1. COPD and Co-morbidities: Chance or Fate? Bartolome R. Celli, MD Brigham and Women’s Hospital Harvard Medical School Boston

2. Chronic Obstructive Pulmonary Disease associated with co-morbidities”“Preventable and treatable disease characterized by airflow limitation, resulting from an abnormal inflammatory reaction to inhaled particles (smoking) and associated with co-morbidities” GOLD accessed May 2013

3. Co-morbidity in COPD In patients with COPD, not all Co- Morbidites are created equal From the Solar System to the Milky Way (Multi-morbidity) We need to re-think how we link diseases….perhaps by pathobiology?

4. Co-morbidity in COPD In patients with COPD, not all Co- Morbidites are created equal From the Solar System to the Milky Way (Multi-morbidity) We need to re-think how we link diseases….perhaps by pathobiology?

5. Lung cancer Cachexia vs myopathy Osteoporosis Anemia CAD/CHF Anxiety and COPD 9 - 20% 30% 30-50% 17% 30-50% 20-60% Barnes and Celli ERJ 2008

6. TORCH: Causes of death as adjudicated by the Endpoint Committee Wise et al PATS 2006

7. Co-morbidities in patients with COPD Crisafulli et al Thorax. 2008;63:487 2900 patients Attending P.R. Aim: Effect of co- morbidities on response to P.R. FEV1 = 49% Age = 71 Comorbidity impacted on response to PR

8. 78 comorbidities Divo et al AJRCCM 2012;186:155

10. Co-morbidity in COPD In patients with COPD, not all Co- Morbidites are created equal From the Solar System to the Milky Way (Multi-morbidity) We need to re-think how we link diseases….perhaps by pathobiology?

12. New Concepts: Network Medicine Barabasi A.L. NEJM 2007;357:4

13. Dynamic Network Approach for the Study of Human Phenotypes Hidalgo et al PLoS Comput Biol 5(4):2009

14. Dynamic Network Approach for the Study of Human Phenotypes Hidalgo et al PLoS Comput Biol 5(4):2009

15. Co-morbidity relationship exists between two diseases whenever they affect the same individual substantially more than chance alone Hidalgo et al PLoS Comput Biol 5(4):2009 Definitions

16. The COPD (Comorbidity + Clinical Characteristics) Network 86 Nodes86 Nodes 79 Comorbidities79 Comorbidities 7 Clinical characteristics7 Clinical characteristics 520 Connections520 Connections + - 50% Divo et al (BODE COHORT)

17. Motif 110% Divo et al (BODE COHORT)

18. Motif 210% Divo et al (BODE COHORT)

19. Motif 310%

20. Objectives COPD and Lung Cancer: Big Problems One agent, two diseases……or is it? Pathobiological symbiosis Facing the problem

21. Objectives COPD and Lung Cancer: Big Problems One agent, two diseases……or is it? Pathobiological symbiosis Facing the problem

22. Top 10 Causes of Death, Years of Life Lost from Premature Death, Years Lived with Disability, and Disability-Adjusted Life-Years (DALYs) in the United States, 2010. Murray CJ, Lopez AD. N Engl J Med 2013;369:448-457.

23. Objectives COPD and Lung Cancer: Big Problems One agent, two diseases……or is it? Pathobiological symbiosis Facing the problem

24. Airflow obstruction and lung Cancer 2. Tockman MS. Ann Intern Med 1987; 106:512 1.Skillrud DM Ann Intern Med 1986;105:503

25. Lung Cancer in Bullous Emphysema Goldstein M, Snider GLS et al Am Rev Respir Dis 1968;97:1062

26. Odds Ratio for a diagnosis of lung cancer IC 95%RR 0,79 – 5,582,10 COPD 1,01– 6,232,51 Emphysema Adjusted for age, sex and pack-years, emphysema or COPD. de Torres et al. CHEST 2007; 132: 1932-8 Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest Number = 1,666 ever-smokers. Screened for Cancer. Spain

27. 95%CIOR 0.87- 2.291.41COPD 1.91– 5.153.14Emphysema Adjusted for age, sex and smoking and emphysema or COPD Wilson et al Am J Respir Crit Care Med 2008;178:738 Number = 3,678 screened for lung cancer. Pittsburgh.

28. 2507 pts mean follow up 60 months 215 cases of lung cancer (8,5%) Incidence density 1.67/100 persons year Most frequent histological type: squamous cell 904 died during the follow up time 174 due to lung cancer de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9 BODE group

29. de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9 Predictors of Lung Cancer development

30. Synergy and Convergence COPD Lung Cancer

31. Objectives COPD and Lung Cancer: Big Problems One agent, two diseases……or is it? Pathobiological symbiosis Facing the problem

32. Common Variants, Low Penetrance GWAS in lung cancer with COPD phenotype considered: SNP in GenesPhenotype CHRNA3/5Lung cancer + COPD FAM13ALung cancer + COPD BAT3Lung cancer + COPD TERTLung cancer HHIPLung cancer + COPD ADAM19Lung cancer + COPD AGERCOPD CRPLung cancer (Young, PLoS ONE, 2011)

33. State of the Art Oxidative stress Gene expression Epigenetics Methylation Cell replication and senescence Microbiota Endogenous modifiers Co-morbidities

34. Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7. Pathobiological Symbiosis

35. Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7. Pathobiological Symbiosis

36. Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7. Pathobiological Symbiosis

37. Objectives COPD and Lung Cancer: Big Problems One agent, two diseases……or is it? Pathobiological symbiosis Facing the problem

38. Lung Cancer US

39. Co-morbidity in COPD In patients with COPD, not all Co- Morbidites are created equal From the Solar System to the Milky Way (Multi-morbidity) We need to re-think how we link diseases….perhaps by pathobiology?

40. Genome Environment Modified from Loscalzo et al Mol Sys Bio 20007;3:124

41. Genome Transcriptome Proteome Environment Inflammation Thrombosis Hemorrhage Fibrosis Immune response Apoptosis Necrosis Cell proliferation Abnormal organ function Disease with different phenotypes Modified from Loscalzo et al Mol Sys Bio 20007;3:124 Metabolome

42. A Road to the Future Some co-morbidities of COPD share pathobiological responses to injurious agents and occur more frequently than chance would have it. We may have to shift from organ oriented pathophysiology to mechanistic pathobiology Comprehensive evaluation of patients for commonly occurring diseases Merging of specialties? Back to Holistic Medicine

43. How do we do it? Clinician Bench scientist Data Integration Manager

44. Nothing is impossible, the word itself says, “I’m possible!” – Audrey Hepburn Thank You