Update on Exercise-Induced Asthma

(1)

“Update on

Exercise-Induced Asthma”

Dr. Stefano Del Giacco, MD

Professor of Internal & Sports Medicine

University of Cagliari, Italy

[email protected]

(2)

Università degli Studi di Cagliari

Treating asthma and allergy in a

competitive athlete:

a trivial matter, a luxury or a

need?

(3)

Immune system

Endocrine system

Nervous system

HOFFMAN-GOETZ L AND PEDERSEN BK. Exercise and the immune system: a model

of the stress response? Immunol Today 15:382–387, 1994.

“Exercise is a quantifiable and reproducible stressor that

can be modified experimentally and thus considered as a

(4)

Summary of the effects of strenuous exercise

on the immune system

From Pedersen BK and Hoffman-Goetz L. “Exercise and the Immune System: Regulation, Integration and Adaptation”.

Physiological Reviews Vol. 80, No. 3, July 2000; 1056-81

(5)

Treating asthma and allergy in a

competitive athlete:

a trivial matter, a luxury or a

need?

(6)

“…61 out of 263 athletic performance-related

deaths were linked to asthma over a 7-year

period in the USA.

…only one of the 61 athletes used inhaled

steroids…”

Mod. from Becker JM et al. “Asthma deaths during sports: report of a 7-year experience”.

J Allergy Clin Immunol 2004;113:264-267

and from

Carlsen KH, Kowalski ML. “Asthma, allergy, the athlete and the Olympics” Allergy

2008;63:383-386

(7)

“Exercise-Induced Asthma (EIA) and Exercise-Induced

Bronchospasm (EIB) are both used to describe acute lung

airway narrowing occurring during and/or after vigorous physical

activity.

EIA is used to describe symptoms and signs of asthma

provoked by exercise and EIB describes reduction in lung

function after an exercise test or a natural exercise”.

(Carlsen KH et al., Allergy 2008, 63:387-403)

Exercise may trigger asthma attacks and EIA represents the

major risk for an asthmatic patient practicing exercise (75-80%

of asthmatic subjects out of therapy may experience an asthma

attack when practicing physical activity) but, at the same time,

exercise can cause respiratory symptoms also in non-asthmatic

subjects.

(8)

(9)

From:

Carlsen KH et al.,

Allergy 2008,

63(4):387-403

(10)

inflammation and airway

physiology: mechanisms for

(11)

Hyperventilation and

osmolar changes

Inflammation

Airways cooling

and rewarming

EIA

(12)

Bronchial inflammation in athletes has a mixed origin

(eosinophilic/neutrophilic)

Eosinophil Peroxidase and Human Neutrophil

Lipocaline are increased in an induced-sputum

supernatant in professional swimmers.

•

Lumme et al. Eur Resp J 2003; 22:113-17

• Karjalainen et al. Am J Respir Crit Care Med 2000;

161:2086-91

(13)

“Repeated hyperventilation challenges

may cause epithelial damage with

eosinophil and neutrophil influx and

increased peptidoleukotriene

concentrations in BAL fluid”

Bonsignore MR, Morici G, Vignola AM

et al.

“Increased airway

inflammatory cells in endurance athletes: what do they mean?” Clin

Exp allergy 2003; 33: 14-21

(14)

Risk factors for EIA/EIB and bronchial

hyperresponsiveness

•

Risk Factors:

Type of Training:

endurance events (cross-country skiing, long distance

running, swimming)

Atopy:

risk factors “sporting event” and “atopy” were combined in a logistic

regression model compared to nonatopic control subjects

Helenius IJ, Tikkanen HO, Sarna S, Haahtela T. “Asthma and increased bronchial hyperresponsiveness in elite athletes: atopy and sport

event as risk factors” J Allergy Clin Immunol 1998; 101: 646-652

Atopic speed and power athletes

25-fold increase

Atopic Long distance runners

42-fold increase

(15)

Eosinophilia in professional swimmers’ induced

sputum

• Eosinophilia in 20% of tested athletes

• After a 5-years follow-up, eosinophilia was present in 38% of the

athletes still practising their sport and only in 8% of those that

quitted their activity.

Bougalt V et al. Eur Respir J 2009; 33:713-4

Helenius et al. Sports Med 2005;

35(7):565-74

Helenius et al. J Allergy Clin Immunol 2002; 109:962-8

(16)

Change in osmolarity of

the periciliary fluid

Increased

output

of

leukotrienes

and

mediators

release

Smooth

muscle

contraction

and

inflammation

Ca

++++

and Cl

--

enter

the

cell

,

leading

to

activation

of

Phospholipase

II

EIA

Mucus

production

+

cough

The “Osmolar Hypothesis”

Respiratory loss of

heat and water

Dry and cold air

inhalation,

Hyperpnoea

(17)

Cold air

inhalation

Vascular

engorgement-oedema

Peribronchial vascular

congestion

Increased vascular flow

Smooth muscle contraction

EIA

(18)

Cooling-rewarming of the airways plays a

fundamental role

- Davis MS, McKiernan B, McCullough S, et al.

Racing Alaskan sled dogs as a

model of "ski asthma".

Am J Respir Crit Care Med 2002; 166: 878–882.

- Davis MS, Freed AN.

Repeated hyperventilation causes peripheral airways

inflammation, hyperreactivity, and impaired bronchodilation in dogs.

Am J Respir

Crit Care Med 2001; 164: 785–789.

- McFadden ER, Lenner KA, Strohl KP.

Post-exertional airway rewarming and

thermally-induced asthma.

J Clin Invest 1986; 78: 18–25.

(19)

Hy

pe

ro

smo

lar

me

diu

m

Cultured human epithelial cells

Co

olin

g-Re

wa

rm

ing

Increased expression of chemokines

like IL-8 and RANTES

•Hashimoto S, Matsumoto K, Gon Y

et al.

“Hyperosmolarity-induced interleukin-8 expression in human bronchial

epithelial cells through p38 mitogen-activated protein kinase” Am J Respir Crit Care Med 1999; 159: 634-640

•Hashimoto S, Gon Y, Matsumoto K

et al.

“Inhalant corticosteroids inhibit hyperosmolarity-induced and

cooling-rewarming induced interleukin-8 and RANTES production by human epithelial cells” Am J Respir Crit Care Med

2000; 162: S3 1075-1080

(20)

Role of inflammation in EIA: lymphoid aggregates in

bronchial mucosa from a skier with asthma

symptoms and bronchial hyperresponsiveness.

Adapted with permission from Sue-Chu M, Karjalainen E-M, Altraja A, et al. Lymphoid

aggregates in endobronchial biopsies from young elite cross-country skiers. Am J

Respir Crit Care Med 1998; 158: 597–601.

Haematoxylin-eosin staining

CD3 stains all T-cells

(21)

VEGF and EIA: the

microvascular theory

•

Microvascular remodeling is induced by several Growth Factors, such as VEGF

•

Effects on Vascular function and on microvascular permeability

Kanazawa H et al.

Involvement of vascular endothelial growth factor in exercise induced bronchoconstriction in asthmatic patients

Thorax. 2002

Oct;57(10):885-8

Kanazawa H

Microvascular theory of exercise-induced bronchoconstriction in asthma: potential implications of vascular endothelial growth factor

Inflamm

Allergy Drug Targets. 2007 Jun;6(2):133-7

Targeting VEGF: possible new strategy for treatment of EIA in

asthmatic patients?

(22)

Imbalance in C/EBPs and increased mithocondrial

activity in astmathic airway smooth muscle cells:

smooth muscle again into the focus?

1. Deregulation of cell differentiation due to low levels of

maturation-regulating transcription factors such as CCAAT/enhancer binding proteins:

reduced cells threshold to proliferate and to secrete pro-inflammatory

cytokines under certain conditions

2. Higher basal energy turnover due to increased number and activity of

mithocondria

3. Modified feedback machanism between cells and the extracellular matrix

they are embedded in

(23)

From: King LS et al.

Nature Reviews Molecular Cell Biology 2004; 5

,

687-698

“Exercise-induced Asthma may be associated with diminished sweat secretion

rates in humans”

(24)

• Increased airway temperature induces a

transient airway constriction

Lin RL et al, J Appl Physiol 2009, Mar (Epub)

• Changes in RANTES and beta-thromboglobulin

after intensive exercise in patients with allergic

asthma

(25)

Exercise

Bronchospasm

IgE

Stimulation and Increased

Releasability

Histamine, LCT4,

D4E4, PGD2

Remodelling

Osmolarity

Variation

IL-4, IL-13, TGF-

β

IL-5

Allergen

Mac

CD4

TH2

MC

AHR

Eos

(26)

Every rhinitic athlete MUST be

screened to look for Asthma!

There is evidence of EIA in 40% of the

patients affected by allergic rhinitis. EIA is

often underdiagnosed in children and athletes.

7-12% of patients not considered to be at risk

of EIA by means of basal spirometry or

negative clinical “background” (Asthma, EIA

or allergic rhinitis), were positive by means of

a simple “exercise test”.

Bonini S et al.”Rhinitis and asthma in athletes: an ARIA document in collaboration with

GA2LEN”. Allergy. 2006;61(6):681-92.

(27)

Possible mechanisms linking rhinitis and asthma in Sports

Direct effects

nasal-bronchial reflex (irritant receptors-cholinergic nerves)

postnasal drip of inflammatory cells/mediators

mucosal hyperosmolarity (exercise-induced rhinitis and asthma)

Indirect effects

(28)

(29)

Is it EIA?

Wheezing

Thoracic constriction

Cough

Dispnoea

EIA

(30)

• Symptoms occur from 2 to 10 minutes (peaking

at around 10-15 min) after exercise

• Symptoms disappear spontaneously after 30-60

min

• Refractory period of 60-180 min

(31)

Condition

Characteristics

Exercise-Induced Asthma

•Symptoms occurring shortly after (sometimes during) physical exercise

•Expiratory dispnoea, expiratory ronchi and other signs of bronchial

obstruction. Spontaneous or bronchodilator-induced improvement

•Reduction of FEV1 of at least 10% after exercise

Vocal cord dysfunction

(exercise-Induced respiratory

Stridor)

•Symptoms during maximum exertion, disappearing after stopping

exercise (unless hyperventilation)

•Inspiratory stridor, audible inspiratory sounds from faringeal area.

•No signs of bronchial obstruction

•No effect of pre-treatment with bronchodilator

•Flattened part of flow-volume loop during stridor

Swimming-Induced pulmonary

oedema

•Shortness of breath and cough during or immediately after swimming,

associated with evidence of pulmonary edema

•Symptoms: shortness of breath, cough, sputum production,

haemoptysis, reduced SpO2 after swimming, restrictive spirometric

pattern persisting up to 1 week

Other Chronic Lung Disorders

•When accompanied by reduced lung function: Limitations during

exercise, with often reduction in SpO2

Other General diseases – Heart

disorders

•Related to underlying disorder

Poor physical fitness

•Related to expectations and training level

•High heart rate after low grade exercise load

•Muscular stiffness

(32)

EIA diagnosis

Free-running test

•5-8 min run

•Flow-volume loop measurement every 5 min (max 30’)

Test is POSITIVE if

(Absolute): reduction of basal VEMS

≥

10% (sedentary subjects) or

≥

15% (athletes)

(Relative): reduction of FEF 25-75

≥

35% or reduction of basal SaO2

> 4%

(33)

Diagnosis of EIA and EIB in professional

sportsmen/women

(34)

(35)

How to prevent and treat

exercise-Induced Asthma

• Inhaled Corticosteroids

• Beta-2 agonist drugs*

• Cromones

• Anti-leukotrienes

* Important: use of these drugs is regulated by the World Anti-doping Agency

(WADA) -International Olympic Committee

(36)

(37)

General warnings on treatment of

Exercise-Induced Asthma

• Treatment should follow the general guidelines

• Report of symptoms must be validated by the

standardized exercise tests and after exclusion of

differential diagnosis

• Problem of Tolerance development to most of the effects

of inhaled

β

2

agonists has been described

•

Salpeter SR, Ormiston TM, Salpeter EE “Meta-analysis: respiratory tolerance to regular

β

₂

agonists use in patients with asthma”. Ann

Intern Med 2004; 18; 140: 802-13

•

Simons FE, Gerstner TV, Cheang MS. “Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced

asthma using concurent inhaled glucocorticoid treatment” Pediatrics 1997; 99: 655-659

• Increased risk of severe cardio-vascular side effects in

patients taking long-acting

β

2

agonists on a regular

basis, with risk of death (FDA issue)

•

Salpeter SR. “Cardiovascular safety of beta(2)-adrenoceptor agonist use in patients with obstructive airway disease: a systematic review” Drugs Aging

2004; 21: 405-14

•

Salpeter SR, Buckley NS, Ormiston TM

et al.

“Meta-Analysis: effect of long acting (beta)-agonists on severe asthma exacerbations and

Asthma-related deaths” Ann Intern Med 2006; 6

(38)

(39)

Irritants

•Cyclist (

•Swimmers (

e.g.

road dust, diesel exhaust)

e.g.

chloramines)

•Skaters (

e.g.

N

2

O, ozone)

Cold, dry air

•Cross-country skiers

•Skaters

Allergens

•Marathon runners

•Cyclists

Viral Infections

•All strenous sport activities (the

“open

(40)

High-risk Sports

• Endurance sports

(long-term effort)

• Winter Sports

(cold, dry air/+long term

effort)

Running

Cycling

Cross-Country Ski

Biathlon

Ice Hockey

Ice Skating

(41)

Medium-risk Sports

• Team Sports in general

(effort is rarely longer

than 5-8 min

continuously)

Football

Basketball

Volleyball

Rugby

(42)

Low-risk Sports

• Short-term effort

(never more than 5-8

min)

Power running

Tennis

Fencing

Swimming

Waterpolo

Boxe

Alpine Ski

Gymnastics

(43)

(44)

Primary pollutants

CO

2

SO

2

NO

metals (coal, graphite, lead)

Secondary pollutants

Ozone (O

3

)

HN

3

H

2

SO

4

Nitrate peoxiacetyl

Other inorganic compounds

(gas or particulate form)

D’Amato G, Liccardi G, D’Amato M, Holgate S. Environmental risk factors and allergic bronchial asthma. Clin Exp Allergy 2005;35:1113-24

(45)

Pollutants: ice indoor sports

CO

2

and NO

2

They may excerbate a pre-existing condition in those people spending

considerable time in these environments, such as professional ice skaters

(ice hockey, short track, speed and figure skating).

Resurfacing machines

•

Propane fueled: 206 ppb (daily mean indoor NO

2

concentration)

•

Gasoline-fueled: 132 ppb

•

Electric-powered: 37 ppb

Other studies (332 rinks worldwide): mean level of 228 ppb (WHO

recommendation: 213 ppb)

Electric ice resurfacers, increased ventilation and emission control systems are

therefore recommended to avoid the risk of airways hyperresponsiveness related

symptoms in athletes and workers operating in ice rinks.

(46)

(47)

(48)

Airway hyperresponsiveness and pollution:

ideal recommendations for preparing athletic

competitions

Organizers of the sport event

•

Investigate the characteristics and

needs for the sport

•

Evaluation of training areas

•

Establish the time of day for the

sport event on the basis of lowest

pollution levels

•

If needed, establish measures to

limit pollution during physical

activities

•

Assess the ventilation of indoor

sports facilities

•

Assess the temperature for

outdoor events

•

Provide pollen forecast and count

for the area of competition

Athletes’ team

•

Plan the arrival of athletes at least

3 days before competition

•

Establish preventive measures in

hyperreactive subjects (asthmatics

and non-asthmatics)

•

Check the accommodation and

living conditions for athletes

•

Check pollen charts and forecast

for the area of competition

(49)

Take home messages (1)

• Always choose the right sport for the individual

• Always test rhinitic athletes for potential Asthma

• Be informed on the updated anti-doping

regulations!

(www.wada-ama.org)

• The athletes’ asthma is often reversible at the

end of the career

(50)

Take home messages (2)

• Role of cytokines in EIA pathogenesis and

remodelling

• Identification of new therapeutic targets

(cytokines, chemokines and their receptors)

• Always follow the recommendations for

preparing a competition (check pollution,

aeroallergens levels, facilities, season)

• Never under-estimate symptoms while

(51)

Cagliari, Sardegna, Italia

Dr. Stefano Del Giacco, MD