98,99]. A subset of patients (mostly Japanese women) with WDEIA may become sensitized through cutaneous exposure to hydrolyzed wheat protein in personal care products (eg, facial soap) applied to the skin [95,96,99]. A Danish report described patients who developed anaphylaxis to a different hydrolyzed wheat protein present in a cake mix [48]. Omega-5 gliadin is not the main allergen in syndromes associated with hydrolyzed wheat proteins.
Many patients who initially present with WDEIA will develop symptoms at rest if enough wheat is ingested or yet-unknown relevant cofactors (eg, stress) are also present [3,11]. The necessity of exercise was brought into question in a 2015 study of patients with WDEIA. In this study, 16 patients who tolerated wheat ingestion at rest and had positive in vitro tests for immunoglobulin (Ig)E to omega-5 gliadin were challenged with increasing amounts of a bread made with pure gluten flour, alone or combined with aspirin, alcohol, and exercise [3]. Gluten flour contains 35 mcg of omega-5-gliadin per mg gluten flour, which is a more than tenfold increase in the concentration of this major allergen compared with normal bread flour. In 14 of 16 patients, objective reactions (most commonly urticaria) could be elicited without exercise, using various combinations of larger amounts of pure gluten flour bread, aspirin, and alcohol. These findings demonstrate that exercise is simply another cofactor for the clinical expression of an underlying food allergy and is not an absolute requirement for symptoms. Another interesting finding in this study was that gastric and intestinal permeability in patients with FDEIA, as measured by absorption of nondigestible sugars, increased after the cofactors aspirin and alcohol in patients with positive challenge results and after exercise in healthy control subjects but did not correlate with plasma gliadin levels, indicating that intestinal permeability to small molecules is greater than permeability to peptides or proteins, and evaluation of the latter is a more appropriate measure in the assessment of allergen absorption.
A 2018 study using a very similar protocol 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 [11]. However, symptoms could not be elicited in approximately one-half of patients, even after ingestion of the equivalent of 55 slices of bread. A follow-up study by the same authors confirmed that exercise, aspirin, and alcohol lowered the threshold dose of wheat and increased the severity of allergic reactions in patients with WDEIA [5]. Combining two cofactors (exercise and aspirin) lowered the threshold dose even further.
Effects of cofactors — In WDEIA, cofactors lower the amount of gluten that is tolerated and increase the severity of reactions [3,5,11]. In a prospective study of 25 patients with WDEIA, the relative efficacy of exercise, aspirin (1000 mg), and alcohol (to produce a blood alcohol level of 0.05 percent) in inducing symptoms following ingestion of high-gluten bread and a standardized exercise challenge was studied [5]. Important findings included the following:
●A positive challenge following gluten ingestion was elicited without cofactors in 44 percent of subjects, and with exercise, aspirin, and alcohol in 92, 84, and 56 percent, respectively. Thus, exercise was the cofactor that most frequently induced symptoms, which is consistent with how the disorder usually presents, but the majority of patients have other cofactors.
●The median cumulative amount of ingested gluten required to produce symptoms was lowest with the combination of exercise and aspirin (4.3 grams), compared with aspirin alone (8 grams), exercise alone (24 grams), and alcohol alone (28 grams) versus 48 grams without cofactors.
●The severity of the reaction on a five-point scale was highest for exercise (2.1/5), followed by aspirin (1.9/5), a combination of exercise and aspirin (1.5/5), and lowest for alcohol (0.8/5) versus 0.8/5 without cofactors.
●The amount of gluten ingestion required to produce symptoms in the absence of exercise or other cofactors is typically more than would normally be consumed at one time, likely explaining why most patients do not have symptoms in the absence of cofactors. Specifically, the amount of gluten required to elicit symptoms without other cofactors in this cohort was equivalent to that found in one kilogram of bread made with normal flour.
EVALUATION AND DIAGNOSIS — The diagnosis of EIA or food-dependent EIA (FDEIA) is most often made clinically, based upon a meticulous history of the events surrounding the episodes. However, the diagnosis is often delayed. In a retrospective series of 132 patients with wheat-dependent EIA (WDEIA), diagnosis was delayed one to five years in 40 percent and more than five years in 29 percent [4].
Typically, patients present with episodes of warmth/flushing and urticaria during exertion, which progress to involve more severe symptoms over time. In EIA, no symptoms occur without exercise. In FDEIA, ingestion of large amounts of the food alone may occasionally produce symptoms, and other cofactors may augment symptoms. (See 'Other cofactors' above.)
The diagnosis also requires exclusion of other disorders that could present similarly. (See 'Differential diagnosis' below.)
Diagnosis of EIA — The diagnosis of EIA is appropriate in a patient with the following:
●Signs and symptoms consistent with anaphylaxis that occurred during (or occasionally shortly after) exercise
●Episodes occur without associated food intake
●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. (See 'Exercise challenge testing' below.)
Diagnosis of FDEIA — The diagnosis of FDEIA 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)
●Instead of exercise, other cofactors may trigger symptoms, such as nonsteroidal anti-inflammatory drugs (NSAIDs), alcoholic beverages, premenstrual phase of the menstrual cycle in women, temperature extremes (high heat/humidity or cold exposure), infections or illness, stress, and perhaps seasonal pollen exposure in pollen-sensitized patients
●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 (Ig)E to the implicated food, either by skin testing, food-specific IgE immunoassays, or by basophil activation tests (see 'Testing for food allergy' below)
●No symptoms upon ingestion of that food in the absence of exertion or other cofactors 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 with the same exercise intensity ± culprit food does not reliably exclude the diagnosis. Sometimes high doses of food allergen (eg, using concentrated gluten) and cofactors are necessary to reproduce symptoms. For WDEIA, a protocol for exercise challenge has been designed and validated, but it is labor-intensive and requires heart-rate controlled ergometer equipment [3]. Thus, in typical cases, challenge is not required for diagnosis. (See 'Exercise challenge testing' below.)
Clinical history — The clinician should carefully review the details of each episode and attempt to discern the following information:
●Was exercise, some type of exertion, or other cofactors 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. (See 'Differential diagnosis' below.)
●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 whether a patient can safely resume very mild exercise or exposure to other cofactors in the future.
●Do symptoms begin to subside shortly after the patient stops all physical activity? This is an important clinical feature of both EIA and FDEIA.
●What medications or other interventions were tried to treat the symptoms or prevent additional episodes?
●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, particularly NSAIDs) 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, heat, cold, 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 FDEIA, 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/cofactors. (See 'Differential diagnosis' below.)
●Since the last attack, has the patient ingested normal portion-sized amounts of the food in question in the absence of exercise, and, if so, did any symptoms result? In FDEIA, the food only causes symptoms if there is associated exercise/cofactors.
●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, hydrolyzed wheat protein, 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 EIA or FDEIA. 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.)
Serum total tryptase — 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 EIA and FDEIA, unless the patient has hereditary alpha tryptasemia or a mast cell disorder. (See "Hereditary alpha-tryptasemia" and "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 [100]. There are very limited data about how often elevations in these mediators are present after episodes of EIA and FDEIA. 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".)
Testing for food allergy — In patients with FDEIA, 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 [101].
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 FDEIA even if the patient is not suspicious of this association [102]. However, the clinical history can usually limit the list of possible causative foods.
If testing for food sensitization is negative but the history is strongly suggestive of FDEIA, we suggest the following:
●Skin prick testing with alternative food sources containing a high concentration of allergen (eg, high-gluten flour) may be used. (See 'Specific tests for wheat allergy' below.)
●Testing should be repeated in six months. We have encountered patients in whom sensitization was not demonstrable at presentation but became so within a period of months.
Specific tests for wheat allergy — In patients with suspected WDEIA, there are several additional measures that may demonstrate an underlying wheat allergy. If testing using commercial extracts is negative, testing with high-gluten flour (also called vital wheat gluten) mixed into saline to form a paste may reveal the allergy. This is available in specialty baking stores or online. In a study of 16 patients with WDEIA, all 16 subjects reacted to skin testing with high-gluten flour, while 15 reacted to regular wheat flour, and 8 reacted to commercial wheat extract [3]. In another study with 47 challenge-positive patients with WDEIA, skin testing with raw wheat (regular wheat flour) was positive in 94 percent (44 of 47) and to vital wheat gluten in 96 percent (45 of 47) [11].
If skin testing with gluten flour is not possible or is negative and WDEIA is strongly suspected based upon the history, a commercially available serum-specific IgE assay for IgE to omega-5 gliadin should be performed. 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 [103]. IgE to omega-5 gliadin may be positive even when IgE to wheat is negative [11,104]. In some cases of WDEIA, it may not be possible to demonstrate sensitization to the full food allergen source (eg, wheat extract or native wheat) but only to molecular allergens (eg, omega-5-gliadin, Tria19) or gluten. In the study of 17 German patients with WDEIA mentioned previously, 82 percent had IgE to omega-5 gliadin, although other allergens (alpha, beta, and gamma gliadins or lipid transfer protein Tri a14) might be also important, as demonstrated with experimental assays [31,97]. The extent to which different populations of patients with WDEIA are sensitized to different wheat allergens has not been systematically evaluated.
Basophil activation testing — Basophil activation testing (BAT), where available (uncommonly used in the United States outside research protocols), appears useful in the diagnosis of WDEIA. In a study of 12 patients with challenge-proven WDEIA and 10 controls, gluten and specific gluten proteins resulted in robust basophil activation in a dose-dependent manner in patients but not in controls [77]. The omega-5‐gliadins and high molecular weight glutenins appeared to be the most important allergen fractions.
Other skin testing — Skin testing or in vitro testing for IgE sensitization to environmental allergens is useful in the evaluation of EIA 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.
Exercise challenge testing — 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. Most studies have reported variable rates of success in eliciting symptoms with exercise challenge (with or without food) [3,5,8,11,44,53,56,67,105]. A standard Bruce protocol for stress testing, with added spirometry before and periodically during the procedure, has been used by several groups [53,56].
●EIA – An exercise challenge protocol may not reliably reproduce symptoms in a patient with EIA. However, if such a challenge is positive in the absence of food ingestion, it confirms the diagnosis of EIA that was not food dependent.
●FDEIA – In a 1998 literature review of 234 cases of FDEIA, food/exercise challenges were performed in 81 and failed to reproduce symptoms in 29 (36 percent) [44]. 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 [3,5,103]. The amount of food, the interval between food ingestion and exercise, and the intensity of the exercise may all be important factors, depending on the patient [3,8,44,100].
Two groups have subsequently established a validated protocol for WDEIA [3,5]. The first study of 16 patients with WDEIA (described previously) determined the measures that may be required to elicit symptoms [3]. Each of these patients had reacted in the past only to the combination of wheat and exercise. However, because the intent of this study was to determine if exercise was absolutely required for reactions, patients were challenged sequentially with and without exercise and other cofactors. Patients ingested between 10 and 80 grams of gluten, which elicited symptoms in four patients. 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'.)
In a follow-up study of 25 patients with WDEIA using a similar protocol, a maximum cumulative dose of 80 grams of gluten at rest led to objective symptoms in only 11/25 subjects (44 percent), 23/25 (92 percent) reacted to gluten plus exercise, 21/25 (84 percent) to gluten plus aspirin, 9/19 (47 percent) to gluten plus alcohol, and 18/22 (82 percent) to a combination of exercise and aspirin [5]. A reaction could be elicited with at least one of the individual cofactors in 24 of 25 (96 percent), with one patient needing a combination of two cofactors.
These studies indicate that large amounts of gliadin (as present in pure gluten flour) may be needed to induce a reaction or, alternatively, more typical amounts in daily life in conjunction with a cofactor. Exercise and other cofactors may reduce the reaction threshold and increase the symptom severity. 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 (eg, emotional stress) must also be present for symptoms to develop and that these have not yet been identified.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of EIA includes cholinergic urticaria, physical urticaria syndromes, primary food allergy exacerbated by exercise, nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/anaphylaxis, mastocytosis, cardiovascular events, exercise-induced asthma, exercise-associated gastroesophageal reflux, and postural orthostatic tachycardia syndrome (POTS).
●Cholinergic urticaria – Cholinergic urticaria is a form of physical urticaria characterized by small punctate wheals (1 to 3 mm in diameter) with surrounding erythema (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 [106-108] (see "Physical (inducible) forms of urticaria", section on 'Cholinergic urticaria'). By contrast, the wheals of EIA are usually large (10 to 15 mm in diameter). This distinction is not true in all cases, and the punctate wheals of cholinergic urticaria may enlarge and coalesce as symptoms progress.
●Cold-induced urticaria – 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 EIA. However, cold ambient conditions may be a cofactor in some patients with EIA [15,109,110]. Questioning about passive cold exposure should reveal other circumstances in which the patient has experienced symptoms separate from exercise. An ice cube challenge may be useful in diagnosing some cold-induced urticarial syndromes [111]. (See "Cold urticaria", section on 'Evaluation'.)
●Acute spontaneous urticaria and other forms of inducible/physical urticarias – Spontaneous acute urticaria and other forms of inducible/physical urticarias (eg, triggered by exposure to heat, visible light, or vibration) can mimic EIA/FDEIA, although there should be some episodes that are not associated with exercise.
●Food allergy exacerbated by exercise – Patients with food allergy may have reactions that are more severe because of concomitant exertion [112]. Thus, it must be determined that a patient with suspected FDEIA 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 FDEIA, it is possible that FDEIA 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".)
●NSAID-induced urticaria/anaphylaxis – Patients with urticaria or anaphylaxis associated with NSAID intake, may suffer from wheat-dependent, cofactor-augmented anaphylaxis, if the reaction is always in combination with wheat intake.
●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 [113].
Patients with systemic mastocytosis often have persistent elevations in serum tryptase, whereas patients with anaphylaxis (from various other causes) may demonstrate elevations of serum tryptase only 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 EIA, 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 EIA. (See "Laryngopharyngeal reflux in adults: Evaluation, diagnosis, and management".)
●Postural orthostatic tachycardia syndrome (POTS) – 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 [114]. 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 [115]. It can be distinguished from EIA by the absence of urticaria, angioedema, or bronchospasm. However, there are rare reports of POTS occurring in association with mast cell disorders [116]. (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
●Definitions and terminology – Exercise-induced anaphylaxis (EIA) is a disorder in which anaphylaxis occurs in response to physical exertion. In the majority of patients, symptoms only develop if exercise takes place within a few hours of eating a specific food to which the patient is allergic, but the food allergy is asymptomatic unless there is associated exertion. This is called food-dependent EIA (FDEIA). A more accurate term for FDEIA would be "cofactor-dependent food allergy" because research has demonstrated that there are cofactors other than exercise that can lower a patient's threshold for developing symptoms. (See 'Terminology' above.)
●Signs and symptoms – Typical manifestations of EIA and FDEIA include generalized pruritus, warmth, flushing, urticaria and angioedema, and sudden fatigue, progressing to gastrointestinal symptoms, upper airway obstruction, and collapse in some cases. Symptoms usually begin during exercise or just after stopping exercise. (See 'Clinical manifestations' above.)
●Possible cofactors – Cofactors other than exercise may include nonsteroidal anti-inflammatory drugs (NSAIDs), alcoholic beverages, infections and other illness, high pollen levels, extremes of heat and humidity, and menstrual status in some women. These factors can lower a patient's threshold for developing symptoms during exercise and worsen the severity of symptoms. In research protocols of FDEIA, mild symptoms can also be elicited by exceedingly high doses of the food allergen, even without exertion. (See 'Other cofactors' above.)
●Epidemiology – Both EIA and FDEIA are rare. The food-dependent form is more common and increasingly recognized. Adolescents and young adults account for most reported cases, although both EIA and FDEIA have occasionally been described in young children and older adults. EIA and FDEIA are usually sporadic, although familial cases have been reported. (See 'Epidemiology' above.)
●Pathogenesis – The specific physiologic changes and/or cellular events that occur during exercise to trigger the development of symptoms in EIA are not fully understood. FDEIA appears to be a subtype of food-induced anaphylaxis, in which the patient is normally tolerant of the food, but the addition of exercise and/or other cofactors causes a breakdown in this tolerance. (See 'Theories of pathogenesis' above.)
●Evaluation and diagnosis – The diagnosis of EIA/FDEIA is usually based upon the clinical history and exclusion of other disorders. In patients with suspected FDEIA, allergen-specific IgE to the food in question should be demonstrable. 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. (See 'Evaluation and diagnosis' above.)
●Differential diagnosis – The differential diagnosis of EIA includes cholinergic urticaria, systemic mastocytosis, cardiovascular events, exercise-induced asthma, and exercise-associated laryngopharyngeal reflux. The differential diagnosis of FDEIA additionally includes primary food allergy exacerbated by exercise. (See 'Differential diagnosis' above.)
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