Editor: Michael Wechsler
Misdiagnosis of exercise-induced bronchoconstriction in professional soccer players
Article first published online: 17 DEC 2011
© 2011 John Wiley & Sons A/S
Volume 67, Issue 3, pages 390–395, March 2012
How to Cite
Ansley, L., Kippelen, P., Dickinson, J. and Hull, J. H. K. (2012), Misdiagnosis of exercise-induced bronchoconstriction in professional soccer players. Allergy, 67: 390–395. doi: 10.1111/j.1398-9995.2011.02762.x
- Issue published online: 11 FEB 2012
- Article first published online: 17 DEC 2011
- Manuscript Accepted: 11 NOV 2011
- bronchial provocation;
- eucapnic voluntary hyperpnoea;
Physicians typically rely heavily on self-reported symptoms to make a diagnosis of exercise-induced bronchoconstriction (EIB). However, in elite sport, respiratory symptoms have poor diagnostic value. In 2009, following a change in international sports regulations, all elite athletes suspected of asthma and/or EIB were required to undergo pulmonary function testing (PFT) to permit the use of inhaled β2-agonists. The aim of this study was to examine the diagnostic accuracy of physician diagnosis of asthma/EIB in English professional soccer players.
Sixty-five players with a physician diagnosis of asthma/EIB were referred for pulmonary function assessment. Medication usage and respiratory symptoms were recorded by questionnaire. A bronchial provocation test with dry air was conducted in 42 players and a mannitol challenge in 18 players. Five players with abnormal resting spirometry performed a bronchodilator test.
Of the 65 players assessed, 57 (88%) indicated regular use of asthma medication. Respiratory symptoms during exercise were reported by 57 (88%) players. Only 33 (51%) of the players tested had a positive bronchodilator or bronchial provocation test. Neither symptoms nor the use of inhaled corticosteroids were predictive of pulmonary function tests’ outcome.
A high proportion of English professional soccer players medicated for asthma/EIB (a third with reliever therapy only) do not present reversible airway obstruction or airway hyperresponsiveness to indirect stimuli. This underlines the importance of objective PFT to support a symptoms-based diagnosis of asthma/EIB in athletes.
Exercise-induced bronchoconstriction (EIB) describes the transient airway narrowing that occurs in association with vigorous exercise and which is reversible spontaneously or through inhalation of β2-agonists. The term EIB is preferred over exercise-induced asthma because exercise triggers bronchoconstriction and does not induce asthma . Elite athletes have a greater risk of developing EIB. In the UK, EIB is reported to affect 8% of the general population , whereas the prevalence in the Great British Olympic Team is ~20% . Prolonged hyperpnoea and increased exposure to aero-allergens and irritants during training and competitions are thought to be the main risk factors for EIB in athletes .
Local water loss is known to occur at high ventilatory rates, which may then cause airway inflammation and epithelial injury . In the presence of aero-allergens, injury repair of the epithelium could lead to ‘passive sensitization’ of the airway smooth muscle and to airway hyperresponsiveness (AHR) . This has implications for field-based sports like soccer. Soccer is an intermittent sprint sport performed at high physiological intensity [85–95% of maximal heart rate ] in a grass environment and often in the cold; all of these factors are recognized to promote EIB. However, to date, there have been few studies addressing EIB in elite soccer players , and there are no data addressing how a diagnosis of EIB should be made in this group of athletes. This is remarkable given that soccer is the most popular sport in the world  and has almost 1.5 million registered players at recreational or professional level in the UK .
Diagnosing and correctly treating EIB in elite athletes is important given its potential detrimental impact on health and performance. Reports in athletic populations highlight that asthma/EIB is associated with increased morbidity and mortality . Inappropriate treatment can also lead to unwanted side-effects (e.g. tremor and tachycardia), increased EIB and suboptimal bronchodilator response to inhaled β2-agonists and, in extreme cases, death . From a performance viewpoint, EIB can reduce exercise capacity and peak running speed . To identify early athletes who require medical attention, many advocate the use of a systematic screening for asthma/EIB in elite sport .
Accurate diagnosis of EIB in athletes has proven to be difficult in the past, mainly because baseline spirometry is poorly predictive of EIB in athletes  and physicians typically rely heavily on self-reported respiratory symptoms. In athletes, the relationship between symptoms and objective evidence of EIB is poor . Recognition of this prompted the International Olympic Committee Medical Commission (IOC-MC) in 2001 to require that athletes present objective evidence of asthma/EIB (e.g. bronchodilator or bronchial provocation test results) prior to being permitted to use inhaled β2-agonists . The World Anti-Doping Agency (WADA) followed the IOC lead in 2009 ; however, the following year, WADA partially rescinded its decision, and in 2010, salbutamol and salmeterol were removed from the banned substance list, along with formoterol in 2012, although all other β2-agonist asthma medications currently still require objective evidence of EIB for use.
In this study, we used the changes in WADA asthma medication regulations between 2009 and 2010 to determine the accuracy of physician diagnosis of asthma/EIB in English professional soccer players. This is important given the latter is the standard approach to diagnosis employed by physicians . Eucapnic voluntary hyperpnoea (EVH) with dry air [i.e. the most sensitive bronchial provocation test to identify EIB in elite athletes ] or mannitol challenge [i.e. a suitable alternative to EVH to identify EIB in summer athletes ] was conducted in a group of English professional soccer players. We hypothesized that a large proportion of soccer players with a physician diagnosis of asthma/EIB would not present objective evidence of reversible airway obstruction or of AHR to indirect stimuli.
Sixty-five elite male soccer players under full-time professional contract to Premiership, Championship or First Division league soccer teams in England were included in the study. All players had either a previous physician-based diagnosis of asthma and/or EIB or were newly diagnosed with EIB. They were all referred for a bronchial provocation challenge to obtain a therapeutic use exemption (TUE) from UK Anti-Doping (UKAD) for the use of permitted inhaled β2-agonists. Testing was carried out at three different testing centres in England between February 2009 and April 2010. All subjects gave informed written consent. The study obtained approval from the local universities’ research ethics committees.
Players were asked to refrain from using short-acting β2-agonists (SABA), long-acting β2-agonists (LABA) and inhaled corticosteroid (ICS) within 24, 48 and 72 h of testing, respectively . They were also instructed to avoid caffeine, smoking and exercise on the day of testing. No assessment was made within 6 weeks of a respiratory tract infection.
On arrival at the laboratory, players completed a self-administered questionnaire evaluating the presence of respiratory symptoms (i.e. cough, wheeze, dyspnoea, tight chest and excess mucus), medical history of asthma/EIB and use of asthmatic medication. A EVH test, mannitol test or bronchodilator challenge was then performed. The choice of the test was based on baseline lung function, medical history and on-site availability of procedures (the three centres had the facility to run EVH tests, but only one centre proposed mannitol challenges).
Pulmonary function testing (PFT)
Baseline lung function was assessed by maximal forced flow-volume spirometry (MicroLoop ML3535; Cardinal Health, Basingstoke, UK) according to international guidelines . Predicted normal values were determined from established reference values . Players who had normal baseline lung function (FEV1 ≥80% predicted and FEV1/FVC ≥ 0.7) proceeded to perform a bronchial provocation challenge (either EVH or mannitol). Players with abnormal baseline spirometry data performed a bronchodilator challenge.
Bronchial provocation challenges
EVH challenge: The protocol for EVH challenge was based on the one initially described by Argyros et al.  and performed according to the specific recommendations for EVH testing in elite athletes . Briefly, athletes were required to breathe a dry gas mixture (21% O2: 5% CO2: 74% N2) for 6 min at a target ventilation rate equivalent to approximately 85% maximal voluntary ventilation (MVV). Target minute ventilation was calculated as 30*FEV1. Post-EVH spirometry was conducted in duplicate at 3-, 5-, 7-, 10-, 15- and 20-min recovery, with the best FEV1 recorded at each time point. The test was considered positive if a fall in FEV1 of ≥10% was observed over two consecutive time points compared with baseline.
Mannitol challenge: A dry powder preparation of mannitol was delivered in gelatine capsules containing 0, 5, 10, 20 or 40 mg (Osmohale, Pharmaxis Pharmaceuticals Ltd, UK). Consecutive doses of 0, 5, 10, 20, 40, 80, 160, 160 and 160 mg (to a maximum cumulative dose of 635 mg) were administered via an inhalator and a controlled deep inhalation to total lung capacity with 5 s of breath holding . FEV1 readings were taken in duplicate 60 s after each dose, and the best value was kept for the analysis. A positive test was defined by a ≥ 15% fall in FEV1 at ≤ 635 mg. The response was expressed as the cumulative dose that provoked a 15% fall in FEV1 (PD15) and as response–dose ratio (RDR; final percentage fall FEV1/total dose of mannitol administered).
Following baseline spirometry, players inhaled four 100-μg doses of a permitted short-acting β2-agonist through a valved spacer device, with a 30-s interval between each inhalation . Postbronchodilator spirometry was performed in duplicate after 15 min. A test was considered positive if FEV1 increased by ≥ 12% over baseline .
Athletes were grouped a posteriori according to their response to bronchodilator/bronchial provocation test; athletes with a positive test result were grouped as PFT+ and those with a negative test result as PFT−. Data are presented as mean ± SD (unless otherwise stated) or 95% confidence intervals (CI). Group differences for normally distributed data were analysed using independent t-tests. Nonparametric data were analysed using Mann–Whitney U test. Fischer's exact tests or chi-square analysis was used to examine the association between variables and quantify the odds ratio. Significance was accepted at P ≤ 0.05. All analyses were conducted on GraphPad Prism 5.0d (La Jolla, CA, USA).
An EVH challenge was performed on 42 (65%) players, a mannitol challenge on 18 (28%) players and a bronchodilator test on five (7%) players. Two players underwent both EVH and mannitol testing. The two tests were negative in both players; therefore, only the result from the first test (EVH) was included in the analysis. A positive test result was noticed in 33 players (51%): 20/42 EVH, 10/18 mannitol and 3/5 bronchodilator tests.
The fall in FEV1 following the EVH challenge for the PFT+ and PFT− groups was 21.5 ± 11% and 6.1 ± 2.8%, respectively (P < 0.0001). The PFT+ group achieved a higher ventilation rate (74.7 ± 6.3% MVV) compared to the PFT− group (68.3 ± 10.1% MVV) (P < 0.03). However, achieving a ventilation rate above either 74% MVV [OR = 0.38 (0.11–1.34); P = 0.2] or 68% MVV [OR = 0.25 (0.06–0.99); P = 0.06] was not predictive of the test outcome. Furthermore, there was no association between %MVV achieved during EVH and magnitude of change in FEV1 (r = 0.23; P = 0.14) (Fig. 1).
For the mannitol challenge, in positive players, PD15 was 273 ± 210 mg, and the maximum fall in FEV1 during the challenge was 19.5 ± 4.1%. The RDR for the positive players was 0.29 ± 0.40%/mg vs 0.007 ± 0.004/mg in negative players (P = 0.07).
For the bronchodilator test, the increase in FEV1 for the three soccer players who had a positive response was 22.6% (range: 12.6–40.0%), whereas in the two players who tested negative, the change in FEV1 was 4.0 and 9.4%.
The anthropometric characteristics did not significantly differ between our two study groups (Table 1), but there was a trend for players’ PFT+ to be older than the players’ PFT− (P = 0.09). Baseline spirometry data were comparable between groups, except for FEV1/FVC ratio, which was significantly lower in the PFT+ players (P = 0.02).
|PFT+ (N = 33)||PFT− (N = 32)||Sig.|
|Age (years)||24 ± 7||21 ± 5||0.09|
|Height (cm)||180 ± 5||180 ± 6||0.69|
|Weight (kg)||79.1 ± 7.6||76.7 ± 9.4||0.27|
|FEV1 (L)a||4.35 ± 0.79||4.50 ± 0.61||0.74|
|FEV1 (% predicted)a||95.4 ± 18.6||97.2 ± 13.0||0.93|
|FVC (L)a||5.54 ± 0.76||5.47 ± 0.75||0.45|
|FVC (% predicted)||102.3 ± 15.0||99.8 ± 12.3||0.23|
|FEV1/FVC||78.2 ± 8.5||82.6 ± 6.2||0.02|
|FEF25–75 (L/s)||4.00 ± 1.27||4.49 ± 0.96||0.08|
|FEF25–75 (% predicted)||77.3 ± 24.7||84.9 ± 18.3||0.16|
|PEF (L/min)||563 ± 105||565 ± 94||0.95|
|PEF (% predicted)||92.2 ± 17.9||91.2 ± 16.7||0.93|
Exercise-related respiratory symptoms were reported by 57 (88%) of the players. Wheeze was reported by 39 (60%) of the players, chest tightness by 32 (49%), cough by 30 (46%), dyspnoea by 29 (45%) and excess mucus by 16 (25%) (Table 2). The median number of symptoms reported was three (Table 3). Out of the eight players who did not complain of any symptoms, three had a positive bronchial provocation test. Report of respiratory symptoms during exercise was not predictive of a positive PFT outcome (Tables 2 and 3). Surprisingly, excess mucus production was significantly associated with a negative PFT outcome (P = 0.004).
|Odds ratio (95% CI)||Sig.|
|Any symptoms||1.85 (0.40–8.50)||0.48|
|Tight chest||1.20 (0.45–3.19)||0.81|
|Excess mucus||0.15 (0.04–0.66)||0.004|
|Number of reported symptoms|
|1 or more||2 or more||3 or more||4 or more||5|
|PFT+||30 (91)||21 (64)||11 (33)||6 (18)||3 (9)|
|PFT−||27 (84)||24 (75)||17 (53)||5 (16)||2 (6)|
|Total||57 (88)||45 (69)||28 (43)||11 (17)||5 (8)|
Of the 65 soccer players referred, 61 (94%) had a previous medical diagnosis of asthma/EIB, and four players had been newly diagnosed. 57 (88%) were prescribed asthma treatment at the time of the study. Out of these 57 players, 24 (42%) reported using inhaled SABA alone, 24 (42%) using combination of SABA and ICS, four (7%) a combination of inhaled LABA and ICS and eight (14%) LABA, ICS and SABA. One player reported using LABA without ICS. Only one player with an abnormal baseline lung function was prescribed ICS. Fifteen of the 32 (47%) players using ICS tested positive to the pulmonary function test; 16 (67%) of players on unopposed SABA were positive. The use of ICS did not predict the outcome to the bronchodilator/bronchial provocation tests [OR = 2.02 (0.69–5.89); P = 0.28] (Fig. 2).
The main finding from this study is that only half of the professional soccer players with a physician diagnosis of asthma/EIB had objective evidence of reversible airway obstruction or of AHR to indirect stimuli. Furthermore, we found no association between self-reported respiratory symptoms and a positive bronchodilator/bronchial provocation test outcome. Therefore, this study reinforces the need, alongside the usual clinical assessment, for objective lung function testing for EIB diagnosis in professional soccer players.
To date, there have been few studies addressing EIB diagnosis in elite soccer players . Nearly all the studies performed in this athletic group have involved cohorts of nonprofessional adolescent players [29-35]. In professional rugby union – a sport that shares many characteristics with soccer – the prevalence of asthma/EIB following objective screening was recently found to be 32% . Therefore, it is legitimate to assume that EIB is a common condition in professional soccer.
Typical distance covered by professional outfield soccer players during a match is 10–13 km, with more than half of the distance covered by jogging or sub-maximal cruising . This aerobic component of the sport may favour (i) evaporative water loss within the small airways, (ii) airway epithelial injury and (iii) inhalation of allergens, which are all potential promoters of a local inflammation . Dehydration-induced injury of the airway epithelium has recently been proposed as a contributing factor to late development of AHR in elite athletes . Atopy is known as a risk factor for EIB in athletes . Grass exposure could therefore potentiate EIB development in atopic soccer players by creating an in vivo model of ‘passive sensitization’ of the airway smooth muscle . During the winter season, inhalation of cold dry air at high flow rates could alter the integrity of the airway epithelium . Altogether, these factors could put soccer players particularly at risk of asthma/EIB.
The reason for a disconnection between the presence of respiratory symptoms and objective evidence of reversible airway narrowing/AHR in athletes is unclear. However, respiratory symptoms are often poorly perceived by athletes or ignored . It is currently recommended that the diagnosis of EIB in elite athletes be made following an initial clinical assessment but, crucially, that it is supported by objective evidence of reversible airway narrowing by performing a bronchial provocation challenge . Exercise tests have traditionally been used to ascertain airway obstruction following exercise. However, owing to limitations associated with this approach in the athletic population (e.g. difficulty to replicate intensity of exercise and environmental conditions) [40, 41], exercise lacks the sensitivity of other indirect challenges [41-43]. Therefore, the use of ‘surrogate’ airway challenges has lately been encouraged by international sports governing bodies . In this study, we selected EVH and mannitol as indirect surrogate methods to identify EIB because these two tests have been shown to display good agreement in both clinical  and summer athletic  populations. Direct challenges, such as methacholine or histamine, seem less suitable for the diagnosis of EIB in elite summer sport athletes. The sensitivity of methacholine for detecting hyperpnoea-induced bronchoconstriction was only 36% in elite Australian athletes .
We acknowledge that there are potential limitations in relying exclusively on the results to a one-off indirect bronchial provocation challenge to make a diagnosis of asthma/EIB. First, AHR is known as a transient phenomenon that fluctuates according to environmental conditions  and/or training status . Following a negative pulmonary function assessment in symptomatic athletes, a second line of investigation is often recommended . In this case, the possibility of a differential diagnosis (e.g. vocal cord dysfunction) should be considered . However, owing to pressures from within and outside the coaching team, additional testing are rarely performed on professional athletes.
A further important limitation of our study is that the relatively short ICS washout period (<3 days) may have led to some false-negative test results. Anderson et al.  previously reported an attenuated bronchoprovocation response in Olympic athletes using regular ICS in combination with reliever therapy. Therefore, although we found no significant difference in the proportion of players who tested positive between those prescribed regular ICS and those who were naive to this therapy (P = 0.28), we do acknowledge that the odds ratio for a negative test [2.02 (0.69–5.89)] may indicate a clinically significant impact of ICS on test outcome. Our approach to the duration of ICS washout was dictated by practical and ethical considerations with respect to withholding asthma medications and is in line with recommendations.
Our findings are alarming, especially so as the large majority (88%) of the players were using inhaled β2-agonists. Serious concerns have been raised over the chronic use of inhaled β2-agonists, with recognized important adverse side-effects (e.g. tremor and tachycardia) and ongoing controversy concerning the apparent association between usage of LABA and increased morbidity and mortality. Furthermore, frequent use of inhaled β2-agonist is known to result in tachyphylaxis, a loss of bronchoprotective effect and possibly an increase in bronchial responsiveness . It is therefore paramount that a sound diagnosis is made before implementation of a pharmacological treatment. In that regard, results from indirect bronchial provocation tests may be particularly useful because they can identify subjects who are likely to respond to inhaled steroids and differentiate between doses of steroids .
In conclusion, in our study, about half of the professional soccer players with a physician diagnosis of asthma/EIB did not present objective evidence of reversible airway obstruction or of AHR to indirect stimuli. Our findings underline the need for objective PFT to support a symptoms-based diagnosis before commencing treatment with pharmacological agents in players.
LA involved in the conception and design of the study; acquisition, analysis and interpretation of data; drafting and critical revision of the manuscript; and final approval of the version to be published. PK and JD involved in acquisition, analysis and interpretation of data; critical revision of the manuscript; and final approval. JH involved in the conception and design of the study; analysis and interpretation of data; drafting and critical revision of the manuscript; and final approval.
Conflict of interest
There is no conflict of interest for any author.
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