American Thoracic Society Documents

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1 American Thoracic Society Documents An Official American Thoracic Society Clinical Practice Guieline: Exercise-inuce Bronchoconstriction Jonathan P. Parsons, Teal S. Hallstran, John G. Mastronare, Davi A. Kaminsky, Kenneth W. Runell, James H. Hull, William W. Storms, John M. Weiler, Fern M. Cheek, Kevin C. Wilson, an Sanra D. Anerson; on behalf of the American Thoracic Society Subcommittee on Exercise-inuce Bronchoconstriction THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY WAS APPROVED BY THE ATS BOARD OF DIRECTORS, DECEMBER 2012 CONTENTS Executive Summary Introuction Methos Pathogenesis Role of the Environment Diagnosis Measuring an Quantifying EIB Exercise Challenge Testing to Ientify EIB Surrogates for Exercise to Ientify EIB Treatment Questions an Recommenations General Comments Regaring Therapy Screening for EIB Exercise, Asthma, an Doping Backgroun: Exercise-inuce bronchoconstriction (EIB) escribes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in iniviuals without known asthma. Methos: Toprovieclinicianswithpracticalguiance,amultiisciplinary panel of stakeholers was convene to review the pathogenesis of EIB an to evelop evience-base guielines for the iagnosis an treatment of EIB. The evience was appraise an recommenations were formulate using the Graing of Recommenations, Assessment, Development, an Evaluation approach. Results: Recommenations for the treatment of EIB were evelope. The quality ofevience supporting the recommenations was variable, ranging from low to high. A strong recommenation was mae for using a short-acting b 2 -agonist before exercise in all patients with EIB. For patients who continue to have symptoms of EIB espite the aministration of a short-acting b 2 -agonist before exercise, strong recommenations were mae for a aily inhale corticosteroi, a aily leukotriene receptor antagonist, or a mast cell stabilizing agent before exercise. Conclusions: The recommenations in this Guieline reflect the currently available evience. New clinical research ata will necessitate a revision an upate in the future. EECUTIVE SUMMARY Exercise-inuce bronchoconstriction (EIB) escribes acute airway narrowing that occurs as a result of exercise. A substantial This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Me Vol 187, Iss. 9, pp , May 1, 2013 Copyright ª 2013 by the American Thoracic Society DOI: /rccm ST Internet aress: proportion of patients with asthma experience exercise-inuce respiratory symptoms. EIB has also been shown to occur in subjects without a known iagnosis of asthma. Diagnosis The iagnosis of EIB is establishe by changes in lung function provoke by exercise, not on the basis of symptoms. Serial lung function measurements after a specific exercise or hyperpnea challenge are use to etermine if EIB is present an to quantify the severity of the isorer. It is preferable to assess FEV 1, because this measurement has better repeatability an is more iscriminating than peak expiratory flow rate. The airway response is expresse as the percent fall in FEV 1 from the baseline value. The ifference between the pre-exercise FEV 1 value an the lowest FEV 1 value recore within 30 minutes after exercise is expresse as a percentage of the pre-exercise value. The criterion for the percent fall in FEV 1 use to iagnose EIB is >10%. The severity of EIB can be grae as mil, moerate, or severe if the percent fall in FEV 1 from the pre-exercise level is >10% but,25%, >25% but,50%, an >50%, respectively. A number of surrogates for exercise testing have been evelope that may be easier to implement than exercise challenge. These surrogates inclue eucapnic voluntary hyperpnea or hyperventilation, hyperosmolar aerosols, incluing 4.5% saline, an ry power mannitol. Treatment For patients with EIB, we recommen aministration of an inhale short-acting b 2 -agonist (SABA) before exercise (strong recommenation, high-quality evience). The SABA is typically aministere 15 minutes before exercise. A controller agent is generally ae whenever SABA therapy is use aily or more frequently. For patients with EIB who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently: We recommen against aily use of an inhale longacting b 2 -agonist as single therapy (strong recommenation, moerate-quality evience). This is base upon a strong concern for serious sie effects. We recommen aily aministration of an inhale corticosteroi (ICS) (strong recommenation, moerate-quality

2 American Thoracic Society Documents 1017 evience). It may take 2 4 weeks after the initiation of therapy to see maximal improvement. We recommen against aministration of ICS only before exercise (strong recommenation, moerate-quality evience). We recommen aily aministration of a leukotriene receptor antagonist (strong recommenation, moeratequality evience). We recommen aministration of a mast cell stabilizing agent before exercise (strong recommenation, highquality evience). We suggest aministration of an inhale anticholinergic agent before exercise (weak recommenation, lowquality evience). In our clinical practices, we generally a a aily inhale ICS or a aily leukotriene receptor antagonist first, with the choice between these agents mae on a case-by-case basis epening upon patient preferences an baseline lung function. Mast cell stabilizing agents an inhale anticholinergic agents play a seconary role. For patients with EIB an allergies who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently, we suggest aministration of an antihistamine (weak recommenation, moerate-quality evience). In contrast, we recommen against aministration of antihistamines in patients with EIB who o not have allergies (strong recommenation, moerate-quality evience). For all patients with EIB, we recommen interval or combination warm-up exercise before planne exercise (strong recommenation, moerate-quality evience). For patients with EIB who exercise in col weather, we suggest routine use of a evice (i.e., mask) that warms an humiifies the air uring exercise (weak recommenation, low-quality evience). For patients with EIB who have an interest in ietary moification to control their symptoms: We suggest implementation of a low-salt iet (weak recommenation, moerate-quality evience). We suggest ietary supplementation with fish oils (weak recommenation, low-quality evience). We suggest against ietary supplementation with lycopene (weak recommenation, low-quality evience). We suggest ietary supplementation with ascorbic aci (weak recommenation, moerate-quality evience). An algorithm summarizing iagnosis an treatment of EIB is provie in Figure 1. INTRODUCTION Exercise-inuce bronchoconstriction (EIB) escribes acute airway narrowing that occurs as a result of exercise. The exact prevalence of EIB in patients with asthma is not known, but exercise is one the most common triggers of bronchoconstriction in patients with asthma, an a substantial proportion of patients with asthma experience exercise-inuce respiratory symptoms. EIB has also been shown to occur in subjects without a known iagnosis of asthma, with prevalence of up to 20% being reporte (1). As a result, this has le to controversy regaring nomenclature relate to bronchoconstriction occurring as a result of exercise. Many experts avocate using the terminology exercise-inuce bronchoconstriction instea of exercise-inuce asthma, as it oes not imply that the patient has unerlying chronic asthma or that exercise actually cause asthma. For the purposes of this ocument, we will use the terminology exercise-inuce bronchoconstriction without regar to whether it occurs in patients with or without asthma. There are substantial ata showing that EIB occurs very commonly in athletes at all levels. Many stuies have been performe in Olympic or elite-level athletes that have ocumente prevalence of EIB varying between 30 an 70%, epening on the population stuie an methos implemente (1). Stuies have also been one on college, high school, an recreational athletes that have shown a significant prevalence of EIB (2 4). The symptoms of EIB are variable an nonspecific, an presence or absence of specific respiratory symptoms has very poor preictive value for objectively confirme EIB (4, 5). Clinical presentation may inclue chest tightness, cough, wheezing, an yspnea. These symptoms may only be provoke by exercise or may only occur in specific environments, such as ice rinks or inoor swimming pools. The symptoms are often mil to moerate in severity an may cause impairment of athletic performance, but are not severe enough to cause significant respiratory istress. However, severe episoes of EIB can occur, an respiratory failure an even eath have occurre in rare cases (6). Given the significant prevalence of EIB, it is critical that evience-base ocuments exist to guie health care proviers with regar to the pathogenesis, iagnosis, management, an treatment of EIB, as well as other critical issues relate to EIB, such as environmental influences an consierations in Olympic/elite-level athletes. To provie such guiance, a multiisciplinary panel was convene to evelop evience-base guielines. METHODS These guielines were evelope in accorance with the American Thoracic Society s (ATS s) stanars for clinical practice guielines (Table 1). The methos are escribe in etail in the online supplement. PATHOGENESIS A moest perio of high-intensity exercise or, alternatively, increase minute ventilation uring isocapnic hyperpnea triggers a prototypical response consisting of bronchoconstriction, which occurs preominantly after the cessation of a short perio of TABLE 1. METHODS CHECKLIST Panel assembly Inclue experts for relevant clinical an nonclinical isciplines Inclue iniviual who represents the views of patients an society at large Inclue a methoologist with appropriate expertise (ocumente expertise in conucting systematic reviews to ientify the evience base an the evelopment of evience-base recommenations) Literature review Performe in collaboration with librarian Searche multiple electronic atabases Reviewe reference lists of retrieve articles Evience synthesis Applie prespecifie inclusion an exclusion criteria Evaluate inclue stuies for sources of bias Explicitly summarize benefits an harms Use PRISMA1 to report systematic review Use GRADE to escribe quality of evience Generation of recommenations Use GRADE to rate the strength of recommenations Yes No N/A

3 1018 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 1. Diagnostic an treatment algorithm for exerciseinuce bronchoconstriction. EIB ¼ exercise-inuce bronchoconstriction; ICS ¼ inhale corticosteroi; LABA ¼ longacting b 2 -agonist; LTRA ¼ leukotriene receptor antagonist; MCSA ¼ mast cell stabilizing agent; SABA ¼ short-acting b-agonist. *Or surrogate challenge, for example, hyperpnea or mannitol. hyperpnea an lasts from 30 to 90 minutes in the absence of treatment. The preisposition to the evelopment of this synrome varies markely among subjects with asthma, an is known to occur in some groups of subjects without asthma, such as elite athletes. Several stuies inicate that subjects who are prone to EIB have increase levels of exhale nitric oxie (7), leukotrienes (8, 9), expression of mast cell genes (10), an epithelial sheing into the airway lumen (9). Although the events that trigger this synrome are not fully unerstoo, it is clear that inflammatory meiators, incluing histamine, tryptase, an leukotrienes, are release into the airways from cellular sources in the airways, incluing eosinophils an mast cells (11, 12). The activation of sensory nerves may play an important role in the pathogenesis of EIB, an may be involve in mucus release into the airways after exercise challenge (13, 14). The epithelium may play a key role in sensing the transfer of water an heat out of the lower airways, but the way in which this epithelial response leas to cellular activation by leukocytes remains incompletely unerstoo. Each is escribe in etail in the online supplement. ROLE OF THE ENVIRONMENT The high prevalence of EIB in populations of athletes may be relate to specific environmental emans of specific sports (15). For example: The approximate 30% prevalence of EIB reporte in ice rink athletes has been linke to the inhalation of col ry air in combination with the high emission pollutants from fossil-fuele ice resurfacing machines (16 18). The high prevalence of airway injury an bronchial hyperresponsiveness reporte among Noric skiers has been attribute to high ventilation inhalation of col, ry air uring training an competition (19 21). The 11 29% prevalence of asthma an EIB reporte among competitive swimmers (22) has been associate with the high levels of trichloramines in the inoor pool air (23 25). The prevalence of EIB among istance runners is higher than that of the general population, an has been attribute to exercising in high allergen (26) an high ozone environments (27). Among the environmental exposures that have been propose to contribute to EIB are col air, ry air, ambient ozone, an airborne particulate matter. Susceptible populations, such as chilren an those with pre-existing cariovascular isease, iabetes, or lung isease, are more sensitive to an acutely increase fraction of particles eposite in the lungs uring exercise. Evience supports increase airway hyperresponsiveness an ecrease lung function from chronic exposure to air pollutants uring exercise. The effects of each exposure an the evience for each are escribe in etail in the online supplement. DIAGNOSIS The iagnosis of EIB is establishe by changes in lung function after exercise, not on the basis of symptoms. Symptoms that are often associate with vigorous exercise, such as shortness of breath, cough, wheeze, an mucus prouction, are neither sensitive nor specific for ientifying those with EIB (4, 5, 28). Among athletes with an without symptoms associate with exercise, EIB can be ientifie in iniviuals without symptoms, an many iniviuals with respiratory symptoms will not have EIB (4, 5, 28 31). Measuring an Quantifying EIB Serial lung function measurements after a specific exercise or hyperpnea challenge are use to etermine if EIB is present an to quantify the severity of the isorer. It is preferable to assess FEV 1, as this measurement has better repeatability (32) an is more iscriminating than peak expiratory flow rate (33 35). The measurement of FEV 0.5 (in 3- to 6-year-ol chilren) an airway resistance using the interrupt technique (in 5- to 12-yearol chilren) have been use successfully to establish a iagnosis of EIB (36, 37). Recovery from EIB is usually spontaneous, an FEV 1 returns to 95% baseline value within minutes. In a group of 7- to 12-year-ol chilren, recovery occurre faster in the younger chilren (38). Accoring to ATS/European Respiratory Society guielines, at least two reproucible FEV 1 maneuvers are measure serially after exercise challenge, with the highest acceptable value recore at each interval (39, 40). FEV 1 is usually measure at 5, 10, 15, an 30 minutes after exercise, but may be more

4 American Thoracic Society Documents 1019 frequent if a severe response is expecte. An FVC maneuver is not require, as repeate efforts may tire the subject. The airway response is expresse as the percent fall in FEV 1 from the baseline value. The ifference between the pre-exercise FEV 1 value an the lowest FEV 1 value recore within 30 minutes after exercise is expresse as a percent of the pre-exercise value (40). The criterion for the percent fall in FEV 1 use to iagnose EIB is >10% in some guielines (40 43). The >10% fall value was base on the mean plus two SDs of the percent fall in FEV 1 in normal healthy subjects without a family history of asthma, atopy, or recent upper respiratory tract infection (35, 44, 45). Higher values for percent fall in FEV 1 (i.e., 15 an 13.2%) have been recommene for iagnosing EIB in chilren (46 48). A fall of >10% at two consecutive time points has been recommene (49). Many laboratories use a criterion of >15% from baseline because of the greater specificity of this criterion. The reproucibility of EIB as etermine by two separate tests is goo, with 76% agreement between tests. The response in FEV 1 (percent ecline) is 614.6% when both tests emonstrate a >10% fall, an 615.7% when only one test emonstrates a >10% fall. Thus, two tests may be require when using exercise to exclue a iagnosis of EIB (44). The severity of EIB can be grae as mil, moerate, or severe if the percent fall in FEV 1 from pre-exercise level is > 10% but,25%, >25% but,50%, an >50%, respectively (50 52). This graing was base on the range of measure values for EIB an before the wiesprea use of inhale sterois. Currently, a ecline in FEV 1 of >30% in a person taking inhale sterois woul be consiere severe. Exercise Challenge Testing to Ientify EIB The type, uration, an intensity of exercise an the temperature an water content of the air inspire are important eterminants of the airway response to exercise (53 60). The time since the last exercise is also important, because some subjects become refractory to another exercise stimulus for up to 4 hours (61 63). The two most important eterminants of EIB are the sustaine highlevel ventilation reache uring exercise an the water content of the air inspire (54, 55, 64 67). The ventilation require for a vali test is at least 17.5 times FEV 1 an preferably greater than 21 times FEV 1 (68). Measurement of ventilation uring testing for EIB permits comparisons to be mae on the effect of the same stimulus over time an between subjects (68). Although heart rate is often use as a surrogate measure of the intensity of exercise, the relationship between heart rate an ventilation varies wiely base on fitness an other factors (69). The ieal protocol to etect EIB involves a rapi increase in exercise intensity over approximately 2 4 minutes to achieve a high level of ventilation. Most protocols recommen breathing ry air (,10 mg H 2 O/L) with a nose clip in place while running or cycling at a loa sufficient to raise the heart rate to 80 90% of preicte maximum (preicte maximum heart rate z age in years) (44, 47, 48, 69 71) or ventilation to reach times FEV 1 (68, 72, 73). Once this level of exercise is attaine, the subject shoul continue exercise at that high level for an aitional 4 6 minutes. These targets are more rapily achieve with running exercise compare with cycling. Sports-specific exercise is probably the most relevant for elite athletes that can be teste uring the activity that causes symptoms (28). The use of shortacting an long-term preventative asthma meications (68, 72, 73), recent intense or intermittent warm-up exercise (61 63), recent use of nonsteroial anti-inflammatory meication (74), an recent exposure to inhale allergens may alter the severity of the response to exercise challenge (75 77). Surrogates for Exercise to Ientify EIB A number of surrogates for exercise testing have been evelope that may be easier to implement than ry air exercise challenge. These surrogates inclue eucapnic voluntary hyperpnea of ry air an inhalation of hyperosmolar aerosols of 4.5% saline or ry power mannitol. Although none of these surrogate tests are completely sensitive or specific for EIB, they all have utility for ientifying airway hyperresponsiveness consistent with a iagnosis of EIB (4, 78 88). The surrogates of exercise are escribe in etail in the online supplement. TREATMENT Treatment for EIB can be broken own into pharmacologic an nonpharmacologic therapy. Currently use pharmacologic therapy inclues short-acting b 2 -agonists (SABAs) an long-acting b 2 -agonists (LABAs), leukotriene receptor antagonists (LTRAs), an inhale corticosterois (ICSs). Mast cell stabilizing agents (MCSAs) have traitionally been use to treat EIB, an, although these agents are no longer available in the Unite States, they remain available in other countries aroun the worl. Other rugs, such as inhale anticholinergic agents (ipratropium) an antihistamines, may play a minor role in treating some patients with EIB. Nonpharmacologic therapy inclues warmup to inuce a refractory perio, maneuvers to prewarm an humiify the air uring exercise (e.g., breathing through a face mask or scarf), improving general physical conitioning, losing weight if obese (89), an moifying ietary intake. The goals of therapy are to relieve bronchoconstriction shoul it occur an to minimize or prevent bronchoconstriction from happening in the first place, thus allowing the athlete or patient with EIB to continue to engage in physical activity or sports with minimal respiratory symptoms. Questions an Recommenations Question 1: Shoul patients with EIB be treate with an inhale SABA before exercise? The most common therapeutic recommenation to minimize or prevent symptoms of EIB is the prophylactic use of shortacting bronchoilators (b 2 -agonists), such as albuterol, shortly before exercise (90). These agents work by stimulating b 2 - receptors on airway smooth muscle, causing muscle relaxation an bronchoilation, as well as possibly preventing mast cell egranulation. SABAs, given by inhalation 5 20 minutes before exercise, are usually effective for 2 4 hours in protecting against or attenuating EIB (91, 92), but may fail to prevent bronchoconstriction in 15 20% of patients with asthma (72). In aition, aily use of b 2 -agonists alone or in combination with ICSs may lea to tolerance, manifeste as a reuction in uration of protection against EIB, an a prolongation of recovery in response to SABA after exercise (93, 94). Tolerance is thought to be ue to esensitization of the b 2 -receptors on mast cells an airway smooth muscle. This is why b 2 -agonists are generally only use on an intermittent basis for prevention of EIB, an why patients who use SABAs on a more regular basis (e.g., aily) are generally starte on a controller agent, such as ICS or LTRAs. Our recommenation for an inhale SABA before exercise is base upon a systematic review of the literature that ientifie eight ranomize trials, of which five were poole. Patients who receive an inhale SABA ha a maximum percent fall in FEV 1 after exercise that was 26.03% less than that among patients who receive placebo. The large magnitue of effect was not offset by risk of bias, inirectness, inconsistency, or imprecision. Thus, the evience provie high confience in the estimate effects of inhale SABA. The recommenation is strong,

5 1020 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL because the committee is certain that the reuction of breathlessness associate with the lower maximum percent fall in FEV 1 after exercise outweighs the relatively minor potential sie effects, burens, an cost of pre-exercise SABA therapy (see Table E1 in APPENDI 2). Recommenation 1: For patients with EIB, we recommen aministration of an inhale SABA before exercise (strong recommenation, high-quality evience). The inhale SABA is typically aministere 15 minutes before exercise. Such use shoul be less than aily, on average. Question 2: Shoul patients with EIB be treate with an inhale LABA? A controller agent is typically ae whenever SABA therapy is use on a aily basis or more frequently. LABAs are effective in treating an preventing EIB (72, 95); however, similar to the use of SABAs, the protective effect affore by LABAs ecreases with aily use (96 98). Although LABAs may initially protect against bronchoconstriction for 6 12 hours, the effect iminishes to lasting only 6 hours after aily use for 30 ays (97). Unfortunately, concomitant use of aily ICS oes not mitigate this loss of effectiveness (96, 98). One stuy foun that formoterol remaine effective as long as it was use three times per week or less; so, as a single agent, LABAs may be use for EIB at this frequency (99). However, there remains serious concern about increase morbiity an mortality with any use of LABAs as monotherapy, without concomitant ICS in patients with asthma (100, 101). Our recommenation against aily LABA monotherapy is base upon our review of the literature, which ientifie two relevant ranomize trials (102, 103). Both trials compare LABA monotherapy to placebo after the withrawal of ICSs an foun an increase rate of treatment failures an acute exacerbations among those receiving LABA monotherapy. Other ranomize trials an meta-analyses that evaluate LABA therapy were also ientifie; however, most inclue patients who were receiving concomitant ICSs. The stuies that either inclue a large proportion of patients receiving LABA as monotherapy or analyze patients who were receiving LABA monotherapy separately supporte the potential for increase averse effects among those receiving LABA monotherapy (100, 101). This evience provies moerate confience in the estimate effects of LABA monotherapy, because the ranomize trials ha inirectness (i.e., the trials inclue patients with asthma in general, not patients with EIB specifically). The recommenation against aily LABA therapy is strong, because the importance of the potential ownsies of LABA monotherapy (i.e., serious averse effects, incluing asthma-relate mortality, exacerbations requiring hospitalization, cost, an burens) substantially outweigh the upsies (i.e., less yspnea, less nee for inhale SABAs), particularly in light of the availability of safer alternative therapies. Recommenation 2: For patients with EIB who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently, we recommen against aily use of an inhale LABA as single therapy (strong recommenation, moerate-quality evience). Question 3: Shoul patients with EIB be treate with ICSs? Daily ICSs are consiere the most effective anti-inflammatory agents for EIB (104). This may be ue not only to better control of unerlying asthma, but perhaps to a irect therapeutic effect on airway inflammation that is associate with EIB (11, 105, 106). ICS can be use alone or in combination with other treatments for EIB. As mentione previously here, ICS therapy oes not prevent the occurrence of tolerance from aily b 2 -agonist use. Stuies on inhale sterois have shown that the maximum beneficial effect in protecting against EIB may take as long as 4 weeks, an is ose epenent (104, 107). Although a single high ose of beclomethasone ipropionate has been shown to have a protective effect against hyperpnea-inuce bronchospasm, this strategy is not recommene clinically (108). Interestingly, ICS o not seem to be as protective in elite athletes without asthma who experience EIB compare with patients with asthma with EIB (109). As with all inhale meications, proper inhaler technique must be taught to the patient an reinforce at follow-up visits. Our recommenation for a aily ICS is base upon a systematic review that foun six ranomize trials, of which four were poole. Patients with EIB who receive a aily ICS ha a mean maximum percent fall in FEV 1 after exercise that was 10.98% less than that seen among patients who receive placebo. The ranomize trials were limite by imprecision (i.e., the ens of the confience intervals le to ifferent clinical ecisions), proviing moerate confience in the estimate effects. The recommenation is strong because the committee is certain that the reuction of yspnea associate with the ecrease in the maximum percent fall in FEV 1 after exercise outweighs the relatively minor burens, cost, an sie effects of ICS therapy (see Table E2A in APPENDI 2). Our recommenation against pre-exercise ICS is base upon a systematic review that ientifie four ranomize trials, of which two were poole. Patients with EIB who receive preexercise ICS ha a mean maximum percent fall in FEV 1 after exercise that was similar to that seen among patients who receive placebo. The ranomize trials were limite by imprecision, proviing moerate confience in the estimate effects. The recommenation is strong because the committee is certain that the ownsies of pre-exercise ICS excee the upsies. There appear to be no significant benefits, but there are potential sie effects, costs, an burens (see Table E2B in APPENDI 2). Recommenation 3A: For patients with EIB who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently, we recommen aily aministration of an ICS (strong recommenation, moerate-quality evience). It may take 2 4 weeks after the initiation of therapy to see maximal improvement. Recommenation 3B: For the same patients, we recommen against aministration of ICS only before exercise (strong recommenation, moerate-quality evience). Question 4: Shoul patients with EIB be treate with LTRAs? LTRAs, such as montelukast, given once aily, will reuce EIB an also improve the recovery to baseline. There is no evelopment of tolerance when taken aily (110). The magnitue of effect may be smaller for LTRAs than either ICS or preexercise SABA. However, the uration of action is longer, lasting up to 24 hours, which may be very useful for patients or athletes engaging in physical activity throughout the ay (111, 112). LTRAs shoul be taken at least 2 hours before exercise to have a maximal prophylactic effect (111). LTRAs appear to protect against EIB regarless of whether patients have asthma or are elite athletes without asthma (113). Our recommenation for a aily LTRA is base upon a systematic review that ientifie 11 ranomize trials, of which 7 were poole. Patients with EIB who receive a aily LTRA ha a mean maximum percent fall in FEV 1 after exercise that was 10.70% less than that seen among patients who receive placebo. The ranomize trials were limite by imprecision, proviing moerate confience in the estimate effects. The recommenation is strong because the committee is certain that the reuction of yspnea associate with the ecrease in the

6 American Thoracic Society Documents 1021 maximum percent fall in FEV 1 after exercise outweighs the comparatively minor burens, cost, an sie effects of LTRA therapy (see Table E3 in APPENDI 2). The choice of whether to a aily ICS or aily LTRA to as-neee use of SABA in patients with EIB who o not respon to intermittent SABA therapy alone, in most cases, is a personal one that shoul be mae on a case-by-case basis. Strictly speaking, the evience supports efficacy of both types of meications in EIB, although ICS therapy may have a more potent antiinflammatory effect in patients with EIB associate with airway inflammation. This may be relevant to the patient with asthma with EIB as oppose to the elite athlete without asthma with EIB, in whom ICS may work better in the former. In cases where baseline lung function is below normal, guielines recommen use of ICS initially (90). Both classes of meicines are reaily available in the Unite States in contrast to MCSAs. Some patients woul prefer to avoi using an inhaler an avoi using aily ICS; in these situations, trying a aily LTRA woul be reasonable, or, if not exercising aily, then using montelukast at least 2 hours before planne exercise. Other patients may prefer to use inhale ICS because they want to avoi any potential systemic effects of aily LTRA therapy; in these cases, trying aily ICS woul be reasonable. In all cases, it is always essential to ensure that unerlying asthma is uner control, an continue an close follow up with the patient is important to achieve therapeutic effect on minimal an acceptable meication. Recommenation 4: For patients with EIB who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently, we recommen aily aministration of an LTRA (strong recommenation, moerate-quality evience). Question 5: Shoul patients with EIB be treate with an MCSA? MCSAs, such as soium cromoglycate an neocromil soium, provie protection against EIB by blocking egranulation of mast cells an release of meiators, such as prostaglanin D 2. Cochrane Reviews (114, 115) have emonstrate consistent protection against EIB, with an attenuation of EIB by about 50%. There are no significant ifferences between soium cromoglycate an neocromil soium. MCSAs appear to be more effective at attenuating EIB than anticholinergic agents, but less effective than SABAs. There appears to be no avantage to combining MCSAs with SABAs, as the effectsaresimilartousing SABAs alone. Our recommenation for an MCSA before exercise is base upon a systematic review that ientifie 24 ranomize trials, of which 20 were poole. Patients with EIB who receive an MCSA before exercise ha a mean maximum percent fall in FEV 1 after exercise that was 15.20% less than that seen among patients who receive placebo. The ranomize trials ha no serious risk of bias, inirectness, inconsistency, or imprecision, thereby proviing a high egree of confience in the estimate effects. The recommenation is strong because the committee is certain that the reuction of yspnea associate with the ecrease in the maximum percent fall in FEV 1 after exercise outweighs the comparatively minor burens, cost, an sie effects of preexercise MCSA therapy (see Table E4 in APPENDI 2). Although the evience for MCSAs is high quality, it is important to note that the lack of availability of these meications in the Unite States may make this recommenation less clinically applicable in the Unite States, although they are reaily available worlwie. Recommenation 5: For patients with EIB who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently, we recommen aministration of an MCSA before exercise (strong recommenation, high-quality evience). Question 6: Shoul patients with EIB be treate with an antihistamine? Antihistamines have been stuie as a treatment for EIB. The results of these stuies are variable, with some protection against EIB seen in a small percentage of patients (116, 117). The inconsistency in the ata may be ue to ifferences in the severity of EIB stuie an the ability of terfenaine, use in some of the positive stuies, to also inhibit leukotrienes, thus confouning the specific role of an antihistamine effect (118). Because controlling allergies in patients with atopy with asthma leas to better asthma control in general, it seems pruent that allergic patients with asthma with EIB may benefit from antihistamine therapy (119). A systematic review of the evience ientifie three ranomize trials, which were poole. Patients with EIB who receive a aily antihistamine ha no significant ecrease in their mean maximum percent fall in FEV 1 after exercise compare with patients who receive placebo. The ranomize trials were limite by imprecision, proviing moerate confience in the fining of no effect (see Table E5 in APPENDI 2). Our recommenation for aily antihistamine therapy in allergic patients inicates the committee s belief that antihistamines may be helpful in EIB, as controlling allergies improves asthma control in general. The weak strength of the recommenation reflects the uncertainty about the balance of potential benefits versus harms, burens, an cost, as the relevant trials i not analyze iniviuals with atopy separately. In contrast, our recommenation against antihistamines in nonallergic iniviuals is strong because the committee is certain that the ownsies excee the upsies. Antihistamines appear to confer no significant benefits in such patients, but have potential sie effects, costs, an burens. Recommenation 6A: For patients with EIB an allergies who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently, we suggest using an antihistamine to prevent EIB (weak recommenation, moerate-quality evience). Recommenation 6B: For nonallergic patients with EIB who continue to have symptoms espite using an inhale SABA before exercise, or who require an inhale SABA aily or more frequently, we recommen against using antihistamines (strong recommenation, moerate-quality evience). Question 7: Shoul patients with EIB be treate with a short-acting inhale anticholinergic? Like antihistamines, anticholinergic treatment with ipratropium has variable effects on preventing or treating EIB. Our recommenation for aministration of an inhale short-acting anticholinergic agent before exercise is base upon a publishe systematic review of 12 ranomize trials, all of which were poole (115). Patients with EIB who receive inhale ipratropium bromie before exercise ha a mean maximum percent fall in FEV 1 after exercise that was 9.80% less than that seen among patients who receive placebo. The evience was limite by inconsistent results an imprecision, proviing low confience in the estimate effects. The recommenation is weak because the committee is uncertain that the reuction of yspnea associate with the ecrease in the maximum percent fall in FEV 1 after exercise outweighs the potential sie effects, burens, an cost. The uncertainty erives from the small effect size an the low quality of evience (see TableE6inAPPENDI 2). Recommenation 7: For patients with EIB who continue to have symptoms espite using an inhale SABA before exercise,

7 1022 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL or who require an inhale SABA aily or more frequently, we suggest aministration of an inhale anticholinergic agent before exercise (weak recommenation, low-quality evience). Question 8: Shoul patients with EIB engage in a physical activity before exercise, to inuce a refractory perio? An important nonpharmacologic strategy to minimize EIB use by many athletes is to engage in physical warm-up before the planne perio of exercise or competition (62, 63, 120, 121). Typically, the warm-up consists of minutes of moerately vigorous exercise, an subsequent EIB is reuce for the next 2 hours, resulting in a so-calle refractory perio. This phenomenon oes not occur in all athletes, an may not occur at all in athletes without asthma with EIB. Various approaches, incluing low-intensity, high-intensity, interval, or continuous exercise, an combinations of these, have been trie (93). A recent review of this subject suggests that a warm-up consisting of variable high-intensity exercise, as oppose to continuous high- or low-intensity exercise, appears to be the most effective strategy to attenuate EIB (122). Our recommenation for interval or combination warm-up exercise before planne exercise is base upon a publishe systematic review of four ranomize trials of interval warm-up, three ranomize trials of low-intensity continuous warm-up, two ranomize trials of high-intensity continuous warm-up, an two ranomize trials of combination warm-up (115). Patients with EIB who unerwent interval, low-intensity continuous, high-intensity continuous, or combination warm-up before exercise ha a mean maximum percent fall in FEV 1 after exercise that was 10.61, 12.60, 7.97%, an 10.94% less than that seen among patients who i not unergo formal warm-up, respectively. These improvements were statistically significant only for interval an combination warm-up. The evience for interval an combination warm-up was limite by imprecision, proviing moerate confience in the estimate effects. In contrast, the evience for low-intensity an high-intensity continuous warm-up was limite by inconsistent results an imprecision, proviing low confience in the estimate effects (see Tables E7A E7D in APPENDI 2). The recommenation is strong, because the committee is certain that the reuction of yspnea associate with the ecrease in the maximum percent fall in FEV 1 after interval an combination warm-up exercise an the effects of warm-up on injury prevention outweigh the buren an risks of the warm-up exercise. General physical conitioning may also help attenuate EIB (89). This likely occurs not on the basis of any irect effect on lung function, but, rather, inirectly ue to the lower minute ventilation require for any given workloa once cariovascular conitioning has been improve. Recommenation 8: For all patients with EIB, we recommen interval or combination warm-up exercise before planne exercise (strong recommenation, moerate-quality evience). Question 9: Shoul patients with EIB use a evice to warm or humiify the air when they exercise in col weather? Another technique to minimize EIB symptoms is to prewarm an humiify the inhale air. This strategy follows from the concept that bronchoconstriction in EIB occurs as a result of the cooling an rying of the airways uring the high minute ventilation of exercise. Two strategies that have been employe are breathing through the nose (123) an use of a facemask (124). In one stuy, breathing through a heat exchanger mask was as effective as albuterol in preventing EIB (125). Our recommenation to use a evice that warms an humiifies air uring exercise in col weather is base upon a systematic review that foun a ranomize trial an two nonranomize controlle trials. In the ranomize trial, patients with EIB who use a evice to warm an humiify air ha a mean maximum percent fall in FEV 1 after exercise that was 14.70% less than that seen among patients who i not use such a evice. The trial was limite by risk for bias an imprecision, proviing low confience in the estimate effects. The result of the ranomize trial was consistent with both nonranomize controlle trials. The weak strength of the recommenation reflects uncertainty about the egree of benefit uncertainty that erives from the low quality of evience (see Table E8 in APPENDI 2). Recommenation 9: For patients with EIB who exercise in col weather, we suggest the routine use of a evice (i.e., mask) that warms an humiifies the air uring exercise (weak recommenation, low-quality evience). Question 10: Shoul patients with EIB change their ietary habits (e.g., low-salt iet, fish oil supplementation, lycopene, vitamin C)? There have been many stuies examining the effects of ietary moification on EIB ( ). Low-soium iet (130), fish oil (omega-3 polyunsaturate fatty acis) supplementation (131), oral lycopene (132), an ascorbic aci supplementation (1,500 mg/ay) (129) have all been stuie in relation to EIB. All were foun to have some effect in reucing the severity of EIB, but all of these stuies ha important limitations, so their finings shoul be consiere preliminary until confirme in larger trials. With regar to fish oil, there may be a ifferential effect of treatment epening on whether the patient has unerlying asthma (in which case, the fish oil supplementation may not attenuate EIB) (133) or not (in which case, fish oil supplementation may attenuate EIB) (134, 135). Given the lack of obvious risk to patients in aministering these ajunctive therapies, it is reasonable to try them in intereste patients, but the evience is not strong enough to conclue that they are effective in a large majority of patients with EIB. Our recommenation for a low-salt iet is base upon a systematic review that ientifie six ranomize trials, which coul not be poole ue to insufficient reporting of the crue ata. In all of the trials, however, patients with EIB who receive a lowsalt iet ha a significantly smaller ecrease in the mean maximum percent fall in FEV 1 after exercise than patients who i not receive a low-salt iet. These trials provie moerate confience in the estimate effect, because they were limite by imprecision (see Table E9A in APPENDI 2). Our recommenation for fish oil supplementation is base upon a systematic review that ientifie one relevant ranomize trial in which patients with EIB who receive fish oil supplementation ha a mean maximum percent fall in FEV 1 after exercise that was 11.50% less than that seen among patients who i not receive fish oil supplementation. The evience provie low confience in the estimate effect because it was limite by imprecision an inconsistency (a subsequent trial that measure ifferent outcomes foun no effect). See Table E9B in APPENDI 2. Our recommenation against lycopene supplementation is base upon a systematic review that ientifie two relevant ranomize trials. In one trial, patients with EIB who receive lycopene ha a mean maximum percent fall in FEV 1 after exercise that was 11.80% less than that seen among patients who i not receive lycopene. In contrast, the other trial foun no effect from lycopene supplementation. The evience provie low confience in the estimate effect because of the inconsistency of the results an imprecision (see Table E9C in APPENDI 2). Our recommenation for ascorbic aci (i.e., vitamin C) supplementation is base upon a systematic review that ientifie two relevant ranomize trials. In both trials, patients with

8 American Thoracic Society Documents 1023 EIB who receive ascorbic aci supplementation ha a mean maximum percent fall in FEV 1 after exercise that was approximately half of that seen among patients who i not receive ascorbic aci supplementation. The evience provie moerate confience in the estimate effect because it was limite by imprecision (see Table E9D in APPENDI 2). All of the recommenations are weak because the committee is uncertain that the reuction of yspnea associate with ietary supplementation outweighs the buren of ietary moification. This uncertainty erives from the limitations of the supportive evience. Recommenation 10A: For patients with EIB who have an interest in ietary moification to control their symptoms, we suggest a low-salt iet (weak recommenation, moeratequality evience). Recommenation 10B: For patients with EIB who have an interest in ietary moification to control their symptoms, we suggest ietary supplementation with fish oils (weak recommenation, low-quality evience). Recommenation 10C: For patients with EIB who have an interest in ietary moification to control their symptoms, we suggest against ietary supplementation with lycopene (weak recommenation, low-quality evience). Recommenation 10D: For patients with EIB who have an interest in ietary moification to control their symptoms, we suggest ietary supplementation with ascorbic aci (weak recommenation, moerate-quality evience). General Comments Regaring Therapy Our overall recommenations regaring therapy leave a lot of options for the iniviual patient, which shoul be iscusse with the patient s physician an trie an evaluate on an ongoing basis. The mainstay of therapy remains maintaining goo control of unerlying asthma (if present) an preventing or treating symptoms of EIB with SABAs. If such therapy oes not work, then the next best options are to a aily ICS or aily LTRA, epening on patient preference. After this, the patient may try aing or substituting with inhale mast cell stabilizing, anticholinergic, or oral antihistamine therapy. Pre-exercise warmup is recommene for all patients, as is wearing a mask or scarf in col weather for those with col weather inuce symptoms. Improving physical fitness an losing weight if obese seem pruent. Finally, although there is not a lot of evience to support ietary moification, patients with an interest in this approach may try a low-salt iet, or supplementing with fish oil or vitamin C. The aition of lycopene is not strongly supporte. SCREENING FOR EIB Screening is efine as the strategy use in a population to etect a conition in a preclinical or asymptomatic phase with the aim of proviing timely intervention to favorably influence outcome. In contrast, case etection is the ientification of iniviuals with isease who are symptomatic, but uniagnose. A number of organizations an investigators avocate screening for asthma in both the general population (136) an in athletes ( ), yet evaluation of screening base upon the Worl Health Organization criteria (escribe in the online supplement) reveals important eficiencies in the ata require to ensure the valiity of this approach (140, 141). Accoringly, an ATS report on screening for asthma that was publishe in 2007 conclue that there was insufficient evience to support the aoption of population-base asthma case etection, base primarily upon a lack of etail regaring health outcome (142). It was, however, felt that case etection programs may be appropriate in areas where there is a high prevalence of uniagnose asthma, an where newly etecte cases have access to high-quality care. This recommenation is pertinent to the athletic population, an, inee, some sporting organizations have establishe EIB screening programs for their internationally competitive athletes (137, 143). Yet, to ate, expert working groups have not irectly aresse EIB screening policy (1, 41, 144). We were unable to locate any ranomize controlle trials or large, well one observational stuies (i.e., case control, cohort stuies) evaluating the overall efficacy of a screening program for EIB on either health or performance outcome. Such stuies are ifficult to conuct (145), but, nevertheless, they remain a prerequisite for a rigorous evaluation of a screening policy. Therefore, there presently remains major uncertainty in the estimates of benefits, harms, an burens of a screening/case etection policy for EIB. For iniviuals who engage in athletic activity, more evience is neee before the value of screening for EIB can be etermine. There is a small number of observational stuies in which population subgroups or athletic teams have unergone an EIB screening assessment. These evaluations have typically involve athletic iniviuals who were members of competitive sporting associations (138, 146, 147), an were preominately conucte with the aim of evaluating prevalence an/or the utility of etection methos as oppose to a irect appraisal of a screening policy. Extrapolating the finings of these stuies, which primarily involve referre, selecte populations, to a general screening policy is inappropriate, but oes provie insight to target further work evaluating the feasibility an potential methoological limitations of screening for EIB. The stuies are escribe separately in the online supplement. EERCISE, ASTHMA, AND DOPING Doping is efine as the use of any banne substance (incluing rugs an bloo proucts) to improve athletic performance. The International Olympic Committee maintains a list of substances an methos prohibite in-competition, out-of-competition an in particular sports. Many of the stanar therapies employe to treat EIB have restricte use in competitive athletes, an it is important for athletes an healthcare proviers to be aware of these restrictions ( For example, all b 2 -agonists are banne in competition except short-acting inhale albuterol (salbutamol) an LABAs salmeterol an formoterol. Other inhale LABAs may be ae in the future. Some LABAs, such as clenbuterol, have been shown to enhance athletic performance an are banne entirely from use both in an out of competition base on their anabolic capacities. Beginning in 2010, the use of albuterol an salmeterol by inhalation no longer requires a therapeutic use exemption (TUE). As of January 1, 2013, inhale formoterol up to a maximum ose of 54 mg/24 hours is no longer prohibite an, hence, oes not require a TUE. The therapeutic maximum aily osage of albuterol is 1,600 mg/24 h by inhalation (148, 149). When albuterol is foun in urine in excess of 1,000 ng/ml, it is presume that the albuterol was not intene to be use therapeutically an is consiere an averse analytical fining unless pharmacokinetic ata are available in the athlete to refute the fining to emonstrate otherwise. All b 2 -agonists are prohibite if aministere orally or by injection. All glucocorticois are prohibite when given by oral, intravenous, or intramuscular route. Inhale sterois are permitte, as are oral an inhale treatments with LTRAs, cromones (not reaily available in the Unite States), an muscarinic receptor antagonists. None of these agents enhance performance in athletes without asthma an, therefore, they o not require a TUE (150, 151).

9 1024 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL The history of the International Olympic Committee an Worl Anti-Doping Agency policies are escribe in the online supplement. This official Clinical Practice Guieline was prepare by an a hoc committee of the American Thoracic Society Assembly on Allergy, Immunology, an Inflammation. Members of the committee: JONATHAN P. PARSONS, M.D., M.Sc. (Chair) TEAL S. HALLSTRAND, M.D., M.P.H. JOHN G. MASTRONARDE, M.D., M.Sc. DAVID A. KAMINSKY, M.D. KENNETH W. RUNDELL, PH.D. JAMES H. HULL, PH.D. WILLIAM W. STORMS, M.D. JOHN M. WEILER, M.D., M.B.A. FERN M. CHEEK, A.M.L.S. KEVIN C. WILSON, M.D. SANDRA D. ANDERSON, PH.D., D.Sc. Author Disclosures: J.P.P. receive lecture fees from AstraZeneca ($10,001 50,000), GlaxoSmithKline ($10,001 50,000), Merck ($1,001 5,000), an Schering Plough ($1,001 5,000). T.S.H. receive lecture fees from Genentech ($1,000 9,999) an Merck ($1,000 9,999). J.G.M. receive lecture fees from GlaxoSmithKline ($1,001 5,000) an research support from Pfizer ($10,001 50,000). D.A.K. receive lecture fees from Meical Graphics Corp. ($1,000 9,999) an Merck ($1,000 9,999). K.W.R. receive lecture fees from Merck ($10,001 50,000). J.H.H. receive training support from GlaxoSmithKline (up to $1,000). W.W.S. serve on avisory committees of Alcon Labs ($10,001 50,000) an Merck ($10,001 50,000), an receive lecture fees from Alcon Labs (up to $1,000), AstraZeneca ($10,001 50,000), Genentech ($10,001 50,000), Merck ($10,001 50,000), an Teva ($5,001 10,000); he receive research support from Alcon Labs ($10,001 50,000), Amgen ($10,001 50,000), Genentech ($10,001 50,000), an Sunovian ($10,001 50,000), an hel stock or options in Strategic Biosciences ($10,001 50,000) an Strategic Pharmaceutical Avisors ($10,001 50,000). J.M.W. was employe by CompleWare Corporation an as an employee hel stock or options in CompleWare Corporation. 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