Presented by Dr.Richard Albert at 8th Pulmonary Medicine Update Course 2008, organized by Scribe (www.scribeofeggypt.com)

1. COPD State-of-the-Art Richard K. Albert, M.D. Chief of Medicine Denver Health Professor of Medicine University of Colorado Adjunct Professor of Engineering and Computer Science University of Denver 8 th Pulmonary Medicine Update February 6, 2008 Denver Health

2. COPD Citations Citationas (N) Denver Health

3. Objectives Definition Epidemiology Phenotyping Genetics P athophysiology Acute Exacerbations Treatment Denver Health

4. Changes in Definition of COPD ATS/ERS Guidelines  COPD has systemic consequences - Systemic inflammation - Weight loss - Skeletal muscles - Cardiac disease and death (Huiart, Chest 2005) > 5648 receiving “1 st Rx for COPD” > HF most common cause of hospitalization > More hospitalizations for CV disease than COPD > CVD more common cause of death than COPD Denver Health

5. COPD Epidemiology Prevalence: 12.4 - 24 million in US Morbidity:  2004: 461,000 hospitalizations (4 th most common)  1.5 million ED visits Mortality:  120,000 deaths in 2001 (6 th most common - 3 rd by 2020)  1 death/4 min (14 during this lecture)  Only cause of death in top 10 that is  Cost:  $6.5 billion Denver Health

6. COPD Epidemiology: Gender Discrepancy in Mortality Machado, AJRCCM 2006  Mortality for women on O 2 Denver Health

7. COPD Phenotyping Correlates with FEV 1  Health status  Resource utilization  AECOPD  Mortality  Small airway wall thickness - Inflammatory cell infiltration - Smooth muscle - Subepithelial fibrosis Does Not Correlate with FEV 1  Emphysema  Hyperinflation  BMI  Peripheral muscle fxn  Dyspnea  Exercise tolerance Denver Health

8. COPD Phenotyping (courtesy John Riley, B & W) FEV 1 : 105% DL CO : 50% FEV 1 : 95% DL CO : 70% FEV 1 : 40% DL CO : 70% Denver Health

9. COPD Phenotyping: Predictors of Mortality (Multivariate Analysis) 609 pts, NETT, medical Rx Martinez, AJRCCM 2006 Denver Health 1.36 DL CO < 22 1.38 Hemoglobin < 13.4 1.48 Modified BODE 1.40 O 2 use 1.48 Maximum work 1.53 Perfusion ratio 1.56 RV (% predicted) 1.72 Age > 70 1.80 % Upper lobe emphysema Hazard Ratio Predictor

10. COPD Phenotyping: CRP Predicts Hospitalization and Prognosis Hospitalization Death Dahl, AJRCCM 2006 Denver Health

11. COPD Phenotyping: BNP Predicts PHT and Prognosis 176 pts “scheduled for RH cath” BNP Predicts PHT PHT predicts survival BNP predicts survival 85% sensitivity 88% specificity (5% with Ppa > 40 torr) Leuchte, AJRCCM 2006 Denver Health

12. COPD Genetics Candidate Gene Abns  SERPINA 1 (  -1-AT)  MMP-9 (C-1562 SNP  promotor activity)  ADAM-33 (adhesion, signaling, proteolysis)  Elastin (Gly  Asp in terminal exon)  Secretory PLA 2 , Group IID  CCL1 SNP (  AECOPD x 2 yr) Denver Health

13. COPD Pathophysiology: Chronic Inflammation No smoking for mean of 9 yrs Retamales, AJRCCM 1997 Denver Health 8 ± 1* 3 ± 1* 220 ± 50* 25 ± 8 Eos (x 10 8 ) 1400 ± 590* 40 ± 17* 250 ± 51* 31 ± 6 CD8+ (x 10 12 ) 750 ± 89* 58 ± 30* 330 ± 58* 45 ± 10 CD4+ (x 10 12 ) 4000 ± 400* 270 ± 80* 71 ± 19* 5 ± 2 Alv Macs (x 10 12 ) 300 ± 50* 20 ± 5 140 ± 29* 24 ± 8 PMNs (x 10 12 ) COPD Control COPD Control Cells (x 10 12 ) Airspace Tissue

14. COPD Pathophysiology Inflammatory Model: Latent Viruses Genetics (?) CD8+ T cells Lack of SP-D  RSV in 33%,   FEV 1 decline (Wilkinson, 2006)  Starvation (Coxson, 2004)  Collagen domain (Kingma, 2006) New Ideas  Dust-induced (Al-SiO 4 , kaolin) (Giron, 2005)  PDE4-dependent (Martorana, 2005)  Blocked by simvistatin (Lee, 2005)  Related to adenosine receptor affinity/density (Varani, 2006)  COHb (Yasuda, 2005) Cigarette Smoke Irritants Inflammatory cells (apoptosis) Oxidative stress Neutrophil elastase Metalloproteinases Denver Health  LTB 4 (Santus, 2005) Peribronchial fibrosis Loss of alveolar units  IL-1  Lappalainen, 2005)  TGF  Smad 2,3

15. COPD Pathophysiology: Vascular Apoptosis Model Klotho gene Vasoconstriction Proteinases, VEGF Cocaine  Vasculitis (Hunt, 2006) New Ideas  Anti-endothelial Abs (immune) (Taraseviciene-Stewart, 2005) Cigarette Smoke Vascular cell death Denver Health Loss of alveolar units (apopotosis)

16. COPD Physiology: Respiratory Muscles Functional diaphragm impairment  Loss of myosin heavy chains   ubiquitin-conjugated proteins (  protein degredation) (Ottenheijm, AJRCCM 2006) Denver Health Myosin-Actin Sarcomere Myosin Caspace-3 Myosin-Ubiquitin E-3 Ligases (Astrigin-1) (MURF-1) 26S Proteosomes Degradation

17. COPD Physiology: Respiratory Muscles Functional diaphragm impairment  Dysfunctional contractile proteins - Ca ++ sensitivity - Alternative titin gene splicing (Moore, 2006) Question  ” Disease” vs epiphenomenon (?) Denver Health

18. COPD Physiology Gas Trapping  P Inspmax Lung Volume TLC RV P Inspmax -100 0 Respiratory Muscle Weakness (? fatigue) Resp Muscles  Weak?  Dysfunctional? Denver Health

20. AECOPD: Dynamic Hyperinflation Stevenson, AJRCCM 2005 22 COPD pts Hospitalized for AECOPD Denver Health

21. AECOPD: Biomarkers CRP IL-6 MPIF-1 PARC ACRP-30 s-ICAM-1 Amphiregulin BDNF  -NGF ENA-78 Eotaxin-2 Erb-B2 Fibrinectin IFN-  IL-1  IL-1RA IL-2R  IL-8 IL-12 p40 IL-15 IL-17 IP-10 ITAC MCP-1 MIP-1  MMP-9 MPO Prolactin RANTES L-selectin TGF-  TIMP-1 TNF-  TNFR1 TNFR2 VEGF 90 pts, stable/exacerbation, most on ICS Abx and/or systemic steroids “ Severity” by sxs and PEF Hurst, 2006 Denver Health

22. AECOPD: Biomarkers Hurst, 2006 Purpose?  Dx AECOPD  Assess severity  Dx other problem  Pathobiology  Etiology Denver Health

23. AECOPD: Left Heart Dysfunction Abroug, AJRCCM 2006  148 consecutive pts with AECOPD - 55 (37%) on mechanical ventilation  All got ECHO, BNP, Troponins  Excluded pneumonia, PE, CPA, inotropes ARF, nonechogenic  LVF and RVF diagnosed by 4 MDs - Definite, Possible, Unlikely - Clinical data (not BNP or Troponins) Denver Health

24. AECOPD: Left Heart Dysfunction 75 (51%) with LV dysfunction  17 (23%) systolic dysfunction  48 (64%) diastolic dysfunction  10 (13%) both 41 (31%) 20 (14%) 82 (55%) BNP > 1000 94% Sensitive 77% Specific (Abroug, AJRCCM 2006) Denver Health

25. AECOPD: Pulmonary Embolism Spiral CT & US  211 consecutive pts with “unexplained” AECOPD - Not requiring mechanical ventilation - No acute bronchitis, pneumonia, PTX - Disparity between CXR and ABGs  49/197 (25%) positive for PE - 43 by CT (19 of whom had + US) - 6 by US  Associations: - Previous PE, malignancy, 5 torr  PaCO 2 (Tillie-Leblond, 2006) Denver Health

26. COPD Rx: Steroid Resistance Limited effect of steroids in stable disease  Cells, cytokines, proteases in BAL  Histology of biopsies  IL-8, TNF  suppression  AM cytokine production Oxidative/nitrative stress inhibits HDAC fxn Denver Health

27. H3 H3 H2A H4 H2B H2A Mechanisms of Transcription Regulation H4 H3 H3 H2A H4 Histone octamer Lysine Denver Health H2B H2A

28. Mechanisms of Transcription Regulation Histone acetyltransferases (HAT) (Co-activators: CBP, p300, PCAF) Histone deacetylases (HDAC) (Co-repressors: NuRD, Sin3, Co-REST) HDAC HAT Denver Health

29. Histone Acetyltransferases IL-1  TNF  ROS NF-  B CBP (HAT activity) II  B2 NF-  B HDAC I  B2 ROS Cell wall Nucleus Denver Health CS GR CS

30. Histone Acetylation in COPD Ito, NEJM 2005 Denver Health

31. COPD Rx What Endpoint?  FEV 1   FEV 1 over time  Mortality  QOL  AECOPD Denver Health

32. COPD Rx: GOLD Guidelines Denver Health

33. COPD Rx: Long-Acting Bronchodilators GOLD Guidelines  Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting agents  Regular use of a long-acting bronchodilator… improves health status  Treatment with a long-acting bronchodilator reduces the rate of AECOPD Denver Health

34. COPD Rx: Do LABAs  AECOPD? (Sin, JAMA 2003) Denver Health

35. COPD Rx: Does Tiotropium  AECOPD? (Sin, JAMA 2003) Denver Health

36. COPD Rx: ICS GOLD Guidelines  Regular treatment with ICS is appropriate for symptomatic patients with COPD with an FEV 1 < 50% predicted (stages III and IV) and repeated AECOPD (e.g., 3/3 yr) (Evidence A).  This treatment has been shown to reduce AECOPD and thus improve health status (Evidence A)  Withdrawal from treatment can lead to AECOPD in some patients. Denver Health

37. COPD Rx: Do ICS  AECOPD? Sin, JAMA 2003 Denver Health

38. Effect of Rx on AECOPD (Suissa, AJRCCM 2006) Methods of Analysis  Unweighted (individual pt data) (Bad) - AEs for each pt/time of f/u for each pt - Each pt contributes equally regardless of f/u time - Exaggerates Rx effect  Weighted (pooled data) (Better) - Total AE for all pts/total time of f/u for all pts - Weights each pt’s AE rate by their f/u time - Produces correct and best estimate (i.e., maximum likelihood estimate) of AE rate (not biased by short f/u) Denver Health

39. Effect of Rx on AECOPD (Suissa, AJRCCM 2006) Analysis of weighted data  Assume Poisson distribution for AEs (Bad) - AEs can occur repeatedly, randomly, independently - Ignores that some pts may have frequent AEs and some may have none  Estimate variability and use “overdispersion parameter” (Better) - p value and CI based on within- and between- subject variability Denver Health

40. COPD Rx: Quality of the Data Cited supporting references  Many used unweighted analyses  None used an overdispersion parameter  Some analyzed adjusted data  One  QOL just exceeded “clinically significant”  (e.g., 5 vs 4)  Many included Pharma employees as authors with analyses performed in-house  Some actually reported NO beneficial effects Denver Health

41. Gold Sponsors Denver Health

42. COPD Rx: Do ICS  AECOPD? Berge (+ Glaxo), BMJ 2000 (ISOLDE)  ICS, LABA, ICS + LABA, placebo  Analyzed by Glaxo  Reported median exacerbation rate  # AEs/# Rx days extrapolated to #/yr  Unweighted analysis (overestimates effect) Denver Health

43. COPD Rx: Do ICS  AECOPD? Van der Valk, AJRCCM 2003  Routine Rx + ICS x 4 M, continue ICS vs P  Primary outcome measures - First and second AE - Rapid recurrent AEs - HRQL  21% crossovers  1.3  1.5 vs 1.3  1.6 AEs/yr - 48% had no AEs  Time to first AE different (“adjusted for smoking status”) Denver Health

44. COPD Rx: Does Tiotropium  AECOPD? Niewoehner, AIM 2005  1829 pts (Mod-Severe)  Tiotropium vs usual Rx AECOPD (1 yr):  Tiotropium: 28%  Placebo: 32%  P < 0.05 “ These treatment effects were small to modest, and their overall clinical importance must be weighed against other considerations, including cost” Denver Health

45. COPD Rx: Do ICS  AECOPD? Szafranski, ERJ 2003 (126)  ICS, LABA, ICS + LABA, placebo  Poisson regression, dispersion adjustment  Corresponding author @ Astra-Zeneca  No correction for multiple comparisons (P < 0.016) Denver Health NS LABA vs Placebo P value Rx NS ICS vs Placebo 0.043 ICS + LABA vs LABA NS ICS + LABA vs ICS 0.035 ICS + LABA vs Placebo

46. COPD Rx: Do ICS  Mortality? TORCH study (NEJM 2007)  6100 pts, FEV1 ~ 1.2 L (44%) - Salmeterol - Salmeterol/fluticasone - Fluticasone - Placebo  Endpoints: - Death (Primary) - Frequency of AECOPD - QOL (SGRQ) - Lung function Calverley, 2007 Denver Health

47. COPD Rx: Do ICS  Mortality? 3-yr mortality:  Placebo: 15.2%  Combination: 12.6%  17.5% relative   P = 0.052 LaVecchia & Fabbri  Salmeterol vs not  13 vs 15.6% (P = 0.004)  Fluticasone vs not  14.3 vs 14.3% (P = 0.99) Calverley, 2007 Denver Health

48. COPD Rx: Do ICS  Mortality? 3-yr COPD mortality:  Placebo: 6.0%  Combination: 4.7%  21.7% relative   P = 0.11  Fluticasone: 6.9%  Combination: 4.7%  31.8% relative   P = 0.008  LABA vs Combo: NS Calverley,NEJM 2007 Denver Health

49. COPD Rx: Do ICS  Mortality? FEV 1 (ml) SGRQ (units) Calverley, NEJM 2007 Denver Health

50. COPD Rx: Do ICS  Mortality? Problems:  40% drop out in placebo group (P < 0.05)  All pts had indications for Rx  Pts with more severe disease might not have enrolled  Pneumonia - Placebo: 12.3% - Combination: 19.6% (P < 0.001) - Ernst, AJRCCM 2007: RR 1.70 (1.63-1.77) Rabe, NEJM 2007 Denver Health

51. COPD Rx: Do ICS  Mortality?  “ All trials are a gamble, and the TORCH investigators came close to winning, but did not win”  “ LABA was a winner, ICS was a clear loser”  Combination Rx better - Health status - Use of oral steroids - AECOPD -  in FEV 1  Combination Rx: severe disease &/or AECOPD (same as GOLD recommendations)  More pneumonia in combination Rx Rabe, NEJM 2007 Denver Health

52. COPD Rx: Novel Therapies PDE4 inhibitors  PDE4 degrades cAMP - Modulates inflammation - Bronchodilator?   FEV 1 , QOL, ? AECOPD vs placebo - Roflumilast (Rabe, 2005) - Cilomilast (Rennard, 2006) Infliximab (anti-TNF  )  No benefit (N = 14) (van der Vaart, 2005) Denver Health

53. Summary Definition Epidemiology Phenotyping Genetics P athophysiology Acute Exacerbations Treatment Denver Health

54. Smoking Addiction Denver Health