One hundred years of respiratory medicine chronic obstructive pulmonary disease (COPD)—Republished article

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R E S P I R AT O RY M E D I C I N E : C O P D U P D AT E 4 ( 2 0 0 8 ) 8 – 2 5

$This article wasCOPD Update read

1745-0454/$ - see frodoi:10.1016/j.rmedu

�Corresponding autE-mail address: m

One hundred years of respiratory medicine chronicobstructive pulmonary disease (COPD)—Republishedarticle$

Mario Cazzolaa,�, Claudio Donnerb, Nicola. A. Hananiac

aDepartment of Internal Medicine, University of Rome ‘Tor Vergata’, Rome, ItalybMondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), ItalycPulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA

a r t i c l e i n f o

Keywords:

COPD

Chronic bronchitis

Emphysema

first published in Respers. Readers are reque

nt matter & 2007 Publish.2007.11.019

hor.ario.cazzola@uniroma2

a b s t r a c t

COPD is an increasing health problem and one of the leading causes of morbidity and

mortality worldwide, but knowledge about its pathogenesis has increased substantially in

recent years. The disease results from interaction between individual risk factors (like

enzymatic deficiencies) and environmental exposures to noxious agents, like cigarette

smoking, occupational dusts, air pollution and infections in childhood. The main

mechanisms that may contribute to airflow limitation in COPD are fixed narrowing of

small airways, emphysema and luminal obstruction with mucus secretions. COPD is

characterized by a chronic inflammatory process in the pulmonary tissue, with a pattern

different from bronchial asthma, associated with extra pulmonary effects and is

considered now a complex, systemic disease. Optimal therapeutic targeting of COPD

depends on a clear understanding of the precise mechanisms of these complex processes

and on early and correct evaluation of disease severity. A combination of pharmacological

and non-pharmacological approaches is used to treat COPD. Bronchodilators are the

mainstay of COPD treatment and can be combined with inhaled corticosteroids for greater

efficacy and fewer side effects. The use of LTOT for hypoxemic patients has resulted in

increased survival, and expanded drug therapy options have effectively improved dyspnoea

and quality of life. Recent studies have documented the benefits of pulmonary

rehabilitation. In addition, noninvasive mechanical ventilation offers new alternatives for

patients with acute or chronic failure.

& 2007 Published by Elsevier Ltd.

Introduction

Chronic obstructive pulmonary disease (COPD) is a relatively

new term for an old disease. Terms such as ‘‘bronchitis’’,

‘‘emphysema’’, ‘‘asthmatic bronchitis’’ and ‘‘chronic bronchi-

tis’’ were more commonly used in the past to describe what

iratory Medicine, Vol. 101sted to cite the original

ed by Elsevier Ltd..it (M. Cazzola).

we currently define as COPD. This review will highlight

important papers published on the topic over the last 100

years in Respiratory Medicine and in its previous versions

British Journal of Tuberculosis; British Journal of Tuberculosis

and Diseases of the Chest and British Journal of Diseases of

the Chest.

, Issue 6, pp. 1049–1065 and is re-published for the benefit ofsource when citing this article.

dx.doi.org/10.1016/j.rmedu.2007.11.019

mailto:[email protected]

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Epidemiology and risk factors of COPD

Several publications have addressed the risk factors of COPD

in the general population although early ones included only

cohorts of working men with limited income. Rimington1,2

analysed data from mass radiography units and concluded

that patients with chronic bronchitis were more likely to be

old, heavy smokers and belong to a low social class.1 The

mean age-adjusted prevalence rate for chronic bronchitis in

that cohort was 12.3% in all men and 5.6% in all women.

However this was highest in-patients who smoked 20 or more

cigarettes per day (20% and 18.5% in men and women,

respectively). In a subsequent publication, the same author

demonstrated that the prevalence of chronic bronchitis in

individuals who inhaled while smoking was 50% higher than

in those who did not.2 It is unclear why only a minority of

smokers develop a clinically significant disease. In addition to

smoking, genetic risk factors such as alpha1-antitrypsin

deficiency play an important role in some patients.3–5

The impact of COPD

COPD is associated with significant morbidity and mortality

worldwide and is currently a global health priority. In 1954, a

study by Stuart-Harris evaluated the epidemiology and

evolution of chronic bronchitis and described morbidity data

collected from practitioners’ visits, industrial records and

National Insurance data.6 These data revealed that in 1950,

‘‘bronchitis’’ was the second leading cause of incapacity from

sickness and the sixth most common cause of claims of

sickness in both men and women in Great Britain. Bronchitis

as a cause of sickness was scattered over the whole ages in

women but was more common in old men than young men.

However, the author admits that there was no way to

differentiate acute bronchitis from chronic bronchitis from

that database. The same paper evaluated another field survey

of patients with bronchitis and described a group of sympto-

matic patients with a ‘‘triple complex’’ syndrome of cough,

sputum and disability (dyspnoea or history of exacerbation).

Patients with this ‘‘triple complex’’ were more likely to be old

and had a high incidence of hospitalization. This was one of

the few papers published at that time which attempted to

classify the severity of COPD. In a subsequent paper published

in 1964, the formation of a bronchitis registry in East London

was described and patients were divided into three groups

(Group 0, 1 and 2) according to severity of symptoms and lung

function abnormality.7 The authors further analysed the

characteristics and the impact of the disease in these groups

demonstrating that patients belonging to Group 2 had the

highest morbidity and had more time lost from work than

patients in the other two groups.7 The burden of COPD in

different countries was a focus of several publications over

the last 100 years.8–13 In a report published in 1960 from the

East London cohort, Caplin and Silver8 reported that un-

This article was first published in Respiratory Medicine, Vol. 101,COPD Update readers. Readers are requested to cite the original

employment and time lost from work were significant in

patients with chronic bronchitis. The authors concluded that

‘‘the chronic bronchitic suffers from two disabilities which

may make it difficult for him to retain his usual employment

or find a new employment. These are increasing shortness of

breath on exertion and lung infections which force him to be

away from worky’’. It is of great interest that almost fifty

years later, the same problems are major causes of disability

in patients with COPD. Utilization of healthcare services and

hospitalizations driven by disease severity account for a

major component of the total cost of COPD worldwide.13–20

The confronting COPD in North America and Europe survey

which was the first large-scale international survey of the

burden of COPD estimated the annual cost of healthcare

utilization in the US at $4119 per patient with COPD, with

indirect cost of $1527 per patient. The annual estimated

societal cost was $5646 per patient. Inpatient hospitalization

accounted for the majority of this cost ($2891).9 The same

survey revealed that patients with COPD often underestimate

the severity of their illness. Exacerbations of COPD account

for 35–45% of the total per capita healthcare costs for COPD;

however, these costs vary considerably with the severity of

the exacerbation as well as the severity of COPD.20

COPD in special populations

Although COPD has for a long time been considered a disease

of old Caucasian men, recent data from the US show that

mortality is rising faster among women and African-Amer-

icans.21 In a recently published study describing the char-

acteristics of patients with COPD from a research database,

Caucasians had less loss of lung function per pack-year

smoked than African-Americans and was also less in men

than women suggesting that indeed African-American wo-

men are most susceptible to the ill effects of smoke compared

to other groups of men and women.22 Findings from the

Confronting COPD International Survey, also indicate that

gender differences in COPD care and outcomes do exist and

need to be further explored.23 Women with COPD were less

likely to have had spirometry testing, but more likely to have

received smoking cessation advice. Furthermore, women

were more likely to report severe dyspnoea, had similar

cough but less sputum production than men.

While any patient above the age of 40 is at risk of this

disease, patients with advanced age are at higher risk of

complications and increased morbidity from this disease.24 A

report from the obstructive lung disease in northern Sweden

studies demonstrated that almost 50% of elderly smokers

fulfilled the criteria for COPD according to both the BTS and

GOLD guidelines.25 However, while guidelines recommend

the use of a post-bronchodilator ratio of forced expiratory

volume in 1 s (FEV1)/FVC o70% to define COPD, the physio-

logic cutoffs for the defining COPD in elderly patients is still

unknown. Furthermore, COPD in the elderly is associated

with impaired health status which may not necessary be

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predicted by lung function tests.26,27 Important determinants

of health status in this population include activity of daily

living (ADL) and emotional status.27

Clinical manifestations and diagnosis of COPD

The clinical presentation of patients with COPD is far from

uniform. This fact has been very well described in several

classic publications in the British Journal of Diseases of the

Chest.28–30 Most patients with COPD present in the fifth or

sixth decade of life although patients with alpha-1-antitryp-

sin deficiency may present at a younger age.4,5 Furthermore,

symptoms of COPD vary among patients. While most patients

with COPD present with symptoms of cough and shortness of

breath on exertion, many others have minimal symptoms

early in their disease process. Several screening question-

naires have been developed for use in everyday clinical

practice to facilitate the diagnosis of COPD in a primary care

setting.31–33

A complete assessment of a COPD patient should include

physiologic measures of lung function. Spirometry is the

most widely used and feasible test which can be performed in

the primary care setting.34 The diagnosis of COPD is made if

the post-bronchodilator FEV1/FVC ratio is o70% although the

FEV1/FEV6 ratio may be used as an alternative as it has been

shown to correlate with FEV1/FVC.35 Evaluation of acute

bronchodilator response should not be used alone as an

index to differentiate asthma from COPD as many patients

with COPD demonstrate significant reversibility to acute

bronchodilator administration.36 Other tests of lung function

such as measurement of lung volumes (e.g.; inspiratory

capacity at rest and during exercise) can shed more details

on the physiologic abnormalities present in COPD although

such tests are rarely needed on routine assessment.37,38

Exercise intolerance in patients with COPD can be assessed

either by measuring the walking distance (e.g., six minute

walk test) or by performing formal exercise testing using

treadmill or cycle ergometry.39–41

Diagnosis of COPD in the community is more likely in

patients with worse lung function and health status and in

patients who are symptomatic.42 However, attaining a correct

and early diagnosis in the primary care setting remains

challenged by the delay and infrequent use of spirometry in

that setting due to lack of adequate training in its use and

interpretation.43 This is compounded by the lack of knowl-

edge about COPD by patients at risk such as heavy smokers.44

Furthermore there is no clear correlation between symptoms,

effort intolerance, and objective measures of lung func-

tion.45,46 This has been clearly described in a classic article

published in the British Journal of Diseases of the Chest in 1961

which studied a group of in-patients with chronic obstructive

airway disease attending the London Chest Hospital.45

Despite being a pilot study, this manuscript sets out to grade

the severity of disease and assess the clinical value of using

various tests in patients with ‘‘chronic obstructive airway


diseases’’. The authors studied effort intolerance, lung func-

tion, arterial blood-gas analysis and exercise desaturation

and suggest that assessing severity of the disease should

include more than one measure. It is of interest that 60 years

later, grading the severity of COPD continues to be an

important clinical dilemma. While current guidelines suggest

using the percent predicted FEV1 to assess severity of the

disease, recent studies suggest that the use of multidimen-

sional grading systems may be more useful in assessing the

severity and impact of COPD.47 Furthermore, the use of

radiological studies to evaluate the lung parenchyma and

airway wall thickness may aid in differentiating between the

different COPD severity phenotypes.48,49

Management guidelines for COPD

Several guidelines for the management of COPD have been

published.50–56 While the main goals for these guidelines are

to achieve better standards for the diagnosis, treatment and

prevention of COPD, unfortunately these guidelines have not

been widely implemented.55–57 Furthermore, primary care

physicians who treat the majority of patients with COPD often

find the guidelines complicated and thus show a major gap in

the knowledge of all core elements of these guidelines.57 A

major problem with existing guidelines is that they are

usually based on efficacy and not on effectiveness studies,

and do not properly focus the process of behavioural changes

of health professionals and patients.56 Furthermore, as rapid

changes may occur in the treatment of COPD, future guide-

lines should be able to adapt to these rapid adjustments.

Prognostic factors and health outcomes in COPD

COPD has a progressive course especially in patients who

continue to smoke. Several studies have addressed risk

factors associated with progression of COPD.58–60 Early

studies performed on case series of patients with COPD,

demonstrate that the severity of airflow obstruction, hypox-

aemia, hypercapnia and dyspnoea, and the presence of co-

morbidities such as congestive heart failure are important

indicators of poor prognosis in COPD.59,60 A more recent paper

described important gender differences in the predictors of

decline of lung function in mild to moderate COPD.58

Although lung function remains the most important

objective outcome in assessing the severity and prognosis of

patients with COPD, success of treatments for this disease is

usually evaluated by measuring the impact of such treat-

ments on a range of patients health outcomes.61,62 The course

of patient-reported outcomes such as health status, dyspnoea

and psychological status often deteriorate significantly over

time and may not strongly correlate with changes in lung

function parameters such as FEV1.63

Change in symptoms of COPD is an important health

outcome although cannot be accurately measured. The


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Breathlessness, Cough and Sputum Scale was shown to be a

reliable, valid and responsive patient-reported outcome

measure of symptom severity in patients with COPD and

can be used in clinical trials.64,65 Several instruments to

measure health status were developed, tested and validated

in patients with COPD.66–72 Heath status in COPD correlates

with severity of the disease and hypoxaemia, and the

presence of co-morbidities.73 One study which compared

the responsiveness of six instruments used to measure health

status, confirmed that the Chronic Respiratory Questionnaire

(CRQ) and the Saint Georges Respiratory Questionnaire

(SGRQ) were substantially more responsive than generic

measures, and suggested particularly strong responsiveness

for the self-administered CRQ.67 Activities of daily living (ADL)

may be severely restricted in patients with COPD and their

assessment requires evaluation of the impact of disability and

handicap on daily life. The London Chest Activity of Daily

Living Scale (LCADL) was shown to be a valid tool for

assessment of patients with severe COPD.74 In a subsequent

study, this scale was also shown to be a valid outcome

measure which is reliable and responsive to change.75

Co-morbidities of COPD

COPD is a multicomponent disease. These components affect

the lungs and organs outside the lungs.76,77 The impact of the

systemic co-morbidities of COPD is substantial,72,78 and

although some studies have addressed the potential mechan-

isms underlying these co-morbidities, many important ques-

tions remain to be answered. Systemic manifestations of

COPD include musculoskeletal,79–81 psychological,82–84 nutri-

tional depletion,85,86 anaemia and sexual dysfunction.87 Other

pulmonary co-morbidities of COPD include cardiovascular

complications and pulmonary hypertension,88–91 obstructive

sleep apnoea92 and lung cancer.93 Thus a comprehensive

assessment of a patient with COPD should also include

assessing the systemic co-morbidities of this disease.

Acute exacerbation of COPD

Acute exacerbation of COPD is associated with increased

morbidity and mortality.94 A variety of definitions for acute

exacerbation of COPD have been used in clinical studies.

These have been traditionally based on change in patients’

symptoms or their requirement for antibiotic therapy, oral

steroids or hospitalization.95 The importance for a standard

definition has been recently emphasized.95 From a recent

survey from 1100 subjects with symptoms compatible with

COPD,96 exacerbations generated a mean of 5.1 medical visits/

year (SD ¼ 4.6) with the mean duration of exacerbation

symptoms being 10.5 days. Increased coughing was the

exacerbation symptom having the strongest impact on well-

being (42%). Fifty-five per cent of patients declared that


quicker symptom relief was the most desired requirement

for treatment.

The role of bacterial and viral infections as causative factors

of acute exacerbation of COPD was extensively described in

several publications over the last 50 years.97–99 In one of these

classic publications, Calder et al.98 described their experience

from a 5-year study of prophylactic antibiotic therapy in

patients with chronic bronchitis. In that study, the use of

prophylactic antibiotics reduced the number of exacerbations

and the isolation of sputum pathogens; however it did not

influence the rate of decline in ventilatory function. This was

one of the very first longitudinal studies that utilized what

later became the gold standard outcome in assessing the

natural history of the disease; the decline in lung function.

Many patients with acute exacerbation of COPD may need

hospitalization. The presence of concurrent diseases such as

heart disease and pneumonia prolong the hospital episodes

of COPD patients78 and the use of long-term oxygen therapy

(LTOT) and of short-acting b-agonists were associated with a

late recovery from acute exacerbation of COPD.100 Factors that

have been associated with re-admission for acute exacerba-

tion of COPD include: hospital admission within 1 year

prior to the current exacerbation, nursing home residency,

dependency in self-care activities, right heart strain pattern

on electrocardiogram, the use of high doses of inhaled

corticosteroids (ICSs) and a serum bicarbonate level

425 mmol/L.101

Treatment

Recent research has focussed on examining the multicompo-

nent nature of COPD (including impairments of metabolism

and inflammation) more carefully, and determining the

effects of treatment on both the systemic and physiological

aspects of COPD. In effect, the multicomponent nature of

COPD has provided a challenging environment in which to

develop successful treatments.

Obviously, many questions remain to be answered, but a

comprehensive approach is now considered essential to the

life-long management of COPD, and will undoubtedly reduce

the considerable socio-economic burden of COPD.102 At

present time, a combination of pharmacological and non-

pharmacological approaches seems to be effective in the

attempt to face with these problems.

Pharmacologic treatment

Pharmacologic treatment for COPD includes antibiotics,

bronchodilators, corticosteroids, and mucolytics. There are

also some other classes of drugs that are still considered of

minor importance, but worthy of clinical investigation.

AntibioticsIn 1943, May103 published an article in which he documented

that the concentrations of penicillin attainable in the sputum


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of patients with chronic bronchitis or bronchiectasis were

correlated with the in vitro sensitivity to penicillin of the

infecting organisms and the clinical and bacteriological

response of the patients to treatment. This observation was

really interesting and nowadays it is still relevant. In fact,

today we consider the interrelationship between pharmaco-

kinetics and pharmacodynamics extremely important in

choosing the appropriate antibiotic and the dosage regimen

for treating acute exacerbations of chronic bronchitis.104 It

must be highlighted that in May’s paper each penicillin

regime investigated gave sputum levels higher than the

sensitivity level of pneumococci, which responded satisfac-

torily to all penicillin preparations. Unfortunately, during the

ensuing decades, penicillin-resistant pneumococci has be-

come an area for great clinical concern worldwide because it

has been associated with treatment failure.

Up to 1980, the journal published a large amount of

papers105–128 on the use of antibiotics in the treatment or

prophylaxis of acute exacerbation of chronic bronchitis. In

effects, at that time there was a lot of interest for the

antibiotic therapy. This likely happened because the ‘‘British

hypothesis’’, which was really popular, raised the concept

that chronic bronchitis could predispose to infection, which

in turn damaged the airways and/or the alveoli, leading to

progressive airflow limitation. The continuous introduction

into the market of new anti-infective agents certainly

facilitated the production of data relating to the use of such

agents. Unfortunately, most of these clinical trials of anti-

biotics have compared new drugs with standard therapy in

patients with exacerbations who, in most cases, would have

never required an antibiotic if treated in real-life conditions.

In general, these studies might have been required for the

pharmaceutical companies to launch their new antibiotics,

but offered limited, if any, useful information to the clinician.

In any case, May105 wrote a review that was really important

for those times. He described in extremely critical manner the

problems related to the bacteriology and chemotherapy of

chronic bronchitis. In his conclusions, May expressed an

anticipatory view. It was his opinion that it was possible that

failure of penetration of antibiotic into mucoid bronchial

secretions in patients whose infection was controlled by

bacteriostatic therapy might explain the failure of such

therapy to give more lasting benefit. If the organisms in the

secretions were inaccessible to the antibiotic, and there

were no phagocytes present, there was no reason why

they should not remain viable indefinitely and able to

cause a fresh infection as soon as the bronchial tissue was

freed from protective antibiotic. For this reason, he suggested

that the approach to chemotherapy of chronic bronchitis

had to change from bacteriostatic, which was common at

that time, to bactericidal and, consequently, treatment

courses had to become intensive but for short period.

Interestingly, several articles 108,111,117,122 have reported that

chemoprophylaxis was of no help in preventing acute

exacerbations of pulmonary infection although the attacks

were milder in nature and the total number of monthly


purulent sputum specimens was less in the group given a

prophylactic antibiotic, it had no effect on time off work in

individual spells of illness and, moreover, it did not influence

the rate of deterioration in ventilatory function. It would be

interesting to know why in the following years many

researchers have spent time and money for getting the same

conclusions!

Even in the last few years, Respiratory Medicine has

published some papers devoted to the use of antibiotics in

the treatment of acute exacerbation of chronic bronchi-

tis.128–139 Also these studies, however, might have been

required for the pharmaceutical companies to launch or

support their new antibiotics (gemifloxacin, moxifloxacin,

telithromycin), but offered limited, if any, useful information

to the clinician. Nonetheless, it must be highlighted that

Banerjee et al.136 reported that treatment of COPD with

clarithromycin during the clinical stable state yields no

clinical advantages and therefore cannot be recommended

as means of eliminating sputum bacteria or preventing

infective exacerbations. This does not seem an unexpected

result that fits well with the prescriptive behaviour of general

practitioners. Miravitlles et al.137 published interesting data

coming from a Spanish cross-sectional observational study of

ambulatory COPD patients. Treatment for exacerbations

included inhaled bronchodilators (90%), antibiotics (89%),

ICSs (71%) and oral corticosteroids (43%); the number of

previous acute exacerbations was the main factor associated

with exacerbation treatment except for oral corticosteroids,

the use of which was associated with more impaired

pulmonary function. More intriguing is the Hasani’s138 paper,

which showed that even only 7 days antibiotic treatment

slightly improved tracheobronchial clearance and signifi-

cantly decreased cough suggested a significant role of the

antibiotic treatment at least in decreasing the risks of further

and greater damage to the airway epithelium. In any case,

there is documentation that pneumococcal vaccination

reduces the possibility that an acute exacerbation of COPD

is caused by Streptococcus pneumoniae.139 This finding allows

the use of antibiotics such as azithromycin, which, otherwise,

should be avoided because of resistances.

BronchodilatorsThe article by Feinman and Newell published in 1963,140 was

the first paper in the journal to focus on the use of

bronchodilators for treating an obstructive airway disease. It

had the great merit of documenting that isoprenaline in a

dose of 0.4 mg delivered by a self-propelled aerosol device,

gave an improvement in FEV1 on average 0.10 L better and an

improvement in VC 0.16 L better than 3 min continuous

inhalation of 1% isoprenaline solution using a standard

hospital nebulizer driven by an oxygen cylinder. The authors

recognized that even though these differences were not large

or important clinically, but the much smaller dose given by

the self-propelled aerosol device reduced the chance of side

effects and justified rejection of the more standard methods

of administration that were popular at that time.


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The development of newer bronchodilators at the end of

1970s slowly moved the interest of the journal towards this

new therapeutic option.141–148 The first papers on this topic

were not really innovative or, at least, interesting, expect for

some sporadic reports. Berend et al.141 documented that the

bronchodilator response to salbutamol by intermittent posi-

tive pressure ventilation (IPPV), was greater than by metered

dose inhaler (MDI) only in patients suffering from chronic

obstructive bronchitis with severe airways obstruction and

little additional benefit was gained with the 10 mg dose.

Jenkins and Moxham147 suggested that there is minimal if

any benefit in terms of functional status administering

regular doses above the equivalent of 200mg of salbutamol

four times daily in COPD, although pulmonary function (FEV1

and PEFR, but not FVC) results showed a trend towards higher

doses producing improved response and a longer duration of

action, with bronchodilation following 2 mg significantly

greater than 400mg salbutamol. This study was broadly

forerunner of the actual tendency to use greater than

traditional dosage of long-acting b2-agonists (LABAs), mainly

formoterol, to prolong their duration of action.149

After 1989, the number of articles that have explored the

use of bronchodilators in COPD is increased in a dramatic

manner. It is almost impossible to quote all these articles,

and, consequently, only those papers that in our opinion have

been innovative, will be discussed. Hansel et al.150 and Hansel

and Andersen151 in 1994 and 1995 published two interesting

papers that documented that the replacement of nebulizers

with multi-dose dry powder inhalers was advantageous both

for the COPD patient, in terms of ease of use and portability,

and for the Local Health Service, in terms of reducing

resources spent on inhalation treatment. Cazzola et al.152 in

1995 circulated one of the first articles on the use of LABAs in

the treatment of COPD. Up to 2000, the majority of these

articles have been focused on the activity of LABAs153–157 and

the possibility of combining these agents with bronchodila-

tors of other classes.158,159 Importantly, an editorial published

in 1999160 raised for the first time the question of considering

LABAs an alternative first choice option for the treatment of

stable COPD.

Because of the understanding of the importance of

bronchodilators in the treatment of stable COPD, as also

acknowledged by international guidelines, the presence in

the journal of papers devoted to bronchodilators in COPD is

increased to a great extent. More recently the interest of

researches has been focused on inhaled long-acting bronch-

odilators161–176, although some interesting new observations

on short-acting bronchodilators have also been pub-

lished,177–182 particularly the documentation that prescription

of ipratropium was associated with increased mortality in

both COPD and asthmatic patients.180 Moreover, there have

been two interesting papers on the use of theophylline, now

considered a third line agent in the therapy of COPD.183,184 In

particular, Ram et al.184 have published an evidence-based

review that has shown that theophylline continues to have a

role in the management of stable COPD, and is preferred by


patients over placebo. However, the benefits of theophylline

in stable COPD have to be weighed against the risk of adverse

effects. The documentation that tolerance to pharmacologic

bronchodilation occurs with LABAs such as salmeterol and

not with long-acting inhaled anticholinergics such as tiotro-

pium169 is a really intriguing finding. It must be highlighted

that the reported diminishment of bronchodilator responses

was relatively small, and a prospective trial designed

specifically to examine for tolerance should be designed.

Nevertheless, the concept of tolerance may need to be

considered when re-evaluating COPD patients during chronic

treatment with LABAs. Fortunately, we have an interesting

alternative to LABAs. Adams et al.175 have documented that

once-daily tiotropium provides significant improvement in

lung function, health status, and dyspnoea when used as

maintenance therapy in undertreated COPD patients who

were not previously receiving maintenance bronchodilator

therapy. In any case, although this potentially important

problem, Jones et al.165 have observed that addition of

salmeterol to COPD patients’ current therapy improved lung

function, health status at the expense of a modest increase in

costs compared with usual therapy. Considering the fact that

both LABAs and tiotropium are effective agents in the

treatment of stable COPD, the present trend is to combine a

LABA and tiotropium.170,172

The fast onset of action of formoterol161,173 has suggested

testing this bronchodilator in the treatment of acute exacer-

bation of COPD. Preliminary data with LABAs162,164,167 seem to

indicate that repeated doses of both formoterol and salme-

terol induce an effective dose-dependent increase in lung

function in patients suffering from COPD exacerbations, but

only formoterol induces a fast onset of action. A suggested

possible alternative to the use of higher than recommended

dose of formoterol is the combination of formoterol and

tiotropium, although the time course of the effects of these

drugs differs significantly from that in stable COPD, with a

shorter bronchodilation both for tiotropium and formo-

terol.185 In any case, because of its pharmacodynamic profile

with both a rapid onset of effect, similar to salbutamol, and a

long duration of action, similar to salmeterol, formoterol is

suitable for both maintenance and as-needed treatment in

COPD.174

CorticosteroidsIn 1958, Ogilvie186 published an article on the treatment of

patients with severe asthma and chronic bronchitis. This

article was surely significant at that time because it had the

merit of stressing the fact that the treatment of patients with

severe asthma and chronic bronchitis was perfectly feasible,

and success might be expected in two-thirds or more of cases.

Moreover, it highlighted the importance of calculating the

cost because it was becoming increasingly clear that there

was an imperative need to reduce the cost of certain remedies

of proved and vital importance, whether by a vast increase in

the scale of production, or by other means. Unfortunately,

Ogilvie considered the treatment of severe asthma and


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chronic bronchitis in the same manner and suggested that it

had to consist of the suppression, first of all, of infective

activity by antibiotic therapy, followed by the exhibition of a

suitable adrenal hormone in adequate dosage. This initial

treatment had to be followed by maintenance therapy, but it

was Olgivie’s opinion that it could fail within six months if it

consisted of hormone alone (mainly, ACTH or prednisone).

Consequently, successful maintenance treatment of persis-

tent asthma with chronic bronchitis depended on the use

both of antibiotics and hormones on a permanent or semi-

permanent basis. In any case, this paper could be considered

important still today because it stressed that the use of

‘‘antispasmodics’’ (adrenaline hydrochloride 1 in 1000 by

injection, aminophylline by mouth, and what he just defined

a new aerosol solution which he was testing prior to

introduction for general use) was ineffective in a number of

patients that, on the contrary, responded very well to

hormone treatment. This is one of the first reports that

patients suffering from chronic bronchitis may present an

irreversible airway obstruction, although today this informa-

tion is considered misleading. On the contrary, the documen-

tation that the use of bronchodilators as a screening device

for the selection of patients for hormone treatment is

valueless is still relevant. In 1960, Ogilvie and Newell187 tested

a maintenance combined treatment with an oral corticoster-

oid (methyl prednisolone) and an antibiotic (terramycin+no-

vobiovin) in a series of asthmatics with chronic bronchitis (?).

They concluded that maintenance treatment by corticoster-

oid had some clinical effect on certain of these patients,

which was annulled by discontinuing it, a view supported by

the frequent clinical observation that deterioration in the

chronic asthmatic with chronic bronchitis occurs much more

readily than the reverse change. This was an intriguing

conclusion that is still relevant considering the existing

debate on the use of corticosteroids in stable COPD.188

In 1963, Hurford et al.189 explored the use of prednisolone in

chronic bronchitis. They observed that only a small propor-

tion (20%) of patients with chronic bronchitis and emphyse-

ma who did not react to more conservative treatment showed

a response to a week on prednisolone at a dose of 30 mg a day

and raised the suspicion that these responders were char-

acterized by something different which would explain their

heterogeneity. The authors also observed that some patients,

who did not respond in the shorter period, responded to

corticosteroids after longer periods than one week. Discuss-

ing these results, they highlighted a concept that is still a

controversial issue, although it is supported by many

researchers in the field. It was their opinion that if there are

occasional cases of chronic bronchitis in which endobron-

chial changes and bronchospasm will be relieved by pre-

dnisolone, they are probably much fewer than would appear if

this drug is used without close control with ventilatory

tests. There is no doubt that it can temporarily bring a

general feeling of well-being which will lead some patients

with chronic bronchitis to feel better able to carry on

despite virtually unchanged exercise tolerance. But this is


certainly not sufficient excuse for continuing the use of

corticosteroids.

In the 1990s, some articles related the use of corticosteroids

were published.190–194 Senderovitz et al.194 documented that

in outpatients with stable COPD and no signs of asthma or

atopy, 2 weeks treatment with prednisolone seems to be of no

value in choosing subsequent long-term therapy. Strom191

reported an increased mortality in women receiving oral

corticosteroid medication that was found to be associated

with an increased need of hospital care due to longer hospital

stays during the terminal stage of the disease. This finding

has an important clinical impact. In fact, since prescriptions

of the same dose of oral corticosteroid medication to male

and female patients in COPD could result in a greater

incidence and severity of side effects in female patients, this

practice should be debated. Jarad et al.193 were able to

document that abrupt withdrawal of ICSs may lead to early

exacerbation in stable COPD. This is an important finding

because it indicates that clinicians should be aware of the risk

of an exacerbation developing within a few weeks of stopping

this treatment and, consequently they should never suggest

to patients to discontinue treatment with ICSs if this is not

giving them immediate benefit.

Some interesting papers194–203 have focused on the admin-

istration of ICSs to COPD patients. They reach contrasting

results and, consequently, they confirm the debate existing

on this topic.188 Thus, it has been documented198 that early

initiation of ICS treatment does not seem to affect the

progressive deterioration of lung function or other respiratory

health outcomes in subjects with early signs and symptoms

of COPD. Therefore, primary care physicians should be careful

to base maintenance treatment with ICSs in subjects at risk

for, or in an early stage of COPD on a single spirometric

evaluation after 3 months. However, Ayres et al.197 reported

that treatment with an ICS was associated with statistically

significant clinical benefits in patients with moderate-to-

severe COPD currently symptomatic on regular bronchodila-

tor therapy. As the differences in direct and total costs

compared with placebo were small and non-significant, they

considered such a type of treatment cost effective in this

patient population. Moreover, Tkacova et al.203 have docu-

mented that ICS may reduce all-cause mortality in patients

with severe COPD and chronic hypoxemia, who require long-

term domiciliary oxygen therapy. These data suggest that ICS

may indeed play an important role in improving clinical

outcomes in patients with advanced COPD.

Combination therapyThe benefit that exists when an ICS is combined with a LABA

has been discussed in several articles.204–209 Analysing results

of the TRISTAN study, Vestbo et al.205 did not find differences

between women and men with COPD in the efficacy and

safety outcomes in comparing the salmeterol/fluticasone

propionate combination versus placebo. Cazzola et al.204

suggested that when treating patients with formoterol, it is

prudent to check their arterial blood gases because this


ARTICLE IN PRESS


bronchodilator can worsen pretreatment hypoxemia. How-

ever, combined administration of formoterol and budesonide

reduces the potential for acute effects of formoterol on blood-

gas tensions. Mapel et al.209 analysed COPD patients from two

different managed care organizations from different parts of

the United States and found that patients who used an ICS, a

LABA, or an ICS plus a LABA had better survival than patients

who were only using short-acting bronchodilators, and that

this survival benefit was preserved even after adjustment for

the other clinical factors likely to affect survival, including

age, disease severity, comorbid diseases, and smoking history.

They found that COPD patients who had a concurrent

diagnosis of asthma had better survival than those who did

not, but the benefits of ICS therapy with or without a LABA

were preserved after adjusting for asthma in the models.

Interestingly, LABA and the combination treatments are likely

to be cost-effective, at least in the United States.207

Mucolytics agentsAlso some papers on the use of mucolytics agents were

published.210–217 In particular, Millar et al.213 were unable to

find significant differences in lung function, mucociliary

clearance curves or sputum viscosity following treatment

with N-acetylcysteine (NAC) compared to control or placebo

measurements. Even more important, Parr and Huitson214

failed to find any statistically significant difference in the

number of exacerbations between NAC or placebo groups

after a 6-month treatment, although there was a slight trend

towards improvement in the NAC group during the first 3

months of the trial. It must be highlighted that the dosage of

NAC used in these studies was really low (200mg thrice daily).

The possibility of influencing tracheobronchial clearance and

in this way, eliciting a beneficial action in chronic bronchitis

was tested again administering NAC. However, NAC adminis-

tered by MDI did not have any significant effect on patients’

feeling of well-being, sensation of dyspnoea, intensity of

coughing, mucus production, or expectoration or lung func-

tion,215 although another study216 documented that orally

administered NAC may improve general well-being in

patients with mild chronic bronchitis. Considering these

findings, it is not surprising that a wide and expensive

randomized controlled long-term (3 years) trial of the effects

of NAC 600 mg on a once-daily basis on the progression of

disease and exacerbation rate in patients with COPD who had

frequent exacerbations (i.e., at least two per year for 2 years)

has only confirmed that NAC at the dosage of 600 mg daily is

ineffective at prevention of deterioration in lung function and

prevention of exacerbations in patients with COPD.217

These results do not support the use of this drug in COPD,

but there has been more recent evidences that NAC may be

considered an antioxidant rather than a mucolytic

agent.218–222 Interestingly, van Schayck et al.223 have hypothe-

sized that that antioxidant treatment might be relatively

more effective among those COPD patients who respond less

well to ICSs (low reversibility and heavy smoking).


Alternative drugsConsidering the need for alternative drugs in the treatment of

COPD, in the last few years the journal has published some

small, but intriguing articles, which described the efficacy of

several different new therapeutic possibilities. These range

from the potential of prescribing montelukast in elderly

patients with moderate-to-severe COPD,224 to the use of

selective phosphodiesterase (PDE)4 inhibitors (cilomilast and

roflumilast) due to their novel mechanism of action and potent

anti-inflammatory effects, coupled with a good safety and

tolerability profile,225 or to the use of a low-dose testosterone to

men with COPD in order to counteract progressive weight loss,

and loss of lean body mass that has specifically been associated

with skeletal muscle dysfunction and is frequent in COPD

patients.226 Recently, Gronke et al.227 have shown that H1

receptor antagonist cetirizine was able to influence hypertonic

saline-induced airflow obstruction in moderate-to-severe COPD.

In view of the mechanisms involved in hypertonic saline

responses, it is an open question whether stronger effects can

be elicited with higher doses and whether such effects would

translate into clinical benefits, e.g. during exacerbations. The

documentation that rebamipide, a gastro-protective agent used

in the treatment of gastritis and ulcerative colitis, is able to

prevent TNF-a release, neutrophil recruitment into the airways,

and MUC5AC mucin synthesis in cigarette smoke-stimulated

airway epithelium228 is another intriguing finding because it

suggests that rebamipide may be used to treat mucus

hypersecretion in cigarette smokers.

Chronic respiratory failure is the end stage of COPD. Home

oxygen therapy is the only treatment which has been demon-

strated to improve survival of COPD patients with chronic

respiratory failure, but the mortality of patients receiving LTOT

is around 50%. These poor results have spurred the search for

coadjuvant or alternative pharmacological treatments. Almi-

trine bismesylate is a peripheral chemoreceptor agonist which

is believed to improve oxygenation, probably by improving the

ventilation perfusion mismatch. Although when used at doses

of 100–200 mg/day it shows an improvement in PaO2 greater

than 5 mmHg, its tolerance is poor, and the number of side-

effects such as dyspnoea and peripheral neuropathy was

unacceptable. For this reason, it has been at doses of 1 mg/kg/

day using an intermittent schedule in a randomized double-

blind placebo-controlled study,229 but while well tolerated, at

these doses, use of almitrine is not effective in long-term

treatment of chronic hypoxemia in COPD patients. Nonetheless,

in short-term treatment, the association of almitrine and

medroxyprogesterone acetate seems to be more efficient than

either drug alone at improving arterial blood gases in these

patients.230 Moreover, it has also been documented that four

days of treatment with almitrine improved gas exchange in a

group of subjects with hepatic cirrhosis.231

Non-pharmacologic treatment

Non-pharmacologic treatments for COPD include LTOT, nasal

positive pressure ventilation (nPPV), pulmonary rehabilitation


ARTICLE IN PRESS


and lung volume reduction surgery (LVRS). In the future, it

will be important to establish the precise value of the

different treatments available for COPD—evaluating both

clinical and physiological endpoints and using the data to

more accurately define candidate patients accordingly. The

challenge will be to develop this base of knowledge in order to

shape future research and allow clinicians to deliver tailored

COPD management programs for the growing number of

patients afflicted with this disease.232

Evaluation of the effectiveness of treatment for COPD

requires the assessment of both clinical and physiological

measures. Parameters such as FEV1 are well established in

providing an indication of the degree of airflow limitation.

However, additional measurements, such as dyspnoea,

functional status and health status, are required to provide

a complete picture of COPD. Indeed, dyspnoea is the

predominant symptom of COPD experienced by the patient,

which treatment is designed to reduce. Methods of assessing

dyspnoea have developed over the previous five decades. The

most widely used instruments for assessing the impact

of dyspnoea are the baseline dyspnoea index, the tran-

sition dyspnoea index and the Medical Research Council

Questionnaire.

A more comprehensive approach to the assessment of

disability caused by dyspnoea and fatigue is provided by

assessments of functional status, such as the pulmonary

functional status and dyspnoea questionnaire. Respiratory-

specific health status questionnaires, such as the St. George’s

Respiratory Questionnaire, attempt to capture the wide range

of effects of COPD into a single score that reflects the overall

impact of the disease.

Developing the means to measure the effects of COPD

is important, both in terms of understanding disease

pathophysiology for research purposes, and accurately asses-

sing the effects of treatment on the patient. Future develop-

ments will include computerising these methodologies to

permit faster and more individual patient-centred measure-

ments.233

Long-term oxygen therapy (LTOT)Apart from smoking cessation, LTOT is the only treatment to

date which has been shown to modify the long-term decline

in lung function that is associated with COPD and, therefore,

improve survival rates in severe cases; thus its role in COPD is

well defined.232

LTOT has also been associated with a variety of benefits in

patients with severe COPD, including increased survival,

reduced secondary polycythemia, improved cardiac function

during rest and exercise, reduction in the oxygen cost of

ventilation and improved exercise tolerance. Of particular

note are the results of a longitudinal study showing that LTOT

significantly improved heath-related quality of life (HRQoL) at

2 and 6 months, compared with a progressive decline in

HRQoL in the non-LTOT group. In the LTOT group, 67% and

68% of patients (at 2 and 6 months, respectively) showed a

clinically significant improvement in their CRQ scores.234


Hence there is a convincing rationale for including LTOT in

the treatment paradigm for patients with severe COPD.

Patients with PaO2 o7.3 kPa (55 mmHg; corresponding to

SaO2 o88%) whose disease is stable despite receiving other-

wise comprehensive medical treatment should receive LTOT.

A patient whose PaO2 is 7.3–7.8 kPa (55–59 mmHg; SaO2 89%)

should receive LTOT if they show signs of pulmonary

hypertension, cor pulmonale, erythrocytosis, oedema from

right heart failure or impaired mental state. If oxygen

desaturation only occurs during exercise or sleep, then

oxygen therapy should be considered specifically under those

conditions. An optimal medical regimen can be established

incorporating these guidelines, with the chief aim of achiev-

ing an optimized ventilation:perfusion ratio matching (V0/Q)

as a means of correcting hypoxaemia.

COPD patients undergo episodes of O2 desaturation of

arterial blood during rapid eye movement sleep. Fletcher et

al.235 revealed that these desaturations occur both in non-

hypoxemic patients and in patients who are hypoxemic

during the day. Further research by Plywaczewski et al.236

showed that 47.6% of COPD patients treated with LTOT spent

430% of the night with a SaO2 of o90%, and thus required

increased oxygen flow during sleep. The administration of

oxygen at a flow rate higher than the daytime setting usually

corrects nocturnal hypoxemia. Conflicting evidence sur-

rounds the contention that patients who only desaturate during

sleep will benefit from nocturnal oxygen treatment. But while

Fletcher et al.235 found a beneficial effect of supplemental

oxygen treatment in this patient group, other well-controlled

studies have not shown that the use of nocturnal supplemental

oxygen alters mortality or clinical course, other than slightly

lowering pulmonary artery pressure.

Oxygen therapy during exercise decreases dyspnoea and

improves exercise tolerance at submaximal exertion. The

mechanical rationale underlying this observation is a de-

crease in dynamic hyperinflation, and reduced ventilatory

drive. LTOT is prescribed for patients who become more

hypoxemic during exercise, or who only become hypoxemic

during exercise, with oxygen settings determined while the

patient is undergoing a typical level of exertion. Studies

evaluating the long-term benefit of oxygen treatment solely

for exercise have yet to be conducted.

In an interesting paper published in 1989237 a total of 43

severely ill COPD patients already on 24 h, or near 24 h, per

day supplemental O2 were randomly assigned to transtra-

cheal oxygen delivery (n ¼ 22) or usual delivery of O2 by nasal

cannula or face mask (n ¼ 21). A few important changes were

found in pulmonary function over time such as decreases of

PEFR, FEF and MVV for both experimental and control groups,

and FEV1% and FEV3% in experimental patients. At the same

time, there was a significant decrease in both haematocrit

and haemoglobin, and per cent shunting for the experimental

group and a significant increase in per cent shunting in the

control group. Physical, social and psychological assessments

showed significant improvement over time for experimental

patients and declines for the control group. Lastly, medical


ARTICLE IN PRESS


costs were positively affected, as fewer days were spent in

hospital post-study enrolment by experimental than control

groups, and post-enrolment relative to pre-enrolment by

experimental patients.

Non-invasive ventilationMechanical ventilation increases or substitutes for an in-

dividual’s spontaneous respiration, as in the case of acute

respiratory or ventilatory pump failure.232 Non-invasive

ventilation, e.g. intermittent negative pressure ventilation

(INPV) or nPPV, have recently re-emerged as popular options

that avoid the risks associated with invasive ventilation.232

nPPV is thought to assist ventilation, by improving inspiratory

flow rate and correcting hypoventilation. Other possible

mechanisms of action include resting respiratory muscles

and resetting the central respiratory drive.232

In contrast to the evidence supporting the use of nPPV to

tackle other causes of chronic respiratory failure, there is

conflicting evidence regarding the benefits of nPPV in

COPD.232 In a 12-week double-blind study of 184 patients

with severe COPD, no significant difference was observed in

6-min walk test results, cycle endurance time, severity of

dyspnoea, HRQoL, respiratory muscle strength or arterial

blood gas compared with sham treatment.238 This suggests

that inspiratory muscle rest has no benefits for patients with

severe stable COPD, although poor patient compliance may

have contributed to the results.

Regarding the administration of nPPV in patients with

severe COPD, two 3-month crossover trials of similar design

came to different conclusions.239,240 The discrepancy between

these results may be explained by the difference between

patient sets at baseline: patients with greater CO2 retention

and more frequent nocturnal oxygen desaturations may

benefit more from nPPV administration.

In addition to this conflicting data on physiological end-

points there is a lack of data showing whether nPPV

treatment actually improves survival rates. Two large multi-

centre trials have focused on nPPV in patients with severe

hypercapnic COPD. One trial published as an abstract by Muir

et al.241, which compared home nPPV plus LTOT with LTOT

alone, indicated that there is no overall survival benefit in

patients receiving nPPV plus LTOT, although there may be a

slight improvement in survival for patients over 65 years of

age. A 2-year Italian multicentre study also examined the

effects of nPPV plus LTOT compared with LTOT alone

(N ¼ 122).242 In this trial, nPPV plus LTOT improved PaCO2

during breathing of the usual oxygen inspiratory fraction.

Long-term improvements were also noted in dyspnoea and

HRQoL in the nPPV plus LTOT group, but survival was similar

between treatment groups.

Currently, there is little evidence supporting the use of

mechanical ventilatory support in the routine management of

COPD.233 However, further large studies may be able to identify

subsets of patients for whom nPPV would be beneficial.

An historical and pioneering paper published in 1958243

showed that inspiratory positive pressure breathing (IPPB) by


itself and independently has therapeutic value, particularly in

asthma, bronchitis and emphysema, concluding that it prob-

ably accomplishes this result by helping to clear the bronchial

airways of obstructing secretions and exudations, although

other effects as yet unknown may be important. The ther-

apeutic results are erratic and the use of IPPB is justified only by

the otherwise inexorable progress to an asphyxial death of

crippling COPD. The authors suggest that this technique may

also be used as a means of temporarily diminishing venous

return in acute pulmonary oedema, and of expanding collapsed

segments of lung in respiratory paralysis and post-operative

immobilization of the lung and they retain that the hazards of

this form of treatment are slight.

LVRS for emphysemaLVRS was originally proposed as a palliative treatment for

patients with severe emphysema. The rationale for LVRS is

based on the premise that these patients have severe hyperin-

flation and the goal of surgery is to remove functionally useless

emphysematous lung. Generally, this involves the removal of

25–30% of lung tissue from both the left and the right sides.

Benefits associated with LVRS are improved lung function

(reduced lung volume and increased FEV1) and exercise

(including the distance walked in 6 min).243 Although carefully

selected patients benefit from LVRS, questions remain concern-

ing the magnitude and duration of positive outcome.232

The National Emphysema Treatment Trial (NETT) was set

up as a multicentre, randomized, large-scale clinical trial

(N ¼ 1218) to evaluate the effects of LVRS.244 Overall results

from the NETT at 2-years post-randomization indicate that

LVRS improves exercise capacity, but does not improve

survival compared with medical therapy. Patients in the LVRS

group also reported improved health status and less dyspnoea

compared with the medical group. Subgroup analyses showed

that patients with upper-lobe predominant emphysema and

low exercise capacity had improved survival with LVRS,

compared with medical therapy; those patients with245

mainly non-upper-lobe emphysema and high exercise capa-

city showed reduced survival. From these results, two key

outcome predictors can be identified: distribution of emphy-

sema and exercise capacity following pulmonary rehabilita-

tion. Combined with the factors placing patients at high risk

for LVRS, these predictors allow more targeted patient

selection than was previously possible.

Key questions remaining concern the role of pre-operative

pulmonary rehabilitation, the mechanisms by which LVRS

improves lung function and survival, and the impact of

different surgical techniques on LVRS outcomes.232 The

identification of long-term predictors of LVRS outcomes

would be a welcome development, while investigating uni-

lateral or repeated LVRS, as well as noninvasive techniques to

reduce lung volume, may prove successful in the future.

RehabilitationPulmonary rehabilitation complements pharmacotherapy

and is now considered central to the management of


ARTICLE IN PRESS


symptomatic COPD.246 This form of management has negli-

gible effects on pulmonary function, yet commonly provides

substantial relief from dyspnoea, increased exercise tolerance

and improved HRQoL.246 Pulmonary rehabilitation appears to

work via several mechanisms, including reducing some of the

comorbidity associated with chronic respiratory disease (such

as the physical de-conditioning associated with sedentarism)

and providing patients with self-management strategies

(through disease-related education).246 Rehabilitation would

also seem to reduce subsequent healthcare utilization, with

the valuable cost reductions that this would imply.246

The logical concept of optimizing the pharmacologic

management of COPD patients prior to, and during, pulmon-

ary rehabilitation to achieve greater benefit is becoming more

widely recognized. Despite a growing body of research

evidence, further work is needed to determine which patients

will benefit most from pulmonary rehabilitation, how this

form of management is best prescribed, and how to identify

the most suitable practice setting, which is dependent on the

stage/phase of the disease.

Pulmonary rehabilitation is defined as an art of medical

practice in which an individually tailored, multidisciplinary

programme is formulated. It is indicated for patients suffering

from complex problems in relation to their pulmonary

disease. The goals of pulmonary rehabilitation are: (1) to

decrease the physical and psychological manifestations of the

underlying disease, i.e. reduce the impairment due to the

disease; (2) to increase physical and mental fitness and

performance, and reduce the disability; (3) to achieve max-

imal social reintegration of the patient, thus lowering the

handicap.247 The ultimate goal is a maximal functional

capacity, as allowed by the pulmonary disturbance and

overall situation. The methods by which these goals may be

achieved are combined in a program tailored to each

individual patient. It consists of: (a) an accurate diagnosis

of the disease and of the functional limitations of the patient,

(b) education about the disease, its pathophysiology, use of

medications, use of a peak flow meter, and the avoidance of

harmful or aggravating stimuli, e.g. smoking, (c) physical

training to improve the physical fitness and performance, and

(d) psychosocial support. The program should be based on an

adequate diagnosis of the extent and character of the

limitations of the individual patient.247

Pulmonary rehabilitation is a therapeutic process, which

entails taking a holistic approach to the welfare of the patient

with chronic respiratory illness—most commonly COPD—and

is considered essential throughout the lifetime management

of patients with symptomatic chronic respiratory disease. It

requires the coordinated action of a multidisciplinary health-

care team in order to deliver an individualized rehabilitation

programme to best effect—incorporating multiple modalities

such as advice on smoking cessation, exercise training and

patient self-management education, among others. As core

components of pulmonary rehabilitation, exercise training

and self-management education have been shown to be

beneficial in improving HRQoL in patients with chronic


respiratory disease. Physical training can help to reduce the

muscle de-conditioning that occurs when the activity of

patients is restricted by their breathlessness and fatigue, and

it is often associated with an increase in patients’ HRQoL.

HRQoL can also be improved by the use of self-management

education, which is designed to provide the patient with the

skills to manage the health consequences of their disease. In

doing so, patients are better able to cope with disease

symptoms, potentially leading to reduced health care

costs.247

In the last decades there was a large debate on the

effectiveness of pulmonary rehabilitation and of its different

components. For example, in a 1982 negative paper eight

patients with chronic obstructive bronchitis and moderate

disability entered a pilot study on the effects of controlled

diaphragmatic breathing. They received 3 weeks of placebo

physiotherapy (shoulder exercises) followed by three weeks of

instruction on controlled diaphragmatic breathing. No bene-

ficial effects were observed on exercise performance or the

perceived strain of exercise.248

Nevertheless, pulmonary rehabilitation is now supported

by a solid body of scientific evidence and is widely available in

North America and in Europe for patients with COPD. As a

paradigmatic example, the feasibility and benefits of provid-

ing a comprehensive but cost effective pulmonary rehabilita-

tion programme in a UK district general hospital has been

reported.249 Two hundred and sixty-seven patients with

respiratory disability were referred for pulmonary rehabilita-

tion. Patients were assessed and recruited into a 7-week

outpatient-based pulmonary rehabilitation program includ-

ing elements of exercise and education without longer-term

maintenance. For all graduates, shuttle distance increased by

58 m (27%) and treadmill endurance time increased by

15.9 min (294%). The Breathing Problems Questionnaire

proved sensitive to changes in quality of life in some

domains. The Chronic Respiratory Disease Questionnaire

showed significant improvements in all domains in a sub-

set of 57 patients who completed it. Longer-term follow-up of

49 patients at a mean of 10.3 months following pulmonary

rehabilitation revealed that previous gains in exercise perfor-

mance and quality of life were maintained with improve-

ments in shuttle walking distance of 33 m (14% over baseline)

and endurance time of 16 min (280% over baseline). The

Breathing Problems Questionnaire showed no overall change

but the Chronic Respiratory Disease Questionnaire showed

continued improvement in a small number of patients.

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One hundred years of respiratory medicine chronic obstructive pulmonary disease (COPD)—Republished article