Exercise-induced bronchoconstriction

Exercise-induced bronchoconstriction
Suparat Sirivimonpan,MD.
14-6-13

Outline
• Definition and overview
• Prevalence
• Pathogenesis
• Diagnosis
• Therapy
• Take-home messages

Definition and overview
• Transient narrowing of the lower airways that
occurs after vigorous exercise
• It may be observed in patients who have or do not
have chronic asthma
• EIA should no longer be used
– Not all patients with EIB have asthma
– Exercise does not induce asthma but rather is
a trigger of bronchoconstriction
Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
Exercise-induced airway narrowing
Eexercise-induced asthma synonymous terms
Exercise-induced bronchospasm
E.R. McFadden Jr. Middleton's Allergy: Principles & Practice, 7th ed

Definition and overview
• Exercise-induced bronchoconstriction (EIB)
– is a manifestation of BHR
– is often the first sign of asthma
– the last to resolve with an asthma exacerbation
• Diagnosis : decrease in FEV1 after exercise of 10-
15% of the preexercise value
T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

Definition
References EIB EIA
E.R. McFadden Jr. Middleton's
Allergy: Principles & Practice,
7th ed
Condition in which vigorous physical activity triggers acute airway
narrowing in people with heightened bronchial reactivity
PRACTALL consensus report.
Allergy 2008; 63:953–961.
Same clinical presentation in
individuals without asthma
Lower airway obstruction &
symptoms of cough, wheezing
or dyspnea induced by exercise
in patients with underlying
asthma.
AAAAI Work Group Report.
J Allergy Clin Immunol 2007;
119:1349–1358
Airway obstruction that occurs
in association with
exercise without regard to the
presence of chronic asthma
Condition in which exercise
induces symptoms of
asthma in patients who have
asthma
NAEPP EPR-3 2007 Bronchospastic event that is
caused by a loss
of heat, water, or both from the
lung during exercise
Not stated
GINA 2010 Physical activity is an important
cause of symptoms for most
asthma patients, and for some
it is the only cause
Not stated

Prevalance
• In the general population : 7-20%
• Asthma patients : occur in up to 90%
– more frequently more severe or less well-controlled asthma
• Competitive athletes :up to 50%
– depending on the type of sport, environmental conditions in
which the exercise is performed, and maximum exercise
level
David A. Khan.Allergy Asthma Proc 2012:33:1–6
prevalence of EIB
-varies considerably based on the type of test and
criteria used for diagnosis
-may also be influenced by age, sex, and ethnicity

In children
Lee So-Yeon et al. Expert Rev Clin Immunol. 2009;5(2):193-207.

David A. Khan.Allergy Asthma Proc 2012:33:1–6

EIB is more common in more strenuous
sports particularly in cold air
Randolph C. Clinic Rev Allerg Immunol. 2008;34:205–216.

Pathogenesis
• EIB occurs in response to heating and humidifying large
volumes of air during a short period
• Heat and water move from mucosa to the inspired air
directly due to local temperature and vapor-pressure
gradients
EIB : Depend on
-ventilation rate
-water content and temperature of the inspired air
-temperature of the airway wall
-availability of airway surface liquid (ASL) to
provide humidification

The greater the heat exchange, the more severe the obstruction.
Relationship between the heat lost from the respiratory tract during
exercise & the severity of obstruction in asthmatic patients

Pathogenesis
• Theory
– Osmotic theory
– Thermal theory
– Airway injury

thermal theory osmotic theory
Cooling and hyperosmolarity
- act independently as stimuli for the airways to narrow
- operate together
Thermal theory does
not include BSM
contraction or
mediator release

Mediator of EIB
• Several mediators are involved
• PGs, LTs, and histamine
↑ cysLTs , PGD2 in induced sputum
↓ PGE2
↑ ratio of cysLTs to PGE2
↑ urinary excretion of LTE4 , 9 ,11β-PGF2
(metabolite of PGD2) (also be found in sputum after exercise)

Mediator of EIB
• ↑sPLA2-X protein in induced sputum supernatant and in
epithelial cells after exercise challenge
 thus providing an explanation for the high levels of
cysLTs and other eicosanoids in EIB

Hallstrand TS et al. JACI 2005;116:586-93.
•Mild intermittent
asthma
•18-59 years of age
•Exercise challenge

Mediator : mast cell, eosinophil
• Mast cells : PGD2, LTs, histamine
• Eosinophils : LTs, ECP
• PGD2 : major mast cell specific mediator in EIB
• The amount of eosinophilia in induced sputum has
been correlated with the degree of EIB severity
• Levels of histamine and tryptase are also elevated
after exercise challenge

Mediator : Epithelium
• Epithelium : generation and regulation of mediators
• Adenosine and adenosine triphosphate
– key regulators of the depth of the airway surface fluid layer
– via A2b receptors act on mast cells to release mediators
• expresses 15-lipoxygenase-1
– which synthesizes the bronchoconstrictive mediator 15S-
hydroxyeicosatetraenoic acid
• major source of PGE2
– bronchoprotective ,inhibit EIB when administered by inhalation
Epithelium may regulate the balance between
the release of bronchoconstricting eicosanoids
and mechanisms, which reduce the synthesis of
PGE2

Mediator : sensory nerve
• Additional mediators are released from sensory
airway nerves
• activated by eicosanoids (ex.cysLTs), in the airway
• Activated sensory nerves release
– Neurokinins
 bronchoconstriction , mucous release
• Mucin 5AC (MUC5AC)
 predominant gel-forming mucin of goblet cells

Airway injury
• important role in elite athletes
• arise from conditioning large volumes of dry air over
months of training
• Epithelial repair
 microvascular leak and plasma exudation
 contractile properties of airway smooth muscle change
and become more sensitive to stimuli (repeated
exposure to plasma-derived products)  AHR
This type of airway injury does not involve
airway remodeling and likely does not predict
chronic disease

Anderson SD, Kippelen P. J Allergy Clin Immunol 2008;122:225-35.

Diagnosis
• Self-reported symptoms alone are not reliable for
diagnosis of EIB
• Optimal EIB management may require confirmation of
the diagnosis using objective methods

History
• Characteristic: develops within 5-10
minutes after completing exercise
• Rarely occurs during exercise
• Spontaneous resolution: ≈ 30 minutes later
• Undertake and finish vigorous activity, but
work achieved is lower than normal
• Exertion needs to be sustained

Less common
• Stomachache, Sore throat (young
children)
• Fatigue with expected exercise for age
• Abdominal pain
• Exacerbation of allergens and asthma
seasonally particularly with exertion
• Muscle cramping
• Side ache
• Headache

Refractory period & EIB: 50% of patients
Repeated bouts of
work within 40
minutes or less
bronchial narrowing
progressively
decreases
(lasting 2-3 hours)
• Mechanism : Unknown
•Increase circulating catecholamines, increase inhibitory prostaglandins??
**first doing warm-up**

Objective methods
• Direct challenges
• Methacholine challenge
• Histamine challenge
• Provoke bronchoconstriction,
exclusive of airway
inflammation
•Indirect challenges
•Exercise challenge (Laboratory-based; sports-
specific)
•Eucapnic voluntary hyperpnea (EVH)
•Hypertonic saline challenge
•Inhaled powdered mannitol
•Inhaled adenosine monophosphate (AMP)
• More effective in identifying EIB
• Reflect severity of inflammation

Methacholine challenge
American Thoracic Society.
AJRCCM 2000;161:309-29
considered positive according to IOC-MC
- PC20 ≤ 4 mg/mL when not taking ICS
- or 4-16 mg/mL when taking ICS for ≥1 month

• Screening for asthma
• Low sensitivity for EIB Not
recommended as screening tool
for EIB
AJRCCM 2000;161:309-29

AJRCCM 2000;161:309-29

AJRCCM 2000;161:309-29
Methacholine challenge

Exercise challenge
Baseline spirometry
Postprovocation spirometry
Exercise challenge
Calculate target FEV1
-Positive result: 10% decrease in FEV1
-Severe bronchoconstriction: 50% decrease in FEV1
-Recovery: 95% of baseline FEV1
-At 1 to 3, 5,10, 15, 20, and 30 to 45 minutes
-2 repeatable FEV1 within 3% of each other
at each time point
Laboratory challenge
-8-minute exercise in ambient
condition (20-25 c, RH<50%)
-80-90% of estimated HRmax
(95% in elite athlete) by 2 minutes
 maintain for remaining 6 minutes
-Inhale dry air (<5 mg H2O/L)
Field-based challenge
-More sensitive than laboratory
-challenge in elite winter athletes
ATS 2013 *  5,10,15, 30 min
more frequent if a severe response is expected
*The American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.

Criteria for EIB
- 10% decrease in FEV1 after exercise (based on 2 SD from the
mean percentage decrease in FEV1 in healthy individuals)
- ≥ 15% decrease in PEFR or an FEV1 of 15% after
challenge with exercise
- 10-15% decrease in FEV1 after exercise
The American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.
Joint Task Force of ERS & EAACI in cooperation with GA2LEN. Allergy 2008:63: 387–403.

Contraindications for exercise challenge
The American Thoracic Society. Am J Respir Crit Care Med 2000;161:309-29

Eucapnic Voluntary Hyperpnea (EVH)
Challenge
• High sensitivity to identify EIB
• IOC MC: optimal test to identify EIB for athletes seeking
approval to inhaled β2–agonist before an event
• Compare with exercise
• Similarities : stimulus, time course of airway
response & recovery, mediators, inhibitory effects
of drugs
• Differences : cardiovascular response or
sympathetic drive
Rundell KW, Slee JB. J Allergy Clin Immunol 2008;122:238-46.

Eucapnic Voluntary Hyperpnea Challenge
• Baseline FEV1 < 80% of predicted  performed with
caution
• Baseline FEV1 < 70% of predicted  should not be
performed

Hypertonic saline challenge
• Effectiveness similar to exercise and EVH
• Advantage : - More economical & easier to administer
- Ability to collect sputum
• Nebulize 4.5% hypertonic saline inhalation in 15-20 minutes
• Exposure time: 30 & 60 sec, 2 & 4 & 8 min (total 15.5 mins)
- FEV1 measurement: 1 min after every
exposure
< 10% fall in FEV1  doubled exposure time
> 10% fall in FEV1  same exposure
•Termination: ≥ 15% fall in FEV1 or total
minimum dose of 23 g (15.5 mins)

Inhaled powder mannitol challenge
• Correlates well with other indirect challenges
• Safe, ease of use, short time to perform, no requirement for
specialized and costly equipment
• Inhalation of dry powder mannitol:
• 5, 10, 20, 40, 80, 160, 160 and 160 mg (dry power inhaler)
(a maximal total cumulative dose of 635 mg)
• FEV1 measurement: 1 min after each dose
Sandra D. Anderson.CHEST 2010; 138(2):25S–30S
A positive response
•15% fall in FEV1 at a total cumulative dose of 635 mg
•Or 10% fall in FEV1 from baseline between doses

Indirect challenges
• Standardized dry air exercise challenge and EVH
– are effective in diagnosing EIB
– equipment is expensive and may not be practical in many clinical
settings.
• Hypertonic saline challenge and inhaled powdered
mannitol
– require less equipment and space
– can be easily performed in the office environment

Confounding factors in diagnosis

EIB therapy
• Primary aim is prophylaxis
• Isolated EIA
• Pretreatment before exercise
• Underlying asthma
• Anti-inflammatory therapy
PRACTALL consensus report. Allergy 2008; 63:953–961.
•EIB is an indication to start regular
preventive treatment and a marker of
inadequate asthma management

Therapy
Nonpharmacological
• Warm-up 10-15 min
• Warm-down; 10-15 min
• Avoidance of triggers
• Nasal breathing
• Wearing a mask in cold environments
• Avoiding exercise in conditions where air is
cold and dry

Therapy
• Controller therapy
• Pretreatment before exercise
• β2-adrenergic receptor agonist
• Leukotriene modifer
• Mast cell stabilizer
• Other: anticholinergic agent,
xanthine, antihistamine
Pharmacological

β2-Adrenergic Receptor Agonists
• single most effective therapeutic group of agents for
– acute prevention of intermittent EIB
– accelerating recovery of FEV1 to baseline
• Daily use of β2-adrenergic agents lead to “tolerance”
 monotherapy with adrenergic agents is
recommended for use only on intermittent basis
for prevention

β2-Adrenergic Receptor Agonists
• are usually effective
– 2 to 4 hours for SABAs
– up to 12 hours for LABAs
• inhaled 5 to 20 minutes before exercise (salmeterol 15-
30 minutes)

Leukotriene receptor antagonist
• Vary in effectiveness
• 50% of patients being responders
• Most patients do not experience complete
protection
• Bronchoprotective activity & accelerating
recovery
• Has no use to reverse airway obstruction
• Daily use does not lead to tolerance

Leukotriene receptor antagonist
Montelukast
• acts within 1 to 2 hours of oral administration
• bronchoprotective activity for 24 hours
-The magnitude of effect may be smaller for
LTRAs than either ICS or preexercise SABA
- duration of action is longer  very useful for
patients or athletes engaging in physical activity
throughout the day

ICS
• Controller
• decrease the frequency and severity of EIB
• symptomatic asthmatic patients : best controlled by
maintenance anti-inflammatory treatment alone or in
combination with other short-term preventive treatment
• Beta2-Adrenergic agonists can be added if necessary for
short-term prevention of EIB

• The choice of whether to add daily ICS or daily LTRA to
as-needed use of SABA in patients with EIB who do not
respond to intermittent SABA therapy alone
 made on a case-by-case basis
– evidence supports efficacy of both types of
medications in EIB
– ICS therapy
• may have a more potent anti-inflammatory effect in
patients with EIB associated with airway
inflammation
• may work better in patient with asthma with EIB >
elite athlete without asthma with EIB
• baseline lung function is below normal  ICS
initially

Mast cell stabillizers (MCS)
• Cromolyn sodium and nedocromil
• Bronchoprotective activity
• No bronchodilator activity
• Interference with mast cell mediator release of
PGD2
• Daily use does not lead to tolerance
• Vary in effectiveness:
• Monotherapy or add-on therapy
• Rapid onset but of short duration (1-2 hours)

• attenuation of EIB by about 50%
• no significant differences between sodium cromoglycate
and nedocromil sodium
• Effectiveness : SABAs >MCSAs > anticholinergic agents
Mast cell stabillizers (MCS)

Other agents
• Anticholinergic
(ipratropium), theophylline, antihistamines, calcium
channel blockers, -adrenergic receptor
antagonists, inhaled furosemide, heparin, and hyaluronic
acid  inconsistent results

An Official American Thoracic Society Clinical Practice Guideline
Am J Respir Crit Care Med 2013;187: 1016–1027
*Or surrogate challenge ex.
hyperpnea or mannitol

Am J Respir Crit Care Med 2013;187:1016-1027.

Take-home messages
• EIB is a transient narrowing of the lower airways
that occurs after vigorous exercise
• Reduction of FEV1 of 10% to 15% of the
preexercise value is a criteria for diagnosis
• Symptoms develop within 5-10 minutes after
completing exercise & spontaneously disappear
about 30 minutes later
• Self-reported symptoms alone are not reliable, so
indirect challenge is recommended

Take-home messages
• Prevention is the main approach to management
• EIB is a marker of inadequate asthma control in
patient with asthma
• Inhaled β2-agonists is an effective prophylactic
medication
• Monotherapy with adrenergic agents is
recommended only on intermittent basis
• Pre-exercise warm-up may be helpful

Exercise-induced bronchoconstriction

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