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Adjunct prednisone therapy for patients with community-acquired pneumonia: A multicentre, double-blind, randomised, placebo-controlled trial

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Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Articles
www.thelancet.com Published online January 19, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62447-8
1
Adjunct prednisone therapy for patients with community-
acquired pneumonia: a multicentre, double-blind,
randomised, placebo-controlled trial
Claudine Angela Blum*, Nicole Nigro*, Matthias Briel, Philipp Schuetz, Elke Ullmer, Isabelle Suter-Widmer, Bettina Winzeler, Roland Bingisser,
Hanno Elsaesser, Daniel Drozdov, Birsen Arici, Sandrine Andrea Urwyler, Julie Refardt, Philip Tarr, Sebastian Wirz, Robert Thomann,
Christine Baumgartner, Hervé Duplain, Dieter Burki, Werner Zimmerli, Nicolas Rodondi, Beat Mueller, Mirjam Christ-Crain
Summary
Background Clinical trials yielded confl icting data about the benefi t of adding systemic corticosteroids for treatment
of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical
stability in patients admitted to hospital for community-acquired pneumonia.
Methods In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years
or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of
presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or
placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratifi ed by
study centre. The primary endpoint was time to clinical stability defi ned as time (days) until stable vital signs for at
least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154.
Findings From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly
assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was
shorter in the prednisone group (3·0 days, IQR 2·5–3·4) than in the placebo group (4·4 days, 4·0–5·0; hazard ratio
[HR] 1·33, 95% CI 1·15–1·50, p<0·0001). Pneumonia-associated complications until day 30 did not diff er between
groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23–1·02];
p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment
(76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31–2·93, p=0·0010). Other adverse events compatible with corticosteroid
use were rare and similar in both groups.
Interpretation Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital
shortens time to clinical stability without an increase in complications. This fi
nding is relevant from a patient
perspective and an important determinant of hospital costs and effi ciency.
Funding Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefl iger Stiftung, Julia und Gottfried
Bangerter-Rhyner Stiftung.
Introduction
Respiratory tract infections and pneumonia in particular
are the third-leading cause of death worldwide.1 Although
outcome of community-acquired pneumonia improved
with the availability of antibiotics, this disorder still
carries a high risk for long-term morbidity and mortality.2
Adjunct therapeutic inter ventions could improve out-
come of patients with this type of pneumonia.
In community-acquired pneumonia, an excessive
release of circulating infl ammatory cytokines can be
harmful and cause pulmonary dysfunction. Systemic
corticosteroids have anti-infl ammatory eff ects, atten-
uating the systemic infl ammatory process in the disorder.3
Therefore, adjunct treatment with cortico steroids has
been discussed since the 1950s, when favourable eff ects
of corticosteroids were noted in pneumococcal pneumonia.4
More recently, a signifi cant reduction of in-hospital
mortality in patients with severe community-acquired
pneumonia was noted in a small randomised trial5 (n=46)
testing a 7-day continuous infusion of hydrocortisone
versus placebo. A retrospective single-centre study6
including 308 patients suggested that the use of
corticosteroids was associated with decreased mortality.
Two recent randomised placebo-controlled trials7,8
including 200–300 patients revealed controversial results.
Whereas the fi rst trial7 did not fi nd any benefi t of adjunct
prednisolone, but an increased recurrence rate, the
second trial8 in which patients received intravenous
dexamethasone over 4 days reported a signifi cant
reduction in length of hospital stay by 1 day. Two systematic
reviews9,10 and three meta-analyses11–13 concluded that
adjunct corticosteroids in community-acquired pneumonia
might be benefi cial, but a large, adequately powered
randomised trial is warranted.
Therefore, we investigated the eff ects of short-term
prednisone versus placebo in patients admitted to
hospital for community-acquired pneumonia with the
primary endpoint of time to clinical stability.
Published Online
January 19, 2015
http://dx.doi.org/10.1016/
S0140-6736(14)62447-8
See Online/Comment
http://dx.doi.org/10.1016/
S0140-6736(14)62391-6
*These authors contributed
equally to this work
Endocrinology, Diabetology
and Metabolism, Department
of Internal Medicine and
Department of Clinical Research
(C A Blum MD, N Nigro MD,
I Suter-Widmer MD,
B Winzeler MD, B Arici MD,
S Andrea Urwyler MD,
J Refardt MD,
Prof M Christ-Crain MD), Basel
Institute for Clinical
Epidemiology and Biostatistics,
Department of Clinical Research
(M Briel MD), and Emergency
Department (R Bingisser MD),
University Hospital Basel, Basel,
Switzerland; Medical University
Clinic, Departments of Internal
and Emergency Medicine and
Department of Endocrinology,
Diabetology and Clinical
Nutrition, Kantonsspital Aarau,
Aarau, Switzerland (C A Blum,
P Schuetz MD, D Drozdov MD,
B Arici, Prof B Mueller MD);
Department of Clinical
Epidemiology and Biostatistics,
McMaster University, Hamilton,
ON, Canada (M Briel); Medical
University Clinic, Kantonsspital
Baselland/Liestal, Liestal,
Switzerland (E Ullmer MD,
H Elsaesser MD,
Prof W Zimmerli MD); Medical
University Clinic, Kantonsspital
Baselland/Bruderholz,
Bruderholz, Switzerland
(P Tarr MD, S Wirz MD);
Department of Internal
Medicine, Bürgerspital,
Solothurn, Switzerland
(R Thomann MD); Department
of General Internal Medicine,
Inselspital, Bern University
Hospital, Bern, Switzerland
(C Baumgartner MD,
Prof N Rodondi MD); Clinic of
Articles
2
www.thelancet.com Published online January 19, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62447-8
Internal Medicine, Hôpital du
Jura, Site de Delémont,
Delémont, Switzerland
(H Duplain MD); and Viollier AG,
Postfach, Basel, Switzerland
(D Burki MD)
Correspondence to:
Prof Mirjam Christ-Crain, Clinic
of Endocrinology, Diabetology
and Metabolism, Department of
Internal Medicine and
Department of Clinical Research,
University Hospital Basel,
Petersgraben 4, 4031 Basel,
Switzerland
mirjam.christ@usb.ch
Methods
Study design and participants
This is an investigator-initiated, multicentre, double-blind,
randomised, placebo-controlled trial. Details of the trial
design have previously been published.14 In brief,
consecutive patients presenting with community-acquired
pneumonia were screened and enrolled at emergency
departments or medical wards in seven tertiary
care hospitals in Switzerland from Dec 1, 2009, to
May 21, 2014, within 24 h of presentation. Inclusion
criteria were age 18 years or older and hospital admission
with community-acquired pneumonia defi ned by a new
infi ltrate on chest radiograph and the presence of at least
one of the following acute respiratory signs and symptoms:
cough, sputum production, dyspnoea, core body temp-
erature of 38·0°C or higher, auscultatory fi ndings of
abnormal breathing sounds or rales, leucocyte count
higher than 10 000 cells per μL or less than 4000 cells
per μL.15 Exclusion criteria were permanent inability for
informed consent, active intravenous drug use, acute
burn injury, gastrointestinal bleeding within the past
3 months, known adrenal insuffi ciency, a condition
requiring more than 0·5mg/kg per day prednisone
equivalent, pregnancy or breastfeeding, and severe
immunosuppression defi ned as one of the following:
infection with human immunodefi ciency virus and a CD4
cell count below 350 cells per μL, immunosuppressive
therapy after solid organ trans plantation, neutropenia
below 500 cells per μL or neutrophils of 500–1000 cells per
μL during ongoing chemotherapy with an expected
decrease to values below 500 cells per μL, cystic fi brosis, or
active tuberculosis. The conduct of the trial adhered to
the declaration of Helsinki and Good Clinical Practice
Guidelines, and ethical committees of all participating
hospitals approved the study before patient recruitment.
All patients provided written informed consent.
Randomisation and masking
Eligible patients were randomly assigned (1:1 ratio) to
receive either 50 mg of prednisone or placebo daily for
7 days. Randomisation was done with variable block
sizes of four to six and patients were stratifi ed at the
time of study entry by study centre. Allocation was
concealed with a prespecifi ed computer-generated
randomisation list, which was centrally kept at the
pharmacy of the main study centre.
Patients were randomly assigned to receive a prepared
set of study medication that contained seven tablets
of 50 mg prednisone or placebo. The placebo drug
was purchased from a local prednisone man ufacturer
(Galepharm AG, Küsnacht, Switzerland), which pro-
duces both prednisone and its corresponding placebo.
The drugs were prepared before the initiation of the
study and packed into identical containers by the
Pharmacology Department, University Hospital, Basel,
according to the randomisation list. Patients, treating
physicians, investi gators, and data assessors were
masked to treatment allocation.
Procedures
After informed consent was obtained, baseline blood
samples were drawn and nasal swabs for virus multiplex
PCR were done. All other microbiological assessments
were at the discretion of the treating physicians. Patients
started antibiotic therapy as soon as community-
acquired pneumonia was confi rmed. Treating physicians
chose the empirical regimen according to the ERS/
ESCMID guidelines adapted for Switzerland.16,17 Most
patients started this regimen either with amoxicillin
plus clavulanic acid or ceftriaxone alone. In patients with
clinical suspicion for legionellosis or in those requiring
treatment in the intensive care unit (ICU), the beta-
lactam was combined with clarithromycin. Treatment
was streamlined and optimised according to the
susceptibility pattern as soon as a specifi c pathogen
was known. Thereafter, patients started receiving study
medication, and we monitored timing in relation to start
of antibiotics. Study nurses assessed patients for clinical
stability every 12 h during hospital stay. All patients were
Figure 1: Trial profi le
No patient was lost to follow-up before reaching the primary endpoint. One patient in the prednisone group and
three patients in the placebo group were lost to follow-up at 30 days.
2911 patients assessed for eligibility
1504 did not meet eligibility criteria
241 informed consent not possible
(dementia, disability)
508 with immunosuppression
667 with indication for steroids
88 with gastrointestinal bleeding
within the past 3 months
605 eligible, but declined to participate
802 randomised
400 assigned to placebo
7 blinded post-randomisation exclusion
393 included in intention-to-treat analysis
366 treated per protocol
27 protocol violations
12 informed consent withdrawn
for study medication
8 application mistakes
7 study medication stopped
4 active glucocorticoid indication
3 potential adverse event
402 assigned to prednisone
392 included in intention-to-treat analysis
362 treated per protocol
30 protocol violations
18 informed consent withdrawn
for study medication
6 application mistakes
6 study medication stopped
1 active glucocorticoid indication
5 potential adverse event
10 blinded post-randomisation exclusion
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3
treated according to published community-acquired
pneumonia guidelines.18 Stewardship of antibiotic
treatment duration by procalcitonin was encouraged by
the study protocol according to Schuetz and colleagues.19
Baseline data included medical history items, relevant
comorbidities, clinical items of pneumonia, and all
variables required for the calculation of the pneumonia
severity index (PSI).20 Routine laboratory tests of
infl ammatory markers (procalcitonin, C-reactive protein
[CRP], white blood cell count) were done in both groups
on days 1, 3, 5, 7, and before discharge and included
four glucose measurements per day.
Structured follow-up telephone interviews for secondary
outcomes after discharge were done on day 30 and
included assessment of adverse events such as infections,
recurrent pneumonia, re-admission to hospital, new
onset diabetes or insulin dependence, and new onset
hypertension.
Outcomes
The primary endpoint was time to clinical stability
defi ned as time (days) until stable vital signs for 24 h or
longer. Stable vital signs were temperature of 37·8°C or
lower, heart rate of 100 beats per min or lower,
spontaneous respiratory rate of 24 breaths per min or
lower, systolic blood pressure of 90 mm Hg or higher
(≥100 mm Hg for patients diagnosed with hypertension)
without vasopressor support, mental status back to level
before occurrence of community-acquired pneumonia,
ability for oral intake, and adequate oxygenation on room
air (PaO₂ ≥60 mm Hg or pulse oximetry ≥90%), which
were based on current community-acquired pneumonia
treatment recomm
endations.15 Instability was defi ned if
at least one of these criteria were not met.
Secondary endpoints were time to eff ective discharge
from hospital, recurrence of pneumonia, re-admission to
hospital, ICU admission, all-cause mortality, duration of
total and intravenous antibiotic treatment, disease activity
scores specifi c to community-acquired pneumonia,21
incidence of complications due to community-acquired
pneumonia (ie, acute respiratory distress syndrome,
empyema, persistence of pneu monia), side-eff ects of
corticosteroids (ie, rate of hyperglycaemia, hypertension,
delirium, nosocomial infections, and weight gain), and
time to earliest possible hospital discharge.
For patients admitted to ICU we recorded length of
ICU stay, time to transfer to ICU, time to discharge from
ICU, duration of vasopressor treatment, and duration of
mechanical ventilation.
Statistical analysis
The statistical analysis was prespecifi ed, and investigators
who analysed the data were masked to treatment
allocation.14 The primary hypothesis of this trial was that
corticosteroids will reduce time to clinical stability in
patients with community-acquired pneumonia without
relevant adverse eff ects. On the basis of previous trials,19,22
we assumed a mortality rate of 10% in the placebo group
and 7·5% in the corticosteroid group over 14 days of
follow-up with a proportion of 75% survivors being
clinically stable after 7 days in the corticosteroid group.
Estimating a decrease in the risk of non-stability after
1 week in survivors by 25% through adjunct corticosteroids,
we calculated that we needed a sample size of 800 patients
followed up for at least 14 days to achieve a statistical
power of 85%.
Prednisone (n=392) Placebo (n=393)
General characteristics
Age, years 74 (61–83) 73 (61–82)
Male sex 241 (61%) 246 (63%)
Clinical variables
Days with symptoms 4·0 (2·0–7·0) 4·0 (2·0–7·0)
Temperature (°C) 37·6 (37·0–38·2) 37·6 (37·0–38·2)
Systolic blood pressure (mm Hg) 124 (110–140) 123 (110–140)
Heart rate (beats per min) 84 (74–95) 82 (72–96)
Respiratory rate (breaths per min) 20 (18–24) 20 (18–24)
SaO2 (%) 95 (92–96) 94 (92–97)
Bacteraemia 39 (10%) 48 (12%)
Confusion 22 (6%) 29 (7%)
CAP score (points)* 43 (30–60) 46 (29–63)
Laboratory values
Procalcitonin (ng/mL) 0·52 (0·18–2·51) 0·50 (0·17–2·63)
C-reactive protein (mg/L) 159 (80·3–245) 164 (79·1–250)
White-blood-cell count (cells per μL) 12 200 (8900–15 800) 11 900 (8700–15 600)
Glucose (fasting morning, mmol/L) 6·3 (5·4–7·8) 6·5 (5·8–7·7)
PSI score†
PSI class I 47 (12%) 45 (11%)
PSI class II 72 (18%) 69 (18%)
PSI class III 71 (18%) 95 (24%)
PSI class IV 148 (38%) 132 (34%)
PSI class V 54 (14%) 52 (13%)
Total PSI score (points) 93 (63–115) 86 (65–110)
Comorbidities
Diabetes mellitus (any type) 77 (20%) 78 (20%)
Insulin treatment 44 (11%) 35 (9%)
Chronic obstructive pulmonary disease 73 (19%) 60 (15%)
Heart failure 80 (20%) 62 (16%)
Cerebrovascular disease 38 (10%) 31 (8%)
Renal insuffi ciency 125 (32%) 126 (32%)
Neoplastic disease 29 (7%) 25 (6%)
Liver disease 17 (4%) 12 (3%)
Co-infections‡ 45 (11%) 46 (12%)
Antibiotic pretreatment 84 (21%) 95 (24%)
Data are median (IQR) or number (%), unless otherwise stated. SaO2=saturation of oxygen. PSI=pneumonia severity
index. *The CAP score is a disease-specifi c activity score for community-acquired pneumonia; it ranges from 0 to 100,
0 marking the worst, 100 the best score.21 †The PSI is a clinical prediction rule to calculate the probability of morbidity
and mortality in patients with community-acquired pneumonia;20 PSI risk class I corresponds to age ≤50 years, and no
risk factors (≤50 points), risk class II to <70 points, risk class III to 71–90 points, risk class IV to 91–130 points, and risk
class V to >130 points. ‡Nine skin infections, 43 urinary tract infections, 28 upper respiratory tract infections,
ten gastrointestinal tract infections, and one joint infection.
Table 1: Baseline characteristics of enrolled patients
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The primary analysis followed the intention-to-treat
principle, which means that patients were analysed in the
groups to which they were randomly assigned, independent
of whether they took the allocated treatment.14 The
per-protocol population focused on patients fully comp-
lying with the trial protocol. For the primary endpoint, we
calculated an unadjusted hazard ratio (HR) and 95% CI
using Cox proportional hazards regression based on a
binary outcome of achieving or not achieving clinical
stability. Patients who died before achieving clinical
stability were censored at the day of death; all surviving
patients not achieving clinical stability were censored at
day 30. For the primary endpoint, none of the patients was
lost to follow-up. As a sensitivity analysis, the primary
analysis was repeated on the per-protocol population.
As a further sensitivity analysis, a multivariable Cox
proportional hazards model was fi tted with treatment
group and prespecifi ed potential confounders patient
age and PSI score as independent variables.14 We did
prespecifi ed subgroup analyses (patient age, initial CRP
concentration, history of chronic obstructive pulmonary
disease [COPD], PSI class, blood culture positivity)
by including appropriate interaction terms in the multi-
variable Cox proportional hazards model.14
For all secondary endpoints, we calculated unadjusted
and adjusted (for patient age and PSI score) estimates of
the eff ect size and corresponding 95% CIs using linear,
logistic, or Cox proportional hazards regression (as
appropriate). We analysed community-acquired pneu-
monia scores using non-parametric linear models (quantile
regression) due to substantially skewed distributions.23
For all time-to-event analyses of secondary endpoints,
patients lost to follow-up were censored at the time of lost
contact; for all other analyses of secondary outcomes we
used complete case analyses.
All reported CIs are two-sided 95% intervals, and tests
were done at the two-sided 5% signifi cance level. We
used STATA 12·1 (Stata Corp, College Station, Texas) for
all analyses. This trial is registered with ClinicalTrials.
gov, number NCT00973154.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing
of the report. The corresponding author had full access
to all the data in the study and had fi nal responsibility
for the decision to submit for publication.
Results
We enrolled 802 eligible patients in the trial and
randomly assigned them to receive either prednisone or
placebo (fi gure 1). After blinded post-randomisation
exclusion of 17 patients retrospectively not meeting
eligibility criteria, 392 patients were allocated to the
prednisone group and 393 patients to the placebo group.
Baseline characteristics of the two groups were well
balanced (table 1). Median age of patients was 74 years, and
487 (62%) of 785 were men. Patients had a high burden of
comorbidities including diabetes, chronic obstructive
pulmonary disease, chronic heart failure, and chronic renal
insuffi ciency. About half the patients were in high-risk
PSI classes IV and V. The appendix shows microbiological
aetiology of community-acquired pneumonia, antibiotics
given to patients, and supplemental data for clinical insta-
bility variables at baseline.
See Online for appendix
Figure 2: Kaplan-Meier-curve of time to clinical stability
Number at risk
Prednisone group
Placebo group
0
392
393
10
37
63
20
12
16
30
6
5
Time (days)
0
0·25
0·50
0·75
1·00
Probability of instability
Prednisone group
Placebo group
HR=1·33 (1·15–1·50), p<0·0001
Prednisone
(n=392)
Placebo (n=393) Regression analysis
HR, OR, or diff erence
(95% CI)
p value
Primary endpoint
Intention-to-treat: time
to clinical stability, days
3·0 (2·5–3·4) 4·4 (4·0–5·0) HR 1·33 (1·15 to 1·50) <0·0001
Per-protocol: time to
clinical stability, days
3·0 (2·5–3·2) 4·4 (4·0–5·0) HR 1·35 (1·16 to 1·56) <0·0001
Secondary endpoints
Time to eff ective hospital
discharge, days
6·0 (6·0–7·0) 7·0 (7·0–8·0) HR 1·19 (1·04 to 1·38) 0·012
Recurrent pneumonia 23 (6%) 18 (5%) OR 1·30 (0·69 to 2·44) 0·42
Re-admission to hospital 32 (9%) 28 (8%) OR 1·14 (0·67 to 1·93) 0·64
ICU admission 16 (4%) 22 (6%) OR 0·72 (0·37 to 1·39) 0·32
Time to ICU admission,
days
1 (1–1) 1 (1–1) HR 0·73 (0·38 to 1·38) 0·33
Time in ICU, days 3 (2–4) 3 (1–12) Diff erence –0·2 days
(–8·7 to 8·2)
0·96
Death from any cause 16 (4%) 13 (3%) OR 1·24 (0·59 to 2·62) 0·57
Time to death, days 8·0 (3·0–22·0) 9·0 (2·0–12·0) HR 1·23 (0·59 to 2·55) 0·59
Total duration of
antibiotic treatment, days
9·0 (7·0–11·0) 9·0 (7·0–12·0) Diff erence –0·47 days
(–1·21 to 0·27 days)
0·22
Intravenous antibiotic
treatment, days
4·0 (3·0–6·0) 5·0 (3·0–7·0) Diff erence –0·89 days
(–1·57 to –0·20) days)
0·011
CAP score* at day 5,
points
59 (41–78) 58 (40–74) Diff erence 1·00 (–5·23 to
7·23)
0·75
CAP score* at day 30,
points
83 (67–88) 84 (72–89) Diff erence –1·00 (–4·38
to 2·38)
0·56
Data are median (IQR) or number (%) unless otherwise stated. HR=hazard ratio. OR=odds ratio. ICU=intensive care
unit. *The CAP score is a disease-specifi c activity score for community-acquired pneumonia. It ranges from 0 to
100, 0 marking the worst, 100 the best score.21
Table 2: Overview of primary and secondary endpoints
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5
In the intention-to-treat analysis, median time to clinical
stability was signifi cantly shorter in the prednisone group
(3·0 days; IQR 2·5–3·4) than in the placebo group
(4·4 days; IQR 4·0–5·0) with an HR of 1·33 (95% CI
1·15–1·50, p<0·0001; fi gure 2 and table 2). Results for the
per-protocol population were similar (table 2) and were
confi rmed by the adjusted analysis (appendix). We noted
no evidence of eff ect modifi cation in diff erent prespecifi ed
subgroups based on median age, initial median CRP
concentration, previous history of COPD, severity of
community-acquired pneumonia defi ned by the PSI score
(I–III vs IV–V), or blood culture positivity (appendix). We
noted no signifi cant eff ect modifi cation in post-hoc
analysis of patients with or without sepsis at randomisation
(data not shown). However, we noted a trend towards a
larger treatment eff ect in patients with sepsis.
Median time to eff ective discharge from hospital was
shorter in the prednisone group than in the placebo group
(table 2). The total duration of antibiotic treatment did not
diff er between groups, but duration of intravenous
antibiotic treatment was lower in the prednisone group
than in the placebo group. Rates of recurrent pneumonia,
re-admission to hospital, and ICU admittance were
similar in both treatment groups. All-cause mortality at
day 30 did not diff er between groups. The community-
acquired pneumonia scores at day 5 and at day 30 did not
diff er between groups.
CRP concentrations were signifi cantly lower in the
prednisone group than in the placebo group on days 3, 5,
and 7 (data not shown); PCT levels did not diff er between
treatment groups (data not shown).
Overall, complications associated with community-
acquired pneumonia (ie, acute respiratory distress
syndrome, empyema, respiratory failure with intubation,
persistence of pneumonia, and mortality associated with
community-acquired pneumonia) tended to be lower
in the prednisone group than in the placebo group
(table 3; appendix).
Incidence of any adverse events compatible with
corticosteroid use was higher in the prednisone group
than in the placebo group (table 3). This fi nding was due
to a higher rate of in-hospital hyperglycaemia needing
insulin treatment in the prednisone group than in the
placebo group. The rates of new need for insulin treatment
at day 30 were low in both groups. The incidence of other
adverse events compatible with corticosteroid use was
small and similar in both groups.
Discussion
In this trial, a 7-day treatment with prednisone in
patients with community-acquired pneumonia led to a
reduction in time to clinical stability of 1·4 days, to an
overall reduction of length of hospital stay of 1 day, and
to a reduction in duration of intravenous antibiotic
treatment of 1 day. This eff ect seemed to be valid across
all PSI classes and independent of age. Incidence of
pneumonia-associated complications until day 30 tended
to be lower in the prednisone group than in the placebo
group. The prednisone group had a higher rate of
inhospital hyperglycaemia needing insulin treatment
than did the placebo group, whereas other adverse
events compatible with corticosteroid use were rare and
similar in both groups.
Pulmonary and circulating infl ammatory cytokine
concentrations are increased in patients with community-
acquired pneumonia, serving as eff ective mechanism for
the elimination of invading pathogens. Although initially
benefi cial, an unrestrained infl ammatory condition
might be detrimental.3 Accordingly, non-survivors of
community-acquired pneumonia show persistently
increased concentrations of circulating infl ammatory
cytokines over time.24 Corticosteroids are the most potent
anti-infl ammatory drugs, with which favourable eff ects
were reported in patients with pneumococcal pneumonia
from as early as 1955.4 Our fi ndings support the hypothesis
that administration of corticosteroids modulates the
Prednisone
(n=392)
Placebo
(n=393)
Regression analysis
OR (95% CI) or
diff erence (95% CI)
p value
Incidence of pneumonia-associated complications until day 30
Complications due to community-
acquired pneumonia, any
11 (3%) 22 (6%) 0·49 (0·23 to 1·02) 0·056
Acute respiratory distress syndrome 0 1 (<1%)
Empyema 1 (0·3%) 5 (1%)
Respiratory failure, intubation 1 (<1%) 6 (2%)
Persistence of pneumonia 6 (2%) 5 (1%)
Mortality associated with community-
acquired pneumonia*
5 (1%) 7 (2%)
Incidence of adverse events compatible with corticosteroid use until day 30
Weight change, kg –1·0
(–3·0 to 1·0)
–1·0
(–3·0 to 0·4)
Diff erence 0·34 (–0·56
to 1·25),
0·46
Adverse events, any 96 (24%) 61 (16%) 1·77 (1·24 to 2·52) 0·0020
In-hospital hyperglycaemia needing
new insulin treatment
76 (19%) 43 (11%) 1·96 (1·31 to 2·93) 0·0010
New insulin dependence at day 30 5 (1%) 1 (<1%)
New hypertension at day 30 6 (2%) 2 (1%)
Delirium 5 (1%) 2 (1%)
Gastrointestinal bleeding 3 (1%) 4 (1%)
Nosocomial infections 13 (3%) 14 (4%)
Other adverse events until day 30
Any 20 (5%) 34 (9%) 0·57 (0·32 to 1·00) 0·052
Falls with fracture 0 4 (1%)
Cardiac decompensation 5 (1%) 10 (3%)
Cardiac event 6 (2%) 3 (1%)
Acute stroke 2 (1%) 2 (1%)
Thrombembolic event 0 3 (1%)
Other 9 (2%) 12 (3%)
Data are median (IQR) or number (%) unless otherwise stated. OR=odds ratio. *Mortality associated with community-
acquired pneumonia was defi ned as death from community-acquired pneumonia or death from complications due to
community-acquired pneumonia.
Table 3: Complications and adverse events
Articles
6
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immune response and thereby shortens time to clinical
stability and length of hospital stay. Importantly, symptom
resolution, reduction of length of hospital stay, and
reduction of intravenous antibiotic therapy are relevant
clinical goals in the treatment of patients with community-
acquired pneumonia. The anti-infl ammatory eff ect of
prednisone treatment has a signifi cant benefi cial eff ect on
these goals. This is not only relevant from a patient
perspective, but is also an important determinant of
hospital costs and effi ciency.
Our results confi rm data of various clinical trials
(panel),4–8,25–30 systematic reviews,9,10 and meta-analyses11–13
showing a benefi cial eff ect of corticosteroids in
community-acquired pneumonia. They are consistent
with a randomised trial8 comparing intravenous
dexamethasone with placebo in 302 patients with
community-acquired pneumonia outside the ICU,
showing a similar reduction in length of hospital stay of
1 day as observed in our study. A small randomised trial
with open-label design in 31 patients with community-
acquired pneumonia of any severity comparing pred-
nisolone for 3 days with placebo reported a reduction in
hospital stay from 16 to 11 days. The small patient
number might have been the reason for the non-
signifi cant results.26
Our results are in contrast to another randomised trial
including 213 patients7 showing that prednisolone once
daily for a week did not improve clinical cure at day 7 nor
length of hospital stay compared with placebo. However,
when analysing these data without including patients
directly admitted to the ICU, a signifi cant reduction in
time to clinical stability as well as an improvement in
length of hospital stay of 1 day was noted.31 This fi nding is
unexpected, since it challenges the recent view that
corticosteroids are benefi cial for patients with severe
community-acquired pneumonia in the ICU, but not
indicated in patients with milder community-acquired
pneumonia outside the ICU.32 In our study, results
remained similar with or without patients admitted to
the ICU. It must be taken into account that patients
in our cohort presented with community-acquired
pneumonia of lower severity than that in previous
studies.7,8 More evidence on patients with severe
community-acquired pneumonia in the ICU setting is
expected by 2016 after completion of the ADRENAL trial
(ClinicalTrials.gov, NCT01448109).
Irrespective of the inclusion or exclusion of patients
with direct ICU admission in the analysis, the study by
Snijders and colleagues7 suggested more recurrences in
the prednisolone group (20 [19%] of 104) than in the
placebo group (10 [9%] of 109), raising concern about the
occurrence of a rebound of infl ammation after initial
suppression by corticosteroids.7 Our larger study could
not confi rm this fi nding, since rates of recurrence of
pneumonia and re-admission to hospital were similar in
the prednisone and placebo groups. A clinically relevant
rebound phenomenon with an increased frequency of
recurrent pneumonia seems therefore unlikely. The
recurrence rate in our study was about 5% in both
groups; considering the small absolute number of
recurrences in the study by Snijders and colleagues, their
nding of slightly more recurrences with corticosteroids
is probably attributable to chance.
Other pneumonia-associated complications in our
study such as incidence of empyema, acute respiratory
distress syndrome, or respiratory failure were low and
tended to be higher in the placebo group than in the
prednisone group.
Hyperglycaemia needing insulin treatment during
hospital admission was higher in the prednisone group
than in the placebo group, similar to the study by
Meijvis and colleagues.8 This increased hyperglycaemia
did not, however, aff ect the clinical outcome and did
not prolong hospital stay. Moreover, the number of
patients with new need for insulin treatment at day 30
was low. Other adverse events compatible with
corticosteroid use in our study were rare, and the
incidence did not diff er between groups. We assume
that the short exposure to corticosteroids, when they
Panel: Research in context
Systematic review
We systematically searched PubMed using
“community-acquired pneumonia” and “corticosteroids” for
randomised, placebo-controlled trials or meta-analyses
investigating the eff ects of corticosteroids as adjunctive
therapy for community-acquired pneumonia. Language
restrictions were not imposed. The last search was done on
Dec 2, 2014. Recent systematic reviews and
meta-analyses9–13 suggest a possible benefi t of adjunct
corticosteroids for community-acquired pneumonia in
severely ill patients, but with moderate disease severity,
evidence is weak. The only two randomised
placebo-controlled trials including 213 and 304 patients
with pneumonia of any severity yielded controversial
results. One study7 did not fi nd any benefi t of adjunct
corticosteroids, but an increased recurrence rate, the other8
reported a reduction in length of hospital stay by 1 day.
Interpretation
Our trial with 785 patients shows that a 7-day course of
50 mg oral prednisone daily shortens time to clinical
stability by 1·4 days in patients admitted for
community-acquired pneumonia of any severity.
Furthermore, time to hospital discharge and duration of
intravenous antibiotic treatment are reduced by 1 day
without an increase in complications associated with
community-acquired pneumonia. When adding our study to
previous evidence, a meta-analysis now shows a signifi cant
reduction of length of hospital stay (appendix). However,
hyperglycaemia has to be anticipated, and the usual
contraindications for corticosteroids must be taken into
consideration .
Articles
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7
are not tapered off during several days but stopped
abruptly after 7 days, has a favourable eff ect on
corticosteroid-associated complications.
We did not note any eff ect modifi cation in diff erent
prespecifi ed subgroups based on median age, initial
median CRP, previous history of COPD, severity of
community-acquired pneumonia defi ned by the PSI
score, or blood culture positivity. In a post-hoc analysis,
we noted a trend towards a larger treatment eff ect in
patients with sepsis. Furthermore, a positive treatment
response to prednisone was not restricted to patients
with a specifi c aetiological diagnosis, but was seen
irrespective of the identifi ed microorganism.
Our study has several strengths as compared with
previous studies. First, it is the largest and thus most
conclusive randomised placebo-controlled trial of
corticosteroids in community-acquired pneumonia
including more than 800 patients; this gave the study
suffi cient power to show a diff erence in time to clinical
stability and length of hospital stay. Second, patients
with all severity classes of community-acquired
pneumonia were included, representing daily routine in
patients admitted to hospital with community-acquired
pneumonia. However, the sickest patients (eg, patients
in the ICU and patients with sepsis) were under-
represented. In these patients, the current guidelines of
the Surviving Sepsis Campaign2 regarding the indication
for gluco corticoids should be applied. Finally, we
used an oral dose of prednisone, which is easier to
apply to patients with community-acquired pneumonia
compared with intravenous doses of dexamethasone,
applied in an earlier trial.8
Our study has also limitations. First, we exclusively
included patients admitted to hospital, which precludes a
generalisation to patients in ambulatory care. Second, our
study was not powered for mortality; therefore, mortality
data have to be acknowledged with care. Third, our primary
endpoint, time to clinical stability, has limitations, since it
is a combined endpoint including several parameters;
however, it is a well accepted and frequently used endpoint
in patients with community-acquired pneumonia.33 Finally,
corticosteroid-induced hyperglycaemia might have led to
unblinding in some patients.
Contributors
CAB, MB, BM, and MC-C designed the study and wrote the protocol.
CAB, NN, EU, IS-W, BW, RB, HE, DD, BA, SAU, JR, PT, SW, RT, CB, HD,
and NR recruited patients for the study and participated in coordination.
CAB, NN, PS, MB, and MC-C had access to all the data, analysed the data,
were responsible for the decision to submit the report, and drafted it. PS,
RB, WZ, PT, DB, NR, BM, and MC-C participated in coordination, gave
nancial and staff support, and critically revised the report. All authors
read and approved the fi nal report.
Declaration of interests
We declare no competing interests.
Acknowledgments
This study was supported by a grant by the Swiss National Foundation
(PP0P3_123346) to MC-C and the Nora van Meeuwen Häfl iger Stiftung and
the Gottfried Julia Bangerter-Rhyner Stiftung. Nasopharyngeal PCR is
supported entirely by Viollier AG, 4002 Basel, Switzerland. MB is supported
by santésuisse and the Gottfried and Julia Bangerter-Rhyner Foundation.
PS is supported by the Swiss National Science Foundation (SNSF
Professorship, PP00P3_150531 / 1). NR was supported for this study by a
grant from Inselspital Bern, University Hospital and by a grant from the
Swiss National Science Foundation (SNSF 320030-138267 and SNSF
320030-150025). BM, CAB, and PS were supported for this study by the
research funds from the Department of Endocrinology, Diabetology and
Metabolism, Medical University Clinic of the Kantonsspital Aarau and the
“Argovia Professorship” of the Medical Faculty of the University of Basel.
We gratefully thank the staff of the emergency departments and
medical wards of all participating hospitals in supporting this study.
Furthermore, we thank the many supporters, study and laboratory
personnel at all participating centres who have made this trial
possible, especially Cemile Bathelt, the study nurse who has
coordinated the trial-related tasks during the 5-year trial duration at
the main study centre. We thank Werner Albrich, Nina Hutter,
Maria Candela, Helga Schneider, Katharina Regez, Ursula Schild,
Eva Grolimund, Alexander Kutz, Martina Bally, Deborah Steiner,
Anna-Christina Rast, Stefanie Schwarz, Anoush Razzaghi,
Ingeborg Schnyder, Judith Siegenthaler, Carla Walti, Cornelia Mueller,
Lukas Burget, Katharina Timper, Stefanie Meyer, Sonja Schwenne,
Merih Guglielmetti, Kristina Schumacher, Nathalie Christa Schwab,
Danielle Krebs, Cornelia Krismer, Manuel Blum, Christina Wirth,
Eveline Hofmann, Sebastian Ott, and Khadija M’Rabet Bensalah for
local study and patient management, Fausta Chiaverio,
Renate Hunziker, Ursina Minder, and Christoph Noppen for
laboratory support, and Patrick Simon, Clinical Trial Unit, University
Hospital Basel, for database support. We also thank the members of
the Data Safety and Monitoring Board for their valuable time,
especially Marc Donath and Benjamin Kasenda. We thank
Christian Schindler for statistical advice and Nicole Salvisberg for
administrative help.
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... This is a secondary analysis of demographic, clinical and biomarker data obtained at baseline from patients enrolled in the observational TripleP cohort [15], and two multicentre randomised controlled trials: the Ovidius trial (NCT00471640) [16] and the Steroids in Pneumonia (STEP) trial (NCT00973154) [17]. All studies included hospitalised adult patients with CAP (see supplementary materials). ...
... In the Ovidius trial, patients with CAP were randomly allocated to receive intravenous dexamethasone 5 mg daily or placebo for 4 days following hospital admission [16]. The STEP trial randomised 727 patients with CAP to either placebo or oral prednisolone 50 mg daily for 7 days in the per protocol analysis [17]. LOS, the primary endpoint in the Ovidius trial and main secondary endpoint in the STEP trial, was significantly reduced in patients assigned to adjunctive treatment with corticosteroids. ...
... LOS, the primary endpoint in the Ovidius trial and main secondary endpoint in the STEP trial, was significantly reduced in patients assigned to adjunctive treatment with corticosteroids. Details of the original studies are published elsewhere [16,17]. ...
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Background Latent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to assess whether LCA can identify clinically distinct subgroups in community-acquired pneumonia (CAP) and whether the treatment effect of adjunctive corticosteroids differs between subgroups. Methods LCA was performed on baseline clinical and biomarker data from the Ovidius trial (n=304) and STEP trial (n=727), both randomised controlled trials investigated adjunctive corticosteroid treatment in CAP, and the observational Triple p cohort (n=201). Analyses were conducted independently in two cohorts (Ovidius-TripleP combined and STEP trial). In both cohorts, differences in clinical outcomes and response to adjunctive corticosteroid treatment were examined between subgroups identified through LCA. Results A two-class model fitted both cohorts best. Class 2 patients had more signs of systemic inflammation compared to Class 1. In both cohorts, length of stay was longer and in-hospital mortality rate was higher in Class 2. In the Ovidius trial, corticosteroids reduced median length of stay in Class 2 (6.5 versus 9.5 days) but not in Class 1 (p-value for interaction=0.02). In the STEP trial, there was no significant interaction for length of stay. We found no significant interaction between class assignment and adjunctive corticosteroid treatment for secondary outcomes. Conclusions In two independent cohorts, LCA identified two classes of CAP patients with different clinical characteristics and outcomes. Given the different response to adjunctive corticosteroids in the Ovidius trial, LCA might provide a useful basis to improve patient selection for future trials.
... However, whether or not wheezing in these patients is mediated by immunoglobulin E (IgE) as typical atopic bronchial asthma is unclear. Recently, several studies indicated that adjunctive systemic corticosteroids were helpful for improving the prognosis and shortening the length of hospital stay (LOHS) in community-acquired pneumonia [5][6][7][8]. However, the efficacy of steroid therapy for LRTI in SMID patients is uncertain. ...
... The demographic and clinical characteristics and outcomes of the enrolled patients are shown in Table 1. The proportion of males was 62%, and the median age was 6 years old [interquartile range (IQR) [3][4][5][6][7][8][9][10]. The proportion of patients with a diagnosis of bronchial asthma was 20% (44/217). ...
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Introduction Children with severe motor and intellectual disabilities (SMID) are susceptible to severe lower respiratory tract infection (LTRI). As SMID patients are prone to develop recurrent wheezing and are often diagnosed with bronchial asthma, they frequently receive systemic corticosteroids as an adjunctive treatment for LRTIs. However, the efficacy of corticosteroid therapy for LTRIs in SMID children is unclear. We investigated whether or not corticosteroid therapy was associated with better clinical outcomes for SMID children with LRTIs. Methods Our retrospective study enrolled 217 SMID children 1–15 years old hospitalized for LTRIs. We compared the clinical characteristics and outcomes between patients with and without corticosteroid therapy. Results Of the 217 patients, 29 (13.3%) received corticosteroid therapy. The proportion of patients with a history of bronchial asthma was higher and LRTI was more severe in patients with corticosteroid therapy than in those without the therapy. The length of hospital stay (LOHS) was significantly longer in patients with corticosteroid therapy (median 13 days) than in those without corticosteroid therapy (median 9 days) (P = 0.02). The same tendency was shown for the LOHS in patients with severe or moderate LRTI, although not to a significant extent. Conclusion Systemic corticosteroid therapy was not associated with better clinical outcomes in SMID children with LRTIs, even if the patients suffer from severe LRTIs. Corticosteroids should be used cautiously for LRTIs in SMID children because bronchial asthma is likely to be overdiagnosed in these children.
... With accumulating data since the 2009 Swine flu pandemic, corticosteroids have fallen out of favor in the management of influenza as they were associated with an increased mortality [13]. Controversy still exists about the use of corticosteroids in patients with pneumonia without COPD [14][15][16][17]. The German S3 guidelines recommend against systemic corticosteroids in patients with severe influenza pneumonia who do not suffer from COPD [18]. ...
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Purpose COPD has large impact on patient morbidity and mortality worldwide. Acute exacerbations (AECOPD) are mostly triggered by respiratory infections including influenza. While corticosteroids are strongly recommended in AECOPD, they are potentially harmful during influenza. We aimed to evaluate if steroid treatment for AECOPD due to influenza may worsen outcomes. Methods A retrospective analysis of a Swiss nation-wide hospitalization database was conducted identifying all AECOPD hospitalisations between 2012 and 2017. In separate analyses, outcomes concerning length-of-stay (LOS), in-hospital mortality, rehospitalisation rate, empyema and aspergillosis were compared between AECOPD during and outside influenza season; AECOPD with and without laboratory-confirmed influenza; and AECOPD plus pneumonia with and without laboratory-confirmed influenza. Results Patients hospitalized for AECOPD during influenza season showed shorter LOS (11.3 vs. 11.6 day, p < 0.001) but higher rehospitalisation rates (33 vs 31%, p < 0.001) compared to those hospitalized outside influenza season. Patients with confirmed influenza infection had lower in-hospital mortality (3.3 vs. 5.5%, p = 0.010) and rehospitalisation rates (29 vs. 37%, p < 0.001) than those without confirmed influenza. Conclusion Using different indicators for influenza as the likely cause of AECOPD, we found no consistent evidence of worse outcomes of AECOPD due to influenza for hospitalized patients. Assuming that most of these patients received corticosteroids, as it is accepted standard of care in Switzerland, this study gives no evidence to change the current practice of using corticosteroids for hospitalized AECOPD independent of the influenza status.
... ensayos y pacientes incluidos, han identificado una reducción importante de la mortalidad (100). Otros estudios han documentado un menor tiempo para alcanzar la estabilidad clínica en los pacientes que reciben esteroides, con beneficios en el tiempo en ventilación mecánica (101). ...
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La neumonía sigue siendo una de las principales causas de consulta y de hospitalización a la que, además de su un alto impacto en términos de morbilidad y mortalidad, se suma la actual problemática de resistencia a los antimicrobianos, por lo que establecer directrices que permitan su adecuado diagnóstico y tratamiento es de gran importancia para obtener mejores desenlaces clínicos y promover un uso racional de antibióticos en estos pacientes. La presente guía de práctica clínica (GPC) contiene recomendaciones basadas en la evidencia para el diagnóstico y tratamiento de la neumonía adquirida en la comunidad en adultos, las cuales fueron realizadas mediante el proceso de adaptación de GPC basadas en la evidencia para el contexto colombiano.
... Cette discordance peut s'expliquer par la différence de gravité initiale des patients hospitalisés présentant une PAC. En effet, deux essais randomisés sur les corticoïdes au cours du traitement des PAC n'ont pas démontré de différence significative si on considère les critères cliniques (34,35). Une différence a été observée concernant le délai de résolution de la fièvre ainsi que les autres critères de stabilité clinique mais sans impact sur la mortalité, la durée de séjour ou une défaillance d'organe. ...
Thesis
Contexte : La réduction de la durée de l'antibiothérapie chez les patients hospitalisés pour une pneumonie aigue communautaire (PAC) devrait permettre de réduire la consommation d'antibiotiques et donc la résistance bactérienne, les événements indésirables et les coûts associés. Notre objectif était d'évaluer la nécessité d'un traitement supplémentaire de 5 jours par bêta-lactamine chez des patients atteints de PAC, atteignant les critères de stabilité après 3 jours de traitement.Méthodologie : Nous avons réalisé un essai de non-infériorité, randomisé, en double aveugle, contrôlé contre placebo (Pneumonia Short Treatment [PTC]) dans 16 centres en France. Les patients adultes admis à l'hôpital avec une PAC modérément sévère (définis comme des patients admis dans une unité hors réanimation) et qui répondaient aux critères de stabilité clinique prédéfinis après 3 jours de traitement par bêta-lactamine ont été randomisés (1:1) pour recevoir un traitement par bêta-lactamine (amoxicilline orale 1 g plus 125 mg de clavulanate trois fois par jour) ou un placebo pendant 5 jours supplémentaires. La randomisation a été stratifiée par site et par score PSI (pneumonia severity index). Le critère de jugement principal était la guérison 15 jours après la première prise d'antibiotiques, définie par l'apyrexie (température 37,8 °C), la résolution ou l'amélioration des symptômes respiratoires et l'absence de traitement antibiotique supplémentaire quelle qu'en soit la cause. Une marge de non-infériorité de 10 % a été choisie. Le critère de jugement principal a été évalué chez tous les patients qui ont été randomisés et ont reçu un traitement (population en intention de traiter [ITT]) et chez tous les patients qui ont reçu le traitement (population per protocole). La sécurité a été évaluée dans la population ITT.Résultats : Entre le 19 décembre 2013 et le 1er février 2018, 706 patients ont été évalués, et après 3 jours de traitement par bêta-lactamine, 310 patients répondaient aux critères d’inclusion et ont été randomisés dans le groupe placebo (n = 157) ou traitement par amoxicilline/clavulanate (n=153). Sept patients ont retiré leur consentement, 5 dans le groupe placebo et 2 dans le groupe bêta-lactamine. Dans la population ITT, l'âge médian était de 73,0 ans (IQR 57,0–84,0) et 123 (41 %) des 303 participants étaient des femmes. Dans l'analyse ITT, la guérison à J15 est survenue chez 117 (77 %) des 152 participants du groupe placebo et 102 (68 %) des 151 participants du groupe bêta-lactamine (différence entre les groupes de 9,42 %, [95 % IC –0,38 à 20,04]), indiquant la non-infériorité. Dans l'analyse per protocole, 113 (78 %) des 145 participants du groupe placebo et 100 (68 %) des 146 participants du groupe bêta-lactamine ont guéri à J15 (différence de 9, 44 % [95 % IC –0,15 à 20,34]), indiquant la non-infériorité.L'incidence des événements indésirables était similaire entre les groupes de traitement (22 [14 %] sur 152 dans le groupe placebo et 29 [19 %] sur 151 dans le groupe bêta-lactamine). Les événements indésirables les plus fréquents ont été des troubles digestifs, rapportés chez 17 (11 %) des 152 patients du groupe placebo et 28 (19 %) des 151 patients du groupe bêta-lactamine. A J30, 3 (2%) patients étaient décédés dans le groupe placebo (un en raison d'une bactériémie à Staphylococcus aureus, un en raison d'un choc cardiogénique après un œdème pulmonaire aigu et un en raison d'une insuffisance cardiaque associée à une insuffisance rénale aiguë) et 2 (1 %) dans le groupe beta-lactamine (en raison d'une récidive de pneumonie et d'un possible œdème pulmonaire aigu).Conclusion : Chez les patients hospitalisés pour PAC répondant aux critères de stabilité clinique, l'arrêt du traitement par bêta-lactamine après 3 jours était non inférieur à 8 jours de traitement. Ces résultats pourraient permettre une réduction substantielle de la consommation d'antibiotiques.
... We did not identify any randomised trial assessing the use of glucocorticoids in adult patients with suspected or confirmed MERS. We identified two randomised trials assessing the use of prednisone in community-acquired pneumonia, including viral influenza 14,15 . Of 785 randomised patients, Blum and colleagues 14 reported 27 patients with laboratory confirmed influenza but outcome data were not assessed separately for this subgroup. ...
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Background Administration of glucocorticoids might reduce mortality in patients with severe COVID-19 but have adverse cardiometabolic effects. Objectives to investigate the effect of systemic administration of glucocorticoids on cardiovascular complications and all-cause mortality in patients hospitalised with respiratory viral infections, including COVID-19, SARS, MERS and influenza. Methods We identified randomised trials published prior to July 28th, 2021. The Mantel-Haenszel random effects method and the Hartung and Knapp adjustment were used to obtain pooled estimates of treatment effect with 95% confidence intervals. Results No randomised trials of glucocorticoids for SARS, MERS or influenza reported relevant outcomes. We included eleven COVID-19 randomised trials (8,109 patients).Overall, compared to placebo or standard care, glucocorticoids were not associated with a reduction of in-hospital mortality (p=0.09). In a pre-specified sub-analysis, in-hospital mortality was reduced by 19% when follow-up was restricted to 14 days from randomisation (5/11 trials, 1,329 patients, p=0.02). With longer follow-up (9/11 trials, 7,874 patients), administration of glucocorticoids was associated with a trend to benefit for those requiring mechanical ventilation (RR 0.86; 95% CI 0.57-1.27) but possible harm for those not receiving oxygen at randomisation (RR 1.27; 95% CI 1.00 – 1.61), an effect that was significantly different amongst subgroups (p = 0.0359). Glucocorticoids reduced the risk of worsening renal function by 37% (4/11 trials); reported rate of other cardiovascular complications was low. Conclusions Administration of systemic glucocorticoids to patients hospitalised with COVID-19 does not lower mortality overall but may reduce it in those requiring respiratory support and increase it in those who do not.
... Corticosteroid treatment for CAP is a controversial topic. Despite several studies showing improved outcomes, such as less treatment failure, shorter hospital stays, shorter time to clinical stability [19,27], or reduced risk of cardiovascular events [28], only one has shown improved mortality [29]. This may be because many studies have lacked the statistical power to find significance differences. ...
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Background Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide despite correct antibiotic use. Corticosteroids have long been evaluated as a treatment option, but heterogeneous effects on survival have precluded their widespread implementation. We aimed to evaluate whether corticosteroids might improve clinical outcomes in patients with severe CAP and high inflammatory responses. Study design and methods We analyzed two prospective observational cohorts of patients with CAP in Barcelona and Rome who were admitted to intensive care with a high inflammatory response. Propensity score (PS) matching was used to obtain balance among the baseline variables in both groups, and we excluded patients with viral pneumonia or who received hydrocortisone. Results Of the 610 patients admitted with severe CAP, 198 (32%) received corticosteroids and 387 had major criteria for severe CAP. All patients had a baseline serum C-reactive protein above 15 mg/dL. Patients who received corticosteroids were more commonly male, had more comorbidities (e.g., cancer or chronic obstructive pulmonary disease), and presented with significantly higher sequential organ failure assessment scores. Eighty-nine patients met major severity criteria (invasive mechanical ventilation and/or septic shock) and were matched per group. Twenty-eight-day mortality was lower among patients receiving corticosteroids (16 patients, 18%) than among those not receiving them (28 patients, 31%; p = 0.037). After PS matching, corticosteroid therapy reduced the 28-day mortality risk in patients who met major severity criteria (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.29–0.98) ( p = 0.043). In patients who did not meet major severity criteria, no benefits were observed with corticosteroid use (HR 0.88 (95%CI 0.32–2.36). Conclusions Corticosteroid treatment may be of benefit for patients with CAP who have septic shock and/or a high inflammatory response and requirement for invasive mechanical ventilation. Corticosteroids appear to have no impact on mortality when these features are not present.
Article
Lung inflammation can be caused by pathogen infection alone or by allergic disease, leading to pneumonitis. Most of the allergens (antigens) that cause allergic lung diseases, including asthma and hypersensitivity pneumonitis (HP), are derived from microorganisms, such as bacteria, viruses, and fungi, but some inorganic materials, such as mercury, can also cause pneumonitis. Certain allergens, including food and pollen, can also cause acute allergic reactions and lead to lung inflammation in individuals predisposed to such reactions. Pattern recognition-associated and damage-associated signaling by these allergens can be critical in determining the type of hypersensitization and allergic disease, as well as the potential for fibrosis and irreversible lung damage. This review discusses the signs, symptoms, and etiology of allergic asthma, and HP. Furthermore, we review the immune response and signaling pathways involved in pneumonitis due to both microbial infection and allergic processes. We also discuss current and potential therapeutic interventions for infection-associated and allergic lung inflammation.
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Background: Glycemic variability (GV) has only been sparsely studied in patients with community-acquired pneumonia (CAP). This study aimed to quantify in-hospital GV in CAP patients, including determining the impact of type 2 diabetes mellitus (T2DM) and glucocorticoid (GC) treatment on GV. Methods: This is a prospective cohort study of CAP patients (N = 40) with or without T2DM and treated or not with GCs. The primary endpoint was GV measured as glucose standard deviation (SD), coefficient of variation (CV), and postprandial glucose excursions (PPGE) based on continuous glucose monitoring (CGM). Analysis of glucose data was split into daytime and nighttime when possible. Results: Patients included had a mean age of 74 (range 55 to 91) years. SD (95%CI) increased by a factor of 1.93 (1.40 to 2.66) and 2.29 (1.38 to 3.81) in patients with T2DM and not treated with GCs during the daytime and the nighttime, respectively (both P < 0.01), and by a factor of 1.42 (1.04 to 1.97) in patients treated with GCs but without T2DM during the daytime (P = 0.031) compared to patients without T2DM and not treated with GCs. CV (95%CI) increased by 5.1 (0.0 to 10.1) and 8.1 (1.0 to 15.2) percentage points during the daytime and the nighttime, respectively, in patients with T2DM and not treated with GCs compared to patients without T2DM and not treated with GCs (P = 0.046 and P = 0.026, respectively). PPGE (95% CI) increased during lunch by 2.5 (0.7 to 4.3) mmol/L (45 (13 to 77) mg/dL) in patients with T2DM and treated with GCs compared to patients without T2DM and not treated with GCs (P = 0.018). Conclusions: CAP patients receiving GCs, especially those with T2DM, are at great risk of developing high GV and therefore require clinical attention to mitigate GV. This applies particularly during the daytime. Results support the 1 to 2-h post-lunch screening procedure for glucocorticoid-induced hyperglycemia in patients without diabetes. SD was positively correlated with hospital length of stay.
Article
Background It is hypothesised that community-acquired pneumonia (CAP) patients with more severe disease or inflammation might benefit more from adjunctive corticosteroid treatment. Neutrophil count, lymphocyte count and neutrophil-lymphocyte ratio (NLR) have been associated with inflammation and disease severity in CAP. We investigated the interaction between these parameters and adjunctive dexamethasone effects on clinical outcomes in CAP. Methods We conducted a post hoc analysis of the randomised placebo-controlled Santeon-CAP trial (n = 401), which showed a positive effect of adjunctive oral dexamethasone on length of stay (LOS) in CAP patients. White blood cell (WBC) count, neutrophil count, NLR (highest tertile vs. lowest two tertiles) and lymphocyte count (lowest tertile vs. highest two tertiles) were examined as potential effect modifiers of treatment with dexamethasone on LOS (primary outcome) and ICU-admission, 30-day mortality and hospital readmission. Results WBC differential counts were available for 354 patients. The effect of dexamethasone on LOS was more pronounced in high WBC count, high neutrophil count or high NLR subgroups (difference in median LOS of 2 days versus zero days in the reference subgroups, p for interaction < 0.05). There was no effect modification for the other outcomes. Patients with low WBC and low neutrophil counts did not benefit from dexamethasone, while hospital readmission rate was higher in those treated with dexamethasone (6% vs. 11%). Conclusions WBC count and/or neutrophil might be easily available biomarkers to guide selection of CAP patients who are more likely to benefit from adjunctive dexamethasone treatment. Future prospective trials are needed to confirm this predictive potential.
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EXECUTIVE SUMMARY This document is an update of the original 1993 statement on community-acquired pneumonia, incorporating new information about bacteriology, patient stratification, diagnostic evaluation , antibiotic therapy, and prevention. The statement includes a summary of the available literature, as well as evidence-based recommendations for patient management, developed by a multidisciplinary group composed of pulmonary, critical care, general internal medicine, and infectious disease specialists. The sections of this document are as follows: an overview of the purpose of our efforts and the methodology used to collect and grade the available data; a review of the likely etiologic pathogens causing community-acquired pneumonia (CAP), including a discussion of drug-resistant Streptococcus pneumoniae (DRSP); a proposed approach to patient stratification for the purpose of predicting the likely etiologic pathogens of different patient populations with CAP; a summary of available and recommended diagnostic studies; suggestions on how to define the need for hospitalization and admission to the intensive care unit (ICU) for patients with CAP; guidelines for antibiotic therapy of CAP, including principles of therapy and specific recommendations for each patient category; an approach to the nonre-sponding patient, as well as a discussion of when to switch to oral therapy and when to discharge an admitted patient with CAP who is responding to initial therapy; and recommendations for the use of pneumococcal and influenza vaccines.
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Background: Despite progress in life-support measures and antimicrobial therapy, the mortality of severe pneumonia has not varied since the mid-1990s, suggesting that other factors are of crucial importance in the evolution of this respiratory infection. Objective: To evaluate the impact of hydrocortisone infusion in community-acquired pneumonia (CAP) in the attenuation of systemic inflammation and reduction of sepsis-related complications. Methods: The study enrolled 80 patients, clinically and radiolodically diagnosed as community-acquired pneumonia, admitted to Chest department, Respiratory Intensive Care Unit, General Medicine Department and General Medicine Intensive Care Unit of Zagazig University Hospitals. Sixty of them were randomized to receive hydrocortisone as a bolus dose of 200 mg intravenously once (only at day 1) then 10 mg/h IV infusion for 7 days and twenty received placebo, along with antibiotics according to IDSA/ATS 2007 guidelines which were given for both groups. The following parameters were compared in both groups; PaO2 and PaO2/FiO2 ratio, length of hospital stay, duration of IV antibiotic treatment, duration of mechanical ventilation, weaning success from mechanical ventilation, pneumonia complication and hospital outcome. Results: Hydrocortisone treated patients showed a significant improvement in PaO2 and PaO2/FiO2 ratio, a significant reduction in White blood cell count, C-reactive protein levels, Erythrocyte sedimentation rate, a significant reduction in the duration of mechanical ventilation, duration of IV antibiotic treatment, pneumonia complications, and length of hospital stay. Also there was an improvement of hospital outcome, weaning success from mechanical ventilation and radiological resolution compared to the placebo group. Conclusion: Adjunctive 7 day course of low dose hydrocortisone IV in patients with CAP hastens clinical recovery and prevents the development of sepsis-related complications with a significant reduction in the duration of mechanical ventilation, duration of IV antibiotics and length of hospital stay with the improvement in hospital outcome and weaning success from mechanical ventilation.
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Importance The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial.Objective To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia.Design, Setting, and Participants Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation.Interventions Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm.Main Outcomes and Measures Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7.Results After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms.Conclusions and Relevance We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy.Trial Registration clinicaltrials.gov Identifier: NCT00818610
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Background Community-acquired pneumonia (CAP) is the third-leading infectious cause of death worldwide. The standard treatment of CAP has not changed for the past fifty years and its mortality and morbidity remain high despite adequate antimicrobial treatment. Systemic corticosteroids have anti-inflammatory effects and are therefore discussed as adjunct treatment for CAP. Available studies show controversial results, and the question about benefits and harms of adjunct corticosteroid therapy has not been conclusively resolved, particularly in the non-critical care setting. Methods/Design This randomized multicenter study compares a treatment with 7 days of prednisone 50 mg with placebo in adult patients hospitalized with CAP independent of severity. Patients are screened and enrolled within the first 36 hours of presentation after written informed consent is obtained. The primary endpoint will be time to clinical stability, which is assessed every 12 hours during hospitalization. Secondary endpoints will be, among others, all-cause mortality within 30 and 180 days, ICU stay, duration of antibiotic treatment, disease activity scores, side effects and complications, value of adrenal function testing and prognostic hormonal and inflammatory biomarkers to predict outcome and treatment response to corticosteroids. Eight hundred included patients will provide an 85% power for the intention-to-treat analysis of the primary endpoint. Discussion This largest to date double-blind placebo-controlled multicenter trial investigates the effect of adjunct glucocorticoids in 800 patients with CAP requiring hospitalization. It aims to give conclusive answers about benefits and risks of corticosteroid treatment in CAP. The inclusion of less severe CAP patients will be expected to lead to a relatively low mortality rate and survival benefit might not be shown. However, our study has adequate power for the clinically relevant endpoint of clinical stability. Due to discontinuing glucocorticoids without tapering after seven days, we limit duration of glucocorticoid exposition, which may reduce possible side effects. Trial registration 7 September 2009 on ClinicalTrials.gov: NCT00973154.
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Background: Pneumonia is the most common cause of community-acquired infection requiring ICU admission. 60% -87% of patients with severe community acquired pneumonia (CAP) admitted to the ICU develops respiratory failure and require mechanical ventilation (MV). Objectives: To assess the efficacy and safety of adjunctive low dose hydrocortisone infusion treatment in Egyptian ICU patients with CAP. Methods: Hospitalized patients, clinically and radiologically diagnosed with CAP, were randomized to receive hydrocortisone 12.5 mg/h IV infusion for 7 days or placebo, along with antibiotics. The end-points of the study were improvement in PaO 2 :FIO 2 (PaO 2 :FIO 2 > 300 or ≥ 100 increase from study entry) and SOFA score by study day 8 and the development of delayed septic shock. Results: 80 patients were recruited, 40 of them received hydrocortisone and the remaining 40 received placebo. By study day 8, hydrocortisone treated pa-tients showed a significant improvement in PaO 2 :FIO 2 and chest radiograph score, and a significant reduction in C-reactive protein (CRP) levels, Sepsis-related Organ Failure Assessment (SOFA) score, and delayed septic shock compared to the control group. Hydrocortisone treatment was associated with a significant reduction in the duration of MV. However, hydrocortisone infusion did not show significant difference in the ICU mortality. Conclusions: adjunctive 7-day course of low dose hydrocortisone IV in patients with CAP hastens recovery of pneumonia and prevents the de-velopment of sepsis related complications with a significant reduction in duration of the mechanical ventilation.
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Context: In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). Objective: To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. Design, Setting, and Patients: A multicenter, noninferiority, randomized controlled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. Intervention: Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. Main Outcome Measures: Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. Results: The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n=103] vs 18.9% [n=130]; difference, -3.5%; 95% CI, -7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, -34.8%; 95% CI, -40.3% to -28.7%) and in the subgroups of patients with community-acquired pneumonia (n=925, 7.2 vs 10.7 days; -32.4%; 95% CI, -37.6% to -26.9%), exacerbation of chronic obstructive pulmonary disease (n=228, 2.5 vs 5.1 days; -50.4%; 95% CI, -64.0% to -34.0%), and acute bronchitis (n=151, 1.0 vs 2.8 days; -65.0%; 95% CI, -84.7% to -37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n=133] vs 28.1% [n=193]; difference, -8.2%; 95% CI, -12.7% to -3.7%). Conclusion: In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects. Trial Registration: isrctn.org Identifier: ISRCTN95122877
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Objective To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, “Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock,” published in 2004.