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Leonardo M. Fabbri fabbri.leonardo@unimo.it

T ü rk Toraks Derne ğ i 11. Yillik Kongresi. http//pneumologia.unimo.it. COPD and systemic inflammation. Maritim Pine Beach Hotel Belek-Antalya 23-27 Nisan 2008. Leonardo M. Fabbri fabbri.leonardo@unimo.it. COPD and systemic inflammation. Complex chronic co-morbidities

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Leonardo M. Fabbri fabbri.leonardo@unimo.it

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  1. Türk Toraks Derneği 11. Yillik Kongresi http//pneumologia.unimo.it COPD and systemic inflammation Maritim Pine Beach Hotel Belek-Antalya 23-27 Nisan 2008 Leonardo M. Fabbri fabbri.leonardo@unimo.it

  2. COPD and systemic inflammation Complex chronic co-morbidities Effects of treatment of COPD on its co-morbidities Effects of treatment of COPD co-morbidities on COPD Guidelines for complex chronic co-morbidities

  3. ERS Research Seminar“Complexity of patients with multiple chronic diseases”Rome, Italy February 10-11, 2007www.ersnet.orgwww.ersnet.org/learning_resources_player/paper/RS/RS-Rome.htm

  4. Chronic diseases represent a huge proportion of human illness • 58 million deaths in 2005: • Cardiovascular disease 30% • Cancer 13% • chronic respiratory diseases 7% • Diabetes 2% WHO, Lancet, 4 December 2007

  5. Alveolar wall destruction EMPHYSEMA Proteases Mucus hypersecretion CHRONIC BRONCHITIS Pathogenesis of COPD Cigarette smokeor air pollutant CD8+ T-cell ? Alveolar macrophage CXCR3 Inflammatory cytokines(IL-8, LTB4) CXCL-10 Neutrophil Courtesy of PJ Barnes, 2005

  6. Leading Causes of Death in U.S. • 1. Myocardial • Infarction • 2. Cancer • 3. Cerebrovascular • Diseases • 4. COPD Cigarette Related Diseases Leading Causes of Death Worldwide 2010

  7. Inhaled particles:pulmonary and heart co-morbidity

  8. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator COEXISTING ILLNESSES Vascular (including hypertension) 64% Cardiac 38% Gastrointestinal 48% Musculoskeletal or connective tissue 46% Metabolic or nutritional 47% Reproductive or urinary 27% Neurologic 22% Niewoehner,et al, Ann Intern Med. 2005;143:317-326

  9. RECOGNISING HEART FAILURE IN ELDERLY PATIENTS WITH STABLE CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN PRIMARY CARE A limited number of items easily available from history and physical examination,with addition of NT-proBNP and electrocardiography, can help general practitioners to identify concomitant heart failure in individual patients with stable COPD F H Rutten et al, BMJ 2005, Dec;331(4):1379-81

  10. ARTERIAL STIFFNESS IS INDEPENDENTLY ASSOCIATED WITH EMPHYSEMA SEVERITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE Emphysema severity is associated with arterial stiffness in patients with COPD Similar pathophysiological processes may be involved in both lung and arterial tissue Further studies are now required to identify the mechanism underlying this newly described association MacNee W et al, AJRCCM 2007; 176:1208-1214

  11. INCREASED RISK OF BOTH ULCERATIVE COLITIS AND CROHN'S DISEASE IN A POPULATION SUFFERING FROM COPD The results of this study suggest that COPD and inflammatory bowel diseases may have inflammatory pathways in common, including genetic variants of genes predisposing for disease Ekbom A et al, Lung 2008 Mar 11 [Epub ahead of print]

  12. INSULIN RESISTANCE AND INFLAMMATION - A FURTHER SYSTEMIC COMPLICATION OF COPD This study demonstrates greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD Bolton CE et al, COPD. 2007 Jun ;4(2):121-6

  13. The „Metabolic Syndrome“ Diabetes mellitus Type 2 P-Glc >6.1mmol/l (IFG), 2x; >7.0mmol/l (Dm)R-Glc / 2h 75g oGTT: >7.8 (IGT); >11 (Dm) Genes OBSTRUCTIVESLEEP APNOEA ObesityCircumferenceM>102; F>88cm (BMI>30mg/kg2 WHR M>0.9; F>0.85) Insulin- Resistance (PCO, "HAIR-AN"-Sy) RESTRICTIONTLC & VC SMOKING HypertensionBD>130/85mmHg (>160/90) DyslipidemiaTriglyzeride >1.7mM HDL-C M <1.0mM F <1.3mM HYPOXEMIASEDENTARY Secondary Complications Alb/Krea i.U. >2.7mg/mmol ATP III: Diabet Med 03; 20: 175-81 Courtesy of B Muller

  14. vanGaal LF et al, Nature 2006; 444: 875

  15. Atherogenic stimuli (dyslipemia, hypertension, smoking) Destabilizing stimuli Inflammation Natural history of atherothrombosis Endothelial dysfunction

  16. Inflammation, atherosclerosis and coronary artery disease Hansson GK, N Engl J Med. 2005;352(16):1685-95 Activation of a type 1 immune response in atheroma formation

  17. Inflammation in the wall of intra-myocardial arteries in DOCA-salt hypertension Courtesy of E Schiffrin Uni-Nx DOCA-salt Larivière & Schiffrin, J Mol Cell Cardiol 1995;27:2123-2131

  18. Mechanism of inflammatory bone loss Takayanagi , J Mol Medicine 2005; 83:170-9

  19. Metabolic Syndrome Type 2 diabetes Muscle Weakness / Wasting TNFa IL-6 ? Local Inflammation Osteoporosis +ve Cardiovascular Events Fabbri LM et al, Eur Respir J 2008; January Liver CRP

  20. Cardiovascular mortality in COPD For every 10% decrease in FEV1, cardiovascular mortality increases by approximately 28% and non-fatal coronary event increases by approximately 20% in mild to moderate COPD Anthonisen et al, Am J Respir Crit Care Med 2002

  21. Active reduction of risk factor(s); influenza vaccination Addshort-acting bronchodilator (when needed) I: Mild II: Moderate III: Severe IV: Very Severe • FEV1/FVC < 70% • FEV1 > 80% predicted Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Addinhaled glucocorticosteroids if repeated exacerbations Addlong term oxygenif chronic respiratory failure. Considersurgical treatments Courtesy of K.F.Rabe, 2007

  22. Prevalence of heart failure in stable ‘COPD’ (aged 65 years or over)Rutten FH et al, Eur Heart J 2005;26:1887-94 Rutten FH et al, Eur Heart J 2005;26:1887-94

  23. 110 100 90 80 70 60 FEV1 / FVC % 50 40 30 20 10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 FEV1 % des Solls not classified at risk FEV1 / IVC % III IIb IIa I n = 500 Köhler D , Fischer J, et al. Thorax 58:825 (2003)

  24. Is COPD a systemic disease ?Is COPD just one component of a systemic chronic disease?Should we examine and treat COPD or the patient with COPD?

  25. COPD and systemic inflammation Complex chronic co-morbidities Effects of treatment of COPD on its co-morbidities Effects of treatment of COPD co-morbidities on COPD Guidelines for complex chronic co-morbidities

  26. Active reduction of risk factor(s); influenza vaccination Addshort-acting bronchodilator (when needed) I: Mild II: Moderate III: Severe IV: Very Severe • FEV1/FVC < 70% • FEV1 > 80% predicted Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Addinhaled glucocorticosteroids if repeated exacerbations Addlong term oxygenif chronic respiratory failure. Considersurgical treatments Courtesy of K.F.Rabe, 2007

  27. Placebo 15.2% FSC 12.6% Primary analysis: all-cause mortality at 3 years HR 0.825, p=0.052 17.5% risk reduction Probability of death (%) 18 16 14 12 10 2.6% absolute reduction 8 6 4 2 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Time to death (weeks) Number alive 1293 Plc 1339 SFC 1524 1533 1464 1487 1399 1426 Vertical bars are standard errors Calverley et al, NEJM, 2007

  28. Cause of death on treatment Deaths (%) 7.0 Placebo SFC 6.0 5.0 4.0 3.0 2.0 1.0 0.0 Cardio-vascular Pulmonary Cancer Other Unknown Calverley et al. NEJM 2007

  29. TORCH Calverley et al NEJM 2007

  30. 2x2 factorial: Independent effects of fluticasone & salmeterol

  31. Understanding the Potential Long-term Impacts on Function with Tiotropium

  32. POSSIBLE PROTECTION BY INHALED BUDESONIDE AGAINST ISCHAEMIC CARDIAC EVENTS IN MILD COPD The results of the present study support the hypothesis that treatment with inhaled budesonide reduces ischaemic cardiac events in patients with mild chronic obstructive pulmonary disease Löfdahl CG et al, Eur Respir J. 2007 Jun;29(6):1115-9

  33. THE IMPACT OF SMOKING CESSATION ON RESPIRATORY SYMPTOMS, LUNG FUNCTION, AIRWAY HYPERRESPONSIVENESS AND INFLAMMATION Smoking cessation reduces symptoms and improves the accelerated decline in FEV1 which strongly indicates that important inflammatory and/or remodelling processes should be positively affected Data from well-designed studies are lacking regarding the effects on inflammation and remodelling In COPD, a few histopathological studies suggest that airway inflammation persists in exsmokers Willemse et al, ERJ 2004; 23:464-76

  34. Pulmonary rehabilitation in chronic obstructive pulmonary disease Today the question is no longer "should patients with chronic obstructive lung disease receive pulmonary rehabilitation?" but rather "how should pulmonary rehabilitation be delivered to patients with COPD?" "which components form the basis of the success of pulmonary rehabilitation programs?" The review focuses the physiological rationale for exercise training, the potential of the multidisciplinary approach during rehabilitation programs Troosters et al Am J Respir Crit Care Med. 2005 Jul 1;172(1):19-38.

  35. COPD and systemic inflammation Complex chronic co-morbidities Effects of treatment of COPD on its co-morbidities Effects of treatment of COPD co-morbidities on COPD Guidelines for complex chronic co-morbidities

  36. REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN RECEPTOR BLOCKERS IN COPD The combination of statins and either ACE inhibitors or ARBs is associated with a reduction in COPD hospitalization and total mortality not only in the high CV risk cohort but also in the low CV risk cohort The combination also reduced myocardial infarction in the high CV risk cohort (RR 0.39, 95% CI 0.31 to 0.49) Benefits were similar when steroid users were included Mancini JB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60

  37. THE USE OF STATINS AND LUNG FUNCTION IN CURRENT AND FORMER SMOKERS In smokers and former smokers, statins are associated with a slower decline in pulmonary function, independent of the underlying lung disease. Prospective, randomized trials are needed to study the effect of statins on lung function Keddissi JI et al, Chest 2007;132(6):1764-71

  38. STATINS REDUCE THE RISK OF LUNG CANCER IN HUMANS: A LARGE CASE-CONTROL STUDY OF US VETERANS Statins appear to be protective against the development of lung cancer, and further studies need to be done to define the clinical utility of statins as chemo protective agents Khurana V et al, Chest, May 2007; 131: 1282 - 1288

  39. EFFECT OF VERY HIGH-INTENSITY STATIN THERAPYON REGRESSION OF CORONARY ATHEROSCLEROSISTHE ASTEROID TRIAL Two year treatment with rosuvastatin 40 mg/d reduced LDL-C to 60.8 mg/dL and increased HDL-C by 14.7%, and resulted in significant regression of atherosclerosis. Further studies are needed to determine the effect of the observed changes on clinical outcome Nissens ES et al, JAMA, April 5, 2006—Vol 295, No. 13

  40. THE JUPITER TRIAL, A TRIAL OF STATIN AMONG INDIVIDUALS WITH LOW LDL CHOLESTEROL AND ELEVATED hsCRP Men 50 years or older, women 60 years or older normal LDL cholesterol (< 130mg/dL) increased C-Reactive Protein (CRP)(> 2.0mg/L) Investigate whether long-term treatment with rosuvastatin compared decreases cardiovascular events Stopped early because of reduction in cardiovascular morbidity and mortality Ridker PM et al Am J Cardiol 2007;100:1659 –1664

  41. Pathophysiology of ACS: Disrupted Plaque Thin cap Plaquerupture High macrophagecontent Completecoronaryocclusion Incomplete coronaryocclusion Spontaneous lysis,repair, and wall remodeling Large lipid core Acute MI Unstable anginaor non–Q-waveMI Temporary resolution of instabilityFuture high-risk lesion Adapted from Yeghiazarians et al. N Engl J Med. 2000;342:101-114.

  42. The Mucosal Immune System in the Airways 1)Cytopatches = Collections of lymphocytes 2)Mature lymphoid follicles with germinal centers and dark zone . M Cells 3) No capsule Dark zone 4)No Afferent lymphatics Germinal center Courtesy of Prof. Jim Hogg

  43. Percent airways with cells in lumen content Percent airways with cells in their walls Courtesy of Prof. Jim Hogg

  44. Centrilobularemphysema Panlobularemphysema Saetta et al. ERJ 1994

  45. Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD • In-hospital mortality was 5.2% • Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not • Beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99) • The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality Dransfield MT, Thorax. 2008 Apr;63(4):301-5.

  46. THE IMPACT OF CARDIOSELECTIVE BETA-BLOCKERS ON MORTALITY IN PATIENTS WITH COPD AND ATHEROSCLEROSIS Beta1-blockers may reduced mortality in COPD patients undergoing vascular surgery In some patients with COPD selective beta1-blockers are safe and may reduce mortality

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