Content uploaded by Gonzalo Valdivia
Author content
All content in this area was uploaded by Gonzalo Valdivia on Jun 18, 2018
Content may be subject to copyright.
The chronic bronchitis phenotype in
subjects with and without COPD: the
PLATINO study
Maria Montes de Oca*, Ronald J. Halbert
#
, Maria Victorina Lopez
"
,
Rogelio Perez-Padilla
+
, Carlos Ta
´lamo*, Dolores Moreno*, Adrianna Muin
˜o
"
, Jose
´
Roberto B. Jardim
1
, Gonzalo Valdivia
e
, Julio Pertuze
´** and Ana Maria B. Menezes
##
ABSTRACT: Little information exists regarding the epidemiology of the chronic bronchitis
phenotype in unselected chronic obstructive pulmonary disease (COPD) populations. We
examined the prevalence of the chronic bronchitis phenotype in COPD and non-COPD subjects
from the PLATINO study, and investigated how it is associated with important outcomes.
Post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ,0.70 was used to
define COPD. Chronic bronchitis was defined as phlegm on most days, at least 3 months per year
for o2 yrs. We also analysed another definition: cough and phlegm on most days, at least
3 months per year for o2 yrs.
Spirometry was performed in 5,314 subjects (759 with and 4,554 without COPD). The proportion
of subjects with and without COPD with chronic bronchitis defined as phlegm on most days, at
least 3 months per year for o2 yrs was 14.4 and 6.2%, respectively. Using the other definition the
prevalence was lower: 7.4% with and 2.5% without COPD. Among subjects with COPD, those with
chronic bronchitis had worse lung function and general health status, and had more respiratory
symptoms, physical activity limitation and exacerbations.
Our study helps to understand the prevalence of the chronic bronchitis phenotype in an
unselected COPD population at a particular time-point and suggests that chronic bronchitis in
COPD is possibly associated with worse outcomes.
KEYWORDS: Asthma, chronic cough, chronic obstructive pulmonary disease, epidemiology
Chronic bronchitis has been defined as
the presence of productive cough for
3 months in two successive years in a
patient in whom other causes of chronic cough,
such as tuberculosis, lung cancer and heart fai-
lure, have been excluded [1, 2]. Chronic bron-
chitis is a common feature associated with
cigarette smoking [3]. Although chronic produc-
tive cough is considered a major manifestation in
chronic obstructive pulmonary disease (COPD)
and is thought to affect ,30–40% of patients,
in reality there is limited information about
the prevalence of chronic bronchitis in COPD
patients.
Earlier studies did not show a relationship between
chronic bronchitis and COPD incidence but sub-
sequent studies suggest that chronic bronchitis may
represent an early marker of susceptibility to the
effects of cigarette smoking and may identify a
subgroup of patients with an increased risk of
developing COPD [4–7]. Recent studies provide
data of chronic bronchitis prevalence in large
selected COPD populations [8, 9]. However, little
information is available regarding the epide-
miological aspects of this COPD phenotype in
unselected populations. The prevalence of COPD
in patients with or without chronic bronchitis and
the factors associated with the chronic bronchitis
phenotype have been assessed in a population-
based survey of COPD conducted in China [10].
This group found that ,30% of patients with
COPD had chronic bronchitis, and most of these
patients were underdiagnosed.
There has been an increased understanding that
that chronic bronchitis is not just an innocent
disorder and, when present in COPD, could be
AFFILIATIONS
*Servicio de Neumonologı
´
a, Hospital
Universitario de Caracas, Facultad de
Medicina, Universidad Central de
Venezuela, Caracas, Venezuela,
#
UCLA School of Public Health, Los
Angeles, CA, USA,
"
Universidad de la Repu
´blica,
Facultad de Medicina, Hospital
Maciel, Montevideo, Uruguay,
+
Institute of Respiratory Diseases,
Mexico City, Mexico,
1
Federal University of Sa
˜o Paulo, Sa
ˆo
Paulo, Brazil,
##
Faculdade de Medicina,
Universidade Federal de Pelotas,
Pelotas, Brazil,
e
Departamento de Salud Publica, and
**Ca
´tedra de Neumologı
´
a, Facultad
de Medicina, Pontifı
´
cia Universidad
Cato
´lica de Chile, Santiago, Chile.
CORRESPONDENCE
M. Montes de Oca
Servicio de Neumonologı
´
a, Piso 8
Hospital Universitario de Caracas
Universidad Central de Venezuela
Los Chaguaramos
1030
Caracas
Venezuela
E-mail: mmdeoca@cantv.net
Received:
Aug 17 2011
Accepted after revision:
Nov 24 2011
First published online:
Jan 26 2012
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
For editorial comments see page 4.
This article has supplemental material available from www.erj.ersjournals.com
28 VOLUME 40 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL
Eur Respir J 2012; 40: 28–36
DOI: 10.1183/09031936.00141611
CopyrightßERS 2012
associated with major outcomes such as worse lung function,
impaired health status, reduced exercise capacity, frequent
exacerbations and, possibly, increased mortality [11–23].
The PLATINO (Proyecto Latinoamericano de Investigacio
´nen
Obstruccio
´n Pulmonar) study offers a good opportunity to
assess different aspects of the chronic bronchitis phenotype in a
large international population-based sample from five Latin
American cities with high (80%) participation and robust, well-
established methods [24]. Therefore, the aims of this study
are: 1) to evaluate the frequency of the chronic bronchitis pheno-
type in subjects with and without COPD in the PLATINO
population using two types of definitions; and 2) to explore how
the coexisting symptoms of chronic bronchitis in the COPD
population are associated with airway obstruction, subjects’
perceptions of their general health status, physical activity
limitation and exacerbations.
METHODS AND MATERIALS
Complete details of the methodology and detailed descrip-
tions of participation rates and sample characteristics of the
PLATINO study have been published previously [24]. Briefly,
a two-stage cluster sampling method was used at each site in
order to obtain a probability sample of households. All adults
aged o40 yrs living in the selected households were invited to
participate. Approval was obtained from the ethical committee
of the institutions involved in the study and written informed
consent was obtained from each subject.
Spirometry was performed using the portable, battery-operated
ultrasound Easy One spirometer (ndd Medical Technologies,
Zurich, Switzerland). Spirometry tests were performed at
baseline and 15 min after the administration of 200 mgof
salbutamol, according to the American Thoracic Society
(ATS) criteria of acceptability and reproducibility [25]. Acute
bronchodilator responsiveness was defined using the follow-
ing criteria: forced vital capacity (FVC) and/or forced expira-
tory volume in 1 s (FEV1)o12% plus o200-mL improve-
ment [26]. We used the definition and severity stratification
of COPD proposed by the Global Initiative for Obstructive
Lung Disease (GOLD) [27]. As a sensitivity analysis, we also
performed parallel analyses using the lower limit of nor-
mal (LLN) post-bronchodilator FEV1/FVC as a criterion to
define COPD.
Information regarding chronic bronchitis was assessed using
the following questions. 1) Do you have phlegm most days, at
least 3 months per year? 2) For how many years have you had
phlegm (o2 yrs)? 3) Do you have cough most days, at least
3 months per year? 4) For how many years have you had
cough (o2 yrs)?
Chronic bronchitis was defined as the presence of phlegm on
most days, at least 3 months per year for o2 yrs. In order
to determine the differences in the prevalence of chronic
bronchitis using another definition, we also analysed the
following definition: cough and phlegm on most days, at least
3 months per year for o2 yrs.
Health status and physical activity limitation due to health
status were assessed using the Short Form-12 generic quality of
life questionnaire, a detailed description of this questionnaire
has been published previously [28]. COPD exacerbations were
self-reported and defined by deterioration of breathing symp-
toms that affected usual daily activities or caused absences
from work. We examined the proportion of subjects with
COPD who reported: 1) any exacerbation within the previous
12 months; 2) an exacerbation requiring a visit to a doctor; or 3)
hospitalisation within the previous 12 months. We also ex-
amined the number of the exacerbation-related events within
the previous 12 months. The questions used for assessing
exacerbation have been published previously [29].
Statistical analyses
Descriptive analyses included group comparisons using
Pearson’s Chi-squared test for nominal variables, the Mann–
Whitney test and ordered logistic regression for ordinal
variables, and the Wald test for continuous variables.
Between-country differences in chronic bronchitis were eval-
uated using the Wald test, and then adjusted for age and sex.
Correlation between variables was evaluated and simple
regression models tested using key variables thought to be
influential due to clinical logic, bivariate analyses and previous
analyses of the PLATINO dataset or published reports. Models
were augmented using multiple additive and subtractive
approaches. For all models tested, standard regression dia-
gnostics were performed, including tests for multicollinearity,
model fit and influential outliers. Variables that did not add
discriminatory power to the model were excluded providing
this did not degrade diagnostic performance. All analyses were
adjusted for survey design and were performed using the
STATA statistical software package (STATA version 11.1;
STATA Corporation, College Station, TX, USA).
RESULTS
Interviews were completed in 5,571 subjects from a total of
6,711 eligible individuals, and spirometry was performed in
5,314 subjects. There were 759 subjects with post-bronchodi-
lator FEV1/FVC ,0.70 and 4,553 individuals with a post-
bronchodilator FEV1/FVC o0.70.
The proportion of COPD subjects with chronic bronchitis using
the two definitions by study site are shown in tables 1 and 2. In
COPD subjects, there were no differences among cities in the
proportion of chronic bronchitis. Tables 3 and 4 show the
proportion of subjects with chronic bronchitis in subjects without
COPD using both definitions. In subjects without COPD, there
was a higher proportion of subjects with chronic bronchitis in
Santiago, Chile, than any other site. After adjustment for age and
sex these differences were considerably smaller. Tables S1 and S2
show a parallel analysis using the LLN to define COPD. As
expected, the overall numbers of subjects with and without
chronic bronchitis have changed; however, the proportion of
subjects in both groups was quite similar.
A descriptive analysis of COPD subjects by presence or
absence of chronic bronchitis is presented in table 5. Subjects
with chronic bronchitis were more likely to: be younger; have
higher exposure to smoking (pack-yrs) and occupational dust;
have higher physical activity limitation; have leisure time; have
self-reported diagnosis of asthma, COPD and tuberculosis; be
current smokers; and report respiratory symptoms (wheezing
and dyspnoea) and use of respiratory medication. Figure 1
shows the proportion of COPD subjects with exacerbation
within the past year by chronic bronchitis status. Subjects with
M. MONTES DE OCA ET AL. COPD
c
EUROPEAN RESPIRATORY JOURNAL VOLUME 40 NUMBER 1 29
chronic bronchitis were more likely to report any exacerbations
and exacerbations requiring a doctor’s visit. A nonsignificant
difference in the exacerbation number was found between
COPD subjects with and without chronic bronchitis (5.3¡3.83
versus 2.1¡0.95; p50.42). Pre- and post-bronchodilator FEV1
and FVC (% predicted) were lower in subjects with chronic
bronchitis compared to those without chronic bronchitis.
GOLD severity distribution of COPD subjects by chronic
bronchitis is shown in figure 2. Subjects with chronic bron-
chitis had more severe COPD; 61% were in GOLD stage 2 or
higher, whereas 62.4% of those without chronic bronchitis
were in stage 1 (p,0.0001). Analyses using the LLN definition
showed similar findings (table S3 and fig. S1). The main
characteristics of COPD subjects according to GOLD stages
and chronic bronchitis status are shown in table S4a–c.
Table 6 provides a description of subjects without COPD
according to chronic bronchitis status. Subjects with chronic
bronchitis were more likely to: have higher exposure to
smoking (pack-yrs), occupational dust and domestic coal; have
higher self-reported diagnosis of asthma, COPD, tuberculosis
and childhood pulmonary hospitalisation; have higher physical
activity limitation; have leisure impairment; be current smokers;
and report respiratory symptoms (wheezing and dyspnoea) and
use of respiratory medication. Pre-bronchodilator FEV1(%
pred), and pre- and post-bronchodilator FEV1/FVC were
significantly lower in subjects with chronic bronchitis. Similar
findings were found using the LLN definition (table S5).
Figure 3 shows general health status assessed in subjects with
and without COPD according to chronic bronchitis status.
Among those with COPD, 59.3% of subjects with and 33.9% of
subjects without chronic bronchitis reported their general
health status as fair to poor (p,0.0001). Similar findings were
observed in subjects without COPD; 55% with and 33.7%
without chronic bronchitis. Analysis using the LLN definition
showed similar findings (fig. S2).
Multivariate analysis of COPD subjects showed that having
chronic bronchitis was significantly associated with respiratory
symptoms (wheezing and dyspnoea), higher smoking exposure,
worse general health status, lower age and higher use of any
respiratory medication (table 7). The other variables tested but
not included in the final model were: sex; body mass index;
race; education; employment; smoking status; prior diagnosis of
COPD and asthma; comorbidity; GOLD stages; exacerbations
TABLE 1 Chronic bronchitis
#
in subjects with chronic obstructive pulmonary disease (COPD) by study site
Total n Proportion with chronic bronchitis
"
Adjusted proportion
+
n (%) (95% CI) % (95% CI)
Country
Sao˜ Paulo, Brazil 152 21 (13.8) (8.4–19.3) 14.3 (10.2–19.6)
Santiago, Chile 198 26 (13.1) (8.4–17.9) 14.4 (11.2–18.3)
Mexico City, Mexico 78 9 (11.5) (5.1–18.0) 14.4 (11.5–17.8)
Montevideo, Uruguay 174 17 (9.8) (5.0–14.6) 14.4 (11.1–18.6)
Caracas, Venezuela 157 23 (14.7) (9.2–20.1) 14.5 (10.1–20.3)
Total 759 96 (12.6) (10.3–15.0) 14.4 (11.5–17.8)
#
: defined as phlegm on most days, at least 3 months per year for o2 yrs;
"
: there were no significant differences between countries, overall p50.699;
+
: of persons with
chronic bronchitis adjusted for age and sex assessed using the Wald test and adjusted for survey design.
TABLE 2 Chronic bronchitis
#
in subjects with chronic obstructive pulmonary disease by study site
Total n Proportion with chronic bronchitis
"
Adjusted proportion
+
n (%) (95% CI) % (95% CI)
Country
Sao˜ Paulo, Brazil 152 9 (5.9) (2.3–9.6) 7.7 (4.8–12.0)
Santiago, Chile 198 18 (9.1) (5.2–13.0) 7.5 (5.3–10.6)
Mexico City, Mexico 78 3 (3.9) (0.0–8.1) 7.4 (5.5–9.9)
Montevideo, Uruguay 174 8 (4.6) (1.3–7.9) 7.3 (5.2–10.2)
Caracas, Venezuela 157 12 (7.6) (3.9–11.3) 7.2 (4.5–11.2)
Total 759 50 (6.6) (4.9–8.3) 7.4 (5.5–9.9)
#
: defined as cough and phlegm on most days, at least 3 months per year for o2 yrs;
"
: there were no significant differences between countries, overall p50.3115;
+
:of
persons with chronic bronchitis adjusted for age and sex assessed using the Wald test and adjusted for survey design.
COPD M. MONTES DE OCA ET AL.
30 VOLUME 40 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL
within past year; number of exacerbations within past year;
occupational dust exposure; domestic exposure to coal or
biomass fuel; and childhood pulmonary hospitalisation. No
significant changes in the models were found when analysis
was performed using the LLN approach (table S6).
DISCUSSION
Using the presence of phlegm on most days, at least 3 months
per year for o2 yrs to define chronic bronchitis, the proportion
of subjects with this phenotype in subjects with and without
COPD was 14.4% and 6.2%, respectively. Among COPD
subjects, those with chronic bronchitis had more severe disease
(worse lung function, more respiratory symptoms and more
exacerbations). They also had worse general health status and
more physical activity limitation. After adjusting for other
factors, the chronic bronchitis phenotype in COPD subjects
was associated with wheezing, dyspnoea, higher smoking
exposure, worse general health status, lower age and higher
use of any respiratory medication.
The Copenhagen City Heart Study found that chronic mucus
hypersecretion was a common symptom in the general
population, with an estimated prevalence of 10.1% [3].
Another study, the French Health Interview Survey, reported
that the prevalence of chronic bronchitis was 3.5% among
adults aged o45 yrs [15]. A population survey conducted in
Brazil indicated that 12.7% of the population was classified as
having chronic bronchitis [30].
In the ECLIPSE study, AGUSTI et al. [8] described the hetero-
geneity of COPD in a well-characterised COPD cohort. They
studied patients with GOLD stages 2–4 and found that 35%
reported the presence of phlegm on most days, at least
3 months per year for o2 yrs. Recently, a large cross-sectional
analysis of COPD subjects (the COPDGene study) showed that
27% (290 out 1,061) had chronic bronchitis defined as chronic
cough and phlegm production at least 3 months per year for
o2 yrs [9]. In a population-based epidemiology study on
COPD prevalence in China, LUet al. [10] reported that 30% of
COPD subjects had history of cough and sputum expectoration
on most days, at least 3 months per year for o2 yrs. The
results of the present study indicate that the proportion of
subjects with and without COPD who had phlegm on most
days, at least 3 months per year for o2 yrs, was 14.4% and
TABLE 3 Chronic bronchitis
#
in subjects without chronic obstructive pulmonary disease by study site
Total n Proportion with chronic bronchitis
"
Adjusted proportion
+
n (%) (95% CI) % (95% CI)
Country
Sao˜ Paulo, Brazil 811 40 (4.9) (3.3–6.5) 7.9 (6.6–9.4)
Santiago, Chile 975 99 (10.2) (8.4–11.9) 7.0 (6.1–8.0)
Mexico City, Mexico 922 62 (6.7) (5.0–8.4) 6.2 (5.5–7.1)
Montevideo, Uruguay 709 33 (4.7) (3.1–6.2) 5.5 (4.7–6.6)
Caracas, Venezuela 1136 50 (4.4) (2.9–5.9) 4.9 (3.9–6.3)
Total 4553 284 (6.2) (5.5–7.0) 6.2 (5.5–7.0)
#
: defined as phlegm on most days, at least 3 months per year for o2 yrs;
"
: there were significant differences between Santiago and all other sites versus Mexico City
(p50.0069) versus all other sites (p,0.0001); overall p,0.0001;
+
: of persons with chronic bronchitis adjusted for age and sex assessed using the Wald test and adjusted
for survey design.
TABLE 4 Chronic bronchitis
#
in subjects without chronic obstructive pulmonary disease by study site
Total n Proportion with chronic bronchitis
"
Adjusted proportion
+
n (%) (95% CI) % (95% CI)
Country
Sao˜ Paulo, Brazil 811 14 (1.7) (0.8–2.7) 3.3 (2.5–4.3)
Santiago, Chile 975 43 (4.4) (3.3–5.5) 2.9 (2.4–3.5)
Mexico City, Mexico 922 24 (2.6) (1.5–3.7) 2.5 (2.1–3.1)
Montevideo, Uruguay 709 17 (2.4) (1.2–3.6) 2.2 (1.7–2.9)
Caracas, Venezuela 1136 17 (1.5) (0.6–2.4) 1.9 (1.4–2.8)
Total 4553 115 (2.5) (2.1–3.0) 2.5 (2.1–3.0)
#
: defined as cough and phlegm on most days, at least 3 months per year for o2 yrs;
"
: there were significant differences between Santiago and all other sites (Sao˜
Paulo p50.0003, Mexico City p50.0207, Montevideo p50.0149, Caracas p50.0001); overall p50.0011;
+
: of persons with chronic bronchitis adjusted for age and sex
assessed using the Wald test and adjusted for survey design.
M. MONTES DE OCA ET AL. COPD
c
EUROPEAN RESPIRATORY JOURNAL VOLUME 40 NUMBER 1 31
6.2%, respectively, and the prevalence of subjects reporting
cough and phlegm on most days, at least 3 months per year for
o2 yrs, was significantly lower (with COPD 7.4% and without
COPD 2.5%). These results clearly indicate that the term used
to define chronic bronchitis has a significant influence on the
prevalence, so it is essential to know the definition being used
when analysing the prevalence of chronic bronchitis. In the
PLATINO study, a much lower proportion of COPD subjects
with chronic bronchitis was found despite using two different
definitions [8–10]. These differences can be partially explained
by differences in the population samples and by the definitions
of chronic bronchitis used. The PLATINO study included all
TABLE 5 Description of subjects with chronic obstructive pulmonary disease (COPD) by chronic bronchitis
#
Variables Without chronic bronchitis With chronic bronchitis p-value
"
Subjects n 663 96
Age yrs 64.6¡0.47 60.6¡1.16 0.0009
Female 319 (48.1) 43 (44.8) 0.5276
Body mass index kg?m
-2
26.8¡0.19 27.2¡0.53 0.5244
Smoking pack-yrs 17.9¡0.96 30.1¡3.43 0.0006
Smoking status
Current 227(34.2) 46 (47.9) 0.0025
Former 216 (32.6) 31 (32.3) 0.0025
Never 220 (33.2) 19 (19.8)
Self-reported diagnosis
COPD 60 (9.1) 26 (27.1) ,0.0001
Asthma 137 (20.7) 36 (37.5) 0.0003
Tuberculosis 30 (4.5) 9 (9.4) 0.0494
Lung cancer 6 (0.9) 2 (2.1) 0.2948
Respiratory symptoms
Wheeze 229 (34.5) 66 (68.8) ,0.0001
Dyspnoea 307 (47.0) 72 (75.8) ,0.0001
Exposures
No occupational dust 322 (48.6) 34 (35.4) 0.0344
,10 yrs 168 (25.3) 32 (33.3)
o10 yrs 173 (26.1) 30 (31.3)
Any occupational dust exposure 341 (51.4) 62 (64.6) 0.0249
Domestic exposure to coal or biomass 421 (63.5) 68 (70.8) 0.1666
Childhood pulmonary hospitalisation 16 (2.4) 3 (3.1) 0.6813
Any respiratory medication 81 (12.2) 32 (33.3) ,0.0001
Any bronchodilator 77 (11.6) 30 (31.3) ,0.0001
Chronic bronchodilator
.
3 months 28 (4.2) 23 (24.0) ,0.0001
Any corticosteroid 25 (3.8) 17 (17.7) ,0.0001
Chronic corticosteroid
.
3 months 12 (1.8) 11 (11.5) ,0.0001
Comorbidity score 1.1¡0.04 1.4¡0.11 0.575
Exacerbations in the past year 2.1¡0.95 5.3¡3.83 0.4258
Short Form-12 physical score 49.5¡0.36 44.6¡1.01 ,0.0001
Limitation due to physical health 148 (22.4) 39 (40.6) 0.0001
Work limitation due to physical health 135 (20.4) 38 (39.6) ,0.0001
Leisure impairment due to physical health 62 (9.4) 19 (19.8) 0.0029
Pre-bronchodilator FEV1% pred 81.0¡0.93 67.6¡2.10 ,0.0001
Post-bronchodilator FEV1% pred 84.9¡0.85 73.0¡2.10 ,0.0001
Absolute FEV1change mL 107.0¡7.7 135.5¡17.6 0.1196
Relative FEV1change % 6.9¡0.53 9.5¡1.37 0.0654
Pre-bronchodilator FVC % pred 99.6¡0.90 90.5¡2.18 0.0001
Post-bronchodilator FVC % pred 104.0¡0.82 96.0¡2.32 0.0013
Absolute FVC change mL 144.5¡14.8 160.4¡41.2 0.7102
Relative FVC change % 5.86¡0.54 6.81¡1.54 0.5487
Pre-bronchodilator FEV1
/
FVC 62.1¡0.39 57.3¡0.97 ,0.0001
Post-bronchodilator FEV1
/
FVC 62.5¡0.32 58.6¡1.02 0.0003
Data are presented as mean¡SE or n (%), unless otherwise stated. FEV1: forced expiratory volume in 1 s; % pred: % predicted; FVC: forced vital capacity.
#
: defined as
phlegm on most days, at least 3 months per year for o2 yrs;
"
: statistical tests for nominal variables: Pearson Chi-squared (adjusted for survey design); for ordinal
variables: Mann-Whitney test; for continuous variables: Wald test (adjusted for survey design).
COPD M. MONTES DE OCA ET AL.
32 VOLUME 40 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL
COPD subjects identified from a survey of five urban
populations (mainly mild COPD), whereas the ECLIPSE and
COPDGene studies included only patients with more severe
COPD (GOLD stages 2–4) [8, 9]. The Chinese study included
urban and rural populations and found that urban residence
was a protective factor for chronic bronchitis, which could help
explain the differences between these two studies [10]. Another
factor explaining the differences is smoking exposure among
subject populations. In the Chinese study, 50% of the COPD
subjects had a smoking exposure of o20 pack-yrs, whereas the
mean values of smoking exposure in the PLATINO COPD
population was ,20 pack-yrs [10, 24]. Patients’ under percep-
tion of respiratory symptoms could also influence the chronic
bronchitis prevalence in PLATINO [28].
AGUSTI et al. [8] found that chronic bronchitis becomes more
frequent as the severity of COPD increases (stage 2: 31%; stage
3: 37%; stage 4: 40%). Other studies found that productive
cough was present in ,10% of mild COPD subjects and in
,40% of subjects with more advanced disease [4]. In the latter
group, results were obtained in only 33 patients. The Chinese
study found that 86% and 70% of COPD subjects with and
without chronic bronchitis, respectively, were in GOLD stage 2
or higher [10]. Our results also show that subjects with chronic
bronchitis had more severe COPD (61% GOLD stage 2 or
higher) and argue in favour of an association between chronic
bronchitis and increased disease severity.
Some studies have suggested an association between chronic
phlegm and lower pulmonary function and greater FEV1
decline in COPD [4, 11–14]. Among patients with a
1
-anti-
trypsin deficiency, DOWSON et al. [11] reported that subjects
with chronic phlegm had worse lung function [11]. The
ECLIPSE study results indicate that in GOLD stage 2 patients,
percentage of FEV1was significantly lower in the presence of
chronic bronchitis (p50.03) [8]. However, no such differences
were reported in more severe COPD patients. Another
important finding was that no difference in the percentage of
FEV1reversibility was found at each GOLD stage between
patients with and without chronic bronchitis [8]. In contrast the
COPDGene study did not report any difference in lung
function between COPD subjects with and without chronic
bronchitis [9]. We found that subjects with COPD and
coexisting chronic bronchitis have worse pulmonary function
compared to those without chronic bronchitis. Interestingly,
we also observed no difference in acute bronchodilator
responsiveness for FEV1or FVC. These findings are consistent
with those reported in selected COPD populations and suggest
that the presence of chronic bronchitis is probably associated
with worse pulmonary function but not with lower acute
bronchodilator responsiveness [8, 9].
Patients with chronic bronchitis appear to display worse
health-related quality of life [11, 15]. In the ECLIPSE and
COPDGene cohorts, patients with chronic bronchitis had a
poorer health status [8, 9]. Our findings are in line with the
previous reports and suggest that the chronic bronchitis
phenotype is associated with worse general health status.
The mechanisms by which chronic bronchitis may affect health
status in COPD are complex and difficult to explain with the
present study data. However, it is possible that the negative
effects of chronic bronchitis could be associated with the
impaired pulmonary function (disease severity) and the
presence of respiratory symptoms (dyspnoea and wheezing)
and exacerbations. Although in COPD the comorbidity score
was similar between subjects with and without chronic
bronchitis, in subjects without COPD it was higher in those
with chronic bronchitis. This suggests a possible adverse effect
of increased comorbidity in the general health status. The lack
of similar information from other population-based studies
similar to the PLATINO study makes it difficult to compare
with our results.
Chronic productive cough has been associated with COPD
exacerbations [9, 16, 23]. MIRAVITLLES et al. [16] reported that
chronic bronchitis was independently associated with in-
creased risk of suffering two or more exacerbations per year;
however, it was not associated with the risk of hospital
admissions. In a large multicentre cohort of COPD subjects,
Exacerbation requiring
hospitalisation within
the past year
Exacerbation requiring
a visit to a doctor
within the past year
Any exacerbation
within the past year
Frequency %
0 5 10 15 20
1.7
4.2
5.3
12.5*
6.6
16.7**
Without chronic bronchitis
With chronic bronchitis
FIGURE 1. Exacerbations in subjects with chronic obstructive pulmonary
disease with or without by chronic bronchitis, defined as phlegm on most days and
at least 3 months per year for o2 yrs. *: p,0.05, chronic bronchitis versus no
chronic bronchitis; **: p,0.01.
100
80
60
40
20
0
Proportion of subjects %
31.7
5.9
62.4
47.9
13.5
38.5
With chronic
bronchitis
Without chronic
bronchitis
Stages 3
and 4
Stage 2
Stage 1
FIGURE 2. Distribution of Global Initiative for Chronic Obstructive Lung
Disease severity stage in 759 chronic obstructive pulmonary disease subjects with
or without chronic bronchitis. Chronic bronchitis was defined as phlegm on most
days, at least 3 months per year for o2 yrs.
M. MONTES DE OCA ET AL. COPD
c
EUROPEAN RESPIRATORY JOURNAL VOLUME 40 NUMBER 1 33
BURGEL et al. [23] found that chronic cough and sputum
production were associated with frequent COPD exacerba-
tions, including severe exacerbations requiring hospitalisa-
tions. In the COPDGene study, subjects with chronic bronchitis
had a higher history of exacerbations and severe exacerbations
[9]. The transversal data of the ECLIPSE study could not
confirm the previous observations [8]. Our findings indicate
that COPD subjects with chronic bronchitis were more likely to
TABLE 6 Description of subjects without chronic obstructive pulmonary disease (COPD) by chronic bronchitis
#
Variables Without chronic bronchitis With chronic
bronchitis
p-value
"
Subjects n 4269 284
Age yrs 55.0¡0.22 55.4¡0.71 0.5839
Female 2684 (62.9) 164 (57.8) 0.0806
Body mass index kg?m
-2
28.2¡0.10 28.9¡0.44 0.1293
Smoking pack-yrs 8.7¡0.29 14.4¡1.24 ,0.0001
Smoking status
Current 1207 (28.3) 103 (36.3) ,0.0001
Former 1131 (26.5) 89 (31.3)
Never 1928 (45.2) 92 (32.4)
Self-reported diagnosis
COPD 113 (2.7) 38 (13.4) ,0.0001
Asthma 400 (9.4) 78 (27.5) ,0.0001
Tuberculosis 74 (1.7) 14 (4.9) 0.0002
Lung cancer 5 (0.1) 0.5571
Exposures
No occupational dust 2223 (52.1) 117 (41.2) 0.0030
,10 yrs 1154 (27.0) 102 (35.9)
o10 yrs 890 (20.9) 65 (22.9)
Any occupational dust exposure 2044 (47.9) 167 (58.8) 0.0009
Domestic coal 1028 (24.1) 100 (35.2) 0.0001
Domestic biomass 2118 (49.6) 152 (53.5) 0.2141
Domestic exposure to coal or biomass 2435 (57.1) 184 (64.8) 0.0148
Childhood pulmonary hospitalisation 86 (2.0) 13 (4.3) 0.0054
Respiratory symptoms
Wheeze 823 (19.3) 150 (52.8) ,0.0001
Dyspnoea 1842 (43.6) 187 (66.8) ,0.0001
Any respiratory medication 176 (4.1) 51 (18.0) ,0.0001
Any bronchodilator 158 (3.7) 47 (16.6) ,0.0001
Chronic bronchodilator
.
3 months 32 (0.8) 10 (3.5) ,0.0001
Any corticosteroid 45 (1.1) 15 (5.3) ,0.0001
Chronic corticosteroid
.
3 months 10 (0.2) 5 (1.8) ,0.0001
Comorbidity score 1.0¡0.02 1.4¡0.07 ,0.0001
Short Form-12 physical score 51.2¡0.14 47.3¡0.60 ,0.0001
Limitation due to physical health 720 (16.9) 96 (33.8) ,0.0001
Work limitation due to physical health 680 (15.9) 99 (34.9) ,0.0001
Leisure impairment due to physical health 361 (8.5) 43 (15.1) 0.0001
Pre-bronchodilator FEV1% pred 98.5¡0.31 95.5¡1.14 0.0088
Post-bronchodilator FEV1% pred 101.7¡0.32 99.7¡1.07 0.0608
Absolute FEV1change mL 82.2¡2.8 103.1¡12.9 0.1096
Relative FEV1change % 3.71¡0.20 4.97¡1.02 0.2229
Pre-bronchodilator FVC % pred 100.3¡0.31 98.5¡1.03 0.0831
Post-bronchodilator FVC % pred 99.4¡0.30 98.7¡0.94 0.5434
Absolute FVC change mL -36.4¡4.11 -7.94¡17.7 0.1150
Relative FVC change % -0.47¡0.23 0.39¡0.79 0.2944
Pre-bronchodilator FEV1
/
FVC 77.5¡0.10 76.2¡0.36 0.0005
Post-bronchodilator FEV1
/
FVC 80.7¡0.08 79.5¡0.30 0.0002
Data are presented as mean¡SE or n (%), unless otherwise stated. FEV1: forced expiratory volume in 1 s; % pred: % predicted; FVC: forced vital capacity.
#
: defined as
phlegm on most days, at least 3 months per year for o2 yrs;
"
: statistical tests for nominal variables: Pearson Chi-squared (adjusted for survey design); for ordinal
variables: Mann-Whitney test; for continuous variables: Wald test (adjusted for survey design).
COPD M. MONTES DE OCA ET AL.
34 VOLUME 40 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL
report any exacerbation and an exacerbation requiring a
doctor’s visit within the past year, although the difference in
the number of exacerbations between COPD subjects with and
without chronic bronchitis was not significant. It is probable
that the characteristics of the PLATINO population (mainly
mild COPD; 59% GOLD stage 1, 34% stage 2 and 7% stage 3
and 4) explain the differences between studies performed in
subjects with more severe COPD (,50% GOLD stage 3 and 4)
[9, 23]. Since our results are based on self-reported exacerba-
tions over the previous year, which may be subject to recall
bias, these findings should be confirmed or refuted in a
prospective follow-up study.
LUet al. [10] assessed the factors associated with coexisting
symptoms of chronic bronchitis in COPD subjects. Their
multiple logistic regression models showed that the indepen-
dent risk factors associated with chronic bronchitis were male
sex, current smoking and dyspnoea severity, whereas living in
an urban region showed a protective effect against chronic
bronchitis compared with living in rural regions. Our results
are consistent with those reported previously and show that
wheezing, dyspnoea, smoking exposure, worse general health
status, lower age and higher use of any respiratory medication
are the main factors associated with the chronic bronchitis pheno-
type. However, we found no sex association with chronic
bronchitis.
Our study has some limitations. We assessed information of
some exposures (tobacco and indoor exposure to coal or
biomass for cooking or heating); however, no detailed
information about other exposures such as occupation or
second-hand smoking was recorded. In addition, we did not
collect information on other known possible causes of chronic
bronchitis (upper airway infections or gastro-oesophageal
reflux). Our definition of exacerbation was based on subjects’
retrospective report of breathing symptoms, which is poten-
tially subject to recall bias. Because the present study is a cross-
sectional and not a longitudinal study investigating a popula-
tion at a given time-point, it only provides the frequency and
characteristics of the disease in the population during the time
the study was conducted. Thus, our results may tend to
underestimate the true rate of COPD exacerbations. Further
epidemiological follow-up studies are needed to address this
matter, as well as the stability of this phenotype over time.
In summary, our study helps to better understand the pre-
valence of the chronic bronchitis phenotype in an epidemiolo-
gical sample at a particular time-point and suggest that co-
existing symptoms of chronic bronchitis in COPD are possibly
associated with increased disease severity (lower pulmonary
function, more respiratory symptoms and exacerbations), worse
health status and more physical activity limitation.
SUPPORT STATEMENT
The original PLATINO Study was funded by Boehringer Ingelheim
GmbH. The funding source had no influence on the analyses or
interpretation of the results presented in this paper, and no external
funding was received for the work presented here. Support was also
provided by the Asociacio
´n Latinoamericana de To
´rax.
STATEMENT OF INTEREST
A statement of interest for R.J. Halbert can be found at www.erj.
ersjournals.com/site/misc/statements.xhtml
REFERENCES
1Standardized questionnaires on respiratory symptoms. Br Med J
1960; 2: 1665.
2Medical Research Council’s Committee on Research into Chronic
Bronchitis. Instructions for the Use of the Questionnaires on
Respiratory Symptoms. Dawlish, W.J. Holman, 1966.
3Lange P, Groth S, Nyboe J, et al. Chronic obstructive lung disease
in Copenhagen: cross-sectional epidemiological aspects. J Intern
Med 1989; 226: 25–32.
4Vestbo J, Lange P. Can GOLD Stage 0 provide information of
prognostic value in chronic obstructive pulmonary disease? Am J
Respir Crit Care Med 2002; 166: 329–332.
5de Marco R, Accordini S, Cerveri I, et al. Incidence of chronic
obstructive pulmonary disease in a cohort of young adults
according to the presence of chronic cough and phlegm. Am J
Respir Crit Care Med 2007; 175: 32–39.
100
80
60
40
20
0
Proportion of subjects %
COPD
Without
chronic
bronchitis
With
chronic
bronchitis
No COPD
Without
chronic
bronchitis
With
chronic
bronchitis
Poor
Fair
Good
Excellant
Very good
FIGURE 3. General health status in 5,314 subjects with and without chronic
obstructive pulmonary disease (COPD) and with or without chronic bronchitis.
Chronic bronchitis was defined as phlegm on most days, at least 3 months per year
for o2 yrs.
TABLE 7 Multivariate analysis of factors associated with
having chronic bronchitis
#
among individuals
with chronic obstructive pulmonary disease
Variable OR (95% CI) p-value
Wheeze 2.40 (1.40–4.12) 0.002
Dyspnoea 2.42 (1.36–4.29) 0.003
Pack-yrs per additional pack-yr 1.02 (1.01–1.02) ,0.001
General health status good to
excellent
0.60 (0.36–0.99) 0.049
Age per additional year 0.97 (0.95–0.99) 0.006
Any respiratory medication 1.93 (1.05–3.56) 0.035
#
: defined as phlegm on most days, at least 3 months per year for o2 yrs.
M. MONTES DE OCA ET AL. COPD
c
EUROPEAN RESPIRATORY JOURNAL VOLUME 40 NUMBER 1 35
6Lindberg A, Jonsson AC, Ro
¨nmark E, et al. Ten-year cumulative
incidence of COPD and risk factors for incident disease in a
symptomatic cohort. Chest 2005; 127: 1544–1552.
7Guerra S, Sherrill DL, Venker C, et al. Chronic bronchitis before
age 50 years predicts incident airflow limitation and mortality risk.
Thorax 2009; 64: 894–900.
8Agusti A, Calverley PM, Celli B, et al. Characterization of COPD
heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11: 122.
9Kim V, Han MK, Vance GB, et al. The chronic bronchitic
phenotype of COPD: an analysis of the COPDGene study. Chest
2011; 140: 626–633.
10 Lu M, Yao W, Zhong N, et al. Chronic obstructive pulmonary
disease in the absence of chronic bronchitis in China. Respirology
2010; 15: 1072–1078.
11 Dowson LJ, Guest PJ, Stockley RA. The relationship of chronic
sputum expectoration to physiologic, radiologic, and health status
characteristics in a
1
-antitrypsin deficiency (PiZ). Chest 2002; 122:
1247–1255.
12 Sherman CB, Xu X, Speizer FE, et al. Longitudinal lung function
decline in subjects with respiratory symptoms. Am Rev Respir Dis
1992; 146: 855–859.
13 Vestbo J, Prescott E, Lange P. Association of chronic mucus
hypersecretion with FEV1decline and chronic obstructive pul-
monary disease morbidity. Copenhagen City Heart Study Group.
Am J Respir Crit Care Med 1996; 153: 1530–1535.
14 Sta˘ nescu D, Sanna A, Veriter C, et al. Airways obstruction, chronic
expectoration, and rapid decline of FEV1in smokers are associated
with increased levels of sputum neutrophils. Thorax 1996; 51:
267–271.
15 Fuhrman C, Roche N, Vergnenegre A, et al. Chronic bronchitis:
prevalence and quality of life. Analysis of data from the French
Health Interview Survey 2002–2003. Rev Mal Respir 2009; 26:
759–768.
16 Miravitlles M, Guerrero T, Mayordomo C, et al. Factors associated
with increased risk of exacerbation and hospital admission in a
cohort of ambulatory COPD patients: a multiple logistic regression
analysis. The EOLO Study Group. Respiration 2000; 67: 495–501.
17 Wiles FJ, Hnizdo E. Relevance of airflow obstruction and mucus
hypersecretion to mortality. Respir Med 1991; 85: 27–35.
18 Speizer FE, Fay ME, Dockery DW, et al. Chronic obstructive
pulmonary disease mortality in six US cities. Am Rev Respir Dis
1989; 140: S49–S55.
19 Lange P, Nyboe J, Appleyard M, et al. The relation of ventilatory
impairment and of chronic mucus hypersecretion to mortality
from obstructive lung disease and from all causes. Thorax 1990; 45:
579–585.
20 Annesi I, Kauffmann F. Is respiratory mucus hypersecretion really
an innocent disorder? Am Rev Respir Dis 1986; 134: 688–693.
21 Vollmer WM, McCamant LE, Johnson LR, et al. Respiratory
symptoms, lung function, and mortality in a screening center
cohort. Am J Epidemiol 1989; 129: 1157–1169.
22 Ekberg-Aronsson M, Pehrsson K, Nilsson JA, et al. Mortality in
GOLD stages of COPD and its dependence on symptoms of
chronic bronchitis. Respir Res 2005; 6: 98.
23 Burgel PR, Nesme-Meyer P, Chanez P, et al. Cough and sputum
production are associated with frequent exacerbations and
hospitalizations in COPD subjects. Chest 2009; 135: 975–982.
24 Menezes AM, Perez-Padilla R, Jardim JR, et al. Chronic obstructive
pulmonary disease in five Latin American cities (the PLATINO
study): a prevalence study. Lancet 2005; 366: 1875–1881.
25 Standardization of spirometry, 1994 update. American Thoracic
Society. Am J Respir Crit Care Med 1995; 152: 1107–1136.
26 Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for
lung function tests. Eur Respir J 2005; 26: 948–968.
27 Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the
diagnosis, management, and prevention of chronic obstructive
pulmonary disease: GOLD executive summary. Am J Respir Crit
Care Med 2007; 176: 532–555.
28 Montes de Oca M, Ta
´lamo C, Halbert RJ, et al. Health status
perception and airflow obstruction in five Latin American cities:
the PLATINO study. Respir Med 2009; 103: 1376–1382.
29 de Oca MM, Ta
´lamo C, Halbert RJ, et al. Frequency of self-reported
COPD exacerbation and airflow obstruction in five Latin
American cities: the Proyecto Latinoamericano de Investigacion
en Obstruccion Pulmonar (PLATINO) study. Chest 2009; 136:
71–78.
30 Menezes AM, Victora CG, Rigatto M. Prevalence and risk factors
for chronic bronchitis in Pelotas, RS, Brazil: a population-based
study. Thorax 1994; 49: 1217–1221.
COPD M. MONTES DE OCA ET AL.
36 VOLUME 40 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL
