CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Risk factors of readmission to hospital for a COPD
exacerbation: a prospective study
J Garcia-Aymerich, E Farrero, M A Félez, J Izquierdo, R M Marrades, J M Antó, on
behalf of the EFRAM* investigators
.............................................................................................................................
Thorax
2003;58:100–105
Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are a leading cause of
admission to hospital among men in many countries, although the factors causing exacerbations are
largely unknown. The association between readmission for a COPD exacerbation and a wide range of
modifiable potential risk factors, after adjusting for sociodemographic and clinical factors, has been
assessed.
Methods: Three hundred and forty patients with COPD recruited during an admission for an exacer-
bation in four tertiary hospitals in the Barcelona area of Spain were followed for a mean period of 1.1
years. Information on potential risk factors, including clinical and functional status, medical care and
prescriptions, medication adherence, lifestyle, health status, and social support, was collected at the
recruitment admission. A Cox’s proportional hazards model was used to obtain independent relative
risks of readmission for COPD.
Results: During the follow up period 63% of patients were readmitted at least once, and 29% died.
The final multivariate model showed the following risk (or protective) factors: >3 admissions for COPD
in the year before recruitment (hazard ratio (HR)=1.66, 95% CI 1.16 to 2.39), forced expiratory vol-
ume in 1 second (FEV
1
) percentage predicted (0.97, 95% CI 0.96 to 0.99), oxygen tension (0.88,
95% CI 0.79 to 0.98), higher levels of usual physical activity (0.54, 95% CI 0.34 to 0.86), and tak-
ing anticholinergic drugs (1.81, 95% 1.11 to 2.94). Exposure to passive smoking was also related to
an increased risk of readmission with COPD after adjustment for clinical factors (1.63, 95% CI 1.04 to
2.57) but did not remain in the final model.
Conclusions: This is the first study to show a strong association between usual physical activity and
reduced risk of readmission to hospital with COPD, which is potentially relevant for rehabilitation and
other therapeutic strategies.
C
hronic obstructive pulmonary disease (COPD) is one of
the leading causes of disability and mortality world-
wide, and is expected to become the third cause of death
and the fifth cause of disability adjusted life years in 2020.
1
Patients with COPD may suffer recurrent exacerbations, with
a worsening of symptoms and reduction in lung function that
may not be recovered in a small proportion of patients.
2
More-
over, exacerbations are associated with an impaired quality of
life,
3
reduced survival,
4
and a high healthcare expenditure.
5
The latter mainly results from admission to hospital which is
frequently a consequence of an exacerbation. Prevention of
exacerbations is therefore an important goal in the manage-
ment of stable COPD,
6
although knowledge about which
factors relate to COPD exacerbations or hospitals admissions
for exacerbations is currently very limited.
7
While influenza
vaccination has been shown to reduce the risk of admission in
elderly subjects with chronic lung disease,
8
the results for res-
piratory rehabilitation
9
and inhaled corticosteroids
10
are still
controversial. The effect on COPD exacerbations of long term
oxygen therapy (LTOT), adherence to medication, consump-
tion of tobacco, alcohol, and sedatives, or usual physical activ-
ity has not been directly assessed in either experimental or
observational studies.
In the EFRAM project we have previously performed a
case-control study to identify risk factors for COPD exacerba-
tions, including a wide range of potential risk factors,
11
and we
found that, after adjusting for COPD severity, only underpre-
scription of LTOT was independently associated with admis-
sion for a COPD exacerbation. Because selection bias is likely
to occur in this type of study,
12
we followed prospectively the
340 patients with COPD recruited in the framework of the
EFRAM study.
13
The objective was to assess the association
between readmission for a COPD exacerbation and a wide
range of modifiable potential risk factors, mainly related to
medical care and lifestyle, after adjusting for socio-
demographic and clinical factors.
METHODS
Recruitment
A systematic sample of one out of every two patients admitted
to hospital or remaining in the emergency room for at least 18
hours for a COPD exacerbation in four tertiary hospitals in the
Barcelona area from 1 May 1997 to 30 April 1998 was identi-
fied, independently of whether they had previous COPD
admissions or not. A diagnosis of COPD was established by the
ward pulmonologist based on medical history, current symp-
toms, and available pulmonary function tests, following the
ERS guidelines.
5
An exacerbation was defined as an increase
in dyspnoea, sputum production, or sputum purulence.
14
Patients were allowed to enter the study as many times as they
were hospitalised during the recruitment period, giving 346
individuals with 404 admissions. In patients with more than
one admission during the recruitment period the first one was
selected as the beginning of the follow up period. Recruitment
methods and diagnosis criteria have been detailed in previous
papers.
11 13
The ethics committees of the participating hospitals
.............................................................
*EFRAM: Estudi dels Factors de Risc d’Agudització de la MPOC (Risk
Factors of COPD Exacerbation Study).
See end of article for
authors’ affiliations
.......................
Correspondence to:
Dr J M Antó, Respiratory
and Environmental Health
Research Unit, Institut
Municipal d’Investigació
Mèdica (IMIM), Doctor
Aiguader 80, E-08003
Barcelona, Spain; e-mail
Revised version received
25 September 2002
Accepted for publication
21 October 2002
.......................
100
www.thoraxjnl.com
approved the protocol and written informed consent was
obtained from all patients.
Information about factors potentially related to COPD
exacerbations was obtained by an extensive bibliographic
search that has been described elsewhere.
13
A large number of
potential risk factors—including variables related to clinical
status, characteristics of medical care, medical prescriptions,
adherence to medication, lifestyle, quality of life, and social
support—was identified and has been reported elsewhere.
11
All the variables were considered in the analysis.
During the recruitment hospital admission, patients were
asked to complete a questionnaire. Most of the questionnaire
content was obtained from previously validated instruments,
while some questions were developed and pilot tested.
Questions for usual physical activity were adapted from the
Spanish validation
15
of the Minnesota Leisure Time Physical
Activity Questionnaire, a measure of physical activity in the
general population.
16
Each specific activity was assigned an
intensity unit based on their rate of energy expenditure
expressed as metabolic equivalent tax (METs), the ratio of
work metabolic rate to resting metabolic rate.
17
The energy
expenditure in physical activity was then expressed as the
total activity metabolic index per day in kcal/day, taking into
account the intensity code for each physical activity, the
number of times that this activity was performed in a usual
day, and the average time spent in each session. In addition,
weight, height and tricipital skinfold thickness were
measured. Sputum samples were collected during the first 48
hours after admission and processed within an hour,
accepting only those considered suitable for culture according
to Murray-Washington criteria,
18
until potentially pathogenic
bacteria
19
were identified and quantified. At least 3 months
after admission to hospital and during a clinically stable
period of COPD, patients performed a forced spirometric test
and provided arterial blood to measure gas tensions. Detailed
information about all the remaining variables, sources of
questions, and methods of spirometric and blood gas
measurementss have been given in previous papers.
11 13
Follow up
Six (1.7%) of the 346 patients recruited did not survive the
recruitment admission; 340 patients were therefore followed
from the day of discharge after the recruitment admission
until 1 May 1999 or the day of death, if earlier. There were no
losses to follow up as all patients were either contacted for
telephone interview, registered as dead in the mortality regis-
try, or visited in the outpatient clinics or hospitalised after 1
May 1999.
Information on readmissions during the follow up period
was obtained from the Minimum Basic Dataset (CMBD), a
national administrative database that is monitored to high
quality standards.
20
The primary study outcome was the time
to readmission for a COPD exacerbation. All admissions with
a main and/or secondary diagnosis fulfilling any of the follow-
ing code combinations (according to the International Classi-
fication of Diseases, 9th revision) were recorded as a COPD
exacerbation: (1) 490–496 (COPD group), 480–486 (pneumo-
nia), 487 (influenza), or 518.81 (respiratory failure) as the
main diagnosis; (2) 428 (cardiac failure) as the main diagno-
sis if 518.81 (respiratory failure) or 491.21 (acute exacerbation
of chronic bronchitis) were the secondary diagnosis; and (3)
any other respiratory problems (011 (tuberculosis), 466 (acute
bronchitis), 500–505 (pneumoconiosis), 277.6 (deficit α
1
-
antitrypsin)) as the main diagnosis if 518.81 or 491.21 was the
secondary diagnosis. Criteria of the expert consensus of the
American Thoracic Society
21
were used to define such
combinations.
Vital status was ascertained through a telephone interview
with patients or their proxies and a record linkage with the
Catalonia mortality registry for the years 1997–9. Additional
institutional ethical approval for the linkage was obtained.
Fields used for linkage were full name, sex, and date of birth,
as described elsewhere.
22
Statistical analysis
Time from recruitment (admission) to first event (following
admission) was used as the outcome variable in a Cox’s
proportional hazards model.
23
Sociodemographic and clinical
variables were assessed and those with an independent statis-
tically significant association with readmission provided a
clinical model. The individual association between all poten-
tial risk factors and readmission, adjusted for the variables of
the clinical model, was then estimated and those factors con-
sidered a priori as clinically relevant, those withapvalue of
<0.25 after adjusting for the clinical model, and those with a
high (>2) or low (<0.5) hazard ratio (HR) after adjusting for
the clinical model
24
were defined as relevant variables. A mul-
tivariate model was then built including all relevant variables
until the final most parsimonious model was fitted. Poisson
regression was used as a complementary approach to obtain
relative risks of readmission for COPD, modelling the
individual number of readmissions and including the loga-
rithm of the individual person-days at risk as the offset. The
analysis was performed using Stata Release 6.0 (StataCorp,
Texas, USA, 1999).
RESULTS
Three hundred and forty patients (92% men) of mean (SD)
age 69 (9) years were followed up; 72% had a low
socioeconomic status (IV or V), a mean of 1.5 (2.0) COPD
admissions in the previous year, mean forced expiratory
volume in 1 second (FEV
1
) of 36 (16)%, and mean PO
2
of 8.5
(1.7) kPa; 90% had any comorbid condition and mean body
mass index (BMI) of 26 (5) kg/m
2
. Patients were followed for
a mean of 1.1 years; 63% were admitted at least once during
the follow up period, and 29% died (table 1). Twenty eight
patients (8%) died without having a readmission during the
follow up period and were excluded from the study of risk
factors for a COPD readmission. The excluded patients were
older (74 v 69 years, p=0.003) and slightly thinner (BMI 24 v
26 kg/m
2
, p=0.070) than the remaining patients.
Among all the sociodemographic and clinical variables,
having had >3 COPD admissions in the year before
recruitment, having had >3 COPD emergency room visits
Table 1 Follow up of patients with COPD recruited
at an admission for a COPD exacerbation
Total number of individuals 340
Mean (SD) total days of follow up (excluding days
in hospital)
410 (181)
Number of readmissions during follow up, n (%)
0 126 (37%)
1 78 (23%)
2 43 (13%)
3 32 (9%)
4 18 (5%)
>5 43 (13%)
Days to first readmission, median (P
25
–P
75
) 186 (40–432)
Vital status: died during follow up, n (%) 98 (29%)
Respiratory causes (ICD-9 460–519) 73 (74%)
COPD group (490–496) 54 (55%)
Respiratory failure (518–519) 5 (5%)
Cardiovascular causes (390–459) 12 (12%)
Ischaemic heart disease (410–414) 5 (5%)
Cancer (140–239) 7 (7%)
Lung cancer (162) 5 (5%)
Other causes 6 (6%)
Excluded individuals*, n (%) 28 (8%)
Number of individuals in follow up analysis, n (%) 312 (92%)
*Individuals who died without having a readmission during the follow
up period.
Risk factors of COPD exacerbation 101
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without admission in the year before recruitment, a lower
percentage predicted FEV
1
and a lower PO
2
were independently
related to a higher risk of readmission for a COPD
exacerbation, and constituted the clinical model (table 2).
Other clinical factors such as P
CO
2
(HR 1.15 (95% CI 1.01 to
1.30), p=0.031) and FEV
1
/FVC (0.99 (95% CI 0.98 to 1.00),
p=0.005) were associated with risk of readmission, but their
significance was lost after including P
O
2
and FEV
1
, respectively.
The individual associations between each of the potential risk
factors and readmission were obtained after adjusting for the
clinical model, and those considered relevant—according to
criteria defined in the Methods section—are shown in table 2.
Only two variables showed a statistically significant reduced
risk of readmission: the highest tertile of usual physical activ-
ity and a higher score of physical quality of life. Being enrolled
in a team based primary care centre was associated with a
lower risk of readmission for COPD, although it did not reach
statistical significance. In contrast, the following variables
were associated with a significantly increased risk of readmis-
sion: being controlled by a pulmonologist, being admitted at
recruitment in hospitals 2 and 3, taking anticholinergics, tak-
ing oral corticosteroids, and being a former smoker exposed to
passive smoking. Influenza vaccination, respiratory rehabilita-
tion, and LTOT were also associated with a higher risk of
readmission for COPD but did not achieve statistical
significance. None of the remaining factors (socioeconomic
status, living alone, pneumococcal vaccination, nutritional
status, adherence to medication, comorbidity, or bacterial
infection at baseline) was significantly associated with
readmission.
In a final multivariate model, a high level of usual physical
activity was associated with a 46% reduction in the risk of a
readmission for COPD, whereas having had >3 COPD admis-
sions in the year before recruitment, a lower percentage
predicted FEV
1
, a lower level of PO
2
, being controlled by a pul-
monologist, and taking anticholinergics were related to an
increased risk (table 3). After allowing for inclusion of the
individual number of readmissions as the outcome, Poisson
regression produced almost identical results as the Cox model
(data not shown; available from the authors).
Table 2 Crude and clinical model adjusted individual associations between relevant variables* and readmission to
hospital for an exacerbation in a cohort of 312 patients with COPD (Cox regression)
Crude HR
(95% CI)† p value
Adjusted HR
(95% CI) by clinical
model† p value
Clinical model
>3 COPD admissions in the year before recruitment‡ 2.27 (1.69 to 3.04) 0.000
>3 COPD emergency room visits without admission in the year
before recruitment‡
1.72 (1.13 to 2.61) 0.012
% predicted FEV
1
§ 0.97 (0.96 to 0.98) 0.000
P
O
2
(kPa)§ 0.78 (0.71 to 0.87) 0.000
Age 1.00 (0.99 to 1.02) 0.703 1.01 (0.99 to 1.04) 0.163
Sex: women 0.98 (0.60 to 1.61) 0.934 1.43 (0.76 to 2.68) 0.265
Medical care
Team based primary care‡ 0.74 (0.57 to 0.97) 0.029 0.77 (0.56 to 1.07) 0.116
Controlled by a:
General practitioner 1.00 1.00
Pulmonologist 2.16 (1.43 to 3.27) 0.000 1.77 (1.07 to 2.92) 0.025
Hospital of recruitment:
Hospital 1 1.00 1.00
Hospital 2 1.88 (1.28 to 2.75) 0.001 1.81 (1.14 to 2.88) 0.012
Hospital 3 1.95 (1.32 to 2.88) 0.001 2.08 (1.33 to 3.27) 0.001
Hospital 4 1.07 (0.69 to 1.65) 0.761 1.19 (0.67 to 2.14) 0.550
Medical prescriptions
Anticholinergics‡ 3.52 (2.37 to 5.21) 0.000 2.02 (1.26 to 3.24) 0.004
Oral corticosteroids‡ 1.55 (1.13 to 2.11) 0.006 1.59 (1.07 to 2.37) 0.021
Influenza vaccination‡ 1.37 (1.01 to 1.87) 0.044 1.43 (0.98 to 2.07) 0.064
Respiratory rehabilitation‡ 1.77 (1.23 to 2.57) 0.002 1.32 (0.85 to 2.05) 0.223
Long term oxygen therapy‡ 2.36 (1.79 to 3.11) 0.000 1.26 (0.87 to 1.84) 0.224
Compliance
Correctly performed essential MDI manoeuvres‡ 1.17 (0.88 to 1.56) 0.277 1.12 (0.79 to 1.59) 0.526
Lifestyle
Smoking:
Ex smoker not exposed to passive smoking 1.00 1.00
Ex smoker exposed to passive smoking 1.18 (0.81 to 1.70) 0.387 1.63 (1.04 to 2.57) 0.034
Current smoker 0.58 (0.41 to 0.82) 0.002 0.97 (0.64 to 1.47) 0.876
Never smoker 0.93 (0.55 to 1.57) 0.781 1.20 (0.61 to 2.33) 0.598
Usual physical activity (in tertiles)¶
<79 kcal/day 1.00 1.00
79–232 kcal/day 0.73 (0.54 to 0.99) 0.043 0.85 (0.59 to 1.24) 0.400
>232 kcal/day 0.46 (0.32 to 0.68) 0.000 0.49 (0.31 to 0.79) 0.003
Other
Physical scale health related QoL§ 0.97 (0.95 to 0.98) 0.000 0.98 (0.96 to 0.99) 0.007
HR=hazard ratio; CI=confidence interval; MDI=metered dose inhaler; QoL=quality of life.
*Relevant variables are: those considered a priori as clinically relevant, those withapvalue<0.250after adjusting for the clinical model, and those with
high (>2) or low (<0.5) HR after adjusting for the clinical model.
†Each line is a single model. Clinical model includes: >3 COPD admissions in the year before recruitment, >3 COPD emergency room visits without
admission in the year before recruitment, % predicted FEV
1
, and PO
2
.
‡Reference categories are: <3 COPD admissions in the year before recruitment; <3 COPD emergency room visits without admission in the year before
recruitment; not team based primary care; no anticholinergics intake; no oral corticosteroids intake; lack of influenza vaccination; lack of respiratory
rehabilitation; lack of long term oxygen therapy; some mistake in any of the essential MDI manoeuvres.
§HR means change in risk for 1 percentual unit in FEV
1
, 1 kPa in PO
2
, and 1 point increase in physical scale of SF-36 score.
¶First tertile means, for instance, patients walking 20 minutes a day every day (“walking” includes time going to the bar, to buy newspapers, going to the
supermarket, or just strolling). Third tertile means patients walking 60 minutes a day every day, or patients walking 20 minutes a day plus practising
exercise in a gymnasium 60 minutes a day three days a week.
102 Garcia-Aymerich, Farrero, Félez, et al
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DISCUSSION
To our knowledge, this is the first study to show that patients
with COPD who perform a relatively high level of physical
activity in their daily life have a substantially reduced risk of
readmission due to exacerbation. Since the third of patients
with COPD who reported an activity equivalent to walking
>60 minutes a day had a reduction in risk of readmission to
hospital of almost 50%, this is potentially relevant. Moreover,
the association did not change when adjusted for COPD
severity, nutritional status factors, or respiratory rehabilita-
tion. Such results are in agreement with the increased risk of
COPD admission associated with a limited 6 minute walking
test reported in a previous group of COPD patients,
25
both
studies suggesting that conditioned patients have a lower risk
of COPD admission which is independent of the way
conditioning is evaluated. Because our finding has not been
reported previously, its mechanism can only be speculated.
One possible explanation is that exercise leads to a better con-
ditioned cardiovascular system
26
that would adapt better to the
increase in oxygen intake in respiratory muscles that occurs
during a COPD exacerbation.
27
In addition, a programme of
endurance training can reduce exercise induced lactic acidosis
and improve the oxidative capacity of the muscles in patients
with moderate to severe COPD,
28
suggesting that such muscles
would be more able to tolerate a COPD exacerbation than
untrained muscles. We found no relationship between
physical activity and rehabilitation or nutritional status,
which suggests that physical activity in this population
depends on other factors. The extent to which these results
may have relevance for rehabilitation programmes
29
or clinical
practice
21
is not yet clear.
Several factors related to medical care or prescriptions—
such as being controlled by a pulmonologist, taking anti-
cholinergics or oral corticosteroids—were associated with a
higher risk of readmission for COPD in the adjusted clinical
model, contrary to what had been expected. Similar results
were also found in the previous case-control EFRAM study,
11
although they were more evident in the follow up analysis. We
consider that a previous COPD admission may play a role of
“confounding by indication”, a term used when the con-
founder represents a perceived high risk or poor prognosis that
results in an indication for treatment.
30
In our study, having
had previous admissions fulfils the two conditions necessary
to qualify as a confounder.
31
Firstly, patients who had had a
previous COPD admission at recruitment (82%) had a higher
prevalence of prescriptions of anticholinergics or oral cortico-
steroids than those who had never had a COPD admission
(18%). Secondly, having had a previous admission (independ-
ent of whether the variable was included as continuous or as
categorical with different cut off points) was associated with
an increased risk of a subsequent readmission for COPD, as
found in previous studies.
311
Moreover, in the present analysis
the positive association of such variables with further COPD
readmissions partially reduced its magnitude and significance
when adjusted for having had >3 COPD admissions in the
year before recruitment. For example, the crude HR for
readmission of taking anticholinergics was 3.52 (95% CI 2.37
to 5.21) compared with 2.40 (95% CI 1.52 to 3.80) when
adjusted for %FEV
1
and PO
2
and 2.10 (95% CI 1.32 to 3.36)
when adjusted for %FEV
1
,PO
2
, and previous admissions. The
increased risk associated with pneumologist care and taking
anticholinergics was not totally removed after adjustment for
previous admissions, which suggests that other mechanisms
such as easier accessibility to hospital or residual
confounding
30
may be operating. Consistent with the possi-
bility of bias by indication, our data showed that, after the
recruitment admission, LTOT was provided to all patients who
fulfilled the necessary criteria with the result that the strong
association between underprescription of LTOT and admission
for COPD reported in the case-control analysis
11
disappeared
after the follow up. With regard to the plausibility of the
association between previous admissions and a subsequent
readmission, it is possible that “previous admissions” is a sur-
rogate of undefined risk factors. In future, to avoid such
biases, the study of the effects of medical care related variables
would probably need randomised controlled trials instead of
observational studies and/or the use of patients in their first
contact with medical care services.
Surprisingly, we found that influenza vaccination was asso-
ciated with an increased risk of admission. Although
randomised trials of influenza vaccination in specific COPD
populations have not been reported, the administration of the
vaccine in elderly patients with chronic lung disease
8
has been
associated with a reduction in the risk of hospital admissions,
outpatient visits, and mortality. The fact that only 28% of our
population was not vaccinated could confer this group with
particular characteristics that were not controlled in the
multivariate models.
Exposure to environmental tobacco smoking was associated
with an increased risk of readmission with COPD among
ex-smokers in the clinical model adjusted analysis. There are
no previous studies assessing the effect of passive smoking on
patients with COPD.
32
Since there is a moderate prevalence of
exposure to passive smoking among non-current smokers
with COPD and a low prevalence of advice against passive
smoking,
13
these results should be seen as potentially
important. A higher score of physical quality of life was asso-
ciated with a decreased risk of readmission with COPD after
adjusting for the clinical model, as in a previous study.
33
Differences in the risk of readmission with COPD between
hospitals were found in the crude and the clinical model
adjusted analysis. In fact, it would be logical that the lack of an
empirical definition of a COPD exacerbation
6
would lead to
some variability between centres. Moreover, geographical
variations in hospital use both for COPD and other diseases
has already been described.
34
Lower FEV
1
and lower PO
2
values were associated with a
higher risk of COPD readmission, as in the previous
case-control EFRAM analysis.
11
Other studies have not found
this association, probably because of the smaller number of
subjects
25
and the use of categorised rather than continuous
variables.
25 35
Interestingly, FEV
1
and PO
2
were not correlated
which suggests that, in patients with a low percentage
predicted FEV
1
,PO
2
acts as an independent factor. Higher lev-
els of P
CO
2
were associated with an increased risk of readmis-
sions, in agreement with the results of Kessler et al.
25
Unfortu-
nately, other physiological parameters—such as
haemodynamic measurements that have been associated with
COPD admission
25
or pulmonary hyperinflation
36
—were not
measured.
Table 3 Multivariate adjusted risk factors of
readmission to hospital for an exacerbation in a cohort
of 312 patients with COPD (Cox regression)
Adjusted HR
(95% CI) p value
>3 COPD admissions in the year
before recruitment*
1.66 (1.16 to 2.39) 0.006
% predicted FEV
1
0.97 (0.96 to 0.99) 0.001
P
O
2
(kPa) 0.88 (0.79 to 0.98) 0.024
Controlled by a:
General practitioner 1.00
Pulmonologist 1.66 (0.98 to 2.80) 0.058
Anticholinergics 1.81 (1.11 to 2.94) 0.017
Usual physical activity (in tertiles):
<79 kcal/day 1.00
79–232 kcal/day 0.87 (0.60 to 1.27) 0.469
>232 kcal/day 0.54 (0.34 to 0.86) 0.010
HR=hazard ratio; CI=confidence interval; FEV
1
=forced expiratory
volume in 1 second.
*HR for “COPD admissions as a continuous variable” 1.19 (95% CI
1.10 to 1.30), p=0.000.
Risk factors of COPD exacerbation 103
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Longitudinal data can be analysed in different ways and, in
our Cox analysis, repeated admissions in the same subject
were not taken into account. However, very similar parameter
estimates were obtained when repeated admissions were
included in a Poisson regression model. Such consistency was
expected since Poisson regression can be seen as a special case
of a proportional hazards model with a constant baseline
hazard.
23
Patients who died without a readmission were excluded, a
decision that could have introduced a degree of survival bias.
However, these patients constituted a small proportion (8%) of
the total and only showed slight differences in age and BMI.
Moreover, when they were included in the analysis by
combining death and readmission as the outcome variable,
the same risk factors for COPD readmission were obtained and
estimates did not change substantially (data available from
the authors).
Patients included in our study were mostly men with a
mean age of 69 years, mean percentage predicted FEV
1
of 36%,
who had experienced a mean of 1.5 admissions in the year
before recruitment. These characteristics represent the usual
pattern of COPD admissions in Barcelona tertiary hospitals
and probably elsewhere, with the exception of the male
predominance. Generalisation of our results should be
restricted to COPD in this stage of the disease since patients in
earlier or advanced stages may differ substantially. Another
potential problem in the method of recruitment is that some
readmissions during the follow up period may not really be
new exacerbations but a relapse of the previous one. In order
to avoid this the analysis was repeated, excluding those
patients whose readmission occurred within 14 days of the
previous discharge (n=38), and very similar results were
obtained (data available from the authors).
This is the first study to show a strong association between
usual physical activity and reduced risk of COPD readmission
which is potentially relevant for rehabilitation and other
therapeutic strategies. Overall, the analysis yielded results
which were consistent with the previous case-control
approach—that is, the association of COPD admission with
clinical variables (previous admissions, lower FEV
1
, and lower
P
O
2
) and the lack of an association with most factors relating
to medical care (influenza and pneumococcal vaccination, res-
piratory rehabilitation, most drug treatments, and adherence
to medication).
ACKNOWLEDGEMENTS
The authors thank M Macharé, M Maresma, A Martín, J Rodríguez, S
Alonso, R Reinón, R Pedreny, N Soler, and A Roig for their help in the
field work, the Registre de Mortalitat de Catalunya (Departament de
Sanitat i Seguretat Social) for providing the information on mortality
data, and Dr J Gea for his help in the interpretation of results for
physical activity.
.....................
Authors’ affiliations
J Garcia-Aymerich, J M Antó, Respiratory and Environmental Health
Research Unit, IMIM, Barcelona, Spain
E Farrero, Department of Pneumology, Ciutat Sanitària I Universitària de
Bellvitge, L’Hospitalet de Llobregat, Spain
M A Félez, Department of Pneumology, Hospital del Mar, Barcelona,
Spain
J Izquierdo, Department of Pneumology, Hospital Germans Trias I Pujol,
Badalona, Spain
R M Marrades, Department of Pneumology, Hospital Clínic I Provincial
de Barcelona, Barcelona, Spain
J M Antó, Department of Experimental and Health Sciences, Universitat
Pompeu Fabra, Barcelona, Spain
EFRAM investigators: J M Antó, J Garcia-Aymerich, J Sunyer, Respiratory
and Environmental Health Research Unit, IMIM, Barcelona; J Alonso,
Health Services Research Unit, IMIM, Barcelona; E Barreiro, M A Félez,
Department of Pneumology, Hospital del Mar, Barcelona; J Escarrabill, E
Farrero, J Redondo, Department of Pneumology, Ciutat Sanitària I
Universitària de Bellvitge, L’Hospitalet de Llobregat; R M Marrades, N
Soler, A Torres, Department of Pneumology, Hospital Clínic I Provincial
de Barcelona, Barcelona; G Bonet, J Izquierdo, E Monsó, J Morera,
Department of Pneumology, Hospital Germans Trias I Pujol, Badalona.
This work was supported in part by grants from Agència d’Avaluació de
Tecnologia Mèdica (5/34/96) and Generalitat de Catalunya-CIRIT
1999SGR 00241; J Garcia-Aymerich was a recipient of a grant from
Instituto de Salud “Carlos III” (97/4365) from 1997 to 2000 and
currently has a fellowship from Institut Municipal d’Investigació Mèdica.
Conflict of interest: none.
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LUNG ALERT .....................................................................................................
Leukotriene receptors are overexpressed in aspirin sensitive asthmatics
m
Sousa AR, Parikh A, Scadding G,
et al
. Leukotriene-receptor expression on nasal mucosal inflammatory cells in
aspirin-sensitive rhinosinusitis.
N Engl J Med
2002;347:1493–9
P
atients with aspirin sensitivity, asthma, and nasal polyps exhibit increased synthesis of cysteinyl
leukotrienes—both basally and in response to exogenous aspirin—and increased responsiveness to
inhaled cysteinyl leukotrienes, in contrast to patients with aspirin tolerant asthma. The authors
hypothesised that the latter effect reflects overexpression of the cysteinyl leukotriene receptor CysLT
1
.
Nasal biopsy specimens were obtained from 22 aspirin sensitive and 12 aspirin tolerant patients with
chronic rhinosinusitis and nasal polyposis. The absolute number (and percentage of CD45+ leucocytes)
of cells expressing the CysLT
1
(but not LTB4) receptor was increased in the aspirin sensitive group, despite
no overall difference in numbers of leucocytes. Subsequently, nasal application of lysine aspirin to aspirin
sensitive patients caused a reduction in the percentage of CD45+ leucocytes expressing the CysLT
1
recep-
tor compared with placebo.
This study raises intriguing questions about the pathogenesis of aspirin sensitive syndromes, provid-
ing evidence for overexpression of the CysLT
1
receptor in addition to increased leukotriene production.
This overexpression is reduced by aspirin desensitisation. Further studies are warranted of leukotriene
antagonists and aspirin desensitisation in patients with nasal polyposis with aspirin sensitivity. Variation
in the response to leukotriene antagonists may well be related to differences in CysLT
1
expression in
inflammatory cells in the upper and lower airway.
S Jenkins
Risk factors of COPD exacerbation 105
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