Global Initiative for Chronic

Obstructive
Lung
Disease
GLOBAL STRATEGY FOR THE DIAGNOSIS,
MANAGEMENT, AND PREVENTION OF
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
UPDATED 2010
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
i
GLOBAL INITIATIVE FOR
CHRONIC OBSTRUCTIVE LUNG DISEASE
GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND
PREVENTION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
(UPDATED 2010)
2010 Global Initiative for Chronic Obstructive Lung Disease, Inc.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
ii
Global Strategy for the Diagnosis, Management, and Prevention of
Chronic Obstructive Pulmonary Disease (UPDATED 2010)
GOLD EXECUTIVE COMMITTEE
Roberto Rodriguez-Roisin, MD, Chair
University of Barcelona
Barcelona, Spain
Antonio Anzueto, MD
(Representing American Thoracic Society)
University of Texas Health Science Center
San Antonio, Texas, USA
Jean Bourbeau, MD
McGill University Health Centre
Montreal, Quebec, Canada
Teresita S. deGuia, MD
Philippine Heart Center
Quezon City, Philippines
David S.C. Hui, MD
The Chinese University of Hong Kong
Hong Kong, ROC
Christine Jenkins, MD
Woolcock Institute of Medical Research
Sydney NSW, Australia
Fernando Martinez, MD
University of Michigan School of Medicine
Ann Arbor, Michigan, USA
Michiaki Mishima, MD
(Representing Asian Pacific Society for Respirology)
Kyoto University
Kyoto, Japan
Mara Montes de Oca, MD, PhD
(Representing Latin American Thoracic Society)
Central University of Venezuela
Los Chaguaramos, Caracas, Venezuela
Robert Stockley, MD
University Hospital
Birmingham, UK
Chris van Weel, MD
(Representing the World Organization of Family Doctors)
University of Nijmegen
Nijmegen, The Netherlands
Jorgen Vestbo, MD
Hvidovre University Hospital,
Hvidore, Denmark
and University of Manchester
Manchester, UK
Observer:
Jadwiga A. Wedzicha, MD
(Representing European Respiratory Society)
University College London
London, England, UK
GOLD SCIENCE COMMITTEE*
Jorgen Vestbo, MD, Chair
Hvidovre University Hospital
Hvidore, Denmark and
University of Manchester
Manchester, England, UK
A. G. Agusti, MD
Hospital University Son Dureta
Palma de Mallorca, Spain
Antonio Anzueto, MD
University of Texas Health Science Center
San Antonio, Texas, USA
Peter J. Barnes, MD
National Heart and Lung Institute
London, England, UK
Peter Calverley, MD
University Hospital Aintree
Liverpool, England, UK
Leonardo M. Fabbri, MD
University of Modena&ReggioEmilia
Modena, Italy
Paul Jones, MD
St Georges Hospital Medical School
London, England, UK
Fernando Martinez, MD
University of Michigan School of Medicine
Ann Arbor, Michigan, USA
Roberto Rodriguez-Roisin, MD
University of Barcelona
Barcelona, Spain
Donald Sin, MD
St Pauls Hospital
Vancouver, Canada
Robert Stockley, MD
University Hospital
Birmingham, UK
Claus Vogelmeier, MD
University of Giessen and Marburg
Marburg, Germany
*Disclosure forms for GOLD Committees are posted on the GOLD Website, www.goldcopd.org
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
iii
PREFACE
Chronic Obstructive Pulmonary Disease (COPD) remains
a major public health problem. It is the fourth leading
cause of chronic morbidity and mortality in the United
States, and is projected to rank ffth in 2020 in burden
of disease caused worldwide, according to a study
published by the World Bank/World Health Organization.
Furthermore, although COPD has received increasing
attention from the medical community in recent years, it
is still relatively unknown or ignored by the public as well
as public health and government offcials.
In 1998, in an effort to bring more attention to COPD, its
management, and its prevention, a committed group of
scientists encouraged the US National Heart, Lung, and
Blood Institute and the World Health Organization to form
the Global Initiative for Chronic Obstructive Lung Disease
(GOLD). Among the important objectives of GOLD are to
increase awareness of COPD and to help the millions of
people who suffer from this disease and die prematurely
from it or its complications.
The frst step in the GOLD program was to prepare a
consensus report, Global Strategy for the Diagnosis,
Management, and Prevention of COPD, which was
published in 2001. The report was written by an Expert
Panel, which was chaired by Professor Romain Pauwels
of Belgium and included a distinguished group of health
professionals from the felds of respiratory medicine,
epidemiology, socioeconomics, public health, and health
education. The Expert Panel reviewed existing COPD
guidelines and new information on pathogenic mechanisms
of COPD, bringing all of this material together in the
consensus document. The present, newly revised
document follows the same format as the original
consensus report, but has been updated to refect the many
publications on COPD that have appeared since 2001.
Since the original consensus report was published in
2001, a network of international experts known as GOLD
National Leaders has been formed to implement the
reports recommendations. Many of these experts havee
initiated investigations of the causes and prevalence of
COPD in their countries, and developed innovative
approaches for the dissemination and implementation
of COPD management guidelines. We appreciate the
enormous amount of work the GOLD National Leaders
have done on behalf of their patients with COPD.
In spite of the achievements since the GOLD report was
originally published, considerable additional work is
ahead of all of us if we are to control this major public
health problem. The GOLD initiative will continue to
bring COPD to the attention of governments, public
health offcials, health care workers, and the general
public, but a concerted effort by all involved in health
care will be necessary.
I would like to acknowledge the work of the members of
the GOLD Science Committee who prepared this revised
report. We look forward to our continued work with
interested organizations and the GOLD National Leaders
to meet the goals of this initiative.
We are most appreciative of the unrestricted educational
grants from Almirall, AstraZeneca, Boehringer Ingelheim,
Chiesi, Dey, Forest Laboratories, GlaxoSmithKline,
Novartis, Nycomed, Pfzer, Philips Respironics and
Schering-Plough that enabled development of this report.
Roberto Rodriguez Roisin, MD
Chair, GOLD Executive Committee, 2007 - 2010
Professor of Medicine
Hospital Clnic, Universitat de Barcelona
Villarroel, Barcelona, Spain
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
iv
TABLE OF CONTENTS
Methodology and Summary of New
Recommendations: 2010 Update....................vii
Introduction.......................................................xi
1. Defnition 1
Key Points 2
Defntion 2
Airfow limitation in COPD 2
COPD and Comorbidities 3
Natural History 3
Spirometric Classifcation of Severity 3
Stages of COPD 4
Scope of the Report 5
Asthma and COPD 5
Pulmonary Tuberculosis and COPD 5
References 5
2. Burden of COPD 7
Key Points 8
Introduction 8
Epidemiology 8
Prevalence 8
Morbity 9
Mortalilty 10
Economic and Social Burden of COPD 11
Economic Burden 11
Social Burden 12
References 12
3. Risk Factors 15
Key Points 16
Introduction 16
Risk Factors 16
Genes 16
Inhalational Exposures 17
Tobacco smoke 17
Occupational dusts and chemicals 17
Indoor air pollution 17
Outdoor air pollution 18
Lung Growth and Development 18
Oxidative Stress 18
Gender 18
Infections 18
Socioeconomic Status 18
Nutrition 18
Asthma 19
References 19
4. Pathology, Pathogenesis, and Pathophysiology 23
Key Points 24
Introduction 24
Pathology 24
Pathogenesis 25
Infammatory Cells 25
Infammatory Mediators 25
Oxidative Stress 25
Protease-Antiprotease Imbalance 26
Differences in Infammation between COPD and
Asthma 26
Pathophysiology 26
Airfow Limitation and Air Trapping 26
Gas Exchange Abnormalities 26
Mucus Hypersecretion 26
Pulmonary Hypertension 28
Systemic Features 28
Exacerbations 28
References 28
5. Management of COPD 31
Introduction 32
Component 1: Assess and Monitor Disease 33
Key Points 33
Initial Diagnosis 33
Assesment of Symptons 33
Dyspnea 34
Cough 34
Sputum production 34
Wheezing and chest tighness 34
Additional features in severe disease 35
Medical History 35
Physical Examination 35
Inspection 35
Auscultation 36
Measurement of Airfow Limitation 36
Assessment of COPD Severity 37
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
v
Additional Investigations 38
Bronchodilator reversibility testing 38
Chest X-ray 38
Aterial blood gas measurement 38
Alpha-1 antitrypsin defciency screening 38
Differential Diagnosis 39
Ongoing Monitoring and Assessment 39
Monitor Disease Progression and
Development of Complications 40
Pulmonary function 40
Arterial blood gas measurement 40
Assessment of pulmonary hemodynamics 40
Diagnosis of right heart failure or cor pulmonale 40
CT and ventilation-perfusion scanning 40
Hematocrit 40
Respiratory muscle function 40
Sleep studies 40
Exercise Testing 40
Monitor Pharmacotherapy and
Other Medical Treatment 41
Monitor Exacerbation History 41
Monitor Comorbidities 41
Component 2: Reduce Risk Factors 42
Key Points 42
Introduction 42
Tobacco Smoke 42
Smoking Prevention 42
Smoking Cessation 43
The role of health care providors in
smoking cessation 43
Counseling 44
Pharmacotherapy 45
Occupational Exposures 45
Indoor/Outdoor Air Pollution 46
Regulation of Air Quality 46
Steps for Health Care Providers/Patients 46
Component 3: Manage Stable COPD 48
Key Points 48
Introduction 48
Education 48
Goals and Educational Strategies 49
Components of an Education Program 49
Cost Effectiveness of Education
Programs for COPD Patients 50
Pharmacologic Treatment 50
Overview of Medications 50
Bronchodilators 51

2
-agonists 52
Anticholinergics 53
Methylxanthines 53
Combination brochodilator therapy 54
Glucocorticosteriods 54
Inhaled glucocorticosteriods 54
Oral glucocorticosteriods: short-term 54
Oral glucocorticosteriods: long-term 54
Pharmacologic Therapy by Disease Severity 56
Other Pharmacologic Treatments 56
Vaccines 56
Alpha-1 antitrypsin augmentation therapy 56
Antibiotics 56
Mucolytic agents 57
Antioxident agents 57
Immunoregulators 57
Antitussives 57
Vasodilators 57
Narcotics (morphine) 57
Others 57
Non-Pharmacologic Treatment 57
Rehabilitation 57
Patient selection and program design 58
Components of pulmonary rehabilitation
programs 58
Assessment and follow-up 59
Economic cost of rehabilitation programs 60
Oxygen Therapy 60
Cost considerations 61
Oxygen use in air travel 61
Ventilatory Support 61
Surgical Treatments 61
Bullectomy 61
Lung volume reduction surgery 62
Lung transplantation 62
Special Considerations 62
Surgery in COPD 62
Component 4: Manage Exacerbations 64
Key Points 64
Introduction 64
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
vi
Diagnosis and Assessment of Severity 64
Medical History 64
Assessement of Severity 65
Spirometry and PEF 65
Pulse oximetry/Arterial blood gases 65
Chest X-ray and ECG 65
Other laboratory tests 65
Differential Diagnosis 66
Home Management 66
Bronchodilator Therapy 66
Glucocorticosteriods 66
Antibiotics 66
Hospital Management 66
Emergency Department or Hospital 67
Controlled oxygen therapy 67
Bronchodilator therapy 67
Glucocorticosteriods 68
Antibiotics 68
Respiratory stimulants 69
Ventilatory support 69
Other measures 71
Hospital Discharge and Follow-Up 71
References 72
6. Translating Guideline Recommendations to the
Context of (Primary) Care 90
Key Points 90
Introduction 90
Diagnosis 90
Respiratory Symptoms 90
Spirometry 90
Comorbidities 91
Reducing Exposure to Risk Factors 91
Integrative Care in the Management of COPD 91
Implementation of COPD Guidelines 92
References 92
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
vii
Methodology and Summary of New Recommendations
Global Strategy for Diagnosis, Management and
Prevention of COPD: 2010 Update
*
When the Global Initiative for Chronic Obstructive Lung
Disease (GOLD) program was initiated in 1998, a goal was to
produce recommendations for management of COPD based
on the best scientifc information available. The frst report,
Global Strategy for Diagnosis, Management and Prevention
of COPD was issued in 2001 and in 2006 a complete revision
was prepared based on research published through June,
2006. These reports, and their companion documents, have
been widely distributed and translated into many languages
and can be found on the GOLD website (www.goldcopd.org).
The GOLD Science Committee

was established in 2002

to review published research on COPD management
and prevention, to evaluate the impact of this research
on recommendations in the GOLD documents related to
management and prevention, and to post yearly updates
on the GOLD website. Its members are recognized leaders
in COPD research and clinical practice with the scientifc
credentials to contribute to the task of the Committee and are
invited to serve in a voluntary capacity.
Updates of the 2006 report have been issued in December
of each year with each update based on the impact of
publications from July 1 of the previous year through June
30 of the year the update was completed. Posted on the
website along with the updated documents is a list of all the
publications reviewed by the Committee.
Process: To produce the updated documents a Pub
Med search is done using search felds established by the
Committee: 1) COPD OR chronic bronchitis OR emphysema,
All Fields, All Adult: 19+ years, only items with abstracts,
Clinical Trial, Human; and 2) COPD OR chronic bronchitis
OR emphysema AND systematic, All Fields, only items with
abstracts, human. The frst search includes publications
for July 1-December 30 for review by the Committee during
the ATS meeting. The second search includes publications
for January 1 June 30 for review by the Committee during
the ERS meeting. (Publications that appear after June 30
will be considered in the frst phase of the following year.)
Publications in peer review journals not captured by Pub Med
can be submitted to the Chair, GOLD Science Committee,
providing an abstract and the full paper are submitted in (or
translated into) English.
All members of the Committee receive a summary of
citations and all abstracts. Each abstract is assigned to two
Committee members, although all members are offered the
opportunity to provide an opinion on any abstract. Members
evaluate the abstract or, up to her/his judgment, the full
publication, by answering four specifc written questions
from a short questionnaire, and to indicate if the scientifc
data presented impacts on recommendations in the GOLD
report. If so, the member is asked to specifcally identify
modifcations that should be made.
The entire GOLD Science Committee meets twice yearly
to discuss each publication that was considered by at least
1 member of the Committee to potentially have an impact
on the COPD management. The full Committee then
reaches a consensus on whether to include it in the report,
either as a reference supporting current recommendations,
or to change the report. In the absence of consensus,
disagreements are decided by an open vote of the full
Committee. Recommendations by the Committee for use
of any medication are based on the best evidence available
from the literature and not on labeling directives from
government regulators. The Committee does not make
recommendations for therapies that have not been approved
by at least one regulatory agency.
As an example of the workload of the Committee, for the
2010 update, between July 1, 2009 and June 30, 2010, 182
articles met the search criteria. Of the 182, 16 papers were
identifed to have an impact on the GOLD report posted on
the website in December 2010 either by: A) modifying, that
is, changing the text or introducing a concept requiring a
new recommendation to the report, or B) confrming, that is,
adding or replacing an existing reference.
*
The Global Strategy for Diagnosis, Management and Prevention of COPD (updated 2010), the Executive Summary (updated 2010), the Pocket Guide
(updated 2010) and the complete list of references examined by the Committee are available on the GOLD website www.goldcopd.org.

Members (2009-2010): J. Vestbo, Chair; A. Agusti, A. Anzueto, P. Barnes, P. Calverley, L. Fabbri, P. Jones, F. Martinez, M. Nishimura,
R. Rodriguez-Roisin, D. Sin, R. Stockley, C. Volgelmeier.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
viii
A. Modifcations in the text
Pg 5, right column, second paragraph, modify last sentence:
Prior tuberculosis has been shown to be an independent
risk factor for airfow obstruction. Thus clinicians should be
aware of the long-term risk of COPD in individuals with prior
tuberculosis, irrespective of smoking status
27
, particularly in
patients from countries with a high burden of tuberculosis
23
.
Reference 27. Lam KB, Jiang CQ, Jordan RE, Miller MR,
Zhang WS, Cheng KK, Lam TH, Adab P. Prior TB, smoking,
and airfow obstruction: a cross-sectional analysis of the
Guangzhou Biobank Cohort Study. Chest 2010;137(3):593-
600.
Pg 33, left column, key points and last paragraph delete:
and FEV
1
< 80% predicted
Pg 35, left column, second paragraph modify last sentence
to read: Psychiatric morbidity, especially anxiety and
depression are increased in COPD
14
and high levels of
anxiety are associated with poorer outcomes
448
. Anxiety
and depression merit specifc enquiry in the clinical history.
Reference 448. Eisner MD, Blanc PD, Yelin EH, Katz PP,
Sanchez G, Iribarren C, Omachi TA. Infuence of anxiety on
health outcomes in COPD. Thorax 2010;65(3):229-34.
Pg 36, Figure 5.1-4 last bullet, delete: .FEV
1
< 80%
predicted together with an ..
Pg 49, left column, ffth paragraph, insert: Adherence to
inhaled medication has been shown to be signifcantly
associated with reduced risk of death and admission to
hospital due to exacerbations in COPD
449
. Reference 449.
Vestbo J, Anderson JA, Calverley PM, Celli B, Ferguson
GT, Jenkins C, Knobil K, Willits LR, Yates JC, Jones PW.
Adherence to inhaled therapy, mortality and hospital
admission in COPD. Thorax 2009;64(11):939-43.
Pg 50, left column, frst paragraph, last sentence replace
with: Self-management programs have produced mixed
results in other jurisdictions, possibly owing to differences
in the study population, disease severity and individual
components in the self-management program
450
. Reference
450. Effng T, Kerstjens H, van der Valk P, Zielhuis G,
van der Palen J. (Cost)-effectiveness of self-treatment of
exacerbations on the severity of exacerbations in patients
with COPD: the COPE II study. Thorax 2009;64(11):956-62.
Pg 51, Figure 5.3-4: Add indacaterol 150-300 (DPI), 24
hours. Add new category: Phosphodiesterase-4 Inhibitors
and add Rofumilast oral 500 mcg, 24 hours. Add a footnote
to indicate that not all formulations are available in all
countries.
Pg 54, right column, second paragraph, delete segment on
side effects in asthma and replace with: Treatment over a
three year period with high dose futicasone propionate alone
or in combination with salmeterol was not associated with
decreased bone mineral density in a population of COPD
patients with high prevalence of osteoporosis
451
. Reference
451. Ferguson GT, Calverley PM, Anderson JA, Jenkins CR,
Jones PW, Willits LR, Yates JC, Vestbo J, Celli B. Prevalence
and progression of osteoporosis in patients with COPD:
results from the TOwards a Revolution in COPD Health
study. Chest 2009;136(6):1456-65.
Pg 54, right column, second paragraph, insert at end of
paragraph: Addition of a long-acting
2
-agonist/inhaled
glucocorticosteroid combination to a anticholinergic
(tiotropium) appears to provide additional benefts
453
.
Reference 453. Welte T, Miravitlles M, Hernandez P,
Eriksson G, Peterson S, Polanowski T, Kessler R. Effcacy
and tolerability of budesonide/formoterol added to tiotropium
in patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2009;180(8):741-50.
Pg 55, left column, insert new paragraph:
Phosphodiesterase-4 inhibitors. The principal action of
phosphodiesterase-4 inhibitors is to reduce infammation
through inhibition of the breakdown of intracellular cyclic
AMP. The phosphodiesterase-4 inhibitor, rofumilast, has
been approved for use only in some countries. It is a once
daily oral medication with no direct bronchodilator activity,
although it has been shown to improve FEV
1

in patients
treated with salmeterol or tiotropium
454
. In patients with Stage
III: Severe COPD or Stage IV: Very Severe COPD and a
history of exacerbations and chronic bronchitis, rofumilast
reduces exacerbations treated with oral or systemic
lucocorticosteroids. Rofumilast also reduced a composite
end-point consisting of moderate exacerbations treated with
oral or systemic gucocorticosteroids or severe exacerbations,
e.g., requiring hospitalization or causing death
454
(Evidence
B). These effects are also seen when rofumilast is added
to long-acting bronchodilators (Evidence B); there are
no comparison studies with inhaled glucocorticosteroids.
Rofumilast and theophylline cannot be given together.
Adverse effects: Phosphodiesterase-4 inhibitors have more
adverse effects than inhaled medications for COPD
454,455
.
The most frequent adverse effects are nausea, reduced
appetite, abdominal pain, diarrhea, sleep disturbances and
headache. Adverse effects led to increased withdrawal
in clinical trials from the group receiving rofumilast.
Adverse effects seem to occur early during treatment, are
reversible and reduce over time with continued treatment.
In controlled studies an average weight loss of 2 kg has
been seen and weight control during treatment is advised
as well as avoiding treatment with rofumilast in underweight
patients. Rofumilast should also be avoided in patients with
depression.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
ix
Reference 454. Fabbri LM, Calverley PM, Izquierdo-Alonso
JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF; M2-
127 and M2-128 study groups. Rofumilast in moderate-to-
severe chronic obstructive pulmonary disease treated with
long-acting bronchodilators: two randomised clinical trials.
Lancet 2009;374(9691):695-703. Reference 455. Calverley
PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM,
Martinez FJ; M2-124 and M2-125 study groups. Rofumilast
in symptomatic chronic obstructive pulmonary disease: two
randomised clinical trials. Lancet 2009;374(9691):685-94.
Pg 56, right column, fourth paragraph, modify last segment
to read: Pneumococcal polysaccharide vaccine is
recommended for COPD patients 65 years and older
178, 179

and has been shown to reduce the incidence of community-
acquired pneumonia in COPD patients younger than age 65
with an FEV
1
< 40% predicted
180
(Evidence B). However
infuenza but not pneumococcal vaccination has been shown
to be associated with a reduced risk of all-cause mortality
in COPD
457
. Reference 457. Schembri S, Morant S,
Winter JH, MacDonald TM. Infuenza but not pneumococcal
vaccination protects against all-cause mortality in patients
with COPD. Thorax 2009;64(7):567-72.
Pg 58, right column, paragraph on functional status, reword:
Benefts have been seen in patients with a wide range of
disability including patients with Stage IV: Very Severe
COPD under long-term oxygen treatment as it achieves
an improvement in exercise tolerance, reduces dyspnea
after effort, and improves quality of life without causing any
complication arising from the performance of the exercises
458
.
Reference 458. Fernndez AM, Pascual J, Ferrando
C, Arnal A, Vergara I, Sevila V. Home-based pulmonary
rehabilitation in very severe COPD: is it safe and useful? J
Cardiopulm Rehabil Prev 2009;29(5):325-31.
Pg 61, right column, third paragraph insert after reference
284: and may improve survival but at the cost of
worsening quality of life
460
. Reference 460. McEvoy RD,
Pierce RJ, Hillman D, Esterman A, Ellis EE, Catcheside PG,
ODonoghue FJ, Barnes DJ, Grunstein RR; Australian trial of
non-invasive Ventilation in Chronic Airfow Limitation (AVCAL)
Study Group. Nocturnal non-invasive nasal ventilation in
stable hypercapnic COPD: a randomized controlled trial.
Thorax 2009;64(7):561-6.
Pg 68, left column, third paragraph antibiotics: delete a
small benefcial effect and insert mixed results. Add
this reference at end of sentence after 365. Reference
461. Daniels JM, Snijders D, de Graaff CS, Vlaspolder
F, Jansen HM, Boersma WG. Antibiotics in addition to
systemic corticosteroids for acute exacerbations of chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2010;181(2):150-7.
B. References that provided confrmation or update of
previous recommendations
Pg 54, right column, third paragraph, add reference.
Reference 452. Crim C, Calverley PM, Anderson JA, Celli
B, Ferguson GT, Jenkins C, Jones PW, Willits LR, Yates JC,
Vestbo J. Pneumonia risk in COPD patients receiving inhaled
corticosteroids alone or in combination: TORCH study
results. Eur Respir J 2009;34(3):641-7.
Pg 56, left column, third paragraph, insert reference.
Reference 456. Decramer M, Celli B, Kesten S, Lystig
T, Mehra S, Tashkin DP; UPLIFT investigators. Effect of
tiotropium on outcomes in patients with moderate chronic
obstructive pulmonary disease (UPLIFT): a prespecifed
subgroup analysis of a randomised controlled trial. Lancet
2009;374(9696):1171-8.
Pg 58, right column, paragraph on motivation, add reference.
Reference 459. Fischer MJ, Scharloo M, Abbink JJ, van
t Hul AJ, van Ranst D, Rudolphus A, Weinman J, Rabe
KF, Kaptein AA. Drop-out and attendance in pulmonary
rehabilitation: the role of clinical and psychosocial variables.
Respir Med 2009;103(10):1564-71.
Pg 71, left column, last line, modify reference 421 to 462.
Pg 91, right column last paragraph, insert reference.
Reference 15: Chavannes NH, Grijsen M, van den Akker M,
Schepers H, Nijdam M, Tiep B, Muris J. Integrated disease
management improves one-year quality of life in primary care
COPD patients: a controlled clinical trial. Prim Care Respir J
2009;18(3):171-6.
C. Revision of GOLD report Global Strategy for the
Diagnosis, Management and Prevention of COPD.
Throughout 2009 and 2010, members of the GOLD
Science Committee have examined publications that
require considerable revision of the current document. At
their meeting in September, 2009, there was unanimous
agreement that a revised document - requiring many
important modifcations - should be prepared for release in
2011. The Committee continues to review available evidence
with regard to the multiple issues:
Assessment of disease severity: the role of
spirometric criteria, symptoms and medical history
for COPD diagnosis
Treatment recommendations in relation to severity
COPD and concomitant disorders
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
xi
GLOBAL STRATEGY FOR THE DIAGNOSIS,
MANAGEMENT, AND PREVENTION OF COPD
Chronic Obstructive Pulmonary Disease (COPD) is a major
cause of chronic morbidity and mortality throughout the
world. Many people suffer from this disease for years and die
prematurely from it or its complications. COPD is the fourth
leading cause of death in the world1, and further increases in
its prevalence and mortality can be predicted in the coming
decades
2
.
The goals of the Global Initiative for Chronic Obstructive
Lung Disease (GOLD) are to increase awareness of COPD
and decrease morbidity and mortality from the disease.
GOLD aims to improve prevention and management of
COPD through a concerted worldwide effort of people
involved in all facets of health care and health care policy,
and to encourage an expanded level of research interest
in this highly prevalent disease. A nihilistic attitude toward
COPD continues among some health care providers, due
to the relatively limited success of primary and secondary
prevention (i.e., avoidance of factors that cause COPD or
its progression), the prevailing notion that COPD is largely
a self-inficted disease, and disappointment with available
treatment options. Another important goal of the GOLD
initiative is to work toward combating this nihilistic attitude by
disseminating information about available treatments (both
pharmacologic and nonpharmacologic), and by working
with a network of experts the GOLD National Leadersto
implement effective COPD management programs
developed in accordance with local health care practices.
Tobacco smoking continues to be a major cause of COPD,
as well as of many other diseases. A worldwide decline
in tobacco smoking would result in substantial health
benefts and a decrease in the prevalence of COPD and
other smoking-related diseases. There is an urgent need
for improved strategies to decrease tobacco consumption.
However, tobacco smoking is not the only cause of COPD,
and it may not even be the major cause in some parts of
the world. Furthermore, not all smokers develop clinically
signifcant COPD, which suggests that additional factors are
involved in determining each individual's susceptibility. Thus,
investigations of COPD risk factors, ways to reduce exposure
to these factors, and the molecular and cellular mechanisms
involved in COPD pathogenesis continue to be important
areas of research to develop more effective treatments that
slow or halt the course of the disease.
One strategy to help achieve the objectives of GOLD is to
provide health care workers, health care authorities, and the
general public with state-of-the-art information about COPD
and specifc recommendations on the most appropriate
management and prevention strategies. The GOLD
report, Global Strategy for the Diagnosis, Management,
and Prevention of COPD, is based on the best-validated
current concepts of COPD pathogenesis and the available
evidence on the most appropriate management and
prevention strategies. The report, developed by individuals
with expertise in COPD research and patient care and
reviewed by many additional experts, provides state-of-
the-art information about COPD for pulmonary specialists
and other interested physicians. The document serves as a
source for the production of various communications for other
audiences, including an Executive Summary, a Pocket Guide
for Health Care Professionals, and a Patient Guide
2
.
The GOLD report is not intended to be a comprehensive
textbook on COPD, but rather to summarize the current
state of the feld. Each chapter starts with Key Points that
crystallize current knowledge. The chapters on the Burden of
COPD and Risk Factors demonstrate the global importance
of COPD and the various causal factors involved. The
chapter on Pathology, Pathogenesis, and Pathophysiology
documents the current understanding of, and remaining
questions about, the mechanism(s) that lead to COPD, as
well as the structural and functional abnormalities of the lung
that are characteristic of the disease.
A major part of the GOLD report is devoted to the clinical
Management of COPD and presents a management plan
with four components: (1) Assess and Monitor Disease;
(2) Reduce Risk Factors; (3) Manage Stable COPD; (4)
Manage Exacerbations.
Management recommendations are presented according
to the severity of the disease, using a simple classifcation
INTRODUCTION
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
xii
of severity to facilitate the practical implementation of
the available management options. Where appropriate,
information about health education for patients is included.
A new chapter at the end of the document will assist readers
in Translating Guideline Recommendations to the Context of
(Primary) Care.
A large segment of the worldis population lives in areas
with inadequate medical facilities and meager fnancial
resources, and fxed international guidelines and rigid
scientifc protocols will not work in many locations. Thus, the
recommendations found in this report must be adapted to ft
local practices and the availability of health care resources.
As the individuals who participate in the GOLD program
expand their work, every effort will be made to interact with
patient and physician groups at national, district, and local
levels, and in multiple health care settings, to continuously
examine new and innovative approaches that will ensure the
delivery of the best care possible to COPD patients, and the
initiation of programs for early detection and prevention of
this disease. GOLD is a partner organization in a program
launched in March 2006 by the World Health Organization,
the Global Alliance Against Chronic Respiratory Diseases
(GARD). Through the work of the GOLD committees, and
in cooperation with GARD initiatives, progress toward better
care for all patients with COPD should be substantial in the
next decade.
A. Preparation of yearly updates: Immediately following the
release of the frst GOLD report in 2001, the GOLD Executive
Committee appointed a Science Committee, charged with
keeping the GOLD documents up-to-date by reviewing
published research, evaluating the impact of this research on
the management recommendations in the GOLD documents,
and posting yearly updates of these documents on the GOLD
Website. The frst update to the GOLD report was posted
in July 2003, based on publications from January 2001
through December 2002. A second update appeared in July
2004, and a third in July 2005, each including the impact of
publications from January through December of the previous
year.
Producing the yearly updates began with a PubMed (http://
www.nlm.nih.gov) search using search felds established
by the Science Committee: 1) COPD OR chronic bronchitis
OR emphysema, All Fields, All Adult, 19+ years, only items
with abstracts, Clinical Trial, Human, sorted by Author;
and 2) COPD OR chronic bronchitis OR emphysema AND
systematic, All Fields, All Adult, 19+ years, only items with
abstracts, Human, sorted by Author. In addition, publications
in peer-reviewed journals not captured by PubMed could be
submitted to individual members of the Science Committee,
provided that an abstract and the full paper were submitted in
(or translated into) English.
All members of the committee received a summary of
citations and all abstracts. Each abstract was assigned
to two committee members (members were not assigned
papers they had authored), although any member was
offered the opportunity to provide an opinion on any abstract.
Each member evaluated the assigned abstracts or, where
s/he judged necessary, the full publication, by answering
specifc written questions from a short questionnaire, and
indicating whether the scientifc data presented affected
recommendations in the GOLD report. If so, the member
was asked to specifcally identify modifcations that should be
made. The GOLD Science Committee met on a regular basis
to discuss each individual publication indicated by at least
one member of the committee to have an impact on COPD
management, and to reach a consensus on the changes
needed in the report. Disagreements were decided by vote.
The publications that met the search criteria for each yearly
update (between 100 and 200 articles per year) mainly
affected Chapter 5, Management of COPD. Lists of the
publications considered by the Science Committee each
year, along with the yearly updated reports, are posted on the
GOLD Website, www.goldcopd.org.
B. Preparation of the New 2006 Report: In January
2005, the GOLD Science Committee initiated its work on
a comprehensively updated version of the GOLD report.
During a two-day meeting, the committee established that
the report structure should remain the same as in the 2001
document, but that each chapter would be carefully reviewed
and modifed in accordance with new published literature.
The committee met in May and September 2005 to evaluate
progress and to reach consensus on the messages to be
provided in each chapter. Throughout its work, the committee
made a commitment to develop a document that would
reach a global audience, be based on the most current
scientifc literature, and be as concise as possible, while
at the same time recognizing that one of the values of the
GOLD report has been to provide background information
on COPD management and the scientifc principles on which
management recommendations are based.
In January 2006, the Science Committee met with the
Executive Committee for a two-day session during which
another in-depth evaluation of each chapter was conducted.
At this meeting, members reviewed the literature that
appeared in 2005-using the same criteria developed for
the update process. The list of 2005 publications that were
considered is posted on the GOLD website. At the January
meeting, it was clear that work remaining would permit the
report to be fnished during the summer of 2006, and the
METHODOLOGY
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
xiii
Science Committee requested that, as publications appeared
throughout early 2006, they be reviewed carefully for their
impact on the recommendations. At the committees next
meeting, in May 2006, publications meeting the search
criteria were considered and incorporated into the current
drafts of the chapters where appropriate. A fnal meeting
of the committee was held in September 2006, at which
time publications that appeared prior to July 31, 2006 were
considered for their impact on the document.
Periodically throughout the preparation of this report
(May and September 2005, May and September 2006),
representatives from the GOLD Science Committee met with
the GOLD National Leaders to discuss COPD management
and issues specifc to each of the chapters. The GOLD
National Leaders include representatives from over 50
countries and many participated in these interim discussions.
In addition, GOLD National Leaders were invited to submit
comments on a DRAFT document and their comments
were considered by the committee. When the committee
completed its work, several other individuals were invited to
submit comments on the document as reviewers. The names
of reviewers and GOLD National Leaders who submitted
comments are in the front material.
NEW ISSUES PRESENTED IN THIS REPORT
1. Throughout the document, emphasis has been made that
COPD is characterized by chronic airfow limitation and a
range of pathological changes in the lung, some signifcant
extrapulmonary effects, and important comorbidities that may
contribute to the severity of the disease in individual patients.
2. In the defnition of COPD, the phrase preventable and
treatable has been incorporated following the ATS/ERS
recommendations to recognize the need to present a positive
outlook for patients, to encourage the health care community
to take a more active role in developing programs for COPD
prevention, and to stimulate effective management programs
to treat those with the disease.
3. The spirometric classifcation of severity of COPD now
includes four stages- Stage I: Mild; Stage II: Moderate;
Stage III: Severe; Stage IV: Very Severe. A ffth category -
Stage 0: At Risk, - that appeared in the 2001 report is no
longer included as a stage of COPD, as there is incomplete
evidence that the individuals who meet the defnition of
At Risk (chronic cough and sputum production, normal
spirometry) necessarily progress on to Stage I. Nevertheless,
the importance of the public health message that chronic
cough and sputum are not normal is unchanged.
4. The spirometric classifcation of severity continues to
recommend use of the fxed ratio, postbronchodilator
FEV
1
/FVC < 0.7, to defne airfow limitation. Using the
fxed ratio (FEV
1
/FVC) is particularly problematic in milder
patients who are elderly as the normal process of aging
affects lung volumes. Postbronchodilator reference values
in this population are urgently needed to avoid potential
overdiagnosis.
5. Chapter 2, Burden of COPD, provides references to
published data from prevalence surveys carried out in a
number of countries, using standardized methods and
including spirometry, to estimate that about 15 to 25% of
adults aged 40 years and older may have airfow limitation
classifed as Stage I: Mild COPD or higher. Evidence is also
provided that the prevalence of COPD (Stage I: Mild COPD
and higher) is appreciably higher in smokers and ex-smokers
than in nonsmokers, in those over 40 years than those under
40, and higher in men than in women. The chapter also
provides new data on COPD morbidity and mortality.
6. Throughout it is emphasized that cigarette smoke is the
most commonly encountered risk factor for COPD and
elimination of this risk factor is an important step toward
prevention and control of COPD. However, other risk factors
for COPD should be taken into account where possible.
These include occupational dusts and chemicals, and indoor
air pollution from biomass cooking and heating in poorly
ventilated dwellings - the latter especially among women in
developing countries.
7. Chapter 4, Pathology, Pathogenesis, and Pathophysiology,
continues with the theme that inhaled cigarette smoke and
other noxious particles cause lung infammation, a normal
response which appears to be amplifed in patients who
develop COPD. The chapter has been considerably updated
and revised.
8. Management of COPD continues to be presented in four
components: (1) Assess and Monitor Disease; (2) Reduce
Risk Factors; (3) Manage Stable COPD; (4) Manage
Exacerbations. All components have been updated based
on recently published literature. Throughout the document, it
is emphasized that the overall approach to managing stable
COPD should be individualized to address symptoms and
improve quality of life.

9. In Component 4, Manage Exacerbations, a COPD
exacerbation is defned as: an event in the natural
course of the disease characterized by a change in the
patientMs baseline dyspnea, cough, and/or sputum that is
beyond normal day-to-day variations, is acute in onset, and
may warrant a change in regular medication in a patient with
underlying COPD.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
xiv
10. It is widely recognized that a wide spectrum of health
care providers are required to assure that COPD is
diagnosed accurately, and that individuals who have COPD
are treated effectively. The identifcation of effective health
care teams will depend on the local health care system, and
much work remains to identify how best to build these health
care teams. A chapter on COPD implementation programs
and issues for clinical practice has been included but it
remains a feld that requires considerable attention.
LEVELS OF EVIDENCE
Levels of evidence are assigned to management
recommendations where appropriate in Chapter 5,
Management of COPD. Evidence levels are indicated in
boldface type enclosed in parentheses after the relevant
statement e.g., (Evidence A). The methodological issues
concerning the use of evidence from meta-analyses were
carefully considered
3
.
This evidence level scheme (Figure A) has been used in
previous GOLD reports, and was in use throughout the
preparation of this document. The GOLD Science Committee
was recently introduced to a new approach to evidence
levels
4
and plans to review and consider the possible
introduction of this approach in future reports.
REFERENCES
1 World Health Report. Geneva: World Health Organization. Available from URL: http://www.who.int/whr/2000/en/statistics.htm; 2000.
2 Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, et al. Chronic obstructive pulmonary disease: current burden and future
projections. Eur Respir J 2006;27(2):397-412.
3 Jadad AR, Moher M, Browman GP, Booker L, Sigouin C, Fuentes M, et al. Systematic reviews and meta-analyses on treatment of
asthma: critical evaluation. BMJ 2000;320(7234):537-40.
4 Guyatt G, Vist G, Falck-Ytter Y, Kunz R, Magrini N, Schunemann H. An emerging consensus on grading recommendations? ACP J Club
2006;144(1):A8-9. Available from URL: http://www.evidence-basedmedicine.com.
Figure A. Description of Levels of Evidence
Randomized controlled
trials (RCTs). Rich body of data.
Evidence
Category
A
B
C
D
Sources of Evidence Definition
Evidence is from endpoints of well-designed RCTs that provide a consistent
pattern of findings in the population for which the recommendation is made.
Category A requires substantial numbers of studies involving substantial
numbers of participants.
Randomized controlled trials
(RCTs). Limited body of data.
Evidence is from endpoints of intervention studies that include only a limited
number of patients, posthoc or subgroup analysis of RCTs, or meta-analysis
of RCTs. In general, Category B pertains when few randomized trials exist,
they are small in size, they were undertaken in a population that differs from
the target population of the recommendation, or the results are somewhat
inconsistent.
Nonrandomized trials.
Observational studies.
Evidence is from outcomes of uncontrolled or nonrandomized trials or from
observational studies.
Panel Consensus Judgment. This category is used only in cases where the provision of some guidance
was deemed valuable but the clinical literature addressing the subject was
deemed insufficient to justify placement in one of the other categories. The
Panel Consensus is based on clinical experience or knowledge that does not
meet the above-listed criteria.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
CHAPTER
1
DEFINITION
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
2 DEFINITION
KEY POINTS:
Chronic Obstructive Pulmonary Disease (COPD) is
a preventable and treatable disease with some
signifcant extrapulmonary effects that may
contribute to the severity in individual patients.
Its pulmonarycomponent is characterized by airfow
limitation that is not fully reversible. The airfow
limitation is usually progressive and associated
with an abnormal infammatory response of the
lung to noxious particles or gases.
The chronic airfow limitation characteristic of COPD
is caused by a mixture of small airway disease
(obstructive bronchiolitis) and parenchymal
destruction (emphysema), the relative contributions
of which vary from person to person.
COPD has a variable natural history and not all
individuals follow the same course. However,
COPD is generally a progressive disease, especially
if a patient's exposure to noxious agents continues.
The impact of COPD on an individual patient
depends on the severity of symptoms (especially
breathlessness and decreased exercise capacity),
systemic effects, and any comorbidities the patient
may have-not just on the degree of airfow limitation.
Chronic obstructive pulmonary disease (COPD) is
characterized by chronic airfow limitation and a range
of pathological changes in the lung, some signifcant
extrapulmonary effects, and important comorbidities which
may contribute to the severity of the disease in individual
patients. Thus, COPD should be regarded as a pulmonary
disease, but these signifcant comorbidities must be taken
into account in a comprehensive diagnostic assessment of
severity and in determining appropriate treatment.
Based on current knowledge, a working defnition is:
Chronic Obstructive Pulmonary Disease (COPD) is a
preventable and treatable disease with some signifcant
extrapulmonary effects that may contribute to the severity in
individual patients. Its pulmonary component is characterized
by airfow limitation that is not fully reversible. The airfow
limitation is usually progressive and associated with an
abnormal infammatory response of the lung to noxious
particles or gases.
Worldwide, cigarette smoking is the most commonly
encountered risk factor for COPD, although in many
countries, air pollution resulting from the burning of wood
and other biomass fuels has also been identifed as a
COPD risk factor.
Airfow Limitation in COPD
The chronic airfow limitation characteristic of COPD is
caused by a mixture of small airway disease (obstructive
bronchiolitis) and parenchymal destruction (emphysema),
the relative contributions of which vary from person
to person (Figure 1-1). Chronic infammation causes
structural changes and narrowing of the small airways.
Destruction of the lung parenchyma, also by infammatory
processes, leads to the loss of alveolar attachments to the
small airways and decreases lung elastic recoil; in turn,
these changes diminish the ability of the airways to remain
open during expiration. Airfow limitation is best measured
by spirometry, as this is the most widely available,
reproducible test of lung function.
CHAPTER 1: DEFINITION
DEFINITION
Figure 1-1. Mechanisms Underlying Airflow
Limitation in COPD
INFLAMMATION
AIRFLOW LIMITATION
Small airway disease
Airway inflammation
Airway remodeling
Parenchymal destruction
Loss of alveolar attachments
Decrease of elastic recall
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
DEFINITION 3
Many previous defnitions of COPD have emphasized the
terms emphysema and chronic bronchitis, which are
not included in the defnition used in this and earlier GOLD
reports. Emphysema, or destruction of the gasexchanging
surfaces of the lung (alveoli), is a pathological term that
is often (but incorrectly) used clinically and describes
only one of several structural abnormalities present in
patients with COPD. Chronic bronchitis, or the presence
of cough and sputum production for at least 3 months in
each of two consecutive years, remains a clinically and
epidemiologically useful term. However, it does not refect
the major impact of airfow limitation on morbidity and
mortality in COPD patients. It is also important to recognize
that cough and sputum production may precede the
development of airfow limitation; conversely, some patients
develop signifcant airfow limitation without chronic cough
and sputum production.
COPD and Comorbidities
Because COPD often develops in long-time smokers in
middle age, patients often have a variety of other diseases
related to either smoking or aging
1
. COPD itself also has
signifcant extrapulmonary (systemic) effects that lead to
comorbid conditions
2
. Data from the Netherlands show
that up to 25% of the population 65 years and older suffer
from two comorbid conditions and up to 17% have three
3
.
Weight loss, nutritional abnormalities and skeletal muscle
dysfunction are wellrecognized extrapulmonary effects of
COPD and patients are at increased risk for myocardial
infarction, angina, osteoporosis, respiratory infection, bone
fractures, depression
24, 25
, diabetes, sleepdisorders, anemia,
and glaucoma
4
. The existence of COPD may actually
increase the risk for other diseases; this is particularly
striking for COPD and lung cancer
58
. Whether this
association is due to common risk factors (e.g., smoking),
involvement of susceptibility genes, or impaired clearance
of carcinogens is not clear.
Thus, COPD should be managed with careful attention
also paid to comorbidities and their effect on the
patient?s quality of life. A careful differential diagnosis
and comprehensive assessment of severity of comorbid
conditions should be performed in every patient with
chronic airfow limitation.
COPD has a variable natural history and not all individuals
follow the same course. However, COPD is generally a
progressive disease, especially if a patient's exposure to
noxious agents continues. Stopping exposure to these
agents, even when signifcant airfow limitation is present,
may result in some improvement in lung function and slow
or even halt progression of the disease. However, once
developed, COPD and its comorbidities cannot be cured
and thus must be treated continuously. COPD treatment
can reduce symptoms, improve quality of life, reduce
exacerbations, and possibly reduce mortality.
Spirometric Classifcation of Severity
For educational reasons, a simple spirometric classifcation
of disease severity into four stages is recommended
(Figure 1-2). Spirometry is essential for diagnosis and
provides a useful description of the severity of pathological
changes in COPD. Specifc spirometric cutpoints (e.g.,
postbronchodilator FEV
1
/FVC ratio < 0.70 or FEV
1
< 80,
50, or 30% predicted) are used for purposes of simplicity:
these cutpoints have not been clinically validated. A
study in a random population sample found that the
postbronchodilator FEV
1
/FVC exceeded 0.70 in all age
groups, supporting the use of this fxed ratio
9
.
However, because the process of aging does affect lung
volumes, the use of this fxed ratio may result in over
diagnosis of COPD in the elderly, and under diagnosis in
adults younger than 45 years
26
, especially of mild disease.
Using the lower limit of normal (LLN) values for FEV
1
/FVC,
that are based on the normal distribution and classify the
bottom 5% of the healthy population as abnormal, is one
way to minimize the potential misclassifcation. In principle,
all programmable spirometers could do this calculation if
reference equations for the LLN of the ratio were available.
However, reference equations using postbronchodilator
FEV
1
and longitudinal studies to validate the use of the LLN
are urgently needed.
NATURAL HISTORY
FEV
1
: forced expiratory volume in one second; FVC: forced vital capacity; respiratory
failure: arterial partial pressure of oxygen (PaO
2
) less than 8.0 kPa (60 mm Hg)
with or without arterial partial pressure of CO
2
(PaCO
2
) greater than 6.7 kPa
(50 mm Hg) while breathing air at sea level.
Figure 1-2. Spirometric Classification of COPD
Severity Based on Post-Bronchodilator FEV
1
Stage I: Mild FEV
1
/FVC < 0.70
FEV
1
80% predicted
Stage II: Moderate FEV
1
/FVC < 0.70
50% FEV
1
< 80% predicted
Stage III: Severe FEV
1
/FVC < 0.70
30% FEV
1
< 50% predicted
Stage IV: Very Severe FEV
1
/FVC < 0.70
FEV
1
< 30% predicted or FEV
1
< 50%
predicted plus chronic respiratory
failure
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
4 DEFINITION
Spirometry should be performed after the administration
of an adequate dose of an inhaled bronchodilator (e.g.,
400 g salbutamol)
10
in order to minimize variability. In a
random population study to determine spirometry reference
values, postbronchodilator values differed markedly from
prebronchodilator values
9
. Furthermore, postbronchodilator
lung function testing in a community setting has been
demonstrated to be an effective method to identify
individuals with COPD
11
.
While postbronchodilator FEV
1
/FVC and FEV
1

measurements are recommended for the diagnosis and
assessment of severity of COPD, the degree of reversibility
of airfow limitation (e.g., FEV
1
after bronchodilator
or glucocorticosteroids) is no longer recommended for
diagnosis, differential diagnosis with asthma, or predicting
the response to longer treatment with bronchodilators or
glucocorticosteroids.
Stages of COPD
The impact of COPD on an individual patient depends
not just on the degree of airfow limitation, but also on
the severity of symptoms (especially breathlessness and
decreased exercise capacity). There is only an imperfect
relationship between the degree of airfow limitation and
the presence of symptoms. Spirometric staging, therefore,
is a pragmatic approach aimed at practical implementation
and should only be regarded as an educational tool and a
general indication to the initial approach to management.
The characteristic symptoms of COPD are chronic and
progressive dyspnea, cough, and sputum production.
Chronic cough and sputum production may precede the
development of airfow limitation by many years. This
pattern offers a unique opportunity to identify smokers and
others at risk for COPD (Figure 1-3), and intervene when
the disease is not yet a major health problem.
Conversely, signifcant airfow limitation may develop
without chronic cough and sputum production. Although
COPD is defned on the basis of airfow limitation, in
practice the decision to seek medical help (and so permit
the diagnosis to be made) is normally determined by the
impact of a particular symptom on a patient's lifestyle.
Thus, COPD may be diagnosed at any stage of the illness.
Stage I: Mild COPD - Characterized by mild airfow limitation
(FEV
1
/FVC < 0.70; FEV
1
80 % predicted). Symptoms of
chronic cough and sputum production may be present, but
not always. At this stage, the individual is usually unaware
that his or her lung function is abnormal.
Stage II: Moderate COPD - Characterized by worsening
airfow limitation (FEV
1
/FVC < 0.70; 50% FEV
1
< 80%
predicted), with shortness of breath typically developing on
exertion and cough and sputum production sometimes also
present. This is the stage at which patients typically seek
medical attention because of chronic respiratory symptoms
or an exacerbation of their disease.
Stage III: Severe COPD - Characterized by further
worsening of airfow limitation (FEV
1
/FVC < 0.70; 30%
FEV
1
< 50% predicted), greater shortness of breath,
reduced exercise capacity, fatigue, and repeated
exacerbations that almost always have an impact on
patients quality of life.
Stage IV: Very Severe COPD - Characterized by severe
airfow limitation (FEV
1
/FVC < 0.70; FEV
1
< 30% predicted
or FEV
1
< 50% predicted plus the presence of chronic
respiratory failure). Respiratory failure is defned as an
arterial partial pressure of O
2
(PaO
2
) less than 8.0 kPa (60
mm Hg), with or without arterial partial pressure of CO
2

(PaCO
2
) greater than 6.7 kPa (50 mm Hg) while breathing
air at sea level. Respiratory failure may also lead to effects
on the heart such as cor pulmonale (right heart failure).
Clinical signs of cor pulmonale include elevation of the
jugular venous pressure and pitting ankle edema. Patients
may have Stage IV: Very Severe COPD even if the FEV
1

is > 30% predicted, whenever these complications are
present. At this stage, quality of life is very appreciably
impaired and exacerbations may be life threatening.
The common statement that only 15-20% of smokers
develop clinically signifcant COPD is misleading
12
. A much
higher proportion may develop abnormal lung function at
some point if they continue to smoke
13
. Not all individuals
with COPD follow the classical linear course as outlined in
the Fletcher and Peto diagram, which is actually the mean
of many individual courses
14
. Causes of death in patients
with COPD are mainly cardiovascular diseases, lung cancer,
and, in those with advanced COPD, respiratory failure
15
.
Figure 1-3. At Risk for COPD
A major objective of GOLD is to increase awareness among
health care providers and the general public of the significance of
COPD symptoms. The classification of severity of COPD now
includes four stages classified by spirometryStage I: Mild
COPD; Stage II: Moderate COPD; Stage III: Severe COPD;
Stage IV: Very Severe COPD. A fifth category - Stage 0: At
Risk, that appeared in the 2001 report is no longer included
as a stage of COPD, as there is incomplete evidence that the
individuals who meet the definition of At Risk (chronic cough
and sputum production, normal spirometry) necessarily
progress on to Stage I. Mild COPD. Nevertheless, the
importance of the public health message that chronic cough
and sputum are not normal is unchanged and their presence
should trigger a search for underlying cause(s).
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
DEFINITION 5
It is not the scope of this report to provide a comprehensive
discussion of the natural history of comorbidities associated
with COPD but to focus primarily on chronic airfow
limitation caused by inhaled particles and gases, the most
common of which worldwide is cigarette smoke. However,
chronic airfow limitation may develop also in nonsmokers
who present with similar symptoms and may be associated
with other diseases, e.g., asthma, congestive heart failure,
lung carcinoma, bronchiectasis, pulmonary tuberculosis,
bronchiolitis obliterans, and interstitial lung diseases. Poorly
reversible airfow limitation associated with these conditions
is not addressed except insofar as these conditions overlap
with COPD.
Asthma and COPD
COPD can coexist with asthma, the other major chronic
obstructive airway disease characterized by an underlying
airway infammation. The underlying chronic airway
infammation is very different in these two diseases (Figure
1-4). However, individuals with asthma who are exposed
to noxious agents, particularly cigarette smoke
16
, may also
develop fxed airfow limitation and a mixture of asthma-
like and COPD-like infammation. Furthermore, there
is epidemiologic evidence that long-standing asthma on
its own can lead to fxed airfow limitation
17
. Other patients
with COPD may have features of asthma such as a mixed
infammatory pattern with increased eosinophils
18
. Thus,
while asthma can usually be distinguished from COPD, in
some individuals with chronic respiratory symptoms and
fxed airfow limitation it remains diffcult to differentiate
the two diseases. Population-based surveys
19,20
have
documented that chronic airfow limitation may occur in
up to 10% of lifetime nonsmokers 40 years and older; the
causes of airfow limitation in nonsmokers needs further
investigation.
Pulmonary Tuberculosis and COPD
In many developing countries both pulmonary tuberculosis
and COPD are common
21
. In countries where tuberculosis
is very common, respiratory abnormalities may be too
readily attributed to this disease
22
. Conversely, where the
rate of tuberculosis is greatly diminished, the possible
diagnosis of this disease is sometimes overlooked.
Prior tuberculosis has been shown to be an independent
risk factor for airfow obstruction. Thus clinicians should
be aware of the long-term risk of COPD in individuals
with prior tuberculosis, irrespective of smoking status
27
,
particularly in patients from countries with a high burden of
tuberculosis
23
.
REFERENCES
1. Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell
AL. Patterns of comorbidities in newly diagnosed COPD and
asthma in primary care. Chest 2005;128(4):2099107.
2. Agusti AG. Systemic effects of chronic obstructive pulmonary
disease. Proc Am Thorac Soc 2005;2(4):36770.
3. van Weel C. Chronic diseases in general practice: the
longitudinal dimension. Eur J Gen Pract 1996;2:1721.
4. van Weel C, Schellevis FG. Comorbidity and guidelines:
conficting interests. Lancet 2006;367(9510):5501.
5. Stavem K, Aaser E, Sandvik L, Bjornholt JV, Erikssen G,
Thaulow E, et al. Lung function, smoking and mortality in
a 26year followup of healthy middleaged males. Eur Respir J
2005;25(4):61825.
6. Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer
in chronic obstructive pulmonary disease. A prospective,
matched, controlled study. Ann Intern Med 1986;105(4):5037.
7. Tockman MS, Anthonisen NR, Wright EC, Donithan MG.
Airways obstruction and the risk for lung cancer. Ann Intern
Med 1987;106(4):5128.
8. Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P.
Ventilatory function and chronic mucus hypersecretion
as predictors of death from lung cancer. Am Rev Respir Dis
1990;141(3):6137.
9. Johannessen A, Lehmann S, Omenaas ER, Eide GE, Bakke
PS, Gulsvik A. Postbronchodilator spirometry reference values
in adults and implications for disease management. Am J
Respir Crit Care Med 2006;173(12):131625.
10. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F,
Casaburi R, et al. Interpretative strategies for lung function
tests. Eur Respir J 2005;26(5):94868.
SCOPE OF THIS REPORT
Figure 1-4. Asthma and COPD
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
6 DEFINITION
11. Johannessen A, Omenaas ER, Bakke PS, Gulsvik A.
Implications of reversibility testing on prevalence and risk
factors for chronic obstructive pulmonary disease: a community
study. Thorax 2005;60(10):8427.
12. Rennard S, Vestbo J. COPD: the dangerous underestimate of
15%. Lancet 2006;367:12169.
13. Lokke A, Lange P, Scharling H, Fabricius P, Vestbo J.
Developing COPD a 25 years followup study of the general
population. Thorax 2006;61:9359.
14. Fletcher C, Peto R. The natural history of chronic airfow
obstruction. BMJ 1977;1(6077):16458.
15. Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on
Obstructive Lung Disease (GOLD) classifcation of lung
disease and mortality: fndings from the Atherosclerosis Risk in
Communities (ARIC) study. Respir Med 2006;100(1):11522.
16. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette
smoking. Eur Respir J 2004;24(5):82233.
17. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15year
followup study of ventilatory function in adults with asthma. N
Engl J Med 1998;339(17):1194200.
18. Chanez P, Vignola AM, O'Shaugnessy T, Enander I, Li
D, Jeffery PK, et al. Corticosteroid reversibility in COPD
is related to features of asthma. Am J Respir Crit Care Med
1997;155(5):152934.
19. Menezes AM, PerezPadilla R, Jardim JR, Muino A, Lopez MV,
Valdivia G, et al. Chronic obstructive pulmonary disease in
fve Latin American cities (the PLATINO study): a prevalence
study. Lancet 2005;366(9500):187581.
20. Centers for Disease Control and Prevention. Surveillance
Summaries. MMWR 2002:51(No. SS6).
21. Fairall LR, Zwarenstein M, Bateman ED, Bachmann M,
Lombard C, Majara BP, et al. Effect of educational outreach
to nurses on tuberculosis case detection and primary care of
respiratory illness: pragmatic cluster randomised controlled
trial. BMJ 2005;331(7519):7504.
22. de Valliere S, Barker RD. Residual lung damage after
completion of treatment for multidrugresistant tuberculosis. Int J
Tuberc Lung Dis 2004;8(6):76771.
23. Bateman ED, Feldman C, O'Brien J, Plit M, Joubert JR.
Guideline for the management of chronic obstructive
ulmonary disease (COPD): 2004 revision. S Afr Med J
2004;94(7 Pt 2):55975.
24. Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive
symptoms and chronic obstructive pulmonary disease:
effect on mortality, hospital readmission, symptom burden,
functional status, and quality of life. Arch Intern Med 2007
Jan 8;167(1):607.
25. Fan VS, Ramsey SD, Giardino ND, Make BJ, Emery CF, Diaz
PT, Benditt JO, Mosenifar Z, McKenna R Jr, Curtis JL, Fishman
AP, Martinez FJ; National Emphysema Treatment Trial (NETT)
Research Group. Sex, depression, and risk of hospitalization
and mortality in chronic obstructive pulmonary disease. Arch
Intern Med. 2007 Nov 26;167(21):234553.
26. Cerveri I, Corisico AG, Accoridini S. Niniano R. Ansaldo E.
Anto JM, et al. Underestimation of airfow obstruction among
young adults using FEV1/FVC <70% as a fxed cutoff: a
longitudinal evaluation of clinical and functional outcomes.
Thorax. 2008 Dec;63(12):10405. Epub 2008 May 20.
27. Lam KB, Jiang CQ, Jordan RE, Miller MR, Zhang WS, Cheng
KK, Lam TH, Adab P. Prior TB, smoking, and airfow
obstruction: a cross-sectional analysis of the Guangzhou
Biobank Cohort Study. Chest 2010;137(3):593-600.

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
CHAPTER
2
BURDEN OF COPD
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
8 BURDEN OF COPD
KEY POINTS:

COPD is a leading cause of morbidity and mortality
worldwide and results in an economic and social
burden that is both substantial and increasing.
COPD prevalence, morbidity, and mortality vary
across countries and across different groups
within countries but, in general, are directly related
to the prevalence of tobacco smoking, although
in many countries, air pollution resulting from the
burning of wood and other biomass fuels has also
been identifed as a COPD risk factor.
The prevalence and burden of COPD are projected
to increase in the coming decades due to continued
exposure to COPD risk factors and the changing age
structure of the worlds population.

COPD is a costly disease with both direct costs
(value of health care resources devoted to diagnosis
and medical management) and indirect costs
(monetary consequences of disability, missed work,
premature mortality, and caregiver or family costs
resulting from the illness).
INTRODUCTION
COPD is a leading cause of morbidity and mortality world-
wide and results in an economic and social burden that
is both substantial and increasing. COPD prevalence,
morbidity, and mortality vary across countries and across
different groups within countries but, in general, are directly
related to the prevalence of tobacco smoking although in
many countries, air pollution resulting from the burning of
wood and other biomass fuels has also been identifed as a
COPD risk factor. The prevalence and burden of COPD are
projected to increase in the coming decades due to contin-
ued exposure to COPD risk factors and the changing age
structure of the worlds population (with more people living
longer, and thus reaching the age at which COPD normally
develops).
EPIDEMIOLOGY
In the past, imprecise and variable defnitions of COPD
have made it diffcult to quantify prevalence, morbidity and
mortality. Furthermore, the underrecognition and underdi-
agnosis of COPD lead to signifcant underreporting. The
extent of the underreporting varies across countries and
depends on the level of awareness and understanding of
COPD among health professionals, the organization of
health care services to cope with chronic diseases, and the
availability of medications for the treatment of COPD
1
.
There are several sources of information on the burden
of COPD: publications such as the 2003 European Lung
White Book
2
, international Websites such as the World
Health Organization (http://www.who.int) and the World
Bank/WHO Global Burden of Disease Study (http://www.
who.int/topics/global_burden_of_disease), and countryspe-
cifc Websites such as the US Centers for Disease Control
and Prevention (http://www.cdc.gov) and the UK Health
Survey for England (http://www.doh.gov.uk).
Prevalence
Existing COPD prevalence data show remarkable variation
due to differences in survey methods, diagnostic criteria,
and analytic approaches
3,4
. Survey methods can include:
Selfreport of a doctor diagnosis of COPD or
equivalent condition
Spirometry with or without a bronchodilator
Questionnaires that ask about the presence of
respiratory symptoms
The lowest estimates of prevalence are usually those based
on selfreporting of a doctor diagnosis of COPD or equiva-
lent condition. For example, most national data show that
less than 6% of the population has been told that they have
COPD
3
. This likely refects the widespread underrecognition
and underdiagnosis of COPD
5
as well as the fact that those
with Stage I: Mild COPD may have no symptoms, or else
symptoms (such as chronic cough and sputum) that are
not perceived by individuals or their health care providers
as abnormal and possibly indicative of early COPD
5
. These
estimates may have value, however, since they may most
accurately refect the burden of clinically signifcant disease
that is of suffcient severity to require health services, and
therefore is likely to generate signifcant direct and indirect
costs.
By contrast, data from prevalence surveys carried out in a
number of countries, using standardized methods and in-
cluding spirometry, estimate that up to about onequarter of
adults aged 40 years and older may have airfow limitation
classifed as Stage I: Mild COPD or higher
69
.
CHAPTER 2: BURDEN OF COPD
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
BURDEN OF COPD 9
Because of the large gap between the prevalence of COPD
as defned by the presence of airfow limitation and the
prevalence of COPD as defned by clinically signifcant
disease, the debate continues as to which of these it is
better to use in estimating the burden of COPD. Early
diagnosis and intervention may help to identify the number
of individuals who progress to a clinically signifcant stage
of disease, but there is insuffcient evidence at this time
to recommend communitybased spirometric screening for
COPD
10
.
Different diagnostic criteria also give widely different
estimates and there is little consensus regarding the most
appropriate criteria for different settings (e.g., epidemiologic
surveys, clinical diagnosis), or the strengths and weakness-
es of the different criteria. It is recognized that defning ir-
reversible airfow obstruction as a postbronchodilator FEV
1
/
FVC ratio less than 0.70 leads to the potential for signifcant
misclassifcation, with underdiagnosis (false negatives) in
younger adults and overdiagnosis (false positives) over
age 50 years
11-13
. This has led to the recommendation that
the use of the lower limit of normal (LLN) of the postbron-
chodilator FEV
1
/FVC ratio rather than the fxed ratio be
used to defne irreversible airfow obstruction
14,15
. However,
more information is needed from populationbased longitudi-
nal studies to determine the outcome of individuals classi-
fed using either defnition.
Many additional sources of variation can affect estimates of
COPD prevalence, including sampling methods, response
rates, quality control of spirometry, and whether spirometry
is performed preor postbronchodilator. Samples that are
not populationbased and poor response rates may give
biased estimates of prevalence, with the direction of bias
sometimes hard to determine. Inadequate emptying of the
lungs during the spirometric maneuver is common and
leads to an artifcially high ratio of FEV
1
/FVC and therefore
to an underestimate of the prevalence of COPD. Failure
to use postbronchodilator value instead of prebronchodila-
tor values leads to an overdiagnosis of irreversible airfow
limitation In future prevalence surveys, postbronchodila-
tor spirometry should be used to confrm the diagnosis of
COPD
16
.
Despite these complexities, data are emerging that enable
some conclusions to be drawn regarding COPD preva-
lence. A systematic review and metaanalysis of studies
carried out in 28 countries between 1990 and 200
43
, and
an additional study from Japan
17
, provide evidence that
the prevalence of COPD (Stage I: Mild COPD and higher)
is appreciably higher in smokers and exsmokers than in
nonsmokers, in those over 40 years than those under 40,
and in men than in women.
The Latin American Project for the Investigation of Obstruc-
tive Lung Disease (PLATINO) examined the prevalence of
postbronchodilator airfow limitation (Stage I: Mild COPD
and higher) among persons over age 40 in fve major Latin
American cities each in a different country - Brazil, Chile,
Mexico, Uruguay, and Venezuela. In each country, the prev-
alence of Stage I: Mild COPD and higher increased steeply
with age (Figure 2-1), with the highest prevalence among
those over 60 years, ranging from a low of 18.4% in Mexico
City, Mexico to a high of 32.1% in Montevideo, Uruguay. In
all cities/countries the prevalence was appreciably higher
in men than in women. The reasons for the differences in
prevalence across the fve Latin American cities are still
under investigation
6, 33
.
In 12 Asia Pacifc countries and regions a study based on a
prevalence estimation model indicated a mean prevalence
rate for moderate to severe COPD among individuals 30
years and older of 6.3% for the region. The rates varied
twofold across the 12 Asian countries and ranged from a
minimum of 3.5% (Hong Kong and Singapore) to a maxi-
mum of 6.7% (Vietnam)
18
.



Figure 2-1. COPD Prevalence by Age in Five
Latin American Cities
6

Prevalence = postbronchodilator FEV1/FVC < 0.70 (Stage I: Mild COPD and higher)
Morbidity
Morbidity measures traditionally include physician visits,
emergency department visits, and hospitalizations. Al-
though COPD databases for these outcome parameters
are less readily available and usually less reliable than
mortality databases, the limited data available indicate that
morbidity due to COPD increases with age and is greater
in men than in women
19-21
. In these data sets, however,
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
10 BURDEN OF COPD
COPD in its early stages (Stage I: Mild COPD and Stage 2:
Moderate COPD) is usually not recognized, diagnosed, or
treated, and therefore may not be included as a diagnosis
in a patients medical record.
Morbidity from COPD may be affected by other comorbid
chronic conditions
22
(e.g., musculoskeletal disease, dia-
betes mellitus) that are not directly related to COPD but
nevertheless may have an impact on the patients health
status, or may negatively interfere with COPD manage-
ment. In patients with more advanced disease (Stage III:
Severe COPD and Stage IV: Very Severe COPD), morbid-
ity from COPD may be misattributed to another comorbid
condition.
Morbidity data are greatly affected by the availability of
resources (e.g,, hospitalization rates are highly dependent
on the availability of hospital beds) and thus have to be
interpreted cautiously and with a clear understanding of
the possible biases inherent in the dataset. Despite the
limitations in the data for COPD, the European White Book
provides good data on the mean number of consultations
for major respiratory diseases across 19 countries of the
European Economic Community
2
. In most countries, con-
sultations for COPD greatly outnumbered consultations for
asthma, pneumonia, lung and tracheal cancer, and tuber-
culosis. In the United States in 2000, there were 8 million
physician offce/ hospital outpatient visits for COPD, 1.5
million emergency department visits, and 673,000 hospital-
izations
23
.
Another way of estimating the morbidity burden of disease
is to calculate years of living with disability (YLD). The
Global Burden of Disease Study estimates that COPD re-
sults in 1.68 YLD per 1,000 population, representing 1.8%
of all YLDs, with a greater burden in men than in women
(1.93% vs. 1.42%)
8,24,25
.
Mortality
The World Health Organization publishes mortality statistics
for selected causes of death annually for all WHO regions;
additional information is available from the WHO Evidence
for Health Policy Department (http://www.who.int/evidence).
Data must be interpreted cautiously, however, because of
inconsistent use of terminology for COPD. Prior to about
1968 and the Eighth Revision of the International Classif-
cation of Diseases (ICD), the terms chronic bronchitis and
emphysema were used extensively. During the 1970s, the
term COPD increasingly replaced those terms in some
but not all countries, making COPD mortality comparisons
in different countries very diffcult. However, the situation
has improved with the Ninth and Tenth Revisions of the
ICD, in which deaths from COPD or chronic airways ob-
struction are included in the broad category of COPD and
allied conditions (ICD9 codes 490496 and ICD10 codes
J4246).
Thus, the problem of labeling has been partly solved, but
underrecognition and underdiagnosis of COPD still affect
the accuracy of mortality data. Although COPD is often a
primary cause of death, it is more likely to be listed as a
contributory cause of death or omitted from the death cer-
tifcate entirely, and the death attributed to another condi-
tion such as cardiovascular disease.
Despite the problems with the accuracy of the COPD mor-
tality data, it is clear that COPD is one of the most impor-
tant causes of death in most countries. The Global Burden
of Disease Study
8,24,25
has projected that COPD, which
ranked sixth as the cause of death in 1990, will become
the third leading cause of death worldwide by 2020. This
increased mortality is driven by the expanding epidemic of
smoking and the changing demographics in most coun-
tries, with more of the population living longer. Of these two
forces, demographics is the stronger driver of the trend.
Trends in mortality rates over time provide further important
information but, again, these statistics are greatly affected
by terminology, awareness of the disease, and potential
gender bias in its diagnosis. COPD mortality trends gener-
ally track several decades behind smoking trends. Trends
in agestandardized death rates for the six leading causes
of death in the United States from 1970 through 2002
26
indicates that while mortality from several of these chronic
conditions declined over that period, COPD mortality
increased (Figure 2-2). Death rates for COPD in Canada,
in both men and women, have also been increasing since
1997. In Europe, however, the trends are different, with de-
creasing mortality from COPD already being seen in many
countries
7
. There is no obvious reason for the difference
between trends in North America and Europe, although pre-
sumably factors such as awareness, changing terminology,
and diagnostic bias contribute to these differences.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
BURDEN OF COPD 11
Figure 2-2. Trends in Age-standardized Death Rates
For the 6 Leading Causes of Death in the United States
1970-2002
26

Reprinted from Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death
in the United States, 19702002. JAMA 2005;294(10):12559. with permission from
JAMA
The mortality trends for COPD have been particularly
striking for women. In Canada, the death rate from COPD
among women accelerated in the 1990s and is expected to
soon overtake the rate among men
21
. In the United States,
COPD deaths among women have been rising steeply
since the 1970s. In 2000, the number of deaths from COPD
in the United States was greater among women than men
(59,936 vs. 59,118), although the mortality rates among
women remain somewhat lower than among men
27
.
Worldwide, recent increases in COPD deaths are likely to
continue. The Global Burden of Disease Study
8,24,25
project-
ed baseline, optimistic, and pessimistic models for COPD
mortality from 1990 to 2020 that take into account the ex-
pected aging of the worlds population, projected increases
in smoking rates, and projected declines in other causes of
death such as diarrheal and HIVrelated diseases.
ECONOMIC AND SOCIAL BURDEN OF COPD
Economic Burden

COPD is a costly disease with both direct costs (value of
health care resources devoted to diagnosis and medical
management) and indirect costs (monetary consequences
of disability, missed work, premature mortality, and caregiv-
er or family costs resulting from the illness)
2
. In developed
countries, exacerbations of COPD account for the greatest
burden on the health care system. In the European Union,
the total direct costs of respiratory disease are estimated to
be about 6% of the total health care budget, with COPD ac-
counting for 56% (38.6 billion Euros) of this cost of respira-
tory disease
2
. In the United States in 2002, the direct costs
of COPD were $18 billion and the indirect costs totaled
$14.1 billion
28
. Costs per patient will vary across countries
since these costs depend on how health care is provided
and paid
7
.
Not surprisingly, there is a striking direct relationship be-
tween the severity of COPD and the cost of care
29
, and the
distribution of costs changes as the disease progresses.
For example, hospitalization and ambulatory oxygen costs
soar as COPD severity increases, as illustrated by data
from Sweden shown in Figure 2-3.


Figure 2-3. Distribution of Direct Costs of
COPD by Severity
29

Printed with permission. Copyright 2002 American College of Chest Physicians.
The presence of COPD greatly increases the total cost
of care for patients, especially when inpatient costs are
considered. In a study of COPDrelated illness costs in the
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
12 BURDEN OF COPD
United States based on the 1987 National Medical Expen-
diture Survey, per capita expenditures for hospitalizations of
COPD patients were 2.7 times the expenditures for patients
without COPD ($5,409 vs. $2,001)
30
. In a 1992 study of
Medicare, the US government health insurance program
for individuals over 65, annual per capita expenditures
for people with COPD ($8,482) were nearly 2.5 times the
expenditures for people without COPD ($3,511)
31
.
Individuals with COPD frequently receive professional med-
ical care in their homes. In some countries, national health
insurance plans provide coverage for oxygen therapy,
visiting nursing services, rehabilitation, and even mechani-
cal ventilation in the home, although coverage for specifc
services varies from country to country
32
. Any estimate of
direct medical expenditures for home care underrepresents
the true cost of home care to society, because it ignores the
economic value of the care provided to those with COPD
by family members. In developing countries, direct medical
costs may be less important than the impact of COPD on
workplace and home productivity. Because the health care
sector might not provide long-term supportive care services
for severely disabled individuals, COPD may force two
individuals to leave the workplace-the affected individual
and a family member who must now stay home to care
for the disabled relative. Since human capital is often the
most important national asset for developing countries, the
indirect costs of COPD may represent a serious threat to
their economies.
Social Burden
Since mortality offers a limited perspective on the human
burden of a disease, it is desirable to fnd other measures
of disease burden that are consistent and measurable
across nations. The authors of the Global Burden of Dis-
ease Study designed a method to estimate the fraction of
mortality and disability attributable to major diseases and
injuries using a composite measure of the burden of each
health problem, the DisabilityAdjusted Life Year
(DALY)
8,24,25
. The DALYs for a specifc condition are the sum
of years lost because of premature mortality and years of
life lived with disability, adjusted for the severity of disability.
In 1990, COPD was the twelfth leading cause of DALYs
lost in the world, responsible for 2.1% of the total. Accord-
ing to the projections, COPD will be the ffth leading cause
of DALYs lost worldwide in 2020, behind ischemic heart
disease, major depression, traffc accidents, and cerebro-
vascular disease. This substantial increase in the global
burden of COPD projected over the next twenty years
refects, in large part, the continued high use of tobacco in
many countries and the changing age structure of popula-
tions in developing countries.
REFERENCES
1. Tirimanna PR, van Schayck CP, den Otter JJ, van Weel C, van
Herwaarden CL, van den Boom G, et al. Prevalence of asthma
and COPD in general practice in 1992: has it changed since
1977? Br J Gen Pract 1996;46(406):27781.
2. European Respiratory Society. European Lung White Book:
Huddersfeld, European Respiratory Society Journals, Ltd
2003.
3. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS,
Mannino DM. Global burden of COPD: systematic review and
metaanalysis. Eur Respir J 2006.

4. Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD
prevalence estimates: what is the true burden of disease?
Chest 2003;123(5):168492.
5. van den Boom G, van Schayck CP, van Mollen MP, Tirimanna
PR, den Otter JJ, van Grunsven PM, et al. Active detection of
chronic obstructive pulmonary disease and asthma in the
general population. Results and economic consequences
of the DIMCA program. Am J Respir Crit Care Med
1998;158(6):17308.
6. Menezes AM, PerezPadilla R, Jardim JR, Muino A, Lopez MV,
Valdivia G, et al. Chronic obstructive pulmonary disease in
fve Latin American cities (the PLATINO study): a prevalence
study. Lancet 2005;366(9500):187581.
7. Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist
AS, Thun MJ, et al. Epidemiology and costs of chronic
obstructive pulmonary disease. Eur Respir J
2006;27(1):188207.
8. Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held
LS, et al. Chronic obstructive pulmonary disease: current
burden and future projections. Eur Respir J 2006;27(2):397412.
9. Buist AS, Vollmer WM, Sullivan SD, Weiss KB, Lee TA,
Menezes AM, et al. The burden of obstructive lung disease
initiative (BOLD): Rationale and Design. J COPD
2005;2:27783.
10. Wilt TJ, Niewoehner D, Kim C, Kane RL, Linabery A, Tacklind
J, et al. Use of spirometry for case fnding, diagnosis, and
management of chronic obstructive pulmonary disease
(COPD). Evid Rep Technol Assess (Summ) 2005(121):17.
11. Hnizdo E, Glindmeyer HW, Petsonk EL, Enright P, Buist AS.
Case Defnitions for Chronic Obstructive Pulmonary Disease. J
COPD 2006;3:16.
12. Roberts SD, Farber MO, Knox KS, Phillips GS, Bhatt NY,
Mastronarde JG, et al. FEV
1
/FVC ratio of 70%
misclasifes patients with obstructin at the extremes of age.
Chest 2006;130:2006.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
BURDEN OF COPD 13
13. Celli BR, Halbert RJ, Isonaka S, Schau B. Population
impact of different defnitions of airway obstruction. Eur Respir
J 2003;22(2):26873.
14. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F,
Casaburi R, et al. Interpretative strategies for lung function
tests. Eur Respir J 2005;26(5):94868.
15. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric
reference values from a sample of the general US population.
Am J Respir Crit Care Med 1999;159:17987.
16. Sterk PJ. Lets not forget: the GOLD criteria for COPD are
based on postbronchodilator FEV1. Eur Respir J 2004;23:4978.
17. Fukuchi Y, Nishimura M, Ichinose M, Adachi M, Nagai A,
Kuriyama T, et al. COPD in Japan: the Nippon COPD
Epidemiology study. Respirology 2004;9(4):45865.
18. COPD Prevalence in 12 AsiaPacifc Countries and regions:
Projections based on the COPD prevalence estimation model.
Regional COPD Working Group. Respirology 2003;8:1928.
19. National Heart, Lung, and Blood Institute. Morbidity & Mortality:
Chartbook on Cardiovascular, Lung, and Blood Diseases.
Bethesda, MD: US Department. of Health and Human
Services, Public Health Service, National Institutes of Health;
1998.
20. Soriano JR, Maier WC, Egger P, Visick G, Thakrar B, Sykes J,
et al. Recent trends in physician diagnosed COPD in women
and men in the UK. Thorax 2000;55:78994.
21. Chapman KR. Chronic obstructive pulmonary disease:
are women more susceptible than men? Clin Chest Med
2004;25(2):33141.
22. Schellevis FG, Van de Lisdonk EH, Van der Velden J,
Hoogbergen SH, Van Eijk JT, Van Weel C. Consultation rates
and incidence of intercurrent morbidity
among patients with chronic disease in general practice. Br J
Gen Pract 1994;44(383):25962.
23. Centers for Disease Control and Prevention. Surveillance
Summaries. MMWR 2002:51(No. SS6).
24. Murray CJL, Lopez AD, editors. In: The global burden of
disease: a comprehensive assessment of mortality and
disability from diseases, injuries and risk factors in 1990 and
projected to 2020. Cambridge, MA: Harvard University Press;
1996.
25. Murray CJ, Lopez AD. Alternative projections of mortality and
disability by cause 19902020: Global Burden of Disease Study.
Lancet 1997;349(9064):1498504.
26. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading
causes of death in the United States, 19702002. JAMA
2005;294(10):12559.
27. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC.
Chronic obstructive pulmonary disease surveillanceUnited
States, 19712000. MMWR Surveill Summ 2002;51(6):116.
28. National Heart, Lung, and Blood Institute. Morbidity and
mortality chartbook on cardiovascular, lung and blood diseases.
Bethesda, Maryland: US Department of Health and Human
Services, Public Health Service, National Institutes of Health.
Accessed at: http://www.nhlbi.nih.gov/resources/docs/chtbook.
htm; 2004.
29. Jansson SA, Andersson F, Borg S, Ericsson A, Jonsson E,
Lundback B. Costs of COPD in Sweden according to disease
severity. Chest 2002;122(6):19942002.
30. Sullivan SD, Strassels S, Smith DH. Characterization
of the incidence and cost of COPD in the US. Eur Respir J
1996;9(Supplement 23):S421.
31. Grasso ME, Weller WE, Shaffer TJ, Diette GB, Anderson GF.
Capitation, managed care, and chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1998;158:1338.
32. Fauroux B, Howard P, Muir JF. Home treatment for chronic
respiratory insuffciency: the situation in Europe in 1992.
The European Working Group on Home Treatment for Chronic
Respiratory Insuffciency. Eur Respir J 1994;7:17216.
33. Menezes AM, PerezPadilla R, Hallal PC, JardimJR, Muio
A, Lopez MV, Valdivia G, Pertuze J, Montes de Oca M,
Tlamo C; PLATINO Team. Worldwide burden of COPD in high
and lowincome countries. Part II. Burden of chronic obstructive
lung disease in Latin America: the PLATINO study. Int J Tuberc
Lung Dis. 2008 Jul;12(7):70912.

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
CHAPTER
3
RISK FACTORS
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
16 RISK FACTORS
KEY POINTS:
Worldwide, cigarette smoking is the most commonly
encountered risk factor for COPD.
The genetic risk factor that is best documented is
a severe hereditary defciency of alpha1 antitrypsin.
It provides a model for how other genetic risk factors
are thought to contribute to COPD.
Of the many inhalational exposures that may be
encountered over a lifetime, only tobacco smoke
and occupational dusts and chemicals (vapors,
irritants, and fumes) are known to cause COPD on
their own. More data are needed to explore the
causative role of other risk factors.
Indoor air pollution, especially from burning biomass
fuels in confned spaces, is associated with increased
risk for COPD in developing countries, especially
among women.
The identifcation of risk factors is an important step toward
developing strategies for prevention and treatment of any
disease. Identifcation of cigarette smoking as the most
commonly encountered risk factor for COPD has led to
the incorporation of smoking cessation programs as a
key element of COPD prevention, as well as an important
intervention for patients who already have the disease.
However, although smoking is the beststudied COPD
risk factor, it is not the only one and there is consistent
evidence from epidemiologic studies that nonsmokers may
develop chronic airfow obstruction
1,2
.
Much of the evidence concerning risk factors for COPD
comes from crosssectional epidemiological studies
that identify associations rather than causeandeffect
relationships. Although several longitudinal studies (which
are capable of revealing causal relationships) of COPD
have followed groups and populations for up to 20 years
3
,
none has monitored the progression of the disease through
its entire course, or has included the preand perinatal
periods which may be important in shaping an individual?s
future COPD risk. Thus, current understanding of risk
factors for COPD is in many respects incomplete.
As the understanding of the importance of risk factors
(Figure 3-1) for COPD has grown, so has the recognition
that essentially all risk for COPD results from a gene-
environment interaction. Thus, of two people with the
same smoking history, only one may develop COPD due
to differences in genetic predisposition to the disease,
or in how long they live. Risk factors for COPD may also
be related in more complex ways. For example, gender
may infuence whether a person takes up smoking or
experiences certain occupational or environmental
exposures; socioeconomic status may be linked to a
child's birth weight (as it impacts on lung growth and
development); and longer life expectancy will allow greater
lifetime exposure to risk factors. Understanding the
relationships and interactions among risk factors requires
further investigation.
Genes
COPD is a polygenic disease and a classic example of
geneenvironment interaction. The genetic risk factor that
is best documented is a severe hereditary defciency of
alpha-1 antitrypsin
4
, a major circulating inhibitor of serine
proteases. This rare recessive trait is most commonly seen
in individuals of Northern European origin
5
. Premature
and accelerated development of panlobular emphysema
and decline in lung function occur in both smokers and
nonsmokers with the severe defciency, although smoking
increases the risk appreciably. There is considerable
variation between individuals in the extent and severity
of the emphysema and the rate of lung function decline.
Although alpha-1 antitrypsin defciency is relevant to only
a small part of the worlds population, it illustrates the
interaction between genes and environmental exposures
leading to COPD. In this way, it provides a model for how
other genetic risk factors are thought to contribute to
COPD.
CHAPTER 3: RISK FACTORS
INTRODUCTION
RISK FACTORS
Figure 3-1. Risk Factors for COPD.
Genes
Exposure to particles
Tobacco smoke
Occupational dusts, organic and inorganic
Indoor air pollution from heating and cooking with bio-
mass in poorly vented dwellings
Outdoor air pollution
Lung Growth and Development
Oxidative stress
Gender
Age
Respiratory infections
Previous tuberculosis
Socioeconomic status
Nutrition
Comorbidities
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
RISK FACTORS 17
A signifcant familial risk of airfow obstruction has been
observed in smoking siblings of patients with severe
COPD
6
, suggesting that genetic factors could infuence this
susceptibility. Through genetic linkage analysis, several
regions of the genome have been identifed that likely
contain COPD susceptibility genes, including chromosome
2q
7
. Genetic association studies have implicated a variety
of genes in COPD pathogenesis, including transforming
growth factor beta 1 (TGF-1)
8
microsomal epoxide
hydrolase 1 (mEPHX1)
9
, and tumor necrosis factor alpha
(TNF)
10
. However, the results of these genetic association
studies have been largely inconsistent, and functional
genetic variants infuencing the development of COPD
(other than alpha-1 antitrypsin defciency) have not been
defnitively identifed
7
.
Inhalational Exposures
Because individuals may be exposed to a variety of
different types of inhaled particles over their lifetime, it
is helpful to think in terms of the total burden of inhaled
particles. Each type of particle, depending on its size and
composition, may contribute a different weight to the risk,
and the total risk will depend on the integral of the inhaled
exposures (Figure 3-2). Of the many inhalational exposures
that may be encountered over a lifetime, only tobacco
smoke
11,12
and occupational dusts and chemicals (vapors,
irritants, and fumes)
13-16
are known to cause COPD on their
own. Tobacco smoke and occupational exposures also
appear to act additively to increase the risk of developing
COPD. However this may refect an inadequate data base
from populations who are exposed to other risk factors,
such as heavy exposures to indoor air pollution from poorly
vented biomass cooking and heating.
Tobacco Smoke: Cigarette smoking is by far the most
commonly encountered risk factor for COPD. Cigarette
smokers have a higher prevalence of respiratory symptoms
and lung function abnormalities, a greater annual rate of
decline in FEV
1
, and a greater COPD mortality rate than
nonsmokers. Pipe and cigar smokers have greater COPD
morbidity and mortality rates than nonsmokers, although
their rates are lower than those for cigarette smokers
11
.
Other types of tobacco smoking popular in various
countries are also risk factors for COPD
17,18
, although their
risk relative to cigarette smoking has not been reported.
The risk for COPD in smokers is dose-related
12
. Age at
starting to smoke, total packyears smoked, and current
smoking status are predictive of COPD mortality. Not
all smokers develop clinically signifcant COPD, which
suggests that genetic factors must modify each individuals
risk
9
.
Passive exposure to cigarette smoke (also known as
environmental tobacco smoke or ETS) may also contribute
to respiratory symptoms19 and COPD
20
by increasing
the lungs total burden of inhaled particles and gases
21,22
.
Smoking during pregnancy may also pose a risk for the
fetus, by affecting lung growth and development in utero
and possibly the priming of the immune system
23,24
.
Occupational Dusts and Chemicals: Occupational
exposures are an underappreciated risk factor for COPD
14-
16,25
. These exposures include organic and inorganic dusts
and chemical agents and fumes. An analysis of the large
US populationbased NHANES III survey of almost 10,000
adults aged 30-75 years, which included lung function
tests, estimated the fraction of COPD attributable to work
was 19.2% overall, and 31.1% among never smokers
16
.
These estimates are consistent with a statement published
by the American Thoracic Society that concluded that
occupational exposures account for 10-20% of either
symptoms or functional impairment consistent with COPD
26
.
Indoor Air Pollution: Wood, animal dung, crop residues,
and coal, typically burned in open fres or poorly functioning
stoves, may lead to very high levels of indoor air pollution.
The evidence that indoor pollution from biomass cooking
and heating in poorly ventilated dwellings is an important
risk factor for COPD (especially among women in
developing countries) continues to grow
27-33
, with case
control studies
32,33
and other robustly designed studies now
available. Almost 3 billion people worldwide use biomass
and coal as their main source of energy for cooking,
heating, and other household needs, so the population at
risk worldwide is very large. In these communities, indoor
air pollution is responsible for a greater fraction of COPD
risk than SO
2
or particulates from motor vehicle emissions,
even in cities densely populated with people and cars.
Biomass fuels used by women for cooking account for
the high prevalence of COPD among nonsmoking women
in parts of the Middle East, Africa, and Asia
34,35
. Indoor




Figure 3-2. COPD Risk is Related to the
Total Burden of Inhaled Particles

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
18 RISK FACTORS
air pollution resulting from the burning of wood and other
biomass fuels is estimated to kill two million women and
children each year
36
.
Outdoor Air Pollution: High levels of urban air pollution are
harmful to individuals with existing heart or lung disease.
The role of outdoor air pollution in causing COPD is
unclear, but appears to be small when compared with that
of cigarette smoking. It has also been diffcult to assess
the effects of single pollutants in long-term exposure to
atmospheric pollution. However, air pollution from fossil
fuel combustion, primarily from motor vehicle emissions
in cities, is associated with decrements of respiratory
function
37
. The relative effects of short-term, highpeak
exposures and long-term, low-level exposures is a question
yet to be resolved.
Lung Growth and Development
Lung growth is related to processes occurring during
gestation, birth, and exposures during childhood
38-40
.
Reduced maximal attained lung function (as measured by
spirometry) may identify individuals who are at increased
risk for the development of COPD
41
. Any factor that affects
lung growth during gestation and childhood has the
potential for increasing an individuals risk of developing
COPD. For example, a large study and metaanalysis
confrmed a positive association between birth weight and
FEV
1
in adulthood
42
.
Oxidative Stress
The lungs are continuously exposed to oxidants
generated either endogenously from phagocytes and
other cell types or exogenously from air pollutants or
cigarette smoke. In addition, intracellular oxidants, such
as those derived from mitochondrial electron transport,
are involved in many cellular signaling pathways. Lung
cells are protected against this oxidative challenge by
welldeveloped enzymatic and nonenzymatic systems.
When the balance between oxidants and antioxidants
shifts in favor of the formeri.e., an excess of oxidants
and/or a depletion of antioxidants oxidative stress occurs.
Oxidative stress not only produces direct injurious effects
in the lungs but also activates molecular mechanisms that
initiate lung infammation. Thus, an imbalance between
oxidants and antioxidants is considered to play a role in the
pathogenesis of COPD
43
.
Gender
The role of gender in determining COPD risk remains
unclear
44
. In the past, most studies showed that COPD
prevalence and mortality were greater among men than
women. Studies from developed countries
45,46
show that
the prevalence of the disease is now almost equal in men
and women, which probably refects changing patterns
of tobacco smoking. Some studies have suggested that
women are more susceptible to the effects of tobacco
smoke than men
44,47,48
. This is an important question
given the increasing rate of smoking among women in
both developed and developing countries. In patients with
severe COPD, women, relative to men, exhibit anatomically
smaller airway lumens with disproportionately thicker
airway walls, and emphysema that is less extensive and
characterized by smaller hole size and less peripheral
involvement
62
.
Infections
Infections (viral and bacterial) may contribute to the
pathogenesis and progression of COPD
49
, and the bacterial
colonization associated with airway infammation
50
, and
may also play a signifcant role in exacerbations
51
. A
history of severe childhood respiratory infection has been
associated with reduced lung function and increased
respiratory symptoms in adulthood
38,41,52
. There are several
possible explanations for this association (which are not
mutually exclusive). There may be an increased diagnosis
of severe infections in children who have underlying airway
hyperresponsiveness, itself considered a risk factor for
COPD. Susceptibility to viral infections may be related
to another factor, such as birth weight, that is related
to COPD. HIV infection has been shown to accelerate
the onset of smoking-related emphysema; HIVinduced
pulmonary infammation may play a role in this process
53
.
A history of tuberculosis has been found to be associated
with airfow obstruction in adults older than 40 years
63
.
Socioeconomic Status
There is evidence that the risk of developing COPD is
inversely related to socioeconomic status
54
. It is not clear,
however, whether this pattern refects exposures to indoor
and outdoor air pollutants, crowding, poor nutrition, or other
factors that are related to low socioeconomic status
55,56
.
Nutrition
The role of nutrition as an independent risk factor for
the development of COPD is unclear. Malnutrition and
weight loss can reduce respiratory muscle strength and
endurance, apparently by reducing both respiratory muscle
mass and the strength of the remaining muscle fbers
57
.
The association of starvation and anabolic/catabolic status
with the development of emphysema has been shown
in experimental studies in animals
58
. Lung CT scans of
women chronically malnourished because of anorexia
nervosa showed emphysemalike changes
59
.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
RISK FACTORS 19
Asthma
Asthma may be risk factor for the development of COPD,
although the evidence is not conclusive. In a report from
a longitudinal cohort of the Tucson Epidemiological Study
of Airway Obstructive Disease adults with asthma were
found to have a twelve-fold higher risk of acquiring COPD
over time than those without asthma, after adjusting for
smoking
60
. Another longitudinal study of people with asthma
found that around 20% of subjects developed functional
signs of COPD, irreversible airfow limitation, and reduced
transfer coeffcient
61
.
REFERENCES
1. Celli BR, Halbert RJ, Nordyke RJ, Schan B. Airway obstruction
in never smokers: results from the Third National Health and
Nutrition Examination Survey. Am J Med 2005;118:136472.
2 . Behrendt CE. Mild and moderatetosevere COPD
in nonsmokers. Distinct demographic profles. Chest
2005;128:123944.
3. Anthonisen NR, Connett JE, Murray RP. Smoking and lung
function of Lung Health Study participants after 11 years. Am J
Respir Crit Care Med 2002;166(5):6759.
4. Stoller JK, Aboussouan LS. Alpha1antitrypsin defciency. Lancet
2005;365(9478):222536.
5. Blanco I, de Serres FJ, FernandezBustillo E, Lara B, Miravitlles
M. Estimated numbers and prevalence of PI*S and PI*Z alleles
of alpha1antitrypsin defciency in European countries. Eur
Respir J 2006;27(1):7784.
6. McCloskey SC, Patel BD, Hinchliffe SJ, Reid ED, Wareham NJ,
Lomas DA. Siblings of patients with severe chronic obstructive
pulmonary disease have a signifcant risk of airfow obstruction.
Am J Respir Crit Care Med 2001;164 (8 Pt 1):141924.
7. Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM,
Brown A, et al. Genomewide linkage analysis of quantitative
spirometric phenotypes in severe earlyonset chronic obstructive
pulmonary disease. Am J Hum Genet 2002;70(5):122939.
8. Wu L, Chau J, Young RP, Pokorny V, Mills GD, Hopkins R, et
al. Transforming growth factorbeta1 genotype and susceptibility
to chronic obstructive pulmonary disease. Thorax
2004;59(2):1269.
9. Smith CA, Harrison DJ. Association between polymorphism
in gene for microsomal epoxide hydrolase and susceptibility to
emphysema. Lancet 1997;350(9078):6303.
10. Huang SL, Su CH, Chang SC. Tumor necrosis factoralpha
gene polymorphism in chronic bronchitis. Am J Respir Crit Care
Med 1997;156(5):14369.
11. US Surgeon General. The health consequences of smoking:
chronic obstructive pulmonary disease. Washington, D.C.: US
Department of Health and Human Services; 1984.
12. Burrows B, Knudson RJ, Cline MG, Lebowitz MD. Quantitative
relationships between cigarette smoking and ventilatory
function. Am Rev Respir Dis 1977;115(2):195205.
13. Becklake MR. Occupational exposures: evidence for a causal
association with chronic obstructive pulmonary disease. Am Rev
Respir Dis 1989;140(3 Pt 2):S8591.
14. Trupin L, Earnest G, San Pedro M, Balmes JR, Eisner MD, Yelin
E, et al. The occupational burden of chronic obstructive
pulmonary disease. Eur Respir J 2003;22(3):4629.
15. Matheson MC, Benke G, Raven J, Sim MR, Kromhout H,
Vermeulen R, et al. Biological dust exposure in the workplace
is a risk factor for chronic obstructive pulmonary disease.
Thorax 2005;60(8):64551.
16. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Association
between chronic obstructive pulmonary disease and
employment by industry and occupation in the US population:
a study of data from the Third National Health and Nutrition
Examination Survey. Am J Epidemiol 2002;156(8):73846.
17. Jindal SK, Aggarwal AN, Chaudhry K, Chhabra SK, D'Souza
GA, Gupta D, et al. A multicentric study on epidemiology of
chronic obstructive pulmonary disease and its relationship with
tobacco smoking and environmental tobacco smoke exposure.
Indian J Chest Dis Allied Sci 2006;48(1):239.
18. AlFayez SF, Salleh M, Ardawi M, AZahran FM. Effects of
sheesha and cigarette smoking on pulmonary function of Saudi
males and females. Trop Geogr Med 1988;40(2):11523.
19. The Health Consequences of Involuntary Exposure to Tobacco
Smoke: A Report of the Surgeon General, Department of Health
and Human Services. Washington, DC, US; 2006.
20. Eisner MD, Balmes J, Katz BP, Trupin L, Yelin E, Blanc P.
Lifetime environmental tobacco smoke exposure and the risk
of chronic obstructive pulmonary disease. Environ Health
Perspect 2005;4:715.
21. Leuenberger P, Schwartz J, AckermannLiebrich U, Blaser K,
Bolognini G, Bongard JP, et al. Passive smoking exposure in
adults and chronic respiratory symptoms (SAPALDIA Study).
Swiss Study on Air Pollution and Lung Diseases in Adults,
SAPALDIA Team. Am J Respir Crit Care Med 1994;150 (5 Pt
1):12228.
22. Dayal HH, Khuder S, Sharrar R, Trieff N. Passive smoking in
obstructive respiratory disease in an industrialized urban
population. Environ Res 1994;65(2):16171.
23. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during
pregnancy. Effects on lung function during the frst 18 months of
life. Am J Respir Crit Care Med 1995;152:97783.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
20 RISK FACTORS
24. Holt PG. Immune and infammatory function in cigarette
smokers. Thorax 1987;42(4):2419.
25. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Airfow obstruction
attributable to work in industry and occupation among U.S.
race/ethnic groups: a study of NHANES III data. Am J Ind Med
2004;46(2):12635.
26. Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K,
Mapp C, et al. American Thoracic Society Statement:
Occupational contribution to the burden of airway disease. Am J
Respir Crit Care Med 2003;167(5):78797.
27. Warwick H, Doig A. Smoke the killer in the kitchen: Indoor
air pollution in developing countries. ITDG Publishing, 103105
Southampton Row, London WC1B HLD, UK 2004:URL: http://
www.itdgpublishing.org.uk.
28. Ezzati M. Indoor air pollution and health in developing countries.
Lancet 2005;366(9480):1046.
29. Smith KR, Mehta S, MaeusezahlFeuz M. Indoor airpollution
from household solid fuel use. In: Ezzati, M., Lopez, A. D.,
Rodgers, M., Murray, C. J., eds. Comparative quantifcation of
health risks: global and regional burden of disease attributable
to selected major risk factors. Geneva: World Health
Organization; 2004.
30. Mishra V, Dai X, Smith KR, Mika L. Maternal exposure to
biomass smoke and reduced birth weight in Zimbabwe. Ann
Epidemiol 2004;14(10):7407.
31. Boman C, Forsberg B, Sandstrom T. Shedding new light on
wood smoke: a risk factor for respiratory health. Eur Respir J
2006;27(3):4467.
32. OroczoLevi M, Garcia Aymerich J, Villar J, RamirezSarmiento
A, Anto JM, Gea J. Wood smoke exposure and risk of chronic
obstructive pulmonary disease. Eur Respir J 2006;27:5426.
33. Sezer H, Akkurt I, Guler N, Marakoglu K, Berk S. A casecontrol
study on the effect of exposure to different substances on the
development of COPD. Ann Epidemiol 2006;16(1):5962.
34. Smith KR. Inaugural article: national burden of disease
in India from indoor air pollution. Proc Natl Acad Sci U S A
2000;97(24):1328693.
35. ChanYeung M, AitKhaled N, White N, Ip MS, Tan WC. The
burden and impact of COPD in Asia and Africa. Int J Tuberc
Lung Dis 2004;8(1):214.
36. Smith K. Pollution management in focus. The World Bank,
Washington, DC 1999.
37. Abbey DE, Burchette RJ, Knutsen SF, McDonnell WF, Lebowitz
MD, Enright PL. Long-term particulate and other air pollutants
and lung function in nonsmokers. Am J Respir Crit Care Med
1998;158(1):28998.
38. Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD,
Shaheen SO. Relation of birth weight and childhood respiratory
infection to adult lung function and death from chronic
obstructive airways disease. BMJ 1991;303(6804):6715.
39. Todisco T, de Benedictis FM, Iannacci L, Baglioni S, Eslami A,
Todisco E, et al. Mild prematurity and respiratory functions. Eur
J Pediatr 1993;152(1):558.
40. Stein CE, Kumaran K, Fall CH, Shaheen SO, Osmond C,
Barker DJ. Relation of fetal growth to adult lung function in
South India. Thorax 1997;52(10):8959.
41. Tager IB, Segal MR, Speizer FE, Weiss ST. The natural history
of forced expiratory volumes. Effect of cigarette smoking and
respiratory symptoms. Am Rev Respir Dis 1988;138(4):83749.
42. Lawlor DA, Ebrahim S, Davey Smith G. Association of
birth weight with adult lung function: fndings from the British
Women's Heart and Health Study and a metaanalysis. Thorax
2005;60(10):8518.
43. MacNee W. Pulmonary and systemic oxidant/antioxidant
imbalance in chronic obstructive pulmonary disease. Proc Am
Thorac Soc 2005;2(1):5060.
44. Xu X, Weiss ST, Rijcken B, Schouten JP. Smoking, changes in
smoking habits, and rate of decline in FEV1: new insight into
gender differences. Eur Respir J 1994;7(6):105661.
45. National Heart, Lung, and Blood Institute. Morbidity and
mortality chartbook on cardiovascular, lung and blood diseases.
Bethesda, Maryland: US Department of Health and Human
Services, Public Health Service, National Institutes of Health,
2004. Accessed at: http://www.nhlbi.nih.gov/resources/docs/
chtbook.htm.
46. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC.
Chronic obstructive pulmonary disease surveillanceUnited
States, 19712000. MMWR Surveill Summ 2002;51(6):116.
47. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC,
Buist AS, et al. Effects of smoking intervention and the use of
an inhaled anticholinergic bronchodilator on the rate of decline
of FEV1. The Lung Health Study. JAMA 1994;272(19):1497505.
48. Silverman EK, Weiss ST, Drazen JM, Chapman HA, Carey V,
Campbell EJ, et al. Genderrelated differences in severe,
earlyonset chronic obstructive pulmonary disease. Am J Respir
Crit Care Med 2000;162(6):21528.
49. Retamales I, Elliott WM, Meshi B, Coxson HO, Pare P, Sciurba
FC, et al. Amplifcation of infammation in emphysema and its
association with latent adenoviral infection. Am J Respir Crit
Care Med 2001;164:46973.
50. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway
infammation and bronchial bacterial colonization in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2006;173:9918.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
RISK FACTORS 21
51. Seemungal T, HarperOwen R, Bhowmik A, Moric I, Sanderson
G, Message S, et al. Respiratory viruses, symptoms, and
infammatory markers in acute exacerbations and stable chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2001;164(9):161823.
52. Shaheen SO, Barker DJ, Shiell AW, Crocker FJ, Wield GA,
Holgate ST. The relationship between pneumonia in early
childhood and impaired lung function in late adult life. Am J
Respir Crit Care Med 1994;149(3 Pt 1):6169.
53. Diaz PT, King MA, Pacht ER, Wewers MD, Gadek JE, Nagaraja
HN, et al. Increased susceptibility to pulmonary
emphysema among HIVseropositive smokers. Ann Intern Med
2000;132(5):36972.
54. Prescott E, Lange P, Vestbo J. Socioeconomic status, lung
function and admission to hospital for COPD: results
from the Copenhagen City Heart Study. Eur Respir J
1999;13(5):110914.
55. Tao X, Hong CJ, Yu S, Chen B, Zhu H, Yang M. Priority among
air pollution factors for preventing chronic obstructive pulmonary
disease in Shanghai. Sci Total Environ 1992;127(12):5767.
56. US Centers for Disease Control and Prevention. Criteria for a
recommended standard: occupational exposure to respirable
coal mine dust: National Institute of Occupational Safety and
Health; 1995.
57. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body
weight in chronic obstructive pulmonary disease. The National
Institutes of Health Intermittent PositivePressure Breathing Trial.
Am Rev Respir Dis 1989;139(6):14358.
58. Sahebjami H, Vassallo CL. Infuence of starvation on
enzymeinduced emphysema. J Appl Physiol 1980;48(2):2848.
59. Coxson HO, Chan IH, Mayo JR, Hlynsky J, Nakano Y,
Birmingham CL. Early emphysema in patients with anorexia
nervosa. Am J Respir Crit Care Med 2004;170(7):74852.
60. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk
factor for COPD in a longitudinal study. Chest
2004;126(1):5965.
61. Vonk JM, Jongepier H, Panhuysen CI, Schouten JP, Bleecker
ER, Postma DS. Risk factors associated with the presence
of irreversible airfow limitation and reduced transfer coeffcient
in patients with asthma after 26 years of follow up. Thorax
2003;58(4):3227.
62. Martinez FJ, Curtis JL, Sciurba F, Mumford J, Giardino ND,
Weinmann G, Kazerooni E, Murray S, Criner GJ, Sin DD, Hogg
J, Ries AL, Han M, Fishman AP, Make B, Hoffman EA,
Mohsenifar Z, Wise R; National Emphysema Treatment Trial
Research Group. Sex differences in severe pulmonary
emphysema. Am J Respir Crit Care Med 2007 Aug
1;176(3):24352. Epub 2007 Apr 12.
63. Menezes AM, Hallal PC, PerezPadilla R, Jardim JR, Muio
A, Lopez MV, Valdivia G, Montes de Oca M, Talamo C, Pertuze
J, Victora CG; Latin American Project for the Investigation of
Obstructive Lung Disease (PLATINO) Team. Tuberculosis
and airfow obstruction: evidence from the PLATINO study in
Latin America. Eur Respir J 2007 Dec;30(6):11805. Epub 2007
Sep 5.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
22 RISK FACTORS
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
CHAPTER
4
PATHOLOGY,
PATHOGENESIS,
AND
PATHOPHYSIOLOGY
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
24 PATHOLOGY, PATHOGENISIS, AND PATHOPHYSIOLOGY
KEY POINTS:
Pathological changes characteristic of COPD are
found in the proximal airways, peripheral airways,
lung parenchyma, and pulmonary
vasculature. These changes include chronic
infammation, and structural changes resulting from
repeated injury and repair.
Inhaled cigarette smoke and other noxious particles
cause lung infammation, a normal response which
appears to be amplifed in patients who develop
COPD.
There is a characteristic pattern of infammation
in the lungs of COPD patients, with increased
numbers of neutrophils (in the airway lumen),
macrophages (airway lumen, airway wall, and
parenchyma), and CD8+ lymphocytes (airway wall
and parenchyma). The pattern is different from that
seen in asthma.
Lung infammation is further amplifed by oxidative
stress and an excess of proteases in the lung.
Physiological changes characteristic of the disease
include mucus hypersecretion, airfow limitation and
air trapping (leading to hyperinfation), gas exchange
abnormalities, and cor pulmonale.
Systemic features of COPD, particularly in patients
with severe disease, include cachexia, skeletal
muscle wasting, increased risk of cardiovascular
disease, anemia, osteoporosis, and depression.
Exacerbations represent a further amplifcation of
the infammatory response in the airways of patients
with COPD, and may be triggered by infection with
bacteria or viruses or by environmental pollutants.
Inhaled cigarette smoke and other noxious particles cause
lung infammation, a normal response which appears to be
amplifed in patients who develop COPD. This abnormal
infammatory response may induce parenchymal tissue
destruction (resulting in emphysema), and disrupt normal
repair and defense mechanisms (resulting in small airway
fbrosis). These pathological changes lead to air trapping
and progressive airfow limitation. A brief overview follows
of the pathologic changes in COPD, their cellular and
molecular mechanisms, and how these underlie physiologic
abnormalities and symptoms characteristic of the disease
1
.
Pathological changes characteristic of COPD are found in
the proximal airways, peripheral airways, lung parenchyma,
and pulmonary vasculature
2
(Figure 4-1). The pathological
changes include chronic infammation, with increased
numbers of specifc infammatory cell types in different
parts of the lung, and structural changes resulting from
repeated injury and repair. In general, the infammatory and
structural changes in the airways increase with disease
severity and persist on smoking cessation.
Figure 4-1. Pathological Changes in COPD
Proximal airways (trachea, bronchi > 2 mm internal diameter)
Inflammatory cells: Macrophages, CD8
+
(cytotoxic) T lymphocytes,
few neutrophils or eosinophils
Structural changes: Goblet cells, enlarged submucosal glands (both
leading to mucus hypersecretion), squamous metaplasia of epithelium
3
Peripheral airways (bronchioles < 2mm i.d.)
Inflammatory cells: Macrophages, T lymphocytes (CD8
+
> CD4
+
),
B lymphocytes, lymphoid follicles, fibroblasts, few neutrophils
or eosinophils
Structural changes: Airway wall thickening, peribronchial fibrosis, luminal
inflammatory exudate, airway narrowing (obstructive bronchiolitis)
Increased inflammatory response and exudate correlated with disease
severity
4
Lung parenchyma (respiratory bronchioles and alveoli)
Inflammatory cells: Macrophages, CD8
+
T lymphocytes
Structural changes: Alveolar wall destruction, apoptosis of epithelial
and endothelial cells
5
Centrilobular emphysema: dilatation and destruction of respiratory
bronchioles; most commonly seen in smokers
Panacinar emphysema: destruction of alveolar sacs as well as respiratory
bronchioles; most commonly seen in alpha-1 antitrypsin deficiency
Pulmonary vasculature
Inflammatory cells: Macrophages, T lymphocytes
Structural changes: Thickening of intima, endothelial cell dysfunction,
smooth muscle pulmonary hypertension
6
.

+Illustrations of many of the topics covered in this chapter can be found on

the GOLD Website: http://www.goldcopd.org.
CHAPTER 4: PATHOLOGY, PATHOGENESIS,
AND PATHOPHYSIOLOGY
INTRODUCTION
PATHOLOGY
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
PATHOLOGY, PATHOGENISIS, AND PATHOPHYSIOLOGY 25
The infammation in the respiratory tract of COPD patients
appears to be an amplifcation of the normal infammatory
response of the respiratory tract to chronic irritants such
as cigarette smoke. The mechanisms for this amplifcation
are not yet understood but may be genetically determined.
Some patients develop COPD without smoking, but the
nature of the infammatory response in these patients
is unknown
7
. Lung infammation is further amplifed by
oxidative stress and an excess of proteinases in the lung.
Together, these mechanisms lead to the characteristic
pathological changes in COPD (Figure 4-2).

Figure 4-2. Pathogenesis of COPD


Infammatory Cells
COPD is characterized by a specifc pattern of infammation
involving neutrophils, macrophages, and lymphocytes
1

(Figure 4-3). These cells release infammatory mediators
and interact with structural cells in the airways and lung
parenchyma.
Infammatory Mediators
The wide variety of infammatory mediators that have
been shown to be increased in COPD patients
10
attract
infammatory cells from the circulation (chemotactic
factors), amplify the infammatory process (proinfammatory
cytokines), and induce structural changes (growth factors).
Examples of each type of mediator are listed in Figure 4-4.
Oxidative Stress
Oxidative stress may be an important amplifying
mechanism in COPD
11
. Biomarkers of oxidative stress
(e.g., hydrogen peroxide, 8isoprostane) are increased in
the exhaled breath condensate, sputum, and systemic
circulation of COPD patients. Oxidative stress is further
increased in exacerbations. Oxidants are generated
by cigarette smoke and other inhaled particulates, and
released from activated infammatory cells such as
macrophages and neutrophils
12
. There may also be a
reduction in endogenous antioxidants in COPD patients.
Oxidative stress has several adverse consequences
in the lungs, including activation of infammatory
genes, inactivation of antiproteases, stimulation of
mucus secretion, and stimulation of increased plasma
PATHOGENESIS
Figure 4-3. Inflammatory Cells in COPD
Neutrophils: in sputum of normal smokers. Further in COPD and
related to disease severity. Few neutrophils are seen in tissue. They may
be important in mucus hypersecretion and through release of proteases
8
.
Macrophages: Greatly numbers are seen in airway lumen, lung
parenchyma, and bronchoalveolar lavage fluid. Derived from blood
monocytes that differentiate within lung tissue. Produce increased
inflammatory mediators and proteases in COPD patients in response
to cigarette smoke and may show defective phagocytosis
9
.
T lymphocytes: Both CD4+ and CD8+ cells are increased in the airway
wall and lung parenchyma, with CD8+:CD4+ ratio. CD8+ T cells
(Tc1) and Th1 cells which secrete interferon- and express the
chemokine receptor CXCR3
9
. CD8+ cells may be cytotoxic to alveolar
cells, contributing to their destruction.
B lymphocytes: in peripheral airways and within lymphoid follicles,
possibly as a response to chronic colonization and infection of the airways
4
.
Eosinophils: eosinophil proteins in sputum and eosinophils in
airway wall during exacerbations.
Epithelial cells: May be activated by cigarette smoke to produce
inflammatory mediators.

Figure 4-4. Inflammatory Mediators Involved in COPD

Chemotactic factors:
Lipid mediators: e.g., leukotriene B
4
(LTB
4
) attracts neutrophils
and T lymphocytes
Chemokines: e.g., interleukin-8 (IL-8) attracts neutrophils and
monocytes.
Proinflammatory cytokines: e.g., tumor necrosis factor- (TNF-),
IL-1, and IL-6 amplify the inflammatory process and may contribute
to some of the systemic effects of COPD.
Growth factors: e.g., transforming growth factor- (TGF-) may induce
fibrosis in small airways.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
26 PATHOLOGY, PATHOGENISIS, AND PATHOPHYSIOLOGY
exudation. Many of these adverse effects are mediated by
peroxynitrite, which is formed via an interaction between
superoxide anions and nitric oxide. In turn, the nitric oxide
is generated by inducible nitric oxide synthase, which is
expressed in the peripheral airways and lung parenchyma
of COPD patients. Oxidative stress may also account
for a reduction in histone deacetylase activity in lung
tissue from COPD patients, which may lead to enhanced
expression of infammatory genes and also a reduction in
the antiinfammatory action of glucocorticosteroids
13
.
Protease-Antiprotease Imbalance
There is compelling evidence for an imbalance in the
lungs of COPD patients between proteases that break
down connective tissue components and antiproteases
that protect against this. Several proteases, derived from
infammatory cells and epithelial cells, are increased in
COPD patients. There is increasing evidence that they may
interact with each other (Figure 4-5). Proteasemediated
destruction of elastin, a major connective tissue component
in lung parenchyma, is an important feature of emphysema
and is likely to be irreversible.
Differences in Infammation Between COPD and
Asthma
Although both COPD and asthma are associated with
chronic infammation of the respiratory tract, there are
marked differences in the infammatory cells and mediators
involved in the two diseases, which in turn account for
differences in physiological effects, symptoms, and
response to therapy (Figure 4-6, Figure 4-7). However,
there are greater similarities between the lung infammation
in severe asthma and COPD. Some patients with
COPD have features of asthma and may have a mixed
infammatory pattern with increased eosinophils. Finally,
people with asthma who smoke develop pathological
features similar to COPD
14
.
There is now a good understanding of how the underlying
disease process in COPD leads to the characteristic
physiologic abnormalities and symptoms. For example,
decreased FEV
1
primarily results from infammation
and narrowing of peripheral airways, while decreased
gas transfer arises from the parenchymal destruction of
emphysema.
Airfow Limitation and Air Trapping
The extent of infammation, fbrosis, and luminal exudates
in small airways is correlated with the reduction in FEV
1
and FEV
1
/FVC ratio, and probably with the accelerated
decline in FEV
1
characteristic of COPD
4
. This peripheral
airway obstruction progressively traps air during expiration,
resulting in hyperinfation. Although emphysema is more
associated with gas exchange abnormalities than with
reduced FEV
1
, it does contribute to air trapping during
expiration. This is especially so as alveolar attachments to
small airways are destroyed when the disease becomes
more severe. Hyperinfation reduces inspiratory capacity
such that functional residual capacity increases, particularly
during exercise (when this abnormality is known as
dynamic hyperinfation), and this results in dyspnea and
limitation of exercise capacity. It is now thought that
hyperinfation develops early in the disease and is the main
mechanism for exertional dyspnea
15
. Bronchodilators acting
on peripheral airways reduce air trapping, thereby reducing
lung volumes and improving symptoms and exercise
capacity.
Gas Exchange Abnormalities
Gas exchange abnormalities result in hypoxemia and
hypercapnia, and have several mechanisms in COPD. In
general, gas transfer worsens as the disease progresses.
The severity of emphysema correlates with arterial PO
2

and other markers of ventilationperfusion (V
A
/Q) imbalance.
Peripheral airway obstruction also results in V
A
/Q
imbalance, and combines with ventilatory muscle impaired
function in severe disease to reduce ventilation, leading
to carbon dioxide retention. The abnormalities in alveolar
ventilation and a reduced pulmonary vascular bed further
worsen the V
A
/Q abnormalities.
Mucus Hypersecretion
Mucus hypersecretion, resulting in a chronic productive
cough, is a feature of chronic bronchitis and is not
necessarily associated with airfow limitation. Conversely,
not all patients with COPD have symptomatic mucus
PATHOPHYSIOLOGY
Figure 4-5. Proteases and Antiproteases
Involved in COPD
Increased Proteases Decreased Antiproteases
Serine proteases
Neutrophil elastase alpha-1 antitrypsin
Cathepsin G alpha-1 antichymotrypsin
Proteinase 3 Secretory leukoprotease inhibitor
Elafin
Cysteine proteinases
Cathepsins B, K, L, S Cystatins
Matrix metalloproteinases (MMPs)
MMP-8, MMP-9, MMP-12 Tissue inhibitors of MMP 1-4 (TIMP1-4)
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
PATHOLOGY, PATHOGENISIS, AND PATHOPHYSIOLOGY 27
Figure 4-6. Differences in Pulmonary Inflammation Between Asthma and COPD
Cells
COPD
Neutrophils ++
Macrophages +++
CD8+ T cells (Tc1)
Eosinophils ++
Macrophages +
CD4+ T cells (Th2)
Neutrophils +
Macrophages
CD4+ T cells (Th2), CD8+
T cells (Tc1)
Key mediators IL-8
TNF-, IL-1, IL-6
NO +
Eotaxin
IL-4, IL-5, IL-13
NO +++
IL-8
IL-5, IL-13
NO ++
Site of disease Peripheral airways
Lung parenchyma
Pulmonary vessels
Proximal airways Proximal airways
Peripheral airways
Consequences Squamous metaplasia
Mucous metaplasia
Small airway fibrosis
Parenchymal destruction
Pulmonary vascular
remodeling
Fragile epithelium
Mucous metaplasia
Basement membrane
Bronchoconstriction
Response to therapy Small b/d response
Poor response to steroids
Large b/d response
Good response to steroids
Smaller b/d response
Reduced response to steroids
Oxidative stress +++ + +++

Figure 4-7. Inflammatory Cascade in COPD and Asthma

NO = nitric oxide, b/d = bronchodilator
Asthma Severe asthma
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
28 PATHOLOGY, PATHOGENISIS, AND PATHOPHYSIOLOGY
hypersecretion. When present, it is due to mucous
metaplasia with increased numbers of goblet cells and
enlarged submucosal glands in response to chronic
airway irritation by cigarette smoke and other noxious
agents. Several mediators and proteases stimulate mucus
hypersecretion and many of them exert their effects
through the activation of epidermal growth factor receptor
(EGFR)
16
.
Pulmonary Hypertension

Mild to moderate pulmonary hypertension may develop
late in the course of COPD and is due to hypoxic
vasoconstriction of small pulmonary arteries, eventually
resulting in structural changes that include intimal
hyperplasia and later smooth muscle hypertrophy/
hyperplasia
17
. There is an infammatory response in
vessels similar to that seen in the airways and evidence
for endothelial cell dysfunction. The loss of the pulmonary
capillary bed in emphysema may also contribute
to increased pressure in the pulmonary circulation.
Progressive pulmonary hypertension may lead to right
ventricular hypertrophy and eventually to rightside cardiac
failure (cor pulmonale).
Systemic features
It is increasingly recognized that COPD involves several
systemic features, particularly in patients with severe
disease, and that these have a major impact on survival
and comorbid diseases
18,19
(Figure 4-8). Cachexia is
commonly seen in patients with severe COPD. There
may be a loss of skeletal muscle mass and weakness
as a result of increased apoptosis and/or muscle disuse.
Patients with COPD also have increased likeliness of
having osteoporosis, depression and chronic anemia
20
.
Increased concentrations of infammatory mediators,
including TNF-, IL-6, and oxygenderived free radicals,
may mediate some of these systemic effects. There is an
increase in the risk of cardiovascular diseases, which is
correlated with an increase in Creactive protein (CRP)
21
.
Exacerbations represent a further amplifcation of the
infammatory response in the airways of COPD patients,
and may be triggered by infection with bacteria or viruses
or by environmental pollutants. There is a relative lack
of information about the infammatory mechanisms
involved in exacerbations of COPD. In mild and moderate
exacerbations there is an increase in neutrophils and in
some studies also eosinophils in sputum and the airway
wall
22
. This is associated with increased concentrations of
certain mediators, including TNF-, LTB
4
and IL-8, and an
increase in biomarkers of oxidative stress. There is even
less information about severe exacerbations, although
one study showed a marked increase in neutrophils in the
airway wall and increased expression of chemokines
23
.
During an exacerbation there is increased hyperinfation
and air trapping, with reduced expiratory fow, thus
accounting for the increased dyspnea
24
. There is also
worsening of V
A
/Q abnormalities resulting in severe
hypoxemia.
REFERENCES
1. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive
pulmonary disease: molecular and cellular mechanisms. Eur
Respir J 2003;22(4):67288.
2. Hogg JC. Pathophysiology of airfow limitation in chronic
obstructive pulmonary disease. Lancet 2004;364(9435):70921.
3. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular
and structural bases of chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2001;163(6):13049.
4. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu
L, et al. The nature of smallairway obstruction in chronic
obstructive pulmonary disease. N Engl J Med
2004;350(26):264553.
5. Cosio MG, Majo J. Infammation of the airways and lung
parenchyma in COPD: role of T cells. Chest 2002;121 (5
Suppl):160S5S.
6. Wright JL, Levy RD, Churg A. Pulmonary hypertension
in chronic obstructive pulmonary disease: current theories
of pathogenesis and their implications for treatment. Thorax
2005;60(7):6059.
7. Birring SS, Brightling CE, Bradding P, Entwisle JJ, Vara DD,
Grigg J, et al. Clinical, radiologic, and induced sputum
features of chronic obstructive pulmonary disease in
nonsmokers: a descriptive study. Am J Respir Crit Care Med
2002;166(8):107883.
EXACERBATIONS
Figure 4-8. Systemic Features of COPD
Cachexia: loss of fat free mass
Skeletal muscle wasting: apoptosis, disuse atrophy
Osteoporosis
Depression
Normochromic normocytic anemia
Increased risk of cardiovascular disease: associated with CRP
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
PATHOLOGY, PATHOGENISIS, AND PATHOPHYSIOLOGY 29
8. Stockley RA. Neutrophils and the pathogenesis of COPD. Chest
2002;121(5 Suppl):151S5S.
9. Barnes PJ. Macrophages as orchestrators of COPD. J COPD
2004;1:5970.
10. Barnes PJ. Mediators of chronic obstructive pulmonary disease.
Pharmacol Rev 2004;56(4):51548.
11. Rahman I. Oxidative stress in pathogenesis of chronic
obstructive pulmonary disease: cellular and molecular
mechanisms. Cell Biochem Biophys 2005;43(1):16788.
12. MacNee W. Oxidative stress and lung infammation in airways
disease. Eur J Pharmacol 2001;429(13):195207.
13. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, et al.
Decreased histone deacetylase activity in chronic obstructive
pulmonary disease. N Engl J Med 2005;352(19):196776.
14. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette
smoking. Eur Respir J 2004;24(5):82233.
15. ODonnell DE, Revill SM, Webb KA. Dynamic hyperinfation and
exercise intolerance in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2001;164(5):7707.
16. Burgel PR, Nadel JA. Roles of epidermal growth factor receptor
activation in epithelial cell repair and mucin production in airway
epithelium. Thorax 2004;59(11):9926.
17. Barbera JA, Peinado VI, Santos S. Pulmonary hypertension in
chronic obstructive pulmonary disease. Eur Respir J
2003;21(5):892905.
18. Wouters EF, Creutzberg EC, Schols AM. Systemic effects in
COPD. Chest 2002;121(5 Suppl):127S30S.
19. Agusti AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets
X. Systemic effects of chronic obstructive pulmonary disease.
Eur Respir J 2003;21(2):34760.
20. Similowski T, Agusti AG, MacNee W, Schonhofer B. The
potential impact of anaemia of chronic disease in COPD. Eur
Respir J 2006;27(2):3906.
21. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association
between chronic obstructive pulmonary disease and systemic
infammation: a systematic review and a metaanalysis. Thorax
2004;59(7):57480.
22. Wedzicha JA. Exacerbations: etiology and pathophysiologic
mechanisms. Chest 2002;121(5 Suppl):136S41S.
23. Drost EM, Skwarski KM, Sauleda J, Soler N, Roca J, Agusti AG.
Oxidative stress and airway infammation in severe
exacerbations of COPD. Thorax 2005;60(4):293300.
24. Parker CM, Voduc N, Aaron SD, Webb KA, ODonnell DE.
Physiological changes during symptom recovery from moderate
exacerbations of COPD. Eur Respir J 2005;26(3):4208.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
30 PATHOLOGY, PATHOGENISIS, AND PATHOPHYSIOLOGY
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
CHAPTER
5
MANAGEMENT
OF COPD
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
32 MANAGEMENT OF COPD
An effective COPD management plan includes four
components: (1) Assess and Monitor Disease; (2) Reduce
Risk Factors; (3) Manage Stable COPD; and (4) Manage
Exacerbations. Management of Mild to Moderate COPD
(Stages I and II) involves the avoidance of risk factors to
prevent disease progression and pharmacotherapy as
needed to control symptoms. Severe (Stage III) and Very
Severe (Stage IV) COPD often require the integration
of several different disciplines, a variety of treatment
approaches, and a commitment of the clinician to the
continued support of the patient as the illness progresses.
In addition to patient education, health advice, and
pharmacotherapy, COPD patients may require specifc
counseling about smoking cessation, instruction in physical
exercise, nutritional advice, and continued nursing support.
Not all approaches are needed for every patient, and
assessing the potential beneft of each approach at each
stage of the illness is a crucial aspect of effective disease
management.
While disease prevention is the ultimate goal, once
COPD has been diagnosed, effective management should
be aimed at the following goals:

Relieve symptoms
Prevent disease progression
Improve exercise tolerance
Improve health status
Prevent and treat complications
Prevent and treat exacerbations
Reduce mortality
These goals should be reached with minimal side effects
from treatment, a particular challenge in COPD patients
because they commonly have comorbidities. The extent
to which these goals can be realized varies with each
individual, and some treatments will produce benefts in
more than one area. In selecting a treatment plan, the
benefts and risks to the individual, and the costs, direct
and indirect, to the individual, his or her family, and the
community must be considered.
Patients should be identifed as early in the course of the
disease as possible, and certainly before the end stage
of the illness when disability is substantial. Access to
spirometry is key to the diagnosis of COPD and should
be available to health care workers who care for COPD
patients. However, the benefts of communitybased
spirometric screening, of either the general population or
smokers, are still unclear.
Educating patients, physicians, and the public to
recognize that cough, sputum production, and especially
breathlessness are not trivial symptoms is an essential
aspect of the public health care of this disease.
Reduction of therapy once symptom control has been
achieved is not normally possible in COPD. Further
deterioration of lung function usually requires the
progressive introduction of more treatments, both
pharmacologic and nonpharmacologic, to attempt to limit
the impact of these changes. Exacerbations of signs and
symptoms, a hallmark of COPD, impair patients quality of
life and decrease their health status. Appropriate treatment
and measures to prevent further exacerbations should be
implemented as quickly as possible.
Important differences exist between countries in the
approach to chronic illnesses such as COPD and in the
acceptability and affordability of particular forms of therapy.
Ethnic differences in drug metabolism, especially for oral
medications, may result in different patient preferences in
different communities. Little is known about these important
issues in relationship to COPD.
CHAPTER 5: MANAGEMENT OF COPD
INTRODUCTION
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 33
KEY POINTS:

A clinical diagnosis of COPD should be considered
in any patient who has dyspnea, chronic cough or
sputum production, and/or a history of exposure to
risk factors for the disease. The diagnosis should
be confrmed by spirometry.
For the diagnosis and assessment of COPD,
spirometry is the gold standard as it is the most
reproducible, standardized, and objective way
of measuring airfow limitation. The presence of
a postbronchodilator FEV
1
/FVC < 0.70 confrms
the presence of airfow limitation that is not fully
reversible.
Health care workers involved in the diagnosis
and management of COPD patients should have
access to spirometry.
Assessment of COPD severity is based on the
patients level of symptoms, the severity of the
spirometric abnormality, and the presence of
complications.
Measurement of arterial blood gas tensions should
be considered in all patients with FEV
1
< 50%
predicted or clinical signs suggestive of respiratory
failure or right heart failure.
COPD is usually a progressive disease and lung
function can be expected to worsen over time,
even with the best available care. Symptoms and
objective measures of airfow limitation should be
monitored to determine when to modify therapy
and to identify any complications that may develop.
Comorbidities are common in COPD and should be
actively identifed. Comorbidities often complicate
the management of COPD, and vice versa.
A clinical diagnosis of COPD should be considered
in any patient who has dyspnea, chronic cough or
sputum production, and/or a history of exposure to risk
factors for the disease (Figure 5.1-1). The diagnosis
should be confrmed by spirometry. The presence of a
postbronchodilator FEV
1
/FVC < 0.70 confrms the presence
of airfow limitation that is not fully reversible..
Assessment of Symptoms
Although exceptions occur, the general patterns of
symptom development in COPD is well established. The
main symptoms of patients in Stage I: Mild COPD are
chronic cough and sputum production. These symptoms
can be present for many years before the development
of airfow limitation and are often ignored or discounted
by patients and attributed to aging or lack of conditioning.
As airfow limitation worsens in Stage II: Moderate COPD,
patients often experience dyspnea, which may interfere
with their daily activities
1
. Typically, this is the stage at
which they seek medical attention and may be diagnosed
with COPD. However, some patients do not experience
cough, sputum production, or dyspnea in Stage I: Mild
COPD or Stage II: Moderate COPD, and do not come to
medical attention until their airfow limitation becomes
more severe or their lung function is worsened acutely by a
respiratory tract infection. As airfow limitation worsens and
the patient enters Stage III: Severe COPD, the symptoms of
cough and sputum production typically continue, dyspnea
worsens, and additional symptoms heralding complications
(such as respiratory failure, right heart failure
436
, weight
loss, and arterial hypoxemia) may develop. It is important
to note that, since COPD may be diagnosed at any stage,
any of the symptoms described below may be present in a
patient presenting for the frst time.
INITIAL DIAGNOSIS
COMPONENT 1: ASSESS AND MONITOR DISEASE
Figure 5.1-1. Key Indicators for
Considering a Diagnosis of COPD
Consider COPD, and perform spirometry, if any of these
indicators are present in an individual over age 40. These
indicators are not diagnostic themselves, but the presence
of multiple key indicators increases the probability of a
diagnosis of COPD. Spirometry is needed to establish a
diagnosis of COPD.
Dyspnea that is: Progressive (worsens over time)
Usually worse with exercise
Persistent (present every day)
Described by the patient as an
increased effort to breathe,
heaviness, air hunger, or gasping.
Chronic Cough May be intermittent and may be
unproductive.
Chronic sputum Any pattern of chronic sputum
production: production may indicate COPD.
History of Tobacco smoke.
exposure to Occupational dusts and chemicals
risk factors, Smoke from home cooking and
especially: heating fuels.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
34 MANAGEMENT OF COPD
Dyspnea. Dyspnea, the hallmark symptom of COPD, is
the reason most patients seek medical attention and is a
major cause of disability and anxiety associated with the
disease. Typical COPD patients describe their dyspnea
as a sense of increased effort to breathe, heaviness, air
hunger, or gasping
2
. However, the terms used to describe
dyspnea vary both by individual and by culture
3
. It is often
possible to distinguish the breathlessness of COPD from
that due to other causes by analysis of the terms used,
although there is considerable overlap with descriptors of
bronchial asthma. A simple way to quantify the impact of
breathlessness on a patients health status is the British
Medical Research Council (MRC) questionnaire (Figure
5.1-2). This questionnaire relates well to other measures of
health status
4
and predicts future mortality risk
5
.
Breathlessness in COPD is characteristically persistent and
progressive. Even on good days COPD patients experience
dyspnea at lower levels of exercise than unaffected people
of the same age. Initially, breathlessness is only noted on
unusual effort (e.g., walking or running up a fight of stairs)
and may be avoided entirely by appropriate behavioral
change (e.g., using an elevator). As lung function
deteriorates, breathlessness becomes more intrusive,
and patients may notice that they are unable to walk at
the same speed as other people of the same age or carry
out activities that require use of the accessory respiratory
muscles (e.g., carrying grocery bags)
6
. Eventually,
breathlessness is present during everyday activities (e.g.,
dressing, washing) or at rest, leaving the patient confned to
the home.
Cough. Chronic cough, often the frst symptom of COPD to
develop
7
, is often discounted by the patient as an expected
consequence of smoking and/or environmental exposures.
Initially, the cough may be intermittent, but later is present
every day, often throughout the day. The chronic cough in
COPD may be unproductive
8
. In some cases, signifcant
airfow limitation may develop without the presence of
a cough. Figure 5.1-3 lists some of the other causes of
chronic cough in individuals with a normal chest X-ray.
Sputum production. COPD patients commonly raise
small quantities of tenacious sputum after coughing bouts.
Regular production of sputum for 3 or more months in 2
consecutive years (in the absence of any other conditions
that may explain it) is the epidemiological defnition
of chronic bronchitis
9
, but this is a somewhat arbitrary
defnition that does not refect the range of sputum
production in COPD patients. Sputum production is often
diffcult to evaluate because patients may swallow sputum
rather than expectorate it, a habit subject to signifcant
cultural and gender variation. Patients producing large
volumes of sputum may have underlying bronchiectasis.
The presence of purulent sputum refects an increase in
infammatory mediators
10
, and its development may identify
the onset of an exacerbation
11
.
Wheezing and chest tightness. Wheezing and chest
tightness are nonspecifc symptoms that may vary
between days, and over the course of a single day. These
symptoms may be present in Stage I: Mild COPD, but are
more characteristic of asthma or Stage III: Severe COPD
and Stage IV: Very Severe COPD. Audible wheeze may
arise at a laryngeal level and need not be accompanied
by auscultatory abnormalities. Alternatively, widespread
inspiratory or expiratory wheezes can be present on
listening to the chest. Chest tightness often follows
Figure 5.1-2: Modified Medical Research Council
Questionnaire for Assessing the
Severity of Breathlessness
4
PLEASE TICK IN THE BOX THAT APPLIES TO YOU
(ONE BOX ONLY)
I only get breathless with strenuous exercise.
I get short of breath when hurrying on the level or
walking up a slight hill.
I walk slower than people of the same age on the
level because of breathlessness, or I have to stop for
breath when walking on my own pace on the level.
I stop for breath after walking about 100 meters or
after a few minutes on the level.
I am too breathless to leave the house or I am
breathless when dressing or undressing.
Figure 5.1-3. Causes of Chronic Cough with a
Normal Chest X-ray
Intrathoracic
Chronic obstructive pulmonary disease
Bronchial asthma
Central bronchial carcinoma
Endobronchial tuberculosis
Bronchiectasis
Left heart failure
Interstitial lung disease
Cystic fibrosis
Extrathoracic
Postnasal drip
Gastroesophageal reflux
Drug therapy (e.g., ACE inhibitors)
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 35
exertion, is poorly localized, is muscular in character, and
may arise from isometric contraction of the intercostal
muscles. An absence of wheezing or chest tightness does
not exclude a diagnosis of COPD, nor does their presence
confrm a diagnosis of asthma.
Additional features in severe disease. Weight loss and
anorexia are common problems in advanced COPD
12
. They
are prognostically important
13
and can also be a sign of
other diseases (e.g., tuberculosis, bronchial tumors), and
therefore should always be investigated. Cough syncope
occurs due to rapid increases in intrathoracic pressure
during attacks of coughing. Coughing spells may also
cause rib fractures, which are sometimes asymptomatic.
Ankle swelling may be the only symptomatic pointer to
the development of cor pulmonale. Psychiatric morbidity,
especially anxiety and depression are increased in COPD
14

and high levels of anxiety are associated with poorer
outcomes
448
. Anxiety and depression merit specifc enquiry
in the clinical history.
Medical History
A detailed medical history of a new patient known or
thought to have COPD should assess:

Patients exposure to risk factors, such as smoking and
occupational or environmental exposures
Past medical history, including asthma, allergy,
sinusitis, or nasal polyps; respiratory infections in
childhood; other respiratory diseases
Family history of COPD or other chronic respiratory
disease
Pattern of symptom development: COPD typically
develops in adult life and most patients are conscious
of increased breathlessness, more frequent winter
colds, and some social restriction for a number of years
before seeking medical help.
History of exacerbations or previous hospitalizations for
respiratory disorder: Patients may be aware of periodic
worsening of symptoms even if these episodes have
not been identifed as exacerbations of COPD.
Presence of comorbidities, such as heart disease,
malignancies, osteoporosis, and musculoskeletal
disorders, which may also contribute to restriction of
activity
15
.
Appropriateness of current medical treatments: For
example, betablockers commonly prescribed for heart
disease are usually contraindicated in COPD.
Impact of disease on patient?s life, including limitation
of activity, missed work and economic impact, effect on
family routines, feelings of depression or anxiety
Social and family support available to the patient
Possibilities for reducing risk factors, especially
smoking cessation
Physical Examination
Though an important part of patient care, a physical
examination is rarely diagnostic in COPD. Physical signs
of airfow limitation are usually not present until signifcant
impairment of lung function has occurred
16,17
, and their
detection has a relatively low sensitivity and specifcity. A
number of physical signs may be present in COPD, but
their absence does not exclude the diagnosis.
Inspection.

Central cyanosis, or bluish discoloration of the mucosal
membranes, may be present but is diffcult to detect in
artifcial light and in many racial groups.
Common chest wall abnormalities, which refect the
pulmonary hyperinfation seen in COPD, include
relatively horizontal ribs, barrel-shaped chest, and
protruding abdomen.
Flattening of the hemidiaphragms may be associated
with paradoxical indrawing of the lower rib cage on
inspiration, and widening of the xiphosternal angle.
Resting respiratory rate is often increased to more than
20 breaths per minute and breathing can be relatively
shallow
17
.
Patients commonly show pursedlip breathing, which
may serve to slow expiratory fow and permit more
effcient lung emptying
18
.
COPD patients often have resting muscle activation
while lying supine. Use of the scalene and
sternocleidomastoid muscles is a further indicator of
respiratory distress.
Ankle or lower leg edema can be a sign of right heart
failure.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
36 MANAGEMENT OF COPD
Palpation and percussion.

These are often unhelpful in COPD.
Detection of the heart apex beat may be diffcult due to
pulmonary hyperinfation.
Hyperinfation also leads to downward displacement
of the liver and an increase in the ability to palpate this
organ without it being enlarged.
Auscultation.
Patients with COPD often have reduced breath sounds,
but this fnding is not suffciently characteristic to make
the diagnosis
19
.

The presence of wheezing during quiet breathing is a
useful pointer to airfow limitation. However, wheezing
heard only after forced expiration has not been
validated as a diagnostic test for COPD.
Inspiratory crackles occur in some COPD patients but
are of little help diagnostically.
Heart sounds are best heard over the xiphoid area.
Measurement of Airfow Limitation (Spirometry)
1

Spirometry should be undertaken in all patients who may
have COPD. It is needed to make a confdent diagnosis of
COPD and to exclude other diagnoses that may present
with similar symptoms. Although spirometry does not
fully capture the impact of COPD on a patients health, it
remains the gold standard for diagnosing the disease and
monitoring its progression. It is the best standardized, most
reproducible, and most objective measurement of airfow
limitation available. Good quality spirometric measurement
is possible and all health care workers who care for COPD
patients should have access to spirometry. Figure 5.1-
4 summarizes some of the factors needed to achieve
accurate test results.
Spirometry should measure the volume of air forcibly
exhaled from the point of maximal inspiration (forced
vital capacity, FVC) and the volume of air exhaled during
the frst second of this maneuver (forced expiratory
volume in one second, FEV
1
), and the ratio of these
two measurements (FEV
1
/FVC) should be calculated.
Spirometry measurements are evaluated by comparison
with reference values20 based on age, height, sex, and
race (use appropriate reference values, e.g., see reference
20).
Figure 5.1-5 shows a normal spirogram and a spirogram
typical of patients with mild to moderate COPD. Patients
with COPD typically show a decrease in both FEV
1
and
FVC. The degree of spirometric abnormality generally
refects the severity of COPD (Figure 1-2). The presence of
airfow limitation is defned by a postbronchodilator FEV
1
/
FVC < 0.70. This approach to is a pragmatic one in view
of the fact that universally applicable reference values
for FEV
1
and FVC are not available. Spirometry should
be performed after the administration of an adequate
Figure 5.1-4. Considerations in
Performing Spirometry
Preparation
Spirometers need calibration on a regular basis.
Spirometers should produce hard copy to permit
detection of technical errors or have an automatic
prompt to identify an unsatisfactory test and the
reason for it.
The supervisor of the test needs training in its effective
performance.
Maximal patient effort in performing the test is required
to avoid errors in diagnosis and management.
Performance
Pirometry should be performed using techniques that
meet published standards
24
.
The expiratory volume/time traces should be smooth
and free from irregularities.
The recording should go on long enough for a volume
plateau to be reached, which may take more than 15
seconds in severe disease.
Both FVC and FEV
1
should be the largest value
obtained from any of 3 technically satisfactory curves
and the FVC and FEV
1
values in these three curves
should vary by no more than 5% or 100 ml, whichever
is greater.
The FEV
1
/FVC ratio should be taken from the
technically acceptable curve with the largest sum of
FVC and FEV
1
.
Evaluation
Spirometry measurements are evaluated by
comparison of the results with appropriate reference
values based on age, height, sex, and race (e.g., see
reference 20).
The presence of a postbronchodilator FEV
1
/FVC<0.70
confirms the presence of airflow limitation that is not
fully reversible

1
Spriometry for Diagnosis of COPD: Insert for GOLD Pocket Guide available at http://www.goldcopd.org.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 37
dose of a short-acting inhaled bronchodilator (e.g., 400 g
salbutamol) in order to minimize variability Where possible,
values should be compared to age-related normal values
to avoid over-diagnosis of COPD in the elderly
21
. Using
the fxed ratio (FEV
1
/FVC) is particularly problematic in
older adults since the ratio declines with age leading to the
potential for labeling healthy older adults as having COPD.
Post- bronchodilator reference values in this population are
urgently needed to avoid potential overdiagnosis.
Peak expiratory fow is sometimes used as a measure
of airfow limitation, but in COPD may underestimate the
degree of airways obstruction
22
. Data from the US National
Health and Nutrition Examination Survey suggest that peak
expiratory fow has good sensitivity, identifying over 90%
of COPD cases that can be diagnosed with spirometry, but
because its specifcity is weaker it cannot be relied on as
the only diagnostic test
23
.
The role of screening spirometry in the general population
or in a population at risk for COPD is controversial. Both
FEV
1
and FVC predict all-cause mortality independent of
tobacco smoking, and abnormal lung function identifes
a subgroup of smokers at increased risk for lung
cancer. This has been the basis of an argument that
screening spirometry should be employed as a global
health assessment tool
25
. However, there are no data to
indicate that screening spirometry is effective in directing
management decisions or in improving COPD outcomes
in patients who are identifed before the development of
signifcant symptoms
26
.
Assessment of COPD Severity
Assessment of COPD severity is based on the patients
level of symptoms, the severity of the spirometric
abnormality (Figure 1-2), and the presence of
complications such as respiratory failure, right heart failure,
weight loss, and arterial hypoxemia.
Although the presence of airfow limitation is key to the
assessment of COPD severity, it may be valuable from a
public health perspective to identify individuals at risk for
the disease before signifcant airfow limitation develops
(Figure 1-3). A majority of people with early COPD
identifed in large studies complained of at least one
respiratory symptom, such as cough, sputum production,
wheezing, or breathlessness
27,28
. These symptoms may be
present at a time of relatively minor or even no spirometric
abnormality. While not all individuals with such symptoms
will go on to develop COPD
29
, presence of these symptoms
should help defne a high-risk population that should be
targeted for preventive intervention. Much depends on the
success of convincing such people, as well as health care
workers, that even minor respiratory symptoms are not
normal and may be markers of future ill health.
When evaluating symptomatic patients presenting to a
physician, the severity of the patients symptoms and
the degree to which they affect his or her daily life, not
just the severity of airfow obstruction, are the major
determinants of health status
30
. The severity of a patients
breathlessness is important and can be usefully gauged
by the MRC scale (Figure 5.1-2). Other forms of symptom
severity scoring have yet to be validated in different
populations and commonly rely on individual clinical
judgment, although a clinical COPD questionnaire has
been validated in family practice
31
.
Objectively measured exercise impairment, assessed
by a reduction in self-paced walking distance
32
or during
incremental exercise testing in a laboratory
33
, is a powerful
indicator of health status impairment and predictor of
prognosis
30
. The ratio of inspiratory capacity to total lung
capacity determined plethysmographically has also been
found to be prognostically useful
34
. Similarly, weight loss
and reduction in the arterial oxygen tension identify patients
at increased risk for mortality
35,36
.
A relatively simple approach to identifying disease severity
using a combination of most of the above variables has
been proposed. The BODE method gives a composite
score (Body mass index, Obstruction, Dyspnea and
Exercise) that is a better predictor of subsequent survival
than any component singly
37
, and its properties as a
measurement tool are under investigation.


Figure 5.1-5. Normal Spirogram and Spirogram
Typical of Patients with Mild to Moderate COPD*

*Postbronchodilator FEV
1
is recommended for the diagnosis
and assesment of the severity of COPD.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
38 MANAGEMENT OF COPD
Additional Investigations
For patients diagnosed with Stage II: Moderate COPD and
beyond, the following additional investigations may be
considered:
Bronchodilator reversibility testing. Despite earlier
hopes, neither bronchodilator nor oral glucocorticosteroid
reversibility testing predicts disease progression, whether
judged by decline in FEV
1
, deterioration of health status,
or frequency of exacerbations
38,39
in patients with a clinical
diagnosis of COPD and abnormal spirometry
39
. Small
changes in FEV
1
(e.g., < 400 ml) after administration of a
bronchodilator do not reliably predict the patients response
to treatment (e.g., change in exercise capacity
40
). Minor
variations in initial airway caliber can lead to different
classifcation of reversibility status depending on the day
of testing
39
, and the lower the pre-bronchodilator FEV
1
,
the greater the chance of a patient being classifed as
reversible even when the 200 ml volume criterion is
included.
In some cases (e.g., a patient with an atypical history
such as asthma in childhood and regular night waking
with cough or wheeze) a clinician may wish to perform a
bronchodilator and/or glucocorticosteroid reversibility test
and a possible protocol is suggested in Figure 5.1-6.
Chest X-ray. An abnormal chest X-ray is seldom diagnostic
in COPD unless obvious bullous disease is present,
but it is valuable in excluding alternative diagnoses and
establishing the presence of signifcant comorbidities
such as cardiac failure. Radiological changes associated
with COPD include signs of hyperinfation (fattened
diaphragm on the lateral chest flm, and an increase in
the volume of the retrosternal air space), hyperlucency
of the lungs, and rapid tapering of the vascular markings.
Computed tomography (CT) of the chest is not routinely
recommended. However, when there is doubt about the
diagnosis of COPD, high resolution CT (HRCT) scanning
might help in the differential diagnosis. In addition, if a
surgical procedure such as lung volume reduction is
contemplated, a chest CT scan is necessary since the
distribution of emphysema is one of the most important
determinants of surgical suitability
41
.
Arterial blood gas measurement. In advanced COPD,
measurement of arterial blood gases while the patient is
breathing air is important. This test should be performed in
stable patients with FEV
1
< 50% predicted or with clinical
signs suggestive of respiratory failure or right heart failure.
Several considerations are important to ensure accurate
test results. The inspired oxygen concentration (FiO
2

normally 21% at sea level) should be noted, a particularly
important point if patient is using an O
2
-driven nebulizer.
Changes in arterial blood gas tensions take time to occur,
especially in severe disease. Thus, 20-30 minutes should
pass before rechecking the gas tensions when the FiO
2
has
been changed, e.g., during an assessment for domiciliary
oxygen therapy. Adequate pressure must be applied at the
arterial puncture site for at least one minute, as failure to do
so can lead to painful bruising.
Alpha-1 antitrypsin defciency screening. In patients of
Caucasian descent who develop COPD at a young age
(< 45 years) or who have a strong family history of the
disease, it may be valuable to identify coexisting alpha-1
antitrypsin defciency. This could lead to family screening or
appropriate counseling. A serum concentration of alpha-1
antitrypsin below 15-20% of the normal value is highly
suggestive of homozygous alpha-1 antitrypsin defciency.
Figure 5.1-6. Bronchodilator Reversibility
Testing in COPD
Preparation
Tests should be performed when patients are clinically
stable and free from respiratory infection.
Patients should not have taken inhaled short-acting
bronchodilators in the previous six hours, long-acting
bronchodilator in the previous 12 hours, or sustained-
release theophylline in the previous 24 hours.
Spirometry
FEV
1
should be measured before a bronchodilator is
given.
The bronchodilator should be given by metered dose
inhaler through a spacer device or by nebulizer to be
certain it has been inhaled.
The bronchodilator dose should be selected to be high
on the dose/response curve.
Possible dosage protocols are 400 g
2
-agonist,
up to 160 g anticholinergic, or the two combined
20
.
FEV
1
should be measured again 10-15 minutes after
a short-acting bronchodilator is given; 30-45 minutes
after the combination.
Results
An increase in FEV
1
that is both greater than 200 ml
and 12% above the pre-bronchodilator FEV
1
is
considered significant
20
. It is usually helpful to report
the absolute change as well as the % change from
baseline to set the improvement in a clinical context.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 39
Differential Diagnosis
In some patients with chronic asthma, a clear distinction
from COPD is not possible using current imaging and
physiological testing techniques, and it is assumed that
asthma and COPD coexist in these patients. In these
cases, current management is similar to that of asthma.
Other potential diagnoses are usually easier to distinguish
from COPD (Figure 5.1-7).
Visits to health care facilities will increase in frequency as
COPD progresses. The type of health care workers seen,
and the frequency of visits, will depend on the health care
system. Ongoing monitoring and assessment in COPD
ensures that the goals of treatment are being met and
should include evaluation of: (1) exposure to risk factors,
especially tobacco smoke; (2) disease progression and
Figure 5.1-7. Differential Diagnosis of COPD
Diagnosis Suggestive Features
COPD Onset in mid-life.
Symptoms slowly progressive.
Long history of tobacco smoking.
Dyspnea during exercise.
Largely irreversible airflow limitation.
Asthma Onset early in life (often childhood).
Symptoms vary from day to day.
Symptoms at night/early morning.
Allergy, rhinitis, and/or eczema also
present.
Family history of asthma.
Largely reversible airflow limitation.
Congestive Heart Failure Fine basilar crackles on auscultation.
Chest X-ray shows dilated heart,
pulmonary edema.
Pulmonary function tests indicate
volume restriction, not airflow limitation.
Bronchiectasis Large volumes of purulent sputum.
Commonly associated with bacterial
infection.
Coarse crackles/clubbing on auscultation.
Chest X-ray/CT shows bronchial
dilation, bronchial wall thickening.
Tuberculosis Onset all ages
Chest X-ray shows lung infiltrate.
Microbiological confirmation.
High local prevalence of tuberculosis.
Obliterative Bronchiolitis Onset in younger age, nonsmokers.
May have history of rheumatoid arthritis
or fume exposure.
CT on expiration shows hypodense areas.
Diffuse Panbronchiolitis Most patients are male and nonsmokers.
Almost all have chronic sinusitis.
Chest X-ray and HRCT show diffuse
small centrilobular nodular opacities
and hyperinflation.
These features tend to be characteristic of the respective diseases,
but do not occur in every case. For example, a person who has
never smoked may develop COPD (especially in the developing
world where other risk factors may be more important than cigarette
smoking); asthma may develop in adult and even elderly patients.
Figure 5.1-8. Suggested Questions for
Follow-Up Visits*
Monitor exposure to risk factors:
Has your exposure to risk factors changed since your last visit?
Since your last visit, have you quit smoking, or are you still
smoking?
If you are still smoking, how many cigarettes/how much tobacco
per day?
Would you like to quit smoking?
Has there been any change in your working environment?
Monitor disease progression and development of complications:
How much can you do before you get short of breath?
(Use an everyday example, such as walking up flights of stairs,
up a hill, or on flat ground.)
Has your breathlessness worsened, improved, or stayed the
same since your last visit?
Have you had to reduce your activities because of your
breathing or any other symptom?
Have any of your symptoms worsened since your last visit?
Have you experienced any new symptoms since your last visit?
Has your sleep been disrupted by breathlessness or other
chest symptoms?
Since your last visit, have you missed any work/had to see a
doctor because of your symptoms?
Monitor pharmacotherapy and other medical treatment:
What medicines are you taking?
How often do you take each medicine?
How much do you take each time?
Have you missed or stopped taking any regular doses of your
medicine for any reason?
Have you had trouble filling your prescriptions (e.g., for financial
reasons, not on formulary)?
Please show me how you use your inhaler.
Have you tried any other medicines or remedies?
Has your treatment been effective in controlling your symptoms?
Has your treatment caused you any problems?
Monitor exacerbation history:
Since your last visit, have you had any episodes/times when
your symptoms were a lot worse than usual?
If so, how long did the episode(s) last? What do you think
caused the symptoms to get worse? What did you do to control
the symptoms?
ONGOING MONITORING AND
ASSESSMENT
*These questions are examples and do not represent a
standardized assessment instrument. The validity and reliability of
these questions have not been assessed.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
40 MANAGEMENT OF COPD
development of complications; (3) pharmacotherapy and
other medical treatment; (4) exacerbation history; (5)
comorbidities.
Suggested questions for followup visits are listed in Figure
5.1-8. The best way to detect changes in symptoms
and overall health status is to ask the patient the same
questions at each visit.

Monitor Disease Progression and Development of
Complications
COPD is usually a progressive disease. Lung function
can be expected to worsen over time, even with the best
available care. Symptoms and objective measures of
airfow limitation should be monitored to determine when
to modify therapy and to identify any complications that
may develop. As at the initial assessment, follow-up visits
should include a physical examination and discussion of
symptoms, particularly any new or worsening symptoms.
Pulmonary function. A patients decline in lung function
is best tracked by periodic spirometry measurements
although useful information about lung function decline is
unlikely from spirometry measurements performed more
than once a year. Spirometry should be performed if there
is a substantial increase in symptoms or a complication.
Other pulmonary function tests, such as fow-volume
loops, diffusing capacity (D
LCO
) measurements, inspiratory
capacity, and measurement of lung volumes are not
needed in a routine assessment but can provide
information about the overall impact of the disease and
can be valuable in resolving diagnostic uncertainties and
assessing patients for surgery.
Arterial blood gas measurement. The development of
respiratory failure is indicated by a PaO
2
< 8.0 kPa (60 mm
Hg) with or without PaCO
2
> 6.7 kPa (50 mm Hg) in arterial
blood gas measurements made while breathing air at sea
level. Screening patients by pulse oximetry and assessing
arterial blood gases in those with an oxygen saturation
(SaO
2
) < 92% is a useful way of selecting patients for
arterial blood gas measurement
42
. However, pulse oximetry
gives no information about CO
2
tensions.
Clinical signs of respiratory failure or right heart failure
include central cyanosis, ankle swelling, and an increase in
the jugular venous pressure. Clinical signs of hypercapnia
are extremely nonspecifc outside of exacerbations.
Assessment of pulmonary hemodynamics. Mild to
moderate pulmonary hypertension (mean pulmonary
artery pressure 30 mm Hg) is only likely to be
important in patients who have developed respiratory
failure. Measurement of pulmonary arterial pressure
is not recommended in clinical practice as it does not
add practical information beyond that obtained from a
knowledge of PaO
2
.
Diagnosis of right heart failure or cor pulmonale.
Elevation of the jugular venous pressure and the presence
of pitting ankle edema are often the most useful fndings
suggestive of cor pulmonale in clinical practice. However,
the jugular venous pressure is often diffcult to assess in
patients with COPD, due to large swings in intrathoracic
pressure. Firm diagnosis of cor pulmonale can be made
through a number of investigations, including radiography,
electrocardiography, echocardiography, radionucleotide
scintigraphy, and magnetic resonance imaging. However,
all of these measures involve inherent inaccuracies of
diagnosis.
CT and ventilation-perfusion scanning. Despite the
benefts of being able to delineate pathological anatomy,
routine CT and ventilation-perfusion scanning are
currently confned to the assessment of COPD patients for
surgery. HRCT is currently under investigation as a way
of visualizing airway and parenchymal pathology more
precisely.
Hematocrit. Polycythemia can develop in the presence
of arterial hypoxemia, especially in continuing smokers
43
,
and can be identifed by hematocrit > 55%. Anemia is
more prevalent than previously thought, affecting almost
a quarter of COPD patients in one hospital series
44
. A low
hematocrit indicates a poor prognosis in COPD patients
receiving long-term oxygen treatment
45
.
Respiratory muscle function. Respiratory muscle
function is usually measured by recording the maximum
inspiratory and expiratory mouth pressures. More complex
measurements are confned to research laboratories.
Measurement of inspiratory muscle force is useful
in assessing patients when dyspnea or hypercapnia
is not readily explained by lung function testing or
when peripheral muscle weakness is suspected. This
measurement may improve in COPD patients when other
measurements of lung mechanics do not (e.g., after
pulmonary rehabilitation)
46,47
.
Sleep studies. Sleep studies may be indicated when
hypoxemia or right heart failure develops in the presence
of relatively mild airfow limitation or when the patient has
symptoms suggesting the presence of sleep apnea.
Exercise testing. Several types of tests are available
to measure exercise capacity, e.g., treadmill and cycle
ergometry in the laboratory or six-minute and shuttle
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 41
walking tests , but these are primarily used in conjunction
with pulmonary rehabilitation programs.
Monitor Pharmacotherapy and Other Medical Treatment
In order to adjust therapy appropriately as the disease
progresses, each followup visit should include a discussion
of the current therapeutic regimen. Dosages of various
medications, adherence to the regimen, inhaler technique,
effectiveness of the current regime at controlling symptoms,
and side effects of treatment should be monitored.
Monitor Exacerbation History
During periodic assessments, health care workers
should question the patient and evaluate any records
of exacerbations, both selftreated and those treated by
other health care providers. Frequency, severity, and likely
causes of exacerbations should be evaluated. Frequency,
severity, likely causes of exacerbations, and the patients
psychological well being
406
should be evaluated. Increased
sputum volume, acutely worsening dyspnea, and the
presence of purulent sputum should be noted. Specifc
inquiry into unscheduled visits to providers, telephone
calls for assistance, and use of urgent or emergency
care facilities may be helpful. Severity can be estimated
by the increased need for bronchodilator medication
or glucocorticosteroids and by the need for antibiotic
treatment. Hospitalizations should be documented,
including the facility, duration of stay, and any use of
critical care or intubation. The clinician then can request
summaries of all care received to facilitate continuity of
care.
Monitor Comorbidities
Comorbidities are common in COPD. Some may be an
indirect result of COPD, arising independently but more
likely to occur when COPD is present, e.g., ischemic
heart disease, bronchial carcinoma, osteoporosis, and
depression.. Other comorbid conditions may coexist with
COPD because they become prevalent as part of the
aging process, e.g., arthritis, diabetes, refux esophagitis
and depression. All comorbid conditions become harder
to manage when COPD is present, either because COPD
adds to the total level of disability or because COPD
therapy adversely affects the comorbid disorder. All
comorbid conditions amplify the disability associated with
COPD and can potentially complicate its management.
Until more integrated guidance about disease management
for specifc comorbid problems becomes available, the
focus should be on identifcation and management of these
individual problems in line with local treatment guidance.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
42 MANAGEMENT OF COPD
KEY 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 effectiveintervention in most people to
reduce the risk of developing COPD and stop its
progression (Evidence A).
Comprehensive tobacco control policies and
programs with clear, consistent, and repeated
nonsmoking messages should be delivered
through every feasible channel.
Efforts to reduce smoking through public health
initiatives should also focus on passive smoking to
minimize risks for nonsmokers.
Many occupationally induced respiratory disorders
can be reduced or controlled through a variety of
strategies aimed at reducing the burden of inhaled
particles and gases.
Reducing the risk from indoor and outdoor air
pollution is feasible and requires a combination
of public policy and protective steps taken by
individual patients.
Identifcation, reduction, and control of risk factors are
important steps toward prevention and treatment of any
disease. In the case of COPD, these factors include
tobacco smoke, occupational exposures, and indoor
and outdoor air pollution and irritants. Since cigarette
smoking is the most commonly encountered risk factor for
COPD worldwide, tobacco control (smoking prevention)
programs should be implemented and smoking cessation
programs should be readily available and encouraged
for all individuals who smoke. Reduction of total personal
exposure to occupational dusts, fumes, and gases and to
indoor and outdoor air pollutants is also an important goal
to prevent the onset and progression of COPD.
Smoking Prevention
Comprehensive tobacco control policies and programs with
clear, consistent, and repeated nonsmoking messages
should be delivered through every feasible channel,
including health care providers, community activities,
schools, and radio, television, and print media. National
and local campaigns should be undertaken to reduce
exposure to tobacco smoke in public forums. Such bans
are proving to be workable and to result in measurable
gains in respiratory health
48
. Legislation to establish
smokefree schools, public facilities, and work environments
should be developed and implemented by government
offcials and public health workers, and encouraged by
the public. Smoking prevention programs should target all
ages, including young children, adolescents, young adults,
and pregnant women. Interventions to prevent smoking
uptake and maximize cessation should be implemented at
every level of the health care system. Physicians and public
health offcials should encourage smokefree homes.
An important step toward a collective international
response to tobaccocaused death and disease was
taken in 1996 by the World Health Organization with the
implementation of an International Framework Convention
on Tobacco Control (Figure 5.2-1).
COMPONENT 2: REDUCE RISK FACTORS
INTRODUCTION
TOBACCO SMOKE
Figure 5.2-1. World Health Organization:
International Framework Convention on
Tobacco Control
In May, 1996, to address the global tobacco pandemic,
the Forty-ninth World Health Assembly requested the
Director-General of the World Health Organization (WHO)
to initiate the development of an international framework
convention for tobacco control. Included as part of this
framework convention is a strategy to encourage Member
States to move progressively towards the adoption of
comprehensive tobacco control policies and to deal with
aspects of tobacco control that transcend national
boundaries.
Information about the work of the WHO tobacco control
program can be found at
http://www.who.int/tobacco/resources/publications/fctc/en/index.html
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 43
Environmental tobacco smoke exposure is also an
important cause of respiratory symptoms and increased
risk for COPD, especially in partners and children of
smokers
49
. Long-term indoor exposure, combined with
crowded living conditions in poorly ventilated homes,
adds to the total burden of particulate exposure and
increases the risk of developing COPD
50
. Efforts to reduce
smoking through public health initiatives should also focus
on passive smoking to minimize risks for nonsmokers.
Partners and parents should not smoke in the immediate
vicinity of nonsmokers or children, nor in enclosed spaces
such as cars and poorly ventilated rooms that expose
others to increased risk.
The frst exposure to cigarette smoke may begin in utero
when the fetus is exposed to bloodborne metabolites from
the mother
51
. Education to reduce in utero risks for unborn
children is also of great importance to prevent the effects
of maternal smoking in reducing lung growth and causing
airways disease in early and later life
52,53
. Neonates and
infants may also be exposed passively to tobacco smoke
in the home if a family member smokes. Children less than
2 years old who are passively exposed to cigarette smoke
have an increased prevalence of respiratory infections,
and are at a greater risk of developing chronic respiratory
symptoms later in life
53,54
.
Smoking Cessation
Smoking cessation is the single most effectiveand cost
effectiveway to reduce exposure to COPD risk factors.
Quitting smoking can prevent or delay the development
of airfow limitation, or reduce its progression
55
, and can
have a substantial effect on subsequent mortality
56
. All
smokersincluding those who may be at risk for COPD
as well as those who already have the diseaseshould be
offered the most intensive smoking cessation intervention
feasible.
Smoking cessation interventions are effective in both
sexes, in all racial and ethnic groups, and in pregnant
women. Age infuences quit rates, with young people less
likely to quit, but nevertheless smoking cessation programs
can be effective in all age groups. International data on
the economic impact of smoking cessation are strikingly
consistent: investing resources in smoking cessation
programs is cost effective in terms of medical and societal
costs per lifeyear gained. Effective interventions include
nicotine replacement with transdermal patches, gums,
and nasal sprays; counseling from physicians and other
health professionals (with or without nicotine replacement
therapy); self-help and group programs; and community-
based stop-smoking challenges.
A review of data from a number of countries estimated
the median societal cost of various smoking cessation
interventions at $990 to $13,000 (US) per lifeyear gained
57
.
Smoking cessation programs are a particularly good value
for the UK National Health Service, with costs from 212 to
873 (US $320 to $1,400) per life-year gained
58
.
The role of health care providers in smoking cessation.
A successful smoking cessation strategy requires a
multifaceted approach, including public policy, information
dissemination programs, and health education through
the media and schools
59
. However, health care providers,
including physicians, nurses, dentists, psychologists,
pharmacists, and others, are key to the delivery of smoking
cessation messages and interventions. Involving as many
of these individuals as possible will help. Health care
workers should encourage all patients who smoke to quit,
even those patients who come to the health care provider
for unrelated reasons and do not have symptoms of COPD,
evidence of airfow limitation, or other smoking-related
disease. Guidelines for smoking cessation entitled
Treating Tobacco Use and Dependence: A Clinical Practice
Guideline were published by the US Public Health
Service
60
. The major conclusions are summarized in Figure
5.2-2.
Figure 5.2-2. US Public Health Service Report:
Treating Tobacco Use and Dependence:
A Clinical Practice GuidelineMajor Findings
and Recommendations
60
1. Tobacco dependence is a chronic condition that warrants
repeated treatment until long-term or permanent abstinence is
achieved.
2. Effective treatments for tobacco dependence exist and all
tobacco users should be offered these treatments.
3. Clinicians and health care delivery systems must
institutionalize the consistent identification, documentation,
and treatment of every tobacco user at every visit.
4. Brief smoking cessation counseling is effective and every
tobacco user should be offered such advice at every contact
with health care providers.
5. There is a strong dose-response relation between the intensity
of tobacco dependence counseling and its effectiveness.
6. Three types of counseling were found to be especially
effective: practical counseling, social support as part of
treatment, and social support arranged outside of treatment.
7. Five first-line pharmacotherapies for tobacco dependence
bupropion SR, nicotine gum, nicotine inhaler, nicotine nasal
spray, and nicotine patchare effective and at least one of
these medications should be prescribed in the absence of
contraindications.
8. Tobacco dependence treatments are cost effective relative to
other medical and disease prevention interventions.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
44 MANAGEMENT OF COPD
The Public Health Service Guidelines recommend a fve-
step program for intervention (Figure 5.2-3), which provides
a strategic framework helpful to health care providers
interested in helping their patients stop smoking
60-63
.
The guidelines emphasize that tobacco dependence is
a chronic disease (Figure 5.2-4)
60
and urge clinicians to
recognize that relapse is common and refects the chronic
nature of dependence and addiction, not failure on the part
of the clinician or the patient.
Most individuals go through several stages before they
stop smoking (Figure 5.2-5)
59
. It is often helpful for the
clinician to assess a patients readiness to quit in order to
determine the most effective course of action at that time.
The clinician should initiate treatment if the patient is ready
to quit. For a patient not ready to make a quit attempt, the
clinician should provide a brief intervention designed to
promote the motivation to quit.
Counseling. Counseling delivered by physicians and
other health professionals signifcantly increases quit rates
over self-initiated strategies
64
. Even a brief (3-minute)
period of counseling to urge a smoker to quit results in
smoking cessation rates of 5-10%
65
. At the very least, this
should be done for every smoker at every health care
provider visit
65,66
. Education in how to offer optimal smoking
cessation advice and support should be a mandatory
element of curricula for health professionals.
There is a strong dose-response relationship between
counseling intensity and cessation success
18,19
. Ways to
intensify treatment include increasing the length of the
treatment session, the number of treatment sessions, and
the number of weeks over which the treatment is delivered.
Sustained quit rates of 10.9% at 6 months have been
achieved when clinician tutorials and feedback are linked to
counseling sessions
67
. With more complex interventions (for
example, controlled clinical trials that include skills training,
problem solving, and psychosocial support), quit rates can
reach 20-30%
68
. In a multicenter controlled clinical trial,
a combination of physician advice, group support, skills
training, and nicotine replacement therapy achieved a quit
rate of 35% at 1 year and a sustained quit rate of 22% at 5
years
55
.
Both individual and group counseling are effective formats
for smoking cessation programs. Several particular items
of counseling content seem to be especially effective,
including problem solving, general skills training, and
provision of intra-treatment support
59,60
. The common
subjects covered in successful promblem solving/skills
training programs include:
Recognition of danger signals likely to be associated
with the risk of relapse, such as being around other
smokers, psychosocial stress, being under time
pressure, getting into an argument, drinking alcohol,
and negative moods
Figure 5.2-3. Brief Strategies to Help the
Patient Willing to Quit
60-63
1. ASK: Systematically identify all tobacco users at every visit.
Implement an office-wide system that ensures that, for EVERY patient
at EVERY clinic visit, tobacco-use status is queried and documented.
2. ADVISE: Strongly urge all tobacco users to quit.
In a clear, strong, and personalized manner, urge every tobacco user to quit.
3. ASSESS: Determine willingness to make a quit attempt.
Ask every tobacco user if he or she is willing to make a quit attempt at
this time (e.g., within the next 30 days).
4. ASSIST: Aid the patient in quitting.
Help the patient with a quit plan; provide practical counseling; provide
intra-treatment social support; help the patient obtain extra-treatment
social support; recommend use of approved pharmacotherapy except
in special circumstances; provide supplementary materials.
5. ARRANGE: Schedule follow-up contact.
Schedule follow-up contact, either in person or via telephone.
Figure 5.2-4. Tobacco Dependence as a
Chronic Disease
10
For most people, tobacco dependence results in true drug
dependence comparable to dependence caused by opiates,
amphetamines, and cocaine.
Tobacco dependence is almost always a chronic disorder
that warrants long-term clinical intervention as do other
addictive disorders. Failure to appreciate the chronic nature
of tobacco dependence may impair the clinician's motivation
to treat tobacco use consistently in a long-term fashion.
Clinicians must understand that tobacco dependence is a
chronic condition requiring sustained effort focused on simple
counseling advice, support, and appropriate pharmacotherapy,
and ongoing support for recent quitters to prevent relapse.
Relapse is common, which is the nature of dependence and
not the failure of the clinician or the patient.
Figure 5.2-5. Stages of Change Model

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 45
Enhancement of skills needed to handle these
situations, such as learning to anticipate and manage
or avoid a particular stress
Basic information about smoking and successful
quitting, such as the nature and time course of
withdrawal, the addictive nature of smoking, and the
fact that any return to smoking, including even a single
puff, increases the likelihood of a relapse
Systematic programs to sustain smoking cessation should
be implemented in health care settings
17
.
Pharmacotherapy. Numerous effective pharmacotherapies
for smoking cessation now exist
59-61
, and pharmacotherapy
is recommended when counseling is not suffcient to
help patients quit smoking. Special consideration should
be given before using pharmacotherapy in selected
populations: people with medical contraindications, light
smokers (fewer than 10 cigarettes/ day), and pregnant and
adolescent smokers.
Nicotine replacement products. Numerous studies
indicate that nicotine replacement therapy in any form
(nicotine gum, inhaler, nasal spray, transdermal patch,
sublingual tablet, or lozenge) reliably increases long-term
smoking abstinence rates
60,69,407
. Nicotine replacement
therapy is more effective when combined with counseling
and behavior therapy
70
, although nicotine patch or
nicotine gum consistently increases smoking cessation
rates regardless of the level of additional behavioral or
psychosocial interventions. Medical contraindications to
nicotine replacement therapy include unstable coronary
artery disease, untreated peptic ulcer disease, and recent
myocardial infarction or stroke
59
. Specifc studies do
not support the use of nicotine replacement therapy for
longer than 8 weeks, although some patients may require
extended use to prevent relapse and, in some studies, use
of multiple nicotine replacement therapy modalities has
been shown to be more effective than only one
60,71
.
All forms of nicotine replacement therapy are signifcantly
more effective than placebo. Every effort should be
made to tailor the choice of replacement therapy to the
individual?s culture and lifestyle to improve adherence.
The patch is generally favored over the gum because it
requires less training for effective use and is associated
with fewer compliance problems. No data are available to
help clinicians tailor nicotine patch regimens to the intensity
of cigarette smoking. In all cases it seems generally
appropriate to start with the higher dose patch.
For most patches, which come in three different doses,
patients should use the highest dose for the frst four weeks
and drop to progressively lower doses over an eightweek
period. Where only two doses are available, the higher
dose should be used for the frst four weeks and the lower
dose for the second four weeks.
When using nicotine gum, the patient needs to be advised
that absorption occurs through the buccal mucosa. For this
reason, the patient should be advised to chew the gum
for a while and then put the gum against the inside of the
cheek to allow absorption to occur and prolong the release
of nicotine. Continuous chewing produces secretions that
are swallowed rather than absorbed through the buccal
mucosa, results in little absorption, and can cause nausea.
Acidic beverages, particularly coffee, juices, and soft
drinks, interfere with the absorption of nicotine. Thus, the
patient needs to be advised that eating or drinking anything
except water should be avoided for 15 minutes before
and during chewing. Although nicotine gum is an effective
smoking cessation treatment, problems with compliance,
ease of use, social acceptability, risk of developing
temporomandibular joint symptoms, and unpleasant taste
have been noted. In highly dependent smokers, the 4 mg
gum is more effective than the 2 mg gum
72
.
Other pharmacotherapy. The antidepressants bupropion
73

and nortriptyline have also been shown to increase long-
term quit rates
59,69,74
, but should always be used as one
element in a supportive intervention program rather than
on their own. Although more studies need to be conducted
with these medications, a randomized controlled trial with
counseling and support showed quit rates at one year
of 30% with sustainedrelease bupropion alone and 35%
with sustainedrelease bupropion plus nicotine patch
73
.
The effectiveness of the antihypertensive drug clonidine is
limited by side effects
69
.
Varenicline, a nicotinic acetylcholine receptor partial
agonist that aids smoking cessation by relieving nicotine
withdrawal symptoms and reducing the rewarding
properties of nicotine has been demonstrated to be safe
and effcacious
75-77
.
In the United States, it has been estimated that up to
19% of COPD in smokers and up to 31% of COPD in
nonsmokers may be attributable to occupational dust
and fume exposure
78-81
, and the burden may be higher
in countries where there is higher exposure to inhaled
particles, fumes and gases. Many occupations have been
shown to be associated with increased risk of developing
COPD, particularly those that involve exposure
to fumes and mineral and biological dusts. Although it is
not known how many individuals are at risk of developing
OCCUPATIONAL EXPOSURES
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
46 MANAGEMENT OF COPD
respiratory disease from occupational exposures in either
developing or developed countries, many occupationally
induced respiratory disorders can be reduced or controlled
through a variety of strategies aimed at reducing the
burden of inhaled particles and gases
82-84
.
Implement, monitor and enforce strict, legally mandated
control of airborne exposure in the workplace.
Initiate intensive and continuing education of exposed
workers, industrial managers, health care workers,
primary care physicians, and legislators.
Educate employers, workers, and policymakers on
how cigarette smoking aggravates occupational lung
diseases and why efforts to reduce smoking where a
hazard exists are important.
The main emphasis should be on primary prevention,
which is best achieved by the elimination or reduction
of exposures to various substances in the workplace.
Secondary prevention, achieved through surveillance and
early case detection, is also of great importance. Both
approaches are necessary to improve the present situation
and to reduce the burden of lung disease
421
. Although
studies as yet have not been done to demonstrate reduced
burden of disease, it is the logical consequence of effective
strategies to reduce workplace exposure to respiratory
irritants and toxic inhalants.
Individuals experience diverse indoor and outdoor
environments throughout the day, each of which has its
own unique set of air contaminants and particulates that
cause adverse effects on lung function
80
.
Although outdoor and indoor air pollution are generally
considered separately, the concept of total personal
exposure may be more relevant for COPD. Reducing the
risk from indoor and outdoor air pollution is feasible and
requires a combination of public policy and protective
steps taken by individual patients. Reduction of exposure
to smoke from biomass fuel, particularly among women
and children, is a crucial goal to reduce the prevalence of
COPD worldwide. Although effcient nonpolluting cooking
stoves have been developed, their adoption has been slow
due to social customs and cost.
Regulation of Air Quality
At the national level, achieving a set level of air quality
standards should be a high priority; this goal will normally
require legislative action. Details on setting and maintaining
air quality goals are beyond the scope of this document, but
public policy to reduce vehicle and industrial emissions to
safe levels is an urgent priority to reduce the development
of COPD as well as symptoms, exacerbations, and hospital
admissions in those with disease. Understanding health
risks posed by local air pollution sources may be diffcult
and requires skills in community health, toxicology, and
epidemiology. Local physicians may become involved
through concerns about the health of their patients or as
advocates for the communitys environment.
Steps for Health Care Providers/Patients
The health care provider should consider COPD risk
factors including smoking history, family history, exposure
to indoor/outdoor pollution) and socioeconomic status for
each individual patient. Some steps to consider:
Individuals at risk for COPD:

Patients should be counseled concerning the
nature and degree of their risk for COPD.
If various solid fuels are used for cooking
and heating, adequate ventilation should be
encouraged.
Respiratory protective equipment has been
developed for use in the workplace in order to
minimize exposure to toxic gases and particles.
Under most circumstances, vigorous attempts
should be made to reduce exposure through
reducing workplace emissions and improving
ventilation measures, rather than simply by using
respiratory protection to reduce the risks of ambient
air pollution.
Ventilation and interventions to meet safe air
quality standards in the workplace offer the
greatest opportunity to reduce worker exposure to
known atmospheric pollutants and reduce the risk
of developing COPD, although to date there are no
studies to quantify these benefts.
Patients who have been diagnosed with COPD:

Persons with advanced COPD should monitor
public announcements of air quality and be aware
that staying indoors when air quality is poor may
help reduce their symptoms.
INDOOR AND OUTDOOR AIR POLLUTION
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 47
The use of medication should follow the usual
clinical indications; therapeutic regimens should
not be adjusted because of the occurrence of a
pollution episode without evidence of worsening of
symptoms or lung function.
Those who are at high risk should avoid vigorous
exercise outdoors during pollution episodes.

Air cleaners have not been shown to have health
benefts, whether directed at pollutants generated
by indoor sources or at those brought in with
outdoor air.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
48 MANAGEMENT OF COPD
KEY POINTS:

The overall approach to managing stable COPD
should be individualized to address symptoms and
improve quality of life.
For patients with COPD, health education plays an
important role in smoking cessation (Evidence A)
and can also play a role in improving skills, ability
to cope with illness and health status.
None of the existing medications for COPD have
been shown to modify the long-term decline in
lung function that is the hallmark of this disease
(Evidence A). Therefore, pharmacotherapy for
COPD is used to decrease symptoms and/or
complications.
Bronchodilator medications are central to the
symptomatic management of COPD (Evidence
A). They are given on an asneeded basis or on a
regular basis to prevent or reduce symptoms and
exacerbations.
The principal bronchodilator treatments are
2

agonists, anticholinergics, and methylxanthines
used singly or in combination (Evidence A).
Regular treatment with long-acting bronchodilators
is more effective and convenient than treatment
with short-acting bronchodilators (Evidence A).
The addition of regular treatment with inhaled
glucocorticosteroids to bronchodilator treatment is
appropriate for symptomatic COPD patients with
an FEV
1
< 50% predicted (Stage III: Severe COPD
and Stage IV: Very Severe COPD) and repeated
exacerbations (Evidence A).
Chronic treatment with systemic glucocortico
steroids should be avoided because of an
unfavorable beneft-to-risk ratio (Evidence A).
In COPD patients infuenza vaccines can reduce
serious illness (Evidence A). Pneumococcal
polysaccharide vaccine is recommended for COPD
patients 65 years and older and for COPD patients
younger than age 65 with an FEV
1
< 40% predicted
(Evidence B).
All COPD patients beneft from exercise training
programs, improving with respect to both exercise
tolerance and symptoms of dyspnea and fatigue
(Evidence A).
The long-term administration of oxygen (> 15 hours
per day) to patients with chronic respiratory failure
has been shown to increase survival (Evidence A).
The overall approach to managing stable COPD should
be characterized by an increase in treatment, depending
on the severity of the disease and the clinical status of
the patient. The stepdown approach used in the chronic
treatment of asthma is not applicable to COPD since COPD
is usually stable and very often progressive. Management
of COPD involves several objectives (see Chapter 5,
Introduction) that should be met with minimal side effects
from treatment. It is based on an individualized assessment
of disease severity (Figure 5.3-1) and response to various
therapies.
The classifcation of severity of stable COPD incorporates
an individualized assessment of disease severity and
therapeutic response into the management strategy. The
severity of airfow limitation (Figure 1-2) provides a general
guide to the use of some treatments, but the selection
of therapy is predominantly determined by the patients
symptoms and clinical presentation. Treatment also
depends on the patients educational level and willingness
to apply the recommended management, on cultural and
local conditions, and on the availability of medications.
Although patient education is generally regarded as an
essential component of care for any chronic disease,
the role of education in COPD has been poorly studied.
Assessment of the value of education in COPD may be
diffcult because of the relatively long time required to
achieve improvements in objective measurements of lung
function.
Studies that have been done indicate that patient education
alone does not improve exercise performance or lung
function
85-88
(Evidence B), but it can play a role in improving
skills, ability to cope with illness, and health status
89
. These
COMPONENT 3: MANAGE STABLE COPD
INTRODUCTION
Figure 5.3-1. Factors Affecting the Severity of COPD
Severity of symptoms
Severity of airflow limitation
Frequency and severity of exacerbations
Presence of one or more complications
Presence of respiratory failure
Presence of comorbid conditions
General health status
Number of medications needed to manage the disease
EDUCATION
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 49
outcomes are not traditionally measured in clinical trials,
but they may be most important in COPD where even
pharmacologic interventions generally confer only a small
beneft in terms of lung function.
Patient education regarding smoking cessation has
the greatest capacity to infuence the natural history of
COPD. Evaluation of the smoking cessation component
in a long-term, multicenter study indicates that if
effective resources and time are dedicated to smoking
cessation, 25% long-term quit rates can be maintained
55

(Evidence A). Education also improves patient response
to exacerbations
90,91
(Evidence B). Prospective end-of-
life discussions can lead to understanding of advance
directives and effective therapeutic decisions at the end of
life
92
(Evidence B).
Ideally, educational messages should be incorporated
into all aspects of care for COPD and may take place
in many settings: consultations with physicians or other
health care workers, home-care or outreach programs, and
comprehensive pulmonary rehabilitation programs.
Goals and Educational Strategies
It is vital for patients with COPD to understand the nature
of their disease, risk factors for progression, and their role
and the role of health care workers in achieving optimal
management and health outcomes. Education should be
tailored to the needs and environment of the individual
patient, interactive, directed at improving quality of life,
simple to follow, practical, and appropriate to the intellectual
and social skills of the patient and the caregivers.
In managing COPD, open communication between patient
and physician is essential. In addition to being empathic,
attentive and communicative, health professionals should
pay attention to patients fears and apprehensions, focus
on educational goals, tailor treatment regimens to each
individual patient, anticipate the effect of functional decline,
and optimize patients practical skills. Adherence to inhaled
medication has been shown to be signifcantly associated
with reduced risk of death and admission to hospital due to
exacerbations in COPD
449
.
Several specifc education strategies have been shown to
improve patient adherence to medication and management
regimens. In COPD, adherence does not simply refer
to whether patients take their medication appropriately.
It also covers a range of nonpharmacologic treatments,
e.g., maintaining an exercise program after pulmonary
rehabilitation, undertaking and sustaining smoking
cessation, and using devices such as nebulizers, spacers,
and oxygen concentrators properly.
Components of an Education Program
The topics that seem most appropriate for an education
program include: smoking cessation; basic information
about COPD and pathophysiology of the disease; general
approach to therapy and specifc aspects of medical
treatment; self-management skills; strategies to help
minimize dyspnea; advice about when to seek help; self-
management and decision-making during exacerbations;
and advance directives and end-of-life issues (Figure 5.3-
2). Education should be part of consultations with health
care workers beginning at the time of frst assessment
for COPD and continuing with each follow-up visit. The
intensity and content of these educational messages
should vary depending on the severity of the patient?s
disease. In practice, a patient often poses a series of
questions to the physician (Figure 5.3-3). Itis important to
answer these questions fully and clearly, as this may help
make treatment more effective.
Figure 5.3-3. Examples of Patient Questions
What is COPD?
What causes COPD?
How will it affect me?
Can it be treated?
What will happen if my disease gets worse?
What will happen if I need to be admitted to the hospital?
How will I know when I need oxygen at home?
What if I do not wish to be admitted to intensive care for
ventilation?
Figure 5.3-2. Topics for Patient Education
For all patients:
Information and advice about reducing risk factors
Stage I: Mild COPD through Stage III: Severe COPD
Above topic, plus:
Information about the nature of COPD
Instruction on how to use inhalers and other treatments
Recognition and treatment of exacerbations
Strategies for minimizing dyspnea
Stage IV: Very Severe COPD
Above topics, plus:
Information about complications
Information about oxygen treatment
Advance directives and end-of-life decisions
Answers to these questions can be developed from this
document and will depend on local circumstances. in all cases it
is important that answers are clear and use terminology that the
patient understands.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
50 MANAGEMENT OF COPD
There are several different types of educational programs,
ranging from simple distribution of printed materials, to
teaching sessions designed to convey information about
COPD, to workshops designed to train patients in specifc
skills. Self-management programs for COPD patients
are being developed and medical/economic benefts
evaluated
408,409
. Limited published data exist evaluating
the effcacy of chronic care model components in COPD
management
93
. However, COPD patients recruited to a
comprehensive COPD education program in Canada had
signifcantly fewer exacerbations and hospitalizations. and
used fewer health care resources
94
. Self-management
programs have produced mixed results in other
jurisdictions, possibly owing to differences in the study
population, disease severity and individual components in
the self-management program
450
.
Although printed materials may be a useful adjunct to other
educational messages, passive dissemination of printed
materials alone does not improve skills or health outcomes.
Education is most effective when it is interactive and
conducted in small workshops
88
(Evidence B) designed to
improve both knowledge and skills. Behavioral approaches
such as cognitive therapy and behavior modifcation lead to
more effective selfmanagement skills and maintenance of
exercise programs.
Cost Effectiveness of Education Programs for
COPD Patients
The cost effectiveness of education programs for COPD
patients is highly dependent on local factors that infuence
the cost of access to medical services and that will vary
substantially between countries. In one costbeneft analysis
of education provided to hospital inpatients with COPD
95
,
an information package resulted in increased knowledge
of COPD and reduced use of health services, including
reductions of hospital readmissions and general practice
consultations. The education package involved training
patients to increase knowledge of COPD, medication
usage, precautions for exacerbations, and peak fow
monitoring technique. However, this study was undertaken
in a heterogeneous group of patients-65% were smokers
and 88% were judged to have an asthmatic component
to their disease-and these fndings may not hold true for
a pure COPD population. In a study of mild to moderate
COPD patients at an outpatient clinic, patient education
involving one 4-hour group session followed by one to
two individual sessions with a nurse and physiotherapist
improved patient outcomes and reduced costs in a
12-month follow-up
96
.
Although a healthy lifestyle is important, and should be
encouraged, additional studies are needed to identify
specifc components of selfmanagement programs that are
effective
97
.
Overview of the Medications
Pharmacologic therapy is used to prevent and control
symptoms, reduce the frequency and severity of
exacerbations, improve health status, and improve exercise
tolerance. Most studies have indicated that the existing
medications for COPD do not modify the long-term decline
in lung function that is the hallmark of this disease
55,98-100

(Evidence A), although there is limited evidence that
regular treatment with long-acting
2
-agonists, inhaled
glucocorticosteroid, and its combination can decrease the
rate of decline of lung function
437
(Evidence B). Therefore,
pharmacotherapy for COPD is mainly used to decrease
symptoms and/or complications. Since COPD is usually
progressive, recommendations for the pharmacological
treatment of COPD refect the following general principles:
Treatment tends to be cumulative with more
medications being required as the disease state
worsens.
Regular treatment needs to be maintained at the
same level for long periods of time unless signifcant
side effects occur or the disease worsens.
Individuals differ in their response to treatment and
in the side effects they report during therapy. Careful
monitoring is needed over an appropriate period
to ensure that the specifc aim of introducing a
therapy has been met without an unacceptable cost
to the patient. The effect of therapy in COPD may
occur sooner after treatment with bronchodilators
and inhaled glucocorticosteroids than previously
thought
101
, although at present, there is no effective
way to predict whether or not treatment will reduce
exacerbations.
The medications are presented in the order in which they
would normally be introduced in patient care, based on the
level of disease severity and clinical symptoms. However,
each treatment regimen needs to be patientspecifc as the
relationship between the severity of symptoms and the
severity of airfow limitation is infuenced by other factors,
such as the frequency and severity of exacerbations, the
presence of one or more complications, the presence of
respiratory failure, comorbidities (cardiovascular disease,
sleeprelated disorders, etc.), and general health status.
The classes of medications commonly used in treating
COPD are shown in Figure 5.3-4. The choice within each
class depends on the availability of medication and the
patients response.
PHARMACOLOGIC TREATMENT
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 51
Bronchodilators
Medications that increase the FEV
1
or change other
spirometric variables, usually by altering airway smooth
muscle tone, are termed bronchodilators
102
, since the
improvements in expiratory fow refect widening of the
airways rather than changes in lung elastic recoil. Such
drugs improve emptying of the lungs, tend to reduce
dynamic hyperinfation at rest and during exercise
103,118
,
and improve exercise performance. The extent of these
changes, especially in more advanced disease, is not
104,105
easily predictable from the improvement in FEV
1
. Regular
bronchodilation with drugs that act primarily on airway
smooth muscle does not modify the decline of function in
Stage I: Mild COPD or, by inference, the prognosis of the
disease
6
(Evidence B).
Bronchodilator medications are central to the symptomatic
management of COPD
106-109
(Evidence A) (Figure 5.3-5).
They are given either on an as-needed basis for relief
Figure 5.3-4. Formulations and Typical Doses of COPD Medications*
Drug Inhaler
(g)
Solution for
Nebulizer
(mg/ml)
Oral Vials for
Injection
(mg)
Duration of
Action (hours)

2
-agonists
Short-acting
Fenoterol 100-200 (MDI) 1 0.05% (Syrup) 4-6
Levalbuterol 45-90 (MDI) 0.21, 0.42 6-8
Salbutamol (albuterol) 100, 200 (MDI & DPI) 5 5mg (Pill), 0.024%(Syrup) 0.1, 0.5 4-6
Terbutaline 400, 500 (DPI) 2.5, 5 (Pill) 4-6
Long-acting
Formoterol 4.5-12 (MDI & DPI) 0.01 12+
Arformoterol 0.0075 12+
Indacaterol 150-300 (DPI) 24
Salmeterol 25-50 (MDI & DPI) 12+
Anticholinergics
Short-acting
Ipratropium bromide 20, 40 (MDI) 0.25-0.5 6-8
Oxitropium bromide 100 (MDI) 1.5 7-9
Long-acting
Tiotropium 18 (DPI), 5 (SMI) 24+
Combination short-acting
2
-agonists plus anticholinergic in one inhaler
Fenoterol/Ipratropium 200/80 (MDI) 1.25/0.5 6-8
Salbutamol/Ipratropium 75/15 (MDI) 0.75/0.5 6-8
Methylxanthines
Aminophylline 200-600 mg (Pill) 240 mg Variable, up to 24
Theophylline (SR) 100-600 mg (Pill) Variable, up to 24
Inhaled glucocorticosteroids
Beclomethasone 50-400 (MDI & DPI) 0.2-0.4
Budesonide 100, 200, 400 (DPI) 0.20. 0.25, 0.5
Fluticasone propionate 50-500 (MDI & DPI)
Combination long-acting
2
-agonists plus glucocorticosteroids in one inhaler
Formoterol/Budesonide 4.5/160, 9/320 (DPI)
Salmeterol/Fluticasone
propionate
50/100, 250. 500 (DPI)
25/50, 125, 250 (MDI)
Systemic glucocorticosteroids
Prednisone 5-60 mg (Pill)
Methyl-prednisolone 4, 8, 16 mg (Pill)
Phosphodiesterase-4 inhibitors
Roflumilast 500 mcg (Pill) 24
*Not all formulations are available in all countries; in some countries, other formulations may be available.
Formoterol nebulized solution is based on the unit dose vial containing 20 gm in a volume of 2.0ml
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
52 MANAGEMENT OF COPD
of persistent or worsening symptoms, or on a regular
basis to prevent or reduce symptoms. The side effects of
bronchodilator therapy are pharmacologically predictable
and dose dependent. Adverse effects are less likely, and
resolve more rapidly after treatment withdrawal, with
inhaled than with oral treatment. However, COPD patients
tend to be older than asthma patients and more likely to
have comorbidities, so their risk of developing side effects
is greater.
When treatment is given by the inhaled route, attention to
effective drug delivery and training in inhaler technique is
essential
422
. The choice of inhaler device will depend on
availability, cost, the prescribing physician, and the skills
and ability of the patient. COPD patients may have more
problems in effective coordination and fnd it harder to
use a simple metereddose inhaler (MDI) than do healthy
volunteers or younger asthmatics. It is essential to ensure
that inhaler technique is correct and to recheck this at each
visit.
Alternative breath-activated or spacer devices are available
for most formulations. Dry powder inhalers (DPIs) may
be more convenient and possibly provide improved
drug deposition, although this has not been established
in COPD. In general, particle deposition will tend to be
more central with the fxed airfow limitation and lower
inspiratory fow rates in COPD
110,111
. Many drugs are
available as nebulizer solutions and for patients who are
severely overinfated and consequently may have very low
inspiratory fow rates, there may be theoretical advantages
of nebulizers. However, there is little randomized trial
evidence for beneft compared to the use of other
devices, and use of nebulizers will often depend on local
preference, availability and price. Beneft should be judged
symptomatically, since changes in lung function may be
small and within the limits of repeatability. Nebulized
treatment should only be continued if the patients report
clear symptomatic beneft.
Dose-response relationships using the FEV
1
as
the outcome are relatively fat with all classes of
bronchodilators
106-109
. Toxicity is also dose related.
Increasing the dose of either a
2
-agonist or an
anticholinergic by an order of magnitude, especially when
given by a nebulizer, appears to provide subjective beneft
in acute episodes
113
(Evidence B) but is not necessarily
helpful in stable disease
114
(Evidence C).
All categories of bronchodilators have been shown to
increase exercise capacity in COPD, without necessarily
producing signifcant changes in FEV
1
115-118
(Evidence
A). Regular treatment with long-acting bronchodilators,
including nebulized formulations
438
, are more effective
and convenient than treatment with short-acting
bronchodilators
119-122
(Evidence A).
Regular use of a long-acting
2-
agonist
120
or a short or
long-acting anticholinergic improves health status
119-121
.
Treatment with a long-acting inhaled anticholinergic
drug reduces the rate of COPD exacerbations
123
and
improves the effectiveness of pulmonary rehabilitation
124

. Theophylline is effective in COPD, but due to its
potential toxicity inhaled bronchodilators are preferred
when available. All studies that have shown effcacy
of theophylline in COPD were done with slow-release
preparations.

2
-agonists. The principal action of
2
-agonists is to
relax airway smooth muscle by stimulating
2
-adrenergic
receptors, which increases cyclic AMP and produces
functional antagonism to bronchoconstriction. Oral therapy
is slower in onset and has more side effects than inhaled
treatment
125
(Evidence A).
Inhaled
2
-agonists have a relatively rapid onset of
bronchodilator effect although this is probably slower in
COPD than in asthma. The bronchodilator effects of short-
acting
2
-agonists usually wear off within 4 to 6 hours
126,127

(Evidence A). For single-dose, as-needed use in COPD,
there appears to be no advantage in using levalbuterol
over conventional nebulized bronchodilators
128
. Long-acting
inhaled
2
-agonists, such as salmeterol and formoterol,
show a duration of effect of 12 hours or more with no loss
of effectiveness overnight or with regular use in COPD
patients
129-132
(Evidence A).
Figure 5.3-5. Bronchodilators in Stable COPD
Bronchodilator medications are central to symptom
management in COPD.
Inhaled therapy is preferred.
The choice between
2
-agonist, anticholinergic,
theophylline, or combination therapy depends on
availability and individual response in terms of symptom
relief and side effects.
Bronchodilators are prescribed on an as-needed or on
a regular basis to prevent or reduce symptoms.
Long-acting inhaled bronchodilators are more effective
and convenient.
Combining bronchodilators of different pharmacological
classes may improve efficacy and decrease the risk of
side effects compared to increasing the dose of a single
bronchodilator.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 53
Adverse effects. Stimulation of
2
-adrenergic receptors
can produce resting sinus tachycardia and has the
potential to precipitate cardiac rhythm disturbances in
very susceptible patients, although this appears to be a
remarkably rare event with inhaled therapy. Exaggerated
somatic tremor is troublesome in some older patients
treated with higher doses of
2
-agonists, whatever the
route of administration, and this limits the dose that can be
tolerated. Although hypokalemia can occur, especially when
treatment is combined with thiazide diuretics
133
, and oxygen
consumption can be increased under resting conditions
134
,
these metabolic effects show tachyphylaxis unlike the
bronchodilator actions. Mild falls in PaO
2
occur after
administration of both short and long-acting
2
-agonists
135
,
but the clinical signifcance of these changes is doubtful.
Despite the concerns raised some years ago, further
detailed study has found no association between
2
-agonist
use and an accelerated loss of lung function or increased
mortality in COPD.
Anticholinergics. The most important effect of
anticholinergic medications, such as ipratropium, oxitropium
and tiotropium bromide, in COPD patients appears to be
blockage of acetylcholines effect on M3 receptors. Current
short-acting drugs also block M2 receptors and modify
transmission at the pre-ganglionic junction, although these
effects appear less important in COPD
136
. The long-acting
anticholinergic tiotropium has a pharmacokinetic selectivity
for the M3 and M1 receptors
137
. The bronchodilating
effect of short-acting inhaled anticholinergics lasts
longer than that of short-acting
2
-agonists, with some
bronchodilator effect generally apparent up to 8 hours after
administration
126
(Evidence A). Tiotropium has a duration
of action of more than 24 hours
119,138,139
(Evidence A). In
a large, long-term clinical trial on patients with COPD,
there was no effect of tiotropium added to other standard
therapies on the rate of lung function decline and no
evidence of cardiovascular risk
439
. Meaningful increases
in lung function can be achieved following administration
of inhaled anticholinergic plus sympathomimetic
bronchodilators even in patients with moderate to severe
COPD
423
. Treatment with long-acting anticholinergic drug
improves the effectiveness of pulmonary rehabilitation
424
.
Adverse effects. Anticholinergic drugs are poorly absorbed
which limits the troublesome systemic effects seen with
atropine. Extensive use of this class of inhaled agents in
a wide range of doses and clinical settings has shown
them to be very safe. The main side effect is dryness of
the mouth. Twenty-one days of inhaled tiotropium, 18 g/
day as a dry powder, does not retard mucus clearance from
the lungs
140
. Although occasional prostatic symptoms have
been reported, there are no data to prove a true causal
relationship. A bitter, metallic taste is reported by some
patients using ipratropium. An unexpected small increase
in cardiovascular events in COPD patients regularly treated
with ipratropium bromide has been reported and requires
further investigation
141
.
Use of nebulizer solutions with a face mask has been
reported to precipitate acute glaucoma, probably by a direct
effect of the solution on the eye. Mucociliary clearance is
unaffected by these drugs, and respiratory infection rates
are not increased.
Methylxanthines. Controversy remains about the
exact effects of xanthine derivatives. They may act as
nonselective phosphodiesterase inhibitors, but have
also been reported to have a range of nonbronchodilator
actions, the signifcance of which is disputed
142-146
.
Data on duration of action for conventional, or even
slowrelease, xanthine preparations are lacking in COPD.
Changes in inspiratory muscle function have been reported
in patients treated with theophylline
142
, but whether this
refects changes in dynamic lung volumes or a primary
effect on the muscle is not clear (Evidence B). All studies
that have shown effcacy of theophylline in COPD were
done with slowrelease preparations. Theophylline is
effective in COPD but, due to its potential toxicity, inhaled
bronchodilators are preferred when available. Low dose
theophylline reduces exacerbations in patients with COPD
but does not increase postbronchodilator lung function
410

(Evidence B). Higher doses of theophylline are effective
bronchodilators in COPD but, due to the potential for
toxicity, inhaled bronchodilators are preferred.
Adverse effects. Toxicity is dose related, a particular
problem with the xanthine derivatives because their
therapeutic ratio is small and most of the beneft occurs
only when neartoxic doses are given
144,145
(Evidence
A). Methylxanthines are nonspecifc inhibitors of all
phosphodiesterase enzyme subsets, which explains
their wide range of toxic effects. Problems include the
development of atrial and ventricular arrhythmias (which
can prove fatal) and grand mal convulsions (which can
occur irrespective of prior epileptic history). More common
and less dramatic side effects include headaches,
insomnia, nausea, and heartburn, and these may occur
within the therapeutic range of serum theophylline. Unlike
the other bronchodilator classes, xanthine derivatives may
involve a risk of overdose (either intentional or accidental).
Theophylline, the most commonly used methylxanthine, is
metabolized by cytochrome P450 mixed function oxidases.
Clearance of the drug declines with age. Many other
physiological variables and drugs modify theophylline
metabolism; some of the potentially important interactions
are listed in Figure 5.36.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
54 MANAGEMENT OF COPD
Combination bronchodilator therapy. Although
monotherapy with long-acting
2
-agonists appears to
be safe
411,412
, combining bronchodilators with different
mechanisms and durations of action may increase the
degree of bronchodilation for equivalent or lesser side
effects
440.
For example, a combination of a short-acting

2
-agonist and an anticholinergic produces greater and
more sustained improvements in FEV
1
than either drug
alone and does not produce evidence of tachyphylaxis
over 90 days of treatment
126,147,148
(Evidence A). In a large
study, combination therapy that includes a long-acting
inhaled bronchodilator/anti-infammatory combination
(salmeterol/futicasone propionate) compared to the long-
acting bronchodilator (tiotropium) showed no difference
in exacerbation rate although more patients randomized
to combination treatment completed the study
425
. The
combination of a
2
-agonist, an anticholinergic, and/ or
theophylline may produce additional improvements in lung
function
126,146151, 441
and health status
126,152
. Increasing the
number of drugs usually increases costs, and an equivalent
beneft may occur by increasing the dose of one broncho
dilator when side effects are not a limiting factor. Detailed
assessments of this approach have not been carried out.
Glucocorticosteroids
The effects of oral and inhaled glucocorticosteroids in
COPD are much less dramatic than in asthma, and their
role in the management of stable COPD is limited to
specifc indications. The use of glucocorticosteroids for the
treatment of acute exacerbations is described in
Component 4: Manage Exacerbations.
Inhaled glucocorticosteroids. Most studies have shown
that regular treatment with inhaled glucocorticosteroids
does not modify the long-term decline of FEV
1
in patients
with COPD
98-100,161
(Evidence A). Based on a single large
study of patients with FEV
1
less than 60% regular treatment
with inhaled glucocorticosteroids can decrease the rate of
decline of lung function
437
(Evidence B). Regular treatment
with inhaled glucocorticosteroids has been shown to reduce
the frequency of exacerbations and thus improve health
status
140
for symptomatic COPD patients with an FEV
1
<
50% predicted (Stage III: Severe COPD and Stage IV: Very
Severe COPD) and repeated exacerbations (for example,
3 in the last 3 years)
162-165
(Evidence A) and withdrawal
from treatment with inhaled glucocorticosteroids can lead to
exacerbations in some patients
166
. Treatment with inhaled
glucocorticosteroids increases the likelihood of pneumonia
and does not reduce overall mortality
411, 442, 443
.
The dose-response relationships and long-term safety
of inhaled glucocorticosteroids in COPD are not known.
Only moderate to high doses have been used in long-
term clinical trials. Two studies showed an increased
incidence of skin bruising in a small percentage of
the COPD patients
98,100
. One long-term study showed
no effect of budesonide on bone density and fracture
rate
98,170
, while another study showed that treatment with
triamcinolone acetonide was associated with a decrease
in bone density
161
. Treatment over a three year period with
high dose futicasone propionate alone or in combination
with salmeterol was not associated with decreased bone
mineral density in a population of COPD patients with
high prevalence of osteoporosis
451.
Treatment with inhaled
glucocorticosteroids can be recommended for patients with
more advanced COPD and repeated exacerbation.
Combination inhaled glucocorticosteroid/bronchodilator
therapy: An inhaled glucocorticosteroid combined
with a long-acting
2
-agonist is more effective than the
individual components in reducing exacerbations and
improving lung function and health status
162,164,165,168,169,411,
422
(Evidence A). Combination therapy increases the
likelihood of pneumonia
452
and a large prospective clinical
trial failed to demonstrate statistically signifcant effects
on mortality
411
, although in patients with an FEV
1
less than
60%, pharmacotherapy with long-acting
2
-agonist, inhaled
glucocorticosteroid and its combination decreased the
rate of decline of lung function
437
. Addition of a long-acting

2
-agonist/inhaled glucocorticosteroid combination to a
anticholinergic (tiotropium) appears to provide additional
benefts
453
.
Oral glucocorticosteroids: short-term. Many existing
COPD guidelines recommend the use of a short course
(two weeks) of oral glucocorticosteroids to identify COPD
patients who might beneft from long-term treatment with
oral or inhaled glucocorticosteroids. This recommendation
is based on evidence
153
that short-term effects predict
long-term effects of oral glucocorticosteroids on FEV
1
, and
evidence that asthma patients with airfow limitation might
not respond acutely to an inhaled bronchodilator but do
show signifcant bronchodilation after a short course of oral
glucocorticosteroids.
Figure 5.3-6. Drugs and Physiological Variables that
Affect Theophylline Metabolism in COPD
Increased
Tobacco smoking
Anticonvulsant drugs
Rifampicin
Alcohol
Decreased
Old age
Arterial hypoxemia
(PaO
2
< 6.0 kPa, 45 mm Hg)
Respiratory acidosis
Congestive cardiac failure
Liver cirrhosis
Erythromycin
Quinolone antibiotics
Cimetidine (not ranitidine)
Viral infections
Herbal remedies (St. Johns Wort)
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 55
There is mounting evidence, however, that a short course
of oral glucocorticosteroids is a poor predictor of the long-
term response to inhaled glucocorticosteroids in COPD
38,100
.
For this reason, there appears to be insuffcient evidence to
recommend a therapeutic trial with oral glucocorticosteroids
in patients with Stage II: Moderate COPD, Stage III: Severe
COPD, or Stage IV: Very Severe COPD and poor response
to an inhaled bronchodilator.
Oral glucocorticosteroids: long-term. Two retrospective
studies
154,155
analyzed the effects of treatment with oral
glucocorticosteroids on long-term FEV
1
changes in clinic
populations of patients with moderate to very severe
COPD. The retrospective nature of these studies, their
lack of true control groups, and their imprecise defnition of
COPD are reasons for a cautious interpretation of the data
and conclusions.
A side effect of long-term treatment with systemic gluco-
corticosteroids is steroid myopathy
156-158
, which contributes
to muscle weakness, decreased functionality, and
respiratory failure in subjects with advanced COPD. In view
of the well-known toxicity of long-term treatment with oral
glucocorticosteroids, prospective studies on the long-term
effects of these drugs in COPD are limited
159,160
.
Therefore, based on the lack of evidence of beneft, and the
large body of evidence on side effects, long-term treatment
with oral glucocorticosteroids is not recommended in COPD
(Evidence A).
Phosphodiesterase-4 inhibitors. The principal action
of phosphodiesterase-4 inhibitors (PDE4-inhibitors) is to
reduce infammation through inhibition of the breakdown
of intracellular cyclic AMP. The PDE4-inhibitor, rofumilast,
has been approved for use only in some countries. It is
a once daily oral medication with no direct bronchodilator
Figure 5.3-7. Therapy at Each Stage of COPD*
*Postbronchodilator FEV
1
is recommended for the diagnosis and assessment of severity of COPD.
FEV
1
/FVC < 0.70
FEV
1
80% predicted

FEV
1
/FVC < 0.70
50% FEV
1
< 80%
predicted
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting bronchodilators
(when needed); Add rehabilitation
Add inhaled glucocorticosteroids if
repeated exacerbations
Add long term oxygen if
chronic respiratory
failure.
Consider surgical
treatments

FEV
1
/FVC < 0.70
30% FEV
1
< 50%
predicted

FEV
1
/FVC < 0.70
FEV
1
< 30% predicted
or FEV
1
< 50%
predicted plus chronic
respiratory failure

I: Mild II: Moderate III: Severe IV: Very Severe

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
56 MANAGEMENT OF COPD
activity, although it has been shown to improve FEV
1

in patients treated with salmeterol or tiotropium
454
. In
patients with Stage III: Severe COPD or Stage IV: Very
Severe COPD and a history of exacerbations and chronic
bronchitis, rofumilast reduces exacerbations treated with
oral glucocorticosteroids; based on a composite end-
point consisting of moderate exacerbations treated with
oral or glucocorticosteroids. Rofumilast also reduced a
composite end-point consisting of moderate exacerbations
treated with oral or systemic glucocorticosteroids or
severe exacerbations, e.g., requiring hospitalization or
causing death
454
(Evidence B). These effects are also seen
when rofumilast is added to long-acting bronchodilators
(Evidence B); there are no comparison studies with inhaled
glucocorticosteroids. Rofumilast and theophylline cannot
be given together.
Adverse effects: PDE4-inhibitors have more adverse
effects than inhaled medications for COPD
454,455
. The
most frequent adverse effects are nausea, reduced
appetite, abdominal pain, diarrhea, sleep disturbances and
headache. Adverse effects led to increased withdrawal in
clinical trials from the group receiving rofumilast. Adverse
effects seem to occur early during treatment, are reversible
and reduce over time with continued treatment. In
controlled studies an average weight loss of 2 kg has been
seen and weight control during treatment is advised as
well as avoiding treatment with rofumilast in underweight
patients. Rofumilast should also be avoided in patients
with depression.
Pharmacologic Therapy by Disease Severity
Figure 5.3-7 provides a summary of recommended
456

treatment at each stage of COPD. For patients with few or
intermittent symptoms (Stage I: Mild COPD), use of a short-
acting inhaled bronchodilator as needed to control dyspnea
is suffcient. If inhaled bronchodilators are not available,
regular treatment with slow-release theophylline should be
considered.
In patients with Stage II: Moderate COPD to Stage IV: Very
Severe COPD) whose dyspnea during daily activities is
not relieved despite treatment with as-needed short-acting
bronchodilators, adding regular treatment with a long-acting
inhaled bronchodilator is recommended (Evidence A).
Regular treatment with long-acting bronchodilators is more
effective and convenient than treatment with short-acting
bronchodilators (Evidence A). There is insuffcient evidence
to favor one long-acting bronchodilator over others. For
patients on regular long-acting bronchodilator therapy who
need additional symptom control, adding theophylline may
produce additional benefts (Evidence B).
Patients with Stage II: Moderate COPD to Stage IV: Very
Severe COPD who are on regular short or long-acting
bronchodilator therapy may also use a short-acting
bronchodilator as needed.
Some patients may request regular treatment with high-
dose nebulized bronchodilators, especially if they have
experienced subjective beneft from this treatment during
an acute exacerbation. Clear scientifc evidence for
this approach is lacking, but one suggested option is to
examine the improvement in mean daily peak expiratory
fow recording during two weeks of treatment in the home
and continue with nebulizer therapy if a signifcant change
occurs
112
.
In patients with a postbronchodilator FEV
1
< 50%
predicted (Stage III: Severe COPD to Stage IV: Very
Severe COPD) and a history of repeated exacerbations
(for example, 3 in the last 3 years), regular treatment
with inhaled glucocorticosteroids reduces the frequency
of exacerbations and improves health status. In
these patients, regular treatment with an inhaled
glucocorticosteroid should be added to long-acting
inhaled bronchodilators. Chronic treatment with oral
glucocorticosteroids should be avoided.
Other Pharmacologic Treatments
Vaccines. Infuenza vaccines can reduce serious illness
172

and death in COPD patients by about 50%
173,174
(Evidence
A). Vaccines containing killed or live, inactivated viruses
are recommended
175
as they are more effective in elderly
patients with COPD
176
. The strains are adjusted each year
for appropriate effectiveness and should be given once
each year
177
. Pneumococcal polysaccharide vaccine is
recommended for COPD patients 65 years and older
178, 179

and has been shown to reduce the incidence of community-
acquired pneumonia in COPD patients younger than
age 65 with an FEV
1
< 40% predicted180 (Evidence B).
However infuenza but not pneumococcal vaccination has
been shown to be associated with a reduced risk of all-
cause mortality in COPD
457
. (Evidence B).
Alpha-1 antitrypsin augmentation therapy. Young patients
with severe hereditary alpha-1 antitrypsin defciency and
established emphysema may be candidates for alpha-1
antitrypsin augmentation therapy. However, this therapy is
very expensive, is not available in most countries, and is
not recommended for patients with COPD that is unrelated
to alpha-1 antitrypsin defciency (Evidence C).
Antibiotics. Prophylactic, continuous use of antibiotics
has been shown to have no effect on the frequency of
exacerbations in COPD
181-183
and a study that examined
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 57
the effcacy of chemoprophylaxis undertaken in winter
months over a period of 5 years, concluded that there was
no beneft
184
. There is no current evidence that the use of
antibiotics, other than for treating infectious exacerbations
of COPD and other bacterial infections, is helpful
185,186

(Evidence A).
Mucolytic (mucokinetic, mucoregulator) agents
(ambroxol, erdosteine, carbocysteine, iodinated glycerol).
The regular use of mucolytics in COPD has been evaluated
in a number of long-term studies with controversial
results
187-189
. Although a few patients with viscous sputum
may beneft from mucolytics
190,191
, the overall benefts seem
to be very small, and the widespread use of these agents
cannot be recommended at present (Evidence D). There
is some evidence, however, that in COPD patients who
have not been treated with inhaled glucocorticosteroids,
treatment with mucolytics such as carbocisteine may
reduce exacerbations
426
.
Antioxidant agents. Antioxidants, in particular
Nacetylcysteine, have been reported in small studies
to reduce the frequency of exacerbations, leading to
speculation that these medications could have a role in
the treatment of patients with recurrent exacerbations
192-195

(Evidence B). However, a large randomized controlled
trial found no effect of Nacetylcysteine on the frequency of
exacerbations, except in patients not treated with inhaled
glucocorticosteroids
196
.
Immunoregulators (immunostimulators,immunomo
dulators). Studies using an immunoregulator in COPD
show a decrease in the severity and frequency of
exacerbations
197,198
. However, additional studies to examine
the long-term effects of this therapy are required before its
regular use can be recommended
199
.
Antitussives. Cough, although sometimes a troublesome
symptom in COPD, has a signifcant protective role
200
.
Thus the regular use of antitussives is not recommended in
stable COPD (Evidence D).
Vasodilators. The belief that pulmonary hypertension in
COPD is associated with a poorer prognosis has provoked
many attempts to reduce right ventricular afterload,
increase cardiac output, and improve oxygen delivery and
tissue oxygenation. Many agents have been evaluated,
including inhaled nitric oxide, but the results have been
uniformly disappointing. In patients with COPD, in whom
hypoxemia is caused primarily by ventilationperfusion
mismatching rather than by increased intrapulmonary
shunt (as in noncardiogenic pulmonary edema), inhaled
nitric oxide can worsen gas exchange because of altered
hypoxic regulation of ventilationperfusion balance
201,202
.
Therefore, based on the available evidence, nitric oxide is
contraindicated in stable COPD.
Narcotics (morphine). Oral and parenteral opioids are
effective for treating dyspnea in COPD patients with
advanced disease. There are insuffcient data to conclude
whether nebulized opioids are effective
203
. However, some
clinical studies suggest that morphine used to control
dyspnea may have serious adverse effects and its benefts
may be limited to a few sensitive subjects
204-208
.
Others. Nedocromil and leukotriene modifers have not
been adequately tested in COPD patients and cannot be
recommended. There was no evidence of beneft and some
evidence of harm (malignancy and pneumonia) from an
antiTNFalpha antibody (infiximab) tested in moderate to
severe COPD
413
. Use of endothelin-receptor antagonist
bosentan fails to improve exercise capacity and may
increase hypoxemia; it should not be used to treat patients
with severe COPD
444
.
There is no evidence of the effectiveness of herbal
medicines for treating COPD
414
and other alternative
healing methods (e.g., acupuncture and homeopathy) have
not been adequately tested.
Rehabilitation
The principal goals of pulmonary rehabilitation are to
reduce symptoms, improve quality of life, and increase
physical and emotional participation in everyday activities.
To accomplish these goals, pulmonary rehabilitation
covers a range of nonpulmonary problems that may not be
adequately addressed by medical therapy for COPD. Such
problems, which especially affect patients with
Stage II: Moderate COPD, Stage III: Severe COPD,
and Stage IV: Very Severe COPD, include exercise de-
conditioning, relative social isolation, altered mood states
(especially depression), muscle wasting, and weight loss.
These problems have complex interrelationships and
improvement in any one of these interlinked processes
can interrupt the vicious circle in COPD so that positive
gains occur in all aspects of the illness (Figure 5.3-9).
Comprehensive statements on pulmonary rehabilitation are
available
209,212
.
Pulmonary rehabilitation has been carefully evaluated
in a large number of clinical trials; the various benefts
are summarized in Figure 5.3-10
89,209-220
. On average,
rehabilitation increases peak workload by 18%, peak
oxygen consumption by 11%, and endurance time by
NON-PHARMACOLOGIC TREATMENT
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
58 MANAGEMENT OF COPD
87% of baseline. This translates into a 49 m improvement
in 6-minute walking distance
221
. Rehabilitation has been
shown to be at least additive to other forms of therapy such
as bronchodilator treatment
124
.
Patient selection and program design. Although more
information is needed on criteria for patient selection for
pulmonary rehabilitation programs, COPD patients at all
stages of disease appear to beneft from exercise training
programs, improving with respect to both exercise tolerance
and symptoms of dyspnea and fatigue
222
(Evidence A).
Data suggest that these benefts can be sustained even
after a single pulmonary rehabilitation program
223-225
. Beneft
does wane after a rehabilitation program ends, but if
exercise training is maintained at home the patients health
status remains above prerehabilitation levels (Evidence
B). To date there is no consensus on whether repeated
rehabilitation courses enable patients to sustain the
benefts gained through the initial course.
Ideally, pulmonary rehabilitation should involve several
types of health professionals. Signifcant benefts can
also occur with more limited personnel, as long as
dedicated professionals are aware of the needs of each
patient. Benefts have been reported from rehabilitation
programs conducted in inpatient, outpatient, and home
settings
214,215,226
. Considerations of cost and availability most
often determine the choice of setting. The educational and
exercise training components of rehabilitation are usually
conducted in groups, normally with 6 to 8 individuals per
class (Evidence D).
The following points summarize current knowledge of
considerations important in choosing patients:
Functional status: Benefts have been seen in patients with
a wide range of disability including patients with Stage IV:
Very Severe COPD under long-term oxygen treatment as
it achieves an improvement in exercise tolerance, reduces
dyspnea after effort, and improves quality of life without
causing any complication arising from the performance of
the exercises
458
.
Severity of dyspnea: Stratifcation by breathlessness
intensity using the MRC questionnaire (Figure 5.1-3) may
be helpful in selecting patients most likely to beneft from
rehabilitation. Those with MRC grade 5 dyspnea may not
beneft
227
(Evidence B).
Motivation: Selecting highly motivated participants
is especially important in the case of outpatient
programs
224,459
.
Smoking status: There is no evidence that smokers will
beneft less than nonsmokers, but many clinicians believe
that inclusion of a smoker in a rehabilitation program should
be conditional on their participation in a smoking cessation
program. Some data indicate that continuing smokers are
less likely to complete pulmonary rehabilitation programs
than nonsmokers
224
(Evidence B).
Components of pulmonary rehabilitation programs.
The components of pulmonary rehabilitation vary widely
from program to program but a comprehensive pulmonary
rehabilitation program includes exercise training, nutrition
counseling, and education.
Exercise training. Exercise tolerance can be assessed
by either bicycle ergometry or treadmill exercise with the
measurement of a number of physiological variables,
including maximum oxygen consumption, maximum heart
rate, and maximum work performed. A less complex
approach is to use a selfpaced, timed walking test (e.g.,
6-minute walking distance). These tests require at least one
practice session before data can be interpreted. Shuttle
walking tests offer a compromise: they provide more
complete information than an entirely self-paced test, but
Figure 5.3-10. Benefits of
Pulmonary Rehabilitation in COPD
Improves exercise capacity (Evidence A).
Reduces the perceived intensity of breathlessness
(Evidence A).
Improves health-related quality of life (Evidence A).
Reduces the number of hospitalizations and days in the
hospital (Evidence A).
Reduces anxiety and depression associated with COPD
(Evidence A).
Strength and endurance training of the upper limbs
improves arm function (Evidence B).
Benefits extend well beyond the immediate period of
training (Evidence B).
Improves survival (Evidence B).
Respiratory muscle training is beneficial, especially when
combined with general exercise training (Evidence C).
Psychosocial intervention is helpful (Evidence C).
Figure 5.3-9. The Cycle of Physical, Social, and
Psychosocial Consequences of COPD
Lack of Fitness
COPD Dyspnea
Depression Social Isolation
Immobility
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 59
are simpler to perform than a treadmill test
228
.
Exercise training ranges in frequency from daily to weekly,
in duration from 10 minutes to 45 minutes per session,
and in intensity from 50% peak oxygen consumption (VO
2

max) to maximum tolerated
229
. The optimum length for an
exercise program has not been investigated in randomized
controlled trials but most studies involving fewer than 28
exercise sessions show inferior results compared to those
with longer treatment periods
221
. In practice, the length
depends on the resources available and usually ranges
from 4 to 10 weeks, with longer programs resulting in larger
effects than longer programs
213
.
Participants are often encouraged to achieve a
predetermined target heart rate
230
, but this goal may have
limitations in COPD. In many programs, especially those
using simple corridor exercise training, the patient is
encouraged to walk to a symptomlimited maximum, rest,
and then continue walking until 20 minutes of exercise
have been completed. Where possible, endurance exercise
training to 60-80% of the symptom-limited maximum is
preferred. Endurance training can be accomplished through
continuous or interval exercise programs. The latter involve
the patient doing the same total work but divided into
briefer periods of highintensity exercise, which is useful
when performance is limited by other comorbidities
231,232
.
Use of a simple wheeled walking aid seems to improve
walking distance and reduces breathlessness in
severely disabled COPD patients
233-235
(Evidence C).
Other approaches to improving outcomes such as use
of oxygen during exercise
236
, exercising while breathing
heliox gas mixtures
237
, unloading the ventilatory muscles
while exercising remain experimental at present. There is
some evidence to suggest that pursed lip breathing may
provide sustained improvement in exertional dyspnea and
physical function
427
. Specifc strength training is possible
but its benefts remain uncertain, as do the effects of
supplementation with anabolic steroids and the use of
neuromuscular electrical stimulation.
The minimum length of an effective rehabilitation program
is 6 weeks; the longer the program continues, the more
effective the results
238-240
(Evidence B). However, as yet,
no effective program has been developed to maintain the
effects over time
241
. Many physicians advise patients unable
to participate in a structured program to exercise on their
own (e.g., walking 20 minutes daily). The benefts of this
general advice have not been tested, but it is reasonable
to offer such advice to patients if a formal program is not
available.
Some programs also include upper limb exercises, usually
involving an upper limb ergometer or resistive training
with weights. There are no randomized clinical trial data
to support the routine inclusion of these exercises, but
they may be helpful in patients with comorbidities that
restrict other forms of exercise and those with evidence
of respiratory muscle weakness
242
. In contrast, inspiratory
muscle training appears to provide additional benefts when
used as part of a comprehensive pulmonary rehabilitation
program
243, 428, 429
. The addition of upper limb exercises or
other strength training to aerobic training is effective in
improving strength, but does not improve quality of life or
exercise tolerance
244
.
Nutrition counseling. Nutritional state is an important
determinant of symptoms, disability, and prognosis
in COPD; both overweight and underweight can be a
problem. Specifc nutritional recommendations for patients
with COPD are based on expert opinion and some
small randomized clinical trials
209
. Approximately 25% of
patients with Stage II: Moderate COPD to Stage IV: Very
Severe COPD show a reduction in both their body mass
index and fat free mass
12,245,246
. A reduction in body mass
index is an independent risk factor for mortality in COPD
patients
13,247,248
(Evidence A).
Health care workers should identify and correct the reasons
for reduced calorie intake in COPD patients. Patients who
become breathless while eating should be advised to take
small, frequent meals. Poor dentition should be corrected
and comorbidities (pulmonary sepsis, lung tumors, etc.)
should be managed appropriately. Improving the nutritional
state of COPD patients who are losing weight can lead
to improved respiratory muscle strength
249-251
. However,
controversy remains as to whether this additional effort is
cost effective
249,250
.
Present evidence suggests that nutritional supplementation
alone may not be a suffcient strategy. Increased calorie
intake is best accompanied by exercise regimes that have
a non-specifc anabolic action, and there is some evidence
this also helps even in those patients without severe
nutritional depletion
252
. Nutritional supplements (e.g.,
creatine) do not augment the substantial training effect of
multidisciplinary pulmonary rehabilitation for patients with
COPD
253
. Anabolic steroids in COPD patients with weight
loss increase body weight and lean body mass but have
little or no effect on exercise capacity
254,255
.
Education. Most pulmonary rehabilitation programs include
an educational component, but the specifc contributions
of education to the improvements seen after pulmonary
rehabilitation remain unclear.
Assessment and follow-up. Baseline and outcome
assessments of each participant in a pulmonary
rehabilitation program should be made to quantify individual
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
60 MANAGEMENT OF COPD
gains and target areas for improvement. Assessments
should include:
Detailed history and physical examination
Measurement of spirometry before and after a
bronchodilator drug
Assessment of exercise capacity
Measurement of health status and impact of
breathlessness
Assessment of inspiratory and expiratory muscle
strength and lower limb strength (e.g., quadriceps)
in patients who suffer from muscle wasting
The frst two assessments are important for establishing
entry suitability and baseline status but are not used
in outcome assessment. The last three assessments
are baseline and outcome measures. Several detailed
questionnaires for assessing health status are available,
including some that are specifcally designed for patients
with respiratory disease (e.g., Chronic Respiratory Disease
Questionnaire
152
, St. George Respiratory Questionnaire
256
),
and there is increasing evidence that these questionnaires
may be useful in a clinical setting. Health status can also
be assessed by generic questionnaires, such as the
Medical Outcomes Study Short Form (SF36)
257
, to enable
comparison of quality of life in different diseases. The
Hospital Anxiety and Depression Scale (HADS)
258
and the
Primary Care Evaluation of Mental Disorders (PRIMEMD)
Patient Questionnaire
415
have been used to improve
identifcation and treatment of anxious and depressed
patients.
Economic cost of rehabilitation programs. A Canadian
study showing statistically signifcant improvements in
dyspnea, fatigue, emotional health, and mastery found
that the incremental cost of pulmonary rehabilitation was
$11,597 (CDN) per person
259
. A study from the United
Kingdom provided evidence that an intensive (6-week,
18-visit) multidisciplinary rehabilitation program was cost
effective
416
and decreased the use of health services
225

(Evidence B). Although there was no difference in
the number of hospital admissions between patients
with disabling COPD in a control group and those who
participated in the rehabilitation program, the number of
days the rehabilitation group spent in the hospital was
signifcantly lower. The rehabilitation group had more
primary-care consultations at the general practitioners
premises than did the control group, but fewer primary-
care home visits. Compared with the control group, the
rehabilitation group also showed greater improvements in
walking ability and in general and diseasespecifc health
status.
Oxygen Therapy
Oxygen therapy, one of the principal nonpharmacologic
treatments for patients with Stage IV: Very Severe
COPD
190,260
, can be administered in three ways: long-term
continuous therapy, during exercise, and to relieve acute
dyspnea. The primary goal of oxygen therapy is to increase
the baseline PaO
2
to at least 8.0 kPa (60 mm Hg) at sea
level and rest, and/or produce an SaO
2
at least 90%, which
will preserve vital organ function by ensuring adequate
delivery of oxygen.
The long-term administration of oxygen (> 15 hours per
day) to patients with chronic respiratory failure has been
shown to increase survival
261,262
(Evidence A). It can also
have a benefcial impact on hemodynamics, hematologic
characteristics, exercise capacity, lung mechanics, and
mental state
263
. Continuous oxygen therapy decreased
resting pulmonary artery pressure in one study
261
but not
in another study
262
. Prospective studies have shown that
the primary hemodynamic effect of oxygen therapy is
preventing the progression of pulmonary hypertension
264,265
.
Long-term oxygen therapy improves general alertness,
motor speed, and hand grip, although the data are less
clear about changes in quality of life and emotional state.
The possibility of walking while using some oxygen devices
may help to improve physical conditioning and have a
benefcial infuence on the psychological state of patients
266
.
Long-term oxygen therapy is generally introduced in Stage
IV: Very Severe COPD for patients who have:
PaO
2
at or below 7.3 kPa (55 mm Hg) or SaO
2
at or
below 88%, with or without hypercapnia (Evidence
B);
or
PaO
2
between 7.3 kPa (55 mm Hg) and 8.0
kPa (60 mm Hg), or SaO
2
of 88%, if there is
evidence of pulmonary hypertension, peripheral
edema suggesting congestive cardiac failure, or
polycythemia (hematocrit > 55%) (Evidence D).
A decision about the use of long-term oxygen should be
based on the waking PaO
2
values. The prescription should
always include the source of supplemental oxygen (gas or
liquid), method of delivery, duration of use, and fow rate at
rest, during exercise, and during sleep. A detailed review
of the uses of oxygen in COPD, together with possible
assessment algorithms and information about methods of
delivery, is available from http://www.thoracic.org/.
Oxygen is usually delivered by a facemask, with
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 61
appropriate inspiratory fow rates varying between 24%
and 35%. The facemask permits accurate titration of
oxygen, which is particularly valuable in patients who are
prone to CO
2
retention. However, facemasks are easily
dislodged and restrict eating and conversation, so many
patients prefer oxygen delivered by nasal cannulae.
Oxygen delivery by this route requires additional blood
gas monitoring to ensure that it is satisfactory, and may
require individual titration. Other, more specialized methods
of oxygen delivery (e.g., transtracheally) are available but
should only be used in specialized centers familiar with the
indications and complications of these delivery methods.
Long-term oxygen is usually provided from a fxed oxygen
concentrator with plastic piping allowing the patient to use
oxygen in their living area and bedroom. Treatment should
be for at least 15 hours per day and preferably longer. In
addition, a supply of oxygen should be provided that will
allow the patient to leave the house for an appropriate
period of time and to exercise without their oxygen
saturation falling below 90%.
A number of physiological studies have shown that
delivering oxygen during exercise can increase the
duration of endurance exercise and/or reduce the
intensity of endexercise breathlessness
267,268
(Evidence
A). This refects a reduction in the rate at which dynamic
hyperinfation occurs, which may be secondary to
the documented reduction in ventilatory demand and
chemoreceptor activation while breathing oxygen during
exercise
269,270
. These changes occur whether or not patients
are hypoxemic at rest and can translate into improved
health status if the treatment is used as an outpatient
271
.
However, good data about the use of ambulatory oxygen
in representative patient populations are presently lacking,
although a small randomized trial has suggested that
compliance is not high
272
. Patients need encouragement to
understand how and when to use ambulatory oxygen and
overcome any anxieties or concerns about using this more
conspicuous treatment.
Oxygen therapy reduces the oxygen cost of breathing and
minute ventilation, a mechanism that although still disputed
helps to minimize the sensation of dyspnea. This has led
to the use of short-burst therapy to control severe dyspnea
such as occurs after climbing stairs. However, there is no
beneft from using short-burst oxygen for symptomatic relief
before or after exercise
273,274
(Evidence B).
Cost considerations. Supplemental home oxygen is
usually the most costly component of outpatient therapy
for adults with COPD who require this therapy
275
. Studies
of the cost effectiveness of alternative outpatient oxygen
delivery methods in the US and Europe suggest that
oxygen concentrator devices may be more cost effective
than cylinder delivery systems
276,277
.
Oxygen use in air travel. Although air travel is safe for
most patients with chronic respiratory failure who are on
long-term oxygen therapy, patients should be instructed to
increase the fow by 12 L/min during the fight
278
. Ideally,
patients who fy should be able to maintain an infight
PaO
2
of at least 6.7 kPa (50 mm Hg). Studies indicate that
this can be achieved in those with moderate to severe
hypoxemia at sea level by supplementary oxygen at 3 L/
min by nasal cannulae or 31% by Venturi facemask
279
.
Those with a resting PaO
2
at sea level of > 9.3 kPa (70
mm Hg) are likely to be safe to fy without supplementary
oxygen
278,280
, although it is important to emphasize that
a resting PaO
2
> 9.3 kPa (70 mm Hg) at sea level does
not exclude the development of severe hypoxemia when
travelling by air (Evidence C). Careful consideration
should be given to any comorbidity that may impair oxygen
delivery to tissues (e.g., cardiac impairment, anemia).
Also, walking along the aisle may profoundly aggravate
hypoxemia
281
.
Ventilatory Support
Noninvasive ventilation (using either negative or positive
pressure devices) is now widely used to treat acute
exacerbations of COPD (see Component 4). Negative
pressure ventilation is not indicated for the chronic
management of Stage IV: Very Severe COPD patients, with
or without CO
2
retention. It has been demonstrated to have
no effect on shortness of breath, exercise tolerance, arterial
blood gases, respiratory muscle strength, or quality of life in
COPD patients with chronic respiratory failure
282, 430
.
Although preliminary studies suggested that combining
noninvasive intermittent positive pressure ventilation
(NIPPV) with long-term oxygen therapy could improve
some outcome variables, current data do not support the
routine use of this combination
283
. However, compared with
long-term oxygen therapy alone, the addition of NIPPV can
lessen carbon dioxide retention and improve shortness of
breath in some patients
284
and may improve survival but at
the cost of worsening quality of life
460
. Thus, although at
present long-term NIPPV cannot be recommended for the
routine treatment of patients with chronic respiratory failure
due to COPD, the combination of NIPPV with long-term
oxygen therapy may be of some use in a selected subset
of patients, particularly in those with pronounced daytime
hypercapnia
285
.
Surgical Treatments
Bullectomy. Bullectomy is an older surgical procedure
for bullous emphysema. Removal of a large bulla that
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
62 MANAGEMENT OF COPD
does not contribute to gas exchange decompresses the
adjacent lung parenchyma. Bullectomy can be performed
thoracoscopically. In carefully selected patients, this
procedure is effective in reducing dyspnea and improving
lung function
286
(Evidence C).
Bullae may be removed to alleviate local symptoms such
as hemoptysis, infection, or chest pain, and to allow
reexpansion of a compressed lung region. This is the
usual indication in patients with COPD. In considering the
possible beneft of surgery it is crucial to estimate the effect
of the bulla on the lung and the function of the nonbullous
lung. A thoracic CT scan, arterial blood gas measurement,
and comprehensive respiratory function tests are essential
before making a decision regarding suitability for resection
of a bulla. Normal or minimally reduced diffusing capacity,
absence of signifcant hypoxemia, and evidence of regional
reduction in perfusion with good perfusion in the remaining
lung are indications a patient will likely beneft from
surgery
287
. However, pulmonary hypertension, hypercapnia,
and severe emphysema are not absolute contraindications
for bullectomy. Some investigators have recommended that
the bulla must occupy 50% or more of the hemithorax and
produce defnite displacement of the adjacent lung before
surgery is performed
288
.
Lung volume reduction surgery (LVRS). LVRS is a
surgical procedure in which parts of the lung are resected
to reduce hyperinfation
289
, making respiratory muscles
more effective pressure generators by improving their
mechanical effciency (as measured by length/tension
relationship, curvature of the diaphragm, and area of
apposition)
290,291
. In addition, LVRS increases the elastic
recoil pressure of the lung and thus improves expiratory
fow rates
292
.
A large multicenter study of 1,200 patients (National
Emphysema Treatment Trial, NETT) comparing LVRS with
medical treatment has shown that after 4.3 years, patients
with upperlobe emphysema and low exercise capacity who
received the surgery had a greater survival rate than similar
patients who received medical therapy (54% vs. 39.7%)
293
.
The surgery patients experienced greater improvements
in their maximal work capacity and their healthrelated
quality of life
293
, and surgery reduced the frequency of
COPD exacerbations and increased the time to frst
exacerbation
431
. Surgery increases Pa(O
2
) and decreases
use of supplemental oxygen during treadmill walking, and
selfreported use of oxygen during rest, exertion, and sleep
for up to 24 months postprocedure
445
. The advantage of
surgery over medical therapy was less signifcant among
patients who had other emphysema distribution or high
exercise capacity prior to treatment.
A prospective economic analysis from the National
Emphysema Treatment Trial indicated that LVRS is
costly relative to other healthcare programs. The cost-
effectiveness of LVRS vs medical therapy was $140,000
per quality-adjusted life year (QALY) gained at 5 years,
and was projected to be $54,000 per QALY gained at 10
years
294
.
Although the results of the large multicenter study showed
some very positive results of surgery in a select group
of patients
41,293
, LVRS is an expensive palliative surgical
procedure and can be recommended only in carefully
selected patients.
Lung transplantation. In appropriately selected patients
with very advanced COPD, lung transplantation has been
shown to improve quality of life and functional capacity
296-299

(Evidence C), although the Joint United Network for Organ
Sharing in 1998 found that lung transplantation does
not confer a survival beneft in patients with endstage
emphysema after two years
298
. Criteria for referral for lung
transplantation include FEV
1
< 35% predicted, PaO
2
<
7.38.0 kPa (5560 mm Hg), PaCO
2
> 6.7 kPa (50 mm Hg),
and secondary pulmonary hypertension
300,301
.
Lung transplantation is limited by the shortage of donor
organs, which has led some centers to adopt the single-
lung technique. The common complications seen in COPD
patients after lung transplantation, apart from operative
mortality, are acute rejection and bronchiolitis obliterans,
CMV, other opportunistic fungal (Candida, Aspergillus,
Cryptococcus, Carinii) or bacterial (Pseudomonas,
Staphylococcus species) infections, lymphoproliferative
disease, and lymphomas
297
.
Another limitation of lung transplantation is its cost. In the
United States, hospitalization costs associated with lung
transplantation have ranged from US$110,000 to well
over $200,000. Costs remain elevated for months to years
after surgery due to the high cost of complications and the
immunosuppressive regimens
302-305
that must be initiated
during or immediately after surgery.
Special Considerations
Surgery in COPD. Postoperative pulmonary complications
are as important and common as postoperative cardiac
complications and, consequently, are a key component
of the increased risk posed by surgery in COPD patients.
The principal potential factors contributing to the risk
include smoking, poor general health status, age, obesity,
and COPD severity. A comprehensive defnition of
postoperative pulmonary complications should include only
major pulmonary respiratory complications, namely lung
infections, atelectasis and/or increased airfow obstruction,
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 63
all potentially resulting in acute respiratory failure and
aggravation of underlying COPD
306-311
.
The incidence of increased risk of postoperative pulmonary
complications in COPD patients may vary according to the
defnition of postoperative pulmonary complications and the
severity of COPD, with relative ranges of the order of 2.7 to
4.7
306
. The surgical site is the most important predictor, and
risk increases as the incision approaches the diaphragm.
Upper abdominal and thoracic surgery represents the
greatest risk, the latter being uncommon after interventions
outside the thorax or abdomen. Most reports conclude that
epidural or spinal anesthesia have a lower risk than general
anesthesia, although the results are not totally uniform.
Individual patient risk factors are identifed by careful
history, physical examination, chest radiography, and
pulmonary function tests. Although the value of pulmonary
function tests remains contentious, there is consensus that
all COPD candidates for lung resection should undergo
a complete battery, including forced spirometry with
bronchodilator response, static lung volumes, diffusing
capacity, and arterial blood gases at rest. One theoretical
rationale behind the assessment of pulmonary function
measurement is the identifcation of COPD patients in
whom the risk is so elevated that surgery should be
contraindicated.
Several studies in highrisk COPD patients suggest that
there is a threshold beyond which the risk of surgery is
prohibitive. The risk of postoperative respiratory failure
appears to be in patients undergoing pneumonectomy
with a preoperative FEV
1
< 2 L or 50% predicted and/or a
DLCO < 50% predicted
310
. COPD patients at high risk due
to poor lung function should undergo further lung function
assessment, for example, tests of regional distribution of
perfusion and exercise capacity
311
. To prevent postoperative
pulmonary complications, stable COPD patients clinically
symptomatic and/or with limited exercise capacity should
be treated, before surgery, intensely with all the measures
already well established for stable COPD patients who are
not about to have surgery. Surgery should be postponed if
an exacerbation is present.
Surgery in patients with COPD needs to be differentiated
from that aimed to improve lung function and symptoms
of COPD. This includes bullectomy, lung volume reduction
surgery, and lung transplantation
311
.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
64 MANAGEMENT OF COPD
KEY POINTS:
An exacerbation of COPD is defned as an event
in the natural course of the disease characterized
by a change in the patients baseline dyspnea,
cough, and/or sputum that is beyond normal
daytoday variations, is acute in onset, and may
warrant a change in regular medication in a
patient with underlying COPD.
The most common causes of an exacerbation
are infection of the tracheobronchial tree and
air pollution, but the cause of about onethird
of severe exacerbations cannot be identifed
(Evidence B).
Inhaled bronchodilators (particularly inhaled
2-
agonists with or without anticholinergics) and oral
glucocorticosteroids are effective treatments for
exacerbations of COPD (Evidence A).
Patients experiencing COPD exacerbations with
clinical signs of airway infection (e.g., increased
sputum purulence) may beneft from antibiotic
treatment (Evidence B).
Noninvasive mechanical ventilation in
exacerbations improves respiratory acidosis,
increases pH, decreases the need for
endotracheal intubation, and reduces PaCO
2
,
respiratory rate, severity of breathlessness, the
length of hospital stay, and mortality (Evidence
A).
Medications and education to help prevent future
exacerbations should be considered as part of
follow-up, as exacerbations affect the quality of
life and prognosis of patients with COPD.
COPD is often associated with exacerbations of
symptoms
312-316
. An exacerbation of COPD is defned as
an event in the natural course of the disease characterized
by a change in the patientts baseline dyspnea, cough, and/
or sputum that is beyond normal daytoday variations, is acute
in onset, and may warrant a change in regular medication
in a patient with underlying COPD
317,318
. Exacerbations are
categorized in terms of either clinical presentation (number
of symptoms
314
) and/or healthcare resources utilization
317
.
The impact of exacerbations is signifcant and a patients
symptoms and lung function may both take several weeks
to recover to the baseline values
319
.
Exacerbations affect the quality of life and prognosis of
patients with COPD. Hospital mortality of patients admitted
for a hypercarbic COPD exacerbation is approximately
10%, and the long-term outcome is poor
320
. Mortality
reaches 40% at 1 year in those needing mechanical
support, and allcause mortality is even higher (up to 49%) 3
years after hospitalization for a COPD exacer
bation
316,320-325
. Older age, decreased lung function, lower
health status, diabetes, and preICU admission quality
of life
417
are important risk factors for mortality in COPD
patients hospitalized for acute exacerbation
418
. In addition,
exacerbations of COPD have serious negative impacts
on patients quality of life
140,406
, lung function
326,327
, and
socioeconomic costs
325
. Thus, prevention, early detection,
and prompt treatment of exacerbations may impact their
clinical progression by ameliorating the effects on quality of
life and minimizing the risk of hospitalization
328
.
The most common causes of an exacerbation are
infection of the tracheobronchial tree and air pollution
329
,
but the cause of about onethird of severe exacerbations
cannot be identifed. The role of bacterial infections is
controversial, but recent investigations with newer research
techniques have begun to provide important information.
Bronchoscopic studies have shown that at least 50% of
patients have bacteria in high concentrations in their lower
airways during exacerbations
330-332
. However, a signifcant
proportion of these patients also have bacteria colonizing
their lower airways in the stable phase of the disease.
There is some indication that the bacterial burden
increases during exacerbations
330
, and that acquisition
of strains of the bacteria that are new to the patient is
associated with exacerbations
332
. Development of specifc
immune responses to the infecting bacterial strains, and
the association of neutrophilic infammation with bacterial
exacerbations, also support the bacterial causation of a
proportion of exacerbations
333-336
.
Medical History
Increased breathlessness, the main symptom of an
COMPONENT 4: MANAGE EXACERBATIONS
INTRODUCTION
DIAGNOSIS AND ASSESSMENT OF
SEVERITY
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 65
exacerbation, is often accompanied by wheezing and chest
tightness, increased cough and sputum, change of the
color and/or tenacity of sputum, and fever.
Exacerbations may also be accompanied by a number
of nonspecifc complaints, such as tachycardia and
tachypnea, malaise, insomnia, sleepiness, fatigue,
depression, and confusion. A decrease in exercise
tolerance, fever, and/ or new radiological anomalies
suggestive of pulmonary disease may herald a COPD
exacerbation. An increase in sputum volume and purulence
points to a bacterial cause, as does prior history of chronic
sputum production3
14,336
.
Assessment of Severity
Assessment of the severity of an exacerbation is based
on the patients medical history before the exacerbation,
preexisting comorbidities, symptoms, physical examination,
arterial blood gas measurements, and other laboratory
tests (Figure 5.4-1). Specifc information is required on
the frequency and severity of attacks of breathlessness
and cough, sputum volume and color, and limitation of
daily activities. When available, prior arterial blood gas
measurements are extremely useful for comparison with
those made during the acute episode, as an acute change
in these tests is more important than their absolute values.
Thus, where possible, physicians should instruct their
patients to bring the summary of their last evaluation when
they come to the hospital with an exacerbation. In patients
with Stage IV: Very Severe COPD, the most important sign
of a severe exacerbation is a change in the mental status of
the patient and this signals a need for immediate evaluation
in the hospital.
Figure 5.4-1. Assessment of COPD Exacerbations:
Medical History and Signs of Severity
Medical History
Severity of FEV
1
Duration of worsening or
new symptoms
Number of previous
episodes (exacerbations/
hospitalizations)
Comordibities
Present treatment regimen
Signs of Severity
Use of accessory respiratory
muscles
Paradoxical chest wall
movements
Worsening or new onset
central cyanosis
Development of peripheral
edema
Hemodynamic instability
Signs of right heart failure
Reduced alertness
Spirometry and PEF. Even simple spirometric tests
can be diffcult for a sick patient to perform properly.
These measurements are not accurate during an
acute exacerbation; therefore their routine use is not
recommended.
Pulse oximetry and arterial blood gas measurement.
Pulse oximetry can be used to evaluate a patients oxygen
saturation and need for supplemental oxygen therapy.
For patients that require hospitalization, measurement of
arterial blood gases is important to assess the severity
of an exacerbation. A PaO
2
< 8.0 kPa (60 mm Hg) and/or
SaO
2
< 90% with or without PaCO
2
> 6.7 kPa (50 mmHg)
when breathing room air indicate respiratory failure. In
addition, moderate-to-severe acidosis (pH < 7.36) plus
hypercapnia (PaCO
2
> 68 kPa, 4560 mm Hg) in a patient
with respiratory failure is an indication for mechanical
ventilation
311,337
.
Chest X-ray and ECG. Chest radiographs (posterior/
anterior plus lateral) are useful in identifying alternative
diagnoses that can mimic the symptoms of an
exacerbation. Although the history and physical signs can
be confusing, especially when pulmonary hyperinfation
masks coexisting cardiac signs, most problems are
resolved by the chest Xray and ECG. An ECG aids in the
diagnosis of right heart hypertrophy, arrhythmias, and
ischemic episodes. Pulmonary embolism can be very
diffcult to distinguish from an exacerbation, especially in
advanced COPD, because right ventricular hypertrophy
and large pulmonary arteries lead to confusing ECG and
radiographic results. A low systolic blood pressure and an
inability to increase the PaO
2
above 8.0 kPa (60 mm Hg)
despite highfow oxygen also suggest pulmonary embolism.
If there are strong indications that pulmonary embolism
has occurred, it is best to treat for this along with the
exacerbation.
Other laboratory tests. The whole blood count may identify
polycythemia (hematocrit > 55%) or bleeding. White blood
cell counts are usually not very informative. The presence
of purulent sputum during an exacerbation of symptoms
is suffcient indication for starting empirical antibiotic
treatment
33
. Streptococcus pneumoniae, Hemophilus
infuenzae, and Moraxella catarrhalis are the most common
bacterial pathogens involved in COPD exacerbations. If
an infectious exacerbation does not respond to the initial
antibiotic treatment, a sputum culture and an antibiogram
should be performed. Biochemical test abnormalities can
be associated with an exacerbation and include electrolyte
disturbance(s) (e.g., hyponatremia, hypokalemia), poor
glucose control, or metabolic acidbase disorder. These
abnormalities can also be due to associated comorbid
conditions (see below Differential Diagnoses).
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
66 MANAGEMENT OF COPD
Differential Diagnoses
A diagnosis of pulmonary embolism should be considered
in patients with exacerbation severe enough to warrant
hospitalization, especially in those with an intermediate
tohigh pretest probability of pulmonary embolism
446
. Ten to
30% of patients with apparent exacerbations of COPD do
not respond to treatment
319,338
. In such cases the patient
should be reevaluated for other medical conditions that can
aggravate symptoms or mimic COPD exacerbations190.
These conditions include pneumonia, congestive heart
failure, pneumothorax, pleural effusion, pulmonary
embolism, and cardiac arrhythmia. Noncompliance with the
prescribed medication regimen can also cause increased
symptoms that may be confused with a true exacerbation.
Elevated serum levels of braintype natriuretic peptide,
in conjunction with other clinical information, identifes
patients with acute dyspnea secondary to congestive heart
failure and enables them to be distinguished from patients
with COPD exacerbations
339,340
.
There is increasing interest in home care for end-stage
COPD patients, although economic studies of homecare
services have yielded mixed results. Four randomized
clinical trials have shown that nurseadministered home
care (also known as hospital-at-home care) represents
an effective and practical alternative to hospitalization in
selected patients with exacerbations of COPD without
acidotic respiratory failure. However, the exact criteria for
this approach as opposed to hospital treatment remain
uncertain and will vary by health care setting
341-344
.
The algorithm reported in Figure 5.4-2 may assist in the
management of an exacerbation at home; a stepwise
therapeutic approach is recommended
190,311,345
.
Bronchodilator Therapy
Home management of COPD exacerbations involves
increasing the dose and/or frequency of existing short-
acting bronchodilator therapy, preferably with a
2
agonist
(Evidence A). There is not suffcient evidence, however,
to indicate a difference in effcacy between the different
classes of short-acting bronchodilators
347
, or to indicate
additional beneft of combinations of short-acting
bronchodilators
348
. However, if not already used, an
anticholinergic can be added until the symptoms improve.
There is no difference in the clinical response between
bronchodilator therapy delivered by MDI with a spacer and
by hand held nebulizer.
Glucocorticosteroids
Systemic glucocorticosteroids are benefcial in the
management of exacerbations of COPD. They shorten
recovery time, improve lung function (FEV
1
) and hypoxemia
(PaO
2
)
349-352
(Evidence A), and may reduce the risk of early
relapse, treatment failure, and length of hospital stay
353
.
They should be considered in addition to bronchodilators
if the patients baseline FEV
1
is < 50% predicted. A
dose of 30-40 mg prednisolone per day for 7-10 days is
recommended
346,349,350
. Therapy with oral prednisolone
is preferable
432
. Budesonide alone, or in combination
with formoterol, may be an alternative (although more
expensive) to oral glucocorticosteroids in the treatment of
exacerbations
352, 419, 447
and is associated with signifcant
reduction of complications.
Antibiotics
The use of antibiotics in the management of COPD
exacerbations is discussed below in the hospital
management section.
The risk of dying from an exacerbation of COPD is closely
related to the development of respiratory acidosis, the
presence of signifcant comorbidities, and the need for
ventilatory support
320
. Patients lacking these features are
not at high risk of dying, but those with severe underlying
COPD often require hospitalization in any case. Attempts
at managing such patients entirely in the community
have met with only limited success
354
, but returning
them to their homes with increased social support and a
supervised medical care package after initial emergency
room assessment has been much more successful
355
.
HOME MANAGEMENT
HOSPITAL MANAGEMENT
Figure 5.4-2. Algorithm for the Management of an
Exacerbation of COPD at Home (adapted from ref
346
)
The exact criteria for home vs. hospital treatment remain uncertain and will vary by health care setting. If it is
determined that care can be initiated at home, this algorithm provides a stepwise therapeutic approach.

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 67
Savings on inpatient expenditures
356
offset the additional
costs of maintaining a communitybased COPD nursing
team. However, detailed costbeneft analyses of these
approaches are awaited.
A range of criteria to consider for hospital assessment/
admission for exacerbations of COPD are shown in Figure
5.4-3. Some patients need immediate admission to an
intensive care unit (ICU) (Figure 5.4-4). Admission of
patients with severe COPD exacerbations to intermediate
or special respiratory care units may be appropriate if
personnel, skills, and equipment exist to identify and
manage acute respiratory failure successfully.
Figure 5.4-3. Indications for Hospital Assessment
or Admission for Exacerbations of COPD*
Marked increase in intensity of symptoms, such as sudden
development of resting dyspnea
Severe underlying COPD
Onset of new physical signs (e.g., cyanosis, peripheral edema)
Failure of exacerbation to respond to initial medical
management
Significant comorbidities
Frequent exacerbations
Newly occurring arrhythmias
Diagnostic uncertainty
Older age
Insufficient home support
*Local resources need to be considered.
Figure 5.4-4. Indications for ICU Admission
of Patients with Exacerbations of COPD*
Severe dyspnea that responds inadequately to initial
emergency therapy
Changes in mental status (confusion, lethargy, coma)
Persistent or worsening hypoxemia (PaO
2
< 5.3 kPa,
40 mmHg), and/or severe/worsening hypercapnia
(PaCO
2
> 8.0 kPa, 60 mmHg), and/or severe/worsening
respiratory acidosis (pH < 7.25) despite supplemental
oxygen and noninvasive ventilation
Need for invasive mechanical ventilation
Hemodynamic instabilityneed for vasopressors
*Local resources need to be considered.
Emergency Department or Hospital
The frst actions when a patient reaches the emergency
department are to provide supplemental oxygen therapy
and to determine whether the exacerbation is life
threatening (Figure 5.4-4). If so, the patient should be
admitted to the ICU immediately. Otherwise, the patient
may be managed in the emergency department or hospital
as detailed in Figure 5.4-5.
Figure 5.4-5. Management of Severe but Not
Life-Threatening Exacerbations of COPD in the
Emergency Department or the Hospital
346
*
Assess severity of symptoms, blood gases, chest X-ray
Administer controlled oxygen therapy and repeat arterial
blood gas measurement after 30-60 minutes
Bronchodilators:
Increase doses and/or frequency
Combine
2
-agonists and anticholinergics
Use spacers or air-driven nebulizers
Consider adding intravenous mehylxanthines, if needed
Add oral or intravenous glucocorticosteroids
Consider antibiotics (oral or occasionally intravenous)
when signs of bacterial infection
Consider noninvasive mechanical ventilation
At all times:
Monitor fluid balance and nutrition
Consider subcutaneous heparin
Identify and treat associated conditions (e.g., heart
failure, arrhythmias)
Closely monitor condition of the patient
*Local resources need to be considered.
Controlled oxygen therapy. Oxygen therapy is the
cornerstone of hospital treatment of COPD exacerbations.
Supplemental oxygen should be titrated to improve the
patients hypoxemia. Adequate levels of oxygenation (PaO
2

> 8.0 kPa, 60 mm Hg, or SaO
2
> 90%) are easy to achieve
in uncomplicated exacerbations, but CO
2
retention can
occur insidiously with little change in symptoms. Once
oxygen is started, arterial blood gases should be checked
30-60 minutes later to ensure satisfactory oxygenation
without CO
2
retention or acidosis. Venturi masks (highfow
devices) offer more accurate delivery of controlled oxygen
than do nasal prongs but are less likely to be tolerated by
the patient
311
.
Bronchodilator therapy. Short-acting inhaled
2
agonists
are usually the preferred bronchodilators for treatment of
exacerbations of COPD
190,311,357
(Evidence A). If a prompt
response to these drugs does not occur, the addition of an
anticholinergic is recommended, even though evidence
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
68 MANAGEMENT OF COPD
concerning the effectiveness of this combination is
controversial. Despite its widespread clinical use, the role
of methylxanthines in the treatment of exacerbations of
COPD remains controversial. Methylxanthines (theophylline
or aminohylline) are currently considered secondline
intravenous therapy, used when there is inadequate or
insuffcient response to short-acting bronchodilators
358-362
(Evidence B). Possible benefcial effects in terms of lung
function and clinical endpoints are modest and inconsistent,
whereas adverse effects are signifcantly increased
363,364
.
There are no clinical studies that have evaluated the
use of inhaled long-acting bronchodilators (either

2
agonists or anticholinergics) with or without inhaled
glucocorticosteroids during an acute exacerbation.

Glucocorticosteroids. Oral or intravenous glucocortico-
steroids are recommended as an addition to other
therapies in the hospital management of exacerbations of
COPD
350,351
(Evidence A). The exact dose that should be
recommended is not known, but high doses are associated
with a signifcant risk of side effects. Thirty to 40 mg of
oral prednisolone daily for 7-10 days is effective and safe
(Evidence C). Prolonged treatment does not result in
greater effcacy and increases the risk of side effects (e.g.,
hyperglycemia, muscle atrophy).
Antibiotics. Randomized placebocontrolled studies
of antibiotic treatment in exacerbations of COPD have
demonstrated mixed results of antibiotics on lung
function
365,461
, and a randomized controlled trial has
provided evidence for a signifcant benefcial effect of
antibiotics in COPD patients who presented with an
increase in all three of the following cardinal symptoms:
dyspnea, sputum volume, and sputum purulence
314
. There
was also some beneft in those patients with an increase in
only two of these cardinal symptoms.
A study on nonhospitalized patients with exacerbations
of COPD showed a relationship between the purulence
of the sputum and the presence of bacteria
11
, suggesting
that these patients should be treated with antibiotics if they
also have at least one of the other two cardinal symptoms
(dyspnea or sputum volume). However, these criteria for
antibiotic treatment of exacerbations of COPD have not
been validated in other studies. A study in COPD patients
with exacerbations requiring mechanical ventilation
(invasive or noninvasive) indicated that not giving
antibiotics was associated with increased mortality and a
greater incidence of secondary nosocomial pneumonia
366
.
Based on the current available evidence
311,62
, antibiotics
should be given to:
Patients with exacerbations of COPD with the
following three cardinal symptoms: increased dyspnea,
increased sputum volume, and increased sputum
purulence (Evidence B).
Patients with exacerbations of COPD with two of the
cardinal symptoms, if increased purulence of sputum is
one of the two symptoms (Evidence C).
Patients with a severe exacerbation of COPD
that requires mechanical ventilation (invasive or
noninvasive) (Evidence B).
The infectious agents in COPD exacerbations can be viral
or bacterial
177,367
. The predominant bacteria recovered from
the lower airways of patients with COPD exacerbations are
H. infuenzae, S. pneumoniae, and M. catarrhalis
177,330,331,368
.
So-called atypical pathogens, such as Mycoplasma
pneumoniae and Chlamydia pneumoniae
368,369
, have
been identifed in patients with COPD exacerbations, but
because of diagnostic limitations the true prevalence of
these organisms is not known.
Studies in patients with severe underlying COPD who
require mechanical ventilation
370,371
have shown that
other microorganisms, such as enteric gram-negative
bacilli and P. aeruginosa, may be more frequent. Other
studies have shown that the severity of the COPD is an
important determinant of the type of microorganism
372,373
.
In patients with mild COPD exacerbations , S. pneumoniae
is predominant. As FEV
1
declines and patients have more
frequent exacerbations and/or comorbid diseases ,
H. infuenzae and M. catarrhalis become more frequent, and
P. aeruginosa may appear in patients with severe airway
limitation (Figure 5.4-6)
177,311
. The risk factors for
P. aeruginosa infection are recent hospitalization, frequent
administration of antibiotics (4 courses in the last year),
severe COPD exacerbations, and isolation of P. aeruginosa
during a previous exacerbation
430
or colonization during a
stable period
372,373
.
Figure 5.4-7
177,311,332
provides recommended antibiotic
treatment for exacerbations of COPD, although it must
be emphasized that most of the published studies
related to the use of antibiotics were done in chronic
bronchitis patients. The route of administration (oral or
intravenous) depends on the ability of the patient to eat
and the pharmacokinetics of the antibiotic. The oral route
is preferred; if the IV route must be used, switching to
the oral route is recommended when clinical stabilization
permits. Based on studies of the length of use of antibiotics
for chronic bronchitis
374-376
, antibiotic treatment in patients
with COPD exacerbations could be given for 3 to 7 days
(Evidence D).
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 69
Figure 5.4-6: Stratification of patients with COPD
exacerbated for antibiotic treatment and potential
microorganisms involved in each group
177,311
Group
Group A Mild exacerbation:
No risk factors for
poor outcome
H. influenzae
S. pneumoniae
M. catarrhalis
Chlamydia
pneumoniae
Viruses
Group B Moderate
exacerbation with
risk factor(s) for
poor outcome
Group A plus,
presence of
resistant organisms
(-lactamase
producing,
penicillin-resistant
S. pneumoniae),
Enterobacteriaceae
(K.pneumoniae,
E. coli, Proteus,
Enterobacter, etc)
Group C Severe
exacerbation with
risk factors for
P. aeruginosa
infection
Group B plus:
P. aeruginosa
Definition
a
Microorganisms
a. Risk factors for poor outcome in patients with COPD exacerbation:
presence of comorbid diseases, severe COPD, frequent exacerbations
(>3 /yr), and antimicrobial use within last 3 months)
177,311,372.
Respiratory Stimulants. Respiratory stimulants are not
recommended for acute respiratory failure
357
. Doxapram,
a nonspecifc but relatively safe respiratory stimulant
available in some countries as an intravenous formulation,
should be used only when noninvasive intermittent
ventilation is not available or not recommended
377
.
Ventilatory support. The primary objectives of mechanical
ventilatory support in patients with COPD exacerbations
are to decrease mortality and morbidity and to relieve
symptoms. Ventilatory support includes both noninvasive
intermittent ventilation using either negative or positive
pressure devices, and invasive (conventional) mechanical
ventilation by orotracheal tube or tracheostomy.
Noninvasive mechanical ventilation. Noninvasive
intermittent ventilation (NIV) has been studied in several
randomized controlled trials in acute respiratory failure,
consistently providing positive results with success rates
of 80-85%
285,378-380
. These studies provide evidence that
NIV improves respiratory acidosis (increases pH, and
decreases PaCO
2
), decreases respiratory rate, severity
of breathlessness, and length of hospital stay (Evidence
A). More importantly, mortality-or its surrogate, intubation
rate-is reduced by this intervention
380-383
. However, NIV
is not appropriate for all patients, as summarized in
Figure5.4-8
285
.
5.4-7: Antibiotic treatment in exacerbations
of COPD
a,b (ref. 177,311,332)
Group A
Patients with
only one
cardinal
symptom
c
should not
receive
antibiotics
If indication then:
-lactam
(Penicillin,
Ampicillin/
Amoxicillin
d
)
Tetracycline
Trimethoprim/
Sulfameth-
oxazole
-lactam/
-lactamase
inhibitor
(Co-amoxiclav)
Macrolides
(Azithromycin,
Clarithromycin,
Roxithromycin
e
)
Cephalosporins
- 2nd or 3rd
generation
Ketolides
(Telithromycin)
Group B
-lactam/
-lactamase
inhibitor
(Co-amoxiclav)
Fluoroquinol-
ones
e
(Gemifloxacin,
Levofloxacin,
Moxifloxacin)
-lactam/
-lactamase
inhibitor
(Co-amoxiclav,
ampicillin/
sulbactam)
Cephalosporins
- 2nd or 3rd
generation
Fluoroquinol-
ones
e
(Levofloxacin,
Moxifloxacin)
Group C
In patients at risk
for pseudomonas
infections:
Fluoroquinol-
ones
e
(Ciprofloxacin,
Levofloxacin -
high dose
f
)
Fluoroquinol-
ones
e
(Ciprofloxacin,
Levofloxacin -
high dose
f
) or
-lactam with
P.aeruginosa
activity
Oral Treatment
(No particular order)
Alternative Oral
Treatment
(No particular order)
Parenteral
Treatment
(No particular order)
a. All patients with symptoms of a COPD exacerbation should be
treated with additional bronchodilators glucocorticosteroids.
b. Classes of antibiotics are provided (with specific agents in parentheses).
In countries with high incidence of S. pneumoniae resistant to penicillin,
high dosages of Amoxicillin or Co-amoxiclav are recommended.
(See Figure 5-4-6 for definition of Groups A, B, and C.)
c. Cardinal symptoms are increased dyspnea, sputum volume, and
sputum purulence.
d. This antibiotic is not appropriate in areas where there is increased
prevalence of -lactamase producing H. influenzae and
M. catarrhalis and/or of S. pneumoniae resistant to penicillin.
e. Not available in all areas of the world.
f. Dose 750 mg effective against P. aeruginosa
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
70 MANAGEMENT OF COPD
Figure 5.4-8. Indications and Relative
Contraindications for NIV
311,378,384,385
Selection criteria
Moderate to severe dyspnea with use of accessory
muscles and paradoxical abdominal motion
Moderate to severe acidosis (pH 7.35 ) and/ or
hypercapnia (PaCO
2
> 6.0 kPa, 45 mm Hg)
386
Respiratory frequency > 25 breaths per minute
Exclusion criteria (any may be present)
Respiratory arrest
Cardiovascular instability (hypotension, arrhythmias,
myocardial infarction)
Change in mental status; uncooperative patient
High aspiration risk
Viscous or copious secretions
Recent facial or gastroesophageal surgery
Craniofacial trauma
Fixed nasopharyngeal abnormalities
Burns
Extreme obesity.
Invasive mechanical ventilation. During exacerbations
of COPD the events occurring within the lungs include
bronchoconstriction, airway infammation, increased
mucus secretion, and loss of elastic recoil, all of which
prevent the respiratory system from reaching its passive
functional residual capacity at the end of expiration,
enhancing dynamic hyperinfation and increasing the work
of breathing
387,388
. The indications for initiating invasive
mechanical ventilation during exacerbations of COPD are
shown in Figure 5.4-9, including failure of an initial trial of
NIV
389
. As experience is being gained with the generalized
clinical use of NIV in COPD, several of the indications for
invasive mechanical ventilation are being successfully
treated with NIV. Figure 5.4-10 details some other factors
that determine the use of invasive ventilation.
The use of invasive ventilation in endstage COPD patients
is infuenced by the likely reversibility of the precipitating
event, the patients wishes, and the availability of intensive
care facilities. When possible, a clear statement of the
patients own treatment wishesan advance directive or
living willmakes these diffcult decisions much easier to
resolve. Major hazards include the risk of ventilatoracquired
pneumonia (especially when multiresistant organisms are
prevalent), barotrauma, and failure to wean to spontaneous
ventilation.
Contrary to some opinions, acute mortality among COPD
patients with respiratory failure is lower than mortality
among patients ventilated for nonCOPD causes
324
.
Despite this, there is evidence that patients who might
otherwise survive may be denied admission to intensive
care for intubation because of unwarranted prognostic
pessimism
434
. A study of a large number of COPD patients
with acute respiratory failure reported inhospital mortality
of 17-49%
316
. Further deaths were reported over the next
12 months, particularly among those patients who had poor
lung function before ventilation (FEV
1
< 30% predicted),
had a nonrespiratory comorbidity, or were housebound.
Patients who did not have a previously diagnosed comorbid
condition, had respiratory failure due to a potentially
reversible cause (such as an infection), or were relatively
mobile and not using long-term oxygen did surprisingly well
with ventilatory support.
Figure 5.4-9. Indications for Invasive
Mechanical Ventilation
Unable to tolerate NIV or NIV failure (for exclusion criteria,
see Figure 5.4-8)
Severe dyspnea with use of accessory muscles and
paradoxical abdominal motion.
Respiratory frequency > 35 breaths per minute
Life-threatening hypoxemia
Severe acidosis (pH < 7.25) and/or hypercapnia
(PaCO
2
> 8.0 kPa, 60 mm Hg)
Respiratory arrest
Somnolence, impaired mental status
Cardiovascular complications (hypotension, shock)
Other complications (metabolic abnormalities, sepsis,
pneumonia, pulmonary embolism, barotrauma, massive
pleural effusion)
Figure 5.4-10. Factors Determining the Decision to
Initiate Invasive Mechanical Ventilation
Cultural attitudes toward chronic disability
Expectations of therapy
Financial resources (especially the provision of ICU facilities)
Perceived likelihood of recovery
Customary medical practice
Wishes, if known, of the patient
Weaning or discontinuation from mechanical ventilation
can be particularly diffcult and hazardous in patients with
COPD. The most infuential determinant of mechanical
ventilatory dependency in these patients is the balance
between the respiratory load and the capacity of the
respiratory muscles to cope with this load
390
. By contrast,
pulmonary gas exchange by itself is not a major diffculty
in patients with COPD
391-393
. Weaning patients from the
ventilator can be a very diffcult and prolonged process
and the best method (pressure support or a T-piece
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 71
trial) remains a matter of debate
394-396
. In COPD patients
that failed extubation, noninvasive ventilation facilitates
weaning and prevents reintubation, but does not reduce
mortality
89,92
. A report that included COPD and nonCOPD
patients showed that noninvasive mechanical ventilation in
patients that failed extubation was not effective in averting
the need for reintubation and did not reduce mortality
397
.
Other measures. Further treatments that can be used
in the hospital include: fuid administration (accurate
monitoring of fuid balance is essential); nutrition
(supplementary when needed); deep venous thrombosis
prophylaxis (mechanical devices, heparins, etc.) in
immobilized, polycythemic, or dehydrated patients with
or without a history of thromboembolic disease; and
sputum clearance (by stimulating coughing and lowvolume
forced expirations as in home management). Manual
or mechanical chest percussion and postural drainage
may be benefcial in patients producing > 25 ml sputum
per day or with lobar atelectasis. There are no data
to support the routine use of inhaled N-acetylcysteine
or any other measures to increase mucus clearance.
Pulmonary rehabilitation by itself is not indicated in COPD
exacerbations but may be useful in patients after they
recover from the acute event.
Hospital Discharge and Follow-Up
Insuffcient clinical data exist to establish the optimal
duration of hospitalization in individual patients developing
an exacerbation of COPD
312,398,399
although units with more
respiratory consultants and better quality organized care
have lower mortality and reduced length of hospital stay
following admission for acute COPD exacerbation
420
.
Consensus and limited data support the discharge
criteria listed in Figure 5.4-11. Figure 5.4-12 provides
items to include in a followup assessment 4 to 6 weeks
after discharge from the hospital. Thereafter, followup
is the same as for stable COPD, including supervising
smoking cessation, monitoring the effectiveness of
each drug treatment, and monitoring changes in
spirometric parameters
355
. Prior hospital admission, oral
glucocorticosteroids, use of long-term oxygen therapy, poor
health related quality of life, and lack of routine physical
activity have been found to be predictive of readmission
435
.
Home visits by a community nurse may permit earlier
discharge of patients hospitalized with an exacerbation of
COPD, without increasing readmission rates
190,400-402
. Use
of a written action plan in COPD increased appropriate
therapeutic interventions for exacerbations of COPD,
an effect that does not decrease healthcare resource
utilization
462
(Evidence B).
In patients hypoxemic during a COPD exacerbation, arterial
blood gases and/or pulse oximetry should be evaluated
prior to hospital discharge and in the following 3 months.
If the patient remains hypoxemic, long-term supplemental
oxygen therapy may be required.
Opportunities for prevention of future exacerbations should
be reviewed before discharge, with particular attention
to smoking cessation, current vaccination (infuenza,
pneumococcal vaccines), knowledge of current therapy
including inhaler technique
32,403,404
, and how to recognize
symptoms of exacerbations.
Figure 5.4-11. Discharge Criteria for Patients
with Exacerbations of COPD
Inhaled
2
-agonist therapy is required no more frequently
than every 4 hrs.
Patient, if previously ambulatory, is able to walk across room.
Patient is able to eat and sleep without frequent
awakening by dyspnea.
Patient has been clinically stable for 12-24 hrs.
Arterial blood gases have been stable for 12-24 hrs.
Patient (or home caregiver) fully understands correct use
of medications.
Follow-up and home care arrangements have been
completed (e.g., visiting nurse, oxygen delivery, meal
provisions).
Patient, family, and physician are confident patient can
manage successfully at home.
Figure 5.4-12. Items to Assess at Follow-Up Visit
4-6 Weeks After Discharge from Hospital
for Exacerbations of COPD
Ability to cope in usual environment
Measurement of FEV
1
Reassessment of inhaler technique
Understanding of recommended treatment regimen
Need for long-term oxygen therapy and/or home nebulizer
(for patients with Stage IV: Very Severe COPD)
Pharmacotherapy known to reduce the number of
exacerbations and hospitalizations and delay the
time of frst/next hospitalization, such as long-acting
inhaled bronchodilators, inhaled glucocorticosteroids,
and combination inhalers, should be specifcally
considered. Early outpatient pulmonary rehabilitation after
hospitalization for a COPD exacerbation is safe and results
in clinically signifcant improvements in exercise capacity
and health status at 3 months
405
. Social problems should be
discussed and principal caregivers identifed if the patient
has a signifcant persisting disability.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
70 MANAGEMENT OF COPD
REFERENCES
1. Mannino DM, Ford ES, Redd SC. Obstructive and restrictive
lung disease and markers of infammation: data from the
Third National Health and Nutrition Examination. Am J Med
2003;114(9):75862.
2. Simon PM, Schwartzstein RM, Weiss JW, Fencl V,
Teghtsoonian M, Weinberger SE. Distinguishable types of
dyspnea in patients with shortness of breath. Am Rev Respir
Dis 1990;142(5):100914.
3. Elliott MW, Adams L, Cockcroft A, MacRae KD, Murphy K, Guz
A. The language of breathlessness. Use of verbal descriptors
by patients with cardiopulmonary disease. Am Rev Respir Dis
1991;144(4):82632.
4. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW,
Wedzicha JA. Usefulness of the Medical Research Council
(MRC) dyspnoea scale as a measure of disability in patients
with chronic obstructive pulmonary disease.
Thorax 1999;54(7):5816.

5. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better
predictor of 5year survival than airway obstruction in patients
with COPD. Chest 2002;121(5):143440.
6. Celli BR, Rassulo J, Make BJ. Dyssynchronous breathing
during arm but not leg exercise in patients with chronic airfow
obstruction. N Engl J Med 1986;314(23):148590.
7. Georgopoulas D, Anthonisen NR. Symptoms and signs of
COPD. In: Cherniack NS, ed. Chronic obstructive pulmonary
disease. Toronto: WB Saunders Co; 1991:35763.
8. Burrows B, Niden AH, Barclay WR, Kasik JE. Chronic
obstructive lung disease II. Relationships of clinical and
physiological fndings to the severity of aiways obstruction. Am
Rev Respir Dis 1965;91:66578.
9. Defnition and classifcation of chronic bronchitis for clinical and
epidemiological purposes. A report to the Medical Research
Council by their Committee on the Aetiology of Chronic
Bronchitis. Lancet 1965;1(7389):7759.
10. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum
infammatory markers in patients with chronic bronchitis. Am J
Respir Crit Care Med 1999;160(3):8938.
11. Stockley RA, OBrien C, Pye A, Hill SL. Relationship of sputum
color to nature and outpatient management of
acute exacerbations of COPD. Chest 2000;117(6):163845.
12. Schols AM, Soeters PB, Dingemans AM, Mostert R, Frantzen
PJ, Wouters EF. Prevalence and characteristics of nutritional
depletion in patients with stable COPD eligible for pulmonary
rehabilitation. Am Rev Respir Dis 1993;147(5):11516.
13. Schols AM, Slangen J, Volovics L, Wouters EF. Weight loss is
a reversible factor in the prognosis of chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 1998;157 (6 Pt
1):17917.
14. Calverley PMA. Neuropsychological defcits in chronic
obstructive pulmonary disease. [editorial]. Monaldi Arch Chest
Dis 1996;51(1):56.
15. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and
mortality in COPDrelated hospitalizations in the United States,
1979 to 2001. Chest 2005;128(4):200511.
16. Kesten S, Chapman KR. Physician perceptions and
management of COPD. Chest 1993;104(1):2548.
17. Loveridge B, West P, Kryger MH, Anthonisen NR. Alteration in
breathing pattern with progression of chronic obstructive
pulmonary disease. Am Rev Respir Dis 1986;134(5):9304.
18. Bianchi R, Gigliotti F, Romagnoli I, Lanini B, Castellani C,
Grazzini M, et al. Chest wall kinematics and breathlessness
during pursedlip breathing in patients with COPD.
Chest 2004;125(2):45965.
19. Badgett RG, Tanaka DJ, Hunt DK, Jelley MJ, Feinberg LE,
Steiner JF, et al. Can moderate chronic obstructive pulmonary
disease be diagnosed by historical and physical fndings
alone? Am J Med 1993;94(2):18896.
20. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F,
Casaburi R, et al. Interpretative strategies for lung function
tests. Eur Respir J 2005;26(5):94868.
21. Hardie JA, Buist AS, Vollmer WM, Ellingsen I, Bakke PS,
Morkve O. Risk of overdiagnosis of COPD in asymptomatic
elderly neversmokers. Eur Respir J 2002;20(5):111722.
22. Kelly CA, Gibson GJ. Relation between FEV1 and peak
expiratory fow in patients with chronic airfow obstruction.
Thorax 1988;43(4):3356.
23. Jackson H, Hubbard R. Detecting chronic obstructive
pulmonary disease using peak fow rate: cross sectional
survey. BMJ 2003;327(7416):6534.
24. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi
R, Coates A, et al. Standardisation of spirometry. Eur Respir J
2005;26(2):31938.
25. Ferguson GT, Enright PL, Buist AS, Higgins MW. Offce
spirometry for lung health assessment in adults: A consensus
statement from the National Lung Health Education Program.
Chest 2000;117(4):114661.
26. Wilt TJ, Niewoehner D, Kim C, Kane RL, Linabery A, Tacklind
J, et al. Use of spirometry for case fnding, diagnosis, and
management of chronic obstructive pulmonary disease
(COPD). Evid Rep Technol Assess (Summ) 2005(121):17.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 71
27. Kanner RE, Connett JE, Williams DE, Buist AS. Effects of
randomized assignment to a smoking cessation intervention
and changes in smoking habits on respiratory symptoms in
smokers with early chronic obstructive pulmonary disease: the
Lung Health Study. Am J Med 1999;106(4):4106.
28. Lofdahl CG, Postma DS, Laitinen LA, Ohlsson SV, Pauwels
RA, Pride NB. The European Respiratory Society study on
chronic obstructive pulmonary disease (EUROSCOP):
recruitment methods and strategies. Respir Med
1998;92(3):46772.
29. Peto R, Speizer FE, Cochrane AL, Moore F, Fletcher CM,
Tinker CM, et al. The relevance in adults of airfow obstruction,
but not of mucus hypersecretion, to mortality from chronic lung
disease. Results from 20 years of prospective observation. Am
Rev Respir Dis 1983;128(3):491500.
30. Jones PW. Health status measurement in chronic obstructive
pulmonary disease. Thorax 2001;56(11):8807.
31. Van Der Molen T, Willemse BW, Schokker S, Ten Hacken NH,
Postma DS, Juniper EF. Development, validity and
responsiveness of the Clinical COPD Questionnaire. Health
Qual Life Outcomes 2003;1(1):13.
32. PintoPlata VM, Cote C, Cabral H, Taylor J, Celli BR. The 6min
walk distance: change over time and value as a predictor of
survival in severe COPD. Eur Respir J 2004;23(1):2833.
33. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of
the factors related to mortality in chronic obstructive pulmonary
disease: role of exercise capacity and health status. Am J
Respir Crit Care Med 2003;167(4):5449.
34. Casanova C, Cote C, de Torres JP, AguirreJaime A, Marin JM,
PintoPlata V, et al. Inspiratorytototal lung capacity ratio predicts
mortality in patients with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 2005;171(6):5917.
35. Long-term domiciliary oxygen therapy in chronic hypoxic
cor pulmonale complicating chronic bronchitis and
emphysema. Report of the Medical Research Council Working
Party. Lancet 1981;1(8222):6816.
36. Schols AM, Broekhuizen R, WelingScheepers CA, Wouters EF.
Body composition and mortality in chronic obstructive
pulmonary disease. Am J Clin Nutr 2005;82(1):539.
37. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca
M, Mendez RA, et al. The bodymass index, airfow obstruction,
dyspnea, and exercise capacity index in chronic obstructive
pulmonary disease. N Engl J Med 2004;350(10):100512.
38. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson
JA. Prednisolone response in patients with chronic obstructive
pulmonary disease: results from the ISOLDE study. Thorax
2003;58(8):6548.
39. Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW.
Bronchodilator reversibility testing in chronic obstructive
pulmonary disease. Thorax 2003;58(8):65964.
40. ODonnell DE, Lam M, Webb KA. Spirometric correlates of
improvement in exercise performance after anticholinergic
therapy in chronic obstructive pulmonary disease. Am J Respir
Crit Care Med 1999;160(2):5429.
41. Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R,
Ries A, et al. A randomized trial comparing
lungvolumereduction surgery with medical therapy for severe
emphysema. N Engl J Med 2003;348(21):205973.
42. Roberts CM, Bugler JR, Melchor R, Hetzel MR, Spiro SG.
Value of pulse oximetry in screening for long-term oxygen
therapy requirement. Eur Respir J 1993;6(4):55962.
43. Calverley PMA, Leggett RJ, McElderry L, Flenley DC. Cigarette
smoking and secondary polycythemia in hypoxic cor
pulmonale. Am Rev Respir Dis 1982;125(5):50710.
44. John M, Lange A, Hoernig S, Witt C, Anker SD. Prevalence of
anemia in chronic obstructive pulmonary disease: Comparison
to other chronic diseases. Int J Cardiol 2005.
45. Chambellan A, Chailleux E, Similowski T. Prognostic value of
the hematocrit in patients with severe COPD receiving long-
term oxygen therapy. Chest 2005;128(3):12018.
46. Dekhuijzen PN, Folgering HT, van Herwaarden CL. Targetfow
inspiratory muscle training during pulmonary rehabilitation in
patients with COPD. Chest 1991;99(1):12833.
47. Heijdra YF, Dekhuijzen PN, van Herwaarden CL, Folgering
HT. Nocturnal saturation improves by targetfow inspiratory
muscle training in patients with COPD. Am J Respir Crit Care
Med 1996;153(1):2605.
48. Jaakkola MS, Jaakkola JJ. Impact of smokefree workplace
legislation on exposures and health: possibilities for prevention.
Eur Respir J 2006 Aug;28(2):397408.
49. Jindal SK, Aggarwal AN, Chaudhry K, Chhabra SK, DSouza
GA, Gupta D, et al. A multicentric study on epidemiology of
chronic obstructive pulmonary disease and its relationship with
tobacco smoking and environmental tobacco smoke exposure.
Indian J Chest Dis Allied Sci 2006;48(1):239.
50. Eisner MD, Balmes J, Katz BP, Trupin L, Yelin E, Blanc P.
Lifetime environmental tobacco smoke exposure and the
risk of chronic obstructive pulmonary disease. Environ Health
Perspect 2005;4:715.
51. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during
pregnancy. Effects on lung function during the frst 18 months
of life. Am J Respir Crit Care Med 1995;152:97783.

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
72 MANAGEMENT OF COPD
52. YuFen L, Gilliand FD, Berhane K, McConnell R, Gauderman
WJ, Rappaport EB, et al. Effects of in utero and environmental
tobacco smoke on lung function in boys and girls with or
without asthma. Am J Respir Crit Care Med 2000;162:2097104.

53. The Health Consequences of Involuntary Exposure to Tobacco
Smoke: A Report of the Surgeon General, Department of
Health and Human Services. Washington, DC, US; 2006.
54. Colley JR, Holland WW, Corkhill RT. Infuence of passive
smoking and parental phlegm on pneumonia and bronchitis in
early childhood. Lancet 1974;2(7888):10314.
55. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC,
Buist AS, et al. Effects of smoking intervention and the use of
an inhaled anticholinergic bronchodilator on the rate of decline
of FEV
1
. The Lung Health Study. JAMA 1994;272(19):1497505.
56. Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner
RE, Connett JE, et al. The effects of smoking cessation
intervention on 14.5 year mortality: a randomized clinical trial.
Ann Intern Med 2005;142(4):2339.
57. Tengs TO, Adams ME, Pliskin JS, Safran DG, Siegel JE,
Weinstein MC, et al. Fivehundred lifesaving interventions and
their costeffectiveness. Risk Anal 1995;15(3):36990.
58. Parrott S, Godfrey C, Raw M, West R, McNeill A. Guidance
for commissioners on the cost effectiveness of smoking
cessation interventions. Health Educational
Authority. Thorax 1998;53 Suppl 5 Pt 2:S138.
59. Fiore MC, Bailey WC, Cohen SJ. Smoking cessation:
information for specialists. Rockville, MD: US Department
of Health and Human Services, Public Health Service, Agency
for Health Care Policy and Research and Centers for Disease
Control and Prevention; 1996.
60. The tobacco use and dependence clinical practice guideline
panel, staff, and consortium representatives. A clinical
practice guideline for treating tobacco use and dependence.
JAMA 2000;28:324454.
61. American Medical Association. Guidelines for the diagnosis
and treatment of nicotine dependence: how to help patients
stop smoking. Washington DC: American Medical Association;
1994.
62. Glynn TJ, Manley MW. How to help your patients stop smoking.
A National Cancer Institute manual for physicians. Bethesda,
MD: US Department of Health and Human Services, Public
Health Service, National Institutes of Health, National Cancer
Institute; 1990.
63. Glynn TJ, Manley MW, Pechacek TF. Physicianinitiated
smoking cessation program: the National Cancer Institute trials.
Prog Clin Biol Res 1990;339:1125.
64. Baillie AJ, Mattick RP, Hall W, Webster P. Metaanalytic review
of the effcacy of smoking cessation interventions. Drug and
Alcohol Review 1994;13:15770.
65. Wilson DH, Wakefeld MA, Steven ID, Rohrsheim RA,
Esterman AJ, Graham NM. Sick of Smoking: evaluation of a
targeted minimal smoking cessation intervention in general
practice. Med J Aust 1990;152(10):51821.
66. Britton J, Knox A. Helping people to stop smoking: the new
smoking cessation guidelines. Thorax 1999;54(1):12.
67. Katz DA, Muehlenbruch DR, Brown RL, Fiore MC, Baker
TB. Effectiveness of implementing the agency for healthcare
research and quality smoking cessation clinical practice
guideline: a randomized, controlled trial. J Natl Cancer Inst
2004;96(8):594603.
68. Kottke TE, Battista RN, DeFriese GH, Brekke ML. Attributes of
successful smoking cessation interventions in medical
practice. A metaanalysis of 39 controlled trials. JAMA
1988;259(19):28839.
69. Lancaster T, Stead L, Silagy C, Sowden A. Effectiveness
of interventions to help people stop smoking: fndings from the
Cochrane Library. BMJ 2000;321(7257):3558.
70. Schwartz JL. Review and evaluation of smoking cessation
methods: United States and Canada, 19781985. Bethesda,
MD: National Institutes of Health; 1987.
71. Fiore MC, Smith SS, Jorenby DE, Baker TB. The effectiveness
of the nicotine patch for smoking cessation. A metaanalysis.
JAMA 1994;271(24):19407.
72. Sachs DP, Benowitz NL. Individualizing medical treatment for
tobacco dependence. Eur Respir J 1996;9(4):62931.
73. Tashkin D, Kanner R, Bailey W, Buist S, Anderson P, Nides
M, et al. Smoking cessation in patients with chronic obstructive
pulmonary disease: a doubleblind, placebocontrolled,
randomised trial. Lancet 2001;357(9268):15715.
74. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston
JA, Hughes AR, et al. A controlled trial of sustainedrelease
bupropion, a nicotine patch, or both for smoking cessation. N
Engl J Med 1999;340(9):68591.
75. Jorenby DE, Hays JT, Rigotti NA, Axoulay S, Watsky EJ,
Williams KE, et al. Effcacy of varenicline, an alpha4beta2
nicotinic acetylcholine receptor partial agonist, vs placebo or
sustainedrelease bupropion for smoking cessation: a r
andomized controlled trial. JAMA 2006;296(1):5663.
76. Nides M, Oncken C, Gonzales D, Rennard S, Watsky EJ,
Anziano R, et al. Smoking cessation with varenicline, a
selective alpha4beta2 nicotinic receptor partial agonist: results
from a 7 week, randomized, placeboand bupropioncontrolled
trial with 1year followup. Arch Intern Med 2006;166(15):15618.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 73
77. Tonstad S, Tonnesen P, Hajek P, Williams KE, Billing CB,
Reeves KR, et al. Effect of maintenance therapy with
varenicline on smoking cessation: a randomized controlled trial.
JAMA 2006;296(1):6471.
78. Celli BR, Halbert RJ, Nordyke RJ, Schan B. Airway obstruction
in never smokers: results from the Third National Health and
Nutrition Examination Survey. Am J Med 2005;118:136472.
79. Kunzli N, Kaiser R, Medina M, Studnicka M, Chanel O,
Filliger P, et al. Publichealth impact of outdoor and traffcrelated
air pollution: a European assessment. Lancet
2000;356:795801.
80. AckermannLiebrich U, Leuenberger P, Schwartz J, Schindler C,
Monn C, Bolognini G, et al. Lung function and long-term
exposure to air pollutants in Switzerland. Study on Air Pollution
and Lung Diseases in Adults (SAPALDIA) Team. Am J Respir
Crit Care Med 1997;155(1):1229.
81. OroczoLevi M, Garcia Aymerich J, Villar J, RamirezSarmiento
A, Anto JM, Gea J. Wood smoke exposure and risk of chronic
obstructive pulmonary disease. Eur Respir J 2006;27:5426.
82. Chapman RS, Xingzhou H, Blair AE, Lan Q. Improvement
in household stoves and risk of chronic obstructive pulmonary
disease in Xuanwei, China: retrospective cohort study. Br Med
J 2005;331:1050.
83. Ghambarian MH, Feenstra TL, Zwanikken P, Kalinina AM. Can
prevention be improved? Proposal for an integrated
intervention strategy. Preventive Medicine 2004;39:33743.
84. Nichter M. Introducing tobacco cessation in developing
countries: an overview of Quit Tobacco International. Tobacco
Control 2006;15(Supplement 1):127.
85. Reis AL. Response to bronchodilators. In: Clausen J, ed.
Pulmonary function testing: guidelines and controversies. New
York: Academic Press; 1982.
86. Janelli LM, Scherer YK, Schmieder LE. Can a pulmonary
health teaching program alter patients ability to cope with
COPD? Rehabil Nurs 1991;16(4):199202.
87. Ashikaga T, Vacek PM, Lewis SO. Evaluation of a
communitybased education program for individuals with
chronic obstructive pulmonary disease. J Rehabil
1980;46(2):237.
88. Toshima MT, Kaplan RM, Ries AL. Experimental evaluation of
rehabilitation in chronic obstructive pulmonary disease:
short-term effects on exercise endurance and health status.
Health Psychol 1990;9(3):23752.
89. Celli BR. Pulmonary rehabilitation in patients with COPD. Am J
Respir Crit Care Med 1995;152(3):8614.
90. Stewart MA. Effective physicianpatient communication and
health outcomes: a review. CMAJ 1995;152(9):142333.
91. Clark NM, Nothwehr F, Gong M, Evans D, Maiman LA, Hurwitz
ME, et al. Physicianpatient partnership in managing chronic
illness. Acad Med 1995;70(11):9579.
92. Heffner JE, Fahy B, Hilling L, Barbieri C. Outcomes of advance
directive education of pulmonary rehabilitation patients. Am J
Respir Crit Care Med 1997;155(3):10559.
93. Adams SG, Smith PK, Allan PF, Anzueto A, Pugh JA, Cornell
JE. Systematic review of the chronic care model in chronic
obstructive pulmonary disease prevention and management.
Arch Intern Med 2007 Mar 26;167(6):55161.
94. Bourbeau J, Julien M, Maltais F, Rouleau M, Beaupre A, Begin
R, et al. Reduction of hospital utilization in patients with chronic
obstructive pulmonary disease: a disease-specifc
self-management intervention. Arch Intern Med
2003;163(5):58591.

95. Tougaard L, Krone T, Sorknaes A, Ellegaard H. Economic
benefts of teaching patients with chronic obstructive
pulmonary disease about their illness. The PASTMA Group.
Lancet 1992;339(8808):151720.
96. Gallefoss F. The effects of patient education in COPD in a
1 year followup randomised, controlled trial. Patient Educ
Couns 2004;52(3):25966.
97. Monninkhof E, van der Valk P, van der Palen J, van
Herwaarden C, Zielhuis G. Effects of a comprehensive
self-management programme in patients with chronic
obstructive pulmonary disease. Eur Respir J 2003;22(5):81520.
98. Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP,
Postma DS, Pride NB, et al. Long-term treatment with inhaled
budesonide in persons with mild chronic obstructive pulmonary
disease who continue smoking. European Respiratory Society
Study on Chronic Obstructive Pulmonary Disease. N Engl J
Med 1999;340(25):194853.
99. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K.
Long-term effect of inhaled budesonide in mild and
moderate chronic obstructive pulmonary disease: a
randomised controlled trial. Lancet 1999;353(9167):181923.
100. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson
JA, Maslen TK. Randomised, double blind, placebo controlled
study of futicasone propionate in patients with moderate to
severe chronic obstructive pulmonary disease: the ISOLDE
trial. BMJ 2000;320(7245):1297303.
101. Vestbo J, Pauwels R, Anderson JA, Jones P, Calverley P. Early
onset of effect of salmeterol and futicasone propionate in
chronic obstructive pulmonary disease. Thorax
2005;60(4):3014.
102. Calverley PMA. Symptomatic bronchodilator treatment. In:
Calverley PMA, Pride NB, eds. Chronic obstructive pulmonary
disease. London: Chapman and Hall; 1995:41945.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
74 MANAGEMENT OF COPD
103. ODonnell DE, Sciurba F, Celli B, Mahler DA, Webb KA,
Kalberg CJ, Knobil K. Effect of futicasone propionate/
salmeterol on lung hyperinfation and exercise endurance
in COPD. Chest 2006 Sep;130(3):64756.
104. Berger R, Smith D. Effect of inhaled metaproterenol on
exercise performance in patients with stable fxed airway
obstruction. Am Rev Respir Dis 1988;138(3):6249.
105. Hay JG, Stone P, Carter J, Church S, EyreBrook A, Pearson
MG, et al. Bronchodilator reversibility, exercise performance
and breathlessness in stable chronic obstructive pulmonary
disease. Eur Respir J 1992;5(6):65964.
106. Vathenen AS, Britton JR, Ebden P, Cookson JB, Wharrad HJ,
Tattersfeld AE. Highdose inhaled albuterol in severe chronic
airfow limitation. Am Rev Respir Dis 1988;138(4):8505.
107. Gross NJ, Petty TL, Friedman M, Skorodin MS, Silvers
GW, Donohue JF. Dose response to ipratropium as a nebulized
solution in patients with chronic obstructive pulmonary disease.
A threecenter study. Am Rev Respir Dis 1989;139(5):118891.
108. Chrystyn H, Mulley BA, Peake MD. Dose response relation to
oral theophylline in severe chronic obstructive airways disease.
BMJ 1988;297(6662):150610.
109. Higgins BG, Powell RM, Cooper S, Tattersfeld AE. Effect of
salbutamol and ipratropium bromide on airway calibre and
bronchial reactivity in asthma and chronic bronchitis. Eur
Respir J 1991;4(4):41520.
110. Ericsson CH, Svartengren K, Svartengren M, Mossberg B,
Philipson K, Blomquist M, et al. Repeatability of airway
deposition and tracheobronchial clearance rate over three days
in chronic bronchitis. Eur Respir J 1995;8(11):188693.
111. Kim CS, Kang TC. Comparative measurement of lung
deposition of inhaled fne particles in normal subjects and
patients with obstructive airway disease. Am J Respir Crit Care
Med 1997;155(3):899905.
112. Reference deleted..
113. ODriscoll BR, Kay EA, Taylor RJ, Weatherby H, Chetty MC,
Bernstein A. A long-term prospective assessment of home
nebulizer treatment. Respir Med 1992;86(4):31725.
114. Jenkins SC, Heaton RW, Fulton TJ, Moxham J. Comparison
of domiciliary nebulized salbutamol and salbutamol from a
metereddose inhaler in stable chronic airfow limitation. Chest
1987;91(6
115. Ikeda A, Nishimura K, Koyama H, Izumi T. Bronchodilating
effects of combined therapy with clinical dosages of ipratropium
bromide and salbutamol for stable COPD: comparison with
ipratropium bromide alone. Chest 1995;107(2):4015.
116. Guyatt GH, Townsend M, Pugsley SO, Keller JL, Short HD,
Taylor DW, et al. Bronchodilators in chronic airfow limitation.
Effects on airway function, exercise capacity, and quality
of life. Am Rev Respir Dis 1987;135(5):106974.
117. Man WD, Mustfa N, Nikoletou D, Kaul S, Hart N, Rafferty
GF, et al. Effect of salmeterol on respiratory muscle activity
during exercise in poorly reversible COPD. Thorax
2004;59(6):4716.
118. ODonnell DE, Fluge T, Gerken F, Hamilton A, Webb K,
Aguilaniu B, et al. Effects of tiotropium on lung hyperinfation,
dyspnoea and exercise tolerance in COPD. Eur Respir J
2004;23(6):83240.
119. Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten
S, Korducki L, et al. Improved health outcomes in patients
with COPD during 1 yrs treatment with tiotropium. Eur Respir J
2002;19(2):20916.
120. Mahler DA, Donohue JF, Barbee RA, Goldman MD, Gross
NJ, Wisniewski ME, et al. Effcacy of salmeterol xinafoate in the
treatment of COPD. Chest 1999;115(4):95765.
121. Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM,
Thomson MH, et al. Inhaled formoterol dry powder versus
ipratropium bromide in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2001;164(5):77884.
122. Oostenbrink JB, Ruttenvan Molken MP, Al MJ, Van Noord
JA, Vincken W. Oneyear costeffectiveness of tiotropium versus
ipratropium to treat chronic obstructive pulmonary disease. Eur
Respir J 2004;23(2):2419.
123. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA,
Jr., Korducki L, et al. Prevention of exacerbations of chronic
obstructive pulmonary disease with tiotropium, a oncedaily
inhaled anticholinergic bronchodilator: a randomized trial. Ann
Intern Med 2005;143(5):31726.
124. Casaburi R, Kukafka D, Cooper CB, Witek TJ, Jr., Kesten
S. Improvement in exercise tolerance with the combination
of tiotropium and pulmonary rehabilitation in patients with
COPD. Chest 2005;127(3):80917.
125. Shim CS, Williams MH, Jr. Bronchodilator response to
oral aminophylline and terbutaline versus aerosol albuterol in
patients with chronic obstructive pulmonary disease. Am J Med
1983;75(4):697701.
126. COMBIVENT Inhalation Aerosol Study Group. In chronic
obstructive pulmonary disease, a combination of ipratropium
and albuterol is more effective than either agent alone. An
85day multicenter trial. Chest 1994;105(5):14119.
127. van Schayck CP, Folgering H, Harbers H, Maas KL, van Weel
C. Effects of allergy and age on responses to salbutamol and
ipratropium bromide in moderate asthma and chronic
bronchitis. Thorax 1991;46(5):3559.
128. Datta D, Vitale A, Lahiri B, ZuWallack R. An evaluation of
nebulized levalbuterol in stable COPD. Chest
2003;124(3):8449.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 75
129. Ulrik CS. Effcacy of inhaled salmeterol in the management of
smokers with chronic obstructive pulmonary disease: a single
centre randomised, double blind, placebo controlled, crossover
study. Thorax 1995;50(7):7504.
130. Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N,
Crawford C. An evaluation of salmeterol in the treatment
of chronic obstructive pulmonary disease (COPD) [published
erratum appears in Eur Respir J 1997 Jul;10(7):1696]. Eur
Respir J 1997;10(4):81521.
131. Cazzola M, Matera MG, Santangelo G, Vinciguerra A, Rossi F,
DAmato G. Salmeterol and formoterol in partially reversible
severe chronic obstructive pulmonary disease: a doseresponse
study. Respir Med 1995;89(5):35762.
132. Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis
J, et al. Comparison of the effcacy, tolerability, and safety of
formoterol dry powder and oral, slowrelease theophylline in the
treatment of COPD. Chest 2002;121(4):105869.

133. Lipworth BJ, McDevitt DG, Struthers AD. Hypokalemic and
ECG sequelae of combined betaagonist/diuretic
therapy. Protection by conventional doses of spironolactone but
not triamterene. Chest 1990;98(4):8115.
134. Uren NG, Davies SW, Jordan SL, Lipkin DP. Inhaled
bronchodilators increase maximum oxygen consumption
in chronic left ventricular failure. Eur Heart J 1993;14(6):74450.
135. Khoukaz G, Gross NJ. Effects of salmeterol on arterial blood
gases in patients with stable chronic obstructive pulmonary
disease. Comparison with albuterol and ipratropium. Am J
Respir Crit Care Med 1999;160(3):102830.
136. Barnes PJ. Bronchodilators: basic pharmacology. In: Calverley
PMA, Pride NB, eds. Chronic obstructive pulmonary disease.
London: Chapman and Hall; 1995:391417.
137. Disse B, Speck GA, Rominger KL, Witek TJ, Jr., Hammer R.
Tiotropium (Spiriva): mechanistical considerations and clinical
profle in obstructive lung disease. Life Sci 1999;64(67):45764.
138. van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen
PJ. A randomised controlled comparison of
tiotropium nd ipratropium in the treatment of chronic
obstructive pulmonary disease. The Dutch Tiotropium Study
Group. Thorax 2000;55(4):28994.
139. Casaburi R, Mahler DA, Jones PW, Wanner A, San PG,
ZuWallack RL, et al. A long-term evaluation of oncedaily
inhaled tiotropium in chronic obstructive pulmonary disease.
Eur Respir J 2002;19(2):21724.
140. Spencer S, Calverley PM, Burge PS, Jones PW. Impact of
preventing exacerbations on deterioration of health status in
COPD. Eur Respir J 2004;23(5):698702.
141. Anthonisen NR, Connett JE, Enright PL, Manfreda J.
Hospitalizations and mortality in the Lung Health Study. Am J
Respir Crit Care Med 2002;166(3):3339.
142. Aubier M. Pharmacotherapy of respiratory muscles. Clin Chest
Med 1988;9(2):31124.
143. Moxham J. Aminophylline and the respiratory muscles: an
alternative view. Clin Chest Med 1988;9(2):32536.
144. Murciano D, Auclair MH, Pariente R, Aubier M. A randomized,
controlled trial of theophylline in patients with severe chronic
obstructive pulmonary disease. N Engl J Med
1989;320(23):15215.
145. McKay SE, Howie CA, Thomson AH, Whiting B, Addis GJ.
Value of theophylline treatment in patients handicapped by
chronic obstructive lung disease. Thorax 1993;48(3):22732.
146. Taylor DR, Buick B, Kinney C, Lowry RC, McDevitt DG. The
effcacy of orally administered theophylline, inhaled salbutamol,
and a combination of the two as chronic therapy in the
management of chronic bronchitis with reversible airfow
obstruction. Am Rev Respir Dis 1985;131(5):74751.
147. The COMBIVENT Inhalation Solution Study Group. Routine
nebulized ipratropium and albuterol together are better than
either alone in COPD. Chest 1997;112(6):151421.
148. Gross N, Tashkin D, Miller R, Oren J, Coleman W, Linberg S.
Inhalation by nebulization of albuterolipratropium combination
(Dey combination) is superior to either agent alone in
the treatment of chronic obstructive pulmonary disease.
Dey Combination Solution Study Group. Respiration
1998;65(5):35462.
149. van Noord JA, de Munck DR, Bantje TA, Hop WC, Akveld ML,
Bommer AM. Long-term treatment of chronic obstructive
pulmonary disease with salmeterol and the additive effect of
ipratropium. Eur Respir J 2000;15(5):87885.
150. ZuWallack RL, Mahler DA, Reilly D, Church N, Emmett A,
Rickard K, et al. Salmeterol plus theophylline combination
therapy in the treatment of COPD. Chest 2001;119(6):166170.
151. Bellia V, Foresi A, Bianco S, Grassi V, Olivieri D, Bensi G,
et al. Effcacy and safety of oxitropium bromide,
theophylline and their combination in COPD patients: a
doubleblind, randomized, multicentre study (BREATH Trial).
Respir Med 2002;96(11):8819.
152. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers
LW. A measure of quality of life for clinical trials in chronic lung
disease. Thorax 1987;42(10):7738.
153. Callahan CM, Dittus RS, Katz BP. Oral corticosteroid therapy
for patients with stable chronic obstructive pulmonary disease.
A metaanalysis. Ann Intern Med 1991;114(3):21623.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
76 MANAGEMENT OF COPD
154. Postma DS, Peters I, Steenhuis EJ, Sluiter HJ. Moderately
severe chronic airfow obstruction. Can corticosteroids slow
down obstruction? Eur Respir J 1988;1(1):226.
155. Postma DS, Steenhuis EJ, van der Weele LT, Sluiter HJ.
Severe chronic airfow obstruction: can corticosteroids slow
down progression? Eur J Respir Dis 1985;67(1):5664.
156. Decramer M, de Bock V, Dom R. Functional and histologic
picture of steroidinduced myopathy in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 1996;153 (6 Pt
1):195864.
157. Decramer M, Lacquet LM, Fagard R, Rogiers P.
Corticosteroids contribute to muscle weakness in chronic
airfow obstruction. Am J Respir Crit Care Med
1994;150(1):116.
158. Decramer M, Stas KJ. Corticosteroidinduced myopathy
involving respiratory muscles in patients with chronic
obstructive pulmonary disease or asthma. Am Rev Respir Dis
1992;146(3):8002.
159. Renkema TE, Schouten JP, Koeter GH, Postma DS. Effects
of long-term treatment with corticosteroids in COPD. Chest
1996;109(5):115662.
160. Rice KL, Rubins JB, Lebahn F, Parenti CM, Duane PG,
Kuskowski M, et al. Withdrawal of chronic systemic
corticosteroids in patients with COPD: a randomized trial. Am J
Respir Crit Care Med 2000;162(1):1748.
161. The Lung Health Study Research Group. Effect of inhaled
triamcinolone on the decline in pulmonary function in chronic
obstructive pulmonary disease: Lung Health Study II. N Engl J
Med 2000;343:19029.
162. Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer
T, et al. Effectiveness of futicasone propionate and salmeterol
combination delivered via the Diskus device in the treatment of
chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 2002;166(8):108491.
163. Jones PW, Willits LR, Burge PS, Calverley PM. Disease
severity and the effect of futicasone propionate on chronic
obstructive pulmonary disease exacerbations. Eur Respir J
2003;21(1):6873.
164. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik
A, et al. Combined salmeterol and futicasone in the treatment
of chronic obstructive pulmonary disease: a randomised
controlled trial. Lancet 2003;361(9356):44956.
165. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R,
Nahabedian S, et al. Effcacy and safety of budesonide/
formoterol in the management of chronic obstructive pulmonary
disease. Eur Respir J 2003;21(1):7481.
166. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van
Herwaarden C. Effect of discontinuation of inhaled
corticosteroids in patients with chronic obstructive pulmonary
disease: the COPE study. Am J Respir Crit Care
Med 2002;166(10):135863.
167. Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge
PS, et al. Inhaled corticosteroids and mortality in chronic
obstructive pulmonary disease. Thorax 2005;60(12):9927.
168. Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis
S, et al. The effcacy and safety of futicasone propionate (250
microg)/salmeterol (50 microg) combined in the Diskus inhaler
for the treatment of COPD. Chest 2003;124(3):83443.
169. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson
S, Olsson H. Maintenance therapy with budesonide and
formoterol in chronic obstructive pulmonary disease. Eur Respir
J 2003;22(6):9129.
170. Johnell O, Pauwels R, Lofdahl CG, Laitinen LA, Postma
DS, Pride NB, et al. Bone mineral density in patients with
chronic obstructive pulmonary disease treated with budesonide
Turbuhaler. Eur Respir J 2002;19(6):105863.
171. Workshop Report: Global Strategy for Diagnosis, Management
and Prevention of COPD Updated 2005. Available from http://
wwwgoldcopdorg 2005.
172. Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U,
Dejsomritrutai W, Charoenratanakul S. Acute
respiratory illness in patients with COPD and the effectiveness
of infuenza vaccination: a randomized controlled study. Chest
2004;125(6):201120.
173. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The
effcacy and cost effectiveness of vaccination against infuenza
among elderly persons living in the community. N Engl J Med
1994;331(12):77884.
174. Wongsurakiat P, Lertakyamanee J, Maranetra KN,
Jongriratanakul S, Sangkaew S. Economic evaluation of
infuenza vaccination in Thai chronic obstructive pulmonary
disease patients. J Med Assoc Thai 2003;86(6):497508.
175. Edwards KM, Dupont WD, Westrich MK, Plummer WD, Jr.,
Palmer PS, Wright PF. A randomized controlled trial of
coldadapted and inactivated vaccines for the prevention of
infuenza A disease. J Infect Dis 1994;169(1):6876.
176. Hak E, van Essen GA, Buskens E, Stalman W, de Melker
RA. Is immunising all patients with chronic lung disease in
the community against infuenza cost effective? Evidence from
a general practice based clinical prospective cohort study in
Utrecht, The Netherlands. J Epidemiol Community Health
1998;52(2):1205.
177. Woodhead M, Blasi F, Ewig S, Huchon G, Ieven M, Ortqvist A,
et al. Guidelines for the management of adult lower respiratory
tract infections. Eur Respir J 2005;26(6):113880.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 77
178. Jackson LA, Neuzil KM, Yu O, Benson P, Barlow WE, Adams
AL, et al. Effectiveness of pneumococcal polysaccharide
vaccine in older adults. N Engl J Med 2003;348(18):174755.
179. Prevention of Pneumococcal Disease: Recommendations
of the Advisory Committee on Immunization Practices
(ACIP). MMWR 1997;46 (RR08):124 http://www.cdc.gov/
mmwr/preview/mmwrhtml/00047135.htm.
180. Alfageme I, Vazquez R, Reyes N, Munoz J, Fernandez
A, Hernandez M, et al. Clinical effciacy of antipneumococcal
vaccination in patients with COPD. Thorax 2006;61:18995.
181. Francis RS, May JR, Spicer CC. Chemotherapy of bronchitis:
infuence of penicillin and tetracylcline administered daily, or
intermittently for exacerbations. BMJ 1961;2:97985.
182. Francis RS, Spicer CC. Chemotherapy in chronic bronchitis:
infuence of daily penicillin and teracycline on exacerbations
and their cost. A report to the research committee of the British
Tuberculosis Assoication by their Chronic Bronchitis
subcommittee. BMJ 1960;1:297303.
183. Fletcher CM, Ball JD, Carstairs LW, Couch AHC, Crofton JM,
Edge JR, et al. Value of chemoprophylaxis and chemotherapy
in early chronic bronchitis. A report to the Medical Research
Council by their Working Party on trials of chemotherpay in
early chronic bronchitis. BMJ 1966;1(5499)(5499):131722.
184. Johnston RN, McNeill RS, Smith DH, Dempster MB, Nairn
JR, Purvis MS, et al. Fiveyear winter chemoprophylaxis for
chronic bronchitis. Br Med J 1969;4(678):2659.
185. Isada CM, Stoller JK. Chronic bronchitis: the role of antibiotics.
In: Niederman MS, Sarosi GA, Glassroth J, eds. Respiratory
infections: a scientifc basis for management. London: WB
Saunders; 1994:62133.
186. Siafakas NM, Bouros D. Management of acute exacerbation
of chronic obstructive pulmonary disease. In: Postma DS,
Siafakas NM, eds. Management of chronic obstructive
pulmonary disease. Sheffeld: ERS Monograph; 1998:26477.
187. Allegra L, Cordaro CI, Grassi C. Prevention of acute
exacerbations of chronic obstructive bronchitis with
carbocysteine lysine salt monohydrate: a multicenter,
doubleblind, placebocontrolled trial. Respiration
1996;63(3):17480.
188. Guyatt GH, Townsend M, Kazim F, Newhouse MT. A controlled
trial of ambroxol in chronic bronchitis. Chest 1987;92(4):61820.
189. Petty TL. The National Mucolytic Study. Results of a
randomized, doubleblind, placebocontrolled study of
iodinated glycerol in chronic obstructive bronchitis. Chest
1990;97(1):7583.

190. Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J,
Howard P, et al. Optimal assessment and management
of chronic obstructive pulmonary disease (COPD).
The European Respiratory Society Task Force. Eur Respir J
1995;8(8):1398420.
191. American Thoracic Society. Standards for the diagnosis and
care of patients with chronic obstructive pulmonary disease
(COPD) and asthma. Adopted by the ATS Board of Directors,
November 1986. Am Rev Respir Dis 1987;136(1):22544.
192. Hansen NC, Skriver A, BrorsenRiis L, Balslov S, Evald T,
Maltbaek N, et al. Orally administered Nacetylcysteine may
improve general wellbeing in patients with mild chronic
bronchitis. Respir Med 1994;88(7):5315.
193. British Thoracic Society Research Committee. Oral
Nacetylcysteine and exacerbation rates in patients
with chronic bronchitis and severe airways obstruction. Thorax
1985;40(11):8325.
194. Boman G, Backer U, Larsson S, Melander B, Wahlander L.
Oral acetylcysteine reduces exacerbation rate in chronic
bronchitis: report of a trial organized by the Swedish Society for
Pulmonary Diseases. Eur J Respir Dis 1983;64(6):40515.
195. Rasmussen JB, Glennow C. Reduction in days of illness
after long-term treatment with Nacetylcysteine
controlledrelease tablets in patients with chronic bronchitis. Eur
Respir J 1988;1(4):3515.
196. Decramer M, Ruttenvan Molken M, Dekhuijzen PN, Troosters
T, van Herwaarden C, Pellegrino R, et al. Effects of
Nacetylcysteine on outcomes in chronic obstructive
pulmonary disease (Bronchitis Randomized on NAC CostUtility
Study, BRONCUS): a randomised placebocontrolled trial.
Lancet 2005;365(9470):155260.
197. Collet JP, Shapiro P, Ernst P, Renzi T, Ducruet T, Robinson
A. Effects of an immunostimulating agent on acute
exacerbations and hospitalizations in patients with chronic
obstructive pulmonary disease. The PARIIS Study Steering
Committee and Research Group. Prevention of Acute
Respiratory Infection by an Immunostimulant. Am J Respir Crit
Care Med 1997;156(6):171924.
198. Li J, Zheng JP, Yuan JP, Zeng GQ, Zhong NS, Lin CY.
Protective effect of a bacterial extract against acute
exacerbation in patients with chronic bronchitis accompanied
by chronic obstructive pulmonary disease. Chin Med J (Engl)
2004;117(6):82834.
199. Anthonisen NR. OM8BV for COPD. Am J Respir Crit Care Med
1997;156(6):17134.
200. Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM, Hoffstein
V, et al. Managing cough as a defense mechanism and as a
symptom. A consensus panel report of the American College
of Chest Physicians. Chest 1998;114(2 Suppl Managing):
133S81S.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
78 MANAGEMENT OF COPD
201. Barbera JA, Roger N, Roca J, Rovira I, Higenbottam TW,
RodriguezRoisin R. Worsening of pulmonary gas exchange
with nitric oxide inhalation in chronic obstructive pulmonary
disease. Lancet 1996;347(8999):43640.
202. Jones AT, Evans TW. NO: COPD and beyond. Thorax 1997;52
Suppl 3:S1621.
203. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE.
A systematic review of the use of opioids in the management of
dyspnoea. Thorax 2002;57(11):93944.
204. Eiser N, Denman WT, West C, Luce P. Oral diamorphine: lack
of effect on dyspnoea and exercise tolerance in the pink
puffer syndrome. Eur Respir J 1991;4(8):92631.
205. Young IH, Daviskas E, Keena VA. Effect of low dose nebulised
morphine on exercise endurance in patients with chronic lung
disease. Thorax 1989;44(5):38790.
206. Woodcock AA, Gross ER, Gellert A, Shah S, Johnson M,
Geddes DM. Effects of dihydrocodeine, alcohol, and caffeine
on breathlessness and exercise tolerance in patients with
chronic obstructive lung disease and normal blood gases.
N Engl J Med 1981;305(27):16116.
207. Rice KL, Kronenberg RS, Hedemark LL, Niewoehner DE.
Effects of chronic administration of codeine and promethazine
on breathlessness and exercise tolerance in patients with
chronic airfow obstruction. Br J Dis Chest 1987;81(3):28792.
208. Poole PJ, Veale AG, Black PN. The effect of sustainedrelease
morphine on breathlessness and quality of life in severe
chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 1998;157(6 Pt 1):187780.
209. Nici L, Donner C, Wouters E, ZuWallack R, Ambrosino N,
Bourbeau J, et al. American Thoracic Society/European
Respiratory Society statement on pulmonary rehabilitation. Am
J Respir Crit Care Med 2006;173(12):1390413.
210. American Thoracic Society. Pulmonary rehabilitation1999. Am
J Respir Crit Care Med 1999;159(5 Pt 1):166682.
211. Fishman AP. Pulmonary rehabilitation research. Am J Respir
Crit Care Med 1994;149(3 Pt 1):82533.
212. Ries AL, Bauldoff GS, Carlin BW, Casaburi R, Emery CF,
Mahler DA, Make B, RoChester CL, Zuwallack R,
Herrerias C. Pulmonary Rehabilitation: Joint ACCP/
AACVPR EvidenceBased Clinical Practice Guidelines. Chest
2007 May;131 (5 Suppl):4S42S.
213. Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstein
RS. Metaanalysis of respiratory rehabilitation in chronic
obstructive pulmonary disease. Lancet 1996;348(9035):11159.
214. Goldstein RS, Gort EH, Stubbing D, Avendano MA, Guyatt
GH. Randomised controlled trial of respiratory rehabilitation.
Lancet 1994;344(8934):13947.
215. Wijkstra PJ, Van Altena R, Kraan J, Otten V, Postma DS,
Koeter GH. Quality of life in patients with chronic obstructive
pulmonary disease improves after rehabilitation at home. Eur
Respir J 1994;7(2):26973.
216. Wijkstra PJ, Ten Vergert EM, van Altena R, Otten V, Kraan
J, Postma DS, et al. Long-term benefts of rehabilitation at
home on quality of life and exercise tolerance in patients with
chronic obstructive pulmonary disease. Thorax
1995;50(8):8248.
217. ODonnell DE, McGuire M, Samis L, Webb KA. The impact of
exercise reconditioning on breathlessness in severe chronic
airfow limitation. Am J Respir Crit Care Med 1995;152 (6 Pt
1):200513.
218. Lake FR, Henderson K, Briffa T, Openshaw J, Musk AW.
Upperlimb and lowerlimb exercise training in patients with
chronic airfow obstruction. Chest 1990;97(5):107782.
219. Ries AL, Ellis B, Hawkins RW. Upper extremity exercise
training in chronic obstructive pulmonary disease. Chest
1988;93(4):68892.
220. Martinez FJ, Vogel PD, Dupont DN, Stanopoulos I, Gray A,
Beamis JF. Supported arm exercise vs unsupported arm
exercise in the rehabilitation of patients with severe chronic
airfow obstruction. Chest 1993;103(5):1397402.
221. Troosters T, Casaburi R, Gosselink R, Decramer M. Pulmonary
rehabilitation in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2005;172(1):1938.
222. Berry MJ, Rejeski WJ, Adair NE, Zaccaro D. Exercise
rehabilitation and chronic obstructive pulmonary disease stage.
Am J Respir Crit Care Med 1999;160(4):124853.
223. Foglio K, Bianchi L, Bruletti G, Battista L, Pagani M, Ambrosino
N. Long-term effectiveness of pulmonary rehabilitation in
patients with chronic airway obstruction. Eur Respir J
1999;13(1):12532.
224. Young P, Dewse M, Fergusson W, Kolbe J. Improvements
in outcomes for chronic obstructive pulmonary disease (COPD)
attributable to a hospitalbased respiratory rehabilitation
programme. Aust N Z J Med 1999;29(1):5965.
225. Griffths TL, Burr ML, Campbell IA, LewisJenkins V, Mullins J,
Shiels K, et al. Results at 1 year of outpatient
multidisciplinary pulmonary rehabilitation: a randomised
controlled trial [published erratum appears in Lancet
2000;355:1280]. Lancet 2000;355(9201):3628.
226. Maltais F, Bourbeau J, Shapiro S, Lacasse Y, Perrault H,
Baltzan M, Hernandez P, et al; Chronic Obstructive Pulmonary
Disease Axis of Respiratory Health Network, Fonds de
recherche en sant du Qubec. Effects of homebased
pulmonary rehabilitation in patients with chronic obstructive
pulmonary disease: a randomized trial. Ann Intern Med. 2008
Dec 16;149(12):86978.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 79
227. Reference deleted.
228. Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE.
Development of a shuttle walking test of disability in patients
with chronic airways obstruction. Thorax 1992;47(12):101924.
229. Mahler DA. Pulmonary rehabilitation. Chest 1998;113 (4
Suppl):263S8S.
230. American College of Sports Medicine position stand. The
recommended quantity and quality of exercise for developing
and maintaining cardiorespiratory and muscular ftness in
healthy adults. Med Sci Sports Exerc 1990;22(2):26574.
231. Vogiatzis I, Nanas S, Roussos C. Interval training as an
alternative modality to continuous exercise in patients with
COPD. Eur Respir J 2002;20(1):129.
232. Puhan MA, Busching G, Schunemann HJ, VanOort E, Zaugg
C, Frey M. Interval versus continuous highintensity exercise
in chronic obstructive pulmonary disease: a randomized trial.
Ann Intern Med 2006 Dec 5;145(11):81625.
233. Yohannes AM, Connolly MJ. Early mobilization with walking
aids following hospital admission with acute exacerbation
of chronic obstructive pulmonary disease. Clin Rehabil
2003;17(5):46571.
234. Roomi J, Yohannes AM, Connolly MJ. The effect of walking
aids on exercise capacity and oxygenation in elderly
patients with chronic obstructive pulmonary disease. Age
Ageing 1998;27(6):7036.
235. Honeyman P, Barr P, Stubbing DG. Effect of a walking aid on
disability, oxygenation, and breathlessness in patients with
chronic airfow limitation. J Cardiopulm Rehabil 1996;16(1):637.
236. Emtner M, Porszasz J, Burns M, Somfay A, Casaburi
R. Benefts of supplemental oxygen in exercise training in
nonhypoxemic chronic obstructive pulmonary disease patients.
Am J Respir Crit Care Med 2003;168(9):103442.
237. Palange P, Valli G, Onorati P, Antonucci R, Paoletti P, Rosato
A, et al. Effect of heliox on lung dynamic hyperinfation,
dyspnea, and exercise endurance capacity in COPD patients. J
Appl Physiol 2004;97(5):163742.
238. Behnke M, Taube C, Kirsten D, Lehnigk B, Jorres RA,
Magnussen H. Homebased exercise is capable of preserving
hospitalbased improvements in severe chronic obstructive
pulmonary disease. Respir Med 2000;94(12):118491.
239. Finnerty JP, Keeping I, Bullough I, Jones J. The effectiveness
of outpatient pulmonary rehabilitation in chronic lung disease: a
randomized controlled trial. Chest 2001;119(6):170510.
240. Green RH, Singh SJ, Williams J, Morgan MD. A randomised
controlled trial of four weeks versus seven weeks of pulmonary
rehabilitation in chronic obstructive pulmonary disease. Thorax
2001;56(2):1435.
241. Ries AL, Kaplan RM, Myers R, Prewitt LM. Maintenance after
pulmonary rehabilitation in chronic lung disease: a randomized
trial. Am J Respir Crit Care Med 2003;167(6):8808.
242. Belman MJ, Botnick WC, Nathan SD, Chon KH. Ventilatory
load characteristics during ventilatory muscle training. Am
J Respir Crit Care Med 1994;149(4 Pt 1):9259.
243. Lotters F, van Tol B, Kwakkel G, Gosselink R. Effects of
controlled inspiratory muscle training in patients with COPD: a
metaanalysis. Eur Respir J 2002;20(3):5706.
244. Bernard S, Whittom F, Leblanc P, Jobin J, Belleau R, Berube
C, et al. Aerobic and strength training in patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
1999;159(3):896901.
245. Engelen MP, Schols AM, Baken WC, Wesseling GJ, Wouters
EF. Nutritional depletion in relation to respiratory and peripheral
skeletal muscle function in outpatients with COPD. Eur Respir J
1994;7(10):17937.
246. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body
weight in chronic obstructive pulmonary disease. The National
Institutes of Health Intermittent PositivePressure Breathing
Trial. Am Rev Respir Dis 1989;139(6):14358.
247. GrayDonald K, Gibbons L, Shapiro SH, Macklem PT, Martin
JG. Nutritional status and mortality in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med
1996;153(3):9616.
248. Gorecka D, Gorzelak K, Sliwinski P, Tobiasz M, Zielinski
J. Effect of long-term oxygen therapy on survival in patients
with chronic obstructive pulmonary disease with moderate
hypoxaemia. Thorax 1997;52(8):6749.
249. Efthimiou J, Fleming J, Gomes C, Spiro SG. The effect of
supplementary oral nutrition in poorly nourished patients
with chronic obstructive pulmonary disease. Am Rev Respir Dis
1988;137(5):107582.
250. Rogers RM, Donahoe M, Costantino J. Physiologic effects of
oral supplemental feeding in malnourished patients with chronic
obstructive pulmonary disease. A randomized control study. Am
Rev Respir Dis 1992;146(6):15117.
251. Whittaker JS, Ryan CF, Buckley PA, Road JD. The effects
of refeeding on peripheral and respiratory muscle function in
malnourished chronic obstructive pulmonary disease patients.
Am Rev Respir Dis 1990;142(2):2838.
252. Steiner MC, Barton RL, Singh SJ, Morgan MD. Nutritional
enhancement of exercise performance in chronic obstructive
pulmonary disease: a randomised controlled trial. Thorax
2003;58(9):74551.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
80 MANAGEMENT OF COPD
253. Deacon SJ, Vincent EE, Greenhaff PL, Fox J, Steiner MC,
Singh SJ, Morgan MD. Randomized controlled trial of
dietary creatine as an adjunct therapy to physical
training in chronic obstructive pulmonary disease. Am J Respir
Crit Care Med. 2008 Aug 1;178(3):2339.
254. Yeh SS, DeGuzman B, Kramer T. Reversal of
COPDassociated weight loss using the anabolic agent
oxandrolone. Chest 2002;122(2):4218.
255. Weisberg J, Wanger J, Olson J, Streit B, Fogarty C, Martin T,
et al. Megestrol acetate stimulates weight gain and ventilation
in underweight COPD patients. Chest 2002;121(4):10708.
256. Deacon SJ, Vincent EE, Greenhaff PL, Fox J, Steiner MC,
Singh SJ, Morgan MD. Randomized controlled trial of
dietary creatine as an adjunct therapy to physical
training in chronic obstructive pulmonary disease. Am J Respir
Crit Care Med. 2008 Aug 1;178(3):2339.
257. Ware JE, Jr., Sherbourne CD. The MOS 36item short-form
health survey (SF36). I. Conceptual framework and item
selection. Med Care 1992;30(6):47383.
258. Dowson C, Laing R, Barraclough R, Town I, Mulder R, Norris
K, et al. The use of the Hospital Anxiety and Depression Scale
(HADS) in patients with chronic obstructive pulmonary disease:
a pilot study. N Z Med J 2001;114(1141):4479.
259. Goldstein RS, Gort EH, Guyatt GH, Feeny D. Economic
analysis of respiratory rehabilitation. Chest 1997;112(2):3709.
260. American Thoracic Society. Standards for the diagnosis and
care of patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 1995;152:S77121.
261. Nocturnal Oxygen Therapy Trial Group. Continuous or
nocturnal oxygen therapy in hypoxemic chronic obstructive
lung disease: a clinical trial. Ann Intern Med 1980;93(3):3918.
262. Report of the Medical Research Council Working Party.
Long-term domiciliary oxygen therapy in chronic hypoxic cor
pulmonale complicating chronic bronchitis and emphysema.
Lancet 1981;1(8222):6816.
263. Tarpy SP, Celli BR. Long-term oxygen therapy. N Engl J Med
1995;333(11):7104.
264. Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M,
Pelletier A. Long-term oxygen therapy can
reverse the progression of pulmonary hypertension in patients
with chronic obstructive pulmonary disease. Am Rev Respir Dis
1985;131(4):4938.
265. Zielinski J, Tobiasz M, Hawrylkiewicz I, Sliwinski P, Palasiewicz
G. Effects of long-term oxygen therapy on pulmonary
hemodynamics in COPD patients: a 6year prospective study.
Chest 1998;113(1):6570.
266. Petty TL. Supportive therapy in COPD. Chest 1998;113 (4
Suppl):256S62S.
267. ODonnell DE, Bain DJ, Webb KA. Factors contributing to relief
of exertional breathlessness during hyperoxia in chronic airfow
limitation. Am J Respir Crit Care Med 1997;155(2):5305.
268. Somfay A, Porszasz J, Lee SM, Casaburi R. Doseresponse
effect of oxygen on hyperinfation and exercise endurance in
nonhypoxaemic COPD patients. Eur Respir J 2001;18(1):7784.
269. Somfay A, Porszasz J, Lee SM, Casaburi R. Effect of
hyperoxia on gas exchange and lactate kinetics
following exercise onset in nonhypoxemic COPD patients.
Chest 2002;121(2):393400.
270. ODonnell DE, DArsigny C, Webb KA. Effects of hyperoxia on
ventilatory limitation during exercise in advanced chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2001;163(4):8928.
271. Eaton T, Garrett JE, Young P, Fergusson W, Kolbe J, Rudkin S,
et al. Ambulatory oxygen improves quality of life of COPD
patients: a randomised controlled study. Eur Respir J
2002;20(2):30612.
272. Lacasse Y, Lecours R, Pelletier C, Begin R, Maltais F.
Randomised trial of ambulatory oxygen in oxygendependent
COPD. Eur Respir J 2005;25(6):10328.
273. Stevenson NJ, Calverley PM. Effect of oxygen on recovery
from maximal exercise in patients with chronic obstructive
pulmonary disease. Thorax 2004;59(8):66872.
274. Lewis CA, Eaton TE, Young P, Kolbe J. Short-burst oxygen
immediately before and after exercise is ineffective in
nonhypoxic COPD patients. Eur Respir J 2003;22(4):5848.
275. Petty TL, ODonohue WJ, Jr. Further recommendations for
prescribing, reimbursement, technology development,
and research in long-term oxygen therapy. Summary of the
Fourth Oxygen Consensus Conference, Washington, D.C.,
October 1516, 1993. Am J Respir Crit Care Med
1994;150(3):8757.
276. PelletierFleury N, Lanoe JL, Fleury B, Fardeau M. The cost of
treating COPD patients with long-term oxygen therapy in a
French population. Chest 1996;110(2):4116.
277. Heaney LG, McAllister D, MacMahon J. Cost minimisation
analysis of provision of oxygen at home: are the drug tariff
guidelines cost effective? BMJ 1999;319(7201):1923.
278. Gong H, Jr. Air travel and oxygen therapy in cardiopulmonary
patients. Chest 1992;101(4):110413.
279. Berg BW, Dillard TA, Rajagopal KR, Mehm WJ. Oxygen
supplementation during air travel in patients with chronic
obstructive lung disease. Chest 1992;101(3):63841.
280. Gong H, Jr., Tashkin DP, Lee EY, Simmons MS.
Hypoxiaaltitude simulation test. Evaluation of patients with
chronic airway obstruction. Am Rev Respir Dis
1984;130(6):9806.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 81
281. Christensen CC, Ryg M, Refvem OK, Skjonsberg OH.
Development of severe hypoxaemia in chronic obstructive
pulmonary disease patients at 2,438 m (8,000 ft) altitude. Eur
Respir J 2
282. Shapiro SH, Ernst P, GrayDonald K, Martin JG,
WoodDauphinee S, Beaupre A, et al. Effect of negative
pressure ventilation in severe chronic obstructive pulmonary
disease. Lancet 1992;340(8833):14259.
283. Elliott MW. Noninvasive ventilation in chronic ventilatory
failure due to chronic obstructive pulmonary disease. Eur
Respir J 2002;20(3):5114.
284. Clini E, Sturani C, Rossi A, Viaggi S, Corrado A, Donner
CF, et al. The Italian multicentre study on noninvasive
ventilation in chronic obstructive pulmonary disease patients.
Eur Respir J 2002;20(3):52938.
285. Consensus conference report. Clinical indications for
noninvasive positive pressure ventilation in chronic respiratory
failure due to restrictive lung disease, COPD, and nocturnal
hypoventilation. Chest 1999;116(2):52134.
286. Mehran RJ, Deslauriers J. Indications for surgery and patient
workup for bullectomy. Chest Surg Clin N Am 1995;5(4):71734.
287. Hughes JA, MacArthur AM, Hutchison DC, HughJones P.
Long-term changes in lung function after surgical treatment of
bullous emphysema in smokers and exsmokers. Thorax
1984;39(2):1402.
288. Laros CD, Gelissen HJ, Bergstein PG, Van den Bosch JM,
Vanderschueren RG, Westermann CJ, et al. Bullectomy
for giant bullae in emphysema. J Thorac Cardiovasc Surg
1986;91(1):6370.
289. Cooper JD, Trulock EP, Triantafllou AN, Patterson GA, Pohl
MS, Deloney PA, et al. Bilateral pneumectomy (volume
reduction) for chronic obstructive pulmonary disease. J Thorac
Cardiovasc Surg 1995;109(1):10616.
290. Criner G, Cordova FC, Leyenson V, Roy B, Travaline J,
Sudarshan S, et al. Effect of lung volume reduction surgery
on diaphragm strength. Am J Respir Crit Care Med 1998;157(5
Pt 1):157885.
291. Martinez FJ, de Oca MM, Whyte RI, Stetz J, Gay SE, Celli BR.
Lungvolume reduction improves dyspnea, dynamic
hyperinfation, and respiratory muscle function. Am J Respir
Crit Care Med 1997;155(6):198490.
292. Fessler HE, Permutt S. Lung volume reduction surgery
and airfow limitation. Am J Respir Crit Care Med 1998;157 (3
Pt 1):71522.
293. Naunheim KS, Wood DE, Mohsenifar Z, Sternberg AL, Criner
GJ, DeCamp MM, et al. Long-term followup of patients
receiving lungvolumereduction surgery versus medical therapy
for severe emphysema by the National Emphysema Treatment
Trial Research Group. Ann Thorac Surg 2006;82(2):43143.
294. Ramsey SD, Shroyer AL, Sullivan SD, Wood DE. Updated
evaluation of the costeffectiveness of lung volume reduction
surgery. Chest 2007 Mar;131(3):82332.
295. Reference deleted
296. Trulock EP. Lung transplantation. Am J Respir Crit Care Med
1997;155(3):789818.
297. Theodore J, Lewiston N. Lung transplantation comes of age. N
Engl J Med 1990;322(11):7724.
298. Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM,
Novick RJ. The Registry of the International Society for Heart
and Lung Transplantation: ffteenth offcial report1998. J Heart
Lung Transplant 1998;17(7):65668.
299. Annual report of the US scientifc registry for transplant
recipients and the Organ Procurement and Transplantation
Network. Transplant data: 1988-1994. Washington, D.C.:
Division of Transplantation, Health Resources and Services
Administraion, US Department of Health and Human Services;
1995.
300. Hosenpud JD, Bennett LE, Keck BM, Edwards EB, Novick
RJ. Effect of diagnosis on survival beneft of lung
transplantation for endstage lung disease. Lancet
1998;351(9095):247.
301. Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville
AR. International guidelines for the selection of lung transplant
candidates. The International Society for Heart and Lung
Transplantation, the American Thoracic Society, the American
Society of Transplant Physicians, the European Respiratory
Society. Transplantation 1998;66(7):9516.
302. Ramsey SD, Patrick DL, Albert RK, Larson EB, Wood DE,
Raghu G. The costeffectiveness of lung transplantation. A pilot
study. University of Washington Medical Center Lung
Transplant Study Group. Chest 1995;108(6):1594601.
303. Al MJ, Koopmanschap MA, van Enckevort PJ, Geertsma
A, van der Bij W, de Boer WJ, et al. Costeffectiveness of lung
transplantation in The Netherlands: a scenario analysis. Chest
1998;113(1):12430.
304. van Enckevort PJ, Koopmanschap MA, Tenvergert EM,
Geertsma A, van der Bij W, de Boer WJ, et al. Lifetime costs of
lung transplantation: estimation of incremental costs. Health
Econ 1997;6(5):47989.
305. van Enckevort PJ, TenVergert EM, Bonsel GJ, Geertsma A,
van der Bij W, de Boer WJ, et al. Technology assessment of
the Dutch Lung Transplantation Program. Int J Technol Assess
Health Care 1998;14(2):34456.
306. Smetana GW. Preoperative pulmonary evaluation. N Engl J
Med 1999;340(12):93744.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
82 MANAGEMENT OF COPD
307. Trayner E, Jr., Celli BR. Postoperative pulmonary
complications. Med Clin North Am 2001;85(5):112939.
308. Weisman IM. Cardiopulmonary exercise testing in the
preoperative assessment for lung resection surgery. Semin
Thorac Cardiovasc Surg 2001;13(2):11625.
309. Bolliger CT, Perruchoud AP. Functional evaluation of the lung
resection candidate. Eur Respir J 1998;11(1):198212.
310. Schuurmans MM, Diacon AH, Bolliger CT. Functional
evaluation before lung resection. Clin Chest Med
2002;23(1):15972.

311. Celli BR, MacNee W. Standards for the diagnosis and
treatment of patients with COPD: a summary of the ATS/ERS
position paper. Eur Respir J 2004;23(6):93246.
312. Regueiro CR, Hamel MB, Davis RB, Desbiens N, Connors AF,
Jr., Phillips RS. A comparison of generalist and pulmonologist
care for patients hospitalized with severe chronic obstructive
pulmonary disease: resource intensity, hospital costs, and
survival. SUPPORT Investigators. Study to Understand
Prognoses and Preferences for Outcomes and Risks of
Treatment. Am J Med 1998;105(5):36672.
313. Gibson PG, Wlodarczyk JH, Wilson AJ, Sprogis A. Severe
exacerbation of chronic obstructive airways disease: health
resource use in general practice and hospital. J Qual Clin Pract
1998;18(2):12533.
314. Anthonisen NR, Manfreda J, Warren CP, Hershfeld ES,
Harding GK, Nelson NA. Antibiotic therapy in exacerbations
of chronic obstructive pulmonary disease. Ann Intern Med
1987;106(2):196204.
315. Warren PM, Flenley DC, Millar JS, Avery A. Respiratory failure
revisited: acute exacerbations of chronic bronchitis between
196168 and 197076. Lancet 1980;1(8166):46770.
316. Gunen H, Hacievliyagil SS, Kosar F, Mutlu LC, Gulbas G,
Pehlivan E, et al. Factors affecting survival of hospitalised
patients with COPD. Eur Respir J 2005;26(2):23441.
317. RodriguezRoisin R. Toward a consensus defnition for COPD
exacerbations. Chest 2000;117(5 Suppl 2):398S401S.
318. Burge S, Wedzicha JA. COPD exacerbations: defnitions and
classifcations. Eur Respir J Suppl 2003;41:46s53s.
319. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ,
Wedzicha JA. Time course and recovery of exacerbations in
patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2000;161(5):160813.
320. Connors AF, Jr., Dawson NV, Thomas C, Harrell FE, Jr.,
Desbiens N, Fulkerson WJ, et al. Outcomes following acute
exacerbation of severe chronic obstructive lung disease. The
SUPPORT investigators (Study to Understand Prognoses and
Preferences for Outcomes and Risks of Treatments). Am J
Respir Crit Care Med 1996;154(4 Pt 1):95967.
321. Kong GK, Belman MJ, Weingarten S. Reducing length of stay
for patients hospitalized with exacerbation of COPD by using a
practice guideline. Chest 1997;111(1):8994.
322. Fuso L, Incalzi RA, Pistelli R, Muzzolon R, Valente S, Pagliari
G, et al. Predicting mortality of patients hospitalized for acutely
exacerbated chronic obstructive pulmonary disease. Am J Med
1995;98(3):2727.
323. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus
WA. Hospital and 1year survival of patients admitted to
intensive care units with acute exacerbation of chronic
obstructive pulmonary disease. JAMA 1995;274(23):18527.
324. Esteban A, Anzueto A, Frutos F, Alia I, Brochard L, Stewart
TE, et al. Characteristics and outcomes in adult patients
receiving mechanical ventilation: a 28day international study.
JAMA 2002;287(3):34555.
325. Wouters EF. The burden of COPD in The Netherlands: results
from the Confronting COPD survey. Respir Med 2003;97 Suppl
C:S519.
326. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha
JA. Relationship between exacerbation frequency and lung
function decline in chronic obstructive pulmonary disease.
Thorax 2002;57(10):84752.
327. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory
illnesses promote FEV
(1)
decline in current smokers but not
exsmokers with mild chronic obstructive pulmonary disease:
results from the lung health study. Am J Respir Crit Care Med
2001;164(3):35864.
328. Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA,
Wedzicha JA. Early therapy improves outcomes of
exacerbations of chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2004;169(12):1298303.
329. White AJ, Gompertz S, Stockley RA. Chronic obstructive
pulmonary disease . 6: The aetiology of exacerbations of
chronic obstructive pulmonary disease. Thorax
2003;58(1):7380.
330. Monso E, Ruiz J, Rosell A, Manterola J, Fiz J, Morera J, et al.
Bacterial infection in chronic obstructive pulmonary disease.
A study of stable and exacerbated outpatients using the
protected specimen brush. Am J Respir Crit Care Med
1995;152(4 Pt 1):131620.
331. Pela R, Marchesani F, Agostinelli C, Staccioli D, Cecarini L,
Bassotti C, et al. Airways microbial fora in COPD patients in
stable clinical conditions and during exacerbations: a
bronchoscopic investigation. Monaldi Arch Chest Dis
1998;53(3):2627.
332. Sethi S, Evans N, Grant BJ, Murphy TF. New strains of
bacteria and exacerbations of chronic obstructive pulmonary
disease. N Engl J Med 2002;347(7):46571.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 83
333. Sethi S, Wrona C, Grant BJ, Murphy TF. Strainspecifc
immune response to Haemophilus infuenzae in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2004;169(4):44853.

334. Sethi S, Muscarella K, Evans N, Klingman KL, Grant BJ,
Murphy TF. Airway infammation and etiology of acute
exacerbations of chronic bronchitis. Chest 2000;118(6):155765.
335. White AJ, Gompertz S, Bayley DL, Hill SL, OBrien C, Unsal
I, et al. Resolution of bronchial infammation is related to
bacterial eradication following treatment of exacerbations
of chronic bronchitis. Thorax 2003;58(8):6805.
336. Murphy TF, Brauer AL, Grant BJ, Sethi S. Moraxella catarrhalis
in Chronic Obstructive Pulmonary Disease: Burden of
Disease and Immune Response. Am J Respir Crit Care Med
2005;172(2):1959.
337. Emerman CL, Connors AF, Lukens TW, Effron D, May ME.
Relationship between arterial blood gases and spirometry in
acute exacerbations of chronic obstructive pulmonary disease.
Ann Emerg Med 1989;18(5):5237.
338. Adams S, J. M, Luther M. Antibiotics are associated with lower
relapse rates in outpatients with acute exacerbations of chronic
obstructive pulmonary disease. Chest 2000;117:134552.
339. Mueller C, LauleKiliam K, Frana B, Rodriguez D, Rudez
J, Swcholer A, et al. The use of Bnatriuretic peptide in the
managment of elderly patients with acute dyspenae. J Intern
Med 2005;258:7785.
340. Richards AM, Nicholls MG, Epiner EA, Lainchbury JD,
Troughton RW, Elliott J, et al. Btype natriuretic peptide
and ejectrion fraction for prognosis after myocardial infarction.
Circulation 2003;107:2786.
341. Casas A, Troosters T, GarciaAymerich J, Roca J, Hernandez
C, Alonso A, del Pozo F, de Toledo P, Anto JM, Rodriguez
Roisin R, Decramer M; members of the CHRONIC Project.
Integrated care prevents hospitalisations for exacerbations in
COPD patients. Eur Respir J 2006 Jul;28(1):12330.
342. Ojoo JC, Moon T, McGlone S, Martin K, Gardiner ED,
Greenstone MA, et al. Patients and carers preferences in
two models of care for acute exacerbations of COPD: results of
a randomised controlled trial. Thorax 2002;57(2):1679.
343. Skwarska E, Cohen G, Skwarski KM, Lamb C, Bushell D,
Parker S, et al. Randomized controlled trial of supported
discharge in patients with exacerbations of chronic obstructive
pulmonary disease. Thorax 2000;55(11):90712.
344. Hernandez C, Casas A, Escarrabill J, Alonso J, PuigJunoy J,
Farrero E, et al. Home hospitalisation of exacerbated
chronic obstructive pulmonary disease patients. Eur Respir J
2003;21(1):5867.
345. Celli BR. Current thoughts regarding treatment of
chronic obstructive pulmonary disease. Med Clin North Am
1996;80(3):589609.
346. RodriguezRoisin R. COPD exacerbations.5: management.
Thorax 2006;61(6):53544.
347. Rebuck AS, Chapman KR, Abboud R, Pare PD, Kreisman H,
Wolkove N, et al. Nebulized anticholinergic and
sympathomimetic treatment of asthma and chronic
obstructive airways disease in the emergency room. Am J Med
1987;82(1):5964.
348. Moayyedi P, Congleton J, Page RL, Pearson SB, Muers MF.
Comparison of nebulised salbutamol and ipratropium bromide
with salbutamol alone in the treatment of chronic obstructive
pulmonary disease. Thorax 1995;50(8):8347.
349. Thompson WH, Nielson CP, Carvalho P, Charan NB, Crowley
JJ. Controlled trial of oral prednisone in outpatients with acute
COPD exacerbation. Am J Respir Crit Care Med 1996;154 (2
Pt 1):40712.
350. Davies L, Angus RM, Calverley PM. Oral corticosteroids
in patients admitted to hospital with exacerbations of chronic
obstructive pulmonary disease: a prospective randomised
controlled trial. Lancet 1999;354(9177):45660.
351. Niewoehner DE, Erbland ML, Deupree RH, Collins D,
Gross NJ, Light RW, et al. Effect of systemic glucocorticoids
on exacerbations of chronic obstructive pulmonary disease.
Department of Veterans Affairs Cooperative Study Group.
N Engl J Med 1999;340(25):19417.
352. Maltais F, Ostinelli J, Bourbeau J, Tonnel AB, Jacquemet N,
Haddon J, et al. Comparison of nebulized budesonide and oral
prednisolone with placebo in the treatment of acute
exacerbations of chronic obstructive pulmonary disease: a
randomized controlled trial. Am J Respir Crit Care Med
2002;165(5):698703.
353. Aaron SD, Vandemheen KL, Hebert P, Dales R, Stiell IG,
Ahuja J, et al. Outpatient oral prednisone after emergency
treatment of chronic obstructive pulmonary disease. N Engl J
Med 2003;348(26):261825.
354. Shepperd S, Harwood D, Gray A, Vessey M, Morgan P.
Randomised controlled trial comparing hospital at home care
with inpatient hospital care. II: cost minimisation analysis. BMJ
1998;316(7147):17916.
355. Gravil JH, AlRawas OA, Cotton MM, Flanigan U, Irwin A,
Stevenson RD. Home treatment of exacerbations of chronic
obstructive pulmonary disease by an acute respiratory
assessment service. Lancet 1998;351(9119):18535.

356. Soderstrom L, Tousignant P, Kaufman T. The health and cost
effects of substituting home care for inpatient acute care: a
review of the evidence. CMAJ 1999;160(8):11515.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
84 MANAGEMENT OF COPD
357. National Institute for Clinical Excellence (NICE). Chronic
obstructive pulmonary disease. National clinical guideline on
management of chronic obstructive pulmonary disease in
adults in primary and secondary care. Thorax 2004;59 Suppl
1:1232.
358. Barbera JA, Reyes A, Roca J, Montserrat JM, Wagner
PD, RodriguezRoisin R. Effect of intravenously administered
aminophylline on ventilation/perfusion inequality during
recovery from exacerbations of chronic obstructive pulmonary
disease. Am Rev Respir Dis 1992;145(6):132833.
359. Mahon JL, Laupacis A, Hodder RV, McKim DA, Paterson
NA, Wood TE, et al. Theophylline for irreversible chronic airfow
limitation: a randomized study comparing n of 1 trials to
standard practice. Chest 1999;115(1):3848.
360. Lloberes P, Ramis L, Montserrat JM, Serra J, Campistol J,
Picado C, et al. Effect of three different bronchodilators
during an exacerbation of chronic obstructive pulmonary
disease. Eur Respir J 1988;1(6):5369.
361. Murciano D, Aubier M, Lecocguic Y, Pariente R. Effects of
theophylline on diaphragmatic strength and fatigue in
patients with chronic obstructive pulmonary disease. N Engl J
Med 1984;311(6):34953.362.
362. Emerman CL, Connors AF, Lukens TW, May ME, Effron D.
Theophylline concentrations in patients with acute exacerbation
of COPD. Am J Emerg Med 1990;8(4):28992.
363. Barr RG, Rowe BH, Camargo CA, Jr. Methylxanthines
for exacerbations of chronic obstructive pulmonary disease:
metaanalysis of randomised trials. BMJ 2003;327(7416):643.
364. Duffy N, Walker P, Diamantea F, Calverley PM, Davies L.
Intravenous aminophylline in patients admitted to hospital with
nonacidotic exacerbations of chronic obstructive pulmonary
disease: a prospective randomised controlled trial. Thorax
2005;60(9):7137.
365. Quon BS, Gan WQ, Sin DD. Contemporary management
of acute exacerbations of COPD: a systematic review and
metaanalysis. Chest. 2008 Mar;133(3):75666. Review.
366. Nouira S, Marghli S, Belghith M, Besbes L, Elatrous S, Abroug
F. Once daily oral ofoxacin in chronic obstructive pulmonary
disease exacerbation requiring mechanical ventilation:
a randomised placebocontrolled trial. Lancet
2001;358(9298):20205.
367. Seemungal T, HarperOwen R, Bhowmik A, Moric I, Sanderson
G, Message S, et al. Respiratory viruses, symptoms, and
infammatory markers in acute exacerbations and stable
chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 2001;164(9):161823.
368. Blasi F, Damato S, Cosentini R, Tarsia P, Raccanelli R,
Centanni S, et al. Chlamydia pneumoniae and chronic
bronchitis: association with severity and bacterial clearance
following treatment. Thorax 2002;57(8):6726.
369. Seemungal TA, Wedzicha JA, MacCallum PK, Johnston SL,
Lambert PA. Chlamydia pneumoniae and COPD exacerbation.
Thorax 2002;57(12):10878; author reply 89.
370. Soler N, Torres A, Ewig S, Gonzalez J, Celis R, ElEbiary M, et
al. Bronchial microbial patterns in severe exacerbations
of chronic obstructive pulmonary disease (COPD) requiring
mechanical ventilation. Am J Respir Crit Care Med 1998;157 (5
Pt 1):1498505.

371. Fagon JY, Chastre J, Trouillet JL, Domart Y, Dombret MC,
Bornet M, et al. Characterization of distal bronchial microfora
during acute exacerbation of chronic bronchitis. Use of the
protected specimen brush technique in 54 mechanically
ventilated patients. Am Rev Respir Dis 1990;142(5):10048.
372. Miravitlles M, Espinosa C, FernandezLaso E, Martos JA,
Maldonado JA, Gallego M. Relationship between bacterial
fora in sputum and functional impairment in patients with
acute exacerbations of COPD. Study Group of Bacterial
Infection in COPD. Chest 1999;116(1):406.
373. Eller J, Ede A, Schaberg T, Niederman MS, Mauch H, Lode
H. Infective exacerbations of chronic bronchitis: relation
between bacteriologic etiology and lung function. Chest
1998;113(6):15428.
374. Fogarty C, de Wet R, Mandel L, Chang J, Rangaraju M, Nusrat
R. Five day Telitromycin once daily is as effective as 10 day
Clarithromycin twice daily for the tretment of Acute
Exacerbations of Chronic Bronchitis and is associated with
reduced healthcare recources utilization. Chest
2005;128:19808.
375. Wilson R, Allegra L, Huchon G, Izquierdo JL, Jones P,
Schaberg T, et al. Short-term and long-term outcomes of
moxifoxacin compared to standard antibiotic treatment in acute
exacerbations of chronic bronchitis. Chest 2004;125(3):95364.
376. Wilson R, Schentag JJ, Ball P, Mandell L. for the 068 Study
Group. A comparison of Gemifoxacin and Clarithromycin in
Acute Exacerbations of Chronic Bronchitis and Long-term
clinical outcomes. Clin Ther 2002;4:63952.
377. Greenstone M, Lasserson TJ. Doxapram for ventilatory failure
due to exacerbations of chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2003(1):CD000223.
378. Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. Noninvasive
positive pressure ventilation to treat respiratory failure
resulting from exacerbations of chronic obstructive pulmonary
disease: Cochrane systematic review and metaanalysis. BMJ
2003;326(7382):185.
379. Meyer TJ, Hill NS. Noninvasive positive pressure ventilation to
treat respiratory failure. Ann Intern Med 1994;120(9):76070.
380. Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss
A, et al. Noninvasive ventilation for acute exacerbations of
chronic obstructive pulmonary disease. N Engl J Med
1995;333(13):81722.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 85
381. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS.
Randomized, prospective trial of noninvasive positive pressure
ventilation in acute respiratory failure. Am J Respir Crit
Care Med 1995;151(6):1799806.
382. Bott J, Carroll MP, Conway JH, Keilty SE, Ward EM, Brown
AM, et al. Randomised controlled trial of nasal ventilation in
acute ventilatory failure due to chronic obstructive airways
disease. Lancet 1993;341(8860):15557.
383. Plant PK, Owen JL, Elliott MW. Early use of noninvasive
ventilation for acute exacerbations of chronic obstructive
pulmonary disease on general respiratory wards: a multicentre
randomised controlled trial. Lancet 2000;355(9219):19315.
384. Esteban A, Anzueto A, Alia I, Gordo F, Apezteguia C, Palizas F,
et al. How is mechanical ventilation employed in the intensive
care unit? An international utilization review. Am J Respir Crit
Care Med 2000;161(5):14508.
385. International Consensus Conferences in Intensive Care
Medicine: noninvasive positive pressure ventilation in acute
respiratory failure. Am J Respir Crit Care Med
2001;163(1):28391.
386. Plant PK, Owen JL, Elliott MW. Noninvasive ventilation in
acute exacerbations of chronic obstructive pulmonary disease:
long-term survival and predictors of inhospital outcome.
Thorax 2001;56(9):70812.
387. Rossi A, Gottfried SB, Zocchi L, Higgs BD, Lennox S,
Calverley PM, et al. Measurement of static compliance of the
total respiratory system in patients with acute respiratory
failure during mechanical ventilation. The effect of
intrinsic positive endexpiratory pressure. Am Rev Respir Dis
1985;131(5):6727.
388. Parker CM, Voduc N, Aaron SD, Webb KA, ODonnell DE.
Physiological changes during symptom recovery from
moderate exacerbations of COPD. Eur Respir J
2005;26(3):4208.
389. Conti G, Antonelli M, Navalesi P, Rocco M, Buf M, Spadetta
G, et al. Noninvasive vs. conventional mechanical ventilation
in patients with chronic obstructive pulmonary disease after
failure of medical treatment in the ward: a randomized trial.
Intensive Care Med 2002;28(12):17017.
390. Purro A, Appendini L, De Gaetano A, Gudjonsdottir M, Donner
CF, Rossi A. Physiologic determinants of ventilator dependence
in long-term mechanically ventilated patients. Am J Respir Crit
Care Med 2000;161(4 Pt 1):111523.
391. Torres A, Reyes A, Roca J, Wagner PD, RodriguezRoisin
R. Ventilationperfusion mismatching in chronic obstructive
pulmonary disease during ventilator weaning. Am Rev Respir
Dis 1989;140(5):124650.
392. Beydon L, Cinotti L, Rekik N, Radermacher P, Adnot S,
Meignan M, et al. Changes in the distribution of ventilation and
perfusion associated with separation from mechanical
ventilation in patients with obstructive pulmonary disease.
Anesthesiology 1991;75(5):7308.
393. Nava S, Ambrosino N, Clini E, Prato M, Orlando G, Vitacca
M, et al. Noninvasive mechanical ventilation in the weaning
of patients with respiratory failure due to chronic obstructive
pulmonary disease. A randomized, controlled trial. Ann Intern
Med 1998;128(9):7218.
394. Esteban A, Frutos F, Tobin MJ, Alia I, Solsona JF, Valverdu
I, et al. A comparison of four methods of weaning patients from
mechanical ventilation. Spanish Lung Failure Collaborative
Group. N Engl J Med 1995;332(6):34550.
395. Brochard L, Rauss A, Benito S, Conti G, Mancebo J, Rekik
N, et al. Comparison of three methods of gradual withdrawal
from ventilatory support during weaning from mechanical
ventilation. Am J Respir Crit Care Med 1994;150(4):896903.
396. Hilbert G, Gruson D, Portel L, GbikpiBenissan G, Cardinaud
JP. Noninvasive pressure support ventilation in COPD patients
with postextubation hypercapnic respiratory insuffciency. Eur
Respir J 1998;11(6):134953.
397. Esteban A, FrutosVivar F, Ferguson ND, Arabi Y,
Apezteguia C, Gonzalez M, et al. Noninvasive positivepressure
ventilation for respiratory failure after extubation. N Engl J Med
2004;350(24):245260.
398. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum
E. Predictive factors of hospitalization for acute exacerbation in
a series of 64 patients with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1999;159(1):15864.
399. Mushlin AI, Black ER, Connolly CA, Buonaccorso KM, Eberly
SW. The necessary length of hospital stay for chronic
pulmonary disease. JAMA 1991;266(1):803.
400. Cotton MM, Bucknall CE, Dagg KD, Johnson MK, MacGregor
G, Stewart C, et al. Early discharge for patients with
exacerbations of chronic obstructive pulmonary disease: a
randomized controlled trial. Thorax 2000;55(11):9026.
401. Hughes SL, Weaver FM, GiobbieHurder A, Manheim L,
Henderson W, Kubal JD, et al. Effectiveness of teammanaged
homebased primary care: a randomized multicenter trial. JAMA
2000;284(22):287785.
402. Hermiz O, Comino E, Marks G, Daffurn K, Wilson S, Harris
M. Randomised controlled trial of home based care of patients
with chronic obstructive pulmonary disease. BMJ
2002;325(7370):938.
403. Stoller JK, Lange PA. Inpatient management of chronic
obstructive pulmonary disease. Respir Care Clin N Am
1998;4(3):42538.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
86 MANAGEMENT OF COPD
404. Peach H, Pathy MS. Followup study of disability among elderly
patients discharged from hospital with exacerbations of chronic
bronchitis. Thorax 1981;36(8):5859.
405. Man WD, Polkey MI, Donaldson N, Gray BJ, Moxham J.
Community pulmonary rehabilitation after hospitalisation for
acute exacerbations of chronic obstructive pulmonary disease:
randomised controlled study. BMJ 2004;329(7476):1209.
406. Kessler R, Stahl E, Vogelmeier C, Haughney J, Trudeau
E, Lofdahl CG, Partridge MR. Patient understanding, detection,
and experience of COPD exacerbations: an observational,
interview-based study. Chest 2006 Jul;130(1):13342.
407. Tonnesen P, Mikkelsen K, Bremann L. Nurseconducted
smoking cessation in patients with COPD using nicotine
sublingual tablets and behavioral support. Chest 2006
Aug;130(2):33442.
408. Bourbeau J, Collet JP, Schwartzman K, Ducruet T, Nault D,
Bradley C. Economic benefts of selfmanagement education in
COPD. Chest 2006 Dec;130(6):170411.
409. McGeoch GR, Willsman KJ, Dowson CA, Town GI, Frampton
CM, McCartin FJ, Cook JM, Epton MJ. Selfmanagement plans
in the primary care of patients with chronic obstructive
pulmonary disease. Respirology 2006 Sep;11(5):6118.
410. Zhou Y, Wang X, Zeng X, Qiu R, Xie J, Liu S, Zheng J,
Zhong N, Ran P. Positive benefts of theophylline in a
randomized, doubleblind, parallelgroup, placebocontrolled
study of lowdose, slowrelease theophylline in the treatment of
COPD for 1 year. Respirology 2006 Sep;11(5):60310.
411. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C,
Jones PW, Yates JC, Vestbo J; TORCH investigators.
Salmeterol and futicasone propionate and survival in
chronic obstructive pulmonary disease. N Engl J Med 2007 Feb
22;356(8):77589.
412. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact
of salmeterol/futicasone propionate versus salmeterol on
exacerbations in severe chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2007 Jan 15;175(2):1449.
413. Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison
J, Mahler D, Saadeh C, Siler T, Snell P, Korenblat P, Smith
W, Kaye M, Mandel M, Andrews C, Prabhu R, Donohue
JF, Watt R, Lo KH, SchlenkerHerceg R, Barnathan ES, Murray
J; COPD Investigators. The safety and effcacy of infiximab in
moderate to severe chronic obstructive pulmonary disease. Am
J Respir Crit Care Med 2007 May 1;175(9):92634.
414. Guo R, Pittler MH, Ernst E. Herbal medicines for the treatment
of COPD: a systematic review. Eur Respir J 2006
Aug;28(2):3308.
415. Kunik ME, Azzam PN, Souchek J, Cully JA, Wray NP, Krishnan
LL, Nelson HA, Stanley MA. A practical screening tool for
anxiety and depression in patients with chronic breathing
disorders. Psychosomatics 2007 JanFeb;48(1):1621.
416. Griffths TL, Phillips CJ, Davies S, Burr ML, Campbell IA.
Cost effectiveness of an outpatient multidisciplinary pulmonary
rehabilitation programme. Thorax 2001;56;779784
417. RiveraFernandez R, NavarreteNavarro P, FernandezMondejar
E, RodriguezElvira M, GuerreroLopez F, VazquezMata G;
Project for the Epidemiological Analysis of Critical 421: Harber
P, Tashkin DP, Simmons M, Crawford L, Hnizdo E, Connett J;
Lung Health Study Group. Effect of occupational exposures
on decline of lung function in early chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2007 Nov
15;176(10):9941000.
418. Gudmundsson G, Gislason T, Lindberg E, Hallin R, Ulrik CS,
Brondum E, Nieminen MM, Aine T, Bakke P, Janson C.
Mortality in COPD patients discharged from hospital: the role of
treatment and comorbidity. Respir Res 2006 Aug 16;7:109.
419. Gunen H, Hacievliyagil SS, Yetkin O, Gulbas G, Mutlu LC. The
role of nebulised budesonide in the treatment of exacerbations
of COPD. Eur Respir J 2007 Apr;29(4):6607.
420. Price LC, Lowe D, Hosker HS, Anstey K, Pearson MG, Roberts
CM; British Thoracic Society and the Royal College of
Physicians Clinical Effectiveness Evaluation Unit (CEEu).
UK National COPD Audit 2003: Impact of hospital resources
and organisation of care on patient outcome following
admission for acute COPD exacerbation. Thorax 2006
Oct;61(10):83742.
421. Harber P, Tashkin DP, Simmons M, Crawford L, Hnizdo
E, Connett J; Lung Health Study Group. Effect of occupational
exposures on decline of lung function in early chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2007 Nov 15;176(10):9941000.
422. AlShowair RA, Tarsin WY, Assi KH, Pearson SB, Chrystyn
H. Can all patients with COPD use the correct inhalation
fow with all inhalers and does training help? Respir Med 2007
Nov;101(11):2395401.
423. Tashkin DP, Celli B, Decramer M, Liu D, Burkhart D, Cassino
C, Kesten S. Bronchodilator responsiveness in patients with
COPD. Eur Respir J 2008 Apr;31(4):74250.

424. Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in
selfreported exercise participation with the combination of
tiotropium and rehabilitative exercise training in COPD patients.
Int J Chron Obstruct Pulmon Dis 2008;3(1):12736.
425. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari
Z, Stockley RA; INSPIRE Investigators. The prevention of
chronic obstructive pulmonary disease exacerbations by
salmeterol/futicasone propionate or tiotropium bromide. Am J
Respir Crit Care Med 2008 Jan 1;177(1):1926.

C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
MANAGEMENT OF COPD 87
426. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L,
Bai CX, Wang CZ, Wang C, Chen BY, Shi Y, Liu CT, Chen
P, Li Q, Wang ZS, Huang YJ, Luo ZY, Chen FP, Yuan JZ, Yuan
BT, Qian HP, Zhi RC, Zhong NS. Effect of carbocisteine on
acute exacerbation of chronic obstructive pulmonary disease
(PEACE Study): a randomised placebocontrolled study. Lancet
2008 Jun 14;371(9629):20138.
427. Nield MA, Soo Hoo GW, Roper JM, Santiago S. Effcacy
of pursedlips breathing: a breathing pattern retraining
strategy for dyspnea reduction. J Cardiopulm Rehabil Prev
2007 JulAug;27(4):23744.
428. Magadle R, McConnell AK, Beckerman M, Weiner P.
Inspiratory muscle training in pulmonary rehabilitation program
in COPD patients. Respir Med 2007 Jul;101(7):15005.
429. OBrien K, Geddes EL, Reid WD, Brooks D, Crowe J.
Inspiratory muscle training compared with other rehabilitation
interventions in chronic obstructive pulmonary
disease: a systematic review update. J Cardiopulm Rehabil
Prev 2008 MarApr;28(2):12841.
430. Kolodziej MA, Jensen L, Rowe B, Sin D. Systematic review of
noninvasive positive pressure ventilation in severe stable
COPD. Eur Respir J.2007 Aug;30(2):293306.
431. Washko GR, Fan VS, Ramsey SD, Mohsenifar Z, Martinez
F, Make BJ, Sciurba FC, Criner GJ, Minai O, Decamp MM,
Reilly JJ; for the National Emphysema Treatment Trial
Research Group. The effect of lung volume reduction surgery
on chronic obstructive pulmonary disease exacerbations. Am J
Respir Crit Care Med 2008 Jan 15;177(2):1649.
432. de Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA,
van den Berg JW. Oral or IV prednisolone in the treatment of
COPD exacerbations: a randomized, controlled, doubleblind
study. Chest 2007 Dec;132(6):17417.
433. Murphy TF, Brauer AL, Eschberger K, Lobbins P, Grove L,
Cai X, Sethi S. Pseudomonas aeruginosa in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2008 Apr 15;177(8):85360.
434. Wildman MJ, Sanderson C, Groves J, Reeves BC, Ayres
J, Harrison D, Young D, Rowan K. Implications of prognostic
pessimism in patients with chronic obstructive pulmonary
disease (COPD) or asthma admitted to intensive care in the UK
within the COPD and asthma outcome study (CAOS):
multicentre observational cohort study. BMJ 2007
Dec1;335(7630):1132.
435. Bahadori K, FitzGerald JM. Risk factors of hospitalization and
readmission of patients with COPD exacerbationsystematic
review. Int J Chron Obstruct Pulmon Dis 2007;2(3):24151.
436. Iversen KK, Kjaergaard J, Akkan D, Kober L, TorpPedersen
C, Hassager C, Vestbo J, Kjoller E; ECHOSLung Function
Study Group. Chronic obstructive pulmonary disease
in patients admitted with heart failure. J Intern Med. 2008
Oct;264(4):3619.
437. Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins
CR, Jones PW, Vestbo J, Knobil K, Yates JC, Calverley
PM. Effect of pharmacotherapy on rate of decline of
lung function in chronic obstructive pulmonary disease: results
from the TORCH study. Am J Respir Crit Care Med. 2008 Aug
15;178(4):3328.
438. Donohue JF, Hanania NA, Fogarty C, Campbell SC, Rinehart
M, DenisMize K. Long-term safety of nebulized formoterol:
results of a twelvemonth openlabel clinical trial. Ther Adv
Respir Dis. 2008 Aug;2(4):199208.
439. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S,
Decramer M; UPLIFT Study Investigators. A 4year trial of
tiotropium in chronic obstructive pulmonary disease. N Engl J
Med. 2008 Oct 9;359(15):154354.
440. Vogelmeier C, Kardos P, Harari S, Gans SJ, Stenglein
S, Thirlwell J. Formoterol monoand combination therapy with
tiotropium in patients with COPD: a 6month study. Respir Med.
2008 Nov;102(11):151120.
441. Rabe KF, Timmer W, Sagkriotis A, Viel K. Comparison of
a combination of tiotropium plus formoterol to salmeterol plus
futicasone in moderate COPD. Chest. 2008 Aug;134(2):25562.
442. Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan
E. Inhaled corticosteroids in patients with stable
chronic obstructive pulmonary disease: a systematic review
and metaanalysis. JAMA. 2008 Nov 26;300(20):240716.
Review.
443: Singh S, Amin AV, Loke YK. Long-term use of inhaled
corticosteroids and the risk of pneumonia in chronic obstructive
pulmonary disease: a metaanalysis. Arch Intern Med. 2009 Feb
9;169(3):21929. Review.
444. Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche
M, Tamm M. A randomised, controlled trial of bosentan in
severe COPD. Eur Respir J. 2008 Sep;32(3):61928.
445. Snyder ML, Goss CH, Neradilek B, Polissar NL, Mosenifar Z,
Wise RA, Fishman AP, Benditt JO; National Emphysema
Treatment Trial Research Group. Changes in arterial
oxygenation and selfreported oxygen use after lung volume
reduction surgery. Am J Respir Crit Care Med.
2008 Aug 15;178(4):33945.
446: Rizkallah J, Man SF, Sin DD. Prevalence of pulmonary
embolism in acute exacerbations of COPD: a systematic
review and metaanalysis. Chest. 2009 Mar;135(3):78693. Epub
2008 Sep 23. Review
447. Stllberg B, Selroos O, Vogelmeier C, Andersson E, Ekstrm
T, Larsson K. Budesonide/formoterol as effective
as prednisolone plus formoterol in acute exacerbations of
COPD. A doubleblind, randomised, noninferiority, parallelgroup,
multicentre study. Respir Res. 2009 Feb 19;10:11.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
88 MANAGEMENT OF COPD
448. Eisner MD, Blanc PD, Yelin EH, Katz PP, Sanchez G, Iribarren
C, Omachi TA. Infuence of anxiety on health outcomes in
COPD. Thorax 2010;65(3):229-34.
449. Vestbo J, Anderson JA, Calverley PM, Celli B, Ferguson GT,
Jenkins C, Knobil K, Willits LR, Yates JC, Jones PW.
Adherence to inhaled therapy, mortality and hospital admission
in COPD. Thorax 2009;64(11):939-43.
450. Effng T, Kerstjens H, van der Valk P, Zielhuis G, van der Palen
J. (Cost)-effectiveness of self-treatment of exacerbations on the
severity of exacerbations in patients with COPD: the COPE II
study. Thorax 2009;64(11):956-62.
451. Ferguson GT, Calverley PM, Anderson JA, Jenkins CR,
Jones PW, Willits LR, Yates JC, Vestbo J, Celli B. Prevalence
and progression of osteoporosis in patients with COPD: results
from the TOwards a Revolution in COPD Health study. Chest
2009;136(6):1456-65.
452. Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT,
Jenkins C, Jones PW, Willits LR, Yates JC, Vestbo J.
Pneumonia risk in COPD patients receiving inhaled
corticosteroids alone or in combination: TORCH study results.
Eur Respir J 2009;34(3):641-7.
453. Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson
S, Polanowski T, Kessler R. Effcacy and tolerability of
budesonide/formoterol added to tiotropium in patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 2009;180(8):741-50.
454. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh
DS, Brose M, Martinez FJ, Rabe KF; M2-127 and M2-128
study groups. Rofumilast in moderate-to-severe chronic
obstructive pulmonary disease treated with long-acting
bronchodilators: two randomised clinical trials.
Lancet 2009;374(9691):695-703.
455. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri
LM, Martinez FJ; M2-124 and M2-125 study groups.
Rofumilast in symptomatic chronic obstructive pulmonary
disease: two randomised clinical trials. Lancet
2009;374(9691):685-94.
456. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP;
UPLIFT investigators. Effect of tiotropium on outcomes
in patients with moderate chronic obstructive pulmonary
disease (UPLIFT): a prespecifed subgroup analysis
of a randomised controlled trial. Lancet 2009;374(9696):11718.
457. Schembri S, Morant S, Winter JH, MacDonald TM. Infuenza
but not pneumococcal vaccination protects against all-cause
mortality in patients with COPD. Thorax 2009;64(7):567-72.
458. Fernndez AM, Pascual J, Ferrando C, Arnal A, Vergara
I, Sevila V. Home-based pulmonary rehabilitation in very
severe COPD: is it safe and useful? J Cardiopulm Rehabil
Prev 2009;29(5):325-31.
459. Fischer MJ, Scharloo M, Abbink JJ, van t Hul AJ, van Ranst
D, Rudolphus A, Weinman J, Rabe KF, Kaptein AA. Drop-out
and attendance in pulmonary rehabilitation: the role of clinical
and psychosocial variables. Respir Med 2009;103(10):1564-71.
460. McEvoy RD, Pierce RJ, Hillman D, Esterman A, Ellis EE,
Catcheside PG, ODonoghue FJ, Barnes DJ, Grunstein
RR; Australian trial of non-invasive Ventilation in Chronic
Airfow Limitation (AVCAL) Study Group. Nocturnal
non-invasive nasal ventilation in stable hypercapnic COPD: a
randomized controlled trial. Thorax 2009;64(7):561-6.
461. Daniels JM, Snijders D, de Graaff CS, Vlaspolder F, Jansen
HM, Boersma WG. Antibiotics in addition to systemic
corticosteroids for acute exacerbations of chronic obstructive
pulmonary disease. Am J Respir Crit Care Med
2010;181(2):150-7.
462. Wood-Baker R, McGlone S, Venn A, Walters EH. Written
action plans in chronic obstructive pulmonary disease increase
appropriate treatment for acute exacerbations. Respirology
2006;11:619-26.
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
CHAPTER
6
TRANSLATING
GUIDELINE
RECOMMENDATIONS
TO THE CONTEXT
OF (PRIMARY) CARE
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
90 TRANSLATING GUIDELINE RECOMMENDATIONS TO THE CONTEXT OF (PRIMARY) CARE
KEY POINTS:

There is considerable evidence that management
of COPD is generally not in accordance with current
guidelines. Better dissemination of guidelines and
their effective implementation in a variety of health
care settings is urgently required.
In many countries, primary care practitioners treat
the vast majority of patients with COPD and may be
actively involved in public health campaigns and in
bringing messages about reducing exposure to risk
factors to both patients and the public.
Spirometric confrmation is a key component of the
diagnosis of COPD and primary care practitioners
should have access to high quality spirometry.
Older patients frequently have multiple chronic health
conditions. Comorbidities can magnify the impact of
COPD on a patient?s health status, and can
complicate the management of COPD.
The recommendations provided in Chapters 1 through 5
defne-from a disease perspective-best practices in the
diagnosis, monitoring, and treatment of COPD. However,
(primary) medical care is based on an engagement with
patients, and this engagement determines the success
or failure of pursuing best practice. For this reason,
medical practice requires a translation of disease-specifc
recommendations to the circumstances of individual
patients the local communities in which they live, and
the health systems from which they receive medical care.
This chapter summarizes a number of key factors in the
application of the recommendations in clinical practice,
particularly primary care. These factors will determine to a
large extent the success with which the GOLD-proposed
best practices will be implemented.
It is recognized that the scope of this chapter is limited. It
does not cover the wide range of health care workers that
provide care for COPD patients, nor the ever increasing
need to develop educational curricula that will lead to better
skills for COPD diagnosis and management, nor does
it explore the essential role of national/regional Medical
Societies from many disciplines working together, and in
collaboration with public health offcials to coordinate key
messages to increase COPD awareness and reduce the
burden of this disease. These topics are very important and
will receive increasing attention in the years to come.
Early diagnosis and implementation of treatment
especially smoking cessationhave been demonstrated to
prevent or delay the onset of airfow limitation or reduce
its progression. In pursuing early diagnosis, a policy of
identifying patients at high risk of COPD, followed by
watchful surveillance of these patients, is advised.
Respiratory Symptoms
Of the chronic symptoms characteristic of COPD
(dyspnea, cough, sputum production), dyspnea is the
symptom that interferes most with a patients daily life
and health status. When taking the medical history of the
patient, it is therefore important to explore the impact of
dyspnea and other symptoms on daily activities, work,
and social activities, and provide treatment accordingly.
History taking is as much listening to the patient as
asking questions, and active listening will often reveal the
impact of signs/ symptoms on the patients health status.
If this process yields insuffcient clarity, it can be helpful
to use a short questionnaire such as the British Medical
Research Council (MRC) questionnaire
1
, which measures
the impact of dyspnea on daily activities, the Clinical
COPD Questionnaire (CCQ)
2
, which measures COPD-
related symptoms, functional status, and mental health,
or the International Primary Care Airways Group (IPAG)
Questionnaire which measures COPDrelated symptoms
and risk factors (http://www.ipag.org).
Spirometry
COPD is both underdiagnosed and overdiagnosed in
most countries. To avoid this, the use and availability of
highquality spirometry should be encouraged. Highquality
spirometry in primary care is possible
3,4
, provided that
good skills training and an ongoing quality assurance
program are provided. An alternative is to ensure that
high quality spirometry is available in the community,
for example, within the primary care practice itself, in a
primary care laboratory, or in a hospital setting, depending
on the structure of the local health care system
5
. Ongoing
collaboration between primary care and respiratory care
also helps assure quality control.
CHAPTER 6: TRANSLATING GUIDELINE RECOMMENDATIONS
TO THE CONTEXT OF (PRIMARY) CARE
INTRODUCTION
DIAGNOSIS
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
TRANSLATING GUIDELINE RECOMMENDATIONS TO THE CONTEXT OF (PRIMARY) CARE 91
Although confrmation of the diagnosis of COPD and
assessment of disease severity are established by
spirometry, in many countries primary care practitioners
diagnose COPD on clinical grounds alone
6
. Several
factors are responsible for this situation, including poor
recognition of the essential role of spirometry in the
diagnosis of COPD, and lack of adequate training in its
use and interpretation
68
. There is a clear necessity for
further education initiatives targeted to all primary care
practitioners in order to address these factors.
However, in many areas practitioners lack access to
spirometry, especially state-of-theart spirometry. Under
such conditions it is not possible to fully apply the
recommendations in this report, and diagnosis of COPD
has to be made with the tools available. Use of peak
fow meters may be considered, provided that the limited
(positive and negative) predictive value of peak fow meters
for the diagnosis of COPD is clearly understood. Low
peak fow is consistent with COPD but has poor specifcity,
since it can be caused by other lung diseases or by poor
performance. The use peak fow should not impede the
implementation of spirometry.
Older patients frequently have multiple chronic health
conditions. It has been estimated that worldwide, 25%
of people over age 65 suffer from two of the fve most
common chronic diseases (which include COPD), and 10%
suffer from three or more. These fgures rise to 40% and
25%, respectively, among those 75 and older
9
.
The severity of comorbid conditions and their impact on a
patients health status will vary between patients and in the
same patient over time. Comorbidities can be categorized
in various ways to aid in the better understanding of
their impact on the patient, and their impact on disease
management
10
.

Common pathway comorbidities: diseases with a
common pathophysiologyfor instance, in the case
of COPD, other smokingrelated diseases such as
ischemic heart disease and lung cancer
Complicating comorbidities: conditions that arise
as a complication of a specifc preexisting diseasein
the case of COPD, pulmonary hypertension and
consequent heart failure. Early intervention is directed
at preventing complications and the effectiveness of
these early interventions should be monitored.
Coincidental comorbidities: Coexisting chronic
conditions with unrelated pathogenesis. Particularly
in diseases like COPD that are related to aging,
there is a high chance of coincidental comorbidity
such as bowel or prostate cancer, depression,
diabetes mellitus, Parkinson?s disease, dementia,
andarthritis. Such conditions may make COPD
management more diffcult.
Intercurrent comorbidities: Acute illnesses that may
have a more severe impact in patients with a given
chronic disease. For example, upper respiratory tract
infections are the most frequent health problem in all
age groups, but they may have a more severe impact
or require different treatment in patients with COPD.
Reduction of total personal exposure to tobacco smoke,
occupational dusts and chemicals, and indoor and outdoor
air pollutants, including smoke from cooking over biomass
fueled fres, are important goals to prevent the onset
and progression of COPD. In many health care systems,
primary care practitioners may be actively involved in
public health campaigns and can play an important part in
bringing messages about reducing exposure to risk factors
to patients and the public. Primary care practitioners can
also play a very important role in reinforcing the dangers
of passive smoking and the importance of implementing
smokefree work environments.
Smoking cessation: Smoking cessation is the most
effective intervention to reduce the risk of developing
COPD, and simple smoking cessation advice from health
care professionals has been shown to make patients more
likely to stop smoking. Primary care practitioners often have
many contacts with a patient over time, which provides
the opportunity to discuss smoking cessation, enhance
motivation for quitting, and identify the need for supportive
pharmacological treatment. It is very important to align the
advice given by individual practitioners with public health
campaigns in order to send a coherent message to the
public.
A systematic review and metaanalysis of the effectiveness
of integrated disease management programs for care
of patients with COPD concluded that these programs
modestly improved exercise capacity, health related
quality of life
15
, and hospital admissions
11, 14
but there is
no effect on mortality
14
. Combining general practitioners
with practice nurses in one model had a positive effect
COMORBIDITIES
REDUCING EXPOSURE TO
RISK FACTORS
INTEGRATIVE CARE IN THE
MANAGEMENT OF COPD
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
92 TRANSLATING GUIDELINE RECOMMENDATIONS TO THE CONTEXT OF (PRIMARY) CARE
on patient compliance
12
. An integrated care intervention
including education, coordination among levels of care,
and improved accessibility, reduced hospital readmissions
in chronic obstructive pulmonary disease (COPD) after 1
year
13
.
GOLD has developed a network of individuals, the GOLD
National Leaders, who are playing an essential role in
the dissemination of information about prevention, early
diagnosis, and management of COPD in health systems
around the world. A major GOLD program activity that has
helped to bring together health care teams at the local level
is World COPD Day, held annually on the third Wednesday
in November (http://www.goldcopd.org/WCDIndex.asp).
GOLD National Leaders, often in concert with local
physicians, nurses, and health care planners, have hosted
many types of activities to raise awareness of COPD.
WONCA (the World Organization of Family Doctors) is
also an active collaborator in organizing World COPD Day
activities. Increased participation of a wide variety of health
care professionals in World COPD Day activities in many
countries would help to increase awareness of COPD.
GOLD is a partner organization in a program launched in
March 2006 by the World Health Organization, the Global
Alliance Against Chronic Respiratory Diseases (GARD).
The goal is to raise awareness of the burden of chronic
respiratory diseases in all countries of the world, and
to disseminate and implement recommendations from
international guidelines.
Information about the GARD program can be found at
http://www.who.int/respiratory/gard/en/
REFERENCES
1. Bestall JC, Paul EA, Garrod R, Garnham R, Jones
PW, Wedzicha JA. Usefulness of the Medical Research
Council (MRC) dyspnoea scale as a measure of
disability in patients with chronic obstructive pulmonary
disease. Thorax 1999;54(7):5816.
2. Van Der Molen T, Willemse BW, Schokker S, Ten
Hacken NH, Postma DS, Juniper EF. Development,
validity and responsiveness of the Clinical COPD
Questionnaire. Health Qual Life Outcomes
2003;1(1):13.
3. Eaton T, Withy S, Garrett JE, Mercer J, Whitlock
RM, Rea HH. Spirometry in primary care practice:
the importance of quality assurance and the impact of
spirometry workshops. Chest 1999;116(2):41623.
4. Schermer TR, Jacobs JE, Chavannes NH, Hartman
J, Folgering HT, Bottema BJ, et al. Validity of spirometric
testing in a general practice population of patients with
chronic obstructive pulmonary disease (COPD). Thorax
2003;58(10):8616.
5. Schermer T, Eaton T, Pauwels R, van Weel C.
Spirometry in primary care: is it good enough to face
demands like World COPD Day? Eur Respir J
2003;22(5):7257.
6. Bolton CE, Ionescu AA, Edwards PH, Faulkner TA,
Edwards SM, Shale DJ. Attaining a correct
diagnosis of COPD in general practice. Respir Med
2005;99(4):493500.
7. Caramori G, Bettoncelli G, Tosatto R, Arpinelli F, Visona
G, Invernizzi G, et al. Underuse of spirometry by
general practitioners for the diagnosis of COPD in Italy.
Monaldi Arch Chest Dis 2005;63(1):612.
8. Walters JA, Hansen E, Mudge P, Johns DP, Walters EH,
WoodBaker R. Barriers to the use of spirometry in
general practice. Aust Fam Physician 2005;34(3):2013.
9. van Weel C. Chronic diseases in general practice: the
longitudinal dimension. Eur J Gen Pract 1996;2:1721.
10. Schellevis FG, Van de Lisdonk EH, Van der Velden
J, Hoogbergen SH, Van Eijk JT, Van Weel C.
Consultation rates and incidence of intercurrent
morbidity among patients with chronic disease in
general practice. Br J Gen Pract 1994;44(383):25962.
11. Rea H, McAuley S, Stewart A, Lamont C, Roseman
P, Didsbury P. A chronic disease management
programme can reduce days in hospital for patients
with chronic obstructive pulmonary disease. Intern Med
J 2004;34(11):60814.
12. Meulepas MA, Jacobs JE, Smeenk FW, Smeele I,
Lucas AE, Bottema BJ, Grol RP. Effect of an integrated
primary care model on the management of middleaged
and old patients with obstructive lung diseases. Scand J
Prim Health Care 2007 Sep;25(3):18692.
13. GarciaAymerich J, Hernandez C, Alonso A, Casas A,
RodriguezRoisin R, Anto JM, Roca J. Effects of an integrated
care intervention on risk factors of COPD readmission. Respir
Med 2007 Jul;101(7):14629.
14. PeytremannBridevaux I, Staeger P, Bridevaux PO, Ghali
WA, Burnand B. Effectiveness of chronic obstructive
pulmonary diseasemanagement programs: systematic review
and metaanalysis. Am J Med. 2008 May;121(5):433443.e4.)
15. Chavannes NH, Grijsen M, van den Akker M, Schepers
H, Nijdam M, Tiep B, Muris J. Integrated disease
management improves one-year quality of life in primary
care COPD patients: a controlled clinical trial. Prim Care Respir
J 2009;18(3):171-6.
IMPLEMENTATION OF COPD
GUIDELINES
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
93
NOTES
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
94
NOTES
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
95
NOTES
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
96
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E
Visit the GOLD website at www.goldcopd.org
2010 Global Initiative for Chronic Obstructive Lung Disease
The Global Initiative for Chronic Obstructive Lung Disease is supported by educational grants from:
C
O
P
Y
R
I
G
H
T
E
D

M
A
T
E
R
I
A
L

-

D
O

N
O
T

A
L
T
E
R

O
R

R
E
P
R
O
D
U
C
E