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COPD and Co-morbidities: Chance or Fate? Bartolome R. Celli, MD Brigham and Women’s Hospital Harvard Medical School Boston Chronic Obstructive Pulmonary Disease • “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 Co-morbidity in COPD • In patients with COPD, not all CoMorbidites 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? Co-morbidity in COPD • In patients with COPD, not all CoMorbidites 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? COPD Lung cancer 9 - 20% 30% Cachexia 30-50% vs myopathy Osteoporosis 20-60% Anxiety and 30-50% 17% CAD/CHF Anemia Barnes and Celli ERJ 2008 TORCH: Causes of death as adjudicated by the Endpoint Committee Other 10% Cancer 21% Unknown 7% Respiratory 35% Cardiac 27% Wise et al PATS 2006 Co-morbidities in patients with COPD 80 Attending P.R. % of patients 2900 patients 60 40 Comorbidity impacted on response to PR Aim: Effect of comorbidities on response to P.R. 20 0 FEV1 = 49% > 1 Comorbidity Metabolic Heart Disease Age = 71 Crisafulli et al Thorax. 2008;63:487 Divo et al AJRCCM 2012;186:155 Celiac disease BOOP Rectal cancer Testicula cancer HIV Thyroid cancer Brain cancer Liver cancer Kidney cancer Inflamatory Bowel disease Parkinson MAI Melanoma Restless leg syndrome Colon cancer Pancreatitis Bronchiectasis Liver cirrhosis Dementia Connective Tissue disorders Nephrolithiasis Hepatitis Neurophaty DM Gout Other arrythmia DVT Pulmonary fibrosis Breast cancer Osteoporosis Prostate cancer Pul HTN+CP Emphysema Erectile dysfunction AF+Flutter CHF Deppresion GERD Degenerative joint disease CAD+MI HTN Prevalence (%) 78 comorbidities 60 50 40 30 20 10 Prevalence (%) 0 Divo et al AJRCCM 2012;186:155 Co-morbidity in COPD • In patients with COPD, not all CoMorbidites 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? New Concepts: Network Medicine Barabasi A.L. NEJM 2007;357:4 Dynamic Network Approach for the Study of Human Phenotypes Hidalgo et al PLoS Comput Biol 5(4):2009 Dynamic Network Approach for the Study of Human Phenotypes Hidalgo et al PLoS Comput Biol 5(4):2009 Definitions 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 The COPD (Comorbidity + Clinical Characteristics) Network • • 86 Nodes • 79 Comorbidities • 7 Clinical characteristics 520 Connections + 50% Divo et al (BODE COHORT) Motif 1 10% Divo et al (BODE COHORT) Motif 2 10% Divo et al (BODE COHORT) Motif 3 10% Objectives • COPD and Lung Cancer: Big Problems • One agent, two diseases……or is it? • Pathobiological symbiosis • Facing the problem Objectives • COPD and Lung Cancer: Big Problems • One agent, two diseases……or is it? • Pathobiological symbiosis • Facing the problem 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. Objectives • COPD and Lung Cancer: Big Problems • One agent, two diseases……or is it? • Pathobiological symbiosis • Facing the problem Airflow obstruction and lung Cancer 1.Skillrud DM Ann Intern Med 1986;105:503 2. Tockman MS. Ann Intern Med 1987; 106:512 Lung Cancer in Bullous Emphysema Goldstein M, Snider GLS et al Am Rev Respir Dis 1968;97:1062 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 Odds Ratio for a diagnosis of lung cancer RR IC 95% Emphysema 2,51 1,01– 6,23 COPD 2,10 0,79 – 5,58 Adjusted for age, sex and pack-years, emphysema or COPD. de Torres et al. CHEST 2007; 132: 1932-8 Number = 3,678 screened for lung cancer. Pittsburgh. OR 95%CI Emphysema 3.14 1.91– 5.15 COPD 1.41 0.87- 2.29 Adjusted for age, sex and smoking and emphysema or COPD Wilson et al Am J Respir Crit Care Med 2008;178:738 BODE group • 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 Predictors of Lung Cancer development de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9 Synergy and Convergence Lung Cancer COPD Objectives • COPD and Lung Cancer: Big Problems • One agent, two diseases……or is it? • Pathobiological symbiosis • Facing the problem Common Variants, Low Penetrance GWAS in lung cancer with COPD phenotype considered: SNP in Genes CHRNA3/5 FAM13A BAT3 TERT HHIP ADAM19 AGER CRP Phenotype Lung cancer + COPD Lung cancer + COPD Lung cancer + COPD Lung cancer Lung cancer + COPD Lung cancer + COPD COPD Lung cancer (Young, PLoS ONE, 2011) State of the Art Oxidative stress Cell replication and senescence Gene expression Epigenetics Methylation Endogenous modifiers Co-morbidities Microbiota Pathobiological Symbiosis Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7. Pathobiological Symbiosis Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7. Pathobiological Symbiosis Brody J and Spira A. Proc Am Thorac Soc. 2006 Aug;3(6):535-7. Objectives • COPD and Lung Cancer: Big Problems • One agent, two diseases……or is it? • Pathobiological symbiosis • Facing the problem Lung Cancer US Co-morbidity in COPD • In patients with COPD, not all CoMorbidites 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? Genome Environment Modified from Loscalzo et al Mol Sys Bio 20007;3:124 Genome Environment Transcriptome Proteome Metabolome Thrombosis Inflammation Hemorrhage Fibrosis Immune Cell Apoptosis response proliferation Necrosis Abnormal organ function Disease with different phenotypes Modified from Loscalzo et al Mol Sys Bio 20007;3:124 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 How do we do it? Bench scientist Clinician Data Integration Manager Thank You Nothing is impossible, the word itself says, “I’m possible!” – Audrey Hepburn