Steroids 205 (2024) 109389

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Steroids
journal homepage: www.elsevier.com/locate/steroids

Comparing the efficacy of corticosteroids among patients with

community-acquired pneumonia in the ICU versus non-ICU settings: A
systematic review and meta-analysis
Luis A. Diaz Caballero a, Ashnah Aijaz b, Neha Saleem Paryani b, Samar Mahmood b,
Madiha Salman b, Mohammad Omer Khan b, Dayal Ahluwalia c, Mohammad Arham Siddiq d,
Ishaque Hameed b, *
a
Department of Pulmonary and Critical Care Medicine, Einstein Medical Center Philadelphia 5501 Old York Road, Philadelphia, PA, USA
b
Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
c
Department of Medicine, Einstein Medical Center Philadelphia 5501 Old York Road, Philadelphia, PA, USA
d
Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Despite the potential of corticosteroids in treating community-acquired pneumonia (CAP), con­
Community-acquired pneumonia flicting evidence exists regarding their effect on mortality. To address this gap and provide new insights, we
Corticosteroids conducted a pre-specified subgroup meta-analysis of corticosteroid use in CAP patients, focusing on the ICU
Intensive-care unit
versus non-ICU subsets.
Mortality
Mechanical ventilation
Methods: We searched PubMed, Cochrane Central Register of Controlled Trials and SCOPUS from inception to
Meta-analysis May 2023 for randomized controlled trials (RCTs). The primary outcomes of interest were mortality, need for
mechanical ventilation, need for ICU admission, and treatment failure. Secondary outcomes analysed were the
need for hospital readmission, length of hospital stay, length of ICU stay, gastrointestinal (GI) bleeding, sec­
ondary infections, and hyperglycaemic events. The results were analysed through the random-effects model. A p-
value < 0.05 was considered significant.
Results: Eighteen randomized controlled trials (n = 4472) analyzing patients with CAP were included. Our results
suggest that corticosteroids significantly reduced the incidence of mortality (RR: 0.66; 95 % CI: 0.54, 0.81; P =
<0.0001) and need for mechanical ventilation (RR: 0.57; 95 % CI: 0.44, 0.73; P = <0.00001). It was also
observed that corticosteroids significantly decrease the lengths of ICU (MD: − 1.67; 95 % CI: − 2.97, − 0.37; P =
0.01) and hospital stay (MD: − 1.94; 95 % CI: − 2.89, − 0.98; P = 0.0001), while increasing the number of hy­
perglycemic events (RR: 1.68; 95 % CI: 1.32, 2.12; P = <0.0001) and hospital readmissions (RR: 1.19; 95 % CI:
1.04, 1.37; P = 0.01).
Conclusions: The results of this meta-analysis demonstrate that corticosteroids yield improved outcomes in CAP
patients with regard to reduced mortality and the need for mechanical ventilation. It highlights the need for
further large-scale RCTs with the proposed, specific stratifications.

1. Introduction
Community-acquired pneumonia (CAP) is the ninth leading cause of
death in the United States with the number of deaths increasing by 7.5 %
in 2020 alone [1]. Around six million people are annually affected by
CAP in the United States, resulting in over four million ambulatory care
visits [2]. Pneumonia is distinguished by severe inflammation of the
lung parenchyma, which results when the equilibrium between the
resident lower respiratory tract microorganisms and the systemic and
local defence mechanisms becomes disrupted [3]. The major therapeutic
strategy for CAP remains to be the use of antimicrobials. However, there
are currently no established strategies or recommendations for
improving mortality or severity [4]. Corticosteroids are widely used
anti-inflammatory agents with great therapeutic benefits and have been

* Corresponding author at: Department of Medicine, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan.
E-mail address: ishaquehameed@hotmail.com (I. Hameed).

https://doi.org/10.1016/j.steroids.2024.109389
Received 28 October 2023; Received in revised form 5 December 2023; Accepted 7 February 2024
Available online 13 February 2024
0039-128X/© 2024 Elsevier Inc. All rights reserved.
L.A. Diaz Caballero et al.
extensively investigated for their use in CAP [5].
Current guidelines conditionally recommend against routinely using
corticosteroids in adults with severe CAP in the in-patient setting, with
moderate quality of evidence supporting this recommendation [6].
Numerous randomized controlled trials (RCTs) have shown practical
benefits of their use in CAP of varying severity [7–9]; however, they
have not shown significant mortality benefits except for a single study
[10]. Discrepancies have also been noted in several meta-analyses con­
ducted using these RCTs, with some demonstrating an improvement in
mortality [11,12], while others showing only the benefit of corticoste­
roids in reducing the length of hospital stay [13]. In a recent meta-
regression analysis by Saleem et al., steroids decreased the need for
mechanical ventilation, but that did not necessarily translate to reduced
mortality [4]. Subsequently, a noteworthy RCT (CAPE COD) conducted
by Dequin et al., has demonstrated a significant reduction in mortality
by day 28 specifically for ICU patients admitted with CAP, deeming it an
important finding to further investigate an overall effect of steroids on
CAP as well as stratifying on the basis of their effects on patients in the
ICU.[7].
Although studies have been conducted to evaluate the use of corti­
costeroids in CAP, there is a dearth of reliable evidence. The lack of
consistent definitions of the severity of pneumonia across previous meta-
analyses as well as the varying indices used to calculate the same can
yield heterogeneous findings, potentially impacting outcomes [14].
Moreover, the severity categorization using these non-uniform scales
has been mentioned in the literature, but no stratification has been done
in the ICU versus non-ICU patient populations, wherein mortality has
been shown to vary significantly [15]. Annually, an estimated 356,326
patients with CAP in the United States were projected to require ICU
admission [16]. Among patients admitted for CAP, it was estimated that
60,576 in-hospital deaths occurred in the ICU annually [16]. Given the
high disease burden, particularly in the ICU, stratifying and evaluating
the effects of initiating corticosteroids in this vulnerable population is
crucial. Thus, to enhance the existing literature and provide valuable
insights regarding mortality reduction, we conducted a pre-specified
subgroup meta-analysis to assess ICU versus non-ICU CAP patients.
2. Methods
2.1. Data sources and search strategy
This systematic review and meta-analysis was conducted according
to the Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) guidelines [17]. Two independent reviewers (IH
and AA) performed a systematic literature search on PubMed, Cochrane
Central Register of Controlled Trials (CENTRAL), and SCOPUS from
inception to May 2023. We used the combination of keywords such as
hydrocortisone, corticosteroids, steroids, methylprednisolone, prednis­
olone, dexamethasone, betamethasone, community acquired pneu­
monia, mortality, mechanical ventilation, ICU admission, secondary
infections, length of ICU Stay, separated by the Boolean operators
“AND” and “OR”. The comprehensive search strategy for each database
is provided in Supplemental Table 1. Articles referenced in the previous
meta-analyses were also manually screened for relevant articles.
2.2. Study selection and eligibility criteria
All articles were exported to EndNote Reference Library (version X9,
Clarivate Analytics, Philadelphia, Pennsylvania), where duplicates were
discarded. Two reviewers (IH and AA) independently selected articles
that met the eligibility criteria: (a) study was a randomized controlled
trial (RCT); (b) compared effects of corticosteroids against placebo; (c)
studied patients with community-acquired pneumonia (CAP); and (d)
evaluated the outcomes of interest. Only article titles and abstracts were
first reviewed, followed by full-text inspections. In case of disagree­
ments, a third reviewer (SM) was consulted to resolve the conflicts. The
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Steroids 205 (2024) 109389
exclusion criteria consisted of: (a) studies with insufficient data to
compute outcomes; (b) duplicate studies or overlapping participants; (c)
observational studies, reviews, editorials, conference papers, case re­
ports, and animal experiments; and (d) papers not published in the
English language.
2.3. Data extraction and quality assessment
The data extracted included study characteristics (first author, pub­
lication year, country), baseline characteristics of patients (age, male
percentage, ICU admissions, patients on mechanical ventilation,
severity, C-reactive protein (CRP)), intervention details (dose, duration,
and type of corticosteroid therapy), and all outcomes of interest. The
primary outcomes investigated were mortality, need for mechanical
ventilation, need for ICU admission, and treatment failure (defined as
radiographic progression (increase of ≥ 50 % of pulmonary infiltrates
compared with baseline), persistence of severe respiratory failure (ratio
of PaO2 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). Secondary outcomes analysed were the need for hospital read­
mission, length of hospital stay, length of ICU stay, gastrointestinal (GI)
bleeding, secondary infections, and hyperglycaemic events (defined as
blood glucose greater than 125 mg/dL while fasting and greater than
180 mg/dL 2 h postprandial). Two investigators (IH and AA) extracted
data independently, with a third investigator (SM) to address
discrepancies.
Selected articles were assessed for quality by two independent re­
viewers (MS and NSP) using the Cochrane risk of bias tool (RoB 2.0)
[18]. The potential risk of bias for each study was categorized as either
low, high, or unclear. A third reviewer (SM) was consulted for resolution
in case of conflicts. We assessed certainty of evidence for each outcome
using the Grading of Recommendations, Assessment, Development, and
Evaluation (GRADE) approach [19].
2.4. Statistical analysis
All statistical analyses were done using RevMan (version 5.3,
Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration,
2014). We reported the effects of corticosteroids using relative risk (RR)
for dichotomous outcomes and mean difference (MD) for continuous
outcomes, both with 95 % confidence intervals (CIs). The results were
analysed through the random-effects model. Statistical heterogeneity
was assessed using the I2 Index, where < 50 %, 50–75 %, and > 75 %
were considered low, moderate, and high heterogeneity, respectively.
Outcomes with heterogeneity > 50 % were put through sensitivity
analysis by the leave-one-out analysis method to determine the study
causing heterogeneity. A p-value < 0.05 was considered significant.
Further subgroup analysis was carried out for outcomes between the ICU
and non-ICU populations. In cases where the stratified data was un­
available, RCTs with > 50 % of the patients admitted to the ICU were
classified as such and vice versa. Furthermore, a funnel plot was created
for the outcome of mortality to evaluate the risk of publication bias.
3. Results
3.1. Literature search and characteristics of included studies
A comprehensive search was conducted, resulting in 662 articles.
After filtration through the eligibility criteria, only 18 RCTs were
deemed suitable for analysis [7–10,20–33]. The study selection process
is visually depicted in Fig. 1 using the PRISMA flowchart. Our analysis
involved a combined total of 2,334 patients who underwent cortico­
steroid therapy and 2,138 patients who received placebo/standard of
care. Detailed information about the primary characteristics can be
found in Table 1.
L.A. Diaz Caballero et al.
Fig. 1. PRISMA Flowchart.
3.2. Quality assessment and publication bias
Out of the 18 RCTs, 13 were classified as high-quality, while two
were considered moderate-quality, and three were low-quality. The
assessment of quality is outlined in Supplemental Figures. 1 and 2. The
funnel plot was symmetrical, indicating low risk of publication bias
Supplemental Figure. 3. The certainty of evidence for each outcome was
graded as either high, moderate, low or very low as presented in sum­
mary of findings table (Table 2 and Supplemental table 2).
3.3. Results of meta-analysis
3.3.1. Mortality
All 18 studies reported data on patient mortality. Meta-analysis of
the data showed that patient mortality was significantly less in the group
of patients who were given steroid therapy as compared to patients who
received the placebo (RR: 0.66; 95 % CI: 0.54, 0.81; P = <0.0001;
moderate certainty; Fig. 2A) (I2 = 9 %).
3.3.2. Need for mechanical ventilation
Amongst the total of 18 studies, only 10 reported data on the oc­
currences in which patients needed mechanical ventilation. Combined
analysis showed that there was a significant reduction in the incidence
of needing mechanical ventilation with corticosteroid therapy (RR: 0.57;
95 % CI: 0.44, 0.73; P = <0.00001; high certainty; Fig. 2B) (I2 = 0 %).
3.3.3. ICU admission
Only one-third of the studies i.e., six out of the total 18, reported data
on the effect on ICU admissions. Combining the results from these
studies identified that giving steroid therapy to patients suffering from
CAP admitted in a non-ICU setting was seen to significantly reduce the
chances of ICU admission as compared to those patients who were given
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Steroids 205 (2024) 109389
the placebo (RR: 0.66; 95 % CI: 0.45, 0.97; P = 0.04; moderate certainty;
Fig. 2C) (I2 = 0 %).
3.3.4. Treatment failure
Only one third, meaning six of the eighteen studies recorded data on
treatment failure. Pooled analysis showed that there was no significant
difference of treatment failure regardless of whether steroids were
added to the regimen or not (RR: 0.78; 95 % CI: 0.36, 1.67; P = 0.52;
very low certainty; Fig. 2D) (I2 = 68 %).
3.3.5. Hospital readmission
Amongst the 18 studies, only five were found to report the events of
hospital readmissions. Meta-analysis of the data showed that steroid use
was associated with significantly more hospital readmissions (RR: 1.19;
95 % CI: 1.04, 1.37; P = 0.01; moderate certainty; Fig. 3A) (I2 = 0 %).
3.3.6. Length of hospital stay
Twelve studies from the total eighteen reported data on the length of
hospital stay. Pooled analysis revealed that steroid therapy significantly
reduced the duration of hospital stay for the patients by almost half a
day in total (MD: − 1.94; 95 % CI: − 2.89, − 0.98; P = 0.0001; low cer­
tainty; Fig. 3B) (I2 = 93 %).
3.3.7. Length of ICU stay
Length of stay in an ICU setting was assessed by nine studies. The
combined results indicate that steroid use significantly decreased the
length of ICU stay by around one-third of a day in total (MD: − 1.67; 95
% CI: − 2.97, − 0.37; P = 0.01; moderate certainty; Fig. 3C) (I2 = 49 %).
3.3.8. Gastrointestinal bleeding
Eleven studies in total reported data on the incidence of gastroin­
testinal bleeding. Integrated analysis shows that there was no significant
L.A. Diaz Caballero et al. Steroids 205 (2024) 109389

Table 1
Baseline characteristics of the included studies.
STUDY COUNTRY MALE AGE ICU MECHANICAL SEVERITY CRP INTERVENTION SAMPLE
(%) (%) VENTILATION (mg/ SIZE
dl)

Lloyd 2019 Australia 57 76.1 10.5 NR Non-severe [50 % of 88.2 Prednisone 50 mg daily for 7 816
(IMPROVe- patients with CORB days
GAP) scores < 2]
Gang 2016 China NR NR 100 NR Severe [majority ICU NR MP 80 mg daily for 7 days 58
patients]
Nafae 2013 Egypt 56.2 49 NR 0 Severe [based on 92.3 Hydrocortisone200 mg IV load, 80
baseline vitals then 10 mg/h IV infusion for 7
indicating mean CORB days
score > 2]
Sabry 2011 Egypt 72.5 62.2 100 75 Severe [majority ICU 568.5 Hydrocortisone200 mg IV load, 80
patients] then 12.5 mg/h IV infusion for 7
days
Confalonieri Italy 69.5 63.5 100 73.9 Severe [majority ICU 420 Hydrocortisone200 mg IV load, 46
2005 patients] then 10 mg/h IV infusion for 7
days
Mikami 2007 Japan 74.2 72 0 0 Non-severe [PSI I–III > 19.7 Prednisolone 40 mg IV daily for 31
50 %] 3 days
Meijvis 2011 Netherlands 56.5 63.6 0 0 Non-severe [PSI I–III > 217 DXM 5 mg IV daily for 4 days 304
(Ovidius) 50 %]
Wittermans Netherlands 67.4 67.5 0 0 Non-severe [PSI I–III > 204.5 DXM 6 mg PO daily for 4 days 401
2021 50 %]*
Snijders 2010 Netherlands 58.2 63.5 10.3 NR Non-severe [PSI I–III > 235.9 Prednisolone 40 mg daily for 7 213
50 %]^ days (IV or PO)
El-Ghamrawy Saudi 61.8 61.8 100 NR Severe [majority ICU NR Hydrocortisone200 mg IV bolus, 34
2006 Arabia patients] then 10 mg/h IV infusion for 7
days
McHardy and Scotland 48.4 60.3 0 NR Non-severe [defined by NR Prednisolone 5 mg every 6 h for 126
Schonell trials, most patients 7 days
1972 classified as
mild–moderate]
Fernández- Spain 66.7 61 (placebo),66 0 0 Severe [fine scores NR MP 200 mg IV bolus, then 20 mg 45
Serrano (MPDN) IV–V > 50 %] IV every 6 h for 3 days, then 20
2011 mg IV every 12 h for 3 days, then
20 mg IV for 3 days
Torres 2015 Spain 61.4 65.3 75 2.5 Severe [PSI scores 258.7 MP 0.5 mg/kg every 12 h for 5 120
IV–V > 50 %] days
Blum 2015 Switzerland 62 74 0 0 Non-severe [PSI I–III > 161.5 Prednisone 5 mg PO daily for 7 785
(STEP) (prednisone), 50 %] days
73 (placebo)
Marik 1993 UK NR 36.44 100 NR Severe [mean Apache NR Hydrocortisone10 mg/kg IV 30
II score 13, all ICU once, 30 min prior to antibiotics
patients]
Wagner 1956 USA 67.3 NR NR NR Non-severe [as defined NR HydrocortisonePO taper over 5 113
by authors] day (starting with 200 mg/day,
down to 2 mg/day)
Meduri 2022 USA 96 68.8 100 33 Severe [PSI scores NR MP 40 mg IV bolus, then 40 mg 584
(ESCAPe) IV–V > 50 %] per day for 7 days, then taper for
20 days
Dequin 2023 France 69.4 67 100 22.2 Severe [PSI scores 250 Hydrocortisone200 mg IV daily 795
(CAPE COD) IV–V > 50 %] for 4–8 days

difference in the number of gastrointestinal bleeding events in patients
with or without the use of steroids (RR: 0.97; 95 % CI: 0.57, 1.62; P =
0.89; low certainty; Fig. 4A) (I2 = 0 %).
3.3.9. Incidence of secondary infection
Ten studies from the included articles provided data on the incidence
of secondary infection. Analysing the results from the studies demon­
strates that there was no significant difference between in the incidence
of secondary infection in patients given steroid therapy as compared to
those who were not (RR: 1.07; 95 % CI: 0.85, 1.35; P = 0.58; low cer­
tainty; Fig. 4B) (I2 = 1 %).
3.3.10. Number of hyperglycaemic events
The number of hyperglycaemic events were reported by 11 studies.
Integrated analyses of the results showed that steroid use in patients was
associated with significantly more hyperglycaemic events as compared
to patients given the placebo (RR: 1.68; 95 % CI: 1.32, 2.12; P =
<0.0001; low certainty; Fig. 4C) (I2 = 29 %).
Of the 10 outcomes, only the results related to treatment failure had
a significant subgroup difference in patients admitted to the ICU versus
non-ICU setting (P = 0.0002; Fig. 2D). In all other outcomes, there was
no significant difference between the subgroups.
4. Discussion
Our meta-analysis of 18 studies represents a significant milestone in
evaluating the effectiveness of steroids in CAP, specifically focusing on
the severity of the condition and its correlation with ICU admission.
Through our analysis, we have demonstrated that the administration of
corticosteroids results in a significant reduction in mortality rates and
the need for mechanical ventilation, in both ICU and non-ICU patients.
Additionally, the utilization of corticosteroids has shown a notable
reduction in ICU admissions. Our study also highlights that the risk of
treatment failure in ICU patients is significantly diminished with the
administration of corticosteroids. Further, their use has proved to
significantly decrease the lengths of ICU and hospital stay, while

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L.A. Diaz Caballero et al. Steroids 205 (2024) 109389

Table 2
Summary of findings table.
Outcomes N◦ of Certainty of the Relative effect Anticipated absolute effects
participants evidence(GRADE) (95 % CI)
Risk with Placebo Risk difference with
(studies)
Corticosteroids
Follow-up

Mortality 4472(18 RCTs) ⊕⊕⊕○ RR 0.66 118 per 1,000 40 fewer per 1,000
Moderatea (0.54 to 0.81) (54 fewer to 22 fewer)
Mechanical Ventilation 3021(10 RCTs) ⊕⊕⊕⊕ RR 0.57 97 per 1,000 42 fewer per 1,000
High (0.44 to 0.73) (54 fewer to 26 fewer)
ICU admission 2575(6 RCTs) ⊕⊕⊕○ RR 0.66 48 per 1,000 16 fewer per 1,000
a
Moderate (0.45 to 0.97) (26 fewer to 1 fewer)
Treatment failure 2060(6 RCTs) ⊕○○○ RR 0.78 58 per 1,000 13 fewer per 1,000
b,c,d
Very low (0.36 to 1.67) (37 fewer to 39 more)
Length of hospital stay 2732(12 RCTs) ⊕⊕○○ – The mean length of hospital stay ranged MD 1.94 days lower
Lowb,e from 3 to 36.2 days (2.89 lower to 0.98 lower)
Incidence of gastrointestinal 3454(11 RCTs) ⊕⊕○○ RR 0.97 17 per 1,000 1 fewer per 1,000
bleeding Lowd,f (0.57 to 1.62) (7 fewer to 11 more)
Number of hyperglycemic 3448(11 RCTs) ⊕⊕○○ RR 1.68 94 per 1,000 64 more per 1,000
g,h
events Low (1.32 to 2.12) (30 more to 106 more)
*The risk in the intervention group (and its 95 % confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95 %
CI).
CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially
different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Explanations.
a. Wide confidence intervals that do not exclude harm or benefit.
b. High I2 with the statistical test for heterogeneity having a p-value less than 0.05.
c. Significant statistical subgroup differences was reported.
d. Optimal information size not reached.
e. Out of the 12 included studies, four had an unclear risk of bias (El Ghamrawy et al., Ferrandez-Serrano et al., Mikami et al. and Nafae et al.) and one study was at high
risk (Gang et al.) for random sequence generation
f. Out of the 11 included studies, four had an unclear risk of bias (El Ghamrawy et al., Ferrandez-Serrano et al., Sabry et al. and Nafae et al.) and one study was at high
risk (Gang et al.) for random sequence generation
g. Out of the nine included studies, three had an unclear risk of bias (Ferrandez-Serrano et al., Mikami et al., and Nafae et al.) and one study was at high risk (Gang et al.)
for random sequence generation. Two studies had a risk of bias (Mikami et al and Gang et al.) for allocation concealment and blinding of participants.
h. Low I2 but variable effects across studies.

increasing the number of hyperglycemic events and hospital
readmissions.
To our knowledge, this is the first prespecified, subgroup meta-
analysis based on ICU admission, rendering a definitive categorization of
the severity of pneumonia. Our findings are in line with the meta-anal­
ysis conducted by Siemieniuk R et al., confirming a reduction in both
mortality and mechanical ventilation with the use of corticosteroids
[12].. However, in their study, a broader classification of the severity of
pneumonia was defined using commonly used criteria (eg CURB 65
score, or, PSI scores) and authors’ classification in the absence of
objective scoring. Similar findings are also attributed to the outcome of
mechanical ventilation [12]. Notably, however, the recent analysis
conducted by Saleem N et al. presented contrasting findings to our
study, showing no significant reduction in mortality [4]. This can
potentially be due to the uncertainty of stratifying patients on the basis
of surrogates of inflammation, level of hypoxemia, or the more
commonly used clinical severity scores. Further, their meta-analysis was
also limited to patients admitted with CAP, with no assessment of those
not admitted to the ICU [4]. Another contrast was seen in the secondary
outcome of ICU admission with the use of corticosteroids. Briel M et al.
showed no significance in the rates of ICU admission and treatment
failure amongst those receiving corticosteroids [34]. This contrasts with
our analysis which showed significant reductions in both these
outcomes.
The therapeutic use of corticosteroids in pneumonia treatment offers
a valuable means to reduce inflammation, mitigate respiratory failure,
and modulate inflammatory markers, contributing significantly to
improved patient outcomes - as observed in our meta-analysis [35].
Pneumonia may present with critical illness-related corticosteroid
insufficiency (extreme physiologic stress in septic shock leading to
suboptimal production of cortisol) requiring therapeutic augmentation
with corticosteroids [35]. The release of inflammatory mediators during
an infection is beneficial, however, an excess can cause pulmonary
inflammation in pneumonia, leading to respiratory failure. Corticoste­
roids aid in further blunting this effect [36]. Additionally, corticoste­
roids have a pertinent effect on neutrophil migration and apoptosis as
well which helps in diminishing C-reactive protein and neutrophil
counts in bronchial aspirates of patients with pneumonia [37]. Overall,
the judicious use of corticosteroids represents a crucial therapeutic
approach in managing pneumonia and its associated complications.
These therapeutic benefits of steroids can be attributed to the decrease in
ICU admission rates, contributing to attenuating the detrimental effects
and progression of CAP and decreasing the length of ICU stay as well
while also benefitting those admitted to the ICU who represent a more
severe form of illness. Interestingly, significant subgroup difference was
observed regarding treatment failure in ICU versus non-ICU setting,
indicating lower risk of treatment failure among ICU patients. It can also
be attributed to the differences in disease severity between these groups.
Our study also demonstrated a higher number of rehospitalizations
in patients who received steroids. A potential reason for this can be due
to the ‘revolving door phenomenon’. To simplify, this term implies a
cycle where patients are discharged from the hospital but end up
returning shortly thereafter. The decreased length of hospital stay could
have contributed to this. This observation aligns with findings from a
study conducted by Tellini et al, which specifically explored this phe­
nomenon in internal medicine patients with conditions like heart failure

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L.A. Diaz Caballero et al. Steroids 205 (2024) 109389

Fig. 2. Forest plot for a) Mortality, b) Mechanical Ventilation, c) ICU admission, and d) Treatment failure.

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L.A. Diaz Caballero et al. Steroids 205 (2024) 109389

Fig. 3. Forest plot for a) Hospital readmission, b) Length of hospital stay, c) Length of ICU stay.

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L.A. Diaz Caballero et al. Steroids 205 (2024) 109389

Fig. 4. Forest plot for a) Gastrointestinal bleeding, b) Incidence of secondary infection, c) Number of hyperglycemic events.

8
L.A. Diaz Caballero et al.
and pneumonia. However, this phenomenon was linked to the
complexity of patients’ conditions which ultimately led to rehospitali­
zation [38].
It is essential to highlight some further prominent differences be­
tween the recently published literature and our own meta-analysis,
which contribute to the strength and uniqueness of our findings. Firstly,
our study was specifically designed to include a study population which
was most representative of a wide range of disease intensities, ensuring a
comprehensive evaluation of corticosteroid therapy in CAP. Secondly,
we conducted a subgroup analysis on the basis of ICU admission to
ensure the inclusion of all relevant published studies on this topic,
providing an in-depth understanding. Thirdly, our analysis demon­
strates a more robust and statistically significant reduction in both
mortality and the need for mechanical ventilation as separate outcomes.
On the contrary, Saleem et al’s meta regression analysis did not show
reduced mortality rates, even though it did demonstrate a reduction in
mechanical ventilation [4]. By including a more representative study
population, a larger sample size and conducting a focused subgroup
analysis, our study provides stronger evidence of the beneficial effects of
corticosteroid therapy in reducing both mortality and the need for me­
chanical ventilation in CAP.
There were several limitations to this meta-analysis. The included
studies used a wide range of the type, doses, and duration of treatment of
corticosteroids. This remains inconclusive and undefined. Additionally,
CAP presents a wide spectrum of different etiologies, and the advantages
of corticosteroid therapy may differ. Even though there are detailed
studies for microbiological evaluations, only 40 % may be able to detect
the pathogen involved in CAP [39]. Due to the paucity of the reporting
of different microbiological pathogens in the studies included, a sub­
group analysis could not be performed. Moreover, another limitation is
the inability to stratify the patients on the basis of diabetes due to limited
available data, which can impact the interpretation of hyperglycemia
outcomes. Lastly, the categorization of the ICU versus non-ICU patients
was done based on the majority present within each RCT which may
impact the resulting stratification.
5. Conclusions
As evidenced by this comprehensive meta-analysis, the beneficial
effects of corticosteroid usage in CAP include the prominent outcomes of
reduced mortality and the need for mechanical ventilation among both
ICU and non-ICU patients. Notably, rates of treatment failures were
significantly lower in ICU patients, highlighting that patients admitted
to ICU with severe CAP can likely benefit the most from steroids. Future
RCTs inclusive of larger patient populations, stratifications according to
ICU vs. non-ICU setting, as well as the types and dosages of corticoste­
roids, are needed to provide additional data to cement these insights.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Luis A. Diaz Caballero: Supervision, Writing – review & editing.
Ashnah Aijaz: Formal analysis, Writing – original draft. Neha Saleem
Paryani: Conceptualization, Writing – review & editing, Formal anal­
ysis. Samar Mahmood: Methodology, Writing – original draft. Madiha
Salman: Methodology, Writing – original draft. Mohammad Omer
Khan: Formal analysis, Writing – original draft. Dayal Ahluwalia:
Writing – review & editing, Validation. Mohammad Arham Siddiq:
Formal analysis, Writing – original draft. Ishaque Hameed: Conceptu­
alization, Supervision, Writing – review & editing.
9
Steroids 205 (2024) 109389
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.steroids.2024.109389.
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