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in category infectious diseases

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1: Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1
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Posted 10 Mar 2020

Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1
869,120 downloads medRxiv infectious diseases

Neeltje van Doremalen, Trenton Bushmaker, Dylan H. Morris, Myndi G Holbrook, Amandine Gamble, Brandi N. Williamson, Azaibi Tamin, Jennifer L. Harcourt, Natalie J. Thornburg, Susan I. Gerber, James O. Lloyd-Smith, Emmie de Wit, Vincent Munster

To the EditorA novel human coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, referred to as HCoV-19 here) that emerged in Wuhan, China in late 2019 is now causing a pandemic1. Here, we analyze the aerosol and surface stability of HCoV-19 and compare it with SARS-CoV-1, the most closely related human coronavirus.2 We evaluated the stability of HCoV-19 and SARS-CoV-1 in aerosols and on different surfaces and estimated their decay rates using a Bayesian regression model (see Supplementary Appendix). All experimental measurements are reported as mean across 3 replicates.

2: Estimating the effective reproduction number of the 2019-nCoV in China
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Posted 29 Jan 2020

Estimating the effective reproduction number of the 2019-nCoV in China
488,254 downloads medRxiv infectious diseases

Zhidong Cao, Qingpeng Zhang, Xin Lu, Dirk Pfeiffer, Zhongwei Jia, Hongbing Song, Daniel Dajun Zeng

We estimate the effective reproduction number for 2019-nCoV based on the daily reported cases from China CDC. The results indicate that 2019-nCoV has a higher effective reproduction number than SARS with a comparable fatality rate. Article Summary LineThis modeling study indicates that 2019-nCoV has a higher effective reproduction number than SARS with a comparable fatality rate.

3: Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
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Posted 21 Apr 2020

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
441,090 downloads medRxiv infectious diseases

Joseph Magagnoli, Siddharth Narendran, Felipe Pereira, Tammy Cummings, James W Hardin, S Scott Sutton, Jayakrishna Ambati

BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

4: Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions
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Posted 24 Jan 2020

Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions
383,091 downloads medRxiv infectious diseases

Jonathan M Read, Jessica R.E. Bridgen, Derek A.T. Cummings, Antonia Ho, Chris P. Jewell

Since first identified, the epidemic scale of the recently emerged novel coronavirus (2019-nCoV) in Wuhan, China, has increased rapidly, with cases arising across China and other countries and regions. using a transmission model, we estimate a basic reproductive number of 3.11 (95%CI, 2.39-4.13); 58-76% of transmissions must be prevented to stop increasing; Wuhan case ascertainment of 5.0% (3.6-7.4); 21022 (11090-33490) total infections in Wuhan 1 to 22 January. Changes to previous versionO_LIcase data updated to include 22 Jan 2020; we did not use cases reported after this period as cases were reported at the province level hereafter, and large-scale control interventions were initiated on 23 Jan 2020; C_LIO_LIimproved likelihood function, better accounting for first 41 confirmed cases, and now using all infections (rather than just cases detected) in Wuhan for prediction of infection in international travellers; C_LIO_LIimproved characterization of uncertainty in parameters, and calculation of epidemic trajectory confidence intervals using a more statistically rigorous method; C_LIO_LIextended range of latent period in sensitivity analysis to reflect reports of up to 6 day incubation period in household clusters; C_LIO_LIremoved travel restriction analysis, as different modelling approaches (e.g. stochastic transmission, rather than deterministic transmission) are more appropriate to such analyses. C_LI

5: Transmission Potential of SARS-CoV-2 in Viral Shedding Observed at the University of Nebraska Medical Center
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Posted 26 Mar 2020

Transmission Potential of SARS-CoV-2 in Viral Shedding Observed at the University of Nebraska Medical Center
225,186 downloads medRxiv infectious diseases

Joshua L Santarpia, Danielle N Rivera, Vicki Herrera, M. Jane Morwitzer, Hannah Creager, George W. Santarpia, Kevin K Crown, David Brett-Major, Elizabeth Schnaubelt, M. Jana Broadhurst, James V. Lawler, St Patrick Reid, John J. Lowe

Lack of evidence on SARS-CoV-2 transmission dynamics has led to shifting isolation guidelines between airborne and droplet isolation precautions. During the initial isolation of 13 individuals confirmed positive with COVID-19 infection, air and surface samples were collected in eleven isolation rooms to examine viral shedding from isolated individuals. While all individuals were confirmed positive for SARS-CoV-2, symptoms and viral shedding to the environment varied considerably. Many commonly used items, toilet facilities, and air samples had evidence of viral contamination, indicating that SARS-CoV-2 is shed to the environment as expired particles, during toileting, and through contact with fomites. Disease spread through both direct (droplet and person-to-person) as well as indirect contact (contaminated objects and airborne transmission) are indicated, supporting the use of airborne isolation precautions. One Sentence SummarySARS-CoV-2 is shed during respiration, toileting, and fomite contact, indicating that infection may occur in both direct and indirect contact.

6: Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster
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Posted 08 Mar 2020

Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster
204,287 downloads medRxiv infectious diseases

Roman Wölfel, Victor M. Corman, Wolfgang Guggemos, Michael Seilmaier, Sabine Zange, Marcel A Müller, Daniela Niemeyer, Terence C. Jones Kelly, Patrick Vollmar, Camilla Rothe, Michael Hoelscher, Tobias Bleicker, Sebastian Brünink, Julia Schneider, Rosina Ehmann, Katrin Zwirglmaier, Christian Drosten, Clemens Wendtner

Coronavirus disease 2019 (COVID-19) is an acute respiratory tract infection that emerged in late 20191,2. Initial outbreaks in China involved 13.8% cases with severe-, and 6.1% with critical courses3. This severe presentation corresponds to the usage of a virus receptor that is expressed predominantly in the lung2,4. By causing an early onset of severe symptoms, this same receptor tropism is thought to have determined pathogenicity but also aided the control of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of COVID-19 cases with mild upper respiratory tract symptoms, suggesting a potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on body site - specific virus replication, immunity, and infectivity. Here we provide a detailed virological analysis of nine cases, providing proof of active virus replication in upper respiratory tract tissues. Pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 x 108 RNA copies per throat swab, day 4). Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples in spite of high virus RNA concentration. Blood and urine never yielded virus. Active replication in the throat was confirmed by viral replicative RNA intermediates in throat samples. Sequence-distinct virus populations were consistently detected in throat- and lung samples of one same patient. Shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 6-12 days, but was not followed by a rapid decline of viral loads. COVID-19 can present as a mild upper respiratory tract illness. Active virus replication in the upper respiratory tract puts prospects of COVID-19 containment in perspective.

7: Indoor transmission of SARS-CoV-2
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Posted 07 Apr 2020

Indoor transmission of SARS-CoV-2
172,663 downloads medRxiv infectious diseases

Hua Qian, Te Miao, Li Liu, Xiaohong Zheng, Danting Luo, Yuguo Li

BackgroundBy early April 2020, the COVID-19 pandemic had infected nearly one million people and had spread to nearly all countries worldwide. It is essential to understand where and how SARS-CoV-2 is transmitted. MethodsCase reports were extracted from the local Municipal Health Commissions of 320 prefectural cities (municipalities) in China, not including Hubei province, between 4 January and 11 February 2020. We identified all outbreaks involving three or more cases and reviewed the major characteristics of the enclosed spaces in which the outbreaks were reported and associated indoor environmental issues. ResultsThree hundred and eighteen outbreaks with three or more cases were identified, involving 1245 confirmed cases in 120 prefectural cities. We divided the venues in which the outbreaks occurred into six categories: homes, transport, food, entertainment, shopping, and miscellaneous. Among the identified outbreaks, 53{middle dot}8% involved three cases, 26{middle dot}4% involved four cases, and only 1{middle dot}6% involved ten or more cases. Home outbreaks were the dominant category (254 of 318 outbreaks; 79{middle dot}9%), followed by transport (108; 34{middle dot}0%; note that many outbreaks involved more than one venue category). Most home outbreaks involved three to five cases. We identified only a single outbreak in an outdoor environment, which involved two cases. ConclusionsAll identified outbreaks of three or more cases occurred in an indoor environment, which confirms that sharing indoor space is a major SARS-CoV-2 infection risk. FundingThe work was supported by the Research Grants Council of Hong (no 17202719, C7025-16G), and National Natural Science Foundation of China (no 41977370).

8: Stability of SARS-CoV-2 in different environmental conditions
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Posted 18 Mar 2020

Stability of SARS-CoV-2 in different environmental conditions
131,512 downloads medRxiv infectious diseases

Alex W.H. Chin, Julie T.S. Chu, Mahen R.A. Perera, Kenrie P.Y. Hui, Hui-Ling Yen, Michael C.W. Chan, Malik Peiris, Leo L.M. Poon

Stability of SARS-CoV-2 in different environmental conditions.

9: Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results
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Posted 15 Oct 2020

Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results
129,083 downloads medRxiv infectious diseases

WHO Solidarity trial consortium, Hongchao Pan, Richard Peto, Quarraisha Abdool Karim, Marissa Alejandria, Ana Maria Henao-Restrepo, César Hernández García, Marie-Paule Kieny, Reza Malekzadeh, Srinivas Murthy, Marie-Pierre Preziosi, Srinath Reddy, Mirta Roses Periago, Vasee Sathiyamoorthy, John-Arne Røttingen, Soumya Swaminathan, as the members of the Writing Committee, assume responsibility for the content and integrity of this article

BACKGROUNDWHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs. METHODSStudy drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-{beta}1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry. RESULTSIn 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration. CONCLUSIONSThese Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151, NCT04315948)

10: ASSESSING THE AGE SPECIFICITY OF INFECTION FATALITY RATES FOR COVID-19: META-ANALYSIS & PUBLIC POLICY IMPLICATIONS
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Posted 24 Jul 2020

ASSESSING THE AGE SPECIFICITY OF INFECTION FATALITY RATES FOR COVID-19: META-ANALYSIS & PUBLIC POLICY IMPLICATIONS
126,952 downloads medRxiv infectious diseases

Andrew T. Levin, William P. Hanage, Nana Owusu-Boaitey, Kensington B. Cochran, Seamus P. Walsh, Gideon Meyerowitz-Katz

Structured AbstractO_ST_ABSObjectiveC_ST_ABSDetermine age-specific infection fatality rates for COVID-19 to inform public health policies and communications that help protect vulnerable age groups. MethodsStudies of COVID-19 prevalence were collected by conducting an online search of published articles, preprints, and government reports that were publicly disseminated prior to 18 September 2020. The systematic review encompassed 113 studies, of which 27 studies (covering 34 geographical locations) satisfied the inclusion criteria and were included in the meta-analysis. Age-specific IFRs were computed using the prevalence data in conjunction with reported fatalities four weeks after the midpoint date of the study, reflecting typical lags in fatalities and reporting. Meta-regression procedures in Stata were used to analyze the infection fatality rate (IFR) by age. ResultsOur analysis finds a exponential relationship between age and IFR for COVID-19. The estimated age-specific IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. Moreover, our results indicate that about 90% of the variation in population IFR across geographical locations reflects differences in the age composition of the population and the extent to which relatively vulnerable age groups were exposed to the virus. DiscussionThese results indicate that COVID-19 is hazardous not only for the elderly but also for middle-aged adults, for whom the infection fatality rate is two orders of magnitude greater than the annualized risk of a fatal automobile accident and far more dangerous than seasonal influenza. Moreover, the overall IFR for COVID-19 should not be viewed as a fixed parameter but as intrinsically linked to the age-specific pattern of infections. Consequently, public health measures to mitigate infections in older adults could substantially decrease total deaths.

11: Hydroxychloroquine plus azithromycin: a potential interest in reducing in-hospital morbidity due to COVID-19 pneumonia (HI-ZY-COVID)?
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Posted 11 May 2020

Hydroxychloroquine plus azithromycin: a potential interest in reducing in-hospital morbidity due to COVID-19 pneumonia (HI-ZY-COVID)?
125,908 downloads medRxiv infectious diseases

Benjamin Davido, Thibaud Lansaman, Christine Lawrence, Jean-Claude Alvarez, Frederique Bouchand, Pierre Moine, Veronique Perronne, Aurelie Le Gal, Djillali Annane, Christian Perronne, Pierre De Truchis, COVID-19 RPC Team

The authors have withdrawn this manuscript and do not wish it to be cited. Because of controversy about hydroxychloroquine and the retrospective nature of their study, they intend to revise the manuscript after peer review.

12: The infection fatality rate of COVID-19 inferred from seroprevalence data
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Posted 19 May 2020

The infection fatality rate of COVID-19 inferred from seroprevalence data
124,594 downloads medRxiv infectious diseases

John Ioannidis

Objective To estimate the infection fatality rate of coronavirus disease 2019 (COVID-19) from data of seroprevalence studies. Methods Population studies with sample size of at least 500 and published as peer-reviewed papers or preprints as of July 11, 2020 were retrieved from PubMed, preprint servers, and communications with experts. Studies on blood donors were included, but studies on healthcare workers were excluded. The studies were assessed for design features and seroprevalence estimates. Infection fatality rate was estimated from each study dividing the number of COVID-19 deaths at a relevant time point by the number of estimated people infected in each relevant region. Correction was also attempted accounting for the types of antibodies assessed. Secondarily, results from national studies were also examined from preliminary press releases and reports whenever a country had no other data presented in full papers of preprints. Results 36 studies (43 estimates) were identified with usable data to enter into calculations and another 7 preliminary national estimates were also considered for a total of 50 estimates. Seroprevalence estimates ranged from 0.222% to 47%. Infection fatality rates ranged from 0.00% to 1.63% and corrected values ranged from 0.00% to 1.31%. Across 32 different locations, the median infection fatality rate was 0.27% (corrected 0.24%). Most studies were done in pandemic epicenters with high death tolls. Median corrected IFR was 0.10% in locations with COVID-19 population mortality rate less than the global average (<73 deaths per million as of July 12, 2020), 0.27% in locations with 73-500 COVID-19 deaths per million, and 0.90% in locations exceeding 500 COVID-19 deaths per million. Among people <70 years old, infection fatality rates ranged from 0.00% to 0.57% with median of 0.05% across the different locations (corrected median of 0.04%). Conclusions The infection fatality rate of COVID-19 can vary substantially across different locations and this may reflect differences in population age structure and case-mix of infected and deceased patients as well as multiple other factors. Estimates of infection fatality rates inferred from seroprevalence studies tend to be much lower than original speculations made in the early days of the pandemic.

13: No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial
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Posted 14 Apr 2020

No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial
124,254 downloads medRxiv infectious diseases

Matthieu Mahevas, Tran Viet-Thi, Mathilde Roumier, Amelie Chabrol, Romain Paule, Constance Guillaud, Sebastien Gallien, Raphael Lepeule, Tali-Anne Szwebel, Xavier Lescure, Frederic Schlemmer, Marie Matignon, Mehdi Khellaf, Etienne Crickx, Benjamin Terrier, Caroline Morbieu, Paul Legendre, Julien Dang, Yoland Schoindre, Jean-Michel Pawlotski, Marc Michel, Elodie Perrodeau, Nicolas Carlier, Nicolas Roche, Victoire De Lastours, Luc Mouthon, Etienne Audureau, Philippe Ravaud, Bertrand Godeau, Nathalie Costedoat

Background Treatments are urgently needed to prevent respiratory failure and deaths from coronavirus disease 2019 (COVID-19). Hydroxychloroquine (HCQ) has received worldwide attention because of positive results from small studies. Methods We used data collected from routine care of all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen [&ge;] 2 L/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day. The composite primary endpoint was transfer to intensive care unit (ICU) within 7 days from inclusion and/or death from any cause. Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Results This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47-1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation. Interpretation These results do not support the use of HCQ in patients hospitalised for documented SARS-CoV-2-positive hypoxic pneumonia.

14: Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications
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Posted 06 Apr 2020

Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications
120,225 downloads medRxiv infectious diseases

Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling, Yuling Zhang, Jingna Xun, Lu Lu, Shibo Jiang, Hongzhou Lu, Yumei Wen, Jinghe Huang

BackgroundThe COVID-19 pandemic caused by SARS-CoV-2 coronavirus threatens global public health. Currently, neutralizing antibodies (NAbs) versus this virus are expected to correlate with recovery and protection of this disease. However, the characteristics of these antibodies have not been well studied in association with the clinical manifestations in patients. MethodsPlasma collected from 175 COVID-19 recovered patients with mild symptoms were screened using a safe and sensitive pseudotyped-lentiviral-vector-based neutralization assay. Spike-binding antibody in plasma were determined by ELISA using RBD, S1, and S2 proteins of SARS-CoV-2. The levels and the time course of SARS-CoV-2-specific NAbs and the spike-binding antibodies were monitored at the same time. FindingsSARS-CoV-2 NAbs were unable to cross-reactive with SARS-CoV virus. SARS-CoV-2-specific NAbs were detected in patients from day 10-15 after the onset of the disease and remained thereafter. The titers of NAb among these patients correlated with the spike-binding antibodies targeting S1, RBD, and S2 regions. The titers of NAbs were variable in different patients. Elderly and middle-age patients had significantly higher plasma NAb titers (P<0.0001) and spike-binding antibodies (P=0.0003) than young patients. Notably, among these patients, there were ten patients whose NAb titers were under the detectable level of our assay (ID50: < 40); while in contrast, two patients, showed very high titers of NAb, with ID50 :15989 and 21567 respectively. The NAb titers were positive correlated with plasma CRP levels but negative correlated with the lymphocyte counts of patients at the time of admission, indicating an association between humoral response and cellular immune response. InterpretationThe variations of SARS-CoV-2 specific NAbs in recovered COVID-19 patients may raise the concern about the role of NAbs on disease progression. The correlation of NAb titers with age, lymphocyte counts, and blood CRP levels suggested that the interplay between virus and host immune response in coronavirus infections should be further explored for the development of effective vaccine against SARS-CoV-2 virus. Furthermore, titration of NAb is helpful prior to the use of convalescent plasma for prevention or treatment. FundingMinistry of Science and Technology of China, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Chinese Academy of Medical Sciences

15: Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients
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Posted 08 May 2020

Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients
111,249 downloads medRxiv infectious diseases

Philip Carlucci, Tania Ahuja, Christopher M. Petrilli, Harish Rajagopalan, Simon Jones, Joseph Rahimian

Background: COVID-19 has rapidly emerged as a pandemic infection that has caused significant mortality and economic losses. Potential therapies and means of prophylaxis against COVID-19 are urgently needed to combat this novel infection. As a result of in vitro evidence suggesting zinc sulfate may be efficacious against COVID-19, our hospitals began using zinc sulfate as add-on therapy to hydroxychloroquine and azithromycin. We performed a retrospective observational study to compare hospital outcomes among patients who received hydroxychloroquine and azithromycin plus zinc versus hydroxychloroquine and azithromycin alone. Methods: Data was collected from electronic medical records for all patients being treated with admission dates ranging from March 2, 2020 through April 5, 2020. Initial clinical characteristics on presentation, medications given during the hospitalization, and hospital outcomes were recorded. Patients in the study were excluded if they were treated with other investigational medications. Results: The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulfate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09) reduction in mortality or transfer to hospice remained significant (OR 0.449, 95% CI 0.271-0.744). Conclusion: This study provides the first in vivo evidence that zinc sulfate in combination with hydroxychloroquine may play a role in therapeutic management for COVID-19.

16: Forecasting COVID-19 impact on hospital bed-days, ICU-days, ventilator-days and deaths by US state in the next 4 months
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Posted 30 Mar 2020

Forecasting COVID-19 impact on hospital bed-days, ICU-days, ventilator-days and deaths by US state in the next 4 months
103,624 downloads medRxiv infectious diseases

IHME COVID-19 health service utilization forecasting team, Christopher J.L. Murray

ImportanceThis study presents the first set of estimates of predicted health service utilization and deaths due to COVID-19 by day for the next 4 months for each state in the US. ObjectiveTo determine the extent and timing of deaths and excess demand for hospital services due to COVID-19 in the US. Design, Setting, and ParticipantsThis study used data on confirmed COVID-19 deaths by day from WHO websites and local and national governments; data on hospital capacity and utilization for US states; and observed COVID-19 utilization data from select locations to develop a statistical model forecasting deaths and hospital utilization against capacity by state for the US over the next 4 months. Exposure(s)COVID-19. Main outcome(s) and measure(s)Deaths, bed and ICU occupancy, and ventilator use. ResultsCompared to licensed capacity and average annual occupancy rates, excess demand from COVID-19 at the peak of the pandemic in the second week of April is predicted to be 64,175 (95% UI 7,977 to 251,059) total beds and 17,380 (95% UI 2,432 to 57,955) ICU beds. At the peak of the pandemic, ventilator use is predicted to be 19,481 (95% UI 9,767 to 39,674). The date of peak excess demand by state varies from the second week of April through May. We estimate that there will be a total of 81,114 (95% UI 38,242 to 162,106) deaths from COVID-19 over the next 4 months in the US. Deaths from COVID-19 are estimated to drop below 10 deaths per day between May 31 and June 6. Conclusions and RelevanceIn addition to a large number of deaths from COVID-19, the epidemic in the US will place a load well beyond the current capacity of hospitals to manage, especially for ICU care. These estimates can help inform the development and implementation of strategies to mitigate this gap, including reducing non-COVID-19 demand for services and temporarily increasing system capacity. These are urgently needed given that peak volumes are estimated to be only three weeks away. The estimated excess demand on hospital systems is predicated on the enactment of social distancing measures in all states that have not done so already within the next week and maintenance of these measures throughout the epidemic, emphasizing the importance of implementing, enforcing, and maintaining these measures to mitigate hospital system overload and prevent deaths. Data availability statementA full list of data citations are available by contacting the corresponding author. Funding StatementBill & Melinda Gates Foundation and the State of Washington Key PointsO_ST_ABSQuestionC_ST_ABSAssuming social distancing measures are maintained, what are the forecasted gaps in available health service resources and number of deaths from the COVID-19 pandemic for each state in the United States? FindingsUsing a statistical model, we predict excess demand will be 64,175 (95% UI 7,977 to 251,059) total beds and 17,380 (95% UI 2,432 to 57,955) ICU beds at the peak of COVID-19. Peak ventilator use is predicted to be 19,481 (95% UI 9,767 to 39,674) ventilators. Peak demand will be in the second week of April. We estimate 81,114 (95% UI 38,242 to 162,106) deaths in the United States from COVID-19 over the next 4 months. MeaningEven with social distancing measures enacted and sustained, the peak demand for hospital services due to the COVID-19 pandemic is likely going to exceed capacity substantially. Alongside the implementation and enforcement of social distancing measures, there is an urgent need to develop and implement plans to reduce non-COVID-19 demand for and temporarily increase capacity of health facilities.

17: Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report
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Posted 22 Jun 2020

Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report
96,581 downloads medRxiv infectious diseases

Peter Horby, Wei Shen Lim, Jonathan R Emberson, Marion Mafham, Jennifer Bell, Louise Linsell, Natalie Staplin, Christopher Brightling, Andrew Ustianowski, Einas Elmahi, Benjamin Prudon, Christopher A Green, Timothy Felton, David Chadwick, Kanchan Rege, Christopher Fegan, Lucy C Chappell, Saul N Faust, Thomas Jaki, Katie Jeffery, Alan Montgomery, Kathryn Rowan, Edmund Juszczak, J Kenneth Baillie, Richard Haynes, Martin J Landray, RECOVERY Collaborative Group

Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.

18: Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection
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Posted 11 Jul 2020

Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection
85,950 downloads medRxiv infectious diseases

Jeffrey Seow, Carl Graham, Blair Merrick, Sam Acors, Kathryn JA Steel, Oliver Hemmings, Aoife O'Bryne, Neophytos Kouphou, Suzanne Pickering, Rui Galao, Gilberto Betancor, Harry D. Wilson, Adrian W. Signell, Helena Winstone, Claire Kerridge, Nigel Temperton, Luke Snell, Karen Bisnauthsing, Amelia Moore, Adrian Green, Lauren Martinez, Brielle Stokes, Johanna Honey, Alba Izquierdo-Barras, Gill Arbane, Amita Patel, Lorcan OConnell, Geraldine O Hara, Eithne MacMahon, Sam Douthwaite, Gaia Nebbia, Rahul Batra, Rocio Martinez-Nunez, Jonathan D Edgeworth, Stuart JD Neil, Michael H Malim, Katie Doores

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy's and St Thomas' Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds. This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

19: The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis
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Posted 02 Jun 2020

The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis
81,709 downloads medRxiv infectious diseases

David Ellinghaus, Frauke Degenhardt, Luis Bujanda, Maria Buti, Agustin Albillos, Pietro Invernizzi, Javier Fernandez, Daniele Prati, Guido Baselli, Rosanna Asselta, Marit Maehle Grimsrud, Chiara Milani, Fatima Aziz, Jan Kassens, Sandra May, Mareike Wendorff, Lars Wienbrandt, Florian Uellendahl-Werth, Tenghao Zheng, Xiaoli Yi, Raul de Pablo, Adolfo Garrido Chercoles, Adriana Palom, Alba-Estela Garcia-Fernandez, Francisco Rodriguez-Frias, Alberto Zanella, Alessandra Bandera, Alessandro Protti, Alessio Aghemo, Ana Lleo de Nalda, Andrea Biondi, Andrea Caballero-Garralda, Andrea Gori, Anja Tanck, Anna Latiano, Anna Ludovica Fracanzani, Anna Peschuck, Antonio Julia, Antonio Pesenti, Antonio Voza, David Jimenez, Beatriz Mateos, Beatriz Nafria Jimenez, Carmen Quereda, Claudio Angelini, Cristina Cea, Aurora Solier, David Pestana, Elena Sandoval, Elvezia Maria Paraboschi, Enrique Navas, Ferruccio Ceriotti, Filippo Martinelli-Boneschi, Flora Peyvandi, Francesco Blasi, Luis Tellez, Albert Blanco-Grau, Giacomo Grasselli, Giorgio Costantino, Giulia Cardamone, Giuseppe Foti, Serena Aneli, Hayato Kurihara, Hesham ElAbd, Ilaria My, Javier Martin, Jeanette Erdmann, Jose Ferrusquia-Acosta, Koldo Garcia-Etxebarria, Laura Izquierdo-Sanchez, Laura Rachele Bettini, Leonardo Terranova, Leticia Moreira, Luigi Santoro, Luigia Scudeller, Francisco Mesonero, Luisa Roade, Marco Schaefer, Maria Carrabba, Maria del Mar Riveiro Barciela, Maria Eloina Figuera Basso, Maria Grazia Valsecchi, Maria Hernandez-Tejero, Marialbert Acosta-Herrera, Mariella D'Angio, Marina Baldini, Marina Cazzaniga, Martin Schulzky, Maurizio Cecconi, Michael Wittig, Michele Ciccarelli, Miguel Rodriguez-Gandia, Monica Bocciolone, Monica Miozzo, Nicole Braun, Nilda Martinez, Orazio Palmieri, Paola Faverio, Paoletta Preatoni, Paolo Bonfanti, Paolo Omodei, Paolo Tentorio, Pedro Castro, Pedro M. Rodrigues, Aaron Blandino Ortiz, Ricard Ferrer, Roberta Gualtierotti, Rosa Nieto, Salvatore Badalamenti, Sara Marsal, Giuseppe Matullo, Serena Pelusi, Valter Monzani, Tanja Wesse, Tomas Pumarola, Valeria Rimoldi, Silvano Bosari, Wolfgang Albrecht, Wolfgang Peter, Manuel Romero Gomez, Mauro D'Amato, Stefano Duga, Jesus M Banales, Johannes Roksund Hov, Trine Folseraas, Luca Valenti, Andre Franke, Tom Hemming Karlsen

Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.

20: A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease
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Posted 17 Apr 2020

A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease
81,246 downloads medRxiv infectious diseases

Angkana T. Huang, Bernardo Garcia-Carreras, Matt D.T. Hitchings, Bingyi Yang, Leah Katzelnick, Susan M Rattigan, Brooke Borgert, Carlos Moreno, Benjamin D. Solomon, Isabel Rodriguez-Barraquer, Justin Lessler, Henrik Salje, Donald S. Burke, Amy Wesolowski, Derek A.T. Cummings

The duration and nature of immunity generated in response to SARS-CoV-2 infection is unknown. Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The timescale of protection is a critical determinant of the future impact of the pathogen. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. The dynamics of immunity and nature of protection are relevant to discussions surrounding therapeutic use of convalescent sera as well as efforts to identify individuals with protective immunity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV-1, MERS-CoV and human endemic coronaviruses (HCoVs). We reviewed 1281 abstracts and identified 322 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While studies of SARS-CoV-2 are necessary to determine immune responses to it, evidence from other coronaviruses can provide clues and guide future research.

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