Exercise-Induced Anaphylaxis: An Update on Diagnosis and Treatment

The trigger of idiopathic anaphylaxis is unknown and unpredictable, but the symptoms are entirely the same as those observed in EIA. Because low-intensity exertion may provoke EIA, a very careful history taking is of crucial importance for distinguishing between those two forms of anaphylaxis.

Cholinergic urticaria results from increasing body temperature, either active (eg, exercise) or passive (eg, hot shower). Lesions are restricted to skin and manifested as punctuate, pinpoint-sized wheals, whereas in EIA, they are usually much larger and diffused. Bronchoconstriction with wheezing may occur, but neither angioedema nor hypotension is present.

Skin lesions are similar to those in EIA. They start in places exposed to cold, usually on the hands, face, and neck, and promptly take up the whole body. Intensive exposure to cold (eg, contact with cold water) may induce a robust histamine release, resulting in cardiovascular symptoms with lowered blood pressure, collapse, or even shock. Cold urticaria can result from exercise with exposure to cold (eg, swimming or outdoor activity in winter).

Mastocytosis is a rare and heterogenic disorder characterized by uncontrolled proliferation and accumulation of mast cells in the skin (cutaneous mastocytosis) or more organs (generalized mastocytosis). Skin involvement is manifested with urticaria pigmentosa, whereas in generalized mastocytosis, gastrointestinal symptoms with cramps, bloating, and sometimes diarrhea, hypotension, and psychiatric disorders may be present. These symptoms are associated with mediator release; thus, the risk of severe anaphylactic reactions is increased, though they are not clearly provoked by exertion. The diagnosis is made based on the elevated serum α-tryptase and presence of mast cell hyperplasia.

Hereditary angioedema is a rare autosomal dominant illness associated with C₁-inhibitor protein disorder, either decreased serum level or presence of abnormal protein. The symptoms may be triggered by major exertion, but in contrast to EIA, the edematic lesions are nonpitting and produce no itching.

Exercise-induced asthma is manifested with typical symptoms of asthma exacerbation resulting from exercise. Consequently, the symptoms are limited to the lower airways, except in life-threatening asthma. In contrast to EIA, exercise-induced asthma is fully preventable with inhaled, rapid-acting β-agonists prior to exercise or regularly inhaled glucocorticosteroids.

In some neoplasmatic disorders with endocrine activity, such as carcinoid, phaeochromocytoma, medullary carcinoma of the thyroid and pancreatic cell tumor, release of bioactive substances may mimic anaphylactic reactions. Although they are not exercise dependent, the release may be triggered by exertion. Skin manifestations with generalized rush or pallor are very rapid, and cardiovascular symptoms are predominant.

Avoidance of potentially precipitating factors is of crucial importance. Thus, patients should not perform outdoor exercises during very cold, hot, or humid weather, or, in those with seasonal atopy, during the pollen season. Aspirin and other NSAIDs should not be taken in association with exercise. Refraining from exercise for 4 to 6 h after food ingestion is a classical recommendation for those with FDEIA. Some evidence suggests that in FDEIA, the sequence of events might be reversed (ie, anaphylaxis may occur after ingestion of causative food following prolonged exercise). Thus, it seems reasonable that patients with FDEIA should refrain not only from postprandial exertion but from food ingestion after exercising as well.

Some pharmacologic protection also seems possible. A case report demonstrated a protective effect of coadministration of cetirizine and montelukast in an adolescent male with FDEIA triggered by peaches [20]. Recently, evidence has started to accumulate indicating that pretreatment with agents that can inhibit cell degranulation may have a preventive effect in FDEIA. It has been demonstrated that in FDEIA to wheat, administration of sodium cromoglycate before ingestion of the causative food and exercise prevented symptoms of anaphylaxis in two children [21•]. A similar effect was observed in a young female after pretreatment with ketotifen [22].

Management of EIA does not differ from that of other types of anaphylaxis [23]. Immediate termination of physical effort at the earliest warning manifestation is of crucial importance to avoid potentially life-threatening cardiovascular symptoms. Base pharmacotherapy includes epinephrine, antihistamines, and systemic corticosteroids. Shadick et al. [13] reported use of those drugs by 31%, 56%, and (surprisingly) only 5% of patients with EIA, respectively.

Exercise increases absorption from the gastrointestinal tract. Although the importance of altered intestinal permeability is still debatable [27], it is speculated that allergens have enhanced contact with the gut-associated immune system. In some cases, FDEIA symptoms depend on the amount of causative food ingested [28]. Increased permeability might also result in absorption of only partially digested allergenic proteins. It has been demonstrated that gliadin, the predominant allergen in wheat-dependant EIA, appears in sera from FDEIA patients and healthy controls after an exercise/food challenge, but not after food ingestion alone [29].

NSAIDs have been shown in aspirin models to induce FDEIA symptoms with co-ingestion of the causative food [30]. Two mechanisms should be taken into consideration. First, it was proven that aspirin increases gastrointestinal permeability and antigen uptake [29], even in a dose as low as 100 mg [31]. Second, aspirin itself might enhance immune cell degranulation. Skin prick test amelioration due to oral aspirin intake was observed in five of eight FDEIA patients [32], possibly due to cyclooxygenase inhibition. Of course, aspirin intake definitely is not a universal factor responsible for anaphylactic symptoms, but it may provide interesting insights into the pathomechanisms of FDEIA and may be used as a substitute for exercise in an experimental model.

Tissue transglutaminase in the intestinal mucosa could be activated by exercise and aspirin. Omega-5 gliadin, a major allergen in FDEIA to wheat, is cross-linked by tissue transglutaminase, which results in the formation of large peptide aggregates and facilitates greater IgE cross-linking [33]. It seems likely that this could elicit allergic reactions in patients with FDEIA to wheat; however, no experiments have confirmed the presence of gliadin–transglutaminase complexes in the circulating blood.

It is well-known that even in mild exercise, a redistribution of blood flow occurs from inactive to active tissues. Cooper and coworkers [34] suggested that food-sensitized, gut-associated immune cells do not elicit symptoms of anaphylaxis as long as they remain in a local (portal) circulation. However, when these sensitized cells are shifted to the skin and skeletal muscle with exercise-induced blood flow redistribution, FDEIA symptoms are present. This hypothesis was recently developed by Robson-Ansley and Toit [35•], who speculated that absorbed food allergens are well-tolerated by intestinal mast cells and thus provoke no symptoms at rest. The exercise-induced redistribution of blood results in displacement of the recently ingested allergens from the gut to the target tissues. Mast cells in the skin and skeletal muscles are phenotypically different from those in the gut [36] and can be induced by the food allergens, increasing the potential for EIA. An argument against this hypothesis is a protective action of sodium cromoglycate against the precipitation of clinical symptoms of FDEIA [21•]. Because this drug inhibits activation of intestinal mast cells, but not skin mast cells [37, 38], it clearly indicates the leading role for intestinal mast cells in initiation of a further cascade of pathological symptoms.

The first step in the cascade of FDEIA events most likely depends on intestinal mast cell activation caused by increased osmolality of the microenvironment. It is known that intestinal blood flow, if increased by administration of vasodilators, significantly decreases tissue osmolality [39]. Tissue osmolality measured at the villous tips was 1,000 to 1,200 mOsm/kg H₂O, while at the villous bases, it was approximately isotonic to plasma. In intestinal blood vessels, exercise-induced blood flow redistribution may subsequently increase tissue osmolality at the villous bases and consequently activate mast cells. In our earlier experiment, we demonstrated that in basophils from FDEIA patients, increased osmolality results in increased histamine release compared with atopic patients and healthy volunteers [40••]. In physiologic osmolality of 280 mOsm, basophil activation determined as CD203c expression on their surface does not differ among FDEIA patients, atopic patients, and healthy controls. In contrast, osmolality increased to 340 mOsm resulted in greater than twofold higher basophil activation in FDEIA patients compared with the other individuals investigated [41•]. Secretion of histamine and other vasoactive mediators results in allergen absorption and its distribution to other organs, such as skin, which leads to augmented IgE-dependent activation of mast cells and spreads the symptoms of anaphylaxis. This proposal is in accordance with previous observations concerning the influence of aspirin on food allergen absorption and skin mast cell reactivity [32] as well as with an earlier observation concerning increased skin mast cell reactivity to codeine after physical exercise seen only in FDEIA syndrome [42].

Whatever the mechanism(s) is, exercise increases gut permeability, resulting in an increased amount of food allergen presented to the mast cells and basophils. However, there is still an open question as to why in FDEIA patients the cells are activated and subsequently produce severe anaphylactic reactions, while in patients with food urticaria or food-dependent atopic dermatitis, they remain silent and do not influence the intensity of symptoms. Therefore, it is likely that the immune systems of FDEIA patients have a “unique property” that elicits different responses to the stimuli. On the basis of our results [40••], we hypothesize that this “unique property” might be an individually decreased threshold for histamine release. In addition, there are two other hypotheses that are not well-documented and seem to be of minor importance.

Endogenous endorphins are known to enhance mast cell degranulation [43], but a significant increase in serum endorphins is observed with prolonged and strenuous exercise [44]. Thus, it seems unlikely that within the short effort of mild intensity that is sufficient to initiate EIA, serum endorphins might rise up enough to trigger cell degranulation.

In contrast to prolonged and strenuous exercise, exertion of moderate intensity does not alter blood pH significantly [45]. Only two cases have reported inhibition of FDEIA symptoms with sodium bicarbonate [46, 47]. The mechanism in which increased serum pH prevents anaphylaxis remains unclear and requires further research.