58

COPD First Session

Embed Size (px)

Citation preview

Page 1: COPD First Session
Page 2: COPD First Session

COPD

Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university

Page 3: COPD First Session
Page 4: COPD First Session

Goal of this learning modules

• To Provide a framework to make informed decisions regarding the diagnosis and treatment of Chronic obstructive pulmonary disease

Page 5: COPD First Session

Learning objectives

After completing this module you should know:

• know the definition of COPD

• Understand the burden of COPD

• know the risk factors of COPD occurrence

• Learn about the pathology, pathogenesis and Pathophysiology of COPD.

Page 6: COPD First Session

History of COPD

• A British medical textbook (1860s )→ C/P of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right-sided heart failure.

• 20th century, Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema → concept of airflow obstruction.

• Chronic bronchitis: chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded).

• Emphysema: an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis

Page 7: COPD First Session

Definition & Overview

Common preventable & treatable disease

Characterized by persistent airflow limitation that is usually progressive

Associated with an enhanced chronic inflammatory response in the airways & the lung to noxious particles or gases

Exacerbations & comorbidities contribute to the overall severity in individual patients

Page 8: COPD First Session

COPD is a progressive disease The Downward Spiral in COPD

Page 9: COPD First Session

Burden of COPD

COPD is a leading cause of morbidity & mortality worldwide

The burden will increase in coming decades due to

continued exposure to risk factors & the aging of the

world’s population

COPD is associated with significant economic burden

Page 10: COPD First Session

Prevalence

Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population -based prevalence study. Lancet. 2007;370:741-750.

11.8% 8.5% 10.1% overall

Page 11: COPD First Session

COPD Misdiagnosis Is Common in Women

Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest. 2001;119:1691-1695

Page 12: COPD First Session

Under diagnosis of COPD in the United States

• Over 12 million people in the United States have been diagnosed with COPD; another 12 million are estimated to be undiagnosed1

• Data from NHANES III indicate that approximately 24 million US adults have evidence of impaired lung function indicative of COPD2,3

• Most (70%) of patients with undiagnosed COPD are <65 years

70%

<Age 65

30%

≥Age 65

Percent With Undiagnosed COPD

1. NHLBI; available at http://www.nhlbi.nih.gov/health/public/lung/copd/index.html. 3. Mannino DM, et al. Proc Am Thorac Soc. 2007;4:502-306

2. Mannino DM, et al. MMWR Surveill Summ. 2002;51:1-16.

Page 13: COPD First Session

Mortality :

Global burden of Disease study: COPD rank

Murray and Lopez Lancet 1997

Page 14: COPD First Session

Mortality :

Global burden of Disease study: COPD rank

Page 15: COPD First Session

Mortality :

Global burden of Disease study

• Almost 90% of COPD deaths occur in low- and middle-income countries.

Page 16: COPD First Session

Economic and social burden

Economic • USA: Direct costs $ 29.5 billion & Indirect costs $ 20.4 billion

• Europe: 38.6 billion Euros

• In developing countries:

– Workplace & home productivity loss > Medical costs loss

Social • Disability-Adjusted Life year (DALY)

– 1990→ 12th leading cause of DALYs

– 2030 → 7th leading cause of DALYs

Page 17: COPD First Session

Risk factors for COPD Influence disease development & progression

Page 18: COPD First Session

Genes

• Gene-environmental interaction are the key for development of COPD.

• Susceptibility to COPD is not dichotomous variable and a range of susceptibility exits.

– Some smokers develop the disease earlier than others.

– Progression in COPD is very heterogeneous

Page 19: COPD First Session

Genes

• In patients with COPD

– emphysema represents accelerated ageing of the lung

– studies showed telomere shortening & dysfunction

• Telomerase null mice with short telomeres – increased emphysema

– double-strand DNA breaks

• after exposure to chronic cigarette smoke

• with evidence of reduced epithelial repair

• Family with a telomerase mutation

– have early-onset emphysema

Page 20: COPD First Session

Cumulative exposure to noxious particles is the key risk factor for COPD

Page 21: COPD First Session

Airway Responsiveness-Dutch Hypothesis

• Increased airways responsiveness and allergy are clinical phenotypes that predict increased susceptibility to cigarette smoke.

• Methacholine and histamine responsiveness precedes and predicts accelerated decline in lung function, thus a risk factor for COPD.*

• Increased airways responsiveness noted among 1st degree relatives of patients with early onset COPD.^

*Silva, GE et al. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126:59.

^Celedon JC et al. Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD. Eur Respir J 1999; 14:1009.

Page 22: COPD First Session

Pathogenesis

Noxious agents

Biomass particles Occupational agents Pollutants

Genetic factors Resp. infection

Page 23: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 23

Apoptotic Pathways in COPD

Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central.

Survival factor Granzyme B Perforin

TNF-α sFasL

cytoplasm

nucleus

ER Stress

Apoptosome

Apaf 1 Procasp-9

Procasp-9 Casp-9

Casp-8 CAD CAD

ICAD

Casp-8

Procasp-8 Procasp-8

FADD Bid tBid

Bax

Bak

Cyt C

ER stress

DNA fragmentation

1 2

4

3

5

?

Fas

COPD Pathogenesis

Page 24: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set

Page 25: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 25

Angiogenesis in COPD

Reprinted f rom International Journal of COPD, 2, Siafakas NM, et al., Role of angiogenesis and vascular remodeling in

chronic obstructive pulmonary disease, 453-462, Copyright 2007, with permission f rom Dove Medical Press Ltd.

extravasated

plasma proteins

Inflammatory cells (Mac, Neu, Epith, Lymph)

Release of angiogenic

mediators

Fibrinogen products

Inflammation Tissue

hypoxia

Airway

fibrosis

Mechanical

Injury

Increased

blood flow

Vessel growth

Angiogenesis

Vascular remodeling

Up-regulation of

Angiogenic factors

Shear stress

on the endothelium

COPD Pathogenesis

Page 26: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set

Angiogenic and Angiostatic Factors in COPD

• Angiogenic CXC Chemokines, CC Chemokines, and Growth Factors:

– CXCL1

– CXCL5

– CXCL8

– CCL2

– VEGF

– bFGF

– Angiopoietin-1

– HGF

– EGF

• Angiostatic CXC Chemokines, CC Chemokines, and Growth Factors:

– CXCL10

– CXCL11

Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462.

COPD Pathogenesis

Page 27: COPD First Session

Pathogenesis

Obstructive Bronchiolitis Emphysema

Page 28: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set

Inflammatory Cells in Stable

COPD

Gamal Agmy 2-5-2014

Inflammation in COPD

Page 29: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 29

Neutrophils in COPD

Mucous hypersecretion

Serine proteases Neutrophil Elastase

Cathepsin G

Proteinase-3

O2-

MPO

LTB4, IL-8, GRO-

LTB4, IL-8

Adapted f rom Barnes PJ. N Engl J Med. 2000; 343: 269-280

Adapted f rom Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688

Emphysema

Severe emphysema

Images courtesy R Buhl.

Inflammation in COPD

Page 30: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 30

Sputum Neutrophil Count Correlates With Declining Lung Function

Reproduced with permission of Thorax f rom “Airways obstruction, chronic expectoration and rapid decline of FEV1 in smokers are

associated with increased levels of sputum neutrophils,” Stanescu et al, Vol 51, Copyright © 1996; permission conveyed through

Copyright Clearance Center, Inc.

> 30 < 20

100

0

Ne

utr

op

hils in

iIn

du

ce

d s

pu

tum

(%

)

90

20 – 30

80

60

70

50

40

FEV1 decline (mL/year)

P<0.01

Inflammation in COPD

Page 31: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 31

Neutrophils Infiltrating Bronchial Glands in COPD

Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission f rom American Thoracic Society.

Copyright © 1997

Inflammation in COPD

Page 32: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 32

Reduction in Neutrophil Apoptosis in COPD

Adapted f rom Brown V, et al. Respir Res. 2009;10:24.

Apoptotic neutrophils

(arrows)

*P<0.05

*P<0.01

Morphology Tunel

NS

HS

COPD

60

50

40

30

20

10

0

Apoptotic

neutrophils [%]

Image courtesy of R Buhl.

NS: nonsmoking controls (n=9) HS:

healthy smoking controls (n=9)

TUNEL: the terminal transferase-

mediated dUTP nick end-labeling method

Inflammation in COPD

Page 33: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 33

Alveolar Macrophages in COPD

Phagocytosis

Cigarette smoke

Wood smoke

Elastolysis MMP-9, MMP-12

Cathepsins K, L, S

Emphysema

Steroid resistance

NO

ROS ONOO-

HDAC Steroid

response

Monocytes

MCP-1

GRO-

Neutrophils

LTB4

IL-8 GRO-

CD8+ Cells

IP-10 Mig I-TAC

Adapted f rom Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 f rom "Alveolar Macrophages as Orchestrators of COPD" by

Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandfrancis.com

Emphysema

Severe emphysema

Images courtesy of R Buhl.

Numbers

Secretion

Inflammation in COPD

Page 34: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 34

Inflammatory Mediators in COPD – Summary

Cell

Neutrophils

Macrophages

T-cell

Epithelial cell

IL-8, TGF- 1, IP-10, Mig, I-TAC, LTB4, GRO- , MCP-1, MMP-9

Granzyme B, perforins, IFN-, TNF-

IL-8, IL-6, TGF-1 TGF-, IP-10, Mig, I-TAC, LTB4, GRO-, MCP-1, ROS, MMP-9

Serine proteases, TNF-, ROS, IL-8, MPO, LTB4

Selected Mediators

Barnes PJ, et al. Eur Respir J. 2003;22:672-888.

Inflammation in COPD

Page 35: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 35

Examples of Chemotactic Factors in COPD

Barnes PJ. Curr Opin Pharmacol. 2004;4:263-272.

Hill AT, et al. Am J Respir Crit Care Med. 1999;160: 893-898.

Montuschi P, et al. Thorax. 2003;58:585-588.

MCP-1

GRO-

Elastin

fragments

LTB4

IL-8

GRO-

Elastin

fragments

IP-10

Mig

I-TAC

Neutrophil Monocyte T-cell

Inflammation in COPD

Page 36: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 36

TNF- Has Pro-inflammatory Actions in COPD

Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission f rom Biomed Central.

Oxidative stress

Activation of NF-B and AP-1

Activation of proinflammatory molecules e.g. VCAM-1, ICAM-1 and RAGE

Subcellular ROS production

TNF-

Antioxidants

e.g. GSH, Catalase

Scavenge free radicals,

detoxify cellular hydrogen peroxide and inhibit ROS generation

Proinflammation

+

+ +

+

+

+

+

-

-

Inflammation in COPD

Page 37: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set

Modulation of Inflammation by

Histone Deacetylase (HDAC)

Inflammation in COPD

Gamal Agmy 2-5-2014

Page 38: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 38

Decreased HDAC Expression May Promote

Inflammation and Decrease Response to

ICS in COPD

Normal

Histone acetylation

Stimuli

Steroid sensitive

Histone hyperacetylation

nitration ubiquitination

oxidation

↑TNF

↑IL-8

↑GM-CSF

Stimuli

Steroid resistant

HAT

TF

HAT

TF

TNF IL-8 GM-CSF

Glucocorticoid

receptor

COPD

HDAC2

HDAC2

Glucocorticoid

peroxynitrite

Reproduced f rom Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inf lammatory lung diseases,” pp249-265.

Copyright © 2007, with permission f rom Elsevier.

Inflammation in COPD

Page 39: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 39

Pulmonary HDAC Levels Decrease With COPD Severity

Adapted f rom Ito K, et al. N Engl J Med. 2005;352:1967-1976.

S = COPD Stage

0

.5

1.0

1.5

2.0

Non-

smoker

N=11

P<0.001

HD

AC

2 e

xp

ressio

n (vs. la

min

A/C

)

P=0.04

P<0.001

P<0.001

S4

N=6

S0

N=9

S1

N=10 S2

N=10

■ ■

Inflammation in COPD

Page 40: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set

Inflammation Leads to Small Airway Narrowing

• Acute and chronic inflammation suspected to contribute to COPD-

related small airway narrowing

• Airway narrowing leads to airway obstruction

• Narrowing results from several factors:

– Collagen deposition and increased lymphoid follicles in outer

airway wall

– Mucosal thickening of airway lumen

– Inflammatory exudate in airway lumen

Barnes PJ, et al. Eur Respir J. 2003;22: 672-688.

Inflammation in COPD

Page 41: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 41

Inflammation and Airway Destruction

Normal COPD

Reproduced f rom The Lancet, Vol 364, Hogg JC. "Pathophysiology of airf low limitation in chronic obstructive pulmonary

disease," pp709-721. Copyright © 2004, with permission f rom Elsevier.

Inflammation in COPD

Page 42: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 42

Exacerbations of Chronic Bronchitis and Inflammatory Cell Types

Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.

Maestrelli P, et al. Am J Respir Crit Care Med. 1995;152:1926-1931.

Barnes PJ. N Engl J Med. 2000;343:269-280.

COPD Exacerbation

Eosinophils

Eosinophils

T-Cells

Neutrophils

Cells Predominant in:

Induced sputum

Biopsy

Neutrophils

Inflammation in

COPD

Page 43: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 43

Clinical Impact of Inflammation in COPD

Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission f rom Biomed Central.

Increased Airway Inflammation

Increased mucous production

Airway wall thickening

Airway wall oedema

Bronchoconstriction

Airway narrowing

V’/Q’ Mismatching Hyperinflation

Worsening of gas exchange

Increased work of breathing

Increased oxygen consumption –

Decreased mixed venous oxygen

Cough, sputum, dyspnoea, Respiratory failure

Inflammation in COPD

Page 44: COPD First Session

These data are communicated for scientific purpose only. Confidential slide set 44

Inflammation: Clinical Consequences

Systemic

• Nutritional abnormalities and weight loss

• Hypoxaemia

• Skeletal muscle dysfunction

• Cardiovascular disease

• Depression

• Osteoporosis

• Anaemia

Agusti AG, et al. Eur Respir J. 2003;21:347-360.

Agusti AG. Proc Am Thorac. 2006;3:478-483.

Barnes PJ, Cell BR. Eur Respir J. 2009;33:1165-1185.

Pulmonary

Dyspnoea

Cough

Sputum production

Exacerbations

Inflammation in COPD

Page 45: COPD First Session

Inflammatory cells and mediators in COPD

Page 46: COPD First Session

Pathogenesis

Page 47: COPD First Session

The site of pathology in COPD

Mucus gland hyperplasia

Goblet cellhyperplasia

Mucus hypersecretion Neutrophils in sputum

Squamous metaplasia of epithelium

↑ Macrophages

No basement membrane thickening

Little increase in

airway smooth muscle

↑ CD8+ lymphocytes

Changes in Large Airways of COPD PatientsChanges in Large Airways of COPD Patients

Source: Peter J. Barnes, MD

Page 48: COPD First Session

Chronic bronchitis

Hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells

Page 49: COPD First Session

The site of pathology in COPD

Disrupted alveolar attachments

Inflammatory exudate in lumen

Peribronchial fibrosisLymphoid follicle

Thickened wall with inflammatory cells

- macrophages, CD8+ cells, fibroblasts

Changes in Small Airways in COPD Patients

Source: Peter J. Barnes, MD

Page 50: COPD First Session

The site of pathology in COPD

Endothelial dysfunction

Intimal hyperplasia

Smooth muscle hyperplasia

↑ Inflammatory cells

(macrophages, CD8+ lymphocytes)

Changes in Pulmonary Arteries in COPD Patients

Source: Peter J. Barnes, MD

Page 51: COPD First Session

The site of pathology in COPD

Page 52: COPD First Session

Emphysema

Page 53: COPD First Session

Emphysema

• Centriacinar – Focal destruction limited to the respiratory

bronchioles and the central portions of the acini.

– associated with cigarette smoking

– most severe in the upper lobes

• Panacinar

– involves the entire alveolus distal to the terminal bronchiole.

– most severe in the lower lung zones

– AAT deficiency

• Distal acinar or paraseptal – least common form and involves distal airway

structures, alveolar ducts, and sacs.

loss of alveolar walls and dilatation

of airspaces in emphysema

Page 54: COPD First Session

Natural History of Emphysema

• In non-smokers, maximal lung function

– attained at age 15 - 25 years

– after a variable plateau phase, declines ~ 20 -25 mL/year

• Lung Health Study (large longitudinal study)

– smoking is associated with an accelerated decline in lung function

• Females are at higher risk of lung damage

– related to smoke exposure than males

Page 55: COPD First Session

Fletcher C et al. 1977

FEV

1 (%

of v

alu

e at

age

25

)

100

25 50 75

Never smoked or not susceptible to smoke

Age (years)

Disability

Smoked regularly and susceptible to its effects

Death

0

25

50

75

Stopped at 65

Stopped at 45

Classical View of “Disease Progression” & “Disease Modification”

Page 56: COPD First Session

Pathogenic mechanisms

Pathological changes in COPD

Physiological abnormalities: Mucous hypersecretion & ciliary dysfunction

Airflow obstruction & hyperinflation

Gas exchange abnormalities

Pulmonary hypertension & systemic effects

Pathophysiology

Page 57: COPD First Session

Spectrum of COPD

Page 58: COPD First Session

Thank you