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(Chest. 2005;127:1935-1941.)
© 2005 American College of Chest Physicians

Bronchial Hyperresponsiveness, Airway Inflammation, and Airflow Limitation in Endurance Athletes*

Samuel Vergès, PhD; Gilles Devouassoux, MD, PhD; Patrice Flore, PhD; Eliane Rossini, CRA; Michèle Fior-Gozlan, MD; Patrick Levy, MD, PhD and Bernard Wuyam, MD, PhD

* From the HP2 Laboratory (Drs. Vergès, Flore, Rossini, Levy, and Wuyam), Department of Medicine, Departments of Respiratory Diseases (Dr. Devouassoux) and Cytology (Dr. Fior-Gozlan), and Exercise and Lung Function Laboratory (Drs. Levy and Wuyam), CHU Grenoble, Joseph Fourier University, Grenoble, France.

Correspondence to: Bernard Wuyam, MD, PhD, Exercise and Lung Function Laboratory, A. Michallon Hospital, BP 217X, 38043 Grenoble Cedex 09, France; e-mail: BWuyam{at}chu-grenoble.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Whereas a high prevalence of bronchial abnormalities has been reported in endurance athletes, its underlying mechanisms and consequences during exercise are still unclear.

Study objectives: The purpose of this study was to assess the following: (1) bronchial responsiveness to methacholine and to exercise; (2) airway inflammation; and (3) airflow limitation during intense exercise in endurance athletes with respiratory symptoms.

Design: Cross-sectional observational study.

Setting: Lung function and exercise laboratory at a university hospital.

Patients and measurements: Thirty-nine endurance athletes and 13 sedentary control subjects were explored for the following: (1) self-reported respiratory symptoms; (2) bronchial hyperresponsiveness (BHR) to methacholine and exercise; (3) airflow limitation during intense exercise; and (4) bronchial inflammation using induced sputum and nitric oxide (NO) exhalation.

Results: Fifteen athletes (38%) showed BHR to methacholine and/or exercise in association with bronchial eosinophilia (mean [± SD] eosinophil count, 4.1 ± 8.5% vs 0.3 ± 0.9% vs 0%, respectively), higher NO concentrations (19 ± 10 vs 14 ± 4 vs 13 ± 4 parts per billion, respectively), a higher prevalence of atopy, and more exercise-induced symptoms compared with nonhyperresponsive athletes and control subjects (p < 0.05). Furthermore, airflow limitation during intense exercise was observed in eight athletes, among whom five had BHR. Athletes with airflow limitation reported more symptoms and had FEV1, FEV1/FVC ratio, and forced expiratory flow at midexpiratory phase values of 14%, 9%, and 29%, respectively, lower compared with those of nonlimited athletes (p < 0.05).

Conclusion: BHR in endurance athletes was associated with the criteria of eosinophilic airway inflammation and atopy, whereas airflow limitation during exercise was primarily a consequence of decreased resting spirometric values. Both BHR and bronchial obstruction at rest with subsequent expiratory flow limitation during exercise may promote respiratory symptoms during exercise in athletes.

Key Words: airflow limitation • airway inflammation • athlete • bronchial • eosinophil • exercise • hyperresponsiveness • nitric oxide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A high prevalence of respiratory symptoms in relation to exercise,12 bronchial hyperresponsiveness (BHR) to physical3 or pharmacologic agents,1 and airway inflammation45678910 have been reported in endurance athletes. Data from animal experiments11 suggest that repeated hyperventilation can induce airway inflammation and BHR to pharmacologic stimuli. In elite athletes, repetitive hyperventilation may induce mild airway narrowing in response to exercise because of bronchial dehydration injuries, excessive mucus production, and/or airway edema.12 However, whether airway inflammation is present in such athletes with BHR as it is in asthmatic subjects remains unclear. Airway inflammation that is in part different from allergic asthma has been reported in cross-country skiers4810 as well as in ice hockey players,7 but whether such inflammation is associated810 or is not associated47 with BHR remains to be clarified in order to define the mechanisms and potential treatment strategies of BHR in elite athletes.13

In addition, the extent to which airway dysfunction may have consequences during exercise-induced hyperventilation has only been partly studied. In asthma patients, airway obstruction generally occurs after exercise (ie, exercise-induced bronchoconstriction [EIB]), but exercise in itself is considered bronchodilating.14 However, the careful monitoring of maximal expiratory flow and airway resistance during exercise indicates that bronchoconstriction may occur during prolonged and/or interval exercise (ie, exercise involving variations in work intensity).15161718 Although ventilatory limitation (VL) has been reported19 in highly fit athletes as a consequence of high air flow generated during exercise, whether BHR in such athletes may induce bronchial obstruction during exercise and subsequently promote airflow limitation remains to be investigated.

In order to clarify the clinical significance of respiratory symptoms in athletes, we investigated two hypotheses. First, are athletes with methacholine-induced or exercise-induced BHR more prone than athletes without BHR to show markers of airway inflammation, as do asthmatic subjects? And, second, are athletes with BHR more prone to display expiratory flow limitation during intense exercise?


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
After informed consent, 39 competitive endurance athletes (29 cross-country skiers and 10 triathletes; 13 women and 26 men; all nonsmokers) and 13 healthy sedentary subjects (6 women and 7 men; all nonsmokers) were enrolled in the study. Subject characteristics are shown in Table 1 . None had a history of allergic asthma. Four athletes had received a previous diagnosis of exercise-induced asthma. All of them used a short-acting ß-mimetic inhaler before exercise, and two athletes received regular inhaled corticoid treatment, which was stopped for 48 h and 3 weeks before the study. All the athletes competed at a national or international level and had trained for > 12 h per week during the 4 months preceding the study. Control subjects were engaged in < 2 h of physical exercise per week. The clinical protocol was approved by the human ethics committee of our institution.


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  		Table 1.. Main Characteristics of BHR+ Athletes, BHR– Athletes, and Control Subjects*

 
Procedures
The study was conducted in March and April 2002, and testing procedures of every subject were performed in 1 day in the following order: questionnaire; nitric oxide (NO) measurement; skin-prick test; methacholine challenge; sputum induction; and exercise test.

Questionnaire
All the subjects completed a 15-item questionnaire, which queried the presence of respiratory symptoms in relation to physical exercise20 (seven items related to the perception of respiratory discomfort at maximum exercise, including following exercise in a cold environment, coughing after reduction in exercise intensity, excessive mucus production, and wheezing) and symptoms in daily life outside training sessions21 (eight items, including cough during the day, cough during the night, chest tightness, arousal with symptoms during the night, and symptoms on waking up). Each item was weighted with 1 point on a maximal symptom score of 15. Medical history, diagnosis of asthma, and potential treatment (three questions) were also investigated.

Measurement of Exhaled NO Concentration
Exhaled NO was assessed by chemiluminescence (Topaze 2020; Cosma; Igny, France). Measurement was performed off-line after exhalation from total lung capacity at a standardized exhalation flow rate (10 L/min) against a slight resistance (10 cm of H2O) in a NO-impermeable bag (Mylar; Dupont; Wilmington, DE) according to standardized laboratory procedures and previous recommendations.22 Environmental NO influence was minimized by inhaling NO-free gas at the time of the maneuver.

Skin-Prick Test
Skin tests were performed using a large panel of allergen extracts (eg, cat, Cladosporium herbarum, olive, birch, ragweed, Alternaria tenuis, timothy grass, Aspergillus fumigatus, mite [Dermatophagoides pteronyssinus], and Blatella germanica). Allergic sensitization was defined by the presence of at least one positive test result (ie, a wheal > 5 mm in diameter).

BHR
BHR was assessed using methacholine and exercise challenge tests in all of the subjects. The methacholine challenge test was performed using the dosimeter method, according to recommendations23 and the standard procedures of our laboratory.24 Cumulative methacholine doses of 0 (diluent), 0.0156, 0.0625, 0.25, 1.0, 2.0, and 4.0 mg were inhaled, and FEV1 was measured 120 s after each inhalation until a decrease of > 20% was observed. When necessary, bronchoconstriction was reversed by inhaling a ß2-mimetic agent (salbutamol, 200 µg).

An exercise test was performed on a bicycle ergometer while subjects were breathing dry medical air in order to assess the presence of EIB, as well as the VL (see below). The power output was increased during the first 4 min in order to reach a target ventilation output that was > 60% of the predicted maximum voluntary ventilation (35 x FEV1) according to standard recommendations.23 To ensure that the ventilatory stimulus for EIB was sufficient, the exercise duration was modified compared with recommendations to a total of 16 min (ie, 12 min at target ventilation). In addition, increased exercise duration may lead to bronchoconstriction during exercise itself,1618 and we hypothesized that this bronchoconstriction may promote VL. Spirometry was performed preexercise and postexercise (1, 3, 5, 7, 10, and 15 min after the end of the exercise). A mean (± SD) interval of 6.2 ± 1.5 h (range, 4 to 10 h) between the methacholine and the exercise challenge tests was allowed in order to avoid any effect of the administration of the ß2-mimetic agent on EIB evaluation.25

A provocative dose of a substance causing a 20% fall in FEV1 of <4 mg124 and/or a decrease in FEV1 of > 10% postexercise23 led to a positive diagnosis of BHR (BHR+).

Sputum Induction
The sputum induction and sample processing26 were performed according to recommendations. Briefly, increased concentrations of hypertonic saline solution (3%, 4%, and 5%) were nebulized using an ultrasonic nebulizer (Fisoneb; Fisons; Pickering, ON, Canada) for three runs of 7 min each. The subjects were then instructed to expectorate. Salivary squamous cells contamination was reduced by pouring the expectorate into a Petri dish and selecting the dense portions. Then, the sputum sample was homogenized using dithiothreitol 0.1%, and the total cell count and viability were determined. Slides were prepared by cytocentrifugation (Shandon Southern Instruments; Sewickley, PA) and were stained using Wright dye to determine the differential cell count by counting a minimum of 400 nonsquamous cells. The results were expressed as the percentages of total nonsquamous cells.

Expiratory Flow Limitation Evaluation
During the exercise test (see above), expiratory flow limitation was assessed27 as previously described. Spontaneous tidal flow-volume loops were collected and followed by a maximal inspiratory capacity maneuver twice during the eighth, 10th, 12th, and 14th min of the exercise test (SensorMedics; Yorba Linda, CA) [Fig 1 ]. When > 30% of the tidal volume was expiratory flow-limited (ie, the expiratory part of the spontaneous exercise tidal flow-volume loops met the boundaries of the maximal flow-volume envelope collected immediately at the end of exercise), the subject was considered as having expiratory airflow limitation during intense exercise (ie, a positive diagnosis of VL [VL+]).



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  		Figure 1.. Spontaneous flow-volume curves collected during intense exercise in two subjects, without expiratory airflow limitation (left, A) and with expiratory airflow limitation (right, B). A maximal inspiratory maneuver was performed in order to plot the spontaneous curves within the maximal flow-volume envelope. Both preexercise and 1-min postexercise maximal envelopes are shown (see "Materials and Methods" section).

 
Statistical Analysis
Results are expressed as the mean ± SD. For continuous variables, comparisons between the control and athlete groups were performed using either analysis of variance with unpaired t test or Kruskal-Wallis test with Mann-Whitney U test. The differences in atopy, BHR diagnosis, and VL between groups were assessed by {chi}2 test with Fisher two-tailed exact test. Correlations were assessed by calculation of Spearman correlation coefficients. A value of p < 0.05 was considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Skiers and triathletes showed similar ages, competitive experience, spirometric values, and number of self-reported symptoms (p > 0.05). The prevalence of BHR (skiers, 41%; triathletes, 40%), airflow limitation during exercise (skiers, 24%; triathletes, 10%), and airway inflammation characteristics were not significantly different between each type of athlete (p > 0.05). Hence, skier and triathlete results were combined.

BHR
Mean values for heart rate and ventilation output during the last 5 min of the exercise test were 171 ± 12 beats/min (ie, 88 ± 5% of the theoretical maximum heart rate) and 96.7 ± 18.2 L/min (67 ± 8% of the theoretical maximum voluntary ventilation), respectively. Fifteen athletes (38%; 11 skiers and 4 triathletes) demonstrated BHR to methacholine (n = 7), exercise (n = 5), or both (n = 3). No sedentary control subject had BHR. No significant difference in age or initial spirometric values was observed among BHR+ athletes, athletes with a negative diagnosis of BHR (BHR–), and control subjects (p > 0.05) [Table 1]. The duration of racing experience was similar between BHR+ and BHR– athletes (p > 0.05). Atopy was more frequent in BHR+ athletes than in BHR– athletes and control subjects (p < 0.05) [Table 1].

VL
Eight athletes (21%; seven skiers and one triathlete) demonstrated expiratory airflow limitation during exercise. No control sedentary subject showed criteria for VL. The VL+ was not significantly different in BHR+ athletes (33%) and BHR– athletes (13%) (p > 0.05) [Table 1]. BHR tended to be more frequent in VL+ athletes (63%) than in athletes with a negative diagnosis of VL (VL–) [32%], although the difference was not statistically significant (p = 0.1). Neither age nor atopy was significantly different among VL+ athletes, VL– athletes, and control subjects (p > 0.05). However, resting spirometric values were significantly lower in VL+ athletes. FEV1, FEV1/FVC, and forced expiratory flow, midexpiratory phase (FEF25–75%), values were 14%, 9%, and 29%, respectively, lower in VL+ athletes than in VL– athletes (p < 0.05) [Fig 2 ]. In addition, the duration of racing experience was significantly longer in VL+ athletes compared with VL– athletes (11 ± 6 vs 8 ± 3 years, respectively; p < 0.05).



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  		Figure 2.. FEV1, FEF25–75% (percentage of theoretical values), and FEV1/FVC ratio (%) in VL+ athletes (black bar), VL– athletes (striped bar), and control subjects (white bar). * = significantly different from VL– and control subjects (p < 0.05).

 
Questionnaire
The number of self-reported respiratory symptoms, both in relation to exercise and in daily life, was significantly greater in athletes than in control subjects (p < 0.05) [Table 1]. Additionally, the number of self-reported symptoms in relation to exercise was higher in BHR+ athletes than in BHR– athletes (p < 0.05) [Table 1], as well as in VL+ athletes compared with VL– athletes (6.1 ± 3.1 vs 3.4 ± 2.1 positive items, respectively; p < 0.05). The number of self-reported symptoms in daily life was not significantly different between the athlete groups.

Sputum Analysis and Exhaled NO Measurement
BHR+ athletes, BHR– athletes, and control subjects had similar total cell counts (1.1 ± 0.7, 2.3 ± 3.0, and 2.2 ± 2.5 106cells/g, respectively; p > 0.05). BHR+ athletes, BHR– athletes, and control subjects did not differ in neutrophil counts (45.6 ± 26.5%, 46.1 ± 28.2%, and 42.8 ± 25.2%, respectively) and macrophage counts (46.6 ± 23.5%, 52.6 ± 28.8%, and 56.3 ± 24.6%, respectively; p > 0.05). However, a significantly higher eosinophil count was observed in BHR+ athletes compared with BHR– athletes and control subjects (4.1 ± 8.5%, 0.3 ± 0.9%, and 0%, respectively; p < 0.05) [Fig 3 ]. Similarly, BHR+ athletes exhibited a significantly higher exhaled NO concentration compared with BHR– athletes and control subjects (19 ± 10, 14 ± 4, and 13 ± 4 parts per billion, respectively; p < 0.05) [Fig 3]. No differences in total cells counts, differential cell counts, and exhaled NO concentration was observed among VL– athletes, VL+ athletes, and control subjects. No correlation was observed between differential cell counts and exhaled NO concentration.



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  		Figure 3.. Eosinophil count and exhaled NO concentration in BHR+ athletes (black bar), BHR– athletes (striped bar), and control subjects (white bar). * = significantly different from BHR– and control subjects (p < 0.05). ppb = parts per billion.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study indicates that an airway inflammation with eosinophilia and increased exhaled NO concentration was present in BHR+ athletes. These athletes were more frequently atopic and reported more exercise-induced respiratory symptoms than BHR– athletes. Ventilatory limited (ie, VL+) athletes also reported more exercise-induced respiratory symptoms, and BHR and VL were not systematically associated. Decreased resting spirometric values were a specific feature of the VL+ athletes.

In the present study, we chose to characterize BHR among endurance athletes with symptoms as a positive response to methacholine and/or exercise, because the results of each of these two tests may be suggestive of bronchial dysfunction. In athletes, few studies2829 have used both challenges. As reported in sedentary asthmatic subjects,30 a positive response to both tests may not be systematic, and each test may reflect the different mechanisms involved in the pathogenesis of BHR. In the present study, comparisons among athletes demonstrating EIB only, BHR to methacholine, or both did not show any difference in airway inflammation, nor any difference in the occurrence of airflow limitation during exercise (results not shown). The small sample size may limit such results, however. Our study confirms that pharmacologic and exercise challenge tests are not similarly affected in athletes, and both tests may be necessary to recognize BHR in this population. The cutoff for the methacholine challenge may, additionally, be debatable, and a gray area may exist when trying to define an abnormal bronchial response to methacholine.31 The definition of BHR to methacholine that was used in the present study (ie, provocative dose of a substance causing a 20% fall in FEV1, < 4 mg) was chosen because it has been considered indicative of an abnormal bronchial response in a large sample of the general population of our center.24 We consider the possibility unlikely that this has led to an overestimation of BHR in athletes, although the severity of BHR observed is usually mild.

The endurance athlete group explored in the present study consisted of both skiers and triathletes. Although one could speculate that skiers may present specific airway dysfunctions because of the inhalation of large quantities of cold (and dry) air,8 we did not observe any differences in BHR or airway inflammation between these athletic specialties. Because skiers and triathletes in the present study displayed a very similar duration of weekly training (ie, > 12 h/wk), this factor and the implied duration of hyperventilation may cause athletes to be at risk for airway dysfunctions, rather than a specific type of endurance sport.

Whereas a high prevalence of BHR13 and criteria of airway inflammation have both been reported in endurance athletes,45678910 the strength of the association between these phenomena is debatable in this population, and a causative relationship of airway inflammation on BHR is not fully proven.13 Our results show increased inflammatory cells in the sputum of endurance athletes, when BHR athletes were compared with non-BHR athletes and control subjects. This does not exclude, however, the possibility that other mechanisms may also be involved32 but emphasizes the role of airway inflammation in BHR athletes. Both eosinophilic and neutrophilic patterns of bronchial inflammation have previously been reported in the sputum of endurance athletes.567 Increased total cell and lymphocyte counts in BAL fluid,8 and an infiltration by lymphocytes, eosinophils, and neutrophils of the submucosa have also been observed in specimens obtained from bronchial biopsies48 performed in cross-country skiers. Although an increased neutrophil count has been proposed as a specific feature of airway inflammation in endurance athletes,13 the BHR+ athletes in the present study showed an airway inflammation with increased eosinophil counts but normal neutrophil counts. Several factors may contribute to airway neutrophilia, such as prolonged and intense acute exercise6 or respiratory tract infection.33 The absence of respiratory tract infection at the time of the experiment, as well as the absence of undergoing an intense training session for at least 48 h before laboratory investigations, may explain the normal neutrophil counts in our study.

Although normal exhaled NO levels have been occasionally reported in skiers with "ski asthma,"9 as in nonasthmatic runners,6 high exhaled NO concentrations were also observed in atopic skiers and atopic asthmatic subjects.9 The increased NO values observed in BHR+ athletes in the present study may be related to the more prevalent atopic status in this group. Hence, our results suggest that the airway inflammation profile in BHR+ athletes presents characteristics that are similar to those encountered in athletes with atopic asthma.34 However, the clinical characteristics of our athletes population rule out the presence of an associated allergic asthma. Chronic exercise hyperventilation and atopic predisposition may, thus, combine as an association of causative factors to account for the bronchial phenotype observed in endurance athletes. Furthermore, our observations of airway inflammation in BHR+ athletes suggest that inhaled corticotherapy may constitute an efficient treatment in this group of symptomatic athletes.

To our knowledge, our study is the first to investigate the relationship between BHR and objective VL in athletes. In asthmatic subjects, constant-load exercise by itself is thought to induce neither a modification35 nor a decrease14 in the bronchomotor tone, and EIB generally occurs after exercise. However, prolonged exercise duration (ie, ≥ 15 min) may induce bronchoconstriction and subsequent expiratory flow limitation.151617 A single study18 has reported an FEV1 decrease during exercise in athletes (cross-country skiers), but whether this may induce abnormal ventilatory constraints remains unknown. In the present study, VL was observed in 5 of 15 BHR+ athletes and in 3 of 24 BHR– athletes. VL+ athletes did not show evidence of bronchoconstriction during exercise and had no significant FEV1 decrease (ie, ≥ 10%) immediately at the end of the exercise (data not shown). Although the small sample size (particularly the VL+ group) does not allow definitive conclusions, these results suggest that BHR and VL during intense exercise may be independent phenomena, at least in such a cross-sectional observational study. In the present study, VL was associated with alterations in resting bronchial caliber. Because no relationship was found between bronchial obstruction and airway inflammation, the mechanisms of such an obstruction remain unclear. Observations of an accelerated decline of spirometric values in trappers of the Canadian Arctic36 and in elite cross-country skiers,37 as well as criteria of airway "remodeling" in skiers4 are in favor of a possible alteration of the bronchial structure as a consequence of dry and/or cold air hyperventilation. The longer competitive experience of VL+ athletes may emphasize the long-term effect of hyperventilation and exposure to stressful environments on the bronchial structure. Although BHR+ athletes are susceptible to improvement by antiinflammatory and/or bronchodilating agents, modalities of VL+ athlete management remain to be more clearly defined.

In conclusion, we have shown that in symptomatic endurance athletes, only BHR+ subjects presented airway inflammation, the characteristics of which are close to those observed in patients with allergic asthma, with an eosinophilic recruitment and an increased exhaled NO concentration. Atopic status appeared to be a major risk factor for the development of BHR in endurance athletes. Moreover, we demonstrated that BHR in athletes was not associated with the presence of a VL during exercise. Interestingly, VL was rather a specific feature of athletes displaying a decrease in resting spirometric values, which may be another consequence of chronic exercise hyperventilation and/or exposure to a stressful environment. This should also be analyzed when investigating athletes with respiratory symptoms.


   Acknowledgements
 
We thank Chrystele Deschaux for her contribution to the statistical analysis, and James Nicholls for his help in preparing the manuscript.


   Footnotes
 
Abbreviations: BHR = bronchial hyperresponsiveness; BHR– = negative diagnosis of bronchial hyperresponsiveness; BHR+ = positive diagnosis of bronchial hyperresponsiveness; EIB = exercise-induced bronchoconstriction; FEF25–75% = forced expiratory flow, midexpiratory phase; NO = nitric oxide; VL = ventilatory limitation; VL– = negative diagnosis of ventilatory limitation; VL+ = positive diagnosis of ventilatory limitation

This study was supported by the Scientific Council of the Respiratory Diseases Association of Grenoble and the Direction de la Recherche Clinique, UF 1452, 1999, CHU de Grenoble grants (Dr.Wuyam).

Received for publication December 9, 2003. Accepted for publication December 15, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Br. J. Sports Med., March 1, 2006; 40(3): 281 - 282.
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