Bronchial hyperresponsiveness testing in athletes of the Swiss Paralympic team

Athletes participating at the Paralympic Games 2008 in Beijing had to apply for a therapeutic use exemption if they wished to use inhaled beta agonists as these were prohibited substances according to the World Anti-Doping Code Prohibited List [1]. They had to provide objective criteria for the existence of exercise-induced bronchoconstriction or exercise induced asthma according to the World Antidoping Agency’s Therapeutic Use Exemption Guidelines [2].

As exercise challenge tests are quite insensitive to identify exercise induced bronchoconstriction in elite athletes [3], easier but also standardized tests would be needed. In addition, standardization with respect to both workload and environmental conditions is almost impossible to achieve for sport-specific exercises in the field [3], and even more so for disabled athletes. Provocation challenge tests such as EVH and the MCT have therefore been used to assess exercise-induced bronchoconstriction and asthma in athletes in a standardized fashion. EVH, where athletes are required to hyperventilate a dry air mixture at room temperature for six minutes, has been established as a standardized test to diagnose exercise-induced asthma [3, 4] and has been recommended in elite athletes [5, 6]. MCT tests athletes’ response to inhalation of dry powder mannitol from a handheld device in increasing doses and has also been shown to identify individuals with exercise-induced bronchoconstriction and asthma [7–9] and correlated well with EVH in able-bodied athletes [10].

Whether these tests can be used to assess athletes with a disability, however, is unknown. We therefore set out to test and compare EVH and MCT and their utility to diagnose exercise-induced asthma in elite athletes with a disability, in particular in athletes with spinal cord injury.

Athletes with a disability from the Swiss national team who were planning to participate in the Paralympic Games 2008 in Beijing were asked to take part in the study. The athletes answered questions about asthma, underwent skin prick testing, spirometry, and exhaled nitric oxide (NO) measurement and were subsequently challenged with EVH and MCT on two separate occasions. The study was approved by the Ethics Committee of the Canton Lucerne, Switzerland. All participants gave written informed consent and the study was carried out in accordance with the Declaration of Helsinki [11].

Bronchoprovocation challenge tests

Each athlete underwent an EVH challenge test and a MCT on separate days. Athletes with previous physician-diagnosed asthma were asked to abstain from their regular medication one week prior to lung function testing. Exercise-induced bronchoconstriction was defined as a fall in FEV1 of ≥10% in either EVH challenge test and/or MCT [9, 17] (Figure 1).

1. 1.

   Eucapnic voluntary hyperventilation

   Before each test FEV1 was measured three times and the highest value was taken as the baseline value for determining maximal voluntary volume (MVV). MVV was calculated as 35 × FEV1. Athletes were then instructed to hyperventilate at minimum level of 65% of their MVV for six minutes breathing a gas mixture containing 5% CO₂ and 21% O₂. The inhaled gas mixture was kept constant using the Eucap Sys™ (SMTEC SA, Nyon, Switzerland). Immediately following the challenge, FEV1 was measured twice and the highest value was taken. Measurements were repeated after 5, 10, 15 and 20 minutes. A fall of 10% or greater to baseline in one time point was considered as positive [17].

    
2. 2.

   Mannitol challenge

   MCT was performed by administering dry mannitol powder (Aridol™ Pharmaxis Ltd, Sydney, Australia), inhaled from a dry powder device (Osmohaler, Pharmaxis Ltd, Frenchs Forest, NSW, Australia) as described previously by Anderson et al. [18]. FEV1 was measured 60 seconds after the delivery of each dose (5, 10, 20, 40, 80, 160, 160, 160 mg). The test continued until the FEV1 had fallen 15% or the maximum cumulative dose of 635 mg had been administered. A fall in FEV1 greater or equal to 10% was noted positive for mannitol-induced bronchoconstriction. PD₁₀ (‘provoking dose-10’) was defined as the cumulative dose of mannitol causing a fall of 10% in FEV1. The response–dose ratio (RDR) for mannitol was calculated by dividing the highest percentage fall in FEV1 by the cumulative mannitol dose needed to cause this fall. RDR was compared to the fall in FEV1 in the EVH challenge.

    

This is the first study reporting the feasibility of bronchial challenge testing with EVH and MCT in athletes with disabilities investigating for the existence of exercise-induced bronchoconstriction or asthma. Ten of the eleven athletes diagnosed by a physician with asthma had at least one positive test for EVH or MCT challenge whereas three athletes with asthma had a positive response to both challenges. EVH and MCT had a high negative predictive value and thus a negative challenge test would allow to exclude asthma in this population.

Baseline lung function testing showed significant differences in VC, ERV, FVC and FEV1 between the groups with spinal cord injury and the group of athletes with other disabilities but no spinal cord injury. Athletes with tetraplegia had lower lung function values compared to athletes with paraplegia. Previous research reports that injury to the cervical and upper thoracic spinal cord decreases the function of inspiratory and expiratory respiratory muscles while the expiration is more impaired in individuals with tetraplegia or paraplegia and high spinal cord lesion [19–21].

The measured exhaled NO did not differ significantly between athletes with spinal cord injury and athletes without spinal cord injury, nor did it differ between subjects with or without physician diagnosed asthma. However the group of tetraplegic individuals tended to have higher NO levels compared to those with lesions leading to paraplegia. This is in concordance with another study reporting elevated levels of exhaled NO in tetraplegic individuals that were in the range of NO levels expected for individuals with mild asthma [22]. However it is currently unclear if elevated exhaled NO levels in tetraplegic individuals are a result of increased activity of the inducible NO synthetase due to inflammation or due to an altered regulation of inducible NO synthetase [22].

In the 2012 version of the world anti-doping agency prohibited list the use of all beta-2 agonists with the exceptions of salbutamol, formoterol and salmeterol are prohibited and athletes that use these substances must apply for exemption and provide objective criteria for the existence of exercise-induced bronchoconstriction or exercise induced asthma [23].

To our knowledge, this is the first study to evaluate exercise-induced bronchoconstriction by EVH or mannitol in athletes with spinal cord injury. As exercise challenge testing is especially difficult to standardize in this group of elite athletes, EVH and inhalation of dry powdered mannitol are two options to diagnose exercise-induced bronchoconstriction and allow the therapeutic use of inhaled beta agonists during competition. Both challenge tests showed a significant association with physician diagnosed asthma. Both EVH and MCT were shown to have a high negative predictive value which suggests that a negative test can reliably exclude asthma in this population of athletes with disabilities. The diagnostic validity of MCT in our study is similar to those previously reported in able-bodied athletes [10, 24, 25].

In our group, 21% of all participants were identified as having exercise-induced bronchoconstriction by eucapnic hyperventilation. In other studies testing able-bodied elite athletes exercise-induced bronchoconstriction was identified in 31% to 50% [10, 26–28] by EVH challenge. This difference cannot be explained by inadequate hyperventilation as the minimum achieved ventilation equalled 63% maximum voluntary volume and the mean ventilation was 82% MVV. Only two athletes failed to reach the proposed 65% MVV for an adequate test. The lower proportion of positive EVH tests is in concordance with a relatively low prevalence of physician diagnosed asthma in our study sample. With the mannitol challenge, 18% tested positive for exercise-induced bronchoconstriction, compared with 52% in an Australian able-bodied elite athlete population [10]. None of the athletes without spinal cord injury had a positive test result in our study group. The difference might be explained by the inclusion of athletes of various sporting disciplines, as substantial differences in the prevalence of exercise-induced asthma have been reported, depending on the type of sport performed [29, 30]. Low prevalences of hyperresponsiveness to mannitol were previously reported for a population of elite cross country skiers [17] as well as Scottish elite swimmers [24].

In the past, it was shown that the majority of patients with tetraplegia demonstrate airway hyperresponsiveness to methacholine [31, 32], histamine [33] and ultrasonically nebulized distilled water [34]. One of the three tetraplegic athletes tested positive on MCT as well as on EVH. This athlete showed the lowest vital capacity and FEV1 of all athletes tested. It has been postulated that with small airway diameters a small further reduction in calibre induced by a bronchoconstrictive agent produces a large increase in resistance as airway resistance is inversely proportional to the fourth power of the radius [35]. The reduced airway calibre in these athletes does probably explain why a larger proportion of athletes with tetraplegia demonstrate airway hyperresponsiveness in the MCT and EVH.

When testing 50 elite able-bodied athletes, Holzer et al. demonstrated a strong association between the response to MCT and to the EVH [10]. In our study, we identified eight and nine athletes with a positive test result, respectively. However, only three athletes had congruent results on both challenges. Holzer et al. set the cut-off defining a positive test at >10% fall in FEV1 in the MCT [10]. In a study testing children for bronchial hyperresponsiveness, Kersten set the cut-off for a positive test result at > 15% in FEV1 in the MCT and concluded that the MCT was especially useful to exclude exercise-induced bronchoconstriction [36]. For children, different cut-off points for exercise testing and inhalational provocation tests are more suitable [37–39]. Had we defined a 15% cut-off in our subjects, only 2 participants would have tested positive on the MCT with a single athlete testing congruently positive on the MCT and the EVH. With only adults included in the study, we chose a cut-off of ≥10% fall in FEV1 in both challenge tests.

A significant relationship between the reactivity to mannitol, defined by the response–dose-ratio (RDR), and the fall in FEV1 after EVH could not be demonstrated in our study. While Kersten and co-workers [36] showed a strong relationship between RDR mannitol and the fall in FEV1 after exercise in able-bodied children, Clearie and co-workers could not find an association between reacitivity to mannitol and standardized field-based testing in elite swimmers [24].

In conclusion, we present results of bronchial hyperresponsiveness testing in a population of elite athletes with a disability. EVH and MCT were found to be feasible and safe in diagnosing exercise-induced asthma in athletes with spinal cord injury. A combination of both challenge tests is recommended in this group of subjects. Eucapnic voluntary hyperventilation and inhalation of dry powder mannitol can be used to identify, but especially exclude asthma in Paralympic athletes due to their relative high negative predictive value for the diagnosis of physician-diagnosed asthma.