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ORIGINAL ARTICLE

Inhaled corticosteroids and systemic inflammatory response in

community-acquired pneumonia: A prospective clinical study

MIQUEL FERRER,1* ANTONI TORRES,1* RAQUEL MARTÍNEZ,2* PAULA RAMÍREZ,3* EVA POLVERINO,1*
BEATRIZ MONTULL,2 SALVADOR SIALER,1* MICHAEL S. NIEDERMAN,4 ALVAR AGUSTI1* AND
ROSARIO MENÉNDEZ2*

1
Department of Pneumology, Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona and 2Department
of Pneumology and 3Intensive Care Unit, University Hospital La Fe, Valencia, Spain, and 4Department of Medicine and
Division of Pulmonary and Critical Care Medicine, Winthrop-University Hospital, Mineola, New York, USA

ABSTRACT
Background and objective: The previous use of
inhaled corticosteroids (ICS) may reduce the inflam-
matory response and mortality in patients with
community-acquired pneumonia (CAP).
Methods: We measured serum levels of several
inflammatory biomarkers, as well as mortality at
various time-points, in 663 consecutive patients hospi-
talized for CAP; 128 (19%) were receiving chronic out-
patient treatment with ICS. Patients on previous oral
corticosteroids were excluded from the analysis.
Results: On admission, patients treated with ICS were
older; had been diagnosed with chronic obstructive
pulmonary disease (COPD), asthma and pneumonia in
the previous year more often; and had higher CAP
severity risk classes and lower tumour necrosis factor
(TNF)-alpha (P < 0.001) and interleukin (IL)-6
(P = 0.015) serum levels. After adjusting for potential
confounders, this association persisted for TNF-alpha
(P < 0.001), but not for IL-6. Mortality at 30 and 90 days
tended to be lower in patients treated with ICS
(P = 0.062 and 0.050, respectively), but mortality was
similar after 1 year in both groups (16, 13% vs 81, 15%
for patients treated and not treated with ICS, respec-
tively). Hospital readmission rate after 1 year was
higher in patients treated with ICS (49, 38% vs 109,
20%, P < 0.001). The association of ICS treatment with
a previous diagnosis of pneumonia, lower levels of
TNF-alpha and IL-6 on admission and higher readmis-
sion rates during follow up persisted in the
subpopulation of 210 patients with COPD.
Conclusions: Previous use of ICS in patients hospital-
ized for CAP is associated with a reduced systemic
inflammatory response without any impact on long-
term mortality.
Correspondence: Miquel Ferrer, UVIR, Pneumology Service,
Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. Email:
miferrer@clinic.ub.es
*Network for Biomedical Research in Respiratory Disease
(CibeRes, CB06/06/0028).
Received 8 January 2014; invited to revise 18 February 2014;
revised 4 March 2014; accepted 4 April 2014 (Associate Editor:
Marcos Restrepo).
Article first published online: 9 June 2014
© 2014 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE
Inhaled corticosteroids treatment in patients with
community-acquired pneumonia is associated
with a reduced systemic inflammatory response
without any impact on long-term mortality. These
results persisted in the subpopulation of chronic
obstructive pulmonary disease patients.
Key words: community-acquired pneumonia, inflammatory
biomarker, inhaled corticosteroid, systemic inflammatory
response, tumour necrosis factor-alpha.
Abbreviations: CAP, community-acquired pneumonia; CI,
confidence interval; COPD, chronic obstructive pulmonary
disease; ICS, inhaled corticosteroid; IDSA/ATS, Infectious
Disease Society of America/American Thoracic Society; IL, inter-
leukin; OR, odds ratio; PSI, Pneumonia Severity Index;
TNF, tumour necrosis factor.
INTRODUCTION
Community-acquired pneumonia (CAP) is a signifi-
cant cause of morbidity and mortality worldwide.1
The inflammatory response to CAP can have dual
effects. On the one hand, the effective host defence
against bacterial infection depends on the activation
and recruitment of phagocytes in response to
cytokine expression.2–4 On the other hand, however,
this inflammatory response can have pulmonary and
systemic deleterious effects.5 In fact, the levels of
several inflammatory biomarkers improve mortality
prediction in patients with CAP when added to sever-
ity scales.6
Systemic glucocorticoids decrease systemic and
lung inflammatory response in patients with severe
pneumonia7 and may reduce their mortality.8–10 Like-
wise, two large, retrospective, observational, database
studies had recently reported that the previous use of
inhaled corticosteroids (ICS) in patients with chronic
Respirology (2014) 19, 929–935
doi: 10.1111/resp.12324
930
obstructive pulmonary disease (COPD) was associ-
ated with reduced CAP mortality.11,12 Whether this was
due to the modulation of the systemic inflammatory
response to CAP13,14 and whether this occurs also in
CAP patients without COPD is unknown. Of note,
however, we have recently reported that previous use
of ICS in patients with CAP is associated with a
reduced incidence of pleural complications.15
We hypothesized that previous treatment with ICS
reduces the systemic inflammatory response and
improves short- and long-term mortality in patients
hospitalized because of CAP, irrespective of the pres-
ence of COPD. We tested this hypothesis by compar-
ing the serum levels of a panel of inflammatory
biomarkers at admission and mortality at various
time-points in a consecutive cohort of patients hos-
pitalized for CAP.
METHODS
Study design and ethics
We prospectively included in the database consecu-
tive patients aged ≥16 years hospitalized with a diag-
nosis of CAP at Hospital Universitario La Fe, Valencia,
and Hospital Clínic, Barcelona, Spain, from January
2003 to October 2005. Pneumonia was defined as a
new pulmonary infiltrate on the admission chest
radiograph and symptoms and signs of lower respira-
tory tract infection. Exclusion criteria were: (i) hospi-
talization in the previous 15 days; (ii) previous use of
oral corticosteroids in the previous 3 months; (iii)
other causes of immunosuppression such as human
immunodeficiency virus infection, solid organ or
hematopoietic transplant, other immunosuppressive
therapy, and leukopenia (<1000 mm−3) or neutropenia
(<500 mm−3) not attributed to pneumonia; and (iv)
previous ICS use for less than 3 months. The study
was approved by the Ethics Committee of both hos-
pitals and written informed consent was obtained.
Diagnosis and management of pneumonia
Causative microorganisms were identified in positive
cultures of sputum or tracheal aspirate, blood or
pleural effusion, and/or by urinary determinations of
the Legionella pneumophila and Streptococcus
pneumoniae antigens. Clinical decisions were taken
by the attending physicians. The empirical antimicro-
bial treatment was chosen following international
guidelines,1 and administered as soon as possible
(always before 6 h after admission to the emergency
department).
Serum inflammatory biomarkers
Blood samples were taken within the first 24 h of
admission, centrifuged and frozen at −80°C. Determi-
nation of the serum levels of interleukin (IL)-1, IL-6,
IL-8, IL-10 and tumour necrosis factor (TNF)-alpha
was performed with a commercial enzyme immuno-
assay technique (BioSource, Nivelles, Belgium).
Limits of detection were 2 pg/mL for IL-6, 0.7 pg/mL
for IL-8, 1 pg/mL for IL-10 and 2 pg/mL for TNF-
alpha and IL-1. An immunoluminometric technique
Respirology (2014) 19, 929–935
M Ferrer et al.
was used to measure Procalcitonin (Liaison Brahms
PCT, DiaSorin, Saluggia, Italy) with a detection limit of
0.09 ng/mL. C-reactive protein was measured using a
commercially immunoturbidimetric method (Bayer
Diagnostics, Leverkusen, Germany) with an Advia
2400 (Siemens Healthcare, Erlangen, Germany; detec-
tion limit 0.1 mg/dL).
Data collection and definitions
The following variables were recorded on admission:
age, gender, tobacco and alcohol consumption, reason
for ICS treatment, particularly COPD and asthma,
presence of other comorbidities (heart, renal, liver,
neurological and neoplastic disease, and diabetes
mellitus), previous antibiotic use, clinical symptoms
and signs, arterial blood gases, chest radiograph,
laboratory parameters, pulmonary complications
(which included pleural effusion, cavitation, atelecta-
sis and multi-lobar radiologic involvement), diagnos-
tic procedures and therapy. Likewise, the length of
hospital stay, mortality at 30 days, 90 days and 1 year,
and hospital readmission rate were noted. We calcu-
lated the Pneumonia Severity Index (PSI)16 and the
confusion, elevated blood urea nitrogen, respiratory
rate and blood pressure plus age ≥65 years (CURB-65)
score17 at admission. Severe CAP was defined accord-
ing to the Infectious Disease Society of America/
American Thoracic Society (IDSA/ATS) guidelines.1
Data analysis
Results are presented as mean ± standard deviation,
proportion or range as appropriate. We compared the
characteristics, including serum levels of biomarkers
taken at hospital admission, and outcomes between
patients with chronic (at least for 3 months prior to
hospital admission) outpatient treatment with ICS or
not both in the entire study population and after
stratification by the presence or absence of COPD. To
this end, we used the chi-square or Fisher’s exact tests
to compare categorical variables and the Student’s
t-test or the non-parametric Mann–Whitney test to
compare continuous variables as appropriate.
We used multivariate logistic regression (P < 0.10) to
adjust the association between ICS use and serum
levels of inflammatory biomarkers for potential con-
founders identified in the bivariate analysis, such as
variables associated with ICS treatment (age, smoking
history, PSI, CURB-65, COPD, asthma, neurological
disease, L. pneumophila and Pseudomonas aeru-
ginosa aetiology), as well as others (severe CAP criteria
and previous macrolide treatment), and adjusted odds
ratio (OR) and 95% confidence intervals (CI) were cal-
culated. Due to the skewed distribution of cytokine
serum levels, results were log transformed. Data were
processed with IBM SPSS Statistics Version 20 (IBM
Corporation, Armonk, NY, USA). The level of signifi-
cance was set at 0.05 (two-tailed).
RESULTS
Patient characteristics on admission
We included 663 consecutive patients with CAP; 128
(19%) were on chronic outpatient treatment with ICS
© 2014 Asian Pacific Society of Respirology
Inhaled corticosteroids in pneumonia 931

at hospital admission. Table 1 presents their main Table 1 Patients’ characteristics on admission
clinical characteristics on hospital admission,
including the indications for ICS treatment (this was No ICS ICS
missing in eight patients receiving ICS). Patients (n = 535) (n = 128) P
treated with ICS were older, had higher PSI and
Gender (male/female) 336/199 91/37 0.098
CURB-65 risk classes, more current or former
Age, years 65 ± 18 72 ± 11 <0.001
smokers, higher rate of pneumonia in the previous
Smoking (current or 303 (57%) 92 (74%) 0.002
year, higher rate of diagnosis of COPD and asthma,
former)
and less frequent underlying neurological disease.
Alcohol abuse (current 67 (13%) 17 (14%) 0.89
Aetiological diagnoses were relatively similar in both
or former)
groups (Table 1) although L. pneumophila was less
Chronic respiratory
frequent in patients with ICS (P = 0.042), with a non-
disease
significant trend for higher rate of P. aeruginosa and
COPD 130 (24%) 80 (63%) <0.001
Enterobacteriaceae in this group. The most frequent
Asthma 12 (2%) 28 (22%) <0.001
combinations of empiric antibiotics were a third-
Bronchiectasis 7 (1%) 4 (3%) 0.29
generation cephalosporin plus a macrolide in 314
Pulmonary sequelae of 10 (2%) 6 (5%) 0.13
(49%) patients, a fluoroquinolone monotherapy
tuberculosis
in 186 (28%), a third-generation cephalosporin plus
Other 9 (2%) 2 (2%) NA
fluoroquinolone in 50 (7%), amoxicillin-clavulanate
Other comorbidities
plus a macrolide in 44 (7%) and amoxicillin-
Chronic heart disease 90 (17%) 29 (23%) 0.17
clavulanate monotherapy in 18 (3%) patients, without
Chronic renal failure 29 (5%) 7 (6%) >0.99
significant differences between both groups.
Chronic liver disease 21 (4%) 2 (2%) 0.30
Although the overall rate of pulmonary complications
Cancer 20 (4%) 5 (4%) >0.99
tended to be less frequent in patients treated with ICS
Diabetes mellitus 95 (18%) 31 (24%) 0.13
(P = 0.063), the proportion of severe CAP by IDSA/ATS
Neurological disease 119 (22%) 16 (13%) 0.020
criteria, the use of non-invasive ventilation and the
Previous antibiotics 178 (33%) 42 (33%) 0.99
rate of intensive care unit admission were similar in
Macrolides 36 (7%) 6 (5%) 0.52
both groups (Table 2).
Fluoroquinolones 27 (5%) 10 (8%) 0.31
Cephalosporins 26 (5%) 12 (9%) 0.082
Inflammatory biomarkers Penicillins 65 (12%) 9 (7%) 0.14
As shown in Table 3, the serum levels on admission Other 27 (5%) 5 (4%) NA
for the majority of systemic inflammatory biomarkers Pneumonia in the 117 (22%) 60 (47%) <0.001
were similar in CAP patients who had received ICS or previous year
not (Table 3), except for those of TNF-alpha Previous influenza 215 (40%) 71 (56%) 0.002
(P < 0.001) and IL-6 (P = 0.015), that were lower in the vaccination
former (Fig. 1). After adjusting for potential con- Previous pneumococcal 72 (14%) 33 (26%) 0.001
founders (see Methods), ICS use remained signifi- vaccination
cantly associated with lower serum levels of Aetiological diagnosis 222 (41%) 57 (45%) 0.60
TNF-alpha (adjusted OR for each log unit 0.506, 95% Streptococcus 110 (50%) 32 (56%) 0.46
CI: 0.361–0.708, P < 0.001), while those of IL-6 just pneumoniae†
failed to reach statistical significance (adjusted OR for Pseudomonas 18 (8%) 10 (18%) 0.066
each logarithmic unit 0.888, 95% CI: 0.775–1.018, aeruginosa†
P = 0.089). Atypical†,‡ 23 (10%) 4 (7%) 0.61
Legionella 25 (11%) 1 (2%) 0.042
pneumophila†
Outcomes Haemophilus 19 (9%) 6 (11%) 0.85
Patients treated with ICS showed lower 30-day and influenzae†
90-day mortality rates that almost reached statistical Staphylococcus 22 (10%) 2 (4%) 0.20
significance, but differences disappeared at 1 year aureus†,§
follow up (Table 2). By contrast, all-cause hospital Enterobacteriaceae† 13 (6%) 8 (14%) 0.075
readmission at 1 year follow up was more frequent in Respiratory viruses† 10 (5%) 4 (7%) 0.67
patients treated with ICS (Table 2). Other† 15 (7%) 3 (5%) NA
The serum levels of CRP, procalcitonin, IL-6 and Mixed aetiology 32 (6%) 12 (9%) 0.24
IL-8 were significantly higher in patients who died
within 30 days, while differences in TNF-alpha and †
Percentages of pathogens related to the number of patients
IL-1 were in the limits of statistical significance with aetiological diagnosis in each group.
‡
(Table 4). Atypical agents include Mycoplasma pneumoniae, Coxiella
burnetti and Chlamydia spp.
§
Includes methicillin-sensitive and methicillin-resistant
Influence of COPD Staphylococcus aureus.
We did not find any major difference in the subgroup COPD, chronic obstructive pulmonary disease; ICS, inhaled
corticosteroids; NA, not applicable.
of patients with COPD only, treated or not with ICS. In
these patients, the rate of pneumonia in the preced-
ing year was also higher in those treated with ICS
© 2014 Asian Pacific Society of Respirology Respirology (2014) 19, 929–935
932 M Ferrer et al.

Table 2 Severity criteria of CAP at admission, length of

stay and mortality

No ICS ICS
(n = 535) (n = 128) P

PSI risk classes: 0.013

Class I–III 286 (53%) 52 (41%)
Class IV–V 249 (47%) 76 (59%)
CURB-65 1.4 ± 1.1 1.7 ± 1.1 0.016
Severe CAP (IDSA/ATS 97 (18%) 22 (17%) 0.90
criteria)
ICU admission 47 (9%) 10 (8%) 0.86
Use of non-invasive 15 (3%) 6 (5%) 0.42
ventilation
Figure 1 Schematic representation of the serum levels of
Patients with pulmonary 191 (36%) 34 (27%) 0.063
tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 at
complications
admission in chronic obstructive pulmonary disease patients
Pleural effusion 84 (16%) 14 (11%) 0.22 with and without chronic outpatient treatment with inhaled
Multi-lobar 122 (23%) 24 (19%) 0.38 corticosteroids (ICS). The upper and lower limits of the boxes
involvement represent the interquartile range, the inner horizontal line repre-
Cavitation 10 (2%) 1 (1%) 0.63 sents the median value, and the upper and lower vertical lines
Atelectasis 12 (2%) 2 (2%) 0.89 represent percentiles 10 and 90, respectively.
Hospital stay, days 9±8 10 ± 9 0.25
Mortality at 30 days 39 (7%) 3 (2%) 0.062
Mortality at 90 days 49 (9%) 5 (4%) 0.050 Table 4 Median (interquartile range) serum levels of
Mortality at 1 year 81 (15%) 16 (13%) 0.44 inflammatory biomarkers at admission and 30-day
Hospital readmission at 109 (20%) 49 (38%) <0.001 mortality
1 year
Alive (n = 619) Dead (n = 42) P
CAP, community-acquired pneumonia; CURB-65, confusion,
elevated blood urea nitrogen, respiratory rate and blood pres- Procalcitonin, 0.46 (0.17–1.97) 1.78 (0.47–15.30) <0.001
sure plus age ≥65 years; ICS, inhaled corticosteroids; ICU, Inten- ng/mL
sive care unit; IDSA/ATS, Infectious Disease Society of America/ C-reactive 15 (8–24) 22 (15–30) 0.001
American Thoracic Society; PSI, Pneumonia Severity Index.
protein,
mg/dL
TNF-alpha, 26 (15–43) 35 (17–67) 0.051
pg/mL
Table 3 Median (interquartile range) serum levels of IL-1, pg/mL 14 (3–31) 17 (5–54) 0.059
inflammatory biomarkers at admission in patients with IL-6, pg/mL 81 (29–217) 195 (78–954) <0.001
and without chronic outpatient treatment with ICS IL-8, pg/mL 8 (2–17) 35 (6–65) <0.001
IL-10, pg/mL 5 (0–17) 10 (0–37) 0.13
No ICS
(n = 535) ICS (n = 128) P IL, interleukin; TNF, tumour necrosis factor.

Procalcitonin, 0.48 (0.19–2.26) 0.52 (0.16–2.16) 0.83

ng/mL
C-reactive protein, 16 (8–25) 13 (7–22) 0.10 DISCUSSION
mg/dL
TNF-alpha, pg/mL 28 (16–46) 17 (11–33) <0.001 Our results show that chronic outpatient ICS treat-
IL-1, pg/mL 15 (3–32) 14 (3–31) 0.67 ment is associated with a reduced systemic inflam-
IL-6, pg/mL 93 (35–233) 66 (18–185) 0.015 matory response without any impact on long-term
IL-8, pg/mL 8 (2–19) 9 (3–18) 0.97 mortality. This is independent of the presence of
IL-10, pg/mL 6 (0–19) 5 (0–13) 0.36 COPD.
Several studies have shown that ICS treatment
ICS, inhaled corticosteroids; IL, interleukin; TNF, tumour necro-
sis factor.
decreases the systemic levels of a number of inflam-
matory biomarkers in COPD.13,14,18 Particularly,
inhaled fluticasone significantly reduced the serum
levels of soluble TNF receptor-2, among other
cytokines.18 Whether this occurs also in patients with
(Table 5), but differences in short-term mortality were CAP is unknown. The present study suggests that ICS
less obvious. The associations of ICS treatment with might result in a selective modulation of the mecha-
reduced TNF-alpha and IL-6 persisted (adjusted OR nisms of defences to infection, with possible suppres-
for each logarithmic unit 0.476, 95% CI: 0.284–0.796, sion of the classical-M1 pathway.19,20 It is known that
P = 0.005 for TNF-alpha; and adjusted OR 0.844, 95% the classic M1 pathway associated with the antimi-
CI: 0.703–1.012, P = 0.067 for IL-6). crobial activity of alveolar macrophages21 is activated
Respirology (2014) 19, 929–935 © 2014 Asian Pacific Society of Respirology
Inhaled corticosteroids in pneumonia
Table 5 Main baseline characteristics and outcome vari-
ables in CAP patients with COPD, treated or not with ICS
No ICS ICS
(n = 130) (n = 80)
Age, years 71 ± 11 74 ± 9
PSI risk classes:
Class I–III 50 (38%) 27 (34%)
Class IV–V 80 (62%) 53 (64%)
CURB-65 1.7 ± 1.1 1.7 ± 1.0 0.82
Pneumonia in the previous 40 (31%) 46 (58%) <0.001
year
Previous influenza vaccination 61 (55%) 48 (68%)
Previous anti-pneumococcal 27 (24%) 25 (35%)
vaccination
Patients with pulmonary 36 (28%) 20 (25%)
complications
Mortality at 30 days 9 (7%) 2 (2.5%)
Mortality at 90 days 14 (11%) 3 (4%)
Mortality at 1 year 22 (17%) 10 (13%)
Hospital readmission at 1 year 36 (28%) 35 (44%)
CAP, community-acquired pneumonia; COPD, chronic obstruc-
tive pulmonary disease; CURB-65, confusion, elevated blood
urea nitrogen, respiratory rate and blood pressure plus age ≥65
years; ICS, inhaled corticosteroids; PSI, Pneumonia Severity
Index.
in patients with CAP without COPD, with significant
increases in the expression of TNF-alpha and IL-6.19 In
our study, we observed the opposite response (an
association of ICS use with decreases in the serum
levels of TNF-alpha and IL-6). Bacterial products may
be involved in this effect, together with different
cytokines or lipid mediators such as lipopoly-
saccharide that also promote and maintain the M1
response, resulting in a positive pro-inflammatory
feedback. By contrast, this type of activation, as well
as the alternative M2 activation of macrophages that
promote tissue regeneration, angiogenesis, cell pro-
liferation and inhibition of the inflammatory
response,22 were not observed in patients with CAP
and COPD.19 This different type of activation induces
different inflammatory responses and may be
involved in the different outcome of CAP observed in
some studies when COPD presents simulta-
neously.23–25 The role that ICS might play in all of these
has been hypothesized.26 Our results may actually
support the hypothesis that there is chronic suppres-
sion of the M1 pathway in alveolar macrophages by
ICS treatment. This could explain the high rate of
pneumonia associated with ICS treatment in COPD
observed in the present study (Table 1).
It has been recently reported that ICS use in hos-
pitalized patients with CAP is associated with higher
severity risk scales at admission, mainly due to older
age.27 In our study, we reproduced these observa-
tions. Likewise, three observational studies in COPD
patients hospitalized with CAP found an association
between outpatient ICS therapy and decreased mor-
tality at 30 and 90 days11,12 and complications.15
Although these associations were not confirmed in a
© 2014 Asian Pacific Society of Respirology
933
more recent prospective, observational study in a
smaller population of patients,28 our results also
support a trend to lower short-term mortality asso-
ciated with ICS, that disappeared after 1 year of
P follow up (Table 2). However, this study was not
powered to assess differences in mortality, and there-
0.10
fore, a larger number of patients would have been
0.59
required for this purpose. Different to our study, the
previous investigations did not follow up patients
beyond 90 days,11,12 and therefore, the lower mortal-
ity associated with ICS treatment was restricted to
this period of time.
In addition, we observed in the group of patients
0.089
treated with ICS, including COPD patients, a signifi-
0.11
cantly higher rate of hospital readmission in the year
following the present episode. We did not register the
0.67
specific cause of hospital readmission, and therefore,
our study does not allow explaining the cause of this
0.16
association. Since COPD patients with frequent exac-
0.070
erbations are more prone to have an ICS prescription
0.44
according to the guidelines and to have an exacerba-
0.017
tion that may lead to a hospitalization, we do not
know if ICS treatment is responsible of this finding or
is simply a marker of hospital readmission. Similarly,
the higher proportion of pneumonia in the previous
year found in patients treated with ICS fits with the
extensive body of knowledge on the association
between ICS treatment and increased risk of pneu-
monia in COPD patients.29–32
Finally, to our knowledge, the association between
treatment with ICS and less frequent L. pneumophila
aetiology in patients with CAP has not been previ-
ously reported. Further studies should explore and
confirm or not this association.
Several limitations of our study need to be acknowl-
edged. First, this is a descriptive study, so no causal
effects can be inferred. Second, compared with previ-
ous series,11,12 it included a relatively low number of
patients albeit our characterization of the systemic
inflammatory response was more detailed. Third, the
diagnosis of COPD and asthma are self-reported by
the patient and not always confirmed by lung func-
tion tests. Fourth, the specific type of ICS and the
previous dose and duration of treatment were not rec-
orded. It is known that fluticasone and budesonide,
the most frequently used drugs in clinical practice,
have different pharmacokinetic properties and differ-
ent suppression of pro-inflammatory cytokine pro-
duction by alveolar macrophages and airway
epithelial cells.33 Indeed, both drugs have been asso-
ciated with different rates of pneumonia and admis-
sion to hospital in COPD patients treated with fixed
combinations of ICS and long-acting β2 agonists.34
Fifth, information regarding treatment with intra-
venous corticosteroids during hospital stay was not
systematically recorded. However, prior oral steroids
were exclusion criteria, and serum levels of
biomarkers and samples for aetiological diagnosis
were collected at admission. We think therefore that it
did not influence the different levels of biomarkers at
hospital admission between both groups. Finally, we
did not systematically collect information on use
of inhaled bronchodilators. Studies in recent years
have shown that long-acting β2 agonists35,36 and
Respirology (2014) 19, 929–935
934
tiotropium,37 often used together with ICS treatment,
can modify the expression of cytokines during rhino-
virus infection.
In conclusion, our results show that previous treat-
ment with ICS in patients with CAP appears to be
associated with a reduced systemic inflammatory
response without any impact on long-term mortality.
This effect is independent of the concomitant pres-
ence of COPD.
Acknowledgements
We thank Drs Jacobo Sellares, Carlos Agusti and Juan Cordoba
for their collaboration in the study design, in the recruitment of
patients and in the microbiologic processing of samples. Finan-
cial support statement came from CibeRes (CB06/06/0028)-ISCiii,
2009 SGR 911, FIS 08/0727 and 08/0472, Marato TV3 (040530),
SEPAR 2011, and IDIBAPS.
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