COPD: Epidemiology, Pathogenesis,

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COPD Epidemiology, Pathogenesis,
Pathophysiology

• Wyatt E. Rousseau, MD
• May 11, 2006

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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.

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COPD Definitions/Terms

• Simple chronic bronchitis
• Asthmatic bronchitis/Chronic asthmatic bronchitis
• Chronic obstructive bronchitis small airways
  disease
• Pulmonary emphysema

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Simple chronic bronchitis

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

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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.

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Obstructive Chronic Bronchitis

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

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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.

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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.

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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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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

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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

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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

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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.

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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

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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

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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

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TORCH

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

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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

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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.