Exercise induced bronchoconstriction

Exercise Induced
Bronchoconstriction
(EIB)
Jintana Chataroopwijit, MD
29 September 2017

Content
• Definition
• Pathogenesis
• Inflammatory mediator release, cellular activation,
contribution of sensory nerves
• Diagnosis and differential diagnosis
• Testing : direct / indirect
• Treatment

Synonymous terms
• Exercise induce asthma : no longer a prefer term
• Exercise induce airway narrowing
• Exercise induce bronchospasm
• Exercise induced bronchoconstriction

Exercise induced asthma (EIA)
• Exercise itself dose not cause asthma  avoid this term
• Asthma  bronchoconstriction
 Nonpharmacologic stimuli
 Nonimmunologic stimuli
• EIB as a component of the asthma syndrome rather than
isolated disorder
• EIA : Predominant in asthma but also some athletes
• Resolve after stop high exercise
Increase hyperventilation and
hypertonic aerosol  airway
obstruction
Teal S. Hallstrand: Middleton ed 8th

Definition
• A syndrome in which a brief period of vigorous
physical exercise triggers airflow obstruction
lasting 30 to 90 min in the absence of
treatment
• Exercise-induced bronchospasm : NAEPP-ERS 3
(2007)

Definition
• Exercise induced bronchoconstriction
• ATS, 2013 : Acute airway narrowing that occurs as
a result of exercise
• Practice parameter, 2016 : Transient narrowing of
the lower airway after exercise in the presence or
absence of clinically recognized asthma
GINA 2017
Middleton ed 8th
ATS 2013
Practice parameter 2016

Epidemiology: Prevalence and relation to
other aspects of asthma
• 30 – 50% in asthma patients
• 10 – 20% children without a recognized diagnosis of
asthma
• Strongest predictors of asthma over at least 6 years
of follow-up
• Parent-reported exercise-induced wheeze
• History of atopy
• AHR to cold dry air–induced hyperpnea in early
childhood  increased risk of persistent asthma at
22 years of age

Pathogenesis: asthma patient
• Inflammatory mediators (histamine, eicosanoids and
leukotrienes) released into the airways from cellular
sources in the airways(eosinophils and mast cells)

Pathogenesis and Etiology
 Theory
 Osmotic theory : predominant theory
 Thermal theory : limited role (Practice parameter;
Exercise induced bronchocontriction update 2016/Teal S. Hallstrand:
Middleton ed 8th)
 Airway injury : especially athletes (Weiler JM et al.
Ann Allergy Asthma Immunol 2010;105:S1-S47.)

Pathogenesis and
Etiology: Osmotic
theory
Increase ventilation>>
water is lost from the
airway surface fluid (ASL)
>> transient
hyperosmolarity >>
passive movement of
water between cells to
restore osmolarity
Loss of water >>
reduction in temperature
but osmotically substance
dose not change airway
temperature
Manitol
Hypertonic saline

Pathogenesis and Etiology:
Thermal theory
• Airway cooling  vasoconstriction of the
bronchial vasculature
• Cessation of exercise(ventilation decreases
and the airways rewarm) : reactive hyperemia
with vascular engorgement and edema of the
airway wall
Practice parameter; Exercise induced bronchocontriction update 2016

Thermal theory

Airway injury
Immunol Allergy Clin N Am 33 (2013) 299–312

Pathogenesis and
Etiology: Airway injury
• Athletes : high ventilation rate (winter or summer)
• Swimming, mountain biking, rowing biathlon, cross
country skiing, skating event
• Breathing high volumes of unconditioned air over
long period
• Repetitive epithelial injury >> bronchial smooth
muscle exposure to plasma derived products from
exudation
• Recommend limit activity rather than pharmacologic
agent (asthma,EIB)

Inflammatory mediator release
• Alteration of airway epithelium
• Leukocyte derived eicosanoid
• Shunting of epithelial derived arachinodicacid away from
the epithelium toward the production of inflammatory
eicosanoids by adjacent leukocyte
• Ep cell>>IL13 >>reduction COX2 & PGE synthase1 >>
PGE2
• Epithelial derived secreted phospholipase A2(sPLA2),
sPLA2-X strongly express activate CysLT synthesis

• CysLT : Pathologic role
• Inhibition EIB by LT modifiers is incomplete
• Other bronchoconstictive eisocanoid;PGD2, 15S-
hydroxyeicosanoidsatetraenoic acid(HETE)
• Reduction of PGE2 (bronchoprotective mediator)

Cellular activation

Contribution of sensory
nerves
• CysLT occurs at least in part
through the activation of
sensory airway nerve
• sensory nerve relase
neurokinin
>>bronchoconstriciton
• Neurokinin>>MUC5AC
>>globet cell>>mucus
release
• Neurokinin-1,2 antagonist
inh. hyperpnea induced
bronchoconstriction (HIB)
in dog model
Significant increase in MUC5AC After exercise challange

Clinical presentation
• Wheeze, chest tightness, shortness of breath, cough
• Chest pain(primarily in children), excessive mucus
production
• Prototypic feature of EIB
– After a modest duration of heavy physical exertion
– Initial, airway dilate >> follow by bronchoconstriction
for first 5-10min after exercise

Clinical presentation
• Risk
 Type of sport : Rapid increase in ventilation; running
outdoors risk more than stationary bike (less minute
ventilation & Indoor air)
 Diurnal variation : afternoon severity more than
morning

Late phase response
• Physiology has been difficult to demonstrate in
many studies in human
• Cellular influx into the airways >>failed to
demonstrated in studies
• CRP, RANTES, FeNO, eotaxin : asthma with EIB
support that inflammatory mediator release
• Some study : second wave of airflow obstruction
consistent with a late phase response to exercise
challenge

Differential Diagnosis
Exercise induced larygeal dysfunction(EILD)
1. Paradoxical VCD
2. Exercise- induced laryngeal prolapse
3. Exercise- induced laryngomalacia
4. Variants, including arytenoid collapse while the vocal cords move normally
Practice parameter; Exercise induced bronchocontriction update 2016 ,
To differentiate between EIB and EILD, perform appropriate challenge tests
(eg, exercise, EVH, and mannitol for EIB) and potentially flexible laryngoscopy
during exercise for diagnosis of EILD. [Strength of Recommendation: Strong;
Evidence: B]

Exercise induced larygeal
dysfunction(EILD)
• Inspiratory stridor with throat tightness during maximal
exercise
• Resolves within approximately 5 minutes of discontinuation of
exercise in patients
• Variations in the timing of the manifestations of EILD
symptoms >> depending on duration and intensity of the exercise
• In EIB
• Dyspnea generally occurs after exercise (peaks 5 to 20 minutes after
stopping)
• Involves expiration rather than inspiration

Exercise- induced dyspnea and hyperventilation
• ‘‘epidemic’’ among adolescents but prevalence is uncertain
• Hypocapnia from hyperventilation without bronchoconstriction
 Chest discomfort perceived as dyspnea during vigorous
exercise can (especially in children and young adolescents)
To determine whether exercise- induced dyspnea and hyperventilation are
masquerading as asthma, especially in children and adolescents, perform
cardiopulmonary exercise testing. [Strength of Recommendation:
Moderate; Evidence: C]

Exercise-induced arterial hypoxemia
• Result of an excessively widened alveolar-arterial oxygen pressure
difference  small intracardiac or intrapulmonary shunts of
deoxygenated mixed venous blood during exercise  fatigue of the
respiratory muscles
• In hypoxic environment of even moderately high altitudes will greatly
exacerbate the negative influences of these respiratory system
limitations to exercise performance, especially in highly fit subjects

 Exercise induces anaphylaxis
 Wheezing can occur, less common than other symptoms
 Serum tryptase, skin testing
 Food-dependent exercise-induced anaphylaxis
 Shellfish, wheat gliadin
Consider a diagnosis of EIAna instead of EIB based on a history of shortness of
breath or other lower respiratory tract symptoms accompanied by systemic
symptoms (eg, pruritis, urticaria, and hypotension). [Strength of
Recommendation: Moderate; Evidence: C]

 Other underlying conditions : COPD, obesity,
skeletal defect, diaphragmatic paralysis,
interstitial fibrosis
 Heart disease : cardiac asthma
 Psychological problems : hyperventilation, anxiety
disorder

Diagnosis testing : Direct
• Metacholine/ Histamine challenge test : dose
not entirely rule in/ rule out EIB
• Low specificity for EIB as a result or reflecting
the effect of only a single agonist (summary state7
:practice parameter; EIB update 2016)
• Fit before challengeFEV1>75% and SaO2 > 94%

Diagnosis testing : Indirect
• Exercise challenge test (ECT)
• Eucapnic voluntary hyperpnea challenge (EVH)
 More sensitivity detection EIB than directed
challenge (strong evidence B: practice parameter; EIB
update2016)
• Other : Hypertonic saline challenge, Inhaled
powder mannitol challange

Gold standard for diagnosis
Indirect challenge
 Exercise challenge test (ECT)
 Eucapnic voluntary hyperpnea challenge (EVH)
 Inhaled powder mannitol challenge
1. Graded : recreational or elite atheles with normal to near
normal pulmonary function test
2. Ungraded : on history of asthma and normal pulmonary
function test

Contraindication for exercise
challenge test

Eucapnic Voluntary
Hyperpnea set-up
Jame H., et al.. Eucapnic Voluntary Hyperpnea: Gold Standard for Diagnosing Exercise-Induced in Athletes?. Sports Med. 2016;

Eucapnic Voluntary Hyperpnea Challenge

Inhaled powder mannitol challenge
• 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)
• Interval 2 minutes or only slightly longer –
cumulative 20-25 min and no longer
• FEV1 measurement: 1 min after each dose
Practice parameter 2016
FDA: approved

positive response
• 15% fall in FEV1 at a total cumulative dose of
635 mg
• 10% fall in FEV1 from baseline between doses
Inhaled powder mannitol challenge
Sandra D. Anderson.CHEST 2010; 138(2):25S–30S Weiler JM et al.
Ann Allergy Asthma Immunol 2010;105:S1-S47.

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
• Positive 10% fall in FEV1
Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

Methacholine challenge
American Thoracic Society. AJRCCM 2000;161:309-29

Contraindication for methacholine challenge
American Thoracic Society. AJRCCM 2000;161:309-29

Medication Withdrawal Schedules
LTRA > ATH > ICS+LABA , caffeiene > SABA > ICS > vigorous exercise

Approach
• The treatment of a patient with EIB
• Should take into account the severity of
chronic asthma and the severity of EIB base on
guideline

Treatment
Pharmacologic therapies
1. Intermittent prophylaxis
• Short and long acting 2
agonist
• LTRA
• Anticholinergic, Chromones
2. Maintainance prophylaxis
• Inhaled corticosteroid, LTRA
Nonpharmacologic therapies
• Preexercise warm up(strong
evidence A)
• Dietary factor(weak evidence A)
• low salt diet
• antioxidant (vitamin C, fruit,
vegetables)
• high PUFA

Approach to therapy in
patient with EIB

Intermittent Prophylaxis:
beta2 agonist
• Intermittent Prophylaxis: beta2 agonist
Inhaled SABA (strong evidence A)
• Most effective for acute prevention of intermittent EIB (<4
times/week)
• 5-20 min before exercise, protection 2-4 hours
• Inhale LABA (strong evidenceA) : Slower onset but formoterol
rapid onset 15-30 minutes, prolonged protection (8-10 hours)
• Caution! Regular treatment >> beta2 agonist tolerance due to loss
of 2-receptor density on mast cell, sensory nerve and ASM

Intermittent Prophylaxis: LTRA
• Daily LTRA do not lead to tolerance and show
attenuate EIB in 50%
• Intermittent or maintainance prophylaxis (strong
evidence A)
• Role of LT : sustain bronchoconstrictive and
inflammatory response

Intermittent Prophylaxis: LTRA
• Montelukast : approved by the FDA for treatment of
EIB in adolescents and adults
• Acts within 1 to 2 hours, bronchoprotective activity
of 24 hours
• Tolerance does not develop with long-term use

Chromone
• Mast cell stabilizer (strong evidenceA)
• Provide consistent protection against EIB
• Reduction severity of EIB 50%
• Inhaled form : not available in USA
• Rapid effect but short duration : 1-2hr
• Safe for used repeatedly to attenuated EIB

Inhaled Anticholinergic
• Weak evidence A
• Variable and inconsistent protective effects
• Lower magnitude than SABA

Useful Short-term Preexercise
Approaches to EIB

Inhaled corticosteroid
• Consider combination with other therapies, ICS can
decrease the frequency and severity of EIB (strong
evidence A)
• Less improvement: Patient with EIB did not have
sputum eosinophilia
• Steroid do not have a major impact on elevated
level of eicosanoid in airway : 2 agonist before
exercise

Inhaled corticosteroid
• Not prevent the occurrence of tolerance from daily
β2- agonist use
• The maximum beneficial effect in protecting against
EIB may take as long as 2-4 weeks, and is dose
dependent

Other Pharmacologic treatment
• ICS +LABA : Do not prescribe to treat EIB
unless needed to treat moderate to severe
persistent asthma (strong evidenceA)
• Antihistamine : Absence definitive studies
determine effectiveness in EIB
• Methyxanthines : Show no benefit
• Vitamin C : Antioxidant  Uncertainly role

• Preexercise Warm up (strong evidence A)
• May be helpful in reducing the severity of EIB
• Mechanism: not well understood, effect from
depletion bronchoconstrictive mediator from
mast cell?
• Should be done 60-80% HRmax to provide
partial attenuation of EIB

• Albuterol plus a warm-up provides better
production than warm-up or albuterol alone
•
• Other : Use face mask  prevent water loss –
No data of limit physical activity?

Summary of treatment :
Pharmacologic therapy
• SABA : most effective at short term protection
• Daily use SABA/LABA+ICS : tolerance SABA recovery EIB
• LTRA : intermittent / maintainance prophylaxis, protection may
be incomplete
• Mast cell stablizer : attenuate EIB, short duration of action
• Regular ICS: reduction of frequency and severity of EIB

Summary of treatment:
Non pharmacologic therapy
• Warm-up reduce severity of EIB
• Albuterol + warm - up : better result
• Questionable in reducing the severity of EIB
• Reduction of sodium intake
• Fish oil
• Ascorbic acid supplementation

Conclusion
• EIB is common feature of asthma
• Strongly related to airway inflammation
• Epithelial shedding, infiltration with leukocytes(esp.
eosinopil, mast cell)
• Uncondition air lower airway, water movement and
heat transfer water movement is critical factor, but
thermal factor may modulate severity
• Therapy : applied before exercise as well as long term
controller therapy to reduce the severity of asthma and
associate EIB

Exercise induced bronchoconstriction

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