Validation Screening Protocol for the Diagnosis of Exercise-induced Bronchoconstriction in Young Elite Athletes (13-18 y)

State of the art Physical exercise, though absolutely beneficial for human well-being, is a well-known trigger to induce bronchoconstriction. Aretaeus of Cappadocia described the first cases of asthma triggered by exercise, already in the second century AD. 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.

The mechanism of exercise-induced bronchoconstriction is not fully clear: airway cooling resulting from conditioning of inspired air and post-exercise rewarming of airways have been proposed as "thermal" mechanism. However, airway dehydration as a result of increased ventilation, resulting in "augmented osmolarity" of the airway-lining fluid, seems to be a major cause. This augmented osmolarity is thought to trigger the release of mediators, such as histamine, cysteinyl leukotrienes and prostaglandins, from airway inflammatory cells, which leads to airway smooth-muscle contraction and airway edema. Last but not least, recent evidence, including data from the investigator' s laboratory, points to "epithelial damage" due to the high ventilation rate, with subsequent release of epithelial cell mediators, as underlying mechanism. This damage, which can be more pronounced if additional triggers are present, might lead to uncontrolled airway inflammation, can exacerbate the process and increase exercise-induced bronchoconstriction, potentially leading to persistent asthma. It is suggested that airway inflammation differ between subjects/athletes with pre-existing asthma (in whom airway eosinophils and Th2 inflammation are present) and those with EIB that developed during their career (in whom neutrophils and Th17 inflammation are present). If symptoms develop during their career, a causal relationship between the intense exercise and EIB can easily be suspected. In order to determine the exact moment of EIB development during their career, longitudinal studies, starting before EIB is present, are needed. Indeed, most adolescent elite athletes start their intense training protocols long before they start to perform at the highest international level.

If diagnosing EIB in adult elite athletes is difficult, its diagnosis in elite high-school athletes is a terrible challenge. Indeed, different diagnostic tests have been suggested by the International Olympic Committee-Medical Commission (IOC-MC) to identify EIB in adult elite athletes. If upon symptoms, classical diagnosis of asthma (e.g. by performing reversibility test after Salbutamol® inhalation) is excluded, airway hyperresponsiveness should be documented with the use of bronchoprovocation testing. These tests include direct challenges (e.g., with inhaled methacholine), which act on airway smooth muscle to cause bronchoconstriction, and indirect challenges, such as Eucapnic Voluntary Hyperpnea (EVH) particularly recommended for athletes, hyperosmolar tests with saline or mannitol, and laboratory or field exercise tests. However, athletes may have a positive response (with a drop in Forced expiratory volume in one second (FEV1) above the cited cut-off) to only one of these types of tests. Therefore, more than one type of test may be needed, and ideally the testing should be performed during a period of intense training.

The investigators recently adapted the EVH test, gold standard diagnostic test recommended by IOC-MC to diagnose EIB in elite athletes for its use in teenagers. Instead of the maximal voluntary ventilation (MVV) of 85% during 6 minutes, usually requested in adult subjects (which is 30XFEV1, but would mean an unrealistic performance of 100% of MVV in adolescents), a ventilatory target of 70% which corresponds to 21 x FEV1 in young athletes is feasible for the majority of athletes (see table 1). Therefore the test aims at a ventilation target of 70% during 6 minutes. Moreover, to exclude exhaustion as a cause of artificial FEV1 drop, the change in Tiffeneau index (TI=FEV1/FVC) was also calculated. Only if TI at the time of maximal fall minus TI at baseline was below zero, the fall in FEV1 is thought to reflect true airway obstruction.

With those small adaptations, the test can be performed in almost all high-school elite athletes aged 12-14 years. Surprisingly, 23% percent of basketball players (3/13), 21% of football players (4/19) and up to 54% of swimmers (6/11) aged 12-14 years, had a positive EVH test at enrollment to an elite sport program compared to 13% of control subjects. During the longitudinal observation (registered at clinicaltrials.gov (NCT02432183) unpublished results), two out of four football players with a positive EVH test, terminated their high-school elite program early. Although sport technical reasons might also be the limiting factor to continue the program, their EIB can also explain impaired performance that can ensue if preventive measures are not taken. It is however not yet clear which medical treatment ideally should be used in those elite athletes. Nevertheless, several treatment opportunities exist, which might at least enable them to perform their sports in optimal conditions.