Thoracic Medicine

CGMH, Chiayi

Obstructive Airway Disease

( Asthma & COPD )

黃東榮 MD, PhD, 嘉義長庚醫院 呼吸胸腔科

Obstructive airway diseases Thoracic Medicine
CGMH, Chiayi

CHRONIC. ASTHMA
BRONCHITIS
?
CHRONIC
BRONCHIOLITIS

EMPHYSEMA

IRREVERSABLE REVERSABLE
 Asthma and COPD
Thoracic Medicine
CGMH, Chiayi

 Similar clinical presentation?

 Similar pathophysiology?
 Similar management?
 Similar clinical Presentation Thoracic Medicine

between Asthma and COPD

CGMH, Chiayi

 Episodic bronchospasm (esp. acute exacerbation)

 Nocturnal variability of airflow limitation

 Associated symptoms:
cough, sputum, wheezing, dyspnea
 Similar risk factors for acute exacerbation:
infections, air-borne stimulants
 Complication:
 Simlilar Pathophysiology Thoracic Medicine
CGMH, Chiayi

between Asthma and COPD

 Chronic airway inflammation

 Airway obstruction
 Respiratory failure
Global INitiative for
Asthma, GINA
The 1st Edition:
1993, WHO, NIH/NHLBL
⇒ The latest revision
December 2006

Revised
2006
 Definition

Asthma (2006, NIH/NHLBL)

(Global INitiative for Asthma, GINA)
• Chronic inflammatory disorder
• Many cells and cellular elements
• Bronchial hyperresponsiveness (BHR, AHR)
• Recurrent episodes of symptoms
• Widespread, variable , and often reversible
airflow limitation
Pathophysiology: Asthma Thoracic Medicine
CGMH, Chiayi
Mechanisms: Asthma
Inflammation

Source: Peter J. Barnes,

MD
Components of the immune response
Antigen
processing

Cellular
immunity

Epithelium
defense barrier

Neurogenic
inflammation

ASM
Remodelling
Air pollutants, Chemicals
 Thoracic Medicine
CGMH, Chiayi

• Normal airway
• Asthmatic airway
 Pathophysiology: Asthma
Thoracic Medicine
CGMH, Chiayi

Airway remodeling
Thickening
of basement
membrane
(BM)
↑mucous
glands Hypertrophy
& hyperplasia

↑extracellular Neovascularisation
matrix (ECM)
Global Initiative for Chronic
Obstructive Lung Disease
Thoracic Medicine
CGMH, Chiayi

In collaboration with:
National Heart, Lung, and
Blood Institute, NIH
and
World Health Organization
Aug, 2005
 Definition Thoracic Medicine
CGMH, Chiayi

Chronic obstructive pulmonary

disease (COPD) (GOLD 2005)
 A disease state characterized by airflow
limitation that is not fully reversible.
 The airflow limitation is usually both
progressive and associated with an
abnormal inflammatory response of the
lungs to noxious particles or gases.
Pathophysiology: COPD Thoracic Medicine
CGMH, Chiayi

Noxious particles
and gases
Host factors

Lung inflammation
Anti-oxidants Anti-proteinases

Oxidative stress Proteinases

Repair mechanisms

COPD pathology
CELLULAR MECHANISMS OF COPD
Perforin
Granzyme B Cigarette smoke
TNF-α
? Alveolar macrophage
CD8 +
MCP-1
lymphocyte
Neutrophil chemotactic factors
Cytokines (IL-8)
Mediators (LTB4)

Neutrophil

PROTEASE Neutrophil elastase

PROTEASES MatrixCathepsins
INHIBITORS
- metalloproteinases

Alveolar wall destruction Mucus hypersecretion

(Emphysema) (Chronic bronchitis)
PROTEASE-ANTIPROTEASE IMBALANCE IN COPD

α 1-Antitrypsin
SLPI
Elafin
Neutrophil elastase TIMPs
Cathepsins
MMP-1, MMP-9, MMP-12
Granzymes, perforins
Others……..
Free Radicals in COPD
 Pathophysiology: COPD
COPD Airways

Epithelial
metaplasia
Goblet cell
hyperplasia
Fibrosis
A Diffuse Small Airway Disease
reversible irreversible
 Pathological Characteristics
of COPD Patients

Need more time to empty their alveoli

Prolonged expiratory phase

A large fraction of lung volume

retained in the lungs (air-trapping)
Air-Trapping in COPD

Increased A-P diameter

Increased Lung volume at end-expiration

Flattening diaphragm
Decreased contractility of diaphragm
Increased Breathing Work in COPD
Inspiratory
IRV effort

IRV
IRV VT

VT

VT

ERV

ERV
ERV Air-Trapping
No enough expiratory time to return to ERV
 Exercise capacity in COPD

75 n = 41 75 n = 41
r = 0.56 r = 0.66
p = 0.0002 p < 0.0001
50 50

FEV1 %
FEV1%

25 25

0 0
0 100 200 300 400 500 600 700 50 60 70 80 90 100
Walking Distance (meters) O2 Saturation (end of exercise)

Relation of six-minute walking with pulmonary function and ventilatory drive

in patients with airflow limitation
Chang Gung Medical J. 2001
 Quality of life in COPD
COPD
bronchospasm Airway inflammation

Loss of recoil Airway narrowing Abnormal gas exchange

Hyperinflation

Muscle wasting

Breathlessness Exercise limitation

Disability
Social withdrawl
Depression and anxiety
 Differential diagnosis Thoracic Medicine
Overview: Clinical aspects & lung function CGMH, Chiayi

COPD Asthma
• Affects elderly, • Affects all ages,
especially smokers including children
• Slowly progressive • Episodic course
• Partially reversible • Fully reversible
• AHR: ± ≈
• AHR: often +
• Lung volume: 10% • Lung volume:
hyperinflation variable
• Diffusion: decrease • Diffusion: normal
• Chest X-ray: • Chest X-ray:
hyperinflation normal

Wheezy bronchitis
Adapted from Barnes PJ. Chest 2000;117(suppl):10S
 Differential diagnosis Thoracic Medicine
Overview: Inflammatory cells and mediators CGMH, Chiayi

COPD Asthma
• Inflammatory cells • Inflammatory cells
–Neutrophils –Eosinophils
–Macrophages –Mast cells
–CD8+ cells –CD4+
• Mediators
≈
–Macrophages
–IL-8 10% –Neutrophils
–TNF-a • Mediators
–LTB4 –Th2 cytokines
–Eotaxin
–LTC4-E4

Wheezy bronchitis
Adapted from Barnes PJ. Chest 2000;117(suppl):10S
 Thoracic Medicine
CGMH, Chia-Yi

10/23/08
 Thoracic Medicine
CGMH, Chiayi

10/23/08
 Similar Management? Thoracic Medicine
CGMH, Chiayi

between Asthma and COPD

 Oxygen
 Theophyllines
 Bronchodilators
 Corticosteroids
 Avoidance of inhaled stimulants
 Thoracic Medicine

Current Therapy for

CGMH, Chiayi

Asthma - GINA
Asthma Management and Prevention
Program: Five Components

1. Develop Patient/Doctor
Partnership
2. Identify and Reduce
Exposure to Risk Factors
3. Assess, Treat and Monitor
Asthma
4. Manage Asthma
Exacerbations
Revised
2006

5. Special Considerations
 Asthma Management and Prevention Program
Component 1: Develop Patient/Doctor Partnership

 Educate continually
 Include the family
 Provide information about asthma
 Provide training on self-management skills
 Emphasize a partnership among health
care providers, the patient, and the patient’s
family
Patient education program in Singapore
Prabhakaran et al, Singapore med J. 2006, 47(3):225-31

 97 hospitalized patients in one year

 30 dropped out
Patient education program in Singapore
Prabhakaran et al, Singapore med J. 2006, 47(3):225-31
Patient education program in Singapore
Prabhakaran et al, Singapore med J. 2006, 47(3):225-31
 Patient education Thoracic Medicine
CGMH, Chiayi

 Nation-wide campaign:
 1980s: New Zealand, Australia, National
Asthma Council
 China: 2001, Easy Asthma mnagement
2002, Breathe Easy Centres
 Korea: 2003, Korea Asthma Foundation
 Taiwan: 2003, Asthma Watch; Asthma Grid
 Web-based net
 Government support ( 國家高速電腦網路 )
 Asthma Management and Prevention Program
Component 2: Identify and Reduce
Exposure to Risk Factors
 Reduce exposure to indoor allergens
 Avoid tobacco smoke
 Avoid vehicle emission
 Identify irritants in the workplace
 Explore role of infections on asthma
development, especially in children and
young infants
 Asthma Management and Prevention Program
Component 2: Identify and Reduce
Exposure to Risk Factors

避開或掌控氣喘危險因子
 改善生活環境
 避免非過敏原的因素
 Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor
Asthma

 Depending on level of asthma control

(not severity!), the patient is assigned
to one of five treatment steps
 Treatment is adjusted in a continuous
cycle involving:
- Assessing Asthma Control
- Treating to Achieve Control
- Monitoring to Maintain Control
 Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor
Asthma

 評估及監測 :
尖峰流量 ( 或尖峰呼氣流速 ; PEF)

10/23/08
 Difference in GINA guideline 2006
Levels of Asthma Control
Controlled Partly controlled
Characteristic Uncontrolled
(All of the following) (Any present in any week)

None (2 or less / More than

Daytime symptoms
week) twice / week
Limitations of
None Any 3 or more
activities
features of
Nocturnal symptoms / partly
None Any controlled
awakening
asthma present
Need for rescue / None (2 or less / More than in any week
“reliever” treatment week) twice / week
< 80% predicted or
Lung function
Normal personal best (if
(PEF or FEV1)
known) on any day

Exacerbation None One or more / year 1 in any week

 Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor
Asthma

 氣喘嚴重度分期 (GINA 1998, 2002,

2006)

嚴重度 症狀頻率 PEF

白天 夜間 % 最佳值 變異度 %
重度持續性 持續 時常 ≦ 60 ＞ 30
中度持續性 ＞1次/天 ≧1次/週 60-80 ＞
30
輕度持續性 ≧1次/週 ＞2次/月 ≧ 80
20-30
Not essential＜for treatment decision!
1次/天
 Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor
Asthma

 A stepwise approach
 The least possible medication
 Traditional methods of healing are not
recommended
 Severity is no longer used as the basis for
treatment decision
 Component 3: Assess, Treat and Monitor Asthma
Controller Medications
 Inhaled glucocorticosteroids
 Leukotriene modifiers
 Long-acting inhaled β2-agonists
 Theophylline
 Cromones
 Long-acting oral β2-agonists
 Anti-IgE
 Systemic glucocorticosteroids
 Component 3: Assess, Treat and Monitor Asthma
Reliever Medications

 Rapid-acting inhaled β2-agonists

 Systemic glucocorticosteroids
 Anticholinergics
 Theophylline
 Short-acting oral β2-agonists
 Component 3: Assess, Treat and Monitor Asthma
Allergen-specific
Immunotherapy
 Greatest benefit in allergic rhinitis
 The role in asthma is limited
 Specific immunotherapy should be considered
only after strict environmental avoidance and
pharmacologic intervention, including inhaled
glucocorticosteroids, have failed
 Perform only by trained physician
 Combined use of LA-β2
agonists and inhaled
corticosteroids
Leukotri
Inhaled ene
Large use corticosteroids modifier
of short- Fear of short-
remodeli
s?
acting β2- acting β2-
ng
agonists agonists
inflammation

bronchospasm

19 1980 1 1 1 2000
75 985 990 995
 Bronchodilators Thoracic Medicine
CGMH, Chiayi

Anticholinergic

M1

M2
M3

Contraction Relaxation
↑cAMP

AMP
SMOOTH MUSCLE CELL
β-agonist
theophylline
Thoracic Medicine
CGMH, Chiayi
 Thoracic Medicine
CGMH, Chiayi

(Sears, 1985, 1986)

 Thoracic Medicine
CGMH, Chiayi

(Pearce, 1995; Sears, 1996)

Glucocorticoids– Mechanism of Action
Cell membrane
GC molecule

GR

Decreased expression Increased expression of:

of proinflammatory • Anti-inflammatory
molecules (e.g., molecules
cytokines, ICAM, VCAM) • β-adrenergic receptors

AP
Gene (DNA)
Nucleus
GRE

© P J Barnes 2005
 Corticosteroids

Eosinophil T-lymphocyte Mast cell Macrophage

Dendritic cell
 Numbers  Cytokines  Numbers  Cytokines
(apoptosis)
 Numbers
 Effects of Inhaled Glucocorticoids
on Inflammation

Pretreatment Posttreatment (3 mo)

600 µg budesonide bid
E=epithelium; BM=basement membrane
Laitinen LA et al. J Allergy Clin Immunol. 1992;90:32
 Low-Dose Inhaled Glucocorticoids
Preventing Death From Asthma
2.5
Rate Ratio for Death From Asthma

2.0

1.5

1.0

0.5

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12
Canisters of Inhaled Glucocorticoids/yr
Adapted from Suissa S et al. N Engl J Med. 2000;343:332
Inhaled Glucocorticoids Reduce
Asthma-Related Hospitalizations
8
β 2-agonists Inhaled Glucocorticoids
7
Total Total
6 Age 0–17 Age 0–17
Relative Risk

5
4
3
2
1
0
None 0–1 1–2 2–3 3–5 5–8 8+
Prescriptions/Person-yr
Donahue JG et al. JAMA.1997;277:887
 Inhaled Corticosteroids:
The mainstay of current treatment for
bronchial asthma
 Long-actingβ2-agonists Thoracic Medicine
CGMH, Chiayi

1980s
 Formoterol: full β2-agonists
 Salmeterol: partial β2-agonists
# Action: > 12 hours
 Long-actingβ2-agonists Thoracic Medicine
CGMH, Chiayi

Possible anti-inflammatory effects

 Reduce airway edema
 Reduce airway sensory nerve activation
 Increase mucociliary transport
 Stabilize mast cells and neutrophils (?)
 Reduce airway smooth muscle responsiveness
 Potentiate steroid effect
Combination therapy
 Complementary effects of
long-acting ß2-agonist / corticosteroid
combination therapy

Smooth Airway
muscle inflammation/
LABA dysfunction remodelling ICS

✓ • Bronchoconstriction • Inflammatory cell ✓✓

✓✓ • Bronchial hyper- infiltration/activation
reactivity • Mucosal oedema ✓✓
✓ • Hyperplasia • Cellular proliferation ✓
• Inflammatory • Epithelial damage ✓
✓ • Basement membrane
mediator release ✓
thickening

Symptoms\exacerbations

Johnson M. Current Allergy Clin Immunol 2002

21 Century First Revolution
Seretide v.s Symbicort
 Serial FEV1 after One Week of
Treatment with Seretide™, FP, SALM
or Placebo
Mean change from baseline in serial FEV1 (L)
Placebo Seretide™ 50/250 µg BID
0.8
FP 250 µg BID SALM 50 µg BID
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
– 0.1
Baseline 1 2 3 4 6 8 10 12
Time (hours)
Sharpiro, Am J Respir Crit Care Med 2000
FACET Study : Severe exacerbations
1

0.8
no. / patient / y

0.6

0.4

0.2

BUD 200 BUD 200 BUD 800 BUD 800

Formoterol Formoterol

Pauwels et al. N Engl J Med 1997

FACET Study : change in am PEF
40

30
change in PEF (l/min)

BUD800+F
20

BUD200+F
10

0 BUD800

-10 BUD200

-20
-10 0 10 1 3 6 9 12
Run-in (days) Treatment (days) Treatment (months)

Pauwels et al. N Engl J Med 1997

Meta-analysis in Asthma

Sin et al. JAMA 2004

 Thoracic Medicine
CGMH, Chiayi

Xanthines
(Theophyllines)
 Methylxanthines Thoracic Medicine
CGMH, Chiayi

 Related to caffeine
 Used in asthma since 1930
 Orally active, slow-releasing preparations
 Less role?
 Bronchodilator (10-20 mg/L)
 Anti-inflammatory (5-10 mg/L)
 Mechanisms of action Thoracic Medicine
CGMH, Chiayi

of theophyllines
 Phosphodiesterase (PDE) inhibition
 Adenosine receptor antagonist
 Stimulation of catecholamine release
 Mediator inhibition
 Inhibition of intracellular calcium release
 Thoracic Medicine
CGMH, Chiayi

Leukotriene
modifier
Leukotriene
in Asthma

 From phospholipids
via FLAP and 5-LO
 Pathway irresponsive
to steroids
 LTB4: chemotaxis for
leukocytes
 LTC4, LTD4 (Cys-
LTs)
 Thoracic Medicine
CGMH, Chiayi

Anti-IgE
 New Anti-IgE antibody Thoracic Medicine
CGMH, Chiayi

 Omalizumab (Xolair Genentech, USA / Tanox, Inc., USA

/ Novartis Pharma AG, Switzerland)
 reduces circulating free IgE and the levels of high-
affinity IgE receptors on basophils
 inhibits the early- and late-phase response to
allergens, suppresses eosinophilic and T cell
inflammation in airways
 In asthma, reduced corticosteroid dosage while
improving peak flows, reducing exacerbations, and
improved quality of life.
 approved by FDA for allergic asthma in 2003.
(Reviewed by Chung,
 REDUCE
LEVEL OF CONTROL TREATMENT OF ACTION

maintain and find lowest

controlled
controlling step
consider stepping up to
partly controlled gain control

INCREASE
uncontrolled step up until controlled

exacerbation treat as exacerbation

REDUCE INCREASE
TREATMENT STEPS
STEP STEP STEP STEP STEP
1 2 3 4 5
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Step 1 – As-needed reliever medication
 Patients with occasional daytime symptoms of
short duration
 A rapid-acting inhaled β2-agonist (SABA) is
recommended (Evidence A)
 When symptoms are more frequent, and/or
worsen periodically, patients require regular
controller treatment (step 2 or higher)
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Step 2 – Reliever medication plus a single controller
 A low-dose inhaled glucocorticosteroid (ICS)
is recommended as the initial controller
treatment for patients of all ages (Evidence
A)
 Alternative controller medications include
leukotriene modifiers (Evidence A)
appropriate for patients unable/unwilling to
use ICS
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Step 3 – Reliever medication plus one or two
controllers
 For adults and adolescents, combine a low-dose
ICS with an inhaled LABA either in a combination
inhaler device or as separate components
(Evidence A)
 Inhaled LABA must not be used as monotherapy
 For children < 6 y/o, increase to a medium-dose
ICS (Evidence A)
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Additional Step 3 Options for Adolescents and Adults
 Increase to medium-dose ICS (Evidence A)
 Low-dose ICS combined with leukotriene
modifiers (Evidence A)
 Low-dose sustained-release theophylline
(Evidence B)
Meta-analysis in Asthma

Sin et al. JAMA 2004

 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Step 4 – Reliever medication plus two or more controllers
 Selection of treatment at Step 4 depends
on prior selections at Steps 2 and 3
 Where possible, patients not controlled on
Step 3 treatments should be referred to a
health professional with expertise in the
management of asthma
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Step 4 – Reliever medication plus two or more controllers
 Medium- or high-dose ICS combined with a
LABA (Evidence A)
 Medium- or high-dose ICS combined with
leukotriene modifiers (Evidence A)
 Low-dose sustained-release theophylline added
to medium- or high-dose ICS combined with a
LABA (Evidence B)
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Step 5 – Reliever medication plus additional controller options

 Addition of oral glucocorticosteroids to other

controller medications may be effective
(Evidence D) but is associated with severe
side effects (Evidence A)
 Addition of anti-IgE treatment improves
control of allergic asthma (Evidence A)
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Stepping down treatment when asthma is controlled

 When controlled on medium- to high-

dose ICS: 50% dose reduction at 3
month intervals (Evidence B)

 When controlled on low-dose ICS: switch

to once-daily dosing (Evidence A)
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Stepping down treatment when asthma is controlled
 When controlled on combination ICS and LABA,
reduce dose of ICS by 50% while continuing the
LABA (Evidence B)
 If control is maintained, reduce to low-dose ICS
and stop LABA (Evidence D)
 If no recurrence of symptoms occur for one year,
the controller may be stopped (Evidence D)
 Component 3: Assess, Treat and Monitor Asthma

Treating to Achieve Asthma

Control
Stepping up treatment in response to loss of control

 Combing a rapid and long-acting inhaled β2-

agonist and an ICS in a single inhaler both as
a controller and reliever is effecting in
maintaining a high level of asthma control and
reduces exacerbations (Evidence A)
 Doubling the dose of ICS is not effective
(Evidence A)
 Asthma Management and Prevention Program
Component 4: Manage Asthma Exacerbations

Primary therapies for exacerbations:

 Repetitive administration of rapid-acting inhaled
β2-agonist
 Early introduction of systemic glucocorticosteroids
 Oxygen supplementation
Closely monitor response to treatment with serial
measures of lung function
 Thoracic Medicine
CGMH, Chiayi

More about
Management for Asthma
 Choice of patients
ICS in asthma: Smoker vs. non-smoker
Figure 2 Mean (95% CI) difference between non-smokers and smokers with asthma in change in
morning PEF (l/min) on different doses of inhaled beclomethasone. *p

Tomlinson, J E M et al. Thorax 2005;60:282-287

 ICS in asthma: Initial dose

high (>800 µg/day beclomethasone (BDP)); moderate (400-800 µg/day); low (<400
µg/day)

Powell, Thorax. 2004 Dec;59(12):1041-5, systemic review

 Difficult
Asthma
 Adequate medication?
 Confirmation of diagnosis (false asthma?,
drug-induced asthma?)
 Evaluation of compliance, allergen
exposure, stress and secondary gain
 Evaluation of associated disorders
 Difficult
Asthma
 False asthma, pseudoasthma
2. Vocal cord dysfunction
3. Airway stenosis
4. Bronchiolitis
5. Cardiac asthma
6. Allergic bronchopulmonary
aspergillosis
 Difficult
Asthma
Associated Disorders
 Respiratory tract infection
 Rhinitis or sinusitis
 GERD
 Associated
Disorders
 Respiratory tract infection and asthma
# Early 70’s: associate respiratory infections with acute
exacerbation of asthma
 Virus: Rhinovirus, RSV, Influenza, Parainfluenza,
Adenovirus, Coronavirus.
 Atypical pathogens: Chlamydia, Mycoplasma
# Viral vaccination is justified ?
 Associated
Disorders
 Rhinitis, sinusitis and asthma
 25 - 70% 過敏性鼻炎患者有鼻竇炎
 40 - 80% 鼻竇炎患者有過敏現象
 1920 年代：鼻竇炎可引發氣喘
 75 - 80% 氣喘患者有鼻炎
 70 - 90% 嚴重氣喘患者有異常鼻竇攝影
 治療鼻炎可改善氣喘控制
Associated Disorders
Impact of allergic
rhinitis on asthma

Bousquet, Clin Exp Allergy. 2005;35:723–727

BMC Pulm Med. 2006; 6(Suppl 1): S4.
Immunotherapy in patients with
allergic rhinitis prevents the
occurrence of asthma

Polosa et al, Respir Res. 2005; 6(1): 153

 Associated
 Disorders
Gastro-esophageal reflux disorder
(GERD) and asthma
 1892, Willium Osler: big meal => asthma
 1962, Kennedy: GERD-related bronchospasm
 GERD in asthma: 34-89%
 Often attacks at night
 Probable mechanism: vagal reflex
Treatment of
GERD
improved
control of
asthma

Treatment:
long-term pantoprazole

Calabrese et al. World J

Gastroenterol, 2005,
11(48):7657-60
 Thoracic Medicine
CGMH, Chiayi

The real world

Patient under-assessment of control
 Asthma control in practice
 Asthma control in practice is poor: Only 5%
of patients achieve GINA-defined control.

 Doctors don't follow guidelines,

underestimate severity
 Patients underestimate the severity
 Guidelines are complex and difficult to follow
Patient under-assessment of control
Self-assessment of control:
% of patients Complete control
Well control
60

50

40

30

20

10

0
USA Europe Asia Pacific Japan
Patients with severe persistent symptoms Rabe et al. Eur Respir J 2000;
www.asthmainamerica.com;
Lai et al. J Allergy Clin Immunol 2003;
Adachi et al. Arerugi 2002
 Asthma control in practice in Taiwan
the prescription patterns of anti-asthmatic medications for children
Sun et al, J Formos Med Assoc. 2006, 105(4)
225,537 anti-asthma prescriptions were collected from the National Health
Insurance Research Database from January 1, 2002 to March 31, 2002
Asthma control in practice in Taiwan
the prescription patterns of anti-asthmatic medications for children
Sun et al, J Formos Med Assoc. 2006, 105(4)
Asthma control in practice in Taiwan
the prescription patterns of anti-asthmatic medications for children
Sun et al, J Formos Med Assoc. 2006, 105(4)
New strategies
 Can we do better?
Asthma is a variable disease
Undertreatment
Excessive rescue use
Courses of inhaled/oral steroids
Poor Asthma
control
control

Fixed
dosing
Optimal
control
Time
(months, weeks, days)
Overtreatment
Unnecessary drug intake
Unnecessary drug costs
+ reliever as needed
 Hypothesis: AMD; SMART
The right dose of Symbicort® at the right time
Symbicort® Asthma
worsening Asthma control
inhalations

Quickly
gain
control
Step down to adequate
Maintain dose that maintains control
2 inh.
control
4 inh.
bid bid*
1 inh. 1 inh. or 2 inh.
bid bid od

Time
+ reliever as needed (months, weeks, days)
*The dosage 4 inh. bid is within the SPC of the
monocomponents but outside the current SPC for Symbicort inh. = inhalation(s)
 Adjustable maintenance dosing
reduced severe exacerbations
Number of
exacerbations p=0.018
70
60 p=0.08

50
Hospitalisation/
40 ER visits
30 Oral steroid course

20
10
0
Symbicort® Symbicort® Seretide™
AMD FD FD
SUND study: Aalbers R et al. Allergy Clin Immunol Int, 15, Suppl. 1 (2003):49-50
 As-needed reliever use
Daytime Symbicort® AMD
reliever use 3.2 Symbicort® FD
(occasions) Seretide™ FD
2.8

2.4

2.0

1.6

1.2

0.8
-30 -20 -10 0 10 20 30
Days relative to exacerbation
Aalbers R, et al (2003)
Symbicort® adjustable maintenance dosing
more cost-effective
Cost (€)
Ställberg B, et al (2003)
500
p<0.001
450

400

350

300

250

200
AMD Fixed
dosing
AMD in asthma: INSPIRE study

INSPIRE study: Partridge et al, BMC Pulm Med. 2006; 6: 13.

AMD in asthma: INSPIRE study

INSPIRE study: Partridge et al, BMC Pulm Med. 2006; 6: 13.

 Can we do better?
 New strategy: Aim for total control => 2000, GOAL
 Gaining Optimal Asthma controL
(GOAL) study
 A 1-year, multicentre, randomised, double-blind,
stratified, parallel-group, trial in adults and
adolescents, comparing:
 Seretide (salmeterol-fluticasone propionate)
vs. Flixotide (fluticasone propionate)
 Dose stepped-up to achieve TOTAL CONTROL
(or until maximum dose reached)
 Conducted between December 2000 and
December 2002
 Involving 326 sites in 44 countries across 6
continents
 GOAL study design
Oral
Phase I 8-week control assessment prednisolone +
SFC 50/500
Phase II 4-week control assessment

SFC 50/500 or FP 500

Stratum 3 SFC 50/250

or FP 250 Step 2

SFC 50/500
Step 1
or FP 500
SFC 50/250
or FP 250 Step 3
Strata 1 & 2
SFC 50/100
or FP 100 Step 2
5068  3421
Step 1

Visit 1 2 3 4 5 6 7 8 9
Week -4 0 4 12 24 36 52 56

SFC, salmeterol/fluticasone propionate combination; FP, fluticasone propionate GSK data on file, 2003
 Patients can achieve total control
regardless of asthma severity
100 Seretide Phase 2
% patients achieving total controlled

Seretide Phase 1
80 FP Phase 2
FP Phase 1
60
asthma

50% *
40%
44% *
40 *
28% 29%

16%
20

0
Steroid naïve Low dose Moderate dose
ICS ICS
*p < 0.001 (Phase 1)
Approximately 50% patients achieved Total Control
More patients achieved well controlled
asthma with Seretide versus FP
Seretide Phase 2
100 Seretide Phase 1
% patients achieving well-controlled

FP Phase 2
80 78% * 75% * FP Phase 1
70%
60% 62% *
60
asthma

47%

40

20

0
Steroid naïve Low dose Moderate dose
*p < 0.001 (Phase 1) ICS ICS
 Aiming for TOTAL CONTROL
reduced exacerbations

Mean exacerbation rate Baseline FP

Baseline Seretide
per patient per year
0.7 * p < 0.01

0.6

0.5

0.4 0.36
*
0.3 0.27

0.2 0.17 *
0.12 0.12
0.1 *
0.07
0
Steroid naïve (S1) Low dose ICS (S2) Moderate dose ICS (S3)
Exacerbations during study defined as requiring either oral steroids or hospitalisation
 Seretide achieves
better levels of quality of life
Seretide
Maximum achievable score = 7 FP
6.5
*
6.0
AQLQ Score

5.5
* p < 0.008
5.0

4.5

4.0
B/L 4 12 24 36 48 52

Week
By aiming for TOTAL CONTROL,
many more patients achieve
WELL CONTROLLED
asthma

5% 75%
 Assessment of Asthma
Control

 Asthma Control Test (ACT)

 Asthma Control Questionnaire
 Asthma Therapy Assessment
Questionnaire
 Asthma Control Scoring System
Copyright © 2007 TAC, All rights reserved. Unauthorized use prohibited.
Copyright © 2007 TAC, All rights reserved. Unauthorized use prohibited.
 There is always hope!
 New Drugs
New steroid
New bronchodilator ?
PDE –IV inhibitor ?
New immune response modifier:
eg. PGI2 analog, anti-TNF-α…
Growth factor antagonist
Smooth muscle modifier: eg. Bronchial thermoplasty…
MMP antagonist
 Anti-MMP-2 & -9
 Anti-ADAM33 protein ?
 Vaccination
 Gene therapy
 Telemedicine
 …
 And the next?
 Gene therapy
 Gene vaccination
 Transfer of genes for
anti-inflammatory proteins
e.g.: IL-10, IL-12, IκB.
 Anti-sense oligonucleotides
e.g. anti-sense IL-4, IL-5.
Telemedicine
利用輸入所在地
結合當地環境
空氣、氣象資訊
提升氣喘照護品質
 Thoracic Medicine
CGMH, Chiayi

Management
for
COPD - GOLD
GOLD Workshop Report, 2005
Four Components of COPD
Management
Thoracic Medicine
CGMH, Chia-Yi

• Assess and monitor

disease

• Reduce risk factors

• Manage stable COPD

● Education
● Pharmacologic
● Non-pharmacologic

• Manage exacerbations
GOLD Workshop Report
Management:
Assess and monitor disease
Thoracic Medicine
CGMH, Chia-Yi
GOLD Workshop Report
Management:
Reduce risk factor
Thoracic Medicine
CGMH, Chia-Yi
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Education
 Health education (Evidence A).
 All COPD-patients benefit from exercise
training programs, improving with respect
to both exercise tolerance and symptoms of
dyspnea and fatigue (Evidence A).
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Pharmacologic
 None of the existing medications for COPD
has been shown to modify the long-term
decline in lung function (Evidence A).
 Pharmacotherapy is used to decrease
symptoms and/or complications.
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Pharmacologic: bronchodilators
 Central to the symptomatic management of COPD
(Evidence A).
 Principal bronchodilator: Beta2-agonists,
anticholinergics, theophylline, and a combination
of these drugs (Evidence A).
 Long-acting bronchodilators are more convenient.
 Combining bronchodilators may improve efficacy
and decrease the risk of side effects (Evidence A).
Patient-centred outcomes:
LABAs versus placebo

Duration (W eeks)

Exacerbations
Medication

Dose (μg)

Dyspnea

Exercise
Rescue

HRQL
Study

N
versus placebo
Jones 1997 283 16 S 50 ↑ - - ↑ -
Boyd 1997 674 16 S 50 ↑ ↑ NS - NS
Mahler 1999 411 12 S 50 ↑ NS - ↑ ↑
Rutten Van Molken 1999 144 12 S 50 - - - NS -
Van Noord 2000 144 12 S 50 ↑ - - - NS
Rennard 2001 405 12 S 50 ↑ NS NS NS NS
Chapman 2002 408 24 S 50 NS - - NS NS
Mahler 2002 691 24 S 50 ↑ NS - NS NS
Brusasco 2003 1207 26 S 50 - ↑ - NS NS
Calverley 2003 1465 52 S 50 ↑ NS - NS ↑
Hanania 2003 723 26 S 50 - ↑ - NS NS
Dahl 2001 780 12 F 12/24 ↑ - - ↑ NS
Aalbers 2002 687 12 F 4.5/9/18 NS/↑/↑ NS/↑/↑ NS - NS
Rossi 2002 854 52 F 12/24 ↑ - - ↑ ↑
Szafranski 2003 812 52 F 9 - - - - NS
 Action of anti-cholinergics
on Muscarinic receptors
Thoracic Medicine
CGMH, Chiayi

Pre-ganglionic
nerve
Sub-types Receptor dissociation
Parasympathetic
(T½, h)
ACh M (+)
ganglion 1
Ipratropium Tiotropium
M1 0.11 14.6

M2(-)
M2 0.03 3.6
ACh
M3 0.26 34.7
Airway M3(+)
smooth muscle

Disse et al, 1999

 Long-acting anti-cholinergics Thoracic Medicine
CGMH, Chiayi

Beneficial Effects of Tiotropium

 Once daily with prolonged

bronchodilatation
 M1-, M3-receptor specific

Maesen, Eur Respir J. 1995; Barnes, Thorax 1998;

Disse , Am J Respir Crit Care Med. 1999
 Bronchodilator activity of tiotropium in
COPD patients Thoracic Medicine
CGMH, Chiayi

0.3 Tiotropium 80µg

Tiotropium 20µg
Placebo
0.2
FEV1(L)

0.1

-0.1

0 2 4 6 8 10 12 14 16 18 20 22 24
Time post-administration (hours)
Maesen et al, Eur Respir J 1995
 Effect of tiotropium on
symptom scores in COPD Thoracic Medicine
CGMH, Chiayi

6.0
Global evaluation score

5.6

5.2
Tiotropium (n=276)

4.8
Placebo (n=188)

4.4

4.0
1 8 29 50 71 92
Test day Casaburi et al, 2000
 Tiotropium improves
Exercise Endurance Time Thoracic Medicine
CGMH, Chiayi

Placebo (n=91) Tiotropium (n=96)

11 **

10 ∆ =105 s (21.4%)
∆ =1 min 7 s
ET (sec)

(13.6%)

8 min 12 s
8
-5 0 5 10 15 20 25 30 35 40 45
Day
Baseline

*P<0.05, **P<0.01 Adapted from O’Donnell DE et al. Eur Respir J (2004)

Number of COPD Exacerbations
vs Ipratropium
p=0.00
1.2 6
0.96
1.0
Events/ Patient

24
Number of

0.73
0.8
%
Year

0.6

0.4

0.2

0.0
Ipratropium Tiotropium
(n=179) (n=356)
Improvement in health stautus in
COPD with tiotropium
Thoracic Medicine
CGMH, Chiayi

Placebo Tiotropium
0
∆ SGRQ total score

-2

-4
*
-6

*p<0.05 versus placebo

-8
Bateman et al, 2001
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Pharmacologic: corticosteroids
 The addition of regular treatment with inhaled
glucorticosteroids to bronchodilator treatment is
appropriate for symptomatic COPD patients with
FEV1<50% predicted (Stage III to IV) and
repeated exacerbations (Evidence A)
 Chronic treatment with systemic
glucorticosteroids should be avoided (Evidence A)
 ISOLDE study: Exacerbations
1.4

Exacerbations/patient/year (mean)
1.32
1.2 25
%
n=751 1.0
40-75 yrs 0.99
FEV1 1.3 L 0.8

0.6

0.4

0.2

0
Placebo Fluticasone 1 mg

M Burge et al: BMJ 2000;320:1297-1303

 EUROSCOP – change of FEV1

75 ∆ FEV1
50
25
0 BUD 400 µg bid
N=1277 -25

FEV1 (ml)
-50
FEV1 2.5 l,
-75
77% pred. -100
-125
-150 Placebo
-175
-200
-225
-6 -3 0 3 6 9 12 15 18 21 24 27 30
33 36

mod. after R Pauwels et al., NEJM 340: 1948, 1999 months

ICS in COPD mortality

DD Sin et al., Thorax 60:992, 2005

 Monotherapy in COPD
(corticosteroid)
ICS long-term study
 Copenhagen, Verbo, 1999
 EUROSCOPE, Pauwells, 1999
 ISLODE, Burge, 2000, BMJ
 LUNG2, NEJM, 2000
 Kiri, AJRCCM, 2005
 TORCH, ongoing, 6000 patients
⇒ Effective in treatment of short-term (3-6 mo)
and acute exacerbations
⇒ No effect on long-term decline of lung function
⇒ Reduction in risk for rehospitalization or death
Combination therapy in COPD
(corticosteroid with long-actingβ2-agonist)
Breaking the vicious cycle

Cazzola et al. Chest. 2004 .Vol.126, Iss. 1; pg. 220

 Budesonide/formoterol
in moderate-severe COPD
Comared to monotherapy
 Reduce severe exacerbation
 Improve FEV1 (vs budesonide)
 Improve morning PEF
 Reduce night-time awakening
 Reduce SOB (vs budesonide)
 Reduce use of oral steroids (vs Formoterol)
Szafranski, ERJ, 2003
 Symbicort Reduces Severe
Exacerbations
Reduction vs Symbicort Budesonide Formoterol
placebo (%) 0

–2%
–5

–10

–15
–15%
–20

*p<0.05 vs placebo
–25
–24% †
p<0.05 Symbicort vs formoterol
*†
–30
Symbicort improves health-related quality of life
(SGRQ Total score)
Adjusted mean
Symbicort Budesonide Formoterol Placebo
change from 0
run-in

–1

–2

–3

–4 MCID

–5

–6 *
MCID = minimum clinically important difference
*p<0.05 vs placebo
 Fluticasone/Salmeterol in COPD
FEV1 Thoracic Medicine
CGMH, Chiayi

Placebo SAL 50 FP 500 SFC 50/500

Mean Change in FEV1 (ml)

160
120
80
40
0
-40
-80
0 2 4 8 16 24 32 40 52

week
TRISTAN, Lancet, 2003
 Fluticasone/Salmeterol in COPD
Moderate and/or severe exacerbations
1.30
number/patient/year

1.5

1.04 1.05
** 0.97
**
1 *

0.5

0
PLA SAL50 FP500 SFC50/500

* p< 0.001 vs PLA ** p = 0.003 vs PLA

TRISTAN, Lancet, 2003
Fluticasone/Salmeterol in COPD
SGRQ
PLA SAL50 FP500 SFC50/500
0

-1

-2

-3

-4

-5 *
-6

* p<0.039 vs PLA and FP

TRISTAN, Lancet, 2003
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Pharmacologic: other treatment

 α - 1 Antitrypsin augmentation Therapy (C)
 Antioxidant (B)
 Immunoregulators (B)
 Antitussives (D)
 Respiratory Stimulant (Doxaparm,Almitrine) (D,B)
Respiratory Care 2001;46:798-825.
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Non-pharmacologic: O2
 The long-term administration of oxygen (> 15
hours per day) to patients with chronic
respiratory failure has been shown to increase
survival (Evidence A).
 Thoracic Medicine
CGMH, Chia-Yi

10/23/08
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Non-pharmacologic: Rehabilitation
 Improves exercise capacity
 Reduces the intensity of breathlessness
 Improves quality of life
 Reduces hospitalizations and hospital stay
 Reduces anxiety and depression
(All evidence A).
 GOLD Workshop Report
Management:
Manage stable COPD
Thoracic Medicine
CGMH, Chia-Yi

● Non-pharmacologic: Surgery
 Bullectomy
 Lung volume reduction surgery (LVRS)
 Lung transplantation
GOLD Workshop Report
Four Components of COPD
Management
Thoracic Medicine
CGMH, Chia-Yi

• Assess and monitor

disease

• Reduce risk factors

• Manage stable COPD

● Education
● Pharmacologic
● Non-pharmacologic

• Manage exacerbations
Common Causes of Acute Exacerbations of COPD

 Primary
 Tracheobronchial infection
 Air pollution
 Secondary
 Pneumonia
 Pulmonary embolism
 Pneumothorax
 Rib fractures/chest trauma
 Inappropriate use of sedatives, narcotics, β-blocking agents
 Right and/or left heart failure or arrhythmias

NHLBI/NIH. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2005.
 Infectious Agents in COPD Exacerbations

Viruses 30% Bacteria 40%–50%

Influenza H. influenzae
Parainfluenza S. pneumoniae
Rhinovirus M. catarrhalis

Other 10%–25%
eg, air pollution Atypical bacteria 5%–10%
C. pneumoniae
 GOLD – COPD severity predicts
hospitalisation rate
12
Patients with ≥ 1 hospitalisation
because of COPD in 3 yrs (%)

10

0
GOLD 3/4 GOLD 2 GOLD 1 GOLD 0
Mannino ERJ 2006
AGE
205 patients hospitalized for AECOPD, follow-up for 3 years

Follow-up days Gunen et al ERJ 2005

Severe exacerbations and mortality in COPD

No exacerb.

1-2 exacerb.

>3 exacerb.

JJ Soler-Cataluna et al., Thorax 60:925, 2005

 GOLD Workshop Report
Management:
Manage exacerbations

 The most common causes: infection and air

pollution. But, about one-third: cannot be identified
(Evidence B).
 Inhaled bronchodilators, theophylline, and systemic
corticosteroids are effective (Evidence A).
 Patients with airway infection may benefit from
antibiotic treatment (Evidence B)
 GOLD Workshop Report
Management:
Manage exacerbations

 Noninvasive intermittent positive pressure

ventilation (NIIPPV) (Evidence A).
 No reliable method to identify high-risk (>90%)
in-hospital or 6-mo mortality.
 Not beneficial (and may be harmful)
 Mucolytic agents
 Chest physiotherapy
 Theophylline
Thoracic Medicine
CGMH, Chia-Yi
 GOLD, 2005
Management:
Thoracic Medicine

Manage stable COPD CGMH, Chia-Yi

Stage Recommended Treatment

ALL • Avoidance of risk factor(s)
• Influenza vaccination
0: At Risk
I: Mild • ADD: Short-acting bronchodilator when needed

II: Moderate • ADD: Regular treatment with one or more long-

acting bronchodilators
• ADD: Rehabilitation
III: Severe • ADD:Inhaled glucocorticosteroids if repeated
exacerbations
III: Very Severe • ADD: Long-term oxygen therapy if
respiratory failure
• Consider surgical treatments
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO 2005.
 Thoracic Medicine
CGMH, Chiayi

COPD as a
Systemic Disease
 Systemic Inflammation
in COPD ?
Target organs

Respiratory system

Systemic
inflammation
Hypothesis Systemic Inflammation

Man SF,. et al. Proc Am

Thorac Soc 2005, 2, 78-82
 Systemic Effects of COPD
Systemic inflammation
Oxidative stress
Activated inflammatory cells
Increased plasma levels of cytokines and
(neutrophils/lymphocytes)
Nutritional abnormalities and
acute phase proteins
Increasedloss
weight resting energy expenditure
Abnormal body composition
Abnormal amino acid metabolism
Skeletal muscle dysfunction
Loss of muscle mass
Abnormal structure/function
Exercise limitation
Other potential systemic effects
Cardiovascular effects
Nervous system effects
Osteoskeletal effects Eur Respir J 2003;
21:347-360
 Limb Muscle
Increased ventilatory demand

Inactivity

Malnutrition

Inflammation

Intrinsic change
Blood flow redistribution
To respiratory muscle Decreased tolerance of
Exercise

Mid-thigh size is closely related to survival of

COPD patients!
 Osteoporosis in COPD
No bone loss Osteopenia Osteoporosis
100%
13
Percentage of subject group

20
80% 41
32
60%
49

40%
48
55
20%
31
11
0%
Healthy subjects FEV1>50% pred FEV1<50% pred
n=38 n=35 n=46
Bolton et al. AJRCCM 2004
 Cardiovascular dysfunction in COPD
Abnormal blood gas tension
Disruption of
Endothelial pulmonary vascular bed
dysfunction

Pulmonary arterial hypertension

Cor-pulmonale

Abnormal
Increased
pulmonary mechanics
Blood velocity
Change in Increased
Blood volume Cardiac output
TORCH 3-year follow-up
Mod-to-severe COPD
"Mild" COPD – causes of death
Lung:35%
Cardiovascular:27%
Carcinoma:21%
[%]
50 25 % – 39 %
40
30
20
10
0
COPD cardiovascular Lung other
carcinoma

EUROSCOP (n = 18/1277) LUNG HEALTH (n = 149/5887) Postma et al. (n = 22/81)

(n = number of deaths/total number)

R. A. Pauwels et al., NEJM 1999; 340:1948–1953.; N. R. Anthonisen et al., JAMA 1994;

272:1497–1505;
D. S. Postma et al., ARRD 1986; 134:276–280.
 COPD Increases the Risk of CV Disease
(i.e. Mortality Morbidity)
A, Relationship of CRP and severe airflow obstruction to CIIS (P for
trend=0.001)

nteraction of CRP and moderate airflow obstruction to CIIS (P for trend=0.001).

Sin, D. D. et al. Circulation
2003;107:1514-1519
Cardiovascular mortality in COPD
Marcus 1.93 (1.46,2.52), men

Hole 1.56 (1.26,1.92), men

Hole 1.88 (1.44,2.47), women

Schunemann 2.11 (1.20,3.71), men

Schunemann 1.96 (0.99,3.88), women

Pooled Estimate 1.75 (1.54, 2.01)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Relative Risk of Cardiovascular Mortality

Sin et al. Chest 2005
(worst FEV1 quintiles vs best FEV1 quintiles
 COPD and systemic inflammation

COPD studies
(n=14)

Markers of
systemic
inflammation

CRP

WQ Gan et al., Thorax 59:574, 2004

 Sodium and water disturbance in COPD
↑ PaCO2
Protective diuresis

RBF

Dopamine
↓ Effective renal plasma flow
↑Filtration fraction
↓ PaO2 ↑ Tubular Na -H + +

↑Peritubular oncotic pressure exchange

Dopamine
ANP ↑ Plasma renin activity
PRA (PRA)
Digoxin-like
substance
ANP ↑ Angiotensin II
Na+ retention
Ang II Natriuresis ANP
oedema

↑ Plasma aldosterone
Dopamine

↑ Arginine vasopressin H2O retention

ANP (AVP) oedema Protective diuresis
AVP
 Sleep in COPD
Sleep hypoxaemia
Polycythaemia In COPD Sleep quality

Hypoventilation Combined with

Sleep apnoea/hypopnoea syndrome
(SAHS)

↓ FRC

COPD SAHS
↓ V/Q matching
2-4% 10%
associated with REM ?
 Anxiety in COPD
Psychosomatic Medicine 65:963-970 (2003)
2% -- 51%
Study Instrument Participants Results

Aghanwa et al., 2001 Clinical evaluation based on ICD-10 N = 30 patients with 10% of COPD patients met ICD-10 criteria
(6) COPD and 30 healthy for Generalized Anxiety Disorder compared
controls with 3.3% of health controls
Aydin et al., 2001 (7) Composite international Diagnostic N = 38 COPD patients 15.8% met DSM-IV criteria for Generalized
Interview (CIDI) Anxiety Disorder
Borak et al., 1998 Manifest Anxiety Scale (MAS) N = 49 COPD patients 49% had high levels of anxiety (scored 7–
(15) 10 on MAS); 51% had moderate levels of
anxiety (scored 4–6 on MAS)
Engtrom et al., 1996 Hospital Anxiety and Depression Scale N = 68 COPD patients 13% had pathological levels of anxiety
(16) (HADS) (>10 on HAD)
Karajgi et al., 1990 Structured Clinical Interview for DSM-III-R N = 50 COPD patients 16% had some anxiety disorder; 8% had
(10) (SCID) panic disorder
Kim et al., 2000 (17) Beck Anxiety Inventory (BAI) N = 43 COPD patients 32.6% had moderate to severe anxiety
(BAI > 15)
Kvaal et al., 2001 State-Trait Anxiety Inventory (STAI) N = 98 geriatric patients, COPD patients had higher on STAI than
(20) including 17 with COPD patients with heart disease, cancer, and
other medical problems
Light et al., 1985 (21) State-Trait Anxiety Inventory (STAI) N = 45 COPD patients 2% had moderate anxiety (>2 SD above
mean on STAI); 13% had mild anxiety (1–2
SD above mean on STAI)
Moore & Zebb, 1999 Panic Attack Questionnaire-Revised; N = 28 COPD patients 32% met DSM-IV criteria for panic disorder
(12) Anxiety Disorders Interview Schedule-IV
modified for self-report
Porzelius et al., 1992 Self-report frequency of panic attacks in N = 48 COPD patients 37% reported a panic attack
(13) last 3 weeks
Prigatano et al., 1984 Profile of Moods States (POMS) N = 985 COPD patients COPD patients scored significantly higher
(51) and 25 healthy controls than healthy controls on tension-anxiety
scale
Withers, Rudkin, & Hospital Anxiety and Depression Scale N = 95 COPD patients 29.2% had significant anxiety
White, 1999 (18) (HADS)
Yellowlees et al., Clinical psychiatric interview N = 50 COPD patients 24% had Panic Disorder; 10% had
1987 (5) Generalized Anxiety Disorder
Yohannes, Baldwin, & Geriatric Mental State Schedule N = 137 COPD patients 18% were clinically anxious
Connolly, 2000 (19)
 Systemic Effects of COPD
 COPD is a systemic disease that affects many

organs

 Extrapulmonary effects have a major impact on

quality of life, symptoms and mortality

 Don’t just treat the lung disease

Reference: Chest, 2002; 121 (5) : 127S-130S
N Engl J Med , 2004; 350(10): 1005-12
 Future for COPD Thoracic Medicine
CGMH, Chiayi

 Bronchodilators: Tiotropium, selective PDE-IV

inhibitors
 Mediator antagonists: for LTB4, TNF-α, chemokines
 Antioxidants
 Anti-inflammatory drugs: Inhibitors for PDE, NF-κB,
adhesion molecule
 Proteinase inhibitors
 Mucoregulators
 Alveolar repair: Retinoic acid, hepatocyte GF.
 Route of delivery
Thank
you
for
your
attention