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Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report

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Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.
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Dexamethasone for COVID-19 Preliminary Report
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Effect of Dexamethasone in Hospitalized Patients with
COVID-19 Preliminary Report
Running title: Dexamethasone for COVID-19Preliminary Report
RECOVERY Collaborative Group*
*The writing committee and trial steering committee are listed at the end of this manuscript and
a complete list of collaborators in the Randomised Evaluation of COVID-19 Therapy
(RECOVERY) trial is provided in the Supplementary Appendix.
Correspondence to: Dr Peter W Horby and Dr Martin J Landray, RECOVERY Central
Coordinating Office, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3
7LF, United Kingdom.
Email: recoverytrial@ndph.ox.ac.uk
Word count:
Abstract 250 words
Main text – 2820
References 40
Tables & Figures 2 + 2
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Dexamethasone for COVID-19 Preliminary Report
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ABSTRACT
Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage.
Corticosteroids may modulate immune-mediated lung injury and reducing progression to
respiratory failure and death.
Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a
randomized, controlled, open-label, adaptive, platform trial comparing a range of possible
treatments with usual care in patients hospitalized with COVID-19. We report the preliminary
results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual
care alone. The primary outcome was 28-day mortality.
Results: 2104 patients randomly allocated to receive dexamethasone were compared with
4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated
dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-
adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The
proportional and absolute mortality rate reductions varied significantly depending on level of
respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths
by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65
[95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive
mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not
reduce mortality in patients not receiving respiratory support at randomization (17.0% vs.
13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14).
Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day
mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but
not among patients not receiving respiratory support.
Trial registrations: The RECOVERY trial is registered with ISRCTN (50189673) and
clinicaltrials.gov (NCT04381936).
Funding: Medical Research Council and National Institute for Health Research (Grant ref:
MC_PC_19056).
Keywords: COVID-19, dexamethasone, clinical trial.
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Dexamethasone for COVID-19 Preliminary Report
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INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus
disease 2019 (COVID-19), emerged in China in late 2019 from a zoonotic source.1 The majority
of COVID-19 infections are either asymptomatic or result in only mild disease. However, a
substantial proportion of older infected individuals develop a respiratory illness requiring hospital
care,2 which can progress to critical illness with hypoxemic respiratory failure requiring
prolonged ventilatory support.3-6 Amongst COVID-19 patients admitted to UK hospitals, the case
fatality rate is over 26%, and is over 37% in patients requiring invasive mechanical ventilation.7
Although remdesivir has been shown to shorten the time to recovery in hospitalized patients,8
no therapeutic agents have been shown to reduce mortality.
The pathophysiology of severe COVID-19 is dominated by an acute pneumonic process with
extensive radiological opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates
and microvascular thromobosis.9,10 The host immune response is thought to play a key role in
the pathophysiology of organ failure in other severe viral pneumonias such as highly pathogenic
avian influenza,11 severe acute respiratory syndrome (SARS),12,13 and pandemic and seasonal
influenza.14 Inflammatory organ injury may occur in severe COVID-19, with a subset of patients
having markedly elevated inflammatory markers such as C-reactive protein, ferritin, and
interleukins 1 and 6.6,15,16 Several therapeutic interventions to mitigate inflammatory organ injury
have been proposed in viral pneumonia but the value of corticosteroids has been widely
debated.17,18
In the absence of reliable evidence from large-scale randomized clinical trials, there is great
uncertainty about the effectiveness of corticosteroids in COVID-19. Prior to RECOVERY, many
COVID-19 treatment guidelines stated that corticosteroids were either ‘contraindicated’ or ‘not
recommended’19 although in China, corticosteroids are recommended for severe cases.20
Practice has varied widely across the world: in some series, as many as 50% of cases were
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Dexamethasone for COVID-19 Preliminary Report
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treated with corticosteroids.21,22 Here we report the results of a randomized controlled trial of
dexamethasone in patients hospitalized with COVID-19.
METHODS
Trial design and participants
The RECOVERY trial is an investigator-initiated, individually randomized, controlled, open-label,
adaptive platform trial to evaluate the effects of potential treatments in patients hospitalized with
COVID-19. The trial was conducted at 176 National Health Service (NHS) hospital organizations
in the United Kingdom (see Supplementary Appendix), supported by the National Institute for
Health Research Clinical Research Network. The trial was coordinated by the Nuffield
Department of Population Health at University of Oxford, the trial sponsor.
Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory
confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the
attending clinician, put the patient at significant risk if they were to participate in the trial. Initially,
recruitment was limited to patients aged at least 18 years but the age limit was removed from 9
May 2020. Pregnant or breast-feeding women were eligible.
Written informed consent was obtained from all patients or from a legal representative if they
were too unwell or unable to provide consent. The trial was conducted in accordance with the
principles of the International Conference on HarmonizationGood Clinical Practice guidelines
and approved by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and
the Cambridge East Research Ethics Committee (ref: 20/EE/0101). The protocol and statistical
analysis plan are available on the study website www.recoverytrial.net.
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Dexamethasone for COVID-19 Preliminary Report
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Randomization
Baseline data collected using a web-based case report form included demographics, level of
respiratory support, major comorbidities, suitability of the study treatment for a particular patient
and treatment availability at the study site. Eligible and consenting patients were assigned in a
ratio of 2:1 to either usual standard of care or to usual standard of care plus dexamethasone 6
mg once daily (oral or intravenous) for up to 10 days (or until discharge if sooner) or to one of
the other suitable and available treatment arms (see Supplementary Appendix) using web-
based simple randomization with allocation concealment. For some patients, dexamethasone
was either unavailable at the hospital at the time of enrolment or considered by the managing
doctor to be either definitely indicated or definitely contraindicated. These patients were
excluded from entry in the randomized comparison of dexamethasone vs. usual care and hence
are not part of this report. The randomly assigned treatment was prescribed by the treating
clinician. Participants and local study staff were not blinded to the allocated treatment.
Procedures
A single online follow-up form was to be completed when participants were discharged, had
died or at 28 days after randomization (whichever occurred earlier). Information was recorded
on adherence to allocated study treatment, receipt of other study treatments, duration of
admission, receipt of respiratory or renal support, and vital status (including cause of death). In
addition, routine health care and registry data were obtained including information on vital status
(with date and cause of death); discharge from hospital; intensive care use; and renal
replacement therapy.
Outcome measures
The primary outcome was all-cause mortality within 28 days of randomization. Secondary
outcomes were time to discharge from hospital, and among patients not receiving invasive
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Dexamethasone for COVID-19 Preliminary Report
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mechanical ventilation at randomization, subsequent receipt of invasive mechanical ventilation
(including extra-corporeal membrane oxygenation) or death. Subsidiary clinical outcomes
included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac
arrhythmia (recorded in a subset), and receipt and duration of ventilation.
Statistical Analysis
For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to
estimate the mortality rate ratio. The few patients (4.8%) who had not been followed for 28 days
by the time of the data cut (10 June 2020) were either censored on 8 June 2020 or, if they had
already been discharged alive, were right-censored at day 29 (that is, in the absence of any
information to the contrary they were assumed to have survived 28 days). Kaplan-Meier survival
curves were constructed to display cumulative mortality over the 28-day period. Cox regression
was used to analyze the secondary outcome of hospital discharge within 28 days, with patients
who died in hospital right-censored on day 29. For the pre-specified composite secondary
outcome of invasive mechanical ventilation or death within 28 days (among those not receiving
invasive mechanical ventilation at randomization), the precise date of invasive mechanical
ventilation was not available and so a log-binomial regression model was used to estimate the
risk ratio.
Pre-specified analyses of the primary outcome were performed in five subgroups defined by
characteristics at randomization: age, sex, level of respiratory support, days since symptom
onset, and predicted 28-day mortality risk. Observed effects within subgroup categories were
compared using a chi-square test for trend. Through the play of chance in the unstratified
randomization, mean age was 1.1 years higher in those allocated dexamethasone than those
allocated usual care (Table 1). To account for this imbalance in an important prognostic factor,
the estimates of rate ratios and risk ratios (both hereon denoted RR) were adjusted for baseline
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Dexamethasone for COVID-19 Preliminary Report
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age. This adjustment was not specified in the first version of the statistical analysis plan, but
was added once the imbalance in age (a key prognostic factor) became apparent. Results with
and without age-adjustment are provided and show that it does not alter the conclusions
materially.
Estimates of rate and risk ratios are shown with 95% confidence intervals. All p-values are 2-
sided and all analyses were done according to the intention-to-treat principle. The full database
is held by the study team which collected the data from study sites and performed the analyses
at the Nuffield Department of Population Health, University of Oxford.
Sample size and decision to stop enrolment
As stated in the protocol, appropriate sample sizes could not be estimated when the trial was
being planned at the start of the COVID-19 pandemic. As the trial progressed, the trial Steering
Committee, blinded to the results of the study treatment comparisons, formed the view that, if
28-day mortality was 20% then a comparison of at least 2000 patients allocated to active drug
and 4000 to usual care alone would yield at least 90% power at two-sided P=0.01 to detect a
clinically relevant absolute difference of 4 percentage points between the two groups (a
proportional reduction of one-fifth). Consequently, on 8 June 2020, the Steering Committee
closed recruitment to the dexamethasone arm since enrolment exceeded 2000 patients.
RESULTS
Patients
Of the 11,320 patients randomized between 19 March and 8 June, 9355 (83%) were eligible to
be randomized to dexamethasone (that is dexamethasone was available in the hospital at the
time and the patient had no known indication for or contraindication to dexamethasone). Of
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Dexamethasone for COVID-19 Preliminary Report
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these, 2104 were randomized to dexamethasone and 4321 were randomized to usual care
(Figure S1), with the remainder being randomized to one of the other treatment arms. Mean age
of study participants in this comparison was 66.1 years (Table 1) and 36% patients were female.
A history of diabetes was present in 24% of patients, heart disease in 27%, and chronic lung
disease in 21%, with 56% having at least one major comorbidity recorded. In this analysis, 82%
of patients had laboratory confirmed SARS-CoV-2 infection, with the result currently awaited for
9%. At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal
membrane oxygenation, 60% were receiving oxygen only (with or without non-invasive
ventilation), and 24% were receiving neither.
Follow-up information was complete for 6119 (95%) of the randomized patients. Of those
allocated to dexamethasone 95% received at least 1 dose (Table S1) and the median number of
days of treatment was 6 days. 7% of the usual care group received dexamethasone. Use of
azithromycin during the follow-up period was similar in both arms (23% vs. 24%) and very few
patients received hydroxychloroquine, lopinavir-ritonavir, or interleukin-6 antagonists during
follow-up (Table S1). Remdesivir only became available for use in the UK under the MHRA
Emergency Access to Medicines Scheme on 26 May 2020.
Primary outcome
Significantly fewer patients allocated to dexamethasone met the primary outcome of 28-day
mortality than in the usual care group (454 of 2104 patients [21.6%] allocated dexamethasone
vs. 1065 of 4321 patients [24.6%] allocated usual care; rate ratio, 0.83; 95% confidence interval
[CI], 0.74 to 0.92; P<0.001) (Figure 1A). In a pre-specified subgroup analysis by level of
respiratory support received at randomization, there was a significant trend showing the
greatest absolute and proportional benefit among those patients receiving invasive mechanical
ventilation at randomization (test for trend p<0.001) (Figure 2). Dexamethasone reduced 28-day
mortality by 35% in patients receiving invasive mechanical ventilation (rate ratio 0.65 [95% CI
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Dexamethasone for COVID-19 Preliminary Report
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0.51 to 0.82]; p<0.001) and by 20% in patients receiving oxygen without invasive mechanical
ventilation (rate ratio 0.80 [95% CI 0.70 to 0.92]; p=0.002) (Figure 1B-C). However, there was
no evidence of benefit among those patients who were not receiving respiratory support (rate
ratio 1.22 [95% CI 0.93 to 1.61]; p=0.14) (Figure 1D). Sensitivity analyses without age-
adjustment produced similar findings (Table S2).
Patients on invasive mechanical ventilation at randomization were on average 10 years younger
than those not receiving any respiratory support and had symptoms prior to randomization for 7
days longer (Table 1). 28-day mortality in the usual care group was highest in those who were
receiving invasive mechanical ventilation at randomization (40.7%), intermediate in those
patients who received oxygen only (25.0%), and lowest among those who were not receiving
respiratory support at randomization (13.2%). Consequently, the greatest absolute reductions in
28-day mortality were seen among those patients on invasive mechanical ventilation.
Patients with longer duration of symptoms (who were more likely to be on invasive mechanical
ventilation at randomization) had a greater mortality benefit, such that dexamethasone was
associated with a reduction in 28-day mortality among those with symptoms for more than 7
days but not among those with more recent symptom onset (test for trend p<0.001) (Figure S2).
Secondary outcomes
Allocation to dexamethasone was associated with a shorter duration of hospitalization than
usual care (median 12 days vs. 13 days) and a greater probability of discharge within 28 days
(rate ratio 1.11 [95% CI 1.04 to 1.19]; p=0.002) (Table 2) with the greatest effect seen among
those receiving invasive mechanical ventilation at baseline (test for trend p=0.002) (Figure S3a).
Among those not on invasive mechanical ventilation at baseline, the number of patients
progressing to the pre-specified composite secondary outcome of invasive mechanical
ventilation or death was lower among those allocated to dexamethasone (risk ratio 0.91 [95% CI
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Dexamethasone for COVID-19 Preliminary Report
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0.82 to 1.00]; p=0.049) (Table 2) but with significantly greater effects among patients receiving
oxygen at randomization (test for trend p=0.008) (Figure S3b).
Subsidiary clinical outcomes
The risk of progression to invasive mechanical ventilation was lower among those allocated
dexamethasone vs. usual care (risk ratio 0.76 [95% CI 0.61 to 0.96]; p=0.021) (Table 2).
Preliminary analyses indicate no excess risk of any particular cause of death (in particular there
was no excess of deaths due to non-COVID infection). More detailed analyses of cause-specific
mortality, need for renal dialysis or hemofiltration, and duration of ventilation are in preparation.
DISCUSSION
These preliminary results show that dexamethasone 6mg per day for up to 10 days reduces 28-
day mortality in COVID-19 patients receiving invasive mechanical ventilation by one third, and
by one fifth in patients receiving oxygen without invasive mechanical ventilation. Similarly,
benefit was clearer in patients treated more than 7 days after treatment onset, when
inflammatory lung damage is likely to have been more common. However, no benefit was
demonstrated in hospitalized COVID-19 patients who were not receiving respiratory support and
the results are consistent with possible harm in this group.
RECOVERY is a large, pragmatic, randomized, controlled adaptive platform trial designed to
provide rapid and robust assessment of the impact of readily available potential treatments for
COVID-19 on 28-day mortality. Around 15% of all UK hospitalized patients with COVID-19 were
enrolled in the trial and the control arm fatality rate is consistent with the overall hospitalized
case fatality rate in the UK.7 Only essential data were collected at hospital sites with additional
information (including long-term mortality) ascertained through linkage with routine data
sources. We did not collect information on physiological, laboratory or virologic parameters. The
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Dexamethasone for COVID-19 Preliminary Report
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protocol combines the methods of large, simple trials of treatments for acute myocardial
infarction in the 1980s with the opportunities provided by digital health care in the 2020s.23-25 It
has progressed at unprecedented speed, as is essential for studies during epidemics.26 These
preliminary results for dexamethasone were announced on 16 June 2020, just 98 days after the
protocol was first drafted, and were adopted into UK practice later the same day.27
Corticosteroids have been widely used in syndromes closely related to COVID-19, including
SARS, MERS, severe influenza, and community acquired pneumonia. However, the evidence to
support or discourage the use of corticosteroids in these conditions has been very weak due to
the lack of sufficiently powered randomized controlled trials.28-31 In addition, the evidence base
has suffered from heterogeneity in corticosteroid doses, medical conditions, and disease
severity studied. It is likely that the beneficial effect of corticosteroids in severe viral respiratory
infections is dependent on using the right dose, at the right time, in the right patient. High doses
may be more harmful than helpful, as may corticosteroid treatment given at a time when control
of viral replication is paramount and inflammation is minimal. Slower clearance of viral RNA has
been observed in patients with SARS, MERS and influenza treated with systemic corticosteroids
but the clinical significance of this is unknown.29,32,33 Unlike SARS, where viral replication peaks
in the second week of illness,34 peak viral shedding in COVID-19 appears to be higher early in
the illness and declines thereafter.35-38 The greater mortality benefit of dexamethasone in
patients with COVID-19 who required respiratory support, and among those recruited after the
first week of their illness, suggests that at this stage the disease is dominated by
immunopathology, with active virus replication playing a secondary role. It is also possible there
is an effect via mineralocorticoid receptor binding in the context of SARS-CoV-2 induced
dysregulation of the renin-angiotensin system.39 This would caution against extrapolating the
effect of dexamethasone in patients with COVID-19 to patients with other viral respiratory
diseases that have a different natural history.
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Dexamethasone for COVID-19 Preliminary Report
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The RECOVERY trial provides clear evidence that treatment with dexamethasone 6 mg once
daily for up to 10 days reduces 28-day mortality in patients with COVID-19 who are receiving
respiratory support. Based on these results, 1 death would be prevented by treatment of around
8 patients requiring invasive mechanical ventilation or around 25 patients requiring oxygen
(which, in the UK, is recommended when oxygen saturations on room air are 92-94%)40 without
invasive mechanical ventilation. There was no benefit (and the possibility of harm) among
patients who did not require oxygen. Prior to the completion of this trial, many COVID-19
treatment guidelines have stated that corticosteroids are either ‘contraindicated’ or ‘not
recommended’ in COVID-19.19 These should now be updated, as has already happened within
the UK.27 Dexamethasone provides an effective treatment for the sickest patients with COVID-
19 and, given its low cost, well understood safety profile, and widespread availability, is one that
can be used worldwide.
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Dexamethasone for COVID-19 Preliminary Report
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Authorship
This manuscript was prepared by the Writing Committee and reviewed and approved by all
members of the trial Steering Committee. The funders had no role in the analysis of the data,
preparation and approval of this manuscript, or the decision to submit it for publication. The first
and last members of the Writing Committee vouch for the data and analyses, and for the fidelity
of this report to the study protocol and data analysis plan.
Writing Committee (on behalf of the RECOVERY Collaborative Group):
Peter Horby FRCP,a,* Wei Shen Lim FRCP,b,* Jonathan Emberson PhD,c,d Marion Mafham MD,c
Jennifer Bell MSc,c Louise Linsell DPhil,c Natalie Staplin PhD,c,d Christopher Brightling
FMedSci,e Andrew Ustianowski PhD,f Einas Elmahi MPhil,g Benjamin Prudon FRCP,h
Christopher Green DPhil,i Timothy Felton PhD,j David Chadwick PhD,k Kanchan Rege
FRCPath,l Christopher Fegan MD,m Lucy C Chappell PhD,n Saul N Faust FRCPCH,o Thomas
Jaki PhD,p,q Katie Jeffery PhD,r Alan Montgomery PhD,s Kathryn Rowan PhD,t Edmund
Juszczak PhD,c J Kenneth Baillie MD PhD,u Richard Haynes DM,c,d† Martin J Landray PhD.c,d,v
a Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
b Respiratory Medicine Department, Nottingham University Hospitals NHS Trust, Nottingham,
United Kingdom
c Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
d MRC Population Health Research Unit, University of Oxford, Oxford, United Kingdom
e Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester,
Leicester, United Kingdom
f Regional Infectious Diseases Unit, North Manchester General Hospital & University of
Manchester, Manchester, United Kingdom
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Dexamethasone for COVID-19 Preliminary Report
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g Research and Development Department, Northampton General Hospital, Northampton, United
Kingdom
h Department of Respiratory Medicine, North Tees & Hartlepool NHS Foundation Trust,
Stockton-on-Tees, United Kingdom
i University Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology &
Infection, University of Birmingham, Birmingham, United Kingdom
j University of Manchester and Manchester University NHS Foundation Trust, Manchester,
United Kingdom
k Centre for Clinical Infection, James Cook University Hospital, Middlesbrough, United Kingdom
l North West Anglia NHS Foundation Trust, Peterborough, United Kingdom
m Department of Research and Development, Cardiff and Vale University Health Board, Cardiff,
United Kingdom
n School of Life Course Sciences, King’s College London, London, United Kingdom
o NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University
Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton,
United Kingdom
p Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom
q MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
r Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
s School of Medicine, University of Nottingham, Nottingham, United Kingdom
t Intensive Care National Audit & Research Centre, London, United Kingdom
u Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
v NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust,
Oxford, United Kingdom
*, equal contribution
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Dexamethasone for COVID-19 Preliminary Report
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Data Monitoring Committee
Peter Sandercock, Janet Darbyshire, David DeMets, Robert Fowler, David Lalloo, Ian Roberts,
Janet Wittes.
Acknowledgements
We would like to thank the many thousands of doctors, nurses, pharmacists, other allied health
professionals, and research administrators at 176 NHS hospital organizations across the whole
of the UK, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public
Health England, Department of Health & Social Care, the Intensive Care National Audit &
Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure
Anonymised Information Linkage (SAIL) at University of Swansea, and the NHS in England,
Scotland, Wales and Northern Ireland. We would especially like to thank the members of the
independent Data Monitoring Committee. But above all, we would like to thank the thousands of
patients who participated in this study.
Funding
The RECOVERY trial is supported by a grant to the University of Oxford from UK Research and
Innovation/National Institute for Health Research (NIHR) (Grant reference: MC_PC_19056) and
by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and
Melinda Gates Foundation, the Department for International Development, Health Data
Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health
Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support
Funding. WSL is supported by core funding provided by NIHR Nottingham Biomedical Research
Centre. TJ received funding from UK Medical Research Council (MC_UU_0002/14). This report
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Dexamethasone for COVID-19 Preliminary Report
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is independent research arising in part from Prof Jaki’s Senior Research Fellowship (NIHR-
SRF-2015-08-001) supported by the National Institute for Health Research.
The views expressed in this publication are those of the authors and not necessarily those of
the NHS, the National Institute for Health Research or the Department of Health and Social
Care (DHCS).
Conflicts of interest
The authors have no conflict of interest or financial relationships relevant to the submitted work
to disclose. No form of payment was given to anyone to produce the manuscript. All authors
have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
The Nuffield Department of Population Health at the University of Oxford has a staff policy of not
accepting honoraria or consultancy fees directly or indirectly from industry (see
https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf).
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Dexamethasone for COVID-19 Preliminary Report
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References
1. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019.
N Engl J Med 2020.
2. Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-
based analysis. Lancet Infect Dis 2020; 20(6): 669-77.
3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-
19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229): 1054-62.
4. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel
coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020.
5. Cao J, Tu WJ, Cheng W, et al. Clinical Features and Short-term Outcomes of 102 Patients with
Corona Virus Disease 2019 in Wuhan, China. Clin Infect Dis 2020.
6. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on
an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020.
7. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19
using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.
Bmj 2020; 369: m1985.
8. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary
Report. N Engl J Med 2020.
9. Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, et al. Pathological evidence of pulmonary
thrombotic phenomena in severe COVID-19. J Thromb Haemost 2020.
10. Carsana L, Sonzogni A, Nasr A, et al. Pulmonary post-mortem findings in a series of COVID-19 cases
from northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020.
11. de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is associated
with high viral load and hypercytokinemia. Nat Med 2006; 12(10): 1203-7.
12. Cameron MJ, Ran L, Xu L, et al. Interferon-mediated immunopathological events are associated
with atypical innate and adaptive immune responses in patients with severe acute respiratory
syndrome. J Virol 2007; 81(16): 8692-706.
13. Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute
respiratory syndrome. Clin Exp Immunol 2004; 136(1): 95-103.
14. Baillie JK, Digard P. Influenza--time to target the host? N Engl J Med 2013; 369(2): 191-3.
15. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in
Wuhan, China. Lancet 2020.
16. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368(6490): 473-4.
17. Shang L, Zhao J, Hu Y, Du R, Cao B. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet
2020; 395(10225): 683-4.
18. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for
2019-nCoV lung injury. Lancet 2020; 395(10223): 473-5.
19. Dagens A, Sigfrid L, Cai E, et al. Scope, quality, and inclusivity of clinical guidelines produced early in
the covid-19 pandemic: rapid review. Bmj 2020; 369: m1936.
20. Zhao JP, Hu Y, Du RH, et al. [Expert consensus on the use of corticosteroid in patients with 2019-
nCoV pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43(3): 183-4.
21. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel
Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020.
22. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel
coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020; 368: m606.
23. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984;
3(4): 409-22.
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 22, 2020. .https://doi.org/10.1101/2020.06.22.20137273doi: medRxiv preprint
Dexamethasone for COVID-19 Preliminary Report
18
24. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of
suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival)
Collaborative Group. Lancet 1988; 2(8607): 349-60.
25. Collins R, Bowman L, Landray M, Peto R. The Magic of Randomization versus the Myth of Real-
World Evidence. N Engl J Med 2020; 382(7): 674-8.
26. Rojek AM, Horby PW. Modernising epidemic science: enabling patient-centred research during
epidemics. BMC Med 2016; 14(1): 212.
27. NHS. Dexamethasone in the treatment of COVID-19: Implementation and management of supply
for treatment in hospitals. 2020.
https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103054
(accessed 20 June 2020).
28. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006;
3(9): e343.
29. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid Therapy for Critically Ill Patients with
Middle East Respiratory Syndrome. Am J Respir Crit Care Med 2018; 197(6): 757-67.
30. Lansbury LE, Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Shen Lim W. Corticosteroids as
Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and
Meta-analysis. Crit Care Med 2020; 48(2): e98-e106.
31. Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid Therapy for Patients Hospitalized
With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis. Annals of internal
medicine 2015; 163(7): 519-28.
32. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-
associated Coronavirus RNA concentrations in adult patients. J Clin Virol 2004; 31(4): 304-9.
33. Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult patients hospitalized
with influenza. J Infect Dis 2009; 200(4): 492-500.
34. Cheng PK, Wong DA, Tong LK, et al. Viral shedding patterns of coronavirus in patients with probable
severe acute respiratory syndrome. Lancet 2004; 363(9422): 1699-700.
35. To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva
samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort
study. Lancet Infect Dis 2020; 20(5): 565-74.
36. Zhou R, Li F, Chen F, et al. Viral dynamics in asymptomatic patients with COVID-19. Int J Infect Dis
2020; 96: 288-90.
37. He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19.
Nat Med 2020; 26(5): 672-5.
38. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with
COVID-2019. Nature 2020; 581(7809): 465-9.
39. Liaudet L, Szabo C. Blocking mineralocorticoid receptor with spironolactone may have a wide range
of therapeutic actions in severe COVID-19 disease. Crit Care 2020; 24(1): 318.
40. NHS. Clinical guide for the optimal use of Oxygen therapy during the coronavirus pandemic. 2020.
https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/04/C0256-specialty-
guide-oxygen-therapy-and-coronavirus-9-april-2020.pdf.
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 22, 2020. .https://doi.org/10.1101/2020.06.22.20137273doi: medRxiv preprint
Dexamethasone for COVID-19 Preliminary Report
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Table and figures
Table 1: Baseline characteristics by randomized allocation and level of respiratory
support received
Results are count (%), mean ± standard deviation, or median (inter-quartile range). * Includes 6
pregnant women. † SARS-Cov-2 test results are captured on the follow-up form, so are
currently unknown for some patients. There was a significant difference (2p=0.008) in mean age
of 1.1 years between those randomly allocated dexamethasone and those randomly allocated
usual care but no significant differences between these groups in any other baseline
characteristic. The ‘oxygen only’ group includes non-invasive ventilation.
Table 2: Effect of allocation to dexamethasone on main study outcomes
RR=Rate Ratio for the outcomes of 28-day mortality and hospital discharge, and risk ratio for
the outcome of receipt of invasive mechanical ventilation or death (and its subcomponents).
Estimates of the RR and its 95% confidence interval are adjusted for age in three categories
(<70 years, 70-79 years, and 80 years or older). * Analyses exclude those on invasive
mechanical ventilation at randomization.
Figure 1: 28−day mortality in all patients (panel a) and separately according to level of
respiratory support received at randomization (panels b-d)
RR=age−adjusted rate ratio. CI=confidence interval. The ‘oxygen only’ group includes non-
invasive ventilation. Note: in the RECOVERY trial press release of 16 June 2020, effects in
subgroups of level of respiratory support received were shown with 99% CIs, not 95% CIs as
inadvertently stated. The age−adjusted rate ratio and 99% confidence intervals remain
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 22, 2020. .https://doi.org/10.1101/2020.06.22.20137273doi: medRxiv preprint
Dexamethasone for COVID-19 Preliminary Report
20
unchanged in this analysis: no oxygen required, RR 1.22 (99% CI 0.86−1.75); oxygen only, RR
0.80 (99% CI 0.67−0.96); invasive mechanical ventilation, RR 0.65 (99% CI 0.480.88).
Figure 2: Effect of allocation to dexamethasone on 28−day mortality by level of
respiratory support received at randomization
RR=age−adjusted rate ratio. CI=confidence interval. Subgroup−specific RR estimates are
represented by squares (with areas of the squares proportional to the amount of statistical
information) and the horizontal lines through them correspond to the 95% confidence intervals.
The ‘oxygen only’ group includes non-invasive ventilation. Note: in the RECOVERY trial press
release of 16 June 2020, effects in subgroups of level of respiratory support received were
shown with 99% CIs, not 95% CIs as inadvertently stated. The age−adjusted rate ratio and 99%
confidence intervals remain unchanged in this analysis: no oxygen required, RR 1.22 (99% CI
0.86−1.75); oxygen only, RR 0.80 (99% CI 0.67−0.96); invasive mechanical ventilation, RR 0.65
(99% CI 0.48−0.88).
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 22, 2020. .https://doi.org/10.1101/2020.06.22.20137273doi: medRxiv preprint
Table 1: Baseline characteristics by randomized allocation and level of respiratory support
received
Treatment allocation
Respiratory support received
at randomization
Dexamethasone
(n=2104)
Usual care
(n=4321)
No oxygen
received
(n=1535)
Oxygen only
(n=3883)
Invasive
mechanical
ventilation
(n=1007)
Age, years
66.9 (15.4)
65.8 (15.8)
66.7 (15.3)
59.0 (11.5)
<70
1142 (54%)
2506 (58%)
2149 (55%)
839 (83%)
70 to <80 467 (22%)
860 (20%)
338 (22%)
837 (22%)
152 (15%)
80 495 (24%)
955 (22%)
537 (35%)
897 (23%)
16 (2%)
Sex
Male
1338 (64%)
2750 (64%)
2462 (63%)
734 (73%)
Female*
766 (36%)
1571 (36%)
1421 (37%)
273 (27%)
Number of days since symptom onset 8 (5-13)
9 (5-13)
6 (3-10)
9 (5-12)
13 (8-18)
Respiratory support received
No oxygen received
501 (24%)
1034 (24%)
0 (0%)
0 (0%)
Oxygen only
1279 (61%)
2604 (60%)
3883 (100%)
0 (0%)
Invasive mechanical ventilation
324 (15%)
683 (16%)
0 (0%)
1007 (100%)
Previous diseases
Diabetes 521 (25%)
1025 (24%)
342 (22%)
950 (24%)
254 (25%)
Heart disease
586 (28%)
1171 (27%)
1074 (28%)
164 (16%)
Chronic lung disease
415 (20%)
931 (22%)
883 (23%)
112 (11%)
Tuberculosis
6 (<0.5%)
19 (<0.5%)
11 (<0.5%)
6 (1%)
HIV
12 (1%)
20 (<0.5%)
21 (1%)
6 (1%)
Severe liver disease
37 (2%)
82 (2%)
72 (2%)
15 (1%)
Severe kidney impairment
167 (8%)
358 (8%)
253 (7%)
152 (15%)
Any of the above
1174 (56%)
2417 (56%)
2175 (56%)
505 (50%)
SARS-Cov-2 test result
Positive
1702 (81%)
3553 (82%)
3144 (81%)
913 (91%)
Negative
213 (10%)
397 (9%)
398 (10%)
30 (3%)
Test result not yet known†
189 (9%)
371 (9%)
341 (9%)
64 (6%)
Results are count (%), mean ± standard deviation, or median (inter-quartile range). * Includes 6 pregnant women. † SARS-Cov-2 test results
are captured on the follow
-up form, so are currently unknown for some. There was a significant (2p=0.008) difference in mean age between
those allocated dexamethasone and those allocated usual care, but no significant differences between these groups in any othe
r baseline
characteristic. The 'oxygen only' group includes non
-invasive ventilation.
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Table 2: Effect of allocation to dexamethasone on main study outcomes
Treatment allocation
Dexamethasone
(n=2104)
Usual care
(n=4321)
RR (95% CI)
p-value
Primary outcome:
28-day mortality 454 (21.6%)
1065 (24.6%)
0.83 (0.74-0.92)
<0.001
Secondary outcomes:
Discharged from hospital within 28 days
1360 (64.6%)
2639 (61.1%)
1.11 (1.04-1.19)
0.002
Receipt of invasive mechanical ventilation or death*
425/1780 (23.9%)
939/3638 (25.8%)
0.91 (0.82-1.00)
0.049
Invasive mechanical ventilation
92/1780 (5.2%)
258/3638 (7.1%)
0.76 (0.61-0.96)
0.021
Death
360/1780 (20.2%)
787/3638 (21.6%)
0.91 (0.82-1.01)
0.07
RR=Rate Ratio for the outcomes of 28-day mortality and hospital discharge, and risk ratio for the outcome of receipt of invasive mechanical
ventilation or death (and its subcomponents). Estimates of the RR and its 95% confidence interval are adjusted for age in thr
ee categories
(<70 years , 70
-79 years, and 80 years or older). * Analyses exclude those on invasive mechanical ventilation at randomization.
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted June 22, 2020. .https://doi.org/10.1101/2020.06.22.20137273doi: medRxiv preprint
0
10
20
30
40
50
Mortality, %
0 7 14 21 28
Days since randomization
RR 0.83 (95% CI 0.74−0.92)
p<0.001
2104 1860 1670 1595 1547
4321 3700 3329 3154 3053
Number at risk:
Dexamethasone
Usual care
Figure 1: 28−day mortality in all patients (panel a) and separately according
to level of respiratory support received at randomization (panels b−d)
a) All participants (n=6425)
Usual care
Dexamethasone
0
10
20
30
40
50
Mortality, %
0 7 14 21 28
Days since randomization
RR 1.22 (95% CI 0.93−1.61)
p=0.14
501 463 420 394 383
1034 969 890 856 832
b) No oxygen received (n=1535)
Usual care
Dexamethasone
0
10
20
30
40
50
Mortality, %
0 7 14 21 28
Days since randomization
RR 0.80 (95% CI 0.70−0.92)
p=0.002
1279 1107 1004 971 940
2604 2162 1965 1880 1832
Number at risk:
Dexamethasone
Usual care
RR=age−adjusted rate ratio. CI=confidence interval. The 'oxygen only' group includes non−invasive ventilation. Note: in the RECOVERY
trial press release of 16 June 2020, effects in subgroups of level of respiratory support received were shown with 99% CIs, not 95% CIs as
inadvertently stated. The age−adjusted rate ratio and 99% confidence intervals remain unchanged in this analysis: no oxygen required,
RR 1.22 (99% CI 0.86−1.75); oxygen only, RR 0.80 (99% CI 0.67−0.96); invasive mechanical ventilation, RR 0.65 (99% CI 0.48−0.88).
c) Oxygen only (n=3883)
Usual care
Dexamethasone
0
10
20
30
40
50
Mortality, %
0 7 14 21 28
Days since randomization
RR 0.65 (95% CI 0.51−0.82)
p<0.001
324 290 246 230 224
683 569 474 418 389
d) Invasive mechanical ventilation (n=1007)
Usual care
Dexamethasone
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0.5 0.75 11.5 2
Figure 2: Effect of allocation to dexamethasone on 28−day mortality by level
of respiratory support received at randomization
Dexamethasone Usual care
Respiratory support at
randomization RR (95% CI)
RR=age−adjusted rate ratio. CI=confidence interval. Subgroup−specific RR estimates are represented by squares (with areas of the squares
proportional to the amount of statistical information) and the lines through them correspond to the 95% confidence intervals. The 'oxygen only'
group includes non−invasive ventilation. Note: in the RECOVERY trial press release of 16 June 2020, effects in subgroups of level of respiratory
support received were shown with 99% CIs, not 95% CIs as inadvertently stated. The age−adjusted rate ratio and 99% confidence intervals remain
unchanged in this analysis: no oxygen required, RR 1.22 (99% CI 0.86−1.75); oxygen only, RR 0.80 (99% CI 0.67−0.96); invasive mechanical
ventilation, RR 0.65 (99% CI 0.48−0.88).
Dexamethasone
better Usual care
better
No oxygen received 85/501 (17.0%) 137/1034 (13.2%) 1.22 (0.93−1.61)
Oxygen only 275/1279 (21.5%) 650/2604 (25.0%) 0.80 (0.70−0.92)
Invasive mechanical ventilation 94/324 (29.0%) 278/683 (40.7%) 0.65 (0.51−0.82)
Trend across three categories: χ1
2=11.49; p<0.001
All participants 454/2104 (21.6%) 1065/4321 (24.6%) p<0.001
0.83 (0.74−0.92)
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... Dexamethasone has recently shown promise (Horby et al. 2020), an anti-inflammatory agent that acts on prostaglandin-endoperoxide synthase 2 (or cyclooxygenase 2, COX-2). It is expected that betamethasone (McAllen et al. 1974), a medication from the same pharmacological class as dexamethasone, will have similar effects on the replication of SARS-CoV-2. ...
... Affinity Recognisably, COVID-19 is a disease that triggers multisystemic inflammatory processes. This observation led Horby et al. (2020) to point out the potential application of dexamethasone in certain patients who remained intubated after complications from COVID-19. According to the results presented by Horby et al. (2020), one in eight deaths could be avoided using dexamethasone. ...
... This observation led Horby et al. (2020) to point out the potential application of dexamethasone in certain patients who remained intubated after complications from COVID-19. According to the results presented by Horby et al. (2020), one in eight deaths could be avoided using dexamethasone. Dexamethasone is a steroid anti-inflammatory and immunosuppressant and can be used only in critically ill patients with COVID-19 symptoms, whose primary role is as a COX-2 inhibitor. ...
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... As the initial ACTIV master protocols were being finalized, results from the early trials of remdesivir were becoming available [3], as were results from the early RECOVERY trials [4,5,6]. ACTIV protocols were therefore generally designed to evaluate new agents as add-on therapy to existing SoC, with allowances for SoC to change during the trial. ...
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... The RECOVERY trial offers compelling evidence indicating that administering dexamethasone at a dosage of 6 mg once daily for duration of up to 10 days' results in a reduction of 28-day mortality among hospitalized patients grappling with COVID-19 respiratory illness (Horby et al., 2020). While the anti-inflammatory properties of the drug are crucial in easing the significant respiratory distress linked to COVID-19, caution is advised due to the potential adverse effect of dexamethasone in non-severe cases of the illness. ...
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... It states that the use of dexamethasone compared with usual care reduces mortality by 28 days in patients who require oxygen therapy or mechanical ventilation. 15 The WHO on September 2, 2020, recommended corticosteroids for the treatment of COVID-19. 16 Although several clinical and observational studies have been conducted to evaluate the effects in infected patients, these results are often inconsistent, leading to uncertainty in clinical practice. ...
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... Синдром высвобождения цитокинов приводит к иммунопатологическому повреждению легких, диффузному альвеолярному повреждению с развитием острого респираторного дистресссиндрома и смерти [2]. Основными направлениями лечения новой коронавирусной инфекции COVID-19 являются поддержание достаточного уровня оксигенации крови (прон-позиция, оксигенотерапия, искусственная вентиляция легких), предупреждение и лечение бактериальных осложнений, а также применение средств, направленных на борьбу с цитокиновым штормом (глюкокортикоиды, ингибиторы провоспалительных цитокинов, янус-киназы -JAK) [3]. ...
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The incidence of neurological complications in COVID-19 can reach 8–10% of all cases of new coronavirus infection; acute cerebrovascular accidents (ACA) dominate in their structure, which cause significant social and economic costs due to the high mortality and disability rates in this group of patients. The main pathophysiological mechanism leading to the development of ischemic cerebrovascular accidents (ischemic stroke, transient ischemic attack) is the phenomenon of hypercoagulation, which, together with the systemic inflammatory response to the viral infection, leads to the formation of macro- and microthrombi and the development of ischemic disorders of cerebral circulation. The ischemic stroke associated with COVID-19 is characterized by the onset at a younger age, the predominance of cryptogenic and cardioembolic pathogenetic variants, a more frequent occlusion of large cerebral vessels and thus a more pronounced clinical picture of the disease. The reserves for reducing mortality and disability in patients with cerebrovascular disease, especially stroke, during the spread of COVID-19 lie both in the prevention, treatment and rehabilitation of COVID-19 in patients at high risk of developing cardiovascular diseases and in ensuring specialized medical care for this category of patients.
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Background The COVID-19 pandemic has had profound impacts on global mental health, with emerging evidence suggesting significant psychiatric complications in both the short and long term. Main body This review consolidates current information on the mental effects of COVID-19, analysing psychosocial and biological factors, temporal progression of symptoms, and impacts on various populations. Acute psychiatric manifestations (0–4 weeks post-infection) include anxiety, acute stress reactions, and delirium. In the mid-term phase (4–12 weeks), persistent symptoms emerge, with studies reporting anxiety (23%), depression (17%), and sleep disturbances (31%). Cognitive impacts such as “brain fog” (32%) and memory issues (28%) also become apparent. Long-term complications (> 12 weeks) include a significant proportion of patients experiencing poor sleep (74.5%) and PTSD (78.3%) up to 9 months post-infection. Vulnerable groups, including healthcare workers, children, and pregnant women, face unique challenges. Biological mechanisms, including potential neuroinvasion by SARS-CoV-2 and neuroinflammation, contribute to these psychiatric manifestations. Conclusion COVID-19 infection has caused a spectrum of psychiatric problems that evolve from acute to chronic stages. The persistence of symptoms beyond the acute phase highlights the need for long-term mental health support and tailored interventions. Future research should focus on understanding the mechanisms underlying persistent psychiatric symptoms and developing targeted treatments for COVID-19-related mental health complications.
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Coronavirus entry into host cells enables the virus to initiate its replication cycle efficiently while evading host immune response. Cell entry is intricately associated with pH levels in the cytoplasm or endosomes. In this study, we observed that the sodium hydrogen exchanger 3 (Na⁺/H⁺ exchanger 3 or NHE3), which is strongly activated by dexamethasone (Dex) to promote cell membrane Na⁺/H⁺ exchange, was critical for cytoplasmic and endosomal acidification. Dex activates NHE3, which increases intracellular pH and blocks the initiation of coronavirus infectious bronchitis virus (IBV) negative-stranded genomic RNA synthesis. Also, Dex antiviral effects are relieved by the glucocorticoid receptor (GR) antagonist RU486 and the NHE3 selective inhibitor tenapanor. These results show that Dex antiviral effects depend on GR and NHE3 activities. Furthermore, Dex exhibits remarkable dose-dependent inhibition of IBV replication, although its antiviral effects are constrained by specific virus and cell types. To our knowledge, this is the first report to show that Dex helps suppress the entry of coronavirus IBV into cells by promoting proton leak pathways, as well as by precisely tuning luminal pH levels mediated by NHE3. Disrupted cytoplasmic pH homeostasis, triggered by Dex and NHE3, plays a crucial role in impeding coronavirus IBV replication. Therefore, cytoplasmic pH plays an essential role during IBV cell entry, probably assisting viruses at the fusion and/or uncoating stages. The strategic modulation of NHE3 activity to regulate intracellular pH could provide a compelling mechanism when developing potent anti-coronavirus drugs. IMPORTANCE Since the outbreak of coronavirus disease 2019, dexamethasone (Dex) has been proven to be the first drug that can reduce the mortality rate of coronavirus patients to a certain extent, but its antiviral effect is limited and its underlying mechanism has not been fully clarified. Here, we comprehensively evaluated the effect of Dex on coronavirus infectious bronchitis virus (IBV) replication and found that the antiviral effect of Dex is achieved by regulating sodium hydrogen exchanger 3 (NHE3) activity through the influence of glucocorticoid receptor on cytoplasmic pH or endosome pH. Dex activates NHE3, leading to an increase in intracellular pH and blocking the initiation of negative-stranded genomic RNA synthesis of coronavirus IBV. In this study, we identified the mechanism by which glucocorticoids counteract coronaviruses in cell models, laying the foundation for the development of novel antiviral drugs.
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Background Given that viral infections can increase the risk of adverse pregnancy outcomes, such as spontaneous miscarriage, preterm premature rupture of membranes, and preterm birth, the effects of COVID-19, a novel emerging coronavirus disease rapidly spreading globally, on pregnancy outcomes have garnered significant attention. Methods We conducted a review of studies related to pregnant women infected with SARS-CoV-2 over the past five years (December 2019 to April 2023), utilizing search engines such as PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI). This study was registered with PROSPERO with ID: CRD42024540849. Results A total of 218 articles were screened, with 15 studies meeting the inclusion criteria for this research, including 12 cohort studies, one cross-sectional study, one case-control study, and one case series. Six studies found that the preterm birth rate was higher in the infected group compared to the control group; five studies showed that the cesarean section rate was higher in the infected group; three studies found that the APGAR scores of newborns were higher in the control group than in the infected group; three studies indicated that the mortality rate of newborns in the infected group was higher than that in the control group. Conclusions Our retrospective review suggests that compared to pregnant women not infected with SARS-CoV-2, those diagnosed with COVID-19 are more likely to experience adverse outcomes such as preterm birth, cesarean delivery, and low birth weight in newborns.
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Background COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes. Methods We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation. Findings All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet–fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes. Interpretation The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet–fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy. Funding None.
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Objective To appraise the availability, quality, and inclusivity of clinical guidelines produced in the early stage of the coronavirus disease 2019 (covid-19) pandemic. Design Rapid review. Data sources Ovid Medline, Ovid Embase, Ovid Global Health, Scopus, Web of Science Core Collection, and WHO Global Index Medicus, searched from inception to 14 Mar 2020. Search strategies applied the CADTH database guidelines search filter, with no limits applied to search results. Further studies were identified through searches of grey literature using the ISARIC network. Inclusion criteria Clinical guidelines for the management of covid-19, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS) produced by international and national scientific organisations and government and non-governmental organisations relating to global health were included, with no exclusions for language. Regional/hospital guidelines were excluded. Only the earliest version of any guideline was included. Quality assessment Quality was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. The quality and contents of early covid-19 guidelines were also compared with recent clinical guidelines for MERS and SARS. Results 2836 studies were identified, of which 2794 were excluded after screening. Forty two guidelines were considered eligible for inclusion, with 18 being specific to covid-19. Overall, the clinical guidelines lacked detail and covered a narrow range of topics. Recommendations varied in relation to, for example, the use of antiviral drugs. The overall quality was poor, particularly in the domains of stakeholder involvement, applicability, and editorial independence. Links between evidence and recommendations were limited. Minimal provision was made for vulnerable groups such as pregnant women, children, and older people. Conclusions Guidelines available early in the covid-19 pandemic had methodological weaknesses and neglected vulnerable groups such as older people. A framework for development of clinical guidelines during public health emergencies is needed to ensure rigorous methods and the inclusion of vulnerable populations. Systematic review registration PROSPERO CRD42020167361.
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Objective To characterise the clinical features of patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United Kingdom during the growth phase of the first wave of this outbreak who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study, and to explore risk factors associated with mortality in hospital. Design Prospective observational cohort study with rapid data gathering and near real time analysis. Setting 208 acute care hospitals in England, Wales, and Scotland between 6 February and 19 April 2020. A case report form developed by ISARIC and WHO was used to collect clinical data. A minimal follow-up time of two weeks (to 3 May 2020) allowed most patients to complete their hospital admission. Participants 20 133 hospital inpatients with covid-19. Main outcome measures Admission to critical care (high dependency unit or intensive care unit) and mortality in hospital. Results The median age of patients admitted to hospital with covid-19, or with a diagnosis of covid-19 made in hospital, was 73 years (interquartile range 58-82, range 0-104). More men were admitted than women (men 60%, n=12 068; women 40%, n=8065). The median duration of symptoms before admission was 4 days (interquartile range 1-8). The commonest comorbidities were chronic cardiac disease (31%, 5469/17 702), uncomplicated diabetes (21%, 3650/17 599), non-asthmatic chronic pulmonary disease (18%, 3128/17 634), and chronic kidney disease (16%, 2830/17 506); 23% (4161/18 525) had no reported major comorbidity. Overall, 41% (8199/20 133) of patients were discharged alive, 26% (5165/20 133) died, and 34% (6769/20 133) continued to receive care at the reporting date. 17% (3001/18 183) required admission to high dependency or intensive care units; of these, 28% (826/3001) were discharged alive, 32% (958/3001) died, and 41% (1217/3001) continued to receive care at the reporting date. Of those receiving mechanical ventilation, 17% (276/1658) were discharged alive, 37% (618/1658) died, and 46% (764/1658) remained in hospital. Increasing age, male sex, and comorbidities including chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease and obesity were associated with higher mortality in hospital. Conclusions ISARIC WHO CCP-UK is a large prospective cohort study of patients in hospital with covid-19. The study continues to enrol at the time of this report. In study participants, mortality was high, independent risk factors were increasing age, male sex, and chronic comorbidity, including obesity. This study has shown the importance of pandemic preparedness and the need to maintain readiness to launch research studies in response to outbreaks. Study registration ISRCTN66726260.
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Data are limited on the viral load, viral shedding patterns and potential infectivity of asymptomatic patients (APs) with coronavirus disease 2019 (COVID-19). We included 31 adult patients who were virologically confirmed to have COVID-19 but were asymptomatic on admission. Among these 31 patients, 22 presented symptoms after admission and were defined as asymptomatic patients in incubation period (APIs); the other 9 patients remained asymptomatic during hospitalization and were defined as asymptomatic patients (APs). The cycle threshold (Ct) values of APs (39.0, IQR 37.5-39.5) was significantly higher than those of APIs (34.5, IQR 32.2-37.0), which indicated a lower viral load in APs, but the duration of viral shedding remained similar between the two groups (7 days IQR 5-14 vs. 8 days IQR 5-16). The study findings demonstrated that although they have a lower viral load, APs with COVID-19 still have certain period of viral shedding, which suggests the possibility of transmission during their asymptomatic period. Further longitudinal surveillance of these asymptomatic cases via virus nucleic acid tests are warranted.
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Between February and March 2020, the Journal of Thrombosis and Hemosthasis has published four papers addressing the intricate, complex and still little understood relation between COVID‐19 and thrombogenesis (1‐4). ARS‐Cov‐2 induces in severe cases a cytokine storm that ultimately leads to the activation of the coagulation cascade, causing thrombotic phenomena (5). There is a further strong link between abnormal coagulation parameters (D‐dimer and fibrin degradation products) and mortality. Tang et al. described that 71.4% of nonsurvivors and 0.6% of survivors showed evidence of disseminated intravascular coagulation (DIC), suggesting that DIC is a frequent occurrence in severe COVID‐19 (4). The frequency of DIC in these patients is much higher than that reported for severe SARS (6).
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Coronavirus disease 2019 (COVID-19) is an acute respiratory tract infection that emerged in late 20191,2. Initial outbreaks in China involved 13.8% cases with severe, and 6.1% with critical courses³. This severe presentation corresponds to the usage of a virus receptor that is expressed predominantly in the lung2,4. By causing an early onset of severe symptoms, this same receptor tropism is thought to have determined pathogenicity, but also aided the control, of severe acute respiratory syndrome (SARS) in 2003⁵. However, there are reports of COVID-19 cases with mild upper respiratory tract symptoms, suggesting the potential for pre- or oligosymptomatic transmission6–8. There is an urgent need for information on body site-specific virus replication, immunity, and infectivity. Here we provide a detailed virological analysis of nine cases, providing proof of active virus replication in upper respiratory tract tissues. Pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 × 10⁸ RNA copies per throat swab, day 4). Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples, in spite of high virus RNA concentration. Blood and urine never yielded virus. Active replication in the throat was confirmed by viral replicative RNA intermediates in throat samples. Sequence-distinct virus populations were consistently detected in throat and lung samples from the same patient, proving independent replication. Shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (14 days in all), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild upper respiratory tract illness. Active virus replication in the upper respiratory tract puts the prospects of COVID-19 containment in perspective.
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Background In the face of rapidly changing data, a range of case fatality ratio estimates for coronavirus disease 2019 (COVID-19) have been produced that differ substantially in magnitude. We aimed to provide robust estimates, accounting for censoring and ascertainment biases. Methods We collected individual-case data for patients who died from COVID-19 in Hubei, mainland China (reported by national and provincial health commissions to Feb 8, 2020), and for cases outside of mainland China (from government or ministry of health websites and media reports for 37 countries, as well as Hong Kong and Macau, until Feb 25, 2020). These individual-case data were used to estimate the time between onset of symptoms and outcome (death or discharge from hospital). We next obtained age-stratified estimates of the case fatality ratio by relating the aggregate distribution of cases to the observed cumulative deaths in China, assuming a constant attack rate by age and adjusting for demography and age-based and location-based under-ascertainment. We also estimated the case fatality ratio from individual line-list data on 1334 cases identified outside of mainland China. Using data on the prevalence of PCR-confirmed cases in international residents repatriated from China, we obtained age-stratified estimates of the infection fatality ratio. Furthermore, data on age-stratified severity in a subset of 3665 cases from China were used to estimate the proportion of infected individuals who are likely to require hospitalisation. Findings Using data on 24 deaths that occurred in mainland China and 165 recoveries outside of China, we estimated the mean duration from onset of symptoms to death to be 17·8 days (95% credible interval [CrI] 16·9–19·2) and to hospital discharge to be 24·7 days (22·9–28·1). In all laboratory confirmed and clinically diagnosed cases from mainland China (n=70 117), we estimated a crude case fatality ratio (adjusted for censoring) of 3·67% (95% CrI 3·56–3·80). However, after further adjusting for demography and under-ascertainment, we obtained a best estimate of the case fatality ratio in China of 1·38% (1·23–1·53), with substantially higher ratios in older age groups (0·32% [0·27–0·38] in those aged <60 years vs 6·4% [5·7–7·2] in those aged ≥60 years), up to 13·4% (11·2–15·9) in those aged 80 years or older. Estimates of case fatality ratio from international cases stratified by age were consistent with those from China (parametric estimate 1·4% [0·4–3·5] in those aged <60 years [n=360] and 4·5% [1·8–11·1] in those aged ≥60 years [n=151]). Our estimated overall infection fatality ratio for China was 0·66% (0·39–1·33), with an increasing profile with age. Similarly, estimates of the proportion of infected individuals likely to be hospitalised increased with age up to a maximum of 18·4% (11·0–7·6) in those aged 80 years or older. Interpretation These early estimates give an indication of the fatality ratio across the spectrum of COVID-19 disease and show a strong age gradient in risk of death. Funding UK Medical Research Council.
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Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.)
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