The major changes that we have seen in asthma in sport in the past 14 years are the tightening of the criteria for the diagnosis of asthma, the use of urine levels to monitor the use of sympathomimetics, the use of a pharmacodynamic tests to assist in deciding whether a sympathomimetic was used therapeutically or for performance enhancement, the allowing of the use of low-dose sympathomimetics in sport and the prevention of taking glucocorticosteroids off the banned list of drugs in sport.

This is what respiratory physicians tried to achieve from 1999 to the present:

• There should be no disconnect between asthma pathogenesis and definition (leading to differences in diagnosis and treatment) as practised by pulmonary physicians and sports medicine physicians
• The definition of asthma should be as written in the pulmonary and allergy/immunology literature
• Diagnosis should be made before therapeutic considerations
• We accept there is a difference between clinical, research and sport asthma, but this should be a measure of severity of pulmonary function test (PFT) changes, not of diagnostic criteria
• Any tests proposed should be standard tests readily available to the majority of practising pulmonary physicians throughout the world
• Our eventual diagnosis and management of asthma should not put the health of the patient or his/her performance at risk 
• Ideally, tests should be done more than six weeks prior to a major sporting event.

Optimal management of asthma in athletes

The main goal of asthma treatment as defined in the GINA guidelines is to control the disease by reducing or preventing respiratory symptoms and optimising pulmonary function. Management of asthma in athletes should be similar to non-athletes, with focus on adequate patient education, reduction of relevant environmental exposures, treatment of associated comorbid conditions, individualised pharmacotherapy, prevention of exacerbations and regular follow-up.

Education, which is often deficient in athletes, should include information on asthma and its management, including inhaler technique and the use of an action plan for exacerbations. Athletes should also be advised to avoid training when air quality is impaired and under extreme conditions of temperature and humidity. The use of a facemask attenuates exercise-induced bronchoconstriction (EIB) in cold air athletes and has a synergistic effect when combined with ß2-agonists. Although the high ventilation rate in these athletes makes these masks difficult to use in competition, use of these heat moisture exchangers should be encouraged during training sessions. 

Measures to reduce chlorine derivatives in swimming pools, ozone, and particulate matter in indoor sports arenas should be considered. Comorbid conditions such as upper-airway diseases, gastro-oesophageal reflux and vocal cord dysfunction should be identified and treated. 

Treatment of asthma

Pharmacotherapy

Pharmacotherapy should be individualised in athletes with the aim of attenuating EIB. This is best achieved by the use of adequate doses of inhaled corticosteroids (ICS) for an adequate time. If EIB is still not controlled despite adequate inhaler technique and good compliance, the dose of ICS can be increased or treatment can be supplemented with another medication, such as a long-acting ß2-agonist or a leukotriene antagonist. However, although quite effective in reducing EIB, ICS and leukotriene antagonists seem to be less effective in reducing airway inflammation, airway hyper-responsiveness (AHR) to methacholine and improving respiratory symptoms in the athlete than in the non-athlete. This may be due to the presence of a more neutrophilic than eosinophilic airway inflammation in the athlete. In this regard, it had been previously shown that asthmatics with a low sputum eosinophil count showed a reduced effect of ICS on symptoms, AHR response, and inflammatory cell counts compared to those with a high sputum eosinophil count. A suboptimal response to ICS may reflect a predominance of airway remodelling over inflammation, a reduced response of glucocorticoid receptors (GCRs) or to the athlete’s symptoms not being related to asthma itself. These possibilities have not been adequately investigated. Athletes should also have a fast-acting bronchodilator for relief of intermittent symptoms and prevention of EIB.

Treatment based on PFT

A positive response to ‘indirect’ stimuli is consistent with currently active airway inflammation and provides an indication to treat ICS. After three to eight weeks of daily treatment with clinically recommended doses of ICS, 50% of subjects could expect remission of their EIB. Further, drugs used acutely for the prevention of EIB, such as the leukotriene receptor antagonists, nedocromil sodium or sodium cromoglycate, and antihistamines, can also reduce the response and enhance recovery. 

Onsite bronchial provocation tests

Although there are lab protocols to investigate patients, a field test involving work-specific challenge of either actual or simulated exercise was found to be more sensitive for identifying EIB than an eight-minute treadmill run at a speed and slope that elicited 95% peak heart rate. Skating has proven a good environmental-specific exercise to identify EIB. However, a field test of cross-country skiing for 7-10km was not sensitive for identifying AHR in elite athletes. As it is the ventilation (rather than the heart rate) and the water content of the air inspired that are the most important factors for identifying EIB, alternative tests were sought to encompass these factors.

The eucapnic voluntary hyperpnoea (EVH) test was developed as a surrogate for exercise in order to test for EIB. It requires the subject to achieve one-minute ventilation equivalent to 22-30 times FEV1 (L) for six minutes while breathing dry air containing 5% carbon dioxide. If necessary, the test duration, temperature and ventilation can be varied to simulate the conditions of the sport performed by the elite athlete. The response to EVH has been compared with exercise and other stimuli and is now well established for assessing elite athletes.

Hyperosmolar aerosols were originally introduced as surrogates for exercise and EVH because they simulated the effects of evaporative water loss on the airways and required less expensive equipment. Hyperosmolar (4.5%) saline is inhaled during tidal breathing as a wet aerosol generated by a large-volume ultrasonic nebuliser. Doses are increased by doubling the time of inhalation. Alternatively, mannitol powder can be delivered from a dry powder inhaler. Doses are increased by varying the dose and the number of capsules of mannitol inhaled. The clinical efficacy and safety of mannitol to identify AHR in healthy and asthmatic subjects have been established in phase III clinical trials, and the test is registered for this indication in Australia, Europe and Korea.

The pharmacological agent or ‘direct test’ most often used to evaluate athletes is methacholine chloride that is registered in North America and in some European countries. The International Olympic Committee-Medical Commission (IOC-MC) has not accepted tests using other pharmacological agents. 

Methacholine stimulates acetylcholine receptors on the bronchial smooth muscle (BSM) to cause smooth muscle contraction. The fall in FEV1 in response to a particular concentration or dose provides an index of sensitivity of the BSM to methacholine. A positive response is consistent with asthma, or airway injury or airway remodelling. As healthy people can also respond to methacholine, it has been necessary to select an adequate dose or concentration to define an asthmatic response. 

There are a number of different techniques and devices used to deliver methacholine and this makes it difficult to be precise about dose/concentration equivalents so that only concentration is used in some guidelines. A value for PC20 of 1mg/ml has a very high specificity for identifying clinically recognised asthma in young adults. A provoking concentration to cause a 20% fall in FEV1 (PC20) of 4mg/ml is equivalent to a cumulative provoking dose (PD20) of 400 micrograms or a noncumulative PD20 of 200 micrograms, and identifies people with mild, moderate and severe AHR. To account for benefits from treatment with ICS, the value for identifying AHR in those taking ICS is higher (a PC20 of 16mg/ml, or PD20 of 1,600 micrograms and 800 micrograms for cumulative and non-cumulative doses, respectively). 

In patients with suboptimal lung function referred by respiratory physicians, methacholine is a sensitive test for identifying AHR. In epidemiological studies, however, pharmacological agents are no more sensitive for identifying AHR than indirect stimuli including exercise and hyperosmolar saline. In elite summer athletes, the sensitivity of methacholine to identify EIB has been reported to be only 36%. This low sensitivity to identify AHR in healthy fit subjects with good lung function is thought to relate to the greater potency of the mediators (prostaglandins and leukotrienes) released in response to the indirect stimuli compared with methacholine. 

In contrast, methacholine appears to be more sensitive to identify AHR in those exposed to cold, dry environments or the high levels of inhaled irritants that are found in swimming pools. AHR in these athletes may be due to airway injury and remodelling rather than the airway inflammation of asthma, although this remains to be confirmed. 

Glucorticosteroids

Pharmacological effects

Glucocorticosteroids (GCs) exert their pharmacological effects via genomic and nongenomic mechanisms. When considering the former mechanism, lipophilic GCs cross the cell membrane in order to bind the cytosolic GCRs. The GC-GCR complex translocates into the nucleus binding to the promoter region of the target genes thus resulting in the regulation of gene expression; a process commonly referred to as transactivation. The opposite mechanism is called transrepression in which the activated receptor interacts with specific transcription factors preventing the transcription of specific genes. This mechanism has been described for the prevention of the transcription of pro-inflammatory genes including interleukins IL-1B, IL-4, IL-5 and IL-8. The duration of both transactivation and transrepression mechanisms may last several hours. However, it is well known that several pharmacological responses to GC administration are observed within seconds or minutes and these responses are mediated by a non-genomic mechanism. It has been demonstrated that binding of GCs to GCRs stimulates the phosphatidylinositol 3 kinase and the protein kinase, AKT.

The most common use of GCs in clinical medicine is for chronic inflammation of asthma. It is a form of first-line treatment of asthma by inhalation. Asthma inflammation is characterised by degranulation of mast cells, infiltration of eosinophils, increased numbers of activated T-lymphocytes (helper-2 cells). Structural cells of the airways, eg. epithelial cells, airway smooth muscle cells, endothelial cells and fibroblasts, are a major source of mediators in asthma. This is especially seen in epithelial cells with its exposure to the environment. One-hundred known inflammatory mediators are released in asthma.  

Ergogenic effects

GCs have been widely used and abused in the belief that the many different beneficial effects of GCs will be elicited during physical efforts. Indeed, when considering their mechanisms of action, GCs may increase the availability of metabolic substrates in muscles, may prevent the release of pro-inflammatory cytokines as a result of exercise-induced muscle damage, may prepare the organism for the next bout of exercise and may enhance the release of dopamine in the CNS with positive mood changes. 

These physiological properties of GCs may explain the putative performance-enhancing effects of GCs. Nevertheless, all presumed ergogenic effects remain speculative since available literature continues to report conflicting results, as recently reviewed by Duclos. Indeed, studies suggesting that GC administration does not affect performances are counterbalanced by several other studies demonstrating that GC administration positively influences time to exhaustion, endurance performance, metabolic responses and perception of fatigue. It must also be noted that the contrasting results reported when examining the ergogenic effect of GCs are likely due to the different protocols adopted and, in particular, differences in the GC dosage, the route of administration, the type and intensity of the physical activity or physiological parameter tested and the composition of the studied population (eg. athletes). 

Finally, at present it is difficult to precisely distinguish a therapeutic injection of GCs from the illicit use of these substances with the purpose of artificially enhancing physical performance. Indeed, high-dose injections may reach metabolite levels comparable to those obtained with a former use of systemic GCs for doping purposes.

The sustained use of GCs should be prohibited due to their potential ergogenic effect and not least the documented harmful effects of long-term GC use. It is also this group’s opinion that the use of occasional one-off GC injections should be allowed for the treatment of musculoskeletal conditions and also as a prophylactic agent for seasonal allergic rhinitis (SAR) and conjunctivitis, as this is common medical practice and should be allowed without the need for a therapeutic use exemption (TUE). 

We should propose keeping GCs on the WADA Prohibited List but setting a urinary metabolite threshold to allow for levels that could be expected 48 hours after an injection. If athletes receive occasional one-off GC injections they will have periods where urinary metabolites are found, but other periods where they are absent. Unscrupulous athletes who try to cheat by taking repetitive low-dose GCs will have a higher metabolite level over longer periods of time – so the presence of urinary GC metabolites in doping samples on repeated tests would imply the continuous intake of GCs. One proposal would be to allow three GC injections in a 12-month period, but require that a TUE be issued for a further GC injection. 

Cellular effects of corticosteroids

Corticosteroids inhibit recruitment of inflammatory cells in the airway including eosinophils, T-lymphocytes, mast cells and dendritic cells. They inhibit the recruitment of inflammatory cells by suppressing the production of chemotactic mediators, adhesion molecules, inhibiting survival in the airways of eosinophils, T-lymphocytes, and mast cells. Epithelial cells may be major targets for inhaled corticosteroids.

GCRs in the cytoplasm are known as molecular chaperones. GCR-α binds corticosteroids. GC-ß is an alternatively spliced form that binds to DNA but is not activated by CSs. GCRs can be modified by phosphorylation which may change binding affinity, nuclear import and export, receptor stability and transactivating efficacy. Steroids enter the nucleus and bind to DNA at specific sequences in the promoter region of steroid response genes known as GC response elements, leading to changes in gene transcription. Activated GCRs regulate the transcription of target genes. This usually increases the protein synthesis. This can be done by switching on the histone acetylation and gene transcription. The activation of genes by corticosteroids is associated with a selective acetylation of lysine residues 5 and 16 on histone-4, resulting in increased gene transcription. 

References available on request.