Exercise inducedbronchoconstriction-140903111351-phpapp01

Exercise-induced
bronchoconstriction
Suvanee Charoenlap, M.D.

Outline
• Introduction and definition
• Clinical presentation
• Pathogenesis
• Prevalence and risk factors
• Diagnosis and treatment

Introduction
• First described
: 150 A.D. by Aretaeus of Cappodocia
• First observed among asthma persons
: Exercise-induced asthma (EIA)
• Post-exercise asthma like symptoms in
persons without asthma
: Exercise-induced bronchoconstriction (EIB)
AHRQ Publication No. 10-E001 ,January 2010 (Web site posting) ,Revised March 2010

Classification of EI-hypersensitivity syndromes
Exercise Induced
Hypersensitivity syndromes
EI-Respiratory disorders
EI-BronchoconstrictionEI-Rhinitis
EI-Anaphylaxis EI-Urticaria
+ Asthma W/O Asthma
Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

Definition of
Exercise-induced bronchoconstriction (EIB)
• “Transient, reversible narrowing of the lower
airways that occurs after vigorous exercise.”
– EIB with chronic asthma based on spirometry
– EIB without chronic asthma
• EIA: not used
“Exercise not induce asthma but rather a trigger of
bronchoconstriction.”

Clinical presentation
• The hallmark of EIB
– Acute airflow obstruction (measured FEV1)
– Peak rapidly 3-15 minutes after exercise stop
– Remits spontaneously within 20 – 40 min
(recovery time not prolonged)

• ATYPICAL presentation
– Appear during prolonged exercise and recovery
time often prolonged
– Late-phase constriction:
• 4 -12 hours after exercise
• Generally less severe
• No predictors and not consistent in the same individual
Clinical presentation

Clinical symptoms in children
Most common
• Cough
• Wheezing
• Chest tightness
• Shortness of breath
• Excess mucus
Non-specific
• Poor performance
• Chest pain
• Prolonged upper
respiratory illness
• Avoidance of activity
• Inability to keep up with
peers
Lee So-Yeon et al, Expert Rev Clin Immunol.2009;5(2):193-207
Self reported symptoms do not significantly correlate with EIB diagnosis

Refractory period in EIB
“A period of diminished responsiveness when
a second period of exercise follows in 1 to 4 hours.”
• 40-50% of EIB have refractory period.
• Mechanism  not fully understood
– Bronchial smooth muscle tolerant to mediators
– Depletion of catecholamines
– Increased circulation of prostaglandin
– Degranulation of mast cell mediators
– PGE2 may be the important mediator in refractory period

Refractory period in EIB
E.R. McFadden Jr. Middleton's Allergy: Principles & Practice, 7th ed

• Thermal theory
• Osmotic theory
Pathophysiologic mechanism of EIB

Water loss by evaporation
from the airway surface
Mucosal dehydration
Increase osmolarity
: Na+,Cl-,Ca2+ ,K+
Cell volume changes
Mediators released
Smooth muscle contraction
Vascular leakage
Edema
Mucosal cooling
Vasoconstriction
Rapid re-warming of Airway
• Reactive hyperemia
• Vascular engorgement
Vascular leakage
And edema
Exercise-induced bronchoconstriction
Thermal theory Osmotic theory

Disease model of exercise-induced
bronchoconstriction (EIB) pathogenesis.
T. Pongdee and J.T. Li / Ann Allergy Asthma Immunol 110 (2013) 311e315
Inflammatory cells & mediators
Neuropeptide
Epithelial
Shedding

Patients who are
susceptible to EIB
(Asthma + Atopy +
increase exhaled FeNO)
Immunopathology of the patient at risk
Epithelial shedding
Overproduction of
inflammatory mediators
Relative underproduction of
protective lipid mediators
Infiltration of the airways with
eosinophils and mast cells
Hallstrand TS. Curr Allergy Asthma Rep 2009; 9:18-25.

Epithelial sheddingPGE2

Epithelial cells
release ATP
ATP
• key regulators of the
depth of ASL layer
• via A2b receptors act
on mast cells to release
mediators
• Expresses 15-lipoxygenase-1
• Major source of PGE2
T. Pongdee and J.T. Li / Ann Allergy Asthma Immunol 110 (2013) 311e315.
Epithelium

Mast cell & Eosinophil
• Mast cells
: PGD2, LTs, histamine
• Eosinophils
: LTs, Eosinophilic cationic protein (ECP)

Sensory nerve
• Eicosanoids (CysLTs) activated sensory nerves
release : Neurokinins
 bronchoconstriction , mucous release
• Mucin 5AC (MUC5AC)  increase in airway
: predominant gel-forming mucin of goblet cells

The concentration of
columnar epithelial cells
The concentration of
eosinophils
EIB+ EIB+EIB- EIB-
Hallstrand et al., J Allergy Clin Immunol. 2005 September ; 116(3): 586–593.
Effects of exercise challenge on the levels of eicosanoids in
induced sputum of individuals with asthma with EIB.

EIB+ EIB+EIB- EIB-
The levels of CysLTs The ratio of CysLT to PGE2
Effects of exercise challenge on the levels of eicosanoids in
induced sputum of individuals with asthma with EIB.

Effects of exercise challenge on the levels of mast cell mediators
in induced sputum of individuals with asthma with EIB.
Histamine Tryptase

Effects of exercise challenge on the levels of
eicosanoids in induced sputum of individuals with
asthma with EIB.
CysLT LTB4

Effects of exercise challenge on the levels of
eicosanoids in induced sputum of individuals with
asthma with EIB.
PGE2 TXB2

EIB and Airway Injury in the Elite Athlete
Airway cooling Recruitment of small airways
into humidifying process
• Epithelial damage
• Loss of PGE2
Microvascular leakage
Repeated exposure to plasma products
Alters airway smooth muscle
Sensitization of airway smooth muscle
Increased response to
Acute increase of LTs, PGs
EIB

• 7 – 20% in general population
• Up to 50% in competitive athletes
• EIB is reported to occur in
– up to 90% of individuals with asthma
– 40% of those with allergic rhinitis
Prevalence of EIB
T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

Prevalence of EIB

• 56 asthmatic children, 6-15 years old
• Criteria : 15% reduction in PEFR or having wheezing
during exercise-challenge test was considered as
having EIB.
• Prevalence of EIB was 41% (n=23)
– 16/23 (69.5 %) had EIB history
– 7/23 (30.4%) had no EIB history
• EIB history (p=0.021) and family history of asthma
(p=0.04) correlated with EIB.
EXERCISE‐INDUCED BRONCHOCONSTRICTION
IN THAI PEDIATRIC ASTHMA
Yimsuwan U, et al. JACI, Vol 219, Page AB3, Feb 2012

Risk factors of EIB in general
Factor Decrease EIB/EIA Increase EIB/EIA
Environmental
conditions
• Warm temperatures
(34-37° C)
• High humidity (100%)
• Low air pollution
• Absence of allergens
• Cold temperatures,
• Dry air,
• Pollutants,
• Allergens,
• Dust Irritants: smoke,
automobile exhaust,
sulphur dioxide,
nitrogen dioxide,
ozone,chlorine
Type, intensity, duration
of exercise
• Short episodes
• Brief rests
• VO2 max <40%
predicted,
• <3 minutes
continuous exercise
• Continuous activities
• Maximum aerobic
capacity VO2 max
≥60% predicted
• 6-8 minutes
continuous exercise

Overall control of
underlying asthma and
BHR
•Good control: FEV1
>70% predicted
•Fall in BHR
•Poor control: FEV1
<65% predicted
•Increase in BHR
Physical conditioning •Good conditioning
•Warm up and cool
down sessions
•Poor conditioning
•Sudden burst of activity
•Emotional stress,
•Athletic overtraining
Respiratory tract
infections, especially
viral
•No respiratory tract
infections
•Presence of respiratory
tract infections,Sinusitis
Rhinitis

Time since last exercise
(12)
•within 40-90 min may
benefit from refractory
period
•>2-3 hr
Concurrent medications •Maintenance anti-
inflammatory
bronchodilator
medication
•Salicylates
•NSAIDS
•ß-blockers
Pre-exercise foods
eaten
None •Peanuts, celery, shrimp,
grain, carrots, bananas,
wheat

Step for evaluation suspected EIB +/- asthma
• History
• Physical examination
• Pulmonary function test (pre/post bronchodilator)
• Diagnostic challenges
• Try treatment of EIB +/- asthma
• Further investigations

History suggest EIB
• Common clinical symptoms :
– coughing, wheezing, shortness of breath,
excessive mucus production, chest tightness,
chest pain prolonged recovery time following
exercise
• Less common clinical symptoms:
– stomach pain, nausea and near-death experiences
• Symptoms relieved or prevented by
SABA/LABA

Physical examination
• Asthma
– Co-morbid allergic disease: AR,AD
• Non-asthma
– Chronic lung disease
– Cardiovascular disease
– Obesity
– Etc.

Pulmonary function test
FEV1 <70%
• Suspected asthma
• Try treat with ICS/ LTRA
• SABA as needed
• Avoid triggers
• Repeat FEV1 after
treatment
– Improve: possible EIB with
asthma need objective
testings
– NOT improve: other diseases
FEV1 >70%
• Suspected EIB without
asthma
• Perform objective testings :
one or more
– Standardized ECT
– Eucapnic Voluntary
Hyperventilation (EVH)
– Mannitol test
– Sport specific field challenge
test

Differential diagnosis
and further investigations
Differential diagnosis
• Physiologic limitation
• VCD,EILD, EIH
• Anxiety hyperventilation
syndrome
• Obesity related dyspnea
• Cardiac abnormality: IHSS,
tachyarrythmia
• Pulmonary AVM.
• Other diagnosis
Further investigations
• EKG
• Echocardiogram
• Holter monitoring
• Chest x-ray
• CT, MRI
• Pulmonary exercise stress
test
• Exercise rhinoscopy
• Laryngoscopy

Diagnostic challenges
• Direct Challenges : Methacholine / Histamine
• Indirect Challenges :
– Exercise Challenge test (ECT)
– Surrogate
• Eucapnic Voluntary Hyperventilation (EVH)
• Inhalation of Mannitol, Adenosine monophosphate
(AMP) or hypertonic saline (4.5%NaCl)
IOC-MC recommend for elite athlete suspected EIB

Exercise challenge test
• At 20-25°C, dry air (10 mg H2O/L) with a nose
clip in place while running or cycling
% of predicted maximum HR
80-90%
mins
2-4 mins Maintain 4-6 mins
• Stop
• Record FEV1 at
5,10,15,20,25,30 mins
After exercise
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, VOL 187 ,2013

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

Contraindications for exercise challenge
Absolute
• Severe airflow limitation
(FEV1 < 50% pred/<1L)
• Heart attack/Stroke in last 3
months
• Uncontrolled hypertension
(syst > 200 or diast > 100)
• Known aortic aneurysm
• Unstable cardiac ischemia
or malignant arrhythmias
Relative
• Moderate airflow limitation
(FEV1<60%pred or < 1.5L)
• Inability to perform
acceptable quality
spirometry
• Pregnancy
• Nursing mothers
• Current use of
cholinesterase medication
of myasthenia
The American Thoracic Society. Am J Respir Crit Care Med 2000;161:309-29

Anderson & Kippelen, Immunol Allergy Clin N Am 33 (2013) 363–380

ECT interpretation
• The criterion for the percent fall in FEV1 used
to diagnose EIB is >10 – 15 %
Severity
• > 10% but < 25% = Mild
• > 25% but < 50% = Moderate
• > 50% or > 30% in steroid treated = Severe
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, VOL 187 ,2013

• High sensitivity to identify EIB
• IOC MC
: optimal test to identify EIB for athletes seeking
approval to inhaled β2–agonist before an event
Eucapnic Voluntary Hyperventilation
(EVH)
Rundell KW, Slee JB. J Allergy Clin Immunol 2008;122:238-46.

Eucapnic Voluntary Hyperventilation
(EVH)
• Induced high ventilation level up to 110 L/min and
maintain near normal alveolar CO2
• Protocol
– Breathing dry air contained: 5%CO2 +21%O2
– Controlled ventilation rate: 60-85% of MVV*
• MVV:max.voluntary ventilation
= 21-30 times of baseline FEV1
– Consistent ventilation for 6 min
– NOT perform in subject with FEV1< 70%
• The criterion for the percent fall in FEV1 used to
diagnose EIB is >10 – 15 %

Inhalation of Mannitol
• Produce hyperosmolar environment
• Protocol (Aridol approved by FDA 2010)
– Mannitol dry powder inhaler progressive doubling
doses of 5,10,20,40,80,160,160 and 160mg with
maximal total dose 635mg
– 1 min. after each dose, FEV1 measured
– +ve test: % fall in FEV1 >15 compare to baseline
: a between dose % fall in FEV1 >10

Hypertonic saline challenge
Protocol
• Nebulize 4.5% hypertonic saline inhalation in 15-
20 minutes
• Exposure time: 30 & 60 sec, 2 & 4 & 8 min
• 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)

Sport specific exercise challenge test
1. Natural setting athlete’s sport in field
exercise
2. Simulated condition in laboratory
• Important test in sports under special
environment
– Winter sport
– Swimming sport
• Low sensitivity than EVH

• Pharmacological treatments
1. Therapies given before exercise
2. Long-term therapies
• Non-pharmacological treatments
Treatment of EIB

• Response rate: 30-60% of EIB with asthma
• Degree of efficacy
: variable(complete no effect)
• Practical use
– Combination of ICS with another agents to
achieve control such as SABA, LABA, LTRA
– After controlled: step down to regular use of ICS
alone
Inhale corticosteroid (ICS)

Symptoms First-line Therapy Second-line Therapy
NORMAL LUNG FUNCTION (FEV1 >80%)
Rare symptoms of
asthma;
mild-moderate EIB
β-Agonist or chromone
before exercise
Leukotriene modifier
2 hr before exercise
Asthma symptoms
> 2×/wk and/or
moderate-severe EIB
Daily leukotriene modifier
± β-agonist before exercise
Daily ICS (low dose)
Approach to Therapy in Patient with
Exercise-induced Bronchoconstriction (EIB)
Teal S. Hallstrand. Middleton's Allergy: Principles & Practice, 8th ed

Symptoms First-line Therapy Second-line Therapy
REDUCED BASELINE LUNG FUNCTION (FEV1 <80%)
Asthma symptoms
> 2×/wk and EIB
Daily ICS(≥ moderate dose)
Add leukotriene modifier
for persistent symptoms.
Avoid LABA if possible.
Approach to Therapy in Patient with
Exercise-induced Bronchoconstriction (EIB)
Teal S. Hallstrand. Middleton's Allergy: Principles & Practice, 8th ed

An Official American Thoracic Society
Clinical Practice Guideline 2013
: Exercise-induced Bronchoconstriction
Recommendation
Short-acting β2-agonist (SABA)
before exercise
is typically administered
15 minutes before exercise.
strong recommendation,
high-quality evidence
A mast cell stabilizing
agent before exercise
high-quality evidence
Inhaled anticholinergic
agent before exercise
weak recommendation,
low-quality evidence
Against administration of
ICS only before exercise
moderate-quality evidence
Am J Respir Crit Care Med 2013;187:1016-1027.

Recommendation
Daily administration of ICS
(2–4 weeks after the initiation of therapy
to see maximal improvement)
Daily administration of
a LTRA

• For patients with EIB and allergies who continue to
have symptoms despite using an inhaled SABA before
exercise,or who require an inhaled SABA daily or more
frequently
we suggest administration of an antihistamine
(weak recommendation, moderate-quality evidence).
• Against administration of antihistamines
in patients with EIB who do not have allergies
(strong recommendation,moderate-quality evidence).

NONPHARMACOLOGIC THERAPIES
• Pre-exercise
: Warm up 60-80% HR max X 10-15 mins
– Given bronchoprotective effect and
extended refractory period from 1 - 4 hr.
– Recommend add on pharmacotherapy better than
warm up alone or SABA alone
• Post-exercise
: Warm down X 10-15 mins

• Avoidance of triggers
• Nasal breathing
• Wearing a mask in cold environments
• Avoiding exercise in conditions where air is
cold and dry
• Low salt diet
• Ѡ-3 fatty acid(fish oil) and Ascorbic acid
supplement
NONPHARMACOLOGIC THERAPIES

Effects of fish oil supplementation on severity of
exercise-induced bronchoconstriction.
Mickleborough TD, et al. Chest 2006; 129:39-49.

Weiler et al, J ALLERGY CLIN IMMUNOL PRACT MAY/JUNE 2014
Symptoms suggestive of EIB and normal FEV1 (>70% of predicted)
Exercise challenge/Surrogate indirect airway challenge
∆ FEV1 post challenge > 10-15%
Consider
Alternative
diagnosis
EIB confirm
Consider treatment
Non-pharmacologic
(prevent symptoms only)
• Warm-up exercise
• Face mask/scarf
• Dietary modification
Pharmacologic
Treat symptoms
: SABAs
Prevent symptoms
: SABAs 5-20 min before exercise
(consider addition of MCSA or
anticholinergic if SABA not working)
Used daily or more?
: Consider addition of controller therapy
(daily ICS+/-LABA, and/or LTRA; AH if allergic
No
Yes

Exercise inducedbronchoconstriction-140903111351-phpapp01

Recommended

Recommended

More Related Content

What's hot

What's hot (17)

Similar to Exercise inducedbronchoconstriction-140903111351-phpapp01

Similar to Exercise inducedbronchoconstriction-140903111351-phpapp01 (20)

Exercise inducedbronchoconstriction-140903111351-phpapp01