Update in Chronic Obstructive Pulmonary Disease 2008

John D. Maclay1, Roberto A. Rabinovich1, and William MacNee1

1

ELEGI Laboratories, Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

The last year has seen important new information published on

chronic obstructive pulmonary disease (COPD), its pathogenesis, systemic effects, exacerbations, and treatment. Several
important new COPD research programs have been initiated
during the past year, including the Sub-Populations and Intermediate Outcomes Measures in COPD Study (SPIROMICS)
program, which will categorize patients on the basis of molecular fingerprinting and will attempt to identify and validate
intermediate outcome measures in COPD. The Evaluation of
COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study (1) aims to define clinically relevant
COPD subtypes and identify genetic factors and biomarkers
that correlate with these COPD subtypes and predict disease
progression. In addition, several large research consortia have
been established, including the COPD clinical research network
and the National Heart, Lung, and Blood Institutefunded lung
tissue research consortium (2).

OUTCOME MEASURES IN COPD

There has been considerable interest in developing better outcome measures in COPD given the realization that FEV1,
although important as a means of defining this condition, is
limited in terms of its use in staging the disease and assessing
a response to therapy.
An ATS/ERS task force reported on outcome measures in
COPD (3). A major conclusion of this task force was that
changes in parameters related to breathlessness, exercise performance, and health-related quality of life with therapeutic
interventions are not always reflected in changes in traditional
measures of disease severity, such as FEV1. Therefore, these
variables could complement measurements of airflow limitation
in assessing the effects of therapeutic interventions in COPD.
COPD is one of the few chronic diseases that have shown an
increase in mortality in recent years. Because treatments that
aim to improve survival in COPD require large numbers of
patients studied over long periods of time, it is desirable to have
an appropriate surrogate marker for survival that would assist in
the evaluation of therapies for this condition. The 6-minute
walking distance (6MWD) is a good predictor of all-cause and
respiratory mortality in patients with moderate COPD. Furthermore, patients who desaturate during a 6MWD have a higher
mortality than those without desaturation (4).
The multidimensional BODE index (body mass index; obstruction, FEV1; dyspnea, Medical Research Council [MRC]
dyspnea scale; exercise, 6MWD) is known to be a better predictor
of mortality in COPD than FEV1. The longitudinal change in the
modified BODE index (mBODE), which uses the University of
California, San Diego Shortness of Breath Questionnaire as the

Correspondence and requests for reprints should be addressed to William

MacNee, M.D., F.R.C.P., ELEGI Colt Laboratories, MRC Centre for Inflammation
Research (Level 2), The Queens Medical Research Institute, 47 Little France
Crescent, Edinburgh EH16 4TJ, UK. E-mail: w.macnee@ed.ac.uk
Am J Respir Crit Care Med Vol 179. pp 533541, 2009
DOI: 10.1164/rccm.200901-0134UP
Internet address: www.atsjournals.org

dyspnea measure in place of the MRC dyspnea score (5), was

studied in a cohort of patients with severe emphysema from the
National Emphysema Treatment Trial (NETT). An increase
greater than one in the mBODE was associated with increased
mortality and the change in mBODE predicted survival better
than changes in its individual components. This study provides
support for the use of this multidimensional composite index as
a surrogate for survival in clinical trials.
There is a need to develop biomarkers that relate to the
pathogenic processes in COPD (6) and that can be used as
intermediate endpoints for short-term clinical trials. Disease
biomarkers should have high sensitivity and specificity as well as
biological relevance to pathogenesis, and changes in the biomarker should be of clinical relevance. Clara cell secretoryprotein 16 (CC-16), a member of the secretoglobin family of
small secreted disulphide-bridged dimeric proteins, is secreted
by nonciliated Clara cells in the bronchi and by nonciliated
columnar cells in the large and small airways. Serum CC-16
levels have been linked to Clara cell toxicity. In a large population of patients with COPD from the ECLIPSE study, CC-16
levels were significantly reduced in current and former smokers
with COPD when compared with those without airflow limitation. However, there are significant limitations to the use of CC16 as a biomarker of disease in that it does not correlate well
with the presence or severity of emphysema or with symptoms
of chronic bronchitis (7).
Surfactant protein D (SP-D) is a relatively specific lung
biomarker because its synthesis is restricted to pulmonary
tissues. In a randomized, controlled trial of 289 patients with
COPD, serum protein D levels increased when inhaled corticosteroids (ICS) and/or long-acting b-adrenergic agonists (LABA)
and theophylline were withdrawn, and the protein D levels
decreased after initiation of treatment with ICS with or without
LABA (8). Changes in serum SP-D levels in response to ICS
may relate to changes in SP-D leakage from the lungs to the
circulation, increased extrapulmonary SP-D production, or decreased SP-D clearance from the circulation. Serum SP-D may
therefore be useful as a marker of the response to steroid
therapy in COPD (9).

SYSTEMIC FEATURES OF COPD

COPD is now established as a disease associated with systemic
characteristics. Recent years have seen an increased understanding of the association of COPD and a number of comorbid
conditions. Analysis of a population-based cohort showed
a higher prevalence of hypertension, diabetes mellitus, and
cardiovascular disease in individuals with airflow limitation of
GOLD stages 3 and 4 (10). A large population-based study
using the Atherosclerosis Risk in Communities cohort, with
a 14-year follow-up, showed an increase in the prevalence of
cardiovascular events in individuals with COPD when compared with controls (11). Interestingly, the relative risks were
markedly reduced after adjusting for covariates that included
traditional cardiovascular risk factors, which suggests that the
increased incidence of cardiovascular disease in COPD may be
mediated by the high prevalence of traditional risk factors in
patients with this condition.

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There has been further work examining the potential mechanisms of the increased cardiovascular morbidity and mortality
associated with COPD, particularly related to abnormal systemic vascular function. A mechanistic study reported impaired
brachial artery vasodilatation in patients with stable COPD
when compared with healthy smokers and nonsmokers (12). A
larger case-control study confirmed previous findings of an
increase in systemic arterial stiffness in COPD when compared
with age- and sex-matched controls (13).
Heart failure is common in COPD and COPD is common in
heart failure patients. A recent study of 186 consecutive patients
with left ventricular systolic dysfunction in a heart failure clinic
found that 39% had COPD diagnosed on spirometry, and those
patients with heart failure and severe COPD had a worse
prognosis than patients with mild to moderate COPD or normal
lung function (14). Higher mortality was again reported among
patients with COPD compared with individuals without lung
disease in a study of 800 patients hospitalized with cardiac
failure (15). In addition, discharge prescription of b-blockers
was significantly lower in individuals with airways disease.
There is now additional evidence on the safety of b-blockers
in COPD. In patients with COPD undergoing vascular surgery,
cardioselective b-blockers reduce mortality (16), and an observational study reported safe use of these agents in exacerbations
of COPD and even a trend to a reduction in mortality with
b-blocker use in COPD exacerbations (17).
Although patients with myocardial dysfunction and comorbid COPD have increased mortality, impaired cardiac function
can also contribute to reduced physical activity in COPD (18).
Both left ventricular function assessed by echocardiography and
N-terminal proB-type natriuretic peptide (NT pro-BNP), a biomarker of left ventricular strain, have negative, independent
associations with physical activity levels after adjustment for
GOLD stage or BODE score. A further study demonstrated an
increase in NT pro-BNP during COPD exacerbations compared
with levels in the recovery period and, in particular, in individuals who required admission to the intensive care unit (19).
Investigations into the mechanism of exertional dyspnea in
patients with mild COPD (GOLD 1) suggested increased ventilatory demand at higher workloads as well as abnormal
dynamic pulmonary mechanics, particularly reduced inspiratory
capacity, when compared with healthy controls (20). Treatments
that target this physiological abnormality may prove useful in
reducing symptoms of dyspnea and improving exercise tolerance. Indeed, a placebo-controlled crossover study that investigated the effects of nebulized furosemide on lung mechanics
during exercise demonstrated improved exertional dyspnea and
increased exercise endurance associated with increases in
dynamic inspiratory capacity, tidal volume, and mean tidal
expiratory flow rates at isotime (21).
Systemic inflammation is an established feature of COPD.
Higher plasma fibrinogen during the stable phase has been
shown to independently predict exacerbation frequency (22).
However, in a study of subjects with moderate to severe COPD,
C-reactive protein (CRP) was not associated with survival,
unlike airflow limitation and the BODE index (23).
A further analysis of the Lung Health Study investigated
whether an imbalance of lung injury and repair (measured using
serum highly sensitive CRP and fibronectin, respectively) could
contribute to mortality (24). In this large study of individuals
with mild to moderate COPD who were followed for up to
15 years, the ratio of fibronectin to highly sensitive CRP was significantly associated with all cause mortality. A cross-sectional
study of 2,553 patients with airflow limitation from the Framingham cohort showed further relationships between systemic
inflammatory markers and severity of COPD (25). There were

2009

negative associations between FEV1 and CRP and IL-6, as well

as between p-selectin and ICAM, markers of endothelial
function and predictors of cardiovascular risk.
It has been suggested that exacerbations of COPD may be
caused or exacerbated by gastroesophageal reflux disease (GERD).
A study of individuals in UK primary care showed that GERD
is more common in patients with COPD when compared with
matched controls (26). Furthermore, a small Japanese study described a modest association between symptoms of GERD and
the frequency of COPD exacerbations (27).
Depression is common in COPD. Two prospective studies
further elucidate relationships between depression, anxiety, and
COPD exacerbations. A diagnosis of depression was associated
with an increased risk of a COPD exacerbation and hospitalization after adjusting for the severity of airflow limitation (28).
In addition, the severity of depression has been associated with
increased frequency of exacerbations and a worse quality of
life (29).
COPD has been linked with increased risk of osteoporosis.
A number of factors have been implicated including smoking,
immobility, and glucocorticoid use. A study of Japanese men
showed that severity of emphysema on computed tomography
(CT) scanning and low body mass index were independent
predictors of reduced bone mineral density after adjusting for
age, sex, and smoking history, implying that COPD itself may
be a risk factor for osteoporosis (30). It is important to note,
however, that this was a slightly unusual cohort, naive to both
inhaled and oral corticosteroids.

GENETICS
Why only a minority of smokers develop clinically significant
COPD and why there is great heterogeneity in the presentation
of COPD are key questions in the pathogenesis of this disorder.
Identification of predisposing genetic factors may provide
answers. Oxidative stress is considered to be an important
mechanism in the pathogenesis of COPD. Antioxidants that
can counter the deleterious effects of the increased release of
reactive oxygen species may be altered in COPD. Novel polymorphisms in the gene that encodes for the antioxidant superoxide dismutase (SOD)3 have been identified. Individuals who
are homozygous for these polymorphisms have an increased
risk of a reduced FEV1/FVC.
Glutamate cysteine ligase (GCL) is the major enzyme in the
synthesis of glutathione, a major antioxidant in the lungs (31).
In population studies from The Netherlands, novel single nucleotide polymorphisms (SNPs) in the GCL gene were associated with low levels of FEV1 and FVC. These associations were
present in subjects with the lowest vitamin C intake, suggesting
interactions between GCL polymorphisms and low vitamin C
intake, which contribute to the increased oxidative burden in
COPD (32). However, in a large population of patients with
COPD that were matched with nondiseased smoking controls,
there was no association with several SNPs in the epoxide hydrolase gene or in the gene encoding GCL and susceptibility to
COPD or disease severity (33).
There have been conflicting results in different populations
for the association between SNPs in the tumor necrosis factor
(TNF) gene and susceptibility to COPD. These inconsistencies
may result from study-design limitations, such as small numbers,
genotyping with a limited number of informative SNPs, and the
failure to adjust for confounding variables. A recent study,
which is one of the larger and more comprehensive studies of
TNF polymorphisms in COPD, showed that the 2308 SNP was
associated with COPD. Additional large independent studies in
different populations are needed to replicate these findings (34).

Pulmonary and Critical Care Updates

In a case-control study of 311 COPD patients and 386 controls, polymorphisms in the type IV collagen a3 gene were
shown to be associated with a high risk of COPD, suggesting
that the type IV collagen a3 gene contributes to genetic susceptibility to COPD (35).
A number of studies have examined genetic associations
with COPD-associated traits, such as exercise capacity. Single
nucleotide polymorphisms in the epoxide hydrolase and SERPIN
2 genes were associated with hypoxemia and SNPs in the surfactant protein B gene were associated with the level of the
pulmonary arterial pressure in two separate study populations
of patients with severe COPD (36).
The genetic susceptibility to the development of chronic
bronchitis was investigated in a population from the Swedish
twin registry and showed that genetic factors, independent of
those related to smoking, may play a role in the development of
chronic bronchitis (37). Other studies have shown that functional SNPs in the CC chemokine ligand 5 gene appear to be
associated with a milder emphysematous phenotype (38).
Whole genome gene expression studies of lung tissue from
patients with COPD provide an opportunity to identify candidate
genes in the pathogenesis of COPD and gain a greater molecular
understanding of the pathogenic processes that contribute to the
heterogeneity of the disease (39). A study of comprehensive
gene-expression profiling in a large sample of human lung tissue
from patients with COPD with a well-characterized phenotype
and from patients who did not have COPD (40) showed that
genes involved in tissue remodeling and repair are differentially
regulated in the lungs of smokers. Genes in these pathways are
involved in the activation of transforming growth factor-b1 and
matrix metalloproteases, which are candidate genes in COPD
and subject to inhibition by SERPIN 2.
Patients with COPD have been shown to have a high
frequency of genetic alterations at the microsatellite DNA level
that can be detected in their sputum cells. Significant associations have now been demonstrated between microsatellite
DNA stability and COPD exacerbations, suggesting that somatic mutations could be involved in the pathogenesis and
natural history of exacerbations of the disease (41).

PATHOPHYSIOLOGY/PATHOGENESIS
The mechanisms involved in the enhanced inflammatory response in the lung that characterizes patients with COPD may
hold the key to the pathogenesis of this condition. IL-32 is
a newly discovered cytokine that may have regulatory functions
in the innate and adaptive immune responses that characterize
the inflammatory profile of patients with COPD. In a small
study of surgically resected lung specimens, immunohistochemical and mRNA expression for IL-32 was increased in macrophages, alveolar walls, and bronchial epithelium in patients with
COPD when compared with control smokers. The expression of
IL-32 correlated positively with TNF-a, phosphorylated p38
mitogen-activated protein kinases, and negatively with the
FEV1, suggesting that IL-32 is implicated in the characteristic
immune responses in COPD (42).
Increased oxidative stress is generally considered to be a key
contributor to the enhanced inflammatory response in COPD.
Nuclear factor erythroid-related factor 2 (NRF2) is a key
transcriptional factor that regulates antioxidant defense systems. Compared with non-COPD lungs, lungs from patients
with COPD have a marked reduction in NRF2-dependent
antioxidant enzyme levels, associated with increased markers
of oxidative stress (43). In addition, patients with COPD
showed a decrease in NRF2 protein and a decrease in the level
of DJ-1, a protein that stabilizes NRF2 protein. Disruption of

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DJ-1 in mouse lungs lowered NRF2 protein stability and

impaired antioxidant induction in response to cigarette smoke.
Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of
oxidative stress.
Two novel hypotheses in the pathogenesis of COPD have
received attention. The first relates to autoimmune mechanisms
in the pathogenesis of COPD. This hypothesis is supported by the
presence of circulating epithelial autoantibodies with the potential to mediate cytotoxicity in patients with COPD (44). In
patients with COPD there are higher CD81CD45RA1 and
lower CD81CD45RO1 peripheral blood lymphocytes than in
smokers with normal lung function. These observations suggest
a blunted regulatory T-cell response to tobacco smoking in patients with COPD, which further supports the involvement of the
acquired immune response in the pathogenesis of COPD (45).
An intriguing hypothesis in the pathogenesis of COPD, and
more specifically emphysema, is that it could represent a feature
of accelerated aging. Telomeres are nuclear protein structures
that cap the ends of chromosomes and prevent end fusion and
their degradation. Telomeres shorten with each cell division and
this process is enhanced by inflammation and oxidative stress.
Somatic cells are triggered into replicative senescence once
telomeres shorten to a critical length. Telomere length is thus
considered to be a marker of biological age. Shortened telomeres have been shown in leukocytes from patients with COPD
compared with controls, a finding that correlated with elevated
markers of systemic inflammation (46). Further support for
accelerated aging as a pathogenic mechanism in COPD comes
from studies of Sirtuin (SIRT1), an antiaging, antiinflammatory
protein, which is reduced in the lungs of patients with COPD
compared with nonsmokers, due to posttranslational modification by oxidants. In addition to its association with aging,
decreased SIRT1 may also have a pivotal role in the regulation
of necrosis factor (NF)-kBdependent proinflammatory mediators and thus the enhanced lung inflammation in patients with
COPD (47).
There is increasing evidence that apoptosis is an important
feature in the pathogenesis of emphysema. Recent studies suggest that oxidative stress and proinflammatory cytokines lead to
increases in the levels of p53 and TRAIL receptor, which may
serve as a mechanism for the increased alveolar cell apoptosis in
emphysema (48). Disregulated apoptosis of epithelial cells and
defective clearance (efferocytosis) of apoptotic cells by macrophages may be further mechanisms leading to enhanced lung
inflammation in COPD. There is the potential for drug intervention to correct defective efferocytosis. The phagocytic
function of alveolar macrophages was improved in patients with
COPD treated for 12 weeks with azithromycin by a mechanism
involving up-regulation of the mannose receptor (49).
Inflammation, oxidative stress, and apoptosis, which are
involved in the pathogenesis of COPD, may activate the p38
subgroup of mitogen-activated protein kinases. Phosphorylated
p38 is indicative of activation of this kinase. In surgical specimens from smokers with COPD and smoking and nonsmoking
subjects with normal lung function, phospho-p381 alveolar
macrophages and phospho-p381 cells in alveolar walls were
increased in patients with severe and mild to moderate COPD,
compared with smoking and nonsmoking controls, and were
inversely related to the FEV1 and FEV1/FVC. Western blot
analysis showed that phosphorylated p38, but not the total p38a
isoform, was specifically increased in alveolar macrophages
from patients with COPD. Thus activation of the p38 mitogen-activated protein kinase pathway may be involved in the
pathogenesis of COPD, and this kinase may be a suitable pharmacological target for intervention (50).

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Defective tissue repair is considered to be an important

aspect of the pathogenesis of lung injury in COPD. Fibroblasts
are thought to be the major cells responsible for the production
and maintenance of extracellular matrix, and thus alteration of
fibroblast function could play a role in the pathogenesis of pulmonary emphysema, which is characterized by inadequate preservation of lung-tissue structure. Fibroblasts from patients with
COPD have reduced activity of several measures associated
with tissue repair, which is mediated by both increased production of prostaglandin E and decreased sensitivity to transforming growth factor-b (51).
Dendritic cells are key cells in immune responses. It has been
suggested that chronic exposure to cigarette smoke impairs the
normal maturation process of dendritic cells and subsequently
alters and suppresses their function, resulting in an imbalance
in immunity that may increase susceptibility of patients with
COPD to respiratory infections (52). Studies indicate that dendritic cells are markedly reduced in the large airways in smokers
and in patients with COPD who continue to smoke (53).

VENTILATORY FUNCTION, RESPIRATORY AND SKELETAL

MUSCLES, AND PULMONARY REHABILITATION
Patients with mild COPD can have significant physiological abnormalities that lead to breathlessness and reduction in exercise
tolerance. Even in mild disease, exercise-induced dynamic
hyperinflation is a major contributor to decreased exercise
capacity in COPD (20). Ventilation feedback training is a technique used to modify the respiratory pattern during exercise by
slowing respiratory rate. When ventilation feedback is applied
to patients with COPD together with exercise training, it decreases hyperinflation and thereby improves exercise tolerance
more than either intervention alone (54).
Panic attacks are a common contributor to breathlessness
and disability in patients with COPD. Patients with a history of
COPD and panic attacks have a heightened sensitivity to inspiratory loads, supporting the influence of psychological factors
in symptom perception of patients with COPD (55).
Bronchodilator responses were studied in 5,756 patients with
COPD from the Understanding the Potential Long-term Impacts
on Function with Tiotropium (UPLIFT) study. The majority of
these patients with moderate to very severe COPD showed
meaningful increases in lung function following administration of
inhaled anticholinergic plus sympathomimetic bronchodilators (56).
Skeletal muscle dysfunction is one of the most important
systemic effects in patients with COPD. It is characterized by
two interrelated phenomena: (1) muscle wasting, affecting approximately 30% of the COPD population, and (2) malfunction
of the remaining muscle. Muscle dysfunction leads to disability
and affects exercise tolerance and is associated with a poor prognosis. The effect of COPD on exercise tolerance has been the
source of an interesting debate (57). This debate provided arguments supporting the roles of dynamic hyperinflation, locomotor
muscle dysfunction, and inadequate energy supply to respiratory
and locomotor muscles and has highlighted the fact that exercise
intolerance in COPD is a multifactorial construct that is not
ascribable to any single structural or functional abnormality. It
is important to acknowledge the heterogeneity of COPD and
the likelihood that one or more of these pathophysiological
mechanisms may be a major contributor to exercise limitation.
Butcher and colleagues (58) provided further evidence of the
multifactorial nature of exercise limitation in COPD. They found
an inverse relationship between dynamic hyperinflation and leg
muscle fatigue during strenuous exercise in those patients with
greater airflow limitation and in those more prone to develop
dynamic hyperinflation before the attainment of significant level

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of leg muscle fatigue. By delaying this ventilatory limitation with

heliox, exercise capacity increases, which eventually leads to
greater level of leg muscle fatigue. The relative balance between
leg muscle fatigue and ventilatory limitation should be considered
in each patient to prescribe more tailored therapy.
Borghi-Silva and colleagues (59) demonstrated that unloading the respiratory muscles during exercise using proportional
assisted ventilation can improve peripheral muscle oxygenation
thus increasing endurance time in patients with COPD and concomitant increments in VO2 at isotime. This indicates that a
fraction of the available cardiac output had been redirected from
ventilatory to peripheral muscles as a consequence of respiratory muscle unloading. The functional heterogeneity of the
COPD population is reflected in studies of physical activity
(60) that demonstrate that significant limitations of physical
activity are present in patients with COPD from GOLD stage
2 and a BODE score of 1 upwards, and that clinical characteristics commonly used to assess COPD severity do not completely reflect physical activity over a broad range of disease
severity.
Mitochondrial dysfunction is particularly prominent in the
skeletal muscle of patients with COPD and low body mass
index. Patients with COPD have a reduction in the number of
mitochondria in skeletal muscle. Picard and colleagues (61)
showed that mitochondrial respiratory rate is reduced in patients with COPD. However, when corrected by citrate synthase
activity (a surrogate of mitochondrial density) these differences
were abolished. This suggests the absence of specific mitochondrial respiratory impairment in patients with COPD and normal
muscle mass, adding interesting information to the disuse versus
dysfunction debate.
Diminished oxidative capacity of the peripheral muscles leads
to early lactate release during exercise. Pyruvate dehydrogenase
complex accelerates the conversion of pyruvate to acetyl coenzyme A, facilitating mitochondrial oxidative metabolism. Calvert
and colleagues (62) showed that dichloroacetate, which activates the pyruvate dehydrogenase complex, reduces peak blood
lactate concentration by 20% during an incremental exercise
test in COPD, improving exercise tolerance. This effect is likely
due to a reduction in lower limb fatigue or an improvement in
mitochondrial ATP delivery in the respiratory muscles.
Exercise training is the cornerstone of pulmonary rehabilitation and can reverse some of the deleterious effects of COPD
on the skeletal muscle, thereby improving exercise tolerance
and quality of life. The optimal way of assessing the impact of
pulmonary rehabilitation on functional status is currently unknown. Laviolette and colleagues (63) showed that endurance
time was more responsive than the 6MWD in detecting improvement in exercise tolerance following pulmonary rehabilitation
and was also better correlated with improvements in health
status. These authors also established a difference in endurance
time of 100200 seconds as a clinically meaningful change.
Dietary creatine supplementation has been shown to augment high-intensity exercise training effects in healthy elderly
individuals. Deacon and colleagues (64) tested this intervention
in patients with COPD during pulmonary rehabilitation encompassing aerobic and resistance exercises but found no difference
from placebo subjects, despite evidence of muscle creatine
uptake that was assessed in muscle biopsies.
Compliance and acceptance of regular visits to health care
centers are major stumbling blocks to the success of pulmonary
rehabilitation programs and alternative approaches should be
considered. Liu and colleagues (65) assessed the effectiveness of
a cell phonebased exercise training using individual tempo
music to reach 80% of maximal walking speed during an incremental shuttle walking test. The program was effective in

Pulmonary and Critical Care Updates

increasing exercise tolerance, quality of life, and in reducing the

number of exacerbations and hospitalizations.
Although exercise training has beneficial effects on skeletal
muscle bioenergetics and exercise performance in patients with
COPD, it may also be associated with increased quadriceps oxidative stress. Barreiro and colleagues (66) showed that a chronic
exercise program enhanced oxidative stress, particularly affecting proteins involved in glycolysis, energy distribution, carbon
dioxide hydration, muscle oxygen transfer, DNA repair, and
contractile function. A number of these findings were more evident in patients with muscle wasting. These potentially deleterious effects of exercise training have been shown previously,
particularly in patients with muscle wasting, and constitute a
case for antioxidant therapy as a supplement to exercise training
in this subpopulation of patients with COPD.
Delample and colleagues (67) provided evidence that
xanthine oxidase is implicated in exercise-induced muscle
oxidative stress in patients with COPD. However, allopurinol,
an inhibitor of xanthine oxidase, appears to improve only
some muscle properties. Therefore, other sources of muscle
oxidative stress must be implicated in the muscle dysfunction
observed in these patients. Modified training regimens may
constitute an alternative for more severe patients or for
patients in situations where interventions with less stress to
the respiratory system are preferable, such as during COPD
exacerbations. Bustamante and colleagues (68) showed that 8
weeks of quadriceps magnetic stimulation in patients with
COPD increased exercise tolerance as measured by the
6MWD, with no changes in fiber type distribution but an
increase in the size of type I fibers. Interestingly, magnetic
stimulation did not induce increased oxidative stress in the
muscle biopsies obtained from these patients after training.
An important issue is whether the benefits associated with
exercise training are translated into a more active lifestyle after
the program. Pitta and colleagues (69) showed that, although
3 months of multidisciplinary pulmonary rehabilitation improved
a variety of outcomes in patients with COPD, patients did not
increase their activities of daily living. Significant improvements
in walking time in daily life without changing the pattern of time
spent walking were observed only after 6 months of pulmonary
rehabilitation.

IMAGING
Advances in imaging techniques using CT scanning have allowed
measurements of airway morphology (70) that can be used
together with a CT-derived assessment of emphysema to better
phenotype patients with COPD (71). Recent studies using CT
scanning to assess both airway morphometry and emphysema in
a large study of over 3,000 individuals from a multicenter
international COPD genetics network suggest that these two
factors make independent contributions to airflow limitation in
COPD. In addition, these phenotypes also show an independent
aggregation within families of individuals with COPD, suggesting
that different genetic factors influence such disease processes (72).
In a study involving 201 male smokers with COPD, body
mass index correlated with emphysema but not with the percentage of airway wall area. These results support the concept
of different COPD phenotypes and suggest that there may be
different systemic manifestations of these phenotypes (73).
Emphysema, as assessed by CT scanning, has also been shown
to be independently related to lung cancer (74).
Optical coherence tomography, a new micron-scale resolutionoptical imaging technique, has been used to measure small
airway wall dimensions that correlate with measurements made
by CT scanning. These studies suggest that optical coherence

537

tomography has a greater sensitivity in detecting changes in

airway wall measurements than does FEV1 in individuals with
obstructive airway disease (75). Thus, this new technique could
be used to study airway changes in vivo in patients with COPD
and to assess the potential of novel therapies that may affect
airway remodeling.
The novel technique of oxygen-enhanced magnetic resonance
imaging (MRI) has been used to assess regional morphology
and functional changes in COPD and has been compared with
quantitative computed tomography. Oxygen-enhanced MRI measurements were related to the clinical stage of the disease and
were able to evaluate COPD as well as pulmonary function testing and quantitative chest CT scanning (76).

EXACERBATIONS
Exacerbations have a marked effect on quality of life, morbidity,
and mortality in COPD. Therefore, reducing exacerbations of
COPD is an important outcome measure in evaluating the efficacy
of therapeutic interventions. Reliable reporting of exacerbations
of COPD is a vital part of this process. However, in comparing
information collected from clinic attendance, completed diary
cards, telephone reporting, and a subsequent patient interview,
for every exacerbation reported by phone call, patients appear to
have two further unreported exacerbations noted on their diary
cards (77). More specifically, older individuals and those patients
with less severe disease are less likely to report exacerbations of
COPD. While patients who suffer exacerbations that are reported have the most marked deterioration in health related
quality of life scores (St. Georges Respiratory Questionnaire),
those patients who suffer unreported exacerbations also have
significant decreases in health status in comparison to those with
no exacerbations.
In addition to using patient-reported changes in symptoms,
disease-specific biomarkers are important in establishing an
objective measure to monitor the development and resolution
of COPD exacerbations. No single biomarker has previously
been successful in confirming an exacerbation. Having isolated
serum amyloid A (SAA) on proteomic analysis of serum
collected from patients with exacerbations of COPD, an
Australian group reported that SAA was a more sensitive and
specific marker of moderate and severe exacerbation of COPD
than the inflammatory mediator, CRP (78). SAA was particularly raised in exacerbations with an infective etiology. Another
study that examined plasma proadrenomedullin in COPD
showed this to be increased in patients hospitalized for exacerbations of COPD, in comparison to stable state, and independently predicted a 2-year mortality in this population (79).
Bacterial infection is thought to account for between 30 and
50 percent of exacerbations of COPD. A study that assessed the
effect of exacerbations of COPD associated with infection with
new bacterial strains showed a markedly increased pulmonary
and systemic inflammatory response in comparison with preexisting or nonpathogenic bacteria (80). The authors suggest
that as exacerbations associated with preexisting pathogens
have similar local and systemic inflammation to nonpathogenic
exacerbations of COPD, the preexisting bacteria may not
contribute to the development of these exacerbations.
Selecting individuals with COPD exacerbations most likely
to deteriorate on admission to hospital may allow a more targeted treatment and enable an early briefing of patient, family,
and healthcare staff regarding prognosis. A study of nonlife
threatening exacerbations of COPD in emergency departments
reported that three simple clinical criteria can predict mortality
in these patients: age greater than 70 years; number of clinical
signs of severity (from cyanosis, impaired neurological status,

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lower-limb edema, asterixis, and use of accessory inspiratory or

expiratory muscles); and dyspnea grade at baseline (81).

TREATMENT
Two large randomized controlled trials assessed the effects of an
inhaled salmeterol-fluticasone combination (SFC) or tiotropium
on the progression of COPD. Whereas the UPLIFT study showed
no reduction in a decline in airflow limitation by tiotropium (82),
a post-hoc analysis from the Towards a Revolution in COPD
Health (TORCH) study revealed a reduction in the rate of decline
in the salmeterol-fluticasone arm in comparison to placebo (83).
This is the first study, apart from smoking cessation, to show that
a therapeutic intervention can slow the progression of this disease.
Although the UPLIFT study did not find a reduction in
decline of FEV1 in patients treated with tiotropium, there was
a reduction in the frequency of COPD exacerbations and in
hospitalizations due to COPD in patients treated with tiotropium. There was no difference in mortality between
tiotropium and placebo. Interestingly, the INSPIRE study,
a randomized comparison of salmeterol-fluticasone with tiotropium in patients with severe COPD, showed no difference
in exacerbation frequency between the two treatments (84).
Inhaled SFC did, however, improve mortality, although the
study was not adequately powered to show this.
Two meta-analyses assessed the effects of ICS (85) and
anticholinergics (86) on mortality. The former reported no
difference in all-cause mortality at 1 year, although there was
a higher risk of pneumonia in the ICS group compared with
a control population taking a variety of inhaled medications.
The latter meta-analysis suggested a higher risk of cardiovascular morbidity and mortality following treatment with inhaled
anticholinergic therapy compared with controls. This finding is
in contrast to the UPLIFT study in which there was no
difference in either all-cause mortality or cardiovascular mortality following treatment for 4 years with tiotropium. Thus the
results of the meta-analysis may be due to the fact that
mortality, and more specifically cardiovascular morbidity and
mortality, were not specific endpoints in the studies selected.
Although the prescription of antibiotics is part of a typical
treatment regimen for acute COPD exacerbations of infectious
etiology, the duration of the antibiotic course is not standardized. A meta-analysis examining 21 randomized controlled trials
investigating length of treatment showed that therapy lasting 5
days or less was as effective as treatment for greater than 5 days
(87). Although macrolide therapy is commonly used to treat
infective exacerbations of COPD, long-term macrolide therapy
is used in cystic fibrosis and has been shown to have antiinflammatory in addition to antibacterial effects. A randomized,
placebo-controlled trial has shown macrolides to be an effective
long-term therapy in COPD, reducing exacerbation duration
and frequency in individuals with moderate to severe COPD,
although it was not well tolerated (17% in the erythromycin arm
withdrew due to side effects) (88). In addition, a randomized,
placebo-controlled trial examining the effect of a mucolytic,
carbocisteine, in a group of Chinese patients with moderate to
severe COPD who were not treated with ICS, reported a reduction in exacerbation frequency over 1 year following the
mucolytic therapy as well as an improvement in health-related
quality of life (89).
Breathing heliox during pulmonary rehabilitation has been
shown to increase the intensity and duration of exercise training
that can be performed and results in greater improvements in
constant load exercise tolerance in patients with COPD (90).
Improvements in healthcare provisions are resulting in
improved survival at the severe end of the COPD disease

2009

spectrum. There have been some small studies assessing novel

therapies in severe COPD. A randomized control trial of
bosentan (a dual endothelin receptor antagonist) showed no
effect on exercise capacity and a detrimental effect on functional status in severe and very severe patients with COPD and
no effect on pulmonary hypertension (91). A group of patients
with moderate to severe COPD was treated with sildenafil in an
attempt to reduce pulmonary vascular resistance and improve
right ventricular function (92). However, there was no improvement in stroke volume or exercise capacity after 3 months of
treatment with sildenafil.
The use of nocturnal noninvasive ventilation in patients
with hypercapnic respiratory failure along with pulmonary
rehabilitation was compared with rehabilitation alone in
a randomized controlled study (93). Those treated with noninvasive ventilation had better quality of life scores, reduced
daytime PaCO2, and improved exercise tolerance. A study
investigating the benefits of ambulatory oxygen in patients
with COPD-related hypoxia and exertional desaturation compared cylinder oxygen and cylinder air after a program of
pulmonary rehabilitation (94). There was no improvement in
domestic activity, health related quality of life, or time spent
outside the home environment. Thus, the benefits of ambulatory oxygen therapy remain controversial.
Preliminary results of airway bypass for emphysema in which
artificial conduits in the wall of the bronchi are created and
stents are implanted to maintain patency suggest that airway
bypass may improve function in severely emphysematous lungs.
The results of these studies in lungs removed at transplant
surgery are encouraging and suggest that this technique could
be applied to patients with severe emphysema (95).
There is still a debate over the survival benefit of lung
transplantation in patients with COPD. A recent study identified characteristics of patients with COPD who were most
likely to benefit from lung transplantation. The major determinants of survival after transplant were systolic pulmonary
arterial pressure, FEV1, BMI, exercise capacity, functional
status, and the need for continuous mechanical ventilation or
oxygen (96).
Conflict of Interest Statement: J.D.M. has been reimbursed for travel to conferences by Boehringer-Ingelheim and GlaxoSmithKline (GSK). R.A.R. has no
financial relationship with a commercial entity that has an interest in the subject
of this manuscript. W.M. has been reimbursed for travel by GSK, Zambon,
AstraZeneca, Boehringer-Ingelheim, Pfizer, and Micromet for attending conferences; he has received honoraria from GSK and AstraZeneca for participating as
a speaker in scientific meetings; he serves on advisory boards for GSK, Pfizer,
Almirall, Amgen, Bayer, and Micromet; he serves as a consultant for Pfizer and
SMB Pharamaceuticals; research grants to support work carried out in his
laboratory comes from SMB, Pfizer, Ceremedix, GSK, Chugi, and Novartis.

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