Seminar

Chronic obstructive pulmonary disease

Klaus F Rabe, Henrik Watz

Chronic obstructive pulmonary disease (COPD) kills more than 3 million people worldwide every year. Despite Lancet 2017; 389: 1931–40
progress in the treatment of symptoms and prevention of acute exacerbations, few advances have been made to Pulmonary Research Institute
ameliorate disease progression or affect mortality. A better understanding of the complex disease mechanisms (H Watz MD), LungenClinic
Grosshansdorf (K F Rabe MD),
resulting in COPD is needed. Smoking cessation programmes, increasing physical activity, and early detection and Airway Research Centre North,
treatment of comorbidities are further key components to reduce the burden of the disease. However, without a German Centre for Lung
global political and economic effort to reduce tobacco use, to regulate environmental exposure, and to find alternatives Research, Grosshansdorf,
to the massive use of biomass fuel, COPD will remain a major health-care problem for decades to come. Germany; and Department of
Medicine, Christian Albrechts
University Kiel, Kiel, Germany
Introduction countries. This risk was similar to the lifetime risk of (K F Rabe)
Chronic obstructive pulmonary disease (COPD) is developing diabetes in Canada and much higher than the Correspondence to:
common worldwide and causes a major health-care risk of congestive heart failure.8 Prof Klaus F Rabe, LungenClinic
burden. Although COPD generally manifests at an older Regionally, there are not only differences in the Grosshansdorf, 22927
Grosshansdorf, Germany
age as part of multimorbidity, there is increasing prevalence of COPD, with the highest prevalence in the
k.f.rabe@lungenclinic.de
evidence that events early in life contribute to impaired Americas (about 15% in 2010), but also in the percentage
lung function in adults,1 which suggests that risk factors increase in COPD over the past 20 years.7 The highest
other than those already known (inhaled particles and increase between 1990 and 2010 occurred in the Eastern
gases from cigarette smoking and biomass fuel) are Mediterranean (119%) and African (102%) regions.7
important in the disease’s aetiology. One of the main difficulties in estimating the global
The term COPD might be too general, since the airway prevalence of COPD is underdiagnosis, especially in low-
abnormalities of chronic bronchitis and the peripheral income countries.9 COPD is especially underdiagnosed
loss of parenchymal lung texture in emphysema are in younger patients, never or current smokers, and
probably caused by diverse cellular and pathophysiological patients with less severe disease or lower education.9
changes with distinct genetic backgrounds. Advances in Although COPD is more common in men than in
lung imaging enable a more detailed view of airway and women,7 the increase in tobacco smoking among women
lung parenchyma abnormalities and novel endoscopic in high-income countries and the higher risk of exposure
interventions play an increasing role in the management to indoor air pollution, such as biomass fuel used for
of advanced emphysema. No drug treatment specifically cooking and heating, in low-income countries, might
targets emphysema except for the augmentation of lead to a similar prevalence in the sexes in the future.10
α1 antitrypsin in patients with emphysema associated The high susceptibility to the development of airflow
with α1 antitrypsin deficiency.2 Although the results of limitation in women compared with men will also
large clinical trials support a shift from anti-inflammatory increase the risk of COPD in women.11–13
treatment with inhaled corticosteroids towards dual The high prevalence of COPD makes it one of the
bronchodilator treatment for airway pathology,3 further leading causes of morbidity and mortality worldwide. In
prospective studies will help to clarify the role of inhaled 2015, COPD ranked third among the global age-
corticosteroid treatment in combination with dual standardised death rates for both sexes, with about
bronchodilator therapy in the prevention of exacerbations.4 3·2 million patients dying of the disease.14 The top two
By contrast with asthma, there is little hope that COPD- causes of death are ischaemic heart disease and cerebro­
specific biological therapies can be developed. vascular disease.14 However, considering that a third of
patients with COPD die of cardiovascular diseases,15,16 and
Epidemiology and causes a third of patients with cardiovascular disease have airflow
The global prevalence of COPD is difficult to estimate limitation,17 global mortality rates attributable to COPD
because of the different approaches used to calculate might be further underestimated. The global mortality
prevalence (eg, spirometry-confirmed airflow limitation
or surveys).5 The Global Burden of Disease Study 2015
estimated the global prevalence of COPD at about Search strategy and selection criteria
174 million cases.6 In 2010, Adeloye and colleagues7 We searched Medline and online publications on COPD and
estimated a global prevalence of 384 million cases on the tobacco use worldwide (eg, WHO) using the terms COPD,
basis of spirometric criteria of fixed airflow limitation emphysema, tobacco use, epidemiology, cause, emphysema,
applied in several epidemiological cohorts. In Canada, comorbidities, lung cancer, treatment, pulmonary
the overall risk of developing COPD by the age of 80 years rehabilitation, physical activity, and exacerbation. We focused
has been calculated to be 28%, according to population- on recent publications in English up to 2016 that might be of
based health administrative data.8 These data might help interest for a general readership.
to estimate the burden of COPD in high-income

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 Seminar

Early life events Risk factors for Escalation of treatment Clinical phenotypes of severe COPD
incidence and progress

Consider
emphysema
intervention
Consider
non-invasive
ventilation
Smoking cessation
• Genes
• Lung function at Physical activity
adolescence and adulthood Vaccination
• Exposure to other pollutants Bronchodilatation Oxygen
• Infections Palliative care
Diagnosis and treatment
• Amount of cigarettes
of comorbidities
• Physical
inactivity Pulmonary
rehabilitition

Consider inhaled
corticosteroids
Consider roflumilast
Consider macrolides

Figure 1: Life course of COPD and the effect of different factors including early life events that might affect disease incidence and disease severity along with
the treatments according to different clinical phenotypes once COPD is established and becomes severe
Patients with the so-called pink-puffer phenotype of COPD (right upper corner) are primarily affected by emphysema, whereas those with the so-called blue bloater
phenotype (right lower corner) predominantly have chronic bronchitis. Credit: Eddie Lawrence/Science Photo Library; Hindustan Times/Getty; Dr P Marazzi/Science
Photo Library; Science Photo Library. COPD=chronic obstructive pulmonary disease.

rate of COPD increased between 2005 and 2015, mainly Pathophysiology

because of an ageing population,14,18 while age-specific
death rates decreased.18 Correspondingly, patients with
disability increased by 16% during the same period.6
Almost 90% of deaths due to COPD occur in low-income
and middle-income countries.10 Therefore, any success in
combating the excessive mortality from COPD can only
be made if future global disease programmes put a
greater emphasis on these countries.
Tobacco smoking is the main cause of COPD globally.19
Even though the proportion of people who smoke declined
between 1990 and 2015 (by 28% in men and 29% in
women)20 1·1 billion people still smoked tobacco in 2015.21
Smoking is most common in males aged 15 years or older
in the western Pacific (49%), Europe (39%), southeast
Asia (32%), and the eastern Mediterranean (26%).22 Other
risk factors, such as inhalation of smoke from biomass
fuel or ambient particulate matter, may become more
important, especially in low-income countries. More
people are exposed to smoke and particles from biomass
fuel worldwide than from tobacco smoke.23 Ambient par­
ticulate matter pollution and occupational exposure to
second-hand smoke has increased substantially over the
past 25 years,20 giving rise to speculation that these factors
might become a greater cause of COPD in the future.
Currently, exposure to indoor smoke from biomass fuels is
estimated to account for 35% of COPD cases in low-
income and middle-income countries.19
Clinical treatment guidelines issued by global
professional societies tend to oversimplify the definition
of COPD, which in fact is a heterogeneous and complex
disease.24 Furthermore, most (if not all) knowledge about
the pathophysiology of the disease is derived from
studies of former or current tobacco smokers. However,
COPD caused by biomass fuel exposure, for example,
might be substantially different from COPD caused by
tobacco smoking in terms of phenotype, comorbidities,
and progression of the disease.23,25
COPD is an often progressive inflammatory disease of
the airways, the alveoli, and the microvasculature; which
of these aspects are preventable and treatable is debated.
The key functional feature of COPD is irreversible
limitation of airflow. The disease process includes
remodelling of the small-airway compartment and loss
of elastic recoil by emphysematous destruction of
parenchyma resulting in a progressive decline of forced
expiratory volume in 1 s (FEV1), inadequate lung
emptying on expiration, and subsequent static and
dynamic hyperinflation.26 Large cohort studies27,28 suggest
that emphysema and airway disease are also present in a
substantial number of symptomatic smokers and former
smokers even without evidence of airflow limitation. In
addition to environmental exposures, genetic risk factors
are increasingly implicated in the development of
nicotine addiction, chronic bronchitis, loss of lung

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function, and early lung development.29,30 Furthermore,
epigenetic regulation has been implicated in the
pathogenesis of COPD.31 In patients with mild airflow
obstruction, several compensatory and adaptive
physiological mechanisms ensure that the respiratory
system fulfils its primary task of maintaining adequate
pulmonary gas exchange.32 However, these patients have
not been studied extensively. Understanding these early
changes and their relation to the development of injury
of small airways and alveoli could aid the development of
effective preventive treatments.
Exposure to common risk factors can lead to mucosal
and glandular inflammation, with increased mucous
discharge and epithelial cell hyperplasia and altered
tissue repair in small conducting airways in the case of
chronic bronchitis.33 With the widespread application
of CT in clinical care, more patients have evidence of
usually mild bronchiectasis on CT scans that is not
readily detectable on conventional chest x-rays.34 These
anatomical airway abnormalities in patients with primary
COPD might represent a further distinct phenotype
within the spectrum of COPD.34 However, McDonough
and colleagues35 have shown that increased airway
resistance in patients with COPD might be the result of
narrowing and disappearance of small conducting
airways and respiratory bronchioles preceding the
development of emphysema. These findings are probably
crucial to the understanding of early disease development
and the pathways that lead to the diverse COPD
phenotypes. The findings also raise the question of when
conducting airways disappear, which also informs
discussion of COPD diversity. By contrast with earlier
ideas, some people with COPD do not show an excess of
lung function decline over time.36 The mounting evidence
that early life changes have a profound effect on the
natural course of the disease through the establishment
of an individual level of lung function has challenged the
concept of a single natural history of COPD (figure 1).1
These data might also help to clarify the somewhat
obscure terminology around the clinical overlap of
asthma and COPD. The trajectory of a lifelong change in
lung function37 is not a prerequisite for persistent asthma
but is common in COPD (figure 1).38
The injury of airway epithelial cells triggers a non-
specific inflammatory response through the release of
endogenous intracellular molecules or danger-associated
molecular patterns. These signals are identified by
pattern-recognition receptors, such as Toll-like receptors 4
and 2 on epithelial cells, and result in the release of
cytokines such as tumour necrosis factor α and
interleukins 1 and 8.33 Macrophages, neutrophils,
eosinophils, and dendritic cells, recruited to the site of
inflammation, constitute the innate immune
response.39–41 Proteolytic enzymes and reactive oxygen
species contribute to tissue damage, particularly when
no antiproteases or antioxidant factors are present.33 As
the disease progresses, lymphoid aggregates can develop
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Seminar
Early life
events
Physical
inactivity
Osteoporosis Depression
Age
Muscle
COPD Lung cancer
depletion
Cardiovascular disease
Inflammation Smoking and
environment
Figure 2: Interactions between risk factors for COPD and comorbidities
Shared risk factors (age, smoking, inflammation, and physical inactivity) predispose people to COPD and other
chronic diseases. COPD might further increase the risk of other chronic diseases via similar mechanisms
(eg, physical inactivity and inflammation). Other chronic diseases in turn worsen morbidity and mortality of COPD.
COPD=chronic obstructive pulmonary disease.
around the small airways;42,43 this might indicate adaptive
or autoimmune reactions that underlie the chronic
mucosal inflammatory responses of bronchitis noted
years after patients with COPD have stopped smoking.33
Impaired immune regulation probably plays a major
part in COPD, and in emphysema in particular. Normal
ageing and pulmonary emphysema share patho­
physiological features, and physiological ageing of the
lung involves enlargement of alveolar space and loss of
elastic recoil.44,45 Cell senescence generally leads to
decreased proliferation with preserved metabolic activity,
resulting in increased inflammation, reduced cell
regeneration, and carcinogenesis.33 This process is
further accelerated through cigarette smoking and
oxidative stress.46 Emphysema in COPD can be
interpreted as accelerated ageing of the lung, since the
disease process shows striking similarities with age-
associated features, such as cellular senescence,
autophagy, defective mitochondrial function, stem-cell
exhaustion, and immunosenescence.47
COPD often presents in elderly individuals as one
component of multimorbidity (figure 2). The term COPD
may one day need correction since the genetic
background, pathophysiology, therapeutic targets, and
disease management differ considerably in patients with
predominant airway abnormalities or dominant
emphysema. Major advances in lung imaging have
helped pave the way for a new idea of COPD diversity
(figure 3).48,49 More detailed knowledge about the risk
factors leading to these different endotypes and
phenotypes is needed to better delineate therapeutic
interventions. In this context, α1 antitrypsin deficiency
might serve as an example in which a known genetic
background (endotype) with a distinct clinical appearance
of emphysema (phenotype) results in a targeted
therapeutic intervention (α1 antitrypsin augmentation).2
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 Seminar
A B
Figure 3: High-resolution CT scans of a patient with severe, bullous emphysema of centrilobular and
paraseptal phenotype
(A) axial view of the left upper lobe, (B) sagittal view of the right lung.
COPD and comorbidities
Patients with COPD are often affected by other diseases,
such as cardiovascular disease, osteoporosis, muscle
weakness, depression, and lung cancer.50–52 Smoking is a
risk factor for comorbidities; others probably include
physical inactivity and yet-to-be-identified inflammatory
mechanisms (figure 2).50,51,53,54 Several pulmonary
mechanisms of inflammation and oxidative stress that
damage DNA and result in an imbalance between tissue
repair and cell proliferation seem to promote the link
between COPD and lung cancer.55–57 Grading severity and
identifying phenotypes of COPD also mean that patients
need to be phenotyped according to their concomitant
diseases; most patients with COPD, particularly those
with mild disease, die from other causes. Lung cancer and
cardiovascular comorbidities dominate COPD mortality
until respiratory causes contribute to overall mortality in
the advanced stages of the disease.15,16,51 Phenotyping the
pulmonary compartment might also be relevant for the
concomitant disease: patients with COPD who have
predominant emphysema have a higher risk of lung
cancer than do patients with a predominant airway type
disease.58–62 Furthermore, patients with emphysema have a
higher risk for osteoporosis and loss of muscle mass than
do patients with a predominant airway type of COPD.52,63
Patients with COPD and a concomitant metabolic
syndrome have a higher risk profile for cardiovascular
disease,64 whereas patients with predominant emphysema
might also have a higher risk of cardiovascular disease
because they have increased arterial stiffness.52,65 Reducing
the mortality of COPD will probably depend on whether
patients at risk for major cardiovascular events and lung
cancer can be identified early by simple and objective
diagnostic assessments. The ankle-brachial index, used to
identify patients with asymptomatic peripheral artery
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disease (a risk factor for major cardiovascular events)66 or
coronary artery calcium scoring on CT scans67 might help
to identify those patients at risk; however, it needs to be
validated in prospective longitudinal studies. Results of
lung cancer screening in patients with COPD show a
doubling of lung cancer incidence, no apparent
overdiagnosis, and a more favourable stage shift compared
with smokers who do not have COPD.68 However,
mortality in this specific group of patients is unclear.
Treatment of COPD
Smoking cessation
Smoking cessation is key to reducing progressive decline
in lung function over time, as well as exacerbations and
smoking-related comorbidities (lung cancer and cardio­
vascular disease), which decreases mortality in patients
with COPD.15,69,70 Reducing indoor air pollution by using a
stove instead of cooking on an open fire reduces
progressive lung function decline in a manner similar to
that of smoking cessation.71 Patients with COPD who
have a high degree of tobacco dependence, and who have
comorbid depression face a major barrier to quitting
smoking.70 Accordingly, up to 40% of patients, even
those with severe COPD, are continuous smokers.70
Interventions such as intensive counselling, nicotine
replacement therapy, and treatment with varenicline or
bupropion increase smoking cessation and are cost-
effective compared with counselling alone.72 However,
intensive smoking cessation programmes are generally
poorly reimbursed (if at all) by national health-care
systems.
Vaccination
Influenza vaccination and pneumococcal vaccination are
generally recommended for patients with COPD,5 as there
is some (albeit limited) evidence for specific benefits from
both vaccinations for patients with COPD, such as
reduced risk of exacerbations or hospital admission.73,74
Physical activity
Increasing physical activity in daily life might be equally
effective as smoking cessation to prevent morbidity and
mortality in patients with COPD.75–77 However, compared
with physician’s knowledge of the harmful effects of
continuous smoking, the consequences of continuous
physical inactivity for COPD might still be under­
estimated.78 Physical inactivity early during the course of
the disease79 is strongly linked to hospital admission75
and mortality.75,77 Counselling strategies and sustained
motivation for patients with COPD are being evaluated
for their ability to overcome sedentary behaviour because
pulmonary rehabilitation and bronchodilator treatment
might be of little help.80–83 Walking as little as 15 min
per day is associated with a 14% reduced risk of all-cause
mortality in the general population,84 and increasing
activity by 600 steps per day is associated with a reduced
risk of hospital admission in patients with COPD.85

These data suggest that even small changes might be
clinically meaningful for patients.
Pulmonary rehabilitation
Pulmonary rehabilitation is an effective multidisciplinary
treatment strategy to improve dyspnoea, exercise
tolerance, and health-related quality of life.86 Although the
classic exercise programme with individualised endurance
and strength training remains the cornerstone of
pulmonary rehabilitation,86,87 education, the promotion of
behavioural changes, and self-management are also
considered essential for any successful intervention.86
Pulmonary rehabilitation reduces hospital admissions
and mortality in patients who have had a recent
exacerbation.88 It has also been shown to be cost-effective.89
Despite the substantial benefits, this treatment is
underutilised worldwide because of insufficient resources,
funding, and reimbursement.89
Pharmacotherapy
Maintenance pharmacotherapy of patients with stable
COPD aims to improve symptoms, health-related quality-
of-life, exercise intolerance, and the risk of exacerbations.5
Inhaled long-acting β2 agonists (LABAs) and long-acting
muscarinic antagonists (LAMAs) have similar positive
effects on airflow limitation, reduction of air trapping,
and improvement of exercise intolerance.5 However, to
prevent exacerbations the LAMA tiotropium seems to be
superior to LABA90,91 and just as effective as a combination
of fixed inhaled corticosteroid and LABA.92 The reason is
largely unknown but may be partly explained by
β2-adrenergic receptor polymorphisms.93 Therefore,
LAMA monotherapy should be favoured over LABA
monotherapy in patients with a history of exacerbations.5
Now that several fixed combination therapies with
LABA and LAMA are available, the escalation of
bronchodilator treatment is easier to handle: patients
need no longer inhale from several inhaler devices.
Although fixed dual bronchodilation has additional
benefits over monotherapy for airflow limitation, it is
difficult to estimate those additional benefits for the
improvement of symptoms based on established patient-
reported outcomes.5 In part, this might be related to study
design, because no studies sought patients in clinical need
of escalation of therapy based on an insufficient response
to monotherapy. One study94 specifically investigated the
occurrence of exacerbations in patients with severe COPD
by comparing the effects of fixed dual bronchodilation
with those of LAMA monotherapy. Significantly fewer
exacerbations occurred during treatment with LABA­ – symptoms of chronic bronchitis might benefit from the
LAMA (indacaterol–glyco­ pyrronium) than with LAMA
(glycopyrronium) monotherapy.94 Furthermore, adding a
LAMA to LABA and an inhaled corticosteroid resulted in
fewer exacerbations than with LABA and inhaled
corticosteroid alone.95
Another study3 compared a fixed combination of
indacaterol–glycopyrronium with the combination of an
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Seminar
inhaled corticosteroid and a LABA (fluticasone–
salmeterol) in patients with moderate-to-severe COPD
and a history of exacerbations. Indacaterol–glyco­
pyrronium was superior to fluticasone–salmeterol in
preventing exacerbations.3 In light of this result, the
question arises whether a further step up from LABA–
LAMA to triple therapy consisting of a LABA, a LAMA,
and an inhaled corticosteroid would result in additional
benefits. For most patients, stepping down therapy from
a LABA, a LAMA, and an inhaled corticosteroid to a LABA
and a LAMA is not associated with an increased risk of
exacerbations.96 However, according to post-hoc analyses
of three large studies97–99 with treatment arms containing
inhaled corticosteroids, a subgroup of patients with
higher blood eosinophil counts seemed to benefit from
continuous inhaled corticosteroids in addition to mono or
dual bronchodilator therapy: fewer exacerbations
occurred when inhaled corticosteroids were part of the
inhaled maintenance therapy. Future studies will need to
clarify the role of inhaled cortico­steroids in combination
with dual bronchodilator therapy for the prevention of
exacerbations in patients with severe COPD.4
In randomised controlled trials,100 bronchodilator
therapy (LABA, LAMA, or a combination of both) has
been shown to be generally safe. However, because
patients with major cardiac diseases are generally
excluded from these trials, clinicians should be aware of
the (usually rare) cardiac events that have been reported
in meta-analyses and observational studies.100 Treatment
with inhaled corticosteroids is associated with a higher
risk of pneumonia in patients with severe COPD,101
especially in patients of older age, a body-mass index of
less than 25  kg/m², or a history of pneumonia.102–104
Therefore, the potential benefit of reducing exacerbations
by adding inhaled corticosteroids to a LABA needs to be
weighed against the potential risk of pneumonia.101
Patients with COPD with low blood eosinophil counts
might have an increased risk of pneumonia when
fluticasone (an inhaled corticosteroid) is added to their
LABA treatment.105 Again, this would indicate that there
is a subgroup of patients with high blood eosinophil
counts in whom the benefits of inhaled corticosteroid
treatment outweigh the risks.
Once inhaled therapy is optimised, there might still be a
subgroup of patients with severe COPD who continue to
have exacerbations. Further treatment options for this
subgroup need to be reviewed carefully in light of
increasing importance of clinical characteristics and
individualised treatment decisions.106 Patients reporting
addition of the oral phosphodiesterase 4 inhibitor
roflumilast.107 In particular, patients who have been
admitted to hospital for a COPD exacerbation or who have
had more than two exacerbations treated in the outpatient
setting seem to benefit from this treatment.108,109 Side-
effects of roflumilast, such as diarrhoea, nausea, headache,
and weight loss, need to be balanced against this benefit.
 Seminar
Macrolide therapy might be another option, especially in
patients who are ex-smokers.110,111 However, macrolide-
related side-effects, uncertainty about treatment beyond
1 year, and bacterial resistance to macrolides need to be
considered.5 Data regarding the addition of the mucolytic
and antioxidative agent N-acetylcysteine to regular COPD
drugs are difficult to interpret for patients with severe
COPD and maximised inhaled therapy.112,113
There are limitations to the evidence base for
pharmacotherapies for COPD. Almost all pharma­
cotherapy studies have included patients who were
continuous or former smokers with a smoking history of
at least 10 pack-years, and excluded patients with
concomitant asthma. It is not known how effective drugs
for COPD are in patients who have never smoked or in
those who also have asthma. Furthermore, large studies
have recruited patients with a certain degree of airflow
limitation, symptoms, or history of exacerbations, but it is
likely that patients with predominant emphysema will
respond differently to therapy than will patients with
predominant airway abnormalities.
Considerable efforts have been made over the past
decade to find new therapies that target inflammation in
COPD,114 but with little success. This might partly be a
result of the complexity of inflammation and related
clinical phenotypes.115 Targeting a single inflammatory
pathway or mechanism might not be sufficient to
persistently suppress inflammation in all patients with
COPD.116,117 Furthermore, although targeting neutrophilic
airway inflammation with a CXCR2 antagonist can
improve lung function and reduce exacerbations in
patients with COPD who still smoke, serious side-effects
such as neutropenia might prohibit further developments.118
Changing the formulation so that patients inhale certain
compounds, such as phosphodiesterase inhibitors, might
help to target the lung but limit side-effects.119,120 Whereas
the efficacy of bronchodilators can be shown in short-term
studies in a small number of patients, longer studies in
highly selected subgroups are needed in early study phases
for drugs to target inflammation, which makes drug
development more difficult.
Interventional treatments
Interventions to reduce emphysema-associated lung
hyperinflation in patients with advanced COPD under
optimal medical care include lung volume reduction
surgery and bronchoscopic interventions such as
endobronchial valves and lung volume reduction coils.5,121
Approval of bronchoscopic interventional therapies by
health authorities, availability, and reimbursement differ
from country to country. Individualised decisions for
treatment should be based on characteristics of the
emphysema (eg, heterogeneous vs homogeneous, intact
lobar fissure or collateral ventilation).121,122 For most
patients, treatment effects are modest and need to be
balanced against potential complications such as
pneumothorax, pneumonia, and bleeding.123,124 Other
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interventions, including treatment with thermal vapour or
sclerosing agents, show some efficacy but might lead to
even more complications.121,125 An intervention using an
endobronchial bypass did not show any sustainable benefit
in patients with severe homogeneous emphysema.126 For
patients with very advanced disease, lung transplantation
is still an option to improve quality of life and exercise
capacity, but has no effect on overall survival.5
Oxygen and ventilatory support
Patients with stable COPD and moderate resting or
exercise-induced desaturation do not benefit from long-
term oxygen therapy in terms of mortality, exacerbations,
or functional status.127 However, long-term oxygen therapy
should still be prescribed for patients with severe resting
hypoxaemia (partial pressure O2 in arterial blood [PaO2]
≤55 mm Hg)128 or patients with more moderate hypoxaemia
(PaO2 ≤60 mm Hg) and signs of heart failure, pulmonary
hypertension, or polycythaemia.5
Studies of survival following non-invasive positive airway
pressure ventilation in patients with stable hypercapnia are
not consistently positive.5 However, non-invasive positive
pressure ventilation in patients with stable hypercapnic
and high inspiratory pressures targeted to reduce partial
pressure of CO2 in arterial blood (PaCO2) by at least 20% or
to achieve PaCO2 values of less than 6·5 kPa can improve
survival.129 Therefore, this option might be considered in
appropriate patients and specialised home-care settings.
Treatment of comorbidities
The treatment of comorbidities has a central role in the
management of patients. Physicians treating COPD
should either treat concomitant disease themselves or
refer the patients to colleagues in the respective
disciplines. In the absence of any COPD-specific data,
each comorbidity should be treated according to the usual
standards for the disease.5 Some drugs for treatment of
COPD have been assessed for treatment effects beyond
the lung. The inhaled combination of fluticasone furoate–
vilanterol (an inhaled corticosteroid and a LABA) did not
affect mortality or cardiovascular outcomes in patients
with moderate COPD and at increased risk for
cardiovascular disease,130 but it improved hyperinflation-
associated underfilling of the heart.131 Roflumilast
treatment was associated with fewer major cardiovascular
events in a pooled analysis,132 but no randomised controlled
study has been done to test the potential benefits of
roflumilast treatment for cardio­ vascular outcomes in
COPD. Roflumilast might have benefits for patients with
COPD and diabetes, as suggested by data on glucose
control in patients with diabetes who do not have COPD.133
Clinical trials in COPD: what is in the pipeline?
There are several early phase trials with novel drugs for
COPD.134 Many ongoing clinical trials with established
therapies are assessing the role of either inhaled dual
bronchodilators compared with LAMA monotherapy

(ClinicalTrials.gov, NCT02296138) or fixed-dose triple
therapy consisting of a LABA, a LAMA, and an
inhaled corticosteroid compared with fixed-dose dual
bronchodilators or fixed-dose treatment with an
inhaled corticosteroid and a LABA4 (ClinicalTrials.gov,
NCT02465567, NCT02579850). Unfortunately, we know
of no ongoing clinical phase 3 studies of truly novel drugs
for patients with COPD.
Treatment of exacerbations of COPD
Exacerbations of COPD are acute episodes of worsening
respiratory symptoms (dyspnoea, cough, sputum
volume, and purulence) that require a change in
treatment.5 Exacerbations negatively affect lung function
decline, health-related quality of life, and prognosis.135
The leading symptom for hospital admissions is
dyspnoea,136 and most events are triggered by viral or
bacterial respiratory tract infections.135 Milder episodes
are usually handled by patients at home by increasing
their use of short-acting reliever medications. More
troublesome and persistent symptoms require further
diagnostic testing to rule out cardiovascular events,
pulmonary embolism, and pneumonia. Systemic
steroid treatment for a short period (eg, 40 mg of
prednisone for 5 days)137 with or without a short course
of antibiotics is the treatment of choice for these acute
events. For moderate events, empirical treatment with
antibiotics added to systemic steroids is controversial.138
Severe exacerbations require hospital admission and
individualised treatments, including non-invasive
ventilatory support, oxygen therapy, treatment of
concomitant diseases (eg, heat failure, pneumonia), and,
ultimately, invasive ventilation with a poor prognosis for
weaning and recovery. Cohort studies show that more
than half of patients admitted to hospital for COPD
exacerbation also have cardiovascular disease.139 Even
without clinical signs of cardiac involvement, biochemical
evidence of cardiac dysfunction (eg, high concentrations
of troponin I or B-type natriuretic peptide) during
exacerbation is common.139 About 20% of exacerbations
might be due to worsening of an underlying cardiovascular
disease.139 Prognosis after hospital admission is poor. In
Europe, 11% of patients died within 90 days of admission
to hospital; half while still in hospital.136 35% of patients
were re-admitted within 90 days.136 These numbers
indicate that management after discharge needs to be
improved by, for example, implementing early
rehabilitation after discharge.140 Mortality from COPD
greatly increases after repeated re-admissions.141
Conclusions and future directions
Globally, COPD will remain a significant public health
problem for the foreseeable future. With risk factors
largely unchanged, demographic developments in high-
income countries and a significant increase in non-com­
municable diseases in low-income countries will
accelerate this health burden. A better genetic molecular
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Seminar
and biological understanding of this disease in its distinct
endotypes and phenotypes is needed to enable innovative
drug development.
Contributors
KFR and HW searched the published work and wrote the Seminar.
Declaration of interests
KFR has received personal fees from AstraZeneca, Takeda, Chiesi,
Novartis, Boehringer Ingelheim, Sanofi Aventis, Berlin Chemie,
and Teva, and grants from Chiesi. HW has received personal fees from
AstraZeneca, Takeda, Chiesi, Novartis, Boehringer Ingelheim,
GlaxoSmithKline, and Berlin Chemie.
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