R ES E A R C H Open Access
Associations between chronic comorbidity
and exacerbation risk in primary care
patients with COPD
Janine A. M. Westerik
1
, Esther I. Metting
2
, Job F. M. van Boven
2
, Waling Tiersma
1
, Janwillem W. H. Kocks
2
and Tjard R. Schermer
1*
Abstract
Background: COPD often coexists with chronic conditions that may influence disease prognosis. We investigated
associations between chronic (co)morbidities and exacerbations in primary care COPD patients.
Method: Retrospective cohort study based on 2012–2013 electronic health records from 179 Dutch general practices.
Comorbidities from patients with physician-diagnosed COPD were categorized according to International Classification
of Primary Care (ICPC) codes. Chi-squared tests, uni- and multivariable logistic, and Cox regression analyses were used
to study associations with exacerbations, defined as oral corticosteroid prescriptions.
Results: Fourteen thousand six hundred three patients with COPD could be studied (mean age 67 (SD 12) years, 53%
male) for two years. At baseline 12,826 (88%) suffered from ≥1 comorbidities, 3263 (22%) from ≥5. The most prevalent
comorbidities were hypertension (35%), coronary heart disease (19%), and osteoarthritis (18%). Several comorbidities
showed statistically significant associations with frequent (i.e., ≥2/year) exacerbations: heart failure (odds ratio [OR], 95%
confidence interval: 1.72; 1.38–2.14), blindness & low vision (OR 1.46; 1.21–1.75), pulmonary cancer (OR 1.85; 1.28–2.67),
depression 1.48; 1.14–1.91), prostate disorders (OR 1.50; 1.13–1.98), asthma (OR 1.36; 1.11–1.70), osteoporosis (OR 1.41;
1.11–1.80), diabetes (OR 0.80; 0.66–0.97), dyspepsia (OR 1.25; 1.03–1.50), and peripheral vascular disease (OR
1.20; 1.00–1.45). From all comorbidity categories, having another chronic respiratory disease beside COPD showed the
highest risk for developing a new exacerbation (Cox hazard ratio 1.26; 1.17–1.36).
Conclusion: Chronic comorbidities are highly prevalent in primary care COPD patients. Several chronic comorbidities
were associated with having frequent exacerbations and increased exacerbation risk.
Background
Although nowadays healthcare systems are largely
configured to manage individual diseases rather than
multimorbidity, there is an increasing awareness of the
importance of comorbidities in patients with chronic
conditions [1]. Chronic obstructive pulmonary disease
(COPD), a prevalent chronic respiratory condition, is a
major cause of morbidity and mortality worldwide [2].
In the past decade several studies have shown that
COPD often coexists with other diseases, [3, 4] and that
comorbidity is associated with poo rer clinical outcomes
[4, 5]. Some of these comorbidities arise independently
of COPD, whereas others may be causally related, either
through shared risk factors (smoking, aging) or shared
pathophysiology, as a complication of COPD, or due to
medication side effects.
Several associations between COPD and particular
comorbidities have been shown. Cardiovascular disease,
metabolic syndrome, skeletal muscle dysfunction, osteo-
porosis, depression and lung cancer are all highly preva-
lent among patients with any severity of COPD, and
cross-sectional studies have shown their significant impact
on patients’ health-related quality of life [2, 6, 7]. Most of
the research on comorbidity in COPD comes from studies
in secondary care populations, thus representing patients
in the more severe part of the COPD severity spectrum
[4]. However, in most developed countries, the vast
* Correspondence: tjard.schermer@radboudumc.nl
1
Department of Primary and Community Care, Radboud University Medical
Center, 117-ELG, Geert Grooteplein Noord 21, Nijmegen 6525 EZ, The
Netherlands
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Westerik et al. Respiratory Research (2017) 18:31
DOI 10.1186/s12931-017-0512-2
majority of patients with COPD are managed in primary
care. Studies performed in general practice settings report
that 21 to 74% of patients with COPD suffer from two or
more additional chronic diseases [6, 8].
As COPD is a progressive disease, factors that influ-
ence its prognosis are important to consider when man-
aging patients. Since exacerbation frequency is a known
predictor of COPD progression, [2] it is important to
know what the potential impact of comorbidities on the
risk of exacerbations is. Recently Putcha et al.reported a
model in which the number of comorbid conditions pre-
dicted dyspnea and exacerbation risk [9]. This prediction
model does, however, not take into account which
particular comorbid conditions are associated with
exacerbation risk. Other previous studies have predom-
inantly looked at mortality as the outco me of interest,
[5, 10, 11 ] but from a patient management perspective it
is important that physicians consider comorbidities that
influence potentially modifiable prognostic factors like
exacerbation rate in their treatment decisions. Therefore,
the aim of the current study was to explore associations
between a wide range of comorbid chronic conditions
and exacerbation risk in a real-life cohort of primary
care patients with COPD.
Methods
Design and dataset
The study used routine data from a general practice data-
base from the Department of Primary and Community
Care at the Radboud University Medical Center,
Nijmegen, the Netherlands. De-identified electronic
medical records from primary care patients diagnosed
with COPD from 179 general practices in the eastern part
of the Netherlands were available in the database.
For each registered subject, the following data were
extracted: age, sex, all diagnoses using the International
Classification of Primary Care (ICPC), extended with
Dutch ICPC sub-codes, [12] and all prescribed medication.
ICPC-2 or ICD10 coding data were recoded into ICPC-1.
Medication prescriptions (i.e., prescription start and
end dates, dosage, f requency, and duration) were ex-
tracted and categorized using the Anatomical Thera-
peutic Chemical (ATC) classification system [13]. For
the current study only the data on prescriptions for
oral corticosteroids were used.
Study population
Subjects aged ≥40 years were included in the study
population when they had physician-diagnosed COPD
(as labeled with ICPC code R95 in the electronic medical
record) before or during the study period. Asthma
(ICPC R96) in addition to the COPD code was not an
exclusion criterion. The follow-up period covered the
years 2012 and 2013. The observation period for patients
terminated either at the end of the study period (31
December 2013), or when a subject died or deregistered
from the practice.
Comorbidities
The selection of chronic comorbid diseases studied was
based on existing literature [1, 14], the authors’ clinical ex-
pertise and expert opinions (Nielen MM, Spronk I, Davids
R, Korevaar JC, Poos MJ, Hoeymans N, Opstelten W, van
der Sande MAB, Biermans MCJ, Schellevis FG, RA V: A
new method for estimating morbidity rates based on rou-
tine electronic medical records in primary care, submitted).
We considered all chronic diseases as comorbidities,
regardless whether the disease had been diagnosed before
the COPD diagnosis or thereafter. Apart from all ‘obliga-
tory’ chronic diseases we also included several recurrent dis-
eases (i.e., depression, anxiety, anemia, dyspepsia, urinary
tract infection) which could potentially influence COPD
outcomes. After reaching consensus about these recurrent
comorbidities within the research team, ICPC (sub)codes
were linked (see Appendix 1). Selection of the recurrent co-
morbidities in our population was based on the patient’s
history in terms of these particular ICPC codes. To define
whether a history of ICPC codes was relevant or irrelevant
for the aim of the study, we added specific selection criteria
based on published clinical guidelines for the respective dis-
eases (see Appendix 1).
Finally, a total of 82 chronic comorbid conditions were
selected and included in the analyses. T he comorbidities
were clustered and analyzed based on their ICPC codes into
the following 14 categories: respiratory; cardiovascular;
digestive; endocrine; metabolic /nutrition; musculoskeletal;
neurologic; psychiatric; urogenital; blood (−forming or-
gans)/lymphatics; infectious; eye/ear/skin; non-pulmonary
cancer; and pulmonary cancer. Low prevalence categories
were merged (see Appendix 2). To restrict ourselves, we
focused on conditions with a high prevalence and cardio-
pulmonary comorbidities (other than COPD) with a lower
prevalence (7 conditions, see Table 2). High-prevalent
comorbidities (19 conditions), further referred to as
‘frequent comorbidities’, were defined as being present in
≥5% of the study population. This resulted in a total of 26
comorbidities remaining for further analyses.
Outcomes
The outcomes for the study were (i) prevalence of
comorbidities in the study population, (ii) annual rate of
exacerbations (dichotomized as <2 versus ≥ 2 exacerba-
tions/year based on the cumulated 2012/13 data), and
(iii) time (in days) until first exacerbation. An exacerba-
tion was defined as a prescription of oral corticosteroids
(i.e., prednisolone (ATC H02AB06) or prednisone (ATC
H02AB07)) with a minimum daily dose of 20 mg for a
minimum duration of 5 days and a maximum duration
Westerik et al. Respiratory Research (2017) 18:31 Page 2 of 17
of 15 days (based on Dutch GP guidelines for treatment
of COPD exacerbations [15]). As there is no consensus
in the literature regarding a cut-off to differentiate be-
tween relapse of an earlier exacerbation and a new
exacerbation, [16] we considered a subsequent pred-
niso(lo)ne prescription after an oral corticosteroid-free
interval of ≥14 days since the end-date of the previ-
ous prescription a s a new exacerbation.
Statistical analysis
Analyses were performed with SPSS statistical software
(version 22, IBM SPSS Statistics, Feltham, Middlesex,
UK) and Microsoft Excel 2007 (Microsoft Corporation,
Redmond, Washington, US). Statistically significant
results were defined as p < 0 · 05. Patients’ baseline
characteristics and comorbidity prevalence rates were
calculated. We performed Chi-square tests for catego-
rized variables and independent t-tests for continuous
variables to analyze differences between the subgroups
with <2 and ≥2 exacerbations per year.
We explored associations between comorbidities and
exacerbation risk using univariable analyses. Hazard
ratios for comorbidities were calculated using Cox
regression, in which the time variable consisted of time
to the first exacerbation. Data from patie nts who died or
were otherwise lost to follow up were right-censored.
Subsequently, all frequent and cardiopulmonary comor-
bidities (Table 2), age, and gender were included a s
covariates in multivariate Cox regression analyses. The
model was reduced through backward exclusion to
produce a final model that consisted of only non-
collinear, independently associated, statistically signifi-
cant covariates. The same modeling approach was used
for comorbidity categories using all other categories ,
with age and gender as covariates.
In addition, we performed multivariable logistic
regression analyses to calculate odds ratio’s(ORs)with
the dichotomous indicator variable for exac erbation
frequency (<2 versus ≥2 exacerbations/year) as the
dependent variable. Predictor variables in the logistic
models were: all frequent comorbidities, all cardiopul-
monary comorbidities , gender, and age. This modeling
approach was also used to a nalyze the 14 categorie s of
comorbidity.
Results
Study population
Overall, data of 16,427 subjects diagnosed with COPD
were available for analyses. Of these patients , 1824
(11 · 1%) were lost to follow-up during the 2-year
study period. Reason for loss to follow-up was known
for 800 (44 · 5%) of these patient s, with d eath b eing
the p redominant reason. Table 1 sho ws baseline char-
acteristics of the patients with complete follow-up
(i.e., the final study population, n = 14,603). Mean
(SD) age was 66 · 5 (11 · 5) years and 53% were males.
At baseline, 89 · 1% of patients suffered from ≥1
chronic comorbid conditions , while 23 · 1% had ≥5
comorbidities. Most pre valent comorbid conditions
were hypertension (35 · 2%), coronary heart d isea se
(19 · 2%), osteoarthritis (17 · 6%), diabetes (17 · 3%), and
peripheral vascular disease (14 · 3%). Table 2 shows the
prevalence rates of the frequent and cardiopulmonary
comorbidities. Table 3 shows the prevalence of ICPC-
categorized comorbidities.
During the 2-year study period the mean number of
exacerbations per patient was 0.72 (SD 1 · 5). 68% of
patients had no exacerbation and 5 · 7% had ≥4 exacer-
bations during the study period.
Associations between comorbidities and exacerbation
frequency
Tables 2 and 3 show the univariable associations be-
tween comorbidities and comorbidity categories and
the exacerbation frequency subgroups, respe ctively.
Overa ll, patients w ith one or more comorbid c ond i-
tions more often had ≥2 exacerbations/year compared
to patients without any comorbidity (5 · 9% vs 4·0%,
p = 0 · 001). Patients with any other chronic respira-
tory disease next to their COPD, (n = 2,294, 15 · 7%)
more often h ad ≥2 exacerbations per year compared
to patients without respiratory comorbidity (8 · 2% vs
5·7%, p < 0 · 001).
Univariable logistic regression analysis showed that
COPD patients with pulmonary cancer had 1.81 higher
odds for ≥2 exacerbations per year compared to patients
without pulmonary cancer (Fig. 1, p = 0.002). Patie nts
who, next to their COPD, also suffered from asthma,
blindness or low vision, coronary heart disease, depres-
sion, dyspepsia, heart failure, osteoporosis or osteopenia,
peripheral va scular disease, or prostate disorders, had a
higher risk of having frequent exacerbations compared
to those who did not suffer from these comorbid condi-
tions (Fig. 1).
Table 4 list s the comorbidities and comorbidity
categories significantly associated with having ≥2
exacerbation per year. I n the multivariable logistic re-
gression analysis , among the statistically significant
associations, the highest ORs for having ≥2 e xacerba-
tions per year were observed for pulmonary cancer
(OR 1 · 85; 95% CI 1 · 28–2 · 67), heart failure (OR 1 ·
72; 1 · 38–2 · 14), prostate disorders (OR 1 · 50; 1 · 13–
1 · 98) and blindness/low vision (OR 1 · 46; 1 · 21–1 · 75)
as comorbid conditions (Table 4). Dislipidemia was
not statistically sig nificant, but did show a trend, with
an OR of 0 · 81 (95% CI 0 · 65–1 · 01, p = 0 · 071).
When looking at comorbidity categories, patients
Westerik et al. Respiratory Research (2017) 18:31 Page 3 of 17
with other chronic respiratory conditions (OR 1 · 37;
1·15–1 · 64) and psychiatric comorbidities (OR 1 · 35;
1·13–1·60)wereathighestriskforfrequent
exacerbations.
Time to first exacerbation
Table 5 summarizes the results from the Cox regression
analyses. Among the statistically significant associations,
the comorbid conditions with the highest risk of devel-
oping a first exacerbation were recurrent sinusitis (Cox
hazard ratio 1 · 53; 95% CI, 1 · 05–2 · 24), bronchiectasis/
chronic bronchitis (HR = 1.50; 1.31–1.73) and heart
failure (1 · 41; 1 · 29–1 · 55). For dislipidemia a non-
statistically HR of 0 · 92 was observed (p = 0 · 067, 95%
CI 0 · 85–1 · 00).
Having another chronic respiratory disease beside
COPD was also associated with risk of developing a first
exacerbation (Cox hazard ratio 1 · 26; 1 · 17–1 · 36), see
Fig. 2.
Discussion
In this paper we explored the prevalence of comorbid
chronic conditions and associations with exacerbation
risk in a real-li fe cohort of primary care COPD patients.
Our findings support the notion that comorbidities are
rather rule than exception in patients with COPD [4],
with 88% having at least one other chronic disease.
Several comorbidities were associated with having fre-
quent exacerbations, with heart failure, blindness/low
vision and pulmonary cancer showing the strongest
associations in terms of statistical significance. In con-
trast, diabetes was associated with a lower risk of having
frequent exacerbations. Bronchiectasis/chronic bron-
chitis, heart failure and depression were the strongest
predictors for developing a new exacerbation.
Table 1 Baseline characteristics of the COPD study population grouped by low (<2/year) versus high (≥2/year) exacerbation rate
Patients with full follow-up (study population)
a
(n = 14,603)
Subgroups of study population
Patient characteristics Patients with <2 exacerbations/year
(n = 13,709)
Patients with ≥2exacerbations/year
(n = 894)
b
Sex, male, n (%) 7,749 (53 · 1) 7,322 (53 · 4) 427 (47 · 8)
‡
Age at study baseline, years;
mean (SD; range)
66 · 5 (11 · 5; 40–110)
‡
66 · 5 (11 · 6; 40–110) 67 · 4 (10 · 3; 40–93)
‡
Full dataset available (censored data), n (%)
Full data available 13,709 (93 · 9) 894 (6 · 1)
Deceased N/A N/A N/A
Moved N/A N/A N/A
Nursing home N/A N/A N/A
Unknown N/A N/A N/A
Comorbidity data
Number of comorbid
diseases
c
, mean (SD; range)
3 · 0 (2 · 3;0–20)
‡
3 · 0 (2 · 3;0–16) 3 · 4 (2 · 5; 0–20)
‡
Number of comorbid diseases categories
c
, n (%)
0 1,777 (12 · 2) 1,700 (12 · 4) 77 (8 · 6)
1 or 2 5,305 (36 · 6) 5,021 (36 · 6) 284 (31 · 8)
3 or 4 4,258 (29 · 2) 3,977 (29 · 0) 281 (31 · 4)
5 and more 3,263 (22 · 3)
‡
3,011 (22 · 0) 252 (28 · 2)
‡
Exacerbations
Number of exacerbations
d
,
mean (SD; range)
0 · 75 (1 · 5;0–15)
‡
0 · 44 (0 · 8;0–2) 5 · 6 (2 · 0;3–15)
‡
SD standard deviation, N/A not applicable
*
p < 0.05,
†
p < 0.01,
‡
p < 0.001
a
p-values displayed are calculated for the difference between patients lost to follow-up versus patients with full follow-up. Chi-square tests for categorized variables and
independent t-tests for continuous variables. p < 0 · 05 was considered statistically significant
b
p-values displayed are calculated for thedifferencebetweenthesubgroups<2versus ≥2 exacerbations/year. Chi-square tests for categorized variables
and independent t-tests for continuous variables. p < 0 · 05 was considered statistically significant
c
presence of any type of comorbid disease was assessed at study baseline, i.e., 1 January 2012
d
Mean number of exacerbations during the study period, 1 January 2012 – 31 December 2013
Baseline characteristics of the initial population of all COPD patients (n = 16,427) and those who were lost to follow-up (n = 1,824) are reported in Appendix 3
Westerik et al. Respiratory Research (2017) 18:31 Page 4 of 17
Comparison with existing literature
Previous research ha s s hown that cardiovascular, psy-
chiatric, and metabolic comorbidity are highly preva-
lent in COPD patients, [8, 17] and o ur result s
confirm these findings. In addition to the finding by
Rutten et al. [18] tha t unrecognized heart failure is
rather common in elderly patients with stable COPD,
our data also indicate that heart failure may increase
the risk of having frequent exacerbations. Rec ent clin-
ical trial data have shown correlations between several
comorbidities and mortality risk if a COPD patient is
admitted to hospital with an acute exacerbation [19, 20].
Our observations support the association between
chronic comorbidity and exacerbation risk in a pri-
mary care study population, i.e., the COPD popula-
tion witho ut selection of any kind , which is
unprecedented and impossible to derive from clinical
trial populations [21].
We observed a trend towards statistical significance
that COPD patients with dislipidemia had less frequent
exacerbations compared to patients without dislipidemia
(HR 0.92; p = 0.067). This observation seems to be in
line with findings by Ingebrigtsen et al., who recently re-
ported that statin use for treatment of dislipidemia was
associated with reduced odds of exacerbations in indi-
viduals with COPD [22] and findings by Chan et al. that
Table 2 Prevalence of frequent and cardiopulmonary comorbidity in the study population, sorted from highest to lowest
prevalence rate
Total study population
a
,
(n = 14,603)
Patients with <2 exacerbations/year,
(n = 13,709)
Patients with ≥2 exacerbations/year,
(n = 894)
p-value
b
Frequent comorbidity
Hypertension 5,116 (35 · 0) 4,805 (35 · 2) 311 (34 · 8) 0 · 873
Coronary heart disease 2,759 (18 · 9) 2,569 (18 · 7) 191 (21 · 4) 0 · 051
Osteoarthritis 2,570 (17 · 6) 2,402 (17 · 5) 168 (18 · 8) 0 · 334
Diabetes 2,464 (16 · 9) 2,330 17 · 0) 134 (15 · 0) 0 · 120
Peripheral vascular disease 2,031 (13 · 9) 1,897 (14 · 8) 150 (16 · 8) 0 · 006
Blindness & low vision 1,938 (13 · 3) 1,772 (12 · 9) 166 (18 · 6) <0 · 001
Dyspepsia, gastroesophageal reflux 1,845 (12 · 6) 1,703 (12 · 4) 142 (15 · 9) 0 · 003
Dislipidemia 1,703 (11 · 7) 1,613 (11 · 8) 90 (10 · 1) 0 · 125
Stroke & transient ischaemic attack 1,357 (9 · 3) 1,259 (9 · 2) 98 (11 · 0) 0 · 076
Chronic kidney diease 1,360 (9 · 3) 1,263 (9 · 2) 97 (10 · 9) 0 · 103
Asthma 1,305 (8 · 9) 1,202 (8 · 8) 103 (11 · 5) 0 · 005
Hearing loss 1,144 (7 · 8) 1,078 (7 · 9) 66 (7 · 4) 0 · 604
Heart failure 1,048 (7 · 2) 943 (6 · 9) 105 (11 · 7) <0 · 001
Atrial fibrillation 1,044 (7 · 1) 964 (7 · 0) 80 (8 · 9) 0 · 031
Skin cancer 913 (6 · 3) 862 (6 · 3) 51 (5 · 7) 0 · 485
Osteoporosis/osteopenia 884 (6 · 1) 801 (5 · 8) 83 (9 · 3) <0 · 001
Thyroid disorder 808 (5 · 5) 757 (5 · 5) 51 (5 · 9) 0 · 817
Depression 800 (5 · 5) 729 (5 · 3) 71 (7 · 9) 0 · 001
Prostate disorders 784 (5 · 4) 719 (5 · 2) 65 (7 · 3) 0 · 009
Cardiopulmonary comorbidity
Heart valve disease 568 (3 · 9) 528 (3 · 9) 40 (7 · 8) 0 · 035
Bronchiectasis/chronic bronchitis 414 (2 · 8) 379 (2 · 8) 35 (3 · 9) 0 · 045
Pulmonary cancer 317 (2 · 2) 284 (2 · 1) 33 (3 · 7) 0 · 001
Sleep apneu syndrome 173 (1 · 2) 161 (1 · 2) 12 (1 · 3) 0 · 653
Other chronic pulmonary disease 157 (1 · 1) 148 (1 · 1) 9 (1 · 0) 0 · 838
Recurrent sinusitis 54 (0 · 4) 49 (0 · 4) 55 (6 · 2) 0 · 335
Congenital cardiovascular anomaly 32 (0 · 2) 28 (0 · 2) 4 (0 · 4) 0 · 132
a
COPD populat ion with complete data available, patients lost to follow-up (n = 1,824) excluded
b
p-values displayed are calculated for the difference between the subgroup <2 versus ≥2 exacerbations/year Chi-square tests for categorized variables. p <0·05
was considered statistically significant
Westerik et al. Respiratory Research (2017) 18:31 Page 5 of 17