Read More »
RECOVERY (RANDOMISED EVALUATION OF COVID 19 THERAPY)
THE RECOVERY trial chief investigators
THE NEW ENGLAND JOURNAL OF MEDICINE
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
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.
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.
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).
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.)
Monica Cortinovis, Norberto Perico, Giuseppe Remuzzi
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
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.
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.
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.
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.)
Hüseyin Can, Ahmet Efe Köseoğlu, Sedef Erkunt Alak, Mervenur Güvendi, Mert Döşkaya, Muhammet Karakavuk, Adnan Yüksel Gürüz, Cemal Ün
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.
NIH (NATIONAL INSTITUTES OF HEALTH)
Esparza, T.J. et al
ACTIV-3/TICO LY-CoV555 Study Group
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.
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.
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).
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.)
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
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
ANNALS OF INTERNAL MEDICINE
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
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.
To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.
Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961)
National U.S. multicenter study.
Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.
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.
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.
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).
The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.
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.
Angela Dardano, Stefano Del Prato
Robert M. Cox, Josef D. Wolf, Richard K. Plemper
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.
ACCADEMIA DI MEDICINA DI TORINO
GRUPPO DI LAVORO ACCADEMIA DI MEDICINA DI TORINO
WHO Solidarity Trial Consortium
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).
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.
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.
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
Giovanni Bolcato, Maicol Bissaro, Matteo Pavan, Mattia Sturlese, Stefano Moro
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.
NIH staff guidance on coronavirus
Anshul Jain, Rachna Chaurasia, Narendra Singh Sengar, Mayank Singh, Sachin Mahor, Sumit Narain
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.
Dietmar Urbach; Friedemann Awiszus; Sven Leiß; Tamsin Venton; Alexander Vincent De Specht; Christian Apfelbacher
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
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
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
NIH (NATIONAL INSTITUTES OF HEALTH)
Peter S. Kim, Sarah W. Read, Anthony S. Fauci
Amy Sarah Ginsburg, Keith P Klugman
Puja Mehta, Emilie Sanchez, Elena Moraitis, Nicky Longley, Dennis W Lendrem, Ian P Giles, Rachel C Chambers, Coziana Ciurtin, John D Isaacs
CELL REPORTS MEDICINE
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
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
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.
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.
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%).
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.)
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
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
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.
Anup Agarwal, Aparna Mukherjee, Gunjan Kumar, Pranab Chatterjee, Tarun Bhatnagar, Pankaj Malhotra
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.
Jonathan B. Parr
Rahul Kalippurayil Moozhipurath, Lennart Kraft, Bernd Skiera
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.
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
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.
Mansoor N Bangash, Andrew Owen, Joseph E Alderman, Minesh Chotalia, Jaimin M Patel, Dhruv Parekh
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
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.
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
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.
PNAS (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF UNITED STATES OF AMERICA)
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
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.
PNAS (PROCEEDINGS OF THE NATIONL ACADEMY OF SCIENCE OF UNITED STATES OF AMERICA)
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
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.
NEJM - JOURNAL WATCH
RECOVERY Collaborative Group
IJID (INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES)
Monica A. Kaminski, Subin Sunny, Khayala Balabayova, Avneet Kaur, Aanchal Gupta, Marie Abdallah, John Quale
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
Faizan Mazhar, Muhammad Abdul Hadi, Chia Siang Kow, Albaraa Mohammed N. Marran, Hamid A. Merchant, Syed Shahzad Hasan
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.
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
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
Semih Baghaki, Can Ege Yalcin, Hayriye Sema Baghaki, Servet Yekta Aydin, Basak Daghan, Ersin Yavuz
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.
Sima Asadi, Christopher D. Cappa, Santiago Barreda, Anthony S. Wexler, Nicole M. Bouvier, William D. Ristenpart
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.
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
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.
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).
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
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
METABOLISM CLINICAL AND EXPERIMENTAL
Shiva Ganjali, Vanessa Bianconi, Peter E. Penson, Matteo Pirro, Maciej Banach, Gerald F. Watts, Amirhossein Sahebkar
Jean Abbott, Daniel Johnson, Matthew Wynia
CLINICAL MICROBIOLOGY AND INFECTION
Focosi Daniele, Tuccori Marco, Antonelli Guido, Maggi Fabrizio
Yadi Zhou, Fei Wang, Jian Tang, Ruth Nussinov, Feixiong Cheng
Moncef Slaoui, Shannon E. Greene, Janet Woodcock
The Lancet Infectious Diseases
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
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
Nicola Squillace, Maria Rosa Pozzi, Giulia Gustinetti, Elena Ricci, Serena Capici, Paola Columpsi, Luca Sala, Paolo Bonfanti
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
The Writing Committee for the REMAP-CAP Investigators
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.
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
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  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.
Hallie C. Prescott, Todd W. Rice
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
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.
WORLD HEALTH ORGANIZATION
WORLD HEALTH ORGANIZATION
Maureen Riordan, Amanda Micklus
Katya Uzunova, Elena Filipova, Velichka Pavlova, Toni Vekovb
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.