COPD and Comorbidities Chance or Fate Bartolome R

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 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?

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 Wise et al PATS 2006

Co-morbidities in patients with COPD 2900 patients Attending P. R. Comorbidity impacted on response to PR Aim: Effect of comorbidities on response to P. R. FEV 1 = 49% Age = 71 Crisafulli et al Thorax. 2008; 63: 487

0 HTN CAD+MI Degenerative joint disease GERD Deppresion CHF AF+Flutter Erectile dysfunction Emphysema Pul HTN+CP Prostate cancer Osteoporosis Breast cancer Pulmonary fibrosis DVT Other arrythmia Gout Neurophaty DM Hepatitis Nephrolithiasis Connective Tissue disorders Dementia Liver cirrhosis Bronchiectasis Pancreatitis Colon cancer Restless leg syndrome Melanoma MAI Parkinson Inflamatory Bowel disease Kidney cancer Liver cancer Brain cancer Thyroid cancer HIV Testicula cancer Rectal cancer BOOP Celiac disease Prevalence (%) Divo et al AJRCCM 2012; 186: 155 78 comorbidities 60 50 40 30 20 10 Prevalence (%)

Divo et al AJRCCM 2012; 186: 155

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?

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

Dynamic Network Approach for the Study of Human Phenotypes Hidalgo et al PLo. S 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 PLo. S 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

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 CHRNA 3/5 FAM 13 A BAT 3 TERT HHIP ADAM 19 AGER CRP Phenotype Lung cancer + COPD Lung cancer + COPD Lung cancer (Young, PLo. S 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.

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 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?

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