Sindhura Bandi and Anand D. Trivedi
PULMONARY SYMPTOMS DURING AND/OR AFTER EXERCISE
Optimal exercise and athletic performance is contingent upon a healthy respiratory system. The respiratory system enables gas exchange and allows oxygen delivery to the exercising body. A number of medical conditions may affect respiratory function with symptoms manifesting during and immediately after exercise. These symptoms and medical conditions occur in both sexes. However, the nature of the symptoms, reporting of symptoms, prevalence, and management vary between men and women. Thus, it is important to consider gender when evaluating an individual with respiratory symptoms during exercise.
The most common respiratory symptoms during or after exercise include dyspnea (shortness of breath), wheezing, cough, chest pain, and chest tightness.
Dyspnea is a normal result of exercise. It can be difficult to determine whether the dyspnea is pathologic or due to deconditioning. A careful history and physical examination are important to differentiate if further evaluation of the shortness of breath is warranted. Common causes of dyspnea in athletes include asthma and exercise-induced bronchoconstriction (EIB), which is discussed in detail later in the chapter. Pulmonary function testing may be required to evaluate for asthma or chronic obstructive pulmonary disease (COPD) as well as other lung etiologies. If pulmonary function testing is normal and/or there is suspicion for a cardiac cause, cardiac testing may be indicated. Dyspnea with exercise can also be secondary to gastroesophageal reflux, aspiration of foreign body, infections, anemia, obesity, and metabolic disorders. Rare acute causes include spontaneous pneumothorax and pulmonary embolism.
The pathophysiologic basis of wheezing is turbulent airflow due to airway narrowing. Wheezing is a common symptom associated with asthma and EIB and, as such, should be evaluated for with pulmonary function testing. However, certain conditions such as foreign body aspiration, vocal cord dysfunction, exercise-induced glottis dysfunction, and laryngeal or subglottic stenosis/obstruction can also masquerade as asthma and present with wheezing and stridor. These conditions may occur only in the setting of exercise or be worsened by exercise. Evaluation by laryngoscopy or challenge testing should be performed if these conditions are suspected.
Cough is a common symptom reported by individuals presenting for evaluation of respiratory symptoms during exercise (1). The clinical history is vital in determining the nature of the cough, including the duration of cough (acute or chronic), associated sputum production, or symptoms of other disorders. Conditions such as allergic rhinitis, sinusitis, postnasal drip, and gastroesophageal reflux can commonly present as a cough, which may worsen with physical activity. Infection or a postinfectious cough must also be ruled out. In addition, medications such as angiotensin converting enzyme (ACE) inhibitors are also associated with a chronic cough. Lastly, asthma may present with a variant that may only manifest with a cough.
Chest Pain or Chest Tightness
Chest pain or chest tightness is commonly associated with cardiac conditions. These symptoms may not be considered when evaluating for asthma or exercise-induced bronchoconstriction. However, they can be common presenting symptoms of asthma. Immediate investigation and evaluation of cardiac etiologies is vital to exclude a life-threatening etiology of symptoms.
Asthma is a chronic disorder characterized by inflammation of the airways. This inflammation can result in mucus hypersecretion and bronchial smooth muscle constriction with subsequent airflow obstruction, which is variable and often reversible. This obstruction results in many of the previously described symptoms, such as dyspnea, wheezing, cough, and/or chest tightness. Asthma is a heterogeneous disorder that varies on the basis of age of onset, severity of disease, triggers or stimuli, and response to treatment.
Asthma is increasing in prevalence both in the United States and worldwide, particularly in industrialized countries. According to the Centers for Disease Control and Prevention (CDC), in 2010 there were 17.2 million (8.7%) adults with asthma and 4.6 million (8.5%) children with asthma in the United States and Puerto Rico. Current asthma prevalence is highest among adults aged 18 to 24, adult females, and multirace and black adults. Asthma prevalence is higher among females (10.7%) compared with males (6.5%) (2). There is significant morbidity and mortality associated with asthma, with approximately 500,000 hospitalizations annually due to asthma and nearly 5,000 deaths per year with asthma reported to be the underlying etiology of death (3). Females have a higher asthma death rate (11.6 per million) compared with males (8.8 per million) (4). Thus, the burden of disease in asthma remains high, especially for women.
There is a strong relationship between family history and development of atopic disease, such as asthma, allergic rhinitis, and/or atopic dermatitis. Studies of gene linkage, twin cohorts, and familial aggregation have confirmed this association. While asthma exhibits a complex inheritance pattern, in the United States, if one parent has allergic asthma the child has approximately a 20% chance of developing asthma. If both parents have allergic asthma this increases to an approximately 40% chance (5). There have been multiple genetic linkages associated with asthma, and this is an ongoing area of research.
Environmental factors affect the development of asthma as well as trigger asthma exacerbations in individuals with preexisting disease. A causal relationship has been established between exposures to house dust mites, cockroaches, tobacco smoke (prenatal exposure and environmental exposure after birth), and respiratory syncytial virus and the subsequent development of asthma in susceptible children (6). Multiple environmental factors exacerbate asthma and should be identified in an individual with asthma and mitigated. The formation of immunoglobulin E (IgE) antibody (sensitization) to environmental allergens typically starts occurring around ages 2 to 3. Indoor allergens, especially cockroach, cat, and dust mite, commonly exacerbate asthma in sensitized individuals.
Other Common Contributors to Asthma
Chronic asthma can also be exacerbated by multiple nonallergic triggers. These include irritants, pollutants, medications, and worsening of comorbid conditions such as chronic rhinosinusitis, tobacco use, obstructive sleep apnea, and gastroesophageal reflux. These must be evaluated for in all patients with asthma. Common triggers of asthma are further discussed in the next section.
Airway inflammation is a hallmark feature of asthma and leads to airway obstruction, reactivity, and remodeling. The specific pattern of inflammation varies depending on the chronicity and severity of the disease, which can affect responsiveness to therapy. Many inflammatory cells contribute to infiltration of the airways including eosinophils, mast cells, macrophages, T lymphocytes, and neutrophils. Inflammation can also affect airway epithelial cells and adhesion proteins. The airway inflammation results in bronchial hyperresponsiveness and respiratory symptoms, especially with exposure to stimuli. These triggers can include cigarette smoke, upper respiratory infections, chronic rhinosinusitis, allergens, irritants or pollutants, exercise, medications, and/or underlying medical conditions such as allergic rhinitis, obstructive sleep apnea, or gastroesophageal reflux. For example, in a sensitized individual, antigen (allergen) exposure will activate mast cells and recruitment of additional inflammatory cells into the airways. The antigen binding with the specific IgE antibody to the allergen leads to mast cell degranulation and release of histamine, prostaglandins, leukotrienes, and cytokines into the airways. These mediators result in bronchoconstriction, mucus secretion, and mucosal edema. Over time, there is hypertrophy of the smooth muscle of the airways and thickening of the lamina reticularis below the basement membrane.
Clinical Presentation and Differential Diagnosis
Asthma, being a heterogeneous disorder, presents in a variety of ways. In children, it may present as a chronic cough. In some patients, it may appear to be isolated, occurring during exercise, allergen exposure, or upper respiratory tract infection. However, typically the characteristic symptoms of asthma are repeated episodes of wheezing, cough, dyspnea, or chest tightness. The onset of asthma typically occurs in childhood and is strongly associated with atopic dermatitis and allergic rhinitis. However, asthma inception can also occur in adulthood and may or may not be associated with allergic disease. The differential diagnosis of asthma is broad (Table 19.1); however, these entities must be considered in all patients, especially those who do not respond to standard treatment for asthma.
Diagnosis and Testing
Pulmonary function testing is used to detect airway flow obstruction on expiration and bronchial hyperresponsiveness. Spirometry measures the maximal volume of air exhaled from the point of maximal inhalation (forced vital capacity, FVC) and the volume of air exhaled during the first second (forced expiratory volume, FEV1). Obstruction is indicated by decreased FEV1 and decreased FEV1/FVC ratio when compared to matched controls. This airway obstruction leads to a classic scooped or concave appearance of the expiratory flow volume loop (Figure 19.1). This concave pattern is due to the dynamic collapse of the airways.
TABLE 19.1: Differential Diagnosis of Asthma
Vocal cord dysfunction
Laryngeal or subglottic stenosis
Chronic obstructive pulmonary disease
Vocal cord dysfunction
Once obstruction is noted on spirometry, reversibility with bronchodilators such as the beta-adrenergic agonist albuterol is assessed. An improvement in FEV1 of at least 12%, with also at least a 200 mL increase in volume after administration of a bronchodilator, suggests bronchial hyperreactivity. If this correlates with a suggestive clinical history, the diagnosis of asthma can be made.
Methacholine bronchoprovocation testing can also be performed to measure the degree of airway hyperresponsiveness. This is typically only performed if the patient has normal baseline spirometry and the diagnosis of asthma remains in question. Methacholine is a cholinergic agonist that acts on airway smooth muscle muscarinic receptors to produce bronchoconstriction. There are different protocols for these challenges, but positive results are often presented as the concentration of methacholine that results in a 20% decrease in FEV1.
Classification of Asthma
While asthma is a disease of various phenotypes, classically it has been divided into two subtypes: allergic asthma and nonallergic asthma, with aspirin-induced asthma (aspirin exacerbated respiratory disease or AERD) representing a smaller subset of asthma patients. The National Asthma Education and Prevention Program Expert Panel Report 3 guidelines classify patients with asthma on the basis of their symptoms and spirometry before treatment has been initiated. Asthma severity is defined by current impairment and future risk. The classification of asthma severity may change with time. The current classification of asthma in individuals 12 years of age or older is detailed in Table 19.2 (7).
Asthma treatment is complex, however; the overall goal is symptom control. Patient education remains a vital component of management. Education should focus on recognizing symptoms and triggers of asthma, emphasizing the rationale for use of medications and the importance of adherence to therapy. The health care provider should review inhaler technique, environmental modifications of potential triggers, and knowledge of appropriate response to asthma symptoms and when to call a physician or seek further care (8).
Medications for asthma are typically divided into two categories: quick-relief medications (also known as rescue medications), which are used on an as-needed basis, and maintenance medications (also known as controller medications) that are used daily. A stepwise approach for management of asthma in patients 12 years or older is detailed in Figure 19.2) (7).
TABLE 19.2: Classification of Asthma Severity
SPECIAL CONSIDERATIONS IN WOMEN WITH ASTHMA
Asthma is an especially relevant and important disease for women. There are sex-related differences in asthma epidemiology. According to the CDC, current asthma prevalence is higher among females (10.7%) compared with males (6.5%) (2). There appears to be an early childhood sex bias in asthma in which prepubertal males are more frequently affected than females (3). However, women experience a peak occurrence of allergic disease, including asthma, in the second decade of life resulting in a higher overall prevalence of asthma in adult females than males (2). In general, the lifetime likelihood of developing asthma is about 10.5% greater in women than men (3).
Worsening of asthma symptoms has been associated with fluctuations in the menstrual cycle and hormone levels, and 20% to 40% of women with asthma report perimenstrual exacerbation of asthma. This perimenstrual worsening is seen most commonly in women who experience a longer menstruation and more premenstrual symptoms (4,9,10). Women with a perimenstrual component to their symptoms tend to have a greater asthma severity and greater health care utilization when compared to other asthmatics. In addition, perimenstrual worsening of asthma seems to be associated with an increase in peripheral eosinophilia, increase in mast cell tryptase in the endometrium, and lower progesterone levels in the luteal phase when compared to women without asthma (4). On pulmonary function testing, there are changes in airflow and diffusion capacity in women with asthma throughout their menstrual cycle (11). Thus, there may be an increased inflammatory response in asthma that correlates with changes in sex hormones.
In the postmenopause phase, there appears to be a generalized decrease in asthma symptoms and IgE level (12). After menopause, the difference in asthma prevalence between men and women lessens. However, patients who have been on hormone replacement therapy for more than 10 years have been shown to have almost twice the incidence of asthma than women who have not been on this therapy (13,14). These hormonal variations illustrate the importance of discussing changes in reproductive health in women with asthma as it may impact their disease progression.
The prevalence of asthma in pregnancy is approximately 7% (5), making it one of the most common illnesses to complicate pregnancy (15). During pregnancy, approximately one third of patients with asthma experience an improvement in symptoms, one third experience a worsening of symptoms, and one third of patients symptomatically remain the same (16). Worsening of symptoms in pregnancy tends to occur during weeks 17 and 36 of gestation. The exact mechanism behind asthma in pregnancy is unknown; however, physiologic changes during pregnancy, immunologic response to the fetus, atopic changes, and underuse of medication are all possibilities (17).
Morbidity, Mortality, and Reporting of Symptoms
There are various other sex-related differences in asthma disease expression. Females have a higher asthma death rate (11.6 per million) compared with males (8.8 per million) (3). Hospitalized asthma patients (age 15 and above) are up to three times more likely to be female. These differences do not appear to be related to differences in adherence to controller medications or differences in health care evaluation and treatment (18–20). In addition, it appears African American women require more intensive care unit admissions than men or white women for asthma (19). This suggests an inherent difference between women and men with asthma.
Multiple studies have noted that women are more likely to report asthma symptoms and activity limitation when compared to men, as well as more likely to describe their symptoms as severe (21). Women with asthma report more frequent use of oral corticosteroids, rescue inhalers, and unscheduled physician visits than men (12,21–23). There is ongoing research examining the nature by which women may perceive airflow obstruction differently than men. This can be influenced by reduced inspiratory muscle strength, improper metered-dose inhaler technique, or anxiety surrounding symptoms of dyspnea and perception of airflow obstruction (4).
There is a greater prevalence of bronchial hyperreactivity, which can be used to assess asthma (i.e., methacholine challenge testing) in women (24). This may be due to the smaller caliber of the large and small airways in women when compared to men or to an intrinsic difference in sensitivity to stimuli. Women appear to have increased bronchial hyperresponsiveness to tobacco smoke. During childhood, girls with tobacco exposure have a greater decrease in FEV1 growth when compared to boys. As adults, women who use tobacco have a greater reduction in their FEV1 when compared to men with similar tobacco use (25,26).
The medical management of asthma between men and women is similar. However, in analysis of the difference between men and women in adherence to asthma guidelines, women are more likely to have a written asthma action plan, use their peak flow meters, and have regularly scheduled outpatient visits for asthma. In a study examining the possible effects of sex-specific asthma education, this type of education appears to improve asthma care as well as quality of life (20,23,27).
Obesity and its relation to asthma is a topic that is especially salient for females. Cross-sectional epidemiologic studies have shown that obesity is a risk factor for asthma among women but not men (28). There appears to be an increased incidence of asthma-like symptoms in obese or overweight school-aged girls (29). There are over 250,000 new adult cases of asthma each year in the United States in which obesity appears to play a role (28,30). The most consistent reported effect of obesity on lung function is a decrease in functional residual capacity and expiratory reserve volume. These mechanical effects of obesity on the lung may also alter airway smooth muscle contractility and increase airway responsiveness.
While an overall understanding of mechanisms of disease in asthma are vital, knowledge of gender differences in asthma epidemiology and disease manifestation is also important to the management of both men and women with asthma. As can be gathered from our findings, there is a need for ongoing research in this area.
EIB refers to the transient narrowing of the airways during or after exercise (31,32). This occurs in individuals both with and without asthma. Airway hyperresponsiveness is seen more commonly in endurance athletes, especially swimmers and winter sports athletes, than in the general population (33).
EIB occurs in approximately 80% to 90% of individuals with asthma. The prevalence of EIB has been increasing in elite athletes, most recently estimated to be at least 30% (34). In elite athletes, EIB occurs more frequently in the absence of asthma. These individuals typically have normal pulmonary function testing at baseline and a variable response to inhaled corticosteroids.
The exact mechanism of the bronchoconstriction in EIB is not completely understood. During exercise, the large airways provide humidity to condition the inspired air. The increase in minute ventilation results in loss of respiratory water and heat. Thus, the airway dehydration and airway cooling during exercise and subsequent rewarming after exercise are proposed mechanisms (35). Furthermore, the change in osmolarity of the airways triggers an increase in inflammatory mediators including histamine, eicosanoids such as cysteinyl leukotrienes (cystLT), and prostaglandin D2 (PGD2) from inflammatory cells, leading to airway smooth muscle contraction and edema (35,36). In elite athletes, high-intensity training and an increase in minute ventilation can lead to a type of “overuse syndrome” that results in injury to the airway. This is especially seen in swimmers training in chlorinated pools and winter sports athletes who are exposed to cold and dry air. The airway damage, inflammation, and remodeling can mirror that seen in individuals with asthma (37,38).
Clinical Presentation and Differential Diagnosis
The primary symptoms of EIB include cough, wheezing, dyspnea, chest pain, and/or chest tightness during or immediately following exercise. The symptoms typically clear within an hour of exercise completion. There is a refractory period of up to 3 hours after the initial exercise in which, if exercise is resumed, there is little or no bronchoconstriction (5). However, respiratory symptoms alone do not correlate well with airway obstruction during exercise and have a poor predictive value for diagnosing EIB (1,39).
The differential diagnosis of EIB is similar to that of asthma. In addition, evaluation for exercise-specific conditions such as exercise-induced glottic dysfunction, supraglottic laryngeal obstruction, and vocal cord dysfunction may be indicated. Shortness of breath and/or stridor that spontaneously resolves after completion of exercise should prompt evaluation for exercise-induced laryngeal obstruction (33). Conditions such as allergic rhinitis, chronic rhinitis, gastroesophageal reflux, and hyperventilation syndrome are also common in athletes and should be considered (40).
Since history alone does not carry a high positive predictive value for EIB, confirmation of airway obstruction during exercise is imperative. It is important to remember that in elite athletes expiratory flows can far exceed those of the predicted values and should be accounted for in determining the degree of obstruction (33).
Tests to evaluate for EIB include direct and indirect challenge tests. Direct challenge tests involve pharmacologic agents, usually methacholine or histamine, which act directly on the airway smooth muscle receptors and trigger bronchoconstriction at varying concentrations. These tests have a high sensitivity to detect bronchial hyperreactivity but a low specificity. Indirect challenge tests include eucapnic voluntary hyperpnea (EVH) (which is recommended for athletes), hyperosmolar tests with saline or mannitol, and laboratory or field exercise challenge tests (39,41).
The exercise challenge is specific but not very sensitive, especially in subjects without asthma. Subjects exercise on a treadmill or ergometric cycle for a period from 4 to 8 minutes with an intensity to raise ventilation to 50% of the predicted maximum voluntary ventilation. A fall in FEV1 of at least 10% is criterion for a positive test. In elite athletes the maximum ventilation is often unable to be reached (31,42,43). In addition, false negatives can occur when the conditions where the testing occurs do not mimic the conditions in which the subject normally exercises. Conditions such as temperature, humidity, air pollution, and environmental allergens can affect these results. In these situations a field exercise test may be required.
EVH is the preferred method for evaluation of EIB in athletes. This requires the voluntary hyperventilation of dry air containing approximately 5% of carbon dioxide. There are established protocols used to elicit bronchoconstriction at differing ventilation rates and times. A fall in FEV1 of at least 10% at two or more time points is criterion for a positive test.
The hyperosmolar (hypertonic) saline challenge involves administration of increasing doses of inhaled 4.5% saline to increase the osmolarity of the airways. Inhalation of hyperosmolar saline leads to an increase in inflammatory mediators and airway narrowing in susceptible individuals. A fall in FEV1 of 15% or more after challenge is criterion for a positive test. The mannitol challenge is similar to this. Mannitol is a hyperosmolar agent in a dry powder formulation. It induces smooth muscle contraction by releasing mediators from airway cells. Graduated doses are administrated in doubling doses until a fall in FEV1 of 15% is noted or a maximum dose of 635 mg of inhaled mannitol is reached.
Management of EIB involves both pharmacologic and nonpharmacologic measures. In patients with coexisting asthma, optimal control of the underlying asthma is essential. Treatment for other exacerbating or comorbid conditions such as gastroesophageal reflux, rhinitis, and exercise-induced laryngeal obstruction should be initiated. Use of facial masks may be beneficial in reducing cold air, pollutants, or allergen exposure, but they are not always tolerated (44). A pre-exercise warm-up can be helpful in reducing subsequent bronchoconstriction (45,46). This is likely due to the refractory period that occurs after exercise in which, after the initial release of inflammatory mediators, airways are less likely to constrict (5).
Pharmacologic therapies to treat EIB depend on the presence or absence of underlying chronic obstructive asthma. In patients with EIB and asthma, the recommendations for therapy follow the guidelines previously discussed in the section on asthma. In individuals with EIB and especially in athletes, a short-acting beta2-agonist should be prescribed for on-demand use. Inhaled short-acting beta2-agonists can be used 15 to 30 minutes prior to exercise for prevention of symptoms and after exercise if symptoms occur. Beta2-agonists work to induce bronchodilation and attenuate the release of inflammatory mediators. However, daily use of a beta2-agonist (or even use greater than two to three times a week) can lead to tolerance and ineffectiveness of the medication (34). In these instances, a controller medication may need to be added. Inhaled corticosteroids are a preferred method of asthma therapy in athletes (and in nonathletes) and are accepted by sports officials (47,48). Inhaled corticosteroids reduce airway inflammation and bronchial hyperreactivity. These medications cannot be used for prophylaxis and should be taken as maintenance therapy. If this does not achieve control, a combination of inhaled corticosteroid and long-acting inhaled beta2-agonist may be initiated (34). Leukotriene modifiers given orally prior to exercise are beneficial in combating the inflammatory effects of leukotrienes during exercise, which lead to mucus production and airway edema (39). Theophylline is not recommended for prophylactic use in EIB and is reserved for individuals with severe chronic asthma not controlled by first-line therapies.
SEX DIFFERENCES IN RESPIRATORY MECHANICS DURING EXERCISE
There are intrinsic differences between men and women that affect respiratory mechanics during exercise. These variations in pulmonary function and other elements of respiratory mechanics are important to consider, especially in the evaluation of the female athlete.
Optimal respiratory function during exercise requires adequate expiratory and inspiratory airflow. During exercise there is an expiratory flow limitation that leads to increased end expiratory lung volumes and increased expiratory flow rates. As a result there is increased elastic work of breathing (WOB) due to decreased lung compliance as the lung volumes increase. This can lead to fatigability and increased respiratory symptoms with exercise. In a study by Guenette et al., the degree of expiratory flow limitation was measured in endurance-trained men and women during cycle exercise. At maximal exercise, endurance-trained female subjects experienced expiratory flow limitation more frequently than endurance-trained male subjects. End expiratory lung volume (EELV), which is the volume of air remaining in the lung at the end of spontaneous expiration, was also assessed. With the onset of exercise, EELV decreased in both men and women when compared to resting measurements. In men, this measure tended to remain decreased, while in women EELV increased at 89% and 100% of maximal exercise. This translates into a significantly higher mechanical WOB in women than men during progressive exercise (49).
This increase in WOB in endurance-trained females does seem to impact perceived respiratory symptoms during exercise. WOB can be divided into resistive WOB and elastic WOB. Elastic WOB is further divided into the WOB required for muscles to overcome the elasticity of the lung during inspiration and the WOB required for expiratory muscles to overcome the elastic outward recoil of the chest wall during expiration. Resistive WOB can be further divided into the airflow resistance during inspiration and airflow resistance during expiration. A follow-up study by Guenette et al. examined these four individual components in order to determine which is responsible for the higher total WOB in women during exercise. They determined that the total WOB is higher in women due to a substantially higher resistive WOB, which is inversely proportional to the size of the lungs and airways. No difference in the elastic WOB was found between women and men during exercise (50).
In addition to this increase in WOB, female long-distance runners display a higher oxygen uptake and higher lactate levels, implying a higher physiological strain for females as compared to males (51).
Another notable measure in exercise is maximal breath hold time, which affects many recreational and athletic activities (e.g., swimming and diving). Females on average weigh less, have lower FVC and FEV1, and have lower hemoglobin and hematocrit levels compared to their male counterparts, which would lead one to assume a physiologic difference in maximal breath hold times between men and women. Despite these anthropometric and physiologic differences, female and male subjects appear to have similar maximal breath hold times (52).
Fatigability of Inspiratory Muscles
As described already, females tend to have more frequent expiratory flow limitation, higher end expiratory lung volumes, and higher total and resistive WOB compared to their male counterparts. The function of the diaphragmatic and respiratory muscles during exercise is also a vital component to optimal respiratory function. However, studies have shown men in fact experience diaphragmatic fatigue more frequently than women. Fatigue was not only more frequent, but also more severe among men (53). In addition, females demonstrate a slower rate of inspiratory muscle fatigue than males. There is no significant difference in the time to recovery between females and males (54).