Special Topic of
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is a
progressive respiratory condition normally related to
tobacco smoking. The condition leads to a narrowing of the
airways, causing shortness of breath, and there is no cure
at present. In the US it is currently the fourth largest
cause of death.
A major problem with COPD is the occurrence of
exacerbations, the periodic worsening of symptoms and lung
function. Exacerbations lead to increased utilization of
healthcare services and a decrease in the quality of
A Special Topics analysis of COPD research over the past decade
shows that the work of Professor Peter Calverley ranks at #2 by total cites
and #3 by total papers, based on 87 papers cited 4,763 times. In
Reuters, he ranks among the top 1% of scientists in the
field of Clinical Medicine.
Calverley is Professor of Respiratory Medicine at the University of
Liverpool in the UK. His research interests include the management of COPD,
on which he has published extensively. He has been one of the principal
investigators in a number of clinical trials that have become highly
In this interview, ScienceWatch.com European
correspondent Dr. Simon Mitton explores the key contributions made by
Professor Calverley and his co-workers on the effective management of
To start our discussion, would you
like to outline how you came to enter the field of respiratory
I started my medical training at the University of Edinburgh where I met a
several inspiring respiratory physicians, particularly the late Professors
John Crofton and David Flemley who were deeply concerned about the problems
of respiratory disease and particularly obstructive lung disease.
As a result of that I became a Medical Research Council training fellow, in
Edinburgh, with a particular interest in seeing whether oxygen treatment at
home would prolong the life of COPD patients, which it did. After the
fellowship I pursued my career in Edinburgh, with a period as a visiting
fellow in Canada, before taking up my position here in the School of
Clinical Sciences at the University of Liverpool. I am also an honorary
consultant physician at University Hospital Aintree, Liverpool.
COPD is obviously a horrible condition which must
be very distressing. What can you tell me about it?
These papers flagged by your analysis are focused on chronic obstructive
pulmonary disease, the term that we now use to describe what people once
called chronic bronchitis and emphysema. These are two aspects of the same
problem, in one of which the airways in the lungs become inflamed, causing
bronchitis, and the substance of the lungs is destroyed, leading to
This is a very common problem, originally thought to be confined to western
developed countries, but now recognized as having global significance.
Rather sadly COPD has steadily increased in importance over the last 20
Patients complain of breathlessness and may have a cough with sputum
production. As the disease progresses they tend to be very disabled by the
breathlessness, and experience frequent flare-ups, or exacerbations, of the
disease. Many of the patients become hospitalized, and many die
prematurely. Here in Liverpool we have tried to prevent the exacerbations
with various treatment approaches.
What are the main risk factors with COPD?
This condition is mainly due to tobacco smoking, but other factors like
health at birth and also occupations through life seem to be important
predictors of developing this particular severe illness. Prolonged exposure
to workplace dust, particularly in combination with smoking, can lead to
Turning to your papers published in the last 10
years, I notice that two of them are clinical guidelines: "Standards
for the diagnosis and treatment of patients with COPD: A summary of
the ATS/ERS position paper," (Eur. Resp. J. 23: 932-46,
June 2004) with Bart Celli, and "Global strategy for the diagnosis,
management, and prevention of chronic obstructive pulmonary
disease—the GOLD executive summary," (Am. J. Resp. Crit.
Care Med. 176: 532-55, 15 September 2007) led by Klaus
"We demonstrated that a combination treatment of
inhaled long-acting beta2 agonists and corticosteroids
produces better control of symptoms and lung function, with
no greater risk of side effects than that with use of
either component alone."
I have conducted many original investigations dealing with both the
physiological assessment of the disease and its treatment. These two
aspects of my research have meant that I have been involved in panels
developing guidelines for the management of COPD.
The 2004 paper publishes the guidelines of the joint American Thoracic
Society (ATS) and the European Respiratory Society (ERS) report produced
under the leadership of Bart Celli, then at Tufts University in
Massachusetts. The 2007 paper gives guidelines from the Global initiative
in managing Obstructive Lung Disease guidelines; that had a wider remit
than the 2004 paper, which was limited to COPD management in the most
Both of these guidelines were highly cited and had an important impact on
how ordinary clinicians managed COPD. In particular, these two
evidence-based studies identified what treatment practices were helpful and
which ones were not. Defining those things that are not useful is as
important in this field as identifying what is positively helpful.
We have set up a classification scheme for COPD severity that is being used
by a range of scientists, from clinicians and epidemiologists through to
basic scientists, all of whom are striving to understand how this disease
impacts on people.
In 2004 the UK National Institute for Clinical
Excellence—NICE—published its guidelines on the
"Management of chronic obstructive pulmonary disease in adults in
primary and secondary care." I believe you contributed to
Yes. I was a member of the Guidelines Group, and helped to draft this
report. NICE is an independent organization that, among other things,
provides best-practice advice to public health authorities the UK,
including National Health Service. The clinical research on COPD that we
have been pursuing in Liverpool therefore feeds through to healthcare
professionals responsible for COPD patients.
Your top papers include several in which you and
your colleagues have studied the effectiveness of different treatments
available for COPD.
Let me tell you first about the background to these papers.
By the late 1980s, it was recognized that COPD was an inflammatory
condition. It seemed sensible then to consider whether existing treatments
known to reduce inflammation, particularly inhaled corticosteroids, could
modify the natural progression of this condition. This led to a series of
studies that were conducted in patients with either very mild or moderate
The impression was that the rate of decline of lung function was not
modified. Unfortunately there were methodological issues in these studies
and many clinicians were more concerned about whether these drugs should be
added to bronchodilator treatment used to relieve breathlessness.
So the first paper, which ranks at #2 on our list
of the top 20 papers published in the past decade, was published in
2000: "Randomised, double-blind, placebo-controlled study of
fluticasone propionate in patients with moderate to severe chronic
obstructive pulmonary disease: the ISOLDE trial," (Brit. Med.
J. 320: 1297-1303, 13 May 2000). What did you
Sherwood Burge and I led this study, which tested the hypothesis that a
high dose of the inhaled corticosteroid fluticasone propionate would change
the rate of decline of lung function in people with symptomatic and
relatively severe COPD. The short answer was that this change did not
However, we did learn (it was the first time this had been looked at) that
we could improve people's symptomatology and well-being (expressed via a
measure of their quality of life), and also reduce the number of flare-ups,
or exacerbations, of the disease. Thus for the first time there was a
clinical justification for adding these corticosteroid drugs into the then
widely used short-acting bronchodilator treatment.
In other words, you had found that
anti-inflammatory therapy was better than just using short-acting
bronchodilators, because you reduced the exacerbations. In 2003
The Lancet published your next study in this series,
"Combined salmeterol and fluticasone in the treatment of chronic
obstructive pulmonary disease: a randomised controlled trial,"
(361: 449-56, 8 February 2003).
That's right. New treatments became available in which inhaled
corticosteroids were combined with long-acting inhaled beta2
agonist drugs. These drugs also worked as effective bronchodilators, so
there was a reasonable question to ask: could further advantage be gained
by adding this extra treatment?
"I have conducted many original investigations dealing
with both the physiological assessment of the disease and
That question arose on the basis of our study published in The
Lancet in 2003. This is a four-armed randomized parallel drug trial
with a large number of 1,465 participants who were followed for one year.
The paper represented a step change in the way studies have been conducted
because this was the first time a treatment intervention with different
arms to the treatment had been tried in this number of people.
We demonstrated that a combination treatment of inhaled long-acting
beta2 agonists and corticosteroids produces better control of
symptoms and lung function, with no greater risk of side effects than that
with use of either component alone. We said this combination treatment
should be considered for patients with COPD.
The paper shaped future clinical practice, because we were able to show
that the combination treatment was more effective than the placebo, it
improved health, and it reduced exacerbations. That is why it has a high
rate of citation.
Your 2007 paper in the New England Journal of
Medicine completes the trio, "Salmeterol and fluticasone
propionate and survival in chronic obstructive pulmonary disease,"
(356: 775-89, 22 February 2007). What did you find?
The final and largest of this trio of studies was a multinational
three-year project in which 6,112 participants were followed. Of these, 875
died within 3 years of the start of the study. We conducted a randomized,
double-blind trial administered with a single inhaler that compared a
placebo, salmeterol, fluticasone propionate, and salmeterol and fluticasone
propionate in combination. We wished to establish whether the combined
treatment resulted in a reduction of death.
Unfortunately, the favorable result we found for the combination treatment
was not quite large enough to achieve our pre-set level of statistical
significance. This probably reflects the large number of people who
withdrew when randomized to placebo treatment and hence decreased the power
of study to demonstrate a difference.
We confirmed, however, the results of the previous two trials, and showed
that even people with mild disease would have benefits from using the
combined treatment if they had episodes of exacerbations. Also we resolved
our original question: treatment did indeed slow disease progression. Our
treatment of symptomatic patients with COPD was beneficial.
This paper has had a widespread impact on the way COPD is managed.
Thank you Peter for those insights into why the
papers we have been discussing are high impact. In conclusion to our
interview, would you like to tell me about the future trajectory of
your research on COPD?
Yes of course! The clinical studies of the past 10 years that I have been
discussing with you have grown out of a better understanding of the
scientific aspects of this pulmonary disease. There are now real challenges
ahead. Many pharmaceutical companies have developed "me too" versions of
the drugs we have tested already.
Although these formulations are likely to produce further improvement of a
modest kind, we are thinking about new approaches to COPD
management—approaches that maximize physical performance of the
patient. We know already that pulmonary rehabilitation is effective. We
continue to study and publish about that.
New ways of monitoring rehabilitation will help us classify the performance
of our patients better. Similarly, structural measurements like CT scanning
to measure the degree of inflammation will also prove to be relevant for
defining individual patient groups.
The future for treatment is to develop more specific disease phenotypes
that are responsible to particular therapies, rather than offering the
one-size-fits-all approach. That's going to be an important challenge for
clinical trials and new science.
My group is strongly motivated by that challenge.
Professor Peter M. A. Calverley FRCP, FRCPE
School of Clinical Sciences
Clinical Sciences Centre
University Hospital Aintree
Liverpool, United Kingdom
Peter Calverley's current most-cited paper in Essential Science
Indicators, with 763 cites:
Celli BR, et al., "Standards for the diagnosis and treatment of
patients with COPD: a summary of the ATS/ERS position paper," Eur.
Resp. J. 23 (6): 932-46, June 2004. Source:
Essential Science Indicators from
KEYWORDS: COPD, EMPHYSEMA, SYMPTOMS, RISK FACTORS, MANAGEMENT GUIDELINES,
EVIDENCE-BASED STUDIES, TREATMENT PRACTICES, UK NATIONAL INSTITUTE FOR
CLINICAL EXCELLENCE (NICE), FLUTICASONE PROPIONATE, LUNG FUNCTION,
EXACERBATIONS, COMBINATION TREATMENT, LONG-ACTING BETA2 AGONISTS,
CORTICOSTEROIDS, SALMETEROL, PULMONARY REHABILITATION, DISEASE PHENOTYPES.