Exercise-induced anaphylaxis: Management and prognosis

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 management and prognosis of patients with EIA and FDEIA are discussed in this topic review. The clinical manifestations, epidemiology, pathogenesis, and diagnosis are presented elsewhere. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

Terminology — Terminology is evolving with improved understanding of the disorder. Research in the pathophysiology of food-dependent, exercise-induced anaphylaxis (FDEIA), which is more prevalent than EIA, has shown that FDEIA is a form of food allergy in which symptoms develop only when there is exposure to one or more cofactors (or augmentation factors). Exercise is the most common cofactor, but alcohol and nonsteroidal anti-inflammatory drugs are others. Thus, the term, "cofactor-dependent food allergy" is a more general and accurate term for FDEIA, although it is not yet widely recognized.

GOALS OF THERAPY — The goals of therapy are to avoid future episodes of significant symptoms, ensure that the patient can recognize and treat anaphylaxis effectively, and allow the patient to continue to exercise to the extent desired. In all but the most severe cases, patients typically have a strong desire to continue some form of exercise, and we make every attempt to construct a personalized management plan that allows them to do so because of the many health benefits. However, modifications in the patient's choice of activities may be required. (See 'Resumption of exercise' below.)

Management is individualized for each patient, to some extent, depending upon the severity and frequency of symptoms, the importance of food or other cofactors, the preference of the patient to avoid the food permanently or only in association with cofactors, and the patient's desire to continue participating in the particular sports or types of exercise that trigger symptoms.

OVERVIEW — For patients with FDEIA, the management is relatively straightforward if a culprit food can be identified. That food can simply be avoided in association with exercise and possibly other cofactors, and this is generally all that is required to prevent future symptoms. Patients who stopped eating culprit foods before exercise no longer developed food-dependent exercise-induced allergic reactions [1]. In contrast, the management of EIA is more challenging, as attacks tend to be unpredictable.

There are no randomized trials of therapies for EIA or FDEIA. The authors' approach is described here and is based upon low-quality evidence and clinical experience.

ACCESS TO EPINEPHRINE — Any patient who has experienced anaphylaxis should be equipped with at least two epinephrine autoinjectors and instructed on how and when to use them. (See "Prescribing epinephrine for anaphylaxis self-treatment".)

At the first sign of symptoms, the patient should stop all exertion and get an epinephrine autoinjector ready. If they are lightheaded, they should sit or lie down. Epinephrine is indicated without delay for cardiovascular or respiratory symptoms (eg, lightheadedness, throat tightening, difficulty breathing) or a reaction that is worsening rapidly despite stopping exertion. When needed, epinephrine should be injected intramuscularly into the anterolateral thigh. (See "Anaphylaxis: Emergency treatment".)

Patients must carry an epinephrine autoinjector or have it immediately at hand (ie, not in a locker in the changing room) whenever they engage in exercise or vigorous physical exertion. Patients with a history of severe reactions should carry two doses and, if symptoms are not resolving after the first dose, inject the second dose 5 to 15 minutes later. Clinicians should help the patient plan how to conveniently carry the epinephrine autoinjectors since some patients (eg, runners) are hesitant to carry bulky items, and addressing this issue upfront can improve compliance. Autoinjectors can be carried in pockets, running belts, or wristbands.

INITIAL MODIFICATION OF BEHAVIORS — When a diagnosis of either EIA or FDEIA is first suspected, the patient should be counseled about modifications in exercise and diet to minimize reactions until an allergy evaluation can be performed.

Safety during exercise — Some patients prefer to refrain from vigorous exercise until they can be evaluated, while others strongly wish to continue exercising. For those who want to continue exercise, we do not object to exercise, provided their past episodes were not life-threatening and provided some precautions are taken. We give the following instructions:

●Avoidance of food for four hours before exercise and one hour after – In many cases, it is not clear from the initial history whether the patient's symptoms are influenced by food. Occasionally it is clear, as in patients who report episodes of symptoms even when exercising first thing in the morning before ingesting anything. However, for most patients, attacks occur after food intake and an allergy evaluation is required to determine if the patient is sensitized to a food. For such patients, we initially advise avoidance of eating any solid food for four hours before exercise and one hour after. Alternatively, patients can try exercising in the morning before eating.

●Stop at the first sign of symptoms – Patients must be vigilant for early symptoms (eg, pruritus, flushing, urticaria, extreme fatigue) and should stop exercising immediately if any of these occur. Often symptoms will start to improve when the patient stops the activity. Patients need to understand that they should not "power through" the initial pruritus and accompanying urticaria.

●Exercise with a companion or in a supervised setting – Initially, patients should exercise with a companion or in a supervised setting at all times. The companion/supervisor/physical education teacher/coach should be educated about the signs and symptoms of anaphylaxis and be capable of administering epinephrine. In addition, a cell phone should be readily available in case it is necessary to call emergency medical services. An anaphylaxis action plan can be completed that can help communicate the symptoms and treatment of anaphylaxis, as discussed separately. (See "Anaphylaxis: Emergency treatment", section on 'Anaphylaxis emergency action plan'.)

●Reduce exercise intensity – Patients who have had episodes of symptoms on a completely empty stomach and are thought to possibly have EIA that is independent of food intake should significantly reduce (ie, to a level that has not caused symptoms) the intensity of their exercise initially, until a more thorough examination and allergy evaluation can be done.

Education about cofactors — Management of patients with identifiable cofactors begins with avoidance of those factors in approximation to exercise or limiting exercise when these cofactors are present. In a few cases, this is all that is required to prevent attacks. Cofactors include the following:

●Nonsteroidal anti-inflammatory drugs (NSAIDs) – Refrain from exercising for 24 hours after taking NSAIDs.

●Alcoholic beverages – Refrain from exercise for one to two hours after drinking alcohol.

●Infections and other illnesses – Refrain from exercising during the acute stages of colds and other minor infections.

●Extremes of temperature (either high heat and humidity or cold exposure) – Exercise in a gym or indoor facility, if one of these conditions were involved in an attack.

●Seasonal pollen exposure in pollen-sensitized patients – Exercise in an indoor facility during peak pollen seasons and reduce exercise intensity during this time.

●Premenstrual and early menstrual phases of the cycle in some females – Avoid the types of exercise that have triggered symptoms during this time, especially if also taking NSAIDs.

Cofactors are discussed in more detail elsewhere. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Other cofactors'.)

Initial testing — If the history suggests that there is a specific food that is associated with the patient's symptoms (such as wheat and other gluten-containing grains such as rye and barley), then an in vitro immunoassay for IgE specific to that food can be obtained. Alternatively, initial testing can target any foods consumed in the six hours before the onset of anaphylaxis (for which IgE immunoassays are available). However, it is not uncommon for commercial immunoassays to be negative, so a negative result does not conclusively exclude a food allergy and the patient should be referred to an allergist. Demonstrating the allergy can be challenging in patients with FDEIA and testing strategies are discussed in more detail elsewhere. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Testing for food allergy'.)

REFERRAL — All patients suspected of having EIA or FDEIA should be referred to an allergist for further evaluation and management, if possible. Evaluation and diagnosis are discussed in detail elsewhere. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Evaluation and diagnosis'.)

SUBSEQUENT MANAGEMENT — Once an allergy evaluation has been performed and the diagnosis of EIA or FDEIA has been determined, management is focused on avoiding the combinations of exercise, food, and cofactors that elicit symptoms in that patient.

Resumption of exercise — We advise all patients with "pure" (not food-dependent) EIA to try alternative forms of exercise to see if these are better tolerated, always with epinephrine readily available and with the other precautions discussed below.

●We advise beginning at a low-level of exertion that will probably be tolerated and gradually increasing their activity over weeks to months while avoiding any possible cofactors that have been identified.

●There have been anecdotal unpublished reports that patients with pure EIA who, by slowly increasing the exercise intensity over days and weeks, can raise their reaction threshold and, by exercising daily, maintain it at a higher level. However, since pure EIA patients are rare, such an approach is experimental. Thus, the other measures described here remain the mainstays of management.

●Whenever possible, patients should participate in forms of exercise that can be interrupted if necessary. Specifically, if a patient is participating in a team sport in which they are an essential member (eg, competitive cheerleading), they may be tempted to "push through" mild symptoms against medical advice for the sake of the team. It is better to avoid these situations by choosing appropriate activities.

●As with prevention of anaphylaxis of any etiology, patients should avoid certain long-term medications, such as beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, if other equally effective medications are available. (See "Anaphylaxis: Confirming the diagnosis and determining the cause(s)", section on 'Concurrent medications and other substances'.)

Food avoidance in patients with FDEIA — Patients with food-dependent, exercise-induced anaphylaxis (FDEIA) should avoid the culprit food for at least four hours before exercise. Some patients also need to avoid the food for an hour after exercising. Exercising in the mornings before eating anything is the simplest way to comply with this restriction, although some patients find this difficult. If no further attacks occur with this degree of avoidance, then the period of fasting before exercise can be gradually reduced, as some patients only need to avoid the food for two or three hours before exercise.

●In a systematic review of 108 patients who were followed between two months and seven years, all 100 patients (93 percent) who stopped eating culprit foods for time periods ranging from one to eight hours before exercise were able to avoid further reactions [1]. On the other hand, the eight patients who continued to eat the culprit foods before exercising all reported recurrent reactions.

●Patients who are sensitized to ubiquitous foods (such as wheat) may find it difficult to avoid the culprit food. In this case, it is helpful to devise a list of "safe" foods that the patient can plan to have available for consumption prior to exercise, as simply advising them to "avoid wheat" before exercise is more prone to error. This approach is particularly helpful for children and adolescents. Alternatively, patients can eliminate the food entirely from their diet on the days they plan to exercise and continue eating it on other days. If the food to which they are allergic is more easily avoided (eg, shrimp), then they may prefer to remove it from their diet completely, although there are preliminary data that continued intake of the food in low, subthreshold amounts may help by increasing the patient's reaction threshold [2,3].

●Some patients have symptoms that are elicited by relatively mild forms of exertion, such as brisk walking, and cannot adequately predict when they will be active and plan their diet accordingly. In such cases, the patient may need to remove the implicated food from their diet altogether.

Avoidance of cofactors — Patients for whom one or more possible cofactors can be identified by history or as a result of exercise and cofactor challenge should avoid those cofactors in association with exercise (see 'Education about cofactors' above). Many patients with FDEIA having only reacted to the culprit food together with exercise in their history also reacted to this food together with nonsteroidal anti-inflammatory drugs (NSAIDs) or alcoholic beverages in the challenge test and are at risk also to react to infections and other illnesses [4,5]. Thus, if one of these factors is present, patients should refrain from exercising.

Prophylactic pharmacotherapy (of uncertain efficacy) — Prophylactic pharmacotherapy is not needed in cases in which behavior can be modified and culprit foods and cofactors avoided. However, this is not practical in all cases, and prophylactic pharmacotherapy, including antihistamines and cromoglycates, can be tried. Of note, the clinician should counsel the patient that, although these medications may help reduce the frequency and severity of mild symptoms (especially urticaria and angioedema), there is currently no evidence that they can prevent anaphylaxis. Thus, patients should not rely on these medications for protection from more serious symptoms and must still make all efforts to avoid the combination of factors that trigger their attacks.

H1 antihistamines — Premedication with H1 antihistamines to prevent EIA has not been systematically studied, and there are concerns about masking early symptoms. We do not generally advocate the use of H1 antihistamines. Our clinical experience suggests that they are not consistently effective and should not be relied upon to prevent future episodes. As antihistamines predominantly act on cutaneous symptoms, some patients' urticaria and pruritus may be reduced in severity by antihistamines, as documented in case reports [6,7]. Thus, antihistamines might be helpful in patients with symptoms largely limited to the skin and also in those who require them to control other concomitant allergic diseases, such as allergic rhinitis [1,8,9]. We discontinue them if there is no apparent benefit.

If used, we prefer nonsedating second-generation antihistamines, such as cetirizine 10 mg orally once or twice daily, fexofenadine 180 mg orally once or twice daily, or loratadine 10 mg orally once or twice daily (at the higher doses, cetirizine and loratadine may be sedating). H1 antihistamines may be given as needed prior to exercise (eg, two hours before) or daily, depending on the patient's exercise frequency.

Montelukast — There are a small number of case reports of EIA and FDEIA in which patients' symptoms were reduced but not fully prevented by H1 antihistamines but were controlled by the addition of montelukast [10,11].

Cromoglycates in FDEIA — Several published case reports suggest that high-dose cromolyn sodium taken orally before food ingestion can be useful in preventing attack in patients with FDEIA [12-15]. The patients in these cases have included children and young adults with FDEIA who were advised not to exercise for four hours after food ingestion but had trouble adhering to this. Oral sodium cromoglycate was administered 20 minutes before lunch, in case there was unexpected exercise in the afternoon [13]. In one report of two children, this approach appeared to prevent the children from developing symptoms, even when they did exercise after eating. The children only developed symptoms on days when they forgot to take the sodium cromoglycate. Over time, both children resumed exercise after eating, as long as they had taken the medication before the preceding meal [13].

In two case reports of adult patients with wheat-dependent FDEIA, premedication with cromoglycates prevented absorption of wheat allergen into the blood in one patient [15] and prevented a rise in plasma histamine in another [12]. However, in another case report of wheat-dependent FDEIA, 100 mg of sodium cromoglycate, which is a lower dose than used in other reports, taken one hour before food/exercise challenge prevented neither symptoms nor absorption of gliadin into the blood [16]. In addition, one of the authors (KB) found that high-dose cromolyn in a patient with wheat-dependent FDEIA was not able to reduce the clinical reaction threshold for urticaria. Thus, controlled studies are required to determine if oral sodium cromoglycate is effective in FDEIA, and, until such studies are performed, we advise caution with its use.

Other agents — Misoprostol (a synthetic analogue of prostaglandin E1) has been helpful in case reports, although it is difficult to take due to side effects (eg, gastrointestinal symptoms and headache) [16,17]. We know of no studies evaluating the use of oral glucocorticoids.

Omalizumab for refractory symptoms — Individual cases of difficult-to-control and refractory EIA have been treated with omalizumab successfully [18,19]. This appears to be the most effective prophylactic pharmacotherapy available, considering the documented effects of omalizumab on preventing anaphylaxis in other settings.

Investigational therapies — Experimental therapies for FDEIA, specifically wheat-dependent EIA, include gluten sublingual immunotherapy to address the underlying wheat allergy and attempts to genetically modify wheat to remove the allergenic proteins.

●Sublingual immunotherapy for food allergy – In a small pilot study, three patients with wheat-dependent EIA underwent daily gluten sublingual immunotherapy, consisting of 1 mg of high gluten flour formed into a paste that was held under the tongue and then swallowed [3]. In each patient, the threshold for reacting to wheat (with or without cofactors) increased (ie, the patient became less sensitive). The effects of immunotherapy were apparent during oral food/exercise challenge but did not correlate closely with skin testing, specific immunoglobulin (Ig)E, or basophil activation testing. These results are consistent with another small study showing that patients who eliminated wheat from their diets completely became more sensitive to it over time [2]. Based on these preliminary findings, we favor continuing to eat wheat but not in association with exercise.

●Genetic modification of wheat – Wheat breeding and biotechnology have been tried to reduce the immunogenic potential of wheat flour without impacting the functional properties of the flour [20-22]. However, this approach is complicated by different locations of the gluten protein genes on more than one chromosome, making it difficult to completely remove all immunogenic proteins [23].

PROGNOSIS — Most patients with diagnosed EIA or FDEIA do well and report fewer attacks over time [6,24]. As the symptoms of EIA/FDEIA are often severe before the diagnosis is made, a key component of management is making the diagnosis and identifying trigger factors. Much of this improvement may be attributable to recognition of early symptoms, modifications in exercise habits, and avoidance of triggering food and cofactors.

A small number of case reports describe fatalities attributed to EIA or FDEIA [25-27]:

●In two of these cases, exercise-related anaphylaxis had not been formally identified, and these patients had significant asthma as a comorbidity [25,27].

●A third case occurred in a patient with known pork-dependent EIA, who ingested wild boar meat at a banquet, then drank alcohol, danced, and did not have an epinephrine autoinjector available [26].

PATIENT EDUCATION — As with all forms of anaphylaxis, patient education is an ongoing process that should be addressed after any recurrent symptoms and at each follow-up visit.

The patient should be provided with a written, personalized, and periodically updated Anaphylaxis Emergency Action Plan. Action plan forms are available in English and Spanish from Food Allergy Research and Education (Food Allergy & Anaphylaxis Emergency Care Plan) and the American Academy of Pediatrics (Allergy and Anaphylaxis Emergency Plan in English and Spanish). These plans are appropriate for patients with anaphylaxis from any cause.

Important information for patients with anaphylaxis is reviewed in detail elsewhere. (See "Anaphylaxis: Confirming the diagnosis and determining the cause(s)".)

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 AND RECOMMENDATIONS

●Definitions – Exercise-induced anaphylaxis (EIA) is a 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). Research in the pathophysiology of FDEIA has shown that it is actually a form of food allergy in which symptoms develop only when there is exposure to one or more cofactors. Exercise is the most common cofactor, but alcohol and nonsteroidal anti-inflammatory drugs are others. Thus, the term "cofactor-dependent food allergy" is a more general and accurate term for FDEIA, although it is not yet widely recognized. (See 'Terminology' above.)

●Goals of treatment – The goals of therapy are to avoid future episodes of significant symptoms, ensure that the patient can recognize and treat anaphylaxis effectively, and allow the patient to continue exercising if desired. Most patients want to continue regular exercise and are able to do so. For patients with FDEIA, the management is relatively straightforward if a culprit food can be identified. That food can simply be avoided in association with exercise and possibly other cofactors, and this is generally all that is required to prevent future symptoms. In contrast, the management of EIA is more challenging, as attacks tend to be unpredictable. (See 'Goals of therapy' above and 'Overview' above.)

●Epinephrine for self-treatment – Any patient who has experienced anaphylaxis should be equipped with at least two epinephrine autoinjectors and instructed on how and when to use them. At the first sign of symptoms, the patient should stop all exertion. Epinephrine is indicated without delay for cardiovascular or respiratory symptoms (eg, lightheadedness, throat tightening, difficulty breathing) or a reaction that is worsening rapidly despite rest. (See 'Access to epinephrine' above.)

●Initial interventions and referral – All patients suspected of having EIA or FDEIA should be referred to an allergist for further evaluation and management, if possible. Most will prove to have an underlying food allergy. Prior to that evaluation, the clinician can advise the patient in how to exercise at a reduced intensity. Important safety measures include avoiding all food for at least four hours before and one hour after exercise, stopping all exertion at the first sign of symptoms (never "push through"), always having epinephrine and a cell phone close by, and exercising in a supervised setting or with a partner. In addition, we teach patients about possible cofactors so they can watch for any relationship between the cofactors and symptoms. (See 'Referral' above and 'Initial modification of behaviors' above.)

●Management after evaluation for food allergy and cofactors

•Food avoidance in FDEIA – After evaluation by an allergist, management of patients with an identified food allergy is essentially avoidance of that food in relation to exercise and avoidance of any other relevant cofactors. In some cases, this is all that is required to prevent attacks. We suggest an initial period of food avoidance of at least four hours. (See 'Subsequent management' above.)

•EIA – EIA is more difficult to manage, especially if there are no identified cofactors to avoid. In our experience, cases of pure EIA without cofactors are rare, and every effort should be made to investigate any potential contributing exposures.

If no cofactors can be identified, the primary intervention is modification of the patient's exercise routine to find activities that do not trigger symptoms. We do not administer prophylactic medications if the patient can find tolerated activities.

For patients who cannot find an activity that doesn't cause symptoms and have symptoms limited to the skin, we suggest H1 antihistamines with or without montelukast (Grade 2C). However, it is important that patients understand that these medications have not been studied sufficiently in this disorder and cannot be assumed to prevent anaphylaxis. (See 'H1 antihistamines' above and 'Montelukast' above.)

•Omalizumab for refractory cases – For patients with FDEIA or EIA whose symptoms are refractory to other measures or who cannot successfully avoid the relevant foods or other cofactors that cause symptoms or find forms of exercise that are tolerated, we suggest omalizumab (Grade 2C). (See 'Omalizumab for refractory symptoms' above.)

●Prognosis – The prognosis of patients with EIA and FDEIA is generally favorable once the diagnosis has been clarified, especially if a food allergy can be identified. Although these disorders do not resolve, most patients experience fewer and less severe attacks over time because of effective avoidance of the combinations of factors that trigger symptoms. (See 'Prognosis' above.)