The prevention of exercise-induced bronchoconstriction: what are the options?

Keywords::

• airway dehydration
• hyperpnea
• mast cells
• mediators

Exercise-induced bronchoconstriction (EIB) describes the transient narrowing of the airways that follows vigorous exercise. It occurs most commonly in people with currently active asthma but has also been identified in school children, elite athletes and defence force recruits with no clinical diagnosis of asthma. EIB is identified by measuring a 10% fall in the forced expiratory volume in 1 s (FEV₁) from the pre-exercise value within 30 min after exercise. The maximum % fall in FEV₁ is used to express the severity of EIB, with the area above the % fall in FEV₁ time curve providing an index of severity over time [1]. A refractory period follows exercise in about 50% of subjects so that the same exercise task repeated within 1 – 2 h results in less than half of the initial fall in FEV₁.

There are many options to prevent EIB and they all relate to modifying either the stimulus or the mechanism of EIB. The stimulus to EIB is the loss of water by evaporation from the airway surface in response to humidifying large volumes of air during exercise [2]. The drier the inspired air and the higher the ventilation during exercise, the greater the potential for EIB to occur in a susceptible subject. When evaporative water loss is prevented during exercise by conditioning the inspired air to body temperature and 100% relative humidity, EIB is prevented in most subjects [3]. Unfortunately, this simple technique cannot be used in most climatic conditions because heat loss from the airways during exercise is usually necessary to maintain normal body temperature. When exercise is performed in subfreezing conditions, face masks that are specifically designed to reduce heat and water loss can be a very effective means for preventing or ameliorating EIB [4]. In temperate climatic conditions, the severity of EIB is reduced as the water content of the air increases above 10 mg H₂0/l (i.e., 50% relative humidity at 20°C) [3].

One mechanism explaining EIB relates to the potential for evaporative water loss to cause a transient increase in osmolarity of the airway surface. This hyperosmolar environment acts as a nonimmunological stimulus for the release of mediators that cause airway smooth muscle contraction with airway narrowing. The source of mediators are the mast cells and eosinophils that are found at or close to the airway surface [5]. While the number of these cells is abnormally high in people with currently active asthma, mast cells are found in high density in healthy nonasthmatic subjects [6]. The mediators include prostaglandins and histamine that contribute to the onset and severity of the EIB, and cysteinyl leukotrienes that sustain the presence of EIB and retard recovery of FEV₁. Sensory nerves are also likely to be involved, in that they respond both to a change in osmolarity and to cysteinyl leukotrienes [7].

There are many options available to prevent EIB by pharmacological agents. Effective agents in EIB include those that prevent the release of mediators or those that block the response at a receptor or act as a functional antagonist on the muscle. For example, EIB is effectively prevented in the majority of asthmatic subjects by inhaling a β₂ agonist at the clinically recommended dose immediately before exercise. Inhalation is the most effective route of administration because a high concentration of drug is immediately achieved at the airway surface. This high concentration is necessary to stimulate β₂ receptors on mast cells to prevent release of contractile mediators and to induce sufficient relaxation of the airway smooth muscle to antagonise the effects of such mediators.

The potential duration of protection afforded by a β₂ agonist is 4–6 h for a short-acting β₂ agonist (SABA), for example albuterol or terbutaline, and twice as long for a long-acting β₂ agonist (LABA), for example formoterol or salmeterol. However, tolerance develops if these drugs are taken daily [8]. This tolerance primarily manifests as a reduction in the duration of protection to 2 h for SABA and 6 h for LABA. This aspect of tolerance probably relates to the downregulation of β₂ receptors on the mast cell so that the agonist is less effective in preventing mediator release. Other aspects of tolerance manifest as a more rapid onset of EIB and a slow and incomplete response to a SABA in the event of using one for breakthrough EIB [9].

The well-documented tolerance that accompanies daily use of β₂ agonists has led to other drugs being recommended to prevent EIB. The leukotriene antagonists are now well established as effective in reducing severity of EIB and reducing the time to recover to pre-exercise FEV₁. While all the leukotriene receptor antagonists ameliorate EIB, only montelukast (Singulair^{TM, Merck, NJ, USA}) has a specific indication for preventing EIB. A single oral dose of 10 mg is effective at 2, 12 and 24 h after dosing [10]. Montelukast reduces the % fall in FEV₁ by 40–60% and reduces the time of recovery of FEV₁ to pre-exercise levels. Furthermore, no tolerance develops to this drug when it is used daily [11]. However, not all subjects have their EIB significantly inhibited by montelukast. This is unsurprising because EIB is associated with release of other contractile mediators such as histamine and prostaglandin D₂. It is most unusual for a single and specific antagonist to prevent EIB. Combining an antihistamine with montelukast has been shown to be more effective than a single agent alone but the combination is not commonly recommended.

Sodium cromoglycate (Intal^TM, sanofi-aventis, Paris, France) and nedocromil sodium (Tilade^TM, sanofi-aventis) are other drugs with an indication for EIB [12]. These drugs are immediately effective against EIB even when used for the first time. They have no action on smooth muscle and tolerance does not develop to their protective effect on EIB. Their protective effect is thought to be via the stabilization of mast cells and sensory nerves. They are effective in preventing the bronchoconstriction provoked by hyperosmolar aerosols [13]. These drugs are no longer in common use in the USA but are still available elsewhere. For those not wishing to take β₂ agonists or inhaled corticosteroids (ICSs), these drugs are most useful when given at twice the clinically recommended dose immediately before exercise. The duration of their protection is usually ≤4 h.

The option that is most attractive to prevent EIB over the long term is to take ICSs daily for 8–12 weeks [14–16]. The results of many studies suggest that ICSs reduce the severity of EIB in all asthmatic patients. When clinically recommended doses of budesonide (Pulmicort^TM, AstraZeneca, London, UK), fluticasone (Flixotide^TM, GlaxoSmithKline, Brentford, UK) and ciclesonide (Alvesco^TM, Nycomed, Langebjerg, Denmark) are used daily, they provide protection against EIB within weeks, with higher doses providing a more rapid benefit [14–16]. If this approach is used, patients could be advised to take their SABA immediately before exercise for the first 3–4 weeks of treatment with ICSs. Then they may withhold the SABA immediately before exercise in order to ascertain the benefit of their treatment with ICSs. The benefit of ICSs alone should be recognized within this timeframe, although treatment is best continued for up to 12 weeks. In the event of breakthrough EIB, a SABA can be used to reverse the EIB. What is not known is how long the benefit of the ICS treatment lasts following cessation of ICS treatment. If the benefit of ICSs against EIB is a reduction in the number of inflammatory cells, for example eosinophils and mast cells, then the benefit should last until these cells return in significant numbers with adequate concentrations of mediators [17,18]. This timing will depend on the subject’s exposure to relevant allergens, viruses and other exacerbating factors. Studies using hyperosmolar aerosols suggest that it may take some months for responsiveness to return.

EIB is often the first sign of asthma to come and the last to go with treatment so that control of EIB is an indicator of asthma control. Unfortunately, neither the presence of EIB nor its severity is revealed by Asthma Control Questionnaires. In one study, the positive-predictive value of the Asthma Control Questionnaires. In one study, the positive-predictive value of the Asthma Control Questionnaire for EIB was 51%, and the negative-predictive value was 59% [19].

A pilot study demonstrated a reduction in EIB in children transferred from combination therapy (β₂ agonist and ICS) to ICS therapy alone in the same dose [20]. LABAs induce tolerance and may become less effective in preventing mediator release. A similar trial in larger numbers of subjects, taking into account the natural variation in EIB severity, needs to be performed to confirm these important findings.

In conclusion, any intervention that reduces the amount of water lost or increases the water content of the inspired air will reduce the severity of EIB. Therefore, improving fitness can reduce the ventilation required for a task and reduce EIB. Warm-up exercise prior to intense exercise may be protective by stimulating release of bronchodilating mediators. Warm-up by increasing bronchial blood flow may enhance replacement of water at the airway surface. These approaches may be impractical, particularly for those who have persistent asthma and have EIB on a regular basis. In these cases, prevention of EIB by using drugs that work acutely within minutes or hours or after some weeks are recommended. A trial of ICSs, without LABAs, is recommended in appropriate doses as a reliable means of reducing the severity of EIB in the long term. In those with more severe EIB, a trial combining ICSs and montelukast may be useful [21].

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.