COPDROBBY AYOUB MD, FCCP

ORANGE COUNTY CRITICAL CARE & PULMONARY

DISCLOSUREO SPEAKER FOR FOREST

PHARMACEUTICAL

OBJECTIVEO •  To review the definition of COPD that describes this

disease as an airway and systemic inflammatory condition. O •  To explore the impact of COPD including morbidity and

mortality. O •  To review the risk factors for COPD. O •  To explore the natural history of COPD O •  To explore the current understanding of the

pathophysiology of COPD: the pathologic consequences of airway inflammation and parenchymal lung destruction.

O •  To explore the systemic consequences of the disease and the co-morbidities associated with COPD.

O •  To review the current state of pharmacologic and non-pharmacologic therapy for COPD including preventive measures such as smoking cessation.

GOLD Definition of COPD

O • COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients.

O • Its pulmonary component is characterised by airflow limitation that is not fully reversible.

O • The airflow limitation is usually progressive and

O associated with an abnormal inflammatory O response of the lung to noxious particles or

gases. O GOLD 2007

STAGINGO The initial Global Initiative for Chronic Obstructive

Lung Disease (GOLD) guidelines used the FEV1 (expressed as a percentage of predicted) to stage disease severity. However, the FEV1 only captures one component of COPD severity, and two patients with the same percent predicted FEV1 can have a substantially different exercise tolerance and prognosis. Other aspects of disease, such as the severity of symptoms, risk of exacerbations, and the presence of comorbidities, are important to the patient’s experience of the disease and prognosis and are included in newer staging systems, such as the revised GOLD classification

2006 GOLD Classification of COPD Staging by Spirometry

O Stage I: Mild O FEV1/FVC < 0.70

FEV1 > 80% predicted

O Stage II: ModerateO FEV1/FVC < 0.70

50% < FEV1 < 80% predicted

O Stage III: Severe O FEV1/FVC < 0.70

30% < FEV1 < 50% predicted

O Stage IV: Very Severe O FEV1/FVC < 0.70

FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

O www.goldcopd.com

STAGINGO Several tools for evaluating symptom severity have

been proposed. The GOLD guidelines suggest using instruments such as the modified Medical Research Council (mMRC) dyspnea scale, the Clinical COPD Questionnaire, or the COPD Assessment Tool (CAT) [7.

O In our practice, we typically use the mMRC scale. O The most widely used tool, the St. George's

Respiratory Questionnaire (SGRQ), is a 76 item questionnaire that includes three component scores (ie, symptoms, activity, and impact on daily life) and a total score.O While valuable for research purposes in patients with

COPD, asthma, and bronchiectasis, it is too long and complicated for use in routine clinical practice

STAGINGO Modified Medical Research Council (MMRC) dyspnea scale:

O Grade Description of breathlessness: O 0 I only get breathless with strenuous exercise O 1 I get short of breath when hurrying on level ground or

walking up a slight hill O 2 On level ground, I walk slower than people of the same age

because of breathlessness, or have to stop for breath when walking at my own pace

O 3 I stop for breath after walking about 100 yards or after a few minutes on level ground

O 4 I am too breathless to leave the house or I am breathless when dressing

O Adapted from: Fletcher CM, Elmes PC, Fairbairn MB, et al. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. British Medical Journal 1959; 2:257.

ATS/ERS Classification of COPD Staging by Spirometry

SEVERITY FEV1/FVC % pred

Post-bronchodilator FEV1

At risk(Smokers, +family hx, etc)

>0.7 ≥80

Mild COPD ≤0.7 ≥80

Moderate COPD

≤0.7 50-80

Severe COPD ≤0.7 30-50

Very severe COPD

≤0.7 <30

QUESTION 1O 53 year old man presented with

a 3 year history of shortness of breath on exertion. He had asthma as a child and was a smoker for 20 years. Pulmonary function testing showed a moderately severe degree of obstruction. Which of the following tests have been shown to distinguish asthma from COPD?

QUESTION 1O Which of the following tests best

distinguish asthma from COPD? O a) Bronchial inhalation challenge

with methacholine O b) An FEV1 response to a short

acting beta agonist of > 12% improvement (and > 200 cc increase)

O c) Measurements of lung volumes (TLC, FRC, RV)

O d Sputum eosinophil count

Distinguishing Asthma and COPD

O Both may lead to fixed airflow obstruction but most show reversibility to short-acting bronchodilators

O •  Differences in lung function tests (diffusing capacity, residual volume, PaO2) statistically significant but there is large overlap

O •  COPD has higher emphysema score on HRCT

O •  Exhaled NO higher in asthmatics but there is overlap

O •  Asthmatics have significantly more eosinophils in the peripheral blood, sputum and BAL

COPD and ASTHMA: Different Diseases

COPD ASTHMA

• Affects elderly, especially smokers • Slowly progressive • Inflammatory cells – Neutrophilic bronchitis – Eosinophils during exacerbation • Partially reversible• Airway remodeling and Lung destruction

• Affects all ages, especially childhood • Episodic course• Inflammatory cells – Eosinophilc bronchitis– Neutrophils in severe disease • May be fully reversible • Airway remodelling no destruction

COPD and ASTHMA: Different Diseases

O “Overlap syndrome” O Some patients with asthma

cannot be distinguished from COPD with the current diagnostic tests.

O The management of these patients should be similar to that of asthma.

O ATS Guidelines 2004

Distinguishing Asthma and COPD

O Sputum Eosinophils >4.6% distinguish the 2 diseases

O Exhaled NO is not able to distinguish O Fabbri et al AJRCCM 2003;167:418-

24

O Nearly 2/3 of patients with severe COPD (mean FEV1 39.3% pred) respond to bronchodilators* (15% or 12% & 200 ml increase in FEV1)

O Tashkin DP, et al. Eur Respir J.2008;31:742-750.

Distinguishing Asthma and COPD

O Majority of COPD patients show Reversibility (Response to Albuterol or Ipratropium) O Albuterol and Ipratropium 35% O Albuterol 27% O Ipratropium 11% O Not reversible to either drug 27%

O Mahler D 1999 Chest;116:1137

Bronchial Hyperresponsiveness (BHR) and COPD

O 63% of men and 87% of women show BHR ( >= 20% fall in FEV1 with<= 25 mg/mL methacholine, indicating airway hyperresponsiveness (AHR)

O •  BHR has negative prognosis: associated with accelerated decline in FEV1 over time

O •  BHR associated with increased mortality O •  Smoking cessation has positive effect on

BHR & improves FEV1 greater in those with BHR

O Tashkin D et al Am Rev Respir Dis 1992; 145(2 Pt 1):301-10

O Wise RA et al Chest 2003;124:449-58

QUESTION 2O A 34 year old patient who

smokes 1-2 packs of cigarettes a day is finding it difficult to quit. His pulmonary function tests show GOLD Stage I disease. He is clinically well and has a negative past medical history. Which statement is most correct about this man with a normal FEV1?

QUESTION 2O a) BAL would show a normal

values for alveolar macrophages and neutrophils at this early stage of disease.

O b) Bronchial biopsy would show submucosal collections of neutrophils (microabscesses)

O c) CD4+ cells are the predominant lymphocytes found on bronchial biopsy

O d) Small airways show hyperplasia of goblet cells and mucous gland hyperplasia

COPD PATHOLOGYO Airways abnormalities in COPD include:

O chronic inflammationO increased numbers of goblet cellsO mucus gland hyperplasiaO fibrosisO narrowing and reduction in the number

of small airwaysO and airway collapse due to the loss of

tethering caused by alveolar wall destruction in emphysema.

COPD PATHOLOGYO Among patients with chronic bronchitis

who have mucus hypersecretion, an increased number of goblet cells and enlarged submucosal glands are typically seen.

O Chronic inflammation in chronic bronchitis and emphysema is characterized by the presence of CD8+ T-lymphocytes, neutrophils, and CD68+ monocytes/macrophages in the airways.

O The Greater the CD8+ Infiltration, the Greater the Airway Obstruction

Photomicrograph showing leukocyte infiltration in a small airway of a smoker with severe COPD (A);

and that of smoker with a mild COPD (B). Immunostaining with monoclonal antibody anti-CD45.

 Leukocytes are stained in red.

ASTHMA PATHOLOGYO In comparison, the bronchial

inflammation of asthma is characterized by the presence of CD4+ T-lymphocytes, eosinophils, and increased interleukin (IL)-4 and IL-5

PATHOLOGY OF ASTHMA AND COPD

QUESTION 3O A 35 year old man is referred because of

dyspnea and airflow obstruction with an FEV1 of 1.5 L (40% predicted). There is no reversibility after an inhaled short-acting bronchodilator. He never smoked but has a history of poorly controlled atopic asthma as a child. There have been no recent asthma attacks but has had many attacks of acute bronchitis in recent winters. Which of the following statements is correct regarding his COPD?

QUESTION 3O Which statement is correct? O a) Alpha-1 antitrypsin deficiency is the

most likely cause of his poor lung function O b) Exposure to parental smoking causes

recurrent bronchial infections but does not lead to lower lung function in early adulthood

O c) Childhood asthma is not a likely cause of his irreversible airflow obstruction

O d) His work as a battery factory worker (cadmium fumes) may have caused COPD in this patient

PATHOGENESIS OF COPD

O NOXIOUS PARTICLES LUNG INFLAMMATIONPROTEINASES COPD PATHOLOGY

Proteinases in COPD

O •  Proteinases involved in alveolar wall destruction

O •  Smokers have high levels of neutrophil elastase (NE) in BAL fluid; & higher when emphysema present

O •  NE degrades elastin in elastic tissue O •  Matrix metalloproteinases (MMP’s)

can degrade all O elements of extracellular matrix O •  Collagen breakdown and synthesis is

also a feature of emphysema

Proteinases in COPD O An imbalance between

neutrophil elastase in the lung, which destroys elastin, and the elastase inhibitor, alpha-1 antitrypsin (AAT), which protects against proteolytic degradation of elastin, causes early COPD in smokers

Alpha-1 Antitrypsin Deficiency

O •  Major manifestation is pan-acinar emphysema- possibly asthma, bronchiectasis

O •  1-3% of patients with COPD O •  Protective threshold level= 11

mcmol/L O •  COPD occurs later in non-

smokers ( 5th decade and beyond): other risk factors are pneumonia, chest colds, wheezing

Alpha-1 Antitrypsin Deficiency

O • Early-onset emphysema< 45 years O • Lower lobe bullae/emphysemaO • Unexplained liver diseaseO • Necrotizing panniculitis O • C-ANCA positive vasculitisO • Family history of COPD,

bronchiectasis, panniculitis O • Unremitting asthma with airflow

obstructionO • No obvious risk factor

Occupational COPD

O •  Dust exposure higher risk than gas/fumes

O •  Effects of dust exposure only found in smokers/ ex-smokers

O Relative Risk of COPD From Smoking and Dust Exposure

O •  Exceptions include: Isocyanate exposure, Bioaerosols (endotoxin), Grain handlers, Cotton workers, Coal workers

O •  Cadmium Fumes cause Emphysema

Occupational COPD High Risk Jobs

O • textiles/tailoring O • constructionO • cement workO • transport O • cotton processing O • furnaceO • wood/paperO • farmingO • miningO • grain handling

Risk Factors for COPD in Childhood

O Impaired growth of lung function during childhood and adolescence, can be caused by recurrent infections and parental smoking and this may lead to lower lung function in early adulthood

O Wang et al Am J Respir Crit Care Med. 1994;149:1420-5.

COPD Caused by Environmental Tobacco Smoke (ETS)

O •  Environmental exposure has been linked to causing asthma in children and adults

O •  Higher cumulative lifetime home and work exposure is also associated with a greater risk of developing COPD

O •  ETS exposure may be an important cause of COPD; the higher the exposure the higher the risk

O Eisner et al Environ Health. 2005;4:7

QUESTION4O A 65 year old man, smoker of 1-2

packs of cigarettes a day, has GOLD Stage III COPD. He complains of chronic cough and dyspnea and has 2-3 exacerbations of his symptoms each year treated at home with oral antibiotics and corticosteroids. Which statement is true about this man?

QUESTION4O Which statement is correct? O a) Unlike asthma, bacterial infections and

not viral infections are the cause of his exacerbations

O b) The frequency of his exacerbations is likely to worsen as his lung function deteriorates

O c) Recovery of lung function occurs within 2 days following an exacerbation

O d) Frequent COPD exacerbations have worsened his quality of life but do not accelerate the decline of lung function

IN COPDO Frequency Increases with Declining FEV1

O Donaldson GC, Wedzicha JA. Thorax. 2006;61:164-168.

O Pulmonary Function Recovers Slowly After an Exacerbation

O Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.

O Frequent Exacerbations Are Associated With More Rapid Decline in Pulmonary Function

Donaldson GC, et al. Thorax. 2002;57:847-852.

Infectious Agentsin COPD Exacerbations

O Bacteria 40%–50% O H. influenzae S. pneumoniae M.

catarrhalis O Viruses 30%

O Influenza Parainfluenza Rhinovirus RSV

O Other 10%–25% O Air pollution, eg

O Atypical bacteria 5%–10% O C. pneumoniae

Viral Infection and the COPD Exacerbation

O •  Investigated the role of viral infection in the exacerbation of COPD using PCR technology

O •  39% were associated with viral infection O •  Inflammatory markers high (IL-6,

fibrinogen) O •  Viral infections asociated with more

severe symptoms and longer duration of illness (13 d)

O •  Rhinovirus was predominant virus (58%) O Seemungal et al AJRCCM 2001; 164:1618-1623