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

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

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C O P D :State of the Art Presentation Transcript

  • 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
  • 19. COPD Physiology: Skeletal Muscles in COPD
    •  Muscle mass
    •  Skeletal muscle weakness assoc’d with:
    • -  exercise capacity
    • -  HRQOL
    • -  mortality
    •  No benefit of nutritional support or
    • testosterone
      •   cytokines (TNF-  NF-  B)
    • -  protein synthesis
    • -  protein degredation
    • -  muscle regeneration
    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