Exercise-Induced
Asthma |
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By Robert
Lawrence, MD; Ken Ettinger, MD; Michael Barrett, MD; Kuo Chang,
MD; Fred Gill, MD; Jean Carney, MD
Exercise-induced asthma is a common disease
affecting at least 15 million people in the United States. The
etiology of exerciseinduced asthma is not completely understood,
although it is most probably triggered by cooling and dehumidifying
of the respiratory airways during physical activity. Symptoms
generally are related to bronchospasm and manifest 3-5 minutes
after the physical activity ceases or 5-10 minutes into continued
activity. Symptoms continue for approximately 10-30 minutes
and are followed by a refractory period of 20-120 minutes. Exerciseinduced
asthma can be diagnosed using medication trials or by exercise
challenge with peak-flow or spirometric monitoring. Treatment
consists of controlling the underlying asthma; use of beta-adrenergic,
mast cell inhibitor, or leukotriene antagonist medications;
and by altering the ambient conditions under which the activity
occurs. As a result, affected persons can live healthier lives
and have better self-image.
Introduction
Exercise-induced asthma (EIA) is a common problem. A 1976 study1
indicated that 63% of children with asthma and approximately
40% of atopic, nonasthmatic children had demonstrable EIA. About
15 million people in the United States are known to have EIA.
In addition, 25% of children who have a decrease of >20%
in peak expiratory flow rate (PEFR) with exercise never complain
of symptoms; they simply stop participating in activities. This
article reviews the pathophysiology, clinical presentation,
diagnosis, and treatment of EIA.
Definition of EIA
Many definitions of asthma have been used over the
years. The most recently revised definition issued by the NIH
National Heart, Lung, and Blood Institute Expert Review Panel
consisted of a lengthy paragraph which essentially underscored
our lack of certainty about the fundamental cause of asthma.2
For our purposes, asthma can be defined as a chronic, inflammatory
disease of the airways triggered by multiple stimuli, resulting
in reversible bronchospasm, and characterized by repeated episodes
of dyspnea, wheezing, chest tightness, cough, and phlegm. EIA
can be defined as bouts of asthma (with bronchospasm the main
component) triggered by exercise.
Pathophysiology of EIA
 |
| Figure 1. Typical pattern of lung function changes in
response to minutes of running by an asthmatic child.
(Adapted and reproduced by permission of the publisher
from: Godfrey S. Exercise-induced asthma. In: Bierman
CW, Pearlman DS, editors. Allergic diseases from infancy
to adulthood. 2nd ed. Philadelphia: Saunders;1988. p.598.3) |
The manifestations of EIA offer some insight into possible causative
mechanisms. In persons who have EIA, the first 3-5 minutes of
physical activity usually have normal effects. When the physical
activity stops, lung function decreases (as measured by PEFR
or forced expiratory volume in one second, FEV
1)
within the 5-10 minutes after the activity stops; if physical
activity resumes, symptoms begin to manifest during the first
5-10 minutes of resumed activity. This decrease in pulmonary
function is usually accompanied by symptoms and persists for
15-40 minutes; pulmonary function then normalizes, and symptoms
resolve (Figure 1).
3 Decreases in FEV
1
or PEFR often range from 20% to 50%. This early-phase response
is the most common manifestation of EIA. In a few individuals,
a late-phase response related more to inflammatory changes may
occur within 3-10 hours after physical activity stops. The degree
of late-phase decrease in pulmonary function is usually greater
and more prolonged than in the early-phase response. A refractory
period ranging from 40 minutes to 2 hours follows an episode
of EIA; during this refractory period, it is difficult to recreate
symptoms.
Multiple factors appear to affect frequency and
severity of the change in pulmonary function and symptoms. To
study possible pathologic pathways by which symptoms are produced,
two primary models of asthma have been used: induction of symptoms
by exercise and induction of symptoms by isocapnic hyperventilation.
Use of these two models has led to the following information:
- The greater the person's baseline level of bronchial hyperreactivity
as measured by histamine or methacholine challenge, the
greater the likelihood of EIA developing or worsening.
- The greater the minute ventilation (with all other factors
controlled), the greater the intensity and duration of EIA
up to a maximum of two thirds of the individual's maximum
working capacity.4
- The less humid the inspired air, the greater the trigger
for EIA (Figure 2).5-8
- The cooler the air, the greater the trigger for EIA (Figure
2).5-8
- Exposure to airborne allergens worsens EIA.
- Certain air pollutants (eg, ozone) may worsen EIA.
 |
Figure 2. Comparison of changes that developed in 1-s
forced expiratory volume (FEV1) after exercise
vs those observed after eucapnic hyperventilation in subjects
breathing air at various temperatures and water contents.
(Figure created from data in: Deal EC Jr,
McFadden ER Jr, Ingram RH Jr, Jaeger JJ. Hypernea and
heat flux: initial reaction sequence in exercise-induced
asthma. J Appl Physiol 1979;46:476-83 [p480(5); Deal EC
Jr, McFadden ER Jr, Ingram RH Jr, Strauss RH, Jaeger JJ.
Role of respiratory heat exchange in production of exercise-induced
asthma. J Appl Physiol 1979;46:467-75(6); Strauss RH,
McFadden ER Jr, Ingram RH Jr, Deal EC Jr, Jaeger JJ. Influence
of heat and humidity on the airway obstruction induced
by exercise in asthma. J Clin Invest 1978;61:433-40(7);
Strauss RH, McFadden ER Jr, Ingram RH Jr, Jaeger JJ. Enhancement
of exercise-induced asthma by cold air. N Engl J Med 1977;297:743-7(8).) |
This work and certain physiologic studies in animal models have
led to two hypotheses of the pathway to EIA: one hypothesis
focusing on water loss and another hypothesis focusing on postexertional
rewarming of the airway.
The water-loss hypothesis (currently preferred)
states that exercise causes decreased airway humidity through
more rapid ventilation and thus increases mucosal osmolarity.
Consequently, osmoreceptors trigger increased bronchial blood
flow, which causes edema. Simultaneously, the increased osmolarity
induces release of mediators that induce contraction of smooth
muscle and additional obstruction of the airway. Slower production
of inhibitory prostaglandins results in bronchodilation that
ultimately reverses the smooth muscle contraction and manifests
as the refractory period (Figure 3).9
This hypothesis is supported by several observed
phenomena: hyperpnea-induced bronchial water losses are substantial;
prolonged hyperpnea reduces the water replacement capability
of the airways; hyperosmolar aerosol inhalation directly triggers
bronchoconstriction; hyperosmolar responsive cells do exist
within the airway; and increased duration of hyperpnea leads
to steadily increasing osmolar changes.
Evidence against the water-loss hypothesis also
exists, however. In particular, the hypothesis does not explain
why the most major constriction of the airways occurs after
cessation of hyperpnea. Nor does the hypothesis explain how
vasoconstrictors can blunt EIA and hyperventilation-induced
asthma (HIA) in controlled settings.
The postexertional airway-rewarming hypothesis
states that the initial airway heat loss associated with hyperpnea
causes a vascular dilation and edema that physically narrows
the airway. This hypothesis is supported by several facts: some
vasodilation in systemic vasculature occurs after cold exposure;
alpha-adrenergic agonists limit HIA; vascular volume redistribution
by antishock trousers limits HIA; and the time required for
redistribution of blood flow theoretically matches the vessel
rewarming time. Evidence against this theory includes the fact
that in animals, pulmonary blood flow increases during cold-air
HIA and decreases during the posthyperpnea period, and no direct
evidence exists to support the possibility that rewarming hyperemia
occurs in lung vessels or airway tissue. Moreover, minimum airway
temperature is reached within two minutes, showing that bronchoconstriction
is delayed even though prolonged hyperpnea causes no further
temperature change.
 |
| Figure 3. Model of pathways involved in exercise-induced
asthma. (Reproduced by permission of the
author and publisher from: Godfrey S, Bar-Yishay E. Exercise-induced
asthma revisited. Respir Med 1993;87:338.9) |
The cellular mechanism of this process has yet to be defined.
Sensory neurons have been implicated in animal models as possible
pathways but have not been identified in humans.
Clinical Manifestations of EIA
The pathophysiologic mechanisms of asthma result in a number
of physiologic changes occurring within the pulmonary tree.
These changes include bronchospasm (the main component of EIA),
hypoxia, hypercarbia (if airway obstruction is sufficiently
severe, ie, FEV1 measured at 25% of predicted value),
edema of the bronchial walls, mucosal sloughing, and excessive
quantities of highly viscous mucus. The most major changes seen
in patients with EIA are bronchospasm and edema. If a late-phase
reaction occurs, all these factors may be involved.
Clinically, this set of changes results in EIA
symptoms that include dyspnea, wheezing, coughing, chest tightness
or pain, phlegm (occasionally), and abdominal pain (rarely).
Onset of symptoms usually occurs as physical activity ceases
or 5-10 minutes after resumption of activity. Symptoms resolve
and pulmonary function tests return to normal about 20-30 minutes
after onset of symptoms. The refractory period (in which further
symptoms cannot be induced) can last from 30 minutes to two
hours.
Conditions likely to elicit EIA include cold,
dry ambient environment; high levels of air pollution and airborne
allergens; and strenuous physical activity, whether of a type
that tends to be highly asthmogenic (eg, long-distance running,
bicycling, basketball, soccer, rugby, ice hockey, ice skating,
cross-country skiing) or moderately asthmogenic (eg, gymnastics,
karate, wrestling, boxing, sprinting, golf, football, baseball,
downhill skiing, isometrics, diving, short-distance swimming).
In addition, EIA may be elicited by individual factors such
as poor control of underlying asthma, recent respiratory infection,
and recent exposure to major airborne allergens.
Diagnosis of EIA
EIA is diagnosed primarily by medical history. In asthmatic
persons, exercise should be assumed to exacerbate asthma. Atopic
persons with or without asthma should be questioned carefully
regarding possible EIA symptoms. Persons who complain of cough,
wheezing, dyspnea, chest pain, or chest tightness after beginning
aerobic activity should be questioned further regarding other
symptoms related to EIA. Children who cannot keep pace with
their peers during physical activity should be asked whether
breathing is difficult during the activity. Any child or young
adult who has stopped physical activity for reasons such as
"I just couldn't do it anymore" should also be questioned
further.
When the diagnosis of EIA is suspected in the
patient who is not known to have asthma, a trial of prophylactic
drug therapy may be initiated first. This approach to diagnosis
is reasonable in persons who can give reliable feedback about
their symptoms and about their response to medication. If any
question exists about the accuracy of the patient's reporting,
however, the diagnosis must be confirmed by EIA testing.
EIA testing is best done by a free-run challenge
in which the patient is asked to run at full speed for 3-5 minutes,
attaining a heart rate at least two thirds of their target heart
rate (or 180 beats per minute in children). The patient should
stop after five minutes (or earlier if symptoms arise). Pulmonary
function should be measured (by FEV1 or by PEFR)
at baseline, immediately after stopping the run, and at 5, 10,
15, 20, and 30 minutes after the activity is completed. A decrease
of 15% in FEV1 or PEFR is diagnostic of EIA, assuming
that the breathing efforts are well done. Clinicians should
be prepared to administer a bronchodilator during or after the
test. Sensitivity of exercise testing ranges from 55% to 80%,
and specificity is 93%.3 Testing should not be done
during episodes of asthma.
Treatment of EIA
EIA can be treated by several methods. The purpose of treatment
is to maximize the patient's ability to participate actively
in aerobic activity, whether it be recreation, serious athletics,
work-related activity, or school-related activity. Treatment
is intended to enhance patients' sense of self-worth, socialization,
physical conditioning, and even to help them retain employment.
Can we successfully treat EIA? Yes! The 1988 US Olympic Team
included 67 (of 597) members affected with EIA. These athletes
won 15 gold, 21 silver, and 5 bronze medals in multiple sports,
including long-distance running.
To successfully control symptoms of EIA in any
person with known asthma, excellent control of the underlying
asthma is necessary.
Nonpharmaceutical Treatment of EIA
Medication is not the only way to treat EIA: Type of physical
activity done by the patient is also important. Clinicians should
encourage patients to choose less asthmogenic activities whenever
possible. Ambient conditions should be considered as well: The
more humid and warmer the air, the less the chance of stimulating
EIA. Thus, indoor activity is less likely to trigger EIA. Wearing
a mask or face covering (ie, a scarf) may help to warm and humidify
outdoor air. Physical activity on days of high air pollution
should be avoided or minimized (early-morning activity may reduce
exposure in some cities). For asthmatic persons who are highly
sensitive to pollen, activity should be timed to occur when
diurnal pollen counts are lowest.
The refractory period also may be used beneficially.
Encouraging an athlete to exercise in several 2- to 3-minute
increments as "warm-ups" 10-20 minutes before the
main physical activity may induce a period of up to one hour
during which EIA does not develop. This precaution benefits
only those whose duration of planned activity is short (eg,
a sprinter).
Pharmaceutical Treatment of EIA
Several factors must be considered when initiating treatment:
Does the patient have predictable periods of aerobic activity
(eg, jogs each morning only, is a day laborer, or is a playful
4-year-old child)? Are the ambient conditions in which activity
takes place controllable? Can the patient effectively use a
metered-dose inhaler? How long will the physical activity continue?
How intense aerobically is the physical activity?
In general, drug therapy is effective for patients
whose physical activity is brief and predictable and who can
use a metered-dose inhaler correctly. If physical activity continues
for more than 2-3 hours or if the patient cannot use a metered-dose
inhaler effectively, consideration of oral medication may be
warranted.
Treatment is selected from three types of medication:
beta-adrenergic drugs, mast cell inhibitors, and leukotriene
antagonists.
Beta-adrenergic drugs are an excellent first-choice
medication for treating patients whose activity must be limited
in duration (ie, <3 hours). These drugs can be used 15 minutes
before activity is begun and are relatively safe if they are
not overused. Because bronchospasm is the main component of
EIA, these drugs are highly effective. Albuterol and terbutaline
are most commonly used. Recent data indicate that salmeterol
can remain effective for 10-12 hours (Figure
4)10; duration of the effect diminishes with
continued use (Fig 5).10
Clinicians should emphasize to patients that salmeterol dosing
should never be repeated more frequently than every 12 hours
because overuse can induce cardiac toxicity. Oral beta-adrenergic
agents may also be used but must be taken at least 30-45 minutes
before the activity is begun. Beta-adrenergic agents may cause
more side effects when taken orally than when they are administered
by metered-dose inhaler.
Another group of medications used to treat EIA
are called mast cell inhibitors, but whether inhibition of mast
cells is their primary mode of action is unclear. These medications
are an excellent choice for preventing EIA, and they have an
excellent safety profile. Cromolyn and nedocromil also have
the advantage of blocking early-phase and late-phase responses.
These drugs are delivered by metered-dose inhaler (2-3 sprays
administered 10-15 minutes before onset of activity) and may
be needed after every 2-4 hours of continuous activity.
Leukotriene antagonists constitute the third group
of medications used to treat EIA. Of these drugs, montelukast
(Singulair) has recently been shown effective in preventing
EIA. Long-term use (ie, use longer than 12 weeks) was not associated
with shortened duration of action or with diminution in protection
offered as measured by FEV1.11 The medication is
given orally in a single dose (tablet) each day. Because long-term
side effects of these medications are not yet known, the drugs
should be used with caution. Montelukast is not approved for
use in children younger than six years. Other medications (eg,
inhaled steroids) have been used but are generally used to decrease
airway hyperreactivity; to achieve this result, a month or more
of moderate- to high-dose daily use may be required. These drugs
are best reserved for use in controlling asthma that is not
specifically related to exercise. Theophylline can be used and
may be beneficial, but timing its use to the activity is more
difficult, and its side-effect profile is not as favorable as
for the other medications listed above.
Overall, medications benefit 60% to 80% of patients
susceptible to EIA and reduce the decrease in FEV1in
these patients from 40% to 80%.
Athletic Competition and EIA
Diagnosis and treatment of athletes participating in formal
competition is essentially the same as for other persons except
that competitive athletes tend to recognize even small changes
in airway function, and this small amount of change may not
respond noticeably to medication therapy. In addition, the degree
of response achieved by using these medications may not warrant
use of the large amounts of medication needed to relieve all
symptoms. This consideration should be discussed carefully with
each affected athlete.
In addition, athletes in competition are also
likely to behave stoically when having physical discomfort and
thus may underreport symptoms. Detailed questions about performance
and the symptoms of EIA are therefore especially necessary for
these persons.
Each sport's governing body has established its
own rules requiring disclosure by athletes regarding their use
of medications as well as the acceptability of specific medications
for athletes participating in formal competition. Athletes participating
in formal competition should obtain these rules from their sport's
governing body.
The US Olympic Committee Drug Hotline can be reached
at 1-800-233-0393.
Conclusion
EIA is a common problem that affects millions of people annually
in the United States. It is often unrecognized by patients and
physicians; a reasonable index of suspicion and some simple
screening questions lead to a presumptive diagnosis in most
cases. EIA is treated pharmaceutically and using nonpharmaceutical
approaches. Most important, control of any underlying asthma
is essential for control of EIA. The importance of recognizing
and treating EIA is essential if we are to provide all affected
persons with the opportunity for better overall health, better
socialization, and better self-image.
References
1. Kawabori I, Pierson WE, Conquest LL, Bierman
CW. Incidence of exercise-induced asthma in children. J Allergy
Clin Immunol 1976;58:447-55.
2. Guidelines for the diagnosis and management of asthma: expert
panel report 2. Bethesda, MD: NIH, NHLBI. April 1997. p. 55-6.
3. Godfrey S. Exercise-induced asthma. In: Bierman CW, Pearlman
DS, editors. Allergic diseases from infancy to adulthood. 2nd
ed. Philadelphia: Saunders;1988. p.597-606.
4. Cypcar D, Lemanske RF Jr. Asthma and exercise. Clin Chest
Med 1994;15:351-68.
5. Deal EC Jr, McFadden ER Jr, Ingram RH Jr, Jaeger JJ. Hyperpnea
and heat flux: initial reaction sequence in exercise-induced
asthma. J Appl Physiol 1979;46:476-83.
6. Deal EC Jr, McFadden ER Jr, Ingram RH Jr, Strauss RH, Jaeger
JJ. Role of respiratory heat exchange in production of exercise-induced
asthma. J Appl Physiol 1979;46:467-75.
7. Strauss RH, McFadden ER Jr, Ingram RH Jr, Deal EC Jr, Jaeger
JJ. Influence of heat and humidity on the airway obstruction
induced by exercise in asthma. J Clin Invest 1979;61:433-40.
8. Strauss RH, McFadden ER Jr, Ingram RH Jr, Jaeger JJ. Enhancement
of exercise-induced asthma by cold air. N Engl J Med 1977;297:743-7.
9. Godfrey S, Bar-Yishay E. Exercise-induced asthma revisited:
Respir Med 1993;87:331-44.
10. Nelson JA, Strauss L, Skowronski M, Ciufo R, Novak R, McFadden
ER Jr. Effect of long-term salmeterol treatment on exercise-induced
asthma. N Engl J Med 1998;339:141-6.
11. Leff JA, Busse WW, Pearlman D, Bronsky EA Kemp J, Hendeles
L, et al. Montelukast, a leukotriene receptor antagonist, for
the treatment of mild asthma and exercise induced bronchoconstriction.
N Engl J Med 1998;339:147-52
