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

COPD and Co-morbidities: Chance or Fate?

Bartolome R. Celli, MDBrigham 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 associated with co-morbidities”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?

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?

Lung cancerLung cancer

Cachexia Cachexia vs vs myopathymyopathy OsteoporosisOsteoporosis

AnemiaAnemiaCAD/CHFCAD/CHF

Anxiety andAnxiety and

COPD

9 - 20%

30%

30-50%

17%

30-50%

20-60%

Barnes and Celli ERJ 2008

TORCH: Causes of death as adjudicated by the Endpoint

CommitteeUnknown

7%

Cardiac 27%

Cancer21%

Other10%

Respiratory35%

Wise et al PATS 2006

Co-morbidities in patients with COPD

Crisafulli et al Thorax. 2008;63:487

0

20

40

60

80

> 1 Co-morbidity

Metabolic Heart Disease

% o

f p

ati

en

ts

2900 patients2900 patients

Attending P.R.Attending P.R.

Aim: Effect of co-Aim: Effect of co-morbidities on morbidities on response to P.R.response to P.R.

FEV1 = 49%FEV1 = 49%

Age = 71Age = 71

Comorbidity impacted on response to PR

78 comorbidities

Divo et al AJRCCM 2012;186:155

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 PLoS Comput Biol 5(4):2009

Dynamic Network Approach for the Study of Human Phenotypes

Hidalgo et al PLoS Comput Biol 5(4):2009Hidalgo et al PLoS Comput Biol 5(4):2009

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

The COPD (Comorbidity + Clinical Characteristics) Network

• 86 Nodes86 Nodes• 79 Comorbidities79 Comorbidities• 7 Clinical characteristics7 Clinical characteristics

• 520 Connections520 Connections

++--

50%50%

Divo et al (BODE COHORT)

Motif 1

10%10%

Divo et al (BODE COHORT)

Motif 2

10%10%

Divo et al (BODE COHORT)

Motif 3

10%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, 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.and Disability-Adjusted Life-Years (DALYs) in the United States, 2010.

Murray CJ, Lopez AD. N Engl J Med 2013;369:448-457.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

2. Tockman MS. Ann Intern Med 1987; 106:5122. Tockman MS. Ann Intern Med 1987; 106:512

1.Skillrud DM Ann Intern Med 1986;105:5031.Skillrud DM Ann Intern Med 1986;105:503

Lung Cancer in Bullous Emphysema

Goldstein M, Snider GLS et al Am Rev Respir Dis 1968;97:1062 Goldstein M, Snider GLS et al Am Rev Respir Dis 1968;97:1062

Odds Ratio for a diagnosis of lung cancer

IC 95%RR

0,79 – 5,582,10COPD

1,01– 6,232,51Emphysema

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

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;178:738Wilson et al Am J Respir Crit Care Med 2008;178:738

Number = 3,678 screened for lung cancer. Pittsburgh.

• 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 ;184:913-9de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9

BODE group

de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9

Predictors of Lung Cancer developmentPredictors of Lung Cancer development

Synergy and Convergence

COPDLung Lung CancerCancer

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 PhenotypeCHRNA3/5 Lung cancer + COPDFAM13A Lung cancer + COPDBAT3 Lung cancer + COPDTERT Lung cancerHHIP Lung cancer + COPDADAM19 Lung cancer + COPDAGER COPDCRP Lung cancer

(Young, PLoS ONE, 2011)

State of the ArtOxidative stressOxidative stress

Gene expressionGene expression

Epigenetics Epigenetics MethylationMethylation

Cell replication and senescenceCell replication and senescence

MicrobiotaMicrobiota

Endogenous modifiersEndogenous modifiers

Co-morbiditiesCo-morbidities

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

Pathobiological Symbiosis

Objectives

• COPD and Lung Cancer: Big Problems

• One agent, two diseases……or is it?• Pathobiological symbiosis• Facing the problem

Lung Lung CancerCancer

USUS

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?

GenomeEnvironment

Modified from Loscalzo et al Mol Sys Bio 20007;3:124

Genome

Transcriptome

Proteome

Environment

InflammationThrombosis

Hemorrhage Fibrosis

Immune

responseApoptosis

Necrosis

Cell

proliferation

Abnormal organ function

Disease with different phenotypes

Modified from Loscalzo et al Mol Sys Bio 20007;3:124

Metabolome

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

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