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DOI: 10.1056/EVIDoa2200283
ORIGINAL ARTICLE
Abstract
BACKGROUND Glucocorticoids reduce mortality in hospitalized patients with severe and
critical coronavirus disease 2019 (Covid-19), although a possible harm was documented
in patients with Covid-19 not requiring oxygen.
METHODS We searched Embase, BioMed Central, medRxiv, bioRxiv, PubMed, and the
Cochrane Central Register of Controlled Trials for any randomized trial or matched study
ever performed on adult patients with Covid-19 not receiving oxygen therapy treated with
intravenous or oral glucocorticoids versus any comparator (standard therapy or placebo);
there were no restrictions on dose or time of administration. The primary end point was
all-cause mortality at the longest available follow-up.
RESULTS Five randomized trials and one propensity-matched study involving 6634 hospi-
talized patients not on oxygen were finally included (3704 received glucocorticoids and
2930 received standard treatment). The overall mortality of patients treated with gluco-
corticoids was significantly higher than the mortality of patients in the control group
(509 of 3704 [14%] in the glucocorticoid group vs. 294 of 2930 [10%] in the control
group; odds ratio, 1.56 [95% confidence interval, 1.27 to 1.92], with three articles report-
ing mortality events and contributing to the combined odds ratio; P,0.001; number
needed to harm527).
G
lucocorticoids were the first drugs with a reported survival benefit in hospitalized Department of Anesthesia and
Intensive Care, IRCCS San
patients with severe and critical coronavirus disease 2019 (Covid-19) and are Raffaele Scientific Institute, Via
now the standard of care in these patients.1 Existing guidelines advise against Olgettina, 60–20132, Milan, Italy.
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the use of glucocorticoids outside of these conditions,2,3 randomized controlled trials (RCTs) evaluating the role of
mainly because of the results of the Randomised Evaluation glucocorticoids in the very early phase of Covid-19 are
of COVID-19 Therapy (RECOVERY) trial,1 which showed no lacking; the data are mainly limited to case series and
effect and a trend toward harm in hospitalized patients not observational studies, with a low level of evidence and
receiving oxygen treated with glucocorticoids. The best tim- inconsistent results.10-18 In a previous meta-analysis of
ing of — and severity threshold for — administering gluco- RCTs evaluating the effects of glucocorticoids on the
corticoids in patients with Covid-19 has been a main issue survival of patients with Covid-19 receiving various types
in clinical practice since the beginning of the pandemic. of respiratory support, we documented increased mortality
Covid-19 is a systemic disease whose clinical manifestations in patients not receiving oxygen therapy treated with glu-
range from asymptomatic infection or only mild symptoms cocorticoids; only two trials were included, however, and
in most of the population to severe viral pneumonia that significance was borderline.19 To test the hypothesis that
may require oxygen support in a minority of patients. glucocorticoids could be detrimental in patients not on
oxygen therapy, we performed an updated meta-analysis
Among all anti-inflammatory and immunosuppressive drugs of all randomized or matched trials that compared gluco-
tested in Covid-19, glucocorticoids are a low-cost, globally corticoids versus placebo or standard treatment in patients
available, easily accessible therapy. At the beginning of the with Covid-19 not on oxygen.
pandemic, glucocorticoids were either “contraindicated” or
“not recommended” by most of the Covid-19 treatment
guidelines, mainly in light of enhanced viral replication,
decreased viral clearance, and poor outcomes in previous
Methods
viral infections such as severe acute respiratory syndrome,
SEARCH STRATEGY
Middle East respiratory syndrome, and influenza.4-8
Electronic searches were independently performed in
In the RECOVERY trial, 6425 hospitalized patients were Embase, BioMed Central, medRxiv, bioRxiv, PubMed, and
randomly allocated to receive either standard therapy or the Cochrane Central Register of Controlled Trials by four
standard therapy plus dexamethasone.1 Overall mortality investigators (last update, January 7, 2023). The full search
of patients treated with dexamethasone was significantly strategies aimed to include any RCT, cluster crossover
lower than mortality of patients in the control group trial, and matched or paired observational data study ever
(22.9% in the dexamethasone group vs. 25.7% in the con- performed with glucocorticoids in patients with Covid-19
trol group). However, mortality rates varied significantly, and are presented in the Supplementary Appendix (Table
depending on the level of respiratory support at randomiza- S1). No language restriction was imposed. In addition,
tion; in patients not receiving any respiratory support, there hand searches were conducted among the reference lists
was a nonsignificant trend toward harm (17.8% mortality in of eligible primary reports and relevant review articles.
the dexamethasone group vs. 14% in the control group; rela- Moreover, international experts were contacted in search
tive risk 1.30; 95% confidence interval [CI], 0.99 to 1.72). of additional publications.
NEJM EVIDENCE 2
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respiratory support (invasive or noninvasive ventilation); items: blinding of participants and personnel, allocation
reports in which patients received inhaled glucocorticoids; sequence generation, incomplete outcome data, allocation
reports involving pediatric patients; more than one publi- concealment, blinding of outcome assessment, selective
cation describing a study or trial (in this case, we extracted outcome reporting, for-profit bias, and overall risk of bias.20
data from the publication with the longest follow-up avail- The quality assessment was completed by two researchers
able); and reports lacking data on the primary outcome. independently, who reached a consensus before moving to
References were examined at the title/abstract level inde- the next step. Any discrepancies between them were resolved
pendently by four investigators and, if potentially suitable through discussions with a third reviewer. Subgroup analysis
for inclusion, were retrieved as complete articles. including only RCTs was performed. Publication bias was
assessed by visually inspecting funnel plots.
DATA ABSTRACTION
DATA ANALYSIS AND SYNTHESIS
Data from the chosen articles were extracted indepen-
dently by four reviewers using an extraction form that was This meta-analysis was registered on PROSPERO (CRD
constructed before the study or trial article review. The 42022342996) and follows the guidelines of The Cochrane
primary end point of our analysis was all-cause mortality Collaboration and Preferred Reporting Items for Systematic
at the longest available follow-up. Secondary end points Reviews and Meta-Analyses.20,21 All the analyses were per-
were intubation rate, intensive care unit admission, length formed with ReviewManager version 5.4 (Nordic Cochrane
of intensive care unit stay, and length of hospital stay. Centre, Cochrane Collaboration). Data were synthesized by
Incidence of adverse events was also recorded. At least using a random-effects model, which better accommodates
statistical and clinical variations compared with the fixed-
two email attempts to contact the corresponding author of
effects model. Pooled relative risk or odds ratios and their
articles with missing data on primary outcome were made.
95% CIs were estimated for categorical outcomes, whereas
pooled mean differences and their 95% CIs were estimated
INTERNAL VALIDITY AND RISK OF BIAS ASSESSMENT for continuous outcomes. The double-arm-zero-event trials
Risk of bias was assessed by using the Cochrane Risk of or studies were discarded from the analyses, and a fixed
Bias tool for RCTs. This tool included the following value of 0.5 was added to trials or studies with no events in
4003
Identification
Articles retrieved
from database screening and manual
searches
34 Articles excluded:
–1 No matched pair trial
–6 Inhaled glucocorticoids
–23 Missing data on patients without oxygen supplementation
–4 Patients with oxygen or respiratory support
Included
Figure 1. Flowchart.
Covid-19 denotes coronavirus disease 2019.
NEJM EVIDENCE 3
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NEJM EVIDENCE
Table 1. Characteristics of the Included Reports.*
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or clinical
worsening)
Prado 2020 RCT 30 42 Ordinary 28-Day mortality Intravenous 5 days Placebo 1 28 d
Jeronimet al.24 ward methylprednisolone standard treatment
(0.5 mg/kg) twice daily
NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society.
RECOVERY Trial1 2020 RCT 501 1034 Ordinary 28-Day mortality Oral or intravenous Up to 10 Standard 28 d
ward dexamethasone 6 mg days (or treatment
once daily hospital
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discharge)
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Tang et al.23 2021 RCT 11 14 Ordinary Clinical Intravenous 7 days Placebo 1 Hospital
ward deterioration methylprednisolone standard treatment discharge
1 mg/kg daily
* Covid-19 denotes coronavirus disease 2019; ICU, intensive care unit; IMV, intermittent mechanical ventilation; and RCT, randomized controlled trial.
4
Table 2. Outcomes.*
one arm. Moreover, a continuity correction method was of Recommendations, Assessment, Development and Eval-
applied to all double-arm-zero-event trials or studies by add- uation) approach was used to assess the certainty of evi-
ing a fixed value of 1. Statistical significance was set at the dence related to each outcome.
two-tailed 0.05 level for hypothesis testing. Unadjusted P
values are reported throughout.
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according to the overall inclusion selection criteria (Fig. 1).
* CI denotes confidence interval; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; PM, propensity-matched study; and RCTs, randomized controlled trials.
Ratio (95% CI)
were then excluded. Details of the excluded articles are
presented in Table S2.
Without
⨁⨁⨁ represents a moderate quality of evidence in a scale ranging from ⨁⨁⨁⨁ to ⨁ (from high to very low quality of evidence). QUANTITATIVE DATA SYNTHESIS
Overall mortality of patients treated with glucocorticoids
Certainty of
Moderate
Moderate
⨁⨁⨁
⨁⨁⨁
Overall
None
None
Bias
† Most of the information is from trials at low or moderate risk of bias (one study at high risk of bias).
Not serious
Moderate‡
1638 (4 RCTs)
ventilation
Mortality
Need for
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Favors Glucocorticoids Need MV control Odds Ratio Odds Ratio Risk of Bias
Study or Subgroup Events Total Events Total Weight M–H, Random (95% Cl) M–H, Random (95% Cl) A B C D E F G
Tang, 2021 0 11 0 14 Not estimable + + – + + +
Les, 2022 0 34 0 37 Not estimable + + + + + + +
Kocks, 2022 1 4 0 3 0.6% 3.00 (0.09 to 102.05) – – + +
RECOVERY trial, 2020 97 501 160 1,034 99.4% 1.31 (0.99 to 1.73) + + – – + +
boundary for harm, and the required information size of Our findings increase the evidence for what had been only
3646 patients was achieved (Fig. S6). presumed in previous reports; that is, administration of
glucocorticoids to patients not receiving supplemental
oxygen may be harmful. This is of public health impor-
tance because the total number of documented severe
Discussion acute respiratory syndrome coronavirus 2–positive patients
Our meta-analysis suggests that the use of glucocorticoids worldwide is more than 600 million; even a small detri-
increases mortality in hospitalized patients with Covid-19 mental effect of glucocorticoids on survival could translate
not receiving oxygen, with a number needed to harm of into thousands of potentially preventable deaths.30 Gluco-
27. A prior meta-analysis of RCTs evaluating the effects corticoids seem to elicit distinct clinical outcomes in
of glucocorticoids on the survival of subgroups of patients patients with Covid-19, depending on the timing and the
with Covid-19 receiving various levels of respiratory inflammatory milieu when they are administered.10 We
support showed increased mortality in the subgroup of speculate that in patients who are sick enough to receive
patients not receiving oxygen, with a number needed to oxygen treatment, the anti-inflammatory actions of glucocor-
harm of 19.19 The conclusion was not strong because only ticoids, as opposed to the delay in viral clearance effects,
1607 patients were included in the analysis, statistical lead to the selective beneficial effects we observed. Con-
significance was fragile, and only two trials reported versely, under physiological conditions, glucocorticoid treat-
events.22,25 In the current meta-analysis, instead of analyz- ment may lead to endothelial dysfunction by decreasing
ing all trials and studies in this area, as previous meta- vascular nitric oxide availability and the adverse outcomes
analyses had done, we specifically focused on reports observed in our meta-analysis.31,32
involving patients with Covid-19 not using oxygen at the
time of enrollment. Our findings are also in line with We acknowledge that our meta-analysis has several
recent observational evidence that reported poor out- limitations. We included only one, very small trial, per-
comes in terms of disease progression or mortality in formed on patients outside the hospital setting.26 There-
patients with Covid-19 who had early or mild disease and fore, selection bias cannot be excluded, and our findings
who received glucocorticoids.27-29 cannot be simply extrapolated to the wider community
NEJM EVIDENCE 7
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because our analysis includes almost only hospitalized 5. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of
patients with an observed mortality rate of 10 to 14%. treatment effects. PLoS Med 2006;3:e343. DOI: 10.1371/journal.
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14651858.CD010406.pub2.
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Author disclosures and other supplementary materials are available at
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1 roid therapy in elderly patients with early Covid-19. Aging Clin Exp
Busto Arsizio Hospital, Busto Arsizio, Lombardia, Italy
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Anesthesia and Intensive Care, Azienda Ospedale-Universita di Padova,
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Department of Anesthesia and Intensive Care, IRCCS San Raffaele mia. BMJ Case Rep 2021;14:e241105. DOI: 10.1136/bcr-2020-241105.
Scientific Institute, Milan
4 14. Ordinola Navarro A, Lopez Luis BA. Corticosteroids prescription
Doctoral School of Theoretical and Translational Medicine, Semmelweis
University, Budapest, Hungary for mild-moderate Covid-19 in primary care. J Infect Dev Ctries
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InCor, Hospital das Clınicas da Faculdade de Medicina, Universidade de 2021;15:1813-1815. DOI: 10.3855/jidc.15069.
S~
ao Paulo, S~
ao Paulo
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Faculty of Medicine, Vita-Salute San Raffaele University, Milan
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