Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs in response to exercise. The term ‘exercise-induced bronchoconstriction’ is preferred to that of ‘exercise-induced asthma’ since asthma is a chronic condition which is not induced by a single bout of exercise. Exercise-induced bronchoconstriction (EIB) is most common in individuals with asthma but also occurs in those without.

EIB is characterised by falls in forced expiratory volume in one second (FEV1) after exercise. This differs from individuals with asthma, who exhibit persistent airway inflammation and recurrent symptoms outside of exercise (commonly with a respiratory infection or following allergen exposure).¹

Who is affected by EIB?

EIB can occur in children and adults of various fitness levels, ranging from recreational to elite competitors, with a reported prevalence of 10-50% or greater in high level athletes, depending on sport and surveillance or diagnostic methodology. 

Triggers

EIB typically occurs after high intensity aerobic exercise during which high ventilation (> 85% of maximal voluntary ventilation) dehydrates the respiratory mucosa and leads to a transient increase in airway osmolarity, mast cell activation with mediator release (including histamine, serine proteases, prostaglandins, and leukotrienes) and bronchoconstriction.

Exacerbations are commonly reported during cold weather but this is usually caused by the greater respiratory water loss of the dry environment, rather than due to the low temperature.²

Increased exposure to allergens and respiratory irritants may exacerbate bronchoconstriction during periods of high ventilation exercise. EIB may also be seasonal in some individuals with atopy, although research on this association is limited.

Certain athletic endeavours and conditions specifically associated with a greater risk of EIB include exercising adjacent to roads with a high traffic volume, regularly skating at ice rinks where ice resurfacers are powered by fossil fuels, participating in winter sports (due to the dry ambient air as mentioned earlier in the article), and swimming in indoor chlorinated swimming pools with high inhalation exposure to chloramines (respiratory irritants created by the reaction of nitrogenous waste products with chlorine).

Presentation

Individuals with EIB typically complain of breathlessness, wheezing, coughing, and chest tightness during or after exercise. Symptoms caused by bronchoconstriction typically develop within 15 minutes after exercise and spontaneously resolve within 60 minutes. Athletes often seek medical input because the associated symptoms impair their sports performance. 

Diagnosing EIB

Where EIB is suspected based on patient history and clinical examination, formal diagnosis requires either direct or indirect challenge tests. These tests are designed specifically to induce bronchoconstriction. FEV1 is considered preferable to peak flow as a marker of bronchoconstriction due to its better repeatability and more discriminating nature.

A direct challenge test involves the use of a nebulised drug to stimulate bronchoconstriction of airway smooth muscle, whereas an indirect challenge test attempts to achieve the same result through dehydration of airway mucosa.

Indirect tests are preferable to direct tests as they replicate the environmental conditions and the pathophysiology, including the inflammatory mediator release, that trigger respiratory symptoms. 

Spirometry before and at five, 10, 15, and 20 minutes after the stimulus measures any change in FEV1. The responsiveness of the airways should be measured as the percentage fall in FEV1 from the baseline, pre-exercise value. 

The difference between the pre-exercise FEV1 value and the lowest FEV1 value recorded within 30 minutes after exercise is expressed as a percentage of the pre-exercise value.

A reduction of > 10-15% in FEV1 at two consecutive post-challenge time points is considered diagnostic for EIB, though specific recommendations vary (for example, the European Respiratory Society recommends a > 12% fall in FEV1). FVC is not required as repeated efforts may tire the subject.

Challenge tests should be conducted only in facilities where a bronchodilator, supplementary oxygen, resuscitation equipment, and medical staff are readily available in the event of a severe response (with the exception of the mannitol challenge).

Direct and indirect challenge tests are contraindicated in patients with baseline impairments in FEV1 (< 70-80% of predicted).³

High intensity exercise challenge

High intensity exercise has the advantage of exposing the individual to sport-specific physiological demands. The ideal protocol to detect EIB involves a rapid increase in exercise intensity over approximately two to four minutes to achieve a high level of ventilation. This is usually conducted with the individual running or cycling and requires sufficient time spent at high intensity activity. Individuals should be working at > 90% of their maximal heart rate for the last four minutes of an eight minute exercise challenge.

As mentioned above, spirometry before and at five, 10, 15 and 20 minutes after the stimulus measures the change in FEV1. 

Approximately half of athletes with EIB will have a negative exercise challenge test result, so two tests may be required in order to exclude the diagnosis. Diagnostic thresholds are based on a greater post-challenge decrease in FEV1 than that shown by 95-99% of the healthy population (two to three standard deviations beyond the mean response).⁴

Other tests

Other indirect tests include the Eucapnic Voluntary Hyperpnoea test (EVH) which requires an athlete to complete a period of voluntary hyperpnea with a dry gas inhalant, which desiccates the airways, mimicking the osmotic priming stimulus to EIB and the mannitol challenge which produces bronchoconstriction in a controlled and stepwise manner with increasing amounts of inhaled powdered mannitol.

The direct challenge involves the inhalation of nebulised methacholine in increasing concentrations until a given decrease (generally > 15%) in FEV1 is achieved in the patient.

False negative challenge results

Common causes of false negative challenge results include: 

• Failure to expose the patient to sufficiently dry air required to induce EIB
• Insufficient exercise intensity (ie. < 90% of maximum heart rate) 
• The use of preventative asthma medications
• Recent intense or intermittent warm-up exercise
• The use of a peak expiratory flow meter as a diagnostic tool instead of a spirometer
• The timing of the test in the incorrect season in those individuals who experience bouts of, or live with, seasonal EIB.

Differential diagnosis

Other than asthma and EIB, there are some differentials that must be considered in the patient presenting with shortness of breath during exertion. These include exercise-induced laryngeal obstruction (EILO), inadequate fitness, exercise-induced hypoxaemia, obesity, thoracic musculoskeletal pathology, anxiety, pneumothorax and more potentially serious causes such as anaemia or cardiorespiratory pathology.

Exercise-induced laryngeal obstruction

EILO, previously termed vocal cord dysfunction, is one of the most common causes of breathlessness in athletes, along with asthma. EILO and EIB are common comorbidities, but most individuals with EILO will not also have EIB.

EILO will often produce an inspiratory stridor that can easily be confused with the wheeze of EIB. The stridor of EILO occurs during inspiration in the laryngeal region during exercise and resolves quickly after stopping exercise, whereas the wheeze associated with EIB typically occurs during exhalation and often lingers after cessation of exercise.

EILO should be considered in athletes who present with symptoms consistent with EIB but who test negative for it in bronchoprovocation testing, or in those who have been diagnosed with EIB but are unresponsive to the appropriate management. If EILO is suspected, the diagnosis can be confirmed with a laryngoscopy during high intensity exercise.

Management

Warm-up

As mentioned earlier in this article, a refractory period can often be elicited following an episode of EIB. This can be used to attenuate the severity of the episode. The most consistent and effective attenuation was observed with high-intensity interval and variable intensity pre-exercise warm-ups. 

A potential warm-up routine for athletes with EIB could include some sprint interval exercise (such as six to eight bouts of 30-second sprints with 45-120 seconds rest between each bout).

Manoeuvres to pre-warm and humidify the air during exercise such as breathing through a face mask or scarf may also be beneficial.

Pharmacological therapy

The most common therapeutic recommendation to minimise or prevent symptoms of EIB is the prophylactic use of short-acting bronchodilators – SABAs (beta2-agonists), shortly before exercise. 

These agents cause muscle relaxation and bronchodilation by stimulating beta2-receptors on airway smooth muscle, as well as possibly preventing mast cell degranulation. SABAs, given by inhalation five to 20 minutes before exercise, are usually effective for two to four hours in protecting against or reducing EIB. They may be ineffective in preventing bronchoconstriction in 15-20% of individuals with asthma.

Pooled data from the American Thoracic Society indicated that patients who received an inhaled SABA had a maximum percentage fall in FEV1 after exercise that was 26.03% less than that among patients who received placebo.

Beta agonists can be used before exercise two to four times a week to prevent bronchoconstriction, They can also be taken as a rescue inhaler as required, but they should not be used daily. Daily use of beta2-agonists alone or in combination with ICSs may lead to tolerance, manifested as a reduction in duration of protection against EIB.

If beta agonists are needed more frequently, add on therapy is recommended with a daily inhaled corticosteroid (ICS), a daily leukotriene receptor antagonist, or a mast cell stabilising agent (MCSA) before exercise.

Long acting

Long-acting beta agonists are not advised as sole management for the treatment of either exercise-induced bronchoconstriction or asthma. It is suggested that there is a small but statistically significant increase in respiratory-related and asthma-related deaths and combined asthma-related deaths, or life-threatening experiences if taking sole long-acting beta agonists. Concomitant ICS should be used if needed.

Inhaled corticosteroids

Daily ICSs are considered the most effective anti-inflammatory agents for EIB. For patients who continue to have symptoms of EIB despite the administration of a short-acting beta2-agonist before exercise, an inhaled corticosteroid may be added on.

Inhaled corticosteroids are most effective when they are administered daily and may take up to four weeks to reach maximum effectiveness. Their response is dependent entirely on dose. As mentioned, ICS therapy does not prevent the occurrence of tolerance from daily beta2-agonist use.

The American Thoracic Society recommendation for a daily ICS is based upon a systematic review which found that patients with EIB who receive a daily ICS had a mean maximum percentage fall in FEV1 after exercise that was 10.98% less than that seen among patients who received a placebo.

There is no known benefit to a pre-exercise ICS and patients with EIB who received pre-exercise ICS had a mean maximum percentage fall in FEV1 after exercise that was similar to that seen among patients who received a placebo.

Leukotriene receptor antagonists

Leukotriene receptor antagonists (LTRAs), such as montelukast or zafirlukast, administered once-daily, will reduce EIB and also improve the patient’s recovery to baseline. There is no development of tolerance when taken daily. LTRAs cannot, however, reverse bronchoconstriction, only aid in its management.

The magnitude of effect may be smaller for LTRAs than either ICS or pre-exercise SABA. However, the duration of action is longer, lasting up to 24 hours, which may potentially be very useful for patients or athletes engaging in physical activity throughout the day.

Pooled data from the American Thoracic Society indicates that patients with EIB who received a daily LTRA had a mean maximum percentage fall in FEV1 after exercise. This fall was found to be 10.70% less than the fall observed among patients who were administered a placebo.

The evidence in this area supports the efficacy of both ICS and LTRA medications in the management of EIB, although ICS therapy may have a more potent anti-inflammatory effect in patients with EIB associated with airway inflammation.

Mast cell stabilising agents (MCSAs)

MCSAs, such as sodium cromoglycate and nedocromil sodium provide protection against EIB by blocking degranulation of mast cells and release of mediators such as prostaglandin D2.

MCSAs appear to be more effective at attenuating EIB than anticholinergic agents, but less effective than SABAs. There appears to be no discernible advantage to combining MCSAs with SABAs, as the effects are similar to using just SABAs alone.

Anti-histamine

Antihistamines may be helpful in EIB in patients with allergies, as controlling allergies improves asthma control in general. 

Significance regarding elite athletes

Doping is defined as the use of any banned substance to improve athletic performance. The International Olympic Committee maintains a list of “substances and methods prohibited in-competition, out-of-competition and in particular sports”.

This has relevance to the management of EIB or asthma in elite athletes as since 2010, the use of salbutamol and salmeterol by inhalation no longer requires a therapeutic use exemption (TUE), as per the World Anti-Doping Agency (WADA). As of January 1, 2013, inhaled formoterol up to a maximum dose of 54µg/24 hours is no longer prohibited and, hence does not require a TUE.

Inhaled terbutaline remains on the banned list both in and out of competition. Inhaled glucocorticoids do not require a TUE.⁵

References

1. Smoliga J, Rundell K. Exercise induced bronchoconstriction in adults: evidence-based diagnosis and management. British Medical Journal 2016;352:h6951
2. Rundell KW, Anderson SD, Sue-Chu M, Bougault V, Boulet LP. Air quality and temperature effects on exercise-induced bronchoconstriction. Comprehensive Physiology 2015; 5: 579-610
3. Weiler JM, Anderson SD, Randolph C, et al; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: a practice parameter. Annals of Allergy, Asthma and Immunology 2010; 105(S): S1-47
4. Parsons J, Hallstrand T et al. An Official American Thoracic Society Clinical Practice Guideline: Exercise Induced Bronchoconstriction.American Journal of Respiratory and Critical Care Medicine. 2013; 187(9)
5. WADA Therapeutic Use Exemptions Physician Guidelines. December 2017