INTRODUCTION — Exercise-induced anaphylaxis (EIAn) is a disorder in which anaphylaxis occurs in response to physical exertion. Food-dependent, exercise-induced anaphylaxis (FDEIAn) is a disorder in which patients only develop symptoms if exercise takes place within a few hours of eating and, in most cases, only if a specific food is eaten during the pre-exercise period.

There are no randomized trials of therapy for EIAn or FDEIAn. Thus, there are only low-quality evidence and clinical experience on which to base recommendations. The author's approach is described here. The management of EIAn and FDEIAn must be individualized for each patient, to some extent, depending upon the severity and frequency of symptoms, the importance of food or other cotriggers, and the patient's desire to continue participating in the particular sports or types of exercise that trigger symptoms.

The management of FDEIAn is relatively straightforward if a culprit food can be identified and is centered on avoidance of that food prior to exercise. In contrast, the management of EIAn is more challenging as attacks tend to be unpredictable.

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 of regular exercise. However, modifications in the patient's choice of activities may be required. (See 'Resumption of exercise' below.)

The management and prognosis of patients with EIAn and FDEIAn 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".)

COFACTOR AVOIDANCE — Management of patients with identifiable cofactors begins with avoidance of those factors 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)

●Alcoholic beverages

●Premenstrual or ovulatory phases of the menstrual cycle in women

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

●Seasonal pollen exposure in pollen-sensitized patients

●Infections and other illnesses

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

Patients with EIAn — Some patients with apparent EIAn present after just one or two episodes of symptoms. Unless it is absolutely clear from the patient's history that eating does not impact the occurrence of symptoms, we initially advise avoidance of eating any solid food for four to six hours before exercise. If no further attacks occur, then the period of fasting before exercise can be gradually reduced and restrictions removed over time. If symptoms recur during this process, then the patient should be reevaluated for sensitization to any foods that were ingested before the most recent attack.

●Patients whose attacks follow ingestion of NSAIDs can avoid these agents altogether or at least refrain from exercise for 24 hours after taking one of these medicines.

●Those affected by high humidity or high pollen counts can exercise in an air-conditioned indoor setting during critical times of year. Allergen immunotherapy may also be helpful in reducing sensitivity to pollen cotriggers, although this has not been specifically studied in patients with EIAn.

Food avoidance in patients with FDEIAn — Patients with food-dependent, exercise-induced anaphylaxis (FDEIAn) should avoid the culprit foods for at least four to six 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 very difficult.

●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 error prone. This approach is particularly helpful for children and adolescents. Alternatively, patients can completely eliminate the food from their diet.

●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 should remove the implicated food from his/her diet altogether. Complete avoidance is appropriate only if other approaches have failed, as a small preliminary study found that patients who avoided the culprit food appeared to have lower reaction thresholds when rechallenged at a later date, although this finding requires additional study [1].

PROPHYLACTIC PHARMACOTHERAPY — Prophylactic pharmacotherapy is not needed in cases in which behavior can be modified and triggering foods and cofactors avoided. However, this is not practical in all cases, and prophylactic pharmacotherapy is sometimes warranted.

Cromoglycates in FDEIAn — Several published case reports suggest that high-dose cromolyn sodium taken orally before food ingestion can be useful in preventing attack in patients with food-dependent, exercise-induced anaphylaxis (FDEIAn) [2-5]. The patients in these cases have included children and young adults with FDEIAn who were advised not to exercise for four hours after food ingestion. In addition, oral sodium cromoglycate was administered 20 minutes before lunch, in case there was unexpected exercise in the afternoon [3]. 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 [3].

In two case reports of adult patients with wheat-dependent FDEIAn, premedication with cromoglycates prevented absorption of wheat allergen into the blood in one patient [5] and prevented a rise in plasma histamine in another [2]. However, in another case report of wheat-dependent FDEIAn, 100 mg of sodium cromoglycate taken one hour before food/exercise challenge prevented neither symptoms nor absorption of gliadin into the blood [6].

These reports are promising, although controlled studies are required to determine if oral sodium cromoglycate is effective in FDEIAn. Until such studies are performed, it seems prudent to offer this therapy to patients with a clear warning that it may not be helpful in all patients. We explain to patients that this approach should NOT be considered a reliable alternative to avoidance of the culprit food but rather an additional protective measure.

Cromolyn sodium comes in an oral formulation (Gastrocrom) in the United States, in ampules of 100 mg/5 mL. The dose used in the reports previously described of children was 100 mg, taken 20 minutes before eating. The dose for adults is 200 mg, which is the dose we have used in our own practice.

H1 antihistamines — Premedication with H1 antihistamines to prevent EIAn has not been systematically studied, and there are concerns about masking early symptoms. Our clinical experience suggests that it is not consistently effective and should NOT be relied upon to prevent future episodes but that some patients' symptoms do appear to be reduced in severity by antihistamines [7,8]. We administer H1 antihistamines empirically to patients with severe and/or frequent attacks and also if needed to control other concomitant allergic diseases, such as allergic rhinitis. We discontinue them if there is no apparent benefit.

H1 antihistamines may be given as needed prior to exercise (eg, two hours before) or daily, depending upon the frequency of exercise. 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).

Other agents — Other therapies, such as misoprostol (a synthetic analogue of prostaglandin E1) [6,9] or omalizumab [10,11], have been helpful in case reports. We know of no studies evaluating the use of oral glucocorticoids or leukotriene-modifying agents.

RESUMPTION OF EXERCISE — We advise all patients to resume exercise gradually, starting with a low-level exertion that will probably be tolerated, and gradually to increase their activity over weeks to months while avoiding any possible cotriggers that have been identified.

Stopping at the first sign of symptoms — Patients must be vigilant for early symptoms (eg, extreme fatigue, flushing, pruritus) and must stop exercising immediately if any of these occur.

Access to epinephrine — At the first sign of symptoms, the patient should get an epinephrine autoinjector ready. If he/she is lightheaded, he/she should sit or lie down. Epinephrine should be injected intramuscularly into the anterolateral thigh, in the recumbent position if possible, without delay if the patient experiences rapidly escalating cardiovascular or respiratory symptoms (eg, lightheadedness, throat tightening, difficulty breathing). (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 have two doses available and, if needed, inject the second dose 5 to 15 minutes after the first dose. Clinicians should help the patient plan how to conveniently carry the epinephrine autoinjectors since some patients (eg, runners) are hesitant to carry bulky items. Addressing this issue upfront can improve compliance. The newer autoinjectors that are similar in size and shape to cell phones are easily carried in pockets or wristbands designed to hold phones.

Other precautions

●Patients with EIAn 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. A phone should be readily available in case it is necessary to call emergency medical services.

●Allowing a period of gradual warm-up before attempting exercise was identified as helpful in a retrospective series of patients with EIAn [7]. The patient should choose an activity that consistently allows for a warm-up period.

●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 he/she is an essential member (eg, competitive cheerleading), he/she 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. Elite athletes with EIAn who have trained in their chosen sport for years are unlikely to be willing to switch sports. These patients may need to have a greater input in developing their personalized management plan and may require more frequent follow-up.

●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 possible. (See "Anaphylaxis: Confirming the diagnosis and determining the cause(s)", section on 'Concurrent medications and other substances'.)

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. This document lists the most common symptoms and signs of anaphylaxis and provides instructions for prompt epinephrine injection (Anaphylaxis Emergency Action Plan - English) (Anaphylaxis Emergency Action Plan - Spanish).

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

PROGNOSIS — A small number of case reports describe fatalities attributed to EIAn or food-dependent, exercise-induced anaphylaxis (FDEIAn) [12-14]:

●In two of these cases, exercise-related anaphylaxis had not been formally identified, and these patients had significant asthma as a comorbidity [12,14].

●A third case occurred in a patient with known pork-dependent EIAn, who danced at a banquet after ingesting wild boar meat and alcohol and did not have his epinephrine autoinjector available [13].

●A complex case was reported in which the patient developed severe melena shortly after severe FDEIAn, and autopsy revealed extensive ulceration of the ileum, suggesting concomitant inflammatory bowel disease [15].

Despite the above, most patients with EIAn or FDEIAn do well, reporting fewer attacks over time [7,16]. Much of this improvement may be attributable to recognition of early symptoms, modifications in exercise habits and triggering food and cofactors. A questionnaire administered to 279 patients with EIAn for longer than 10 years found that the average number of episodes per year in this group decreased from 14.5 at the time of diagnosis to 8.3 in the year of the study. The following behavioral modifications were identified as helpful by multiple patients: avoiding exercise after eating; during extremely hot, cold, or humid weather conditions; during pollen season (pollen-allergic patients); and after taking nonsteroidal anti-inflammatory drugs (NSAIDs) [17].

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

●Exercise-induced anaphylaxis (EIAn) is a disorder in which anaphylaxis occurs in response to physical exertion. In the food-dependent form (FDEIAn), 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.)

●Management of patients with identifiable culprit foods and cofactors begins with avoidance of those factors. In some cases, this is all that is required to prevent attacks. (See 'Cofactor avoidance' above.)

●Patients with FDEIAn and demonstrable immunoglobulin E (IgE) to the suspect food should avoid that food prior to exercise. We suggest an initial period of avoidance of at least four hours (Grade 2C). (See 'Food avoidance in patients with FDEIAn' above.)

●A period of fasting of at least four hours should also be suggested, at least initially, to patients with FDEIAn who appear to have symptoms after ANY food ingestion, as well as to patients who appear to have EIAn but in whom there is insufficient history to exclude food as a triggering factor. (See 'Patients with EIAn' above.)

●In addition to fasting before exercise, we suggest oral sodium cromolyn solution, taken 20 minutes before eating, for patients with FDEIAn who have trouble avoiding situations that precipitate symptoms (Grade 2C). However, patients must understand that the effectiveness of this medication has not been studied in large numbers of patients, and so they must not rely upon this medication to protect them. (See 'Cromoglycates in FDEIAn' above.)

●H1 antihistamines may be helpful in reducing the frequency and severity of symptoms in some patients with EIAn, although these agents do not appear to prevent attacks. We suggest administration of an H1 antihistamine to patients with frequent or severe symptoms or symptoms elicited by relatively mild forms of exercise that are hard to avoid (eg, brisk walking) or patients with FDEIAn who have difficulty avoiding the culprit food before exercise (Grade 2C). Antihistamines may be given as needed before exercise or on a daily basis, depending on the patient's exercise habits. (See 'H1 antihistamines' above.)

●We do not counsel patients that they must avoid all future exercise. Instead, we encourage them to identify an activity and an exercise schedule that are unlikely to precipitate symptoms. (See 'Resumption of exercise' above.)

●Patients must stop exercise immediately at the first sign of symptoms. We also advise that patients exercise with a companion or in a supervised setting. (See 'Resumption of exercise' above.)

●All patients with EIAn or FDEIAn should carry epinephrine for self-injection and understand how and when to use it. (See 'Access to epinephrine' above.)

●The prognosis of patients with EIAn and FDEIAN is generally favorable. Few deaths have been attributed to these disorders, and most patients experience fewer and less severe attacks over time. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Albert L Sheffer, MD, now deceased, who contributed to an earlier version of this topic review.