Introduction

The ability to exercise comfortably is of central importance in the lives of patients of all ages. Exercise-induced bronchoconstriction (EIB) and exercise-induced asthma (EIA) are two similar conditions which can significantly impair this ability. EIB is defined as transient airflow obstruction in response to an exercise stimulus. In patients with previously diagnosed asthma, the term EIA describes the same phenomenon.

These conditions are important for several reasons. From a public health standpoint, in an age when guidelines from several health oversight committees strongly advocate frequent and vigorous exercise, the most important impact of bronchospasm is its tendency to make exercise uncomfortable, decreasing the frequency, intensity and duration of exercise bouts in children and adults. Additionally, from a performance standpoint, bronchospasm may impair performance through either ventilatory limitation or dyspnea.

Our understanding of the pathophysiology of bronchospasm is evolving in an age of improved biometric analyses. This insight has led to improved diagnostic strategies and may continue to do so among different groups of patients across different ages and performance requirements. It may also lead to therapeutic advances and more personalized strategies.

This chapter focuses mainly on the clinical features, pathophysiology, diagnostic strategies and treatments for EIA. When appropriate, the chapter makes specific reference to data applicable to isolated EIB. A section is devoted to specific groups of patients and athletes that require more individualized considerations. For completeness, it briefly reviews the epidemiology and impact of EIA as well as the differential diagnosis of exertional dyspnea.

Epidemiology

The number of people that suffer from EIA is staggering. In 2010, in the USA alone, over 25 million people were estimated to have asthma. Worldwide, an estimated 300 million people are affected. Specific high-risk groups include people of Puerto Rican, African American, and multiple race heritage as well as those living in urban areas or born to low-income parents. The majority of these patients with baseline asthma describe characteristic symptoms associated with EIA.

In addition to isolated asthma patients, the preterm birthrate is nearly 12% in the USA and the rate of associated chronic lung disease varies inversely with gestational age. Patients with chronic lung disease of prematurity are much more likely than controls to experience EIA.

Prevalence estimates for isolated EIB vary, but may be as high as 20% of casual adult exercisers. Among athletes, this number can be much higher, depending on the specific sport studied and testing methodology employed. Excellent summaries of EIB prevalence studies among athletes have been published.

Children are also affected by EIA, and prevalence varies by location and methodology from 4% to 20% in different studies. There is debate as to the existence of isolated EIB in young children because airway hyperreactivity is such a strong predictor of asthma onset at a future date, although many children diagnosed with EIA do not show signs of respiratory disease outside of exercise.

Impact

The burden of EIA takes many forms, including mortality and quantified morbidity. Death due to EIA is exceedingly rare, but has been reported. From the public health perspective, exercise avoidance due to EIA may be the most important burden on health. Children with untreated asthma have been shown to be less fit than age-matched controls. Moreover, asthma has been identified as a barrier to activity in children with measured inactivity, although this finding has not been replicated in all populations. The causal relationships between asthma and obesity are not fully understood, although both appear to affect each other. Moreover, there is reasonable fear that increased sedentary time in response to an asthma diagnosis or symptoms could lead to future increases in obesity, cardiovascular disease and death. From a cognitive perspective, in addition to asthma being a barrier to activity, EIA is associated with a decreased health-related quality of life.

The effect of untreated or undertreated EIA on performance is somewhat more difficult to quantify for ethical reasons. It is common for patients to complain of symptoms related to exercise and performance, but the effect of the bronchoconstriction that causes symptoms likely has variable effects on specific task performance. Possible causes of decreased performance related to bronchoconstriction include ventilatory limitation, increased work of breathing leading to decreased substrate delivery to performance muscles (without observed ventilatory limitation), and performance limitation due to dyspnea.

Treated EIB seems to have minimal impact on performance. In Olympic competition, using medals as the outcome of performance, there are no important differences between patients that carry a diagnosis of active asthma and nonasthmatic athletes.

Pathophysiology

There has been considerable debate regarding the mechanisms leading to EIA in the last four decades. It is possible that there is no unifying theory explaining all laboratory and clinical observations in EIA, but rather multiple phenotypes of disease which may vary across ages, exposures and characteristics of the underlying asthma. It is recognized that the central event in EIB is rapid airway epithelial water loss extending to smaller generations of airways due to an inability of the upper airway to adequately condition inspired air. EIB can be largely blunted simply by inspiring warm humid air. Two competing, but not mutually exclusive, hypotheses explain many of the downstream clinical phenomena observed in EIB: the osmotic hypothesis and the thermal hypothesis.

According to the osmotic hypothesis, the airway epithelial water loss leads to an increased osmolarity of the airway surface lining fluid. In response to this change, water then flows from epithelial and subepithelial cells in order to maintain equilibrium. This secondary flow of water causes intracellular changes and leads to the release of mediators which ultimately lead to bronchoconstriction. In 2014, it appears that experimental evidence favors this osmotic hypothesis over the thermal hypothesis.

According to the thermal hypothesis, airway cooling and subsequent bronchial vasoconstriction are followed by a reactive hyperemia. This vascular engorgement is considered to cause airway narrowing. Among other evidence consistent with this hypothesis are the interesting findings that inhalation of cold dry air or norepinephrine after exercise can attenuate EIB. It is important to note that airway warming and cooling are not required to trigger bronchospasm, an observation which has called into question the role of thermal change in EIA.

In addition to osmotic and thermal changes, the hyperpnea associated with exercise exposes the epithelium to increased mechanical stress as well as increased exposure to noxious agents. Airway desquamation is known to occur in response to exercise challenge in patients with EIA, although controls may also exhibit this phenomenon. There is evidence the oxidative stress at an epithelial level may be somewhat higher in patients that suffer from EIA. Through mechanisms that are not entirely elucidated, it is felt that dysfunctional injury repair mechanisms may predispose patients to both the acute and chronic changes seen in EIA. This is, in part, supported by observations that exercise challenges in patients with EIA, compared to controls, increase epithelial-derived 15S-hydroxyeicosatetranoic acid (proinflammatory) and decrease epithelial-derived prostaglandin E ₂ (PGE ₂ ) (anti-inflammatory).

The osmotic, thermal, and mechanical stresses that occur during exercise indirectly cause bronchospasm via a complex and incompletely understood cascade involving multiple effector cells and mediators ( Figure 36-1 ). In addition to epithelial sources, key mediators of bronchospasm have been linked to increased numbers of mast cells and eosinophils. A possible link between epithelial stress and effector cells is a combination of interleukin 33 (IL-33) and thymic stromal lymphopoietin, epithelial-derived mediators which affect mast cell differentiation and release of cysteinyl leukotrienes (cysLTs) and PGD ₂ .

Disease model of exercise-induced bronchoconstriction (EIB) pathogenesis. Asthmatics with EIB have increased concentrations of shed epithelial cells, cysteinyl leukotrienes (cysLTs) and cysLT-to-prostaglandin E ₂ (PGE ₂ ) ratio in induced sputum. Exercise challenge initiates the production of cysLTs, PGD ₂ , and 15S-hydroxyeicosatetraenoic acid (15S-HETE), and a reduction in PGE ₂ . An increase in secreted phospholipase A ₂ group X (sPLA ₂ -X) may increase the release of arachidonic acid (AA) by the epithelium or by adjacent inflammatory cells. Contraction of the airway smooth muscle and mucin release occurs in part through retrograde axonal transmission in sensory nerves that release neurokinin A. 15-LO-1 – 15-lipoxygenase-1; 5-LO – 5-lipoxygenase; COX – cyclooxygenase; cPLA ₂ – cytosolic phospholipase A ₂ ; MUC5AC – mucin 5AC; PL – phospholipids.

(From Hallstrand TS, Henderson WR. Role of leukotrienes in exercise-induced bronchoconstriction. Curr Allergy Asthma Rep 2009;9:18–25. Copyright © 2009 by Current Medicine Group LLC, reproduced with permission.)

cysLTs, derived from mast cells and eosinophils, have been strongly implicated in the pathogenesis of EIB, although their actions do not explain all observed bronchospasm. They have been detected in increased amounts in both exhaled breath condensate and sputum of patients with EIA. Clinical trials using leukotriene receptor antagonists (LTRAs) and leukotriene synthesis inhibitors for prevention of bronchoconstriction consistently demonstrate incomplete inhibition of bronchospasm.

Histamine is also implicated in EIA. Released primarily from mast cells in response to an exercise stimulus, it is thought to mediate the initial events in EIA. Antagonism seems to prevent bronchospasm in response to surrogate challenge, but has not consistently shown clinical benefit in exercise challenges.

There are mediators which may play protective roles in EIA, although much remains to be studied in this area. Lipoxin A4 levels appear to decrease in patients with notable EIA compared to controls. Prostaglandins may play a role in EIA, as suggested by antagonism studies using cyclooxygenase inhibitors as well as in primary studies of the airway in EIA, but mechanisms are poorly understood. Prostaglandins have been most convincingly implicated by their role in modulating refractoriness to repeated exercise challenges (a phenomenon which will be described later), although the precise mechanisms are far from clear.

Our understanding of the roles of sensory nerves and parasympathetic efferents is evolving. Neurokinins are released from sensory nerve fibers in response to a variety of stimuli, including hyperosmolar stimuli. Among other functions, neurokinins can stimulate secretion of mucin 5AC. Parasympathetic innervation, known to be involved in asthmatic responses due to the tendency for patients with asthma to demonstrate bronchoconstriction in response to methacholine, likely plays a more variable role in EIA across patients (as has been shown for decades). Some of the variability may be a result of differences in baseline vagal tone across subjects.

It is plausible to consider potential constitutive or induced differences in airway smooth muscle as predisposing factors to developing EIA for a variety of reasons, but there is a paucity of data regarding causal links in the area (especially in pure EIB). In addition to presumed mass-bronchoconstriction force mechanisms, the muscle itself may act to secrete mediators perpetuating inflammatory responses. Future research is needed in this area to clarify these possibilities as well as their relative importance to the overall clinical phenotype of EIA.

Refractoriness to EIA, the phenomenon in which repeated exercise challenge elicit a decremental bronchospastic response over a period of hours, may involve mediators other than those described above (although a precise mechanism is unknown). The mediators are likely similar to those induced by other indirect airway challenges as cross-refractoriness is known to occur between hyperventilation and exercise as well as mannitol and exercise. However, refractoriness does not necessarily exist between indirect and direct challenges. Catecholamine release, while initially suspected, is not thought to play an important role. Prostaglandin release in response to indirect stimuli (implicated due to the ability of indomethacin to eliminate refractoriness) and tachyphylaxis of cysLT receptors are the most widely accepted mechanisms of refractoriness at this time.

Characteristic Clinical Features

Patients describe EIA in terms of a variety of symptoms. Cough is generally the most common in study settings. Wheeze, chest tightness, disproportionate dyspnea for a given task and increased mucus production are also common symptoms. Symptoms generally occur after at least 8 to 10 minutes of exercise and persist for 30 to 45 minutes. At times, patients describe a phenomenon in which symptoms improve after continued exercise (the spirometric physiology of which is detailed below). Symptoms may vary in terms of frequency and severity with multiple environmental and exercise-associated factors, specifically worsening in cold, dry environments with high allergen or pollutant content. Activities with high ventilatory requirements (e.g. cross country skiing) are more likely to trigger symptoms than activities with low ventilatory requirements (e.g. golf). Generally, patients do not describe loud, audible breathing, severe distress or cyanosis (although fatal events are rarely documented in the literature). Generally, chest pain, pallor and syncope are not features of the disease.

On physical examination, patients generally appear normal in a clinic setting. Given the high proportion of patients that suffer from baseline asthma and atopy, stigmata of asthma and atopic disease may be present. Cyanosis, an extreme barrel chest, auscultated crackles and clubbing are not features of EIA and suggest alternative diagnoses.

In terms of diagnostic testing commonly available in the clinic setting, findings are often completely normal, but like the physical exam, may suggest baseline asthma and atopy. Resting spirometry may be normal or suggest obstruction. Bronchodilator response above resting spirometry may be present as well. Skin testing and exhaled nitric oxide testing are often positive. Chest radiography is generally normal, but may demonstrate hyperinflation. Definitive provocative testing is described in a later section.

The classic spirometric pattern demonstrated with bouts of exercise is one in which airflow may increase slightly during and immediately after exercise, decline to nadir values roughly 10–15 minutes after exercise and spontaneously resolve to near-baseline levels within 60 minutes. For unclear reasons, young children may demonstrate a slightly different pattern, with an earlier onset of measurable bronchoconstriction associated with a more depressed nadir.

One feature of EIA that is distinct from most other causes of dyspnea is refractoriness. Patients often describe this as the ability to ‘run through asthma’. Many patients with EIA, following an initial airway stress (which may or may not cause measured airway obstruction), can exercise without the degree of bronchoconstriction typically experienced for a given task. As noted above, the mechanisms behind this phenomenon are unclear and are likely similar across multiple indirect airway challenges.

The existence of a second phase in EIA is controversial and will not be reviewed in this chapter.

Groups Requiring Special Consideration

Several individual groups of patients with EIA require special consideration due to the frequency and severity of symptoms. Winter sport athletes who participate in activities requiring high ventilation are particularly susceptible to EIA and isolated EIB. Warm weather endurance athletes suffer EIA and EIB at a somewhat lower rate. The reasons for this are likely related to the magnitude of osmotic stress induced by the activities involved.

In addition to endurance exercise and cold weather exercise, exercise in environments with a high degree of particulate pollution is associated with high rates of EIA. This may particularly affect those who exercise in an urban area and those who exercise at indoor facilities cleaned or serviced by machines that emit particulate matter, including ice polishers.

Swimmers, while experiencing warm humid air while exercising, are exposed to high levels of a variety of compounds formed by the interaction of nitrogen-containing compounds and chlorine. In terms of acute bronchospasm, a high proportion of competitive swimmers suffer from symptoms. Chronic effects are less clear, with some authors suggesting a role for chlorine as a causative agent for asthmatic phenotypes later in life.

There are some young children who demonstrate severe EIA once old enough to perform spirometry. This seems to be associated or predicted by airflow limitation detected during (rather than after) exercise bouts, a phenomenon described as ‘breakthrough EIB.’ The mechanisms behind this severe decline are unclear. It is possible that the small airway caliber of children is to blame. It is also possible that large airway dysfunction plays a more important role than in older populations.

Differential Diagnosis

The differential diagnosis of EIA is quite broad, although several competing causes of exertional dyspnea are quite rare, especially in younger populations.

It cannot be overstated that the most important diagnosis to consider in a patient with known or suspected EIA or EIB is poorly-treated baseline asthma, especially in younger populations. Bronchial hyperresponsiveness is strongly suggestive of asthma and predictive of the development of asthma.

Inducible laryngeal obstruction at the glottic and supraglottic level should be strongly considered in patients that do not respond to inhaled bronchodilators. This is an umbrella term that includes paradoxical vocal fold motion as well as prolapse of the arytenoid cartilages. Clinically, patients with these conditions often describe rapid onset and resolution of symptoms when compared to typical cases of EIA. Rather than describe a typical refractory period, patients often describe worsening dyspnea with repetitive exercise. Symptoms often are associated with a high degree of distress as opposed to the mild discomfort typically associated with EIA. Inspiratory stridor can be present, but is not seen in all cases as it is likely a function of both the degree of obstruction and the instantaneous air flow rate. Regardless of stridor, hypoxemia is rare. The gold standard for diagnosis of these conditions is direct laryngoscopic visualization, but the intermittent nature of the condition can present challenges. Some highly-specialized centers advocate the use of continuous laryngoscopy during exercise.

Hypoxemia can be the cause of exertional dyspnea and performance limitation in the absence of overt distress. It can be normal for well-trained athletes to achieve mild hypoxemia (from the high 80s to low 90s) even at sea level. Generally, more important hypoxemia is associated with a degree of cyanosis. Intrapulmonary shunts have been described as a potential cause of hypoxemia. In younger populations, undiagnosed conditions leading to this degree of hypoxemia are rare (largely because cyanotic heart disease is detected at earlier ages).

Dysrhythmias have been described as a cause of exertional dyspnea. Generally, they should not be associated with cyanosis or hypoxemia. Rarely, muscle disease can manifest as dyspnea out of proportion to work rate.

The deconditioned patient presents challenges from a diagnostic perspective. There are no widely accepted criteria to quantitatively diagnose deconditioning. Moreover, a diagnosis of deconditioning does not exclude other causes of dyspnea.