Screening and Diagnosing Exercise-induced Bronchoconstriction in Recreational Young Athletes (12-18 y)

Background: Physical exercise, though absolutely beneficial for human well-being, is a well-known trigger to induce bronchoconstriction. Exercise can provoke bronchoconstriction in subjects with pre-existing asthma but can also induce bronchoconstriction in otherwise healthy subjects. The latter phenomenon is called exercise-induced bronchoconstriction (EIB). EIB is frequent in the general population and might affect between 5 and 10% of them, although population based reports are scarce. EIB is most prevalent in individuals performing endurance sport disciplines, such as long distance running, duathlon and triathlon, cycling and cross-country skiing. Due to frequent intense physical training, its incidence is higher in elite athletes compared to non-elite athletes. Its prevalence in elite athletes within these endurance sport disciplines is estimated to be up to 13%. The percentage in aquatic endurance sports was surprisingly even higher and reached 20% in the Olympic games of 2008. Besides intense physical training, environmental factors such as chlorine or cold air exposure are therefore also linked to the appearance of EIB.

It remains very difficult to screen all athletes yearly for EIB. Therefore, the goal of this study is to define risk factors and/or biomarkers that might predict EIB, already at the start of their sport career. This would allow physicians to follow their lung function parameters very closely and regularly; and, if necessary, start treatment early after the first signs of EIB.

The investigators already found that atopic individuals in a young cohort of elite athletes (12-13y) had increased risk to test positive for EIB (Fisher exact test p=0.04). However, due to the high number of subjects with a positive EIB test but negative Atopy/AQUA questionnaire, the AQUA questionnaire by itself can't be used to predict EIB (p=0.4). However, one out of five questions added by our group to this questionnaire ("Do the participant suffer from wheeze during exercise?") by itself predicted EIB with 93% specificity and 24% sensitivity. Adding a second question to this ("Has a doctor ever diagnosed the participant with an allergic condition?") increased the specificity to predict a positive EIB test to 99% but lowered sensitivity to 15% only (Jonckheere AC, J Allergy Clin Immunol, 2019). Based on the preliminary data of the slightly older cohort of also elite athletes (13-18 y), fractional exhaled nitric oxide (FeNO) levels (cut off 16 ppb) may be a useful indicator of atopic phenotypes among young elite athletes. Whether atopy is a risk factor for EIB in recreational young athletes who perform intense physical exercise has to be further studied.

Hypothesis: The investigators hypothesize that the findings in the cohort of elite athletes will be similar in the cohort of recreational athletes, performing at least 12 hours of sport a week. This means that:

• They hypothesize that questionnaires (including AQUA questionnaire) can be used to screen for EIB
• They hypothesize that atopy will be a risk factor for EIB
• They hypothesize that increased FeNO levels will be a risk factor for EIB
• They hypothesize that adding blood based biomarkers increase the predictive value of the screening protocol

Aim of the study: Therefore the aim of the study is to validate the screening protocol and diagnostic EIB test in a powered (n=500) group of recreational adolescent athletes who perform their sports at least 12h/week.

Material and method: 500 recreational athletes who perform at least 12 hours of sports a week will be recruited amongst different youth sport branches including indoor sports, outdoor sports, swimming and even winter sports. Subjects will be contacted in collaboration with their local sport doctors. Subjects from East-and West Flanders will be studied at AZ Maria Middelares in Ghent by dr J Leus, subjects from Limburg will be studied at the Jessa Hospital in Hasselt and subjects from Antwerp and Flemish-Brabant will be studied in Leuven, UZ Gasthuisberg in close collaboration with prof L Dupont, copromotor of the study.

Measurements at the visit:

• Lung function will be assessed by spirometry.
• Questionnaires, including the AQUA questionnaire
• Atopy will be assessed by skin prick test for common environmental allergens
• Fractional exhaled Nitric Oxide (FeNO) measurement
• Venous puncture (1 tube)
• Eucapnic voluntary hyperventilation (EVH) test will be used as a test for EIB (adapted for this young age).

Statistical analysis: Power analysis to study the sample size has been performed based on the previous study in first grade elite athletes. Atopy was present in 35% of the subjects and EVH test was positive in 27% of these atopic subjects and 12.5% in non-atopic subjects. Probably atopy rate was accidently higher than expected in the general population (25%) Therefore a sample size of 405 subjects would allow to predict the presence of atopy and EIB with a type I error rate of 0.05 as well as a type II error rate of 0.05 at a power of 95%. The investigators expect drop-out of 15-20% of the subjects (which is more than the investigators observed in elite athletes, but consider their willingness to adhere at a screening protocol in elite athletes to be higher than that in non-elite athletes), aiming to recruit 500 subjects.

Feasibility: FWO-TBM study budget granted