2004 ATS/ERS Definition - Pulmonary, Critical Care & Sleep Medicine

2004 ATS/ERS Definition of COPD
“. . . a preventable and treatable disease state
characterised by airflow limitation that is not
fully reversible. The airflow limitation is
usually progressive and is associated with an
abnormal inflammatory response of the lungs
to noxious particles or gases, primarily
caused by cigarette smoking. Although COPD
affects the lungs, it also produces significant
systemic consequences.”
Differentiating COPD and Asthma:
Physiologic Similarities and Differences
• On average and in the extremes of presentation,
asthma and COPD are easily distinguished from
one another
• In clinical practice, significant proportions of
patients are indistinguishable on the basis of
structural and functional evaluations
• Significant overlap exists in individual patients
with respect to airway wall thickening,
abnormalities on CT scans, reversibility to
bronchodilators, airway hyperreactivity, and
others
Celli et al. Eur Respir J. 2004;23:932-946.
Sciurba. Chest. 2004;126(2 suppl):117S-124S.
Asthma as a Risk Factor for COPD
in a Longitudinal Study
• Objective: To evaluate the association between physiciandiagnosed
asthma and the subsequent development of
COPD in a cohort of 3,099 adult subjects from Tucson, AZ
• Design and methods:
– Prospective observational study
– Participants were selected from a random stratified cluster
sample of white, non-Mexican-American households
– Participants completed up to 12 standard respiratory
questionnaires and 11 spirometry lung function
measurements over a period of 20 years
– Survival curves (with time to development of COPD as the
dependent variable) were compared between subjects with
asthma and subjects without asthma at the initial survey
Silva et al. Chest. 2004;126:59-65.
Proportion of Patients COPD-Free
1.0
0.9
0.8
0.7
Time to Development of COPD*
by Asthma Categories
No Asthma
Inactive Asthma
Active Asthma
0 5 10 15 20
Time in Years
Silva et al. Chest. 2004;126:59-65.
Hazard ratio for
development of COPD
for active asthma vs
no asthma: 12.5
(95% CI, 6.84 to 22.84).
Adjusted for age, sex,
smoking, log IgE, and
skin test reactivity.
* COPD was defined as having either chronic bronchitis, emphysema, or both and having either
FEV 1 or DLCO values

Inflammation in COPD
Inflammatory Cells in Subjects
Not Currently Smoking:
Methods
• Objective: Assess the differences in
inflammatory parameters between subjects
with COPD and healthy volunteers
• Sputum induction and bronchoscopy with
BAL and biopsies were performed
• Subjects
– 18 patients with COPD (according to ATS criteria)
• 16 had chronic bronchitis
– 11 healthy controls (matched for age and pack-years)
Transverse section of a small airway showing
peribronchiolitis consisting predominantly of lymphocytes
Jeffery. Am J Respir Crit Care Med. 2001;164:S28-S38. Official journal of the American Thoracic Society.
©American Lung Association. Reprinted with permission.
Rutgers et al. Thorax. 2000;55:12-18.
Inflammatory Cells in Subjects
Not Currently Smoking:
Methods (cont’d)
• Inclusion criteria
– Impaired lung function in COPD patients
– Negative history of atopy, negative skin tests to
18 common aeroallergens, negative specific
serum IgE for 11 common aeroallergens
– Not current smokers
• 4 subjects with COPD were never smokers
• All other subjects, including healthy controls, had quit
smoking >1 year before study entry
• Inhaled steroids were discontinued
≥1 month before study entry
Rutgers et al. Thorax. 2000;55:12-18.
Sputum Neutrophils (%)
100
90
80
70
60
50
40
30
20
10
0
Inflammatory Cells in Subjects
Not Currently Smoking
Neutrophils
P=0.0001
Values are expressed as percentages of the total number of nonsquamous cells.
* The role of eosinophils in COPD is not well defined.
Rutgers et al. Thorax. 2000;55:12-18.
Lymphocytes
P=0.0161
Eosinophils*
P=0.0083
10
8
6
4
2
0
Sputum Lymphocytes
and Eosinophils (%)
Patients with COPD
Healthy controls
Inflammatory Cells in
Various GOLD Stages of COPD:
Study Design
Inflammatory Cells in
Various GOLD Stages of COPD:
Baseline Characteristics
• Objective: Evaluate the relationship between progression of
COPD (as reflected by GOLD stage) and the pathological
findings in airways

Association Between Total Airway
Wall Thickness and FEV 1
V:SA (mm)
0.25
0.20
0.15
0.10
0.05
GOLD
Stage 4
GOLD GOLD
Stage 3 Stage 2
GOLD
Stages 0 & 1
0.00
0 20 40 60 80 100 120
Small Airway Obstruction in COPD
• Progression of COPD was strongly
associated with increased volume of tissue
in the wall (P

“NETT Lung Transplant and New
Pharmaceuticals for COPD”
James F. Donohue, MD
Professor of Medicine
&
Chief, Division of Pulmonary & Critical Care Medicine
University of North Carolina School of Medicine
At
Chapel Hill, North Carolina
Number of Transplants
1800
1600
1400
1200
1000
800
600
400
200
0
NUMBER OF LUNG TRANSPLANTS REPORTED
BY YEAR AND PROCEDURE TYPE
Bilateral/Double Lung
Single Lung
408
185
13 15 47 80
685
902
1417 1508 1537
14131410
1342 1337
1206
1069
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
ADULT LUNG TRANSPLANTATION: Indications (1/1995-6/2002)
DIAGNOSIS
SLT (N = 5,000)
BLT (N = 4,488)
TOTAL (N = 9,488)
LUNG TRANSPLANTATION
Actuarial Survival (Transplants: January 1990 - June 2001)
COPD/Emphysema
IPF
CF
Alpha-1
PPH
Sarcoidosis
Bronchiectasis
Congenital Heart Disease
LAM
Re-TX: OB
OB (Non-ReTX)
Re-TX: Non-OB
Connective Tissue Disorder
Cancer
2,698 ( 54.0% )
1,186 ( 24.0% )
49 ( 1.0% )
429 ( 8.6% )
66 ( 1.3% )
127 ( 2.5% )
11 ( 0.2% )
10 ( 0.2% )
45 ( 0.9% )
47 ( 0.9% )
30 ( 0.6% )
35 ( 0.7% )
21 ( 0.4% )
3 ( 0.1% )
1,000 ( 22.0% )
403 ( 9.0% )
1,447 ( 32.0% )
434 ( 9.7% )
361 ( 8.0% )
113 ( 2.5% )
192 ( 4.3% )
99 ( 2.2% )
58 ( 1.3% )
47 ( 1.0% )
52 ( 1.2% )
37 ( 0.8% )
22 ( 0.5% )
25 ( 0.6% )
3,698 ( 39.0% )
1,589 ( 17.0% )
1,496 ( 16.0% )
863 ( 9.1% )
427 ( 4.5% )
240 ( 2.5% )
203 ( 2.1% )
109 ( 1.1% )
103 ( 1.1% )
94 ( 1.0% )
82 ( 0.9% )
72 ( 0.8% )
43 ( 0.5% )
28 ( 0.3% )
Survival (%)
100
80
60
40
20
0
Double lung: 1/2-life = 4.8 Years; Conditional 1/2-life = 8.1 Years
Single lung: 1/2-life = 3.7 Years; Conditional 1/2-life = 5.8 Years
All lungs: 1/2-life = 4.0 Years; Conditional 1/2-life = 6.5 Years
Bilateral/Double Lung (N=6,068)
Single Lung
(N=7,385)
All Lungs
(N=13,453)
p < 0.0001
0 1 2 3 4 5 6 7 8 9 10 11 12
Years
Histiocytosis X
11 ( 0.2% )
8 ( 0.2% )
19 ( 0.2% )
Other
232 ( 4.6% )
190 ( 4.2% )
422 ( 4.4% )
Smoking Cessation in
Patients with COPD: Results
Rates of Continuous Abstinence from Smoking
Proportion of Patients Abstinent (%)
35
30
25
20
15
10
5
0
Bupropion SR
Placebo
0 5 6 7 10 12 26
Study Week
*P < .05.
Tashkin DP et al. Lancet. 2001;357:1571-1575.
*
* *
*
*
*
(cont)
Mean FEV 1 (L)
2.80
2.75
2.70
2.65
2.60
2.55
2.50
2.45
Lung Health Study: Results
Mean Postbronchodilator FEV 1
for All Participants
SIP
SI + Ipratropium
UC
Follow-Up (Years)
Anthonisen NR et al. JAMA. 1994;272:1497-1505.
Postbronchodilator FEV 1 (L)
Mean Postbronchodilator FEV 1
for Sustained Quitters and
Continuous Smokers Receiving
Smoking Intervention and Placebo
2.9
2.8
2.7
2.6
2.5
Sustained Quitters
Continuing Smokers
2.4
Screen 2 1 2 3 4 5 Screen 2 1 2 3 4 5
Follow-Up (Years)

Effect of Smoking Cessation on the
Lung Function of Participants
in the LHS: Results
• Women who quit had a larger improvement in the first year
compared with men
• Women who continued to smoke had a greater loss of function
than men with comparable smoking rates
• Heavy smokers benefited from quitting more than light smokers
• Baseline respiratory symptoms did not predict change in lung
function
Patients at High Risk of Death After
LVRS: Early NETT Results
• 1033 patients randomized by June 2001
– 69 high-risk patients
• FEV 1 ≤ 20% predicted and either a homogeneous
distribution of emphysema on computed
tomography or a carbon monoxide diffusing
capacity ≤ 20% of predicted
• Among high-risk patients
– 30-day mortality after surgery was 16% vs 0%
among medically treated patients
– Overall mortality 0.43 deaths per person-year vs
0.11 among medically treated patients
Scanlon PD et al. Am J Respir Crit Care Med. 2000;161:381-390.
(cont)
National Emphysema Treatment Trial Research Group. N Engl J Med. 2001;345:1075-1083.
(cont)
LVRS: National Emphysema
Treatment Trial
Results
Probability of Death
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Medical Therapy
Surgery
0.0
0 12 24 36 48 60
Months After Randomization
P = .90.
(cont)
Overall mortality rate = 0.11 deaths per person-year in both treatment groups.
National Emphysema Treatment Trial Research Group. N Engl J Med. 2003;348:2059-2073.
Patients (%)
40
35
30
25
20
15
10
5
0
LVRS: National Emphysema
Treatment Trial
Results
Improvement in Exercise Capacity at 24 Months
LVRS
Medical
Therapy
*
All patients
*
Low EC High EC Low EC High EC
Predominantly Upper-
Lobe Emphysema
*
Predominantly Non–Upper-
Lobe Emphysema
EC = exercise capacity.
(cont)
*P < .05 vs medical therapy.
National Emphysema Treatment Trial Research Group. N Engl J Med. 2003;348:2059-2073.
LVRS: National Emphysema
Treatment Trial
Conclusions
• Overall, LVRS increases the chance of improved exercise capacity, lung function,
dyspnea, and quality of life but does not confer survival advantage vs medical
therapy alone
• Poor candidates for LVRS include
– High-risk patients (ie, those with FEV 1 ≤ 20% predicted and either
homogenous emphysema or carbon monoxide diffusing capacity ≤ 20%
predicted)
– Patients with non–upper-lobe emphysema and high baseline exercise
capacity
• Good candidates for LVRS include patients with predominantly upper-lobe
emphysema and low baseline exercise capacity
National Emphysema Treatment Trial Research Group. N Engl J Med. 2003;348:2059-2073.
Novel and Future Therapies for COPD
Products in Late-Phase
Development
• Bronchodilators
– Tiotropium
– (R,R)-formoterol
• Phosphodiesterase-4 (PDE4)
inhibitors
– Roflumilast
– Cilomilast
• Combination therapy
– Fluticasone + salmeterol
– Budesonide + formoterol
Products in Early-Phase
Development
• Inflammatory mediators
– Inhibitors of
leukotriene B4,
interleukin-8, and
related chemokines
– Anti–TNF-α agents
• Antioxidants
• Antiproteases
• Retinoids

Tiotropium
• New-generation anticholinergic agent
• Structurally related to ipratropium bromide
• Slow dissociation from the muscarinic M 3 receptor
found on bronchial smooth muscle
• Long duration of action (≈ 24 hours)
• Inhaled as a dry powder
• Suggested first-line maintenance therapy in GOLD
guidelines (stages II-IV)
Tiotropium vs Salmeterol:
Study Objective and Design
• Objective: to compare the efficacy and safety of tiotropium with
salmeterol
• Design: randomized, placebo-controlled, double-blind, double-dummy,
parallel group study
• 623 patients were randomized to either
– Tiotropium 18 µg q.d.
– Salmeterol 50 µg b.i.d.
– Placebo
• Patients were followed for 6 months
Barnes PJ. Expert Opin Investig Drugs. 2001;10:733-740.
Pauwels RA et al. Available at: http://www.goldcopd.com. Accessed July 15, 2003.
Donohue JF et al. Chest. 2002;122:47-55.
Tiotropium vs Salmeterol: Results
Mean FEV 1 Before and After Administration of
Study Drug
FEV 1 (L)
1.35
1.30
1.25
1.20
1.15
1.10
Donohue JF et al. Chest. 2002;122:47-55.
Tiotropium (n = 202)
Salmeterol (n = 203)
1.05
Day 1
Placebo (n = 179)
1.00
Day 15
Day 169
0.95
-1 0 1 2 3 4 5 6 7 8 9 10 11 12
Time After Administration (Hours)
(cont)
Tiotropium vs Salmeterol: Results
Mean SGRQ Total Score
SGRQ Total Score
47
Salmeterol (n = 187)
46
Placebo (n = 159)
Tiotropium (n = 186)
45
44
43
42
41
40
0 57 113 169
Test Day
SGRQ = St. George’s Respiratory Questionnaire.
P < .05 for tiotropium vs placebo. Salmeterol vs placebo is not significant. Tiotropium vs
salmeterol is not significant.
Donohue JF et al. Chest. 2002;122:47-55.
Improvement
(cont)
Oral Steroids – Effects on lung function
in acute COPD exacerbation
Forest Plot Showing the Effect of Estimate of Each
Study and Respective 95% Cls
1) Aaron – N Engl J Med 2003
Study (Reference)
Patients, n
Study (Reference)
147 patients in ED – 10 days of oral Prednisone 40mg
-lower relapse
-Increase in FEV 1 34% vs 15% or 0.30liters vs 0.16L with
placebo
Vestbo et al (3)
Weir et al (9)
Pauwels et al (6)
Lung Health Study
Research Group (7)
Renkema et al (10)
290
98
1277
1116
39
3.1 ± 11.4 (-12.8 to 19.0)
-36.3 ± 22.6 (-80.6 to 8.0)
-12.0 ± 14.0 (-39.4 to 15.4)
-2.8 ± 4.03 (-11.0 to 5.4)
-30.0 ± 93.8 (-213.8 to 153.8)
2) Scope Trial
Burge et al (8)
751
-9.0 ± 6.38 (-21.5 to 3.5)
Niewoehner – N Engl J Med 1999
-active treatment – FEV 1 increases 100ml within 24 hours
3) Davies – Lancet 1999
Total 3571
-5.0 ± 3.2 (-11.2 to 1.2)
-300 -200 -100 0 100 200 300
Difference Between Placebo and Treatment Groups in FEV 1 , Decline mL/y

Effect of FP in COPD
• ISOLDE – Run in – Fall of FEV 1 of 75ml on ICS –
89ml FEV 1 fall – not on ICS 47ml
• Oral steroides – 60ml increase in FEV 1
• Rate of decline – 59 verses 50ml
• At 3 and 6 months – 76ml and 100ml higher
• At all points FEV 1 70ml higher with FP
• No relationship to oral CS
Exacerbation in COPD
• Associated with mortality
• Multiple causes – infections, irritants
• Defining event
• Costly – drugs, hospital, loss
• Correlates with Hs QOL
Reduced Risk of Mortality and Repeat
Hospitalization with Inhaled
Corticosteroids
COPD Hospitalization Free Survival
1.0
0.9
0.8
0.7
0.6
No Inhaled Corticosteroids
Inhaled Corticosteroids
0.5
0 2 4 6 8 10 12
Months After Discharge
ICS associated with a 26% lower
relative risk for all-cause mortality
and repeat hospitalization
FP Reduces Median Annual Exacerbation
Rate: ISOLDE Study
Exacerbations/patient/year
1.4
1.2
1
0.8
0.6
0.4
0.2
0
1.3
2
Placebo
O.99*
Fluticasone 500mcg
BID
*p=0.026
Adapted from Sin DD, Tu JV. Am J Respir Crit Care Med 2001;164:580-584
Burge PS et al. Br Med J. 2000;320:1297-1303
Study Design
ADVAIR 250/50 mcg b.i.d.
p.r.n.
albuterol
Placebo
run-in
Fluticasone propionate 250 mcg b.i.d.
Salmeterol 50 mcg b.i.d.
Placebo b.i.d.
2 weeks
24 weeks
All treatments administered via the DISKUS ® device.
Patients were stratified based on reversibility to albuterol.
Hanania et al. Chest. 2003;124:834-843.

∆ FEV 1 (mL)
200
150
100
50
0
Superior Improvement in Predose FEV 1
Demonstrates Contribution of Fluticasone Propionate
PLA SAL 50 ADV 250/50
(1%)
(9%)
(17%)
-50
Endpoint
0 2 4 6 8 12 16 20 24 (last evaluable FEV 1 )
Time (weeks)
* P

* # * # *
∆ Inspiratory Capacity (L)
Salmeterol reduces dynamic
hyperinflation during exercise in
COPD
0.4
0.3
0.2
0.1
0
*
SLM
PLAC
a
b
c
Effect of salmeterol on mucosal
damage
Epithelial ciliated cells (% surface area)
50
40
30
20
10
0
Haemophilus
influenzae
(a) Basal (b) Control (c) Salmeterol
* p=0.002 vs. placebo
Man et al. Thorax 2004
Dowling et al, Eur Respir J 1998
Synergistic interactions between
salmeterol and fluticasone
propionate
Seretide onset of action: Significant
improvement in lung function from day
1
Improvement in
PEF (L/min)
30
Seretide 50/500mcg bd
Salmeterol 50mcg bd
Fluticasone propionate 500mcg bd
20
10
*
0
Day 1 Days 1-14
* p

What do improvements in health
status actually mean for a patient?
A 4 unit improvement in SGRQ
score means that the patient
No longer walks more slowly
than others of their age
and
Is no longer breathless on
bending over
and
Is no longer breathless when
washing and dressing
A 2.7 unit improvement in
SGRQ score means that the
patient
No longer takes a long time
to wash or dress
and
Can now climb a flight of
stairs without stopping
Jones Data on file
Conclusion:
COPD management can be
improved today
• Combination therapy of fluticasone
propionate and salmeterol is an effective
treatment for COPD
– Functional impairement
– Breathlessness
– Health status
• Patient condition can be rapidly improved:
– In a few days for functional impairement and
dyspnea
– In a few weeks for health status
Conclusions: COPD
• Bronchodilators increase time to
exacerbations
• Inhaled corticosteroids reduce
exacerbation rate
• Exacerbation have effects on Hs QOL
• And recovery of pulmonary function