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26/10/2023 Articles
Convalescent Plasma for Covid-19–Induced ARDS in Mechanically Ventilat...

Convalescent Plasma for Covid-19–Induced ARDS in Mechanically Ventilated Patients

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Benoît Misset, M.D., Michael Piagnerelli, M.D., Ph.D., Eric Hoste, M.D., Ph.D., Nadia Dardenne, M.Sc., David Grimaldi, M.D., Ph.D., Isabelle Michaux, M.D., Ph.D., Elisabeth De Waele, M.D., Ph.D., Alexander Dumoulin, M.D., Philippe G. Jorens, M.D., Ph.D., Emmanuel van der Hauwaert, M.D., Frédéric Vallot, M.D., Stoffel Lamote, M.D., Walter Swinnen, M.D., Nicolas De Schryver, M.D., Vincent Fraipont, M.D., Nathalie de Mey, M.D., Nicolas Dauby, M.D., Ph.D., Nathalie Layios, M.D., Jean‐Baptiste Mesland, M.D., Ph.D., Geert Meyfroidt, M.D., Ph.D., Michel Moutschen, M.D., Ph.D., Veerle Compernolle, M.D., Ph.D., André Gothot, M.D., Ph.D., Daniel Desmecht, D.V.M., Ph.D., Maria I. Taveira da Silva Pereira, M.D., Ph.D., Mutien Garigliany, D.V.M., Ph.D., Tome Najdovski, Ph.D., Axelle Bertrand, M.Sc., Anne‐Françoise Donneau, Ph.D., and Pierre‐François Laterre

Abstract
BACKGROUND
Passive immunization with plasma collected from convalescent patients has been regularly used to treat coronavirus disease 2019 (Covid-19). Minimal data are available regarding the use of convalescent plasma in patients with Covid-19–induced acute respiratory distress syndrome (ARDS).

METHODS
In this open-label trial, we randomly assigned adult patients with Covid-19–induced ARDS who had been receiving invasive mechanical ventilation for less than 5 days in a 1:1 ratio to receive either convalescent plasma with a neutralizing antibody titer of at least 1:320 or standard care alone. Randomization was stratified according to the time from tracheal intubation to inclusion. The primary outcome was death by day 28.

RESULTS
A total of 475 patients underwent randomization from September 2020 through March 2022. Overall, 237 patients were assigned to receive convalescent plasma and 238 to receive standard care. Owing to a shortage of convalescent plasma, a neutralizing antibody titer of 1:160 was administered to 17.7% of the patients in the convalescent-plasma group. Glucocorticoids were administered to 466 patients (98.1%). At day 28, mortality was 35.4% in the convalescent-plasma group and 45.0% in the standard-care group (P=0.03). In a prespecified analysis, this effect was observed mainly in patients who underwent randomization 48 hours or less after the initiation of invasive mechanical ventilation. Serious adverse events did not differ substantially between the two groups.

CONCLUSIONS
The administration of plasma collected from convalescent donors with a neutralizing antibody titer of at least 1:160 to patients with Covid-19–induced ARDS within 5 days after the initiation of invasive mechanical ventilation significantly reduced mortality at day 28. This effect was mainly observed in patients who underwent randomization 48 hours or less after ventilation initiation. (Funded by the Belgian Health Care Knowledge Center; ClinicalTrials.gov number, NCT04558476. opens in new tab.)

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26/09/2023 Original Paper
Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
David R. Boulware, M.D., M.P.H., Christopher J. Lindsell, Ph.D., Thomas G. Stewart, Ph.D., Adrian F. Hernandez, M.D., M.H.S., Sean Collins, M.D., Matthew William McCarthy, M.D., Dushyantha Jayaweera, M.D., Nina Gentile, M.D., Mario Castro, M.D., M.P.H., Mark Sulkowski, M.D., Kathleen McTigue, M.D., M.P.H., G. Michael Felker, M.D., M.H.S., Adit A. Ginde, M.D., M.P.H., Sarah E. Dunsmore, Ph.D., Stacey J. Adam, Ph.D., Allison DeLong, B.S., George Hanna, M.D., April Remaly, B.A., Florence Thicklin, Rhonda Wilder, M.S., Sybil Wilson, R.N., Elizabeth Shenkman, Ph.D., and Susanna Naggie, M.D., M.H.S., for the ACTIV-6 Study Group and Investigators

Abstract

BACKGROUND

The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear.

METHODS

We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 μg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28.

RESULTS

Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups.

CONCLUSIONS

Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530. opens in new tab.)

13/07/2023 Articles
Real-life comparison of mortality in non-hospitalised patients with SA...

Real-life comparison of mortality in non-hospitalised patients with SARS-CoV-2 infection at risk for clinical progression treated with molnupiravir or nirmatrevir plus ritonavir during the Omicron era in Italy: a nationwide, cohort study

THE LANCET

Authors
Carlo Torti,a,∗ Pier Paolo Olimpieri,b,c Paolo Bonfanti,d Carlo Tascini,e Simone Celant,b Danilo Tacconi,f Emanuele Nicastri,g Evelina Tacconelli,h Bruno Cacopardo,i Alessandro Perrella,j Giovanni Battista Buccoliero,k Giustino Parruti,l Matteo Bassetti,m,n Carlo Biagetti,o Andrea Giacometti,p Elke Maria Erne,q Maria Frontuto,r Massimiliano Lanzafame,s Summa Valentina,b Alessandra Spagnoli,c Annarita Vestri,c Giovanni Di Perri,t Pierluigi Russo,b,u and Giorgio Palù

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10/07/2023 Original Investigation
Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospita...

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia

JAMA

Authors
Jane A. O’Halloran, MD, PhD; Emily R. Ko, MD, PhD; Kevin J. Anstrom, PhD; Eyal Kedar, MD; Matthew W. McCarthy, MD; Reynold A. Panettieri Jr, MD; Martin Maillo, MD; Patricia Segura Nunez, MD; Anne M. Lachiewicz, MD; Cynthia Gonzalez, MS; P. Brian Smith, MD, MPH, MHS; Sabina Mendivil-Tuchia de Tai, MD; Akram Khan, MD; Alfredo J. Mena Lora, MD; Matthias Salathe, MD; Gerardo Capo, MD; Daniel Rodríguez Gonzalez, MD; Thomas F. Patterson, MD; Christopher Palma, MD, ScM; Horacio Ariza, MD; Maria Patelli Lima, MD; John Blamoun, MD; Esteban C. Nannini, MD; Eduardo Sprinz, MD; Analia Mykietiuk, MD; Radica Alicic, MSc, MD; Adriana M. Rauseo, MD; Cameron R. Wolfe, MBBS, MPH; Britta Witting; Jennifer P. Wang, MD; Luis Parra-Rodriguez, MD; Tatyana Der, MD, MHSc; Kate Willsey, BS; Jun Wen, MS; Adam Silverstein, MS; Sean M. O’Brien, PhD; Hussein R. Al-Khalidi, PhD; Michael A. Maldonado, MD; Richard Melsheimer; William G. Ferguson, PhD; Steven E. McNulty, MS; Pearl Zakroysky, MPH; Susan Halabi, PhD; Daniel K. Benjamin Jr, MD, MPH, PhD; Sandra Butler, PhD; Jane C. Atkinson, DDS; Stacey J. Adam, PhD; Soju Chang, MD, MPH; Lisa LaVange, PhD; Michael Proschan, PhD; Samuel A. Bozzette, MD, PhD; William G. Powderly, MD; for the ACTIV-1 IM Study Group Members

Abstract
Importance Immune dysregulation contributes to poorer outcomes in COVID-19.

Objective To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.

Design, Setting, and Participants Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021.

Interventions Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day).

Main Outcomes and Measures The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale.

Results Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies.

Conclusions and Relevance Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.

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01/04/2023 Viewpoint
Effectiveness assessment of non-pharmaceutical interventions: lessons ...

Effectiveness assessment of non-pharmaceutical interventions: lessons learned from the COVID-19 pandemic

THE LANCET

Authors
Adrian Lison*, Nicolas Banholzer*, Mrinank Sharma, Sören Mindermann , H Juliette T Unwin, Swapnil Mishra, Tanja Stadler, Samir Bhatt, Neil M Ferguson, Jan Brauner, Werner Vach

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21/03/2023 Original Investigation
Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patient...

Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19

JAMA

Authors
Ewan C. Goligher, MD, PhD; Patrick R. Lawler, MD, MPH; Thomas P. Jensen, MS; Victor Talisa, PhD; Lindsay R. Berry, PhD; Elizabeth Lorenzi, PhD; Bryan J. McVerry, MD; Chung-Chou Ho Chang, PhD; Eric Leifer, PhD; Charlotte Bradbury, MD, PhD; Jeffrey Berger, MD; Beverly J. Hunt, MD, PhD; Lana A. Castellucci, MD; Lucy Z. Kornblith, MD; Anthony C. Gordon, MD; Colin McArthur, MD; Steven Webb, MD; Judith Hochman, MD; Matthew D. Neal, MD; Ryan Zarychanski, MD, MSc; Scott Berry, PhD; Derek C. Angus

Abstract
Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making.

Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE.

Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial.

Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis.

Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival.

Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline.

Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs.

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15/03/2023 Articles
Effectiveness of nirmatrelvir–ritonavir in preventing hospital admissi...

Effectiveness of nirmatrelvir–ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system

THE LANCET

Authors
Joseph A Lewnard, John M McLaughlin, Debbie Malden, Vennis Hong, Laura Puzniak, Bradley K Ackerson, Bruno J Lewin, Jeniffer S Kim, Sally F Shaw, Harpreet Takhar, Luis Jodar, Sara Y Tartof

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21/02/2023 Highlights
Early treatment for COVID-19

NATURE

Authors
Andrea Du Toit

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09/02/2023 Articles
Early Treatment with Pegylated Interferon Lambda for Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
G. Reis, E.A.S. Moreira Silva, D.C. Medeiros Silva, L. Thabane, V.H.S. Campos, T.S. Ferreira, C.V.Q. Santos, A.M.R. Nogueira, A.P.F.G. Almeida, L.C.M. Savassi, A.D. Figueiredo-Neto, A.C.F. Dias, A.M. Freire Júnior, C. Bitarães, A. C. Milagres, E.D. Callegari, M.I.C. Simplicio, L.B. Ribeiro, R. Oliveira, O. Harari, L.A. Wilson, J.I. Forrest, H. Ruton, S. Sprague, P. McKay, C.M. Guo, E.H. Limbrick-Oldfield, S. Kanters, G.H. Guyatt, C.R. Rayner, C. Kandel, M.J. Biondi, R. Kozak, B. Hansen, M.A. Zahoor, P. Arora, C. Hislop, I. Choong, J.J. Feld, E.J. Mills, J.S. Glenn

Abstract
BACKGROUND
The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear.

METHODS

We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 μg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization.

RESULTS
A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19–related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups.

CONCLUSIONS
Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424. opens in new tab.)

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09/02/2023 Articles
Early Treatment with Pegylated Interferon Lambda for Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
G. Reis, E.A.S. Moreira Silva, D.C. Medeiros Silva, L. Thabane, V.H.S. Campos, T.S. Ferreira, C.V.Q. Santos, A.M.R. Nogueira, A.P.F.G. Almeida, L.C.M. Savassi, A.D. Figueiredo-Neto, A.C.F. Dias, A.M. Freire Júnior, C. Bitarães, A. C. Milagres, E.D. Callegari, M.I.C. Simplicio, L.B. Ribeiro, R. Oliveira, O. Harari, L.A. Wilson, J.I. Forrest, H. Ruton, S. Sprague, P. McKay, C.M. Guo, E.H. Limbrick-Oldfield, S. Kanters, G.H. Guyatt, C.R. Rayner, C. Kandel, M.J. Biondi, R. Kozak, B. Hansen, M.A. Zahoor, P. Arora, C. Hislop, I. Choong, J.J. Feld, E.J. Mills, J.S. Glenn

Abstract
BACKGROUND
The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear.

METHODS

We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 μg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization.

RESULTS
A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19–related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups.

CONCLUSIONS
Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424. opens in new tab.)

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31/01/2023 Articles
Antimicrobial resistance in patients with COVID-19: a systematic revie...

Antimicrobial resistance in patients with COVID-19: a systematic review and meta-analysis

THE LANCET

Authors
Bradley J Langford, Miranda So, Marina Simeonova, Valerie Leung, Jennifer Lo, Tiffany Kan, Sumit Raybardhan, Mia E Sapin, Kwadwo Mponponsuo, Ashley Farrell, Elizabeth Leung, Jean-Paul R Soucy, Alessandro Cassini, Derek MacFadden, Nick Daneman, Silvia Bertagnolio

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27/01/2023 Comment
Too many antibiotics for patients with COVID-19 despite low bacterial ...

Too many antibiotics for patients with COVID-19 despite low bacterial infections

THE LANCET

Authors
Daniele Roberto Giacobbe, Matteo Bassetti

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01/09/2022 Articles
Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Ronen Arbel, Ph.D., Yael Wolff Sagy, Ph.D., Moshe Hoshen, Ph.D., Erez Battat, M.B.A., Gil Lavie, M.D., Ruslan Sergienko, M.A., Michael Friger, Ph.D., Jacob G. Waxman, M.D., Noa Dagan, M.D., Ran Balicer, M.D., Yatir Ben-Shlomo, B.Sc., Alon Peretz, M.D., Shlomit Yaron, M.D., Danielle Serby, M.Sc., Ariel Hammerman, Ph.D., Doron Netzer,

Abstract
BACKGROUND
The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited.

METHODS
We obtained data for all members of Clalit Health Services who were 40 years of age or older at the start of the study period and were assessed as being eligible to receive nirmatrelvir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of nirmatrelvir treatment with hospitalization and death due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and previous SARS-CoV-2 immunity status.

RESULTS
A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75).

CONCLUSIONS
Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.

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18/08/2022 Articles
Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-1...

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
C.T. Bramante, J.D. Huling, C.J. Tignanelli, J.B. Buse, D.M. Liebovitz, J.M. Nicklas, K. Cohen, M.A. Puskarich, H.K. Belani, J.L. Proper, L.K. Siegel, N.R. Klatt, D.J. Odde, D.G. Luke, B. Anderson, A.B. Karger, N.E. Ingraham, K.M. Hartman, V. Rao, A.A. Hagen, B. Patel, S.L. Fenno, N. Avula, N.V. Reddy, S.M. Erickson, S. Lindberg, R. Fricton, S. Lee, A. Zaman, H.G. Saveraid, W.J. Tordsen, M.F. Pullen, M. Biros, N.E. Sherwood, J.L. Thompson, D.R. Boulware, and T.A. Murray, for the COVID-OUT Trial Team

Abstract
BACKGROUND
Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.

METHODS

In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs — metformin, ivermectin, and fluvoxamine — in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.

RESULTS
A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P=0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P=0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P=0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine.

CONCLUSIONS
None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194. opens in new tab.)

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20/04/2022 Articles
Intramuscular AZD7442 (Tixagevimab– Cilgavimab) for Prevention of Covi...

Intramuscular AZD7442 (Tixagevimab– Cilgavimab) for Prevention of Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
M.J. Levin, A. Ustianowski, S. De Wit, O. Launay, M. Avila, A. Templeton, Y. Yuan, S. Seegobin, A. Ellery, D.J. Levinson, P. Ambery, R.H. Arends, R. Beavon, K. Dey, P. Garbes, E.J. Kelly, G.C.K.W. Koh, K.A. Near, K.W. Padilla, K. Psachoulia, A. Sharbaugh, K. Streicher, M.N. Pangalos, M.T. Esser

Abstract

BACKGROUND

The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.

METHODS

In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase–polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.

RESULTS

A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group.

CONCLUSIONS

A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725. opens in new tab.)

09/03/2022 Correspondence
Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Rebecca Rockett, Kerri Basile, Winkie Fong, Jessica Johnson-Mackinnon, Alicia Arnott, Shona Chandra, Mailie Gall, Jenny Draper, Elena Martinez, Eby M. Sim, Clement Lee, Christine Ngo, Marc Ramsperger, Andrew N. Ginn, Qinning Wang, Michael Fennell, Danny Ko, Nicky Gilroy, Matthew V.N. O’Sullivan, Sharon C.-A. Chen, Jen Kok, Dominic E. Dwyer, Vitali Sintchenko

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09/03/2022 PERSPECTIVE
Once Viewed as a Promising COVID-19 Treatment, Convalescent Plasma Fal...

Once Viewed as a Promising COVID-19 Treatment, Convalescent Plasma Falls Out of Favor

JAMA

Authors
RITA RUBIN

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09/03/2022 Correspondence
Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvarian...

Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Emi Takashita, Noriko Kinoshita, Seiya Yamayoshi, Yuko Sakai-Tagawa, Seiichiro Fujisaki, Mutsumi Ito, Kiyoko Iwatsuki-Horimoto, Peter Halfmann, Shinji Watanabe, Kenji Maeda, Masaki Imai, Hiroaki Mitsu Norio Ohmagari, Makoto Takeda, Hideki Hasegawa, Yoshihiro Kawaoka

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03/03/2022 News
Covid-19: Anti-inflammatory treatment baricitinib reduces deaths in pa...

Covid-19: Anti-inflammatory treatment baricitinib reduces deaths in patients admitted to hospital, finds trial

THE BMJ

Authors
ELISABETH MAHASE

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31/01/2022 Research
Prone positioning of patients with moderate hypoxaemia due to covid-19...

Prone positioning of patients with moderate hypoxaemia due to covid-19: multicentre pragmatic randomised trial (COVID-PRONE)

THE BMJ

Authors
Michael Fralick, Michael Colacci, Laveena Munshi, Kevin Venus, Lee Fidler, Haseena Hussein, Karen Britto, Rob Fowler, Bruno R da Costa, Irfan Dhalla, Richard Dunbar-Yaffe, Leora Branfield Day, Thomas E MacMillan, Jonathan Zipursky, Travis Carpenter, Terence Tang, Amanda Cooke, Rachel Hensel, Melissa Bregger, Alexis Gordon, Erin Worndl, Stephanie Go, Keren Mandelzweig, Lana A Castellucci, Daniel Tamming, Fahad Razak, Amol A Verma

Abstract
Objectives To assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients admitted to hospital with covid-19.

Design Multicentre pragmatic randomised clinical trial.

Setting 15 hospitals in Canada and the United States from May 2020 until May 2021.

Participants Eligible patients had a laboratory confirmed or a clinically highly suspected diagnosis of covid-19, needed supplemental oxygen (up to 50% fraction of inspired oxygen), and were able to independently lie prone with verbal instruction. Of the 570 patients who were assessed for eligibility, 257 were randomised and 248 were included in the analysis.

Intervention Patients were randomised 1:1 to prone positioning (that is, instructing a patient to lie on their stomach while they are in bed) or standard of care (that is, no instruction to adopt prone position).

Main outcome measures The primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as needing at least 60% fraction of inspired oxygen for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to fraction of inspired oxygen.

Results The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomisation was 1 day, the median age of patients was 56 (interquartile range 45-65) years, 89 (36%) patients were female, and 222 (90%) were receiving oxygen via nasal prongs at the time of randomisation. The median time spent prone in the first 72 hours was 6 (1.5-12.8) hours in total for the prone arm compared with 0 (0-2) hours in the control arm. The risk of the primary outcome was similar between the prone group (18 (14%) events) and the standard care group (17 (14%) events) (odds ratio 0.92, 95% confidence interval 0.44 to 1.92). The change in the ratio of oxygen saturation to fraction of inspired oxygen after 72 hours was similar for patients randomised to prone positioning and standard of care.

Conclusion Among non-critically ill patients with hypoxaemia who were admitted to hospital with covid-19, a multifaceted intervention to increase prone positioning did not improve outcomes. However, wide confidence intervals preclude definitively ruling out benefit or harm. Adherence to prone positioning was poor, despite multiple efforts to increase it. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning.

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24/01/2022 Original Investigation
Effect of Noninvasive Respiratory Strategies on Intubation or Mortalit...

Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19 The RECOVERY-RS Randomized Clinical Trial

JAMA

Authors
Gavin D. Perkins, MD; Chen Ji, PhD; Bronwen A. Connolly, PhD; Keith Couper, PhD; Ranjit Lall, PhD; J. Kenneth Baillie, PhD; Judy M. Bradley, PhD; Paul Dark, PhD; Chirag Dave, MD; Anthony De Soyza, PhD; Anna V. Dennis, MBBS; Anne Devrell, BPhil; Sara Fairbairn, MB, BCh; Hakim Ghani, MSc; Ellen A. Gorman, MB, BCh; Christopher A. Green, DPhil; Nicholas Hart, PhD; Siew Wan Hee, PhD; Zoe Kimbley, MB, ChB; Shyam Madathil, MD; Nicola McGowan, MRes; Benjamin Messer, MA; Jay Naisbitt, MB, ChB; Chloe Norman, PGCE; Dhruv Parekh, PhD; Emma M. Parkin, MSc; Jaimin Patel, PhD; Scott E. Regan, BA; Clare Ross, MBBS; Anthony J. Rostron, PhD; Mohammad Saim, MBBS; Anita K. Simonds, MD; Emma Skilton, BSc; Nigel Stallard, PhD; Michael Steiner, MD; Rama Vancheeswaran, PhD; Joyce Yeung, PhD; Daniel F. McAuley, MD

Abstract
Importance Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies.

Objective To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19–related acute hypoxemic respiratory failure.

Design, Setting, and Participants A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19–related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021.

Interventions Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475).

Main Outcomes and Measures The primary outcome was a composite of tracheal intubation or mortality within 30 days.

Results The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, −8% [95% CI, −15% to −1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, −1% [95% CI, −8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group.

Conclusions and Relevance Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings.

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24/01/2022 Editorial
Defining Optimal Respiratory Support for Patients With COVID-19

JAMA

Authors
Fernando G. Zampieri, Juliana C. Ferreira

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24/01/2022 Original Investigation
Clinical Outcomes Among Patients With 1-Year Survival Following Intens...

Clinical Outcomes Among Patients With 1-Year Survival Following Intensive Care Unit Treatment for COVID-19

JAMA

Authors
Hidde Heesakkers, Johannes G. van der Hoeven, Stijn Corsten, Inge Janssen, Esther Ewalds, Koen S. Simons, Brigitte Westerhof, Thijs C. D. Rettig, Crétien Jacobs; Susanne van Santen, Arjen J. C. Slooter, Margaretha C. E. van der Woude, Mark van den Boogaard, Marieke Zegers

Abstract
Importance One-year outcomes in patients who have had COVID-19 and who received treatment in the intensive care unit (ICU) are unknown.

Objective To assess the occurrence of physical, mental, and cognitive symptoms among patients with COVID-19 at 1 year after ICU treatment.

Design, Setting, and Participants An exploratory prospective multicenter cohort study conducted in ICUs of 11 Dutch hospitals. Patients (N = 452) with COVID-19, aged 16 years and older, and alive after hospital discharge following admission to 1 of the 11 ICUs during the first COVID-19 surge (March 1, 2020, until July 1, 2020) were eligible for inclusion. Patients were followed up for 1 year, and the date of final follow-up was June 16, 2021.

Exposures Patients with COVID-19 who received ICU treatment and survived 1 year after ICU admission.

Main Outcomes and Measures The main outcomes were self-reported occurrence of physical symptoms (frailty [Clinical Frailty Scale score ≥5], fatigue [Checklist Individual Strength—fatigue subscale score ≥27], physical problems), mental symptoms (anxiety [Hospital Anxiety and Depression {HADS} subscale score ≥8], depression [HADS subscale score ≥8], posttraumatic stress disorder [mean Impact of Event Scale score ≥1.75]), and cognitive symptoms (Cognitive Failure Questionnaire—14 score ≥43) 1 year after ICU treatment and measured with validated questionnaires.

Results Of the 452 eligible patients, 301 (66.8%) patients could be included, and 246 (81.5%) patients (mean [SD] age, 61.2 [9.3] years; 176 men [71.5%]; median ICU stay, 18 days [IQR, 11 to 32]) completed the 1-year follow-up questionnaires. At 1 year after ICU treatment for COVID-19, physical symptoms were reported by 182 of 245 patients (74.3% [95% CI, 68.3% to 79.6%]), mental symptoms were reported by 64 of 244 patients (26.2% [95% CI, 20.8% to 32.2%]), and cognitive symptoms were reported by 39 of 241 patients (16.2% [95% CI, 11.8% to 21.5%]). The most frequently reported new physical problems were weakened condition (95/244 patients [38.9%]), joint stiffness (64/243 patients [26.3%]) joint pain (62/243 patients [25.5%]), muscle weakness (60/242 patients [24.8%]) and myalgia (52/244 patients [21.3%]).

Conclusions and Relevance In this exploratory study of patients in 11 Dutch hospitals who survived 1 year following ICU treatment for COVID-19, physical, mental, or cognitive symptoms were frequently reported.

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17/01/2022 Research
Healthcare use in 700000 children and adolescents for six months after...

Healthcare use in 700000 children and adolescents for six months after covid-19: before and after register based cohort study

THE BMJ

Authors
Karin Magnusson, Katrine Damgaard Skyrud, Pål Suren, Margrethe Greve-Isdahl, Ketil Størdal, Doris Tove Kristoffersen, Kjetil Telle

Abstract
Objectives To explore whether and for how long use of healthcare services is increased among children and adolescents after covid-19.

Design Before and after register based study.

Setting General population of Norway.

Participants Norwegians aged 1-19 years (n=706 885) who were tested for SARS-CoV-2 from 1 August 2020 to 1 February 2021 (n=10 279 positive, n=275 859 negative) or not tested (n=420 747) and were not admitted to hospital, by age groups 1-5, 6-15, and 16-19 years.

Main outcome measures Monthly percentages of all cause and cause specific healthcare use in primary care (general practitioner, emergency ward) and specialist care (outpatient, inpatient) from six months before to about six months after the week of being tested for SARS-CoV-2, using a difference-in-differences approach.

Results A substantial short term relative increase in primary care use was observed for participants during the first month after a positive SARS-CoV-2 test result compared with those who tested negative (age 1-5 years: 339%, 95% confidence interval 308% to 369%; 6-15 years: 471%, 450% to 491%; 16-19 years: 401%, 380% to 422%). Use of primary care for the younger age groups was still increased at two months (1-5 years: 22%, 4% to 40%; 6-15 years: 14%, 2% to 26%) and three months (1-5 years: 26%, 7% to 46%, 6-15 years: 15%, 3% to 28%), but not for the oldest group (16-19 years: 11%, −2% to 24% and 6%, −7% to 19%, respectively). Children aged 1-5 years who tested positive also showed a minor long term (≤6 months) relative increase in primary care use (13%, −0% to 26%) that was not observed for the older age groups, compared with same aged children who tested negative. Results were similar yet the age differences less pronounced compared with untested controls. For all age groups, the increase in primary care visits was due to respiratory and general or unspecified conditions. No increased use of specialist care was observed.

Conclusion Covid-19 among children and adolescents was found to have limited impact on healthcare services in Norway. Preschool aged children might take longer to recover (3-6 months) than primary or secondary school students (1-3 months), usually because of respiratory conditions.

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21/12/2021 World Review
The European clinical research response to optimise treatment of patie...

The European clinical research response to optimise treatment of patients with COVID-19: lessons learned, future perspective, and recommendations

THE LANCET

Authors
Herman Goossens, Lennie Derde, Peter Horby, Marc Bonten

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17/11/2021 Articles
Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a r...

Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

THE LANCET

Authors
RECOVERY Collaborative Group

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15/11/2021 Original Investigation
Mortality Risk Among Patients With COVID-19 Prescribed Selective Serot...

Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants

JAMA

Authors
Tomiko Oskotsky; Ivana Marić; Alice Tang, Boris Oskotsky; Ronald J. Wong; Nima Aghaeepour, Marina Sirota, David K. Stevenson

Importance  Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)—specifically fluoxetine hydrochloride and fluvoxamine maleate—with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size.

Objective  To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs).

Design, Setting, and Participants  This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US.

Exposures  Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine).

Main Outcomes and Measures  Death.

Results  A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06).

Conclusions and Relevance  These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.

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27/10/2021 Articles
Effect of early treatment with fluvoxamine on risk of emergency care a...

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial

THE LANCET

Authors
Gilmar Reis, Eduardo Augusto dos Santos Moreira-Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Aline Cruz Milagres, Thiago Santiago Ferreira, Castilho Vitor Quirino dos Santos, Vitoria Helena de Souza Campos, Ana Maria Ribeiro Nogueira, Ana Paula Figueiredo Guimaraes de Almeida, Eduardo Diniz Callegari, Adhemar Dias de Figueiredo Neto, Leonardo Cançado Monteiro Savassi, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, Rosemary Oliveira, Ofir Harari, Jamie I Forrest, Hinda Ruton, Sheila Sprague, Paula McKay, Alla V Glushchenko, Craig R Rayner, Eric J Lenze, Angela M Reiersen, Gordon H Guyatt, Edward J Mills, for the TOGETHER investigators

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14/10/2021 Letter
Administration of Monoclonal Antibody for COVID-19 in Patient Homes

JAMA

Authors
Anurag N. Malani, Beth LaVasseur, Jason Fair, Robert Domeier, Rita Vershum, Robin Fowler, Curtis D. Collins

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23/09/2021 Research
Antibody and cellular therapies for treatment of covid-19: a living sy...

Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis

THE BMJ

Authors
AA.VV.

Abstract
Objective To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19).

Design Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data.

Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021).

Study selection Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate.

Methods After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm.

Results As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) −4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD −4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD −3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD −4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative.

Conclusion In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.

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24/08/2021 Articles
Early Convalescent Plasma for High-Risk Outpatients with Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
F.K. Korley, V. Durkalski-Mauldin, S.D. Yeatts, K. Schulman, R.D. Davenport, L.J. Dumont, N. El Kassar, L.D. Foster, J.M. Hah, S. Jaiswal, A. Kaplan, E. Lowell, J.F. McDyer, J. Quinn, D.J. Triulzi, C. Van Huysen, V.L.W. Stevenson, K. Yadav, C.W. Jones, B. Kea, A. Burnett, J.C. Reynolds, C.F. Greineder, N.L. Haas, D.G. Beiser, R. Silbergleit, W. Barsan, C.W. Callaway

Abstract

BACKGROUND

Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19.

METHODS

In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause.

RESULTS

A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, −6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups.

CONCLUSIONS

The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767. opens in new tab.)

10/08/2021 Reviews
Clinical Characteristics and Pharmacological Management of COVID-19 Va...

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine–Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis A Review

JAMA

Authors
John G. Rizk, Aashish Gupta, Partha Sardar, Brandon Michael Henry, John C. Lewin, Giuseppe Lippi, Carl J. Lavie

Abstract
Importance The COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST.

Observations VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk.

Conclusions and Relevance Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

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23/07/2021 Original Paper
Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
M. Dougan, A. Nirula, M. Azizad, B. Mocherla, R.L. Gottlieb, P. Chen, C. Hebert, R. Perry, J. Boscia, B. Heller, J. Morris, C. Crystal, A. Igbinadolor, G. Huhn, J. Cardona, I. Shawa, P. Kumar, A.C. Adams, J. Van Naarden, K.L. Custer, M. Durante, G. Oakley, A.E. Schade, T.R. Holzer, P.J. Ebert, R.E. Higgs, N.L. Kallewaard, J. Sabo, D.R. Patel, M.C. Dabora, P. Klekotka, L. Shen, D.M. Skovronsky

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07/07/2021 Articles
Informing selection of drugs for COVID‐19 treatment through adverse ev...

Informing selection of drugs for COVID‐19 treatment through adverse events analysis

NATURE

Authors
Wenjing Guo, Bohu Pan, Sugunadevi Sakkiah, Zuowei Ji, Gokhan Yavas, Yanhui Lu, Takashi E. Komatsu, Madhu Lal-Nag, Weida Tong, Tucker A. Patterson, Huixiao Hong

Abstract
Coronavirus disease 2019 (COVID-19) is an ongoing pandemic and there is an urgent need for safe and effective drugs for COVID-19 treatment. Since developing a new drug is time consuming, many approved or investigational drugs have been repurposed for COVID-19 treatment in clinical trials. Therefore, selection of safe drugs for COVID-19 patients is vital for combating this pandemic. Our goal was to evaluate the safety concerns of drugs by analyzing adverse events reported in post-market surveillance. We collected 296 drugs that have been evaluated in clinical trials for COVID-19 and identified 28,597,464 associated adverse events at the system organ classes (SOCs) level in the FDA adverse events report systems (FAERS). We calculated Z-scores of SOCs that statistically quantify the relative frequency of adverse events of drugs in FAERS to quantitatively measure safety concerns for the drugs. Analyzing the Z-scores revealed that these drugs are associated with different significantly frequent adverse events. Our results suggest that this safety concern metric may serve as a tool to inform selection of drugs with favorable safety profiles for COVID-19 patients in clinical practices. Caution is advised when administering drugs with high Z-scores to patients who are vulnerable to associated adverse events.

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07/06/2021 Articles
Mask related acne (“maskne”) and other facial dermatoses

THE BMJ

Authors
Emily Rudd, Sarah Walsh

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03/06/2021 Articles
Drug repurposing screens identify chemical entities for the developmen...

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions

NATURE

Authors
Malina A. Bakowski, Nathan Beutler, Karen C. Wolff, Melanie G. Kirkpatrick, Emily Chen, Tu-Trinh H. Nguyen, Laura Riva, Namir Shaabani, Mara Parren, James Ricketts, Anil K. Gupta, Kastin Pan, Peiting Kuo, MacKenzie Fuller, Elijah Garcia, John R. Teijaro, Linlin Yang, Debashis Sahoo, Victor Chi, Edward Huang, Natalia Vargas, Amanda J. Roberts, Soumita Das, Pradipta Ghosh, Ashley K. Woods, Sean B. Joseph, Mitchell V. Hull, Peter G. Schultz, Dennis R. Burton, Arnab K. Chatterjee, Case W. McNamara, Thomas F. Rogers

Abstract
The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

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14/05/2021 Articles
Convalescent plasma in patients admitted to hospital with COVID-19 (RE...

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

THE LANCET

Authors
RECOVERY Collaborative Group

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07/05/2021 Articles
Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in t...

Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study

THE LANCET

Authors
Thomas M Drake, Cameron J Fairfield, Riinu Pius, Stephen R Knight, Lisa Norman, Michelle Girvan, Hayley E Hardwick, Annemarie B Docherty, Ryan S Thwaites, Peter J M Openshaw, J Kenneth Baillie, Ewen M Harrison, Malcolm G Semple

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05/05/2021 Articles
A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19

MOLECULAR THERAPY

Authors
Adi Idris, Alicia Davis, Aroon Supramaniam, Dhruba Acharya, Gabrielle Kelly, Yaman Tayyar, Nic West, Ping Zhang, Christopher L.D. McMillan, Citradewi Soemardy, Roslyn Ray, Denis O’Meally, Tristan A. Scott, Nigel A.J. McMillan, Kevin V. Morris

Abstract
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans. Despite several emerging vaccines, there remains no verifiable therapeutic targeted specifically to the virus. Here we present a highly effective siRNA therapeutic against SARS-CoV-2 infection using a novel lipid nanoparticle delivery system. Multiple small-interfering RNAs (siRNAs) targeting highly conserved regions of the SARS-CoV-2 virus were screened and three candidate siRNAs emerged that effectively inhibit virus by greater than 90% either alone or in combination with one another. We simultaneously developed and screened two novel lipid nanoparticle formulations for the delivery of these candidate siRNA therapeutics to the lungs, an organ that incurs immense damage during SARS-CoV-2 infection. Encapsulation of siRNAs in these LNPs followed by in vivo injection demonstrated robust repression of virus in the lungs and a pronounced survival advantage to the treated mice. Our LNP-siRNA approaches are scalable and can be administered upon the first sign of SARS-CoV-2 infection in humans. We suggest that an siRNA-LNP therapeutic approach could prove highly useful in treating COVID-19 disease as an adjunctive therapy to current vaccine strategies.

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01/05/2021 Articles
Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a ...

Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns

CMI (CLINICAL MICROBIOLOGY AND INFECTION)

Authors
Anthony Touafchia, Haleh Bagheri, Didier Carrie, Genevieve Durrieu, Agnes Sommet, Laurent Chouchana, François Montastruc

Abstract
Objectives
In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia.
Methods
Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23 September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% CI.
Results
We found 302 cardiac effects including 94 bradycardia (31%) among the 2603 reports with remdesivir prescribed in COVID-19 patients. Most of the 94 reports were serious (75, 80%), and in 16 reports (17%) evolution was fatal. Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65; 95% CI 1.23–2.22). Consistent results were observed in other sensitivity analyses.
Discussion
This post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. This result is in line with the pharmacodynamic properties of remdesivir.

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01/05/2021 Articles
Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY):...

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

THE LANCET

Authors
RECOVERY Collaborative Group

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26/04/2021 Articles
Drug‐utilisation profles and COVID‐19

NATURE

Authors
Valentina Orlando, Enrico Coscioni, Ilaria Guarino, Sara Mucherino, Alessandro Perrella, Ugo Trama, Giuseppe Limongelli, Enrica Menditto

Abstract
Coronavirus disease 2019 (COVID-19) has substantially challenged healthcare systems worldwide. By investigating population characteristics and prescribing profiles, it is possible to generate hypotheses about the associations between specific drug-utilisation profiles and susceptibility to COVID-19 infection. A retrospective drug-utilisation study was carried out using routinely collected information from a healthcare database in Campania (Southern Italy). We aimed to discover the prevalence of drug utilisation (monotherapy and polytherapy) in COVID-19 versus non-COVID-19 patients in Campania (~ 6 million inhabitants). The study cohort comprised 1532 individuals who tested positive for COVID-19. Drugs were grouped according to the Anatomical Therapeutic Chemical (ATC) classification system. We noted higher prevalence rates of the use of drugs in the ATC categories C01, B01 and M04, which was probably linked to related comorbidities (i.e., cardiovascular and metabolic). Nevertheless, the prevalence of the use of drugs acting on the renin-angiotensin system, such as antihypertensive drugs, was not higher in COVID-19 patients than in non-COVID-19 patients after adjustments for age and sex. These results highlight the need for further case–control studies to define the effects of medications and comorbidities on susceptibility to and associated mortality from COVID-19.

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22/04/2021 Original Investigation
Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Rit...

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19 The TOGETHER Randomized Clinical Trial

JAMA

Authors
Gilmar Reis, Eduardo Augusto dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Gurmit Singh, Jay J. H. Park, Jamie I. Forrest, Ofir Harari, Castilho Vitor Quirino dos Santos; Ana Paula Figueiredo Guimarães de Almeida, Adhemar Dias de Figueiredo Neto, Leonardo Cançado Monteiro Savassi, Aline Cruz Milagres, Mauro Martins Teixeira, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, RN; Rosemary Oliveira; Edward J. Mills

Abstract
Importance Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed.

Objective To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting.

Design, Setting, and Participants This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020.

Interventions Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo.

Main Outcomes and Measures The primary outcomes were COVID-19–associated hospitalization and death assessed at 90 days after randomization. COVID-19–associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events.

Results Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19–associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group.

Conclusions and Relevance In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19–associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic.

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19/04/2021 News
Large clinical trial to study repurposed drugs to treat COVID-19 sympt...

Large clinical trial to study repurposed drugs to treat COVID-19 symptoms

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
NIH (NATIONAL INSTITUTES OF HEALTH)

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17/04/2021 Reviews
Management of COVID-19: current status and future prospects

ELSEVIER

Authors
Md Alamgir Kabir, Rajib Ahmed, Rasheduzzaman Chowdhury, Sheikh Muhammad Asher Iqbal, Ramasamy Paulmurugan, Utkan Demirci, Waseem Asghar

Abstract
COVID-19, a highly transmissible pandemic disease, is affecting millions of lives around the world. Severely infected patients show acute respiratory distress symptoms. Sustainable management strategies are required to save lives of the infected people and further preventing spread of the virus. Diagnosis, treatment, and vaccination development initiatives are already exhibited from the scientific community to fight against this virus. In this review, we primarily discuss the management strategies including prevention of spread, prophylaxis, vaccinations, and treatment for COVID-19. Further, analysis of vaccine development status and performance are also briefly discussed. Global socioeconomic impact of COVID-19 is also analyzed as part of this review.

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10/04/2021 Articles
A call to caution when hydroxychloroquine is given to elderly patients...

A call to caution when hydroxychloroquine is given to elderly patients with COVID-19

ELSEVIER

Authors
Julian J. Gabora,d, *, Andrea Kreidenweissa,k , Stefan Webera , Moaaz Salamad , Mihaly Sulyoka,d,g , Zita Sulyoka,n , Erik Koehnea,d , Meral Esena,k , Benno Kreuelsf , Parichehr Shamsrizif , Erwin Bieckerd , Benjamin Mordmüllera,l , Christoph P. Bergc , Stefano Fuscoc , Carsten Köhlera,k , Stefan Kubickae , Jens Leitleine , Marylyn Addof,k , Michael Ramharterb,f,k , Matthias Schwabh,m, Alfred Lennart Bissingera , Thirumalaisamy P. Velavana,i , Sanjeev Krishnaj , Peter G. Kremsnera,b,k

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01/04/2021 Original Investigation
Mortality and Readmission Rates Among Patients With COVID-19 After Dis...

Mortality and Readmission Rates Among Patients With COVID-19 After Discharge From Acute Care Setting With Supplemental Oxygen

JAMA

Authors
Josh Banerjee, Catherine P. Canamar, Christian Voyageur, Soodtida Tangpraphaphorn, Anabel Lemus, Charles Coffey Jr, Noah Wald- Dickler, Paul Holtom, Jan Shoenberger, Michael Bowdish, Hal F. Yee, Brad Spellberg

Abstract
Importance To optimize patient outcomes and preserve critical acute care access during the COVID-19 pandemic, the Los Angeles County Department of Health Services developed the SAFE @ HOME O2 Expected Practice (expected practice), enabling ambulatory oxygen management for COVID-19.

Objective To assess outcomes of patients with COVID-19 pneumonia discharged via the expected practice approach to home or quarantine housing with supplemental home oxygen.

Design, Setting, and Participants This retrospective cohort study included 621 adult patients with COVID-19 pneumonia who were discharged from 2 large urban public hospitals caring primarily for patients receiving Medicaid from March 20 to August 19, 2020. Patients were included in the analysis cohort if they received emergency or inpatient care for COVID-19 and were discharged with home oxygen.

Interventions Patients receiving at least 3 L per minute of oxygen, stable without other indication for inpatient care, were discharged from either emergency or inpatient encounters with home oxygen equipment, educational resources, and nursing telephone follow-up within 12 to 18 hours of discharge. Nurses provided continued telephone follow up as indicated, always with physician back-up.

Main Outcomes and Measures All-cause mortality and all-cause 30-day return admission.

Results A total of 621 patients with COVID-19 pneumonia (404 male [65.1%] and 217 female [34.9%]) were discharged with home oxygen. Median age of these patients was 51 years (interquartile range, 45-61 years), with 149 (24.0%) discharged from the emergency department and 472 (76%) discharged from inpatient encounters. The all-cause mortality rate was 1.3% (95% CI, 0.6%-2.5%) and the 30-day return hospital admission rate was 8.5% (95% CI, 6.2%-10.7%) with a median follow-up time of 26 days (interquartile range, 15-55 days). No deaths occurred in the ambulatory setting.

Conclusions and Relevance In this cohort study, patients with COVID-19 pneumonia discharged on home oxygen had low rates of mortality and return admission within 30 days of discharge. Ambulatory management of COVID-19 with home oxygen has an acceptable safety profile, and the expected practice approach may help optimize outcomes, by ensuring right care in the right place at the right time and preserving access to acute care during the COVID-19 pandemic.

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31/03/2021 Original Investigation
Association Between Renin-Angiotensin-Aldosterone System Inhibitors an...

Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19

JAMA

Authors
Ranu Baral, Vasiliki Tsampasian, Maciej Debski, Brendan Moran, Pankaj Garg, Allan Clark, Vassilios S. Vassiliou

Abstract
Importance The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes.

Objective To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19.

Data Sources PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020.

Study Selection The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs.

Data Extraction and Synthesis Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs.

Main Outcomes and Measures Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19.

Results A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101 949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P < .001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P = .01; aOR, 0.51 [95% CI, 0.32-0.84]; P = .008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P = .007; aOR, 0.55 [95% CI, 0.36-0.85]; P = .007).

Conclusions and Relevance In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to establish causality.

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30/03/2021 Articles
Role of phytoconstituents in the management of COVID-19

ELSEVIER

Authors
Amiya Das, Deepti Pandita, Gaurav Kumar Jain, Pallavi Agarwal, Ajmer Singh Grewal, Roop K. Khar, Viney Lather

Abstract
Background
COVID-19, a severe global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged as one of the most threatening transmissible disease. As a great threat to global public health, the development of treatment options has become vital, and a rush to find a cure has mobilized researchers globally from all areas.

Scope and approach
This review focuses on deciphering the potential of different secondary metabolites from medicinal plants as therapeutic options either as inhibitors of therapeutic targets of SARS-CoV-2 or as blockers of viral particles entry through host cell receptors. The use of medicinal plants containing specific phytomoieties could be seen in providing a safer and long-term solution for the population with lesser side effects.

Key Findings and Conclusions: Considering the high cost and time-consuming drug discovery process, therapeutic repositioning of existing drugs was explored as treatment option in COVID-19, however several molecules have been retracted as therapeutics either due to no positive outcomes or the severe side effects. These effects call for exploring the alternate treatment options which are therapeutically effective as well as safe. Keeping this in mind, phytopharmaceuticals derived from medicinal plants could be explored as important resources in the development of COVID-19 treatment, as their role in the past for treatment of viral diseases like HIV, MERS-CoV, and influenza has been well reported. Considering this fact, different phytoconstituents such as flavonoids, alkaloids, tannins and glycosides etc. Possessing antiviral properties against coronaviruses and possessing potential against SARS-CoV-2 have been reviewed in the present work.

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19/03/2021 Research
Drug treatments for covid-19: living systematic review and network met...

Drug treatments for covid-19: living systematic review and network meta-analysis

THE BMJ

Authors
Reed AC Siemieniuk, Jessica J Bartoszko, Long Ge, Dena Zeraatkar, Ariel Izcovich, Elena Kum, Hector Pardo-Hernandez, Anila Qasim, Juan Pablo Díaz Martinez, Bram Rochwerg, Francois Lamontagne, Mi Ah Han, Qin Liu, Arnav Agarwal, Thomas Agoritsas, Derek K Chu, Rachel Couban, Ellen Cusano, Andrea Darzi, Tahira Devji, Bo Fang, Carmen Fang, Signe Agnes Flottorp, Farid Foroutan, Maryam Ghadimi, Diane Heels-Ansdell, Kimia Honarmand, Liangying Hou, Xiaorong Hou, Quazi Ibrahim, Assem Khamis, Bonnie Lam, Mark Loeb, Maura Marcucci, Shelley L McLeod, Sharhzad Motaghi, Srinivas Murthy, Reem A Mustafa, John D Neary, Gabriel Rada, Irbaz Bin Riaz, Behnam Sadeghirad, Nigar Sekercioglu, Lulu Sheng, Ashwini Sreekanta, Charlotte Switzer, Britta Tendal, Lehana Thabane, George Tomlinson, Tari Turner, Per O Vandvik, Robin WM Vernooij, Andrés Viteri-García, Ying Wang, Liang Yao, Zhikang Ye, Gordon H Guyatt, Romina Brignardello-Petersen

Abstract
Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19).

Design Living systematic review and network meta-analysis.

Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis.

Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.

Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.

Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low.

Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain.

Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material.

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12/03/2021 News
COVID antibody treatments show promise for preventing severe disease

NATURE

Authors
Heidi Ledford

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10/03/2021 Articles
Neutralization of SARS-CoV-2 with IgG from COVID-19-convalescent plasm...

Neutralization of SARS-CoV-2 with IgG from COVID-19-convalescent plasma

NATURE

Authors
Kenji Maeda, Nobuyo Higashi-Kuwata, Noriko Kinoshita, Satoshi Kutsuna, Kiyoto Tsuchiya, Shin-ichiro Hattori, Kouki Matsuda, Yuki Takamatsu, Hiroyuki Gatanaga, Shinichi Oka, Haruhito Sugiyama, Norio Ohmagari, Hiroaki Mitsuya

Abstract
While there are various attempts to administer COVID-19-convalescent plasmas to SARS-CoV-2-infected patients, neither appropriate approach nor clinical utility has been established. We examined the presence and temporal changes of the neutralizing activity of IgG fractions from 43 COVID-19-convalescent plasmas using cell-based assays with multiple endpoints. IgG fractions from 27 cases (62.8%) had significant neutralizing activity and moderately to potently inhibited SARS-CoV-2 infection in cell-based assays; however, no detectable neutralizing activity was found in 16 cases (37.2%). Approximately half of the patients (~ 41%), who had significant neutralizing activity, lost the neutralization activity within ~ 1 month. Despite the rapid decline of neutralizing activity in plasmas, good amounts of SARS-CoV-2-S1-binding antibodies were persistently seen. The longer exposure of COVID-19 patients to greater amounts of SARS-CoV-2 elicits potent immune response to SARS-CoV-2, producing greater neutralization activity and SARS-CoV-2-S1-binding antibody amounts. The dilution of highly-neutralizing plasmas with poorly-neutralizing plasmas relatively readily reduced neutralizing activity. The presence of good amounts of SARS-CoV-2-S1-binding antibodies does not serve as a surrogate ensuring the presence of good neutralizing activity. In selecting good COVID-19-convalescent plasmas, quantification of neutralizing activity in each plasma sample before collection and use is required.

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04/03/2021 Articles
Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
A.C. Kalil, T.F. Patterson, A.K. Mehta, K.M. Tomashek, C.R. Wolfe, V. Ghazaryan, V.C. Marconi, G.M. Ruiz-Palacios, L. Hsieh, S. Kline, V. Tapson, N.M. Iovine, M.K. Jain, D.A. Sweeney, H.M. El Sahly, A.R. Branche, J. Regalado Pineda, D.C. Lye, U. Sandkovsky, A.F. Luetkemeyer, S.H. Cohen, R.W. Finberg, P.E.H. Jackson, B. Taiwo, C.I. Paules, H. Arguinchona, N. Erdmann, N. Ahuja, M. Frank, M. Oh, E.-S. Kim, S.Y. Tan, R.A. Mularski, H. Nielsen, P.O. Ponce, B.S. Taylor, L.A. Larson, N.G. Rouphael, Y. Saklawi, V.D. Cantos, E.R. Ko, J.J. Engemann, A.N. Amin, M. Watanabe, J. Billings, M.-C. Elie, R.T. Davey, T.H. Burgess, J. Ferreira, M. Green, M. Makowski, A. Cardoso, S. de Bono, T. Bonnett, M. Proschan, G.A. Deye, W. Dempsey, S.U. Nayak, L.E. Dodd, J.H. Beigel

Abstract
BACKGROUND
Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.

METHODS
We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.

RESULTS
A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P=0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3; P=0.03), as were new infections (5.9% vs. 11.2%; difference, −5.3 percentage points; 95% CI, −8.7 to −1.9; P=0.003).

CONCLUSIONS
Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579. opens in new tab.)

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26/02/2021 Original Investigation
Association of Convalescent Plasma Treatment With Clinical Outcomes in...

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19

JAMA

Authors
Perrine Janiaud, Cathrine Axfors, Andreas M. Schmitt, Viktoria Gloy, Fahim Ebrahimi, Matthias Hepprich, Emily R. Smith, Noah A. Haber, Nina Khanna, David Moher, Steven N. Goodman, John P. A. Ioannidis, Lars G. Hemkens

Abstract
Importance Convalescent plasma is a proposed treatment for COVID-19.

Objective To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).

Data Sources PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021.

Study Selection The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting.

Data Extraction and Synthesis Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance–weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.

Main Outcomes and Measures All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events.

Results A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was −1.21% (95% CI, −5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was −2.56% [95% CI, −13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences.

Conclusions and Relevance Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

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24/02/2021 Comment
COVID-19 drug practices risk antimicrobial resistance evolution

THE LANCET

Authors
Ebrahim Afshinnekoo, Chandrima Bhattacharya, Ana Burguete-García, Eduardo Castro-Nallar, Youping Deng, Christelle Desnues, Emmanuel Dias-Neto, Eran Elhaik, Gregorio Iraola, Soojin Jang, Paweł P Łabaj, Christopher E Mason, Niranjan Nagarajan, Michael Poulsen, Bharath Prithiviraj, Rania Siam, Tieliu Shi, Haruo Suzuki, Johannes Werner, Maria Mercedes Zambrano, Malay Bhattacharyya

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17/02/2021 Editorial
Vitamin D3 to Treat COVID-19 Different Disease, Same Answer

JAMA

Authors
David E. Leaf, Adit A. Ginde

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17/02/2021 Original Investigation
Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay ...

Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19 A Randomized Clinical Trial

JAMA

Authors
Igor H. Murai, Alan L. Fernandes, Lucas P. Sales, Ana J. Pinto, Karla F. Goessler, Camila S. C. Duran, Carla B. R. Silva, André S. Franco, Marina B. Macedo, Henrique H. H. Dalmolin, Janaina Baggio, Guilherme G. M. Balbi, Bruna Z. Reis, Leila Antonangelo, Valeria F. Caparbo, Bruno Gualano, Rosa M. R. Pereira

Abstract
Importance The efficacy of vitamin D3 supplementation in coronavirus disease 2019 (COVID-19) remains unclear.

Objective To investigate the effect of a single high dose of vitamin D3 on hospital length of stay in patients with COVID-19.

Design, Setting, and Participants This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020.

Interventions Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120).

Main Outcomes and Measures The primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein.

Results Of 240 randomized patients, 237 were included in the primary analysis (mean [SD] age, 56.2 [14.4] years; 104 [43.9%] women; mean [SD] baseline 25-hydroxyvitamin D level, 20.9 [9.2] ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D3 (7.0 [4.0-10.0] days) and placebo groups (7.0 [5.0-13.0] days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82-1.39]; P = .62). The difference between the vitamin D3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% [95% CI, –4.1% to 9.2%]; P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, –5.2% [95% CI, –15.1% to 4.7%]; P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, –6.8% [95% CI, –15.1% to 1.2%]; P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3 vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL [95% CI, 19.5-28.7]; P < .001). There were no adverse events, but an episode of vomiting was associated with the intervention.

Conclusions and Relevance Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19.

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16/02/2021 Original Investigation
Extremely potent human monoclonal antibodies from COVID-19 convalescen...

Extremely potent human monoclonal antibodies from COVID-19 convalescent patients

CELL

Authors
Emanuele Andreano, Emanuele Nicastri, Ida Paciello, Piero Pileri, Noemi Manganaro, Giulia Piccini, Alessandro Manenti, Elisa Pantano, Anna Kabanova, Marco Troisi, Fabiola Vacca, Dario Cardamone, Concetta De Santi, Jonathan L. Torres, Gabriel Ozorowski, Linda Benincasa, Hyesun Jang, Cecilia Di Genova, Lorenzo Depau, Jlenia Brunetti, Chiara Agrati, Maria Rosaria Capobianchi, Concetta Castilletti, Arianna Emiliozzi, Massimiliano Fabbiani, Francesca Montagnani, Luisa Bracci, Giuseppe Sautto, Ted M. Ross, Emanuele Montomoli, Nigel Temperton, Andrew B. Ward, Claudia Sala, Giuseppe Ippolito, Rino Rappuoli

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12/02/2021 Original Investigation
Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Ca...

Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection The COVID A to Z Randomized Clinical Trial

JAMA

Authors
Suma Thomas, Divyang Patel, Barbara Bittel, Kathy Wolski, Qiuqing Wang, Anirudh Kumar, Zachary J. Il’Giovine, Reena Mehra, Carla McWilliams, Steve E. Nissen, Milind Y. Desai

Abstract
Importance There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression.

Objective To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection.

Design, Setting, and Participants This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020.

Intervention Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care.

Outcomes The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements.

Results A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups.

Conclusions and Relevance In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care.

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12/02/2021 PERSPECTIVE
Single-domain antibodies make a difference

SCIENCE

Authors
Xavier Saelens, Bert Schepens

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11/02/2021 Research
Early initiation of prophylactic anticoagulation for prevention of cor...

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study

THE BMJ

Authors
Christopher T Rentsch, Joshua A Beckman, Laurie Tomlinson,Walid F Gellad, Charles Alcorn, Farah Kidwai-Khan, Melissa Skanderson, Evan Brittain, Joseph T King Jr, Yuk-Lam Ho, Svetlana Eden, Suman Kundu, Michael F Lann, Robert A Greevy Jr, P Michael Ho, Paul A Heidenreich, Daniel A Jacobson, Ian J Douglas, Janet P Tate, Stephen J W Evans, David Atkins, Amy C Justice, Matthew S Freiberg

Abstract
Objective To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States.

Design Observational cohort study.

Setting Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system.

Participants All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation.

Main outcome measures The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion.

Results Of 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses.

Conclusions Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.

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08/02/2021 News
Clinical trial in hospitalized COVID-19 patients evaluates long-acting...

Clinical trial in hospitalized COVID-19 patients evaluates long-acting antibody therapy

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
NIH (NATIONAL INSTITUTES OF HEALTH)

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05/02/2021 Articles
Peginterferon lambda for the treatment of outpatients with COVID-19: a...

Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial

THE LANCET

Authors
Jordan J Feld, Christopher Kandel, Mia J Biondi, Robert A Kozak, Muhammad Atif Zahoor,Camille Lemieux, Sergio M Borgia, Andrea K Boggild, Jeff Powis, Janine McCready, Darrell H S Tan, Tiffany Chan, Bryan Coburn, Deepali Kumar, Atul Humar, Adrienne Chan, Braden O’Neil, Seham Noureldin, Joshua Booth, Rachel Hong, David Smookler, Wesam Aleyadeh, Anjali Patel, Bethany Barber, Julia Casey, Ryan Hiebert, Henna Mistry, Ingrid Choong, Colin Hislop, Deanna M Santer, D Lorne Tyrrell, Jeffrey S Glenn, Adam J Gehring, Harry L A Janssen, Bettina E Hansen

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04/02/2021 Articles
Association between antidepressant use and reduced risk of intubation ...

Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study

NATURE

Authors
Nicolas Hoertel, Marina Sánchez-Rico, Raphaël Vernet, Nathanaël Beeker, Anne-Sophie Jannot, Antoine Neuraz, Elisa Salamanca, Nicolas Paris, Christel Daniel, Alexandre Gramfort, Guillaume Lemaitre, Mélodie Bernaux, Ali Bellamine, Cédric Lemogne, Guillaume Airagnes, Anita Burgun, Frédéric Limosin

Abstract
A prior meta-analysis showed that antidepressant use in major depressive disorder was associated with reduced plasma levels of several pro-inflammatory mediators, which have been associated with severe COVID-19. Recent studies also suggest that several antidepressants may inhibit acid sphingomyelinase activity, which may prevent the infection of epithelial cells with SARS-CoV-2, and that the SSRI fluoxetine may exert in-vitro antiviral effects on SARS-CoV-2. We examined the potential usefulness of antidepressant use in patients hospitalized for COVID-19 in an observational multicenter retrospective cohort study conducted at AP-HP Greater Paris University hospitals. Of 7230 adults hospitalized for COVID-19, 345 patients (4.8%) received an antidepressant within 48 h of hospital admission. The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received antidepressants and those who did not in time-to-event analyses adjusted for patient characteristics, clinical and biological markers of disease severity, and other psychotropic medications. The primary analysis was a multivariable Cox model with inverse probability weighting. This analysis showed a significant association between antidepressant use and reduced risk of intubation or death (HR, 0.56; 95% CI, 0.43–0.73, p < 0.001). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggest that this association was also significant for SSRI and non-SSRI antidepressants, and for fluoxetine, paroxetine, escitalopram, venlafaxine, and mirtazapine (all p < 0.05). These results suggest that antidepressant use could be associated with lower risk of death or intubation in patients hospitalized for COVID-19. Double-blind controlled randomized clinical trials of antidepressant medications for COVID-19 are needed.

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02/02/2021 Comment
Azithromycin, RECOVERY, and the power of large, simple trials

THE LANCET

Authors
Otavio Berwanger

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29/01/2021 Articles
Remdesivir in COVID-19 Patients with Impaired Renal Function

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY

Authors
Sanna Gevers, Jan Welink and Cees van Nieuwkoop

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27/01/2021 Editorial
Covid-19 controversies: the tocilizumab chapter

THE BMJ

Authors
Erin K McCreary, Nuala J Meyer

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25/01/2021 Articles
Broad and potent activity against SARS-like viruses by an engineered h...

Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

SCIENCE

Authors
C. Garrett Rappazzo, Longping V. Tse, Chengzi I. Kaku, Daniel Wrapp, Mrunal Sakharkar, Deli Huang, Laura M. Deveau, Thomas J. Yockachonis, Andrew S. Herbert, Michael B. Battles, Cecilia M. O’Brien, Michael E. Brown, James C. Geoghegan, Jonathan Belk, Linghang Peng, Linlin Yang, Yixuan Hou, Trevor D. Scobey, Dennis R. Burton, David Nemazee, John M. Dye, James E. Voss, Bronwyn M. Gunn, Jason S. McLellan, Ralph S. Baric, Lisa E. Gralinski, Laura M. Walker

Abstract
The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

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22/01/2021 Institutional Recommendations
Managing the long term effects of covid-19: summary of NICE, SIGN, and...

Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline

THE BMJ

Authors
Waqaar Shah, Toby Hillman, E Diane Playford, Lyth Hishmeh

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21/01/2021 Original Investigation
Effect of Bamlanivimab as Monotherapy or in Combination With Etesevima...

Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19 A Randomized Clinical Trial

JAMA

Authors
Robert L. Gottlieb, Ajay Nirula, Peter Chen, Joseph Boscia, Barry Heller, Jason Morris, Gregory Huhn, Jose Cardona, Bharat Mocherla, Valentina Stosor, Imad Shawa, Princy Kumar, Andrew C. Adams, Jacob Van Naarden, Kenneth L. Custer, Michael Durante, Gerard Oakley, Andrew E. Schade, Timothy R. Holzer, Philip J. Ebert, Richard E. Higgs, Nicole L. Kallewaard, Janelle Sabo, Dipak R. Patel, Paul Klekotka, Lei Shen, Daniel M. Skovronsky

Abstract
Importance Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.

Objective To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.

Design, Setting, and Participants The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020.

Interventions Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).

Main Outcomes and Measures The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19–related hospitalization, an emergency department [ED] visit, or death at day 29).

Results Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was –3.72 for 700 mg, –4.08 for 2800 mg, –3.49 for 7000 mg, –4.37 for combination treatment, and –3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, –0.35 to 0.52; P = .69) for 700 mg, –0.27 (95% CI, –0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, –0.13 to 0.76; P = .16) for 7000 mg, and –0.57 (95% CI, –1.00 to –0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19–related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment.

Conclusions and Relevance Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.

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21/01/2021 Articles
Baricitinib treatment resolves lower-airway macrophage inflammation an...

Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

CELL

Authors
Timothy N. Hoang, Maria Pino, Arun K. Boddapati, ..., Raymond F. Schinazi, Steven E. Bosinger, Mirko Paiardini

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21/01/2021 Articles
REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid...

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
D.M. Weinreich, S. Sivapalasingam, T. Norton, S. Ali, H. Gao, R. Bhore, B.J. Musser, Y. Soo, D. Rofail, J. Im, C. Perry, C. Pan, R. Hosain, A. Mahmood, J.D. Davis, K.C. Turner, A.T. Hooper, J.D. Hamilton, A. Baum, C.A. Kyratsous, Y. Kim, A. Cook, W. Kampman, A. Kohli, Y. Sachdeva, X. Graber, B. Kowal, T. DiCioccio, N. Stahl, L. Lipsich, N. Braunstein, G. Herman, G.D. Yancopoulos

Abstract
BACKGROUND
Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.

METHODS
In this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients.

RESULTS
Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.

CONCLUSIONS
In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629. opens in new tab.)

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20/01/2021 Research
Effect of tocilizumab on clinical outcomes at 15 days in patients with...

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

THE BMJ

Authors
Viviane C Veiga, João A G G Prats, Danielle L C Farias, Regis G Rosa, Leticia K Dourado, Fernando G Zampieri, Flávia R Machado, Renato D Lopes, Otavio Berwanger, Luciano C P Azevedo, Álvaro Avezum, Thiago C Lisboa, Salomón S O Rojas, Juliana C Coelho, Rodrigo T Leite, Júlio C Carvalho, Luis E C Andrade, Alex F Sandes, Maria C T Pintão, Claudio G Castro Jr, Sueli V Santos, Thiago M L de Almeida, André N Costa, Otávio C E Gebara, Flávio G Rezende de Freitas, Eduardo S Pacheco, David J B Machado, Josiane Martin, Fábio G Conceição, Suellen R R Siqueira, Lucas P Damiani, Luciana M Ishihara, Daniel Schneider, Denise de Souza, Alexandre B Cavalcanti, Phillip Scheinberg

Abstract
Objective To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).

Design Randomised, open label trial.

Setting Nine hospitals in Brazil, 8 May to 17 July 2020.

Participants Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.

Interventions Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).

Main outcome measure The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met.

Results A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab.

Conclusions In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.

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15/01/2021 News
COVID research updates: Two anti-inflammatory drugs prevent COVID deat...

COVID research updates: Two anti-inflammatory drugs prevent COVID deaths

NATURE

Authors
NATURE

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15/01/2021 News
RECOVERY trial closes recruitment to convalescent plasma treatment for...

RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19

RECOVERY (RANDOMISED EVALUATION OF COVID 19 THERAPY)

Authors
THE RECOVERY trial chief investigators

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13/01/2021 Articles
Convalescent Plasma Antibody Levels and the Risk of Death from Covid-1...

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
M.J. Joyner, R.E. Carter, J.W. Senefeld, S.A. Klassen, J.R. Mills, P.W. Johnson, E.S. Theel, C.C. Wiggins, K.A. Bruno, A.M. Klompas, E.R. Lesser, K.L. Kunze, M.A. Sexton, J.C. Diaz Soto, S.E. Baker, J.R.A. Shepherd, N. van Helmond, N.C. Verdun, P. Marks, C.M. van Buskirk, J.L. Winters, J.R. Stubbs, R.F. Rea, D.O. Hodge, V. Herasevich, E.R. Whelan, A.J. Clayburn, K.F. Larson, J.G. Ripoll, K.J. Andersen, M.R. Buras, M.N.P. Vogt, J.J. Dennis, R.J. Regimbal, P.R. Bauer, J.E. Blair, N.S. Paneth, D.L. Fairweather, R.S. Wright, A. Casadevall

Abstract
BACKGROUND
Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown.

METHODS
In a retrospective study based on a U.S. national registry, we determined the anti–SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti–SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis.

RESULTS
Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti–SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32).

CONCLUSIONS
Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti–SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360. opens in new tab.)

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08/01/2021 Articles
Returning to physical activity after covid-19

THE BMJ

Authors
D Salman

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08/01/2021 Comment
Long-term follow-up of recovered patients with COVID-19

THE LANCET

Authors
Monica Cortinovis, Norberto Perico, Giuseppe Remuzzi

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06/01/2021 Articles
Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Ad...

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
R. Libster, G. Pérez Marc, D. Wappner, S. Coviello, A. Bianchi, V. Braem, I. Esteban, M.T. Caballero, C. Wood, M. Berrueta, A. Rondan, G. Lescano, P. Cruz, Y. Ritou, V. Fernández Viña, D. Álvarez Paggi, S. Esperante, A. Ferreti, G. Ofman, Á. Ciganda, R. Rodriguez, J. Lantos, R. Valentini, N. Itcovici, A. Hintze, M.L. Oyarvide, C. Etchegaray, A. Neira, I. Name, J. Alfonso, R. López Castelo, G. Caruso, S. Rapelius, F. Alvez, F. Etchenique, F. Dimase, D. Alvarez, S.S. Aranda, C. Sánchez Yanotti, J. De Luca, S. Jares Baglivo, S. Laudanno, F. Nowogrodzki, R. Larrea, M. Silveyra, G. Leberzstein, A. Debonis, J. Molinos, M. González, E. Perez, N. Kreplak, S. Pastor Argüello, L. Gibbons, F. Althabe, E. Bergel, F.P. Polack

Abstract
BACKGROUND
Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

METHODS
We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

RESULTS
A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

CONCLUSIONS
Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163. opens in new tab.)

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28/12/2020 Articles
In silico discovery of antigenic proteins and epitopes of SARS‐CoV‐2 f...

In silico discovery of antigenic proteins and epitopes of SARS‐CoV‐2 for the development of a vaccine or a diagnostic approach for COVID‐19

NATURE

Authors
Hüseyin Can, Ahmet Efe Köseoğlu, Sedef Erkunt Alak, Mervenur Güvendi, Mert Döşkaya, Muhammet Karakavuk, Adnan Yüksel Gürüz, Cemal Ün

Abstract
In the genome of SARS-CoV-2, the 5′-terminus encodes a polyprotein, which is further cleaved into 15 non-structural proteins whereas the 3′ terminus encodes four structural proteins and eight accessory proteins. Among these 27 proteins, the present study aimed to discover likely antigenic proteins and epitopes to be used for the development of a vaccine or serodiagnostic assay using an in silico approach. For this purpose, after the full genome analysis of SARS-CoV-2 Wuhan isolate and variant proteins that are detected frequently, surface proteins including spike, envelope, and membrane proteins as well as proteins with signal peptide were determined as probable vaccine candidates whereas the remaining were considered as possible antigens to be used during the development of serodiagnostic assays. According to results obtained, among 27 proteins, 26 of them were predicted as probable antigen. In 26 proteins, spike protein was selected as the best vaccine candidate because of having a signal peptide, negative GRAVY value, one transmembrane helix, moderate aliphatic index, a big molecular weight, a long-estimated half-life, beta wrap motifs as well as having stable, soluble and non-allergic features. In addition, orf7a, orf8, and nsp-10 proteins with signal peptide were considered as potential vaccine candidates. Nucleocapsid protein and a highly antigenic GGDGKMKD epitope were identified as ideal antigens to be used in the development of serodiagnostic assays. Moreover, considering MHC-I alleles, highly antigenic KLNDLCFTNV and ITLCFTLKRK epitopes can be used to develop an epitope-based peptide vaccine.

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22/12/2020 News
NIH neuroscientists isolate promising mini antibodies against COVID-19...

NIH neuroscientists isolate promising mini antibodies against COVID-19 from a llama

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
Esparza, T.J. et al

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22/12/2020 Articles
A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covi...

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
ACTIV-3/TICO LY-CoV555 Study Group

Abstract
BACKGROUND
LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.

METHODS
In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.

RESULTS
On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P=0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P=0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).

CONCLUSIONS
Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978. opens in new tab.)

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17/12/2020 Articles
Renin–angiotensin system blockers and susceptibility to COVID-19: an i...

Renin–angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis

THE LANCET

Authors
Daniel R Morales, Mitchell M Conover, Seng Chan You, Nicole Pratt, Kristin Kostka, Talita Duarte-Salles, Sergio Fernández-Bertolín, Maria Aragón, Scott L DuVall, Kristine Lynch, Thomas Falconer, Kees van Bochove, Cynthia Sung, Michael E Matheny, Christophe G Lambert, Fredrik Nyberg, Thamir M Alshammari, Andrew E Williams, Rae Woong Park, James Weaver, Anthony G Sena, Martijn J Schuemie, Peter R Rijnbeek, Ross D Williams, Jennifer C E Lane, Albert Prats-Uribe, Lin Zhang, Carlos Areia, Harlan M Krumholz, Daniel Prieto-Alhambra, Patrick B Ryan, George Hripcsak, Marc A Suchard

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14/12/2020 Articles
Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a rand...

Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

MEDRXIV

Authors
Peter W Horby, Alistair Roddick, Enti Spata, Natalie Staplin, Jonathan R Emberson, Guilherme Pessoa-Amorim, Leon Peto, Mark Campbell, Christopher Brightling, Ben Prudon, David Chadwick, Andrew Ustianowski, Abdul Ashish, Stacy Todd, Bryan Yates, Robert Buttery, Stephen Scott, Diego Maseda, J Kenneth Baillie, Maya H Buch, Lucy C Chappell, Jeremy N Day, Saul N Faust, Thomas Jaki, Katie Jeffery, Edmund Juszczak, Wei Shen Lim, Alan Montgomery, Andrew Mumford, Kathryn Rowan, Guy Thwaites, Marion Mafham, Richard Haynes, Martin J Landray

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11/12/2020 Letter
An EUA for Bamlanivimab—A Monoclonal Antibody for COVID-19

JAMA

Authors
JAMA

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08/12/2020 Original Research
Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute...

Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection

ANNALS OF INTERNAL MEDICINE

Authors
Ruanne V. Barnabas, Elizabeth R. Brown, Anna Bershteyn, Helen C. Stankiewicz Karita, Christine Johnston, Lorna E. Thorpe, Angelica Kottkamp, Kathleen M. Neuzil, Miriam K. Laufer, Meagan Deming, Michael K. Paasche-Orlow, Patricia J. Kissinger, Alfred Luk, Kristopher Paolino, Raphael J. Landovitz, Risa Hoffman, Torin T. Schaafsma, Meighan L. Krows, Katherine K. Thomas, Susan Morrison, Harald S. Haugen, Lara Kidoguchi, Mark Wener, Alexander L. Greninger, Meei-Li Huang, Keith R. Jerome, Anna Wald, Connie Celum, Helen Y. Chu, Jared M. Baeten

Abstract
Background:
Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.

Objective:
To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.

Design:
Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961)

Setting:
National U.S. multicenter study.

Participants:
Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.

Intervention:
Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.

Measurements:
Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.

Results:
Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026).

Limitation:
The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.

Conclusion:
This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.

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03/12/2020 Comment
Metformin: an inexpensive and effective treatment in people with diabe...

Metformin: an inexpensive and effective treatment in people with diabetes and COVID-19?

THE LANCET

Authors
Angela Dardano, Stefano Del Prato

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03/12/2020 Letter
Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801...

Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets

NATURE

Authors
Robert M. Cox, Josef D. Wolf, Richard K. Plemper

Abstract
The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6,7,8,9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.

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03/12/2020 Articles
Caught on Camera: Neutralizing Antibodies Interacting with SARS-CoV-2

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
FRANCIS COLLINS

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03/12/2020 Press Release
Vitamina D nella prevenzione e nel trattamento del COVID-19: nuove evi...

Vitamina D nella prevenzione e nel trattamento del COVID-19: nuove evidenze

ACCADEMIA DI MEDICINA DI TORINO

Authors
GRUPPO DI LAVORO ACCADEMIA DI MEDICINA DI TORINO

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02/12/2020 Original Research
Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial...

Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
WHO Solidarity Trial Consortium

BACKGROUND
World Health Organization expert groups recommended mortality trials of four

repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and inter-
feron beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19).

METHODS
We randomly assigned inpatients with Covid-19 equally between one of the trial
drug regimens that was locally available and open control (up to five options, four

active and the local standard of care). The intention-to-treat primary analyses ex-
amined in-hospital mortality in the four pairwise comparisons of each trial drug

and its control (drug available but patient assigned to the same care without that
drug). Rate ratios for death were calculated with stratification according to age
and status regarding mechanical ventilation at trial entry.
RESULTS
At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750
were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir
(without interferon), 2063 to interferon (including 651 to interferon plus lopinavir),
and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment,
with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death,
day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8%
(39.0% if the patient was already receiving ventilation at randomization and 9.5%
otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303
of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to
1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of
906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of
1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio,

1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving inter-
feron and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39;

P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or re-
duced initiation of ventilation or hospitalization duration.

CONCLUSIONS
These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little

or no effect on hospitalized patients with Covid-19, as indicated by overall mortal-
ity, initiation of ventilation, and duration of hospital stay. (Funded by the World

Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov
number, NCT04315948.)

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01/12/2020 Articles
Targeting the coronavirus SARS-CoV-2: computational insights into the ...

Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

NATURE

Authors
Giovanni Bolcato, Maicol Bissaro, Matteo Pavan, Mattia Sturlese, Stefano Moro

Abstract
Coronavirus SARS-CoV-2 is a recently discovered single-stranded RNA betacoronavirus, responsible for a severe respiratory disease known as coronavirus disease 2019, which is rapidly spreading. Chinese health authorities, as a response to the lack of an effective therapeutic strategy, started to investigate the use of lopinavir and ritonavir, previously optimized for the treatment and prevention of HIV/AIDS viral infection. Despite the clinical use of these two drugs, no information regarding their possible mechanism of action at the molecular level is still known for SARS-CoV-2. Very recently, the crystallographic structure of the SARS-CoV-2 main protease (Mpro), also known as C30 Endopeptidase, was published. Starting from this essential structural information, in the present work we have exploited supervised molecular dynamics, an emerging computational technique that allows investigating at an atomic level the recognition process of a ligand from its unbound to the final bound state. In this research, we provided molecular insight on the whole recognition pathway of Lopinavir, Ritonavir, and Nelfinavir, three potential C30 Endopeptidase inhibitors, with the last one taken into consideration due to the promising in-vitro activity shown against the structurally related SARS-CoV protease.

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25/11/2020 Case Report
Use of dexamethasone, remdesivir, convalescent plasma and prone positi...

Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report

ELSEVIER

Authors
Jennifer Jacobson, Kathleen Antony, Michael Beninati, William Alward, Kara K. Hoppe

Abstract
Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection.

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24/11/2020 Articles
Study Aims to Identify Drugs That Could Be Repurposed for COVID-19

JAMA

Authors
RITA RUBIN

Read More »

24/11/2020 Articles
Hydroxychloroquine doesn’t benefit hospitalized COVID-19 patients

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
NIH staff guidance on coronavirus

Read More »

19/11/2020 News
Covid-19: Critically ill patients treated with arthritis drug tocilizu...

Covid-19: Critically ill patients treated with arthritis drug tocilizumab show improved outcomes, researchers report

THE BMJ

Authors
Jacqui Wise

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19/11/2020 Articles
Analysis of vitamin D level among asymptomatic and critically ill COVI...

Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers

NATURE

Authors
Anshul Jain, Rachna Chaurasia, Narendra Singh Sengar, Mayank Singh, Sachin Mahor, Sumit Narain

Abstract
COVID-19 is characterized by marked variability in clinical severity. Vitamin D had recently been reviewed as one of the factors that may affect the severity in COVID-19. The objective of current study is to analyze the vitamin D level in COVID-19 patients and its impact on the disease severity. After approval from Ethics Committee, M.L.B Medical College the current study was undertaken as continuous prospective observational study of 6 weeks. Participants were COVID-19 patients of age group 30–60 years admitted during the study period of 6 weeks. Study included either asymptomatic COVID-19 patients (Group A) or severely ill patients requiring ICU admission (Group B). Serum concentration of 25 (OH)D, were measured along with serum IL-6; TNFα and serum ferritin. Standard statistical analysis was performed to analyze the differences. Current Study enrolled 154 patients, 91 in Group A and 63 patients in Group B. The mean level of vitamin D (in ng/mL) was 27.89 ± 6.21 in Group A and 14.35 ± 5.79 in Group B, the difference was highly significant. The prevalence of vitamin D deficiency was 32.96% and 96.82% respectively in Group A and Group B. Out of total 154 patients, 90 patients were found to be deficient in vitamin D (Group A: 29; Group B: 61). Serum level of inflammatory markers was found to be higher in vitamin D deficient COVID-19 patients viz. IL-6 level (in pg/mL) 19.34 ± 6.17 vs 12.18 ± 4.29; Serum ferritin 319.17 ± 38.21 ng/mL vs 186.83 ± 20.18 ng/mL; TNFα level (in pg/mL) 13.26 ± 5.64 vs 11.87 ± 3.15. The fatality rate was high in vitamin D deficient (21% vs 3.1%). Vitamin D level is markedly low in severe COVID-19 patients. Inflammatory response is high in vitamin D deficient COVID-19 patients. This all translates into increased mortality in vitamin D deficient COVID-19 patients. As per the flexible approach in the current COVID-19 pandemic authors recommend mass administration of vitamin D supplements to population at risk for COVID-19.

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16/11/2020 PRE PUBLICATIONS RELEASE
Typical COVID-19 symptoms are inversely associated with statin medicat...

Typical COVID-19 symptoms are inversely associated with statin medication: cross-sectional digital study in Lower Saxony, Germany Results of the first German Symptom Surveillance Study for COVID-19

JMIR PUBLICATIONS

Authors
Dietmar Urbach; Friedemann Awiszus; Sven Leiß; Tamsin Venton; Alexander Vincent De Specht; Christian Apfelbacher

Abstract
Background: As the Coronavirus pandemic continues to spread across the globe, the world continues in its search for a
medication to cure, or attenuate, the symptoms of COVID-19 infection.
It would be desirable, and fortuitous, to identify such a medication already in use for another condition, and whose side effect
profile and safety data are already known and approved.
Objective: To design an ‘app’ with the purpose of tracking the incidence of typical COVID-19 symptoms in the population
under study, and to detect possible associations between symptom severity and pre-existing medical conditions or medication
therapies.
Methods: Between early April and late July 2020, 3990 people in Lower Saxony, Germany, participated in an online symptom
tracker application, ‘covid-nein-danke.de’. The questionnaire contained items on typical COVID-19 symptoms, age range,
gender, work in patient-facing healthcare, community life, postal code, previous illnesses, permanent medication, vaccination
status, and results of PCR and antibody test for COVID-19, and COVID-19 treatment if performed.
Results: Analysis of the results have demonstrated a statistically significant relationship between a lower incidence of typical
COVID-19 symptoms and concomitant statin therapy and, to a lesser extent, with antihypertensive therapy. Defining COVID-19
infection by restrictive symptom criteria (4 out of 7 symptoms) the association was found solely for statins with a statistically
significance (OR 0,28 (0,1 - 0,78)). These findings are in line with recent studies.
Conclusions: People taking statin medication may not present with the typical COVID-19 symptoms. This relates especially to
the symptoms of “sore throat”, “headache”, and “dry cough”. The results of this study should be incorporated into all
‘symptoms-based ‘surveillance and decision-making protocols in respect to COVID-19. Furthermore, we conclude with the
assumption that people taking statin therapy may be more likely to have an asymptomatic COVID-19 infection, in which case
they may be at an increased risk of transmitting it unknowingly.
Whether statin therapy has a beneficial effect in combating COVID-19 infection should be investigated by further study. Our
ongoing digital surveillance study will continue to investigate the possible preventative role of statin therapy in symptomatic
SARS-CoV-2 infection. Currently the results should not be misinterpreted as a recommendation to take statins for prevention or
treatment of COVID-19. Clinical Trial: German Clinical Trial Register No. DRKS000022185, WHO International Clinical Trials
Registry Platform U1111-1252-6946

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12/11/2020 Articles
Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) f...

Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial

THE LANCET

Authors
Phillip D Monk, Richard J Marsden, Victoria J Tear, Jody Brookes, Toby N Batten, Marcin Mankowski, Felicity J Gabbay, Donna E Davies, Stephen T Holgate, Ling-Pei Ho, Tristan Clark, Ratko Djukanovic, Tom M A Wilkinson

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11/11/2020 News
Treatments for people with early COVID-19 infection is an urgent resea...

Treatments for people with early COVID-19 infection is an urgent research focus

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
NIH (NATIONAL INSTITUTES OF HEALTH)

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11/11/2020 Viewpoint
Therapy for Early COVID-19 A Critical Need

JAMA

Authors
Peter S. Kim, Sarah W. Read, Anthony S. Fauci

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11/11/2020 Comment
COVID-19 pneumonia and the appropriate use of antibiotics

THE LANCET

Authors
Amy Sarah Ginsburg, Keith P Klugman

Read More »

10/11/2020 Comment
Influenza vaccination and interruption of methotrexate in adult patien...

Influenza vaccination and interruption of methotrexate in adult patients in the COVID-19 era: an ongoing dilemma

THE LANCET

Authors
Puja Mehta, Emilie Sanchez, Elena Moraitis, Nicky Longley, Dennis W Lendrem, Ian P Giles, Rachel C Chambers, Coziana Ciurtin, John D Isaacs

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09/11/2020 Articles
Hydroxychloroquine Inhibits the Trained Innate Immune Response to Inte...

Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons

CELL REPORTS MEDICINE

Authors
Nils Rother, Cansu Yanginlar, Rik G.H. Lindeboom, Siroon Bekkering, Mandy M.T. van Leent, Baranca Buijsers, Inge Jonkman, Mark de Graaf, Marijke Baltissen, Lieke A. Lamers, Niels P. Riksen, Zahi A. Fayad, Willem J.M. Mulder, Luuk B. Hilbrands, Leo A.B. Joosten, Mihai G. Netea, Michiel Vermeulen, Johan van der Vlag, Raphaël Duivenvoorden

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05/11/2020 Articles
Remdesivir for the Treatment of Covid-19 — Final Report

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
J.H. Beigel, K.M. Tomashek, L.E. Dodd, A.K. Mehta, B.S. Zingman, A.C. Kalil, E. Hohmann, H.Y. Chu, A. Luetkemeyer, S. Kline, D. Lopez de Castilla, R.W. Finberg, K. Dierberg, V. Tapson, L. Hsieh, T.F. Patterson, R. Paredes, D.A. Sweeney, W.R. Short, G. Touloumi, D.C. Lye, N. Ohmagari, M. Oh, G.M. Ruiz-Palacios, T. Benfield, G. Fätkenheuer, M.G. Kortepeter, R.L. Atmar, C.B. Creech, J. Lundgren, A.G. Babiker, S. Pett, J.D. Neaton, T.H. Burgess, T. Bonnett, M. Green, M. Makowski, A. Osinusi, S. Nayak, H.C. Lane

Abstract
BACKGROUND
Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.

METHODS
We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. 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 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).

CONCLUSIONS
Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705. opens in new tab.)

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05/11/2020 Articles
Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality...

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform

THE LANCET

Authors
Christopher T Rentsch, Nicholas J DeVito, Brian MacKenna, Caroline E Morton, Krishnan Bhaskaran, Jeremy P Brown, Anna Schultze, William J Hulme, Richard Croker, Alex J Walker, Elizabeth J Williamson, Chris Bates, Seb Bacon, Amir Mehrkar, Helen J Curtis, David Evans, Kevin Wing, Peter Inglesby, Rohini Mathur, Henry Drysdale, Angel Y S Wong, Helen I McDonald, Jonathan Cockburn, Harriet Forbes, John Parry, Frank Hester, Sam Harper, Liam Smeeth, Ian J Douglas, William G Dixon, Stephen J W Evans, Laurie Tomlinson, Ben Goldacre

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04/11/2020 Articles Selection, biophysical and structural analysis of synthetic nanobodies...

Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2

NATURE

Authors
Tânia F. Custódio, Hrishikesh Das, Daniel J. Sheward, Leo Hanke, Samuel Pazicky, Joanna Pieprzyk, Michèle Sorgenfrei, Martin A. Schroer, Andrey Yu. Gruzinov, Cy M. Jeffries, Melissa A. Graewert, Dmitri I. Svergun, Nikolay Dobrev, Kim Remans, Markus A. Seeger, Gerald M. McInerney, Ben Murrell, B. Martin Hällberg, Christian Löw

Abstract
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC50 of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed an unusual conformation of the spike where two RBDs are in the ‘up’ ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.

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22/10/2020 Research
Convalescent plasma in the management of moderate covid-19 in adults i...

Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)

THE BMJ

Authors
Anup Agarwal, Aparna Mukherjee, Gunjan Kumar, Pranab Chatterjee, Tarun Bhatnagar, Pankaj Malhotra

Abstract
Objective To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India.

Design Open label, parallel arm, phase II, multicentre, randomised controlled trial.

Setting 39 public and private hospitals across India.

Participants 464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm).

Interventions Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study.

Main outcome measure Composite of progression to severe disease (PaO2/FiO2 <100 mm Hg) or all cause mortality at 28 days post-enrolment.

Results Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54).

Conclusion Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19.

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20/10/2020 Editorial
Time to Reassess Tocilizumab’s Role in COVID-19 Pneumonia

JAMA

Authors
Jonathan B. Parr

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19/10/2020 Articles
Evidence of protective role of Ultraviolet-B (UVB) radiation in reduci...

Evidence of protective role of Ultraviolet-B (UVB) radiation in reducing COVID-19 deaths

NATURE

Authors
Rahul Kalippurayil Moozhipurath, Lennart Kraft, Bernd Skiera

Abstract
Prior studies indicate the protective role of Ultraviolet-B (UVB) radiation in human health, mediated by vitamin D synthesis. In this observational study, we empirically outline a negative association of UVB radiation as measured by ultraviolet index (UVI) with the number of COVID-19 deaths. We apply a fixed-effect log-linear regression model to a panel dataset of 152 countries over 108 days (n = 6524). We use the cumulative number of COVID-19 deaths and case-fatality rate (CFR) as the main dependent variables and isolate the UVI effect from potential confounding factors. After controlling for time-constant and time-varying factors, we find that a permanent unit increase in UVI is associated with a 1.2 percentage points decline in daily growth rates of cumulative COVID-19 deaths [p < 0.01] and a 1.0 percentage points decline in the CFR daily growth rate [p < 0.05]. These results represent a significant percentage reduction in terms of daily growth rates of cumulative COVID-19 deaths (− 12%) and CFR (− 38%). We find a significant negative association between UVI and COVID-19 deaths, indicating evidence of the protective role of UVB in mitigating COVID-19 deaths. If confirmed via clinical studies, then the possibility of mitigating COVID-19 deaths via sensible sunlight exposure or vitamin D intervention would be very attractive.

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17/10/2020 Articles
Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthc...

Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial

OXFORD ACADEMY

Authors
Radha Rajasingham, Ananta S Bangdiwala, Melanie R Nicol, Caleb P Skipper, Katelyn A Pastick, Margaret L Axelrod, Matthew F Pullen, Alanna A Nascene, Darlisha A Williams, Nicole W Engen, Elizabeth C Okafor, Brian I Rini, Ingrid A Mayer, Emily G McDonald, Todd C Lee, Peter Li, Lauren J MacKenzie, Justin M Balko, Stephen J Dunlop, Katherine H Hullsiek, David R Boulware, SARAH M LOFGREN

Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS CoV-2 in healthcare workers at high-risk of exposure. Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with Covid-19, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations. Results: We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16; P=0.18) and for twice weekly was 0.74 (95%CI 0.46 to 1.19; P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19 (154 ng/mL) versus participants without Covid-19 (133 ng/mL; P=0.08). Conclusions: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.

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12/10/2020 Comment
COVID-19 recovery: potential treatments for post-intensive care syndro...

COVID-19 recovery: potential treatments for post-intensive care syndrome

THE LANCET

Authors
Mansoor N Bangash, Andrew Owen, Joseph E Alderman, Minesh Chotalia, Jaimin M Patel, Dhruv Parekh

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12/10/2020 Articles
SARS-CoV-2 neutralizing antibody structures inform therapeutic strateg...

SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

NATURE

Authors
Christopher O. Barnes, Claudia A. Jette, Morgan E. Abernathy, Kim-Marie A. Dam, Shannon R. Esswein, Harry B. Gristick, Andrey G. Malyutin, Naima G. Sharaf, Kathryn E. Huey-Tubman, Yu E. Lee, Davide F. Robbiani, Michel C. Nussenzweig, Anthony P. West Jr, Pamela J. Bjorkman

Abstract
The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike1–5 show therapeutic promise and are being evaluated clincally6–8. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs5 in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to “up” RBDs, (2) ACE2-blocking hNAbs that bind both “up” and “down” RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize “up” and “down” RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only “up” RBDs9. Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent “down” RBDs, thereby locking the spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.

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09/10/2020 Report
REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus ...

REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters

SCIENCE

Authors
Alina Baum, Dharani Ajithdoss, Richard Copin, Anbo Zhou, Kathryn Lanza, Nicole Negron, Min Ni, Yi Wei, Kusha Mohammadi, Bret Musser, Gurinder S. Atwal, Adelekan Oyejide, Yenny Goez-Gazi, John Dutton, Elizabeth Clemmons, Hilary M. Staples, Carmen Bartley, Benjamin Klaffke, Kendra Alfson, Michal Gazi, Olga Gonzalez, Edward Dick Jr., Ricardo Carrion J, Laurent Pessaint, Maciel Porto, Anthony Cook, Renita Brown, Vaneesha Ali, Jack Greenhouse, Tammy Taylor, Hanne Andersen, Mark G. Lewis, Neil Stahl, Andrew J. Murphy, George D. Yancopoulos, Christos A. Kyratsous

Abstract
An urgent global quest for effective therapies to prevent and treat COVID-19 disease is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987+REGN10933) targeting non-overlapping epitopes on the SARS-CoV-2 spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in lower and upper airways and decrease virus induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail.

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09/10/2020 Research
Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−...

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity

PNAS (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF UNITED STATES OF AMERICA)

Authors
Suzanne J. F. Kaptein, Sofie Jacobs, Lana Langendries, Laura Seldeslachts, Sebastiaan ter Horst, Laurens Liesenborghs, Bart Hens, Valentijn Vergote, Elisabeth Heylen, Karine Barthelemy, Elke Maas, Carolien De Keyzer, Lindsey Bervoets, Jasper Rymenants, Tina Van Buyten, Xin Zhang, Rana Abdelnabi, Juanita Pang, Rachel Williams, Hendrik Jan Thibaut, Kai Dallmeier, Robbert Boudewijns, Jens Wouters, Patrick Augustijns, Nick Verougstraete, Christopher Cawthorne, Judith Breuer, Caroline Solas, Birgit Weynand, Pieter Annaert, Isabel Spriet, Greetje Vande Velde, Johan Neyts, Joana Rocha-Pereira, Leen Delang

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2−infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.

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07/10/2020 Research
Remdesivir targets a structurally analogous region of the Ebola virus ...

Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases

PNAS (PROCEEDINGS OF THE NATIONL ACADEMY OF SCIENCE OF UNITED STATES OF AMERICA)

Authors
Michael K. Lo, César G. Albariño, Jason K. Perry, Silvia Chang, Egor P. Tchesnokov, Lisa Guerrero, Ayan Chakrabarti, Punya Shrivastava-Ranjan, Payel Chatterjee, Laura K. McMullan, Ross Martin, Robert Jordan, Matthias Götte, Joel M. Montgomery, Stuart T. Nichol, Mike Flint, Danielle Porter, Christina F. Spiropoulou

Abstract
Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention’s Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.

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06/10/2020 Comment
Rescue Therapy for Pregnant Women with Severe COVID-19

NEJM - JOURNAL WATCH

Authors
ANNA WALD

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05/10/2020 Articles
Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RE...

Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

THE LANCET

Authors
RECOVERY Collaborative Group

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28/09/2020 Articles
Tocilizumab Therapy of COVID-19: A Comparison of Subcutaneous and Intr...

Tocilizumab Therapy of COVID-19: A Comparison of Subcutaneous and Intravenous Therapies

IJID (INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES)

Authors
Monica A. Kaminski, Subin Sunny, Khayala Balabayova, Avneet Kaur, Aanchal Gupta, Marie Abdallah, John Quale

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25/09/2020 Articles
Extracorporeal membrane oxygenation support in COVID-19: an internatio...

Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry

THE LANCET

Authors
Ryan P Barbaro, Graeme MacLaren, Philip S Boonstra, Theodore J Iwashyna, Arthur S Slutsky, Eddy Fan, Robert H Bartlett, Joseph E Tonna, Robert Hyslop, Jeffrey J Fanning, Peter T Rycus, Steve J Hyer, Marc M Anders, Cara L Agerstrand, Katarzyna Hryniewicz, Rodrigo Diaz, Roberto Lorusso, Alain Combes, Daniel Brodie

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24/09/2020 Articles
Use of hydroxychloroquine and chloroquine in COVID-19: How good is the...

Use of hydroxychloroquine and chloroquine in COVID-19: How good is the quality of randomized controlled trials?

IJID (INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES)

Authors
Faizan Mazhar, Muhammad Abdul Hadi, Chia Siang Kow, Albaraa Mohammed N. Marran, Hamid A. Merchant, Syed Shahzad Hasan

Abstract
Objectives: We critically evaluated the quality of evidence and quality of harms reporting in clincal
trials that recently evaluated the effectiveness of HCQ/CQ in COVID-19.
Study Design and Setting: Scientific databases were systematically searched to identify relevant trials
of HCQ/CQ in COVID-19 published until 10th September, 2020. The Cochrane risk-of-bias tools for
randomized trials and non-randomized studies of interventions were used to assess risk of bias of
included studies. A 10-item Consolidated Standards of Reporting Trials (CONSORT) harms extension
was used to assess for quality of harms reporting.
Results: Sixteen trialsincluding fourteen randomized and two non-randomized trials met the inclusion
criteria. The results from included trials were conflicting, lacked effect estimates adjusted for
confounders and baseline disease severity or comorbidities in many cases, and recruited a fairly small
cohort of patients. None of the clinical trials met the CONSORT criteria in full for reporting harms data
in clinical trials. None of the sixteen trials had an overall ‘low’ risk of bias, while four of the trials had
‘high’, ‘critical’, and ‘serious’ risk of bias. Biases observed in these trials arise from the randomization
process, potential deviation from intended interventions, outcome measurement, selective reporting,
confounding, participant selection, and/or classification of interventions

Conclusion: In general, the quality of currently available evidence for the effectiveness of CQ/HCQ in
COVID-19 is suboptimal. The importance of a properly designed and reported clinical trial cannot be
overemphasized amid the COVID-19 pandemic and its dismissal could lead to poorer clinical and policy
decisions resulting in wastage of already stretched invaluable healthcare resources.

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24/09/2020 Articles
Ultrapotent human antibodies protect against SARS-CoV-2 challenge via ...

Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms

SCIENCE

Authors
M. Alejandra Tortorici, Martina Beltramello, Florian A. Lempp, Dora Pinto, Ha V. Dang, Laura E. Rosen, Matthew McCallum, John Bowen, Andrea Minola, Stefano Jaconi, Fabrizia Zatta, Anna De Marco, Barbara Guarino, Siro Bianchi3, Elvin J. Lauron, Heather Tucker, Jiayi Zhou, Alessia Peter, Colin Havenar- Daughton, Jason A. Wojcechowskyj, James Brett Case, Rita E. Chen, Hannah Kaiser, Martin Montiel-Ruiz, Marcel Meury, Nadine Czudnochowski, Roberto Spreafico, Josh Dillen, Cindy Ng, Nicole Sprugasci, Katja Culap, Fabio Benigni, Rana Abdelnabi, Shi-Yan Caroline Foo, Michael A. Schmid, Elisabetta Cameroni, Agostino Riva, Arianna Gabrieli, Massimo Galli, Matteo S. Pizzuto, Johan Neyts, Michael S. Diamond, Herbert W. Virgin, Gyorgy Snell, Davide Corti, Katja Fink, David Veesler

Abstract
Efficient therapeutic options are needed to control the spread of SARS-CoV-2 that has caused more than 922,000 fatalities as of September 13th, 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block ACE2 attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Cocktails including S2M11, S2E12 or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants

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24/09/2020 PRE PUBLICATIONS RELEASE
COX2 Inhibition in the Treatment of COVID-19: Review of Literature to ...

COX2 Inhibition in the Treatment of COVID-19: Review of Literature to Propose Celecoxib Repositioning for Randomized Controlled Studies

IJID (INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES)

Authors
Semih Baghaki, Can Ege Yalcin, Hayriye Sema Baghaki, Servet Yekta Aydin, Basak Daghan, Ersin Yavuz

ABSTRACT
Coronavirus triggered pulmonary and systemic disease, i.e. systemic inflammatory response to
virally triggered lung injury, named as COVID-19 and still ongoing discussions on refining
immunomodulation in COVID-19 without COX2 inhibition directed us to search the related
literature to point out a potential target (COX2) and a weapon (celecoxib). The impression of
selectively targeting COX2 and closely related cascades might be worth to try in the treatment
of COVID-19 given the substantial amount of data regarding COX2, p38 MAPK, IL-1b, IL-6
and TGF-b are playing pivotal roles in coronavirus related cell death, cytokine storm and
pulmonary interstitial fibrosis. Considering lack of definitive treatment and importance of
immunomodulation in COVID-19; COX2 inhibition might be a valuable adjunct to still
evolving treatment strategies. Celecoxib has credentials to be proposed and evaluated in
randomized controlled studies besides being available to be used off label.

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24/09/2020 Articles
Efficacy of masks and face coverings in controlling outward aerosol pa...

Efficacy of masks and face coverings in controlling outward aerosol particle emission from expiratory activiti

NATURE

Authors
Sima Asadi, Christopher D. Cappa, Santiago Barreda, Anthony S. Wexler, Nicole M. Bouvier, William D. Ristenpart

Abstract
The COVID-19 pandemic triggered a surge in demand for facemasks to protect against disease transmission. In response to shortages, many public health authorities have recommended homemade masks as acceptable alternatives to surgical masks and N95 respirators. Although mask wearing is intended, in part, to protect others from exhaled, virus-containing particles, few studies have examined particle emission by mask-wearers into the surrounding air. Here, we measured outward emissions of micron-scale aerosol particles by healthy humans performing various expiratory activities while wearing different types of medical-grade or homemade masks. Both surgical masks and unvented KN95 respirators, even without fit-testing, reduce the outward particle emission rates by 90% and 74% on average during speaking and coughing, respectively, compared to wearing no mask, corroborating their effectiveness at reducing outward emission. These masks similarly decreased the outward particle emission of a coughing superemitter, who for unclear reasons emitted up to two orders of magnitude more expiratory particles via coughing than average. In contrast, shedding of non-expiratory micron-scale particulates from friable cellulosic fibers in homemade cotton-fabric masks confounded explicit determination of their efficacy at reducing expiratory particle emission. Audio analysis of the speech and coughing intensity confirmed that people speak more loudly, but do not cough more loudly, when wearing a mask. Further work is needed to establish the efficacy of cloth masks at blocking expiratory particles for speech and coughing at varied intensity and to assess whether virus-contaminated fabrics can generate aerosolized fomites, but the results strongly corroborate the efficacy of medical-grade masks and highlight the importance of regular washing of homemade masks.

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23/09/2020 Articles
Early Hydroxychloroquine but not Chloroquine use reduces ICU admission...

Early Hydroxychloroquine but not Chloroquine use reduces ICU admission in COVID-19 patients

IJID (INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES)

Authors
A.J.J. Lammers, R.M. Brohet, R.E.P. Theunissen, C. Koster, R. Rood, D.W.M. Verhagen, K. Brinkman, R.J. Hassing, A. Dofferhoff, R. el Moussaoui, G. Hermanides, J. Ellerbroek, N. Bokhizzou, H. Visser, M. van den Berge, H. Bax, D.F. Postma, P.H.P. Groeneveld

Abstract
Background
The global push for the use of hydroxychloroquine (HCQ) and chloroquine (CQ) against
COVID-19 resulted in an ongoing discussion about the effectivity and toxicity of these drugs.
Recent studies report no effect of (H)CQ on 28 day-mortality. We investigated the effect of
HCQ and CQ in hospitalized patients on the non-ICU COVID-ward.
Methods
A nationwide, observational cohort study was performed in The Netherlands. Hospitals
were given the opportunity to decide independently on the use of three different COVID-19
treatment strategies: HCQ or CQ, or no treatment. We compared the outcome between
these groups. The primary outcomes were 1) death on the COVID-19 ward, and 2) transfer
to the Intensive Care Unit (ICU).
Results
Journal Pre-proof
The analysis contained 1064 patients from 14 hospitals: 566 patients received treatment
with either HCQ (n=189) or CQ (n=377), and 498 patients received no treatment. In a
multivariate propensity matched weighted competing regression analysis, there was no
significant effect of (H)CQ on mortality on the COVID-ward. HCQ however was associated
with a significant decreased risk of transfer to the ICU (Hazard ratio (HR) = 0.47, 95%CI =
0.27 - 0.82, p = 0.008), when compared to controls. This effect was not found in the CQ
group (HR = 0.80; 95%CI = 0.55 - 1.15, p = 0.207), and remained significant after competing
risk analysis.
Conclusion
The results of this observational study demonstrate a lack of effect of (H)CQ on non-ICU
mortality. However, we show that the use of HCQ - but not CQ - is associated with 53%
decreased risk of transfer of COVID-19 patients from the regular ward to the ICU. Recent
prospective studies have reported on 28 days all-cause mortality only, therefore additional
prospective data on the early effect of HCQ in preventing transfer to the ICU is still needed.
Abbreviations: HCQ = hydroxychloroquine, CQ = chloroquine, AZM= azithromycin
ICU = intensive care unit, ED = emergency department

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22/09/2020 Articles
Statins, COVID-19, and coronary artery disease: killing two birds with...

Statins, COVID-19, and coronary artery disease: killing two birds with one stone

METABOLISM CLINICAL AND EXPERIMENTAL

Authors
Shiva Ganjali, Vanessa Bianconi, Peter E. Penson, Matteo Pirro, Maciej Banach, Gerald F. Watts, Amirhossein Sahebkar

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21/09/2020 Viewpoint
Ensuring Adequate Palliative and Hospice Care During COVID-19 Surges

JAMA

Authors
Jean Abbott, Daniel Johnson, Matthew Wynia

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21/09/2020 News
Covid-19: Experts divide into two camps of action—shielding versus bla...

Covid-19: Experts divide into two camps of action—shielding versus blanket policies

THE BMJ

Authors
Jacqui Wise

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18/09/2020 Comment
What is the optimal usage of Covid-19 convalescent plasma donations?

CLINICAL MICROBIOLOGY AND INFECTION

Authors
Focosi Daniele, Tuccori Marco, Antonelli Guido, Maggi Fabrizio

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18/09/2020 World Review
Artificial intelligence in COVID-19 drug repurposing

THE LANCET

Authors
Yadi Zhou, Fei Wang, Jian Tang, Ruth Nussinov, Feixiong Cheng

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15/09/2020 PERSPECTIVE
Bridging the Gap at Warp Speed — Delivering Options for Preventing an...

Bridging the Gap at Warp Speed — Delivering Options for Preventing and Treating Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Moncef Slaoui, Shannon E. Greene, Janet Woodcock

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15/09/2020 PERSPECTIVE
Convalescent plasma therapy for COVID-19: a tried-and-true old strateg...

Convalescent plasma therapy for COVID-19: a tried-and-true old strategy?

NATURE

Authors
Yongzhi Xi

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10/09/2020 Editorial
Curing COVID-19

THE LANCET

Authors
The Lancet Infectious Diseases

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09/09/2020 News
COVACTA trial raises questions about tocilizumab’s benefit in COVID-19

THE LANCET

Authors
Bryant Furlow

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04/09/2020 Rapid Communication
A living WHO guideline on drugs for covid-19

THE BMJ

Authors
Reed Siemieniuk, Bram Rochwerg, Thomas Agoritsas, François Lamontagne, Yee-Sin Leo, Helen Macdonald, Arnav Agarwal, Linan Zeng, Lyubov Lytvyn, John Adabie Appiah, Wagdy Amin, Yaseen Arabi, Lucille Blumberg, Erlina Burhan, Frederique Jacquerioz Bausch, Carolyn S Calfee, Bin Cao, Maurizio Cecconi, Duncan Chanda, Graham Cooke, Bin Du, Jake Dunning, Heike Geduld, Patrick Gee, Madiha Hashimi, David S Hui, Sushil Kabra, Seema Kanda, Leticia Kawano-Dourado, Yae-Jean Kim, Niranjan Kissoon, Arthur Kwizera, Jon Henrik Laake, Flavia R Machado, Imelda Mahaka, Hela Manai, Greta Mino, Emmanuel Nsutebu, Natalia Pshenichnaya, Nida Qadir, Saniya Sabzwari, Rohit Sarin, Michael Sharland, Yinzhong Shen, Shalini Sri Ranganathan, Joao Souza, Sebastian Ugarte, Sridhar Venkatapuram, Vu Quoc Dat, Dubula Vuyiseka, Miriam Stegemann, Ananda Wijewickrama, Brittany Maguire, Dena Zeraatkar, Jessica Bartoszko, Long Ge, Romina Brignardello-Petersen, Andrew Owen, Gordon Guyatt, Janet Diaz, Michael Jacobs, Per Olav Vandvik

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04/09/2020 Articles
Azithromycin in addition to standard of care versus standard of care a...

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

THE LANCET

Authors
Remo H M Furtado, Otavio Berwanger, Henrique A Fonseca, Thiago D Corrêa, Leonardo R Ferraz, Maura G Lapa, Fernando G Zampieri, Viviane C Veiga, Luciano C P Azevedo, Regis G Rosa, Renato D Lopes, Alvaro Avezum, Airton L O Manoel, Felipe M T Piza, Priscilla A Martins, Thiago C Lisboa, Adriano J Pereira, Guilherme B Olivato, Vicente C S Dantas, Eveline P Milan, Otavio C E Gebara, Roberto B Amazonas, Monalisa B Oliveira, Ronaldo V P Soares, Diogo D F Moia, Luciana P A Piano, Kleber Castilho, Roberta G R A P Momesso, Guilherme P P Schettino, Luiz Vicente Rizzo, Ary Serpa Neto, Flávia R Machado, Alexandre B Cavalcanti

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04/09/2020 Manuscript
Therapy of Sars-Coronavirus-2 pneumonia: is there an optimal IL-6 cut-...

Therapy of Sars-Coronavirus-2 pneumonia: is there an optimal IL-6 cut-off for successful tocilizumab treatment?

OXFORD ACADEMY

Authors
Nicola Squillace, Maria Rosa Pozzi, Giulia Gustinetti, Elena Ricci, Serena Capici, Paola Columpsi, Luca Sala, Paolo Bonfanti

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04/09/2020 Articles
Hydroxychloroquine and Chloroquine Prescribing Patterns by Provider Sp...

Hydroxychloroquine and Chloroquine Prescribing Patterns by Provider Specialty Following Initial Reports of Potential Benefit for COVID-19 Treatment — United States, January–June 2020

CDC

Authors
Lara Bull-Otterson, Elizabeth B. Gray, Daniel S. Budnitz, Heather M. Strosnider, Lyna Z. Schieber, Joseph Courtney, Macarena C. García, John T. Brooks, William R. Mac Kenzie, Adi V. Gundlapalli

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04/09/2020 Institutional Recommendations
A living WHO guideline on drugs for covid-19

THE BMJ

Authors
AA.VV.

Abstract
Updates This is the eighth version (seventh update) of a living guideline. It replaces earlier versions (4 September 2020, 20 November 2020, 17 December 2020, 31 March 2021, 6 July 2021, 23 September 2021, and 6 December 2021). The previous versions can be found as data supplements. New recommendations will be published as updates to this guideline.

Clinical question What is the role of drugs in the treatment of patients with covid-19?

Context The evidence base for therapeutics for covid-19 is increasing with numerous recently completed randomised controlled trials (RCTs). This update adds new recommendations on Janus kinase (JAK) inhibitors based on three RCTs with 2659 participants for baricitinib, two RCTs with 475 participants for ruxolitinib, and one RCT with 289 participants for tofacitinib. It also adds a recommendation for sotrovimab (monoclonal antibody) based on one RCT with 1057 participants, that was completed before the emergence of the omicron variant.

New recommendations The Guideline Development Group (GDG) made:

• A strong recommendation for the use of baricitinib as an alternative to interleukin-6 (IL-6) receptor blockers, in combination with corticosteroids, in patients with severe or critical covid-19

• A conditional recommendation against the use of ruxolitinib and tofacitinib for patients with severe or critical covid-19

• A conditional recommendation for the use of sotrovimab in patients with non-severe covid-19, restricted to those at highest risk of hospitalisation.

Following the publication of a previous conditional recommendation for casirivimab- imdevimab, pre-clinical evidence has emerged suggesting that this monoclonal antibody combination lacks neutralisation activity against the omicron variant in vitro. Sotrovimab has been reported to retain activity against omicron in pseudovirus assays but with higher concentrations being required for neutralisation. More data are required to ascertain whether efficacy against the omicron variant will be maintained at the studied doses of monoclonal antibodies, and these living guidelines will be updated when additional data becomes available.

Understanding the new recommendations When moving from evidence to recommendations, the GDG considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. The strong recommendation for baricitinib in those with severe or critical illness reflects moderate certainty evidence for benefits on mortality, duration of mechanical ventilation, and hospital length of stay, with no observed increase in adverse events leading to drug discontinuation. Baricitinib and IL-6 receptor blockers have similar effects; when both are available, choose one based on issues including cost and clinician experience. The conditional recommendation against the use of ruxolitinib and tofacitinib was driven by low certainty evidence from small trials, failing to demonstrate benefit, and suggesting a possible increase in serious adverse events for tofacitinib. A conditional recommendation for the monoclonal antibody sotrovimab in patients with non-severe illness reflects substantial reduction in risk of hospitalisation in those at higher risk, and trivial benefits in those at lower risk. There were insufficient data to recommend one monoclonal antibody treatment over another, and evidence on their efficacy for emerging variants is likely to influence future recommendations.

Prior recommendations

• Recommended for patients with severe or critical covid-19—a strong recommendation for systemic corticosteroids; a strong recommendation for IL-6 receptor blockers (tocilizumab or sarilumab); and a conditional recommendation for casirivimab-imdevimab, for those having seronegative status.

• Recommended for patients with non-severe covid-19—a conditional recommendation for casirivimab-imdevimab, for those at highest risk of severe illness.

• Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids; and a strong recommendation against convalescent plasma.

• Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma, except in the context of a clinical trial.

• Not recommended, regardless of covid-19 illness severity—a conditional recommendation against remdesivir; a strong recommendation against hydroxychloroquine; a strong recommendation against lopinavir/ritonavir; and a recommendation against ivermectin, except in the context of a clinical trial.

About this guideline This living guideline from the World Health Organization (WHO) incorporates three new recommendations on two therapies for covid-19, and updates existing recommendations. The GDG typically evaluates a therapy when WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations.

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02/09/2020 Original Investigation
Effect of Hydrocortisone on Mortality and Organ Support in Patients Wi...

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

JAMA

Authors
The Writing Committee for the REMAP-CAP Investigators

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.

02/09/2020 Original Investigation
Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients ...

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19 The CoDEX Randomized Clinical Trial

JAMA

Authors
Bruno M. Tomazini, Israel S. Maia, Alexandre B. Cavalcanti, Otavio Berwanger, Regis G. Rosa, Viviane C. Veiga, Alvaro Avezum, Renato D. Lopes, Flavia R. Bueno, Maria Vitoria A. O. Silva; Franca P. Baldassare; Eduardo L. V. Costa, Ricardo A. B. Moura, Michele O. Honorato, Andre N. Costa, Lucas P. Damiani, Thiago Lisboa, Letícia Kawano-Dourado, Fernando G. Zampieri, Guilherme B. Olivato, Cassia Righy, Cristina P. Amendola, Roberta M. L. Roepke, Daniela H. M. Freitas, Daniel N. Forte, Flávio G. R. Freitas, Caio C. F. Fernandes, Livia M. G. Melro, Gedealvares F. S. Junior, Douglas Costa Morais; Stevin Zung, Flávia R. Machado, Luciano C. P. Azevedo

ABSTRACT
Importance Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.
Objective To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19–associated ARDS.
Design, Setting, and Participants Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.
Interventions Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).
Main Outcomes and Measures The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.
Results A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, −1.16; 95% CI, −1.94 to −0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.
Conclusions and Relevance Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.

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02/09/2020 Editorial
Corticosteroids in COVID-19 ARDS Evidence and Hope During the Pandemic

JAMA

Authors
Hallie C. Prescott, Todd W. Rice

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02/09/2020 Original Investigation
Association Between Administration of Systemic Corticosteroids and Mor...

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19 A Meta-analysis

JAMA

Authors
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group

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 I2 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 < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.
Conclusions and Relevance In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

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02/09/2020 Guidelines
Corticosteroids for COVID-19

WORLD HEALTH ORGANIZATION

Authors
WORLD HEALTH ORGANIZATION

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01/09/2020 News
Medtech dealmaking and financing trends in 2019

NATURE

Authors
Maureen Riordan, Amanda Micklus

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01/09/2020 Reviews
Insights into antiviral mechanisms of remdesivir, lopinavir/ritonavir ...

Insights into antiviral mechanisms of remdesivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine affecting the new SARS-CoV-2

ELSEVIER

Authors
Katya Uzunova, Elena Filipova, Velichka Pavlova, Toni Vekovb


ABSTRACT
Coronavirus disease 2019 (COVID-19) is a kind of viral pneumonia with an unusual outbreak in Wuhan, China, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is currently no licensed antiviral treatment available to prevent human CoV infection. The widespread clinical use and existing knowledge on antiviral mechanisms of remdesivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine in the treatment of previous epidemic diseases, namely, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), may be helpful in the combat with novel SARS-CoV-2 infection. Recent clinical evidence didn’t confirm the beneficial role of lopinavir/ritonavir and chloroquine/hydroxychloroquine for COVID-19 patients and their use was reassessed. We provide an overview of the current evidence into the mechanisms of action of these available drugs which are repurposed for treatment of the new virus. Available data identifies remdesivir as an adenosine analogue that can target the RNA-dependent RNA polymerase and block viral RNA synthesis. It has been a promising antiviral drug against a wide array of RNA viruses. 3CLpro is a major CoV protease that cleaves the large replicase polyproteins during viral replication and can be targeted by the protease inhibitor lopinavir/ritonavir but the clinical effects are controversial. Chloroquine/Hydroxychloroquine could impair the replication of SARSCoV-2 by multiple mechanisms and their immunomodulatory properties could ameliorate clinical manifestations that are mediated by immune reactions of the host although its beneficial effects are under question and need to be proven at the clinical level. Existing in vitro and in vivo evidence delineate the molecular mechanisms of these drugs in CoV-infected cells. Numerous studies demonstrated the ability of remdesivir to inhibit SARS-CoV-2 replication but future research would be needed to understand the exact mode of action of lopinavir/ritonavir and chloroquine/hydroxychloroquine in SARS-CoV-2 infected cells and to use this knowledge in the treatment of the current COVID-19.

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01/09/2020 News
Hunting for antibodies to combat COVID-19

NATURE

Authors
Biopharma Dealmakers

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31/08/2020 Articles
COVID-19, SARS CoV-2

SANFORD GUIDE WEB EDITION

Authors
SANFORD GUIDE

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31/08/2020 Viewpoint
Emergency Use Authorizations During the COVID-19 Pandemic Lessons From...

Emergency Use Authorizations During the COVID-19 Pandemic Lessons From Hydroxychloroquine for Vaccine Authorization and Approval

JAMA

Authors
Kyle Thomson, Herschel Nachlis

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25/08/2020 Articles
Use of hydroxychloroquine in hospitalised COVID-19 patients is associa...

Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study

EUROPEAN JOURNAL OF INTERNAL MEDICINE

Authors
The COVID-19 RISK and Treatments (CORIST) Collaboration members


ABSTRACT
Background
Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19. Objective We set-up a multicenter Italian collaboration to investigate the relationship between HCQ therapy and COVID-19 in-hospital mortality. Methods In a retrospective observational study, 3,451 unselected patients hospitalized in 33 clinical centers in Italy, from February 19, 2020 to May 23, 2020, with laboratory-confirmed SARS-CoV-2 infection, were analyzed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received HCQ with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores, with the addition of subgroup analyses. Results Out of 3,451 COVID-19 patients, 76.3% received HCQ. Death rates (per 1,000 person-days) for patients receiving or not HCQ were 8.9 and 15.7, respectively. After adjustment for propensity scores, we found 30% lower risk of death in patients receiving HCQ (HR=0.70; 95%CI: 0.59 to 0.84; E-value=1.67). Secondary analyses yielded similar results. The inverse association of HCQ with inpatient mortality was particularly evident in patients having elevated C-reactive protein at entry. Conclusions HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.

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24/08/2020 Comment
Not just antibodies: B cells and T cells mediate immunity to COVID-19

NATURE

Authors
Rebecca J. Cox , Karl A. Brokstad

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23/08/2020 Articles
Effectiveness of remdesivir in patients with COVID-19 under mechanical...

Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU

JOURNAL OF ANTIMICROB CHEMOTHERAPY

Authors
Zeno Pasquini, Roberto Montalti, Chiara Temperoni, Benedetta Canovari, Mauro Mancini, Michele Tempesta, Daniela Pimpini, Nicoletta Zallocco, Francesco Barchiesi


ABSTRACT
Background Remdesivir is a prodrug with in vitro activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Its clinical efficacy in patients with COVID-19 under mechanical ventilation remains to be evaluated.
Methods This study includes patients under mechanical ventilation with confirmed SARS-CoV-2 infection admitted to the ICU of Pesaro hospital between 29 February and 20 March 2020. During this period, remdesivir was provided on a compassionate use basis. Clinical characteristics and outcome of patients treated with remdesivir were collected retrospectively and compared with those of patients hospitalized in the same time period.
Results A total of 51 patients were considered, of which 25 were treated with remdesivir. The median (IQR) age was 67 (59–75.5) years, 92% were men and symptom onset was 10 (8–12) days before admission to ICU. At baseline, there was no significant difference in demographic characteristics, comorbidities and laboratory values between patients treated and not treated with remdesivir. Median follow-up was 52 (46–57) days. Kaplan–Meier curves showed significantly lower mortality among patients who had been treated with remdesivir (56% versus 92%, P < 0.001). Cox regression analysis showed that the Charlson Comorbidity Index was the only factor that had a significant association with higher mortality (OR 1.184; 95% CI 1.027–1.365; P = 0.020), while the use of remdesivir was associated with better survival (OR 3.506; 95% CI 1.768–6.954; P < 0.001).
Conclusions In this study the mortality rate of patients with COVID-19 under mechanical ventilation is confirmed to be high. The use of remdesivir was associated with a significant beneficial effect on survival.

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21/08/2020 Articles
Corticosteroid prevents COVID-19 progression within its therapeutic wi...

Corticosteroid prevents COVID-19 progression within its therapeutic window: a multicentre, proof-of-concept, observational study

TAYLOR & FRANCIS ONLINE

Authors
Yang Li, Xian Zhou, Tao Li , Shiji Chan, Yiqi Y , Jing-Wen Ai , Haocheng Zhang, Feng Sun, Qiran Zhang, Lei Zhu, Lingyun Shao, Bin Xu, Wenhong Zhang

ABSTRACT
Critically ill patients with coronavirus diseases 2019 (COVID-19) are of grave concern. Those patients usually underwent a stage of excessive inflammation before developing acute respiratory distress syndrome. In this study, we test the hypothesis that short-term, low-to-moderate-dose corticosteroids would benefit patients when used in the early phase of excessive inflammation, namely, the therapeutic window. Among a Shanghai cohort and a validation cohort, we enrolled COVID-19 patients showing marked radiographic progression. Short-term, low-to-moderate-dose corticosteroids were considered for them. After identifying the possible markers for the therapeutic window, we then divided the patients, based on whether they were treated with corticosteroids within the therapeutic window, into the early-start group and control group. We identified that the therapeutic window for corticosteroids was characterized by a marked radiographic progression and lactase dehydrogenase (LDH) less than two times the upper limit of normal (ULN). The Shanghai cohort comprised of 68 patients, including 47 in the early-start group and 21 in the control group. The proportion of patients requiring invasive mechanical ventilation was significantly lower in the early-start group than in the control group (10.6% vs. 33.3%, difference, 22.7%, 95% confidence interval 2.6–44.8%). Among the validation cohort of 51 patients, similar difference of the primary outcome was observed (45.0% vs. 74.2%, P = 0.035). Among COVID-19 patients with marked radiologic progression, short-term, low-to-moderate-dose corticosteroids benefits patients with LDH levels of less than two times the ULN, who may be in the early phase of excessive inflammation.

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18/08/2020 Letter
Unethical not to Investigate Radiotherapy for COVID-19

SAGE JOURNALS

Authors
Jerry M. Cuttler, Joseph J. Bevelacqua, S. M. J. Mortazavi


ABSTRACT
The primum non nocere letter by Boon et al. urged caution and careful examination of the evidence and logistics of low-dose radiotherapy in COVID-19 patients. This is exactly what was requested in March and what has occurred since late April 2020 when the first phase I/II clinical trial was approved at the Winship Cancer Institute, Emory University Hospital. The preprint of day-7 interim results by the investigators concluded, “In a small pilot trial of 5 oxygen-dependent patients with COVID-19 pneumonia, low-dose whole-lung radiation led to rapid improvement in clinical status, encephalopathy, and radiographic infiltrates without acute toxicity or worsening the cytokine storm. Low-dose whole-lung radiation appears to be safe, shows early promise of efficacy, and warrants larger prospective trials.” Preliminary results from another clinical trial gave similar results. In conclusion, the authors believe it would be unethical not to investigate radiotherapy as a potential remedy against COVID-19 induced pneumonia

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18/08/2020 Reviews
Perspectives on the Early Quality of Evidence Guiding the Therapeutic ...

Perspectives on the Early Quality of Evidence Guiding the Therapeutic Management of SARS-CoV-2: A Systematic Literature Review

SPRINGER LINK

Authors
Kaushik Subramanian, Anuradha Nalli, Vinitha Senthil, Saurabh Jain, Aravind Nayak, Amit Bhat


ABSTRACT
Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a serious health concern. Repurposing of existing drugs indicated for other conditions seems to be the first choice for immediate therapeutic management. The quality of early evidence favoring the different treatment options needs to be apprised for informed decision-making.
Methods In this systematic literature review, we apprised the quality of available evidence for different therapeutic options and also the basis for different treatment guidelines. To include all studies that are in different stages of publication, we also included studies from the preprint servers BioRxiv and MedRxiv and published studies from PubMed.
Results We retrieved 5621 articles and included 22 studies for the systematic review. Based on our study, chloroquine/hydroxychloroquine, either alone or in combination with azithromycin, remdesivir, corticosteroids, convalescent sera, ritonavir/lopinavir, tocilizumab and arbidol were evaluated as therapeutic options. The data from different study designs reveal contradictory findings except for convalescent sera for which the evidence available is only from case series. Based on this early evidence, various national guidelines recommend remdesivir, convalescent sera, corticosteroids and hydroxychloroquine in different subsets of patients.
Conclusion Establishing consensus with respect to the end points to be assessed for respiratory viruses may enhance the quality of evidence in case of future pandemics. The systematic review highlighted the lacuna and methodologic deficiency in early clinical evidence and included an update on different therapeutic management guidelines. Further clinical evidence from the ongoing trials may lead to evolution of treatment guidelines with the addition of more therapeutic options.

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18/08/2020 Articles
Pharmacogenomics of COVID-19 therapies

NATURE

Authors
Takuto Takahashi, Jasmine A. Luzum, Melanie R. Nicol, Pamala A. Jacobson


ABSTRACT
A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β -1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.

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14/08/2020 Articles
New Anti SARS-Cov-2 Targets for Quinoline Derivatives Chloroquine and ...

New Anti SARS-Cov-2 Targets for Quinoline Derivatives Chloroquine and Hydroxychloroquine

MDPI

Authors
Davide Gentile, Virginia Fuochi, Antonio Rescifina, Pio Maria Furneri


ABSTRACT
The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a severe global health crisis. In this paper, we used docking and simulation methods to identify potential targets and the mechanism of action of chloroquine (CQ) and hydroxychloroquine (HCQ) against SARS-CoV-2. Our results showed that both CQ and HCQ influenced the functionality of the envelope (E) protein, necessary in the maturation processes of the virus, due to interactions that modify the flexibility of the protein structure. Furthermore, CQ and HCQ also influenced the proofreading and capping of viral RNA in SARS-CoV-2, performed by nsp10/nsp14 and nsp10/nsp16. In particular, HCQ demonstrated a better energy binding with the examined targets compared to CQ, probably due to the hydrogen bonding of the hydroxyl group of HCQ with polar amino acid residues

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12/08/2020 Manuscript
Methylprednisolone as Adjunctive Therapy for Patients Hospitalized Wit...

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial

OXFORD ACADEMY

Authors
Christiane Maria Prado Jeronimo, Maria Eduarda Leão Farias, Fernando Fonseca Almeida Val, Vanderson Souza Sampaio, Marcia Almeida Araújo Alexandre, Gisely Cardoso Melo, Izabella Picinin Safe, Mayla Gabriela Silva Borba, Rebeca Linhares Abreu-Netto, Alex Bezerra Silva Maciel, João Ricardo Silva Neto, Lucas Barbosa Oliveira, Erick Frota Gomes Figueiredo, Kelry Mazurega Oliveira Dinelly, Maria Gabriela de Almeida Rodrigues , Marcelo Brito, Maria Paula Gomes Mourão, Guilherme Augusto Pivoto João, Ludhmila Abrahão Hajjar, Quique Bassat, Gustavo Adolfo Sierra Romero, Felipe Gomes Naveca, Heline Lira Vasconcelos; Michel de Araújo Tavares, José Diego Brito-Sousa, Fabio Trindade Maranhão Costa, Maurício Lacerda Nogueira, Djane Baía-da-Silva, Mariana Simão Xavier, Wuelton Marcelo Monteiro, Marcus Vinícius Guimarães Lacerda


ABSTRACT
Background Steroid use for COVID-19 is based on the possible role of these drugs in mitigating the inflammatory response, mainly in the lungs, triggered by SARS-CoV-2. This study aimed at evaluating at evaluating the efficacy of methylprednisolone (MP) among hospitalized patients with suspected COVID-19.
Methods Parallel, double-blind, placebo-controlled, randomized, phase IIb clinical trial was performed with hospitalized patients aged ≥ 18 years with clinical, epidemiological and/or radiological suspected COVID-19, at a tertiary care facility in Manaus, Brazil. Patients were randomly allocated (1:1 ratio) to receive either intravenous MP (0.5 mg/kg) or placebo (saline solution), twice daily, for 5 days. A modified intention-to-treat (mITT) analysis was conducted. The primary outcome was 28-day mortality. ClinicalTrials Identifier NCT04343729.
Findings From April 18 to June 16, 2020, 647 patients were screened, 416 randomized, and 393 analyzed as mITT, MP in 194 and placebo in 199 individuals. SARS-CoV-2 infection was confirmed by RT-PCR in 81.3%. Mortality at day 28 was not different between groups. A subgroup analysis showed that patients over 60 years in the MP group had a lower mortality rate at day 28. Patients in the MP arm tended to need more insulin therapy, and no difference was seen in virus clearance in respiratory secretion until day 7.
Conclusion The findings of this study suggest that a short course of MP in hospitalized patients with COVID-19 did not reduce mortality in the overall population.

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11/08/2020 News
CORONAVIRUS: WILL THE WORLD BENEFIT FROM ANTIBODY THERAPIES?

NATURE

Authors
Heidi Ledford

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11/08/2020 Articles
The effect of 5-day course of hydroxychloroquine and azithromycin comb...

The effect of 5-day course of hydroxychloroquine and azithromycin combination on QT interval in non-ICU COVID19(+) patients

ELSEVIER

Authors
Nijad Bakhshaliyev, Mahmut Uluganyan, Asim Enhos, Erdem Karacop, Ramazan Ozdemir


ABSTRACT
Background: The combination of Hydroxychloroquine (HCQ) and azithromycin showed effectiveness as a treat- ment for COVID-19 and is being used widely all around the world. Despite that those drugs are known to cause prolonged QT interval individually there is no study assessing the impact of this combination on electrocar- diography (ECG). This study aimed to assess the impact of a 5-day course of HCQ and azithromycin combination on ECG in non-ICU COVID19(+) patients. Methods: In this retrospective observational study, we enrolled 109 COVID19(+) patients who required non-ICU hospitalization. All patients received 5-day protocol of HCQ and azithromycin combination. On-treatment ECGs were repeated 3-6 h after the second HCQ loading dose and 48-72 h after the first dose of the combination. ECGs were assessed in terms of rhythm, PR interval, QRS duration, QT and QTc intervals. Baseline and on- treatment ECG findings were compared. Demographic characteristics, laboratory results were recorded. Daily phone call-visit or bed-side visit were performed by attending physician. Results: Of the 109 patients included in the study, the mean age was 57.3 ± 14.4 years and 48 (44%) were male. Mean baseline PR interval was 158.47 ± 25.10 ms, QRS duration was 94.00 ± 20.55 ms, QTc interval was 435.28 ± 32.78 ms, 415.67 ± 28.51, 412.07 ± 25.65 according to Bazett's, Fridericia's and Framingham Heart Study formulas respectively. ΔPR was −2.94 ± 19.93 ms (p = .55), ΔQRS duration was 5.18 ± 8.94 ms (p = .03). ΔQTc interval was 6.64 ± 9.60 ms (p = .5), 10.67 ± 9.9 ms (p = .19), 14.14 ± 9.68 ms (p = .16) according to Bazett's, Fridericia's and Framingham Heart Study formulas respectively. There were no statistically significant differences between QTc intervals. No ventricular tachycardia, ventricular fibrillation or significant conduction delay was seen during follow-up. There was no death or worsening heart function. Conclusion: The 5-day course of HCQ- AZM combination did not lead to clinically significant QT prolongation and other conduction delays compared to baseline ECG in non-ICU COVID19(+) patients.

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10/08/2020 Articles
Early administration of lopinavir/ritonavir plus hydroxychloroquine do...

Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS‐CoV‐2 infection: a retrospective cohort study

WILEY ONLINE LIBRARY

Authors
Andrea Giacomelli, Gabriele Pagani, Anna Lisa Ridolfo, Letizia Oreni, Federico Conti, Laura Pezzati, Lucia Bradanini, Giacomo Casalini, Cinzia Bassoli, Valentina Morena, Simone Passerini, Giuliano Rizzardini, Chiara Cogliati, Elisa Ceriani, Riccardo Colombo, Stefano Rusconi, Cristina Gervasoni, Dario Cattaneo, Spinello Antinori, Massimo Galli


ABSTRACT
Background As it has been shown that lopinavir (LPV) and hydroxychloroquine (HCQ) have in vitro activity against coronaviruses, they were used to treat COVID‐19 during the first wave of the epidemic in Lombardy, Italy.
Methods To compare the rate of clinical improvement between those who started LPV/ritonavir (LPV/r)+HCQ within five days of symptom onset (early treatment, ET) and those who started later (delayed treatment, DT). This was a retrospective intent‐to‐treat analysis of the hospitalized patients who started LPV/r+HCQ between 21 February and 20 March 2020. The association between the timing of treatment and the probability of 30‐day mortality was assessed using uni‐ and multivariable logistic models.
Results The study involved 172 patients: 43 (25%) in the ET and 129 (75%) in the DT group. The rate of clinical improvement increased over time to 73.3% on day 30, without any significant difference between the two groups (Gray's test P=0.213). After adjusting for potentially relevant clinical variables, there was no significant association between the timing of the start of treatment and the probability of 30‐day mortality (adjusted odds ratio [aOR] ET vs DT=1.45, 95% confidence interval 0.50‐4.19). Eight percent of the patients discontinued the treatment because of severe gastrointestinal disorders attributable to LPV/r.
Conclusion The timing of the start of LPV/r+HCQ treatment does not seem to affect the clinical course of hospitalised patients with COVID‐19. Together with the severe adverse events attributable to LPV/r, this raises concerns about the benefit of using this combination to treat COVID‐19.

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09/08/2020 Reviews
SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Vi...

SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells

MDPI (INTERNATIONAL JOURNAL OF MOLECOLAR SCIENCES)

Authors
Rolando Cannalire, Irina Stefanelli, Carmen Cerchia, Andrea R. Beccari, Sveva Pelliccia, Vincenzo Summa

Abstract
The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.

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31/07/2020 Manuscript
The Multidimensional Challenge of Treating COVID-19: Remdesivir is a F...

The Multidimensional Challenge of Treating COVID-19: Remdesivir is a Foot in the Door

OXFORD ACADEMY

Authors
Rajesh T Gandhi



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31/07/2020 Articles
Recombinant SARS-CoV-2 spike S1-Fc fusion protein induced high levels ...

Recombinant SARS-CoV-2 spike S1-Fc fusion protein induced high levels of neutralizing responses in nonhuman primates

ELSEVIER

Authors
Wenlin Ren, Hunter Sun, George F. Gao, Jianxin Chen, Sean Sun, Rongqing Zhao, Guang Gao, Yalin Hu, Gan Zhao, Yuxin Chen, Xia Jin, Feng Fang, Jinggong Chen, Qi Wang, Sitao Gong, Wen Gao, Yufei Sun, Junchi Su, Ailiang He, Xin Cheng, Min Li, Chenxi Xia, Maohua Li, Le Sun



ABSTRACT
The COVID-19 outbreak has become a global pandemic responsible for over 2,000,000 confirmed cases and over 126,000 deaths worldwide. In this study, we examined the immunogenicity of CHO-expressed recombinant SARS-CoV-2 S1-Fc fusion protein in mice, rabbits, and monkeys as a potential candidate for a COVID-19 vaccine. We demonstrate that the S1-Fc fusion protein is extremely immunogenic, as evidenced by strong antibody titers observed by day 7. Strong virus neutralizing activity was observed on day 14 in rabbits immunized with the S1-Fc fusion protein using a pseudovirus neutralization assay. Most importantly, in <20 days and three injections of the S1-Fc fusion protein, two monkeys developed higher virus neutralizing titers than a recovered COVID-19 patient in a live SARS-CoV-2 infection assay. Our data strongly suggests that the CHO-expressed SARS-CoV-2 S1-Fc recombinant protein could be a strong candidate for vaccine development against COVID-19.

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30/07/2020 Research
Drug treatments for covid-19: living systematic review and network met...

Drug treatments for covid-19: living systematic review and network meta-analysis

THE BMJ

Authors
Reed AC Siemieniuk, Jessica J Bartoszko, Long Ge, Dena Zeraatkar, Ariel Izcovich, Hector Pardo-Hernandez, Bram Rochwerg, Francois Lamontagne, Mi Ah Han, Elena Kum, Qin Liu, Arnav Agarwal, Thomas Agoritsas, Paul Alexander, Derek K Chu, Rachel Couban, Andrea Darzi, Tahira Devji, Bo Fang, Carmen Fang, Signe Agnes Flottorp, Farid Foroutan, Diane Heels-Ansdell, Kimia Honarmand, Liangying Hou, Xiaorong Hou, Quazi Ibrahim, Mark Loeb, Maura Marcucci, Shelley L McLeod, Sharhzad Motaghi, Srinivas Murthy, Reem A Mustafa, John D Neary, Anila Qasim, Gabriel Rada, Irbaz Bin Riaz, Behnam Sadeghirad, Nigar Sekercioglu, Lulu Sheng, Charlotte Switzer, Britta Tendal, Lehana Thabane, George Tomlinson, Tari Turner, Per O Vandvik, Robin WM Vernooij, Andrés Viteri-García,Ying Wang, Liang Yao, Zhikang Ye, Gordon H Guyatt, Romina Brignardello-Petersen


ABSTRACT
Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19).
Design Living systematic review and network meta-analysis.
Data sources US Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020.
Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.
Methods After duplicate data abstraction, a bayesian random effects network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.
Results 23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation.
Conclusion Glucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.

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30/07/2020 PERSPECTIVE
Emerging evidence of a COVID-19 thrombotic syndrome has treatment impl...

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications

NATURE

Authors
Joan T. Merrill, Doruk Erkan, Jerald Winakur, Judith A. James



ABSTRACT
Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.

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29/07/2020 Manuscript
The risk of COVID-19 transmission in train passengers: an epidemiologi...

The risk of COVID-19 transmission in train passengers: an epidemiological and modelling study

OXFORD ACADEMY

Authors
Maogui Hu, Hui Lin, Jinfeng Wang, Chengdong Xu, Andrew J Tatem, Bin Meng, Xin Zhang, Yifeng Liu, Pengda Wang, Guizhen Wu, Haiyong Xie, Shengjie Lai



ABSTRACT
Background Train is a common mode of public transport across the globe; however, the risk of COVID-19 transmission among individual train passengers remains unclear.
Methods We quantified the transmission risk of COVID-19 on high-speed train passengers using data from 2,334 index patients and 72,093 close contacts who had co-travel times of 0–8 hours from 19 December 2019 through 6 March 2020 in China. We analysed the spatial and temporal distribution of COVID-19 transmission among train passengers to elucidate the associations between infection, spatial distance, and co-travel time.
Results The attack rate in train passengers on seats within a distance of 3 rows and 5 columns of the index patient varied from 0 to 10.3% (95% confidence interval [CI] 5.3% – 19.0%), with a mean of 0.32% (95%CI 0.29% – 0.37%). Passengers in seats on the same row as the index patient had an average attack rate of 1.5% (95%CI 1.3% – 1.8%), higher than that in other rows (0.14%, 95%CI 0.11% – 0.17%), with a relative risk (RR) of 11.2 (95%CI 8.6 –14.6). Travellers adjacent to the index patient had the highest attack rate (3.5%, 95%CI 2.9% – 4.3%) of COVID-19 infections (RR 18.0, 95%CI 13.9 – 23.4) among all seats. The attack rate decreased with increasing distance, but it increased with increasing co-travel time. The attack rate increased on average by 0.15% (p = 0.005) per hour of co-travel; for passengers at adjacent seats, this increase was 1.3% (p = 0.008), the highest among all seats considered.
Conclusions COVID-19 has a high transmission risk among train passengers, but this risk shows significant differences with co-travel time and seat location. During disease outbreaks, when travelling on public transportation in confined spaces such as trains, measures should be taken to reduce the risk of transmission, including increasing seat distance, reducing passenger density, and use of personal hygiene protection.

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28/07/2020 Articles
Computational Studies of SARS-CoV-2 3CLpro: Insights from MD Simulatio...

Computational Studies of SARS-CoV-2 3CLpro: Insights from MD Simulations

MDPI

Authors
Alessandro Grottesi, Neva Bešker, Andrew Emerson , Candida Manelfi, Andrea R. Beccari, Francesco Frigerio, Erik Lindahl ,Carmen Cerchia, Carmine Talarico

Abstract
Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most important proteins of the virus is an enzyme, called 3CLpro or main protease, already identified as an important pharmacological target also in SARS and Middle East respiratory syndrome virus (MERS) viruses. This protein triggers the production of a whole series of enzymes necessary for the virus to carry out its replicating and infectious activities. Therefore, it is crucial to gain a deeper understanding of 3CLpro structure and function in order to effectively target this enzyme. All-atoms molecular dynamics (MD) simulations were performed to examine the different conformational behaviors of the monomeric and dimeric form of SARS-CoV-2 3CLpro apo structure, as revealed by microsecond time scale MD simulations. Our results also shed light on the conformational dynamics of the loop regions at the entry of the catalytic site. Studying, at atomic level, the characteristics of the active site and obtaining information on how the protein can interact with its substrates will allow the design of molecules able to block the enzymatic function crucial for the virus.

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28/07/2020 Articles
Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SA...

Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS‐CoV‐2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti‐Infectives Study Group of the European Society of Antimicrobial Agents

CLINICAL PHARMACOKINETICS

Authors
Markus Zeitlinger, Birgit C P Koch, Roger Bruggemann, Pieter De Cock, Timothy Felton, Maya Hites, Jennifer Le, Sonia Luque, Alasdair P MacGowan, Deborah J E Marriott, Anouk E Muller, Kristina Nadrah, David L Paterson, Joseph F Standing, João P Telles, Michael Wölfl-Duchek, Michael Thy, Jason A Roberts



ABSTRACT
There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.

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28/07/2020 Reviews
Antiviral Agent Therapy Optimization in Special Populations of COVID-1...

Antiviral Agent Therapy Optimization in Special Populations of COVID-19 Patients

DOVEPRESS

Authors
Lu Li, Xiaojuan Wang, Rongrong Wang, Yunzhen Hu, Saiping Jiang, Xiaoyang Lu


ABSTRACT
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global outbreak of disease. The antiviral treatment acts as one of the most important means of SARS-CoV-2 infection. Alteration of physiological characteristics in special populations may lead to the change in drug pharmacokinetics, which may result in treatment failure or increased adverse drug reactions. Some potential drugs have shown antiviral effects on SARS-CoV-2 infections, such as chloroquine, hydroxychloroquine, favipiravir, lopinavir/ritonavir, arbidol, interferon alpha, and remedsivir. Here, we reviewed the literature on clinical effects in COVID-19 patients of these antiviral agents and provided the potential antiviral agent options for pregnant women, elderly patients, liver or renal dysfunction patients, and severe or critically ill patients receiving renal replacement therapy or ECMO after SARS-CoV-2 infection.

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24/07/2020 Articles
Discovery of SARS-CoV-2 antiviral drugs through large-scale compound r...

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

NATURE

Authors
Laura Riva, Shuofeng Yuan, Xin Yin, Laura Martin-Sancho, Naoko Matsunaga, Lars Pache, Sebastian Burgstaller-Muehlbacher, Paul D. De Jesus, Peter Teriete, Mitchell V. Hull, Max W. Chang, Jasper Fuk-Woo Chan, Jianli Cao, Vincent Kwok-Man Poon, Kristina M. Herbert, Kuoyuan Cheng, Tu-Trinh H. Nguyen, Andrey Rubanov, Yuan Pu, Courtney Nguyen, Angela Choi, Raveen Rathnasinghe, Michael Schotsaert, Lisa Miorin, Marion Dejosez, Thomas P. Zwaka, Ko-Yung Sit, Luis Martinez-Sobrido, Wen-Chun Liu, Kris M. White, Mackenzie E. Chapman, Emma K. Lendy, Richard J. Glynne, Randy Albrecht, Eytan Ruppin, Andrew D. Mesecar, Jeffrey R. Johnson, Christopher Benner, Ren Sun, Peter G. Schultz, Andrew I. Su, Adolfo García-Sastre, Arnab K. Chatterjee, Kwok-Yung Yuen & Sumit K. Chanda



ABSTRACT
The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. We report the identification of 100 molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely commensurate with achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2–4, and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334. Notably, MDL-28170, ONO 5334, and apilimod were found to antagonize viral replication in human iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.

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23/07/2020 Letter
High doses of hydroxychloroquine do not affect viral clearance in pati...

High doses of hydroxychloroquine do not affect viral clearance in patients with SARS-CoV-2 infection.

WILEY ONLINE LIBRARY

Authors
Lucia Taramasso, Antonio Di Biagio, Malgorzata Mikulska, Daniele Roberto, Giacobbe Antonio Vena, Chiara Dentone, Andrea De Maria, Emanuele Delfino, Marco Berruti, Chiara Russo, Andrea Orsi, Bianca Bruzzone, Matteo Bassetti



ABSTRACT
The use of hydroxychloroquine (HCQ) has been considered a therapeutic option by international guidelines and expert opinions during the first phase of COVID‐19 pandemics, 1‐10 although scientific evidence remained too scarce to make a definitive recommendation 11. While HCQ use has now been questioned by recent data 7, some previous works draw attention to contrasting results on enhanced viral clearance after HCQ treatment

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23/07/2020 Articles
Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Co...

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
A.B. Cavalcanti, F.G. Zampieri, R.G. Rosa, L.C.P. Azevedo, V.C. Veiga, A. Avezum, L.P. Damiani, A. Marcadenti, L. Kawano-Dourado, T. Lisboa, D.L.M. Junqueira, P.G.M. de Barros e Silva, L. Tramujas, E.O. Abreu-Silva, L.N. Laranjeira, A.T. Soares, L.S. Echenique, A.J. Pereira, F.G.R. Freitas, O.C.E. Gebara, V.C.S. Dantas, R.H.M. Furtado, E.P. Milan, N.A. Golin, F.F. Cardoso, I.S. Maia, C.R. Hoffmann Filho, A.P.M. Kormann, R.B. Amazonas, M.F. Bocchi de Oliveira, A. Serpa-Neto, M. Falavigna, R.D. Lopes, F.R. Machado, O. Berwanger



ABSTRACT
BACKGROUND Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.
METHODS We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.
RESULTS A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P=1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P=1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.
CONCLUSIONS Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123. opens in new tab.)

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22/07/2020 Articles
Chloroquine does not inhibit infection of human lung cells with SARS-C...

Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2

NATURE

Authors
Markus Hoffmann, Kirstin Mösbauer, Heike Hofmann-Winkler, Artur Kaul, Hannah Kleine-Weber, Nadine Krüger, Nils C. Gassen, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann



ABSTRACT
The COVID-19 pandemic, which is caused by the novel coronavirus SARS-CoV-2, has been associated with more than 470,000 fatal cases worldwide. In order to develop antiviral interventions quickly, drugs used for treatment of unrelated diseases are currently being repurposed to combat COVID-19. Chloroquine is a anti-malaria drug that is frequently employed for COVID-19 treatment since it inhibits SARS-CoV-2 spread in the kidney-derived cell line Vero1–3. Here, we show that engineered expression of TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells4, renders SARS-CoV-2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block SARS-CoV-2 infection of the TMPRSS2-positive lung cell line Calu-3. These results indicate that chloroquine targets a pathway for viral activation that is not operative in lung cells and is unlikely to protect against SARS-CoV-2 spread in and between patients.

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21/07/2020 Articles
A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-...

A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0

MDPI

Authors
Silvia Gervasoni, Giulio Vistoli Carmine Talarico, Candida Manelfi, Andrea R. Beccari, Gabriel Studer, Gerardo Tauriello, Andrew Mark Waterhouse, Torsten Schwede, Alessandro Pedretti

Abstract
(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies; (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines); such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs; (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection; and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download.

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20/07/2020 Articles
Immunogenicity and safety of a recombinant adenovirus type-5-vectored ...

Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo- controlled, phase 2 trial

THE LANCET

Authors
Feng-Cai Zhu, Xu-Hua Guan, Yu-Hua Li, Jian-Ying Huang, Tao Jiang, Li-Hua Hou, Jing-Xin Li, Bei-Fang Yang, Ling Wang, Wen-Juan Wang, Shi-Po Wu, Zhao Wang, Xiao-Hong Wu, Jun-Jie Xu, Zhe Zhang, Si-Yue Jia, Bu-Sen Wang, Yi Hu, Jing-Jing Liu, Jun Zhang, Xiao-Ai Qian, Qiong Li, Hong-Xing Pan, Hu-Dachuan Jiang, Peng Deng, Jin-Bo Gou, Xue-Wen Wang, Xing-Huan Wang, Wei Chen


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20/07/2020 Articles
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-...

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

THE LANCET

Authors
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


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16/07/2020 Communication
Convalescent plasma treatment for SARS-CoV-2 infection: analysis of th...

Convalescent plasma treatment for SARS-CoV-2 infection: analysis of the first 436 donors in England, 22 April to 12 May 2020

EUROSUIRVELLANCE

Authors
Heli Harvala, Jennifer Mehew, Matthew L Robb, Samreen Ijaz, Steven Dicks, Monika Patel, Nicholas Watkins, Peter Simmonds, Tim Brooks, Rachel Johnson, Robin Gopal, David J Roberts, Maria Zambon



ABSTRACT
Serological reactivity was analysed in plasma from 436 individuals with a history of disease compatible with COVID-19, including 256 who had been laboratory-confirmed with SARS-CoV-2 infection. Over 99% of laboratory-confirmed cases developed a measurable antibody response (254/256) and 88% harboured neutralising antibodies (226/256). Antibody levels declined over 3 months following diagnosis, emphasising the importance of the timing of convalescent plasma collections. Binding antibody measurements can inform selection of convalescent plasma donors with high neutralising antibody levels.

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16/07/2020 Articles
Pharmacological and non-pharmacological efforts at prevention, mitigat...

Pharmacological and non-pharmacological efforts at prevention, mitigation, and treatment for COVID-19

FRANCIS & TAYLOR ONLINE

Authors
Mohammed M. Alvi ,Sowmya Sivasankaran, Mahima Singh



ABSTRACT
A global outbreak of the SARS-CoV-2 virus has infected millions of people over a short period of time. The communicability and increased mortality from the SARS-CoV-2 infection mandated the WHO to declare COVID-19 a worldwide pandemic. The virus outbreak has spread when there are no approved vaccines, treatments, or prophylactic therapies available. Researchers from all over the world have prioritised development of vaccines and antivirals. Several vaccine projects have seen successes in preclinical, phase I, and phase II clinical trials using recombinant DNA, mRNA, live attenuated virus, S-protein subunits, virus like particles, and viral vectors. Initial findings from antivirals such as remdesivir, favipiravir, danoprevir or lopinavir with ritonavir are presented. Immunomodulatory molecules such as sarilumab, tocilizumab, janus kinase inhibitors, and hyperimmune convalescent plasma have mixed outcomes from initial clinical findings; however, pending randomised controlled trials will assist national health institutions to make treatment recommendations for COVID-19. Where compassionate use of remdesivir has shown some benefits, therapies such as hydroxychloroquine have proven harmful due to their toxicities. This review discusses pharmacological interventions at play and evidence-based successes and limitations of non-pharmacological therapies such as social distancing, personal protective equipment, and ventilator support associated with the prevention and treatment of COVID-19.

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14/07/2020 Articles
An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
L.A. Jackson, E.J. Anderson, N.G. Rouphael, P.C. Roberts, M. Makhene, R.N. Coler, M.P. McCullough, J.D. Chappell, M.R. Denison, L.J. Stevens, A.J. Pruijssers, A. McDermott, B. Flach, N.A. Doria-Rose, K.S. Corbett, K.M. Morabito, S. O’Dell, S.D. Schmidt, P.A. Swanson II, M. Padilla, J.R. Mascola, K.M. Neuzil, H. Bennett, W. Sun, E. Peters, M. Makowski, J. Albert, K. Cross, W. Buchanan, R. Pikaart-Tautges, J.E. Ledgerwood, B.S. Graham, J.H. Beigel



ABSTRACT
BACKGROUND The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.
METHODS We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.
RESULTS After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.
CONCLUSIONS The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461. opens in new tab).

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13/07/2020 Highlights
Successful treatment with plasma exchange followed by intravenous immu...

Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19

ELSEVIER

Authors
Hua Shi, Chaomin Zhoua, Pinghong Hea, Sheng Huang, Youjun Duanb, Xuesheng Wang , Kexiong Linb, Chao Zhoub, Xiangyan Zhangc, Yan Zhaa



ABSTRACT
Here we report a case of a laboratory-confirmed 2019 novel coronavirus (2019-nCoV)-infected patient with COVID-19 (coronavirus disease 2019) who developed respiratory failure and shock accompanied by persistent diarrhoea despite conventional therapeutic interventions. The patient avoided mechanical ventilation and showed an immediate clinical and radiological improvement following treatment with intensive plasma exchange (PE) followed by intravenous immunoglobulin (IVIG). Successful therapeutic strategies in this case suggest that timely initiation of PE treatment followed by IVIG in critically ill patients with COVID-19 may prevent the disease from worsening and help to reduce the requirement for mechanical ventilation and intensive supportive care. Moreover, it may improve poor clinical outcomes of these patients.

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13/07/2020 Articles
Immune-mediated approaches against COVID-19

NATURE

Authors
Helena F. Florindo, Ron Kleiner, Daniella Vaskovich-Koubi, Rita C. Acúrcio, Barbara Carreira, Eilam Yeini, Galia Tiram, Yulia Liubomirski, Ronit Satchi-Fainaro



ABSTRACT
The coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The long incubation period of this new virus, which is mostly asymptomatic yet contagious, is a key reason for its rapid spread across the world. Currently, there is no worldwide-approved treatment for COVID-19. Therefore, the clinical and scientific communities have joint efforts to reduce the severe impact of the outbreak. Research on previous emerging infectious diseases have created valuable knowledge that is being exploited for drug repurposing and accelerated vaccine development. Nevertheless, it is important to generate knowledge on SARS-CoV-2 mechanisms of infection and its impact on host immunity, to guide the design of COVID-19 specific therapeutics and vaccines suitable for mass immunization. Nanoscale delivery systems are expected to play a paramount role in the success of these prophylactic and therapeutic approaches. This Review provides an overview of SARS-CoV-2 pathogenesis and examines immune-mediated approaches currently explored for COVID-19 treatments, with an emphasis on nanotechnological tools.

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12/07/2020 Letter
Insights from compassionate use of tocilizumab for COVID‐19 to inform ...

Insights from compassionate use of tocilizumab for COVID‐19 to inform appropriate design of randomised controlled trials

BRITISH PHARMACOLOGICAL SOCIETY

Authors
Emma H. Baker Kamal Patel Jonathan Ball Sarah Edwards Thomas S. Harrison Arvind Kaul Mickey Koh Sanjeev Krishna Susannah Leaver Vinodh Kumar Daniel M. Forton


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10/07/2020 Reviews
That Escalated Quickly: Remdesivir's Place in Therapy

SPRINGER LINK

Authors
Matthew R. Davis, Erin K. McCreary, Jason M. Pogue



ABSTRACT
Remdesivir is a nucleoside antiviral recently studied in several randomized trials for treatment of COVID-19. The available observational and prospective data are conflicting, requiring clinicians to critically evaluate and reconcile results to determine patient populations that may optimally benefit from remdesivir therapy, especially while drug supply is scarce. In this review, we analyze pertinent clinical remdesivir data for patients with COVID-19 from January 1, 2020, through May 31, 2020.

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09/07/2020 Comment
Retraction and republication: cardiac toxicity of hydroxychloroquine i...

Retraction and republication: cardiac toxicity of hydroxychloroquine in COVID-19

THE LANCET

Authors
Christian Funck-Brentano, Lee S Nguyen, Joe-Elie Salem


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09/07/2020 Reviews
Current pharmacological modalities for management of novel coronavirus...

Current pharmacological modalities for management of novel coronavirus disease 2019 (COVID‐19) and the rationale for their utilization: A review

WILEY ONLINE LIBRARY

Authors
Richard A. Giovane, Shadi Rezai, Ellen Cleland, Cassandra E. Henderson



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03/07/2020 Articles
COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus ...

COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study

PRE PRINTS

Authors
Martin Scholz , Roland Derwand , Vladimir Zelenko



ABSTRACT
Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-60; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.

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02/07/2020 Articles
A candidate multi‐epitope vaccine against SARS‐CoV‐2

NATURE

Authors
Tamalika Kar, Utkarsh Narsaria, Srijita Basak, Debashrito Deb, Filippo Castiglione, David M. Mueller, Anurag P. Srivastava



ABSTRACT
In the past two decades, 7 coronaviruses have infected the human population, with two major outbreaks caused by SARS-CoV and MERS-CoV in the year 2002 and 2012, respectively. Currently, the entire world is facing a pandemic of another coronavirus, SARS-CoV-2, with a high fatality rate. The spike glycoprotein of SARS-CoV-2 mediates entry of virus into the host cell and is one of the most important antigenic determinants, making it a potential candidate for a vaccine. In this study, we have computationally designed a multi-epitope vaccine using spike glycoprotein of SARS-CoV-2. The overall quality of the candidate vaccine was validated in silico and Molecular Dynamics Simulation confirmed the stability of the designed vaccine. Docking studies revealed stable interactions of the vaccine with Toll-Like Receptors and MHC Receptors. The in silico cloning and codon optimization supported the proficient expression of the designed vaccine in E. coli expression system. The efficiency of the candidate vaccine to trigger an effective immune response was assessed by an in silico immune simulation. The computational analyses suggest that the designed multi-epitope vaccine is structurally stable which can induce specific immune responses and thus, can be a potential vaccine candidate against SARS-CoV-2.

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02/07/2020 Articles
Treatment with Hydroxychloroquine, Azithromycin, and Combination in Pa...

Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19

ELSEVIER

Authors
Samia Arshad, Paul Kilgore, Zohra S. Chaudhry, Gordon Jacobsen, Dee Dee Wang, Kylie Huitsing, Indira Brar, George J. Alangaden, Mayur S. Ramesh, John E. McKinnon, William O’Neill, Marcus Zervos, Henry Ford, Varidhi Nauriyal, Asif Abdul Hamed, Owais Nadeem, Jennifer Swiderek, Amanda Godfrey, Jeffrey Jennings, Jayna Gardner-Gray, Adam M Ackerman, Jonathan Lezotte, Joseph Ruhala, Raef Fadel, Amit Vahia, Smitha Gudipati, Tommy Parraga, Anita Shallal, Gina Maki, Zain Tariq, Geehan Suleyman, Nicholas Yared, Erica Herc, Johnathan Williams, Odaliz Abreu Lanfranco, Pallavi Bhargava, Katherine Reyes, Anne Chen



ABSTRACT
Significance The United States is in an acceleration phase of the COVID-19 pandemic. Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies. Objective The purpose of this study was to evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19. Design Multi-center retrospective observational study Setting The Henry Ford Health System (HFHS) in Southeast Michigan: large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan. Participants Consecutive patients hospitalized with a COVID-related admission in the health system from March 10,2020 to May 2,2020 were included. Only the first admission was included for patients with multiple admissions. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48 hours unless expired within 24 hours. Exposure Receipt of hydroxychloroquine alone, hydroxychloroquine in combination with azithromycin, azithromycin alone, or neither. Main Outcome The primary outcome was in-hospital mortality. Results Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4-10 days), median age was 64 years (IQR:53-76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3-53). Overall in-hospital mortality was 18.1% (95% CI:16.6%-19.7%); by treatment: hydroxychloroquine + azithromycin, 157/783 (20.1% [95% CI: 17.3%-23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%-15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%-30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%-31.0%])​. Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age>65 years (HR:2.6 [95% CI:1.9-3.3]), white race (HR:1.7 [95% CI:1.4-2.1]), CKD (HR:1.7 [95%CI:1.4-2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1-2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4-3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment (p < 0.001). Conclusions and Relevance In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Prospective trials are needed to examine this impact.

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02/07/2020 Editorial
Potential drug‐drug interactions associated with drugs currently propo...

Potential drug‐drug interactions associated with drugs currently proposed for COVID‐19 treatment in patients receiving other treatments

WILEY ONLINE LIBRARY

Authors
Nicolas Venisse



ABSTRACT
Pharmacologists, pharmacists and other drug experts have been at the forefront during the COVID‐19 outbreak. Pharmacological expertise was required in various areas such as the daily healthcare of patients admitted to our hospitals [1], the implementation of pharmacokinetic and pharmacokinetic‐pharmacodynamic studies in clinical trials of repurposed drugs [2] and even in providing up‐to‐date information to the general population [3].

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01/07/2020 Advanced Research
COVID-19 Resources

AMERICAN SOCIETY OF HEMATOLOGY

Authors
AMERICAN SOCIETY OF HEMATOLOGY


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01/07/2020 Research
Treatment with ACE inhibitors or ARBs and risk of severe/lethal COVID-...

Treatment with ACE inhibitors or ARBs and risk of severe/lethal COVID-19: a meta-analysis

BMJ JOURNALS

Authors
Maria Elena Flacco, Cecilia Acuti Martellucci, Francesca Bravi, Giustino Parruti, Rosaria Cappadona, Alfonso Mascitelli, Roberto Manfredini, Lorenzo G Mantovani, Lamberto Manzoli



ABSTRACT
Objective It has been hypothesised that the use of ACE inhibitors and angiotensin receptor blockers (ARBs) might either increase or reduce the risk of severe or lethal COVID-19. The findings from the available observational studies varied, and summary estimates are urgently needed to elucidate whether these drugs should be suspended during the pandemic, or patients and physicians should be definitely reassured. This meta-analysis of adjusted observational data aimed to summarise the existing evidence on the association between these medications and severe/lethal COVID-19. Methods We searched MedLine, Scopus and preprint repositories up to 8 June 2020 to retrieve cohort or case–control studies comparing the risk of severe/fatal COVID-19 (either mechanical ventilation, intensive care unit admission or death), among hypertensive subjects treated with: (1) ACE inhibitors, (2) ARBs and (3) both, versus untreated subjects. Data were combined using a random-effect generic inverse variance approach. Results Ten studies, enrolling 9890 hypertensive subjects were included in the analyses. Compared with untreated subjects, those using either ACE inhibitors or ARBs showed a similar risk of severe or lethal COVID-19 (summary OR: 0.90; 95% CI 0.65 to 1.26 for ACE inhibitors; 0.92; 95% CI 0.75 to 1.12 for ARBs). The results did not change when both drugs were considered together, when death was the outcome and excluding the studies with significant, divergent results. Conclusion The present meta-analysis strongly supports the recommendation of several scientific societies to continue ARBs or ACE inhibitors for all patients, unless otherwise advised by their physicians who should thus be reassured.

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01/07/2020 Articles
Identification of a druggable binding pocket in the spike protein reve...

Identification of a druggable binding pocket in the spike protein reveals a key site for existing drugs potentially capable of combating Covid-19 infectivity

BMC

Authors
Elliot D. Drew, Robert W. Janes



ABSTRACT
Background Following the recent outbreak of the new coronavirus pandemic (Covid-19), the rapid determination of the structure of the homo-trimeric spike glycoprotein has prompted the study reported here. The aims were to identify potential “druggable” binding pockets in the protein and, if located, to virtual screen pharmaceutical agents currently in use for predicted affinity to these pockets which might be useful to restrict, reduce, or inhibit the infectivity of the virion.
Results Our analyses of this structure have revealed a key potentially druggable pocket where it might be viable to bind pharmaceutical agents to inhibit its ability to infect human cells. This pocket is found at the inter-chain interface that exists between two domains prior to the virion binding to human Angiotensin Converting Enzyme 2 (ACE2) protein. One of these domains is the highly mobile receptor binding domain, which must move into position to interact with ACE2, which is an essential feature for viral entry to the host cell. Virtual screening with a library of purchasable drug molecules has identified pharmaceuticals currently in use as prescription and over the counter medications that, in silico, readily bind into this pocket.
Conclusions This study highlights possible drugs already in use as pharmaceuticals that may act as agents to interfere with the movements of the domains within this protein essential for the infectivity processes and hence might slow, or even halt, the infection of host cells by this new coronavirus. As these are existing pharmaceuticals already approved for use in humans, this knowledge could accelerate their roll-out, through repurposing, for affected individuals and help guide the efforts of other researchers in finding effective treatments for the disease.

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29/06/2020 Articles
Numerical evaluation of spray position for improved nasal drug deliver...

Numerical evaluation of spray position for improved nasal drug delivery

NATURE

Authors
Saikat Basu, Landon T. Holbrook, Kathryn Kudlaty, Olulade Fasanmade, Jihong Wu, Alyssa Burke, Benjamin W. Langworthy, Zainab Farzal, Mohammed Mamdani, William D. Bennett, Jason P. Fine, Brent A. Senior, Adam M. Zanation, Charles S. Ebert Jr., Adam J. Kimple, Brian D. Thorp, Dennis O. Frank-Ito, Guilherme J. M. Garcia, Julia S. Kimbell


ABSTRACT
Topical intra-nasal sprays are amongst the most commonly prescribed therapeutic options for sinonasal diseases in humans. However, inconsistency and ambiguity in instructions show a lack of definitive knowledge on best spray use techniques. In this study, we have identified a new usage strategy for nasal sprays available over-the-counter, that registers an average 8-fold improvement in topical delivery of drugs at diseased sites, when compared to prevalent spray techniques. The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Simulated dose in representative models is validated through in vitro spray measurements in 3D-printed anatomic replicas using the gamma scintigraphy technique. This work breaks new ground in proposing an alternative user-friendly strategy that can significantly enhance topical delivery inside human nose. While these findings can eventually translate into personalized spray usage instructions and hence merit a change in nasal standard-of-care, this study also demonstrates how relatively simple engineering analysis tools can revolutionize everyday healthcare. Finally, with respiratory mucosa as the initial coronavirus infection site, our findings are relevant to intra-nasal vaccines that are in-development, to mitigate the COVID-19 pandemic.

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29/06/2020 Reviews
Drug targets for COVID-19 therapeutics: Ongoing global efforts

SPRINGER LINK

Authors
Ambrish Saxena



ABSTRACT
The current global pandemic COVID-19 caused by the SARS-CoV-2 virus has already inflicted insurmountable damage both to the human lives and global economy. There is an immediate need for identification of effective drugs to contain the disastrous virus outbreak. Global efforts are already underway at a war footing to identify the best drug combination to address the disease. In this review, an attempt has been made to understand the SARS-CoV-2 life cycle, and based on this information potential druggable targets against SARS-CoV-2 are summarized. Also, the strategies for ongoing and future drug discovery against the SARS-CoV-2 virus are outlined. Given the urgency to find a definitive cure, ongoing drug repurposing efforts being carried out by various organizations are also described. The unprecedented crisis requires extraordinary efforts from the scientific community to effectively address the issue and prevent further loss of human lives and health.

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28/06/2020 Articles
Effects of Hydroxychloroquine Treatment on QT Interval

ELSEVIER

Authors
MatthewHooks, Bradley Barty, OrlyVardeny, Anders Westanmo, Selçuk Adabag



ABSTRACT
Background Hydroxychloroquine (HCQ) has been promoted as a potential treatment for COVID-19 but there are safety concerns.
Objectives To determine the effect of HCQ treatment on QT interval
Methods We retrospectively studied the electrocardiograms of 819 patients treated with HCQ for rheumatologic diseases from 2000 to 2020. The primary outcome was corrected QT (QTc) interval, by Bazett formula, during HCQ therapy.
Results The patients were 64.0 (±10.9) years in age and 734 (90%) were men. The median dosage and duration of HCQ were 400mg daily and 1006 (471-2075) days, respectively. The mean on-treatment QTc was 430.9 (±31.8) msec. In total, 55 (7%) patients had QTc 470-500 msec and 12 (1.5%) had QTc >500msec. Chronic kidney disease (CKD), history of atrial fibrillation (AF) and heart failure were independent risk factors for prolonged QTc. In a subset of 591 patients who also had a pre-treatment ECG, the mean QTc increased from 424.4 (±29.7) msec. to 432.0 (±32.3) msec (p<0.0001) during HCQ treatment. Of these, 23 (3.9%) patients had either prolongation of QTc >15% or an on-treatment QTc >500 msec. Over 5.97 (3.33-10.11) years of follow-up, 269 (33%) patients died. QTc >470 msec during HCQ treatment was associated with a greater mortality risk of (hazard ratio 1.78, 95% confidence interval 1.16-2.71; p=0.008) in univariable but not in multivariable analysis.
Conclusion Hydroxychloroquine is associated with QT prolongation in a significant fraction of patients. The risk of QT prolongation is higher among patients with CKD, AF and heart failure, who may benefit from greater scrutiny.

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27/06/2020 Reviews
Corticosteroid administration for viral pneumonia: COVID-19 and beyond

ELSEVIER

Authors
W.Yang, L.Yang, R.-G.Luo, J.-F.Xu



ABSTRACT
Background Corticosteroids are commonly used as adjuvant therapy for acute respiratory distress syndrome by many clinicians because of their perceived anti-inflammatory effects. However, for patients with severe viral pneumonia, the corticosteroid treatment is highly controversial.
Objectives The purpose of this review is to systematically evaluate the effect and potential mechanism of corticosteroid administration in pandemic viral pneumonia.
Sources We comprehensively searched all manuscripts on corticosteroid therapy for influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and SARS coronavirus 2 (SARS-CoV-2) viral pneumonia from the PubMed, EMBASE, Web of Science and Cochrane Library databases.
Content We systematically summarized the effects of corticosteroid therapy for pandemic viral pneumonia and the potential mechanism of action for corticosteroids in coronavirus disease 2019 (COVID-19).
Implications Observational studies showed that corticosteroid treatment was associated with increased mortality and nosocomial infections for influenza and delayed virus clearance for SARS-CoV and MERS-CoV. Limited data on corticosteroid therapy for COVID-19 were reported. Corticosteroids were used in about a fifth of patients (670/2995, 22.4%). Although clinical observational studies reported the improvement in symptoms and oxygenation for individuals with severe COVID-19 who received corticosteroid therapy, case fatality rate in the corticosteroid group was significantly higher than that in the non-corticosteroid group (69/443, 15.6% versus 56/1310, 4.3%). Compared individuals with non-severe disease, those with severe disease were more likely to receive corticosteroid therapy (201/382, 52.6% versus 201/1310, 15.3%). Although there is no evidence that corticosteroid therapy reduces mortality in people with COVID-19, some improvements in clinical symptoms and oxygenation were reported in some clinical observational studies. Excessive inflammatory response and lymphopenia might be critical factors associated with severity of and mortality from COVID-19. Sufficiently powered randomized controlled trials with rigorous inclusion/exclusion criteria and standardized dose and duration of corticosteroids are needed to verify the effectiveness and safety of corticosteroid therapy.

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27/06/2020 Articles
Ventricular Arrhythmia Risk Based on Ethnicity in COVID-19 Patients on...

Ventricular Arrhythmia Risk Based on Ethnicity in COVID-19 Patients on Hydroxychloroquine and Azithromycin Combination: Viewpoint

SPRINGER LINK

Authors
Sayak Roy, MainakMukhopadhyay



ABSTRACT
There are many reports available now, which are mostly observational or registry trial outcomes having varied results on coronavirus 2019 (COVID-19) patients put on hydroxychloroquine and azithromycin combination. Some are showing increased in-hospital mortality and ventricular arrhythmia increase, while some are showing overall benefit with significant viral RNA load reduction. Everyday things are getting more complicated with the publication of these different outcomes. This needs to be addressed.

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27/06/2020 Case Report
Successful recovery from COVID-19 pneumonia after receiving baricitini...

Successful recovery from COVID-19 pneumonia after receiving baricitinib, tocilizumab, and remdesivir. A case report: Review of treatments and clinical role of computed tomography analysis

ELSEVIER

Authors
Pietro Sodani, Luciano Mucci, Rita Girolimetti, Silvia Tedesco, Francesca Monaco, Daniele Campanozzi, Marino Brunori, Stefania Maltoni, Samuele Bedetta, Anna M. Di Carlo, Piero Candoli, Mauro Mancini, Alberto Rebonato, Francesca D'Adamo, Maria Capalbo, Gabriele Frausini



ABSTRACT
The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic, threatening global public health. In the current paper, we describe our successful treatment of one COVID-19 pneumonia patient case with high mortality risk factors. Our experience underlines the importance of the use of a multidisciplinary therapeutic approach in order to achieve a favorable clinical outcome. Further, enhancing the capability of the COVID-19 diagnosis with the use of the chest imaging modalities is discussed.

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27/06/2020 News
New potential interaction with emergency COVID-19 medicine remdesivir

SPRINGER LINK

Authors
SPRINGER LINK


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26/06/2020 Comment
Can tocilizumab calm the cytokine storm of COVID-19?

THE LANCET

Authors
Grant S Schulert


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25/06/2020 Press Release
First COVID-19 treatment recommended for EU authorisation

EUROPEAN MEDICINES AGENCY

Authors
EMA press office


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24/06/2020 Articles
Tocilizumab in patients with severe COVID-19: a retrospective cohort s...

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

THE LANCET

Authors
Giovanni Guaraldi, Marianna Meschiari, Alessandro Cozzi-Lepri, Jovana Milic, Roberto Tonelli, Marianna Menozzi, Erica Franceschini, Gianluca Cuomo, Gabriella Orlando, Vanni Borghi, Antonella Santoro, Margherita Di Gaetano, Cinzia Puzzolante, Federica Carli, Andrea Bedini, Luca Corradi, Riccardo Fantini, Ivana Castaniere, Luca Tabbì, Massimo Girardis, Sara Tedeschi, Maddalena Giannella, Michele Bartoletti, Renato Pascale, Giovanni Dolci, Lucio Brugioni, Antonello Pietrangelo, Andrea Cossarizza, Federico Pea, Enrico Clini, Carlo Salvarani, Marco Massari, Pier Luigi Viale, Cristina Mussini


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24/06/2020 Original Investigation
Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biom...

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019

JAMA

Authors
Spyridon G. Deftereos, Georgios Giannopoulos Dimitrios A. Vrachatis, Gerasimos D. Siasos, Sotiria G. Giotaki, Panagiotis Gargalianos, Simeon Metallidis, George Sianos, Stefanos Baltagiannis, Periklis Panagopoulos, Konstantinos Dolianitis, Efthalia Randou, Konstantinos Syrigos, Anastasia Kotanidou, Nikolaos G. Koulouris, Haralampos Milionis, Nikolaos Sipsas, Charalampos Gogos, George Tsoukalas, Christoforos D. Olympios, Eleftheria Tsagalou, Ilias Migdalis, Styliani Gerakari, Christos Angelidis, Dimitrios Alexopoulos, Pericles Davlouros, George Hahalis, Ioannis Kanonidis, Demosthenes Katritsis, Theofilos Kolettis, Antonios S. Manolis, Lampros Michalis, Katerina K. Naka, Vlasios N. Pyrgakis, Konstantinos P. Toutouzas, Filippos Triposkiadis, Konstantinos Tsioufis, Emmanouil Vavouranakis, Luis Martinèz-Dolz, Bernhard Reimers, Giulio G. Stefanini, Michael Cleman, John Goudevenos, Sotirios Tsiodras, Dimitrios Tousoulis, Efstathios Iliodromitis, Roxana Mehran, George Dangas, Christodoulos Stefanadis


ABSTRACT
Importance Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile.
Objective To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19).
Design, Setting, and Participants In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece.
Intervention Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks.
Main Outcomes and Measures Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis.
Results A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003).
Conclusions and Relevance In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution.

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22/06/2020 Articles
COVID-19 treatment: Combining anti-inflammatory and antiviral therapeu...

COVID-19 treatment: Combining anti-inflammatory and antiviral therapeutics using a network-based approach

CLEVELAND CLINICLE JOURNAL OF MEDICINE

Authors
Feixiong Cheng, Sujata Rao, Reena Mehra



ABSTRACT
To date, there are no effective antiviral medications for COVID-19. Drug repurposing, a strategy that uses existing drugs, offers potential prevention and treatment options for COVID-19. We discuss one treatment strategy that combines anti-inflammatory (melatonin) and antiviral (toremifene) agents for patients infected with SARS-CoV-2 from network medicine-based findings. We also describe the pathobiology and immunologic characteristics of COVID-19 and highlight the rationale of combination drug treatment to rescue the pulmonary and cardiovascular conditions resulting from COVID-19. A preliminary analysis reveals a high potential for the synergistic effects of melatonin and toremifene to reduce viral infection and replication, and the aberrant host inflammatory responses, offering strong biologic plausibility as an effective therapy for COVID-19.

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22/06/2020 Comment
Use of aerosolised medications at home for COVID-19

THE LANCET

Authors
Arzu Ari


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21/06/2020 Letter
Clinical feedback from experience with COVID-19: specific consideratio...

Clinical feedback from experience with COVID-19: specific considerations for ExtraCorporeal Membrane Oxygenation

ELSEVIER

Authors
Antonio Fiore, Quentinde Roux, Nejla Daami, Simon Clariot, Thierry Folliguet, Fabio SilvioT accone, Nicolas Mongardon



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19/06/2020 Articles
Structure-based design of antiviral drug candidates targeting the SARS...

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

SCIENCE

Authors
Wenhao Dai, Bing Zhang, Xia-Ming Jiang, Haixia Su, Jian Li, Yao Zhao, Xiong Xie, Zhenming Jin, Jingjing Peng, Fengjiang Liu, Chunpu Li, You Li , Fang Bai, Haofeng Wang, Xi Cheng, Xiaobo Cen , Shulei Hu, Xiuna Yang, Jiang Wang, Xiang Liu, Gengfu Xiao, Hualiang Jiang, Zihe Rao, Lei-Ke Zhang, Yechun Xu, Haitao Yang, Hong Liu



ABSTRACT
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

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18/06/2020 Editorial
The Urgency of Care during the Covid-19 Pandemic — Learning as We Go

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Eric J. Rubin, David P. Harrington, Joseph W. Hogans, Constantine Gatsonis, Lindsey R. Baden, Mary Beth Hamel


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17/06/2020 Research Letter
Prone Positioning in Awake, Nonintubated Patients With COVID-19 Hypoxe...

Prone Positioning in Awake, Nonintubated Patients With COVID-19 Hypoxemic Respiratory Failure

JAMA

Authors
Alison E. Thompson, Benjamin L. Ranard, Ying Wei, Sanja Jelic


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16/06/2020 Articles
GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and sys...

GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study

THE LANCET

Authors
Giacomo De Luca, Giulio Cavalli, Corrado Campochiaro, Emanuel Della-Torre, Piera Angelillo, Alessandro Tomelleri, Nicola Boffini, Stefano Tentori, Francesca Mette, Nicola Farina, Patrizia Rovere-Querini, Annalisa Ruggeri, Teresa D’Aliberti, Paolo Scarpellini, Giovanni Landoni, Francesco De Cobelli, John F Paolini, Alberto Zangrillo, Moreno Tresoldi, Bruce C Trapnell, Fabio Ciceri, Lorenzo Dagna

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08/06/2020 Articles
Association between angiotensin blockade and COVID-19 severity in Hong...

Association between angiotensin blockade and COVID-19 severity in Hong Kong

CMAJ

Authors
Ka Shing Cheung, Ivan F.N. Hung, Wai K. Leung


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08/06/2020 Articles
Re-envisioning Discharge Planning and Expanding Post-Acute Care Capaci...

Re-envisioning Discharge Planning and Expanding Post-Acute Care Capacity During a Pandemic

NEJM CATALYST

Authors
Amelia Shapiro, Nancy O’Toole, Donna Tinling-Solages, Timothy McGarvey, Michael Tretola, Paul Dunphey


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04/06/2020 ORIGINAL INVESTIGATION
Association of Noninvasive Oxygenation Strategies With All-Cause Morta...

Association of Noninvasive Oxygenation Strategies With All-Cause Mortality in Adults With Acute Hypoxemic Respiratory Failure A Systematic Review and Meta-analysis

JAMA

Authors
Bruno L. Ferreyro, Federico Angriman, Laveena Munshi, Lorenzo Del Sorbo, Niall D. Ferguson, Bram Rochwerg, Michelle J. Ryu, Refik Saskin, Hannah Wunsch, Bruno R. da Costa, Damon C. Scales

ABSTRACT

Importance Treatment with noninvasive oxygenation strategies such as noninvasive ventilation and high-flow nasal oxygen may be more effective than standard oxygen therapy alone in patients with acute hypoxemic respiratory failure.
Objective To compare the association of noninvasive oxygenation strategies with mortality and endotracheal intubation in adults with acute hypoxemic respiratory failure.
Data Sources The following bibliographic databases were searched from inception until April 2020: MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and LILACS. No limits were applied to language, publication year, sex, or race.
Study Selection Randomized clinical trials enrolling adult participants with acute hypoxemic respiratory failure comparing high-flow nasal oxygen, face mask noninvasive ventilation, helmet noninvasive ventilation, or standard oxygen therapy.
Data Extraction and Synthesis Two reviewers independently extracted individual study data and evaluated studies for risk of bias using the Cochrane Risk of Bias tool. Network meta-analyses using a bayesian framework to derive risk ratios (RRs) and risk differences along with 95% credible intervals (CrIs) were conducted. GRADE methodology was used to rate the certainty in findings.
Main Outcomes and Measures The primary outcome was all-cause mortality up to 90 days. A secondary outcome was endotracheal intubation up to 30 days.
Results Twenty-five randomized clinical trials (3804 participants) were included. Compared with standard oxygen, treatment with helmet noninvasive ventilation (RR, 0.40 [95% CrI, 0.24-0.63]; absolute risk difference, −0.19 [95% CrI, −0.37 to −0.09]; low certainty) and face mask noninvasive ventilation (RR, 0.83 [95% CrI, 0.68-0.99]; absolute risk difference, −0.06 [95% CrI, −0.15 to −0.01]; moderate certainty) were associated with a lower risk of mortality (21 studies [3370 patients]). Helmet noninvasive ventilation (RR, 0.26 [95% CrI, 0.14-0.46]; absolute risk difference, −0.32 [95% CrI, −0.60 to −0.16]; low certainty), face mask noninvasive ventilation (RR, 0.76 [95% CrI, 0.62-0.90]; absolute risk difference, −0.12 [95% CrI, −0.25 to −0.05]; moderate certainty) and high-flow nasal oxygen (RR, 0.76 [95% CrI, 0.55-0.99]; absolute risk difference, −0.11 [95% CrI, −0.27 to −0.01]; moderate certainty) were associated with lower risk of endotracheal intubation (25 studies [3804 patients]). The risk of bias due to lack of blinding for intubation was deemed high.
Conclusions and Relevance In this network meta-analysis of trials of adult patients with acute hypoxemic respiratory failure, treatment with noninvasive oxygenation strategies compared with standard oxygen therapy was associated with lower risk of death. Further research is needed to better understand the relative benefits of each strategy.

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04/06/2020 Editorial
Alternatives to Invasive Ventilation in the COVID-19 Pandemic

JAMA

Authors
Bhakti K. Patel, John P. Kress, Jesse B. Hall

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03/06/2020 Editorial
Hydroxychloroquine for the Prevention of Covid-19 — Searching for Evid...

Hydroxychloroquine for the Prevention of Covid-19 — Searching for Evidence

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Myron S. Cohen

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03/06/2020 Articles
Tocilizumab for treatment of mechanically ventilated patients with COV...

Tocilizumab for treatment of mechanically ventilated patients with COVID-19

MEDRXIV

Authors
Emily C Somers, Gregory A Eschenauer, Jonathan P Troost, Jonathan L Golob, Tejal N Gandhi, Lu Wang, Nina Zhou, Lindsay A Petty, Ji Hoon Baang, Nicholas O Dillman, David Frame, Kevin S Gregg, Dan R Kaul, Jerod Nagel, Twisha S Patel, Shiwei Zhou, Adam S Lauring, David A Hanauer, Emily Toth Martin, Pratima Sharma, Christopher M Fung, Jason M Pogue



ABSTRACT
Background Severe COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers. This presentation is consistent with cytokine release syndrome in chimeric antigen receptor T cell therapy, for which IL-6 blockade is approved treatment. Methods We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW). Findings 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42]. Interpretation In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with a decreased likelihood of death despite higher superinfection occurrence. Randomized controlled trials are urgently needed to confirm these findings.

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01/06/2020 New Result
Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a po...

Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

BIORXIV

Authors
Zhe Lv, Yong-Qiang Deng, Qing Ye, Lei Cao, Chun-Yun Sun, Changfa Fan, Weijin Huang, Shihui Sun, Yao Sun, Ling Zhu, Qi Chen, Nan Wang, Jianhui Nie, Zhen Cui, Dandan Zhu, Neil Shaw, Xiao-Feng Li, Qianqian Li, Liangzhi Xie, Youchun Wang, Zihe Rao, Cheng-Feng Qin, Xiangxi Wang



ABSTRACT
The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 replication and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.
One sentence summary A potent neutralizing antibody conferred protection against SARS-CoV-2 in an hACE2 humanized mouse model by sterically blocking the interaction of the virus with its receptor.

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27/05/2020 Articles
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Jason D. Goldman, M.D., M.P.H., David C.B. Lye, M.B., B.S., David S. Hui, M.D., Kristen M. Marks, M.D., Raffaele Bruno, M.D., Rocio Montejano, M.D., Christoph D. Spinner, M.D., Massimo Galli, M.D., Mi-Young Ahn, M.D., Ronald G. Nahass, M.D., Yao-Shen Chen, M.D., Devi SenGupta, M.D., Robert H. Hyland, D.Phil., Anu O. Osinusi, M.D., Huyen Cao, M.D., Christiana Blair, M.S., Xuelian Wei, Ph.D., Anuj Gaggar, M.D., Ph.D., Diana M. Brainard, M.D., William J. Towner, M.D., Jose Muñoz, M.D., Kathleen M. Mullane, D.O., Pharm.D., Francisco M. Marty, M.D., Karen T. Tashima, M.D., George Diaz

ABSTRACT
BACKGROUND Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
METHODS We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
RESULTS In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P=0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P=0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
CONCLUSIONS In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899. opens in new tab.)

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27/05/2020 Article
STEMI Care and COVID-19: The Value Proposition of Fibrinolytic Therapy...

STEMI Care and COVID-19: The Value Proposition of Fibrinolytic Therapy and the Pharmacoinvasive Strategy

AHA JOURNALS

Authors
Kevin R. Bainey, Eric R. Bates, Paul W. Armstrong

ABSTRACT

The Coronavirus 2019 (COVID-19) pandemic has dramatically altered the delivery of reperfusion therapy for patients with ST-elevation myocardial infarction (STEMI). At this crucial time, it seems prudent to re-evaluate STEMI reperfusion pathways.

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26/05/2020 Communication
AIFA sospende l’autorizzazione all’utilizzo di idrossiclorochina per i...

AIFA sospende l’autorizzazione all’utilizzo di idrossiclorochina per il trattamento del COVID-19 al di fuori degli studi clinici

AIFA

Authors
AIFA

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26/05/2020 Articles
Can Stem Cells Beat COVID-19: Advancing Stem Cells and Extracellular V...

Can Stem Cells Beat COVID-19: Advancing Stem Cells and Extracellular Vesicles Toward Mainstream Medicine for Lung Injuries Associated With SARS-CoV-2 Infections

FRONTIERS IN BIOENGENEERING AND BIOTECHNOLOGY

Authors
Wojciech Chrzanowski, Sally Yunsun Kim, Lana McClements


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22/05/2020 Original Article
Remdesivir for the Treatment of Covid-19 — Preliminary Report

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
J.H. Beigel, K.M. Tomashek, L.E. Dodd, A.K. Mehta, B.S. Zingman, A.C. Kalil, E. Hohmann, H.Y. Chu, A. Luetkemeyer, S. Kline, D. Lopez de Castilla, R.W. Finberg, K. Dierberg, V. Tapson, L. Hsieh, T.F. Patterson, R. Paredes, D.A. Sweeney, W.R. Short, G. Touloumi, D.C. Lye, N. Ohmagari, M. Oh, G.M. Ruiz-Palacios, T. Benfield, G. F&auml;tkenheuer, M.G. Kortepeter, R.L. Atmar, C.B. Creech, J. Lundgren, A.G. Babiker, S. Pett, J.D. Neaton, T.H. Burgess, T. Bonnett, M. Green, M. Makowski, A. Osinusi, S. Nayak, and H.C. Lane,

ABSTRACT

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. opens in new tab.)

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22/05/2020 Articles
Hydroxychloroquine or chloroquine with or without a macrolide for trea...

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19...

The Lancet

Authors
Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel

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22/05/2020 Articles
Efficacy and safety of tocilizumab in severe COVID-19 patients: a sing...

Efficacy and safety of tocilizumab in severe COVID-19 patients: a single- centre retrospective cohort study

EUROPEAN JOURNAL OF INTERNAL MEDICINE

Authors
Corrado Campochiaro, Emanuel Della-Torre, Giulio Cavalli, Giacomo De Luca, Marco Ripa, Nicola Boffini, Alessandro Tomelleri, Elena Baldissera, Patrizia Rovere-Querini, Annalisa Ruggeri, Giacomo Monti, Francesco De Cobelli, Alberto Zangrillo, Moreno Tresoldi, Antonella Castagna, Lorenzo Dagna



ABSTRACT
Background Tocilizumab (TCZ), a humanized monoclonal antibody targeting the interleukin-6 (IL-6) receptor, has been proposed for the treatment of COVID-19 patients; however, limited data are available on the safety and efficacy. Methods We performed a retrospective study on severe COVID-19 patients with hyper-inflammatory features admitted outside intensive care units (ICUs). Patients treated with intravenous TCZ in addition to standard of care were compared to patients treated with standard of care alone. Safety and efficacy were assessed over a 28-day follow-up. Results 65 patients were included. Among them, 32 were treated with TCZ. At baseline, all patients were on high-flow supplemental oxygen and most (78% of TCZ patients and 61% of standard treatment patients) were on non-invasive ventilation. During the 28-day follow-up, 69% of TCZ patients experienced a clinical improvement compared to 61% of standard treatment patients (p = 0.61). Mortality was 15% in the tocilizumab group and 33% in standard treatment group (p = 0.15). In TCZ group, at multivariate analysis, older age was a predictor of death, whereas higher baseline PaO2:FiO2 was a predictor of clinical improvement at day 28. The rate of infection and pulmonary thrombosis was similar between the two groups. Conclusions At day 28, clinical improvement and mortality were not statistically different between tocilizumab and standard treatment patients in our cohort. Bacterial or fungal infections were recorded in 13% of tocilizumab patients and in 12% of standard treatment patients. Confirmation of efficacy and safety will require ongoing controlled trials.


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22/05/2020 Articles
Remdesivir for the Treatment of Covid-19 — Preliminary Report

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
John H. Beigel, Kay M. Tomashek, Lori E. Dodd, Aneesh K. Mehta, Barry S. Zingman, Andre C. Kalil, Elizabeth Hohmann, Helen Y. Chu, Annie Luetkemeyer, Susan Kline, Diego Lopez de Castilla, Robert W. Finberg, Kerry Dierberg, Victor Tapson, Lanny Hsieh, Thomas F. Patterson, Roger Paredes, Daniel A. Sweeney, William R. Short, Giota Touloumi, David Chien Lye, Norio Ohmagari, Myoung-don Oh, Guillermo M. Ruiz-Palacios, Thomas Benfield, Gerd Fätkenheuer, Mark G. Kortepeter, Robert L. Atmar, C. Buddy Creech, Jens Lundgren, Abdel G. Babiker, Sarah Pett, James D. Neaton, Timothy H. Burgess,, Tyler Bonnett, Michelle Green, Mat Makowski, Anu Osinusi, Seema Nayak, H. Clifford Lane



ABSTRACT
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; ACTT-1 ClinicalTrials.gov number, NCT04280705. opens in new tab.)

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21/05/2020 Editorial
High dose intravenous immunoglobulins as a therapeutic option for COVI...

High dose intravenous immunoglobulins as a therapeutic option for COVID-19 patients

European Review for Medical and Pharmacological Sciences

Authors
C. SCOPPETTA, G. DI GENNARO, F. POLVERINO

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20/05/2020 Case Report
Successful Q1 recovery of severe COVID-19 with cytokine storm 3 treati...

Successful Q1 recovery of severe COVID-19 with cytokine storm 3 treating with extracorporeal blood purification

ELSEVIER

Authors
Qiang Wang, Zhao Hu

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20/05/2020 In Focus
Vitamin-D and COVID-19: do deficient risk a poorer outcome?

The Lancet

Authors
FIONA MITCHELL

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20/05/2020 Articles
SARS-CoV-2 infection protects against rechallenge in rhesus macaques

SCIENCE

Authors
Abishek Chandrashekar, Jinyan Liu, Amanda J. Martinot, Katherine McMahan, Noe B. Mercado

ABSTRACT

An understanding of protective immunity to SARS-CoV-2 is critical for vaccine and public health strategies aimed at ending the global COVID-19 pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against re-exposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. Following initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with primary infection. Anamnestic immune responses following rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against re-exposure in nonhuman primates.

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20/05/2020 Articles
DNA vaccine protection against SARS-CoV-2 in rhesus macaques

SCIENCE

Authors
Jingyou Yu, Lisa H. Tostanoski, Lauren Peter, Noe B. Mercado, Katherine McMahan, Shant H. Mahrokhian, Joseph P. Nkolola, Jinyan Liu, Zhenfeng Li, Abishek Chandrashekar, David R. Martinez, Carolin Loos, Caroline Atyeo, Stephanie Fischinger, John S. Burke, Matthew D. Slein, Yuezhou Chen, Adam Zuiani, Felipe J. N. Lelis, Meghan Travers, Shaghayegh Habibi, Laurent Pessaint, ET ALL.

ABSTRACT

The global COVID-19 pandemic caused by the SARS-CoV-2 virus has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 Spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. Following vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.

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18/05/2020 Opinion
COVID-19 Pandemic: Hopes from Proteomics and Multiomics Research

OMICS

Authors
Sandipan Ray, Sanjeeva Srivastava

ABSTRACT

The successful sequencing of the novel coronavirus SARS-CoV-2 nucleic acid paved the way for exploration of omics systems science and integrative biology research approaches for combating this unprecedented planetary health challenge. Omics-scale studies on this viral infection are emerging rapidly and offer a tremendous potential to unravel the puzzles of the SARS-CoV-2 pathobiology, and ways forward for diagnostic and therapeutic innovation.

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17/05/2020 Research Letter
Favipiravir, an antiviral for COVID-19?

Oxford University Press

Authors
Eric A Coomes, Hourmazd Haghbayan

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15/05/2020 Articles
Low dose of hydroxychloroquine reduces fatality of critically ill pati...

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

PUBLMED

Authors
Bo Yu, Chenze Li, Peng Chen, Ning Zhou, Luyun Wang , Jia Li , Hualiang Jiang, Dao-Wen Wang

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high fatality. The most urgent need is to find effective treatments. We sought to determine whether hydroxychloroquine (HCQ) application may reduce the death risk of critically ill COVID-19 patients. In this retrospective study, we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital, Wuhan, from February 1, 2020 to April 4, 2020. All 550 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them were treated with oral HCQ treatment (200 mg twice a day for 7-10 days) in addition to the basic treatments. Primary endpoint is fatality of patients, and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine (NHCQ) treatments. We found that fatalities are 18.8% (9/48) in HCQ group, which is significantly lower than 47.4% (238/502) in the NHCQ group (P<0.001). The time of hospital stay before patient death is 15 (10-21) days and 8 (4-14) days for the HCQ and NHCQ groups, respectively (P<0.05). The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2 (8.3-118.9) pg mL-1 at the beginning of the treatment to 5.2 (3.0-23.4) pg mL-1 (P<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group. These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives. hydroxychloroquine, IL-6, mortalities, COVID-19.

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13/05/2020 Summary
TOCIVID-19 è il primo e più ampio studio sul tocilizumab aut...

TOCIVID-19 è il primo e più ampio studio sul tocilizumab autorizzato...

ISTITUTO NAZIONALE TUMORI DI NAPOLI

Authors
ISTITUTO NAZIONALE TUMORI DI NAPOLI

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11/05/2020 Original Investigation
Association of Treatment With Hydroxychloroquine or Azithromycin...

JAMA

Authors
Eli S. Rosenberg, Elizabeth M. Dufort, Tomoko Udo, Larissa A. Wilberschied, Jessica Kumar, James Tesoriero, Patti Weinberg, James Kirkwood, Alison Muse, Jack DeHovitz, Debra S. Blog, Brad Hutton, David R. Holtgrave, Howard A. Zucker

ABSTRACT Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events.

Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19.

Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020.

Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither.

Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation).

Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings.

Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.

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11/05/2020 Pharmacological Research
Compassionate remdesivir treatment of severe Covid-19 pneumonia in int...

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU)...

ELSEVIER

Authors
Spinello Antinori, Maria Vittoria Cossu, Anna Lisa Ridolfo, Roberto Rech, Cecilia Bonazzetti, Gabriele Pagani, Guido Gubertini, Massimo Coen, Carlo Magni, Antonio Castelli, Beatrice Borghi, Riccardo Colombo, Riccardo Giorgi, Elena Angeli, Davide Mileto, Laura Milazzo, Stefania Vimercati, Martina Pellicciotta, Massimo Galli

ABSTRACT

SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤94% in air or a National Early Warning Score 2 of ≥4. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63%) and discontinued by 13, of whom eight (22.8%) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3%) patients from IDW were discharged, two were still hospitalized and one died (5.9%), whereas in ICU 6 (33.3%) were discharged, 8 (44.4%) patients died, three (16.7%) were still mechanically ventilated and one (5.6%) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8% and 22.8% of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.

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11/05/2020 News
EMA recommends expanding remdesivir compassionate use to patients not ...

EMA recommends expanding remdesivir compassionate use to patients not on mechanical ventilation

EMA

Authors
EUROPEAN MEDICINES AGENCY

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09/05/2020 Editorial
New Zealand eliminates COVID-19

The Lancet

Authors
Sophie Cousins

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09/05/2020 Articles
Tocilizumab for Treatment of Severe COVID-19 Patients: Preliminary Res...

Tocilizumab for Treatment of Severe COVID-19 Patients: Preliminary Results...

MDPI

Authors
Marta Colaneri, Laura Bogliolo, Pietro Valsecchi, Paolo Sacchi, Valentina Zuccaro, Fabio Brandolino, Carlomaurizio Montecucco, Francesco Mojoli, Emanuele Maria Giusti, Raffaele Bruno and the COVID IRCCS San Matteo Pavia Task Force

ABSTRACT

Objective: This study aimed to assess the role of Tocilizumab therapy (TCZ) in terms of ICU admission and mortality rate of critically ill patients with severe COVID-19 pneumonia. Design: Patients with COVID-19 pneumonia were prospectively enrolled in SMAtteo COvid19 REgistry (SMACORE). A retrospective analysis of patients treated with TCZ matched using propensity score to patients treated with Standard Of Care (SOC) was conducted. Setting: The study was conducted at IRCCS Policlinico San Matteo Hospital, Pavia, Italy, from March 14, 2020 to March 27, 2020. Participants: Patients with a confirmed diagnosis of COVID-19 hospitalized in our institution at the time of TCZ availability. Interventions: TCZ was administered to 21 patients. The first administration was 8 mg/kg (up to a maximum 800 mg per dose) of Tocilizumab intravenously, repeated after 12 h if no side effects were reported after the first dose. Main Outcomes and Measures: ICU admission and 7-day mortality rate. Secondary outcomes included clinical and laboratory data. Results: There were 112 patients evaluated (82 were male and 30 were female, with a median age of 63.55 years). Using propensity scores, the 21 patients who received TCZ were matched to 21 patients who received SOC (a combination of hydroxychloroquine, azithromycin and prophylactic dose of low weight heparin). No adverse event was detected following TCZ administration. This study found that treatment with TCZ did not significantly affect ICU admission (OR 0.11; 95% CI between 0.00 and 3.38; p = 0.22) or 7-day mortality rate (OR 0.78; 95% CI between 0.06 and 9.34; p = 0.84) when compared with SOC. Analysis of laboratory measures showed significant interactions between time and treatment regarding C-Reactive Protein (CRP), alanine aminotransferase (ALT), platelets and international normalized ratio (INR) levels. Variation in lymphocytes count was observed over time, irrespective of treatment. Conclusions: TCZ administration did not reduce ICU admission or mortality rate in a cohort of 21 patients. Additional data are needed to understand the effect(s) of TCZ in treating patients diagnosed with COVID-19.

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08/05/2020 Editorial
Our recommendations for acute management of COVID-19

BMC

Authors
Francesco Mojoli, Silvia Mongodi, Anita Orlando, Eric Arisi, Marco Pozzi, Luca Civardi, Guido Tavazzi, Fausto Baldanti, Raffaele Bruno, Giorgio Antonio Iotti & COVID-19 Pavia Crisis Unit

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08/05/2020 Review
COVID-19 and ECMO: the interplay between coagulation and inflammation—...

COVID-19 and ECMO: the interplay between coagulation and inflammation—a narrative review

CRITICAL CARE

Authors
Mariusz Kowalewski, Dario Fina, Artur Słomka, Giuseppe Maria Raffa, Gennaro Martucci, Valeria Lo Coco, Maria Elena De Piero, Marco Ranucci, Piotr Suwalski, Roberto Lorusso

ABSTRACT

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presently become a rapidly spreading and devastating global pandemic. Veno-venous extracorporeal membrane oxygenation (V-V ECMO) may serve as life-saving rescue therapy for refractory respiratory failure in the setting of acute respiratory compromise such as that induced by SARS-CoV-2. While still little is known on the true efficacy of ECMO in this setting, the natural resemblance of seasonal influenza’s characteristics with respect to acute onset, initial symptoms, and some complications prompt to ECMO implantation in most severe, pulmonary decompensated patients. The present review summarizes the evidence on ECMO management of severe ARDS in light of recent COVID-19 pandemic, at the same time focusing on differences and similarities between SARS-CoV-2 and ECMO in terms of hematological and inflammatory interplay when these two settings merge.

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07/05/2020 Release
Coronavirus (COVID-19) related deaths by ethnic group, England and Wal...

Coronavirus (COVID-19) related deaths by ethnic group, England and Wales...

Office for National Statistics

Authors
Office for National Statistics

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07/05/2020 Articles
Interleukin-1 blockade with high-dose anakinra in patients with COVID-...

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19...

THE LANCET

Authors
Giulio Cavalli, Giacomo De Luca, Corrado Campochiaro, Emanuel Della-Torre, Marco Ripa, Diana Canetti, Chiara Oltolini, Barbara Castiglioni, Chiara Tassan Din, Nicola Boffini, Alessandro Tomelleri, Nicola Farina, Annalisa Ruggeri, Patrizia Rovere-Querini, Giuseppe Di Lucca, Sabina Martinenghi, Raffaella Scotti, Moreno Tresoldi, Fabio Ciceri, Giovanni Landoni, Alberto Zangrillo, Paolo Scarpellini, Lorenzo Dagna

ABSTRACT

Background Mortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population.

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07/05/2020 Articles
Observational Study of Hydroxychloroquine in Hospitalized Patients wit...

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Joshua Geleris, Yifei Sun, Jonathan Platt, Jason Zucker, Matthew Baldwin, George Hripcsak, Angelena Labella, Daniel Manson, Christine Kubin, R. Graham Barr, Magdalena E. Sobieszczyk, Neil W. Schluger

ABSTRACT

BACKGROUND

Hydroxychloroquine has been widely administered to patients with Covid-19 with- out robust evidence supporting its use.

METHODS We examined the association between hydroxychloroquine use and intubation or death at a large medical center in New York City. Data were obtained regarding consecutive patients hospitalized with Covid-19, excluding those who were intu- bated, died, or discharged within 24 hours after presentation to the emergency department (study baseline). The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who re- ceived hydroxychloroquine with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score.

RESULTS Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within 24 hours after presentation and were excluded from the analysis. Of the remaining 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxy- chloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emer- gency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloro- quine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses.

CONCLUSIONS In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed. (Funded by the National Institutes of Health.)

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07/05/2020 Letter
Baseline use of hydroxychloroquine in systemic lupus erythematosus doe...

Baseline use of hydroxychloroquine in systemic lupus erythematosus does not...

BMJ

Authors
Maximilian F Konig , Alfred HJ Kim, Marc H Scheetz, Elizabeth R Graef, Jean W Liew, Julia Simard, Pedro M Machado , Milena Gianfrancesco, Jinoos Yazdany, Daman Langguth, Philip C Robinson

Read More »

05/05/2020 Letter
Tocilizumab for cytokine storm syndrome in COVID-19 pneumonia: an incr...

Tocilizumab for cytokine storm syndrome in COVID-19 pneumonia: an increased risk for candidemia?

ELSEVIER

Authors
Spinello Antinori, Cecilia Bonazzetti, Guido Gubertini, Amedeo Capetti, Cristina Pagani, Valentina Morena, Sara Rimoldi, Laura Galimberti, Piercarlo Sarzi-Puttini, Anna Lisa Ridolfo

Read More »

05/05/2020 Review
Continuous hydroxychloroquine or colchicine therapy does not prevent i...

Continuous hydroxychloroquine or colchicine therapy does not prevent infection with...

ELSEVIER

Authors
Omer Gendelman, Howard Amital, Nicola Luigi Bragazzi, Abdulla Watad, Gabriel Chodick

Background Some disease-modifying agents commonly used to treat patients with rheumatic diseases/autoimmune disorders, such as hydroxychloroquine and colchicine, are under investigation as potential therapies for the “coronavirus disease 2019” (COVID-19). However, the role of such agents as prophylactic tools is still not clear.

Methods This is a retrospective study based on a large healthcare computerized database including all patients that were screened for the “Severe Acute Respiratory Syndrome Coronavirus type 2” (SARS-CoV-2) in the study period from February 23rd 2020 to March 31st 2020. A comparison was conducted between subjects tested positive for SARS-CoV-2 and those found negative in terms of rate of administration of hydroxychloroquine/colchicine therapy.

Results An overall sample of 14,520 subjects were screened for SARS-CoV-2 infection and 1317 resulted positive. No significant difference was found in terms of rates of usage of hydroxychloroquine or colchicine between those who were found positive for SARS-CoV-2 and those who were found negative (0.23% versus 0.25% for hydroxychloroquine, and 0.53% versus 0.48% for colchicine, respectively).

Conclusion These findings raise doubts regarding the protective role of these medications in the battle against SARS-CoV-2 infection.

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05/05/2020 Editorial
The Urgency of Care during the Covid-19 Pandemic — Learning as We Go

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Eric J. Rubin, David P. Harrington, Joseph W. Hogan, Constantine Gatsonis, Lindsey R. Baden and Mary Beth Hamel

Read More »

05/05/2020 Review
Convalescent plasma in Covid-19: Possible mechanisms of action

ELSEVIER

Authors
Manuel Rojas, Yhojan Rodriguez, Diana M. Monsalve, Yeny Acosta-Ampudia, Bernardo Camacho, Juan Esteban Gallo, Adriana Rojas-Villarraga, Carolina Ram&iacute;rez-Santana, Juan C. D&iacute;az-Coronado, Rub&eacute;n Manrique, Ruben D. Mantilla, Yehuda Shoenfeld, Juan-Manuel Anaya

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible of the coronavirus disease 2019 (COVID-19) pandemic. Therapeutic options including antimalarials, antivirals, and vaccines are under study. Meanwhile the current pandemic has called attention over old therapeutic tools to treat infectious diseases. Convalescent plasma (CP) constitutes the first option in the current situation, since it has been successfully used in other coronaviruses outbreaks. Herein, we discuss the possible mechanisms of action of CP and their repercussion in COVID-19 pathogenesis, including direct neutralization of the virus, control of an overactive immune system (i.e., cytokine storm, Th1/Th17 ratio, complement activation) and immunomodulation of a hypercoagulable state. All these benefits of CP are expected to be better achieved if used in non-critically hospitalized patients, in the hope of reducing morbidity and mortality.

Read More »

05/05/2020 Articles
Early treatment of COVID-19 patients with hydroxychloroquine and azith...

Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin...

ELSEVIER

Authors
Matthieu Million, Jean-Christophe Lagier, Philippe Gautret, Philippe Colson, Pierre- Edouard Fournier, Sophie Amrane, Marie Hocquart, Morgane Mailhe, Vera Esteves- Vieira, Barbara Doudier, Camille Aubry, Florian Correard, Audrey Giraud-Gatineau, Yanis Roussel, Cyril Berenger, Nadim Cassir, Piseth Seng, Christine Zandotti, Catherine Dhiver, Isabelle Ravaux, Christelle Tomei, Carole Eldin, Hervé Tissot- Dupont, Stéphane Honoré, Andreas Stein, Alexis Jacquier, Jean-Claude Deharo, Eric Chabrière, Anthony Levasseur, Florence Fenollar, Jean-Marc Rolain, Yolande Obadia, Philippe Brouqui, Michel Drancourt, Bernard La Scola, Philippe Parola, Didier Raoult

ABSTRACT

Background In France, the combination hydroxychloroquine (HCQ) and azithromycin (AZ) is used in the treatment of COVID-19.

Methods We retrospectively report on 1061 SARS-CoV-2 positive tested patients treated for at least three days with the following regimen: HCQ (200 mg three times daily for ten days) + AZ (500 mg on day 1 followed by 250 mg daily for the next four days). Outcomes were death, clinical worsening (transfer to ICU, and >10 day hospitalization) and viral shedding persistence (>10 days).

Results A total of 1061 patients were included in this analysis (46.4% male, mean age 43.6 years – range 14–95 years). Good clinical outcome and virological cure were obtained in 973 patients within 10 days (91.7%). Prolonged viral carriage was observed in 47 patients (4.4%) and was associated to a higher viral load at diagnosis (p < .001) but viral culture was negative at day 10. All but one, were PCR-cleared at day 15. A poor clinical outcome (PClinO) was observed for 46 patients (4.3%) and 8 died (0.75%) (74–95 years old). All deaths resulted from respiratory failure and not from cardiac toxicity. Five patients are still hospitalized (98.7% of patients cured so far). PClinO was associated with older age (OR 1.11), severity of illness at admission (OR 10.05) and low HCQ serum concentration. PClinO was independently associated with the use of selective beta-blocking agents and angiotensin II receptor blockers (p < .05). A total of 2.3% of patients reported mild adverse events (gastrointestinal or skin symptoms, headache, insomnia and transient blurred vision).

Conclusion Administration of the HCQ+AZ combination before COVID-19 complications occur is safe and associated with a very low fatality rate in patients.

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01/05/2020 Articles
Treatments Administered to the First 9152 Reported Cases of COVID-19: ...

Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

MEDRXIV

Authors
David C. Fajgenbaum . Johnson S. Khor . Alexander Gorzewski . Mark-Avery Tamakloe . Victoria Powers . Joseph J. Kakkis . Mileva Repasky . Anne Taylor . Alexander Beschloss . Laura Hernandez-Miyares . Beatrice Go . Vivek Nimgaonkar . Madison S. McCarthy . Casey J. Kim . Ruth-Anne Langan Pai . Sarah Frankl . Philip Angelides . Joanna Jiang . Rozena Rasheed . Erin Napier . Duncan Mackay . Sheila K. Pierson

ABSTRACT
Background The emergence of SARS-CoV-2/2019 novel coronavirus (COVID19) has created a global pandemic with no approved treatments or vaccines. Repurposing existing drugs and rapidly launching clinical trials present the greatest near-term opportunities for mitigating COVID19s impact. Many treatments have already been administered to COVID19 patients but have not been systematically evaluated. We performed a systematic literature review to identify and assess all treatments reported to be administered to COVID19 patients. Methods We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID19 patients published between Dec 1, 2019 and Mar 27, 2020. All studies reporting treatments were included. Data for each paper were manually extracted by two independent extractors. Outcomes included the duration from drug administration to clinically-meaningful response (complete symptom resolution or hospital discharge). Data were analysed descriptively. Results We identified 2,706 articles from single patient case reports to single-centre interventional studies. Of these, 155 studies met inclusion criteria, comprising 9,152 patients from 14 different countries. The cohort was 45.4% female and 98.3% hospitalised, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a response time of 11.7 (1.09) days. Discussion A large number of treatments have been administered to the first 9,152 reported cases of COVID19. Further work is needed to prioritise drugs for investigation in well-controlled clinical trials and treatment protocols. Funding None.

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01/05/2020 Accepted Manuscript
COVID-19, superinfections and antimicrobial development: What can we e...

COVID-19, superinfections and antimicrobial development: What can we expect?

Oxford Academy

Authors
Cornelius J Clancy, M Hong Nguyen

Read More »

01/05/2020 Articles
Five “P”s to Watch

AVAC

Authors
AVAC

Read More »

01/05/2020 News
Covid-19: Remdesivir is helpful but not a wonder drug, say researchers

BMJ

Authors
Elisabeth Mahase

Read More »

01/05/2020 Letter
Remdesivir-EUA-Letter-Of-Authorization

U.S. Food and Drug Administration

Authors
U.S. Food and Drug Administration

Read More »

01/05/2020 News Release
Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization ...

Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for...

U.S. Food and Drug Administration

Authors
U.S. Food and Drug Administration

Read More »

01/05/2020 Editorial
Hydroxychloroquine, Coronavirus Disease 2019, and QT Prolongation

JAMA

Authors
Robert O. Bonow, Adrian F. Hernandez, Mintu Turakhia

Read More »

01/05/2020 Review
Convalescent plasma transfusion for the treatment of COVID-19: Systema...

Convalescent plasma transfusion for the treatment of COVID-19: Systematic review

WILEY ONLINE LIBRARY

Authors
Karthick Rajendran, Krishnasamy Narayanasamy, Jayanthi Rangarajan, Jeyalalitha Rathinam, Murugan Natarajan, Arunkumar Ramachandran

ABSTRACT

The recent emergence of COVID-19 pandemic has reassessed the usefulness of historic convalescent plasma transfusion (CPT). This review was conducted to evaluate the effectiveness of CPT therapy in COVID-19 patients based on the publications reported till date. To our knowledge, this is the first systematic review on convalescent plasma on clinically relevant outcomes in individuals with COVID-19.

Methods PubMed, EMBASE and Medline databases were searched upto 19 April 2020. All records were screened as per the protocol eligibility criteria.

Results We included 5 studies reporting CPT to COVID-19 patients. The main findings from available data are as follows: (1) Convalescent plasma may reduce mortality in critically ill patients (2) Increase in neutralizing antibody titers and disappearance of SARS-CoV-2 RNA was observed in almost all the patients after CPT therapy (3) Beneficial effect on clinical symptoms after administration of convalescent plasma.

Conclusions Based on the limited scientific data, CPT therapy in COVID-19 patient appears safe, clinically effective and reduces mortality. Well-designed large multi center clinical trial

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01/05/2020 Brief Report
Risk of QT Interval Prolongation Associated With Use of Hydroxychloroq...

Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine...

JAMA

Authors
Nicholas J. Mercuro; Christina F. Yen, David J. Shim; Timothy R. Maher, Christopher M. McCoy; Peter J. Zimetbaum; Howard S. Gold

Read More »

01/05/2020 Report
Structural basis for inhibition of the RNA-dependent RNA polymerase fr...

Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

SCIENCE

Authors
Wanchao Yin, Chunyou Mao, Xiaodong Luan, Dan-Dan Shen, Qingya Shen, Haixia Su, Xiaoxi Wang, Fulai Zhou, Wenfeng Zhao, Minqi Gao, Shenghai Chang, Yuan-Chao Xie , Guanghui Tian, He-Wei Jiang, Sheng-Ce Tao, Jingshan Shen, Yi Jiang, Hualiang Jiang, Yechun Xu, Shuyang Zhang, Yan Zhang, H. Eric Xu

ABSTRACT

The pandemic of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global crisis. The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a target of the antiviral drug, Remdesivir. Here we report the cryo-EM structure of the SARS-CoV-2 RdRp either in the apo form at 2.8 Å resolution or in complex with a 50-base template-primer RNA and Remdesivir at 2.5 Å resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is covalently incorporated into the primer strand at the first replicated base pair and terminates chain elongation. Our structures provide critical insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

Read More »

01/05/2020 Letter
Assessment of QT Intervals in a Case Series of Patients With Coronavir...

Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease...

JAMA

Authors
Bessière F, Roccia H, Delinière A, Charrière R, Chevalier P, Argaud L, Cour M

Read More »

30/04/2020 Medical News & Perspectives
Testing an Old Therapy Against a New Disease: Convalescent Plasma for ...

Testing an Old Therapy Against a New Disease: Convalescent Plasma for COVID-19

JAMA

Authors
Rita Rubin

Read More »

30/04/2020 Press Release
EMA starts rolling review of remdesivir for COVID-19

EMA

Authors
EUROPEAN MEDICINES AGENCY

Read More »

29/04/2020 Comment
Remdesivir for COVID-19: challenges of underpowered studies

The Lancet

Authors
JOHN DAVID NORRIE

Read More »

29/04/2020 Articles
Remdesivir in adults with severe COVID-19: a randomised, double-blind....

Remdesivir in adults with severe COVID-19: a randomised, double-blind...

The Lancet

Authors
Yeming Wang, Dingyu Zhang, Guanhua Du, Ronghui Du, Jianping Zhao, Yang Jin, Shouzhi Fu, Ling Gao, Zhenshun Cheng, Qiaofa Lu, Yi Hu, Guangwei Luo, Ke Wang, Yang Lu, Huadong Li, Shuzhen Wang, Shunan Ruan, Chengqing Yang, Chunlin Mei, Yi Wang, Dan Ding, Feng Wu, Xin Tang, Xianzhi Ye, Yingchun Ye, Bing Liu, Jie Yang, Wen Yin, Aili Wang, Guohui Fan, Fei Zhou, Zhibo Liu, Xiaoying Gu, Jiuyang Xu, Lianhan Shang, Yi Zhang, Lianjun Cao, Tingting Guo, Yan Wan, Hong Qin, Yushen Jiang, Thomas Jaki, Frederick G Hayden, Peter W Horby, Bin Cao, Chen Wang

Read More »

29/04/2020 Articles
The first case of COVID-19 treated with the complement C3 inhibitor AM...

The first case of COVID-19 treated with the complement C3 inhibitor AMY-101

ELSEVIER

Authors
Sara Mastaglioa, Annalisa Ruggeria, Antonio M. Risitanob, Piera Angelilloa, Despina Yancopoulouc, Dimitrios C. Mastellosd, Markus Huber-Lange, Simona Piemontesea, Andrea Assanellia, Cecilia Garlandaf, John D. Lambrish, Fabio Ciceria

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a “cytokine storm” involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.

Read More »

28/04/2020 Mini-Review
Rapid review for the anti-coronavirus effect of remdesivir

Drug Discoveries & Therapeutics

Authors
Ziyi Li, Xiaojie Wang, Donglin Cao, Ruilin Sun, Cheng Li, Guowei Li

ABSTRACT

The outbreak of SARS-CoV-2 rapidly spread across China and worldwide. Remdesivir had been proposed as a promising option for treating coronavirus disease 2019 (COVID-19). We provided a rapid review to critically assess the potential anti-coronavirus effect of remdesivir on COVID-19 and other coronaviruses based on the most up-to-date evidence. Even though remdesivir was proposed as a promising option for treating COVID-19 based on laboratory experiments and reports from compassionate use, its safety and effect in humans requires high-quality evidence from well- designed and adequately-powered clinical trials for further clarification.

Read More »

26/04/2020 Review
Repurposing Antiviral Protease Inhibitors Using Extracellular Vesicles...

Repurposing Antiviral Protease Inhibitors Using Extracellular Vesicles for...

MDPI

Authors
Santosh Kumar, Kaining Zhi, Ahona Mukherji and Kelli Gerth

Abstract

In January 2020, Chinese health agencies reported an outbreak of a novel coronavirus-2 (CoV-2) which can lead to severe acute respiratory syndrome (SARS). The virus, which belongs to the coronavirus family (SARS-CoV-2), was named coronavirus disease 2019 (COVID-19) and declared a pandemic by the World Health Organization (WHO). Full-length genome sequences of SARS-CoV-2 showed 79.6% sequence identity to SARS-CoV, with 96% identity to a bat coronavirus at the whole-genome level. COVID-19 has caused over 133,000 deaths and there are over 2 million total confirmed cases as of April 15th, 2020. Current treatment plans are still under investigation due to a lack of understanding of COVID-19. One potential mechanism to slow disease progression is the use of antiviral drugs to either block the entry of the virus or interfere with viral replication and maturation. Currently, antiviral drugs, including chloroquine/hydroxychloroquine, remdesivir, and lopinavir/ritonavir, have shown effective inhibition of SARS-CoV-2 in vitro. Due to the high dose needed and narrow therapeutic window, many patients are experiencing severe side effects with the above drugs. Hence, repurposing these drugs with a proper formulation is needed to improve the safety and efficacy for COVID-19 treatment. Extracellular vesicles (EVs) are a family of natural carriers in the human body. They play a critical role in cell-to-cell communications. EVs can be used as unique drug carriers to deliver protease inhibitors to treat COVID-19. EVs may provide targeted delivery of protease inhibitors, with fewer systemic side effects. More importantly, EVs are eligible for major aseptic processing and can be upscaled for mass production. Currently, the FDA is facilitating applications to treat COVID-19, which provides a very good chance to use EVs to contribute in this combat.

Read More »

26/04/2020 Technical report
Disinfection of environments in healthcare and non-healthcare settings...

Disinfection of environments in healthcare and non-healthcare settings potentially contaminated with SARS-CoV-2

European Centre for Disease Prevention and Control

Authors
European Centre for Disease Prevention and Control

Read More »

24/04/2020 Review Article
The Current and Future State of Vaccines, Antivirals and Gene Therapie...

The Current and Future State of Vaccines, Antivirals and Gene Therapies...

FRONTIERS IN MICROBIOLOGY

Authors
Longping V. Tse, Rita M. Meganck, Rachel L. Graham, Ralph S. Baric

Read More »

24/04/2020 Letter
COVID-19 and Diabetes Mellitus: May Old Anti-diabetic Agents Become th...

COVID-19 and Diabetes Mellitus: May Old Anti-diabetic Agents Become the New Philosopher’s Stone?

SPRINGER LINK

Authors
Theano Penlioglou, Stella Papachristou, Nikolaos Papanas

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible of the coronavirus disease 2019 (COVID-19) pandemic. Therapeutic options including antimalarials, antivirals, and vaccines are under study. Meanwhile the current pandemic has called attention over old therapeutic tools to treat infectious diseases. Convalescent plasma (CP) constitutes the first option in the current situation, since it has been successfully used in other coronaviruses outbreaks. Herein, we discuss the possible mechanisms of action of CP and their repercussion in COVID-19 pathogenesis, including direct neutralization of the virus, control of an overactive immune system (i.e., cytokine storm, Th1/Th17 ratio, complement activation) and immunomodulation of a hypercoagulable state. All these benefits of CP are expected to be better achieved if used in non-critically hospitalized patients, in the hope of reducing morbidity and mortality.

Read More »

24/04/2020 Editorial
Caution Needed on the Use of Chloroquine and Hydroxychloroquine for Co...

Caution Needed on the Use of Chloroquine and Hydroxychloroquine for Coronavirus Disease 2019

JAMA

Authors
Stephan D. Fihn; Eli Perencevich; Steven M. Bradley

Read More »

22/04/2020 Head to head
Is it wrong to prioritise younger patients with covid-19?

BMJ

Authors
Dave Archard , Arthur Caplan William F, Virginia Connolly Mitty

Read More »

20/04/2020 Review
Transfusion and Apheresis Science

ELSEVIER

Authors
Bethany L. Browna, Jeffrey McCulloughb

Abstract Use of convalescent plasma transfusions could be of great value in the current pandemic of coronavirus disease (COVID-19), given the lack of specific preventative and therapeutic options. This convalescent plasma therapy is of particular interest when a vaccine or specific therapy is not yet available for emerging viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. This report summarizes ex- isting literature around convalescent plasma as a therapeutic option for COVID-19. It also includes re- commendations for establishing a convalescent plasma program, enhancement considerations for convalescent plasma, and considerations around pathogen reduction treatment of convalescent plasma. Time is of the essence to set up protocols for collection, preparation, and administration of apheresis-collected convalescent plasma in response to the current pandemic. The immediate use of convalescent plasma provides prompt availability of a promising treatment while specific vaccines and treatments are evaluated and brought to scale. Further devel- opment of improved convalescent plasma, vaccines and other therapeutics depends on quick generation of additional data on pathogenesis and immune response. Additionally, given the lack of information around the natural history of this disease, PRT should be considered to add a layer of safety to protect recipients of con- valescent plasma.

Read More »

20/04/2020 Articles
Nafamostat mesylate blocks activation of SARS-CoV New treatment option...

Nafamostat mesylate blocks activation of SARS-CoV New treatment option 2 for COVID-19

American Society for Microbiology.

Authors
Markus Hoffmann, Simon Schroeder, Hannah Kleine-Weber, Marcel A. M&uuml;ller, Christian Drosten, Stefan P&ouml;hlmann

Read More »

17/04/2020 Articles
Weak Induction of Interferon Expression by SARS-CoV-2...

OXFORD ACADEMY

Authors
Thomas R O&rsquo;Brien, David L Thomas, Sarah S Jackson, Ludmila Prokunina-Olsson, Raymond P Donnelly, Rune Hartmann

Read More »

17/04/2020 Articles
COVID-19 and Renin Angiotensin Blockers: Current Evidence and Recommen...

COVID-19 and Renin Angiotensin Blockers: Current Evidence and Recommendations

AMERICAN COLLEGE OF CARDIOLOGY

Authors
Messerli FH, Siontis GC, Rexhaj E.

Read More »

17/04/2020 Articles
What’s happening in covid-19 ICUs? An intensive care doctor answers so...

What’s happening in covid-19 ICUs? An intensive care doctor answers some common questions

THE BMJ

Authors
Abi Rimmer , Emma Wilkinson

Read More »

16/04/2020 Letter
Off-label Use of Tocilizumab in Patients with SARS-CoV-2 Infection

WILEY ONLINE LIBRARY

Authors
Simona Di Giambenedetto, Arturo Ciccullo, Alberto Borghetti, Giovanni Gambassi, Francesco Landi, Elena Visconti, Lorenzo Zileri Dal Verme, Roberto Bernabei, Enrica Tamburrini, Roberto Cauda, Antonio Gasbarrini, GEMELLI AGAINST COVID‐19 group

ABSTRACT
The spread of the novel-Coronavirus infection worldwide represents a challenge for physicians. Particularly, no approved therapy has demonstrated to have an impact in treating patients who develop severe respiratory insufficiency so far. The use of humanized anti-human inteleukine-6 receptor antibody tocilizumab seems a promising strategy for these patients.

Read More »

16/04/2020 Editorial
Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in ...

Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in Times of Urgency

The American Journal of Tropical Medicine and Hygiene

Authors
Carlos Chaccour, Felix Hammann, Santiago Ram&oacute;n-Garc&iacute;a, N. Regina Rabinovich

Read More »

13/04/2020 Review
Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) A Rev...

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) A Review

JAMA

Authors
James M. Sanders, Pharm; Marguerite L. Monogue, Pharm; Tomasz Z. Jodlowski, Pharm; James B. Cutrell

Read More »

11/04/2020 World Report
Regulators split on antimalarials for COVID-19

The Lancet

Authors
Susan Jaffe

Read More »

10/04/2020 Perspectives
Compassionate Use of Remdesivir for Patients with Severe Covid-19

The New England Journal of Medicine

Authors
J. Grein, N. Ohmagari, D. Shin, G. Diaz, E. Asperges, A. Castagna, T. Feldt, G. Green, M.L. Green, F.-X. Lescure, E. Nicastri, R. Oda, K. Yo, E. Quiros-Roldan, A. Studemeister, J. Redinski, S. Ahmed, J. Bernett, D. Chelliah, D. Chen, S. Chihara, S.H. Cohen, J. Cunningham, A. D&rsquo;Arminio Monforte, S. Ismail, Kato, G. Lapadula, E. L&rsquo;Her, T. Maeno, S. Majumder, M. Massari, AA.VV.

Read More »

09/04/2020 PERSPECTIVE
Mesenchymal Stromal Cell Secretome for Severe COVID-19 Infections: Pre...

Mesenchymal Stromal Cell Secretome for Severe COVID-19 Infections: Premises for the Therapeutic Use

MPDI

Authors
Elia Bari, Ilaria Ferrarotti, Laura Saracino, Sara Perteghella, Maria Luisa Torre, Angelo Guido Corsico

Read More »

09/04/2020 Comment
Attention should be paid to venous thromboembolism prophylaxis in the ...

Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19

The Lancet

Authors
Tao Wang, Ruchong Chen, Chunli Liu, Wenhua Liang, Weijie Guan, Ruidi Tang, Chunli Tang, Nuofu Zhang, Nanshan Zhong, Shiyue Li

Read More »

07/04/2020 Communication
Farmaci utilizzabili per il trattamento della malattia COVID19

AIFA

Authors
AIFA

Read More »

07/04/2020 Research
Should chloroquine and hydroxychloroquine be used to treat COVID-19? A...

Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review

BJGP OPEN

Authors
Kome Gbinigie, Kerstin Frie

ABSTRACT

Background
On the 11 March 2020, the World Health Organization (WHO) declared that COVID-19 was a pandemic. To date, there are no medical treatments for COVID-19 with proven effectiveness. Novel treatments and/or vaccines will take time to be developed and distributed to patients. In light of this, there has been growing interest in the use of existing medications, such as chloroquine (CQ) and hydroxychloroquine (HCQ), as potential treatments of this disease. Aim To establish the current evidence for the effectiveness of CQ and HCQ in treating COVID-19. Design & setting A rapid review of the literature was conducted. Method Electronic searches in PubMed and Google Scholar were conducted on 21 March 2020. A further search was conducted in Google for relevant literature on 28 March 2020. 

Results
There is limited evidence of in vitro activity of CQ/HCQ against SARS-CoV-2. A number of in vivo clinical trials are underway. The empirical data available from two of these trials reveal conflicting results. Both trials are characterised by small numbers of participants (n = 30 and n = 36) and suffer methodological limitations. No medium or long-term follow-up data is available. 

Conclusion
At present, there is insufficient evidence to determine whether CQ/HCQ are safe and effective treatments for COVID-19. High quality, adequately powered randomised clinical trials in primary and secondary care settings are urgently required to guide policymakers and clinicians. These studies should report medium- and long-term follow-up results, and safety data.

Read More »

06/04/2020 Correspondence
Preventing COVID-19-induced pneumonia with anticytokine therapy

The Lancet

Authors
Giovanni Monteleone, Pier Carlo Sarzi-Puttini, Sandro Ardizzone

Read More »

06/04/2020 Articles
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in...

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in...

SCIENCE

Authors
Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham

ABSTRACT

Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (β-D-N4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.

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06/04/2020 Review
Prediction models for diagnosis and prognosis of covid-19 infection...

The bmj

Authors
Laure Wynants, Ben Van Calster, Marc M J Bonten, Gary S Collins, Thomas P A Debray, Maarten De Vos, Maria C Haller, Georg Heinze

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06/04/2020 Articles
In Silico Discovery of Candidate Drugs against Covid-19

Research Gate

Authors
Peter J Richardson, Mario Corbellino, Justin Stebbing

ABSTRACT 

Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.

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05/04/2020 Letter
Macrolide treatment for COVID-19: Will this be the way forward?

BioScience Trends

Authors
Masashi Ohe, Haruki Shida, Satoshi Jodo, Yoshihiro Kusunoki, Masahide Seki, Ken Furuya, Houman Goudarzi

Abstract:
ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that has developed in late 2019 and 2020 is a serious threat to human health. With no vaccines or drugs approved for prevention and treatment until now, all efforts at drug design and/or clinical trials of already approved drugs are worthy and creditable. Using structure-based drug selection for identification of SARS-CoV-2 protease inhibitors, old drugs such as macrolides (MAC) were predicted to be effective for COVID-19. Lately, the anti-viral effects of macrolides have attracted considerable attention. Very recently, hydroxychloroquine in combination with azithromycin treatment was reported to be effective for COVID-19. We believe that treatments with macrolides alone or in combination with other drugs are promising and open the possibility of an international strategy to fight this emerging viral infection. 

KEYWORDS
COVID-19, SARS-CoV-2, macrolide

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04/04/2020 Articles
Review of safety and minimum pricing of nitazoxanide for potential tre...

Review of safety and minimum pricing of nitazoxanide for potential treatment of COVID-19

ELSEVIER

Authors
Toby Pepperrell, Victoria Pilkington, Andrew Owen, Junzheng Wang, Andrew M Hill


ABSTRACT
Background Many treatments are being assessed for repurposing to treat coronavirus disease 2019 (COVID-19). One drug that has shown promising results in vitro is nitazoxanide. Unlike other postulated drugs, nitazoxanide shows a high ratio of maximum plasma concentration (Cmax), after 1 day of 500 mg twice daily (BD), to the concentration required to inhibit 50% replication (EC50) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Cmax : EC50 roughly equal to 14:1). As such, it is important to investigate the safety of nitazoxanide for further trials. Furthermore, treatments for COVID-19 should be cheap to promote global access, but prices of many drugs are far higher than the costs of production. We aimed to conduct a review of the safety of nitazoxanide for any prior indication and calculate its minimum costs of production.
Methods A review of nitazoxanide clinical research was conducted using EMBASE and MEDLINE databases, supplemented by ClinicalTrials.gov. We searched for phase 2 or 3 randomised controlled trials (RCTs) comparing nitazoxanide with placebo or active control for 5–14 days in participants experiencing acute infections of any kind. Data extracted were grade 1–4 and serious adverse events (AEs). Data were also extracted on gastrointestinal (GI) AEs, as well as hepatorenal and cardiovascular effects.
Active pharmaceutical ingredient cost data from 2016 to 2019 were extracted from the Panjiva database and adjusted for 5% loss during production, costs of excipients, formulation, a 10% profit margin and tax. Two dosages, at 500 mg BD and a higher dose of 1100 mg three times daily (TDS), were considered. Our estimated costs were compared with publicly available list prices from a selection of countries.
Results Nine RCTs of nitazoxanide were identified for inclusion. These RCTs accounted for 1514 participants and an estimated 95.3 person-years-of-follow-up. No significant differences were found in any of the AE endpoints assessed, across all trials or on subgroup analyses of active- or placebo-controlled trials. Mild GI AEs increased with dose. No hepatorenal or cardiovascular concerns were raised, but few appropriate metrics were reported. There were no teratogenic concerns, but the evidence base was very limited.
Based on a weighted-mean cost of US $61/kg, a 14-day course of treatment with nitazoxanide 500 mg BD would cost $1.41. The daily cost would therefore be $0.10. The same 14-day course could cost $3944 in US commercial pharmacies, and $3 per course in Pakistan, India and Bangladesh. At a higher dose of 1100 mg TDS, our estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day.
Conclusion Nitazoxanide demonstrates a good safety profile at approved doses. However, further evidence is required regarding hepatorenal and cardiovascular effects, as well as teratogenicity. We estimate that it would be possible to manufacture nitazoxanide as generic for $1.41 for a 14-day treatment course at 500 mg BD, up to $4.08 at 1100 mg TDS. Further trials in COVID-19 patients should be initiated. If efficacy against SARS-CoV-2 is demonstrated in clinical studies, nitazoxanide may represent a safe and affordable treatment in the ongoing pandemic.

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03/04/2020 Correspondence
Baricitinib for COVID-19: a suitable treatment?

The Lancet

Authors
Ennio G Favalli, Martina Biggioggero,Gabriella Maioli, Roberto Caporali

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03/04/2020 News
Rheumatologists rapidly adjust patient care during COVID-19 pandemic

The Lancet

Authors
Tony Kirby

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02/04/2020 Articles
The possible of immunotherapy for COVID-19: A systematic review

NCBI

Authors
Akram AminJafaria, Sorayya Ghasemib

ABSTRACT

The novel coronavirus (2019-nCoV) is an emerging pathogen that was first described in late December 2019 and causes a severe respiratory infection in humans. Since the outbreak of COVID-19, international attention has raised to develop treatment and control options such as types of immunotherapies. The immunotherapy is an effective method for fighting against similar viral infections such as SARS-CoV, and MERS-CoV. These methods include several types of vaccines, monoclonal antibody candidates, and etc. This systematic review article was designed to evaluate the existing evidence and experience related to immunotherapy for 2019-nCoV. Web of Science (ISI), PubMed, and Scopus databases were used to search for suitable keywords such as 2019-nCoV, novel coronavirus, Immunotherapy, interleukin, vaccine and the related words for relevant publications up to 24.3.2020. The present systematic review was performed based on PRISMA protocol. Data extraction and quality valuation of articles were performed by two reviewers. 51 articles were the results of the search and based on the inclusions and exclusions criteria, 7 articles were included in the final review. As a conclusion of these studies demonstratedthat although no serious research has been done on this subject at the time of writing this article, similar studies on the related viruses showed notable results. So immunotherapy for this virus can also be a suitable option

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02/04/2020 Articles
Microneedle array delivered recombinant coronavirus vaccines...

Elsevier

Authors
Eun Kim, Geza Erdos, Shaohua Huang, Thomas W. Kenniston, Stephen C. Balmert, Cara Donahue Carey, V. Stalin Raj, Michael W. Epperly, William B. Klimstra, Bart L. Haagmans, Emrullah Korkmaz, Louis D. Falo Jr., Andrea Gambotto

Abstract:
Background

Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. The coronavirus spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection.

Methods
We first generated codon optimized MERS-S1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. In variant constructs, we engineered immune stimulants (RS09 or flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric design. We comprehensively tested the pre-clinical immunogenicity of MERS-CoV vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (MNAs) by evaluating virus specific IgG antibodies in the serum of vaccinated mice by ELISA and using virus neutralization assays. Driven by the urgent need for COVID-19 vaccines, we utilized this strategy to rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with MNA MERS-CoV vaccines.

Findings
Here we describe the development of MNA delivered MERS-CoV vaccines and their pre-clinical immunogenicity. Specifically, MNA delivered MERS-S1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. Building on our ongoing efforts to develop MERS-CoV vaccines, promising immunogenicity of MNA-delivered MERS-CoV vaccines, and our experience with MNA fabrication and delivery, including clinical trials, we rapidly designed and produced clinically-translatable MNA SARS-CoV-2 subunit vaccines within 4 weeks of the identification of the SARS-CoV-2 S1 sequence. Most importantly, these MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses that were evident beginning 2 weeks after immunization.

Interpretation
MNA delivery of coronaviruses-S1 subunit vaccines is a promising immunization strategy against coronavirus infection. Progressive scientific and technological efforts enable quicker responses to emerging pandemics. Our ongoing efforts to develop MNA-MERS-S1 subunit vaccines enabled us to rapidly design and produce MNA SARS-CoV-2 subunit vaccines capable of inducing potent virus-specific antibody responses. Collectively, our results support the clinical development of MNA delivered recombinant protein subunit vaccines against SARS, MERS, COVID-19, and other emerging infectious diseases. 

Keywords
Subunit vaccines / Trimerization / Microneedle array/ MERS-CoV S1 / SARS-CoV-2 /COVID-19

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02/04/2020 Comment
Caution and clarity required in the use of chloroquine for COVID-19

The Lancet

Authors
Yin Kwan Wong, Jing Yang, Yingke He

Read More »

01/04/2020 Communication
Raccomandazioni sull’uso dei farmaci nella popolazione esposta al viru...

Raccomandazioni sull’uso dei farmaci nella popolazione esposta al virus

AIFA

Authors
AIFA

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01/04/2020 News
NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced...

NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19

NIH: National Institute of Allergy and Infectious Diseases

Authors
NIH: National Institute of Allergy and Infectious Diseases

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01/04/2020 Articles
Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia...

NULL

Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature

FRONTIERS IN MEDICINE

Authors:
Nicola Veronese, Jacopo Demurtas, Lin Yang, Roberto Tonelli, Mario Barbagallo, Pierluigi Lopalco, Erik Lagolio, Stefano Celotto, Damiano Pizzol, Liye Zou, Mark A. Tully, Petre Cristian Ilie, Mike Trott, Guillermo F. López-Sánchez, Lee Smith

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27/03/2020 Preliminary Communication
Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent...

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

JAMA

Authors
Chenguang Shen, Zhaoqin Wang, Fang Zhao, Yang Yang, Jinxiu Li, Jing Yuan, Fuxiang Wang, Delin Li, Minghui Yang, Li Xing, Jinli Wei, Haixia Xiao, Yan Yang, Jiuxin Qu, Ling Qing, Li Chen, Zhixiang Xu, Ling Peng, Yanjie Li; Haixia Zheng, Feng Chen; Kun Huang; Yujing Jiang; Dongjing Liu; Zheng Zhang; Yingxia Liu; Lei Liu

Abstract

Importance Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments.

Objective To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Design, Setting, and Participants Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; Pao2/Fio2 <300; and mechanical ventilation. All 5 were treated with convalescent plasma transfusion. The study was conducted at the infectious disease department, Shenzhen Third People's Hospital in Shenzhen, China, from January 20, 2020, to March 25, 2020; final date of follow-up was March 25, 2020. Clinical outcomes were compared before and after convalescent plasma transfusion.

Exposures Patients received transfusion with convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission.

Main Outcomes and Measures Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion.

Results All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and Pao2/Fio2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion.

Conclusions and Relevance In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.

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27/03/2020 Editorials
Non-steroidal anti-inflammatory drugs and covid-19

The bmj

Authors
Paul Little

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26/03/2020 Correspondence
Antihypertensive drugs and risk of COVID-19?

The Lancet

Authors
Christopher J Tignanelli, Nicholas E Ingraham, Matthew A Sparks, Ronald Reilkoff, Tamara Bezdicek, Bradley Benson, Timothy Schacker, Jeffrey G Chipman, Michael A Puskarich

Abstract:
Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we per- formed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically en- gineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43- ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro. We screened 56 hits from the HTS data and validated 36 compounds in vitro using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazo- pyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs in vitro at low-micromolar concentra- tions. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV- OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of in vivo real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection.


IMPORTANCE
Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identi- fied seven compounds with broad-spectrum efficacy against the replication of four CoVs in vitro. Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.

Coronaviruses, bioluminescence imaging, broad-spectrum, high-throughput screening, inhibitor, mice

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26/03/2020 Review
Management of Critically Ill Adults With COVID-19

JAMA

Authors
Jason T. Poston, Bhakti K. Patel, Andrew M. Davis

Abstract:

Summary of the Clinical Problem Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, a pandemic that has affected more than 400 000 individuals and caused nearly 20 000 deaths as of late March 2020. Approximately 5% to 10% of patients require intensive care unit (ICU) admission and mechanical ventilation.1

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25/03/2020 Articles
Urgent Guidance for Navigating and Circumventing the QTc Prolonging...

Authors
John R. Giudicessi, Peter A. Noseworthy,, Paul A. Friedman, Michael J. Ackerman

Abstract:
As the COVID-19 global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the “off label” re-purposing of drugs such as hydroxychloroquine and lopinavir/ritonavir with the potential for unwanted QT interval prolongation, and a risk of druginduced sudden cardiac death. With the possibility that a significant proportion of the world’s population could receive soon COVID-19 pharmacotherapies with torsadogenic potential for therapy or post-exposure prophylaxis, this document serves to help healthcare providers mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk to personnel of COVID19 exposure and conserving the limited supply of personal protective equipment

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24/03/2020 Viewpoint
Potential inhibitors against 2019-nCoV coronavirus M protease from cli...

Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines

JAMA

Authors
Andre C. Kalil

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20/03/2020 Articles
A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covi...

A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

The New England Journal of Medicine

Authors
B. Cao, Y. Wang, D. Wen, W. Liu, Jingli Wang, G. Fan, L. Ruan, B. Song, Y. Cai, M. Wei, X. Li, J. Xia, N. Chen, J. Xiang, T. Yu, T. Bai, X. Xie, L. Zhang, C. Li, Y. Yuan, H. Chen, Huadong Li, H. Huang, S. Tu, F. Gong, Y. Liu, Y. Wei, C. Dong, F. Zhou, X. Gu, J. Xu, Z. Liu, Y. Zhang, Hui Li, L. Shang, K. Wang, K. Li, X. Zhou, X. Dong, Z. Qu, S. Lu, X. Hu, S. Ruan, S. Luo, J. Wu, L. Peng, F. Cheng, L. Pan, J. Zou, C. Jia, Juan Wang, X. Liu, S. Wang, X. Wu, Q. Ge, J. He, H. Zhan, F. Qiu, L. Guo, C. Huang, T. Jaki, F.G. Hayden, P.W. Horby, D. Zhang, and C. Wang

BACKGROUND
No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.

METHODS
We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2 ) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

RESULTS
A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The per- centages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.

CONCLUSIONS
In hospitalized adult patients with severe Covid-19, no benefit was observed with lopi- navir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)

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20/03/2020 Comment
Treatment for severe acute respiratory distress syndrome

The Lancet

Authors
Michael A Matthay, J Matthew Aldrich, Jeffrey E Gotts

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20/03/2020 Articles
Hydroxychloroquine and azithromycin as a treatment of COVID-19...

Elsevier

Authors
Philippe Gautret , Jean-Christophe Lagier , Philippe Parola , Thuan Hoang , Line Meddeb , Morgane Mailhe , Barbara Doudier , Johan Courjon , Valerie Giordanengo, Vera Esteves Vieira , Herve Tissot Dupont , Stephane Honor, Philippe Colson , Eric Chabriere , Bernard La Scola, Jean-Marc Rolain , Philippe Brouqui , Didier Raoult

Abstract:


Conclusions:
Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. 

Patients and methods
French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. 

Results
Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. 

Conclusion
Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin. 

 

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20/03/2020 Articles
COVID-19: a recommendation to examine the effect of hydroxychloroquine...

COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression

Oxford Academy

Authors
Dan Zhou, Sheng-Ming Dai, Qiang Tong

Abstract:
A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.

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19/03/2020 World view
Don’t rush to deploy COVID-19 vaccines and drugs

Springer Nature

Authors
Shibo Jiang

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19/03/2020 Correspondence
Use of antiviral drugs to reduce COVID-19 transmission

The Lancet

Authors
Oriol Mitj&agrave;, Bonaventura Clotet

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18/03/2020 Research Articles
Effectiveness of convalescent plasma therapy in severe COVID-19 patien...

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

PNAS

Authors
Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, Cheng Peng, Mingchao Yuan, Jinyan Huang, Zejun Wang, Jianhong Yu, Xiaoxiao Gao, Dan Wang, Xiaoqi Yu, Li Li, Jiayou Zhang, Xiao Wu, Bei Li, Yanping Xu, Wei Chen, Yan Peng, Yeqin Hu, Lianzhen Lin, Xuefei Liu, Shihe Huang, Zhijun Zhou, Lianghao Zhang, Yue Wang, Zhi Zhang, Kun Deng, Zhiwu Xia, Qin Gong, Wei Zhang, Xiaobei Zheng, Ying Liu, Huichuan Yang, Dongbo Zhou, Ding Yu, Jifeng Hou, Zhengli Shi, Saijuan Chen, Zhu Chen, Xinxin Zhang, and Xiaoming Yang

ABSTRACT Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe pa- tients confirmed by real-time viral RNA test were enrolled prospec- tively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary end- point was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, in- cluding increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109 /L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Ra- diological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The opti- mal dose and time point, as well as the clinical benefit of CP ther- apy, needs further investigation in larger well-controlled trials.

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18/03/2020 Editorial
Covid-19 — The Search for Effective Therapy

The New England Journal of Medicine

Authors
Lindsey R. Baden, M.D., and Eric J. Rubin, M.D., Ph.D.

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16/03/2020 Editorial
Treatment of COVID-19: old tricks for new challenges

Springer Nature

Authors
Anne Catherine Cunningham, Hui Poh Goh, David Koh

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15/03/2020 Review
Targeting the Endocytic Pathway and Autophagy Process as a Novel Thera...

Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19

International Journal of Biological Sciences

Authors
Naidi Yang, Han-Ming Shen

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13/03/2020 Correspondence
COVID-19, ECMO, and lymphopenia: a word of caution

The Lancet

Authors
Brandon Michael Henry

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10/03/2020 Articles
A systematic review on the efficacy and safety of chloroquine for the ...

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

ELSEVIER

Authors
Andrea Cortegiani, Giulia Ingoglia, Mariachiara Ippolito, Antonino Giarratano, Sharon Einav

Purpose:
COVID-19 (coronavirus disease 2019) is a public health emergency of international concern. As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patient contracting the severe form of the disease. The aim of this systematic review was to summarize the evidence regarding chlo- roquine for the treatment of COVID-19.

Methods:
PubMed, EMBASE, and three trial Registries were searched for studies on the use of chloroquine in pa- tients with COVID-19.

Results:
We included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (virus causing COVID-19) in vitro.

Conclusions:
There is rationale, pre-clinical evidence of effectiveness and evidence of safety from long-time clin- ical use for other indications to justify clinical research on chloroquine in patients with COVID-19. However, clin- ical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or be ethically approved as a trial as stated by the World Health Organization. Safety data and data from high-quality clinical trials are urgently needed.

SARS-CoV-2, COVID-19, Chloroquine, Pneumonia, Coronavirus

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06/03/2020 Articles
Patients of COVID-19 may benefit from sustained lopinavir-combined reg...

Patients of COVID-19 may benefit from sustained lopinavir-combined regimen...

JAMA

Authors
Fang Liu, Aifang Xu, Yan Zhang, Weiling Xuan, Tingbo Yan, Kenv Pan, Wenyan Yu, Jun Zhang

Abstract

Objectives
To explore the epidemiological information, clinical characteristics, therapeutic outcomes and temporal progression of laboratory findings in 2019-coronavirus disease (COVID-19) patients exposed to lopinavir.

Methods
We collected data from ten COVID-19 patients admitted between January 22, 2020 and February 11, 2020 at Xixi hospital in Hangzhou, China.

Results
Of ten patients, secondary, tertiary and quartus patients emerged, the incubation period was 3–7 days. Mainly initial symptoms were cough and low fever (37.3–38.0 ℃). An asymptomatic case presented normal radiography, the others existed ground glass opacities. All cases (three transferred, seven discharged) exposed to lopinavir on initial hospitalization. Three patients stopped lopinavir using because of adverse effect, two of them deteriorated, one hospitalized longer than others who with sustained lopinavir using. Levels of potassium, albumin, lymphocyte were low, but increased persistently after treatment. Eosinophil values were low on initial hospitalization, then all returned to normal before discharge. Viral load of SARS-CoV-2, radiography and eosinophil improved continuously in 3–14, 6–8 and 7–9 days, respectively.

Conclusions
Increasing eosinophils may be an indicator of COVID-19 improvement. The COVID-19 patients may benefit from sustained lopinavir using. More researches on a larger scale are needed to verify these points.

Keywords
2019-Coronavirus disease / Lopinavir / Asymptomatic infection /Eosinophil

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05/03/2020 Editorial
Remdesivir as a possible therapeutic option for the COVID-19

ELSEVIER

Authors
Al-Tawfiq JA, Al-Homoud AH, Memish ZA

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05/03/2020 Correspondence
Respiratory support for patients with COVID-19 infection

The Lancet

Authors
Silvio A &Ntilde;amendys-Silva

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04/03/2020 Press Release
Chloroquine and hydroxychloroquine as available weapons to fight COVID...

Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

ELSEVIER

Authors
Philippe Colson, Jean-Marc Rolain, Jean-Christophe Lagier, Philippe Brouqui, Didier Raoult

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01/03/2020 Articles
COVID-19 Drug Therapy — Potential Options

ELSEVIER

Authors
Tim Smith, Tony Prosser

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14/02/2020 Short Communication
Case of the Index Patient Who Caused Tertiary Transmission of Coronavi...

Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea...

JKMS

Authors
Jaegyun Lim ,Seunghyun Jeon ,Hyun-Young Shin ,Moon Jung Kim ,Yu Min Seong ,Wang Jun Lee ,Kang-Won Choe ,Yu Min Kang ,Baeckseung Lee, Sang-Joon Park

Abstract:
Since mid-December of 2019, coronavirus disease 2019 (COVID-19) has been spreading from Wuhan, China. The confirmed COVID-19 patients in South Korea are those who came from or visited China. As secondary transmissions have occurred and the speed of transmission is accelerating, there are rising concerns about community infections. The 54-year old male is the third patient diagnosed with COVID-19 in Korea. He is a worker for a clothing business and had mild respiratory symptoms and intermittent fever in the beginning of hospitalization, and pneumonia symptoms on chest computerized tomography scan on day 6 of admission. This patient caused one case of secondary transmission and three cases of tertiary transmission. Hereby, we report the clinical findings of the index patient who was the first to cause tertiary transmission outside China. Interestingly, after lopinavir/ritonavir (Kaletra, AbbVie) was administered, β-coronavirus viral loads significantly decreased and no or little coronavirus titers were observed.

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11/02/2020 Correspondence
On the use of corticosteroids for 2019-nCoV pneumonia

The Lancet

Authors
Lianhan Shang, Jianping Zhao, Yi Hu, Ronghui Du, Bin Cao

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29/05/2019 Articles
High-Throughput Screening and Identification of Potent Broad-Spectrum ...

High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses

American Society for Microbiology - Journal of Virology

Authors
Liang Shen, Junwei Niu, Chunhua Wang, Baoying Huang, Wenling Wang, Na Zhu, Yao Deng, Huijuan Wang, Fei Ye, Shan Cen, Wenjie Tana

Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we per- formed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically en- gineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43- ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro. We screened 56 hits from the HTS data and validated 36 compounds in vitro using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazo- pyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs in vitro at low-micromolar concentra- tions. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV- OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of in vivo real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection.

IMPORTANCE
Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identi- fied seven compounds with broad-spectrum efficacy against the replication of four CoVs in vitro. Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.

Coronaviruses, bioluminescence imaging, broad-spectrum, high-throughput screening, inhibitor, mice

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