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REVIEW
COPD and its comorbidities:
Impact, measurement and mechanisms
NETSANET A. NEGEWO,1 PETER G. GIBSON1,2 AND VANESSA M. MCDONALD1,2,3
1
Priority Research Centre for Asthma and Respiratory Diseases and Hunter Medical Research Institute, Faculty of Health and
Medicine, 3School of Nursing and Midwifery, The University of Newcastle, Callaghan, and 2Department of Respiratory and
Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia
ABSTRACT
Chronic obstructive pulmonary disease (COPD) fre-
quently coexists with other conditions often known as
comorbidities. The prevalence of most of the common
comorbid conditions that accompany COPD has
been widely reported. It is also recognized that
comorbidities have significant health and economic
consequences. Nevertheless, there is scant research
examining how comorbidities should be assessed and
managed in the context of COPD. Also, the underlying
mechanisms linking COPD with its comorbidities are
still not fully understood. Owing to these knowledge
gaps, current disease-specific approaches provide cli-
nicians with little guidance in terms of managing
comorbid conditions in the clinical care of multi-
diseased COPD patients. This review discusses the con-
cepts of comorbidity and multi-morbidity in COPD in
relation to the overall clinical outcome of COPD man-
agement. It also summarizes some of the currently
available clinical scores used to measure comorbid
conditions and their prognostic abilities. Furthermore,
recent developments in the proposed mechanisms
linking COPD with its comorbidities are discussed.
Key words: chronic obstructive pulmonary
comorbidity, multi-morbidity, prognostic index.
Abbreviations: 6MWD, 6-min walk distance test; ADO, age, dys-
pnoea and air flow obstruction; AUC, area under the curve;
BODE, body mass index, airflow obstruction, dyspnoea and exer-
cise capacity; BODEx, body mass index, airflow obstruction, dys-
pnoea and exacerbation; CCI, Charlson Comorbidity Index; CI,
confidence interval; CODEx, comorbidity, airway obstruction,
dyspnoea and previous exacerbation; COMCOLD, comorbidities
in chronic obstructive lung disease; COPD, chronic obstructive
pulmonary disease; COTE, comorbidity test; CRP, C-reactive
protein; CVDs, cardiovascular diseases; DECAF, dyspnoea,
eosinopenia, consolidation, acidaemia and atrial fibrillation;
Correspondence: Vanessa M. McDonald, Priority Research
Centre for Asthma and Respiratory Diseases and Hunter Medical
Research Institute, Faculty of Health and Medicine, The Univer-
sity of Newcastle, Level 2 West Wing, Locked Bag 1000,
Newcastle, New Lambton, NSW 2305, Australia. Email:
vanessa.mcdonald@newcastle.edu.au
Received 15 January 2015; invited to revise 17 March 2015;
revised 14 June 2015; accepted 13 July 2015 (Associate Editor:
Robert Young).
Article first published online: 16 September 2015
© 2015 Asian Pacific Society of Respirology
DOSE, dyspnoea, airflow obstruction, smoking status and exac-
erbation; eBODE, severe exacerbation plus BODE index; eMRCD,
extended Medical Research Council dyspnoea score; FEV1, forced
expiratory volume in 1 s; FT, feeling thermometer; GesEPOC,
Guía Española de la EPOC; GI, gastrointestinal; GOLD, Global
Initiative for Chronic Obstructive Lung Disease; GORD, gastro-
oesophageal reflux disease; HR, hazard ratio; mBODE, modified
BODE index; TNF-α, tumour necrosis factor-alpha.
INTRODUCTION
Chronic diseases are the biggest emerging threat to
global health, with two of every three deaths around
the world attributed to non-communicable diseases.1
Alarmingly, chronic obstructive pulmonary disease
(COPD) is now the third leading cause of death glob-
ally.1 Although COPD primarily affects the lungs, it is
now also recognized as a complex multi-component
disease characterized by chronic systemic inflamma-
tion that frequently coexists with other conditions
known as comorbidities.2–5 Comorbidities in COPD
are common at any stage of the disease.6 They are
important determinants of outcome2 and have
disease,
enormous economic consequences.7 Yet, disease
management strategies fail to provide clear recom-
mendations on how comorbidities should be identi-
fied, assessed and managed in the presence of
COPD.8–10 Moreover, the underlying mechanisms
linking COPD with its comorbidities are still not com-
pletely clear.3 The intention of this review is to discuss
the concepts of comorbidity and multi-morbidity in
COPD in relation to the overall clinical outcome of
COPD management. Currently available clinical tools
used to quantify comorbid conditions and their prog-
nostic abilities will be described and critiqued, and
recent developments in the proposed mechanisms
linking COPD with its comorbidities will be discussed.
COMORBIDITY OR MULTI-MORBIDITY?
The term comorbidity has historically been defined as
‘any distinct additional clinical entity that has existed
or that may occur during the clinical course of a
patient who has the index disease under study’.11
Nonetheless, several other definitions of comorbidity
Respirology (2015) 20, 1160–1171
doi: 10.1111/resp.12642
COPD and its comorbidities
have also been suggested with no agreement on a
unified definition.12,13 Much of the discussion about
the accuracy of the term revolves around which of the
multiple conditions ought to be the primary or index
disease and the manner in which these multiple con-
ditions interact, that is, the cause–effect associations,
the role of common risk factors and common under-
lying mechanisms, or whether it is purely coincidence
that the two diseases occur together.12,13 For instance,
Starfield14 defines comorbidity as ‘the simultaneous
presence of multiple conditions when there is an
index disease and other unrelated conditions’. The
requirement for the comorbid condition to be ‘unre-
lated’ to the index disease may not be useful in COPD
as some of the co-occurring conditions may actually
be complications of the disease, or linked to the index
disease by a common mechanism, such as systemic
inflammation.15 Similarly, the choice of a particular
condition as the index disease is somewhat arbitrary
and may vary depending on the primary disease con-
sidered in a person with multiple morbidities.12
Recently, a broader view has been proposed that
recognizes that a patient may be suffering from multi-
ple diseases. This concept, termed ‘multimorbidity’,
has attained a growing interest particularly in relation
to the management of chronic diseases in the ageing
population.4,16,17 Multi-morbidity is defined as ‘any
co-occurrence of medical conditions within a
person’.18 The concept of multi-morbidity in the man-
agement of COPD has been insightfully explored in
recently published works.2,19,20 For example, in a study
that investigated the overall impact of ‘COPD-
specific’ comorbidities on the outcome of mortality in
COPD patients followed over 4 years, Divo et al.2 have
shown that risk of death was closely related to coex-
istent comorbid conditions like anxiety, gastric/
duodenal ulcer, solid organ cancers and pulmonary
fibrosis. Another example is the work of van
Remoortel et al.,20 a cross-sectional case–control
study that investigated the prevalence of premorbid
cardiovascular and metabolic risk factors and
comorbidities in newly diagnosed COPD patients and
age-matched never-smokers and smokers without
COPD. In this study, a considerably higher prevalence
of comorbid diseases (cardiovascular, metabolic and
musculoskeletal diseases) and shared risk factors
(smoking and physical inactivity) were reported in
recently diagnosed COPD patients compared with
never-smokers. Intriguingly, however, the same
observation was also made in the smokers without
COPD, indicating that COPD may just be one of a
number of multiple conditions resulting from
common risk factors.20 The results of this study
further confirm the challenges and limitations of a
single-disease management approach. Certainly,
future interventions and treatment approaches need
to consider multiple co-occurring diseases in the
clinical care of COPD patients in order to maximize
outcome and reduce the illness burden associated
with the disease.21 One pilot study by the present
authors has attempted to do this by using personal-
ized disease management approaches based on
multi-dimensional assessment of a COPD population
resulting in improved outcomes in older patients.22
© 2015 Asian Pacific Society of Respirology
1161
Personalized disease management approaches are
also described in the Spanish COPD guideline (Guía
Española de la EPOC—GesEPOC). GesEPOC pro-
poses an innovative approach to managing COPD
based on clinically relevant phenotypes, which iden-
tify groups of patients with different disease prognosis
and response to treatments.23 The concept of pheno-
type in COPD refers to ‘a single or combination of
disease attributes that describe differences between
individuals with COPD as they relate to clinically
meaningful outcomes’.24 In view of that, the four dis-
tinct phenotypes described in GesEPOC include (i)
non-exacerbators; (ii) mixed COPD–asthma; (iii)
exacerbators with emphysema; and (iv) exacerbators
with chronic bronchitis. Although no specific recom-
mendation for the detection and treatment of
comorbidities that coexist with COPD was provided,
GesEPOC is a shift towards personalized manage-
ment based on pathophysiological features of the
disease and takes into account the COPD–asthma
overlap phenotype.23
WHY ARE COMORBIDITIES IMPORTANT
IN THE MANAGEMENT OF COPD?
Comorbidities are ubiquitous among COPD
patients.3,25,26 In an observational study of 213 COPD
patients, nearly all participants (97.7%) were reported
to have one or more comorbid diseases and almost
54% had at least four.19 COPD patients also present
with combinations of comorbidities that tend to
cluster more frequently together.19 The most common
comorbidities that accompany COPD include cardio-
vascular diseases (CVDs), metabolic disorders,
osteoporosis, skeletal muscle dysfunction, anxiety/
depression, cognitive impairment, gastrointestinal
(GI) diseases and respiratory conditions such as
asthma, bronchiectasis, pulmonary fibrosis and lung
cancer.2,27 The prevalence of most of these diseases
in COPD patients has been widely reported in the
literature.3,27,28
Comorbidities are known to pose a challenge in the
assessment and effective management of COPD. For
example, conditions such as obesity may obscure the
diagnosis of COPD by preventing accurate assess-
ment of airflow limitation and hyperinflation, which
are defining characteristics of COPD.29 COPD patients
who also suffer from coexistent asthma experience
more symptoms, have poorer quality of life, more
exacerbations and increased health-care utilization
compared with those without asthma.30,31 Evidence
from the literature suggests that COPD patients with
coexisting anxiety and/or depression are at increased
risk of experiencing more exacerbations, frequent
hospital admissions, impaired quality of life and
increased mortality compared with COPD patients
without these conditions.32,33 Similarly, in COPD, skel-
etal muscle dysfunction and cognitive impairment
have been associated with impaired quality of life,34,35
whereas gastro-oesophageal reflux disease (GORD)
and bronchiectasis, with frequent exacerbations.36,37
Additionally, bronchiectasis in moderate-to-severe
COPD patients is associated with an increased risk of
Respirology (2015) 20, 1160–1171
1162
all-cause mortality.37 Furthermore, COPD patients
with CVDs have worse lung function and poor quality
of life, consume more health resources and are at
increased risk of hospitalizations and mortality.38,39
Despite these, however, CVDs are often under-
diagnosed40 and under-treated in COPD.41
Comorbidities may also impact disease manage-
ment. Clinical interventions recommended for COPD
can have either beneficial or detrimental effects in the
management of a coexisting comorbid condition.12
For example, in a COPD patient with a coexistent
diabetes mellitus, a physical exercise programme rec-
ommended for COPD may benefit the diabetes. Con-
versely, oral corticosteroid treatment for COPD may
adversely impact the control of diabetes.12 Also,
although they are a mainstay treatment in hyperten-
sion, coronary artery disease and post-myocardial
infarction,10 beta-blockers are often withheld in
COPD patients with comorbid CVDs due to their
potential antagonism with beta-2-agonists.41 Conse-
quently, only one third of patients with congestive
heart failure and COPD are reported to receive beta-
blocker therapy.41 Based on recent literature, however,
this is an erroneous omission of treatment as the use
of beta-blockers may improve outcomes for COPD
patients with coexistent CVDs.42,43
With regard to length of hospital stay, Wang et al.44
have shown that in COPD patients hospitalized for
an acute exacerbation, a prolonged length of stay
(longer than 11 days) was associated with having
comorbidities such as ischaemic heart disease, heart
failure, cardiac arrhythmia, diabetes and stroke. Most
importantly, a significant proportion of deaths in
COPD patients is attributable to causes other than
their index disease,45 with lung cancer and CVDs being
the two leading ones.27,46 Even in COPD patients with
no clinical evidence of comorbid CVDs, elevated bio-
chemical markers of cardiac dysfunction (troponin T
and N-terminal pro-brain natriuretic peptide) can
predict short-term mortality during exacerbation.47
Moreover, multiple comorbidities are known to have
cumulative effects on mortality in COPD.48
In addition to the abovementioned clinical implica-
tions, a huge amount of the health-care costs associ-
ated with COPD are due to comorbid conditions.3
Menn et al.49 examined the direct medical costs in
COPD (costs associated with physician and hospital
visits, and respiratory medications) among 375 COPD
patients and 1880 control subjects in Germany. Of the
frequently reported comorbidities, including arthri-
tis, cancer, diabetes, GI diseases, coronary heart
disease, renal disease, liver problems and stroke, all
ailments except for GI diseases were found to have
substantial impact on cost. Likewise, in a US study,
comorbid diseases were reported to account for
nearly 46% of the observed excess health-care cost
associated with COPD in 2004.7
Notwithstanding these, current disease-specific
strategies provide clinicians with little guidance in
terms of identifying, assessing and managing
the multiple components of COPD including
comorbidities.21 For instance, despite their known
association with poor clinical outcomes, comorbi-
dities such as cognitive impairment, obesity and
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NA Negewo et al.
GORD are often overlooked in the clinical care of
COPD patients.29,50,51 Even for comorbidities that are
described as directly related to COPD (for example,
anxiety, depression and osteoporosis), no clear
recommendation exists for their detection and man-
agement in COPD patients.9 Certainly, a better under-
standing of (i) the overall clinical implications of
comorbidities, (ii) which comorbidities to specifically
assess and how to quantify and manage them in
research and clinical practices and (iii) the underlying
mechanisms linking comorbidities with COPD are
urgently needed in order to improve disease manage-
ment and reduce the associated health-care cost.
WHAT LINKS COPD WITH ITS
COMORBIDITIES?
Although the mechanistic links between COPD and
its comorbidities are still not fully understood, a
number of potential determinants have been sug-
gested.3,15,27,52 Ageing, for instance, is strongly associ-
ated with the likelihood of developing multiple
chronic conditions.17 Ageing is characterized by
chronic, low grade systemic inflammation (also
referred to as inflammageing), which is a common
element of the majority of age-related diseases53
including COPD.5 Genetic susceptibility is another
intrinsic factor that has been described as a potential
link.3 For example, van Suylen et al.54 have reported a
negative association between DD genotypes of the
angiotensin converting enzyme gene and the devel-
opment of right ventricular hypertrophy in male
COPD patients. Likewise, several gene candidates that
might explain the association between lung cancer
and COPD over and above the known effects of
smoking as a shared risk factor have been reported.55
Candidate genes recognized to relate to both COPD
and lung cancer (FAM13A, HHIP, ADAM19 and
CHRNA) are associated with airway epithelial recep-
tors involved in mediating airway inflammation and
apoptosis.56 Other possible mechanisms that have
been proposed to link COPD with its comorbidities
include common risk factors like smoking and physi-
cal inactivity and common pathways such as oxida-
tive stress and systemic inflammation.3,15,52
Of the aforementioned mechanisms, systemic
inflammation is hypothesized as the most likely link
due to its role in the pathogenesis of both COPD and
its major comorbidities.5 Systemic inflammation is
classically defined as a twofold to fourfold elevation in
circulating levels of pro-inflammatory and anti-
inflammatory cytokines (e.g. interleukins 1β (IL-1β)
and 6 (IL-6) and tumour necrosis factor-alpha (TNF-
α)), naturally occurring cytokine antagonists and
acute phase proteins (e.g. C-reactive protein (CRP),
serum amyloid A).57 Many of the comorbidities that
accompany COPD (such as CVDs, osteoporosis and
metabolic syndrome) are characterized by low-grade
systemic inflammation.25 It is also known that a
subset of COPD patients have high circulating levels
of CRP, fibrinogen, IL-6, leukocytes and TNF-α during
stable conditions, indicating the existence of persis-
tent systemic inflammation.58,59 The relationship
© 2015 Asian Pacific Society of Respirology
COPD and its comorbidities
between biomarkers of systemic inflammation and
outcomes in COPD, including comorbidities, is well
documented.48 For instance, one study has revealed
that simultaneously elevated levels of CRP, fibrinogen
and leukocytes are associated with a twofold to
fourfold increased risk of comorbidities including
ischaemic heart disease, myocardial infarction, heart
failure, type II diabetes, lung cancer and pneumonia
in COPD.60 Similarly, in another study, a subset of
COPD patients with multiple coexisting cardiovascu-
lar and related diseases, a high circulating levels of
white blood cells, fibrinogen, surfactant protein-D,
IL-6 and IL-8 were identified.61 Notably, these
‘inflammed comorbids’ had the worst survival during
a 3-year follow-up.61 As a side note, systemic inflam-
mation is an important determinant of exacerbation
risk in COPD.62,63
Nevertheless, whether systemic inflammation is a
result of a ‘spill-over’ of airway inflammatory process
from the lungs into the circulation or, alternatively,
COPD is a consequence of a systemic inflammatory
state involving many organs remains to be deter-
mined.25,64 Addressing this gap and establishing the
mechanisms of association between COPD and its
major comorbidities is deemed crucial as improved
understanding might (i) help identify and character-
ize specific phenotypes of COPD24 and (ii) be indica-
tive of pathway specific treatment targets that can
possibly be beneficial in the treatment of multi-
diseased COPD patients. Perhaps a good example in
this regard is the potential role of statin therapy in
COPD. A number of observational studies suggest
that in a group of COPD patients, statins can modify
disease prognosis and improve clinical outcomes
including quality of life, exacerbations and exercise
tolerance,65–67 possibly owing to their anti-
inflammatory effects mediated through inhibition of
prenylation and isoprenylation of small GTPases.64
Nonetheless, the findings of a recent randomized
controlled trial68 suggest that the beneficial effects of
statins in COPD may need a closer investigation.
Other promising agents that are currently being
investigated for their potential use in COPD include
sulforaphane (NRF2 (nuclear erythroid-2-related
factor 2) activator), celastrol (NADPH oxidase (NOX)
inhibitor), p38 mitogen-activated protein kinase
inhibitors and phosphoinositide 3-kinase (P13K)
inhibitors.69
HOW ARE COMORBIDITIES MEASURED
IN COPD?
The complexities and frequent comorbidities of
COPD necessitate assessment beyond airflow limita-
tion (forced expiratory volume in 1 s—FEV1).6,21,25,70 Of
interest, the notion that the volume of air exhaled
from a fully inflated lung could be an important pre-
dictor of premature death dates back to the mid-
19th century.71 Interestingly enough, when it was first
put forward, the measurement was used in the insur-
ance industry to identify people who were at risk of
dying prematurely.72 Much has evolved over the years
and it is now recognized that FEV1 is poorly related to
© 2015 Asian Pacific Society of Respirology
1163
the severity of breathlessness, exercise limitation,
health status impairment and the extra pulmonary
dimensions of COPD.6,9 Henceforth, other multi-
dimensional indices are now being used for prognos-
tic purposes.73 Over the last few years there have been
many new publications that propose, validate and
recommend new multi-dimensional indices for
the assessment, management or prognostication of
COPD and its comorbidities. Some have been devel-
oped specifically for comorbidities, such as the
Charlson Comorbidity Index (CCI),74 comorbidity test
(COTE index),2 CODEx index (comorbidity, airway
obstruction, dyspnoea and previous exacerbation),75
COMCOLD index (comorbidities in chronic obstruc-
tive lung disease)76 and DECAF score (dyspnoea,
eosinopenia, consolidation, acidaemia and atrial
fibrillation).77 Others were developed to provide a
multi-dimensional approach to assessing COPD,
excluding comorbidities (e.g. BODE index (body mass
index, airflow obstruction, dyspnoea and exercise
capacity), modified BODE indices (mBODE, e-BODE,
BODEx), ADO (age, dyspnoea and air flow obstruc-
tion), DOSE (dyspnoea, airflow obstruction, smoking
status and exacerbation) and GOLD (Global Initiative
for Chronic Obstructive Lung Disease) quadrant).78–84
The characteristics and measurement properties of
these clinical scores are shown in Table 1. Table 2
summarizes how each of these tools relate to clinical
outcomes.
Multi-dimensional prognostic COPD indices
The BODE index, which encompasses body mass
index (BMI), airflow obstruction (FEV1), dyspnoea
(modified Medical Research Council (mMRC) score)
and exercise capacity (6-min walk distance test
(6MWD)) is one of the most effective multi-
dimensional grading systems.78 The aforementioned
four variables were chosen to construct BODE index
owing to their strong association with one year mor-
tality in a cohort of 207 COPD patients. The index
was further validated in a different cohort of 625
patients.78
The calculation of BODE involves the summation of
point scores assigned to each variable, that is 0–3
points for FEV1, 6MWD and mMRC and 0 or 1 point
for BMI. Hence, the total BODE score ranges from a
minimum of 0 to a maximum of 10 points, with higher
score indicating the poorest prognosis.78 In terms of
predictive ability, BODE index has been shown to be a
better tool than FEV1 alone78 and GOLD quadrant91 in
assessing the risk of death in the short and long term
in COPD patients. BODE index also correlates with
CCI (r = 0.29, P < 0.01), indicating that it can possibly
be used to measure comorbidities in COPD.92 More-
over, in a cross-sectional study of COPD patients,
higher BODE scores were found to associate with
higher prevalence of arrhythmias (supraventricular
tachycardia, atrial fibrillation and flutter) and greater
recurrence of pneumonia, particularly in male
patients and those in the age group of 60–65 years.93
Since the original BODE publication78 a number of
modified indices have been described. A modified
BODE index (mBODE) substituting the 6MWD with
Respirology (2015) 20, 1160–1171
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Table 1 Characteristics and measurement properties of currently available clinical scores

Respirology (2015) 20, 1160–1171

Characteristics of clinical scores Measurement properties

Exercise Easily Response to

Clinical scores BMI FEV1 capacity Dyspnoea Exacerbation Comorbidities Age Smoking Predictive Discriminative applicable intervention

BODE78,85,86 ✓ ✓ ✓ ✓ X X X X ✓ ✓ X ✓
mBODE79,84 ✓ ✓ ✓ ✓ X X X X ✓ — X —
eBODE80 ✓ ✓ ✓ ✓ ✓ X X X ✓ ✓ X —
BODEx80 ✓ ✓ X ✓ ✓ X X X ✓ ✓ ✓ —
ADO82,87 X ✓ X ✓ X X ✓ X ✓ — ✓ —
DOSE83,88 X ✓ X ✓ ✓ X X ✓ ✓ — ✓ —
GOLD quadrant61 X ✓ X ✓ ✓ X X X ✓ ✓ ✓ —
CCI74,89,90 X X X X X ✓ ✓† X ✓ — X —
COTE2 X X X X X ✓ X X ✓ — ✓ —
CODEx75 X ✓ X ✓ ✓ ✓ X X ✓ — ✓ —
COMCOLD76 X X X X X ✓ X X ✓ — ✓ —
DECAF77* X X X ✓ X ✓ X X ✓ ✓ ✓ —

*DECAF also incorporates eosinopenia, consolidation and acidaemia; †age-adjusted CCI; ADO, age, dyspnoea and air flow obstruction; BMI, body mass index; BODE, body mass index,
airflow obstruction, dyspnoea and exercise capacity; BODEx, body mass index, airflow obstruction, dyspnoea and severe exacerbation; CCI, Charlson Comorbidity Index; CODEx, comorbidity,
airway obstruction, dyspnoea and previous exacerbation; COMCOLD, comorbidities in chronic obstructive lung disease; COTE, comorbidity test; DECAF, dyspnoea, eosinopenia, consolida-
tion, acidaemia and atrial fibrillation; DOSE, dyspnoea, airflow obstruction, smoking status and exacerbation; eBODE, severe exacerbation plus BODE index; FEV1, forced expiratory volume
in 1 s; GOLD quadrant, Global Initiative for Chronic Obstructive Lung Disease quadrant; mBODE, modified BODE index. Blue and red shadings in the table mean the two distinct types of
properties of the clinical scores.
NA Negewo et al.

© 2015 Asian Pacific Society of Respirology

 COPD and its comorbidities

Table 2 Multi-dimensional indices and their prognostic abilities

Outcomes

© 2015 Asian Pacific Society of Respirology

All-cause Mortality from COPD specific In hospital Decline in Decline in Health care
Scales mortality respiratory conditions mortality mortality lung function health status Exacerbation Hospitalization utilization

BODE78,85,86 ● ● ● ● ● ● ●
mBODE79 ● ● ●
eBODE80 ●
BODEx80 ●
ADO82,87 ●
DOSE83,88 ● ● ● ● ●
GOLD quadrant81 ● ● ● ●
CCI74,89,90 ● ●
COTE2 ● ● ●
CODEx75 ● ● ● ●
COMCOLD76 ●
DECAF77 ●

ADO, age, dyspnoea and air flow obstruction; BODE, body mass index, airflow obstruction, dyspnoea and exercise capacity; BODEx, body mass index, airflow obstruction, dyspnoea and
severe exacerbation; CCI, Charlson Comorbidity Index; CODEx, comorbidity, airway obstruction, dyspnoea and previous exacerbation; COMCOLD, comorbidities in chronic obstructive lung
disease; COPD, chronic obstructive pulmonary disease; COTE, comorbidity test; DECAF, dyspnoea, eosinopenia, consolidation, acidaemia and atrial fibrillation; DOSE, dyspnoea, airflow
obstruction, smoking status and exacerbation; eBODE, severe exacerbation plus BODE index; GOLD quadrant, Global Initiative for Chronic Obstructive Lung Disease quadrant; mBODE,
modified BODE index.

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peak oxygen uptake (Vo2) as a measurement of exer-
cise capacity has been reported.84 BODE and mBODE
have similar prognostic abilities.79 Likewise, e-BODE
and BODEx are two other indices related to BODE but
incorporate frequency of severe exacerbations requir-
ing hospital admission or emergency visit in the pre-
vious year.80 Although the incorporation of a COPD
severe exacerbation as a variable in BODE index
(eBODE) did not improve BODE’s predictive ability,
the replacement of 6MWD by severe exacerbation has
resulted in the index BODEx, with a comparable pre-
dictive ability as BODE.80
As an alternative to BODE, the ADO82 and DOSE83
indices have been suggested for their increased appli-
cability in routine clinical settings. ADO is used for
assessing the risk of mortality,82 whereas DOSE is a
measure of health status and relates to other clinical
outcomes such as exercise tolerance, respiratory
failure and health-care consumption.83 The prognos-
tic capabilities of BODE and the abovementioned
tools have been compared in different geographic
populations.94,95
Another multi-dimensional assessment tool that
has been proposed for its severity classification and
prognostic abilities is the GOLD quadrant.9 This clas-
sification system was originally proposed in 2011 to
take into consideration the multi-dimensional com-
ponents and heterogeneity of COPD9 and has
since been demonstrated to be able to predict
prognosis including hospitalization (all-cause and
respiratory)81 and mortality (all-cause, respiratory
and cardiovascular).81,96
Specific comorbidity indices
Charlson Comorbidity Index (CCI)
CCI is perhaps the most widely used tool for assessing
the impact of comorbid diseases on overall survival.97
It was initially developed using a cohort of 604 inpa-
tients and subsequently verified in 685 patients with
primary carcinoma of the breast.74 The original index
focused on a list of 19 diseases, which were assigned
scores corresponding to their risks of mortality. A total
comorbidity score was then obtained by adding
together the individual score assigned to each
comorbid condition that a patient suffered from.74 In
their validation cohort, the authors found age to be an
independent predictor of risk of dying from comorbid
conditions. Hence, a composite age-comorbidity
index74 was suggested by adding an extra 1 point for
every 10 years of increase in age for people over the
age of 40 years and later validated.89 Another modified
version of CCI that incorporated depression, hyper-
tension, skin ulcers/cellulitis and use of warfarin,
besides the conditions included in the original index,
has been shown to predict the cost of care (includes
cost incurred for ambulatory visits, laboratory tests,
radiographic studies, consultations and hospitaliza-
tions) in addition to mortality.90
Although CCI has extensively been used for
measuring the impact of comorbidities in COPD
patients,98,99 the fact that it does not take into account
some common comorbid conditions that coexist with
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NA Negewo et al.
COPD (for instance, hypertension, atrial fibrillation,
anxiety, pulmonary fibrosis and depression) has been
indicated as its potential limitation.2,100
COmorbidity TEst (COTE)
The COTE index, which is the first COPD-specific
comorbidity index that predicts the risk of death asso-
ciated with comorbidities accompanying COPD, was
developed by Divo et al.2 The index is based on 12
comorbidities, which exhibited significant associa-
tion with mortality. These comorbidities included
solid organ cancers (lung, oesophageal, pancreatic
and breast), anxiety (in the female population only),
liver cirrhosis, atrial fibrillation/flutter, diabetes with
neuropathy, pulmonary fibrosis, congestive heart
failure, gastric/duodenal ulcers and coronary artery
disease. For the calculation of COTE index, point
scores ranging from 1 to 6 were assigned to these
comorbidities in proportion to their hazard ratios
(HR)—6 points for solid organ cancers and anxiety; 2
points for all other cancers, liver cirrhosis, atrial
fibrillation/flutter, diabetes with neuropathy and pul-
monary fibrosis; and 1 point for congestive heart
failure, gastric/duodenal ulcers and coronary artery
disease. The maximum total score in the COTE index
is 25.2
According to Divo et al.,2 an increase in COTE index
is associated with increased risk of death from COPD-
related causes (HR 1.13; (95% confidence interval
(CI): 1.08–1.18; P < 0.001)) and causes other than
COPD (HR 1.18; (95% CI: 1.15–1.21; P < 0.001)). The
predictive ability of COTE index (C statistics = 0.66;
P < 0.0001) was also similar to that of CCI (C statis-
tics = 0.66; P < 0.0001) but with the added advantage
of (i) being specific to COPD and (ii) incorporating
diseases not included in CCI, namely, atrial fibrilla-
tion, anxiety and pulmonary fibrosis.
Moreover, when used in conjunction with the
BODE index, the COTE index could provide further
prognostication.2 For instance, a patient with a BODE
score of 5 and COTE index of 4 or more would be
expected to have a 2.2-fold increase in risk of dying
compared with a patient with the same BODE score
but a COTE index of less than 4.2 This was further
corroborated by de Torres et al.91 in a study where they
compared GOLD quadrant, BODE index and the com-
binations of BODE and COTE indices in terms of their
ability to predict overall survival in patients followed
for an average of 50 months. The combination of
BODE and COTE had the highest predictive capacity
of all (area under the curve (AUC) of 0.81, 95% CI:
0.77–0.85), followed by BODE alone (AUC of 0.71, 95%
CI: 0.67–0.76) and then GOLD quadrant (AUC of 0.68,
95% CI: 0.64–0.73).91
The fact that COTE index does not incorporate
comorbidities, which often remain unrecognized and
ought to be looked for, such as cognitive dysfunction,
has been suggested as a potential limitation of the
index by some authors,101 although no data were pro-
vided to support this assertion. In response to such
scepticism, Divo et al. have pointed out the chal-
lenges associated with the identification and meas-
urement of cognitive impairment particularly in
outpatient clinical practices.102 In our opinion, the
© 2015 Asian Pacific Society of Respirology
COPD and its comorbidities
work of Divo et al.,2 which is apparently the only study
that attempted to unravel the overall burden of
COPD-related comorbidities, may advance our
understanding of the global assessment of patients
with COPD. Nevertheless, the applicability of the
COTE index in different geographical populations
may need to be investigated further.
Comorbidity, airway Obstruction, Dyspnea, and
previous Exacerbation (CODEx) index
Almagro et al.75 developed and validated the CODEx
index, which comprises comorbidity, airway obstruc-
tion, dyspnoea and exacerbation in the last 12 months
as a prognostic tool to assess mortality, hospital read-
mission and their composite impact for 3–12 months
after hospital discharge in patients hospitalized for
exacerbation of COPD. The data used for the develop-
ment of this index came from the EPOC en los
Servicios de Medicina Interna study—a longitudinal
observational multi-centre study conducted in
Spain.103 To construct the index,75 comorbidities were
evaluated using the age-adjusted CCI, while the
remaining three variables of the index (i.e. airway
obstruction, dyspnoea and exacerbation) were
assessed as described for BODEx.80 In using the age-
adjusted CCI,74 the authors stratified CCI in tertiles
and allocated a score point of 0 for CCI ranging from 0
to 4; 1 for CCI ranging from 1 to 7; and 2 for a CCI score
of 8 and above. Therefore, when adding the points for
each variable, the CODEx index has a minimum score
of 0 and a maximum score of 10.75
According to the authors,75 CODEx index is signifi-
cantly associated with mortality at 3 months (HR 1.5;
(95% CI: 1.2–1.8; P < 0.0001)) and 1 year (HR 1.3; (95%
CI: 1.2–1.5; P < 0.0001)) following hospital discharge.
When compared with existing multi-dimensional
indices using receiver operating characteristic curve
comparisons, CODEx (AUC of 0.72, 95% CI: 0.69–0.75)
was shown to have a better predictive ability of mor-
tality 3 months after hospital discharge than BODEx
(AUC 0.62, 95% CI: 0.58–0.65; P < 0.005), DOSE (AUC
0.60, 95% CI: 0.57–0.63; P < 0.01) and the updated
ADO (AUC 0.65, 95% CI: 0.58–0.65; P < 0.05). In the
case of predicting mortality 12 months after hospital
discharge, the performance of CODEx was similar to
that of the updated ADO but better than those of
BODEx (P < 0.02) and DOSE (P < 0.02).75
COMorbidities in Chronic Obstructive Lung
Disease (COMCOLD) index
Frei et al.76 developed an index that measures the col-
lective impact of comorbidities on patient-reported
health status, as measured by the feeling thermom-
eter (FT)—a visual analogue scale ranging from 0
(dead) to 100 (perfect health). The results of this
multi-centre cross-sectional study revealed that
nearly 38% of the 408 patients from primary care
practices in Switzerland and the Netherlands had four
or more comorbidities. Out of the 12 most prevalent
comorbidities (i.e. a prevalence of over 5%), depres-
sion, anxiety, peripheral artery disease, cerebrovascu-
lar disease (defined as cerebrovascular accident or
transient ischaemic heart disease) and symptomatic
heart disease (defined as coronary heart disease
© 2015 Asian Pacific Society of Respirology
1167
and/or heart failure) were found to have the strongest
association with FT scores, after adjusting for %FEV1
predicted. A point score of 6 was assigned for depres-
sion, 4 for anxiety and 3 for the remaining diseases in
order to construct the COMCOLD index (minimum
score 0 and maximum score 19). As noted by the
authors, the aim of this index is to guide clinicians
and researchers in identifying comorbidities that
have the greatest impact on health status from the
patient’s perspective and accordingly develop appro-
priate treatment plan.76 At this juncture, it may be
worth mentioning that in the above described study,
as is the case in many studies of comorbidity in COPD,
asthma was not considered as a comorbidity.76 This
implies that the potential impact of comorbid asthma
is frequently overlooked in studies of COPD.
DECAF score
The DECAF score is a prognostic tool developed for
predicting in-hospital mortality in patients hospital-
ized for acute exacerbations of COPD.77 It incorpo-
rates dyspnoea (extended MRC dyspnoea score
(eMRCD 5a and eMRCD 5b)), eosinopenia
(<0.05 × 109/L), consolidation, acidaemia (pH < 7.3)
and atrial fibrillation.77 These five variables were
chosen to construct the index due to their strong pre-
dictive ability of in-hospital mortality in 920 patients
hospitalized with acute exacerbation of COPD over 18
months period in the UK.77 DECAF assigns 1 point to
each of the above listed variables except for eMRCD
5b, which is assigned 2 points. eMRCD 5b applies to
patients requiring assistance to manage washing
and/or dressing because they are too breathless to do
so, as opposed to those who can do both indepen-
dently (eMRCD 5a). Maximum total DECAF score is
therefore 6 points.77 The score exhibited excellent dis-
crimination for in-hospital mortality (AUC of 0.86,
(95% CI: 0.82–0.89)) and was shown to have better
prognostic ability than the Acute Physiology and
Chronic Health Evaluation II prognostic index (AUC
of 0.73, P < 0.001), COPD and Asthma Physiology
Score (AUC of 0.71, P < 0.001) and the elevated blood
urea nitrogen, altered mental status, pulse >109/min,
age >65 years score (BAP-65) (AUC of 0.68,
P < 0.001).77 Of note, DECAF is the first index to incor-
porate biomarkers and clinical variables. The use of
biomarkers may add to the value of score properties.
Although several indices that assist in the assess-
ment and prognosis of various outcomes in COPD
have been reported in the literature, they all possess
different degrees of predictive ability and applicabil-
ity. The preference of using one index over the other
should largely be guided by the outcome of interest.
Certainly, more information on (i) how each index
performs in different clinical settings (primary, sec-
ondary or tertiary care) and different geographic
populations and (ii) the responsiveness of indices to
interventions would further aid the use of these tools
among clinicians and researchers.
COPD is a multi-dimensional heterogeneous
disease encompassing multiple disease phenotypes
and sub-phenotypes including those that involve
comorbidities.61 In managing COPD, we recommend
timely diagnosis of both the pulmonary condition
Respirology (2015) 20, 1160–1171
1168
and its associated comorbidities, followed by targeted
treatment of the specific sub-phenotypes of the indi-
vidual. Although current management strategies and
guidelines largely fail to address these complexities,
novel approaches to the assessment and manage-
ment of the disease have been proposed. For
instance, Agusti et al. have suggested the ‘COPD
control panel’ as a disease management model.70 This
conceptual model consists of three modules, namely,
severity, activity and impact, each with their own
modifiable variables, to guide clinicians to manage
COPD effectively. Similarly, the present authors have
proposed a multi-dimensional assessment and indi-
vidualized management approach integrating dis-
tinct domains that address the different dimensions
of COPD (i.e. airways component, risk factor modifi-
cation, disease management skills and effective man-
agement of comorbidities),21,22 with promising results.
However, it should be highlighted that more data are
needed to furnish better insight into an improved,
efficient and cost-effective management of COPD
patients who also suffer from multiple chronic
conditions.
In summary, comorbidities in COPD are common
and significantly contribute to disease burden and
mortality. As a result, greater attention needs to be
paid to the assessment and management of
comorbidities in COPD in both clinical and research
settings. In addition, there is an urgent need for a
better understanding of the mechanisms linking
COPD with its comorbidities. Of equal importance for
the effective management of comorbidities in COPD
is the selection of reliable measurement tools that can
assist in improving clinical outcomes.
Acknowledgements
Netsanet A. Negewo is supported by the Priority Research Centre
for Asthma and Respiratory Diseases PhD Scholarship and
Emlyn and Jennie Thomas Postgraduate Medical Research
Scholarship through the Hunter Medical Research Institute.
Vanessa M. McDonald is supported by the Lung Foundation of
Australia and Boehringer Ingelhiem COPD Research Fellowship.
Peter G. Gibson is supported by a NHMRC practitioner
fellowship.
REFERENCES
1 Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V,
Abraham J, Adair T, Aggarwal R, Ahn SY et al. Global and
regional mortality from 235 causes of death for 20 age groups in
1990 and 2010: a systematic analysis for the Global Burden of
Disease Study 2010. Lancet 2013; 380: 2095–128.
2 Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata
V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G et al.
Comorbidities and risk of mortality in patients with chronic
obstructive pulmonary disease. Am. J. Respir. Crit. Care Med.
2012; 186: 155–61.
3 Decramer M, Janssens W. Chronic obstructive pulmonary
disease and comorbidities. Lancet Respir. Med. 2013; 1: 73–83.
4 Faner R, Cruz T, López-Giraldo A, Agusti A. Network medicine,
multimorbidity and the lung in the elderly. Eur. Respir. J. 2014;
44: 775–88.
5 Fabbri LM, Rabe KF. From COPD to chronic systemic inflam-
matory syndrome? Lancet 2007; 370: 797–9.
Respirology (2015) 20, 1160–1171
NA Negewo et al.
6 Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas
DA, MacNee W, Miller BE, Rennard S, Silverman EK et al.
Characterisation of COPD heterogeneity in the ECLIPSE cohort.
Respir. Res. 2010; 11: 122.
7 Menzin J, Boulanger L, Marton J, Guadagno L, Dastani H, Dirani
R, Phillips A, Shah H. The economic burden of chronic obstruc-
tive pulmonary disease (COPD) in a U.S. Medicare population.
Respir. Med. 2008; 102: 1248–56.
8 Fabbri LM, Boyd C, Boschetto P, Rabe KF, Buist AS, Yawn B, Leff
B, Kent DM, Schünemann HJ, ATS/ERS Ad Hoc Committee on
Integrating and Coordinating Efforts in COPD Guideline Devel-
opment. How to integrate multiple comorbidities in guideline
development: article 10 in integrating and coordinating efforts
in COPD guideline development. An official ATS/ERS Workshop
Report. Proc. Am. Thorac. Soc. 2012; 9: 274–81.
9 Global Initiative for Chronic Obstructive Lung Disease (GOLD).
Global Strategy for the Diagnosis, Management and Prevention
of COPD. 2015. [Accessed 1 Jun 2015.] Available from URL:
http://www.goldcopd.org/uploads/users/files/GOLD_Report
_2015_Apr2.pdf..
10 Abramson M, Brown J, Crockett AJ, Dabscheck E, Frith PA,
George J, Glasgow N, Jenkins S, McDonald CF, McDonald V
et al. The COPDX Plan: Australian and New Zealand Guidelines
for the management of Chronic Obstructive Pulmonary
Disease, Version 2.39. 2013. [Accessed 14 Jun 2015.] Available
from URL: http://copdx.org.au.
11 Feinstein AR. The pre-therapeutic classification of
co-morbidity in chronic disease. J. Chronic Dis. 1970; 23: 455–
68.
12 Valderas JM, Starfield B, Sibbald B, Salisbury C, Roland M.
Defining comorbidity: implications for understanding health
and health services. Ann. Fam. Med. 2009; 7: 357–63.
13 Jakovljević M, Ostojić L. Comorbidity and multimorbidity in
medicine today: challenges and opportunities for bringing
separated branches of medicine closer to each other. Psychiatr.
Danub. 2013; 25(Suppl. 1): 18–28.
14 Starfield B. Threads and yarns: weaving the tapestry of
comorbidity. Ann. Fam. Med. 2006; 4: 101–3.
15 Barnes PJ. Chronic obstructive pulmonary disease: effects
beyond the lungs. PLoS Med. 2010; 7: e1000220.
16 van Oostrom SH, Picavet HSJ, de Bruin SR, Stirbu I, Korevaar JC,
Schellevis FG, Baan CA. Multimorbidity of chronic diseases and
health care utilization in general practice. BMC Fam. Pract.
2014; 15: 61.
17 Divo MJ, Martinez CH, Mannino DM. Ageing and the epidemi-
ology of multimorbidity. Eur. Respir. J. 2014; 44: 1055–68.
18 van den Akker M, Buntinx F, Knottnerus JA. Comorbidity or
multimorbidity: what’s in a name? A review of literature. Eur. J.
Gen. Pract. 1996; 2: 65–70.
19 Vanfleteren LEGW, Spruit MA, Groenen M, Gaffron S, van
Empel VPM, Bruijnzeel PLB, Rutten EPA, Op’t Roodt J, Wouters
EFM, Franssen FME. Clusters of comorbidities based on vali-
dated objective measurements and systemic inflammation in
patients with chronic obstructive pulmonary disease. Am. J.
Respir. Crit. Care Med. 2013; 187: 728–35.
20 van Remoortel H, Hornikx M, Langer D, Burtin C, Everaerts S,
Verhamme P, Boonen S, Gosselink R, Decramer M, Troosters T
et al. Risk factors and comorbidities in the preclinical stages of
chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care
Med. 2014; 189: 30–8.
21 Gibson PG, McDonald VM, Marks GB. Asthma in older adults.
Lancet 2010; 376: 803–13.
22 McDonald VM, Higgins I, Wood LG, Gibson PG. Multidimen-
sional assessment and tailored interventions for COPD:
respiratory utopia or common sense? Thorax 2013; 68: 691–
4.
23 Miravitlles M, Soler-Cataluna JJ, Calle M, Molina J, Almagro P,
Quintano JA, Riesco JA, Trigueros JA, Pinera P, Simon A et al.
Spanish guideline for COPD (GesEPOC). Update 2014. Arch.
Bronconeumol. 2014; 50(Suppl. 1): 1–16.
© 2015 Asian Pacific Society of Respirology
COPD and its comorbidities
24 Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL,
Fabbri LM, Goldin JG, Jones PW, Macnee W et al. Chronic
obstructive pulmonary disease phenotypes: the future of
COPD. Am. J. Respir. Crit. Care Med. 2010; 182: 598–604.
25 McDonald VM, Higgins I, Gibson PG. Managing older patients
with coexistent asthma and chronic obstructive pulmonary
disease: diagnostic and therapeutic challenges. Drugs Aging
2013; 30: 1–17.
26 Barr RG, Celli BR, Mannino DM, Petty T, Rennard SI, Sciurba
FC, Stoller JK, Thomashow BM, Turino GM. Comorbidities,
patient knowledge, and disease management in a national
sample of patients with COPD. Am. J. Med. 2009; 122: 348–
55.
27 Patel ARC, Hurst JR. Extrapulmonary comorbidities in chronic
obstructive pulmonary disease: state of the art. Expert Rev.
Respir. Med. 2011; 5: 647–62.
28 Negewo NA, McDonald VM, Gibson PG. Comorbidity in chronic
obstructive pulmonary disease. Respir. Investig. 2015. doi:
10.1016/j.resinv.2015.02.004.
29 O’Donnell DE, Ciavaglia CE, Neder JA. When obesity and
chronic obstructive pulmonary disease collide: physiological
and clinical consequences. Ann. Am. Thorac. Soc. 2014; 11: 635–
44.
30 Hardin M, Cho M, McDonald M-L, Beaty T, Ramsdell J, Bhatt S,
van Beek EJR, Make BJ, Crapo JD, Silverman EK et al. The clini-
cal and genetic features of COPD-asthma overlap syndrome.
Eur. Respir. J. 2014; 44: 341–50.
31 Gibson PG, McDonald VM. Asthma–COPD overlap 2015: now
we are six. Thorax 2015; 70: 683–91. doi: 10.1136/thoraxjnl-
2014-206740.
32 Cafarella PA, Effing TW, Usmani Z-A, Frith PA. Treatments for
anxiety and depression in patients with chronic obstructive
pulmonary disease: a literature review. Respirology 2012; 17:
627–38.
33 Ng T-P, Niti M, Tan W-C, Cao Z, Ong K-C, Eng P. Depressive
symptoms and chronic obstructive pulmonary disease: effect
on mortality, hospital readmission, symptom burden, func-
tional status, and quality of life. Arch. Intern. Med. 2007; 167:
60–7.
34 Kim HC, Mofarrahi M, Hussain SNA. Skeletal muscle dysfunc-
tion in patients with chronic obstructive pulmonary disease.
Int. J. Chron. Obstruct. Pulmon. Dis. 2008; 3: 637–58.
35 Cleutjens FAHM, Janssen DJA, Ponds RWHM, Dijkstra JB,
Wouters EFM. Cognitive-pulmonary disease. Biomed. Res. Int.
2014; 2014: 697825.
36 Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H,
Tal-Singer R, Miller B, Lomas DA, Agusti A, MacNee W et al.
Susceptibility to exacerbation in chronic obstructive pulmo-
nary disease. N. Engl. J. Med. 2010; 363: 1128–38.
37 Martínez-García M-A, de la Rosa Carrillo D, Soler-Cataluña J-J,
Donat-Sanz Y, Serra PC, Lerma MA, Ballestín J, Sánchez IV,
Selma Ferrer MJ, Dalfo AR et al. Prognostic value of bronchiec-
tasis in patients with moderate-to-severe chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med. 2013; 187:
823–31.
38 Tsiligianni IG, Kosmas E, van der Molen T, Tzanakis N. Manag-
ing comorbidity in COPD: a difficult task. Curr. Drug Targets
2013; 14: 158–76.
39 de Miguel-Diez J, Carrasco-Garrido P, Rejas-Gutierrez J,
Martin-Centeno A, Gobartt-Vazquez E, Hernandez-Barrera V,
de Miguel AG, Jimenez-Garcia R. The influence of heart disease
on characteristics, quality of life, use of health resources, and
costs of COPD in primary care settings. BMC Cardiovasc.
Disord. 2010; 10: 8.
40 Rutten FH, Cramer M-JM, Grobbee DE, Sachs APE, Kirkels JH,
Lammers J-WJ, Hoes AW. Unrecognized heart failure in elderly
patients with stable chronic obstructive pulmonary disease.
Eur. Heart J. 2005; 26: 1887–94.
41 Egred M, Shaw S, Mohammad B, Waitt P, Rodrigues E. Under-
use of beta-blockers in patients with ischaemic heart disease
© 2015 Asian Pacific Society of Respirology
1169
and concomitant chronic obstructive pulmonary disease. QJM
2005; 98: 493–7.
42 Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW.
β-blockers may reduce mortality and risk of exacerbations in
patients with chronic obstructive pulmonary disease. Arch.
Intern. Med. 2010; 170: 880–7.
43 Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ.
Effect of β blockers in treatment of chronic obstructive pulmo-
nary disease: a retrospective cohort study. BMJ 2011; 342:
d2549.
44 Wang Y, Stavem K, Dahl FA, Humerfelt S, Haugen T. Factors
associated with a prolonged length of stay after acute exacer-
bation of chronic obstructive pulmonary disease (AECOPD).
Int. J. Chron. Obstruct. Pulmon. Dis. 2014; 9: 99–105.
45 Celli BR, Cote CG, Lareau SC, Meek PM. Predictors of survival in
COPD: more than just the FEV1. Respir. Med. 2008; 102(Suppl.
1): S27–35.
46 Mannino DM, Doherty DE, Buist AS. Global Initiative on
Obstructive Lung Disease (GOLD) classification of lung disease
and mortality: findings from the Atherosclerosis Risk in Com-
munities (ARIC) study. Respir. Med. 2006; 100: 115–22.
47 Chang CL, Robinson SC, Mills GD, Sullivan GD, Karalus NC,
McLachlan JD, Hancox RJ. Biochemical markers of cardiac dys-
function predict mortality in acute exacerbations of COPD.
Thorax 2011; 66: 764–8.
48 Miller J, Edwards LD, Agustí A, Bakke P, Calverley PMA, Celli B,
Coxson HO, Crim C, Lomas DA, Miller BE et al. Comorbidity,
systemic inflammation and outcomes in the ECLIPSE cohort.
Respir. Med. 2013; 107: 1376–84.
49 Menn P, Heinrich J, Huber RM, Jörres RA, John J, Karrasch S,
Peters A, Schulz H, Holle R, KORA Study Group. Direct medical
costs of COPD—An excess cost approach based on two
population-based studies. Respir. Med. 2012; 106: 540–8.
50 Tulek B, Atalay NB, Yildirim G, Kanat F, Süerdem M. Cognitive
function in chronic obstructive pulmonary disease: relation-
ship to Global Initiative for Chronic Obstructive Lung Disease
2011 categories. Respirology 2014; 19: 873–80.
51 Miyazaki M, Nakamura H, Chubachi S, Sasaki M, Haraguchi M,
Yoshida S, Tsuduki K, Shirahata T, Takahashi S, Minematsu N
et al. Analysis of comorbid factors that increase the COPD
assessment test scores. Respir. Res. 2014; 15: 13.
52 Decramer M, Rennard S, Troosters T, Mapel DW, Giardino N,
Mannino D, Wouters E, Sethi S, Cooper CB. COPD as a lung
disease with systemic consequences—clinical impact, mecha-
nisms, and potential for early intervention. COPD 2008; 5: 235–
56.
53 Franceschi C, Campisi J. Chronic inflammation (inflammaging)
and its potential contribution to age-associated diseases. J.
Gerontol. A. Biol Sci. Med Sci 2014; 69(Suppl. 1): S4–9.
54 van Suylen RJ, Wouters EF, Pennings HJ, Cheriex EC, van Pol PE,
Ambergen AW, Vermelis A-M, Daemen MJ. The DD genotype of
the angiotensin converting enzyme gene is negatively associ-
ated with right ventricular hypertrophy in male patients with
chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care
Med. 1999; 159: 1791–5.
55 Schwartz AG, Ruckdeschel JC. Familial lung cancer: genetic sus-
ceptibility and relationship to chronic obstructive pulmonary
disease. Am. J. Respir. Crit. Care Med. 2006; 173: 16–22.
56 Young RP, Hopkins RJ. How the genetics of lung cancer may
overlap with COPD. Respirology 2011; 16: 1047–55.
57 Brüünsgaard H, Pedersen BK. Age-related inflammatory
cytokines and disease. Immunol. Allergy Clin. North Am. 2003;
23: 15–39.
58 Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association
between chronic obstructive pulmonary disease and systemic
inflammation: a systematic review and a meta-analysis. Thorax
2004; 59: 574–80.
59 Fu J-J, McDonald VM, Gibson PG, Simpson JL. Systemic inflam-
mation in older adults with asthma–COPD overlap syndrome.
Allergy Asthma Immunol. Res. 2014; 6: 316–24.
Respirology (2015) 20, 1160–1171
1170
60 Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG.
Inflammatory biomarkers and comorbidities in chronic
obstructive pulmonary disease. Am. J. Respir. Crit. Care Med.
2012; 186: 982–8.
61 Rennard SI, Locantore N, Delafont B, Tal-Singer R, Silverman
EK, Vestbo J, Miller BE, Bakke P, Celli B, Calverley PMA et al.
Identification of five chronic obstructive pulmonary disease
subgroups with different prognoses in the ECLIPSE cohort
using cluster analysis. Ann. Am. Thorac. Soc. 2015; 12: 303–12.
62 Thomsen M, Ingebrigtsen TS, Marott JL, Dahl M, Lange P,
Vestbo J, Nordestgaard BG. Inflammatory biomarkers and exac-
erbations in chronic obstructive pulmonary disease. JAMA
2013; 309: 2353–61.
63 Fu J-J, McDonald VM, Baines KJ, Gibson PG. Airway IL-1β and
systemic inflammation as predictors of future exacerbation risk
in asthma and COPD. Chest 2015; 148: 618–29. doi: 10.1378/
chest.14-2337.
64 Barnes PJ, Celli BR. Systemic manifestations and comorbidities
of COPD. Eur. Respir. J. 2009; 33: 1165–85.
65 Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM,
Brophy JM. Reduction of morbidity and mortality by statins,
angiotensin-converting enzyme inhibitors, and angiotensin
receptor blockers in patients with chronic obstructive pulmo-
nary disease. J. Am. Coll. Cardiol. 2006; 47: 2554–60.
66 Bartziokas K, Papaioannou AI, Minas M, Kostikas K, Banya W,
Daniil ZD, Haniotou A, Gourgoulianis KI. Statins and outcome
after hospitalization for COPD exacerbation: a prospective
study. Pulm. Pharmacol. Ther. 2011; 24: 625–31.
67 Lawes CM, Thornley S, Young R, Hopkins R, Marshall R, Chan
WC, Jackson G. Statin use in COPD patients is associated with a
reduction in mortality: a national cohort study. Prim. Care
Respir. J. 2012; 21: 35–40.
68 Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi
R, Cooper JA Jr, Curtis JL, Dransfield MT, Han MK et al.
Simvastatin for the prevention of exacerbations in moderate-
to-severe COPD. N. Engl. J. Med. 2014; 370: 2201–10.
69 Barnes PJ. New anti-inflammatory targets for chronic
obstructive pulmonary disease. Nat. Rev. Drug Discov. 2013; 12:
543–59.
70 Agusti A, MacNee W. The COPD control panel: towards person-
alised medicine in COPD. Thorax 2013; 68: 687–90.
71 Hutchinson J. On the capacity of the lungs, and on the respira-
tory functions, with a view of establishing a precise and easy
method of detecting disease by the spirometer. Med. Chir.
Trans. 1846; 29: 137–252.
72 Petty TL. John Hutchinson’s mysterious machine revisited.
Chest 2002; 121(Suppl. 5): 219S–23S.
73 van Dijk WD, van den Bemt L, van den Haak-Rongen S, Bischoff
E, van Weel C, Veen JC, Schermer TR. Multidimensional prog-
nostic indices for use in COPD patient care. A systematic
review. Respir. Res. 2011; 12: 151.
74 Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method
of classifying prognostic comorbidity in longitudinal studies:
development and validation. J. Chronic Dis. 1987; 40: 373–83.
75 Almagro P, Soriano JB, Cabrera FJ, Boixeda R, Alonso-Ortiz MB,
Barreiro B, Diez-Manglano J, Murio C, Heredia JL, Working
Group on COPD, Spanish Society of Internal Medicine. Short-
and medium-term prognosis in patients hospitalized for COPD
exacerbation: the CODEX index. Chest 2014; 145: 972–80.
76 Frei A, Muggensturm P, Putcha N, Siebeling L, Zoller M, Boyd
CM, ter Riet G, Puhan MA. Five comorbidities reflected the
health status in patients with chronic obstructive pulmonary
disease: the newly developed COMCOLD index. J. Clin.
Epidemiol. 2014; 67: 904–11.
77 Steer J, Gibson J, Bourke SC. The DECAF score: predicting hos-
pital mortality in exacerbations of chronic obstructive pulmo-
nary disease. Thorax 2012; 67: 970–6.
78 Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M,
Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index,
airflow obstruction, dyspnea, and exercise capacity index in
Respirology (2015) 20, 1160–1171
NA Negewo et al.
chronic obstructive pulmonary disease. N. Engl. J. Med. 2004;
350: 1005–12.
79 Cote CG, Pinto-Plata VM, Marin JM, Nekach H, Dordelly LJ,
Celli BR. The modified BODE index: validation with mortality in
COPD. Eur. Respir. J. 2008; 32: 1269–74.
80 Soler-Cataluña JJ, Martínez-García MA, Sánchez LS, Tordera
MP, Sánchez PR. Severe exacerbations and BODE index: two
independent risk factors for death in male COPD patients.
Respir. Med. 2009; 103: 692–9.
81 Johannessen A, Nilsen RM, Storebø M, Gulsvik A, Eagan T,
Bakke P. Comparison of 2011 and 2007 Global Initiative for
Chronic Obstructive Lung Disease guidelines for predicting
mortality and hospitalization. Am. J. Respir. Crit. Care Med. 2013;
188: 51–9.
82 Puhan MA, Garcia-Aymerich J, Frey M, ter Riet G, Antó JM,
Agustí AG, Gómez FP, Rodríguez-Roisín R, Moons KGM, Kessels
AG et al. Expansion of the prognostic assessment of patients
with chronic obstructive pulmonary disease: the updated
BODE index and the ADO index. Lancet 2009; 374: 704–11.
83 Jones RC, Donaldson GC, Chavannes NH, Kida K,
Dickson-Spillmann M, Harding S, Wedzicha JA, Price D, Hyland
ME. Derivation and validation of a composite index of severity
in chronic obstructive pulmonary disease: the DOSE Index. Am.
J. Respir. Crit. Care Med. 2009; 180: 1189–95.
84 Cardoso F, Tufanin AT, Colucci M, Nascimento O, Jardim JR.
Replacement of the 6-min walk test with maximal oxygen con-
sumption in the BODE index applied to patients with COPD: an
equivalency study. Chest 2007; 132: 477–82.
85 Cote CG, Celli BR. Pulmonary rehabilitation and the BODE
index in COPD. Eur. Respir. J. 2005; 26: 630–6.
86 Marin JM, Cote CG, Diaz O, Lisboa C, Casanova C, Lopez MV,
Carrizo SJ, Pinto-Plata V, Dordelly LJ, Nekach H et al. Prognos-
tic assessment in COPD: health related quality of life and the
BODE index. Respir. Med. 2011; 105: 916–21.
87 Schünemann H. From BODE to ADO to outcomes in
multimorbid COPD patients. Lancet 2009; 374: 667–8.
88 Sundh J, Janson C, Lisspers K, Ställberg B, Montgomery S. The
dyspnoea, obstruction, smoking, exacerbation (DOSE) index is
predictive of mortality in COPD. Prim. Care Respir. J. 2012; 21:
295–301.
89 Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a
combined comorbidity index. J. Clin. Epidemiol. 1994; 47: 1245–
51.
90 Charlson ME, Charlson RE, Peterson JC, Marinopoulos SS,
Briggs WM, Hollenberg JP. The Charlson Comorbidity Index is
adapted to predict costs of chronic disease in primary care
patients. J. Clin. Epidemiol. 2008; 61: 1234–40.
91 de Torres JP, Casanova C, Marín JM, Pinto-Plata V, Divo M,
Zulueta JJ, Berto J, Zagaceta J, Sanchez-Salcedo P, Cabrera C
et al. Prognostic evaluation of COPD patients: Gold 2011 versus
BODE and the COPD comorbidity index COTE. Thorax 2014;
69: 799–804.
92 Corlateanu A, Montanari G, Botnaru V. Can we assess COPD
comorbidities by BODE index? Eur. Respir. J. 2011; 38(Suppl. 55):
3565.
93 Grabicki M, Parysek H, Batura-Gabryel H, Brodnicka I.
Comorbidities as an element of multidimensional prognostic
assessment of patients with chronic obstructive pulmonary
disease. J. Physiol. Pharmacol. 2008; 59(Suppl. 6): 297–301.
94 Ou C-Y, Chen C-Z, Yu C-H, Shiu C-H, Hsiue T-R. Discriminative
and predictive properties of multidimensional prognostic
indices of chronic obstructive pulmonary disease: a validation
study in Taiwanese patients. Respirology 2014; 19: 694–9.
95 Marin JM, Alfageme I, Almagro P, Casanova C, Esteban C,
Soler-Cataluña JJ, de Torres JP, Martínez-Camblor P, Miravitlles
M, Celli BR et al. Multicomponent indices to predict survival in
COPD: the COCOMICS study. Eur. Respir. J. 2013; 42: 323–32.
96 Agusti A, Edwards LD, Celli B, MacNee W, Calverley PMA,
Müllerova H, Lomas DA, Wouters E, Bakke P, Rennard S et al.
Characteristics, stability and outcomes of the 2011 GOLD
© 2015 Asian Pacific Society of Respirology
COPD and its comorbidities
COPD groups in the ECLIPSE cohort. Eur. Respir. J. 2013; 42:
636–46.
97 de Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to
measure comorbidity: a critical review of available methods.
J. Clin. Epidemiol. 2003; 56: 221–9.
98 Ferrari R, Tanni SE, Faganello MM, Caram LMO, Lucheta PA,
Godoy I. Three-year follow-up study of respiratory and systemic
manifestations of chronic obstructive pulmonary disease. Braz.
J. Med. Biol. Res. 2011; 44: 46–52.
99 Simon-Tuval T, Scharf SM, Maimon N, Bernhard-Scharf BJ,
Reuveni H, Tarasiuk A. Determinants of elevated healthcare uti-
lization in patients with COPD. Respir. Res. 2011; 12: 7.
100 Lin P-J, Shaya FT, Scharf SM. Economic implications of
comorbid conditions among Medicaid beneficiaries with
COPD. Respir. Med. 2010; 104: 697–704.
© 2015 Asian Pacific Society of Respirology
1171
101 Dodd JW, Jones PW. Potential limitation of the COTE index in
assessing the impact of comorbidities on mortality in chronic
obstructive pulmonary disease. Am. J. Respir. Crit. Care Med.
2012; 186: 804–5, author reply: 805.
102 Divo M, Celli B. Reply: to COTE or not to COTE: generalizability,
validity, and other issues. Am. J. Respir. Crit. Care Med. 2012; 186:
805.
103 Almagro P, Cabrera FJ, Diez J, Boixeda R, Alonso Ortiz MB,
Murio C, Soriano JB, Working Group on COPD, Spanish Society
of Internal Medicine. Comorbidities and short-term prognosis
in patients hospitalized for acute exacerbation of COPD: the
EPOC en Servicios de Medicina Interna (ESMI) study. Chest
2012; 142: 1126–33.
Respirology (2015) 20, 1160–1171