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doi: 10.3810/psm.2010.12.1828
The Physician and Sportsmedicine: Volume 38: No.4
Treatment Options for the Management of Exercise-Induced Asthma and Bronchoconstriction
David T. Millward, MD, MSc; Lindsay G. Tanner, MD; And Mark A. Brown, MD
Copyright 2010 All rights reserved. Cover and contents may not be reproduced in whole or in part without prior written permission. The Physician and Sportsmedicine is a registered trademark of JTE Multimedia, LLC. Sending and distribution of any document from this site is strictly prohibited either for free and or a service fee, and will be sited as a violation of copyright under the laws of THE UNITED STATES OF AMERICA

Abstract: Treatment for exercise-induced bronchospasm and exercise-induced asthma includes both pharmacologic and nonpharmacologic options. Pharmacologic agents that have been proven to be effective for treating these conditions include short- and long-acting β2-adrenoceptor agonists, mast cell–stabilizing agents, anticholinergics, leukotriene receptor antagonists, and inhaled corticosteroids (ICS). When selecting the most appropriate medication, factors to consider include the effectiveness of each, the duration of action, frequency of administration, potential side effects, and tolerance level. Long-acting β2-adrenoceptor agonists should not be used without ICS. Nonpharmacologic treatments include physical conditioning, incorporating a warm-up before and a cool-down period after exercise, performing nasal breathing, avoiding cold weather or environmental allergens, using a face mask or other aid to warm and humidify inhaled air, and modifying dietary intake. The data to support nonpharmacologic treatments are limited; however, they are routinely recommended because of the low risk associated with their use. This article highlights the advantages and limitations of each treatment option.

Keywords: exercise; asthma; treatment; bronchospasm; bronchoconstriction

Introduction

Our article aims to discuss treatment options in the management of exercise-induced asthma (EIA) and exercise-induced bronchoconstriction (EIB). Exercise-induced asthma and EIB are terms commonly used to describe the transient increase in airway resistance triggered by exercise.1 Though often used interchangeably, we prefer to define EIA as the condition in which exercise induces bronchial obstruction in patients with clinical asthma and EIB as airway obstruction that occurs in association with exercise in the absence of evidence of clinical asthma.2

The goal of therapy is to allow patients with either EIB or EIA to participate in vigorous activity without symptoms and difficulty. There are multiple treatment options, both pharmacologic and nonpharmacologic. Although many studies have been conducted to date, there is no single agent that has been consistently shown to prevent EIB. Many questions remain regarding the treatment of this complex condition. This article reviews each treatment option, including the evidence to support their use, as well as advantages and limitations of different therapies.

Materials and Methods

A literature search was conducted using PubMed/Medline and the Cochrane Library. The search included peer-reviewed research, clinical trials, meta-analyses, and other relevant articles, using the search terms “exercise,” “induced,” “asthma,” “bronchoconstriction,” “bronchospasm,” and “treatment.” This search yielded 84 articles from the literature (English-speaking) between 1975 and 2010. Reference lists of all available primary studies and review articles were reviewed to identify potential relevant citations. From these articles, 60 were selected as being informative (original studies, meta-analyses, or comprehensive reviews).

Pharmacologic Therapy
β2-Adrenoceptor Agonists

Multiple studies have shown that using short-acting β2-agonists (SABAs) before exertion attenuates the decrease in forced expiratory volume in 1 second (FEV1) due to exercise in susceptible individuals.3-8 This protection is thought to be due to relaxation of the bronchial smooth muscles brought on by stimulation of the β2 receptors. The effectiveness of long-acting β2-agonists (LABAs) for the treatment of EIA also has been well studied. In a review of 32 trials of LABAs, including 9 single-dose studies on EIA, they were shown to effectively reduce bronchoconstriction due to exercise.9

Despite the multitude of studies documenting their efficacy, there are important limitations to the use of both SABAs and LABAs. β2-Adrenoceptor agonists do not prevent bronchoconstriction in approximately 15% to 20% of asthmatics, even with concomitant regular use of inhaled corticosteroids (ICS).3,10 In addition, daily use of a LABA leads to a decrease in the duration of its protective effects.11 Originally, LABAs were thought to offer a protective effect for 12 hours; however, further studies show the protection lasts for 6 hours, after which the effect begins to wane.3 This was initially thought (and later confirmed by Ramage et al11 ) to be due to tolerance. These investigators observed that inhaled salmeterol initially provided protection from 6 to 12 hours at the beginning of the study period, but after daily use of the medication for 30 days, this effect was limited to 6 hours.11 This waning of protective effects can be seen with both LABAs and SABAs and persists despite the addition of an ICS.12,13 The tolerance does not appear to occur if the bronchodilator is used ≤ 3 times per week.14 Therefore, LABAs have been recommended in patients who have normal spirometry and require the medication ≤ 3 times per week.15 Physicians must be cautious when prescribing these medications because LABA use without a concomitant corticosteroid carries an increased risk of sudden death in some populations.16,17 Readers are referred to Currie et al18 for a detailed discussion of the risks in using LABAs.

In addition to decreased protective effects with duration of use, regular use of LABAs may decrease response to a β-agonist when treating EIB. If breakthrough EIB occurs, recovery of lung function has been shown to be slower in response to a β2-adrenoreceptor agonist, and additional doses are often required to achieve pre-exercise values.19 The problems associated with the use of β2-adrenoceptor agonists are thought to occur as a result of the desensitization of the receptor on the mast cell, which leads to increased mediator release and desensitization of the receptor on the smooth muscle, which then lead to increased bronchoconstriction.20 The daily use of these medications may reduce their effectiveness in preventing EIA. Despite the lack of definitive evidence, patients with EIA should have their anti-inflammatory therapy optimized so that β2-adrenoceptor agonists can be used on an intermittent basis only.20

Mast Cell–Stabilizing Agents

Mast cell–stabilizing agents (MCSAs) provide protection against bronchoconstriction by blocking a calcium channel on the mast cell, preventing degranulation and release of histamine. The Cochrane Collaboration reviewed the use of MCSAs and their effectiveness in treating patients with EIB. The study was a systematic review and meta-analysis of 20 randomized, crossover trials, including 280 adults and children, 8 countries, and covering 10 years. They found the use of a single dose of nedocromil sodium (NCS) was a safe and effective pharmaceutical option if taken 15 to 60 minutes prior to strenuous physical activity.21 The maximum percentage decrease in FEV1 with NCS treatment was significantly improved compared with placebo (weighted mean difference [WMD], 15.5%; 95% confidence interval [CI], 13.2–18.1). Treatment with NCS shortened the duration of EIB to < 10 minutes and provided a clinically significant protection over placebo of 51%.21 The benefit of using NCS may also provide a more rapid return to normal lung function. Within the studies included in the review, NCS was well tolerated, with only minor adverse effects reported, including throat irritation and an unpleasant taste. The authors found that most studies used a 4-mg dose of NCS, and were thus not able to determine the influence of increasing the dose because of insufficient data. However, there were no appreciable adverse effects across a wide range of doses. Within subgroup analysis, individuals with more severe EIB appeared to exhibit greater protective effects from NCS use compared with those with less severe EIB.

A second review involving MCSAs was performed by the Cochrane Collaboration to determine which MCSA, NCS or cromoglycate, provided superior therapeutic benefit. The reviewers concluded that the 2 medications were equally effective in reducing or preventing EIB for up to 2 hours post-inhalation.22 Neither medication was effective beyond this period. At all doses, both drugs appeared to be equally effective, and there was no advantage associated with the use of a higher dose. The only discerning disadvantage was a bad taste associated with nedocromil.22 Mast cell–stabilizing agents can be used many times a day without serious side effects or reduced efficacy because of decreased tolerance,23 which gives them a potential advantage over β2-adrenoceptor agonists. Although MCSAs are effective and well tolerated, they are no longer available for use in the United States because of the Montreal Treaty, which restricts the use of metered-dose inhalers containing chlorofluorocarbons.

Anticholinergics

Anticholinergic (AC) medications are effective at attenuating EIB. They work by blocking the muscarinic cholinergic receptors in bronchial smooth muscle, thus preventing bronchoconstriction. In a Cochrane review comparing AC medications with MCSAs, ACs decreased the EIB response in most participants. The meta-analysis included combined data from 8 trials (n = 183) that demonstrated a mean maximum fall in postexercise pulmonary function test (PFT) on AC medication of 13.8%. A total of 56% of participants received complete protection while using ACs. There was no subgroup difference based on age, severity, or study quality, and no adverse effects were reported. The authors of this meta-analysis concluded that ACs provided protection to many study participants, and therefore could be a beneficial treatment choice.24

Leukotriene Receptor Antagonists and Leukotriene Synthesis Inhibitors

The identification of leukotrienes in the airway of patients with EIB and EIA prompted research into whether leukotriene receptor antagonists (LTRAs) could be used as a treatment for this condition.25-27 The LTRA montelukast was first approved in the United States in March 1998 for the treatment of persistent asthma in adults (10 mg) and children as young as 1 year (4 or 5 mg). Montelukast was later approved for use in allergic rhinitis and EIB.28 In one of the larger studies performed, a positive effect of montelukast was demonstrated in 110 adults with EIB over a 12-week period.29 Subjects received either a placebo or montelukast prior to a treadmill test at 80% of maximum cardiac heart rate for 5 minutes while breathing cool, dry air. The subjects were subsequently monitored for 60 minutes to determine when their FEV1 returned to baseline. An exercise challenge was performed at weeks 4, 8, and 12 during the study, and 2 weeks after the medication was stopped. After the 12-week treatment period, patients who were pretreated with montelukast had a mean decrease of 18% in FEV1 compared with the patients taking the placebo, who experienced a mean decrease of 30%. To date, montelukast has not gained approval to treat EIB in children. Similar findings were noted in children aged 6 to 14 years;30 however, further studies are needed to gain approval by the US Food and Drug Administration (FDA). A tolerance effect with continued montelukast use during the 12-week period was not seen, nor was there a rebound effect after the medication was discontinued.29

A potential advantage of montelukast in the treatment of EIB is the duration of action. Although SABAs are effective, they are limited by their 2- to 4-hour duration of action. In an athlete who wishes to practice or compete at multiple periods during the day, this may provide suboptimal treatment or an inconvenience. In multiple studies, montelukast has been shown to decrease the fall in FEV1 for up to 24 hours.31,32 Long-acting β2-agonists have also shown an extended effect lasting 10 to 12 hours;15,33 however, there is a risk of tolerance with repeated use,34,35 which makes them a less-attractive option.

Serious side effects have been linked to the use of LTRAs. Soon after it was first approved for use, Churg-Strauss syndrome (CSS) began to appear in some patients taking montelukast and other leukotriene-modifying medications.28 Further analysis of these patients suggests the association with CSS was not likely due to the effects of the LTRAs themselves, but from the withdrawal of corticosteroid treatment.36 In addition to CSS, neuropsychiatric conditions have been listed within the side effects profile, including behavior, and mood-related changes (agitation, including aggressive behavior, bad/vivid dreams, depression, anxiety, hallucinations, irritability, restlessness, suicidal thoughts and actions [including suicide], tremors, or trouble sleeping). Neither the vascular nor neuropsychiatric conditions associated with LTRAs are known to be causally associated. Nonetheless, an association exists, and must be taken into consideration prior to medication use.28 In spite of these complications, which are rare, montelukast remains a reasonable medication to consider in patients with EIB.

Inhaled Corticosteroids

The use of ICS to prevent EIB was evaluated by a Cochrane review.37 This review found that the use of ICS for ≥ 4 weeks before exercise significantly reduced EIB. Eight randomized controlled trials (2 adult, 6 pediatric) involving 162 participants met the inclusion criteria and were analyzed. The results were combined for 3 of the studies in which participants took ICS for ≥ 4 weeks. A decreased fall in FEV1 was demonstrated (WMD [fixed]: 11.74%; 95% CI, 10.06–13.42). The authors also highlighted 1 crossover study in which ICS were used for ≥ 4 weeks, and a similar attenuation of percent fall in FEV1 was reported (WMD, 11.70%; 95% CI, 7.51–15.90).37 Further study is warranted to confirm the use of ICS in the treatment of EIB given the few available studies and their small sample sizes. Questions regarding the appropriate dose and duration of treatment remain unanswered.

Additional Pharmacologic Options

Allergens and irritants cause airway inflammation and may worsen symptoms of EIB. Histamine has historically been thought to be an important mediator in EIA. However, studies on the effects of antihistamines in EIA show mixed results, with some demonstrating a protective effect and others showing no effect.38 Allergic rhinitis can be effectively treated with antihistamines and intranasal steroids.39 In addition to providing relief from allergy symptoms, treatment of seasonal allergies may also improve asthma control.40 Evaluation by an allergist may be helpful in cases of refractory allergy symptoms. Immunotherapy should be considered in individuals with severe seasonal allergies refractory to pharmacologic treatment, as it has been shown to decrease bronchial hyperresponsiveness and asthma symptoms.41 When seasonal allergies are poorly controlled, exposure to known environmental allergens during exercise should be avoided.42

Comparing Pharmacologic Therapies

A large study comparing all of the pharmacologic agents discussed has not been completed. Several meta-analyses have attempted to consolidate existing studies so that comparisons can be made. The use of SABAs and MCSAs were compared within a Cochrane review.25 Both medication categories decreased the EIB response in most participants. Short-acting β2-agonists were somewhat more effective at attenuating bronchoconstriction than MCSAs. Within 12 trials (n = 271), the mean maximum fall in postexercise FEV1 using an MCSA was 11.2% compared with 4.3% on a SABA (WMD, 6.8%; 95% CI, 4.5–9.2). The subgroup comparison by age favored SABAs, but the pooled results between groups was not significantly different. The mean maximum decrease in children (n = 91) receiving MCSAs was 11.9% compared with those receiving SABAs, which was 4.6% (WMD, 7.3%; 95% CI, 3.9–10.7) while the mean maximum decrease in adults (n = 180) receiving MCSAs was 10.0% compared with those receiving SABAs, which was 3.5% (WMD, 6.4%; 95% CI, 2.7–10.1). The subgroup comparison by severity of EIB indicates that participants with more severe EIB obtain a greater benefit from SABAs than MCSAs compared with those with milder EIB. The mean maximum decrease in mild EIB (n = 136) with MCSA use was 7.5% compared with 3.5% with use of SABAs (WMD, 4.0%; 95% CI, 1.7–6.4), while the mean maximum decrease in moderate-to-severe EIB (n = 135) treated with MCSAs was 16.2% compared with 5.4% with SABAs (WMD, 10.8%; 95% CI, 2.3–15.9). Significantly more participants obtained complete protection using SABAs (85%) compared with MCSA (66%) agents (odds ratio [OR] for MCS, 0.3; 95% CI, 0.2–0.5). Trials using SABAs reported more side effects, including tremor and distress (11% vs 3%; n = 2). Patients did not have to stop taking SABAs based on these side effects.25

Some individuals may gain a small advantage when combining an MCSA with a SABA. There was no statistically or clinically significant advantage identified when SABAs alone were compared with a combination of a SABA plus MCSA; however, in all but 1 study, the combination demonstrated a favorable trend. Clinical protection was obtained by 70% of participants on SABAs alone versus 86% on the combination (OR, 0.4; 95% CI, 0.1–1.2). Complete protection was obtained in 68% on SABAs compared with 80% using the combination (OR, 0.5; 95% CI, 0.2–1.4). Short-acting β2-agonists appear to be more effective over a short duration when compared with MCSAs and ACs. Overall, complete protection was experienced by 81% with SABAs compared with 69% with MCS. Short-acting β2-agonists produced a small increase in side effects, which may be bothersome, but not harmful to the user. Combining a SABA and an MCSA prior to exercise may provide additional benefit to some, but not all individuals with EIB.25

When comparing MCSAs with ACs, both ACs and MCSAs lessened the EIB response in most patients; however, MCSAs appeared to be more effective. In the meta-analysis by Spooner et el,24 a mean maximum fall in postexercise FEV1 on MCSA was 7.1% compared with 13.8% on ACs (WMD, 6.7; 95% CI, 3.3–10.0). Significantly more participants obtained complete protection on MCSAs (73%) than ACs (56%) (OR, 2.2; 95% CI, 1.3–3.7). Although both medications provided protection, MCSAs were more effective and provided more protection than ACs.

Although β2-adrenoceptor agonists appear to be superior to MCSAs and ACs, these latter agents can be used routinely without the development of a tolerant effect. The same can be said about LTRAs. Mast cell–stabilizing agents and ACs are fast-acting, and the dose can be repeated on the same day without serious side effects. The use of these medications on a routine basis should be considered, reserving SABAs for rescue relief of breakthrough bronchoconstriction.

Future studies are needed to evaluate the use of anti-inflammatory agents, such as ICS and LTRAs, and compare their effectiveness with β2-adrenoceptor agonists, MCSAs, and ACs. Outcome measurements besides the physiologic benefit could be considered, including patient preference or performance improvement. The pathophysiology of EIA and EIB is complex. Although single-drug therapy is always preferred, combination therapy is reasonable and should be studied.

Nonpharmacologic Therapy

Nonpharmacologic methods can also be used in the management of EIB. Proposed options for nonpharmacologic management include physical conditioning, incorporating a warm-up before and a cool-down period after exercise, nasal breathing, avoidance of cold weather or environmental allergens, and using a face mask or other aid to warm and humidify inhaled air. More recent evidence also suggests that dietary modification may play a role in controlling EIB.43-45

Exercise programs involving aerobic activity in asthmatics have consistently shown benefit in terms of cardiorespiratory fitness.46-48 A study by Neder et al46 suggested that regular aerobic activity may lead to a decrease in the use of oral or inhaled steroids. Ram et al47,48 confirmed the benefits of exercise training in relation to cardiorespiratory fitness in asthmatics, but concluded that aerobic exercise did not affect resting lung function. Despite this finding, many asthmatics report symptomatic improvement with improvements in aerobic fitness. This may result from lower minute ventilation during aerobic activity in individuals with superior fitness levels.48

Some athletes performing a 10- to 15-minute warm-up prior to exercise experience a significant decrease in EIB symptoms during exertion for 2 hours after the warm-up.49-51 There is debate over the mechanism responsible for the phenomenon of the refractory period. It was initially thought that exercise resulted in depletion of bronchoconstricting mast cell mediators.52 O’Byrne and Jones53 suggest that release of inhibitory prostaglandins in response to an exercise stimulus is responsible for the refractory period. More recently, it has been proposed that catecholamine release that occurs with exercise leads to bronchodilation, and may provide explanation for the refractory period.52 It is important to note that the refractory period has only been observed in asthmatic athletes, and may not occur in nonasthmatic athletes with EIB.54 Results vary regarding the type of warm-up that best reduces bronchoconstriction with subsequent exercise, but there is evidence to support both continuous and interval warm-up strategies as a means of decreasing EIB.50,51

A cool-down period has also been suggested to minimize EIB symptoms. It is thought that the rapid rewarming of airways on completion of exercise leads to increased vascular permeability and edema, and may contribute to airway obstruction. Gradually decreasing the intensity of exercise and avoiding rapid airway rewarming may decrease the severity of EIB.55

Inhalation of cool, dry air during exercise is a mechanism shown to contribute to EIB. If an alternative is available, avoiding exertion in cold, dry environments is likely to decrease EIB symptoms. Other strategies can be implemented to overcome the effects of inhaling cool, dry air if a change in exercise environment is unavoidable. Effects of cold air inhalation can be eliminated in part by breathing through the nose instead of the mouth.56 As air enters nasal passages, it is filtered, warmed, and humidified, thus providing less of a stimulus for bronchoconstriction. Use of a face mask may decrease symptoms of EIB in a cool, dry environment through the same mechanisms.57 Beuther and Martin58 demonstrated that use of a heat exchanger mask to warm and humidify inspired air was as effective as albuterol pretreatment in preventing EIB.

Though not yet widely studied, dietary modification may also play a role in EIB. Research by Mickleborough et al44,45 suggests that dietary supplementation with fish oil may help to reduce symptoms of EIB in asthmatics. In a randomized, double-blind crossover study, they found that after 3 weeks of fish oil supplementation, the decrease in pulmonary function following exercise fell below the diagnostic threshold for EIB, demonstrating less than a 10% fall in postexercise FEV1. Study participants also had a significant decrease in bronchodilator use.44 The protective effects of fish oil supplementation on EIB are thought to be secondary to its anti-inflammatory properties.44 Gotshall et al43 showed that study participants on a low-sodium diet had improved postexercise pulmonary function, whereas those on a high-sodium diet experienced a decline in postexercise pulmonary function. Although there are several theories to explain the beneficial effects of a low-sodium diet on EIB, the exact mechanism is unknown.43

It is important to note that few systematic reviews or large randomized controlled trials have been published on this topic. Although the level of evidence is not high for several of the aforementioned therapies, most have little or no adverse effects. Nonpharmacologic therapy for EIB is an area with several opportunities for continued research.

Conclusion

Effective treatment of EIB or EIA can allow participation in strenuous exercise without hindrance and with minimal symptoms. Whenever possible, prevention strategies should be implemented. Despite a lack of evidence supporting their use, nonpharmacologic treatment options should be given consideration for their potential benefit with minimal risks or side effects. When choosing pharmacologic therapy, β2-adrenoceptor agonists are the most effective, but their use should be limited to avoid impaired tolerance and to ensure they remain an effective rescue medication. Mast cell–stabilizing agents, ACs, LTRAs, and ICS should be considered for patients who require a β2-agonist ≥ 3 times per week. With proper therapy, neither EIB nor EIA should limit athletic achievement or pose a health risk to patients.



Conflict of Interest Statement
David T. Millward, MD, MSc, Lindsay G. Tanner, MD, and Mark A. Brown, MD disclose no conflicts of interest.
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David T. Millward, MD, MSc 1
Lindsay G. Tanner, MD 1
Mark A. Brown, MD 2

1University of Arizona, Sports Medicine, Tuscon, AZ 2Department of Pediatrics and Arizona Respiratory Center, The University of Arizona, Tuscon, AZ

Correspondence: David T. Millward, MD, Msc, University of Arizona, Sports Medicine, 1224 E. Lowell St., Bldg. 95, Tucson, AZ 85721-0095.
Tel: 520-621-4447,
Fax: 520-626-5736,
E-mail: [email protected]
Disclaimer
In an effort to provide information that is scientifically accurate and consistent with accepted standards of medical practice, the editors and publisher of The Physician and Sportsmedicine routinely consult sources believed to be reliable. However, readers are encouraged to confirm this information with other sources. For example and in particular, physicians are advised to consult the prescribing information in the manufacturer's package insert before prescribing any drug mentioned.




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