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00005768-200809000-0000300005768_2008_40_1567_pedersen_methacholine_9article< 99_0_16_4 >Medicine & Science in Sports & Exercise©2008The American College of Sports MedicineVolume 40(9)September 2008pp 1567-1572Airway Responses to Eucapnic Hyperpnea, Exercise, and Methacholine in Elite Swimmers[CLINICAL SCIENCES: Clinically Relevant]PEDERSEN, LARS1; WINTHER, SIMON1; BACKER, VIBEKE1; ANDERSON, SANDRA D.2; LARSEN, KLAUS R.11Respiratory and Allergy Research Unit, Department of Respiratory Medicine L, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, DENMARK; and 2Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, AUSTRALIAAddress for correspondence: Lars Pedersen, M.D., Respiratory and Allergy Research Unit, Department of Respiratory Medicine L, Bispebjerg Hospital, Copenhagen University Hospital, Bispebjerg Bakke 23, DK-2400, Copenhagen NV, Denmark; E-mail: for publication December 2007.Accepted for publication March 2008.ABSTRACTPurpose: The International Olympic Committee Medical Commission (IOC-MC) requires athletes to provide the result of an objective test to support a diagnosis of asthma or exercise-induced bronchoconstriction (EIB) if they want to inhale a beta-2-agonist. The purpose of the study was to evaluate the airway response to a methacholine challenge and to hyperpnea induced by exercise in the field and in the laboratory or that induced voluntarily by eucapnic hyperpnea in a group of female elite swimmers.Methods: Sixteen female nonasthmatic elite swimmers performed a eucapnic voluntary hyperpnea (EVH) test, a field-based exercise test (FBT), a laboratory-based exercise test (LBT), and a methacholine challenge. The criteria suggested by the IOC-MC were used to define a positive response to the challenges (EVH, field test, and laboratory test: minimum 10% decrease in FEV1; methacholine: PD20 ≤2 μmol).Results: Eight swimmers (50%) had at least one positive test to hyperpnea. Five were identified with the EVH test, four with FBT, and four with LBT. None were identified using methacholine. Three swimmers with airway hyperresponsiveness to exercise would have been identified using a higher cutoff for methacholine (PD20 ≤8 μmol).Conclusions: The EVH test is the test that diagnoses most swimmers with an abnormal response to hyperpnea, but not all cases of EIB are identified with the EVH test. Performing a methacholine test using IOC-MC's cutoff value does not improve the chances of diagnosing EIB. We recommend performing the EVH test when diagnosing and evaluating EIB in elite swimmers and if EVH test negative then proceeding to a strenuous LBT.A high prevalence of airway hyperresponsiveness (AHR), exercise-induced bronchoconstriction (EIB), and respiratory symptoms has been reported in elite athletes performing endurance sports. Although different methods have been used to evaluate AHR and EIB, documentation of respiratory symptoms to identify asthma has been more consistent and usually included cough, breathlessness, wheeze, and chest tightness, in keeping with the Global Initiative for Asthma guidelines (11). However, respiratory symptoms are unreliable predictors of EIB or asthma in elite athletes. For example, many athletes with respiratory symptoms do not have EIB whereas others with EIB do not have respiratory symptoms (13,27). Thus, the diagnosis of EIB or asthma in elite athletes should neither be based on the presence nor excluded by the absence of respiratory symptoms, and objective measurement is the preferred approach to diagnosis. In keeping with this, the International Olympic Committee Medical Commission (IOC-MC) and the International Association of Athletics Federations now require athletes to provide the result of an objective test to support a diagnosis of asthma or EIB if they want to inhale a beta-2-agonist before an event (2,3).Pharmacological agents, such as histamine or methacholine, are stimuli that act directly on specific receptors on bronchial smooth muscle to cause contraction and the airways to narrow. In contrast, tests that act indirectly provokethe release of endogenous mediators that cause the muscle to contract. The stimuli that act directly have been reported to be less sensitive in assessing summer athletes than may be expected (13,17). One reason for this may be due to EIB being the result of many mediators, some of which (e.g., prostaglandins and leukotrienes) are more potent than histamine or methacholine (4). Another reason may relate to normal or super normal lung function in athletes. A higher prevalence of AHR is found at less than normal levels of lung function (21) because preexisting airway narrowing serves to amplify the effects of smooth muscle contraction (20).If exercise is used to make the diagnosis in athletes, it needs to be of high intensity and, if possible, sports specific (28). These requirements make exercise tests difficult to perform in most laboratories that have limited access to ergometers. Eucapnic voluntary hyperpnea (EVH) test is an indirect test that has been found sensitive to identify EIB and is one of the tests recommended by the IOC-MC to confirm EIB in athletes (3).Studies have compared some of the different challenge tests used for diagnosing EIB in athletes (13,17,25). Most of these studies have been carried out in winter sport athletes, and most studies compare only two tests. The aim of our study was to evaluate the airway response to a methacholine challenge and to hyperpnea induced by exercise in the field and in the laboratory or that induced voluntarilyby eucapnic hyperventilation in a group of female elite swimmers.MATERIAL AND METHODSSubjects.Twenty-one female elite swimmers were invited to participate in the study. Five had a diagnosis of asthma (three used inhaled 8.8 (SD 4.7) yr and their mean weekly training amount was 22.2 (4.0) h (Table 1). All swimmers were white. One swimmer had hyperthyroidism and used the antithyroid agent methimazole. None else had any comorbid conditions. Two used contraceptive pills and one used beta-carotene. The participants attended four visits at least 24 h apart. Three visits were to the laboratory and one in a swimming pool arena (field-based exercise test; FBT). No swimmer had had an upper respiratory track infection in the previous 4 wk. We conducted the study during one of the swimmers' competitive season with most of the tests being done from January to April. The study was approved by the Ethics Committee of Copenhagen. All participants gave written informed consent.TABLE 1. Subject characteristics.EVH test.The participants inhaled a dry gas containing 5% CO2, 20.93% O2, and balance N2 at room temperature for 6 min with a target minute ventilation of 30 times FEV1 (1) equivalent to 85% the maximum voluntary ventilation (MVV). The gas flowed from a cylinder via a 120-L reservoir bag to the subject. The gas flow from the cylinder to the bag was regulated with a high-pressure regulator (Gloor Bros, Burgdorf, Switzerland) and controlled by a calibrated flowmeter (GT1000; Brooks Instrument, Veenendaal, The Netherlands). From the bag, the subjects breathed through a two-way valve and mouthpiece (Hans Rudolph, Kansas City, MO). Exhaled gas passed through a sensor recording the ventilation rate (Universal Ventilation Meter; VacuMed, Ventura, California). The forced expiratory volume in1 s (FEV1) was measured before and 1, 3, 5, 10, 15, and 20 min after hyperpnea. The lowest FEV1 value after the test was used to determine the maximum decrease in FEV1.Field-Based Exercise Challenge.The swimmers performed a sport-specific field-based exercise challenge. If possible, the challenge was carried out under race conditions at The National Danish Swimming Championships. All tests were done at the swimmers' favorite distance although the 50-m sprint was excluded. The shortest distance was 200 m or equivalent to at least 2-min work time at highest possible speed during a race. Eleven swam 200 m, three swam 400 m, and two swam 800 m. FEV1 was measured before exercise and 1, 3, 5, 10, 15, and 20 min after the race. The lowest of the postexercise FEV1 values was used to calculate the fall in FEV1.Methacholine Challenge.The methacholine challenge was performed with a Nebicheck nebulizer (#61 650 DeVilbiss, Gillingham, UK) according to the procedure described by Yan et al. (30). The swimmers were challenged first with saline (0.9%) and then with increasing doses of methacholine. Measurements of FEV1 were performed before the first inhalation and repeated after each inhalation. The challenge was terminated when a 20% or more decrease in FEV1 from the postsaline value was measured or when a cumulative dose of methacholine (8 μmol) had been administered.Laboratory-based exercise test (LBT).The LBT was performed on a treadmill. The participants ran until exhaustion at constant speed with the gradient of the treadmill increasing by 2% every second minute (15). The mean time of running was 300 (66) s. The heart rate was measured throughout (Polar Vantage; Polar Electro, Oy, Finland), and FEV1 was measured before (baseline) and 1, 3, 5, 10, 15, and 20 min after the test.Lung Function Measurements.Spirometry was done in accordance with ATS/ERS recommendations (19). The methacholine and the LBT were done using a 7-L dry wedge spirometer (Vitalograph, Buckingham, UK), which was calibrated weekly. The EVH and the FBT were done using a Vitalograph 2120 (Vitalograph calibrated daily. Predicted values of FEV1 were based on reference values according to Nysom et al. (22).Skin Prick Test.A skin prick test to 10 aeroallergens (birch, grass, mugwort, horse, dog, cat, house-dust mites (Dermatophagoides pteronyssinus and Dermatophagoides farinae) and moulds (Alternaria iridis and Cladosporium herbarium) (Soluprick SQ system, ALK-Abelló, Hoersholm, Denmark) was performed in duplicate according to the EAACI recommendations (9). A positive result (atopy) was defined as a wheal of at least 3 mm in diameter to at least one of the allergens.Questionnaire.We used a modified version of a questionnaire, which is normally used in elite athletes in our clinic and in research(16). The questionnaire focused on respiratory symptoms (wheezing, breathlessness, chest tightness, and cough) at rest and at exercise, use of medication, and doctor-diagnosed asthma. The swimmers were classified as having or not having experienced respiratory symptom four times or more per week within the last 4 wk. Furthermore, a respiratory physician blinded to the test results classified all swimmers as having EIB or not based on the swimmers' answers to the questionnaire.Analysis.Data are expressed as mean (SD). In accordance with the IOC criteria, FEV1 was chosen as the parameter for evaluating the response to the challenges. A positive EVH test, FBT, and LBT was defined as a fall in FEV1 of at least 10 percent of the prechallenge value. A positive response to methacholine was defined as a 20% fall in FEV1 at a cumulative dose of methacholine of either PD20 2 μmol or less, PD20 4 μmol or less, or PD20 8 μmol or less (equivalent to 4 mg·mL−1, 8 or 16 mg·mL−1, or cumulative dose of 400, 800, or 1600 μg). We used PD20 ≤2 μmol (∼4 mg·mL−1) to be consistent with the cutoff value used by the IOC-MC at the Olympic Winter Games in 2006 in Turin and the value that will be used for Beijing 2008 for use of beta-2-agonists in subjects not taking inhaled corticosteroids. The cumulative dose of methacholine required to provoke a 20% fall in FEV1 was calculated by linear interpolation of the dose-response curve.Values of P < 0.05 were considered statistically significant. Statistical analyses were done using the statistical software program SPSS 14.0 (SPSS Inc., Chicago, IL).RESULTSOf 16 swimmers, 8 (50%) had at least one positive test to hyperpnea with exercise or the EVH test. Of the eight swimmers with AHR to hyperpnea, five (63%) were identified with the EVH test, four (50%) with the FBT, and four (50%) with the LBT (Fig. 1). None of these had a response to methacholine challenge of PD20 ≤2 μmol, and only three of the swimmers with AHR to exercise would have been identified as having AHR to methacholine using a PD20 ≤8 μmol. Only one swimmer was atopic, but the subject showed no signs of AHR.FIGURE 1-AHR to challenge tests.The baseline lung function tests showed significantly higher values of FEV1 and FVC than predicted (FEV1 110.8 (14.6%) predicted and FVC 108.4 (15.0%) predicted) with a mean FEV1 of 4.34 (0.57 L) and a mean FVC of 5.10 (0.71 L) (Table 2, P < 0.05). The absolute and relative responses tothe different challenge tests are shown in Table 3. The mean fall in FEV1 for the swimmers with a positive EVH test was 0.70 (0.35 L) corresponding to 18.0 (8.4%) compared with 0.22 (0.13 L) or 5.2 (3.1%) for the swimmers with a negative EVH test. The FEV1 fall for swimmers with a positive FBT was 0.73 (0.36 L) or 16.6 (6.7%) versus 0.10 (0.18 L) or 2.3 (4.3%) for swimmers with a negative FBT. The numbers for the LBT were 0.65 (0.22 L) or 14.5 (4.4%) versus 0.15 (0.12 L) or 3.4 (2.6%).TABLE 2. Lung function.TABLE 3. Airway responsiveness.Cough was the most reported respiratory symptom. We found no difference in the prevalence of having or not having a positive challenge between swimmers with or without respiratory symptoms or between swimmers with EIB assessed by a respiratory physician (data not shown).DISCUSSIONIn this study of female elite swimmers without an asthma diagnosis, we found a high prevalence of AHR with 50% of the swimmers having one or more positive responses to a challenge test using the criteria suggested by the IOC-MC. This finding is in accordance with earlier findings showing a prevalence of AHR in swimmers of up to 79% (31). Our results support the theory that elite swimming affects the airways and leads to an increased prevalence of AHR and respiratory symptoms (12,24,25). The reason for this is unclear but may relate to the environment in which the swimmers spend many hours training.We could not predict the presence of EIB on respiratory symptoms alone, which is in line with other studies (13,27). Further, it was not possible for a physician to make the diagnosis based on the answers given in a comprehensive questionnaire. Thus, an objective test is necessary when diagnosing EIB in elite athletes.Using the cutoff values identified by IOC-MC, the EVH test was the most sensitive for identifying AHR in these swimmers. However, only 63% of the swimmers with at least one positive bronchial challenge test had a positive EVH test. This percentage is low compared with reports in other athletes. As in our study, Dickinson et al. (7) found that the EVH test was superior to a field-based sport specific or a laboratory-based exercise challenge test when screening elite winter athletes for EIB. In their study, the EVH test diagnosed all cases of EIB, whereas the sport-specific exercise test diagnosed only 30% and the field-based exercise did not diagnose any at all. The intensity of exercise for the field tests performed in our study was higher than the intensity used by Dickinson et al., and this may account for our finding of positive tests. It has been shown that exercise load is important (6), and this is why we chose to do the tests as all out maximum performance tests both in the laboratory and at the poolside. In the LBT, the swimmers reached an average of 99% of their predicted maximal heart rate. We did not use a heart rate monitor during the FBT because it could have hampered the performance, but it seems likely that the swimmers performed at maximal intensity during competition. Our study design could be criticized for not standardizing the exercise tests for duration and intensity, which could limit the conclusion about the data from this test. However, most elite athletes with respiratory symptoms experience symptoms when they are engaged in competition, and it seems important that the FBT is sport/environmental specific (28). Our FBT simulates the circumstances where the swimmers may be getting their symptoms, as it was sport/environmental specific, and it is reasonable to assume that the intensity was high because it was primarily done as part of a competition.Other studies comparing the FBT and the EVH test have shown similar results with the EVH test being the most effective in identifying EIB. In figure skaters, 75% had positive responses to 5 min of EVH and 56% to field-based exercise (18). In a study on elite cold weather athletes, the EVH test identified 89% of the elite athletes with AHR compared with 58% identified by the FBT (26). As in our study, the target ventilation during the EVH test was 30 times FEV1. In their study, the actual ventilation achieved was 28 times FEV1, which surpasses the average ventilation of 25 times FEV1 in our study, and this could explain why they identified more hyperresponsive subjects with the EVH test. In our study, only two swimmers reached the target of 30 times FEV1 equivalent to 85% MVV, and 12 swimmers reached 65% MVV, which has been proposed as the minimum threshold for an adequate challenge (Table 3). All four swimmers who did not reached 65% MVV had a negative EVH test. Two of them had a positive LBT and one had a positive LBT as well as a positive FBT. It is likely that these three swimmers would have had a positive EVH test had they reached 65% MVV. This would have meant that all swimmers with EIB would have been diagnosed with the EVH test. We can only speculate why not all swimmers managed to reach 65% MVV.When performing the EVH test, we used dry air. The use of dry air is of key importance whereas the use of cold air does not seem to affect the airway response to EVH (10). We did not use changes in midexpiratory flow rates to identify AHR to EVH as this has been shown to be of no additional value (8). In accordance with the IOC-MC criteria, we used FEV1 as an outcome for all four challenges, and FEV1 has been shown to be a reliable parameter when judging a response to EVH (14). However, studies have shown that other measurements such as FVC and peak expiratory flow rate (PEFR) can also be of value and using only one criterion might result in an underestimation in the prevalence of EIB. In a study by Parsons et al. (23), EVH was used to document EIB. When FEV1 was used as the only criterion for a positive test, the prevalence of EIB was 19%, but when more criteria were added (decline if FEV1 >5%, and decline in PEFR >20%), the prevalence increased to 38%.Although these studies cited above used only indirect tests, Holzer et al. (13) used both a direct and an indirect test in a study on 50 elite summer sport athletes unselected for previous respiratory symptoms. They found that half of the subjects had a positive EVH test (25/50) and nine of the25 positive to EVH had a positive methacholine challenge defined as a PD20 <9.47 μmol giving a sensitivity of36% for methacholine to identify an abnormal response to EVH in summer athletes. We also found 50% of our swimmers positive to exercise or EVH (8/16). None of these eight were identified using a PD20 ≤2 μmol for methacholine, but three of the eight (37.5%) were identified at a PD20 <4 μmol or PD20 <8 μmol. Importantly two swimmers with falls in FEV1 of 24.6% and 29.4% to EVH did not achieve a PD20 to methacholine at the top dose of 8μmol. Identifying an abnormal response to the stimuli to which an athlete is exposed would seem important to the cause of taking a beta-2-agonist immediately before an event. Thus, it seems inappropriate to rely upon either a negative or positive response to methacholine challenge as a guide to response to exercise or EVH.We used the criteria suggested by the IOC-MC to define a positive response to all the challenges used. Cutoff values are important and necessary when setting up regulations, as is the case in regard to usage of asthma medication in relation to elite sport. From a clinical point of view, there is a gray zone when working with arbitrary threshold and cutoff values. The clinical difference between having for example a FEV1 fall of 9.4% versus 10.6% is probably limited but important in regard to receiving an authorization from IOC-MC to inhale beta-2-agonist.We used PD20 ≤2 μmol as the cutoff value when defining AHR to methacholine in accordance with the IOC-MC criteria for those not taking inhaled corticosteroids. Had we used PD20 <4 μmol as the cutoff instead, four swimmers would have had a positive methacholine challenge with one swimmer having methacholine challenge as the only positive test. Had we used a cutoff value PD20 <8μmol, two more swimmers with no other positive test would have had a positive response to methacholine, and a total of 11 (69%) swimmers would have had AHR to one or more of the challenge tests.In a study on 39 endurance athletes (cross-country skiers and triathletes), 15 (38%) had AHR to methacholine only (n= 7) or exercise only (n = 5) or both (n = 3) (29). A higher cutoff value for defining AHR to methacholine (PD20 < 4mg equivalent to 20 μmol) and a less strenuous exercise test (88% of maximal heart rate) was used compared with our study.Five swimmers were excluded from the data analysis because they used asthma medication. However, these five swimmers had all the tests done as well. Despite using asthma medication, all five swimmers had at least one positive test. Two of them had three positive tests (EVH test, FBT, and methacholine challenge with PD20 <2 μmol), two had two positive tests (EVH test and FBT) and one had a single positive test (EVH test). These data show that even for treated asthmatics, the methacholine only had a 40% sensitivity to identify those positive to EVH or exercise. Although the swimmers with asthma were allowed to use their reliever medication before the test, four of them still had a positive field test. For the methacholine challenge, IOC regulations allow a higher cutoff point for a positive test for those taking inhaled steroids (PD20 cumulative dose of ≤ 68 μmol), but this different cutoff did not affect our findings.This study showed a high prevalence of AHR in female elite swimmers using different tests and the cutoff values recommended by the IOC-MC. The EVH test was the test that diagnosed most swimmers as having an abnormal response to hyperpnea. However, the EVH test diagnosed only 63% of the cases with AHR to hyperpnea, and our data suggest that the diagnosis of EIB in elite swimmers cannot only be based on the EVH test. Performing a methacholine test with PD20 ≤2 μmol as the cutoff value does not seem to improve the chances of diagnosing EIB in female elite swimmers. Using a higher cutoff will increase the change of identifying EIB but will also result in more subjects with AHR to methacholine as the only positive test. In conclusion, we would recommend performing the EVH test when diagnosing and evaluating EIB in elite swimmers and if EVH test negative then proceeding to a strenuous LBT.The authors thank all the swimmers, their clubs, and The Danish Swimming Federation. Furthermore, they also thank Nurse Elise Fritzbøger from the Department of Respiratory Medicine L at Bispebjerg Hospital for her help with the EVH tests. 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R.CLINICAL SCIENCES: Clinically Relevant940InternalMedicine & Science in Sports & Exercise10.1249/MSS.0b013e31817d818b20084091565-1566SEP 2008EIB or Not EIB? That Is the QuestionBONINI, S