Series

Chronic obstructive pulmonary disease 2

Current concepts in targeting chronic obstructive pulmonary
disease pharmacotherapy: making progress towards
personalised management
Prescott G Woodruff, Alvar Agusti, Nicolas Roche, Dave Singh, Fernando J Martinez

Chronic obstructive pulmonary disease (COPD) is a common, complex, and heterogeneous disorder that is Lancet 2015; 385: 1789–98
responsible for substantial and growing morbidity, mortality, and health-care expense worldwide. Of imperative See Editorial page 1697
importance to decipher the complexity of COPD is to identify groups of patients with similar clinical characteristics, This is the second in a Series of
prognosis, or therapeutic needs, the so-called clinical phenotypes. This strategy is logical for research but might be of two papers on chronic
obstructive pulmonary disease
little clinical value because clinical phenotypes can overlap in the same patient and the same clinical phenotype could
result from different biological mechanisms. With the goal to match assessment with treatment choices, the latest Division of Pulmonary, Critical
Care, Sleep and Allergy,
iteration of guidelines from the Global Initiative for Chronic Obstructive Lung Disease reorganised treatment Department of Medicine and
objectives into two categories: to improve symptoms (ie, dyspnoea and health status) and to decrease future risk (as Cardiovascular Research
predicted by forced expiratory volume in 1 s level and exacerbations history). This change thus moves treatment closer Institute, University of
to individualised medicine with available bronchodilators and anti-inflammatory drugs. Yet, future treatment options California, San Francisco, CA,
USA (Prof P G Woodruff MD);
are likely to include targeting endotypes that represent subtypes of patients defined by a distinct pathophysiological Thorax Institute, Hospital
mechanism. Specific biomarkers of these endotypes would be particularly useful in clinical practice, especially in Clinic, IDIBAPS, University of
patients in which clinical phenotype alone is insufficient to identify the underlying endotype. A few series of potential Barcelona, CIBERES, Barcelona,
Spain (Prof A Agusti MD);
COPD endotypes and biomarkers have been suggested. Empirical knowledge will be gained from proof-of-concept
Cochin Hospital Group,
trials in COPD with emerging drugs that target specific inflammatory pathways. In every instance, specific endotype Assistance Publique Hôpitaux
and biomarker efforts will probably be needed for the success of these trials, because the pathways are likely to be de Paris, University Paris
operative in only a subset of patients. Network analysis of human diseases offers the possibility to improve Descartes (EA2511), Paris,
France (Prof N Roche MD);
understanding of disease pathobiological complexity and to help with the development of new treatment alternatives
University of Manchester,
and, importantly, a reclassification of complex diseases. All these developments should pave the way towards University Hospital of South
personalised treatment of patients with COPD in the clinic. Manchester Foundations Trust,
Manchester, UK
(Prof D Singh MD); Weill
Introduction short-acting beta-2 agonists [SABA] and long-acting
Department of Medicine,
Chronic obstructive pulmonary disease (COPD) is a beta-2 agonists [LABA]), antimuscarinics (eg, short- New York-Presbyterian
common, complex, and heterogeneous condition that is acting antimuscarinic agent [SAMA] and long-acting Hospital/Weill Cornell Medical
responsible for substantial and growing morbidity, antimuscarinic agent [LAMA]), and inhaled College, New York, NY, USA
(Prof F J Martinez MD); and
mortality, and health-care expenses worldwide.1 In this corticosteroids. University of Michigan Health
context, complexity relates to many different components The Global Initiative for Chronic Obstructive Lung System, Ann Arbor, MI, USA
with non-linear dynamic interactions, whereas Disease (GOLD) was established in 1998 to improve (Prof F J Martinez)
heterogeneity implies that not all of these components the diagnosis, management, and prevention of COPD.
are present in all patients at any given timepoint or in the
same patient at different timepoints.2 To address this
complexity and heterogeneity, identification of groups of Search strategy and selection criteria
patients with similar clinical characteristics, prognosis or For this Series paper, we used several search approaches. We searched the Cochrane Library,
treatment needs (so-called clinical phenotypes), is Medline, and Embase using the search term “COPD” in combination with “clinical trial”,
imperative.3 On one hand, this strategy is logical for “effectiveness”, or “systematic review”, for 1 year between Jan 1, 2014 and Feb 28, 2015. For
research because it might create an increasingly the years preceding this search we used the bibliography cited in the Global Initiative for
homogeneous selection of patients in whom to decipher Chronic Obstructive Lung Disease (GOLD) document (GOLD search strategy used COPD,
the complexity of COPD. On the other hand, this strategy filters “human”, “all adult”, or “items” with “abstracts”, “clinical trial”, or “systematic review”).
might be of restricted clinical value because, first, clinical Additionally, we used the search terms “COPD”, “chronic obstructive pulmonary disease”,
phenotypes can overlap in the same patient and, second, “emphysema”, or “chronic bronchitis”, in combination with “LABA”, “LAMA”, “LABA/LAMA”,
the same clinical phenotype could result from different “ICS”, “ICS/LABA”, “COPD”, “chronic obstructive pulmonary disease”, “emphysema”, or
biological mechanisms (ie, aetiological heterogeneity). “chronic bronchitis” in combination with “endotype”, “molecular phenotype”, “biomarker-
Although the development of therapeutic approaches has directed”, “biomarker-driven”, or “targeted therapy”. Because some of these terms have only
increasingly attempted to address these complexities, so recently entered the medical vocabulary, we then searched for relevant references in the
far most treatment options belong to a restricted number bibliographies of selected articles.
of pharmacological classes—ie, bronchodilators (eg,

www.thelancet.com Vol 385 May 2, 2015 1789

 Series
Correspondence to:
Prof Fernando J Martinez,
Weill Department of Medicine,
Weill Cornell Medical College,
New York-Presbyterian Hospital/
Weill Cornell Medical College,
New York, NY 10065, USA
fjm2003@med.cornell.edu
1790
A challenge for GOLD has since been to provide
recommendations for the correct use of the available
treatments and at the same time to flexibly position
recommendations to allow the use of future innovative
treatments that have the potential to target a personalised
medicine approach. Another challenge faced by GOLD
and other guideline or strategy documents is the paucity
of evidence on how clinicians can identify patients who
are most likely to benefit from available COPD
treatments. This difficulty underlines the need for new
treatment approaches in conjunction with refining of the
way treatment indications are established. Finally, in
most patients COPD is associated with other chronic
diseases, a factor that should be addressed globally. This
comorbidity might decrease the likelihood that
treatments targeting only the COPD component will
change the natural history of a patient’s disease.
This Series paper addresses the strengths and
limitations, including gaps in the evidence, of the
approaches taken to move treatment of COPD towards
personalised medicine, and also addresses potential
future approaches to position emerging treatments that
will probably target specific biological pathways. As such,
we review the concept of an endotype, a subtype of a
clinical disorder defined by a distinct pathophysiological
mechanism,4 because it could be associated with future
COPD treatments, and also review the role of biomarkers
in marking endotypes and directing treatment.
Present treatment options
GOLD revolution
The GOLD 20015 and 20066 reports used airflow limitation
alone (as assessed by the forced expiratory volume in 1 s
[FEV1] value) to assess disease severity. Bronchodilators
were recommended as treatments to improve lung
function and reduce symptoms in all patients, with
inhaled corticosteroids reserved for patients with severe
and very severe airflow limitation and repeated exacer-
bations. In 2011, the GOLD document acknowledged that
use of FEV1 alone to assess disease severity was an overly
simplistic approach,1 because FEV1 is often a poor
predictor of the extent of symptoms, health status
impairment, and risk of exacerbations.7 Treatment
objectives were reorganised into two categories: relief of
present symptoms and reduction in the risk of future
adverse events to health. A well known system of
four-quadrant assessment characterises patients into
broad phenotypic categories based on symptoms and risk
of exacerbations (assessed by FEV1 and the history of
exacerbations in the past year). The four-quadrant system
was introduced with the goal to match assessment with
treatment choices, thus moving COPD treatment towards
individualised medicine by matching the patient’s
treatment to their needs. This development was a major
step forward in the strategy for COPD management
and other groups have proposed conceptually similar
approaches, but with several variations.8,9
GOLD treatment propositions
For all GOLD groups, short-acting bronchodilators are
recommended for symptom relief. These drugs could be
sufficient for patients in group A (of low risk and low
symptom burden). In patients who present more
symptomatic limitations (GOLD B; of low risk but with
increased symptom burden), long-acting bronchodilators
are recommended as maintenance treatment to decrease
symptoms. Patients who are at an increased risk of
exacerbation (GOLD groups C [of high risk and low
symptom burden] and D [of high risk and increased
symptom burden]), the first choice of pharmacotherapy
includes inhaled corticosteroids and LABA combinations
or LAMA, because both of these drug classes reduce
exacerbation rates and improve lung function and health
status.1 LABA and LAMA combinations are suggested as
an option for patients of GOLD groups B, C, and D because
evidence showed that these drugs are more effective than
long-acting bronchodilator monotherapy is; although,
most of these studies were not designed to report effects
on exacerbations10 or were undertaken in patients who did
not have a history of frequent exacerbations.11 Roflumilast,
a phosphodiesterase-4 inhibitor, is positioned to prevent
exacerbations in patients in GOLD groups C or D who
have a chronic bronchitic phenotype, a novel example of
phenotypically driven treatment.3,12
Strengths and weaknesses of GOLD propositions
The overall concept to increase the close match between
the clinical assessment of an individual patient and
specific treatment options is an appealing one and is a
first step towards personalised therapy. For example,
patients with many symptoms (GOLD groups B and D)
need more bronchodilators, whereas those patients
at high risk (groups C and D) might need anti-
inflammatory treatment. However, some treatment
propositions from GOLD could be criticised for not
being strictly evidence-based,13 which is largely a result
of the paucity of evidence for treatment effects in
different subgroups of patients. For example, additional
studies are needed to investigate the effects of LABA
and LAMA combinations in patients with a history
of exacerbations.14 Additionally, triple therapy (the
combination of inhaled corticosteroids and LABA plus
LAMA) is a treatment option for patients in GOLD
group D and is frequently prescribed in clinical practice,
but evidence for this regimen preventing exacerbations
is scarce.15 Patients in GOLD groups C and D are
heterogeneous with respect to their future risk,
depending on the way that they were assigned to one of
these categories (ie, low FEV1, history of exacerbations,
or both). Use of the inhaled corticosteroids and LABA
combination would logically thus be restricted to
patients who have a history of exacerbations with or
without severe airflow limitation, and long-acting
bronchodilators being preferred for those with low
FEV1 and no exacerbation history.16 Furthermore,
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although results of the ECLIPSE study17 identified a
stable clinical phenotype of patients with 2 or more
exacerbations every year (supporting GOLD’s threshold
to define patients at risk), inhaled corticosteroids and
LABA combinations have been studied mainly in
populations with an annual exacerbation rate nearer to
one per year; thus, the corresponding GOLD treatment
position does not quite match the evidence generated
by clinical, randomised controlled trials (RCTs). No
therapeutic trial reported before the 2011 GOLD
document and only a few reported after this date did
use selection criteria that strictly matched the present
GOLD classification.18
Evidence from clinical trials: do they support, enrich, or
challenge treatment propositions?
Use of inhaled corticosteroids in patients with COPD
should mainly focus on prevention of exacerbations
because studies have shown inconsistent effects of
these drugs on the rate of FEV1 decrease.19 Inhaled
corticosteroids are generally used as part of fixed-dose
combinations with LABAs to maximise their clinical
benefits. Since the early 2000s,20 many clinical trials
assessing these fixed-dose combinations included
patients with FEV1 of less than 50% predicted and a
history of exacerbations.21,22 By contrast, the TORCH
study23 included patients with FEV1 of less than 60%
predicted (before administration of a bronchodilator)
to study fluticasone propionate and salmeterol, and
patients with FEV1 of less than 70% predicted (after
treatment with a bronchodilator) were included to study
the effects of the combination fluticasone furoate and
vilanterol.24 In both studies,23,24 these combinations of
inhaled corticosteroids and LABA had a greater effect
than the use of LABA alone on exacerbation rates. This
result suggests that for patients with a history of
exacerbations, the extent of airflow limitation is not as
important to predict benefit from inhaled corticosteroids.
Furthermore, combination of 25 μg vilanterol with
fluticasone furoate (an inhaled corticosteroid) at doses
of 50 μg, 100 μg, and 200 μg was studied, addressing for
the first time the scarcity of evidence on dose-response
associations for long-term effects of inhaled cortico-
steroids.24 The dose-response curve was quite flat in
terms of exacerbations, suggesting that high doses of
inhaled corticosteroids are not needed to achieve an
optimum benefit in COPD. However, of note is that the
number of side-effects of interest (ie, pneumonia and
bone fractures) was not decreased at lower dosages of
these drugs.
In 2011, a systematic review25 concluded that inhaled
corticosteroids withdrawal was not associated with
important deterioration in overall patient outcomes, but
that this result could be affected by the definition of
exacerbations and concomitant treatments. In 2014,
results of the WISDOM trial were reported.26 This RCT26
included patients with severe airflow limitation and a
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Series
history of exacerbations despite often being on inhaled
corticosteroids treatment (70% were taking inhaled
corticosteroids treatment at screening), and those who
received triple-therapy during a run-in period before
being randomly assigned into either the inhaled
corticosteroids withdrawal or control (inhaled cortico-
steroids maintained) groups. In the withdrawal group,
the dose of fluticasone propionate was progressively
reduced (from 1000 μg/day, to 500 μg/day, and then to
200 μg/day) every 6 weeks before the drug was
eventually stopped after 12 weeks. No difference in the
occurrence of exacerbations was reported between the
two groups, but a difference was recorded between
groups of 40 mL loss of FEV1 during the 40 weeks after
complete drug withdrawal. Despite extensive subgroup
analyses27 the study did not identify patients at an
increased risk of withdrawal-associated exacerbations,
but of note is that the overall exacerbation rate in
both groups was quite low (about 0·5 exacerbations
per patient per year), which probably made it difficult to
detect a treatment difference in the context of a low rate
of events. As for many clinical trials, the WISDOM
trial26 was not powered for such subgroup analysis.
Nevertheless, the loss of lung function after inhaled
corticosteroids withdrawal, also reported by two other
previous studies,28,29 suggests some benefit for this type
of drug in these patients. Likewise, these results also
suggest that low doses of inhaled corticosteroids might
be sufficient in some patients to prevent exacerbations
and to maintain lung function.
The question remains for when to use combination
treatments. Comparisons between inhaled corticosteroids
with LABA fixed-dose combinations and LAMAs did not
show any consistent difference in terms of exacerbation
rate.30 Generally, combination treatments including
inhaled corticosteroids and LABA, LABA and LAMA, and
inhaled corticosteroids with LABA plus LAMA were
better than bronchodilator monotherapy treatments, at
least for some clinical endpoints.30–35 However, the scale
of the overall difference between combination treatments
and monotherapy is often small and less than the
expected additive effect of the components in the
combinations. Furthermore, most studies of LABA and
LAMA combination inhalers included patients that
were previously treated with at least one long-acting
bronchodilator monotherapy. Thus, to restrict the use of
combination treatments seems logical for patients with
dyspnoea or persisting exacerbations despite previous
long-acting bronchodilator monotherapy. GOLD does
not include such a step-by-step approach in its
recommendations, but this could be what many
clinicians expect from therapeutic guidance, provided
that the rules and criteria to guide choices are simple
enough and evidence-based. Combination of precision
and simplicity, as a prerequisite for successful guidelines’
implementation, is a major challenge for personalised
medicine.36
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Individual presentation and Individual risk factors and

characteristics.43–46 With respect to inhaled corticosteroids,
underlying mechanisms comorbidities growing concerns about these drugs are associated with
• Mortality • Pneumonia the risk of pneumonia and systemic side-effects.47 Yet,
• Disease progression • Tuberculosis these risks should be balanced with an apparent reduction
• Lung function • Skin bruising
• Symptoms: • Osteoporosis or fractures of a composite outcome of death and admissions to
cough, Individualisation of • Muscle dysfunction hospital for COPD, as described in patients who received
sputum production, and treatment choices in COPD • Nutritional impairment
dyspnoea • Cataract
LABA and inhaled corticosteroids compared with those
• Excercise tolerance • Diabetes given LABA alone.48 However, as these data are from an
• Exacerbations • Tremour observational database study they warrant further
• Disability • Cardiovascular events
• Health status and quality • Neuropsychological effects confirmation.
of life • Gastrointestinal symptoms

Expected benefits
Present COPD pharmacological
Expected risks
treatments
LABA;
LAMA;
LABA + LAMA;
LABA + ICS;
LABA + LAMA + ICS;
LABA + roflumilast;
LAMA + roflumilast
Figure 1: Benefit–risk balance and its individual determinants with personalised COPD treatment choices
When a clinician is deciding which pharmacological treatment options to prescribe to a patient, they have to
consider expected benefits (determined by individual presentation and underlying mechanisms of disease) and
possible risks (which depend on individual risk factors and comorbidities). COPD=chronic obstructive pulmonary
disease. LABA=long-acting beta-2 agonists. LAMA=long-acting antimuscarinic agents. ICS=inhaled corticosteroids.
Future treatment directions
Disappointingly, the overall scale of clinical benefit of the
different pharmacological treatment options in patients
with COPD is somewhat restricted. Although
symptomatic benefits and reductions in exacerbation
frequency can be achieved with available treatments,
effects on the decrease of lung function and mortality in
long-term studies have been disappointing.23,37 This poor
effect can be at least partly accounted for by the presence
of some extent of irreversible morphological
abnormalities, including emphysema and loss of small
airways.38 Various inflammatory mechanisms involved in
COPD do not respond well to corticosteroids, thus also
restricting treatment effects.39 Furthermore, the response
to corticosteroids seems to differ based on inflammatory
cells present—eg, the presence of eosinophils suggests
the increased likelihood of response to corticosteroids.40
Because morphological changes and biological features
are substantially heterogeneous in people with COPD,41,42
the sensitivity to pharmacological treatments will vary
between patients. These observations suggest that
individualising available treatments based on increasing
in-depth individual characterisation of pathophysiology
might optimise effectiveness; and, development of new
treatments that target specific mechanisms involved in
subgroups of patients might be an effective strategy.
Additionally, we need to use a benefit–risk approach for
treatments36 rather than an approach purely based on
effectiveness (figure 1). For long-acting bronchodilators,
the risk of cardiovascular events has been the topic of
several studies with, somehow, contradictory results
depending on study designs and population
Identification of responders or patients at increased risk
of side-effects
Although some patient characteristics clearly affect
treatment choice for invasive approaches, such as
surgery for lung volume reduction,49 most large trials
investigating COPD pharmacological treatments have
not clearly identified predictors of responders or non-
responders, or patients at increased risk of side-effects.
Importantly, the common way to analyse data from
clinical RCTs is to compare mean effects between
treatment arms, which could miss a patient who goes in
a direction opposite to most participants. An example of
this is the identification of a subgroup of patients with
COPD and persistent systemic inflammation by
network analysis that was not identified by use of the
comparison between conventional group means.50
Furthermore, most RCTs do not fully represent real-life
populations and contexts,51 and sample sizes are too
small for extensive and powerful subgroup analyses.
An exception is roflumilast, which was shown to
be especially effective when used with long-acting
bronchodilators in patients with symptoms of chronic
bronchitis, FEV1 less than 50% predicted, and a history
of exacerbations.52 Similarly, azithromycin was most
effective at reducing exacerbations in older patients
(aged >65 years) with mild disease who have stopped
smoking.53 In terms of side-effects, a greater increase in
the risk of pneumonia related to inhaled corticosteroids
was found in current smokers, and patients with prior
pneumonia, body-mass index less than 25 kg/m² and
severe airflow limitation.54 Beyond intrinsic patient
characteristics, environmental factors could also affect
the benefit–risk ratio of inhaled corticosteroids, as was
suggested55 for the inhaled corticosteroids-associated
risk of tuberculosis, which is increased in countries
with a high prevalence of tuberculosis.
Additional progress in the identification of specific
characteristics associated with response or adverse effects
from treatment can be provided by several approaches:
post-hoc exploratory analyses of available treatment trials;
observational cohort studies (retrospective [eg, with
databases] or prospective), especially with a comparative
effectiveness design; pragmatic RCTs; novel analytical
strategies, such as cluster and network analysis;51 and,
large, long term, classic RCTs. All these studies should
be undertaken in carefully selected and extensively

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characterised patients. In addition to precise clinical
characterisation (including physiology and imaging),
biomarkers will most likely be of major interest to both
identify target patients and assess treatment effects. In
view of the complex associations between different
biological levels (eg, genomics, epigenetics, proteomics,
metabolomics, cell physiology, inflammation, and repair
mechanisms), their identification of these associations (or
interactions) is likely to come from multilevel, dynamic
network analyses.50,56 In fact, studies of gene signatures
that used this analytical approach have already generated
hypotheses regarding mechanisms and predictors of
steroid response independent of the clinical phenotype.57,58
All these avenues of research were emphasised in an
American Thoracic Society and European Respiratory
Society statement about research questions in COPD.59
Potential effect of endotyping and biomarker-
directed approaches to future treatment
decisions
COPD endotypes
As previously discussed, an endotype4 is a subtype of a
clinical disorder defined by a distinct pathophysiological
mechanism, whereas a clinical phenotype3 is a single
or combination of disease attributes that describe
differences between individuals with COPD as they
relate to clinically meaningful outcomes (ie, symptoms,
exacerbations, response to treatment, rate of disease
progression, or death; figure 2). In the past decade,
studies aiming to identify and characterise sub-
populations of patients with COPD were directed at
clinical phenotyping. By use of various statistical
techniques to explore cohorts and link cross-sectional
characteristics together with longitudinal outcomes,
some phenotypes have been reproducibly identified,
including patients with metabolic and cardiovascular
comorbidities, patients with severe airflow limitation
that occurred with an onset when aged 40–45 years,61
frequent exacerbators, and patients with predominant
emphysema versus predominant airways disease.62,63
Some, but not all, of these phenotypes have been
associated with specific biological mechanisms
(eg, endotypes), whereas many can actually correspond
with several endotypes (eg, frequent exacerbators or
patients with cardiovascular comorbidities). As noted
previously, linking of endotypes to clinical phenotypes
and to endotype-specific biomarkers will be crucial
because phenotypes and biomarkers are more accessible
to clinicians than endotypes are. Therefore, formal
identification of an endotype implies the recognition of
several shared features including clinical characteristics,
biomarkers, physiology, genetics, histopathology, epi-
demiology, and treatment response.4 A well recognised
subset of COPD is α-1 antitrypsin deficiency, which
already meets all criteria for an endotype. Although
other potential COPD endotypes that we identify in this
Series paper only partly fulfil these criteria, we believe
www.thelancet.com Vol 385 May 2, 2015
Series
Symptom
Clinical phenotype
driven Tx
Endotype
Biomarker-
directed Tx
Risk factors
avoidance Exposome Genome
Figure 2: Interrelations between exposome, genome, endotype, and clinical
phenotype of COPD
Diagram of the interrelations (thin black arrows) between the exposome (the
totality of human environmental exposures, from conception onwards60),
genome (the genetic background of the individual), the endotype (biological
networks that enable and restrict reactions), and the clinical phenotype (final
clinical expression of the disease; eg, symptoms, exacerbations, response to
treatment, rate of disease progression, or death). Large arrows represent
different treatment strategies. COPD=chronic obstructive pulmonary disease.
Tx=treatment.
that they are worthy of further investigation as potential
endotypes. Three of the potential endotypes of COPD we
refer to are based on markers of inflammation or airway
colonisation with pathogenic bacteria. Both of these
processes can contribute to disease progression in
patients with COPD through persistent activation of the
immune response (eg, neutrophil inflammation in
response to bacterial colonisation), production of factors
that injure lung cells or the extracellular matrix (eg,
neutrophil elastase), structural changes that result from
cellular and extracellular matrix injury (eg, emphysema),
and physiological dysfunction that is recognised as
COPD (eg, loss of elastic recoil and resulting airflow
obstruction; figure 3).
α-1 antitrypsin (α1AT) deficiency
α-1 antitrypsin (α1AT) deficiency meets all of the criteria
for an endotype of COPD. It has known genetic under-
pinnings, distinct clinical characteristics, characteristic
histopathology, distinct epidemiology, and a mechanism-
directed treatment approach that is guided by biomarkers
(such as serum α1AT concentration, α1AT protein
phenotyping, and α1AT genotyping).64 However, α1AT
deficiency is a quite unique endotype of COPD in that it is
a Mendelian disorder. Other endotypes of COPD, as they
are identified, are likely to be complex diseases in which
predispositions are dependent on several genes and
developmental and environmental effects are prominent.
Persistent systemic inflammation
A subgroup of patients with COPD has persistently
raised concentrations of inflammatory biomarkers in the
blood (including the white blood cell count, C-reactive
protein, interleukin 6, and fibrinogen) and this group has
significantly increased all-cause mortality and
exacerbation frequency.65 However, whether this
persistent systemic inflammation can be treated
pharmacologically and which biomarkers would be most
relevant to target with specific treatments, is not yet clear.
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Endotypes Exposome
• COPD with persistent
systemic inflamation
• eosinophilic or Th2
high COPD Inflammation
(variable) Endotype
Biomarker- • α-1 antitrypsin
directed
personalised
Infection deficiency
(variable)
medicines Cellular and matrix changes
approaches Extracellular matrix destruction;
abnormal cell repair or apoptosis;
Endotype ciliary dysfunction, mucus
• COPD with persistent
pathogenic bacterial
colonisation Structural changes
Airways remodelling; alveolar destruction
Physiological dysfunction
Clinical manifestations of COPD
Figure 3: Present understanding of potential COPD endotypes
Shown in black are the relations between inflammation, cellular changes, structural changes, and physiological
dysfunction in COPD, and the role that chronic infection can have in perpetuating inflammation. In red are
potential endotypes of COPD that relate to subtypes of inflammation, the presence of pathogenic bacterial
colonisation, and the absence of a mechanism to protect against extracellular matrix destruction (α-1 antitrypsin
deficiency). COPD=chronic obstructive pulmonary disease. Th2=T-helper-2 cell.
Raised eosinophil or T-helper-2 cell concentrations
Patients with COPD who have raised sputum
or blood eosinophils or inflammation associated with
T-helper-2 (Th2) cells might constitute an endotype of
this disease. Accumulating evidence shows that this
subgroup of patients with COPD who have sputum or
blood eosinophilia might respond to corticosteroids and
possibly to blockers of cytokines produced by Th2 cells.66
For example, the presence of raised sputum eosinophils
in patients with stable COPD was associated with
improvement in symptoms, post-bronchodilator FEV1,
and shuttle walk (a test of functional capacity) in a
crossover, randomised trial of systemic corticosteroids.67
Another study67 accorded with this result that sputum
eosinophilia predicts benefit with systemic
corticosteroids, and other studies68–70 showed that this
predictive association extends to inhaled corticosteroids
too. Thus, sputum eosinophils are a biomarker that
could be useful in future decisions relevant to the
targeted use of inhaled corticosteroid in COPD. Blood
eosinophils could possibly be a useful surrogate for
sputum eosinophils. Persistent blood eosinophilia (>2%)
was present in 37% of participants with COPD in the
ECLIPSE study.71 Additionally, post-hoc analyses from the
2014 reported randomised trial72 of benralizumab (an
anti-interleukin-5-receptor α monoclonal antibody) in
patients with COPD and sputum eosinophilia, suggested
a response in a subgroup with raised concentrations of
blood eosinophils (defined as either ≥200 cells per μL or
≥300 cells per μL). As in asthma, several Th2 cytokines
could drive inflammation in eosinophilic or Th2 high
COPD. Since these Th2 cytokines (interleukin 5, 4, and
13) are difficult to measure directly, specific biomarkers
of these cytokines could be valuable. In 2015, Christenson
and colleagues57 identified molecular biomarkers of the
1794
asthma COPD overlap syndrome that might be useful to
Biomarker- distinguish between the effects of Th2 cytokines and
directed
personalised
could point to blood biomarkers that might be clinically
medicines useful in addition to or as an alternative to eosinophilia.
approaches
Bacterial colonisation
Bacterial colonisation is common in COPD, is thought to
drive inflammation and risk for exacerbation,73 and
characterises an important subset of patients with stable
Genetics
COPD. Thus COPD with bacterial colonisation represents
a clinical phenotype and, so far as this colonisation
contributes to the biological mechanisms that perpetuate
COPD, it could be regarded as an endotype. A new
therapy that reduces the risk for exacerbation in COPD is
with an antibiotic azithromycin.53,74 Whether this benefit
is due to the antibacterial effect of azithromycin on
bacterial colonisation or more from direct anti-
inflammatory effects is uncertain, but biomarkers of
bacterial colonisation in COPD could be valuable to target
azithromycin or other emerging antibacterial approaches.
Although procalcitonin has been mostly assessed as a
marker of bacterial infection rather than colonisation,75,76
the electric nose (E-nose) is a method that measures
volatile organic compounds in exhaled breath and could
help to identify patients colonised with bacteria.77 This
beneficial reduction in risk for exacerbation of
azithromycin is accompanied by a reduction in plasma
concentrations of soluble tumour necrosis factor receptor 2,
which suggests a possible surrogate outcome measure.78
Overall, because different bacteria can elicit different host
responses,79–81 the optimum endotype of COPD based on
bacterial colonisation could depend on methods that are
specific for pathogenic species.
Biological subtypes of COPD endotypes
Exacerbations of COPD are associated with a clinically-
relevant negative effect in both the short term (ie,
morbidity, mortality, and increased cost of treatment)
and the long term (ie, by accelerating decrease in lung
function).82,83 Optimised strategies to prevent and treat
exacerbations better are therefore an important medical
need. To maximise the benefit of corticosteroids and
antibiotics in COPD exacerbations, and to develop new
therapeutic alternatives, it would be valuable to have
biomarkers that identify subtypes of exacerbations that
respond to specific therapies. Bafadhel and colleagues84
in 2011 described four subtypes of exacerbations
(bacterial, viral, eosinophilic, and pauci-inflammatory)
defined by distinct biomarker profiles (sputum
interleukin 1β, serum CXCL10, and blood eosinophils,
respectively), which they postulated to represent distinct
underlying biology. Randomised trial data85 and a meta-
analysis86 suggest that blood eosinophil levels could be
used to target use of oral corticosteroids for the acute
treatment of COPD exacerbations. Other data suggest
that procalcitonin and C-reactive protein could be used to
guide antibiotic use.76,87
www.thelancet.com Vol 385 May 2, 2015

Comorbidities
Comorbidities such as cardiovascular disease or
sarcopenia (muscle wasting) are prevalent in patients
with COPD and negatively affect its clinical course and
prognosis.88 Yet, not all patients with COPD have them or,
if they do, present the same pattern. Analyses published
in the past year89,90 suggest that specific comorbidities
share molecular pathways and might constitute shared
treatment targets. Therefore, efforts to understand the
biology of clinical phenotypes of COPD characterised by
specific constellations of comorbidities could lead to the
identification of specific endotypes of COPD characterised
by specific biomarkers and treatment responses.
Lung cancer
Lung cancer is highly prevalent in patients with COPD
and is one of the main causes of death in this
population, especially in those patients with mild to
moderate airflow limitation.91 Smoking is the main risk
factor for both COPD and lung cancer, but not all
smokers develop either of these diseases.1,92 Yet, people
who develop COPD, particularly if emphysema is
present, have a much higher risk of developing lung
cancer than those without COPD,93,94 suggesting a
synergistic effect between COPD (and emphysema) and
lung cancer. Molecular mechanisms linking COPD
with lung cancer are unclear, but accumulating
evidence suggests that the chronic inflammatory
response that characterises COPD is likely to have a key
pathogenic role.95 Improvements in understanding of
the complex molecular networks that characterise such
response is essential to design effective chemopreventive
and immune-treatment strategies.
Conclusions and future directions
We will gain empiric knowledge from proof-of-concept
trials in COPD with emerging drugs that target specific
inflammatory pathways (eg, monoclonal antibodies
against interleukins 4, 5, 6, 13, 17, and 1β).96 Yet, at least
two reasons exist for caution as these clinical trials are
approached. First, a given endotype might possibly be
relevant for only a small subset of the population with
this disease. If so, these trials will have to consider either
enrolment of only people who are likely to respond to the
treatment based on a specific biomarker, or enrolment of
all people with COPD and stratification of participants
based on concentrations of biomarkers. This second
approach, has the advantage of allowing for assessment
of response in the biomarker negative group. Second, an
endotype or biomarker-directed treatment could be weak
if it were to target a pathway that represents only one of
several contributing pathways to COPD in a patient.
However, from experience in other respiratory diseases,
such as lung cancer (epidermal growth factor receptor),
asthma (Th2 high, based on periostin), and even in COPD
(steroids for eosinophilic COPD and augmentation
therapy for α1AT), the benefits of targeted treatment
www.thelancet.com Vol 385 May 2, 2015
Series
could be argued to be of sufficient magnitude amount to
make them clinically relevant. Another important future
direction is the longitudinal study of biomarker-defined
subgroups to improve understanding of the stability of
these subgroupings. Finally, of importance is to consider
that the subgroups of patients with COPD defined by
these groupings who might themselves be extremely
complex and include non-linear dynamic interactions
mediated by biological networks that enable, filter,
condition, and buffer them.97 Systems biology and
network medicine offer an integrative, multilevel, and
dynamic approach to understand and eventually lead to
treatment changes of these complex molecular,
functional, clinical, and environmental networks,50,98,99 a
strategy that studies42,100,101 published in the past year have
used. Network analysis of human diseases not only offers
the possibility of a better understanding of pathobiological
complexity of different disease subtypes (endotypes), but
also helps with the development of new therapeutic
alternatives and, importantly, a reclassification of complex
diseases.36,102,103 In essence, all these developments should
pave the way towards personalised medicine, also known
as P4 medicine or precision medicine.2,104,105 In this context,
the precision medicine initiative106 launched by the
US president Barack Obama on Jan 20, 2015, suggests
how to progress towards better health. In the meantime,
the concept of a so-called control panel for COPD107 that
identifies treatable clinical traits could represent an
appropriate way forward to the implementation of an
increasingly personalised treatment of COPD in
the clinic.2
Contributors
All authors contributed equally in writing the first version and the
revisions of this Series paper.
Declaration of interests
PGW has received a grant from Genentech to study interleukin 13 in
asthma. PGW has received personal fees for being on the advisory board
for Genentech, Johnson and Johnson, and Neostem, and received
personal fees for being a consultant for Roche, AstraZeneca, and
Novartis, all outside the submitted work. PGW has a pending patent
(12/935822) for compositions and methods for treating and diagnosing
asthma. PGW is supported by grants from the National Institute of
Health (HL126493, HL107202, AI077439, HL114447, and SPIROMICS
contract HHSN268200900014C). DS has received grants and personal
fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi,
GlaxoSmithKline (GSK), Glenmark, Johnson and Johnson, Merck,
NAPP, Novartis, Pfizer, Takeda, Teva, Therevance, and Verona, outside
the submitted work. DS has received personal fees from Genentech and
Skyepharma, outside the submitted work. FJM has received grants from
National Heart, Lung, and Blood Institute for studies into chronic
obstructive pulmonary disease. FJM has received personal fees from
Actelion, American College of Chest Physicians, Amgen, AstraZeneca,
Bayer, Boehringer Ingelheim, Carden Jennings, CME Incite, Center for
Healthcare Education, CSA Medical, Forest, Genentech, Grey Healthcare,
GSK, Ikaria, Informa, Inova Health System, Janssens, MedScape, Merck,
Merion, Miller Medical, National Association for Continuing Education,
Nycomed/Takeda, Paradigm, Peer Voice, Pearl, Pfizer, Projects in
Knowledge, St John’s Hospital (Livonia, MI, USA), St Mary’s Hospital
(Detroit, MI, USA), Sudler and Hennessey, Roche, University of Illinois
(Chicago, USA), University of Virginia (Virginia, USA), UpToDate,
Wayne State University (Detroit, USA), and Western Society of Allergy
and Clinical Immunology, all outside the submitted work. NR has
1795
 Series
received grants from Boehringer Ingelheim, Novartis, and Pfizer. NR has
received personal fees from Boehringer Ingelheim, Novartis, Pfizer, Teva,
GSK, AstraZeneca, Chiesi, Mundipharma, Almirall, Aerocrine,
Stallergenes, and Merck Sharp & Dohme (MSD). AA has received grants
from Almirall, GSK, MSD, AstraZeneca, Menarini, Instituto de Salud
Carlos III (PI12/01117), Recercaixa-2012 (AA084096), SEPAR (PI065/2013,
PI192/2012), and FUCAP 2012, outside the submitted work. AA has
received personal fees from Almirall, GSK, Teva, Novartis, AstraZeneca,
and Menarini, outside the submitted work.
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