Università di Cagliari Update on Exercise-Induced Asthma Dr. Stefano Del Giacco, MD Professor of Internal & Sports Medicine University of Cagliari, Italy stedg@medicina.unica.it
Treating asthma and allergy in a competitive athlete: a trivial matter, a luxury or a need? Carlsen KH, Kowalski ML. Asthma, allergy, the athlete and the Olympics Allergy 2008;63:383-386
Exercise is a quantifiable and reproducible stressor that can be modified experimentally and thus considered as a model of stress HOFFMAN-GOETZ L AND PEDERSEN BK. Exercise and the immune system: a model of the stress response? Immunol Today 15:382 387, 1994. Endocrine system Nervous system Immune system
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
Treating asthma and allergy in a competitive athlete: a trivial matter, a luxury or a need? Carlsen KH, Kowalski ML. Asthma, allergy, the athlete and the Olympics Allergy 2008;63:383-386
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
Exercise-Induced Asthma 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.
Epidemiology
From: Carlsen KH et al., Allergy 2008, 63(4):387-403
inflammation and airway physiology: mechanisms for development
EIA Hyperventilation and osmolar changes Airways cooling and rewarming Inflammation
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 Helenius et al. J Allergy Clin Immunol 2002; 109:962-8
Hyperventilation 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
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 Atopic speed and power athletes Atopic Long distance runners Atopic Swimmers 25-fold increase 42-fold increase 97-fold increase 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
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 Athletes Asthma?
Dry and cold air inhalation, Hyperpnoea EIA Respiratory loss of heat and water Mucus production + cough Smooth muscle contraction and inflammation Ca ++ and Cl - enter the cell, leading to activation of Phospholipase II Increased output of leukotrienes and mediators release Change in osmolarity of the periciliary fluid The Osmolar Hypothesis
The Vascular hypothesis Cold air inhalation Increased vascular flow Peribronchial vascular congestion Vascular engorgement-oedema Smooth muscle contraction EIA
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.
Cultured human epithelial cells Hyperosmolar medium Increased expression of chemokines like IL-8 and RANTES Cooling- Rewarming 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 coolingrewarming induced interleukin-8 and RANTES production by human epithelial cells Am J Respir Crit Care Med 2000; 162: S3 1075-1080
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 CD20 stains all B-cells
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?
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 maturationregulating 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 Roth M, Black JL Br J Pharmacol 2009 Apr. 3 (Epub)
Mice lacking the gene for Aquaporin 5 show bronchial hyperreactivity 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 Park C et al. Chest 2008; Epub 2008 Jul 18
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 Zietkowski Z et al, Int Arch Allergy Immunol 2008; 45:705-9
Exercise Allergen IgE MC Stimulation and Increased Releasability Histamine, LCT4, D4E4, PGD2 Osmolarity Variation Bronchospasm IL-4, IL-13, TGF-β AHR Mac Remodelling CD4 TH2 IL-5 Eos SR Del Giacco and GS Del Giacco, 2005 Chemokines
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.
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 Oral breathing pattern (loss of nasal air conditioning due to obstruction)
Diagnosis and Therapy of EIA
Is it EIA? Cough Wheezing EIA Dispnoea Thoracic constriction
Is it EIA? 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
Condition Exercise-Induced Asthma Vocal cord dysfunction (exercise-induced respiratory Stridor) Swimming-Induced pulmonary oedema Other Chronic Lung Disorders Other General diseases Heart disorders Poor physical fitness Exercise-Induced artherial Hypoxemia Characteristics 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 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 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 When accompanied by reduced lung function: Limitations during exercise, with often reduction in SpO2 Related to underlying disorder Related to expectations and training level High heart rate after low grade exercise load Muscular stiffness Well trained athletes with high VO2 max Mainly due to diffusion limitations and ventilation-perfusion inequality. Incomplete diffusion in the healthy lung may be due to a rapid red blood cells transit time through the pulmonary capillary district
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%
Diagnosis of EIA and EIB in professional sportsmen/women From: Carlsen KH et al., Allergy 2008, 63(4):387-403
Treatment
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
From: Carlsen KH et al., Allergy 2008, 63(5):492-505
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
Which sport for an asthmatic?
Irritants Cold, dry air Cyclist (e.g. road dust, diesel exhaust) Swimmers (e.g. chloramines) Skaters (e.g. N 2 O, ozone) Cross-country skiers Skaters Allergens Marathon runners Cyclists Viral Infections All strenous sport activities (the open window theory)
High-risk Sports Endurance sports (long-term effort) Running Cycling Winter Sports (cold, dry air/+long term effort) Cross-Country Ski Biathlon Ice Hockey Ice Skating
Medium-risk Sports Team Sports in general (effort is rarely longer than 5-8 min continuously) Football Basketball Volleyball Rugby
Low-risk Sports Short-term effort (never more than 5-8 min) Power running Tennis Fencing Swimming Waterpolo Boxe Alpine Ski Gymnastics
Environmental issues
Pollutants Primary pollutants Secondary pollutants CO CO 2 SO 2 NO metals (coal, graphite, lead) 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
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.
Airway hyperresponsiveness and pollution: ideal recommendations for preparing athletic competitions Organizers of the sport event Athletes team 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 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
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
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 exercising!
Cagliari, Sardegna, Italia Dr. Stefano Del Giacco, MD stedg@medicina.unica.it