Inflammatory Biomarkers and Comorbidities in Chronic
Obstructive Pulmonary Disease
Mette Thomsen1,2, Morten Dahl1,2,3, Peter Lange2,4,5,6, Jørgen Vestbo7,8, and Børge G. Nordestgaard1,2,4
1Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev,
Denmark;2Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;3Department of Clinical Biochemistry,
Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark;4The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen
University Hospital, Copenhagen, Denmark;5Respiratory Section, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre, Denmark;
6Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen, Denmark;7Department of Respiratory
Medicine, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and8Respiratory Research Group, Manchester Academic
Health Science Centre, University Hospital South Manchester National Health Service Foundation Trust, Manchester, United Kingdom
Rationale: Patients with chronic obstructive pulmonary disease
(COPD) have evidence of systemic inflammation that may be impli-
cated in the development of comorbidities.
matory biomarkers are associated with increased risk of comorbid-
ities in COPD.
hospital admissions due to major comorbidities as endpoints.
Measurements and Main Results: We measured baseline C-reactive
hip fracture, and depression for all participants. Multifactorially ad-
justed risk of ischemic heart disease was increased by a factor of 2.19
(95% confidence interval, 1.48–3.23) in individuals with three bio-
markers elevated (CRP . 3 mg/L, fibrinogen . 14 mmol/L, and leuko-
cyte count. 9 3 109/L) versus individualswith allthree biomarkersat
or below these limits. Corresponding hazard ratios were 2.32 (1.34–
4.04) for myocardial infarction, 2.63 (1.71–4.04) for heart failure, 3.54
(2.03–6.19) for diabetes, 4.00 (2.12–7.54) for lung cancer, and 2.71
of pulmonary embolism, hip fracture, or depression as a function of
these three biomarkers.
clinicians to conduct stratified management of comorbidities in COPD.
Keywords: chronic obstructive pulmonary disease; comorbidities; in-
Chronic obstructive pulmonary disease (COPD) is associated
with an enhanced inflammatory response by the lungs to inhaled
particles and gases, particularly cigarette smoke (1). Also, patients
with COPD have increased levels of circulating cytokines, acute
phase proteins, and inflammatory cells, indicating the presence
of additional systemic inflammation (2–7). Such systemic in-
flammation may be implicated in the development of comorbid-
ities in COPD (5, 6), such as cardiovascular disease, diabetes,
lung cancer, pneumonia, pulmonary embolism, hip fracture, and
depression (8–12). C-reactive protein (CRP), fibrinogen, and
leukocyte count are biomarkers of systemic inflammation that
are commonly used to monitor disease in patients with COPD.
Also, these biomarkers have in a number of studies been reported
to be elevated in COPD (3). Thus, elevated levels of any or all of
these three biomarkers may be associated with increased risk of
development of comorbidities in patients with COPD.
We tested the hypothesis that elevated levels of CRP, fibrin-
ogen, and/or leukocyte count associate with increased risk of
comorbidities in COPD. For this purpose we measured baseline
CRP, fibrinogen, and leukocyte count in 8,656 patients with
COPD from two large population-based studies consisting of
(Received in original form June 25, 2012; accepted in final form August 23, 2012)
Supported by Herlev Hospital, Copenhagen University Hospital, The Danish Lung
Foundation, The Danish Heart Foundation, Copenhagen County Foundation,
and University of Copenhagen, all from Denmark. The funding sources had no
role in the design and conduct of the study, in the collection, management,
analysis, and interpretation of the data, or in the preparation, review, or approval
of the manuscript.
Author Contributions: M.D., P.L., J.V., and B.G.N. designed the study. M.T. col-
lected data and performed all analysis. M.D., P.L., J.V., and B.G.N. oversaw all
analysis and contributed to the interpretation of data. M.T. wrote the first draft of
the paper. M.D., P.L., J.V., and B.G.N. edited the paper, and all authors approved
this paper in its final form.
Correspondence and requests for reprints should be addressed to Børge G.
Nordestgaard, M.D., D.M.Sc., Department of Clinical Biochemistry, Herlev Hospi-
tal, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med
Copyright ª 2012 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201206-1113OC on September 13, 2012
Internet address: www.atsjournals.org
Vol 186, Iss. 10, pp 982–988, Nov 15, 2012
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Chronic obstructive pulmonary disease (COPD) is associ-
ated with an enhanced inflammatory response by the lungs
to inhaled particles and gases, particularly cigarette smoke.
Also, patients with COPD have increased levels of circu-
lating cytokines, acute phase proteins, and inflammatory
systemic inflammation may be implicated in the develop-
ment of comorbidities in COPD.
What This Study Adds to the Field
We tested the hypothesis that elevated levels of three in-
flammatory biomarkers are associated with increased risk of
comorbidities in COPD by examining 8,656 patients with
COPD from two large Danish population studies. During
a median 5 years’ follow-up, we recorded hospital admis-
sions due to major comorbidities as endpoints. We found
that simultaneously elevated levels of CRP, fibrinogen, and
leukocyte count are associated with a two- to fourfold risk
of major comorbidities in COPD. These biomarkers may
be an additional tool for clinicians to conduct stratified
management of comorbidities in patients with COPD.
more than 70,000 participants. During a median of 5 years’
follow-up, we recorded hospital admissions and deaths due to
ischemic heart disease, myocardial infarction, heart failure, diabe-
tes, lung cancer, pneumonia, pulmonary embolism, hip fracture,
and depression for use as endpoints. We examined combinations
of the three biomarkers and stratified analyses according to grades
of COPD defined in accordance with Global Initiative for Chronic
Obstructive Lung Disease (GOLD) (1). Finally, we calculated
absolute 5-year risks and in addition retested the hypothesis
using the lower limit of normal in the definition of COPD as
a sensitivity analysis.
We studied age-stratified randomly selected white individuals from the
CopenhagenCity Heart Study and the CopenhagenGeneral Population
Study (13–15), two similar studies recruiting individuals from the adult
Danish general population; there was no overlap of participants be-
tween studies. Individuals were selected on the basis of the national
Danish Civil Registration System to reflect the population aged 20 to
100 years. The studies were approved by Herlev Hospital and Danish
ethical committees. Written informed consent was obtained from all
participants. The participants were analyzed as one collective cohort to
obtain maximal statistical power.
The Copenhagen City Heart Study is a prospective population study
initiatedin 1976.At each examination,participants filled out a question-
naire and had physical measurements taken. During the 1991 to 1994
and the 2001 to 2003 examination, 9,995 individuals had spirometry per-
formed and plasma levels of CRP and fibrinogen measured. In addition,
1,753 of the individuals from the 2001 to 2003 examination had leuko-
cyte count measured.
The Copenhagen General Population Study is a prospective popu-
lation study initiated in 2003 and still recruiting participants. Data on
each participant collected in this study are identical to those in the
Copenhagen City Heart Study. Between 2003 and 2009, 60,005 individ-
uals had spirometry performed and plasma levels of CRP, fibrinogen,
and leukocyte count measured.
After excluding 475 individuals younger than 40 years with self-
reported asthma, we had 69,525 individuals available for analyses in
thetwostudies.Of these,8,656individuals hadCOPD,definedasa ratio
between FEV1and FVC less than 0.7, and had all three biomarkers
measured. Numbers of individuals included in analysis of each bio-
marker separately and in combination are seen in Table E1 in the
FEV1and FVC were determined without inhalation of a bronchodilator
using a dry wedge spirometer (Vitalograph; Maids Moreton, Bucking-
hamshire, UK) in the Copenhagen City Heart Study and an EasyOne
Spirometer (ndd Medizintechnik, Zurich, Switzerland) in the Copen-
hagen General Population Study. Reference values for FEV1and the
lower limit of normal for FEV1/FVC (5th percentile of a frequency
distribution) were internally derived for men and women separately
in a subsample of healthy never smokers using linear and quantile
regression with age and height as covariates. COPD was defined as
FEV1/FVC less than 0.7 and was grouped according to GOLD (1):
GOLD 1 to 2 with FEV1% predicted greater than or equal to 50%
and GOLD 3 to 4 with FEV1% predicted less than 50%. For sensi-
tivity analyses, COPD was defined as FEV1/FVC below the lower limit
Plasma levels of high-sensitivity CRP, fibrinogen, and whole blood leu-
kocyte count were measured using standard hospital assays at a central
laboratory. The samples were analyzed in real time except for plasma
levels of CRP in the 1991 to 1994 examination of the Copenhagen City
Heart Study, which were measured on plasma frozen at 2808C for 12 to
To test the hypothesis that elevated levels of these three biomarkers
associate with increased risk of comorbidities in COPD, we defined clin-
ically useful cut-points for each biomarker. Although categorization may
lead to loss of information compared with using the biomarkers as a con-
tinuous variable, we used these cut-points because they are simple and
clinically useful. CRP levels were categorized using two cut-points, 1
and 3 mg/L, that previously have been used by us and others in
cardiovascular/pulmonary medicine (4, 7, 15). We next defined equiva-
lent cut-points for fibrinogen and leukocyte count: 9 and 14 mmol/L for
fibrinogen and 6 and 9 3 109/L for leukocyte count, so that the numbers
in each of the low groups for each biomarker were roughly the same.
In the combined analyses, levels of CRP, fibrinogen, and leukocyte count
were defined as high or low according to cut-points of 3 mg/L for CRP,
14 mmol/L for fibrinogen, and 9 3 109/L for leukocyte count. If the three
biomarkers were divided into tertiles or quintiles, results were largely
similar to those presented. Leukocyte count was not determined in the
1991 to 1994 examination of the Copenhagen City Heart Study, explain-
ing the lower number of individuals included in these analyses.
On a subset of individuals (n ¼ 430) from the Copenhagen City
Heart Study 1991 to 1994 and 2001 to 2003 examinations, we had
replicate measurements of CRP and fibrinogen. The stability of these
biomarkers over this 10-year period is shown in Figure E1. Due to
combined effects of measurement errors, long-term fluctuations, and
changes within persons, these values tend to attenuate toward the ac-
tual mean over time, and this may underestimate true associations (16).
Risk estimates can be corrected for this regression dilution bias when
examining biomarkers separately. However, it is not possible to apply
this correction when biomarkers are analyzed in combination, and we
have therefore not corrected for this in the presented analyses.
heart failure, type II diabetes, lung cancer, pneumonia, pulmonary embo-
lism, hip fracture, and depression was collected by reviewing all hospital
the national Danish Cancer Registry, and the national Danish Causes of
Death Registry. Records include admission and/or death date and diag-
noses according to the World Health Organization International Classi-
fication of Diseases (ICD8 or ICD10). All individuals with records of
ischemic heart disease (ICD8: 410–414; ICD10: I20–I25), myocardial
infarction (ICD8: 410; ICD10: I21–I22), heart failure (ICD8: 427.09–
427.11; ICD10: I50), type II diabetes (ICD8: 250; ICD10: E11, E13,
E14), lung cancer (ICD10: C34), pneumonia (ICD8: 480–486; ICD10:
J12–J18), pulmonary embolism (ICD8: 450.99, 673.99; ICD10: I26.0,
I26.9, O88.2), hip fracture (ICD8: 820; ICD10: S720–S722), and depres-
sion (ICD8: 296.0, 296.2, 298.0, 300.4; ICD10: F32–F33) from study entry
to end of follow-up in May 2011 were considered as having an event. If
an individual had multiple records of one endpoint, the first occurrence
was considered the event. The data obtained from the national Danish
Causes of Death Registry report death from all comorbidities; the Na-
tional Danish Cancer Registry describes death/hospitalization from can-
cer comorbidities. However, data from the Danish Patient Registry
combine hospitalization from or with comorbidities.
Participants were categorized as current smokers, former smokers, or
never smokers. Cumulative tobacco consumption was calculated in
pack-years, defined as 20 cigarettes/d/yr or equivalent. Body mass index
squared (meters squared). Hypertension was self-reported use of antihy-
pertensive medication. Plasma levels of total cholesterol, triglycerides, and
assays. A COPD exacerbation was defined as hospitalization from COPD
(ICD8: 490–492; ICD10: J44) and/or respiratory failure (ICD10: J96) in
patients with COPD. Exacerbation rate per year was number of exacer-
bations for each individual divided by years of follow-up.
Statistical analyses were performed using STATA/SE version 11.1. We
useda Cox proportionalhazardsregressionmodel with age as time scale
Thomsen, Dahl, Lange, et al.: Inflammation and Comorbidities in COPD983
to estimate hazard ratios with 95% confidence intervals (CIs). The pro-
portional hazard assumption was judged by visual inspection of cumu-
lative hazard logarithm plots against age; no major violations were
observed. For each endpoint, individuals with events before study entry
and cumulative tobacco consumption or multifactorially for age, sex,
smoking status, cumulative tobacco consumption, body mass index, hy-
pertension, cholesterol, triglycerides, and high-density lipoprotein cho-
lesterol. The first model was included to avoid overadjustment of
estimates for endpoints such as lung cancer and pneumonia, where con-
ventional cardiovascular risk factors included in the multifactorially ad-
justed model may be of limited importance. Continuous covariates were
grouped into deciles before analyses. For test for trend of risk estimates,
groups based on increasing levels of CRP, fibrinogen, and/or leukocyte
count were coded 1, 2, 3, etc. Absolute 5-year risk by groups of the three
biomarkers was estimated using the regression coefficients from a Pois-
son regression model (17).
Numbers of individuals with missing values for covariates are seen in
Table E2. For continuous covariates, missing values were imputed using lin-
Baseline characteristicsofthe8,656 participantswithCOPDiden-
tified by FEV1/FVC less than 0.7 with measurements of all three
biomarkers are shown in Table 1. As expected, individuals with
GOLD 3 to 4 were older, more likely to be male and current
smokers, had higher cumulative tobacco consumption, and had
higher levels of inflammatory biomarkers than individuals with
GOLD 1 to 2. Defining COPD by FEV1/FVC below the lower
limit of normal identified 6,555 individuals, who were younger,
more likely to be current smokers, and had lower FEV1%
predicted than individuals identified by FEV1/FVC less than 0.7
(Table E3). During a median of 5 years’ follow-up of the 8,656
participants with COPD, 368 individuals were diagnosed with
ischemic heart disease, 179 with myocardial infarction, 292 with
heart failure, 143 with type II diabetes, 93 with lung cancer, 657
with pneumonia, 92 with pulmonary embolism, 141 with hip
fracture, and 84 with depression. Number of individuals with
diagnosed comorbidities before study entry is seen in Table 2.
Characteristics of participants according to groups of CRP, fi-
brinogen, and leukocyte count are shown in Tables E4 to E6.
One Inflammatory Biomarker
Risk of ischemic heart disease, myocardial infarction, heart fail-
ure, type II diabetes, lung cancer, and pneumonia was increased
by factors of 1.69 to 1.94 in individuals with CRP greater than
3 mg/L versus individuals with CRP less than 1 mg/L in multi-
factorially adjusted models (P for trend < 0.006) (Figure E2).
There were no differences in risk of pulmonary embolism, hip
fracture, and depression by levels of CRP (P for trend, 0.09–
0.86). Slightly different results were seen for fibrinogen and
leukocyte count (Figures E3 and E4).
Three Inflammatory Biomarkers
To see whether high levels of three biomarkers in combination
aided in identifying individuals at increased risk of comor-
bidities, we divided individuals into groups according to com-
binations of CRP, fibrinogen, and leukocyte count. Risk of
TABLE 1. BASELINE CHARACTERISTICS OF STUDY PARTICIPANTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE
COPD by FEV1/FVC , 0.70
GOLD 1–4GOLD 1–2 (FEV1% Predicted > 50%)GOLD 3–4 (FEV1% Predicted , 50%)
Current smokers, %
Former smokers, %
Cumulative tobacco consumption, pack-years
Body mass index, kg/m2
High-density lipoprotein cholesterol, mmol/L
C-reactive protein, mg/L
Leukocyte count, 3109/L
65 (57–74)65 (56–74) 69 (62–76)
53 54 48
75 (61–86)77 (66–87) 42 (36–46)
Definition of abbreviations: COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease. Values are median
(interquartile range) for continuous variables and frequencies for categorical variables. Characteristics were collected at study entry.
TABLE 2. NUMBER OF INDIVIDUALS WITH COMORBIDITIES BEFORE STUDY ENTRY IN PARTICIPANTS WITH CHRONIC
OBSTRUCTIVE PULMONARY DISEASE
COPD by FEV1/FVC , 0.70
GOLD 1–4GOLD 1–2 (FEV1% Predicted > 50%)GOLD 3–4 (FEV1% Predicted , 50%)
Ischemic heart disease
Type II diabetes
984AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1862012
ischemic heart disease was 2.19 (95% CI, 1.48–3.23) in individ-
uals with three biomarkers elevated (CRP . 3 mg/L, fibrinogen
. 14 mmol/L, and leukocyte count . 9 3 109/L) compared with
individuals with all three biomarkers at or below these limits in
multifactorially adjusted models (Figure 1). Corresponding haz-
ard ratios were 2.32 (1.34–4.04) for myocardial infarction, 2.63
(1.71–4.04) for heart failure, 3.54 (2.03–6.19) for diabetes, 4.00
(2.12–7.54) for lung cancer, and 2.71 (2.03–3.63) for pneumonia
(P for trend < 0.002). There were no overall differences in risk
of pulmonary embolism, hip fracture, and depression by combi-
nations of the three biomarkers (P for trend, 0.17–0.75); how-
ever, risk of hip fracture was 2.14 (1.19–3.85) in those with three
high biomarkers versus individuals with three low biomarkers.
For each endpoint, individuals with an event before study entry
were excluded. If individuals with an event in the first year of
follow-up were excluded, results were similar to those presented
Figure 1. Risk of ischemic heart
disease, myocardial infarction,
heart failure, type II diabetes,
lung cancer, pneumonia, pul-
monary embolism, hip fracture,
and depression according to lev-
els of three inflammatory bio-
markers in individuals from the
general population with chronic
obstructive pulmonary disease.
Plasma C-reactive protein and
fibrinogen and blood leukocyte
count were defined as high or
low according to cut-points of
3 mg/L, 14 mmol/L, and 9 3
109/L, respectively. Hazard ratios
(HRs) were adjusted either for
age, sex, smoking status, and
cumulative tobacco consump-
tion or multifactorially for age,
sex, smoking status, cumulative
mass index, hypertension, cho-
lesterol, triglycerides, and high-
density lipoprotein cholesterol.
Individuals with events before
study entry were excluded for
each endpoint, explaining the
difference in number of partici-
pants. CI ¼ confidence interval.
Thomsen, Dahl, Lange, et al.: Inflammation and Comorbidities in COPD985
(Figure E5). Also, exclusion of individuals with a record of any
of the nine endpoints before study entry (n ¼ 1,898) did not
change main results (Figure E6).
Individuals with three high biomarkers had increased rates of
severe exacerbations per year during follow-up compared with
individuals with three low biomarkers (Table E7). If we excluded
individuals with exacerbations in the year before date of exami-
nation (data not shown), or adjusted for exacerbation rate during
follow-up, results were similar to those presented (Figure E7).
In stratified analyses, risk estimates for ischemic heart disease,
nia in individuals with GOLD 1 to 2 remained statistically signif-
icantly increased and were similar to those presented in Figure 1
(Figure 2). A similar trend was observed for ischemic heart dis-
ease, myocardial infarction, heart failure, type II diabetes, and
pneumonia in individuals with GOLD 3 to 4; however, not all risk
estimates were statistically significant, and confidence intervals
were wider due to the reduced statistical power. For lung cancer,
risk was increased a factor of 5.76 (95% CI, 2.76–12.02), whereas
there were no significant differences in GOLD 3 to 4.
In sensitivity analyses using FEV1/FVC below the lower limit
of normal as COPD definition, risk estimates were similar to
those presented in Figure 1 (Figure E8). Also, stratifying for
smoking status showed similar results (Figure E9).
There was a stepwise increase in the absolute 5-year risk of is-
chemic heart disease, myocardial infarction, heart failure, type
II diabetes, lung cancer, and pneumonia across groups of the
three biomarkers combined in never smokers, formers smokers,
and current smokers (Figure 3). In former smokers, the absolute
5-year risk for ischemic heart disease was 14% in individuals
with three high biomarkers and 5% for individuals with three
low biomarkers. Corresponding numbers were 7% and 2% for
myocardial infarction, 11% and 4% for heart failure, 8% and
1% for type II diabetes, 5% and 1% for lung cancer, and 21%
and 8% for pneumonia. In current smokers, numbers were sim-
ilar but attenuated for all endpoints except lung cancer, where
the absolute 5-year risk was 7% in individuals with three high
biomarkers and 2% for individuals with three low biomarkers.
Similar results were seen across age groups and body mass index
categories (Figures E10 and E11).
This study examined baseline measurements of CRP, fibrinogen,
and leukocyte count in 8,656 individuals with COPD from two
large population studies. We found that increased levels of these
three inflammatory biomarkers in combination were associated
Figure 2. Risk of ischemic heart disease, myocardial infarction, heart failure, type II diabetes, lung cancer, and pneumonia according to levels of
three inflammatory biomarkers in individuals from the general population with chronic obstructive pulmonary disease, by stages defined in
accordance with Global Initiative for Chronic Obstructive Lung Disease (GOLD). Plasma C-reactive protein and fibrinogen and blood leukocyte
count were defined as high or low according to cut-points of 3 mg/L, 14 mmol/L, and 9 3 109/L, respectively. Hazard ratios (HRs) were adjusted
multifactorially for age, sex, smoking status, cumulative tobacco consumption, body mass index, hypertension, cholesterol, triglycerides, and high-
density lipoprotein cholesterol. Individuals with events before study entry were excluded for each endpoint, explaining the difference in number of
participants. GOLD 1 to 2 was FEV1% predicted > 50%; GOLD 3 to 4 was FEV1% predicted , 50%. CI ¼ confidence interval.
986AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1862012
with increased risk of ischemic heart disease, myocardial infarc-
tion, heart failure, type II diabetes, lung cancer, and pneumonia
in individuals with COPD. Risk estimates were largely indepen-
dent of smoking and ranged from a 2.2-fold increased risk of is-
chemic heart disease to a 4.0-fold increased risk of lung cancer
when comparing individuals with three high biomarkers versus
low values of these three biomarkers. These findings are novel.
The association between COPD and its comorbidities may be
caused by common risk factors, such as smoking. However, stud-
ies taking smoking and similar factors into account still find
a robust association (18). Several studies have suggested that
common inflammatory pathways might be the link between
COPD and its comorbidities (6, 18, 19), although the exact bi-
ological mechanisms remain unclear. In support of this hypoth-
esis, studies from the non-COPD population show that high
levels of CRP associate with increased risk of ischemic heart
disease (15), cancer (20), and depression (21). However, it
seems that for some diseases (e.g., depression) associations ap-
parent in the non-COPD population cannot be reproduced in
our COPD population. One explanation could be that the state
of low-grade inflammation in patients with COPD due to pul-
monary manifestations alone masks the associations otherwise
found in healthy individuals. In any case, markers of systemic
inflammation seem to be valuable in identifying patients with
COPD at increased risk of cardiovascular disease, type II dia-
betes, lung cancer, and pneumonia, as seen in our study.
endpoints except lung cancer, suggesting that findings are indepen-
dent of lung function. In line with this, a recent study found that
persistent systemic inflammation in patients with COPD associate
pared with noninflamed patients despite similar lung function im-
pairment in the two groups (22). The lack of significant association
for lung cancer in GOLD 3 to 4 and the wider confidence intervals
in general in GOLD 3 to 4 are most likely due to lower power.
Also, frequent exacerbations, infections, and medication in these
individuals (23) may affect levels of inflammatory biomarkers (6,
24); thus, associations apparent in GOLD 1 to 2 may not be seen in
GOLD 3 to 4 due to much lower number of individuals in the
latter subgroup. Elevated levels of CRP have previously been as-
sociated with increased risk of pulmonary embolism, hip fracture,
and depression in general population studies (21, 25–27), but we
were not able to find these associations in our COPD cohort. One
explanation could be that the degree of systemic inflammation in
COPD blurs these associations or that inflammation perhaps plays
a limited role in the pathophysiology for these diseases.
Some limitations of our study must be considered in evaluat-
ing our results. Despite including several important potential
confounders in the Cox regression model, such as cumulative to-
bacco consumption and smoking status, we cannot exclude that
our results might be influenced by residual confounding. An-
other limitation is that we only had prebronchodilator measure-
ments available. Also, recruitment of patients with COPD from
the general population could lead to selection bias due to possi-
but this would tend to draw the results in a direction toward the
null hypothesis and cannot explain our positive results. Another
limitation is that our results have not been validated externally.
Figure 3. Absolute 5-year risk of ischemic heart
disease, myocardial infarction, heart failure, type
II diabetes, lung cancer, and pneumonia in per-
centage, by levels of three inflammatory bio-
markers and smoking status. Plasma C-reactive
protein and fibrinogen, and blood leukocyte
count were defined as high or low according to
cut-points of 3 mg/L, 14 mmol/L, and 9 3 109/L,
Thomsen, Dahl, Lange, et al.: Inflammation and Comorbidities in COPD 987
Also, we were not able to correct for regression dilution bias,
(16); however, lack of such correction will only tend to underes-
timate real risk associations. We have not corrected P values for
multiple comparisons, but all major findings remained statistically
significant if results were Bonferroni corrected for the tests per-
formed on the nine parallel endpoints.
Comorbidities contribute to poor health outcome in COPD,
with cardiovascular disease and lung cancer being leading causes
of morbidity and mortality in patients with COPD (12, 28–30).
Thus, early detection and treatment of comorbidities will have
beneficial effects on the clinical course of individuals with COPD.
However, due to an extensive overlap of symptoms (e.g., with dys-
pnea in heart failure and weight loss in lung cancer), it may
be difficult to distinguish between symptoms related to comor-
bidities from those related to COPD itself. Therefore, measure-
ments of CRP, fibrinogen, and leukocyte count in patients with
COPD may, in addition to the usual clinical examination and
assessment of traditional risk factors, help select individuals
with increased risk and need of additional diagnostic evaluation.
This is especially relevant for cardiovascular disease and type
II diabetes, where prophylactic approaches are feasible and ef-
fective, and for lung cancer, where early detection by computed
tomography screening will improve prognosis (31).
In conclusion, simultaneously elevated levels of CRP, fibrin-
ogen, and leukocyte count are associated with a two- to fourfold
risk of major comorbidities in COPD. These biomarkers may be
of comorbidities in patients with COPD.
Author disclosures are available with the text of this article at www.atsjournals.org.
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