The role of the bronchial provocation challenge tests in the diagnoisis of exercise-induced bronchoconstriction in elite swimmers

The role of the bronchial provocation challenge
tests in the diagnosis of exercise-induced
bronchoconstriction in elite swimmers

A Castricum, K Holzer, P Brukner, et al.
2010 44: 736-740 originally published online October 23, Br J Sports Med2008doi: 10.1136/bjsm.2008.051169 Updated information and services can be found at:
This article cites 29 articles, 11 of which can be accessed free at:
Email alerting
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
To order reprints of this article go to:
British Journal of Sports Medicine
Original article
The role of the bronchial provocation challenge testsin the diagnosis of exercise-inducedbronchoconstriction in elite swimmers A Castricum,1 K Holzer,1 P Brukner,2 L Irving2 a recognised incidence of EIB/asthma misdiagno- Background The International Olympic Committee– sis.6–8 Infrequently, the diagnosis was confirmed Medical Commission (IOC-MC) accepts a number of with a bronchial provocation challenge (BPC).
Royal Melbourne Hospital,Melbourne, Australia bronchial provocation tests for the diagnosis of exercise- Formalised testing for the confirmation of induced bronchoconstriction (EIB) in elite athletes, none of asthma and EIB was thus introduced by the IOC- which have been studied in elite swimmers. With the MC for the 2002 Winter Olympic Games in Salt suggestion of a different pathogenesis involved in the Lake City, and for subsequent Summer and Winter Olympic Games. Although both airway reversibil- development of EIB in swimmers, there is a possibility that the recommended test for EIB in elite athletes, the ity on spirometry and the presence of airway eucapnic voluntary hyperpnoea (EVH) challenge, may be hyperreactivity to a number of BPCs have been missing the diagnosis in elite swimmers.
accepted by the IOC-MC, the eucapnic voluntary Dr Adam Castricum, SportsPhysician, Olympic Park Sports Objective The aim of this study was to assess the hyperpnoea (EVH) challenge has been recognised effectiveness of the EVH challenge, the field swim as the gold standard challenge for the diagnosis of challenge and the laboratory cycle challenge in the EIB in elite athletes.9 This recommendation was 3004, Australia; based on studies including winter athletes. The Design 33 elite swimmers were evaluated on separate EVH challenge has since been shown to be highly days for the presence of EIB using 3 different bronchial sensitive and specific for the diagnosis of EIB in provocation challenge tests: an 8 minute field swim challenge, a 6 minute laboratory EVH challenge, and an It has been suggested that the high prevalence of 8 minute laboratory cycle challenge.
EIB in the various endurance athlete subgroups Main outcome measurements Change in forced may be due to different triggers of airway hyperreactivity. In winter athletes, this may be a result of airway inflammation secondary to airway exposure of large volumes of cold air.11 In summer Results Only 1 of the 33 subjects (3%) had a positive athletes, the trigger is thought to be exposure to large allergen loads.12 The prevalence of EIB in baseline. 18 of the 33 subjects (55%) had a positive EVH swimmers is remarkably high; up to 47% in some elite swimming teams.5 This was initially thought from baseline. 4 of the subjects (12%) had a positive to occur as a consequence of people with asthma laboratory cycle challenge, with a mean fall in FEV being encouraged to swim.13 However, it is now 14.8 (4.7)% from baseline. Only 1 of the 33 subjects was accepted that the high prevalence of EIB in swimmers is due to injury of the airways as a Conclusions These results suggest that the EVH consequence of repetitive and prolonged exposure challenge is a highly sensitive challenge for identifying EIB to the gases of chlorine and their metabolites, in elite swimmers, in contrast to the laboratory and field- which accumulate at the water/gas interface on based exercise challenge tests, which significantly underdiagnose the condition. The EVH challenge, a well- All but one of the diagnostic challenge tests established and standardised test for EIB in elite winter recommended by the IOC-MC fail to account for and summer land-based athletes, should thus be used for the exposure of the swimmer’s airways to chlorineand its metabolites, and through this omission may the diagnosis of EIB in elite swimmers, as recommended result in a significant number of missed diagnoses of EIB in swimmers. The accepted field swimchallenge may account for these missed diagnoses.
Furthermore, none of the currently recommended Currently the International Olympic Committee- challenges have been studied in elite swimmers.
Medical Commission (IOC-MC) requires that all The aim of this study is thus to assess the athletes provide objective evidence of exercise- effectiveness of the EVH challenge, the field swim induced bronchoconstriction (EIB) or asthma to challenge and the laboratory cycle challenge in the obtain approval for the use of inhaled beta 2 Recent Olympic data suggests an increasing prevalence of EIB/asthma amongst elite endurance athletes,1–5 especially swimmers.1 Such data were Thirty-three volunteer elite swimmers, defined as obtained using various methodologies. These were State Level or above, were recruited from commonly based on clinical diagnoses, which have swim clubs throughout Melbourne, Australia, to Br J Sports Med 2010;44:736–740. doi:10.1136/bjsm.2008.051169
Original article
participate in this prospective study. All subjects were aged average heart rate was recorded at the end of the challenge.
14 years and older and were required to have a baseline forced Ambient conditions in the lab were 21 (0.8)uC and 60.5 (2.1)% expiratory volume in 1 second (FEV1) greater than 60% predicted for their age, height and gender to exclude anysubject with an active exacerbation of asthma. Subjects with a past history of asthma were not excluded from the study.
Prechallenge values for percent predicted FEV1 were compared Subjects were excluded if they had had a recent respiratory with postchallenge values using a paired Student t test. The infection or exacerbation of their asthma. The research protocol maximum percent fall in FEV1 from baseline for each challenge was approved by both the University of Melbourne and the test was calculated by subtracting the lowest FEV1 value Royal Melbourne Hospital Ethics Committees.
recorded post challenge from the best baseline value and Once accepted into the study and having given informed expressing it as a percentage of the baseline value. A fall in consent, each subject completed a standardised Respiratory FEV1 >10% from baseline was considered positive for EIB.20 A Questionnaire adapted from the European Community bronchodilator response of >12% rise in FEV1 from baseline was considered positive for asthma.21 Within-subject comparisons Each subject was evaluated for the presence of EIB using three between the EVH and swim challenge tests, between the bike different BPCs: a field swim challenge, an EVH challenge and a and swim challenge tests, and between the EVH and bike laboratory cycle challenge. Testing order was random, and challenge tests were made using paired t tests. Differences consecutive tests were separated by more than 24 h but less between EIB-positive and EIB-negative subjects were examined than 1 week. All testing occurred in the morning to control for using independent t tests. A p value ,0.05 was considered diurnal variation in airway calibre. The subjects were asked to statistically significant for all analyses. All values are presented refrain from caffeine and exercise on the days of the testing and withhold their asthma medications for designated times as perHolzer et al.10 Baseline spirometry was performed prior to each challenge All 33 subjects (23 male: age 19.3(5.3) years; 10 female: age 15.6 and the best of three values for FEV1 and forced vital capacity (2.1) years) completed each of the challenges without complica- (FVC) were recorded and used for subsequent calculations.
tion. Baseline spirometry and fall in FEV Spirometry prior to and during the EVH and laboratory cycle response to each of the challenges for the 33 subjects are challenge was performed on the System 2310 Spirometer, Vmax presented in table 1. Baseline spirometry exceeded the normal series (Sensormedics BV) and for the field swim challenge on a predictive values for age, gender and height and correlated well portable MicroMedical Superspiro Spirometer (Rochester, Kent, with existing resting values for elite athletes. There was no significant difference in baseline values between those who Spirometry was performed at 1, 3, 5, 7 and 10 minutes were EIB-positive or negative, for any challenge.
following the cessation of each of the exercise/hyperpnoeastimuli. At each of these measurement times the better of two values for FEV1 was recorded to be used in subsequentcalculations. Following the 10 minute measurement, or earlier Thirteen of the 33 subjects (39%) had a previous clinical diagnosis of asthma. Of these, three (23%) were regularly using 1 fell greater than 30%, 200 mg of salbutamol was inhaled from a volumatic spacer; further spirometry was an inhaled corticosteroid, three (23%) were regularly using an performed 10 minutes following this.
inhaled corticosteroid/long-acting beta agonist combination, The field swim challenge was conducted at the Melbourne one (8%) was using an inhaled mast cell stabiliser prior to Sports and Aquatic Centre, in a chlorine and ozone-filtered exercise, four (44%) were only using an as-required inhaled beta indoor 50 m competition pool used for national championships.
2 agonist, and two subjects (23%) were not using any asthma The challenge required the subject to swim for 8 minutes at the medication. One of the 13 (8%) subjects with a previous highest intensity sustainable, aiming to maintain a heart rate of diagnosis of asthma had a positive field swim challenge, 11 (85%) had a positive EVH challenge and three (23%) had a max (HRmax = 220 2 age), for the duration of the test. Subjects were fitted with a wireless Polar Heart Rate positive laboratory cycle challenge. Only two (15%) of thosepreviously diagnosed with asthma showed a positive broncho- Monitor (Polar Electro; Oy, Finland) and the average heart ratewas taken at the completion of the challenge. Ambient dilator response for asthma. Two subjects (15%) with aprevious asthma diagnosis were negative for EIB on all three conditions for the indoor pool were 30 (SD 2.7) uC and 82 BPCs and had negative bronchodilator responses. Both of these (4.5)% relative humidity, with a pool temperature of 27 (0.3)uC.
subjects were using only an as-required inhaled beta 2 agonist.
The laboratory EVH challenge was conducted according to the single-stepped protocol of Argyros and coworkers.18 Thischallenge required the subject to inhale a dry gas containing 5% carbon dioxide, 21% oxygen and balance nitrogen (BOG Gases, Of the 20 subjects with no previous diagnosis of asthma, seven Melbourne, Australia) at room temperature for 6 minutes at a (35%) had a positive EVH challenge with one (5%) of these also target ventilation of 85% maximum voluntary ventilation having a positive laboratory cycle challenge test diagnostic of (MVV), equivalent to 30 times the resting FEV EIB. None of these subjects had a positive field swim challenge.
conditions in the laboratory were 21 (0.8)uC and 60.5 (2.1)% Further, one of these subjects had a positive bronchodilator response for asthma, and negative EVH, swim and cycle tests The laboratory cycle challenge used the stepped protocol recommended by the American Thoracic Society.19 The 8 min-ute challenge was performed on the Ergometrics 800 (Ergoline, Germany) cycle ergometer. A Polar Heart Rate Monitor Watch Only one of the 33 subjects (3%) had a positive field swim test (Polar Electro; Oy, Finland) was worn by the subject and the with a fall in FEV1 of 16% from baseline compared with 3.0 Br J Sports Med 2010;44:736–740. doi:10.1136/bjsm.2008.051169
Original article
Table 1 Subject baseline spirometry and fall in FEV1 in response to the EVH, swim and cycle challengesSubject EVH fall in FEV1 (%) Swim fall in FEV1 (%) Cycle fall in FEV1 (%) EIB-positive swimmers identified in bold. pred, predicted.
*Subjects 1, 7 and 18 had a positive bronchodilator response for asthma (2.4)% in the 32 (97%) who were negative. The swim-positive challenge. This subject also had a positive bronchodilator subject swam at 93% of his predicted HRmax and had a response for asthma. This subject reported a mean symptom postchallenge symptom score of 4/4, whilst the swim-negative score of 4/4 following each challenge.
subjects swam at 87 (4)% their predicted HRmax (p.0.05), with Of the 32 subjects negative to the swim challenge, 17 had a positive EVH and three a positive cycle challenge, with mean Eighteen of the 33 subjects (55%) had a positive EVH falls in FEV1 from baseline of 19.1 (10.6)% and 14.8 (5.8)% challenge test, with a mean fall in FEV1 of 20.4 (11.7)% from baseline compared with a mean fall of 5.8 (2.3)% in the 15 Two subjects were negative to the swim and positive to both subjects (45%) who were negative. The EVH-positive subjects the EVH and cycle challenges, with a mean fall in FEV1 from demonstrated a mean predicted MVV of 78 (11)% during the baseline of 36 (2.8)% for the EVH and 17 (6.2)% for the cycle challenge, compared with a mean predicted MVV of 75 (9)% in challenge. One subject positive on the laboratory cycle challenge the EVH-negative subjects (p,0.05). The EVH-positive subjects had a mean number of 3.5/4 symptoms compared with 2/4symptoms in those subjects who were EVH-negative (p,0.01).
Four of the subjects (12%) had a positive laboratory cycle test, The results of this study have shown a significant and with a mean fall in FEV1 of 14.8 (4.7)% from baseline, compared substantial discrepancy between the diagnostic results of three with 2.4 (3.5)% in the 29 (88%) who were negative. The cycle- BPCs commonly used for the diagnosis of asthma/EIB in elite positive subjects exercised at 91 (3)% their predicted HRmax and swimmers. The field swim challenge found that only one of the had a mean symptom score of 3.5/4, whilst the cycle-negative 33 swimmers (3%) tested had a result consistent with the subjects exercised at 91 (5)% their predicted HRmax (p.0.05) presence of EIB. In contrast, the EVH challenge identified EIB in and had a mean symptom score of 1.5/4.
18 of the 33 subjects (55%) tested. These results suggest thateither the EVH challenge is overdiagnosing the presence of EIB in swimmers or the field swim challenge is significantly Only one of the 33 subjects was positive to all three challenges, with a fall in FEV1 from baseline values of 16% for the field In this study to investigate the diagnostic efficacy of different swim, 43% for the EVH and 15% for the laboratory cycle BPCs for EIB in elite swimmers, we used challenges all Br J Sports Med 2010;44:736–740. doi:10.1136/bjsm.2008.051169
Original article
considered acceptable by the IOC-MC for objective evidence ofEIB. In regards to the EVH challenge, Phillips et al22 demon- strated that the airway response in asthmatics, as measured bychanges in FEV EIB and asthma are common conditions in elite swimmers. The 1 and specific conductance, to hyperpnoea with cause is thought to be the repeated exposure to ozone, chlorine 2 was similar to that provoked in the same asthmatic subjects by exercise at the same ventilation. EVH has been and their metabolites which accumulate at the pool/air interface.
reported to have a high specificity for active asthma, diagnosing These conditions are commonly diagnosed and confirmed with a number of objective bronchial provocation tests.
abnormal and 100% when a 15% fall is considered abnormal.23The symptoms provoked by EVH are very similar to those thatoccur following exercise. The major advantage in using EVH over exercise is that subjects’ ventilation levels are monitoredand are able to be sustained at high enough levels to induce This study shows a wide discrepancy between a number of bronchial provocation tests accepted by the IOC-MC as objective Few studies have been performed comparing the efficacy of evidence of EIB in elite swimmers. It further shows that exposure the EVH challenge with exercise challenges. Until recently, to chlorine or its metabolite gases is not required to induce EIB at these had only been performed in winter athletes and the time of the challenge. It shows that the EVH challenge test is concluded, similarly to our results, that the EVH challenge highly sensitive at identifying EIB in elite swimmers.
was superior to both the field25 26 and laboratory27 exercisechallenges in the diagnosis of EIB. A recently published,concurrent study by Pedersen et al has suggested that the unaccustomed exercise rather than ventilatory restriction.
EVH challenge is a BPC superior to the field swim, laboratory During the EVH challenge, there was no such limitation.
exercise and the methacholine challenge in the diagnosis of EIB Second, and perhaps more importantly, the air inhaled during in 16 female non-asthmatic elite swimmers.28 Whilst it showed the laboratory cycle challenge was the ambient room air, which that the EVH challenge was the superior challenge for EIB had an average relative humidity of 60%, greater than the diagnosis, it did not show a significant difference over the recommended 50% stated in the exercise guidelines.19 To exercise challenges, perhaps a reflection of its smaller sample overcome this, the subjects should have inspired dry air during size and different exercise challenge protocols.
Although field exercise challenges are known to be highly Perhaps the major limitation of this study relates to the specific for EIB, the sensitivity of these in the detection of EIB is humidity of the air inhaled during each of the challenges. The only moderate.24 29 30 Unlike the EVH challenge, a number of hypercapnic dry gas mixture used for the EVH challenge test has variables may unknowingly influence the results of the exercise a low enough water content to promote EIB, whereas the air challenges. Although the subjects’ average HRmax exceeded 85% inhaled during the field swim challenge was of such high water for both the exercise challenges, we were unable to monitor content that it was protective against EIB.32 The relative falls in their ventilation rates. Rundell et al suggested that the exercise FEV1 following each of these challenges, as well as the challenge should be performed at race pace, or greater than 95% postchallenge EIB symptom scores, reflects this.
HRmax, to achieve and maintain ventilations high enough to In conclusion, the results of this study display the wide induce bronchoconstriction.31 The Pedersen study, whilst not discrepancy that occurs between the different BPCs in the directly monitoring ventilation or heart rates, attempted to diagnosis of EIB in swimmers. Importantly, it demonstrates address this by asking subjects to exercise at the highest that exposure to chlorine or its metabolite gases is not required intensity possible until exhaustion, reflecting a higher preva- to induce the airway hyperresponsiveness at the time of the lence of positive field swim and laboratory treadmill challenges challenge. Our study shows that the EVH challenge is highly sensitive at identifying EIB in elite swimmers, whilst the For the field swim challenge, difficulties in standardising the exercise challenge tests may significantly underdiagnose the environmental conditions at the pool surface may have affected condition. As the EVH challenge test is a well-established and the respiratory response to the swim challenge and thus the standardised test for EIB in elite winter and summer land-based results. Although the poolside ambient air conditions and pool athletes, it supports the recommendations of the IOC-MC that temperature were measured on each occasion, factors such as the EVH challenge test should be used for the diagnosis of EIB in the concentration of ozone, chlorine and its metabolite gases on all elite athletes, including swimmers. However, where the EVH the pool surface, pool chlorine and ozone concentrations and challenge test is not available, a laboratory exercise challenge poolside ventilation were not measured.
where the subject exercises until exhaustion whilst breathing In both the laboratory-based challenges, despite standardisa- dry air should be considered for identifying EIB in elite tion of the environmental conditions, the athletes were not exposed to the potential environmental triggers that are in thepool environment. This may have potentially reduced the sensitivity of these challenges for EIB in swimmers. However,the results of this study, in particular the high prevalence of positive EVH challenges, suggest that the airway hyperrespon- Corrigan B, Kazlauskas R. Medication use in athletes selected for doping control at siveness that develops in response to repetitive exposure to the Sydney Olympics (2000). Clin J Sport Med 2003;13:33–40.
chlorine is non-specific and, once developed, does not rely on Voy RO. The U.S. Olympic Committee experience with exercise-induced bronchospasm, 1984. Med Sci Sports Exerc 1986;18:328–30.
Furthermore, the sensitivity of the laboratory cycle challenge Weiler JM, Ryan EJ 3rd. Asthma in United States olympic athletes who participatedin the 1998 olympic winter games. J Allergy Clin Immunol 2000;106:267–71.
may have been artificially reduced for two reasons. First, a Wilber RL, Rundell KW, Szmedra L, et al. Incidence of exercise-induced bronchospasm number of subjects were limited by leg fatigue from the in Olympic winter sport athletes. Med Sci Sports Exerc 2000;32:732–7.
Br J Sports Med 2010;44:736–740. doi:10.1136/bjsm.2008.051169
Original article
Dickinson JW, Whyte GP, McConnell AK, et al. Impact of changes in the IOC-MC Report Working Party Standardization of Lung Function Tests, European Community asthma criteria: a British perspective. Thorax 2005;60:629–32.
for Steel and Coal. Official Statement of the European Respiratory Society. Eur Rice SG, Bierman CW, Shapiro GG, et al. Identification of exercise-induced asthma among intercollegiate athletes. Ann Allergy 1985;55:790–3.
Tikkanen HO, Peltronen JE. Asthma and Cross Country Skiing. Med Sci Sports Exerc Phillips YY, Jaeger JJ, Laube BL, Rosenthal RR. Eucapnic voluntary hyperventilation of compressed gas mixture. A simple system for bronchial challenge by respiratory Langdeau JB, Boulet LP. Is asthma over- or under-diagnosed in athletes? Respir heat loss. Am Rev Respir Dis 1985;131:31–5.
Eliasson AH, Phillips YY, Rajagopal KR, Howard RS. Sensitivity and specificity of Anderson SD, et al. Provocation by eucapnic voluntary hyperpnoea to identify bronchial provocation testing. An evaluation of four techniques in exercise-induced exercise induced bronchoconstriction. Br J Sports Med 2001;35:344–7.
bronchospasm. Chest 1992;102:347–55.
Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: Challenges for Holzer K, Brukner P. Screening of athletes for exercise-induced bronchoconstriction.
diagnosis. J Allergy Clin Immunol 2002;110:374–80.
Rundell KW, Jenkinson DM. Exercise-induced bronchospasm in the elite athlete.
Rundell KW, et al. Field exercise vs laboratory eucapnic voluntary hyperventilation to identify airway hyperresponsiveness in elite cold weather athletes. Chest Helenius I, Haahtela T. Allergy and asthma in elite summer sport athletes. J Allergy Mannix ET, Manfredi F, Farber MO. A comparison of two challenge tests for identifying Bar-Or O, Inbar O. Swimming and asthma. Benefits and deleterious effects. Sports exercise-induced bronchospasm in figure skaters. Chest 1999;115:649–53.
Dickinson JW, Whyte GP, McConnell AK, Harries MG. Screening elite winter Drobnic F, et al. Assessment of chlorine exposure in swimmers during training. MedSci Sports Exerc 1996;28:271–4.
athletes for exercise induced asthma: a comparison of three challenge methods.
Helenius IJ, et al. Respiratory symptoms, bronchial responsiveness, and cellular Br J Sports Med 2006;40:179–82; discussion 179–82.
characteristics of induced sputum in elite swimmers. Allergy 1998;53:346–52.
Pedersen L, Winther S, Backer V, et al. Airway responses to eucapnic hyperpnea, Zwick H, et al. Increased sensitization to aeroallergens in competitive swimmers.
exercise and methacholine in elite swimmers. Med Sci Sports Exerc 2008;40:1567–72.
Haby MM, Anderson SD, Peat JK, et al. An exercise challenge protocol for Burney P, Luczynska C, Chinn S, Jarvis D. The European Community Respiratory epidemiological studies of asthma in children: comparison with histamine challenge.
Health Survey. Eur Respir J 1994;7:954–60.
Argyros GJ, Roach JM, Hurwitz KM, et al. Eucapnic voluntary hyperventilation as a Rundell KW, Wilber RL, Szmedra L, et al. Exercise-induced asthma screening of elite bronchoprovocation technique: development of a standarized dosing schedule in athletes: field versus laboratory exercise challenge. Med Sci Sports Exerc asthmatics. Chest 1996;109:1520–4.
Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise Rodwell LT, Anderson SD, du Toit J, Seale JP. Different effects of inhaled amiloride challenge testing-1999. This official statement of the American Thoracic Society was and frusemide on airway responsiveness to dry air challenge in asthmatic subjects.
adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med Bundgaard A, Ingemann-Hansen T, Schmidt A, Halkjaer-Kristensen J. Influence of Sterk PJ, Fabbri LM, Quanjer PH, et al. Airway responsiveness. Standardized temperature and relative humidity of inhaled gas on exercise-induced asthma.
challenge testing with pharmacological, physical and sensitizing stimuli in adults.
Br J Sports Med 2010;44:736–740. doi:10.1136/bjsm.2008.051169


Sbfsem 7-26-2010me

NCMIR METHODS FOR 3D EM: A NEW PROTOCOL FOR PREPARATION OF BIOLOGICAL SPECIMENS FOR SERIAL BLOCK FACE SCANNING ELECTRON MICROSCOPY Thomas J. Deerinck, Eric A. Bushong, Andrea Thor and Mark H. Ellisman Center for Research in Biological Systems and the National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA Note: This protocol was desig


Sicherheitsdatenblatt gemäß 1907/2006/EG, Artikel 31 ABSCHNITT 1: Bezeichnung des Stoffs bzw. des Gemischs und des Unternehmens · Erstellungsdatum/Erstausgabe: 01.02.2012 · 1.1 Produktidentifikator · Handelsname: IBK 2012 · 1.2 Relevante identifizierte Verwendungen des Stoffs oder Gemischs und Verwendungen, von denen abgeraten wird keine Daten verfügb

Copyright © 2010-2014 Medical Pdf Finder