An increased risk for asthma has been recognized in elite athletes who take part in endurance sports, such as swimming.1 Classical postulated mechanisms behind exercise-induced asthma (EIA) include the osmotic, or airway-drying, hypothesis.2 As water is evaporated from the airway surface liquid, it becomes hyperosmolar and provides an osmotic stimulus for water to move from any cell nearby, resulting in cell shrinkage and release of inflammatory mediators that cause airway smooth muscle contraction. In fact, the airways of athletes present increased inflammatory cells and levels of histamine, cysteinyl leukotrienes and chemokines; however these inflammatory changes are not consistently related to lung function or disease exacerbations and it has been thought that they represent physical injury secondary to rigorous hyperpnoea that will heal with rest.3,4 Alternative hypotheses to explain EIA have been pursued.

Besides inflammatory mediators, the autonomic system also mediates the contraction and relaxation of bronchial smooth muscle. Cholinergic-parasympathetic nerves stimulate bronchoconstriction, whereas β2-adrenergic sympathetic and/or noncholinergic parasympathetic nerves cause bronchodilation.3,4 Intensive training can have affect autonomic regulation by promoting the predominance of vagal activity, as a compensatory response to the sympathetic stimulation associated with frequent and intense training.2 It has been hypothesized that repeated intensive training could provoke vagal hegemony, which induces not only the well-known resting bradycardia of athletes, but could also lead to a predisposition for increased bronchomotor tone and therefore susceptibility to bronchospasm.2 This autonomic nervous system imbalance is known as dysautonomia and it has been previously shown, using pupillometry, that pupillary light reflex of endurance runners reveals an increased parasympathetic activity and reduced sympathetic activity.5 But the relationship between these observations and asthma is not established.

Research into the hypothesis of dysautonomia in the pathogenesis of asthma in athletes is urgently needed because definite answers would allow for better targeted treatment of this specific asthmatic population. In the particular case of elite swimmers, in both asthmatic and healthy ones, an increase in bronchial responsiveness correlating with exercise intensity was demonstrated after 3000m swimming in an indoor swimming pool.6 Moreover, neurogenic airway inflammation was recently associated with swimmers-asthma.7 Therefore, we aimed to assess the relationship between autonomic nervous system and airway responsiveness of elite swimmers with asthma. It was hypothesized that airway hyperesponsiveness in asthmatic swimmers is related to increased parasympathetic activity.

Twenty-seven elite swimmers were enrolled, of which 11 (41%) had asthma. Demographic, personal and clinical features are presented in Table 1. Regarding their normal medication, 2 swimmers were under inhaled corticosteroids, 4 with a combination of long-acting β2-agonists plus inhaled corticosteroids and 2 were treated with anti-leukotrienes. All refrained from taking their regular medication prior to the study.

Pupillary response curves were easily recorded in all subjects (Fig. 2). Pupillometry was repeated if blink artifacts occurred, but all participants were able to complete the measurements, except for T75 which was not retrieved by the device for all athletes. None reported discomfort.

Figure 2.

Results of pupillary response variables: Mean (bold line)±SD (traced lines) values of pupillary diameters among asthmatic and non-asthmatic swimmers.

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Pupillometry measurements in asthmatics compared with non-asthmatic swimmers are presented in Table 1 and Fig. 2. Although lower pupil diameters and a higher percentage of constriction were observed in asthmatics, differences were not statistically significant.

When stratified by AHR severity, pupil diameters before (maximal) and at constriction peak (minimum) as well as the percentage of constriction were significantly lower among those with severe AHR (Table 2).

In the 18 swimmers with clinically relevant AHR, a significant correlation was found between PD20 and maximal (r=0.67, p=0.002), and minimal pupil's diameters (r=0.75, p<0.001), percentage of constriction (r=−0.59, p=0.011) and latency (r=0.490, p=0.039), but not with ACV (r=0.243, p=0.332), MCV (r=0.061, p=0.810), ADV (r=0.075, p=0.776), and T75 (r=0.373, p=0.351).

In our exploratory study, no significant differences were observed in parasympathetic parameters between asthmatics and non-asthmatic elite swimmers. However, for those with severe AHR a significant difference became clear, suggesting that the increased parasympathetic tonus is particularly associated with the contraction of the bronchial smooth muscle.

Previous studies supporting this hypothesis of dysautonomy associated with training match our findings. Pichon et al. demonstrated that subjects with an increased AHR had a higher vagal tone,14 which was corroborated by Park et al. findings of a relationship between AHR to methacholine and a diminished sweat secretion, tearing and salivary flow rate in healthy athletes.15 All these studies have used AHR as an outcome measure, rather than asthma status. This also seems to be the case with swimmers. Among elite competitive adolescent swimmers, for both asthmatic and healthy ones, an increase in bronchial responsiveness correlating with the exercise intensity was demonstrated after 3000m swimming in an indoor swimming pool.6 Together with our results, this seems to point out that dysautonomia might contribute to the severity of airway reactivity in swimmers.

The lack of significant differences in parasympathetic outcomes between asthmatic and non-asthmatic swimmers is probably related to the fact that asthma a complex disease to which, besides AHR, there are many more parameters contributing. Asthma is defined as a clinical syndrome of intermittent respiratory symptoms triggered by viral infections, environmental allergens, or other stimuli, and is characterized by nonspecific airway hyperesponsiveness and inflammation.16 While bronchoconstriction is largely dependent on airway smooth muscle cells and might be related to increased parasympathetic tonus, inflammation is a multi-cellular process involving airway epithelium, eosinophils, neutrophils, lymphocytes and mast cells.17 Although in the particular case of athletes it has been proposed that inflammatory changes represent physical injury secondary to rigorous exercise,3,4 there are several issues that are unique to this population. In athletes, two different clinical phenotypes of asthma have been suggested by Haahtela et al. The pattern of “classical asthma” characterized by early onset childhood asthma, methacholine responsiveness, atopy and signs of eosinophilic airway inflammation; and another distinct phenotype with onset of symptoms during sports career, bronchial responsiveness to eucapnic hyperventilation test and a variable association with atopic markers and eosinophilic airway inflammation.18 Our group has recently observed that athletes involved in water sports have a 3-fold increased risk of presenting the later phenotype of asthma – called “sports asthma”, not related to atopy but rather developed through their career (unpublished data). This suggests different predominant pathophysiological mechanisms of EIA in athletes and therefore a different role of the parasympathetic tonus.

In the particular case of swimming, EIA has been mainly thought to be associated with epithelial damage resulting from exposure to chloramines.19 In recent years, the observation that regular pool attendance, especially by young children, was associated with lung hyperpermeability and increased risk of developing asthma led to the “pool chlorine hypothesis”.20,21 According to this, the increasing and largely uncontrolled exposure of young children to chlorination by-products contaminating the air of indoor swimming pools could have contributed to the childhood asthma rise in industrialized countries.20,21 In their studies, Bernard et al. described an association between asthma prevalence and cumulated pool attendance, as well as lung hyperpermeability and total IgE levels.22 In fact, also in elite swimmers it has been shown that the endothelial cell layer, through vascular adhesion and permeability control, determines the infiltration of immune cells and leads to edema in the lungs.23 It has been hypothesized that regular attendance at chlorinated swimming pools might have a role in the development of asthma by causing an increased lung permeability, which in turn would facilitate allergen sensitization.23 We have previously demonstrated that swimmers that remain active at a 3-year follow-up significantly increase their levels of airway inflammation compared to those who quit swimming, but asthma incidence remained similar.24 Taken together all these studies suggest that the EIA explanatory model in swimmers is not only related to inflammation and allergy, but will probable include the interplay between environmental training factors including allergens and ambient conditions and the athlete's personal risk factors such as genetic and neuro-immune-endocrine determinants.2

As a major ambient factor, chloramines, and trichloramine in particular, are quite volatile and they are very easily inhaled and therefore act as potent irritants in the airways. Chemical stimulation of vagal sensory fibers by irritants reaching the lower airways can trigger tracheal and bronchial constriction, bronchospasm, mucus secretion, and neurogenic inflammation.25 This neurogenic pathway is connected to release and action of neuropeptides, such as tachykinins, including substance P, or calcitonin gene related peptide (CGRP) from primary sensory nerve terminals, by activation of transient receptor potential (TRP) channels as a response of sensory neurons to noxious stimuli.26–28 In a recent study, the role of TRP-ankyrin 1 channel on nociceptive airway sensory nerves in nonallergic AHR in relation with chloramines exposure was highlighted.7 It was demonstrated in a mouse model, that AHR can be induced by a single hypochlorite-ovalbumin instillation, independently of bronchial influx of inflammatory cells.7 These chemoreceptors are expressed on substance P-producing airway sensory nerve fibers and are involved in irritant-induced airway disease. The activation of substance P receptor leads to bronchoconstriction.28 Our results help to support the influence of the nervous system in this hypothesis of an interaction between exposure to hypochlorite and AHR independent of bronchial inflammation.

A proof of concept of this hypothesis of a higher parasympathetic activity as an etiological mechanism for bronchoconstriction in athletes would require a better responsive effect to inhaled anticholinergics, than to other drugs. It has been confirmed by practical experiments arising from Norwegian competitive endurance athletes that revealed that they respond particularly well and with a higher reversibility to inhaled ipratropium bromide than to inhaled beta2-agonists.29

Our study has important limitations. First, the reduced number of subjects included, which may prevent the study from reaching statistical significance; however, they were all elite swimmers. Secondly, the cross-sectional nature of our data. Though, it must be highlighted as a strength of our study, that a highly controlled evaluation was performed for all variables known to possibly interfere with the pupillometry.8 Also, this is the first study to address the question of dysautonomia assessed by pupillometry related with swimmers asthma and AHR. Previous studies using this method to evaluate autonomic nervous system have not addressed the relationship with bronchial outcomes. An evaluation of Portuguese Olympic athletes showed that they have higher parasympathetic control, with concomitant reduction of the sympathetic tone.30 Capão-Filipe et al. reported an increased parasympathetic activity and a reduced sympathetic activity of endurance runners when compared to other sports.5 In our study, swimmers with clinically relevant AHR, showed a significant correlation between PD20 and 4 of the parasympathetic parameters, reflecting the reliability of pupillometry, since methacholine acts as a non-selective muscarinic receptor agonist in the parasympathetic nervous system. The recent development of a portable, user-friendly, and reliable infrared pupillometer, which allows for accurate, easy, and reproducible quantitative pupillary measurements, has revived the initial enthusiasm about the clinical usage of pupillometry.7 It has been employed to evaluate a large number of conditions as it allows quantitative pupillary measurement of several parameters,7 and now has revealed itself as a reliable tool to assess parasympathetic activity in elite swimmers.

To conclude, no significant differences were observed between asthmatic and non-asthmatic swimmers regarding parasympathetic parameters, but among those with clinically relevant airway hyperresponsiveness an association was seen. Although limited by the sample size, these findings provide further support for the role of autonomic nervous system in airway responsiveness development in elite swimmers and might be a new target for future therapeutic options in this particular population.

The authors have no conflicts of interest to declare.