Respiratory symptoms are commonly reported by athletes of all abilities and impact on their health and performance (19). Indeed, in some series, up to 70% of athletes report troublesome dyspnea (21), and asthma is the most commonly diagnosed chronic medical condition in Olympians (13).
The differential diagnosis for dyspnea in an athlete is broad and includes exercise-induced bronchoconstriction (EIB), hyperventilation, exercise-induced laryngeal dysfunction, and cardiac conditions (29). In athletes, EIB is often considered the primary and most important differential diagnosis and yet is often diagnosed and treated after a symptom-based appraisal alone (20). This is despite studies consistently highlighting a poor correlation between the presence of asthma-like symptoms and the objective evidence of EIB, that is, athletes clinically diagnosed with EIB often have little evidence to support the diagnosis (2,9,21,27). The reason for the poor predictive value of symptoms in this setting is uncertain but may relate to a high prevalence of conditions that mimic asthma (30), for example, wheeze and dyspnea being generated by a temporary obstruction at the level of the larynx (25,28).
The term exercise-induced laryngeal obstruction (EILO) has been used to encompass several entities that can result in exercise-associated obstruction of the larynx, including exercise-induced laryngomalacia, laryngochalacia, and vocal cord dysfunction (8,23). In its mildest form, EILO is seen as a minor decrease in the cross-sectional area of the laryngeal inlet, whereas in its most severe form, the laryngeal inlet may be completely obstructed (16,23). Obstruction of the laryngeal inlet during exercise can arise at either the supraglottic (i.e., arytenoids and supporting structures) or glottic level (i.e., vocal cords) (7,22).
The gold standard for diagnosing EILO is continuous laryngoscopy during exercise (CLE) (16). This technique uses flexible nasendoscopy to provide a continuous image recording of the larynx throughout exercise, thereby enabling a dynamic recording of the movement of the laryngeal structures. The uninterrupted nature of this recording is important, given the fact that symptoms may rapidly abate on exercise cessation (i.e., as ventilation falls rapidly) and thus be undetected if only assessed before and after a challenge. It also permits characterization of the anatomical location of the obstruction, which is recognized to have treatment implications (22,24).
At the Bispebjerg University Hospital in Copenhagen, Denmark, athletes referred with unexplained respiratory symptoms undergo a comprehensive workup that includes CLE testing in addition to evaluation of airway function and inflammation. The aim of this study was therefore to report our experience with this approach and specifically the prevalence and characteristics of EILO in a cohort of athletes referred for a 2-yr period. We hypothesized that EILO would be highly prevalent and would explain the differential diagnosis of exercise-associated respiratory symptoms in a significant proportion of the athletes referred. We also hypothesized that the assessment performed would detect several athletes on inappropriate treatment.
MATERIALS AND METHODS
Design
All athletes referred to the asthma service at Bispebjerg University Hospital in Copenhagen, Denmark, for the investigation of exercise-induced respiratory symptoms between 2010 and 2011 were evaluated. Clinical files were assessed using a questionnaire-based data sheet. Files were reviewed for clinical symptoms at presentation, pulmonary function tests, bronchoprovocation testing outcome, and airway inflammatory status.
Subjects
After clinical assessment and baseline pulmonary function evaluation, 91 athletes were referred for CLE testing during the study period. An athlete was defined as an individual who undertook >10 h of exercise every week (12). Athletes with incomplete records were excluded from review. The present study was assessed by the Danish Ethics Committee (H-3-2012-FSP59) and was found not to require ethics approval, being a retrospective study of clinical routine investigations. Informed consent was obtained from all subjects.
Test Procedures
Clinical assessment
Respiratory symptoms (dyspnea and wheezing) at rest and during exercise were assessed by a senior respiratory physician during the initial clinical interview. Dyspnea and wheezing were classified according to phase in the respiratory cycle as inspiratory, expiratory, or both.
Anthropometric data
Age, sex, height, and weight were recorded, and body mass index (kg·m−2) was calculated.
Atopic status
A skin prick test was performed according to European standards with a panel of allergen extracts (11). When no skin prick test was performed, allergen-specific IgE was measured in serum using a radioallergosorbent test (14).
Pulmonary Function and Bronchodilator Reversibility Testing
Lung function and bronchodilator reversibility testing were measured using maximum expiratory flow volume in accordance with the standards specified by the European Respiratory Society and the American Thoracic Society (26).
Fractional exhaled nitric oxide was analyzed using equipment from Eco Medics (Duernten, Switzerland) or Aerocrine (Solna, Sweden) following the recommendations of the European Respiratory Society and the American Thoracic Society (3). A positive response was defined as >25 ppb (3).
Bronchoprovocation Testing
Athletes were diagnosed with asthma on the basis of the presence of symptoms and a positive bronchoprovocation test (BPT) or bronchodilator reversibility test.
Subjects withheld asthma medications in line with recommendations (4) before BPT. However, to ensure that a BPT was not falsely negative secondary to the influence of inhaled corticosteroid (ICS) treatment, those athletes taking ICS with a negative BPT had a repeated BPT after 8 wk of ICS treatment cessation. The ICS withdrawal was performed out of season for elite athletes.
If bronchodilator reversibility (BDR) testing was negative, one or more BPT were performed to confirm or rule out asthma. The BPT were done sequentially on different days in the following order: mannitol, methacholine, eucapnic voluntary hyperventilation until achieving a positive test, or until all three tests had been performed. If the referring physician had performed a recent BDR or BPT, this was not repeated. The BPT results in the present study are the tests performed after ICS withdrawal.
Methacholine challenge testing was performed on all athletes with forced expiratory volume in 1 s (FEV1) >70% predicted in accordance with the method of Yan et al. (31). Using a breath actuated dosimeter APS (Jaeger GmbH, Germany), the athlete inhaled incremental doses of nebulizer Methacholine (19.63 mg·mL−1) until reaching a drop in FEV1 of 20% or more compared with the pretest FEV1, which was considered a positive test (provocative dose of methacholine causing a fall in FEV1 of 20% or more ≤ 1.548 mg), or until reaching a maximum of 1.548 mg inhaled methacholine.
Mannitol bronchial provocation was performed as described by Brannan et al. (5). Airway hyperresponsiveness as a dichotomy variable with a cutoff value of 635 mg (PD15 ≤ 635 mg) was used. A reduction in FEV1 of 15% or more from baseline FEV1 was considered a positive test.
Eucapnic voluntary hyperventilation testing was performed as described by Anderson et al. (1). The athlete hyperventilated dry air (5% carbon dioxide) for 6 min until reaching a required ventilation volume of 30 times the prechallenge FEV1. A reduction in FEV1 of 10% or more in at least two consecutive postchallenge measurements was considered a positive test.
Continuous laryngoscopy during exercise
CLE testing was performed using the protocol previously described by Heimdal et al. (16), excluding ergospirometry. In brief, the larynx was visualized during exercise using a flexible video laryngoscope and Visera video recording equipment (Olympus, Tokyo, Japan). Topical xylometazoline hydrochloride and lidocaine gel and spray were used to prepare the nares and were not applied to the oropharynx. Before warm-up exercise, athletes were requested to inhale beta-2 agonist (1 mg of terbutaline or 0.4 mg of salbutamol) to minimize any bronchoconstriction that would potentially prevent the patient from exercising at maximum effort.
CLE scoring
The video recordings were graded by an asthma specialist, with experience in diagnosing EILO (V.B.), using the Norwegian standardized 0–3 scoring system (23) (Fig. 1). A diagnosis of EILO was based on the presence of symptoms and a Norwegian grade score of 2 or greater (i.e., at least moderate). To determine interobserver agreement, a second observer (E.W.N.) rated the recordings. The observers were blinded to other measures.
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FIGURE 1: Norwegian grading of EILO (
23).
Statistical analysis
Mean ± SD values are reported for normally distributed data, and median and interquartile ranges otherwise. Athletes with and without EILO were compared using an unpaired t-test or Mann–Whitney U test as appropriate. Fischer’s exact test was used to compare categorical, unpaired data. A P value of <0.05 was considered significant. Observer agreement was calculated using weighted kappa. All data analysis was performed using the Statistical Package for the Social Sciences (version 20.0; SPSS Inc., Chicago, IL).
RESULTS
Subject characteristics and pulmonary function results
Of the 91 athletes referred for assessment, 88 underwent a complete assessment including CLE (n = 3 excluded secondary due to incomplete data). Thirty-one athletes (35.2%) had EILO, whereas 57 (64.8%) were classified as having normal laryngeal function during exercise. EILO was more prevalent in women than that in men (OR = 4.09, 95% CI = 1.52–11.04, P < 0.01) (Table 1).
TABLE 1: Population and group characteristics.
Of the 88 athletes, 38 had evidence of asthma diagnosed by BPT in 94% and/or BDR in 10%. In athletes with EILO, 12 (13.6% of all athletes) also had a positive BPT and/or BDR (Fig. 2). There was no difference in the frequency of positive BDR/BPT between the EILO (38.7%) and the non-EILO groups (45.6%) (P = 0.65, Table 1). There was also no difference in age, body mass index, FEV1, fractional exhaled nitric oxide, atopic status, or reversibility to β2-agonists between athletes with and without EILO.
FIGURE 2: Asthma and EILO diagnosis. EILO, exercise-induced laryngeal obstruction.
Supraglottic EILO was the predominant type and was seen in 22 athletes (25% of all athletes), whereas glottic EILO was seen in 3 athletes (3.4%), and a combination of supraglottic and glottic EILO was seen in 6 athletes (6.8%). There were no differences in anatomic location in athletes with positive BPT compared with those with negative BPT.
Symptoms
When subjects were evaluated according to the presence or absence of EILO, the character of symptoms was similar between the groups (P = 0.67). Importantly, a clinical report of inspiratory wheeze or dyspnea did not discriminate athletes with or without EILO, 48.4% and 47.4%, respectively. These results were similar in athletes with (P = 0.69) and without (P = 0.61) evidence of a positive BPT (Table 2).
TABLE 2: Symptom prevalence in athletes with and without EILO.
Asthma treatment
At the time of referral, 53 athletes (60.2%) were taking regular asthma treatment, including the following: ICS, 43.2%; short-acting β2-agonists, 52.3%; and leukotriene receptor antagonists (LTRA), 14.8%. Of athletes treated for asthma, 33 (62.3%) did not have pulmonary function or bronchoprovocation evidence to support a diagnosis of asthma. Importantly, 62% of athletes with no evidence of asthma or EILO as well as 60% of those classified as nonasthmatic athletes with EILO were taking regular asthma medication (Fig. 3).
FIGURE 3: Medication at the time of referral grouped by final diagnosis. EILO, exercise-induced laryngeal obstruction.
DISCUSSION
In a cohort of athletes referred with unexplained exercise-induced respiratory symptoms, one-third had evidence of EILO. This abnormality was commensurate with symptoms and in all cases was graded as at least moderate in severity. A further third of athletes were found to have bronchial hyperreactivity, and in 12.5% of athletes, EILO was found to coexist with evidence of bronchial hyperreactivity. These findings underpin the fact that EILO is a key differential diagnosis in athletes presenting with unexplained exercise-induced respiratory symptoms and has implications for the way in which athletes are appraised and treated.
Making a correct assessment and diagnosis of respiratory symptoms in athletes can be difficult (30). Many athletes presenting with wheeze and dyspnea receive asthma treatment without objective tests to confirm the underlying diagnosis (20,29). Our finding that the clinical assessment of the timing of symptoms and wheeze (i.e., inspiratory vs expiratory) was not of discriminatory value may explain the numerous prior reports of the poor predictive value of symptoms in predicting EIB in athletes (2,9,21,27). Moreover, other characteristics (e.g., atopic status and resting lung function) apart from sex were similar between athletes with and without EILO.
The limitations of clinical assessment alone are further emphasized by the finding that half of those reporting predominantly inspiratory features did not have EILO when tested with CLE. The high prevalence of EILO (35.2%), including those with both EILO and asthma (12.5%) in this population, might explain why some athletes still have exercise-induced respiratory symptoms despite receiving appropriate asthma treatment. Rundell et al. (28) found a similar overlap 9% of between EILO and asthma. These findings should highlight to clinicians that a diagnosis of EIB should not simply be discarded on the basis of a high clinical suspicion of EILO as the cause of symptoms.
The current study is the first to accurately describe the anatomical location of EILO in a cohort of athletes. Accordingly, 10% of the EILO occurred at the glottic level and 71% at the supraglottic level, whereas 19% had combined closure. This is consistent with other studies using CLE, where 17%–21% of EILO-positive subjects had glottic obstruction (6,7). A characterization of the nature and location of EILO is important and may have implications for treatment. Specifically, Maat et al. (22,24) have reported successful surgical intervention for those with supraglottic EILO.
Our findings of a high prevalence of EILO are supported by recent reports in other athletic groups (15) but are at variance with some previous studies (27). Specifically, Hanks et al. (15) reported vocal cord dysfunction in up to 70% of 148 collegiate athletes referred with exertional dyspnea, whereas Rundell et al. (28) reported a prevalence of 5.1%. This variance likely relates to the methods and diagnostic criteria used. Studies to date have predominantly evaluated laryngeal function before and after an exercise challenge and used crude estimates of upper airway obstruction (e.g., auscultation for stridor), whereas CLE permits a continuous assessment of symptoms as they occur. Furthermore, in some studies, it is not clear what is considered an abnormal constriction, and no graduation of the constriction is made. A slight constriction of the vocal cords during or after exercise might not be pathologic, and this might at least in part explain the prevalence variance from our work. Assessing an individual when symptoms are present remains the gold standard, and thus we suspect that our findings present a true representation of the impact of EILO in this clinical scenario. Further, interobserver variation exists when grading the EILO using the Norwegian method. Maat et al. (23) previously reported an interobserver agreement of 0.70–0.86 using weighted kappa. This is consistent with the present study, which presents a weighted kappa of 0.67 for supraglottic obstruction and 0.73 for glottic obstruction. Nevertheless, it is important that studies are replicated in other centers and in other athletic populations.
It is alarming to find that a significant number of athletes with EILO, but without asthma (N = 12, 13.6% of all athletes), were treated with asthma medication. In total, 33 athletes (62.3% of athletes taking asthma medication) received medication without having objective evidence of airway hyperreactivity. Although airway hyperresponsiveness might fluctuate over time, and thereby potentially have hidden cases of mild asthma in the present study, this emphasizes the importance of verifying the true underlying diagnosis with objective tests. However, even when verified objectively, asthma remains difficult to treat in some athletes, and our current findings suggest that EILO should be considered as a coexistent diagnosis.
The mechanism underlying EILO in athletes is currently unknown, and several questions remain. More specifically, the natural clinical course of EILO in athletes remains unclear, and it is not apparent why there exists a higher prevalence of EILO in female athletes (OR = 4.09 in this study). The ineffectiveness of existing asthma medication, such as inhaled β2-agonists, corticosteroids, or leukotriene antagonists, suggests that mechanisms are different from those in asthma, and it may be that processes relating to airway dimension, inhibition of laryngeal reflexes, or impairment of the power and innervation of the laryngeal muscles (17,18) are relevant. Larynx dimensions are known to cause expiratory flow limitation in women, particularly in aerobically fit individuals (10). It is possible that smaller upper airway dimensions could contribute to EILO, but this is yet to be investigated.
Methodological considerations
The high prevalence of EILO in this cohort may be influenced by a selection bias based on the fact that athletes were referred to our tertiary referral clinic, which specializes in asthma and sports. The present study is also limited by the retrospective nature of the analysis. Further prospective work would therefore be informative to provide prevalence in different centers using the CLE test.
A further limitation relates to our lack of current knowledge with respect to the repeatability of CLE testing or day-to-day variability of EILO. This is important because symptoms and the presence of EILO may vary, thus limiting estimates of prevalence based on a one-off assessment. Furthermore, it is possible that athletes without evidence of EILO or asthma when assessed in the laboratory setting might have different results if it was possible to assess symptoms “in the field” or under intense competition scenarios.
CONCLUSIONS
This study has established that EILO is a prevalent and important differential diagnosis in athletes presenting with unexplained exercise-induced respiratory symptoms. In this population, symptoms arising from EILO can mimic asthma and are not discernible by clinical appraisal alone.
These findings have significant implications for the diagnosis and ultimately treatment of respiratory symptoms in this group of individuals, and further work is needed to explore the mechanisms underlying EILO and optimum treatment.
The authors did not receive any funds from external sources for the present study. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
The authors wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome.
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