US Pharm. 2006;7:42-48.


Exercise-induced asthma (EIA) is a condition characterized by airway obstruction following exercise. Symptoms include wheezing, shortness of breath, chest tightness or pain during or after exercise, coughing, and difficulty breathing. Some patients may have more subtle symptoms not clearly recognized as being due to asthma, such as cramps, stomach pain, sore throat, and headache. EIA is common in patients with chronic asthma, but it is also seen in those who do not have other forms of asthma. In athletes, these symptoms may be misinterpreted as a prolonged recovery time or being "out of shape." EIA may affect people of any age and at any level of exercise.1,2

Exercise-induced bronchospasm (EIB) is an intermittent bronchial narrowing occurring after exercise in those with normal lung function at rest. The main difference between EIB and EIA is the absence of subjective symptoms in EIB, despite a measurable drop in airflow.1,2 Chronic asthma is an inflammatory disorder that results in airway hyperreactivity (AHR) to various stimuli. Cold air inhalation, mold, pollen, animal dander, upper respiratory infections, and exercise are common triggers for AHR in patients with chronic asthma. In 45% to 90% of these patients, exercise can significantly decrease the forced expiratory volume in one second (FEV1).3 Inflammation and AHR cause recurrent episodes of chest tightness, wheezing, breathlessness, and coughing. If the inflammation goes unchecked, airway remodeling may occur, possibly leading to chronic irreversible airway obstruction.1,3

Some individuals with EIA have symptoms only with exercise and do not otherwise have asthma. This may be a normal physiologic response or may be due to the extreme exercise of top athletes, e.g., athletes competing in the Olympics.4 EIA can occur in up to 50% of cold-weather athletes, possibly a direct result of inhalation of large volumes of cold air. Studies report airway inflammation in cross-country skiers and speed skaters, but these subjects did not respond to inhaled steroids or short-acting beta-2 agonists, suggesting a condition unique to cold-weather athletes that differs from asthma.5,6

Etiology
EIA's underlying mechanisms are not fully understood; however, two hypotheses have been proposed:the water-loss and postexercise rewarming hypotheses. The first  theorizes that evaporation from respiratory mucosa during exercise results in hyperosmolarity within the airway cells. This leads to mast cell release of inflammatory mediators, e.g., histamine, prostaglandins, chemotactic factors, and leukotrienes, causing vasodilation and bronchial smooth muscle contraction, which eventually results in airway obstruction. The obstruction may ultimately worsen the condition because inflammation may facilitate further water loss.1,2,7

The postexercise rewarming hypothesis suggests that hyperventilation from exercise causes heat loss from the respiratory mucosa, reducing bronchial blood flow. After exercise, a rewarming process causes dilatation of the bronchiolar vessels around the airways, leading to reactive hyperemia of the airway lining, vascular engorgement, edema, and subsequent mediator release and airway obstruction. 1,2,7

Prevalence
At least 11% to 15% of children, adolescents, and adults are estimated to have EIA.2 It occurs in up to 90% of those with chronic asthma.8 In the 1996 Summer and 1998 Winter Olympics, about 17% of athletes reported a previous case of asthma, with the highest occurrence in endurance athletes.9-11 In the 2002 Olympics, about 15% of cross-country skiers used beta-agonists for EIA.12 The highest incidence is found in competitive athletes in cold-weather sports, with an overall incidence of 23%; in cross-country skiers, the incidence is as high as 50%.10

Diagnosis
EIA is often underdiagnosed due to an individual's denial of symptoms. This denial is commonly because of peer pressure, embarrassment, fear of losing one's position in team sports, or the misinterpretation of postexercise fatigue. The first step in diagnosis is to rule out chronic asthma. Certain factors in the patient's history help increase the chance of an EIA diagnosis. These include increased symptoms with continuous hard exercise, such as running; exercise in a cold environment, in polluted air, during the pollen season, or during a respiratory infection; a family history of asthma; or a personal history of recurrent allergic rhinitis or sinsusitis.1,3 To confirm the diagnosis of EIA, a standardized exercise challenge that includes spirometry is recommended. This involves a treadmill, cycle, or free-running asthma screening test to induce symptoms and measurement of FEV1.2 A drop of at least 10% in FEV1 is typically required for diagnosis; 2 however, a 20% to 25% drop in FEV1 has been suggested. 13 Another test is the eucapnic voluntary hyperventilation challenge with dry air, recommended by the International Olympic Committee (IOC) Medical Commission for testing of Olympic athletes with asthma. Disadvantages with this challenge are the expensive equipment required and the complexity of the test.1

Nonpharmacologic Management
Management initially involves discussion with the individual on the types of exercise least likely to induce EIA: intermittent exercise or team sports; swimming; and exercise in nonpolluted air, outside of the pollen season, or in warm, humid air.1,2 Athletes should also be encouraged to follow a regular regimen of warm-up and cool-down to minimize symptoms. A warm-up to about 80% of maximal output before a full routine has been shown to partially reduce the severity of EIA. A gradual cool-down is beneficial to minimize postexercise fatigue.14

Pharmacologic Management
Eight main medication classes are used in the pharmacologic management of EIA: short-acting beta-agonists, long-acting beta-agonists, mast cell stabilizers, inhaled corticosteroids, anticholinergics, leukotriene antagonists, antihistamines, and anti-IgE monoclonal antibodies (Table 1). Therapy should be individualized based on severity of symptoms and level of exercise performed.





Both the short-acting and long-acting beta-agonists are direct-acting sympathomimetic agents with selective activity on beta-2 adrenoceptors, with the long-acting agents displaying greater selectivity for these receptors than the short-acting agents. These agonists cause bronchial smooth muscle relaxation and inhibit release of immediate hypersensitivity mediators from mast cells.15 First-line therapy is a short-acting beta-agonist administered five to 15 minutes prior to exercise.3 Side effects are typically minor but may include palpitations, tremor, or tachycardia. A long-acting beta-agonist (e.g., salmet­ erol) may be given several hours before exercise; however, a short-acting beta-agonist must also be provided for acute relief of symptoms. As treatment for EIA, long-acting beta-agonists are most effective when used intermittently and when the short-acting beta-agonists are not used on a daily basis. Regular daily use may result in tolerance to the product due to down-regulation of the beta-2 receptors on the airway cells.1-3

A new black box warning has recently been added to the prescribing information for long-acting beta-2 agonists. Data from a recent placebo-controlled trial showed an increase in asthma-related deaths in patients receiving salmeterol, compared to those on placebo (0.099% vs. 0.023%, respectively).These agents should be prescribed only to patients whose asthma symptoms are not controlled on other asthma medications or whose disease severity warrants the addition of these agents.

If EIA is not controlled with a short-acting beta-agonist, the mast cell stabilizers--cromolyn or nedocromil--may be added to the regimen. They inhibit the release of several mediators of inflammation from various cell types, e.g., mast cells, macrophages, eosinophils, neutrophils, monocytes, and platelets.15 Their efficacy lasts for only about two hours, and they do not cause bronchodilation. Side effects reported are bad taste, headache, dizziness, nausea, sore throat, and stinging eyes.1-3

The leukotriene antagonists such as montelukast have been efficacious to treat EIA when used as adjunctive therapy. These agents selectively bind to the cysteinyl leukotriene 1 receptors found in airway smooth muscle and airway macrophages, preventing the binding of cysteinyl leukotrienes to these receptors. Leukotriene-mediated effects in asthma include smooth muscle contraction, airway edema, and inflammatory reactions.15 Leff et al. reported significant protection against EIB with montelukast vs. placebo.16 Again, a short-acting beta-agonist must be provided for acute relief of symptoms. All three drugs in this class are metabolized by the cytochrome P450 (CYP) system. Zileuton is metabolized by CYP 1A2, 2C9, and 3A4; montelukast by CYP 3A4, 2C9, and 2A6; and zafirlukast by CYP 2C9. Therefore, significant drug interactions are possible. Adverse events are usually mild and include headache, somnolence, and nausea. A Churg––Strauss-like syndrome (CSS), a rare and potentially fatal reaction, has been reported as a complication in asthmatics who are steroid-dependent and are treated with a leukotriene antagonist. This syndrome typically occurs in association with reduction of their oral steroid dose. CSSis a granulomatous vasculitis that affects small- to medium-sized vessels.1-3

The anticholinergics antagonize the action of acetylcholine, blocking the bronchoconstriction caused by acetylcholine and methacholine.15 Both ipratropium and tiotropium have shown efficacy in EIA, with peak bronchial effects attained at one to two hours. Due to a duration of action of only three to six hours, these drugs are often dosed three to four times daily. Their most frequent adverse effects are dry mouth and cough.1-3

Inhaled corticosteroids are typically reserved for those with EIA who also have chronic asthma. They are often given in combination with a long-acting beta-agonist.1-3 They have potent glucocorticoid but weak mineralocorticoid activity, together with potent anti-inflammatory effects.15 Adverse effects are generally mild and include pharyngitis and oropharyngeal candidiasis if the mouth is not rinsed after use. Pretreatment before exercise is advised, and a short-acting beta-agonist should be available to control acute symptoms.1-3

Second-generation antihistamines can be used for patients with both EIA and atopy. Atopy is an inherited type I hypersensitivity or allergic reaction involving elevated immunoglobulin E (IgE), resulting in hay fever, asthma, or such skin problems as urticaria or eczema. First-generation antihistamines are not typically used in asthma because of their anticholinergic effects, which  can result in the drying of bronchial secretions. In contrast, second-generation antihistamines have greater selectivity for the H1receptor and fewer anticholinergic side effects, and they may inhibit other inflammatory processes involved in asthma. Adverse effects are typically mild, e.g., nausea, headache, drowsiness, and dry mouth.15

Omalizumab (Xolair) may be an alternative for those with EIA and IgE-mediated chronic asthma. Omal­ izumab is an anti-IgE monoclonal antibody given by subcutaneous injection. Its major drawback is its cost, ranging from $600 to $700 per month.17 It is generally well tolerated; urticarial rashes and injection site reactions are the most common adverse reactions.15

Professional athletes should be advised to check with the appropriate athletic governing bodies regarding which medications are permitted for a given professional competition. Both the IOC and the National Collegiate Athletic Association established guidelines for allowable medications to prevent the use of performance-enhancing agents during competitive sports.

Dietary Supplements

Accumulating evidence suggests that a diet low in salt and high in omega-3 fatty acids and antioxidants can reduce the incidence of EIA. Animal studies indicate that salt loads can affect leukotriene release. Many studies show a beneficial effect of a low-salt diet of about 1,500 mg per day, while other authors suggest less than 2,400 mg per day of sodium to reduce the severity of EIA.8,18,19 Eicosapentaenoic and docosahexaenoic acid are omega-3 polyunsaturated fatty acids found in fish oils. These agents competitively inhibit arachidonic acid metabolism, thereby reducing the generation of inflammatory prostaglandins and leukotriene mediators, as well as the inflammatory cell production of cytokines. Therefore, it has been postulated that diets high in fish oils may reduce diseases caused by inflammation, including EIA. To date, clinical data of the short-term use of fish oil supplements for asthma are controversial. Further clinical trials are needed to evaluate the effects of omega-3 fatty acids in people with asthma.17,20,21

Evidence suggests that oxidants produced during the inflammatory process may contribute to asthma; thus, antioxidants may be effective in reducing the severity of EIA. Ascorbic acid (vitamin C), in doses ranging from 500 to 2,000 mg taken one to two hours before exercise, has been shown to improve EIA to subclinical levels in several clinical trials.22-24 Beta-carotene, dosed at 64 mg daily for one week, and lycopene, dosed at 30 mg daily for one week, have also demonstrated efficacy.25,26

Caffeine causes bronchiolar smooth muscle relaxation and can reduce EIA severity. However, the doses required to achieve this exceed the limits permitted for international competition (<12 mcg/mL in urine) and are likely to result in disqualification from professional athletic events. The doses of caffeine required to show benefit (7 to 10 mg/kg taken 90 minutes to two hours prior to exercise) are also likely to cause significant diuresis.27,28

Conclusions

Proper treatment of EIA is essential to enable those affected to participate in sports and activities from which they might otherwise be restricted. Management should focus on prevention and the nonpharmacologic and pharmacologic therapy specifically tailored to the individual.

References
1. Storms WW. Review of exercise-induced asthma. Med Sci Sports Exerc. 2003;35:1464-1470.
2. Weiler JM. Exercise-induced asthma: a practical guide to definitions, diagnosis, prevalence, and treatment. Allergy Asthma Proc. 1996;17:315-325.
3. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics--2002. J Allergy Clin Immunol. 2002;110(5 suppl):S141-S219.
4. Anderson SD, Holzer K. Exercise-induced asthma: is it the right diagnosis in elite athletes? J Allergy Clin Immunol. 2000;106:419-428.
5. Sue-Chu M, Karjalainen EM, Laitinen A, et al. Placebo-controlled study of inhaled budesonide on indices of airway inflammation in bronchoalveolar lavage fluid and bronchial biopsies in cross-country skiers. Respiration. 2000;67:417-425.
6. Wilber RL, Rundell KW, Judelson DA. Efficacy of asthma medication regimen in elite athletes with exercise-induced asthma. Med Sci Sports Exerc. 2001;33:S12.
7. Cypcar D, Lemanske RF Jr. Asthma and exercise. Clin Chest Med. 1994;15:351-368.
8. Mickleborough TD, Gotshall RW. Dietary salt intake as a potential modifier of airway responsiveness in bronchial asthma. J Altern Complement Med. 2004;10:633-642.
9. Weiler J, Ryan EJ. Asthma in United States Olympic athletes who participated in the 1998 Olympic winter games. J Allergy Clin Immunol. 2000;106:267-271.
10. Wilber RL, Rundell KW, Szmedra L, et al. Incidence of exercise-induced bronchospasm in Olympic winter sport athletes. Med Sci Sports Exerc. 2000;32:732-737.
11. Weiler JM, et al. Asthma in United States Olympic athletes who participated in the 1996 Summer Games. J Allergy Clin Immunol. 1998;102:722-726.
12. Anderson SDK, Fitch K, Perry CP, et al. Responses to bronchial challenge submitted for approval to use inhaled beta2-agonists before an event at the 2002 Winter Olympics. J Allergy Clin Immunol. 2003;111:45-50.
13. Tan RA, Spector SL. Exercise-induced asthma. Sports Med. 1998;25:1-6.
14. McKenzie DC, McLuckie SL, Stirling DR. The protective effects of continuous and interval exercise in athletes with exercise-induced asthma. Med Sci Sports Exerc. 1994;26:951-956.
15. Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons; 2006.
16. Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med. 1998;339:147-152.
17. Fleming T, editor. 2006 Drug Topics Red Book. Pharmacy's Fundamental Reference. Montvale, NJ: Medical Economics Co.; 2006.
18. Mickleborough TD, Gotshall RW. Dietary components with demonstrated effectiveness in decreasing the severity of exercise-induced asthma. Sports Med. 2003;33:671-681.
19. Mickleborough TD, Gotshall RW, et al. Dietary salt alters pulmonary function during exercise in exercise-induced asthmatics. J Sports Sci. 2001;19:865-873.
20. Stephensen CB. Fish oil and inflammatory disease: is asthma the next target for n-3 fatty acid supplements? Nutr Rev. 2004;62:486-489.
21. Mickleborough TD, Murray RL, Lindley MR. Elevating dietary omega-fatty acid consumption reduces the severity of exercise-induce bronchoconstriction. Med Sci Sports Exerc . 2003;35:S10.
22. Hatch GE. Asthma, inhaled oxidants, and dietary antioxidants. Am J Clin Nutr. 1995;61(3 suppl):625S-630S.
23. Schachter EN, Schlesinger A. The attenuation of exercise-induced bronchospasm by ascorbic acid. Ann Allergy. 1982;49:146-151.
24. Cohen HA, Neuman I, Nahum H. Blocking effect of vitamin C in exercise-induced asthma. Arch Pediatr Adolesc Med. 1997;151:367-370.
25. Neuman I, et al. Prevention of exercise-induced asthma by a natural isomer mixture of beta-carotene. Ann Allergy Asthma Immunol. 1999;82:549-553.
26. Neuman I, Nahum H, Ben-Amotz A. Reduction of exercise-induced asthma oxidative stress by lycopene, a natural antioxidant. Allergy. 2000;55:1184-1189.
27. Kivity S, Ben Aharon Y, Man A, et al. The effect of caffeine on exercise-induced bronchoconstriction. Chest. 1990;97:1083-1085.
28. Duffy P, Phillips YY. Caffeine consumption decreases the response to bronchoprovocation challenge with dry gas hyperventilation. Chest. 1991;99:1374-1377.

To comment on this article, contact editor@uspharmacist.com.