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1. Impact of domiciliary administration of NSAIDs on COVID-19 hospital outcomes: an unCoVer analysis.

Author

Salvador, Elena, Mazzi, Cristina, De Santis, Nicoletta, Bertoli, Giulia, Jonjić, Antonija, Coklo, Miran, Majdan, Marek, Peñalvo, José L., and Buonfrate, Dora

Subjects
COVID-19, NONSTEROIDAL anti-inflammatory agents, ANTI-inflammatory agents, LOGISTIC regression analysis, REGRESSION analysis
Abstract

Background: Effective domiciliary treatment can be useful in the early phase of COVID-19 to limit disease progression, and pressure on hospitals. There are discrepant data on the use of non-steroidal anti-inflammatory drugs (NSAIDs). Aim of this study is to evaluate whether the clinical outcome of patients who were hospitalized for COVID-19 is influenced by domiciliary treatment with NSAIDs. Secondary objective was to explore the association between other patient characteristics/therapies and outcome. Methods: A large dataset of COVID-19 patients was created in the context of a European Union-funded project (unCoVer). The primary outcome was explored using a study level random effects meta-analysis for binary (multivariate logistic regression models) outcomes adjusted for selected factors, including demographics and other comorbidities. Results: 218 out of 1,144 patients reported use of NSAIDs before admission. No association between NSAIDs use and clinical outcome was found (unadj. OR: 0.96, 95%CI: 0.68-1.38). The model showed an independent upward risk of death with increasing age (OR 1.06; 95% CI 1.05-1.07) and male sex (1.36; 95% CI 1.04-1.76). Conclusion: In our study, the domiciliary use of NSAIDs did not show association with clinical outcome in patients hospitalized with COVID-19. Older ages and male sex were associated to an increased risk of death. [ABSTRACT FROM AUTHOR]

Published
2023
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2. Impact of domiciliary administration of NSAIDs on COVID-19 hospital outcomes: an unCoVer analysis

Author

Elena Salvador, Cristina Mazzi, Nicoletta De Santis, Giulia Bertoli, Antonija Jonjić, Miran Coklo, Marek Majdan, José L. Peñalvo, and Dora Buonfrate

Subjects
COVID-19, SARS-CoV-2, outcome, treatment, NSAIDs, uncover, Therapeutics. Pharmacology, RM1-950
Abstract

Background: Effective domiciliary treatment can be useful in the early phase of COVID-19 to limit disease progression, and pressure on hospitals. There are discrepant data on the use of non-steroidal anti-inflammatory drugs (NSAIDs). Aim of this study is to evaluate whether the clinical outcome of patients who were hospitalized for COVID-19 is influenced by domiciliary treatment with NSAIDs. Secondary objective was to explore the association between other patient characteristics/therapies and outcome.Methods: A large dataset of COVID-19 patients was created in the context of a European Union-funded project (unCoVer). The primary outcome was explored using a study level random effects meta-analysis for binary (multivariate logistic regression models) outcomes adjusted for selected factors, including demographics and other comorbidities.Results: 218 out of 1,144 patients reported use of NSAIDs before admission. No association between NSAIDs use and clinical outcome was found (unadj. OR: 0.96, 95%CI: 0.68-1.38). The model showed an independent upward risk of death with increasing age (OR 1.06; 95% CI 1.05-1.07) and male sex (1.36; 95% CI 1.04-1.76).Conclusion: In our study, the domiciliary use of NSAIDs did not show association with clinical outcome in patients hospitalized with COVID-19. Older ages and male sex were associated to an increased risk of death.

Published
2023
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3. Pathogen-sugar interactions revealed by universal saturation transfer analysis

Author

Buchanan, Cj, Gaunt, B, Harrison, Pj, Yang, Y, Liu, J, Khan, A, Giltrap, Am, Le Bas, A, Ward, Pn, Gupta, K, Dumoux, M, Tan, Tk, Schimaski, L, Daga, S, Picchiotti, N, Baldassarri, M, Benetti, E, Fallerini, C, Fava, F, Giliberti, A, Koukos, Pi, Davy, Mj, Lakshminarayanan, A, Xue, X, Papadakis, G, Deimel, Lp, Casablancas-Antràs, V, Claridge, Tdw, Bonvin, Amjj, Settentau, Qj, Furini, S, Gori, M, Huo, J, Owens, Rj, Schaffitzel, C, Berger, I, Renieri, A, GEN-COVID Multicenter Study, Naismith, Jh, Baldwin, Aj, Davis, Bg, and Study, GEN-COVID Multicenter

Subjects
Multidisciplinary, SARS-CoV-2, Cryoelectron Microscopy, Bristol BioDesign Institute, UNCOVER, COVID-19, Genetic Variation, Covid19, Protein Domains, Polysaccharides, Max Planck Bristol, Host-Pathogen Interactions, Spike Glycoprotein, Coronavirus, Sialic Acids, Humans, General, Nuclear Magnetic Resonance, Biomolecular, Protein Binding
Abstract

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.

Published
2022
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4. At what times during infection is SARS-CoV-2 detectable and no longer detectable using RT-PCR-based tests? A systematic review of individual participant data

Author

Amanda Winter, Philip J. Turner, Chris Hyde, A Joy Allen, Susan Mallett, Stuart A. Taylor, Nia Roberts, Jaime Peters, Penny Whiting, Kile Green, Gauraang Bhatnagar, Jana Suklan, Lavinia Ferrante di Ruffano, Bethany Shinkins, Sara Graziadio, Brian D Nicholson, Steve Halligan, Naomi S Sakai, Zhivko Zhelev, and Robert Wolff

Subjects
0301 basic medicine, medicine.medical_specialty, Pneumonia, Viral, UNCOVER, RT-PCR, lcsh:Medicine, Disease, medicine.disease_cause, QUADAS-2, Virus, Betacoronavirus, 03 medical and health sciences, COVID-19 Testing, 0302 clinical medicine, Internal medicine, medicine, Humans, Longitudinal Studies, 030212 general & internal medicine, Pandemics, Coronavirus, Infectivity, Clinical Laboratory Techniques, Reverse Transcriptase Polymerase Chain Reaction, business.industry, SARS-CoV-2, lcsh:R, Anatomical sampling, COVID-19, Covid19, General Medicine, Diagnostic test, Confidence interval, IPD, Reverse transcription polymerase chain reaction, 030104 developmental biology, Real-time polymerase chain reaction, medicine.anatomical_structure, Systematic review, Coronavirus Infections, Duration virus detection, business, Research Article, Respiratory tract
Abstract

BackgroundTests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity.MethodsWe conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites.ResultsOf 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from − 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset.ConclusionsRT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated.

Published
2020
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5. Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2

Author

Kapil Gupta, Christine Toelzer, Maia Kavanagh Williamson, Deborah K. Shoemark, A. Sofia F. Oliveira, David A. Matthews, Abdulaziz Almuqrin, Oskar Staufer, Sathish K. N. Yadav, Ufuk Borucu, Frederic Garzoni, Daniel Fitzgerald, Joachim Spatz, Adrian J. Mulholland, Andrew D. Davidson, Christiane Schaffitzel, and Imre Berger

Subjects
Protein Conformation, Science, viruses, UNCOVER, General Physics and Astronomy, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, Evolution, Molecular, Linoleic Acid, Max Planck Bristol, Animals, Humans, Furin, Multidisciplinary, SARS-CoV-2, Bristol BioDesign Institute, Cryoelectron Microscopy, virus diseases, COVID-19, Covid19, General Chemistry, Virus Internalization, Viral proteins, Viral Tropism, Mutation, Spike Glycoprotein, Coronavirus, Molecular modelling, Protein Binding
Abstract

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants with increased transmissibility and pathology. In addition to this entrenched diversity, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriSΔ variant, originally identified as a viral subpopulation from SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike an eight amino-acid deletion encompassing a furin recognition motif and S1/S2 cleavage site. We elucidate the structure, function and molecular dynamics of this spike providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity of this SARS-CoV-2 variant. Our results reveal long-range allosteric communication between functional domains that differ in the wild-type and the deletion variant and support a view of SARS-CoV-2 probing multiple evolutionary trajectories in distinct cell types within the same infected host., BriSΔ, a SARS-CoV-2 variant from clinical isolate hCoV/England/02/2020, comprises a deletion in a spike cleavage site. The structure and molecular dynamics of this spike provides mechanistic insights into how the deletion modulates virus infectivity.

Published
2022
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6. Correlation of SARS-CoV-2 Serology and Clinical Phenotype Amongst Hospitalised Children in a Tertiary Children’s Hospital in India

Author

S Senthilnathan, S. Balasubramanian, Anu Goenka, Anand Manoharan, Sulochana Putilibai, R Amutha, Sumanth Amperayani, S Lakshan Raj, Athimalaipet V Ramanan, Kalaimaran Sadasivam, Aishwarya Venkataraman, and Arokia Sophi

Subjects
Pediatrics, serology, Disease, Serology, 0302 clinical medicine, hemic and lymphatic diseases, Pandemic, Epidemiology, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Child, biology, seroprevalence, Antibody titer, Covid19, Systemic Inflammatory Response Syndrome, Infectious Diseases, Phenotype, Child, Preschool, Antibody, COVID 19, medicine.medical_specialty, IgM, Coronavirus disease 2019 (COVID-19), IgG, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), UNCOVER, India, 03 medical and health sciences, 030225 pediatrics, medicine, Seroprevalence, Humans, Clinical phenotype, Pandemics, Original Paper, business.industry, SARS-CoV-2, COVID-19, Infant, medicine.disease, Systemic inflammatory response syndrome, Pediatrics, Perinatology and Child Health, biology.protein, business, AcademicSubjects/MED00670, PIMS-TS, Child, Hospitalized, Blood sampling
Abstract

Introduction Children usually present with minimal or no symptoms of COVID-19 infection. Antibody responses to SARS-CoV-2 in children from low- and middle-income countries (LMIC) have not been well described. We describe the prevalence of anti-SARS-CoV-2 antibodies and clinical phenotype of seropositive children admitted to a tertiary children’s hospital in South India. Methods To determine the seropositivity and describe the clinical characteristics of COVID-19 infection amongst hospitalised children, we performed a prospective clinical data collection and blood sampling of children admitted to Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India over 4 months of the COVID-19 pandemic. In seropositive children, we compared antibody titres between children with and without PIMS-TS. Results Of 463 children, 91 (19.6%) were seropositive. The median (range) age of seropositive children was 5 years (1 month–17 years). Clinical presentation was consistent with Paediatric inflammatory multisystem syndrome associated or related with SARS-CoV-2 infection (PIMS-TS) in 48% (44/91) of seropositive children. The median (range) antibody titre was 54.8 (11.1–170.9) AU/ml among all seropositive children. The median antibody titre among the children with PIMS-TS (60.3 AU/mL) was significantly (p = 0.01) higher when compared to the children without PIMS-TS (54.8 AU/mL). Conclusion We describe the antibody responses to SARS-CoV-2 amongst hospitalised children in a LMIC tertiary children’s hospital. Almost half of the seropositive children had PIMS-TS. Antibody levels may be helpful in the diagnosis and disease stratification of PIMS-TS. LAY SUMMARY Children usually present with minimal or no symptoms of COVID-19 infection. However, Multisystem Inflammatory Syndrome in Children (MIS-C) or Paediatric inflammatory multisystem syndrome associated or related with SARS-CoV-2 infection (PIMS-TS) has emerged as a distinctive paediatric illness related to SARS-CoV-2. Recently, antibody testing for SARS-CoV-2 is being used increasingly as a diagnostic test for PIMS-TS. However, data on the antibody responses to SARS-CoV-2 in children are sparse. We, therefore, attempted to identify the seropositivity and describe the clinical spectrum of COVID-19 infection amongst infants and children getting hospitalised in a children’s hospital in south India. Nearly one-fifth of the hospitalised children tested serology positive over 4 months. Antibody levels in children with PIMS-TS were significantly higher in comparison to the other two groups (acute COVID-19 infection and children without PIMS-TS). Results from our study suggest that all children are at risk of COVID-19 infection though they may present with mild illness or no symptoms. We also observed that antibody testing may have a possible role in diagnosis of PIMS-TS.

Published
2021
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7. A quantitative evaluation of aerosol generation during tracheal intubation and extubation

Author

Jules Brown, Bryan R. Bzdek, Jonathan P. Reid, Andrew J Shrimpton, Tim Cook, Florence K. A. Gregson, and Anthony E. Pickering

Subjects
Operating Rooms, medicine.medical_treatment, law.invention, 0302 clinical medicine, 030202 anesthesiology, law, Extubation, Intubation, Medicine, Anesthesia, 030212 general & internal medicine, Prospective Studies, Airway Management, aerosol‐generating procedure, Covid19, respiratory system, Ventilation (architecture), Original Article, Risk assessment, AERATOR, Environmental Monitoring, SARS‐COV‐2, 2019-20 coronavirus outbreak, extubation, Coronavirus disease 2019 (COVID-19), Patients, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), UNCOVER, SARS-COV-2, Airway Extubation, intubation, 03 medical and health sciences, COVID‐19, Correspondence, Intubation, Intratracheal, Humans, Particle Size, Personal protective equipment, Personal Protective Equipment, Aerosols, business.industry, SARS-CoV-2, Tracheal intubation, COVID-19, Original Articles, Respiration, Artificial, Ventilation, Aerosol, Anesthesiology and Pain Medicine, Cough, Aerosol Generating Procedure, Anesthetists, Airway management, business, Anaesthesia Pain and Critical Care
Abstract

The potential aerosolised transmission of severe acute respiratory syndrome coronavirus-2 is of global concern. Airborne precaution personal protective equipment and preventative measures are universally mandated for medical procedures deemed to be aerosol generating. The implementation of these measures is having a huge impact on healthcare provision. There is currently a lack of quantitative evidence on the number and size of airborne particles produced during aerosol-generating procedures to inform risk assessments. To address this evidence gap, we conducted real-time, high-resolution environmental monitoring in ultraclean ventilation operating theatres during tracheal intubation and extubation sequences. Continuous sampling with an optical particle sizer allowed characterisation of aerosol generation within the zone between the patient and anaesthetist. Aerosol monitoring showed a very low background particle count (0.4 particles.l−1) allowing resolution of transient increases in airborne particles associated with airway management. As a positive reference control, we quantitated the aerosol produced in the same setting by a volitional cough (average concentration, 732 (418) particles.l−1, n = 38). Tracheal intubation including facemask ventilation produced very low quantities of aerosolised particles (average concentration, 1.4 (1.4) particles.l−1, n = 14, p < 0.0001 vs. cough). Tracheal extubation, particularly when the patient coughed, produced a detectable aerosol (21 (18) l−1, n = 10) which was 15-fold greater than intubation (p = 0.0004) but 35-fold less than a volitional cough (p < 0.0001). The study does not support the designation of elective tracheal intubation as an aerosol-generating procedure. Extubation generates more detectable aerosol than intubation but falls below the current criterion for designation as a high-risk aerosol-generating procedure. These novel findings from real-time aerosol detection in a routine healthcare setting provide a quantitative methodology for risk assessment that can be extended to other airway management techniques and clinical settings. They also indicate the need for reappraisal of what constitutes an aerosol-generating procedure and the associated precautions for routine anaesthetic airway management.

Published
2020
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8. Neuropilin-1 is a host factor for SARS-CoV-2 infection

Author

Deborah K. Shoemark, James L. Daly, Maia Kavanagh Williamson, Peter Horvath, David A. Matthews, Lorena Simón-Gracia, Yohei Yamauchi, Carlos Antón-Plágaro, Reka Hollandi, Urs F. Greber, Boris Simonetti, Ari Helenius, Julian A. Hiscox, Tambet Teesalu, Brett M. Collins, Andrew D. Davidson, Richard B. Sessions, Peter J. Cullen, Kai-En Chen, Michael Bauer, Katja Klein, University of Zurich, and Simonetti, Boris

Subjects
medicine.medical_treatment, viruses, UNCOVER, BrisSynBio, Plasma protein binding, Peptidyl-Dipeptidase A, Multidisciplinary / COVID, Article, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Neuropilin 1, medicine, Humans, Furin, 030304 developmental biology, Host factor, chemistry.chemical_classification, Infectivity, 0303 health sciences, 1000 Multidisciplinary, Protease, Multidisciplinary, biology, SARS-CoV-2, Bristol BioDesign Institute, COVID-19, Covid19, Virus Internalization, Virology, 10124 Institute of Molecular Life Sciences, Neuropilin-1, 3. Good health, chemistry, biology.protein, 570 Life sciences, Glycoprotein, 030217 neurology & neurosurgery
Abstract

Another host factor for SARS-CoV-2 Virus-host interactions determine cellular entry and spreading in tissues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the earlier SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as a receptor; however, their tissue tropism differs, raising the possibility that additional host factors are involved. The spike protein of SARS-CoV-2 contains a cleavage site for the protease furin that is absent from SARS-CoV (see the Perspective by Kielian). Cantuti-Castelvetri et al. now show that neuropilin-1 (NRP1), which is known to bind furin-cleaved substrates, potentiates SARS-CoV-2 infectivity. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial and epithelial cells. Daly et al. found that the furin-cleaved S1 fragment of the spike protein binds directly to cell surface NRP1 and blocking this interaction with a small-molecule inhibitor or monoclonal antibodies reduced viral infection in cell culture. Understanding the role of NRP1 in SARS-CoV-2 infection may suggest potential targets for future antiviral therapeutics. Science , this issue p. 856 , p. 861 ; see also p. 765

Published
2020
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9. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Author

Wei Shen Lim, John C. Marshall, Viviane C Veiga, Bin Du, Jonathan Emberson, Judit Villar, Marie Leclerc, Azevedo Lcp., Otavio Berwanger, Flávia Ribeiro Machado, Derek C. Angus, Bruno Giraudeau, Richard Haynes, A. Le Gouge, Arthur S. Slutsky, Dequin P-F., Peter Horby, Srinivas Murthy, Cameron Green, Morten Hylander Møller, Janet V. Diaz, Anders Granholm, Higgins Jpt., Martin J Landray, Steven A R Webb, N Heming, Jelena Savović, Anthony C. Gordon, Sterne Jac., Peter Jüni, Bruno Martins Tomazini, Ferhat Meziani, Alexandre Biasi Cavalcanti, Colin McArthur, M W Petersen, Anders Perner, David Fisher, and Djillali Annane

Subjects
medicine.medical_specialty, Hydrocortisone, Critical Illness, UNCOVER, Pneumonia, Viral, Placebo, 01 natural sciences, Methylprednisolone, Dexamethasone, law.invention, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Randomized controlled trial, law, Interquartile range, Adrenal Cortex Hormones, Internal medicine, Cause of Death, medicine, Humans, 030212 general & internal medicine, 0101 mathematics, Adverse effect, Glucocorticoids, Pandemics, Original Investigation, Randomized Controlled Trials as Topic, business.industry, SARS-CoV-2, 010102 general mathematics, COVID-19, Covid19, General Medicine, Odds ratio, COVID-19 Drug Treatment, Clinical trial, Relative risk, Meta-analysis, business, Coronavirus Infections
Abstract

IMPORTANCE: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. OBJECTIVE: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I(2) statistic. The primary analysis was an inverse variance–weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios. EXPOSURES: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). MAIN OUTCOMES AND MEASURES: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. RESULTS: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P

Published
2020
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10. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19:The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

Author

Angus, Derek C, Derde, Lennie, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen C, de Jong, Menno, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Higgins, Alisa M, Horvat, Christopher, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Lawler, Patrick R, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, McAuley, Daniel, McGlothin, Anna, McGuinness, Shay, McVerry, Bryan, Montgomery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Rowan, Kathryn, Sanil, Ashish, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Turner, Anne, van de Veerdonk, Frank, Venkatesh, Balasubramanian, Zarychanski, Ryan, Berry, Scott, Lewis, Roger J, McArthur, Colin, Webb, Steven A, Gordon, Anthony C, Writing Committee for the REMAP-CAP Investigators, Angus, Derek, Cheng, Allen, De Jong, Menno, Gordon, Anthony, Lawler, Patrick, Webb, Steve, Campbell, Lewis, Forbes, Andrew, Gattas, David, Heritier, Stephane, Higgins, Lisa, Peake, Sandra, Presneill, Jeffrey, Seppelt, Ian, Trapani, Tony, Young, Paul, Bagshaw, Sean, Daneman, Nick, Ferguson, Niall, Misak, Cheryl, Hullegie, Sebastiaan, Pletz, Mathias, Rohde, Gernot, Rowan, Kathy, Alexander, Brian, Basile, Kim, Girard, Timothy, Huang, David, Vates, Jennifer, Beasley, Richard, Fowler, Robert, McGloughlin, Steve, Morpeth, Susan, Paterson, David, Venkatesh, Bala, Uyeki, Tim, Baillie, Kenneth, Duffy, Eamon, Fowler, Rob, Hills, Thomas, Orr, Katrina, Patanwala, Asad, Tong, Steve, Netea, Mihai, Bihari, Shilesh, Carrier, Marc, Fergusson, Dean, Goligher, Ewan, Haidar, Ghady, Hunt, Beverley, Kumar, Anand, Laffan, Mike, Lawless, Patrick, Lother, Sylvain, McCallum, Peter, Middeldopr, Saskia, McQuilten, Zoe, Neal, Matthew, Pasi, John, Schutgens, Roger, Stanworth, Simon, Turgeon, Alexis, Weissman, Alexandra, Adhikari, Neill, Anstey, Matthew, Brant, Emily, de Man, Angelique, Lamonagne, Francois, Masse, Marie-Helene, Udy, Andrew, Arnold, Donald, Begin, Phillipe, Charlewood, Richard, Chasse, Michael, Coyne, Mark, Cooper, Jamie, Daly, James, Gosbell, Iain, Harvala-Simmonds, Heli, Hills, Tom, MacLennan, Sheila, Menon, David, McDyer, John, Pridee, Nicole, Roberts, David, Shankar-Hari, Manu, Thomas, Helen, Tinmouth, Alan, Triulzi, Darrell, Walsh, Tim, Wood, Erica, Calfee, Carolyn, O’Kane, Cecilia, Shyamsundar, Murali, Sinha, Pratik, Thompson, Taylor, Young, Ian, Bihari, Shailesh, Hodgson, Carol, Laffey, John, McAuley, Danny, Orford, Neil, Neto, Ary, Lewis, Roger, McGlothlin, Anna, Miller, Eliza, Singh, Vanessa, Zammit, Claire, van Bentum Puijk, Wilma, Bouwman, Wietske, Mangindaan, Yara, Parker, Lorraine, Peters, Svenja, Rietveld, Ilse, Raymakers, Kik, Ganpat, Radhika, Brillinger, Nicole, Markgraf, Rene, Ainscough, Kate, Brickell, Kathy, Anjum, Aisha, Lane, Janis-Best, Richards-Belle, Alvin, Saull, Michelle, Wiley, Daisy, Bion, Julian, Connor, Jason, Gates, Simon, Manax, Victoria, van der Poll, Tom, Reynolds, John, van Beurden, Marloes, Effelaar, Evelien, Schotsman, Joost, Boyd, Craig, Harland, Cain, Shearer, Audrey, Wren, Jess, Clermont, Giles, Garrard, William, Kalchthaler, Kyle, King, Andrew, Ricketts, Daniel, Malakoutis, Salim, Marroquin, Oscar, Music, Edvin, Quinn, Kevin, Cate, Heidi, Pearson, Karen, Collins, Joanne, Hanson, Jane, Williams, Penny, Jackson, Shane, Asghar, Adeeba, Dyas, Sarah, Sutu, Mihaela, Murphy, Sheenagh, Williamson, Dawn, Mguni, Nhlanhla, Potter, Alison, Porter, David, Goodwin, Jayne, Rook, Clare, Harrison, Susie, Williams, Hannah, Campbell, Hilary, Lomme, Kaatje, Williamson, James, Sheffield, Jonathan, van’t Hoff, Willian, McCracken, Phobe, Young, Meredith, Board, Jasmin, Mart, Emma, Knott, Cameron, Smith, Julie, Boschert, Catherine, Affleck, Julia, Ramanan, Mahesh, D’Souza, Ramsy, Pateman, Kelsey, Shakih, Arif, Cheung, Winston, Kol, Mark, Wong, Helen, Shah, Asim, Wagh, Atul, Simpson, Joanne, Duke, Graeme, Chan, Peter, Cartner, Brittney, Hunter, Stephanie, Laver, Russell, Shrestha, Tapaswi, Regli, Adrian, Pellicano, Annamaria, McCullough, James, Tallott, Mandy, Kumar, Nikhil, Panwar, Rakshit, Brinkerhoff, Gail, Koppen, Cassandra, Cazzola, Federica, Brain, Matthew, Mineall, Sarah, Fischer, Roy, Biradar, Vishwanath, Soar, Natalie, White, Hayden, Estensen, Kristen, Morrison, Lynette, Smith, Joanne, Cooper, Melanie, Health, Monash, Shehabi, Yahya, Al-Bassam, Wisam, Hulley, Amanda, Whitehead, Christina, Lowrey, Julie, Gresha, Rebecca, Walsham, James, Meyer, Jason, Harward, Meg, Venz, Ellen, Williams, Patricia, Kurenda, Catherine, Smith, Kirsy, Smith, Margaret, Garcia, Rebecca, Barge, Deborah, Byrne, Deborah, Byrne, Kathleen, Driscoll, Alana, Fortune, Louise, Janin, Pierre, Yarad, Elizabeth, Hammond, Naomi, Bass, Frances, Ashelford, Angela, Waterson, Sharon, Wedd, Steve, 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Virginie, Rochwerg, Bram, Karachi, Tim, Oczkowski, Simon, Centofanti, John, Millen, Tina, Duan, Erick, Tsang, Jennifer, Patterson, Lisa, English, Shane, Watpool, Irene, Porteous, Rebecca, Miezitis, Sydney, McIntyre, Lauralyn, Brochard, Laurent, Burns, Karen, Sandhu, Gyan, Khalid, Imrana, Binnie, Alexandra, Powell, Elizabeth, McMillan, Alexandra, Luk, Tracy, Aref, Noah, Andric, Zdravko, Cviljevic, Sabina, Đimoti, Renata, Zapalac, Marija, Mirković, Gordan, Baršić, Bruno, Kutleša, Marko, Kotarski, Viktor, Vujaklija Brajković, Ana, Babel, Jakša, Sever, Helena, Dragija, Lidija, Kušan, Ira, Vaara, Suvi, Pettilä, Leena, Heinonen, Jonna, Kuitunen, Anne, Karlsson, Sari, Vahtera, Annukka, Kiiski, Heikki, Ristimäki, Sanna, Azaiz, Amine, Charron, Cyril, Godement, Mathieu, Geri, Guillaume, Vieillard-Baron, Antoine, Pourcine, Franck, Monchi, Mehran, Luis, David, Mercier, Romain, Sagnier, Anne, Verrier, Nathalie, Caplin, Cecile, Siami, Shidasp, Aparicio, Christelle, Vautier, Sarah, Jeblaoui, Asma, Fartoukh, Muriel, Courtin, Laura, Labbe, Vincent, Leparco, Cécile, Muller, Grégoire, Nay, Mai-Anh, Kamel, Toufik, Benzekri, Dalila, Jacquier, Sophie, Mercier, Emmanuelle, Chartier, Delphine, Salmon, Charlotte, Dequin, PierreFrançois, Schneider, Francis, Morel, Guillaume, L’Hotellier, Sylvie, Badie, Julio, Berdaguer, Fernando Daniel, Malfroy, Sylvain, Mezher, Chaouki, Bourgoin, Charlotte, Megarbane, Bruno, Voicu, Sebastian, Deye, Nicolas, Malissin, Isabelle, Sutterlin, Laetitia, Guitton, Christophe, Darreau, Cédric, Landais, Mickaël, Chudeau, Nicolas, Robert, Alain, Moine, Pierre, Heming, Nicholas, Maxime, Virginie, Bossard, Isabelle, Nicholier, Tiphaine Barbarin, Colin, Gwenhael, Zinzoni, Vanessa, Maquigneau, Natacham, Finn, André, Kreß, Gabriele, Hoff, Uwe, Friedrich Hinrichs, Carl, Nee, Jens, Hagel, Stefan, Ankert, Juliane, Kolanos, Steffi, Bloos, Frank, Petros, Sirak, Pasieka, Bastian, Kunz, Kevin, Appelt, Peter, Schütze, Bianka, Kluge, Stefan, Nierhaus, Axel, Jarczak, Dominik, Roedl, Kevin, Weismann, Dirk, Frey, Anna, Klinikum Neukölln, Vivantes, Reill, Lorenz, Distler, Michael, Maselli, Astrid, Bélteczki, János, Magyar, István, Fazekas, Ágnes, Kovács, Sándor, Szőke, Viktória, Szigligeti, Gábor, Leszkoven, János, Collins, Daniel, Breen, Patrick, Frohlich, Stephen, Whelan, Ruth, McNicholas, Bairbre, Scully, Michael, Casey, Siobhan, Kernan, Maeve, Doran, Peter, O’Dywer, Michael, Smyth, Michelle, Hayes, Leanne, Hoiting, Oscar, Peters, Marco, Rengers, Els, Evers, Mirjam, Prinssen, Anton, Bosch Ziekenhuis, Jeroen, Simons, Koen, Rozendaal, Wim, Polderman, F, de Jager, P, Moviat, M, Paling, A, Salet, A, Rademaker, Emma, Peters, Anna Linda, de Jonge, E, Wigbers, J, Guilder, E, Butler, M, Cowdrey, Keri-Anne, Newby, Lynette, Chen, Yan, Simmonds, Catherine, McConnochie, Rachael, Ritzema Carter, Jay, Henderson, Seton, Van Der Heyden, Kym, Mehrtens, Jan, Williams, Tony, Kazemi, Alex, Song, Rima, Lai, Vivian, Girijadevi, Dinu, Everitt, Robert, Russell, Robert, Hacking, Danielle, Buehner, Ulrike, Williams, Erin, Browne, Troy, Grimwade, Kate, Goodson, Jennifer, Keet, Owen, Callender, Owen, Martynoga, Robert, Trask, Kara, Butler, Amelia, Schischka, Livia, Young, Chelsea, Lesona, Eden, Olatunji, Shaanti, Robertson, Yvonne, José, Nuno, Amaro dos Santos Catorze, Teodoro, de Lima Pereira, Tiago Nuno Alfaro, Neves Pessoa, Lucilia Maria, Castro Ferreira, Ricardo Manuel, Pereira Sousa Bastos, Joana Margarida, Aysel Florescu, Simin, Stanciu, Delia, Zaharia, Miahela Florentina, Kosa, Alma Gabriela, Codreanu, Daniel, Marabi, Yaseen, Al Qasim, Eman, Moneer Hagazy, Mohamned, Al Swaidan, Lolowa, Arishi, Hatim, Muñoz-Bermúdez, Rosana, Marin-Corral, Judith, Salazar Degracia, Anna, Parrilla Gómez, Francisco, Mateo López, Maria Isabel, Rodriguez Fernandez, Jorge, Cárcel Fernández, Sheila, Carmona Flores, Rosario, León López, Rafael, de la Fuente Martos, Carmen, Allan, Angela, Polgarova, Petra, Farahi, Neda, McWilliam, Stephen, Hawcutt, Daniel, Rad, Laura, O’Malley, Laura, Whitbread, Jennifer, Kelsall, Olivia, Wild, Laura, Thrush, Jessica, Wood, Hannah, Austin, Karen, Donnelly, Adrian, Kelly, Martin, O’Kane, Sinéad, McClintock, Declan, Warnock, Majella, Johnston, Paul, Gallagher, Linda Jude, Mc Goldrick, Clare, Mc Master, Moyra, Strzelecka, Anna, Jha, Rajeev, Kalogirou, Michael, Ellis, Christine, Krishnamurthy, Vinodh, Deelchand, Vashish, Silversides, Jon, McGuigan, Peter, Ward, Kathryn, O’Neill, Aisling, Finn, Stephanie, Phillips, Barbara, Mullan, Dee, Oritz-Ruiz de Gordoa, Laura, Thomas, Matthew, Sweet, Katie, Grimmer, Lisa, Johnson, Rebekah, Pinnell, Jez, Robinson, Matt, Gledhill, Lisa, Wood, Tracy, Morgan, Matt, Cole, Jade, Hill, Helen, Davies, Michelle, Antcliffe, David, Templeton, Maie, Rojo, Roceld, Coghlan, Phoebe, Smee, Joanna, Mackay, Euan, Cort, Jon, Whileman, Amanda, Spencer, Thomas, Spittle, Nick, Kasipandian, Vidya, Patel, Amit, Allibone, Suzanne, Genetu, Roman Mary, Ramali, Mohamed, Ghosh, Alison, Bamford, Peter, London, Emily, 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Henning, Jeremy, Bonner, Stephen, Hugill, Keith, Cirstea, Emanuel, Wilkinson, Dean, Karlikowski, Michal, Sutherland, Helen, Wilhelmsen, Elva, Woods, Jane, North, Julie, Sundaran, Dhinesh, Hollos, Laszlo, Coburn, Susan, Walsh, Joanne, Turns, Margaret, Hopkins, Phil, Smith, John, Noble, Harriet, Depante, Maria Theresa, Clarey, Emma, Laha, Shondipon, Verlander, Mark, Williams, Alexandra, Huckle, Abby, Hall, Andrew, Cooke, Jill, Gardiner-Hill, Caroline, Maloney, Carolyn, Qureshi, Hafiz, Flint, Neil, Nicholson, Sarah, Southin, Sara, Nicholson, Andrew, Borgatta, Barbara, Turner-Bone, Ian, Reddy, Amie, Wilding, Laura, Chamara Warnapura, Loku, Agno Sathianathan, Ronan, Golden, David, Hart, Ciaran, Jones, Jo, Bannard-Smith, Jonathan, Henry, Joanne, Birchall, Katie, Pomeroy, Fiona, Quayle, Rachael, Makowski, Arystarch, Misztal, Beata, Ahmed, Iram, KyereDiabour, Thyra, Naiker, Kevin, Stewart, Richard, Mwaura, Esther, Mew, Louise, Wren, Lynn, Willams, Felicity, Innes, Richard, Doble, Patricia, Hutter, Joanne, Shovelton, Charmaine, Plumb, Benjamin, Szakmany, Tamas, Hamlyn, Vincent, Hawkins, Nancy, Lewis, Sarah, Dell, Amanda, Gopal, Shameer, Ganguly, Saibal, Smallwood, Andrew, Harris, Nichola, Metherell, Stella, Lazaro, Juan Martin, Newman, Tabitha, Fletcher, Simon, Nortje, Jurgens, Fottrell-Gould, Deirdre, Randell, Georgina, Zaman, Mohsin, Elmahi, Einas, Jones, Andrea, Hall, Kathryn, Mills, Gary, Ryalls, Kim, Bowler, Helen, Sall, Jas, Bourne, Richard, Borrill, Zoe, Duncan, Tracey, Lamb, Thomas, Shaw, Joanne, Fox, Claire, Moreno Cuesta, Jeronimo, Xavier, Kugan, Purohit, Dharam, Elhassan, Munzir, Bakthavatsalam, Dhanalakshmi, Rowland, Matthew, Hutton, Paula, Bashyal, Archana, Davidson, Neil, Hird, Clare, Chhablani, Manish, Phalod, Gunjan, Kirkby, Amy, Archer, Simon, Netherton, Kimberley, Reschreiter, Henrik, Camsooksai, Julie, Patch, Sarah, Jenkins, Sarah, Pogson, David, Rose, Steve, Daly, Zoe, Brimfield, Lutece, Claridge, Helen, Parekh, Dhruv, Bergin, Colin, Bates, Michelle, Dasgin, Joanne, McGhee, Christopher, Sim, Malcolm, Hay, Sophie Kennedy, Henderson, Steven, Phull, Mandeep-Kaur, Zaidi, Abbas, Pogreban, Tatiana, Rosaroso, Lace Paulyn, Harvey, Daniel, Lowe, Benjamin, Meredith, Megan, Ryan, Lucy, Hormis, Anil, Walker, Rachel, Collier, Dawn, Kimpton, Sarah, Oakley, Susan, Rooney, Kevin, Rodden, Natalie, Hughes, Emma, Thomson, Nicola, McGlynn, Deborah, Walden, Andrew, Jacques, Nicola, Coles, Holly, Tilney, Emma, Vowell, Emma, Schuster-Bruce, Martin, Pitts, Sally, Miln, Rebecca, Purandare, Laura, Vamplew, Luke, Spivey, Michael, Bean, Sarah, Burt, Karen, Moore, Lorraine, Day, Christopher, Gibson, Charly, Gordon, Elizabeth, Zitter, Letizia, Keenan, Samantha, Baker, Evelyn, Cherian, Shiney, Cutler, Sean, Roynon-Reed, Anna, Harrington, Kate, Raithatha, Ajay, Bauchmuller, Kris, Ahmad, Norfaizan, Grecu, Irina, Trodd, Dawn, Martin, Jane, Wrey Brown, Caroline, Arias, Ana-Marie, Craven, Thomas, Hope, David, Singleton, Jo, Clark, Sarah, Rae, Nicola, Welters, Ingeborg, Hamilton, David Oliver, Williams, Karen, Waugh, Victoria, Shaw, David, Puthucheary, Zudin, Martin, Timothy, Santos, Filipa, Uddin, Ruzena, Somerville, Alastair, Tatham, Kate Colette, Jhanji, Shaman, Black, Ethel, Dela Rosa, Arnold, Howle, Ryan, Tully, Redmond, Drummond, Andrew, Dearden, Joy, Philbin, Jennifer, Munt, Sheila, Vuylsteke, Alain, Chan, Charles, Victor, Saji, Matsa, Ramprasad, Gellamucho, Minerva, Creagh-Brown, Ben, Tooley, Joe, Montague, Laura, De Beaux, Fiona, Bullman, Laetitia, Kersiake, Ian, Demetriou, Carrie, Mitchard, Sarah, Ramos, Lidia, White, Katie, Donnison, Phil, Johns, Maggie, Casey, Ruth, Mattocks, Lehentha, Salisbury, Sarah, Dark, Paul, Claxton, Andrew, McLachlan, Danielle, Slevin, Kathryn, Lee, Stephanie, Hulme, Jonathan, Joseph, Sibet, Kinney, Fiona, Senya, Ho Jan, Oborska, Aneta, Kayani, Abdul, Hadebe, Bernard, Orath Prabakaran, Rajalakshmi, Nichols, Lesley, Thomas, Matt, Worner, Ruth, Faulkner, Beverley, Gendall, Emma, Hayes, Kati, Hamilton-Davies, Colin, Chan, Carmen, Mfuko, Celina, Abbass, Hakam, Mandadapu, Vineela, Leaver, Susannah, Forton, Daniel, Patel, Kamal, Paramasivam, Elankumaran, Powell, Matthew, Gould, Richard, Wilby, Elizabeth, Howcroft, Clare, Banach, Dorota, Fernández de Pinedo Artaraz, Ziortza, Cabreros, Leilani, White, Ian, Croft, Maria, Holland, Nicky, Pereira, Rita, Zaki, Ahmed, Johnson, David, Jackson, Matthew, Garrard, Hywel, Juhaz, Vera, Roy, Alistair, Rostron, Anthony, Woods, Lindsey, Cornell, Sarah, Pillai, Suresh, Harford, Rachel, Rees, Tabitha, Ivatt, Helen, Sundara Raman, Ajay, Davey, Miriam, Lee, Kelvin, Barber, Russell, Chablani, Manish, Brohi, Farooq, Jagannathan, Vijay, Clark, Michele, Purvis, Sarah, Wetherill, Bill, Dushianthan, Ahilanandan, Cusack, Rebecca, de Courcy-Golder, Kim, Smith, Simon, Jackson, Susan, Attwood, Ben, Parsons, Penny, Page, Valerie, Zhao, Xiao Bei, Oza, Deepali, Rhodes, Jonathan, Anderson, Tom, Morris, Sheila, Xia Le Tai, Charlotte, Thomas, Amy, Keen, Alexandra, Digby, Stephen, Cowley, Nicholas, Southern, David, Reddy, Harsha, Campbell, Andy, Watkins, Claire, Smuts, Sara, Touma, Omar, Barnes, Nicky, Alexander, Peter, Felton, Tim, Ferguson, Susan, Sellers, Katharine, Bradley-Potts, Joanne, Yates, David, Birkinshaw, Isobel, Kell, Kay, Marshall, Nicola, Carr-Knott, Lisa, Writing Committee for the REMAP-CAP Investigators, Menon, David [0000-0002-3228-9692], Apollo - University of Cambridge Repository, Medical Microbiology and Infection Prevention, and AII - Infectious diseases

Subjects
Male, Hydrocortisone, Anti-Inflammatory Agents, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 01 natural sciences, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Adrenal Cortex Hormones, Clinical endpoint, Medicine, 030212 general & internal medicine, Hydrocortisone/administration & dosage, Original Investigation, 2. Zero hunger, Mortality rate, Shock, Covid19, General Medicine, Middle Aged, Intensive care unit, 3. Good health, Intensive Care Units, Treatment Outcome, Early Termination of Clinical Trials, Corticosteroid, Female, Coronavirus Infections, medicine.drug, Adult, medicine.medical_specialty, Respiration, Artificial/statistics & numerical data, medicine.drug_class, Anti-Inflammatory Agents/administration & dosage, Pneumonia, Viral, UNCOVER, Adrenal Cortex Hormones/therapeutic use, 03 medical and health sciences, Betacoronavirus, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Humans, 0101 mathematics, Adverse effect, Pandemics, business.industry, SARS-CoV-2, 010102 general mathematics, COVID-19, Odds ratio, Coronavirus Infections/drug therapy, Pneumonia, Viral/drug therapy, Respiration, Artificial, COVID-19 Drug Treatment, Shock/drug therapy, Human medicine, business
Abstract

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Published
2020
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11. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

Author

Pedro M Folegatti, Katie J Ewer, Parvinder K Aley, Brian Angus, Stephan Becker, Sandra Belij-Rammerstorfer, Duncan Bellamy, Sagida Bibi, Mustapha Bittaye, Elizabeth A Clutterbuck, Christina Dold, Saul N Faust, Adam Finn, Amy L Flaxman, Bassam Hallis, Paul Heath, Daniel Jenkin, Rajeka Lazarus, Rebecca Makinson, Angela M Minassian, Katrina M Pollock, Maheshi Ramasamy, Hannah Robinson, Matthew Snape, Richard Tarrant, Merryn Voysey, Catherine Green, Alexander D Douglas, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Andrew J Pollard, Jeremy Aboagye, Kelly Adams, Aabidah Ali, Elizabeth Allen, Jennifer L. Allison, Rachel Anslow, Edward H. Arbe-Barnes, Gavin Babbage, Kenneth Baillie, Megan Baker, Natalie Baker, Philip Baker, Ioana Baleanu, Juliana Ballaminut, Eleanor Barnes, Jordan Barrett, Louise Bates, Alexander Batten, Kirsten Beadon, Rebecca Beckley, Eleanor Berrie, Lisa Berry, Amy Beveridge, Kevin R. Bewley, Else Margreet Bijker, Tracey Bingham, Luke Blackwell, Caitlin L. Blundell, Emma Bolam, Elena Boland, Nicola Borthwick, Thomas Bower, Amy Boyd, Tanja Brenner, Philip D. Bright, Charlie Brown-O'Sullivan, Emily Brunt, Jamie Burbage, Sharon Burge, Karen R. Buttigieg, Nicholas Byard, Ingrid Cabera Puig, Anna Calvert, Susana Camara, Michelangelo Cao, Federica Cappuccini, Melanie Carr, Miles W. Carroll, Victoria Carter, Katrina Cathie, Ruth J. Challis, Sue Charlton, Irina Chelysheva, Jee-Sun Cho, Paola Cicconi, Liliana Cifuentes, Helen Clark, Elizabeth Clark, Tom Cole, Rachel Colin-Jones, Christopher P. Conlon, Aislinn Cook, Naomi S. Coombes, Rachel Cooper, Catherine A. Cosgrove, Karen Coy, Wendy E.M. Crocker, Christina J. Cunningham, Brad E. Damratoski, Lynne Dando, Mehreen S. Datoo, Hannah Davies, Hans De Graaf, Tesfaye Demissie, Claudio Di Maso, Isabelle Dietrich, Tao Dong, Francesca R. Donnellan, Naomi Douglas, Charlotte Downing, Jonathan Drake, Rachael Drake-Brockman, Ruth Elizabeth Drury, Susanna Jane Dunachie, Nick J. Edwards, Frances D.L. Edwards, Chris J. Edwards, Sean C. Elias, Michael J. Elmore, Katherine R.W. Emary, Marcus Rex English, Susanne Fagerbrink, Sally Felle, Shuo Feng, Samantha Field, Carine Fixmer, Clare Fletcher, Karen J. Ford, Jamie Fowler, Polly Fox, Emma Francis, John Frater, Julie Furze, Michelle Fuskova, Eva Galiza, Diane Gbesemete, Ciaran Gilbride, Kerry Godwin, Giacomo Gorini, Lyndsey Goulston, Caroline Grabau, Lara Gracie, Zoe Gray, Lucy Belle Guthrie, Mark Hackett, Sandro Halwe, Elizabeth Hamilton, Joseph Hamlyn, Brama Hanumunthadu, Irasha Harding, Stephanie A. Harris, Andrew Harris, Daisy Harrison, Clare Harrison, Thomas C. Hart, Louise Haskell, Sophia Hawkins, Ian Head, John Aaron Henry, Jennifer Hill, Susanne H.C. Hodgson, Mimi M. Hou, Elizabeth Howe, Nicola Howell, Cecilia Hutlin, Sabina Ikram, Catherine Isitt, Poppy Iveson, Susan Jackson, Frederic Jackson, Sir William James, Megan Jenkins, Elizabeth Jones, Kathryn Jones, Christine E. Jones, Bryony Jones, Reshma Kailath, Konstantinos Karampatsas, Jade Keen, Sarah Kelly, Dearbhla Kelly, David Kerr, Simon Kerridge, Liaquat Khan, Uzma Khan, Annabel Killen, Jasmin Kinch, Thomas B. King, Lloyd King, Jade King, Lucy Kingham-Page, Paul Klenerman, Francesca Knapper, Julian C. Knight, Daniel Knott, Stanislava Koleva, Alexandra Kupke, Colin W. Larkworthy, Jessica P.J. Larwood, Anna Laskey, Alison M. Lawrie, Arlene Lee, Kim Yee Ngan Lee, Emily A Lees, Helen Legge, Alice Lelliott, Nana-Marie Lemm, Amelia M. Lias, Aline Linder, Samuel Lipworth, Xinxue Liu, Shuchang Liu, Raquel Lopez Ramon, May Lwin, Francesca Mabesa, Meera Madhavan, Garry Mallett, Kushal Mansatta, Ines Marcal, Spyridoula Marinou, Emma Marlow, Julia L. Marshall, Jane Martin, Joanne McEwan, Lorna McInroy, Gretchen Meddaugh, Alexander J. Mentzer, Neginsadat Mirtorabi, Maria Moore, Edward Moran, Ella Morey, Victoria Morgan, Susan Jane Morris, Hazel Morrison, Gertraud Morshead, Richard Morter, Yama F. Mujadidi, Jilly Muller, Tatiana Munera-Huertas, Claire Munro, Alasdair Munro, Sarah Murphy, Vincent J. Munster, Philomena Mweu, Andrés Noé, Fay L. Nugent, Elizabeth Nuthall, Katie O'Brien, Daniel O'Connor, Blanché Oguti, Jennifer L. Oliver, Catarina Oliveira, Peter John O'Reilly, Mairead Osborn, Piper Osborne, Cathy Owen, Daniel Owens, Nelly Owino, Mihaela Pacurar, Kaye Parker, Helena Parracho, Maia Patrick-Smith, Victoria Payne, Jennifer Pearce, Yanchun Peng, Marco Polo Peralta Alvarez, James Perring, Katja Pfafferott, Dimitra Pipini, Emma Plested, Helen Pluess-Hall, Katrina Pollock, Ian Poulton, Laura Presland, Samuel Provstgaard-Morys, David Pulido, Kajal Radia, Fernando Ramos Lopez, Jade Rand, Helen Ratcliffe, Thomas Rawlinson, Sarah Rhead, Amy Riddell, Adam John Ritchie, Hannah Roberts, Joanna Robson, Sophie Roche, Cornelius Rohde, Christine S. Rollier, Rossana Romani, Indra Rudiansyah, Stephen Saich, Sara Sajjad, Stephannie Salvador, Lidia Sanchez Riera, Helen Sanders, Katherine Sanders, Shari Sapaun, Chloe Sayce, Ella Schofield, Gavin Screaton, Beatrice Selby, Calum Semple, Hannah R. Sharpe, Imam Shaik, Adam Shea, Holly Shelton, Sarah Silk, Laura Silva-Reyes, Donal T. Skelly, Heather Smee, Catherine C. Smith, David J. Smith, Rinn Song, Alexandra J. Spencer, Elizabeth Stafford, Amy Steele, Elena Stefanova, Lisa Stockdale, Anna Szigeti, Abdessamad Tahiri-Alaoui, Moira Tait, Helen Talbot, Rachel Tanner, Iona Jennifer Taylor, Victoria Taylor, Rebecca Te Water Naude, Nazia Thakur, Yrene Themistocleous, Andreas Themistocleous, Merin Thomas, Tonia M. Thomas, Amber Thompson, Samantha Thomson-Hill, Jennifer Tomlins, Susan Tonks, James Towner, Nguyen Tran, Julia A. Tree, Adam Truby, Kate Turkentine, Cheryl Turner, Nicola Turner, Sally Turner, Toby Tuthill, Marta Ulaszewska, Rachel Varughese, Neeltje Van Doremalen, Kristin Veighey, Marije K. Verheul, Iason Vichos, Elia Vitale, Laura Walker, Marion E.E. Watson, Benjamin Welham, Julie Wheat, Caroline White, Rachel White, Andrew T. Worth, Danny Wright, Suzie Wright, Xin Li Yao, Yasmine Yau, and Hodgson, S

Subjects
Male, T-Lymphocytes, Booster dose, 030204 cardiovascular system & hematology, Antibodies, Viral, law.invention, 0302 clinical medicine, Immunogenicity, Vaccine, Randomized controlled trial, law, Oxford COVID Vaccine Trial Group, Medicine, Single-Blind Method, 030212 general & internal medicine, 11 Medical and Health Sciences, Viral Vaccine, Immunogenicity, Covid19, General Medicine, Analgesics, Non-Narcotic, Vaccination, Spike Glycoprotein, Coronavirus, Female, Coronavirus Infections, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, COVID-19 Vaccines, UNCOVER, Genetic Vectors, Pneumonia, Viral, Immunization, Secondary, Department of Error, Article, 03 medical and health sciences, Betacoronavirus, Medicine, General & Internal, Internal medicine, General & Internal Medicine, Humans, Adverse effect, Pandemics, Acetaminophen, Reactogenicity, Science & Technology, business.industry, SARS-CoV-2, COVID-19, Viral Vaccines, Antibodies, Neutralizing, United Kingdom, Clinical trial, Immunoglobulin G, Adenoviruses, Simian, business, ACUTE RESPIRATORY SYNDROME
Abstract

Background: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 10 10 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT 50]; a microneutralisation assay [MNA 50, MNA 80, and MNA 90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings: Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p80 and in 35 (100%) participants when measured in PRNT 50. After a booster dose, all participants had neutralising activity (nine of nine in MNA 80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R 2=0·67 by Marburg VN; p

Published
2020
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12. Hyper-inflammatory Syndrome in a Child With COVID-19 Treated Successfully With Intravenous Immunoglobulin and Tocilizumab

Author

Bala Ramachandran, T M Nagendran, S Balasubramanian, and Athimalaipet V Ramanan

Subjects
Male, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Immunologic Factors, Clinical Case Letters, Pneumonia, Viral, UNCOVER, Antibodies, Monoclonal, Humanized, Gastroenterology, chemistry.chemical_compound, Betacoronavirus, Tocilizumab, Internal medicine, medicine, Humans, Child, Pandemics, biology, business.industry, SARS-CoV-2, COVID-19, Immunoglobulins, Intravenous, Covid19, medicine.disease, Systemic Inflammatory Response Syndrome, Systemic inflammatory response syndrome, Pneumonia, chemistry, Pediatrics, Perinatology and Child Health, Monoclonal, biology.protein, Antibody, business, Coronavirus Infections
Abstract

[No abstract]

Published
2020
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13. COVID-19 in Older People:A Rapid Clinical Review

Author

Sandra Neumann, Victoria J. Haunton, Tomas J. Welsh, Emma Tenison, Katherine Lloyd, Fiona E Lithander, Hannah Christensen, Lily Scourfield, Julian P T Higgins, Emily J. Henderson, and Jonathan C L Rodrigues

Subjects
Aging, Comorbidity, Disease, 0302 clinical medicine, Pandemic, Medicine, 030212 general & internal medicine, Disease management (health), older adults, Social distance, Age Factors, Disease Management, Covid19, General Medicine, Prognosis, virology, Older adults, Coronavirus Infections, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Inclusion (disability rights), Pneumonia, Viral, UNCOVER, Antiviral Agents, Betacoronavirus, 03 medical and health sciences, Virology, Humans, Intensive care medicine, Pandemics, non-pharmaceutical interventions, Aged, SARS-CoV-2, business.industry, Non-pharmaceutical interventions, pandemic, COVID-19, medicine.disease, Clinical trial, Ageing, Ageing and Movement Research Group, Systematic Review, prognosis, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Introduction the COVID-19 pandemic poses a high risk to older people. The aim of this article is to provide a rapid overview of the COVID-19 literature, with a specific focus on older adults. We frame our findings within an overview of the disease and have also evaluated the inclusion of older people within forthcoming clinical trials. Methods we searched PubMed and bioRxiv/medRxiv to identify English language papers describing the testing, treatment and prognosis of COVID-19. PubMed and bioRxiv/medRxiv searches took place on 20 and 24 March 2020, respectively. Results screening of over 1,100 peer-reviewed and pre-print papers yielded n = 22 on COVID-19 testing, n = 15 on treatment and n = 13 on prognosis. Viral polymerase chain reaction (PCR) and serology are the mainstays of testing, but a positive diagnosis may be increasingly supported by radiological findings. The current evidence for the effectiveness of antiviral, corticosteroid and immunotherapies is inconclusive, although trial data are largely based on younger people. In addition to age, male gender and comorbidities, specific laboratory and radiology findings are important prognostic factors. Evidence suggests that social distancing policies could have important negative consequences, particularly if in place for an extended period. Conclusion given the established association between increasing age and poor prognosis in COVID-19, we anticipate that this rapid review of the current and emergent evidence might form a basis on which future work can be established. Exclusion of older people, particularly those with comorbidities, from clinical trials is well recognised and is potentially being perpetuated in the field of current COVID-19 research.

Published
2020
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14. The SARS-CoV-2 Spike protein alters human cardiac pericyte function and interaction with endothelial cells through a non-infective mechanism involving activation of CD147 receptor signalling

Author

Massimo Caputo, Michele Carrabba, Paolo Madeddu, Kapil Gupta, Rebecca R. Foster, Imre Berger, Andrew D. Davidson, M Kavanagh Williamson, Rachel Milligan, Elisa Avolio, Monica Gamez, and Darryl J. Hill

Subjects
Angiogenesis, UNCOVER, Artery morphogenesis, Abstract Supplement, pericyte, Medicine, SPIKE, AcademicSubjects/MED00200, Endothelial dysfunction, cardiac pericytes, business.industry, Bristol BioDesign Institute, Covid19, medicine.disease, Epithelium, microvascular disease, Cell biology, medicine.anatomical_structure, covid-19, Angiotensin-converting enzyme 2, CD147, Phosphorylation, Pericyte, Microcirculation, Angiogenesis, Arteriogenesis, Cardiology and Cardiovascular Medicine, business, Function (biology)
Abstract

Background Human cardiac pericytes (PC) were proposed as the main cellular target for SARS-CoV-2 in the heart due to high transcriptional levels of the angiotensin-converting enzyme 2 (ACE2) receptor. Emerging reports indicate CD147/Basigin (BSG), highly expressed in endothelial cells (EC), is an alternative SARS-CoV-2 receptor. To date, the mechanism by which the virus infects and disrupts the heart vascular cells was not identified yet. Moreover, cleaved Spike (S) protein molecules could be released into the bloodstream from the leaking pulmonary epithelial-endothelial barrier in patients with severe COVID-19, opening to the possibility of non-infective diseases in organs distant from the primary site of infection. Purposes (1) to confirm that human primary cardiac PC express ACE2 and CD147; (2) to verify if PC are permissible to SARS-CoV-2 infection; (3) to investigate if the recombinant SARS-CoV-2 S protein alone, without the other viral elements, can trigger molecular signalling and induce functional alterations in PC; (4) to explore which viral receptor is responsible for the observed events. Methods and results Cardiac PC express both the ACE2 and CD147 receptors at mRNA and protein level. Incubation of PC for up to 5 days with SARS-CoV-2 expressing the green fluorescent protein (GFP) did not show any evidence of cell infection or viral replication. Next, we exposed the PC to the recombinant S protein (5.8 nM) and confirmed that the protein engaged with cellular receptors (western blot analysis of S protein in treated and control PC). Incubation with the S protein increased PC migration (wound closure assay, P Conclusions We propose the novel hypothesis that COVID-19 associated heart's microvascular dysfunction is prompted by circulating S protein molecules rather than by the direct coronavirus infection of PC. Besides, we propose CD147, and not ACE2, as the leading receptor mediating S protein signalling in cardiac PC. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): BHF project grant “Targeting the SARS-CoV-2 S-protein binding to the ACE2 receptor to preserve human cardiac pericytes function in COVID-19” BHF Centre for Vascular Regeneration II

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