Chronic Obstructive Lung Disease Contemporary Issues in Management

1
Chronic Obstructive Lung Disease Contemporary
Issues in Management

• John Popovich, Jr., MD, MACP
• Chair, Department of Internal Medicine
• Henry Ford Hospital

2
Goals and Disclosures

• Goals
• Review the epidemiology, causal factors, and
  clinical aspects of chronic obstructive lung
  disease
• Provide new insights into traditional management
  of chronic obstructive lung disease
• Understand the rationale driving new approaches
  to treatment of chronic obstructive lung disease
• Disclosures
• None

3
What is COPD?

• Chronic obstructive pulmonary disease is a
  preventable and treatable disease that is
• Characterized by airflow limitation that is not
  fully reversible (FEV1/FVC ratio less than 70)
• Airflow limitation is usually both progressive
  and associated with an abnormal inflammatory
  response of the lungs to noxious particles or
  gases

4
What is COPD?

• Chronic obstructive pulmonary disease is
• A disease that primarily affects the lungs, but
  also produces significant systemic consequences
• Clinically characterized by chronic airflow with
  acute exacerbations (dyspnea, cough, sputum
  production)
• Exacerbations may be triggered by
  tracheobronchial infections or environmental
  exposures

5
COPDEpidemic, Lethal, and Indiscriminate

• COPD is highly prevalent
• 7-19 prevalence affecting an estimated 32
  million people in the Unites States and 280
  million people worldwide
• COPD is highly lethal
• The 4th leading cause of death in the United
  States (behind heart disease, cancer, and
  cerebrovascular disease)
• Of the six leading causes of death in the United
  States, only COPD has been increasing steadily
  since 1970
• COPD is indiscriminate
• Gender and racial gaps closing
• Fastest rising cause of death in Asia

6
Causes of Death in Patients with COPD
Lethal in many ways
Rabe K. N Engl J Med 2007356851-854
7
Expanding Service and Economic Burden

• Direct medical expenditures amounted to an
  estimated 14.7 billion in 1993 by 2002 this was
  estimated at 32.1 billion
• During 2000, COPD in the United States was
  responsible for the following
• 8 million physician office and hospital
  outpatient visits
• 1.5 million emergency department visits
• 726,000 hospitalizations for COPD
• 119,000 deaths
• Median annual costs of disease by stage of
  disease (Friedman et al. Unpublished data. 2000
• Mild, 2,000
• Moderate, 5,000
• Severe, 11,000
• Two thirds of costs related to exacerbations
  (Hilleman et al. Chest 20001181278-85)

8
The Risk of Disease

• Host Factors
• Genes
• alpha-1 antitrypsin deficiency
• SERPINA1 (alpha-1 AT) polymorphisms
• Genes of oxidative stress, mucins, inflammatory
  mediators
• Hyperresponsiveness
• Lung growth
• birth weight less than 5.5 pound
• maximally obtained lung function
• Nutrition
• n-3 fatty acids (protective)
• Socioeconomic status

• Exposure
• Tobacco smoke
• Primary
• Environmental tobacco smoke
• Occupational dusts and chemicals/fumes
• Multiple industries manufacturing and services
• 31 attribution in non-smokers 19 in smokers
• Environmental exposures- biomass fuel exposures,
  high altitude
• Indoor and outdoor pollution
• Infection
• Gender

9
Pathogenesis of COPD
An inflammatory cascade triggered by noxious
agents, stimulating epithelial cells and
alveolar macrophages, and lead by MCP-1
charged CD8 lymphocytes and IL-8 and leukotriene
B4 charged neutrophils
Barnes P. N Engl J Med 2000343269-280
10
Protease-Antiprotease Imbalance in COPD
Destructive
Protective
Barnes P. N Engl J Med 2000343269-280
11
Oxidative Stress in COPD
Protean inflammatory manifestations
Barnes P. N Engl J Med 2000343269-280
12
Systemic Inflammation in COPD

• Systemic inflammation in COPD is an independent
  risk factor for exacerbations and fatal
  hospitalizations
• Weight loss (decreased fat free mass)
• Skeletal muscle dysfunction
• Anemia
• Cardiovascular disease (pulmonary hypertension,
  cor pulmonale)
• Others
• Osteoporosis
• Depression and fatigue
• Cancer

Greeneweger KH, et al. Chest 2008 133 350-359
13
Mechanisms of Airflow Limitation in COPD

• Alveolar wall destruction with loss of
  elasticity small airways no longer tethered
  patent
• Destruction of pulmonary capillary bed
• Fibrosis and narrowing of airways (obliterative
  bronchiolitis

Barnes P. N Engl J Med 2000343269-280
14
Airflow Obstruction in COPD Irreversible and
Reversible

• Irreversible
• Fibrosis and narrowing of the airways-respiratory
  bronchiolitis
• Loss of elastic recoil due to alveolar
  destructions-emphysema
• Destruction of alveolar support that maintains
  patency of small airway
• Reversible
• Accumulation of inflammatory cells, mucus, and
  plasma exudate in bronchi- chronic bronchitis
• Smooth muscle contraction in peripheral and
  central airways
• Dynamic hyperinflation during exercise

Barnes P. N Engl J Med 2000343269-280
15
Diagnosis of COPD

• History of exposure to risk factors, especially
• Tobacco smoke
• Occupational dusts, fumes, chemicals
• Smoke from home cooking and heating fuels
• Chronic cough
• May be intermittent and may be unproductive
• Chronic sputum production
• Any pattern of chronic sputum production may
  indicate COPD

• Dyspnea
• Progressive (worsens over time)
• Usually worse with exercise
• Persistent and daily
• Described by patient as
• increased effort to breathe
• heaviness
• air hunger
• gasping

16
Dyspnea

• Exertional breathlessness presenting as an
  inability to perform tasks
• Degree of dyspnea correlates only indirectly with
  FEV1 reductions
• Physiological correlation with dynamic
  hyperinflation
• Air trapping with more rapid breathing
• PFT correlation with inspiratory capacity

Sutherland E and Cherniack R. N Engl J Med
20043502689-2697
17
Pulmonary Hyperinflation in COPD

• Independent from degree of airflow obstruction,
  major cause of symptoms and limitations in
  advanced disease
• Dyspnea with walking more correlative with
  dynamic hyperinflation than FEV1
• Estimate by inspiratory capacity/TLC ratio

Pinto-Plata VM, Cote C, Cabral H, et al. The
6-minute walk distance change over time and
value as a predictor of survival in severe COPD.
Eur Repir J 2004 1 28-33
18
Differential Diagnosis of COPD

• COPD
• Asthma
• Congestive heart failure
• Bronchiectasis
• Tuberculosis
• Obliterative bronchiolitis
• Diffuse panbronchiolitis

19
Why COPD is Often Undiagnosed

• Patient Issues
• Patients under perceive their complaints as
  smoking related
• Exercise limitations often attributed to be
  natural for a smoker
• Functional decline is insidious and allows
  compensatory exertional reduction (deal with
  exertion by not exerting)
• Physician Issues
• Inappropriate attribution of complaints
• Limitations of the history and physical
  examination to identify airflow obstruction

Bottom line alert to smoking history and
wheezing to trigger diagnosis
Smetana, G. W. JAMA 20072972121-2130.
20
Spirometry The Key to Diagnosis
Normal
COPD

• Perform spirometry in patients who have chronic
  cough and dyspnea with a history of exposure to
  risk factors
• COPD is defined as an FEV1/FVC , 70 and a post
  bronchodilator FEV1 lt 80

21
Further Thoughts about Spirometry

• FEV1
• Insensitive indicator of early chronic airflow
  obstruction
• Good predictor of subsequent decline
• Severity of COPD may not be accurately reflected
  by the FEV1 alone
• Reversibility of less than 15-important to
  exclude asthma as an underlying diagnosis
• Routine spirometry for COPD?
• No AHRQ, 2005
• Yes Ann Intern Med 2006 144 390-396

22
Further Thoughts about Spirometry

• Optimal frequency of spirometry for patients with
  COPD
• No clear guidelines or evidence
• Pragmatic recommendation of every two years
• Purpose of regular monitoring is staging and to
  identify patients with increasing severity of
  disease who may benefit from referral for more
  intensive treatments.

23
Factors Determining Severity of COPD

• Severity of symptoms
• Severity of airflow limitation
• Frequency and severity of exacerbations

• Presence of respiratory insufficiency
• Co-morbidity
• General health status, especially cardiac and
  nutritional
• Number of medications needed to manage the
  disease
• Presence of complications of COPD

24
Staging COPD

• Stage 0 (at risk)
• normal spirometry
• chronic symptoms of cough and sputum production
• chronic non-obstructive bronchitis
• Stage I (mild)
• FEV1/FVC lt 70
• FEV1 gt 80 of predicted
• With or without chronic symptoms (cough, sputum,
  dyspnea)

25
Staging COPD

• Stage II (moderate)
• FEV1/FVC lt 70
• FEV1 gt 30 and lt 80 of predicted
• IIA FEV1 gt 50 and lt 80of predicted
• IIB FEV1 gt 30 and lt 50of predicted
• With or without chronic symptoms (cough, sputum,
  dyspnea)
• Important stage for intervention

26
Staging COPD

• Stage III (severe)
• FEV1/FVC lt 70
• FEV1 lt 30 of predicted, or
• FEV1 lt 50 of predicted plus respiratory failure
  of clinical signs of right heart failure
• Identifies a group of patients likely to require
  oxygen, transplantation, lung volume reduction,
  or palliative/end-stage care

27
COPD Progression Is Not Scripted and Can Be
Changed

• Normal decline in lung function is less than 40
  cc/year
• Decline in lung function significantly more steep
  in patients with COPD and continued smoking
  history
• There is a decline in slope of reduction with
  smoking cessation (Lung Health Study)

28
Better Metrics for COPD?

• Inspiratory capacity (IC/TLC ratio)
• 6-minute walk distance
• Dyspnea measures (Medical Research Council scale)
• Health status
• St. Georges Respiratory Questionnaire
• Chronic Respiratory Questionnaire
• Multidimensional indices
• BODE index
• Acute exacerbations

29
BODE Index for COPD
Celli B et al. N Engl J Med 20043501005-1012
30

BODE Index versus COPD Stages of Severity

• Higher scores on the body-mass index, degree of
  airflow obstruction and dyspnea, and exercise
  capacity (BODE) index indicate a greater risk of
  death
• BODE quartiles by score
• Quartile 1 0 to 2
• Quartile 2 3 to 4
• Quartile 3 5 to 6
• Quartile 4 7 to 10

Celli B et al. N Engl J Med 20043501005-1012
31
Managing COPD

32
Five Components of COPD Management

• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Education
• Pharmacologic
• Non-pharmacologic
• Manage exacerbations
• Manage complex severe disease

33
Objectives of COPD Management

• Prevent disease progression
• Relieve symptoms
• Improve exercise tolerance
• Improve health status (QOL)
• Prevent and treat exacerbations
• Prevent and treat complications
• Reduce mortality-prolong meaningful life
• Minimize side effects from treatment

34
No Need for Therapeutic Nihilism

• Effective evidence-based therapy for survival
• Smoking cessation
• Long term oxygen therapy in hypoxemic patients
• Non-invasive mechanical ventilation in some
  patients with acute on chronic respiratory
  failure
• Lung volume reduction for patients with upper
  lobe emphysema and poor exercise capacity

35
No Need for Therapeutic Nihilism

• Effective evidence-based therapy for improved
  symptoms and quality of life
• Pulmonary rehabilitation
• Lung transplantation
• Improved lung function, health status and
  possibly relative risk of dying
• TORCH study of combined salmeterol and
  fluticasone inhaled therapy

36
Management of COPD
HEALTH MAINTENANCE
Sutherland E and Cherniack R. N Engl J Med
20043502689-2697
37
Managing Stable COPDHealth Care Maintenance

• All stages of COPD should be managed with
• Avoidance of noxious agents
• Smoking cessation
• Reduction of indoor pollution
• Reduction of occupational exposure
• Influenza vaccination
• Pneumococcal vaccination
• Healthy lifestyle choices, relating to exercise,
  nutrition, mind-body health, and general care
• Health education

38
Wrong Choice
Brandt A. N Engl J Med 2008359445-448
39
Reducing the RiskKey Points

• Reduction of total personal exposure to tobacco
  smoke, occupational dusts, and chemicals, and
  indoor and outdoor air pollutants are important
  goals to prevent the onset and progression of
  COPD
• Smoking cessation is the single most effective-
  and cost-effective-intervention to reduce the
  risk of developing COPD and stop its progression
  (Evidence A)

40
Strategies to Help the Patient Willing to Quit
Smoking

• ASK Systematically identify all tobacco users
  at every visit
• ADVISE
• Strongly urge all tobacco users to quit
• ASSESS Determine willingness to make an attempt
  to quit
• ASSIST
• Aid the patient in quitting

41
Strategies to Help the Patient Willing to Quit
Smoking

• Counseling
• Use combination of behavioral interventions and
  pharmacologic therapy
• The "maximum acceptable" behavioral therapy will
  often be a brief, office-based intervention
• Varenicline
• First line therapy
• Note safety concerns
• There is currently no evidence to support
  combination of other modalities with varenicline
  and until data are available, we suggest not
  combining varenicline with bupropion or with
  nicotine replacement therapy

42
Varenicline (Chantix) InformationFDA Alert,
February 1, 2008

• Serious neuropsychiatric symptoms have occurred
  in patients taking varenicline (Chantix)
  including
• changes in behavior
• agitation
• depressed mood
• suicidal ideation
• attempted and completed suicide.
• Although symptoms and events may be a result of
  nicotine withdrawal, some patients experienced
  serious neuropsychiatric symptoms and events
  despite continuing to smoke
• In most cases, neuropsychiatric symptoms
  developed during treatment, but in others,
  symptoms developed following withdrawal of
  varenicline therapy

43
Strategies to Help the Patient Willing to Quit
Smoking

• Nicotine replacement
• Buproprion
• Second line therapy
• Bupropion (especially in history of depression)
  or nicotine (any preparation) replacement if
  patients have not had success with varenicline
• Bupropion can be combined with multiple
  formulations of nicotine replacement,
  particularly an as-needed dosing formulation plus
  a transdermal system

44
Pneumococcal Vaccination and COPD

• Level "A" CDC recommendation but limited data in
  patients with COPD
• Clinical and laboratory studies have suggested
  that the currently approved vaccine is less
  effective in the population of COPD patients than
  in healthier patients
• To date no randomized-controlled trial of
  pneumococcal vaccination for COPD patients has
  demonstrated any beneficial effect
• New laboratory methods have been developed and
  more accurate determination of the immunogenicity
  of pneumococcal vaccines is now possible
• There is considerable interest in the development
  of an improved pneumococcal vaccine for patients
  with COPD
• Advances in vaccine design hold considerable
  promise for improved prevention against pneumonia
  and acute exacerbations caused by Streptococcus
  pneumoniae

Schenkein JG at al. Chest. 2008 133767-774.
45
Management of COPD
STEPWISE DRUG THERAPY
Sutherland E and Cherniack R. N Engl J Med
20043502689-2697
46
Managing Stable COPD

• The overall approach to managing stable COPD
  should be characterized by a stepwise increase in
  the treatment, depending of the severity of the
  disease
• None of the existing medications for COPD has
  been convincingly shown to modify the long-term
  decline in lung function that is the hallmark of
  the disease (Evidence A-Lung Health Study I).
  Therefore, pharmacotherapy for COPD is used
  primarily to decrease symptoms and/or
  complications

47
Managing Stable COPDBronchodilators

• Bronchodilator medications are central to the
  symptomatic management of COPD (Evidence A).
  They are given on an as needed basis or on a
  regular basis to prevent or reduce symptoms
• The principal bronchodilator treatments are
  beta2-agonists, anticholinergics, theophylline,
  and a combination of these drugs (Evidence A).
• The choice between drug therapy choices depends
  on availability and individual response in terms
  of symptoms relief and side effects

• Important Concepts
• Inhaled therapy is preferred
• Mucosal delivery leads to side effects, such as
  tremor
• MDI use may be difficult for older adults use
  spacer of nebulizer delivery
• Use short acting beta agonist drugs for rescue,
  on-the-go therapy
• Long acting bronchodilators are safe (e.g. once
  or twice daily nebulizer bronchodilators such as
  formoterol) are more effective than short acting
  drugs
• FEV1 changes maybe small with symptomatic benefit
  due to other mechanisms, e.g. decrease in lung
  hyperinflation

48
Managing Stable COPDTherapy Consider

• Appropriate dosing
• Ipratropium 2-4 puffs up to four times daily
  benefit when used in combination with albuterol
  (the COMBIVENT trial)
• LABA adverse QOL consequences of doses higher
  than recommended maximum
• Theophylline targeted ranges of 8-13 mg/dL,
  lower than prior recommendations
• Unproven therapeutic benefit to date
• Non-steroidal anti-inflammatory medications (e.g.
  cromolyn)
• Anti-interleukin 8
• Anti-tumor necrosis factor
• Leukotriene inhibitors (e.g., montelukast)
• Mucolytic agents (possible organic iodide)
• Antiprotease (unless alpha-1 antitrypsin
  deficiency)
• unless associated respiratory tract allergy or
  asthma coexistent

49
Toward Long Acting Bronchodilators

• Salmeterol versus ipratropium
• Prolonged bronchodilator effect of salmeterol
  (10-12 hours versus 4-6 hours)
• Decrease in exacerbation during the 12 week study
  period raising the question, is salmeterol
  cytoprotective?
• Tiotropium superior to ipratropium
• Decrease in exacerbations by 24 compared to
  ipratropium
• Meta-analysis favored benefits of long acting
  beta agonists or tiotropium in COPD exacerbations

Mahler et al. Chest 1999 115957-6 Casaburi et
al. Eur Respir J 200218217-224 Sin, D. D. et
al. JAMA 20032902301-2312
50
Managing Stable COPDBronchodilators
Yes supports an improvement in outcome Yes (A)
is supported by more than one randomized trial
Celli BR. Chest 20081331451-1462
51
Combined bronchodilator therapy?

• Long-acting beta-2 agonists in combination with
  theophylline
• Improved bronchodilation with combined salmeterol
  and theophylline than either alone, as well as a
  reduction in exacerbations in 1,000 patients
• Long-acting beta-2 agonists in combination with
  anticholinergics
• Improved bronchodilation with salmeterol or
  formoterol and ipratropium

ZuWallack et al . Chest 20011191347-56 van
Noord et al. Eur Respir J 2000181578-85 Durzo
et al. Chest 2001 1191247-56
52
Managing Stable COPDCombination Therapy
Yes supports an improvement in outcome Yes (A)
is supported by more than one randomized trial
Celli BR. Chest 20081331451-1462
53
Combined Long Acting Therapy in Moderate COPD

• Canadian tiotropium trial (OPTIMAL)
• Comparison of tiotropium plus placebo versus
  tiotropium and salmeterol or tiotropium with
  salmeterol and fluticasone
• Exacerbation rate the same but the tiotropium
  with salmeterol and fluticasone had better lung
  function, improved quality of life, and fewer
  COPD-related hospital admissions

Aaron SD, et al. Ann Intern Med 2007 146
545-55
54
Combined Long Acting Therapy in Moderate COPD

• Combination of two bronchodilators (e.g.
  tiotropium and LABA) if one is insufficient
• 605 patients studied
• Tiotropium plus formoterol was reported to have
  better 6 week daytime lung function than
  salmeterol/fluticasone in GOLD stages II and III

Rabe KF et al. Chest 2008 134255-262.
55
Tiotropium and Stroke

• FDA notified by the manufacturer of a possible
  increased risk of stroke in patients who take
  this medicine 
• Pooled data analysis of the safety data from 29
  placebo controlled clinical studies including
  approximately 13,500 patients with COPD. 
• preliminary estimates of the risk of stroke are 8
  patients per 1000 patients treated for one year
  with Spiriva, and 6 patients per 1000 patients
  treated for one year with placebo.  
• This means that the estimated excess risk of any
  type of stroke due to Spiriva is 2 patients for
  each 1000 patients using Spiriva over a one year
  period

56
Novel Pharmacological Treatment of COPD

• New long-acting agents
• New beta-2 agonists
• Arformoterol
• Carmoterol
• Indacaterol
• New anticholinergic agents
• GSK-233705
• Combination of long acting beta-2 agonists and
  anticholinergic agents

57
Novel Pharmacological Treatment of COPD

• Phosphodiesterase-4 (PDE4) inhibitors (e.g.,
  cilomilast, roflumiast)
• Actions
• Bronchodilator effect
• Anti-inflammatory effects on smooth muscles and
  neutrophils
• Pulmonary function effect
• Reduction in lung volume
• Reduction in hyperinflation

Gamble W. Am J Respir Crit Care 2002
165A227 Gamble et al Am J Respir Crit Care 2003
168976-982 Zamel et al. Am J Respir Crit Care
2002 165A226
58
Novel Pharmacological Treatment of COPD

• NAC (N-acetylcysteine)
• Provides cysteine for increased production of the
  antioxidant glutathione
• Meta-analyses and retrospective analyses
  suggesting oral NAC was associated with
  significant (22-29) reduction in acute
  exacerbations of chronic bronchitis or COPD or in
  readmission to hospital for COPD
• BRONCHUS study randomized trial showing NAC is
  ineffective at prevention of lung function
  decline or exacerbations

Poole et al BMJ 2001 3221271-1274 Decramer et
al, Lancet 2005 365 1552-60
59
Novel Pharmacological Treatment of COPD

• Stereoisomer agents (e.g. racemic albuterol)
• Separating the good twin from the bad
• Conflicting laboratory and clinical studies
• S-isomers are harmful in the laboratory but more
  inert in clinical studies

60
Inhaled CorticosteroidsGOLD COPD Guidelines

• Regular treatment with inhaled glucocorticosteroid
  s should only be prescribed for symptomatic COPD
  patients with documented spirometric response to
  glucocorticosteroids or in those with Stage IIB
  disease and repeated exacerbations requiring
  treatment with antibiotics and/or oral
  glucocorticosteroid
• Six week to three month trial should be
  considered

61
Inhaled CorticosteroidsEarly Support of Use in
COPD

• Fluticasone decreased rate of loss of quality of
  life and reduced frequency of exacerbations
  (Inhaled Steroids in Obstructive Lung Disease in
  Europe (ISOLDE) Trial
• Is there a mortality effect?
• Observational analysis of 22,620 Canadian
  patients
• 30 reduction in mortality in patients who were
  prescribed inhaled corticosteroids following
  admission to the hospital

Burge et al. BMJ 20003201297-1303 Sin et al. Am
J Respir Crit Care Med 2001164580-84
62
Benefits of Inhaled Steroid Therapy in Moderate
COPD

• TORCH Toward a Revolution in COPD
• 6,112 patients 3 year follow up
• Placebo versus salmeterol and/or fluticasone-no
  statistically significant mortality difference
• Benefits
• Decreased frequency of exacerbations placebo
  versus salmeterol and fluticasone-decreased (1.13
  to 0.85) annual exacerbations
• Decreased use of oral corticosteroids
• Protection against decline in lung function
  post hoc analysis suggests slowing of disease
  progression (39 mL/yr with combined therapy
  versus 55 mL/yr with placebo alone)
• Risk
• Increased rate of pneumonia

Calverley PM, et al. N Eng J Med 2007
316775-785 Celli BR, , et al. Am J Respir Crit
Care Med 2008 178 332-338
63
Benefits of Inhaled Steroid Therapy in Moderate
COPD

• No definitive comparative dosing studies of
  inhaled corticosteroids in COPD
• Most studies (ISOLDE, TORCH) have used high dose
  (e.g. fluticasone 1,000 mcg/day)
• Current data suggests optimal effectiveness is
  provided by combined inhaled corticosteroid and
  long acting beta-agonists

64
Whats the Bottom Line

• COPD is a heterogeneous disease with some
  heterogeneous response to inhaled corticosteroids
• Stepwise drug therapy based on staging is
  rational
• Short acting bronchodilator (s) for intermittent
  symptoms
• Single long acting bronchodilator if (1) is
  ineffective
• Decision point
• Combination of long acting bronchodilators in
  moderate disease (per OPTIMAL study), or
• Long acting beta agonist/inhaled corticosteroid
  combination with or without tiotropium if failure
  to achieve therapeutic goal, exacerbations, or
  positive response to n of 1 trial

65
Oral Steroids in COPD

• Use in moderate COPD
• 1991 Meta-Analysis
• Combined 10 Studies (299 patients)
• Rx 40 mg prednisone for 14 days
• Response ? 20 increase in FEV1
• Control 11 (29/256)
• Steroids 21 (54/256)

• Use in severe exacerbations (e.g. requiring
  hospitalization)
• Exact dose not known 30 to 40 mg of oral
  prednisolone daily to 7-14 days only
• Prolonged therapy provides no advantage
• Remember osteoporosis in patients with frequent
  courses

Callahan et al. Ann Intern Med 1991 114 216-23
66
Management of COPD
SUPPLEMENTAL THERAPY
Sutherland E and Cherniack R. N Engl J Med
20043502689-2697
67
Physical Activity in COPD

• All COPD patients benefit from exercise training,
  improving with respect to both exercise tolerance
  and symptoms of dyspnea and fatigue (Evidence A).
  
• Significant improvements in health-related
  quality of life reported by patients (Evidence A)
• Exercise rehabilitation does not improve
  pulmonary function (e.g. spirometry)
• General health benefits (cardiovascular fitness,
  weight control, depression)

68
Physical Activity in COPD

• Determination of contribution of pulmonary and
  extrapulmonary factors leading to reduced
  physical activity in COPD
• Two thirds of a spectrum of COPD patients have
  low physical activity
• Two thirds of variance related to degree of
  airflow obstruction
• One third of variance due to a combination of
  extrapulmonary factors (systemic inflammation,
  left cardiac dysfunction)
• Presence of nutritional depletion, depression,
  anemia, peripheral arterial disease, pulmonary
  hypertension, and/or peripheral muscle strength
  did not contribute significantly to physical
  activity variances.
• No improvements in whole body exercise and QOL
  with anabolic steroids, growth hormone, or
  phosphocreatine

Watz et al. Am J Respir Crit Care Med 2008
743-751
69
Pulmonary Rehabilitation

• Randomized trial of 100 patients receiving either
  standard care or six-month rehabilitation program
  
• No change in FEV1
• Significant improvement in six-minute walking
  distance
• Increased in the first six months then stabilized
  in the rehabilitation group
• Decline in control group
• Pronounced improvement in quality of life as
• measure by the Chronic Respiratory Disease
  Questionnaire (CRDQ)
• Basically the most effective intervention to
  improve exercise capacity and/or health in
  patients with COPD

• Troosters et al. Am J Med 2000 109207-12
• Sin, D. et al. JAMA 20032902301-2312

70
Oxygen Therapy

• Benefits of supplemental oxygen in hypoxemic
  (rest PaO2 lt 55 mm Hg) patients COPD
• Must be provided continuously (at least 20 hours
  a day) versus intermittently
• Nocturnal oxygen inadequate to achieve outcome
  improvements

NOTT Group Ann Intern Med 1980 93 391-8
71
Oxygen Therapy

• Benefits of supplemental oxygen in hypoxemic
  (rest PaO2 lt 55 mm Hg) patients COPD
• Improved survival (40), neuropsychiatric testing
  and exercise
• Reductions in polycythemia, pulmonary artery
  pressures, dyspnea, hypoxemia during sleep, and
  nocturnal arrhythmias

NOTT Group Ann Intern Med 1980 93 391-8
72
Oxygen Therapy Few More Points

• Benefits of supplemental oxygen in
• exercising patients (SaO2 lt 88) with COPD
• Improved exercise performance
• No survival improvement
• Does not predict nocturnal desaturation
• Diffusing capacity gt 55 of predicted was 100
  specific in excluding exercise desaturation

Cell BR. Chest 2008 23932-946 www.oqp.med.va.go
v
73
Oxygen Therapy Few More Points

• Hypercapnia (gt 45 mm Hg) during the day predicts
  a high prevalence of nocturnal desaturation
  detect by one overnight oximetry study
• Up to 40 of patients will no longer require
  oxygen when retest 1 to 3 months after initiation
  of therapy
• One area where pulmonary specialist referral can
  assist in management

Celli BR. Chest 2008 23932-946 www.oqp.med.va.g
ov
74
Managing Exacerbations of COPD

• Exacerbations in respiratory symptoms requiring
  medical intervention are important and costly
  clinical events in COPD
• Nearly half of patient discharged from hospital
  for exacerbations are readmitted more than once
  within 6 months

• Inhaled bronchodilators, theophylline, and
  systemic (oral or intravenous) glucocorticosteroid
  s are effective for the treatment of COPD
  exacerbations
• Systemic corticosteroids should not be used for
  more than two weeks (unless there is very good
  reason)

75
Management of Acute Exacerbation of COPD
The importance of stage of disease
Celli, B. R. JAMA 20032902721-2729
76
Optimal Management Exacerbations of COPD

• Quality of patient care for patients hospitalized
  for acute exacerbations may be improved by
  increasing the use of systemic corticosteroid and
  antibiotic therapy, decreasing use of unnecessary
  and harmful treatments, and reducing variation in
  practice across hospitals

• Unnecessary and harmful treatments included
  methylxanthine bronchodilators, sputum testing,
  acute spirometry, chest physiotherapy, and
  mucolytic medications
• Only a third of nearly 70,000 US patients
  received ideal care

• Lindenauer et al. Ann Intern Med 2006
  144894-903

77
Antibiotics in Acute COPD Exacerbation

• Patients experiencing COPD exacerbations with
  clinical signs of airway infection (e.g.,
  increased volume and change in color of sputum,
  and/or fever) may benefit from antibiotic
  treatment (Evidence B)
• Appropriate use of antibiotics in acute
  exacerbations of COPD is imperative to help
  control the emergence of multidrug-resistant
  organisms

Saint et al. JAMA 1996 273 957-60
78
Exacerbations of COPDThe Role of Bacteria

• Exacerbations in chronic obstructive pulmonary
  disease are frequently associated with a new
  strain of a bacterial pathogen, using molecular
  typing
• Isolation of a new strain of H. Influenza, M.
  catarrhalis, or S. pneumoniae was associated with
  a significantly increased risk of an exacerbation
• Newer studies suggest a change in strain of
  bacteria creates more intense inflammatory
  response in COPD

Sethi S et al. N Eng J Med 2002
347465-471 Sethi et al, Am J Respir Crit Care
Med 2008 177291-497
79
Novel Pharmacological Treatment of COPD

• Macrolides
• Actions
• Bactericidal effects
• Inhibition of neutrophil oxidative bursts
• Reduce IL-6 and IL-8
• Impact on lipopolysaccharide damage and mucous
  hypersecretion
• Application of chronic macrolide therapy is
  subsets of patients with progressive airflow
  obstruction and mucous hypersecretion
• No randomized studies to support use at this time

80
Unexplained Exacerbation in COPD

• Unexplained exacerbation of COPD think- pulmonary
  embolism?
• No
• 6 incidence in this population
• No indication for routine evaluation for PE
• Yes
• 19-29 incidence reported
• Reasonable to maintain high level of clinical
  suspicion
• Most important in patients without signs of overt
  infectious causation of the exacerbation
• Important to re-evaluate patients not responding
  to COPD therapy

Wedzicha JA, Hurst JR. Thorax 2007 62
121-125 Tillie-Leblond I, et al. Ann Intern Med.
2006 144 390-6 Qaseem A et al. Ann Intern .
2007 146 454-8
81
Non-invasive Ventilation

• Noninvasive intermittent positive pressure
  ventilation (NIPPV) in acute exacerbations
  improves blood gases and pH, reduces in-hospital
  mortality, and decreases the need for invasive
  mechanical ventilation and intubation, and
  decreases the length of hospital stay (Evidence
  A)

Brochard et al, N Eng J Med 1995333817-822
82
Non-invasive Ventilation

• Mode is synchronized
• Pressure targeted modes most frequent
• Generally provided for only a few hours per day
• Controversy about the use on general nursing
  wards need for specialized nursing
• Note the contraindications relating to airway,
  secretions, mental status, and severity

Girou, E. et al. JAMA 20032902985-2991 Plant et
al. Lancet 2000 3551931-1935
83
Quality Indictors in COPD
ACP Clinical Practice Guidelines-2007
COPD HEDIS Indicators-2008

• Screen patients with spirometry only if symptoms,
  especially with dyspnea (note USPSTF
  recommendation, 2008)
• Treat only those with symptoms and FEV1 less than
  60 predicted
• Treat with monotherapy and consider combination
  therapies
• Prescribe oxygen for those with resting hypoxemia
  (PaO2 less than 56 mm Hg
• Consider pulmonary rehabilitation in those with
  symptoms and FEV1 less than 50 predicted

• Use of spirometry testing in the assessment and
  diagnosis of COPD
• Ages 40 and older
• Adults with a new (within the measurement year)
  diagnosis or newly active COPD who received
  spirometry testing to confirm the diagnosis.
• Spirometry testing must occur 730 days prior to
  or 180 days after the diagnosing event.
• Pharmacotherapy Management of COPD exacerbation
• Adults aged 40 or older by December 31 of the
  measurement year who had an acute inpatient
  discharge or an ED encounter with a principal
  diagnosis of COPD who were dispensed both
• A systemic corticosteroid within 14 days of
  discharge
• Bronchodilator within 30 days of discharge

NOTE the eligible population for this measure is
based on the discharges and ED visits, not the
patient. It is possible for the denominator for
this measure to include multiple events for the
same patient
84
Approach to Inhomogeneous Emphysema

• Evolution in thinking about approaches to
  management
• Surgical lung volume reduction
• NETT trial
• Confirmation of benefits of surgical resection of
  areas of heterogeneous emphysema
• Benefit offset by surgical morbidity/mortality
• Endobronchial valve placement

85
Patient Selection COPD for Lung Volume Reduction

• Hyperinflation
• Total lung capacity gt120 predicted
• Residual volume gt150 predicted
• Severe obstruction
• Forced expiratory volume in 1 second (FEV1) lt40
  but higher than 20 predicted
• Inhomogeneous emphysema by computed tomography
  and by scintillographic scan
• Able to complete pulmonary rehabilitation
• Decreased exercise capacity due to ventilatory
  limitation
• Lack of important hypercapnia (arterial carbon
  dioxide partial pressure PaCO2 lt55 mm Hg)
• Absence of pulmonary hypertension and no
  clinically important bronchiectasis
• Receiving lt10 mg/d of corticosteroids
• No alpha 1-antitrypsin deficiency

86
Surgical Treatment of COPD

• National Emphysema Treatment Trial Research Group
  (NETT)
• Improvements in lung mechanics, exercise,
  quality of life, and mortality in patients with
  upper lobe predominant, inhomogeneous emphysema
  and exercise intolerance
• Risk of death high in patients with low FEV1,
  DLCO, and homogeneous emphysema

Goal to resect 20-35 per cent of lungs
N Eng J Med 20033482059-2073
87
Endobronchial Valve Treatment of COPD

• Valve for Emphysema palliatioN Trial (VENT)
• One way valve allowing air to exit but not
  reenter from the lung parenchyma
• Safe procedure with minimal morbidity
• Questions to answer regarding efficacy, patient
  selection criteria, optimal number of valves, and
  areas of deployment

88
Endobronchial Valve Treatment of COPD
Expiratory view
Inspiratory view
89
Endobronchial Treatment of COPD

• Infusion of endobronchially delivered biological
  reagent to remodel and shrink emphysema
• Phase 1 trial reagents create fibrin hydrogel,
  promoting atelectasis, inflammation, and
  remodeling

• Reilly et al. Chest 20071311108

90
Questions?