N Engl J Med 2015; 372:641-648February 12, 2015DOI: 10.1056/NEJMra1407552
Louis-Philippe Boulet, M.D., and Paul M. O’Byrne, M.B.
Regular exercise is one of the most effective means to maintain good health. A substantial proportion of the general population engages in competitive sports, including many people with asthma; when controlled, asthma does not restrict exercise performance. Indeed, exercise training can improve asthma symptoms, quality of life, exercise capacity, and pulmonary function, as well as reduce airway responsiveness.1
Intense exercise imposes demands on the cardiorespiratory system. Cardiac output increases, as does minute ventilation, which can reach 200 liters per minute in high-level athletes.2 At high minute ventilations, the airways are the site of intense respiratory heat and water exchange as they condition inspired air to body temperature and humidity levels. Furthermore, because mouth breathing is common during exercise, there is an increased penetration of allergens and pollutants — such as chloramines from chlorinated pools, ozone, and particulate matter from ambient air — into the lower airways. Therefore, it is not surprising that as compared with nonathletes, high-level endurance athletes have an increased prevalence of various respiratory ailments, such as asthma and rhinitis, and related coexisting conditions.3-5
The term exercise-induced bronchoconstriction describes the transient narrowing of the airways after exercise, a phenomenon that occurs frequently among athletes who may not have a diagnosis of asthma or even have any respiratory symptoms.5-8 Exercise-induced bronchoconstriction is a distinct form of airway hyperresponsiveness, which is defined as the tendency of airways to constrict more easily and more forcefully than normal airways in response to a wide variety of bronchoconstrictor stimuli. Airway hyperresponsiveness, which is a cardinal feature of asthma, is more common among endurance athletes — particularly winter-sports athletes and swimmers — than in the general population.7,8
The mechanism of exercise-induced bronchoconstriction has not been established with certainty; both airway cooling resulting from conditioning of inspired air and postexercise rewarming of airways have been proposed as mechanisms. However, the key stimulus is probably airway dehydration as a result of increased ventilation, resulting in augmented osmolarity of the airway-lining fluid.9 This is thought to trigger the release of mediators — such as histamine, cysteinyl leukotrienes, and prostaglandins — from airway inflammatory cells, which leads to airway smooth-muscle contraction and airway edema. However, uncontrolled airway inflammation can exacerbate this process and increase exercise-induced bronchoconstriction.10 Furthermore, not only can osmotic and mechanical stress to the airways play a role in the acute response to exercise, but they may also be involved in the development of airway remodeling in athletes, probably through their effects on airway epithelial cells.4,8,9 Finally, transient immunosuppression may also develop in athletes during periods of intense training, with increased susceptibility to respiratory infections, particularly viral infections11; this may increase airway response to exercise acutely and affect overall asthma control.
High-intensity training may therefore contribute to the development of asthma, exercise-induced bronchoconstriction, and airway hyperresponsiveness.12,13 For example, swimmers training in chlorinated pools and cross-country skiers exposed to cold, dry air can have airway epithelial damage, inflammation, and remodeling similar to that seen in asthmatic airways.8,14,15 This observation has led to the inference that preventive strategies to protect airways, as recommended for persons with other types of relevant occupational exposures, may be a useful therapeutic option for high-level athletes. This reasoning is supported by the fact that airway hyperresponsiveness can improve or even normalize in swimmers after they refrain from competitive swimming for a sustained period (the duration differs among athletes but is usually weeks to years).16
In this article, we review the current management of asthma and exercise-induced bronchoconstriction in athletes. We focus particularly on athletes who engage in endurance sports, and we provide specific recommendations for high-level athletes.
DIAGNOSING ASTHMA AND BRONCHOCONSTRICTION IN ATHLETES
An early diagnosis of asthma or exercise-induced bronchoconstriction in an athlete may prevent the impaired performance that can ensue if preventive measures are not taken.17 In athletes, the diagnosis of asthma can be made on the basis of a history of characteristic symptom patterns and documentation of variable airflow limitation, by means of bronchodilator reversibility testing or other means, such as bronchoprovocation tests. However, respiratory symptoms alone have poor predictive value for making a diagnosis of asthma and exercise-induced bronchoconstriction in athletes.4,18 The documentation of variable airway obstruction is a requirement for a diagnosis of these conditions in all patients. Furthermore, expiratory flows can be supranormal (e.g., >120% of the predicted value) in some athletes, such as swimmers, and therefore maximal achievable expiratory flows should always be documented. In this regard, the demonstration of more than 10% diurnal variability in peak expiratory flows measured twice daily over a period of 2 weeks, or more than 12% (and >200 ml) variability in forced expiratory volume in 1 second (FEV1) over time or after 4 weeks of treatment, is consistent with a diagnosis of asthma or exercise-induced bronchoconstriction (Figure 1
).
The likelihood of airways to narrow can also be demonstrated, if airflow limitation is present, by a more than 12% (and >200 ml) change in the FEV1after inhalation of an aerosolized β2-agonist; if the baseline airway caliber is normal, this likelihood can be assessed as the presence of airway hyperresponsiveness documented with the use of bronchoprovocation testing. These tests include direct challenges (e.g., with inhaled methacholine), which act on airway smooth muscle to cause bronchoconstriction, and indirect challenges, such as eucapnic voluntary hyperpnea (particularly recommended for athletes19), hyperosmolar tests with saline or mannitol, and laboratory or field exercise tests.20-22 However, athletes may have a positive response to only one of these types of tests, and airway responsiveness can normalize a few weeks after they stop intense training.16 Therefore, more than one type of test may be needed, and ideally the testing should be performed during a period of intense training. There is a lack of data on the value of noninvasive measurements of airway inflammation, such as induced sputum analysis or measures of fractional exhaled nitric oxide (Fe NO), in the diagnosis of asthma and exercise-induced bronchoconstriction and assessment of treatment needs in athletes.
Particular attention has to be devoted to identifying asthma confounders and coexisting conditions, which can mimic or be associated with asthma in athletes (Figure 1). One of the most common is exercise-induced glottic or supraglottic laryngeal obstruction, including vocal-cord dysfunction, a paradoxical closure of vocal cords during inspiration. Other conditions, such as rhinitis, gastroesophageal reflux, and hyperventilation syndrome, are common among athletes and should be considered if the tests described above are inconclusive or if the response to a therapeutic trial (see below) is poor.23
MANAGEMENT OF ASTHMA AND BRONCHOCONSTRICTION IN ATHLETES
The goals of asthma treatment are to achieve and maintain asthma control, optimize pulmonary function, and prevent risk factors for acute events, such as exacerbations.24 The management of asthma in athletes, however, requires some specific considerations ( Table 1
). In high-level athletes, minimizing the possible deleterious effects of exercise on airway function is mandatory to allow optimal performance. Unfortunately, athletes are often unaware of, or do not report, respiratory symptoms.
Nonpharmacologic Measures
As for all patients with asthma, education about asthma self-management is essential; this should include advice about environmental measures, inhaler-use technique, and the use of an asthma action plan for the management of exacerbations, in addition to regular follow-up.24 Mechanical barriers such as face masks, although they are not always well tolerated, can help reduce the effects of cold air exposure in winter-sports athletes25 or the inhalation of particulate air pollutants. A pre-exercise warm-up (i.e., low-intensity or variable-intensity precompetitive exercise) can result in a reduction in exercise bronchoconstriction in more than half of persons. 26 This is attributed to a “refractory period” induced by the release of protective prostaglandins and by airway smooth-muscle tachyphylaxis to mediators of bronchoconstriction,26,27 during which time (about 2 hours) airways are less likely to constrict after exercise. Treatment should be offered for coexisting conditions associated with asthma, such as gastroesophageal reflux, rhinitis, or exercise-induced laryngeal obstruction; in the case of exercise-induced laryngeal obstruction, treatment should mainly involve the use of specific breathing exercises and removal of laryngeal irritants.
Although it is preferable for athletes not to train in conditions of very cold, dry air or during times of high levels of exposure to allergens or atmospheric pollutants, this is often difficult to avoid. However, whenever possible, it is preferable to avoid exercise close to busy roads or, for sensitized athletes, to avoid exercise activities and timing that would result in high allergen exposure, such as running through a ragweed field in the autumn.13,28 Improved ventilation of pool environments, measures to reduce chloramine formation in chlorinated pools, and reduction of exposure to other indoor and outdoor pollutants, including ozone, particulate matter, and nitrogen oxides, should also be promoted.13,29 There are insufficient data to recommend fish oil (n−3 fatty acids),30 vitamins,31or antioxidants as treatment.
Pharmacotherapy
Recommendations for the treatment of asthma and exercise-induced bronchoconstriction in athletes are shown in Table 2
.3,4,21,24 These are largely based on expert opinion, because there have been few adequately powered randomized clinical trials on asthma management in elite athletes.
Inhaled glucocorticoids are the mainstay of asthma therapy in athletes, as they are in nonathletes4,24; these agents are allowed by sports authorities. Inhaled glucocorticoids have been underused in the treatment of athletes, and β2-agonists have been overused.32 Apart from helping to control asthma and improve pulmonary function, an additional benefit of treatment with inhaled glucocorticoids is a progressive reduction, with regular use, in airway responses to various stimuli, including exercise. 33 In our opinion, inhaled glucocorticoids, usually at a low daily dose, should be considered if an athlete needs to use a rescue β2-agonist more than twice per week — including doses required to prevent exercise-induced bronchoconstriction — or if asthma is limiting exercise tolerance (i.e., the ability to exercise without troublesome symptoms). However, recent recommendations suggest that for some patients, inhaled glucocorticoids can be considered even earlier (e.g., if asthma symptoms occur or rescue medication is needed more than twice per month, particularly if there are risk factors for exacerbations).24 If low doses of inhaled glucocorticoids do not achieve asthma control, the addition of another controller drug should be considered, preferably a long-acting inhaled β2-agonist.
Leukotriene modifiers also reduce exercise-induced bronchoconstriction34,35 and have protective effects against the bronchoconstriction caused by exposure to pollutants.36 Cromolyn sodium and nedocromil sodium also protect against exercise-induced bronchoconstriction, but inhaled β2-agonists are more effective. As is the case with nasal inhaled glucocorticoids and nasal ipratropium, antihistamines may help to control associated rhinitis but are not considered effective against exercise-induced bronchoconstriction. Immunotherapy has limited efficacy in the treatment of asthma and has not been formally studied in athletes.24
Currently used inhaled β2-agonists have no performance-enhancing effect in athletes, with or without asthma. Short-acting inhaled β2-agonists are the most effective drugs for the relief of bronchoconstriction and are also effective in preventing exercise-induced bronchoconstriction when used 5 to 10 minutes before exercise. However, the regular or frequent use of inhaled β2-agonists may increase airway responsiveness to bronchoconstrictor stimuli and lead to tolerance to β2-agonists and to a decrease in their bronchoprotective effects during exercise,37 possibly as a result of down-regulation of the β2 receptor. This effect may be particularly detrimental in athletes with asthma or exercise-induced bronchoconstriction, because they exercise frequently and need highly effective protection against exercise-induced bronchoconstriction. If asthma is well controlled, an athlete will only occasionally (less than daily) need these agents to prevent and treat exercise-induced bronchoconstriction. Long-acting inhaled β2-agonists are used, together with inhaled glucocorticoids, to better control asthma when low doses of inhaled glucocorticoids alone are insufficient24; as in nonathletes, long-acting inhaled β2-agonists should never be used without an inhaled glucocorticoid.
The most common management strategy for athletes with asthma or exercise-induced bronchoconstriction who are exercising daily is daily treatment with inhaled glucocorticoids, with short-acting inhaled β2-agonists used occasionally before exercise. Leukotriene-receptor antagonists are also an option for maintenance treatment, and the combination of inhaled glucocorticoids and leukotriene-receptor antagonists may provide additional protection. 35 However, current asthma drugs that are effective for many persons with asthma who are not athletes are often unable to provide excellent asthma control in athletes, possibly because of the supranormal stimuli to the airways, a wrong diagnosis of asthma, concomitant conditions, nonadherence to therapy, poor technique in using inhalers, or a more treatment-resistant phenotype of asthma.38-40
ANTIDOPING REGULATIONS
Athletes with documented asthma or exercise-induced bronchoconstriction should review and adhere to antidoping regulations. Inhaled glucocorticoids and leukotriene-receptor antagonists do not currently require a Therapeutic Use Exemption by sports authorities. All β2-agonists, including optical isomers, are prohibited, except inhaled albuterol, formoterol, and salmeterol, when used in accordance with the World Anti-Doping Agency (WADA) specifications (Table 3). Other inhaled β2-agonists and oral or systemic glucocorticoids require a Therapeutic Use Exemption. Athletes should check the WADA website (www.wada-ama.org/en) regularly to keep updated on these regulations.
CONCLUSIONS
The prevalence of asthma and exercise-induced bronchoconstriction among athletes is uncertain but has been estimated to be between 30% and 70% among elite athletes, depending on the type of sports performed; however, much remains to be learned about the reasons for this and how to reduce the risk.42 Asthma and exercise-induced bronchoconstriction can usually be well managed in athletes, most often with the use of maintenance inhaled glucocorticoids and occasional inhaled short-acting β2-agonists before exercise. Knowledge of and adherence to antidoping regulations regarding asthma drugs are important for developing an asthma-management plan for competitive athletes. The approach outlined here is based largely on expert opinion. We need better data from controlled trials on ways to manage asthma and exercise-induced bronchoconstriction in athletes, who undertake frequent and intense efforts, often in challenging environmental conditions.
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