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Louis-Philippe Boulet MD FCCP FRCPC

World Allergy Forum Asthma Phenotypes and Heterogeneity of Therapeutic Responses: Personalized Medicine in the 21st Century Asthma in the obese vs non-obese. Louis-Philippe Boulet MD FCCP FRCPC. AAAAI 2010. Asthma in the obese vs non-obese. Synopsis The links between asthma and obesity

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Louis-Philippe Boulet MD FCCP FRCPC

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  1. World Allergy Forum Asthma Phenotypes and Heterogeneity of Therapeutic Responses: Personalized Medicine in the 21st CenturyAsthma in the obese vs non-obese Louis-Philippe Boulet MD FCCP FRCPC AAAAI 2010

  2. Asthma in the obese vs non-obese Synopsis • The links between asthma and obesity • Pulmonary function and airway inflammation • Clinical features and asthma control • Asthma treatment responses • Remaining questions Botero

  3. Phenotyping asthma “The general consensus now emerging is that, even in adults, asthma is unlikely to be a single disease entity … or perhaps, asthma as a symptom is really only the clinical manifestation of several distinct diseases…”A plea to abandon asthma as a disease concept The Lancet 2006 “Phenotype” refers to 'a set of observable characteristics of an individual or group resulting from the interaction of its genotype with its environment Oxford English Dictionary

  4. Asthma and Obesity • Canada (global): • 23% Obese • 36% Overweight 25 Men Women 20 15 Asthmatics (%) 10 5 0 Under weight < 18.5 Obese Over weight 25.0-29.9 Obese Obese Normal weight 18.5-24.9 BMI = kg/m2 Class III ≥ 40 Class I 30.0 -34.9 Class II 35.0-39.9 Boulet & Descormiers Can Resp J 2007

  5. Prevalence of asthma (---) or obesity () in USA Sin & al. 2008 R: 1.51 (CI: 1.27-1.80) + Dose-response relationship Beuther AJRCCM 2007

  6. BMI as a predictor of asthma Hjellvik et al. ERJ 2010

  7. How many subjects with MD-diagnosed asthma had a diagnosis of asthma excluded after thorough investigation ? Obese group: 77/242 = 31.8%(95% CI: 26.3-37.9%). Non-obese group: 73/254= 28.7%(95% CI: 23.5-34.6%).

  8. The linkbetweenobesity and asthma • Systemic inflammation • Cytokines (TNFα, IL-6) • Chemokines(eotaxin, MCP-1) • Oxydative mechanisms • Acute phase reactants • Otherfactors(VEGF) • Energyregulating hormones • Leptin • Adiponectin • Visfatin • Common etiologies • In utero conditions • Genetics • Environmental exposures • Dietary factors • (e.g. antioxidants, omega-3, fatty acids) • Effects of obesity on lung mechanics • ↓FRC • ↓VT • Airway closure • Loss of bronchoprotective mechanisms • Co-morbidities • Dyslipidemia • GERD • SDB • Type 2 diabetes • Hypertension Adapted from Shore 2008

  9. Candidate genes of potential relevance for both obesity and asthma Beuther et al. AJRCCM 2006 Murphy et al. Am J Hum Genet 2009

  10. Pulmonary function and obesity • ↓FRCbut not RV = ↓ ERV • ↓tidal volume Rapid shallow breathing • ERV may approach or be exceeded by closing volume • VC and TLC normal but if marked obesity • FEV1 and FVC ↓ with increasing BMI • Loss of bronchoprotection from deep inspiration Sin et al. 2008

  11. Obesity is associated with a loss of bronchoprotective effect of deep inspiration P = 0.006 80 20.3 & 40.0 % 18.5 & 23.6 % 60 40 Change in FEV1 (No DI for 20 min/Normal breathing) 20 0 -20 -40 BMI < 30 BMI 30 Boulet et al. Can Resp J 2005

  12. Obesity and airway responsiveness • Obesity associated with increased airway responses in animal models 1,2 • Increased airway responses in leptin deficient, leptin receptor deficient, and overfed mice • Leptin increases allergic and nonallergic airway responses • Adiponectin infusion reduces allergic airway responses • Controversial data in humans: • Associated with increased AHR (weak)3,4 • Not associated with AHR 5,6 1 Shore et al. JAP 2006 4Sood J Asthma 2006 2 Shore et al. PharmTher 2007 5 Schachter et al. Thorax 2001 3Chinn Thorax 2002 6 Salome et al. Int J Obes 2008

  13. Eosinophil HistamineLeucotrienes IL-4IL-5IL-10IL-13 leptin IgE Mastocyte Lymphocyte B leptin Phagocyte TNF-αIL-2IFN-γ IgG Lymphocyte B TNF-α IL-6 Leucotrienes Neutrophil TNF-α IL-4 IL-5 Macrophage leptin VEGFfibronectineTIMP-1/MMP-9 Remodeling ? IL-6 ASTHMA VS OBESITY: two inflammatory conditions Asthma Chronic airway inflammation CD4TH2 lymphos Mast cells Eosinophils IL4, IL5, IL13 RANTES, eotaxin, MCP-1 Obesity Chronic low-grade inflammation Total leucocytes count  BMI Adipose tissue macrophages  Leptin  (IL6) Adiponectin  Th2 Th1

  14. 6 5 4 3 2 Markers of systemic inflammation p= 0,03 p= 0,47 p= 0,001 16 14 12 14 10 8 C-reactive protein (mg/L) 8 Eosinophils (%) 6 Fibrinogen (g/L) 6 4 4 2 2 0 0 O O N-O N-O N-O O • Levels of C-reactive protein and fibrinogen were elevated in obese women suggesting systemic inflammation Lessard 2008

  15. How can systemic inflammation influence asthmatic inflammation ? • Biomarkers of systemic inflammation increased in obese versus normal-weight individuals (e.g., IL-6 and CRP) – highest levels in the obese asthmatic group, but no difference with non-obese subjects with asthma • Biomarkers in sputum supernatant (IL-1β, IL-5, IL-6, IL-8) significantly increased in subjects with asthma compared with subjects without asthma - highest in the obese asthmatic group, but no significant differences compared with nonobese • For CRP, the effects of obesity and asthma were additive. • No clear evidence of an interaction between obesity-related adipokines and airway inflammation Sutherland et al. AJRCCM 2008

  16. Systemic inflammation/ adipokines and asthma in the obese patient Lessard 2008 • C-reactive protein increased in obesity, but not always associated with asthma • Most human studies (apart from a small pediatric study) did not show a convincing association between adipokines and asthma • Oxidative stress (e.g. Plasma F2-isoprostane) have been associated with elevated BMI but not asthma

  17. Neutrophils Macrophages 100 100 80 80 60 60 Total number of cells 40 40 2 20 20 1.5 0 x106/ml 0 1 .5 Cell differential (%) Eosinophils Lymphocytes 0 8 4 BMI < 30 BMI 30 = medians 6 3 4 2 2 1 0 0 BMI < 30 BMI 30 BMI < 30 BMI 30 Non-asthmatic subjects with normal AR Obesity and airway inflammation Todd et al. Clin Exp Allergy 2007 Boulet et al. Unpublished data

  18. Bronchial inflammation r=-0.38 p=0.01 r=0.42 p=0.01 60 80 70 50 60 40 50 Leptin (IS) (pg/ml) 30 40 Eosinophils (IS) (%) 30 20 20 10 10 0 0 15 20 25 30 35 40 45 50 55 60 80 100 120 140 BMI (kg/m2) Waist circumference (cm) Lessard et al. CHEST 2008

  19. Relationships between obesity and airway inflammation Van Veen et al. Allergy 2008

  20. Asthma and co-morbidities Boulet LP. Eur Resp J 2009

  21. Reported Asthma Control during the last week Symptom perception at PC20 Obeses Non Obeses 3,5 3,5 3 3 2,5 2,5 2 2 Scale 0 (no symptom) to 10 (max.) Scale 0 (no symptom) to 6 (max.) 1,5 1,5 1 1 0,5 0,5 0 0 Awaked Cough Wheezing Secretion Wheezing Using of BD/d Breathlessness Breathlessness Chest tightness Activities limitation Morning symptoms Asthma Control & Symptoms Perception Obese women have poorer asthma control than non-obese women (p > 0.05) Boulet et al. Unpublished data

  22. Influence of obesity on asthma control % Patients who achieve asthma control with salmeterol+ fluticasone vs fluticasone only Boulet & Franssen. Resp Med 2007

  23. Placebo-adjusted LS mean Asthma control days by BMI category for montelukast and beclomethasone Peters-Golden et al. ERJ 2006

  24. BMI category and change in outcome in inhaledglucocorticoidtreated-subjects Adaptedfrom Sutherland ER et al JACI 2009

  25. Influence of weight loss on asthma:a systematic review Eneli et al. Thorax 2008 • Few studies have addressed reversibility of obesity in regard to asthma features • Heterogeneity of interventions • All 15 studies showed improvements of at least one asthma outcome

  26. 40% 30% -10% 0% 10% 20% 30% 40% 20% -10% 0% 10% Correlation between weight loss & lung function Aaron et al, Chest 2004 r = 0.271 P = 0.057 r = 0.290 P = 0.040 1.0 0.8 0.6 0.5 6-month absolute change in FEV (l) 6-month absolute change in FVC (l) 0.2 0.2 -0.1 -0.2 -0.4 -0.6 Relative weight loss at 6 months Relative weight loss at 6 months

  27. The “obesity” asthma phenotype Etiology: genetics ? change in lung mechanics ? fat intake ? Systemic inflammation ? Clinical Features: predominant in women more difficult-to-control asthma increased prevalence of co-morbidities Physiological findings: low ERV (breathing at low lung volumes) increased work of breathing loss of DI protective effect Inflammatory patterns: less eosinophilic systemic inflammation Treatment response: reduced, particularly ICS Outcomes: improves with weight reduction long-term outcome uncertain

  28. Asthma in the obese vs non-obese Remaining questions • How can obesity promote the development of asthma ? • Can systemic inflammation influence airway function ? • What is the optimal asthma pharmacological treatment of asthma in the obese • What is the natural history of asthma in the obese ?

  29. Conclusion Asthma in the obese is a specific phenotype • Different clinical features, airway function & inflammatory pattern • Increased severity, morbidity and poorer control • Reduced response to standard therapy More research needed…

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