Exercise-induced bronchoconstriction

INTRODUCTION — Exercise-induced bronchoconstriction describes the acute onset of bronchoconstriction occurring during or, more frequently, minutes after exercise. The term "exercise-induced asthma" is often used to describe episodic bronchoconstriction following exercise, but this wording is potentially misleading, since exercise is not an independent risk factor for asthma, but rather a trigger of bronchoconstriction in patients with underlying asthma [1]. In fact, there is some speculation that decreased physical activity is a risk factor for asthma, and that exercise may be helpful in preventing the onset of asthma in children [2]. Thus, the term exercise-induced bronchoconstriction (EIB) is a more accurate reflection of the underlying pathophysiology and is generally preferred.

The clinical manifestations, diagnosis, and management of exercise-induced bronchoconstriction will be discussed here. The clinical manifestations, evaluation, and management of asthma are reviewed separately. (See "Asthma in children younger than 12 years: Initial evaluation and diagnosis" and "Asthma in adolescents and adults: Evaluation and diagnosis" and "Pulmonary function testing in asthma" and "Wheezing phenotypes and prediction of asthma in young children" and "An overview of asthma management in children and adults" and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)

EPIDEMIOLOGY — The estimated prevalence of exercise-induced bronchoconstriction (EIB) varies from approximately 5 to 20 percent in the general population [3-6]. In comparison, up to 90 percent of patients with symptomatic asthma have some degree of EIB [7]. The magnitude of EIB is most strongly correlated with the underlying degree of airway hyperresponsiveness and the presence of airway inflammation, as measured by the number of airway eosinophils [8,9]. Thus, many patients with mild, episodic asthma characterized by minimally increased airway responsiveness and mild airway inflammation do not experience clinically significant bronchoconstriction even with strenuous exercise.

The prevalence of EIB appears to be higher among elite athletes and has been evaluated in a number of studies [6,10-13]. As an example, in a study of athletes participating in the summer Beijing and Athens Olympic Games, the sports most commonly associated with a Therapeutic Use Exemption for asthma were swimming, cycling, triathlon, pentathlon, and rowing, with prevalences of approximately 18, 16, 12, 13, 7 percent, respectively [10]. In contrast, the prevalence of asthma among athletes in disciplines without endurance demands, such as gymnastics, fencing, and sailing, was less than 5 percent. In a separate study, positive eucapnic hyperventilation was noted in 39 percent of swimmers and 24 percent of winter sport athletes [13].

PATHOGENESIS — Minute ventilation, the volume of air inhaled or exhaled from a person's lungs per minute, rises with exercise. EIB probably results from changes in airway physiology triggered by the large volume of relatively cool, dry air inhaled during vigorous activity [14,15]. This is supported by the finding that EIB is attenuated when the inspired gas is more fully humidified and closer to body temperature [16,17]. The effect of large-volume dry air inhalation on airway surface osmolality may be the primary stimulus responsible for bronchoconstriction [18]. Other relevant observations regarding EIB include the following:

●Levels of bronchoconstrictive and inflammatory mediators are increased, particularly leukotrienes LTC4 and LTD4 [19], histamine [20], and interleukin (IL)-8 [21]. (See "Antileukotriene agents in the management of asthma".)

●Peripheral Th2-type lymphocytes are activated, with an increase in T cells expressing CD25 (IL-2R), and B cells expressing CD23 [22]. These changes favor production of IgE and activation of eosinophils. (See "Normal B and T lymphocyte development", section on 'Th2 cells' and "The biology of IgE", section on 'Regulation of synthesis'.)

●Eosinophil influx and activation, measured using eosinophilic cationic protein levels, sputum eosinophils, or peripheral eosinophil counts, have been noted in some [23,24], but not all [17,25], studies of experimental EIB.

●In contrast, the fraction of exhaled nitric oxide (FE_NO) levels, which generally reflect airway inflammation, do not appear to correlate well with the development or severity of EIB [26-28]. (See "Exhaled nitric oxide analysis and applications".)

CLINICAL MANIFESTATIONS — Patients with exercise-induced bronchoconstriction (EIB) typically have initial bronchodilation during the first six to eight minutes of exercise [29,30]. The initial bronchodilation is followed by bronchoconstriction, which begins by three minutes after exercise, generally peaks within 10 to 15 minutes, and resolves by 60 minutes (figure 1). Typical symptoms are shortness of breath, chest tightness, and cough. Associated hoarseness or stridor is uncommon and should raise the possibility of paradoxical vocal fold motion. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)".)

In most patients with EIB, bronchoconstriction is followed by a refractory period, during which repeated exertion causes less bronchoconstriction [31]. This refractory period is generally less than four hours. Inhibitory prostaglandins (particularly prostaglandin E2) released during the refractory period probably protect against repeated episodes of EIB (figure 2) [32].

Acute bronchoconstriction was previously believed to be followed by late phase bronchoconstriction in some patients [33]. Findings in subsequent studies have been variable [34,35]; however, it does appear that the risk and severity of late phase bronchoconstriction due to EIB is substantially less than that associated with allergen-induced asthma [36,37].

Among atopic asthma patients with sensitization to inhalant allergens, EIB may be more likely to occur when the exercise includes exposure to the relevant allergen. As an example, runners are more likely to report exercise-related asthma symptoms during their pollen or mold allergy season [38,39].

DIAGNOSIS — The diagnosis of exercise-induced bronchoconstriction (EIB) is based on the combination of compatible clinical symptoms (eg, exercise-related symptoms of dyspnea, cough, or wheeze) and demonstration of reversible airflow limitation in response to exercise or a surrogate challenge [6,30,40]. In patients with well-documented asthma and typical asthma symptoms following exercise, formal exercise testing may not be needed unless symptoms do not resolve with, or are not prevented by, pretreatment with inhaled beta agonists.

In patients without documented asthma, further assessment is helpful to ensure that alternative causes of dyspnea are not overlooked and that unnecessary therapy is not prescribed. This is particularly true when an adult develops new onset exercise related symptoms. Formal testing is also helpful in evaluating highly trained athletes, as exercise related respiratory symptoms are poor predictors of EIB in this setting [6,41-43]. (See "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Diagnosis'.)

●Exercise challenge – An exercise challenge test is the most direct and preferred way to establish a diagnosis of EIB [30]. This usually involves 6 to 10 minutes of ergometer or treadmill exercise, sufficient to raise the heart rate to 80 to 90 percent of the predicted maximum. A test is generally considered positive if the forced expiratory volume in one second (FEV₁) decreases by 10 percent or more, although a fall of 15 percent is more diagnostic [6,30]. (See "Bronchoprovocation testing", section on 'Exercise challenge'.)

●Surrogate provocation tests – Alternatively, surrogate tests to assess bronchial hyperresponsiveness (eg, eucapnic voluntary hyperventilation, methacholine, histamine, or mannitol inhalation challenge) may be performed in specialized laboratories [44,45]. Depending on the available facilities, a surrogate test can be used instead of an exercise challenge test. Or, if the direct test is negative, an indirect test may identify patients with EIB who have a false negative exercise test [46]. Among the surrogate tests, eucapnic voluntary hyperventilation appears to have the greatest sensitivity for EIB [47,48]. (See "Bronchoprovocation testing", section on 'Eucapnic voluntary hyperpnea' and "Bronchoprovocation testing", section on 'Pharmacologic challenge'.)

●Diagnosis in elite athletes – The International Olympic Committee and the World Anti-Doping Agency require an objective test to confirm the diagnosis of asthma, such as spirometry demonstrating airflow limitation with reversibility following inhaled bronchodilator OR a positive bronchoprovocation test, as described above [40,46]. (See 'World Anti-Doping Agency' below.)

Measurement of peak expiratory flow rates before and after exercise frequently leads to inaccurate results, but portable devices that record forced expiratory volume in one second (FEV₁) are more accurate [30]. After a baseline value has been established, FEV₁ can be measured before and 2.5, 5, 10, 15, and 30 minutes after exercise and correlated with symptoms.

DIFFERENTIAL DIAGNOSIS — Other causes of exercise-induced dyspnea must be considered in the differential diagnosis of exercise-induced bronchoconstriction (EIB), particularly in patients who have no other manifestations of asthma, have normal baseline spirometry, and derive no benefit from pretreatment with bronchodilators. Central airway obstruction, paradoxical vocal fold motion (PVFM), laryngomalacia, exercise-induced anaphylaxis, interstitial lung disease, gastroesophageal reflux, poor cardiovascular conditioning, coronary heart disease, and exercise-induced dysrhythmias should be considered in adults who present with atypical exercise-induced dyspnea. A general approach to the diagnosis of dyspnea and wheezing illnesses are provided separately. (See "Evaluation of wheezing illnesses other than asthma in adults" and "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Evaluation'.)

The following exercise-associated airway processes may be missed on routine pulmonary function testing. Diagnosis may require direct visualization or a high index of suspicion:

●Central airway obstruction – Features that suggest central airway obstruction include a lack of response to inhaled bronchodilator, associated hemoptysis, and risk factors for lung cancer or metastasis to the airway. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

●Exercise-induced laryngeal obstruction (EILO) – The hallmark of EILO (previously known as paradoxical vocal fold motion and vocal cord dysfunction) is inspiratory stridor accompanied by respiratory distress that occurs during exercise. However, a portion of patients have expiratory stridor due to expiratory adduction of the vocal folds. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)" and "Exercise-induced laryngeal obstruction".)

●Exercise-induced laryngomalacia – Exercise-induced laryngomalacia is associated with inspiratory stridor during exercise caused by abnormal movement of the aryepiglottic folds into the endolarynx, resulting in subtotal glottic obstruction [49-52]. It is distinct from tracheomalacia. The diagnosis is made by flexible laryngoscopy during exercise. Exercise-induced laryngomalacia is a form of exercise-induced laryngeal obstruction. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Differential diagnosis'.)

●Exercise-induced anaphylaxis – Exercise-induced anaphylaxis is characterized by the abrupt onset of signs and symptoms of anaphylaxis during exercise. Prodromal symptoms may include generalized pruritus, warmth, urticaria, and fatigue. A food co-factor may be implicated. Some patients develop laryngeal angioedema as a component, although hypotension and/or cardiovascular collapse are more common. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Clinical manifestations'.)

●Exercise-associated reflux – Laryngopharyngeal reflux during exercise can mimic mild symptoms of EIB and exercise-induced anaphylaxis, including flushing, throat discomfort, dysphonia, and chest tightness/cough. However, it is not associated with severe dyspnea, pruritus, or urticaria. (See "Laryngopharyngeal reflux in adults: Evaluation, diagnosis, and management".)

●Dysfunctional breathing – Dysfunctional breathing (eg, hyperventilation, deep sighing, thoracic-dominant breathing, mouth breathing, accessory muscle use at rest, and thoraco-abdominal asynchrony) can contribute to persistent dyspnea during exercise and may be present in association with exercise-induced bronchoconstriction or as an independent diagnosis [53-57]. Physical therapy may help by improving muscle balance, posture, and diaphragmatic function [57].

The differential diagnosis of EIB is similar among children. In one retrospective review, treadmill exercise testing was performed in 142 children referred to a pediatric allergy and pulmonology clinic with exercise-induced dyspnea who had no other signs of asthma or in whom treatment with beta-2-agonists had failed [58]. Symptoms of exercise-induced dyspnea were reproduced in 82 percent. Among these 117 children, only 11 (9 percent) had EIB (defined by reproduction of symptoms and ≥15 percent decrease in FEV₁ from baseline). Other diagnoses included normal physiologic exercise limitation (63 percent), restrictive abnormalities (13 percent), vocal cord dysfunction (11 percent); laryngomalacia (2 percent), and hyperventilation and supraventricular tachycardia, each in one patient.

MANAGEMENT — The combination of general measures and pharmacologic intervention can prevent exercise-induced bronchoconstriction (EIB) in almost all patients. A major goal is to ensure that exercise is not avoided by patients with EIB. Asthmatics should exercise as much as desired and should be encouraged by the fact that athletes have won Olympic medals and played professional sports despite symptomatic asthma.

Monitoring — Response to therapy can be assessed subjectively in terms of symptom control and exercise tolerance. Peak expiratory flow (PEF) measurement before and after exercise may be helpful, although measurements of forced expiratory volume in one second (FEV₁) are more reliable [30]. If objective measurement of a patient's response to therapy is required, a formal exercise test, rather than the more widely available methacholine challenge, should be considered [59,60]. (See "Bronchoprovocation testing".)

While monitoring of PEF at home or during athletic practice lacks documented benefits in prevention of EIB, sports medicine clinicians and athletic programs have utilized PEF monitoring to help detect athletes with subclinical or unrecognized bronchoconstriction. These athletes may be given a slower warm up, modified workout, and suggestions for improved compliance or better technique in inhaler use. Should the athlete continue to experience a reduction in PEF or frequent EIB, a medical evaluation for medication adjustment would likely be indicated. (See "Peak expiratory flow monitoring in asthma".)

Nonpharmacologic measures to reduce EIB — Improved understanding of the pathophysiology of EIB has resulted in general recommendations that can help reduce its severity. These measures are based upon observed relationships between the severity of bronchoconstriction and the following factors:

●The magnitude of minute ventilation

●The temperature and humidity of the inspired air

Improving a patient's cardiovascular fitness reduces the minute ventilation required for a given level of exercise, thereby decreasing the stimulus for bronchoconstriction. Similarly, bronchoconstriction is lessened when the inspired gas is warmer and more humid. Patients should be instructed to breathe through a loosely fitting scarf or mask when exercising in cold, dry conditions [61,62].

The role of a pre-exercise warm-up is unclear. Some studies suggest that high intensity and variable intensity warm-up routines attenuate the fall in forced expiratory volume in one second (FEV₁), but data are conflicting [46,63,64]. Finally, ensuring that patients know when and how to use a metered dose or dry powder inhaler correctly can greatly enhance the efficacy of pharmacologic measures.

The role of controlling adverse environments in reducing symptoms of EIB has not been formally studied, although it seems reasonable to reduce chloramines in indoor pool environments, use a heat-exchanger or other face mask during cold weather endurance exercise, and, for urban athletes, schedule outdoor training around low-traffic hours [30,65].

Selection of pharmacologic therapy — Treatment of EIB has been studied primarily in patients with both EIB and underlying asthma [30]. Therapeutic options for patients with EIB as the only manifestation of airway hyperresponsiveness are less well researched. In general, if EIB occurs frequently in patients with poorly controlled asthma, the most important strategy is to improve overall asthma control [30,66]. Inhaled glucocorticoids and leukotriene-modifying agents are often useful in this regard. Prophylactic treatment of EIB prior to exercise, using an inhaled short-acting beta-2 agonist, should be considered in all patients with EIB, even if EIB is the sole manifestation of airway hyperresponsiveness. The following sections describe the pharmacologic management of various patient presentations (table 1).

Pre-exercise treatments for EIB

General approach — Short-acting beta-agonists (SABAs; albuterol [salbutamol], levalbuterol) are the most effective therapy for quick relief of EIB. All patients who report exercise-related symptoms should have access to a SABA for quick relief and be instructed on correct technique. Two inhalations (eg, albuterol 90 mcg/inhalation) are generally sufficient; occasionally four inhalations are needed.

Ipratropium is generally not used for quick relief as bronchodilation is delayed (onset at 15 minutes and peak at one to two hours) compared with SABAs.

Patients who have well-controlled asthma, but frequently have asthma symptoms with exercise, should be instructed to use prophylactic treatment approximately 5 to 20 minutes before exercise, usually with two inhalations of a SABA (eg, albuterol, levalbuterol) [30,67]. An alternative is to use a combination budesonide-formoterol (160 mcg/4.5 mcg) inhaler, 1 inhalation 5 to 20 minutes prior to exercise [66,68]. (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Patients with infrequent symptoms (Step 1)'.)

Equipotent doses of formoterol, salmeterol, and terbutaline appear to be equally effective in providing short-term control of EIB, although the onset of action is slower with salmeterol than with the other agents (table 2) [69]. However, frequent use of inhaled beta-agonists may lead to tolerance and decreased efficacy, and long-acting beta-agonists (eg, salmeterol, formoterol) should never be used as monotherapy in asthma [70]. Thus, it is preferable for athletes who exercise regularly to aim for sufficient control of their asthma that beta-agonist pretreatment is not routinely needed [46]. (See "Beta agonists in asthma: Acute administration and prophylactic use".)

Children often present a difficult clinical situation by exercising vigorously and intermittently throughout the day making pretreatment prior to exercise difficult. In this setting, it might be tempting to add a long-acting inhaled beta-2 agonist (LABA; such as salmeterol and formoterol) to provide protection against EIB for 12 or more hours [71,72]. However, LABAs are not recommended for monotherapy in asthma and should be prescribed in combination with inhaled glucocorticoid. Alternative strategies, such as use of leukotriene receptor antagonists, are described below. (See 'Prolonged or recurrent exercise' below.)

Approach in patients with intolerance of short-acting beta-agonists — Some patients are intolerant of the adverse effects of SABAs, such as jitteriness and increased heart rate. Several strategies can be used in these patients, including adjusting type or dose of SABAs or trials of alternative agents for EIB control.

●Altering SABA type, dose, or technique – For some patients, switching to an alternate SABA such as levalbuterol, using a chamber device (spacer) to reduce oral deposition, or using one inhalation instead of two allows improved tolerance of SABA pretreatment. Levalbuterol is an isomer of albuterol, R-albuterol. The use of levalbuterol and chamber devices are discussed separately. (See "The use of inhaler devices in adults", section on 'Spacers and holding chambers' and "The use of inhaler devices in children", section on 'Spacers and holding chambers' and "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Levalbuterol'.)

●Leukotriene receptor antagonists – LTRAs reduce EIB in most patients and improve recovery to baseline (table 3) based upon a review of 11 randomized trials in the American Thoracic Society guideline [30]. Protection from EIB is apparent by two hours after a single dose of montelukast, and postexercise recovery is accelerated [73,74]. The long half-life of montelukast allows once-daily dosing with durable protection from EIB for up to 12 hours [75,76]. However, LTRAs are not effective in all patients [77]. While LTRAs can be used to prevent EIB, patients will need to keep a SABA on hand for quick relief of any breakthrough symptoms. (See "Antileukotriene agents in the management of asthma".)

●Ipratropium – When used to prevent EIB, the inhaled muscarinic antagonist (anticholinergic agent), ipratropium, reduces the decrease in FEV₁ relative to placebo, but is less effective than SABAs [30,78,79]. For patients who are intolerant of SABAs, pretreatment with ipratropium will likely provide partial protection against EIB.

Prolonged or recurrent exercise — Patients who exercise for more than three hours or more than once a day represent a challenge in that use of a SABA multiple times a day is likely to lead to tachyphylaxis. One might imagine that an inhaled LABA might be useful in this situation. However, in concert with current guidelines, we do not recommend regular use of LABAs (ie, once or twice daily) as monotherapy for EIB, because of concerns about a loss of bronchoprotective effect over time [30,79,80]. Thus, for patients who would require regular, daily dosing of a SABA or LABA to control EIB, we suggest concomitant use of inhaled glucocorticoid or a leukotriene receptor antagonist (LTRA; montelukast, zafirlukast). (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Tolerance'.)

LTRAs must be taken at least two hours prior to exercise to have a maximal protective effect, but the effect lasts 12 (zafirlukast) to 24 (montelukast) hours [30]. While not effective in all patients, LTRAs appear superior to LABAs when treating asthmatics with EIB. In one multicenter trial, asthmatics with EIB were randomly assigned to either montelukast or salmeterol for eight weeks [81]. Therapy was protective within three days for both groups; however, tolerance to salmeterol developed, and by eight weeks, the bronchoprotective effect of montelukast was significantly better (figure 3).

As mentioned above, children with EIB can pose a therapeutic challenge, because they tend to exercise intermittently throughout the day and often neglect to premedicate with an inhaled SABA. LTRAs are an effective option in this setting. In a randomized trial of EIB in children, montelukast and montelukast with budesonide were superior to budesonide and budesonide with formoterol [82].

Improving asthma control to the point that specific pretreatment is not necessary before exercise is an additional strategy. This goal can often be accomplished with use of inhaled glucocorticoids according to current guidelines [30,66]. (See 'Persistent EIB symptoms despite premedication' below and "An overview of asthma management in children and adults".)

Persistent EIB symptoms despite premedication — When EIB is refractory to premedication with a SABA, poor asthma control is often the cause. The most effective method of achieving asthma control involves appropriate step-up therapies including the use of inhaled glucocorticoids (table 4A-C). Other agents frequently involved in asthma control of these patients include inhaled glucocorticoid-LABA combination therapies, or leukotriene receptor antagonists (LTRA). (See "An overview of asthma management in children and adults", section on 'Initiating pharmacologic treatment' and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)

Although inhaled glucocorticoids do not have an immediate protective effect on EIB, they do improve airway hyperresponsiveness and, over weeks to months, decrease the magnitude of bronchoconstriction that occurs with a given workload [82-85]. Some studies have noted that inhaled glucocorticoids do not decrease EIB in a dose-related manner [59,60]. In contrast, a decrease in methacholine sensitivity (as determined by methacholine challenge) is generally well-correlated with the inhaled glucocorticoid dose. These findings suggest both a mechanism for EIB distinct from methacholine, and considerable variability in response to inhaled glucocorticoid therapy. This variability is partially explained by a greater magnitude of benefit from inhaled glucocorticoids in patients with higher sputum eosinophilia [9].

Inhaled glucocorticoids do not require a therapeutic use exception (TUE) from the World Anti-Doping Agency [86], although oral and intravenous glucocorticoids do require a TUE. (See 'World Anti-Doping Agency' below.)

Refractory EIB due to extreme conditions — Data are limited in terms of strategies to prevent EIB in high performance athletes and patients exercising in extreme conditions (eg, very cold, dry air). Therapies that may be useful when added to pretreatment with a SABA include regular use of an LTRA (eg, montelukast, zafirlukast) or pretreatment with ipratropium [87]. Nonpharmacologic measures may also be helpful. (See "Antileukotriene agents in the management of asthma", section on 'Clinical use of leukotriene-modifying drugs in asthma' and 'Nonpharmacologic measures to reduce EIB' above.)

●Leukotriene receptor antagonists – LTRAs, when added to pretreatment with a SABA may provide better protection in extreme conditions than either agent alone, based on clinical experience [88], although the response is variable [87,89]. LTRAs do not require a TUE from the World Anti-Doping Agency (WADA). (See 'World Anti-Doping Agency' below.)

●Ipratropium – Among elite cross-country skiers, inhaled ipratropium was associated with greater improvement in FEV₁ than inhaled albuterol (salbutamol) [90]. In addition, the improvement in FEV₁ correlated with greater airways hyperresponsiveness to methacholine challenge. Whether this response to ipratropium translates into better protection against EIB during high intensity cold air exercise has not been determined.

Dietary modification — Data are inconclusive about whether dietary interventions are useful in the management of EIB. Diets rich in anti-inflammatory omega-3 fatty acids have not been conclusively demonstrated to be helpful in the general population of patients with asthma [91]. Despite early data suggesting benefit of increased dietary omega-3 fatty acids in EIB, subsequent data do not support a benefit [30,92,93]. In a randomized trial of 23 patients treated for three weeks with either fish oil supplements (containing omega-3 fatty acids) or placebo, the group on fish oil was not different from control in sputum eosinophils, FEV₁ percent predicted, symptom score, or response to mannitol challenge (a surrogate for EIB) [93].

Systematic reviews have reached different opinions about the effect of vitamin C in reducing EIB possibly due to the small number of subjects and differing choices of outcome measurements [94,95]. Overall, the data appear inconclusive. Lycopene supplements have not been shown to reduce EIB [30].

Other therapies — Other types of asthma therapy are not very effective in protecting against EIB. As an example, oral beta-2 agonists and methylxanthines are marginally effective or ineffective in almost all patients [96,97].

Oral antihistamines appear to provide modest protection against EIB in patients with inhalant allergies, but not in nonatopic patients [30].

Several other drugs have been tested as possible prophylactic agents against EIB. Inhaled medications, such as furosemide [98], prostaglandin E2 [99], indomethacin [100], and heparin [101], may protect against EIB. However, long-term clinical use of these compounds has not been directly compared with the prophylactic use of inhaled beta-2 agonists. For this reason, their role in clinical practice is unclear.

WORLD ANTI-DOPING AGENCY — The World Anti-Doping Agency (WADA), which governs medication use by athletes in international competition, has published guidelines for the diagnosis and management of asthma in athletes [102] and a list of medications that require a Therapeutic Use Exemption (TUE) [86].

The WADA lists beta-agonists on its prohibited medication list due to concerns about performance enhancement [53,86]. However, inhaled albuterol (salbutamol), maximum dose 1600 mcg/24 hours and 800 mcg/12 hours, inhaled formoterol, maximum delivered dose 54 mcg/24 hours, and inhaled salmeterol, maximum dose 200 mcg/24 hours, are acceptable and do not need a Therapeutic Use Exception [86]. Nebulized beta-agonists may reach levels above those permitted. Urinary levels of albuterol over 1000 ng/mL or formoterol over 40 ng/mL are considered to be in excess of therapeutic use to prevent EIB.

In terms of potential effects on performance, a study of 16 athletes found that high-dose salbutamol (albuterol) 1600 mcg/day for six weeks did not increase strength, power, or endurance relative to placebo [103].

Inhaled glucocorticoids are permitted by the WADA and do not need a Therapeutic Use Exception [86]. Systemic glucocorticoids are prohibited in competition, and a Therapeutic Use Exception may need to be filed for use outside of competition [86,104]. Leukotriene receptor antagonists (montelukast, zafirlukast) and omalizumab are permitted agents.

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: Exercise-induced bronchoconstriction and exercise-induced laryngeal obstruction".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Exercise-induced asthma (The Basics)")

●Beyond the Basics topics (see "Patient education: Exercise-induced asthma (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Exercise-induced bronchoconstriction (EIB) refers to the episodic bronchoconstriction that follows exercise in many asthmatic patients. The term EIB reflects the view that exercise is a trigger of bronchoconstriction in patients with underlying asthma. (See 'Introduction' above.)

●Avoidance measures – Improving a patient's cardiovascular fitness reduces the minute ventilation required for a given level of exercise, thereby decreasing the stimulus for bronchoconstriction. Avoiding exercise in cold, dry air can also reduce the stimulus for exercise-induced bronchoconstriction. (See 'Nonpharmacologic measures to reduce EIB' above.)

●Pharmacologic therapy – Therapy for EIB varies somewhat with the clinical setting (table 1). All patients with EIB should have access to a short-acting beta-agonist (SABA) available when exercising for relief of asthma symptoms. (See 'General approach' above.)

•Pre-exercise treatments for EIB – For patients who have otherwise well-controlled asthma, but who frequently have asthma symptoms with exercise, we recommend prophylactic use of a SABA (eg, albuterol 90 mcg/inhalation, 2 inhalations) or combination inhaled glucocorticoid and formoterol (eg, budesonide-formoterol 160 mcg/4.5 mcg, 1 inhalation), approximately 5 to 20 minutes prior to exercise rather than observation alone (Grade 1B). (See 'Pre-exercise treatments for EIB' above.)

Alternatives for prophylaxis in patients who prefer not to use or cannot tolerate a SABA include leukotriene receptor antagonists (LTRA) or inhaled ipratropium. However, neither of these alternatives reverse bronchoconstriction as rapidly as a SABA or formoterol, so the patient will still need to keep a SABA- or formoterol-containing inhaler on hand for break-through symptoms. (See 'Approach in patients with intolerance of short-acting beta-agonists' above.)

•Prolonged or recurrent exercise – For patients who require daily therapy for EIB due to prolonged or recurrent exercise, we suggest regular use of an LTRA or an inhaled glucocorticoid in addition to a short-acting beta-agonist, rather than regular daily use of a beta-agonist alone (Grade 2B). The use of an LTRA may be particularly attractive in children, in whom exercise may be unpredictable or repeated throughout the day, and who may not use their inhalers as directed. (See 'Prolonged or recurrent exercise' above and 'Pre-exercise treatments for EIB' above.)

•Persistent EIB symptoms despite pretreatment – Most patients with persistent EIB symptoms despite use of exercise pretreatment therapies have undiagnosed poorly controlled asthma. For these patients, asthma control should be prioritized with step-up therapy including an inhaled glucocorticoid, inhaled glucocorticoid-LABA combination, or LTRA. (See 'Persistent EIB symptoms despite premedication' above and "An overview of asthma management in children and adults".)

●Ineffective treatments – Antihistamines, theophylline and oral beta agonists are minimally effective or ineffective for EIB. (See 'Other therapies' above.)