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COPD: Epidemiology, Pathogenesis, & Pathophysiology

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COPD: Epidemiology, Pathogenesis, & Pathophysiology Wyatt E. Rousseau, MD May 11, 2006 COPD Definition Chronic obstructive pulmonary disease (COPD) is a preventable ... – PowerPoint PPT presentation

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Title: COPD: Epidemiology, Pathogenesis, & Pathophysiology


1
COPD Epidemiology, Pathogenesis,
Pathophysiology
  • Wyatt E. Rousseau, MD
  • May 11, 2006

2
COPD Definition
  • Chronic obstructive pulmonary disease (COPD) is a
    preventable and treatable disease state
    characterized by airflow limitation that is not
    fully reversible. The airflow limitation is
    usually progressive and is associated with an
    abnormal inflammatory response of the lungs to
    noxious particles or gases, primarily caused by
    cigarette smoking. Although COPD affects the
    lungs, it also produces significant systemic
    consequences.

3
COPD Definitions/Terms
  • Simple chronic bronchitis
  • Asthmatic bronchitis/Chronic asthmatic bronchitis
  • Chronic obstructive bronchitis small airways
    disease
  • Pulmonary emphysema

4
Simple chronic bronchitis
  • Exposure to irritants without hyperreactive
    airways. Characterized by mucoid sputum
    production, decreased ciliary activity, and
    impaired resistance to infection.

5
Chronic asthmatic bronchitis or COPD with asthma
  • Exposure to irritants in individuals with
    reactive or twitchy airways. Bronchospasm is
    frequently accompanied by excessive mucous
    production and edema of bronchial walls.
    Episodic worsening of airway obstruction often
    called asthma, but there is persisting
    obstruction, and often productive cough, with the
    episodic bronchospasm.

6
Obstructive Chronic Bronchitis
  • Irreversible narrowing of airways, usually
    bronchioles or bronchi smaller than 2 mm.,
    associated with increased resistance to airflow,
    hypoxemia, hypercapnea.

7
Pulmonary Emphysema
  • Permanent, abnormal distension of the air spaces
    distal to the terminal bronchiole with
    destruction of alveolar septae, with or without
    fibrosis. Reduces lung elastic recoil causing
    airway collapse and irreversible airway
    obstruction.

8
Histology
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Pathology Chronic Bronchitis
  • Hypertrophy of mucous glands in submucosa of
    airways. Reid index (submucosa to bronchial
    wall).
  • Small airways obstruction esp. with goblet cell
    hyperplasia, mucosal and submucosal inflammatory
    cells, edema, peribronchial fibrosis, mucous
    plugs, and increased smooth muscles.
  • Alveolar epithelium is the target and the
    initiator of inflammation in CB, with
    neutrophils, macrophages, and CD8 lymphocytes
    causing epithelial cell release of IL-8 and other
    chemotactic and proinflammatory cytokines, and
    colony stimulating factors released in response
    to toxic, infectious, or inflammatory stimuli.

12
More CB Pathology
  • Injured epithelium may release reduced amounts of
    regulatory products such as ACE or neutral
    peptidase.
  • Sputum production is stimulated by increased
    exocytosis from secretory cells, lipid mediators,
    and inflammatory cell products.
  • Mucin gene expression is amplified by TNF-alpha,
    and secretory cell hyperplasia by the neutrophil
    enzymes elastase and cathepsin G.

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Pathology - Emphysema
  • Classified by pattern of involvement of the acini
    distal to terminal bronchiole.
  • Centriacinar or Centrilobular limited to
    respiratory bronchioles primarily with little
    change in acinus. Normal aging is associated
    with this.
  • Panacinar or Panlobular involves both central
    and peripheral portions of the acinus.

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21
Epidemiology
  • Background - Lung function over time
  • Cigarette smoking
  • Airway responsiveness and Allergy
  • Air Pollution
  • Occupational exposure to environmental dust and
    organic antigens
  • Infection
  • Antioxidant deficiency
  • Molecular/Genetic risk factors

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Cigarette Smoking
  • Responsible for 80 of risk of Chronic Bronchitis
  • Doubles or triples rate of FEV1 decline
  • Responsible for 2-20 fold increase in death from
    COPD
  • Never smokers account for 23 of COPD
  • Only 15 of white and 5 Asian smokers develop
    COPD

24
Cigarette Smoking
  • Impairs ciliary movement
  • Inhibits alveolar macrophages
  • Leads to hypertrophy and hyperplasia of
    mucus-secreting glands
  • Probably inhibits antiprotease
  • Acutely increases vagally mediated smooth-muscle
    constriction

25
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._at_
  • Silva, GE et al. Asthma as a risk factor for
    COPD in a longitudinal study. Chest 2004 12659.
  • _at_Celedon JC et al. Bronchodilator responsiveness
    and serum total IgE levels in families of
    probands with severe early-onset COPD. Eur Respir
    J 1999 141009.

26
Air Pollution
  • Increased incidence and higher mortality rates of
    COPD in industrialized urban areas.
  • Exacerbations of CB clearly related to periods of
    heavy sulfur dioxide pollution and particulates.
  • Nitrogen dioxide NOT implicated in human airways
    obstruction.

27
Occupational Exposures
  • Environmental dusts gold and coal miners
  • Organic antigens COPD is most common
    respiratory syndrome in agricultural workers, and
    there is a 10 prevalence of COPD among farm
    workers
  • Accelerated decline in lung function among
    plastics workers exposed to toluene diisocyanate
    and in carding room workers in cotton mills

28
Infection
  • Severe viral pneumonia in childhood may lead to
    small airways obstruction (SAO).
  • Mortality, morbidity, and frequency of ARI are
    higher in patients with chronic bronchitis.
  • The Rhinovirus is found more often during COPD
    exacerbationspathogenic bacteria, other viruses,
    mycoplasmas found as often between as during
    exacerbations. However there is increased chance
    of detecting bacteria if sputum purulent, and
    isolating new strain of bacteria may be
    associated with exacerbations._at_
  • Stockley RA et al. Relationship of sputum color
    to nature and outpatient management of acute
    exacerbation of COPD. Chest 2000 117 1638.
  • _at_Sethi S et al. New strains of bacteria and
    exacerbations of COPD. N Engl J Med 2002 347
    465.

29
Antioxidant Deficiency
  • Oxidizing radicals derive from cigarette smoke or
    may be released by phagocytes in the lung.
    Deficiencies of antioxidants vitamins may impair
    host defenses against oxidative radicals and
    permit tissue destruction leading to COPD.
  • Sanguinetti, CM. Oxidant/antioxidant imbalance
    role in the pathogenesis of COPD. Respiration
    1992 59 Suppl 120.

30
Molecular/Genetic Risk Factors
  • Protease/antiprotease
  • TNF-a gene polymorphisms
  • Microsomal epoxide hydrolase
  • Glutathione S-transferase P1
  • Transforming growth factor beta 1
  • Metalloproteinase dysregulation
  • Hersh, CP et al. Genetic association analysis of
    functional impairment in chronic obstructive
    pulmonary disease. Am J Respir Crit Care Med
    2006 173 977-984.

31
Protease/Antiprotease
  • Alpha 1- antitrypsin/elastase imbalance.
  • Alveolar macrophages from COPD patients express
    more matrix metalloproteinase (MMP)-9 than
    normals. Elevated MMP-9 is associated with an
    increase in degradation of elastin.
  • Russell RE et al. Release and activity of matrix
    metalloproteinase-9 and tissue inhibitor of
    metalloproteinase-1 by alveolar macrophages from
    patients with chronic obstructive pulmonary
    disease. Am J Respir Cell Mol Biol.
    2002283L867-L873.

32
TNF alpha gene polymorphisms
  • May influence host immune responses, increase
    inflammatory tissue damage, and favor the
    development of chronic bronchitis- a specific
    TNF-a polymorphism found in 19 CB vs. 5
    schoolchildren vs. 2 of controls
  • Huang SL et al. Tumor necrosis factor-alpha gene
    polymorphism in chronic bronchitis. Am J Respir
    Crit Care Med 1997 1561436

33
Microsomal epoxide hydrolase
  • Microsomal epoxide hydrolase (MEH) reduces highly
    reactive epoxide intermediates generated by
    smoking. The genotypes associated with decreased
    activity of MEH were found in 19 and 22 per cent
    of COPD patients vs. 6 controls
  • Smith CAD, Harrison DJ. Association between
    polymorphism in gene for microsomal epoxide
    hydrolase and susceptibility to emphysema. Lancet
    1997 350630.

34
Glutathione S-transferase P1
  • Glutathione S-transferase P1 aids in the
    detoxification of substances in cigarette smoke,
    and COPD may occur more frequently among persons
    with decreased activity of this enzyme by virtue
    of genetic polymorphisms.
  • Ishii, T et al. Glutathione S-transferase P1
    polymorphism in patients with chronic obstructive
    pulmonary disease. Thorax 1999 54693.

35
Transforming growth factor beta 1
  • Transforming growth factor beta 1 is a member of
    a large family of polypeptides involved in
    cellular growth, differentiation, and activation.
    Specific, single nucleotide polymorphisms of the
    gene encoding transforming growth factor beta 1
    have been associated with the development of COPD
    in smokers.
  • Wu, L et al. Transforming growth factor beta1
    genotype and susceptibility to chronic
    obstructive pulmonary disease. Thorax 2004
    59126.

36
Systemic Inflammation in Pathogenesis of COPD
  • COPD is a systemic disease.
  • Cytokines and other inflammatory markers are a
    response to cigarette smoke.
  • They circulate and may impact other diseases and
    symptoms, e.g. cardiac disease and cachexia.
  • Reduced lung function associated with increased
    levels of systemic inflammatory markers,
    including CRP, fibrinogen, WBCs, and TNF-alpha.
  • Gan WQ et al. Association between chronic
    obstructive pulmonary disease and systemic
    inflammation a systematic review and
    meta-analysis. Thorax 2004 59574.

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Elastic Recoil Pressure of the Lung
  • Provides radial support.
  • Major determinant of maximal expiratory flow.
  • Static recoil pressure of the lung is alveolar
    pressure minus pleural pressure.
  • Maximum expiratory flow rates represent a complex
    and dynamic interplay between airways caliber,
    elastic recoil pressures, and collapsibility of
    the airways.

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Lung Volumes and Capacities in COPD
  • RV increased
  • FRC is the volume at which inward recoil of lung
    outward recoil of chest wallloss of elastic
    recoil will increase FRC
  • TLC increased due to loss of elastic recoil
  • VC may be normal to decreased

44
Time Constants
  • Prolonged in all obstructive diseases due to
    increased airways resistance and/or increased
    compliance.
  • If sufficiently prolonged, there is insufficient
    time for expiration, progressively increasing
    lung volume, moving tidal breathing to a higher,
    less compliant portion of the P/V curve,
    increasing work of breathing.
  • The increased elastic recoil pressure associated
    with the higher end-tidal volume is termed
    auto-PEEP or intrinsic PEEP, and this represents
    and additional threshold load that must be
    overcome.

45
Vd/Vt
  • Areas of wasted ventilation and wasted blood flow
    in COPD
  • Some maintain increased minute volume, with
    normal to low pCO2, and relatively high pO2
  • Others may have less dyspnea, accepting higher
    pCO2 and a depressed pO2
  • Difference debated ventilatory drive related to
    peripheral or central chemoreceptor sensitivity
    or through other afferent pathways

46
Pulmonary Circulation Malfunctions
  • Regional maldistribution of blood flow
  • Abnormal pressure-flow relationships
  • Pulmonary hypertension often present
  • Reduced cross-sectional area due to anatomic
    changes and destruction of alveolar septae
  • Vessel constriction due to alveolar hypoxemia
  • Erythrocytosis also due to chronic hypoxemia

47
Clinical Correlates
  • Dyspnea and work capacity impairment
  • Emphysema usually greater impairment with less
    airways obstruction than chronic bronchitis
  • Usually dyspnea when FEV1lt50
  • Dyspnea at rest when FEV1lt25
  • CO2 retention and cor pulmonale often when
    FEV1lt25
  • Survival 20-30 live gt5years with CO2 retention

48
TORCH
  • Towards a Revolution in COPD Health
  • The TORCH Study Group. Eur Respir J 2004 24
    2006-210.

49
TORCH
  • Multicenter, randomised, double-blind,
    parallel-group, placebo-controlled
  • 6200 patients, mod-severe COPD
  • Salmeterol/fluticasone 500/50 vs. Salmeterol 50
    vs. Fluticasone 500 vs. placebo

50
TORCH preliminary results- to be published late
2006
  • 17 relative reduction in mortality over 3 years
    cf. placebo.
  • Reduced exacerbations of COPD by 25 cf. placebo.
  • Improved QOL by St. Georges Respiratory
    Questionnaire.
  • Despite reduced rate of excerbations overall,
    there was increased reporting of adverse events
    classified as LRI cf. placebo.
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