Exercise-Induced Bronchoconstriction

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-Bronchoconstriction
EI-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 shedding
PGE2

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
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.

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

Factor
Decrease EIB/EIA
Increase EIB/EIA
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

Factor
Decrease EIB/EIA
Increase EIB/EIA
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)
± β-agonist before exercise
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)
± β-agonist before exercise
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
strong recommendation, high-quality evidence
Inhaled anticholinergic
agent before exercise
weak recommendation, low-quality evidence
Against administration of ICS only before exercise
strong recommendation, 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
Δ 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-Induced Bronchoconstriction

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