Asthma in the elite athlete

Asthma in the elite athlete Sergio Bonini Professor of Medicine Second University of Naples, Italy se.bonini@gmail.com Dubai. December 5,2010

Prevalence of asthma among summer sports athletes

Prevalence of asthma among winter sports athletes

The Olympic study 21,6% 10,9% 21.6% 10.9% n = 265 n = 373

Allergy is a risk factor for EIA and EIB, particularly in athletes When allergy and intense exercise are combined, the risk of asthma is increased by : 25 folds in speed and power athletes 42 folds in endurance athletes 97 folds in swimmers from Helenius and Haahtela

Why asthma is so frequent in elite athletes? Effects of intense exercise on allergy Effects of intense exercise on the airways

Why asthma is so frequent in elite athletes? Effects of intense exercise on allergy Effects of intense exercise on the airways

Effect of intense and prolonged physical exercise on allergy Th2 Th1 Increased Th1 susceptibility to infections Th1 Increased Th2 prevalence Th2 Th2 Th2 of allergy and asthma

The GA2LEN Olympic Study Parameters Para-Olympics Olympics Pre-Olympics No. of athletes 72 207 (347) 228 Questionnaires t.b.d 144 162 SPT 48 138 170 PFT n.a. 136 168 Mannitol 0 2 6 Sera 72 207 228

The increasing prevalence of Allergy and Asthma in Athletes Bonini M. et al. The Ga2len Olympic Study Sensitization 32.6% Sensitization 56.5% in 84.4 % to multiple allergens

Allergens responsible for sensitisation 35 Any Sensitisation (1) 30 25 20 15 Dermatophagoides pteronyssinus (2) Grasses (2) Cat dander (2) Olive tree (2) Pellitory (2) 10 5 Alternaria tenuis (2) Wormwood (2) Ragweed (2) 0 (1) % of athletes, (2) % of positive skin tests

Infectious diseases AIDA study: Allergy and Infectious Diseases in Athletes 265 pre-olympic athletes 3 or more than 3 URTI episodes in the last 12 months in 15.9% More than 1 Herpes labialis episode in the last 12 months in 12.1% Decreased number of CD3+ lymphocytes in 17.0% of athletes with a preferential reduction of CD4+ subpopulation (40,7+/-8,2), well related to clinical picture AIDA Study Group J Allegy Clin Immunol 2003;111:S142

Cytokine AA vs CTRL ANA vs CTRL A vs CTRL AA vs ANA IL-1ra <0,0001 <0,0001 < 0,0001 NS (0,9280) IL-6 < 0,0001 0,0005 < 0,0001 NS (0,1882) IL-7 0,0001 < 0,0001 < 0,0001 NS (0,3663) IL-8 < 0,0001 < 0,0001 < 0,0001 NS (0,9875) IL-12 < 0,0001 < 0,0001 < 0,0001 NS (0,9093) IL-10 0,0002 0,0011 < 0,0001 NS (0,1366) IL-13 NS (0,2450) NS (0,2236) NS (0,1659) NS (0,9436) IL-17 0,0002 0,0008 < 0,0001 NS (0,3984) Eotaxin < 0,0001 < 0,0001 < 0,0001 NS (0,9749) Cytokine and in Allergic Growth Factor Serum Profile and Non- Allergic Top Atletes AA = 41; ANA = 51; CTRL = 49; Luminex assay For all cytokines measured, apart from IL-13, TNFa and MIP-1a, serum levels in athletes were significantly lower than in controls. IFN-gamma < 0,0001 < 0,0001 < 0,0001 NS (0,8752) IP-10 < 0,0001 0,0004 < 0,0001 NS (0,5584) MCP-1 < 0,0001 < 0,0001 < 0,0001 NS (0,5427) MIP-1alfa NS (0,1298) NS (0,1467) NS (0,0852) NS (0,9187) MIP-1beta < 0,0001 < 0,0001 < 0,0001 NS (0,2979) RANTES 0,0141 0,0274 < 0,05 NS (0,8690) TNF-alfa NS (0,2048) NS (0,5124) NS (0,2762) NS (0,4579) Abs. submitted to the AAAAI 2011 Congress

NGF serum levels in elite athletes 470.7 ± 882.2 281.7 Measured in... athletes trough a Means ±670.7 174.1 ±483.7 double-antibody ELISA 3000 2500 pg/ml pg/ml pg/ml 2000 1500 AA + AnA vs HC P<0.001 1000 500 0-500 AA NAA Non allergic HC athletes n = 52 Allergic athletes n = 44 Healthy controls n = 49

Why asthma is so frequent in elite athletes? Effects of intense exercise on allergy Effects of intense exercise on the airways

Physical exercise as a trigger on airways Increased ventilation Nasal filter by-pass Climate condition (cold-dry air) Exposure to indoor and outdoor allergens Exposure to pollutants (O3, PM2.5-10, NO2, SO2) Exposure to irritants (chlorine)

Physical exercise

Working definitions of Exercise-Induced Asthma (EIA) and Exercise-Induced Brochospasm (EIB) EIA: the condition in which exercise induces symptoms of asthma in patients who have asthma EIB: the airways obstruction that occurs in association with exercise without regard to the presence of chronic asthma Weiler JM, Bonini S, Coifman R, et al. J Allergy Clin Immunol 2007; 119: 1349-58

Prevalence of EIB in Athletes Swimmers Controls Zwick et al., Lung 1990; 168: 111-115 Potts, Sports Med 1996; 21: 256-261 78% 36% 60% 12%

EIB in Athletes Higher prevalence than in other populations Reported and objectively assessed in a higher number of athletes than those with clinical asthma, particularly in winter sports Peculiar mechanisms (osmotic, thermal and mechanical) linked to hyperpnea. Often associated with neutrophilic rather than eosinophilic inflammation. Epithelial damage? Autonomic deregulation? Poorly predicted by baseline pulmonary function tests More frequently associated with a positive indirect provocation test (office or field exercise, eucapnic voluntary hyperventilation, mannitol, etc.) than with direct provocation tests (methacholine, histamine) Less responsive to inhaled corticosteroids than EIA.

Diagnosis of Asthma and EIB in Athletes

AQUA (Methodology) Derived from the ECRHS questionnaire On the basis of interviews with team doctors, coaches and athletes specific questions were added Preliminary administration to verify comprehensiveness and reproducibility Administration to 128 professional soccer players of 6 elite teams Validation against documented clinical allergy (Anamnesis, OE, Skin-prick-test and/or Phadiatop) Key-questions scored from 1 to 5 on the basis of their positive likelihood ratio

AQUA (Results) A total score > 5 showed the best positive predictive value for allergy (0.93) with a specificity of 97.1% and a sensitivity of 58.3%. The questionnaire, translated in 10 languages was used in the framework of the GA2LEN Olympic Study The questionnaire, protected by copyright, is available on request (free for non commercial use)

Bonini M. et al. Allergy 2007; 62: 1166-70

Provocative challenges Direct Methacoline challenge Histamine challenge Indirect Exercise challenge On the field Free running athletic screening test FRAST Specific sport challenge (appropriate for elite athletes) In the laboratory Treadmill Cycle ergometer Eucapnic voluntary hyperpnea Mannitol challenge

2011 WADA antidoping rules Treatment WADA rules Notes Antihistamines Leukotriene modifiers Inhaled steroids Oral steroids Inhaled b2 agonists Salbutamol (max 1600 mcg/24h) Salmeterol Oral β2 agonists Ephedrine, methylephedrine Permitted Permitted Permitted And do not require any more a Declaration of Use Prohibited in competition (Do not require any more a Declaration of Use) Prohibited in and out competition Prohibited in competition Second generation molecules should be preferred to avoid side effects Topical preparations for dermatological, auricolar, nasal, buccal, ophtalmic use are not prohibited A concentration of salbutamol greater than 1000 ng/ml is considered an adverse analytical finding unless proven as due to therapeutic use A concentration in urine greater than 10 ug/ml represent an adverse analytical findings

EIB or not EIB? That is the question S.Bonini Med Sci Sports Exerc 2008;40:1565-66

IOC criteria for the diagnosis of asthma at the 2008 Beijing Olympic Games Diagnostic procedure Criteria Pulmonary function Bronchodilator test Eucapnic Voluntary Hyperpnea (EVH) FEV 1 <70%, FEV 1 /VC<55% FEV 1 12% e >200 ml FEV 1 10% Exercise challenge FEV 1 10% Methacoline challenge Hyperosmolar test (Mannitol, Saline) FEV 1 20% with a: PC 20 4 mg/ml (for subjects not taking ICS) or PC 20 16 mg/ml (for subjects taking ICS for at least 1 month) FEV 1 15% To be allowed to use beta-2 agonists, a positive clinical history associated to at least one positive test is required.

Treatment of EIB The two main principles of treating exerciseinduced bronchospasm consist in: reversing the bronchial obstruction induced by exercise with bronchodilators preventing it either by the chronic use of controller drugs in subjects with asthma or by administering, just before exercise, drugs which have been shown to be able to inhibit symptoms as well as the decrease of pulmonary function parameters

The FDA and safe Use of Long-Acting Beta-Agonists in the treatment of Asthma Chowdhury BA and Dal Pan G New Engl J Med 2010;362:1-3 Specific Label Changes for Long-Acting Beta-Agonists (LABAs) 1. Contraindicate the use of LABAs for asthma in patients of allages without con-comitant use of an asthma-controller medication such as an inhaled cortico-steroid. 2. Stop use of the LABA, if possible, once asthma control is achieved and maintain the use of an asthma-controller medication, such as an inhaled corticosteroid. 3. Recommend against LABA use in patients whose asthma is adequately controlled with a low-or medium-dose inhaled corticosteroid. 4. Recommend that a fixed-dose combination product containing a LABA and an inhaled corticosteroid be used to ensure compliance with concomitant therapy in pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid.

Beta-2 agonist effects on physical performance Carlsen KH et al.

Do β2-agonists really enhance physical performance? An in vitro study on their effect on a skeletal muscle cell line B2-agonist effect on myogenin and myosin 3A myogenin mrna (arbitrary units) 3 2,5 2 1,5 1 0,5 5A 1 2 3 4 5 MyHC slow MyHC fast α-tubulina 0 Untreated Formoterol Clenbuterol Salbutamol Salmeterol 3B 1 2 3 4 5 myogenin α-tubulina 5B MyHC slow/αtubulin (arbitrary units) 100 80 60 40 20 0 Untreated Clenbuterol Formoterol Salbutamol Salmeterol 3C myogenin/αtubulin (arbitrary units) 100 80 60 40 20 0 Untreated Clenbuterol Formoterol Salbutamol Salmeterol 5C MyHC fast/α /αtubulin (arbitrary units) 120 100 80 60 40 20 0 Untreated Clenbuterol Formoterol Salbutamol Salmeterol

Do β2-agonists really enhance physical performance? An in vitro study on their effect on a skeletal muscle cell line Results: B2-agonist effect on atrophy markers 6A 9 Atrogin 6B 2,5 Murf1 mrna (arbitrary units) 8 7 6 5 4 3 2 ** mrna (arbitrary units) 2 1,5 1 0,5 ** 1 0 Untreated Formoterol Clenbuterol Salbutamol Salmeterol 0 Untreated Formoterol Clenbuterol Salbutamol Salmeterol 6 6C Catepsin L mrna (arbitrary units) 5 4 3 2 1 0 ** Untreated Formoterol Clenbuterol Salbutamol Salmeterol **: p<0,001

Beta-2 agonist cardiovascular side effects

Bronchoprotection (Average max % FEV 1 fall at baseline max % fall FEV 1 after salmeterol) Average max % FEV 1 fall at baseline Mean BP: 65.1% Mean BP: 3.1% % Bronchoprotection Mean LOB: 95.2% Bonini M. Data presented at the 2010 ATS Congress

. and in the real life? Italian top Olympic athlete with a history of severe persistent rhinitis and mild intermittent asthma Negative physical examination Sensitization to Der.pt., Parietaria, Grass FEV1 110% ; FVC 107% : MMEF50% 104% Salbutamol test : 8% ; Exercise test : -18% Treatment : High doses of Bud/Form plus Salmeterol before exercise!

The elite athlete: Yes, with allergy we can S.Bonini, T.Craig J Allergy Clin Immunol 2008;122:249-50