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doi:10.1016/j.rmedu

1 The conferencFor further details g

Conference

Clinical consensus on COPD

Compared to other public-enemy diseases things could

hardly be worse for COPD patients, carers and COPD-focused

healthcare professionals. The body count continues to

rise—2.75 million deaths documented in 2002, with an untold

number unrecognised, and this will certainly get worse as the

trend for smoking in S.E. Asia manifests itself in a wave of

COPD. Moreover, the gender gap will start to close as women

catch up with men as a result of lifestyle and workplace

equality.

At a recent conference in London,1 over 800 healthcare

professionals and clinical experts from across primary and

secondary care gathered to discuss and debate the latest

advances in managing the causes and clinical outcomes for

COPD patients.

COPD: The burden of disease

In Europe alone, the estimated yearly cost of COPD is h39

billion, of which h3 billion is directly hospital-related.

Mortality is rising especially fast in women (more women

died in the USA from COPD than men in the period

1980–2000), yet according to the latest GOLD definition in

November 2006, COPD is both preventable and treatable (S.

Buist). In 1990, it was the sixth leading cause of death—and

this is set to become the third by 2020 if trends continue—yet

many countries are completely unaware of the disease! In

Japan, a study found that 91% of patients with chronic

obstruction were undiagnosed by the Ministry of Health and

Welfare. Using strictly standardised measurements, the BOLD

and PLATINO initiatives were designed to look at the

prevalence of COPD in 23 countries to assess this burden

and to try to correlate it with known risk factors.

Occupational exposure, even in developed countries like

the USA, is a causative risk factor for COPD, and it doesn’t

take much to extrapolate this finding to the impact on people

in poorer, developing countries. One surprise was the much

lower prevalence in Hannover, Germany, versus Salzburg, not

that far way, both in terms of distance and culture, in Austria.

These studies are crucial to further GOLD staging guidelines

.2007.03.001

e ‘Clinical Consensus on COPD’ was held March 2no to: www.clinical-consensus-copd.com.

and the Chinese statistics illustrate how important it is to

normalise/standardise ‘‘symptomology’’—the BOLD study in

China took place just after the SARS epidemic, and ‘‘nobody

would admit to having any symptoms’’.

Disease mechanisms

COPD is characterised by small-airway inflammation and

peribronchiolar fibrosis in the lung, and we are beginning to

understand the mechanisms behind each of these phenom-

ena (P. Barnes, London; I. Adcock, London). Critically, there is

a COPD-specific pattern of inflammation, different to that of

asthma.

Cigarette smoke stimulates the alveolar macrophages to

release TNFa, which leads to NF-kB production and subse-

quently IL-8, which activates neutrophils. The latter is well

known as an activator of many inflammatory genes, but it

also activates the gene for MMP9, an enzyme that destroys

elastin, which is never replaced. TGFb is also released in COPD

patients, and this causes fibrosis of the small airways,

explaining one of the paradoxes of COPD, in that the loss of

elastin structure is accompanied by a thickening of small

airway epithelia.

IL-8 binds to the CXCR2 receptor on neutrophils with high

affinity, as does GROa, a chemoattractant found in COPD

sputum, and thought to play an important role in the

chemotaxis of monocytes to the COPD lung, which then

differentiate into macrophages. There is a strong correlation

between the number of CD8+ lymphocytes in the lung and

disease severity, again indicative of an ongoing inflammatory

process.

Alveolar cells play a crucial role in orchestrating this

inflammatory response and, in COPD, this inflammation is

largely resistant to steroids. Why is this, is there an active

steroid resistance mechanism in COPD? A model is emerging

in which histone deacetylation by HDAC2 (activated by

steroids) normally switches off inflammatory genes, but

shows reduced activity in COPD patients (in stage 4 COPD,

its activity is reduced by 93%). At the same time it has been

d–3rd 2007 at the Novotel West Conference Centre in London, UK.

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found that histone acetylation within the IL-8 gene is

increased. It is thought that the mechanism behind this is

that oxidative stress creates peroxynitrite, which attacks a

tyrosine residue on HDAC2, effectively labelling it for

destruction in the peroxisome.

This also neatly explains why theophyllines are effective

in reducing some inflammatory aspects of COPD. Long

known as an anti-inflammatory at very low doses, it inhibits

PI3 kinase d, thereby activating HDACs. Theophylline in fact

reverses steroid resistance in COPD cells of smoking mice.

An explanation of why steroids have some effectiveness in

treating acute exacerbations might be due to the accompany-

ing reduction in oedema.

Genetic basis of COPD

a1-antitrypsin deficiency, caused by the mutation of 342Glu to

Lys, affects one in 1700 north Europeans. The protein

polymerises and 85% of it is retained in the liver, causing

cirrhosis and excessive inflammation. a1-antitrypsin is a

strong and specific inhibitor of elastase, and apart from

destroying elastin, the active enzyme also stimulates macro-

phages to secrete LTB4, a chemoattractant. Augmentation of

a1-antitrypsin as a therapy was not shown to work in the large

NIH study NHLBI (R. Stockley, Birmingham), but there are

several other studies ongoing. The search is on for small

molecules that block this polymerisation, but only 1–2% of

COPD patients have this condition, begging the question—are

there other genetic factors in COPD?

There is evidence for COPD clusters within families—a

major study looked at COPD markers among siblings, reveal-

ing that the familial emphysema clusters were not well

correlated to pack-years smoked (D. Lomas, Cambridge).

Small-airway thickness measurements clustered similarly.

Recent association studies have revealed several candidate

genes as biomarkers, including TGF-b, heme oxygenase-1,

superoxide dismutase, glutathione S transferase, and (the one

to watch, apparently) SERPINE 2. Using CT scans and image

analysis, strong genetic linkage has been localised to areas on

chromosomes 1p, 2q, 4p and 13q.

We still have no idea ‘‘what’’ COPD is in non-smokers and

there is an urgent need to characterise mechanisms in COPD

patients who have never smoked. It is quite possible that,

independent of smoking, some people are born with a

‘‘proinflamatory genotype’’—understanding the genetics of

disease susceptibility will aid evidence-based therapies (A.

Agusti, Palma de Mallorca).

Inflammatory biomarkers

In the search for inflammatory biomarkers in COPD, a largely

unmet need, a combination of profiling and single marker

approaches is needed (S. Kharitonov, London). Of two notable

markers under development, nitric oxide (NO) is simple and

reproducible, such that sensitive technologies are able to

distinguish between alveolar NO (typical of asthma) and

bronchial NO (found in COPD). A reduced forced expiratory

volume at 1 s (FEV1) is strongly associated with aortic

stiffness, and this can be accurately quantified by measuring

the speed of the reflected pulse from the heart beat.

Except for the fact that there is no murine equivalent of

MMP-1 and the difficulty of surgery, mouse models of COPD

are successful (McG. Houghton, Pittsburgh). Driven by etiology

(i.e. smoking) the models show that inhibition of MMP-12, the

mouse elastase, reduces the presence of cytokines. CD8-

knockout mice are protected from smoke-induced emphyse-

ma, and PDE4 inhibitors have even reversed emphysema in

smoking mice.

Lumenal content, measurable airway thickening and ex-

ercise capacity are all metrics that show heterogeneity in

COPD patients and it is very important to distinguish the sub-

phenotypes in order to identify those particularly responsive

to intervention (F. Sciurba, Pittsburgh).

Diagnosis is critical, but not always easy

The level of undiagnosed COPD is a factor that obscures an

accurate assessment of the overall disease burden and

prevents the benefits of early treatment being realised. But

just how much of the iceberg is beneath the surface?

The Dutch study on Detection, Intervention and Monitoring

of Asthma and COPD (DICMA) suggests that up to 7% of the

general population have obstructive respiratory symptoms,

two-thirds of whom have never presented themselves to their

GP (C. van Schayck, Maastricht). Furthermore, of those who

had presented themselves to their GP one-in-five had still not

been diagnosed with obstructive airway disease.

Effective application of spirometry is the best weapon in the

GP armoury when patients present in the practice with

symptoms of cough. However, from a practical standpoint,

COPD-directed case finding is realistic only if smokers are

screened in the GP clinic, rather than all patients with cough.

The age of smokers is also an important criteria for selection

of those in whom to use spirometry.

Some of the contributing factors in the failure to properly

diagnose can be assigned to poor perception by sufferers of

their own early symptoms, as well as resistance of sufferers

with obvious symptoms to present themselves—fearing that

they will be told to stop smoking. COPD sufferers avoid the

clinic (so-called cognitive dissonance). To further compound

the issue, once a diagnosis of COPD has been made and

treatment initiated, patients continue to under-report the

occurrence of acute exacerbations by as much as 50%, thus

worsening their own long-term prognosis. A vicious cycle

indeed.

Screening for COPD-related systemic disease in general

practice is also a considerable challenge, since COPD sufferers

may be poorer at perceiving or presenting comorbid symp-

toms than non-smokers, especially where these may be

undifferentiated from their respiratory issues (C. van Weel,

Nijmegen). Where the comorbidity appears to the patient to

be unconnected with smoking, e.g. diabetes, depression or

joint pain, the COPD sufferer may end up in the GP clinic and

this is where the GP needs to seize the opportunity to make a

full diagnosis. As always, spirometry is a great tool to apply in

such cases.

However, once inside the GP clinic an accurate diagnosis

does not always result, even if respiratory distress is obvious.

When faced with complex patient history and overlapping

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symptoms, the critical issue can often be whether to diagnose

and treat asthma or COPD (R. Buhl, Mainz). Age at onset of

disease and smoking history are obviously important, but

critical features to use in differentiating the two are the

paroxysmal nature of dyspnoea in asthma versus persistent,

exercise-limiting dyspnoea in COPD. Bronchial hyper-reactiv-

ity is more indicative of asthma, whereas a history of one or

more acute exacerbations makes COPD likely, as does green

or yellow sputum. If possible, spirometry should be used to

confirm a diagnosis by establishing a less-than 15% improve-

ment in FEV1 post bronchodilator. By combining scores

against each type of symptom, a general practitioner may

increase their confidence of making an accurate diagnosis.

Further (although more-expensive) tests for blood gases

and allergic responses can clarify difficult cases, but there will

be a small set of patients in whom both diseases are present.

It is worth making a final word of caution—after all symptoms

are taken into account, if you are still unsure then treat the

patient for asthma. This is the safest path should the

diagnosis be wrong.

Assessing the loss of lung function in COPD

As with many diseases, COPD has a natural history that is

reproduced in each patient independently of external factors.

Unlike other diseases, the key milestones for COPD are poorly

mapped out such that treatment options and disease

management goals are often unclear.

The classic 1977 Fletcher and Peto study on the link

between smoking, COPD and mortality colours much of our

thinking as to the prevalence of COPD amongst smokers—of-

ten being paraphrased to indicate that ‘‘yonly 15% of heavy

smokers develop COPD’’. This is simply wrong (J. Soriano, Illes

Balears). The Fletcher and Peto study merely stated that, in

order to study susceptibility to COPD amongst all smokers, it

would be useful to compare the 15% of smokers with the

lowest FEV1 (i.e. COPD susceptible) against those with the

highest FEV1 (non-susceptible). In reality, above 60 years of

age 40% of smokers will have COPD by GOLD criteria, rising to

50% above age 75.

Progression through the natural history of COPD is slowed

by several factors, including drug treatment, pulmonary

rehabilitation, oxygen therapy and lung volume reduction

strategies. However, the most important modifier is to quit

smoking.

Lung hyperinflation is the main determinant of exercise

capacity for COPD sufferers and is therefore a very useful

clinical indicator of disease progression (N. Koulouris,

Athens). There is a vibrant debate as to the transition from

peripheral airway disease to overt COPD in smokers, char-

acterised by three sequential stages in which expiratory flow

limitations (EFL) during tidal breathing plays a central role. In

stage I, the closing volume (CV) eventually exceeds the

functional residual capacity; in stage II, EFL first develops as

a result of sequential dynamic heterogeneous compression of

the peripheral airways during expiration and re-expansion

during inspiration, and; stage III, during which dynamic

hyperinflation (DH) progressively increases leading to dys-

pnoea and exercise limitation.

Therapeutic approaches in COPD

Despite the apparent clarity of the GOLD guidelines, national

approaches to therapy of COPD vary greatly, especially in the

application of pharmacological therapies and home oxygen

(B. Celli, Boston). From a physician standpoint the holy grail of

COPD disease modification is to halt, or at least slow down,

the rate of decline of FEV1. However, from a patient

perspective the Holy Grail is simply to be able to breathe

easier.

The joint ATS/ERS Task Force is about to publish their study

‘‘Outcomes for COPD pharmacological trials: from lung

function to biomarkers’’. At present, no surrogate markers

for COPD have been identified other than FEV1. Although

mortality is the gold standard to evaluate predictors and

therapies as a primary endpoint, the study suggests that

consideration should be given to other surrogate markers as

secondary endpoints in future clinical trials (M. Cazzola,

Rome). Where more than spirometry was measured, a meta-

analysis of the studies available revealed five possible

biomarkers: PaO2, sputum neutrophils, IL-8, and systemic

TNFa and C reactive protein. The use of a multidimensional

tool like the BODE index is recommended. This combines

body mass index, airflow obstruction, dyspnoea and exercise

capacity into one measure, thus crucially encompassing the

systemic, as well as the pulmonary effects of COPD. However,

it’s applicability and reliability in trials has yet to be

determined.

One aspect of clinical studies on COPD mortality requires

much better definition—whether COPD is the cause of death

or was simply present at the point of a death due to other

factors (e.g. heart disease). The Copenhagen City Heart Study

reveals that death certificates are not the easiest source of

information on the actual cause of death—given the number

and influence of other potentially contributing factors.

As part of the TORCH study, an expert panel reviewed all

clinical records for trial subjects who died, in order to assign

the most accurate cause of death and thus document true

COPD-related mortality. Thus it was possible to conclude that

35% of deaths were due to respiratory causes during the

TORCH trial (P. Calverley, Liverpool). This seminal, 156-week

world-wide study recruited more than 6100 patients with

moderate-to-severe COPD in a trial to determine the impact

of salmeterol/fluticasone propionate combination and the

individual components on the survival of COPD patients.

A heated debate continues around the TORCH outcomes for

the difference in all-cause mortality of those on the placebo

(15.2%) and those on the combination therapy (12.6%)—many

arguing that this represents a 17.5% risk reduction that

clinicians ignore at their peril. However, TORCH did not

statistically prove that the combination of inhaled corticos-

teroids and long-acting beta agonists had an effect on

mortality when used to treat COPD. What is not in doubt is

that, as compared with placebo, the combination therapy

significantly reduced the annual rate of exacerbations and

improved both health status and spirometry.

Importantly, a critical issue for future clinical trials is

whether it is ethical to recruit a genuine placebo group from

amongst severely ill patients and thus deny them potentially

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life-enhancing or life-prolonging treatment. If not, the test

treatment would have to be compared against the baseline

metrics of the best currently available therapy. Ethical, but

likely to create more hurdles where many already exist.

Triple-combinations outscore other therapies, although a

trial showed a negative outcome in terms of the frequency of

exacerbations. Future approaches are sure to involve safe,

long-acting anticholinergics in combinations with long-acting

beta agonists. The race is also on to develop safe and

efficacious therapies using PDE4 inhibitors like roflumilast

and cilomilast (B. O’Connor, London). However, it is unlikely

that blocking any single mediator will ultimately work (e.g.

the failure of anti-TNF therapy) for COPD, in contrast with

rheumatoid arthritis, for example (P. Barnes, London).

Although there has been much interest and hope in the

potential therapy of rebuilding lung epithelia with bone

marrow-derived stem cells, this approach has suffered major

problems from the start—mesenchymal stem cells perfused

into the lung do establish in alveoli, but unfortunately

generate osteosarcomas rather than lung tissue (S. Janes,

London). In theory, transdifferentiated stem cells still prob-

ably offer the greatest hope for those with end-stage

respiratory disease, but this is for the future.

The NETT study showed that lung volume-reduction

surgery (LVRS) works in carefully selected patients with

severe disease, but it is expensive (estimated at $98,000 per

quality-adjusted life year) and associated with high mortality

(P. Shah, London). In the hyperinflated lung, there is another

option that achieves the same volume reduction, but without

the trauma and expense of LVRS: valve delivery via endo-

scopy. A variety of valves and umbrellas, which allow

secretions and air to be cleared, but prevent the entry of air

into the lung segment, are being developed. The VENT trial

conducted recently for this technique is now closed and the

data are anticipated. Other options are to create new

pulmonary channels communicating out of the chest (spira-

cles), the introduction of fibrosis-inducing ‘‘glues’’ into lung

segments (sclerosants) and the creation of new airways

(bypasses) to allow more effective emptying of the lung

segment.

Non-invasive ventilation (NIV) is very effective in reducing

mortality during acute exacerbations in COPD, particularly in

those with acidosis and hypercapnia (M. Elliott, Leeds).

Although there are no robust RCT data to support the chronic

use of NIV in stable COPD patients, it should be considered in

a minority of cases.

The cause and impact of acute exacerbation

Acute exacerbations are associated with both upper and

lower airway inflammation, along with systemic inflamma-

tion. The mechanical aspects of inflammatory obstruction

help create and sustain a vicious cycle that quickly involves

neuropsychological stresses resulting in a downward spiral

for the patient. A clear definition as to what constitutes an

acute exacerbation and its severity is not easy to come by, yet

this is essential to optimise primary and emergency manage-

ment, and to guide physicians towards the appro-

priate pharmacological and non-pharmacological therapies

(R. Rodriguez-Roisin, Barcelona). The frequency, duration and

symptomology of acute exacerbation have all factored into

efforts to standardise on approach but, at this point, each

physician must still fall back on their own experience when

assessing options for each patient.

Whether it is the presence of serum markers of infection or

the winter-intensive frequency of hospital admissions, the

signs are there for respiratory tract infections (RTI) to be a

major contributing factor in exacerbations. Of course, the

presence of existing COPD may simply predispose patients to

RTI and other seasonal respiratory stresses but mounting

evidence is pointing to a direct role for persistent or recurring

RTI as a major cause of acute exacerbations of COPD (S. Sethi,

Buffalo). This makes understanding the host-pathogen inter-

action a critical factor in the pathogenesis and recovery from

acute exacerbation.

It is known that RTI with a few strains of bacteria is

common in patients with symptoms of exacerbation—these

are Streptococcus pneumoniae, Moraxella cattarhalis and Haemo-

philus influenzae. An important hypothesis being tested is that

acquisition of new strains or new strain subtypes is a driver of

acute exacerbation. Certainly it is possible to show that a

proportion of exacerbations follow a cycle that involves

immune-mediated or antibiotic-mediated clearance of colo-

nisation, followed by acquisition with a new strain or

subtype. Viral infection is also identified as a cause of acute

exacerbation, with indications that the interplay between

viral and bacterial infection intensify the acute inflammation.

In understanding the impact of acute exacerbations, it is

acknowledged that COPD patients can be broadly divided into

infrequent and frequent ‘‘exacerbators’’ (W. Wedzicha, London).

Not surprisingly, frequent exacerbators have poorer outcomes

for most clinical outcomes, including FEV1, dyspnoea, quality

of life, incidence of comorbidities and ultimately mortality.

Frequent exacerbators also suffer more common colds, in line

with the RTI hypothesis, but this equally begs the chicken-and-

egg question as to what is cause and what is effect.

Measurement of inflammatory biomarkers suggests a

propensity for a more-rapid and persistent change in certain

pro-inflammatory proteins, such as C-reactive protein (CRP),

in frequent exacerbators but the utility of this as a real

predictive indicator is not yet proven.

A single acute exacerbation can result in as much lean

muscle damage in the chest as three years of ageing, and may

be argued to be no less serious than a myocardial infarction

(L. Fabbri, Modena). Prevention and treatment is critical, but

the cause of acute exacerbation is not always clear and is

complicated by the need to diagnose and treat comorbid

diseases such as congestive heart failure, pulmonary embo-

lism or diabetes.

Furthermore, there is no agreed classification of exacerba-

tions, although the clinical relevance of the episode and its

outcome may be ranked as—level I: treated at home, Level II:

requires hospitalisation, Level III: leads to respiratory failure.

Hospital at home (HaH) is possible for level 1 cases (see

below), whereas therapy with oral corticosteroids, (procalci-

tonin-guided) use of antibiotics, increased bronchodilator

therapy and non-invasive positive-pressure ventilatory sup-

port are effective approaches to treatment in more-severe

cases.

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Patient-centred approaches

Acute exacerbation is to COPD what myocardial infarction is

to cardiovascular disease, and patients express real fear of

suffocating breathlessness and the next, possibly fatal,

exacerbation (M. Partridge, London). Patients do not however

refer to ‘‘exacerbation’’ since 60% do not know or understand

the term, rather referring to ‘‘infections’’, ‘‘attacks’’, ‘‘crisis’’ or

‘‘breathlessness’’. On the other hand, although the symptoms

of exacerbation vary greatly from patient-to-patient, 85% of

patients experience the same symptoms each time they have

an exacerbation and two-thirds of patients are aware of when

an exacerbation is imminent.

Patient awareness is a critical factor in developing self-

management protocols for mitigating the impact and cost of

exacerbations, since the earlier the intervention starts, the

better the outcomes. Early intervention in exacerbation,

either in hospital or at home, not only decreases the risk of

hospitalisation, but leads to faster recovery and better health-

related quality of life. For each day of delay in initiation of

treatment patients will spend 0.42 additional days in hospital.

Clinical studies have shown that patients with active

involvement in managing their disease, including early self-

treatment of signs of exacerbation with prednisone and

antibiotics, have up to 40% fewer hospital admissions and

medical emergency attendance (J. Bourbeau, Montreal). These

protocols tend to include a component of pulmonary

rehabilitation and active patient support, also proven to

reduce hospitalisation, thus it is still contentious that patient

self-management of exacerbations is effective in isolation.

Since involving the patient in an integrated approach is

preferable, the implementation of ‘‘action plans’’ is becoming

more common. However, this brings its own challenges since

the critical improvements in patient health and quality of life

can be achieved only with training and changes in patient

behaviour. This is not simple to achieve, up to 15% of patients

may be functionally illiterate (M. Partridge, London) and

respond better to guidelines in cartoon format. Once patient

involvement is confirmed, the reductions in short and long-

term hospitalisation do seem evident. It must be pointed out

that not everyone is convinced, and a more-focused clinical

study is needed to confirm the benefits of action plans and

self-management.

Keeping COPD patients out of hospital

Of the stated components of the ERS-ATS guidelines for

hospital admission for COPD patients, the clinical indicators

that are likely to have most value are worsening hypoxemia

and hypercapnea, accompanied by respiratory acidosis. But

where these do not necessarily make medical admission

unavoidable, there is a good case for treating patients at home

as much as possible (R. Stevenson, Edinburgh). It frees up

valuable hospital resource and is better for the patient’s sense

of well-being.

So-called ‘‘admission avoidance’’ and ‘‘early supported

discharge’’ do work if there is both an effective screening

mechanism and reliable ‘‘Hospital at Home’’ (HaH) support.

Screening by pulmonary medical teams in emergency rooms

of COPD patients with worsening symptoms can reduce

admissions by 30%, although this is most effective in larger

urban units with sufficient staff to provide the screen. In

smaller community-oriented hospitals, admission may be the

best option initially but followed up with early supported

discharge following assessment. Up to 38% of patients can be

sent home early under these schemes.

What does HaH really mean? In reality HaH is a ‘‘package’’

of medical tools (bronchodilators, oral steroids, antibiotics,

oxygen, etc.) delivered in parallel with nursing and/or

physiotherapy care along with social support (L. Davies,

Liverpool). A well-trained, enthusiastic multidisciplinary

team, led by a consultant respiratory physician is vital, as is

effective patient screening and the right expectations on the

part both of patient and team members. With experience,

HaH can take a patient from presentation to the point of

discharge in as few as 3.8 home visits by the team.

Getting these components right can have dramatic benefits

to patient quality of life and mortality, and as a bonus saves

the health service money—the per-patient cost of HaH in

available studies can be reduced by up to 62% of the typical

cost of treating them in hospital. Obviously, even if they fit the

basic clinical criteria for HaH, not all patients want to be cared

for at home and some are simply unsuitable. Overall though,

the clear message is that keeping patients out of hospital and

supporting them at home is an important part of the modern

approach to COPD management.

Critically, managing patients at home requires much better

communication with patients and their carers. This is

especially true towards the end of life (J. Scullion, Leicester).

The diagnosis of COPD is not always communicated clearly or

consistently to patients, resulting in confusion about the

nature and cause of their symptoms. More than one-in-three

do not understand that their disease will get progressively

worse, and over 50% felt they had received no advice or help

on the emotional and psychological aspects of COPD.

The stage at which death is likely has been mapped out

through a series of clinical indicators, yet patients and carers

are often not advised when they reach this. Consequently, a

range of important end-of-life options and choices in regard

of patient and carer support may be tacitly denied. It is

unthinkable that this would happen in other terminal

diseases, such as cancer, and strenuous efforts are now being

made to develop a protocol that puts patients and carers at

the centre of the palliative approach.

Oxygen therapy in COPD—not as straightforward as youmight think

The NOTT and MRC clinical trials in the 1980s confirmed that

mortality could be significantly improved for COPD patients

with resting hypoxemia if they received long-term oxygen

therapy (LTOT). Since then, oxygen at home has been

augmented with ambulatory oxygen therapy (AOT) and

short-burst oxygen therapy (SBOT), and there is good

evidence that each of these can provide many benefits—

dyspnoea, work-rate endurance and sleep apnoea all show

short-term improvement. However, the reality of oxygen

therapy differs greatly from the controlled approach of the

landmark studies and the setting and application for oxygen

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therapy is important to manage appropriately. Moreover, it is

critical to ensure that you take the patient’s perspective into

account when assessing the effectiveness and suitability of

treatment—as a healthcare professional you may be con-

vinced that it will do them good, but often as patients they are

not.

For patients still able to undertake exercise, either as part of

their therapy or their regular daily lives, AOT and SBOT can

provide benefit during exercise and on recovery, and also to

help them cope with breathlessness at rest (W. Wedzicha,

London). However, patient compliance is variable and there is

evidence that, despite the availability in the home of AOT or

SBOT, many patients rely very heavily on the standard LTOT

set-up, thus negating the additional exercise-related benefits

that AOT or SBOT can provide in terms of improved mobility

and social activity (R. Casaburi, Los Angeles).

Taking a patient-centred perspective uncovers a critical set

of issues not documented by disease-centred studies. Once

domiciliary LTOT is put in place patients and their carers

often struggle with feelings of loss of self-worth and social

identity, as well as finding it hard to cope with what LTOT

really means for them—many are unclear that the role of

LTOT is not short-term as part of a ‘‘cure’’, and that ultimately

they are now on a therapy that will accompany them to their

death (K. Clancy, Rochdale).

Despite the disease-centred scientific metrics, LTOT pa-

tients and carers often perceive no benefit, rather talking of

‘‘just existing’’ with no quality to their lives. The more

negative of these perceptions may be skewed towards

patients who have not been hospitalised prior to being put

on LTOT. Those who have had frequent admissions do seem

to appreciate more the benefit that LTOT provides.

Overall, two clear imperatives emerge from this: (1) a new

LTOT study is needed to further define and clarify the genuine

benefits of oxygen therapy, with a sufficiently large study

group (3500 patients) and able to collect data over at least

a 4 year period, and; (2) a better protocol for connecting

patients and carers with their oxygen therapy, to help them

manage feelings of isolation and loss. Combining LTOT with

cognitive therapy and better palliative approaches may prove

valuable here.

Pulmonary rehabilitation—by no means a walkin the park

Exercise limitation is a major cause of disability in COPD and

is closely linked to disease progression. If you ask a COPD

patient what they want from pulmonary rehabilitation they

are most likely to answer—‘‘to be able to walk further’’. If this

is the criteria by which you measure success then there is no

doubt that pulmonary rehabilitation works. The critical factor

may be to put in place a pulmonary rehabilitation team who

are able to motivate patients to participate in a well-designed

programme (S. Singh, Leicester). Team performance in this

regard is variable, and there is plenty of scope for further

development of team skills and best-practice.

Given the patients own stated goal, improvements in the 6-

min walking test (6MWT) or the shuttle walking test (SWT)

are highly desirable outcomes, and this should be reflected in

the balance between training based on endurance versus

strength or high intensity. Strength training has health-status

benefits for patients, but only endurance training improves

VO2 and endurance time.

Patient selection is a critical factor in successful pulmonary

rehabilitation in COPD, since not everyone can or wants

to undertake the training involved. If your resources are

limited, you need to focus on those who are most likely to

respond. Age, disability or smoking status are not good

selective criteria, whereas patients who are obese or who

have low motivation (and may be clinically depressed) are

unlikely to benefit until these underlying factors have been

addressed.

COPD is a system-wide disease

It is becoming accepted that the lung inflammation in COPD

is associated with a concomitant systemic inflammation (A.

Agusti, Palma de Mallorca), the degree of which is a strong

predictor of health status, functional status, hospitalisations

and death in COPD (C. Donner, Borgomanero). An important

chicken-and-egg question to answer is whether the systemic

inflammation seen in COPD is result of pulmonary inflamma-

tion or vice versa.

Pulmonary hypertension (PH) in COPD has been linked to

‘‘GG’’ variants in the IL-6 gene promoter (A. Chaouat,

Strasbourg). It is estimated that 60,000 people are at risk in

the UK, and 300,000 in the USA. Causative factors include

chronic alveolar hypoxia, inflammation and emphysema, all

of which produce intimal and medial thickening in the

pulmonary arteries, reducing the luminal volume and thereby

increasing vascular resistance. In COPD patients, the condi-

tion is usually mild to moderate, but can worsen with

exercise, sleep and during exacerbations. Right-heart cathe-

terization is the gold standard way of measuring PH but this is

obviously invasive and probably only beneficial in severe

cases. Other metrics include increased levels of brain

natriuretic peptide, and Doppler echocardiography, although

the latter can be inaccurate.

New pharmacological vasodilators are needed to treat

pulmonary arterial hypertension in COPD patients. Acute

cardiovascular events are the primary cause of death in

patients with COPD—every 10% reduction in FEV1 is asso-

ciated with a 28% increase in cardiovascular mortality (W.

MacNee, Edinburgh). The mechanism in COPD appears to be

related to oxidative stress and systemic inflammation, thus

treatment of the latter might improve patient outcomes. In a

study of acute exacerbations in COPD, 67% of the patients had

chest pains, which could easily be cardiovascular events.

Whatever the etiology, the systemic inflammation can be

linked to weight loss (cachexia), skeletal muscle dysfunction,

cardiovascular disease, osteoporosis, depression, cancer and

other problems (E. Wouters, Maastricht). The interplay

between symptoms is complex, such that changes in FEV1

are as important as cholesterol in predicting mortality from

ischaemic heart disease.

Smoking itself can have systemic pro-inflammatory effects,

but in COPD patients these persist following smoking cessa-

tion. Lung hyperinflation can lead to systemic inflammation,

as can tissue hypoxia and abnormal exercise responses in

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COPD. In COPD-associated cachexia you can show an increase

in pro-inflammatory mediators and molecules such as TNF-a,

iNOS, NF-kB and nitrotyrosinated proteins. However, along

with these markers, the smaller muscle fibres and apoptotic

nuclei seen in COPD-associated cachexia fit the theory that

the systemic inflammation seen in so-called ‘‘pink puffers’’

may be different to that in COPD patients with normal or

elevated BMI.

What about treating systemic inflammation? The inhaled

and oral corticosteroids used to treat the pulmonary symp-

toms of COPD are effective in reducing serum CRP levels in

patients with COPD and suggest their potential use for

improving cardiovascular outcomes in COPD. This also stirs

a debate as to the interplay between systemic markers of

COPD and those of cardiovascular disease, and whether

treatments that lower the risk of cardiovascular injury (e.g.

statins) may improve outcomes in COPD. The jury seems still

to be out on this.

There is clearly a link between cachexia and poor health

status in COPD. Moreover, there is also a case that chronically

poor nutrition on its own can lead to respiratory problems.

Consequently, much work has been done to establish the

value of nutritional therapy. Reducing involuntary weight loss

and improving muscle performance certainly improves mor-

tality (A. Schols, Maastricht), and this approach can be

implemented even during acute exacerbation. Equally, thera-

pies that improve lung function also result in improved body

mass in underweight subjects.

More detailed work shows that, rather than total BMI, it is

the change in the fat-free mass (FFM) that has most effect on

outcomes in COPD. Thus, it is possible that overall BMI may

remain unaffected but that a decrease in FFM is contributing

to poor health status in some subjects.

COPD in body and mind?

The physical toll that is exacted on patients with COPD is

relatively easy to measure, but what about psychological

effects? Clinical depression is often listed as a comorbid

feature of COPD yet the published literature is equivocal on

this issue, with many studies claiming that depression is no

more frequent for COPD patients than non-sufferers (P. Jones,

London). It is possible to correlate changes in health status to

depression, but treating symptoms of depression in the short

term (over a 6-week period) does not improve either the

symptoms of depression or of COPD. There may be benefits to

longer-term treatment (3 months and beyond) but a full-scale

clinical trial would be needed to prove this.

Cognitive function in COPD patients is also a topic of

debate, again generating mixed opinion. Against a battery of

cognitive tests, only slight changes can be seen in non-

hypoxic COPD, with a higher incidence in hypoxic patients.

The main concern in cognitive-impaired hypoxic patients

would be that they became poorly compliant with their

medication regime. However, this seems unavoidable since

treating COPD patients for cognitive impairment makes little

or no difference.

Quit smoking? I want to, buty

Despite the much discussed pharmacotherapies and other

support mechanisms for COPD sufferers, nobody doubts that

the most effective intervention is one that results in early

cessation of smoking. Simple to point out, almost impossible

to achieve. Everybody knows that smoking is bad for

you—really bad—and approximately 70% of all smokers say

they want to quit.

How best can this group be supported? The primary care

clinic is the obvious place for advice, encouragement and

therapy to begin, yet only 25% of primary care professionals in

the UK have had specific training in smoking cessation

therapy and management (K. Lewis, Swansea).

Pharmacological assistance is possible, not just with

nicotine-replacement therapy (NRT) but with bupropion (an

anti-depressant) and varenicline (a specific anti-smoking

drug) each showing a level of effectiveness in supporting

those who want to quit smoking, including amongst COPD

sufferers. The real success with pharmacotherapy comes if

additional cognitive support is provided in the form of advice

from a healthcare professional, with managed follow-up.

With this regime, up to 20% of quitters can maintain

abstinence over a 12-month follow up period. In terms of

cost-per-life saved, this approach is stunningly effective—no

more than £630. Compared to the £45,000 cost per-life-saved

via prescription of ACE-inhibitors in cardiovascular disease, it

is shameful that more resources aren’t allocated to such

smoking cessation schemes.

The goal of large-scale smoking cessation as a means of

reducing all-cause mortality remains an uphill struggle. Over

the last 10 years, despite the ever increasing cost of cigarettes

and the ever-decreasing number of public places where

smoking is permitted, there has been only a net 5% reduction

in active smoking across Europe (C. van Schayck, Maastricht).

Robert Brines, Matthew Thorne

C/o Reed Medical Education, Gateway House, 28 The Quadrant,

Richmond, Surrey, TW9 1DN

E-mail address: rob.brines@reedexpo.co.uk (R. Brines)