Asthma or exercise-induced bronchoconstriction – a diagnostic challenge

Pichler Hefti Jacqueline
Swiss Sportclinic, Sempachstrasse 22, 3014 Bern, Schweiz

Introduction

Globally, asthma has been shown to be the most prevalent disorder among chronic respiratory diseases with 262.4 million (224.1–309.5) cases during the period of 1990-2019. [1] In Switzerland, the cumulative incidence of asthma in adults is reported to range from 4.5% to 6.4% and even a higher prevalence of 9.1% is found in children. [2,3] Also, asthma contributes to the most relevant medical problems at the Olympic Games. [4]
Although it is a very common medical problem, there is a substantial proportion of both, underdiagnosis and misdiagnosis in all age groups. [5]
Asthma refers to a heterogenous group of inflammatory airway diseases. The non-specific symptoms are breathlessness, chest tightness, cough and wheezing. Wheezing refers to an expiratory high frequent noise, which is the most specific symptom for asthma. Typically, symptoms vary in intensity and frequency.
A hallmark of asthma is airway hyperresponsiveness (AHR) resulting in a variable expiratory flow limitation. [6] In asthmatic patients, exercise might trigger bronchoconstriction. Usually, the more severe and uncontrolled the asthma, the more often exercise triggers asthma symptoms.
Some athletes develop asthma symptoms who do not have an asthma. In these subjects, repetitive rigorous exercise with high minute ventilation induces airway inflammation and AHR, leading to exercise-induced bronchoconstriction (EIB). The pathophysiological processes are not fully understood and includes mainly mucosal dehydration and airway cooling. Both are promoted by intense physical activity with increased mouth breathing over a prolonged time. Inhalation of cold and dry air and/or exposure to pollutants such as ozone/chlorine (swimming pools), ozone/smog (e.g. triathlon, long distance running) might predispose even more to EIB. [7,8] Prevalence of EIB ranges from 30-70% and some sports are at particular risk (table 1). [9] In general, AHR in athletes with EIB resolves when they no longer train extensively.

Evaluation of athletes and diagnostic challenges

The diagnosis of asthma should not rely on symptoms alone, as they have a low sensitivity and specificity. A combination of symptoms and objective testing should always lead to the diagnosis and respective treatment.[6]
Asthma and EIB are characterized by AHR [7], which corresponds to an abnormal reduction of the airway airflow to non allergic stimuli. [11] A wide variety of triggers can initiate bronchoconstriction and today there are several options to test for AHR (table 2).

Methacholine challenge test is categorized as a direct test because it directly stimulates airway smooth muscle cells. Indirect tests, e.g. exercise, eucapnic voluntary hyperpnea, or hypertonic saline challenge, act on neuronal and inflammatory cells leading to bronchoconstriction by release of cytokines and other mediators in prone subjects. [12] The airway response to different stimuli can vary and AHR to direct and indirect test are not correlated in any way. [13] Since indirect test are based on the inflammatory cascade of AHR they offer not only a diagnostic tool but might objectify treatment effect.
It is important to recognize that in athletes with EIB, AHR might be present only during intense training and competition phase and therefore, sometimes multiple and different testing modalities are needed to confirm the diagnosis. A therapy trial with inhaled bronchodilator combined with inhaled corticosteroid (ICS) to observe a subjective benefit is not recommended for diagnosis of asthma or EIB. [6] Treating subjects and especially athletes without a diagnosis should be refrained from due to the unspecific symptoms and since the treatment of choice (beta-2-agonists) is only conditionally allowed, according to the World Antidoping Agency (WADA) Prohibited List. [14]
Several points contribute to the contraindication to perform bronchial challenge tests: 1) FEV₁ < 60% predicted for methacholine and <75% predicted for exercise challenge or eucapnic voluntary hyperpnea; 2) reduced spirometry quality and inability to perform reliably repetitive manoeuvres; 3) cardiovascular problems or other acute medical conditions (e.g. myocardial infarction or stroke within the last 3 months, aortic aneurysm, recent eye surgery). [15]
To ensure patient safety and test quality, any of the tests should be conducted under the supervision of trained personnel with immediate access to bronchodilators and other treatment to reverse bronchoconstriction if needed. Also, a physician needs to be available to respond quickly to an emergency. [15]

Lung function testing and bronchodilator response

If asthma or EIB contribute to the differential diagnosis in a patient or athletes lung function testing is the first step to assess whether a ventilatory obstruction is present or not. Today interpretation of measurements is based on the lower limit of normal which corresponds to a Z-Score of <1.645. Obstruction is defined by abnormal low FEV₁/FVC. [16] In addition, a second spirometry after inhalation of short acting beta agonist (SABA) is recommended to assess for a positive bronchodilator response (increase in FEV₁ ≥12%/200ml after inhalation of SABA), which is a sign of AHR (figure 1). [6] Normal spirometry values do not exclude an asthma or EIB and especially athletes do have supranormal lung volumes. The presence of supranormal lung volumes does not exclude of a positive bronchodilator response per se.

Methacholine challenge testing

The methacholine challenge test involves the controlled serial inhalation of increasing concentrations of methacholine. It is recommended to use tidal breathing with a nebulizer for inhalation of methacholine to avoid bronchoprotective effects of deep-breath methods. [14] Baseline lung function is first assessed by spirometry, measuring the forced expiratory volume in one second (FEV₁). Methacholine is then administered in progressively increasing doses, with spirometry and FEV₁ measured after each dose. There exist several protocols of dosing regimen for methacholine. I recommend the technical standard of the European Respiratory Society. [14] The challenge continues until a ≥20% fall in FEV₁ is observed compared to baseline or the highest dose is reached without a significant response. The result is expressed in the provocative dose leading to a ≥ 20% fall in FEV₁ (PD20). A PD20 >400ug is considered as normal. [15]

Exercise challenge testing

This indirect test includes a baseline spirometry followed by specific rigorous exercise challenge. FEV1 is again measured 5, 10, 15, and 30 minutes after exercise. A fall in FEV₁ of
≥ 10% compared to baseline denotes a positive test. [17] The ideal exercise to provoke EIB has only a short warm up phase of 2-4 minutes followed by high intense exercise of 6-8 minutes with a heart rate of 85-95% of the predicted maximum and a ventilation of at least 17.5 x FEV₁. Usually, this kind of test has a high positive predictive value to detect EIB, although sensitivity might be low in the laboratory setting.

Eucapnic voluntary hyperpnea

This test is based on an inhalation of a gas mixture with an increased fraction of CO₂ of 5% and 21% O₂ over at least 6 minutes. During this period, a high voluntary minute ventilation of 85% predicted is needed to maintain a high test sensitivity. Post inhalation serial lung functions at 1, 5, 10, 15 and 20 minutes are performed and compared to base line values. A fall in FEV1 ≥ 10% is considered positive. [18]

Summary and conclusion

Asthma subsumes a heterogeneous group of inflammatory airway diseases with variable expiratory flow limitation. Exercise is a common trigger in asthmatic patients. But intensive exercise with high minute ventilation can lead to airflow limitation with EIB in athletes without asthma. The main underlying processes are dehydration of the airway mucosa, airway cooling and rewarming, as well as physical stimuli. Depending on the sport athletes perform they are at substantially increased risk to develop EIB. Although the discrimination of asthma and EIB is often difficult, it is essential to choose a diagnostic meaningful approach. In addition, in subjects with EIB repetitive and/or different tests are needed to confirm the diagnosis. It is not possible to exclude EIB with one single test.
The International Olympic Committee (IOC) demands a careful diagnosis based on objective tests and with a focus on relevant comorbidities and differential diagnosis such as exercise-induced laryngeal obstruction (EILO) and dysfunctional breathing. [19]
Also, it is recommended to confirm an asthma or EIB diagnosis in athletes who were diagnosed in childhood.

• Exercise-induced bronchoconstriction might present very similar to asthma but in contrast to asthma, airway hyperresponsiveness is usually reversible if athletes refrain from intensive sporting activities.
• Cross-country skiing and ski mountaineering, ice hockey, swimming, long distance running, triathlon, and cycling contribute to the high-risk sports for athletes to develop exercise-induced bronchoconstriction.
• Diagnosis and treatment of asthma and/or EIB needs an objective diagnostic procedure.
• Airway challenge testing is a key point in the diagnosis of asthma or exercise-induced bronchoconstriction.
• Negative methacholine challenge testing can exclude an asthma but not exercise-induced bronchoconstriction.
• Several indirect challenge tests might be needed to detect exercise-induced bronchoconstriction.
• Standard treatment of asthma and EIB needs special considerations in athletes. Always check and recheck in order to respect antidoping regulations on http://www.globaldro.com

Corresponding author

PD Dr. med. Jacqueline Pichler Hefti
Swiss Sportclinic Bern
Sempachstrasse 22, 3014 Bern
Switzerland
Jacqueline.pichler@swiss-sportclinic.ch


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