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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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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
. 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
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).
. 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
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.
. 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
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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... Studies of corticosteroids in patients with viral pneumonia and ARDS have yielded mixed results (13,14). In the Randomized Evaluation of COVID-19 Therapy (RECOVERY) study, in which 2,104 patients with COVID-19 were randomized to receive 6 mg of dexamethasone daily for up to 10 days, showed that dexamethasone reduced 28-day all-cause mortality (15), and the greatest benefit was noted in patients who had been symptomatic for more than 7 days and required mechanical ventilation. Conversely, there was no benefit to patients who were symptomatic for a shorter period and that did not require any supplemental oxygen. ...
... Computed tomography showed bilateral consolidation in the lung Chest X-ray showed radiological progression on the 3 rd day of hospitalization Chest X-ray showed radiological regression on postoperative day15 ...
... It is also likely that in patients with influenza, extensive prescription of oseltamivir in the initial phase of infection attenuated the intensity of the lesions by accelerating viral clearance. Finally, some of the patients included in the SARS-CoV-2 group were managed at the beginning of the pandemic and were not receiving corticosteroids or reinforced preventive and/or curative anticoagulation, the only treatments yet shown to be of benefit in the management of SARS-CoV-2 patients [27]. However, a causal link was recently shown between the use of steroids and ICU-acquired infections [28]. ...
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Antiviral therapies are integral in the fight against SARS-CoV-2, the causative agent of COVID-19. Antiviral therapeutics can be divided into categories based on how they combat the virus, including viral entry into the host cell, viral replication, protein trafficking, post-translational processing, and immune response regulation. Drugs that target how the virus enters the cell include: Evusheld, REGEN-COV, bamlanivimab and etesevimab, bebtelovimab, sotrovimab, Arbidol, nitazoxanide, and chloroquine. Drugs that prevent the virus from replicating include: Paxlovid, remdesivir, molnupiravir, favipiravir, ribavirin, and Kaletra. Drugs that interfere with protein trafficking and post-translational processing include nitazoxanide and ivermectin. Lastly, drugs that target immune response regulation include interferons and the use of anti-inflammatory drugs such as dexamethasone. Antiviral therapies offer an alternative solution for those unable or unwilling to be vaccinated and are a vital weapon in the battle against the global pandemic. Learning more about these therapies helps raise awareness to the general population about the options available to them to aid in the reduction of the severity of COVID-19 infection. In this 'A Guide To' article, we provide an in-depth insight into the development of antiviral therapeutics against SARS-CoV-2 and their ability to help fight COVID-19.
... Moreover, the JAK inhibitors, like tofacitinib, lestaurtinib, tozasertib were top-ranked. Interestingly, the dexamethasone and JAK2 inhibitors, are the first and second reported drugs to be able to significantly reduce the mortality rate of COVID-19 patients validated in clinical trials 28,29 . Thus, drugs from different categories with potentially different modes of action (MOA), and their combinations/cocktails (targeting multi-signaling modules/dysfunctional signaling pathways in AD) can be potentially effective and synergistic to inhibit neuron inflammation for AD treatment and prevention. ...
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Background: Systemic corticosteroids are used to treat people with COVID-19 because they counter hyper-inflammation. Existing evidence syntheses suggest a slight benefit on mortality. Nonetheless, size of effect, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated. Objectives: To assess whether and at which doses systemic corticosteroids are effective and safe in the treatment of people with COVID-19, to explore equity-related aspects in subgroup analyses, and to keep up to date with the evolving evidence base using a living systematic review approach. Search methods: We searched the Cochrane COVID-19 Study Register (which includes PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 6 January 2022. Selection criteria: We included randomised controlled trials (RCTs) that evaluated systemic corticosteroids for people with COVID-19. We included any type or dose of systemic corticosteroids and the following comparisons: systemic corticosteroids plus standard care versus standard care, different types, doses and timings (early versus late) of corticosteroids. We excluded corticosteroids in combination with other active substances versus standard care, topical or inhaled corticosteroids, and corticosteroids for long-COVID treatment. Data collection and analysis: We followed standard Cochrane methodology. To assess the risk of bias in included studies, we used the Cochrane 'Risk of bias' 2 tool for RCTs. We rated the certainty of the evidence using the GRADE approach for the following outcomes: all-cause mortality up to 30 and 120 days, discharged alive (clinical improvement), new need for invasive mechanical ventilation or death (clinical worsening), serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections. Main results: We included 16 RCTs in 9549 participants, of whom 8271 (87%) originated from high-income countries. A total of 4532 participants were randomised to corticosteroid arms and the majority received dexamethasone (n = 3766). These studies included participants mostly older than 50 years and male. We also identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design. Hospitalised individuals with a confirmed or suspected diagnosis of symptomatic COVID-19 Systemic corticosteroids plus standard care versus standard care plus/minus placebo We included 11 RCTs (8019 participants), one of which did not report any of our pre-specified outcomes and thus our analyses included outcome data from 10 studies. Systemic corticosteroids plus standard care compared to standard care probably reduce all-cause mortality (up to 30 days) slightly (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.84 to 0.97; 7898 participants; estimated absolute effect: 274 deaths per 1000 people not receiving systemic corticosteroids compared to 246 deaths per 1000 people receiving the intervention (95% CI 230 to 265 per 1000 people); moderate-certainty evidence). The evidence is very uncertain about the effect on all-cause mortality (up to 120 days) (RR 0.74, 95% CI 0.23 to 2.34; 485 participants). The chance of clinical improvement (discharged alive at day 28) may slightly increase (RR 1.07, 95% CI 1.03 to 1.11; 6786 participants; low-certainty evidence) while the risk of clinical worsening (new need for invasive mechanical ventilation or death) may slightly decrease (RR 0.92, 95% CI 0.84 to 1.01; 5586 participants; low-certainty evidence). For serious adverse events (two RCTs, 678 participants), adverse events (three RCTs, 447 participants), hospital-acquired infections (four RCTs, 598 participants), and invasive fungal infections (one study, 64 participants), we did not perform any analyses beyond the presentation of descriptive statistics due to very low-certainty evidence (high risk of bias, heterogeneous definitions, and underreporting). Different types, dosages or timing of systemic corticosteroids We identified one RCT (86 participants) comparing methylprednisolone to dexamethasone, thus the evidence is very uncertain about the effect of methylprednisolone on all-cause mortality (up to 30 days) (RR 0.51, 95% CI 0.24 to 1.07; 86 participants). None of the other outcomes of interest were reported in this study. We included four RCTs (1383 participants) comparing high-dose dexamethasone (12 mg or higher) to low-dose dexamethasone (6 mg to 8 mg). High-dose dexamethasone compared to low-dose dexamethasone may reduce all-cause mortality (up to 30 days) (RR 0.87, 95% CI 0.73 to 1.04; 1269 participants; low-certainty evidence), but the evidence is very uncertain about the effect of high-dose dexamethasone on all-cause mortality (up to 120 days) (RR 0.93, 95% CI 0.79 to 1.08; 1383 participants) and it may have little or no impact on clinical improvement (discharged alive at 28 days) (RR 0.98, 95% CI 0.89 to 1.09; 200 participants; low-certainty evidence). Studies did not report data on clinical worsening (new need for invasive mechanical ventilation or death). For serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections, we did not perform analyses beyond the presentation of descriptive statistics due to very low-certainty evidence. We could not identify studies for comparisons of different timing and systemic corticosteroids versus other active substances. Equity-related subgroup analyses We conducted the following subgroup analyses to explore equity-related factors: sex, age (< 70 years; ≥ 70 years), ethnicity (Black, Asian or other versus White versus unknown) and place of residence (high-income versus low- and middle-income countries). Except for age and ethnicity, no evidence for differences could be identified. For all-cause mortality up to 30 days, participants younger than 70 years seemed to benefit from systemic corticosteroids in comparison to those aged 70 years and older. The few participants from a Black, Asian, or other minority ethnic group showed a larger estimated effect than the many White participants. Outpatients with asymptomatic or mild disease There are no studies published in populations with asymptomatic infection or mild disease. Authors' conclusions: Systemic corticosteroids probably slightly reduce all-cause mortality up to 30 days in people hospitalised because of symptomatic COVID-19, while the evidence is very uncertain about the effect on all-cause mortality up to 120 days. For younger people (under 70 years of age) there was a potential advantage, as well as for Black, Asian, or people of a minority ethnic group; further subgroup analyses showed no relevant effects. Evidence related to the most effective type, dose, or timing of systemic corticosteroids remains immature. Currently, there is no evidence on asymptomatic or mild disease (non-hospitalised participants). Due to the low to very low certainty of the current evidence, we cannot assess safety adequately to rule out harmful effects of the treatment, therefore there is an urgent need for good-quality safety data. Findings of equity-related subgroup analyses should be interpreted with caution because of their explorative nature, low precision, and missing data. We identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design, suggesting there may be possible changes of the effect estimates and certainty of the evidence in the future.
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Background: There is ongoing debate whether lung physiology of COVID-19-associated acute respiratory distress syndrome (ARDS) differs from ARDS of other origin. Objective: The aim of this study was to analyze and compare how critically ill patients with COVID-19 and Influenza A or B were ventilated in our tertiary care center with or without extracorporeal membrane oxygenation (ECMO). We ask if acute lung failure due to COVID-19 requires different intensive care management compared to conventional ARDS. Methods: 25 patients with COVID-19-associated ARDS were matched to a cohort of 25 Influenza patients treated in our center from 2011 to 2021. Subgroup analysis addressed whether patients on ECMO received different mechanical ventilation than patients without extracorporeal support. Results: Compared to Influenza-associated ARDS, COVID-19 patients had higher ventilatory system compliance (40.7 mL/mbar [31.8–46.7 mL/mbar] vs. 31.4 mL/mbar [13.7–42.8 mL/mbar], p = 0.198), higher ventilatory ratio (1.57 [1.31–1.84] vs. 0.91 [0.44–1.38], p = 0.006) and higher minute ventilation at the time of intubation (mean minute ventilation 10.7 l/min [7.2–12.2 l/min] for COVID-19 vs. 6.0 l/min [2.5–10.1 l/min] for Influenza, p = 0.013). There were no measurable differences in P/F ratio, positive end-expiratory pressure (PEEP) and driving pressures (ΔP). Respiratory system compliance deteriorated considerably in COVID-19 patients on ECMO during 2 weeks of mechanical ventilation (Crs, mean decrease over 2 weeks −23.87 mL/mbar ± 32.94 mL/mbar, p = 0.037) but not in ventilated Influenza patients on ECMO and less so in ventilated COVID-19 patients without ECMO. For COVID-19 patients, low driving pressures on ECMO were strongly correlated to a decline in compliance after 2 weeks (Pearson’s R 0.80, p = 0.058). Overall mortality was insignificantly lower for COVID-19 patients compared to Influenza patients (40% vs. 48%, p = 0.31). Outcome was insignificantly worse for patients requiring veno-venous ECMO in both groups (50% mortality for COVID-19 on ECMO vs. 27% without ECMO, p = 0.30/56% vs. 34% mortality for Influenza A/B with and without ECMO, p = 0.31). Conclusion: The pathophysiology of early COVID-19-associated ARDS differs from Influenza-associated acute lung failure by sustained respiratory mechanics during the early phase of ventilation. We question whether intubated COVID-19 patients on ECMO benefit from extremely low driving pressures, as this appears to accelerate derecruitment and consecutive loss of ventilatory system compliance.
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The pandemic of coronavirus disease 2019 (COVID-19), for which there does not appear to be an approved cure, the primary treatment options consist of non-pharmacological preventive measures and supportive treatment that are aimed at halting the progression of the disease. Nuclear factor kappa B (NFkB) presents a promising therapeutic opportunity to mitigate COVID-19-induced cytokine storm and reduce the risk of severe morbidity and mortality resulting from the disease. However, the effective clinical application of NFkB modulators in COVID-19 is hampered by a number of factors that must be taken into consideration. This paper therefore explored the modulation of the NFB pathway as a potential strategy to mitigate the severe morbidity and mortality caused by COVID-19. The paper also discusses the factors that form the barrier, and it offers potential solutions to the various limitations that may impede the clinical use of NFkB modulators against COVID-19. This paper revealed and identified three key potential solutions for the future clinical use of NFkB modulators against COVID-19. These solutions are pulmonary tissue-specific NFkB blockade, agents that target common regulatory proteins of both canonical and non-canonical NFkB pathways, and monitoring clinical indicators of hyperinflammation and cytokine storm in COVID-19 prior to using NFkB modulators.
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Objective To assess the trustworthiness (ie, complete and consistent reporting of key methods and results between preprint and published trial reports) and impact (ie, effects of preprints on meta-analytic estimates and the certainty of evidence) of preprint trial reports during the covid-19 pandemic. Design Retrospective review. Data sources World Health Organization covid-19 database and the Living Overview of the Evidence (L-OVE) covid-19 platform by the Epistemonikos Foundation (up to 3 August 2021). Main outcome measures Comparison of characteristics of covid-19 trials with and without preprints, estimates of time to publication of covid-19 preprints, and description of differences in reporting of key methods and results between preprints and their later publications. For the effects of eight treatments on mortality and mechanical ventilation, the study comprised meta-analyses including preprints and excluding preprints at one, three, and six months after the first trial addressing the treatment became available either as a preprint or publication (120 meta-analyses in total, 60 of which included preprints and 60 of which excluded preprints) and assessed the certainty of evidence using the GRADE framework. Results Of 356 trials included in the study, 101 were only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. The median time to publication of preprints was about six months. Key methods and results showed few important differences between trial preprints and their subsequent published reports. Apart from two (3.3%) of 60 comparisons, point estimates were consistent between meta-analyses including preprints versus those excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. For nine (15%) of 60 comparisons, the rating of the certainty of evidence was different when preprints were included versus being excluded—the certainty of evidence including preprints was higher in four comparisons and lower in five comparisons. Conclusion No compelling evidence indicates that preprints provide results that are inconsistent with published papers. Preprints remain the only source of findings of many trials for several months—an unsuitable length of time in a health emergency that is not conducive to treating patients with timely evidence. The inclusion of preprints could affect the results of meta-analyses and the certainty of evidence. Evidence users should be encouraged to consider data from preprints.
Chapter
Coronavirus disease 2019 (COVID-19) has affected millions of people across the world. Clinicians and scientists across the globe need all the information of this pandemic on one platform. Today, it is also necessary to find out the association of COVID-19 with various medical comorbidities, and its effect on vulnerable populations that require special medical attention. This information will be helpful for the management of COVID-19. COVID-19: Effects in Comorbidities and Special Populations is a concise and visual reference for information about this viral disease and its relationship with different medical conditions. The book provides comprehensive knowledge covering COVID-19 comorbidities (for example, CVD, Diabetes, lung diseases, etc.), and the incidence in specific groups (for example, children and the elderly). Chapters outline the features and the management of the disease in specific conditions. Key Features: ✓ 12 chapters covering several aspects of COVID-19 management, making this a perfect text book for virologist and medical students ✓ Focused and structured description of different effects of COVID-19 in specific patient groups ✓ Multiple tables and figures which summarizes and highlight important points ✓ Multiple choice questions for learners ✓ Detailed list of references, abbreviations and symbols This book is an essential reference for practicing and training virologists, pulmonologists, medical students and scientists working in research labs, pharmaceutical and biotechnology industries in connection with the control of COVID-19 infection.
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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.
Article
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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