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Copyright 2015 American Medical Association. All rights reserved.
Effect of Corticosteroids on Treatment Failure Among
Hospitalized Patients With Severe Community-Acquired
Pneumonia and High Inflammatory Response
A Randomized Clinical Trial
Antoni Torres, MD, PhD; Oriol Sibila, MD, PhD; Miquel Ferrer, MD,PhD; Eva Polverino, MD, PhD; Rosario Menendez, MD,PhD; Josep Mensa, MD, PhD;
Albert Gabarrús, MSc; Jacobo Sellarés, MD, PhD; Marcos I. Restrepo,MD, MSc; Antonio Anzueto, MD, PhD; Michael S. Niederman, MD; Carles Agustí, MD,PhD
IMPORTANCE In patients with severe community-acquired pneumonia, treatment failure is
associated with excessive inflammatory response and worse outcomes. Corticosteroids may
modulate cytokine release in these patients, but the benefit of this adjunctive therapy
remains controversial.
OBJECTIVE To assess the effect of corticosteroids in patients with severe community-
acquired pneumonia and high associated inflammatory response.
DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized,double-blind,
placebo-controlled trial conducted in 3 Spanish teaching hospitals involving patients with
both severe community-acquired pneumonia and a high inflammatory response, which was
defined as a level of C-reactive protein greater than 150 mg/L at admission. Patients were
recruited and followed up from June 2004 through February 2012.
INTERVENTIONS Patients were randomized to receive either an intravenous bolus of
0.5 mg/kg per 12 hours of methylprednisolone (n = 61) or placebo (n = 59) for 5 days started
within 36 hours of hospital admission.
MAIN OUTCOMES AND MEASURES The primary outcome was treatment failure (composite
outcome of early treatment failure defined as [1] clinical deterioration indicated by
development of shock, [2] need for invasive mechanical ventilation not present at baseline, or
[3] death within 72 hours of treatment; or composite outcome of late treatment failure defined
as [1] radiographic progression, [2] persistence of severe respiratory failure, [3] development of
shock, [4] need for invasive mechanical ventilation not present at baseline, or [5] death
between 72 hours and 120 hours after treatment initiation; or both early and late treatment
failure). In-hospital mortality was a secondary outcome and adverse events were assessed.
RESULTS There was less treatment failure among patients from the methylprednisolone
group (8 patients [13%]) compared with the placebo group (18 patients [31%]) (P= .02), with
a difference between groups of 18% (95% CI, 3% to 32%). Corticosteroid treatment reduced
the risk of treatment failure (odds ratio, 0.34 [95% CI, 0.14 to 0.87]; P= .02). In-hospital
mortality did not differ between the 2 groups (6 patients [10%] in the methylprednisolone
group vs 9 patients [15%] in the placebo group; P= .37); the difference between groups was
5% (95% CI, −6% to 17%). Hyperglycemia occurred in 11 patients (18%) in the
methylprednisolone group and in 7 patients (12%) in the placebo group (P= .34).
CONCLUSIONS AND RELEVANCE Among patients with severe community-acquired pneumonia
and high initial inflammatory response, the acute use of methylprednisolone compared with
placebo decreased treatment failure. If replicated, these findings would support the use of
corticosteroids as adjunctive treatment in this clinical population.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00908713
JAMA. 2015;313(7):677-686. doi:10.1001/jama.2015.88
Editorial page 673
Author Audio Interview at
jama.com
Supplemental content at
jama.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Antoni
Torres, MD,PhD, Servei de
Pneumologia, Hospital Clinic,
C/ Villarroel 170, 08036 Barcelona,
Spain (atorres@ub.edu).
Section Editor: Derek C. Angus, MD,
MPH, Associate Editor,JAMA
(angusdc@upmc.edu).
Research
Original Investigation |CARING FOR THE CRITICALLY ILL PATIENT
(Reprinted) 677
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Community-acquired pneumonia is the leading infec-
tious cause of death in developed countries. Despite ad-
vances in antibiotic treatment, mortality among hos-
pitalized patients with community-acquiredpneumonia is still
high, especially in those with severe pneumonia
1,2
and in those
who experience treatment failure
3,4
(observed in 10%-20% of
patients). In an earlier study conducted by the Neumofail
Group,
3
patients with treatment failure had higher mortality
compared with those who did not experience treatment fail-
ure (25% vs 2%, respectively), and it was possible to use treat-
ment failure as a surrogate parameter for mortality. In pa-
tients with community-acquired pneumonia, an excessive host
inflammatory response is associated with treatment failure dur-
ing intensive care unit (ICU) admission
5
and mortality.
6
Corticosteroids inhibit the expression and action of many
cytokines involved in the inflammatory response associated
with pneumonia.
7
In clinical practice, use of corticosteroids
for patients with community-acquired pneumonia remains
controversial, with some studies showing a benefit in clinical
outcomes (radiographic progression, prevention of shock, re-
spiratory failure, length of stay, and mortality),
8-11
and an-
other study showing no effect.
12
However, most of these studies
10,11,13
did not include
patients with the most severe cases of community-acquired
pneumonia and all of them enrolled patients without con-
sideration of the level of initial systemic inflammatory
response. Two meta-analyses
14,15
found improved mortality
in the subgroup of patients with severe community-
acquired pneumonia who received corticosteroid treatment.
Our hypothesis was that corticosteroids may modulate
cytokine release in these patients. Reducing inflammation may
be followed by a decrease in treatment failure in hospitalized
patients with community-acquired pneumonia. By examin-
ing treatment failure in a placebo-controlled intervention lim-
ited to only patients with severe community-acquired pneu-
monia and a high inflammatory response, we targeted those
most likely to benefit (and least likely to be harmed due to su-
perinfection) from corticosteroids.
Methods
Design and Patients
We undertook a multicenter, randomized, double-blind, pla-
cebo-controlled trial in patients with severe community-
acquired pneumonia and a high inflammatory response at 3
Spanish teaching hospitals. Patients were prospectively en-
rolled and followed up from June 2004 through February 2012.
Additional details about the trial protocol appear in Supplement
1 and in the eMethods in Supplement 2. The local ethics com-
mittees approved the study protocoland written informed con-
sent was obtained from all participants or their authorized rep-
resentatives.
Patients were eligible if they met the following criteria:
(1) were aged 18 years or older, (2) had clinical symptoms sug-
gesting community-acquired pneumonia (cough, fever, pleu-
ritic chest pain, or dyspnea), (3) had a new chest radiographic
infiltrate, (4) met severe community-acquired pneumonia
criteria (defined by modified American Thoracic Society
criteria
16
or risk class V for the Pneumonia Severity Index
17
),
and (5) had a C-reactive protein (CRP) level of greater than
150 mg/L at admission (to convert CRP to mmol/L, multiply
by 9.524). The rationale for this cutoff comes from the analy-
ses performed in the study by the Neumofail Group,
3
which
included some of us. A CRP level of 150 mg/L was the 25th
percentile of patients with community-acquired pneumonia
and treatment failure, and we expected that choosing the
25th percentile would increase the chance of recruiting
patients with a high inflammatory response. We published
these data in 2008.
18
Patients were excluded if they had 1 of the following
criteria: (1) prior treatment with systemic corticosteroids,
(2) nosocomial pneumonia, (3) reported severe immunosu-
pression (human immunodeficiency virus infection, immu-
nosuppressive conditions or medications), (4) preexisting
medical condition with a life expectancy of less than 3
months, (5) uncontrolled diabetes mellitus, (6) major gastro-
intestinal bleeding within 3 months, or (7) a condition requir-
ing acute treatment with greater than 1 mg/kg/d of methyl-
prednisolone or its equivalent. Patients with pandemic H1N1
influenza A pneumonia were excluded.
Procedures
Patients were randomized to receiveeither an intravenous bo-
lus of 0.5 mg/kg per 12 hours of methylprednisolone or pla-
cebo for 5 days started within 36 hours of hospital admission.
Randomization was based on 1-to-1 allocation of prenum-
bered boxes containing dosing units with identical appear-
ance for methylprednisolone and placebo. Patients, investi-
gators, and data assessors were blinded to treatmentalloc ation.
All patients were treated with antibiotics according to in-
ternational guidelines.
19
Antibiotic treatments were not guided
by levels of procalcitonin.
Definitions
The primary efficacy outcome was the rate of treatment fail-
ure, which includes treatment failure that occurred early,
late, or at both times. Early treatment failure was defined as
clinical deterioration within 72 hours of treatment (included
development of shock, need for invasive mechanical ventila-
tion not present at baseline, or death). Late treatment failure
was defined as radiographic progression (increase of ≥50% of
pulmonary infiltrates compared with baseline), persistence
of severe respiratory failure (ratio of PaO
2
to fraction of
inspired oxygen <200 mm Hg, with respiratory rate ≥30
breaths/min in patients not intubated), development of
shock, need for invasive mechanical ventilation not present
at baseline, or death between 72 hours and 120 hours after
treatment initiation. These criteria have been used previ-
ously with modifications.
3
Secondary efficacy outcomes included time to clinical sta-
bility, length of ICU and hospital stays, and in-hospital mor-
tality. Clinical stability was modified from the definition by
Halm et al,
20
and was determined when the following values
were achieved for all parameters: temperature of 37.2°C or
lower, heart rateof 100 beats/min or lower, systolic blood pres-
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sure of 90 mm Hg or higher, and arterial oxygen tension of
60 mm Hg or higher when the patient was not receiving supple-
mental oxygen. In patients receiving oxygen therapy at home,
stability was considered to be achieved when their oxygen
needs were the same as before admission. Oral switch was de-
fined when intravenous antibiotics for patients with commu-
nity-acquired pneumonia were stopped and the same class of
them were administered orally.
Microbiological examination was performed at the time of
clinical presentation and included collection of a sputum
sample, urine sample, 2 samples of blood, and nasopharyn-
geal swab samples. Thoracocentesis and bronchoscopic
samples were obtained when possible. The criteria for micro-
biological diagnosis were described elsewhere.
21
Standard laboratory assessment performed at presenta-
tion included renal and liver functions, electrolytes, blood
glucose, CRP, and hematology. Arterial blood gases were per-
formed at admission and thereafter as clinically indicated.
Interleukin 6, IL-8, IL-10, procalcitonin, and CRP levels
were obtained on the first day and after 3 days and 7 days of
treatment. The laboratory techniques used were described
elsewhere.
5
Adverse events during hospitalstay included hyperglyce-
mia, superinfection, gastrointestinal bleeding, delirium, acute
kidney injury, and acute hepatic failure. Superinfection was
considered to have occurred when patients tested positive for
a nosocomial infection of any source.
Statistical Analysis
The study was based on the assumption that the placebo group
would have a treatment failure rate of 35%.
3
According to a
2-sided type I error of 0.05 and 80% power to detect an abso-
lute 20% reduction in treatment failure by methylpredniso-
lone compared with placebo, the sample size was 60 patients
in each group. The rationale comes from the study by the
Neumofail Group,
3
which included some of us and was a pro-
spective, multicenter,obser vational study designed to evalu-
ate the rates of treatment failure in a general populationof pa-
tients with community-acquired pneumonia. In that study, we
found a total treatment failure rate of 15% and a mortality rate
of25%inpatientswithtreatmentfailure;however,only2%
of the study population did not experience treatment failure.
Even though mortality was not the primary study outcome,
we thought that a 20% rate of treatment failure was clinically
relevant because this could have an important effect on other
outcomes such as the need for mechanical ventilation and
length of ICU and hospital stay.
A prespecified interim analysis was planned at 50% (60 of
120) of patient accrual. In the primary efficacy outcome com-
parison, a Pvalue of less than .03 was considered to indicate
significance to maintain an overall type I error of 0.05 for the
interim and final analyses (Pocock test). The interim analysis
showed no significant differences with regard to treatment fail-
ure (3 of 30 patients [10%] in the methylprednisolone group
vs 9 of 30 patients [30%] in the placebo group, P= .05); there-
fore, the study was continued as planned.
Efficacy data were analyzed for both the intention-to-
treat and the per-protocol populations. The intention-to-treat
population included all randomized patients who received at
least 1 dose of the study drug. The per-protocol population in-
cluded all randomized patients who met all inclusion criteria,
received at least 6 doses of the study drug, and did not have se-
rious deviations from the protocol.
We report the number and percentage of patients for cat-
egorical variables, the median and interquartile range for con-
tinuous variables with nonnormal distribution, and the mean and
standard deviation for those with normal distribution. Categori-
cal variables were compared using the χ
2
test or the Fisher exact
test. Continuous variables were compared using the ttest or the
nonparametric Mann-Whitney test. We calculated 95% confi-
dence intervals for differences in outcome rates and medians.
As sensitivity analyses, we performed logistic regression mod-
els to examine differences in the primary outcome between
the 2 groups, as well as in early and late treatment failure and
the single components, to provide supportive information.
We assessed differences in time to treatment failure be-
tween groups using the Kaplan-Meier method (log-rank test).
Differences in secondary outcomes (time to clinical stability
and length of ICU and hospital stay) between both treatment
groups were also analyzed with Cox proportional hazard re-
gression models. In-hospital mortality was analyzed using lo-
gistic regression models. The primary and secondary out-
comes were analyzed both without an adjustment for baseline
variables and with adjustment for potential confounders, in-
cluding 2 predefined covariates (ie, the year of admission and
the center) and all the variables for which there was an imbal-
ance between the 2 groups at baseline (P< .10).
The goodness of fit of the models was tested using the
Hosmer-Lemeshow test or deviance residuals. Proportional
hazards assumptions were tested with log minus log plots.
We performed post hoc subanalyses according to treatment
failure and late treatment failure that did not include the
radiographic progression.
All tests were 2-tailed and significance was set at .05. All
analyses were performed with SPSS Statistics version 20.0
(SPSS Inc).
Results
Of 519 patients screened, 120 patients were randomized, and
112 (93%) completed the study (Figure 1). The data are re-
ported on an intention-to-treat basis unless otherwise indi-
cated. The differences in baseline characteristics between pa-
tients enrolled in 2004-2007 and those enrolled in 2008-2012
are summarized in eTable 1 in Supplement 2.
Baseline characteristics comparing patients who
received methylprednisolone with those who received pla-
cebo appear in Table 1. Both groups had similar baseline
characteristics, except for lower levels of procalcitonin and
IL-10 at day 1, and lower proportions of patients with septic
shock in the methylprednisolone group (Table 1). Ninety
patients (75%) were admitted to the ICU at the time of enroll-
ment. Patients admitted to the ward initially and then trans-
ferred to the ICU are summarized in Table 1 and eTable 2 in
Supplement 2. We did not find differences in time to first
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dose of antibiotics (both in patients with and without shock)
in those initially admitted to the ward and transferred to the
ICU, from emergency department arrival, and randomization
(eTable 3 in Supplement 2).
The rate of etiologic diagnosis was higher in the methyl-
prednisolone group (eTable 4 in Supplement 2). Streptococ-
cus pneumoniae was the most common etiologic agent in both
groups. Distribution of the pathogens did not differ between
groups.
Antimicrobial treatment was similar in both study groups
(eTable 5 in Supplement 2). Combinations of ceftriaxone with
levofloxacin and with azithromycin werethe most common an-
tibiotics used at admission. There were no differences in the per-
centage of patients treated with a macrolide plus another anti-
biotic. Among the 49 patients with a positive microbiologic
diagnosis, the initial empirical treatment was changed in 15 cases
after these results were obtained (in 6 cases for treatment ad-
justment [ie, narrowing the antimicrobial spectrum], in 5 cases
due to treatment failure, and in 4 cases for oral switch).
The initial adequacy of antibiotic treatment was similar
(97% in each group according to guidelines and according to
microbiological results). There were 49 cases with microbial
etiology (excluding the 6 cases with only viruses detected). In
the remaining 43 patients, initial antibioticadequac y was 94%
in the placebo group (16/17 patients) and 100% in the treat-
ment group (26 patients). The time to first antibiotic dose and
the duration of antibiotic treatment did not differ between
groups either.
There was less treatment failure in the methylpredniso-
lone group (8 patients [13%]) compared with the placebo group
(18 patients [31%]) (P= .02). The difference between groups was
18% (95% CI, 3%-32%) due to fewerc ases of late treatment fail-
ure and radiographic progression (Table 2). Similar results were
obtained in the per-protocol population.
Post hoc subanalyses showed a significant difference in
late treatment failure that did not include the radiographic
progression in favor of the methylprednisolone group (8
patients [14%] vs 2 patients [3%] in the placebo group;
P= .04) in the intention-to-treat population (difference
between groups, 10% [95% CI, 0%-20%]). There was not a
significant difference in the per-protocol population in favor
of the methylprednisolone group (8 patients [14%] vs 2
patients [4%] in the placebo group; P= .05; difference
between groups, 10% [95% CI, 0%-21%]).
Logistic regression analyses revealed that methylpred-
nisolone reduced the risk of treatment failure, both without
adjustment for baseline variables and with adjustment for
septic shock, procalcitonin, and IL-10 at day 1, year of
admission, and center (Table 3). Similar results were
obtained in the per-protocol population. Late treatment fail-
ure also reflected a protective effect with corticosteroids
both in the intention-to-treat and the per-protocol popula-
tions. Time to treatment failure differed significantly
between groups in the Kaplan-Meier analysis (Figure 2). In
eFigure 1 in Supplement 2, the proportions of patients with
septic shock and the need for mechanical ventilation (early
and late treatment failure combined) did not differ between
groups, whereas patients included in the methylpredniso-
lone group had less radiographic progression compared
with the placebo group. Similar results were obtained in the
per-protocol population.
No statistically significant differences were observed
among secondary clinical outcomes (Table 2 and Table 3). In-
hospital mortality did not differ between groups (6 patients
[10%] in the methylprednisolone group vs 9 patients [15%] in
the placebo group; P= .37;difference between groups, 5% [95%
CI, −6% to 17%]), even after adjustment for potential con-
founders. Similar results were obtained in the per-protocol
Figure 1. Flow Diagram of the Study With Detailed Information on Allocation and the ExcludedPatients
519 Patients assessed for eligibility
399 Excluded
258 Did not meet inclusion criteria
42 Refused to participate
99 Other reasons
12 Immunocompromised
124 Currently taking or need to take
corticosteroidsa
122 C-reactive protein level <150 mg/L
120 Randomized
61 Included in intention-to-treat analysis
55 Included in per-protocol analysis
59 Included in intention-to-treat analysis
57 Included in per-protocol analysis
61 Randomized to receive methylprednisolone
61 Received methylprednisolone as
randomized
59 Randomized to receive placebo
59 Received placebo as randomized
6Discontinued intervention 2Discontinued intervention
a
Indicates those who were treated
with corticosteroids for any other
reason.
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Table 1. Baseline Characteristics of the Intention-to-Treat Population
Methylprednisolone
(n = 61)
Placebo
(n = 59)
Age, mean (SD), y 64.5 (19.1) 66.1 (20.1)
Male sex, No. (%) 35 (57) 39 (66)
Current smoker, No. (%) 15 (25) 17 (29)
Preexisting comorbid conditions, No. (%)
a
Diabetes mellitus 10 (16) 13 (22)
Chronic pulmonary disease 7 (11) 12 (20)
Congestive heart failure 22 (36) 24 (41)
History of malignancy 3 (5) 8 (14)
Ischemic heart disease 12 (20) 9 (15)
Symptoms, No. (%)
Fever 48 (79) 41 (69)
Altered mental status 13 (21) 14 (24)
Breathlessness 35 (57) 36 (61)
Cough 46 (75) 40 (68)
Chills 23 (38) 20 (34)
Chest pain 21 (34) 26 (44)
Clinical signs, mean (SD)
Temperature, °C 37.6 (1.1) 37.6 (1.0)
Respiratory rate, breaths/min 30.0 (8.0) 29.7 (8.9)
Heart rate, beats/min 105.5 (20.6) 113.5 (23.7)
Serum levels, median (IQR)
Glucose, mg/dL 131 (106-159) 129 (107-180)
Creatinine, mg/dL 1.3 (0.9-1.8) 1.3 (1.0-1.8)
Platelets, × 10
9
/L 214 (176-282) 217 (175-283)
White blood cell count, × 10
9
/L 12.7 (9.0-17.2) 14.4 (9.2-23.0)
C-reactive protein, mg/L
b
273 (202-292) 244 (172-289)
Procalcitonin, ng/dL
b
1.3 (0.4-4.4) 3.1 (0.8-9.5)
IL-6, pg/dL
b
256 (133-674) 316 (182-834)
IL-8, pg/dL
b
74 (34-107) 88 (55-182)
IL-10, pg/dL
b
4.7 (2.8-9.2) 8.1 (4.0-13.5)
Ratio of IL-6 to IL-10
b
0.02 (0.01-0.03) 0.02 (0.01-0.04)
Ratio of PaO
2
to fraction of inspired oxygen,
mean (SD), mm Hg
236 (75) 230 (83)
Pleural effusion, No. (%) 11 (18) 12 (20)
Pneumonia Severity Index score, mean (SD)
17
107 (38) 110 (35)
Risk class, No. (%)
c
I-III 18 (30) 14 (24)
IV 21 (34) 26 (44)
V 22 (36) 19 (32)
Major severity criteria,
16
No. (%)
d
Mechanical ventilation 5 (8) 10 (17)
Noninvasive alone 3 (5) 5 (8)
Noninvasive followed by invasive 1 (2) 3 (5)
Invasive alone 1 (2) 2 (3)
Septic shock 10 (17) 18 (31)
Minor severity criteria, No. (%)
16
Systolic blood pressure <90 mm Hg 11 (18) 17 (29)
Multilobar involvement 37 (61) 34 (58)
Ratio of PaO
2
to fraction of inspired oxygen
<250 mm Hg, No. (%)
42 (70) 40 (68)
ICU admission, No. (%) 43 (70) 47 (80)
Time to first antibiotic dose, No. (%)
Within1hinpatientswithsepticshock
e
3 (30) 5 (28)
Within4hinpatientswithout septic shock
f
35 (74) 27 (71)
Macrolide combination therapy, No. (%) 15 (24) 13 (23)
Time from emergency department presentation
to randomization, median (IQR), d
1 (0-1) 0 (0-1)
Abbreviations: ICU, intensive care
unit; IQR, interquartile range.
SI conversion factors: Toconvert
C-reactive protein to mmol/L,
multiply by 9.524; creatinine to
μmol/L, multiply by 88.4; glucose to
mmol/L, multiply by 0.0555.
a
Could have more than 1 comorbid
condition.
b
Calculated at day 1.
c
Stratified according to 30-day risk
mortality for community-acquired
pneumonia: risk classes I-III (ⱕ90
points) have low mortality (range,
0%-10%) and risk class IV (91-130
points) and risk class V (>130 points)
have the highest mortality (range,
10%-35%).
d
Twopatients(3%)inthe
methylprednisolone group and 4
patients (7%) in the placebo group
had both septic shock and the need
for mechanical ventilation.
e
Ten patients in the
methylprednisolone group and 18
patients in the placebo group were
used to calculate the percentages.
f
Forty-seven patients in the
methylprednisolone group and 38
patients in the placebo group were
used to calculate the percentages.
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population. Causes of death were similar between the 2 groups
(eTable 6 in Supplement 2).
Changes from day 1 in CRP, procalcitonin, IL-6, IL-8, and
IL-10 at days 3 and 7 are shown in eFigure 2 in Supplement 2.
At day 3, the decrease in levels of CRP and IL-10 were higher
in the methylprednisolone group. At day7, the decrease in lev-
els of CRP remained higher in the methylprednisolone group.
We did not observe a rebound of inflammation 2 days (day 7)
after stopping methylprednisolone. However, we did not col-
lect blood samples after day 7 and cannot comment on the cyto-
kine levels after day 7. The hospital outcomes of patients with
a still high level of CRP at day 7 compared with those in whom
it was decreased at the same time are summarized in eTable 7
in Supplement 2. Patients with a persistently high inflamma-
tory response at day 7 had a higher percentage of treatment
failure and mortality.
Adverse events wereevenly distributed across the 2 groups
(eTable 8 in Supplement 2). Hyperglycemia occurred in 11 pa-
tients (18%) in the methylprednisolone group and in 7 pa-
tients (12%) in the placebo group (P= .34). Acute kidney in-
jury occurred in 8 patients (13%) in the methylprednisolone
group and in 8 patients (14%) in the placebo group (P=.85).
One patient in the methylprednisolone group had a superin-
fection. Another patient in the methylprednisolone group had
delirium. Another patient in the methylprednisolone group de-
veloped an acute hepatic failure. One patient in the placebo
group had gastrointestinal bleeding.
Discussion
The results demonstrated that the acute administration of
methylprednisolone was associated with less treatment fail-
ure and a lower inflammatory response in a prospectively iden-
tified population of patients with both severe community-
acquired pneumonia and a high inflammatory response
(defined as a CRP level >150 mg/L at admission).
Severe community-acquired pneumonia remains a major
cause of mortality,and despite effective antibiotic therapy, 12%
to 36% of patients admitted to the ICU die within a short
period.
2,22,23
In addition, patients in risk class V for the Pneu-
monia Severity Index also have a high mortality risk.
24
There-
fore, the development of an efficacious adjunctive treatment has
important implications for reducing this high rate of mortality.
Table 2. Clinical Outcomes Using Descriptive Statistics for the Intention-to-Treat and Per-ProtocolPopulations
Intention-to-Treat Population Per-Protocol Population
Methylprednisolone
Group
(n = 61)
Placebo
Group,
(n = 59)
P
Value
Difference
Between
Groups,
% (95% CI)
Methylprednisolone
Group
(n = 55)
Placebo
Group
(n = 57)
P
Value
Difference
Between
Groups,
% (95% CI)
Primary Clinical Outcome
Treatment failure, No. (%)
a
8 (13) 18 (31) .02 18 (3 to 32) 5 (9) 16 (28) .01 19 (5 to 33)
Early treatment failure
(0-72 h), No. (%)
b
6 (10) 6 (10) .95 0 (−10 to 11) 3 (5) 4 (7) >.99 2 (−7 to 11)
Early mechanical
ventilation
4 (7) 5 (8) .74 2 (−8 to 11) 2 (4) 3 (5) >.99 2 (−6 to 9)
Early septic shock 2 (3) 3 (5) .68 2 (−5 to 9) 1 (2) 2 (4) >.99 2 (−4 to 8)
Death 2 (3) 2 (3) >.99 0 (−6 to 7) 0 0
Late treatment failure
(72-120 h), No. (%)
b
2 (3) 15 (25) .001 22 (10 to 34) 2 (4) 14 (25) .002 21 (9 to 33)
Radiographic progression 1 (2) 9 (15) .007 14 (4 to 23) 1 (2) 8 (14) .03 12 (3 to 22)
Respiratory failure 1 (2) 5 (8) .11 7 (−1 to 15) 1 (2) 5 (9) .21 7 (−1 to 15)
Late mechanical
ventilation
1 (2) 4 (7) .20 5 (−2 to 12) 1 (2) 4 (7) .36 5 (−2 to 13)
Late septic shock 0 4 (7) .06 7 (0 to 13) 0 4 (7) .12 7 (0 to 14)
Death 0 0 0 0
Secondary Clinical Outcomes
Time to clinical stability,
median (IQR), d
c
4 (3 to 6) 5 (3 to 7) .28 1 (−0.4 to 2.4) 4 (3 to 6) 5 (3 to 7) .13 1 (0 to 2)
Length of stay, median (IQR), d
Hospital 11
(7.5 to 14)
10.5
(8 to 15)
.83 −0.5
(−4.6 to 3.6)
11
(8 to 14)
11.5
(8 to 15)
.70 0.5
(−3.3 to 4.3)
ICU
d
5 (3 to 8) 6 (4 to 8) .63 1 (−0.4 to 2.4) 5 (3 to 8) 6 (4 to 8) .38 1 (0 to 2)
In-hospital mortality, No. (%) 6 (10) 9 (15) .37 5 (−6 to 17) 3 (5) 7 (12) .21 7 (−4 to 17)
Abbreviations: ICU, intensive care unit; IQR, interquartile range.
a
Defined as the presence of early or late failure or both.
b
Several patients had more than 1 criteria of failure.
c
Clinical stability was considered to be attained when the following values were
achieved for all parameters: temperature of 37.2°C or lower; heart rate of 100
beats/min or lower; systolic blood pressure of 90 mm Hg or higher; and
arterial oxygen tension of 60 mm Hg or higher when the patient was not
receiving supplemental oxygen. In patients who were receiving home oxygen
therapy,stability was considered to be achieved when their oxygen needs
were the same as before admission.
d
There were 42 patients in the methylprednisolone group and 46 patients in
the placebo group in the intention-to-treat population and 37 patients in the
methylprednisolone group and 44 patients in the placebo group in the
per-protocol population.
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A key factor determining the evolution of severe commu-
nity-acquired pneumonia is the host response. Studies on se-
vere pneumonia have shown an increase in serum levels for
cytokines such as IL-6, IL-8, and IL-10.
25-27
A recent study
showed that excess serum levels for IL-6 and IL-10 were asso-
ciated with a high mortality rate among patients with com-
munity-acquired pneumonia.
28
Corticosteroids are the most effective and widely used anti-
inflammatory drugs. Experimental studies have shown that
acute administration of corticosteroids reduces inflamma-
tory cytokines in patients with severe pneumonia.
29,30
More-
over, we previously demonstrated that use of methylpred-
nisolone and antibiotics in a piglet model of severe pneumonia
also decreased bacterial burden better than antibiotics alone.
29
Therefore, we limited our intervention to patients with both
severe community-acquired pneumonia and a high initialsys-
temic inflammatory response only.
The rate of treatment failure in the control group was 31%,
which is consistent with a previous study
3
that reported a treat-
ment failure rate of 35% in patients with severe community-
acquired pneumonia. Treatment failure was reduced from 31%
to 13% in patients treated with methylprednisolone. Treat-
ment failure can occur either early or late,
3,18
and we ob-
served a reduction in late treatment failure with steroid therapy,
primarily due to a decrease in radiographic progression and
the late appearance of septic shock. These 2 variables have been
Figure 2. Kaplan-Meier Analysis of the Effect of Methylprednisolone
on Time to Treatment Failure
50
40
30
20
10
0
0
59
61
1
57
59
2
53
56
4
41
53
3
53
55
5
41
53
Patients, %
Time to Treatment Failure, d
No. at risk
Placebo
Placebo
Log-rank P
=
.03
Methylprednisolone
Methylprednisolone
Table 3. Clinical Outcomes for the MethylprednisoloneGroup vs Placebo Group Using Logistic Regression or Cox Proportional Hazards Models
for the Intention-to-Treat and Per-Protocol Populations
Intention-to-Treat Population Per-Protocol Population
Unadjusted OR or
HR (95% CI)
P
Value
Adjusted OR
or HR (95% CI)
a
P
Value
Unadjusted OR
or HR (95% CI)
P
Value
Adjusted OR
or HR (95% CI)
a
P
Value
Primary Clinical Outcome
Treatment failure
b
0.34 (0.14-0.87) .02 0.33 (0.12-0.90) .03 0.26 (0.09-0.76) .01 0.26 (0.08-0.79) .02
Early treatment failure
(0-72 h)
c
0.96 (0.29-3.18) .95 1.14 (0.28-4.67) .86 0.76 (0.16-3.58) .73 0.93 (0.17-5.06) .94
Early mechanical
ventilation
0.76 (0.19-2.97) .69 1.02 (0.18-5.83) .98 0.68 (0.11-4.23) .68 0.77 (0.09-6.46) .81
Early septic shock 0.63 (0.10-3.93) .62 0.38 (0.03-4.42) .44 0.51 (0.05-5.78) .59 0.42 (0.04-4.90) .49
Death 0.97 (0.13-7.09) .97 1.35 (0.04-40.84) .86
Late treatment failure
(72-120 h)
c
0.10 (0.02-0.46) .003 0.09 (0.02-0.47) .004 0.12 (0.03-0.54) .006 0.11 (0.02-0.52) .006
Radiographic progression 0.09 (0.01-0.76) .03 0.09 (0.01-0.78) .03 0.11 (0.01-0.94) .04 0.10 (0.01-0.84) .03
Respiratory failure 0.18 (0.02-1.59) .12 0.14 (0.01-1.35) .09 0.19 (0.02-1.71) .14 0.15 (0.02-1.50) .11
Late mechanical ventilation 0.23 (0.03-2.11) .19 0.20 (0.02-1.91) .16 0.25 (0.03-2.27) .22 0.22 (0.02-2.10) .19
Late septic shock 0 (0-⬁)
d
>.99 0 (0-⬁)
d
>.99 0 (0-⬁)
d
>.99 0 (0-⬁)
d
>.99
Death 0 0 0 0
Secondary Clinical Outcomes
Time to clinical stability, d
e
1.16 (0.78-1.73) .46 1.11 (0.72-1.71) .64 1.24 (0.83-1.87) .29 1.20 (0.77-1.85) .42
Length of stay, d
Hospital 0.66 (0.23-1.85) .43 0.61 (0.19-1.93) .40 0.47 (0.12-1.81) .27 0.40 (0.10-1.63) .20
ICU
f
0.18 (0.02-1.46) .11 0.13 (0.01-1.44) .10 0.02 (0-60.31) .33 0 (0-⬁)
d
.29
In-hospital mortality 0.61 (0.20-1.82) .37 0.57 (0.16-2.00) .38 0.41 (0.10-1.68) .22 0.38 (0.08-1.70) .21
Abbreviation: HR, hazard ratio; ICU, intensive care unit; OR, odds ratio.
a
Adjusted for septic shock, procalcitonin, and IL-10 at day 1, year of admission,
and center.
b
Defined as the presence of early or late failure or both.
c
Several patients had more than 1 criteria of failure.
d
Estimation failed due to numerical problem. Because the coefficients did not
converge, no further models were fitted.
e
Clinical stability was considered to be attained when the following values were
achieved for all parameters: temperature of 37.2°C or lower; heart rate of
100 beats/min or lower; systolic blood pressure of 90 mm Hg or higher; and
arterial oxygen tension of 60 mm Hg or higher when the patient was not
receiving supplemental oxygen. In patients who were receiving home oxygen
therapy,stability was considered to be achieved when their oxygen needs
were the same as before admission.
f
There were 42 patients in the methylprednisolone group and 46 patients in
the placebo group in the intention-to-treat population and 37 patients in the
methylprednisolone group and 44 patients in the placebo group in the
per-protocol population.
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associated with higher mortality in patients with severe
community-acquired pneumonia.
31,32
The main benefit of our study was the decrease in radio-
graphic progression (>50% progression in the pulmonary
infiltrates). This variable has been found as an independent
surrogate marker of mortality in previous studies of
community-acquired pneumonia.
33
We performed post hoc
analyses excluding radiographic progression and the statisti-
cal differences for lower rates of treatment failure remained
in favor of the methylprednisolone group. This indicates that
even with excluding radiographic progression (the dominant
individual component of treatment failure), the beneficial
effects of corticosteroids remained.
After adjusting for potential confounders such as septic
shock, levels of procalcitonin and IL-10 at day 1, year of ad-
mission, and center, methylprednisoloneuse reduced the risk
of late treatment failure, particularly for radiographic progres-
sion. Confalonieri et al
8
also reported an improvement in chest
radiograph score in patients with severe community-
acquired pneumonia treated with corticosteroids. No other re-
cent randomized control trials have evaluated treatment fail-
ure in patients with severe community-acquired pneumonia
receiving corticosteroids as adjunctive therapy.
8,10,11
Never-
theless, Nie et al
14
performed a meta-analysis including all ran-
domized control trials that used corticosteroids in popula-
tions with community-acquired pneumonia from 1956 to 2011.
Even though treatment failure was not evaluated, Nie et al
14
showed that the use of corticosteroids was associated with im-
proved survival in patients with severe community-acquired
pneumonia.
In another meta-analysis that included trials with severe
and nonsevere community-acquired pneumonia, Confaloni-
erietal
15
observed a decrease in mortality in favor of steroids
in the population with severe community-acquired pneumo-
nia. Wefound no differences in mortality when comparing both
study groups. However, the sample size was chosen based on
treatment failure rather than in-hospital mortality. We specu-
late that having less treatment failures could lead to de-
creased mortality in community-acquired pneumonia, but if
this outcome had been chosen, a larger study population would
have been required.
3,4
A systemic reduction in inflammatory biomarkers was
observed during the study in both groups, with higher
decreases in levels of CRP and IL-10 in patients receiving
methylprednisolone. These findings are consistent with
previous studies that have found those patients with
community-acquired pneumonia treated with corticoste-
roids experienced a greater decline in levels of CRP
8,10,11,13
and IL-6.
10,11
The effects of steroids on the immune system are many
and complex. Corticosteroids can switch off genes that en-
code proinflammatory cytokines (eg, IL-6, IL-8) and switch on
genes that encode anti-inflammatory cytokines (eg, IL-10).
7
However, the use of steroids also exerts an influence on the
immune function of different host defenses against bacteria
when high dosages and prolonged treatmentare used,
7,34
which
was not the case in our study. The Corticosteroid Therapy of
Septic Shock study
33
reported more episodes of superinfec-
tion (including sepsis and septic shock) in patients treated with
corticosteroids; however,when only superinfections were ex-
amined, the rates for both the treatment and placebo groups
were similar.
In our study, the use of methylprednisolone was not as-
sociated with superinfection or other adverse events. Previ-
ous studies of community-acquired pneumonia did not find
higher rates of superinfection or other potentially adverse
events in patients treated with corticosteroids,
8,10,11,13
except
for hyperglycemia.
11,14
In a subset analysis of a prospective ran-
domized control trial, corticosteroid therapy for community-
acquired pneumonia reduced mortality for those with a high
inflammatory response and a low cortisol level.
35
These find-
ings are consistent with the data in our study, although we did
not measure cortisol levels. According to that study and oth-
ers in the literature, the immunosuppression caused by cor-
ticosteroids was probably not relevant when administered
acutely,in contrast to chronic treatment. In addition, high dos-
ages are not the same as the relatively low dosages used in our
study.
The duration of treatment with steroids in our trial was
5 days and was not followed by a gradual tapering. We
obtained only 1 blood collection during the treatment inter-
vention (day 3); we interpret the CRP data on day 7 to indi-
cate a lack of rebound inflammation within 48 hours of
stopping treatment. Others have reported rebound inflam-
mation 72 hours after discontinuing corticosteroids without
tapering.
11,36
The main strength and the most important characteristic
of our trial, differing from previous studies, was the inclusion
of patients with severe community-acquired pneumonia and
a high systemic inflammatory response. Thus, we selected the
patients most likely to benefit from our intervention. Initial
high levels of inflammation are associated with higher rates
of treatment failure in patients with community-acquired
pneumonia.
18
Thus, the results of this trial cannot be applied
to patients with a CRP level lower than 150 mg/L.
In fact, 24% of screened patients were not included due
to having CRP levels lower than this cutoff (Figure 1). In addi-
tion, using a novel clinical outcome such as treatment failure
(mainly late treatment failure) may assist future studies in un-
derstanding the benefits of this therapy without including a
large population that would be needed if mortalitywas the out-
come chosen.
37
The beneficial effects found in our study with
regard to treatment failure (mainly radiographic progression)
fit with previous trials in the literature; one was stopped
prematurely
8
and another was very small.
10
Our study has limitations. First, the results cannot be
generalized to all patients with community-acquired pneu-
monia. Second, no assessment of adrenal function was per-
formed and it is possible that administration of methylpred-
nisolone may have helped patients with relative adrenal
insufficiency and may have been less valuable in those with-
out adrenal insufficiency, as recently suggested.
35
Third, we used methylprednisolone for 5 days only;recent
studies suggested a beneficial effect when corticosteroid treat-
ment was prolonged for more than 5 daysin patients with com-
munity-acquired pneumonia.
14
Fourth, we did not set up rules
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to reduce use or dosage of antibiotics according to clinical evo-
lution and this might explain why we did not observe differ-
ences in the period of antibiotic treatment between the 2
groups.
Fifth, patient accrual was very slow,mainly due to the fact
that nearly half (49%) of the patients with severecommunity-
acquired pneumonia evaluated did not meet inclusion crite-
ria. Sixth, the sample size calculation was based on a previ-
ous study performed in 15 hospitals
3
that used similar inclusion
criteria as were used in the current trial. However, the treat-
ment failure in the placebo group in this study (31%) was lower
than in the control group in the earlier study. Given the ob-
served treatment failure in our placebo group, the current study
had less statistical power than predicted.
Another major limitation is the long duration of the study
because the care of patients could have evolved during this
time or many intervening diseases might have influenced the
results. However, our protocol for managing patients with
community-acquired pneumonia did not change during
these years. We excluded patients with H1N1 influenza.
Time to the first antibiotic dosage was similar in both
groups. In addition, we adjusted for the year of admission in
the corresponding statistical models. Last, the small differ-
ence in the number of events (a difference of only 10 pa-
tients) indicates the need for study replication. A new trial is
currently ongoing.
38
Conclusions
Among patients with severe community-acquired pneumo-
nia and high initial inflammatory response, the acute use of
methylprednisolone compared with placebo decreased treat-
ment failure. If replicated, these findings would support the
use of corticosteroids as adjunctive treatment in this clinical
population.
ARTICLE INFORMATION
Author Affiliations: Servei de Pneumologia,
Institut Clínic del Torax,Hospital Clínic, Barcelona,
Spain (Torres, Ferrer, Polverino, Gabarrús, Sellarés,
Agustí); Institut d'Investigacions Biomèdiques
August Pi i Sunyer,Barcelona, Spain (Torres, Ferrer,
Polverino, Mensa, Gabarrús, Sellarés, Agustí);
Centro de Investigación Biomédica En Red-
Enfermedades Respiratorias, Islas Baleares, Spain
(Torres, Ferrer, Polverino, Menendez, Gabarrús,
Sellarés, Agustí); University of Barcelona,
Barcelona, Spain (Torres); Servei de Pneumologia,
Hospital de la Santa Creu i Sant Pau, Barcelona,
Spain (Sibila); Institut d
´
Investigació Biomèdica Sant
Pau, Barcelona, Spain (Sibila); Servicio de
Neumologia, Hospital Universitario La Fe, Valencia,
Spain (Menendez); Servei de Malalties Infeccioses,
Hospital Clinic, Barcelona, Spain (Mensa);
University of TexasHealth Science Center,
San Antonio (Restrepo, Anzueto); South Texas
Veterans Health Care System, Audie L. Murphy
Division, San Antonio (Restrepo, Anzueto);
VERDICT,San Antonio, Texas (Restrepo);
Winthrop-University Hospital, Mineola, New York
(Niederman).
Author Contributions: Dr Torres had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Torres, Sibila, Ferrer,
Polverino, Mensa, Anzueto, Agusti.
Acquisition, analysis, or interpretation of data:
Torres, Sibila, Ferrer, Polverino, Menendez,
Gabarrus, Sellares, Restrepo, Anzueto, Niederman.
Drafting of the manuscript: Torres,Sibila, Ferrer,
Polverino, Gabarrus, Restrepo, Anzueto,
Niederman, Agusti.
Critical revision of the manuscript for important
intellectual content: Ferrer, Polverino, Menendez,
Mensa, Sellares, Restrepo, Niederman.
Statistical analysis: Ferrer, Gabarrus, Restrepo.
Obtained funding: Torres, Anzueto.
Administrative, technical, or material support:
Torres, Sibila, Polverino, Anzueto.
Study supervision: Torres, Polverino,Menendez,
Sellares, Anzueto, Agusti.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Anzueto reported serving as a consultant to,
receiving honoraria from, and serving on speakers
bureaus for GlaxoSmithKline, Dey Pharma, Pfizer,
Boehringer Ingelheim, Bayer-Shering Pharma, and
AstraZeneca. Dr Niederman reported receiving
grant support and personal fees from Bayer and
Cubist; and receiving personal fees from Pfizer,
Thermo Diagnostics, and Theravance. No other
disclosures were reported.
Funding/Support: This study was supported by the
Sociedad Española de Neumologia, the Societat
Catalana de Pneumologia, the Fundació Catalana de
Pneumologia, the Grup de Recerca de Qualitat de la
Generalitat de Catalunya (grant SGR-2011),the
Fondo de Investigación Sanitaria (grant PI030113),
the Institut d
´
Investigacions Biomèdiques
August Pi i Sunyer,and the Centro de Investigación
Biomédica En Red-Enfermedades Respiratorias
(grant CB06/06/0028).
Role of the Funder/Sponsors:The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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686 JAMA February 17, 2015 Volume 313, Number 7 (Reprinted) jama.com
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