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

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 narrowingEexercise-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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

DefinitionReferences 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

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

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

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

Pathogenesis• Theory

– Osmotic theory– Thermal theory– Airway injury

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

↑ 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)

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315

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

Diagnosis

• Self-reported symptoms alone are not reliable for diagnosis of EIB

• Optimal EIB management may require confirmation of the diagnosis using objective methods

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

Randolph C. Clinic Rev Allerg Immunol. 2008;34:205–216.

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

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

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

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

Randolph C. Clinic Rev Allerg Immunol. 2008;34:205–216.

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**

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

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

• Screening for asthma• Low sensitivity for EIB Not

recommended as screening tool for EIB

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

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

American Thoracic Society.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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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 minmore 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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

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< 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)

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

A positive response • 15% fall in FEV1 at a total cumulative dose of 635

mg• Or 10% fall in FEV1 from baseline between doses

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

Confounding factors in diagnosis

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

Treatment

EIB therapy• Primary aim is prophylaxis

• Isolated EIA• Pretreatment before exercise

• Underlying asthma• Anti-inflammatory therapy

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

Therapy

• Controller therapy• Pretreatment before exercise

• β2-adrenergic receptor agonist• Leukotriene modifer• Mast cell stabilizer• Other: anticholinergic agent,

xanthine, antihistamine

Pharmacological

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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)

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

Leukotriene receptor antagonist

Montelukast• acts within 1 to 2 hours of oral administration• bronchoprotective activity for 24 hours

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

- 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

The American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

• 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

The American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.

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)

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

• attenuation of EIB by about 50%• no significant differences between sodium cromoglycate

and nedocromil sodium• Effectiveness : SABAs >MCSAs > anticholinergic agents

Mast cell stabillizers (MCS)

The American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.

Other agents

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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.

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

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

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

Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.

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

Thank you