Exercise induced bronchoconstriction

EXERCISE INDUCED
BRONCHOCONSTRICTION
THITIMA KANTACHATVANICH, M.D.

Case presentation
• A Thai nurse woman 40 year
• Occupation: nurse from the General Police Hospital
• Severe asthma, AR S/P HDM SCIT
• After 20 min from onset of running, she always develops chest tightness
and dyspnea
• Recoverd spontaneously after rest within 5-10 min but afraid to resume
running afterward
• Stretching exercise before running 3-5 minute
• Current medication
• Flixotide(250mcg) 2 puff bid
• Singulair 10 mg/d
• Avamys 2 puff hs
• She avoids SABA due to palpitation

Definition
• Transient narrowing of the lower airway after exercise… (Practice
Parameter 2016)
• With or without asthma
• Acute airway narrowing that occurs as a result of exercise…(ATS 2013)
• A brief period of high-intensity exercise or increased ventilation triggers
airway narrowing that lasts 30 to 90 minutes in the absence of
treatment…(Middleton 8th edition)
• Should not use the term “EIA”
• Not induced but rather trigger
Middleton 8th edition
Practice Parameter 2016

Epidemiology
• Occur in asthma (30-50%), non-asthma (10-20%)
• In asthma: indicate lack of asthma control, inflammation
• In non-asthma: indicate BHR
• Variable prevalence
• Higher prevalence in elite athlete than in normal
• Depend on sport, environment
• Adult&children: each 10-20%
• One study: ↑Age↓EIB
• Gender, Race
• Some studies: female > male
• African American, asian
• Season: winter > summer

Pathophysiology
• Osmotic theory
• Thermal(or Vascular) theory
• Airway injury: athletes
MC, Eo activation
Epithelial activation
Sensory nerve stimulation

Osmotic Theory: Predominant Role

Airway Surface Liquid
• Bilayer: superficial mucous layer + periciliary fluid layer
• Separated by surfactant
• Mucous layer: mucin Gp.
• Mucin: MUC5AC, MUC5B
Exercise and other indirect challenges to demonstrate asthma or
exercise-induced bronchoconstriction in athletes. JACI 2008;122:238-46

Water Loss vs Bronchoconstriction During EVH
Use gases with Identical heat-carrying, but different water-carrying

Disease Model of EIB Pathogenesis
(↑vascular permeability)
MC: CysLTs, PGD2
Eo: CysLTs, ECP
Epithelial cell: regulartory proteins
(to activate MC, Eo)

Mediators
• Early: histamine, tryptase (MC degranulation)
• Sustained: CysLTs (LTC4, LTD4, LTE4)

Sputum After Exercise Challenge
(Asthma with EIB vs Nonasthmatic Control)

Thermal(or Vascular) Theory: Additional Role
• Normal physiology
• Conditioned air to distal lung
*during expiration : rewarm exhaled air  heat (+water) return to mucosa
• EIB
• If hyperpnea: unconditioned (dry, cold) air inspired to distal lung
• ↓expiration time: heat loss > heat return
• Vasoconstriction after inhaled cold air  cessation of exercise  “reactive
hyperemia”  vascular engorge, airway edema

Thermal Theory
Inspiring warm humidiﬁed air after exercise
 Induce bronchoconstriction 5-15 minutes
(further engorgement of microvasculature)

Airway Injury (Overuse Syndrome): Athletes
• Hyperpnea  repetitive epithelial injury
• BSM exposed to plasma-derived products from exudation  contractile
property changes
• High ventilation rate (swimming, mountain biking, rowing, biathlon,
cross country skiing/skating)
• Evidence: ↑CC16 (marker of lung injury) in serum, urine of athletes

Sensory Nerve
• Osmotic stimuli
• CysLTs  Neurokinin
• CysLTs
Retrograde axonal transmission
Globlet cells release major gel forming mucin MUC5AC

Clinical Presentations
• Prototypic features: symptoms occur during or after a modest period
of high endurance physical exertion
• Shortness of breath, chest tightness, wheezing, cough, ↑mucus
• Chest pain (primarily in children)
• High ventilation and endurance sport

Refractoriness
• Additional exercise produce less bronchoconstriction
• 50% of patients
• 1-3 (occasionally to 4 hours)
• Not fully understand mechanism
• Tolerance to the effect of mediator release
*Protective PGs generation: NSAIDs decrease refractoriness to exercise/LTD4
challenge
• Tachyphylaxis at airway SM to mediators
• Warm up: Non-pharmacologic Mx (Recommendation A)

Differential Diagnosis of EIB
• Exercise-induced laryngeal dysfunction (e.g., VCD)
• Exercise-induced hyperventilation/dyspnea–healthy obese
• Exercise-induced anaphylaxis
• Exercise-induced dyspnea–age appropriate
• Exertional GERD
Can be coexist or DDx

Differential Diagnosis of EIB
• Pulmonary diseases
• Obstructive/restrictive lung disease, ILD
• Extrapulmonary diseases
• Obesity, skeletal defects, diaphragmatic paralysis, myopathies
• Cardiovascular, gastrointestinal diseases
• Psychological
Can be coexist or DDx

Diagnosis
• Need objective exercise/surrogate challenge tests (not only from Hx)
• Symptoms: poor predictors of positive challenge tests
• No gold standard Dx
• No universal validated positivity criteria of challenge tests

Assessment of Airway Hyperresponsiveness
• Direct
• Exogenous provoking substance applies to act directly through receptors
• Methacholine, histamine
• Low specificity for EIB (reflecting only single agonist)
• For R/O asthma in currently clinical asthma patients
• Indirect
• Trigger endogenous mediators release
• Assessing the presence of inflammatory cells and their mediators compared with
direct tests that directly provoke SM contraction.
• Exercise, osmotic agent
• More specific to Dx BHR from airway inflammation (asthma, ICS need)
• Recommended for asthma monitoring
• More sensitive than direct

Precaution in Bronchoprovocation Tests
• Direct challenge:
• Elite athletes
• Remote asthma (not currently clinical asthma)
• Medications: Beta-agonist, anticholinergic
• TLC inhalations (Eosinophilic bronchitis)
• Normal (5-15%)
• Rhinitis (20-40%)
• COPD
• Indirect challenge:
• Mild, well controlled asthma
• Medications: Beta-agonist, anticholinergic

Standardized Exercise Challenge Test
• Control MVV, water content (dry air <10 mg H2O/L) of inh. Air
• Prefer treadmill > cycle ergometry
• Field challenge, free running: difficult to standard
• FEV1 ≥ 75%, SpO2 > 94%
• Adequate ventilation: ≥ 60% of the maximum voluntary ventilation by
using dry medical grade air
• If not available to measure MVV  target HR(max)
• ≥ 85% in adults (≥ 90% in very well conditioned subj)
• ≥ 95% in children and elite athletes
• Formula: 220-Age (in years); more accurate equation, 208-0.7xAge

Standardized Exercise Challenge Test
• On nose clip
• Exercise ramp up to target: within 2-3 min
• Maintain 4-6 min (no more than 8 min)
• Spirometry: BL, (1, 3,) 5, 10, 15, 30, 45-60 min after exercise
• After exercise: FEV1 not in full maneuvers
• Repeat FEV1 in each time point, use highest FEV1
• Positive:
• ≥ 10% drop of FEV1 compared to BL x 2 consecutive time points
• ≥ 20% drop of FEV1 compared to BL x 1 time points

Positive Spirometric Criteria
• ≥ 10% drop of FEV1 compared to BL x 2 consecutive time points
• ≥ 15% in field challenge
• ≥ 6-10% in laboratory challenge
• ≥ 20% drop of FEV1 compared to BL x 1 time points
• Most nadir 5-10 min postexercise
• Severity from AUC
ATS 2013
Age 3-6 years old: use FEV0.5

Typical Change in FEV1 in 8-minute Exercise
Challenge in EIB-positive Individuals
Exercise and other indirect challenges to demonstrate asthma or
exercise-induced bronchoconstriction in athletes. JACI 2008;122:238-46

Severity of EIB
Before the widespread use of ICS
• Mild: ∆ ≥10% but <25%
• Moderate: ∆ ≥25% but <50%
• Severe: ∆ ≥50%
• Currently, a decline in FEV1 of >30% in a person taking ICS would be
considered severe.
An Ofﬁcial American Thoracic Society Clinical Practice Guideline:
Exercise-induced Bronchoconstriction, Am J Respir Crit Care Med Vol 18, 2013

EVH (Eucapnic Voluntary Hyperventilation)
• Indirect ungraded challenge
• Eucapnic gas mixture (5% CO2, 21% O2, and balance N2)
• Target 60-85% MVV for 6 min  spirometry
• FEV1 ≥ 75% predicted (if < 80% done with caution)

LTRA>LAMA>Ultra-LABA>AH>LABA+/-ICS, Long acting ICS, Xanthine, Caffeine>Zileuton
>SAMA>SABA>ICS>Vigorous exercise>Cromone

Recommendations to Tests
• Use indirect challenge
• Athletes, normal PFT, no asthma: indirect ungraded challenge
(exercise, EVH)
• Athletes, normal to near-normal lung function + currently require Tx
for EIB or asthma: indirect graded challenge (mannitol)
• If negative indirect graded challenge + still suspected EIB
Indirect ungraded challenge
• If negative all + still suspected EIB  repeat (esp. milder response)

Pharmacologic & Nonpharmacologic Tx
• Prevent symptoms before exercise: prophylaxis drug, warm up
• Relieve symptoms induced by exercise: rescuer
• Enhance asthma control: controller (↓severity of EIB)
“*Patient education”
Goal of Therapy
*
None completely eliminates EIB (just shift dose-response relationship)
Need regular F/U: variable responses to medications in different times (evidence A)

Pharmacologic Mx Avoid beta-agonist in regular manner

Pharmacologic Mx: Middleton 8th edition
Avoid beta-agonist in regular manner

Preexercise Prevention

Pharmacologic Mx: ATS 2013
• SABA before exercise
• Mast cell stabilizing agents and Inh anticholinergic: secondary role
• If Symptoms despite inhaling SABA before exercise, or require
inh.SABA daily or more frequently
Daily ICS or LTRA ﬁrst, made on a case-by-case basis
• Patient preferences, lung function
• Antihistamine if EIB+Allergies
• against antihistamines in EIB without allergies
• Against daily inh.LABA as single therapy
ATS 2013

Exercise induced bronchoconstriction in adults: evidence based diagnosis and management, BMJ 2016;352:h6951

Pharmacologic Mx: Practice Parameter 2016
• Preexercise prevention
• SABA/LABA, LTRA, Mast cell stabilizer
• Inh. anticholinergic for prevent EIB: inconsistent results in studies
• Rescuers
• SABA
• Inh. anticholinergic: if not responsive to SABA
• Maintenance
• Daily ICS
• LTRAs: if ICS alone was not effective
• Add on theophylline (adjunctive Tx)
• Not use daily SABA/LABAs with or without ICS
• (except ICS/LABA in moderate to severe persistent asthma)
• No definitive study on anitihistamine in EIB

β-Agonists: use < 4 times/wk
Handb Exp Pharmacol. 2017; 237: 23–40.

Tolerance of β-Agonists
Effect of the drug: require a large fraction of available β2 receptors
• ↓Duration
• ↓Magnitude of protection,recovery after
FEV1 dropping
• Prolong recover after EIB
• Cross-tolerance
• Can occur rapid (12-24 hr after a 1st dose),
recover in 72hr from last dose
• Interval to prevent: 48-72hr
• Occur in most pts
• Mechanism: uncoupling, internalize β2
receptors
• ICS does not prevent tolerance

LT Inhibitors
• Not lead to tolerance
• Incomplete protection (not inhibit other mediators)
• Unable to reverse AWO but accerelate time to recover
• Efficacy: 30-80% (50% = responder) attenuate EIB
• FDA approved montelukast for Tx EIB in adolescent, adult
• LTRA: Onset 1-2 hr, duration 24 hr
• 5-LO inhibitor: duration 4 hr (not currently recommended for EIB)

Mast Cell Stabilizer
• Inhaled cromolyn sodium, nedocromil sodium
• Not available in US now
• Rapid onset, short duration (1.5-2 hr)
• No bronchodilator activity
• Excellent safety profile, no tolerance
• MonoTx or combine Tx

ICSs
• Decrease frequency, severity of EIB
• Controller for moderate-to-severe persistent asthma
• High dose ICS: seen effect as early as 4 hr
• Time dependent (longer duration > 12 wk)
• No difference between different doses
• Variable interpersonal responses
• INS + ICS or ICS alone in EIB with AR?
• LABA+ICS for on-demand Tx vs low dose ICS: same magnitude
reduction of EIB over 6 weeks

Anticholinergic
• Inhaled ipratropium bromide
• If no response to other agents
• Bronchodilator activity
• Inconsistent effect in all patients and each patient

Methylxanthines
• Theophylline, aminophylline
• Non-selective phosphodiesterase inhibitors of cAMP, cGMP
• Mild bronchodilator (no effect by oral route)
• Narrow therapeutic index
• SE: seizure
• Roflumilast: selective PDE4 inhibitor  attenuate mild EIB, lower SE
• Caffeine 6-10mg/kg  attenuate EIB

Antihistamines
• Inconsistent results
• Less potent mediator in EIB
• No definitive study to prove efficacy in EIB

International Olympic Committee Criteria
(TUE of Beta-2 Agonist)
Bonini and Palange Asthma Research and Practice (2015) 1:2

Nonpharmacologic Mx
• Preexercise warm up: target 60-80% HR max (combine to SABA)
• ATS 2013: interval or moderately vigorous exercise
• Humidification of inspired air (face mask)
• Limit activity rather than pharmacologic Tx in airway injury model
• Diet (3 weeks)…Evidence A (but weak recommendation)
• Low salt diet (2-5 weeks)
• Omega-3 FA (PUFA)
• Ascorbic acid
• β-carotene
• Lycopene

Warm-Up Exercise
• ATS 2013: Interval high intensity or Combination(variable) intensity1
• Interval high intensity
Schnall RP, et al protocol2
• Sprint 30 sec to reach ≥100%VO2 max X 7
• 2.5 minutes separate each sprint
• Rest 20 minutes
Mickleborough, et al3
• After stretching 5 min, sprint 30 sec X 8
• 45 seconds separate each sprint
• Rest 15 minutes
• Combination(variable) intensity
Schnall RP, et al protocol2
• 6 minutes run
• Rest 10 minutes
• Sprint 30 sec to reach ≥100%VO2 max X 7
• 2.5 minutes separate each sprint
• Rest 20 minutes
1.Parsons JP, et al. An ofﬁcial American Thoracic Society clinical practice guideline:
exercise induced bronchoconstriction. AmJRespirCritCareMed 2013;187:1016-27.(IV).
2.Schnall RP, Landau LI. Protective effects of repeated short sprints in exercise-induced
asthma. Thorax. 1980;35(11):828–32.

Stickland MK, et al. Effect of warm-up exercise on exercise-induced
bronchoconstriction. Med Sci Sports Exerc 2012;44:389–391.

Effects of Fish Oil Supplementation on Severity of
Exercise-Induced Bronchoconstriction
Another study showed no inhibition of EIB by fish oil

Summary
• EIB in asthma: Osmotic change  MC, Eo release bronchoconstrictive
mediators
• EIB in athletes: Airway injury
• DDx to cardiopulmonary diseases
• Indirect challenge test
• Key Mx: Pharmacologic and nonpharmacologic

Exercise induced bronchoconstriction

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