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1: Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
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Posted 28 Mar 2020

Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
354,980 downloads medRxiv epidemiology

Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H Otazu

COVID-19 has spread to most countries in the world. Puzzlingly, the impact of the disease is different in different countries. These differences are attributed to differences in cultural norms, mitigation efforts, and health infrastructure. Here we propose that national differences in COVID- 19 impact could be partially explained by the different national policies respect to Bacillus Calmette-Guerin (BCG) childhood vaccination. BCG vaccination has been reported to offer broad protection to respiratory infections. We compared large number of countries BCG vaccination policies with the morbidity and mortality for COVID-19. We found that countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies. Countries that have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. We also found that BCG vaccination also reduced the number of reported COVID-19 cases in a country. The combination of reduced morbidity and mortality makes BCG vaccination a potential new tool in the fight against COVID-19.

2: COVID-19 Antibody Seroprevalence in Santa Clara County, California
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Posted 17 Apr 2020

COVID-19 Antibody Seroprevalence in Santa Clara County, California
277,148 downloads medRxiv epidemiology

Eran Bendavid, Bianca Mulaney, Neeraj Sood, Soleil Shah, Emilia Ling, Rebecca Bromley-Dulfano, Cara Lai, Zoe Weissberg, Rodrigo Saavedra-Walker, James Tedrow, Dona Tversky, Andrew Bogan, Thomas Kupiec, Daniel Eichner, Ribhav Gupta, John Ioannidis, Jay Bhattacharya

Background Addressing COVID-19 is a pressing health and social concern. To date, many epidemic projections and policies addressing COVID-19 have been designed without seroprevalence data to inform epidemic parameters. We measured the seroprevalence of antibodies to SARS-CoV-2 in a community sample drawn from Santa Clara County. Methods On April 3-4, 2020, we tested county residents for antibodies to SARS-CoV-2 using a lateral flow immunoassay. Participants were recruited using Facebook ads targeting a sample of individuals living within the county by demographic and geographic characteristics. We estimate weights to adjust our sample to match the zip code, sex, and race/ethnicity distribution within the county. We report both the weighted and unweighted prevalence of antibodies to SARS-CoV-2. We also adjust for test performance characteristics by combining data from 16 independent samples obtained from manufacturer's data, regulatory submissions, and independent evaluations: 13 samples for specificity (3,324 specimens) and 3 samples for sensitivity (157 specimens). Results The raw prevalence of antibodies to SARS-CoV-2 in our sample was 1.5% (exact binomial 95CI 1.1-2.0%). Test performance specificity in our data was 99.5% (95CI 99.2-99.7%) and sensitivity was 82.8% (95CI 76.0-88.4%). The unweighted prevalence adjusted for test performance characteristics was 1.2% (95CI 0.7-1.8%). After weighting for population demographics of Santa Clara County, the prevalence was 2.8% (95CI 1.3-4.7%), using bootstrap to estimate confidence bounds. These prevalence point estimates imply that 54,000 (95CI 25,000 to 91,000 using weighted prevalence; 23,000 with 95CI 14,000-35,000 using unweighted prevalence) people were infected in Santa Clara County by early April, many more than the approximately 1,000 confirmed cases at the time of the survey. Conclusions The estimated population prevalence of SARS-CoV-2 antibodies in Santa Clara County implies that the infection may be much more widespread than indicated by the number of confirmed cases. More studies are needed to improve precision of prevalence estimates. Locally-derived population prevalence estimates should be used to calibrate epidemic and mortality projections.

3: Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
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Posted 30 Mar 2020

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
246,460 downloads medRxiv epidemiology

Zhaowei Chen, Jijia Hu, Zongwei Zhang, Shan Jiang, Shoumeng Han, Dandan Yan, Ruhong Zhuang, Ben Hu, Zhan Zhang

AimsStudies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19. Main methodsFrom February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ. Key findingsFor the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia. SignificanceAmong patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia. Trial registrationURL: https://www.clinicaltrials.gov/. The unique identifier: ChiCTR2000029559.

4: Relationship between the ABO Blood Group and the COVID-19 Susceptibility
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Posted 16 Mar 2020

Relationship between the ABO Blood Group and the COVID-19 Susceptibility
195,527 downloads medRxiv epidemiology

Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, Yunjiao He, Bin Sun, Meilan Wei, Guangyu Yang, Xinghuan Wang, Li Zhang, Xiaoyang Zhou, Mingzhao Xing, Peng George Wang

The novel coronavirus disease-2019 (COVID-19) has been spreading around the world rapidly and declared as a pandemic by WHO. Here, we compared the ABO blood group distribution in 2,173 patients with COVID-19 confirmed by SARS-CoV-2 test from three hospitals in Wuhan and Shenzhen, China with that in normal people from the corresponding regions. The results showed that blood group A was associated with a higher risk for acquiring COVID-19 compared with non-A blood groups, whereas blood group O was associated with a lower risk for the infection compared with non-O blood groups. This is the first observation of an association between the ABO blood type and COVID-19. It should be emphasized, however, that this is an early study with limitations. It would be premature to use this study to guide clinical practice at this time, but it should encourage further investigation of the relationship between the ABO blood group and the COVID-19 susceptibility.

5: Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters
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Posted 08 Apr 2020

Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters
167,913 downloads medRxiv epidemiology

John P.A. Ioannidis, Cathrine Axfors, Despina G. Contopoulos-Ioannidis

OBJECTIVETo evaluate the relative risk of COVID-19 death in people <65 years old versus older individuals in the general population, to provide estimates of absolute risk of COVID-19 death at the population level, and to understand what proportion of COVID-19 deaths occur in non-elderly people without underlying diseases in epicenters of the pandemic. ELIGIBLE DATACountries and US states or major cities with at least 250 COVID-19 deaths as of 4/4/2020 and with information available on death counts according to age strata, allowing to calculate the number of deaths in people with age <65. Data were available for Belgium, Germany, Italy, Netherlands, Portugal, Spain, Sweden, and Switzerland, as well as Louisiana, Michigan, Washington states and New York City as of April 4, 2020. MAIN OUTCOME MEASURESProportion of COVID-19 deaths that occur in people <65 years old; relative risk of COVID-19 death in people <65 versus [&ge;]65 years old; absolute risk of death in people <65 and in those [&ge;]80 years old in the general population as of 4/4/2020; absolute death risk expressed as equivalent of death risk from driving a motor vehicle. RESULTSIndividuals with age <65 account for 5%-9% of all COVID-19 deaths in the 8 European epicenters, and approach 30% in three US hotbed locations. People <65 years old had 34- to 73-fold lower risk than those [&ge;]65 years old in the European countries and 13- to 15-fold lower risk in New York City, Louisiana and Michigan. The absolute risk of COVID-19 death ranged from 1.7 per million for people <65 years old in Germany to 79 per million in New York City. The absolute risk of COVID-19 death for people [&ge;]80 years old ranged from approximately 1 in 6,000 in Germany to 1 in 420 in Spain. The COVID-19 death risk in people <65 years old during the period of fatalities from the epidemic was equivalent to the death risk from driving between 9 miles per day (Germany) and 415 miles per day (New York City). People <65 years old and not having any underlying predisposing conditions accounted for only 0.3%, 0.7%, and 1.8% of all COVID-19 deaths in Netherlands, Italy, and New York City. CONCLUSIONSPeople <65 years old have very small risks of COVID-19 death even in the hotbeds of the pandemic and deaths for people <65 years without underlying predisposing conditions are remarkably uncommon. Strategies focusing specifically on protecting high-risk elderly individuals should be considered in managing the pandemic.

6: OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients.
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Posted 07 May 2020

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients.
158,868 downloads medRxiv epidemiology

The OpenSAFELY Collaborative, Elizabeth J Williamson, Alex J Walker, Krishnan Bhaskaran, Sebastian CJ Bacon, Christopher Bates, Caroline E Morton, Helen J Curtis, Amir Mehrkar, David H. Evans, Peter Inglesby, Jonathan Cockburn, Helen I Mcdonald, Brian MacKenna, Laurie Tomlinson, Ian J Douglas, Christopher T Rentsch, Rohini Mathur, Angel YS Wong, Richard Grieve, David A Harrison, Harriet Forbes, Anna Schultze, Richard Croker, John Parry, Frank Hester, Sam Harper, Rafael Perera, Stephen Evans, Liam Smeeth, Ben Goldacre

Background Establishing who is at risk from a novel rapidly arising cause of death, and why, requires a new approach to epidemiological research with very large datasets and timely data. Working on behalf of NHS England we therefore set out to deliver a secure and pseudonymised analytics platform inside the data centre of a major primary care electronic health records vendor establishing coverage across detailed primary care records for a substantial proportion of all patients in England. The following results are preliminary. Data sources Primary care electronic health records managed by the electronic health record vendor TPP, pseudonymously linked to patient-level data from the COVID-19 Patient Notification System (CPNS) for death of hospital inpatients with confirmed COVID-19, using the new OpenSAFELY platform. Population 17,425,445 adults. Time period 1st Feb 2020 to 25th April 2020. Primary outcome Death in hospital among people with confirmed COVID-19. Methods Cohort study analysed by Cox-regression to generate hazard ratios: age and sex adjusted, and multiply adjusted for co-variates selected prospectively on the basis of clinical interest and prior findings. Results There were 5683 deaths attributed to COVID-19. In summary after full adjustment, death from COVID-19 was strongly associated with: being male (hazard ratio 1.99, 95%CI 1.88-2.10); older age and deprivation (both with a strong gradient); uncontrolled diabetes (HR 2.36 95% CI 2.18-2.56); severe asthma (HR 1.25 CI 1.08-1.44); and various other prior medical conditions. Compared to people with ethnicity recorded as white, black people were at higher risk of death, with only partial attenuation in hazard ratios from the fully adjusted model (age-sex adjusted HR 2.17 95% CI 1.84-2.57; fully adjusted HR 1.71 95% CI 1.44-2.02); with similar findings for Asian people (age-sex adjusted HR 1.95 95% CI 1.73-2.18; fully adjusted HR 1.62 95% CI 1.43-1.82). Conclusions We have quantified a range of clinical risk factors for death from COVID-19, some of which were not previously well characterised, in the largest cohort study conducted by any country to date. People from Asian and black groups are at markedly increased risk of in-hospital death from COVID-19, and contrary to some prior speculation this is only partially attributable to pre-existing clinical risk factors or deprivation; further research into the drivers of this association is therefore urgently required. Deprivation is also a major risk factor with, again, little of the excess risk explained by co-morbidity or other risk factors. The findings for clinical risk factors are concordant with policies in the UK for protecting those at highest risk. Our OpenSAFELY platform is rapidly adding further NHS patients' records; we will update and extend these results regularly. Keywords COVID-19, risk factors, ethnicity, deprivation, death, informatics.

7: The Novel Coronavirus, 2019-nCoV, is Highly Contagious and More Infectious Than Initially Estimated
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Posted 11 Feb 2020

The Novel Coronavirus, 2019-nCoV, is Highly Contagious and More Infectious Than Initially Estimated
134,827 downloads medRxiv epidemiology

Steven Sanche, Yen Ting Lin, Chonggang Xu, Ethan Romero-Severson, Nick Hengartner, Ruian Ke

The novel coronavirus (2019-nCoV) is a recently emerged human pathogen that has spread widely since January 2020. Initially, the basic reproductive number, R0, was estimated to be 2.2 to 2.7. Here we provide a new estimate of this quantity. We collected extensive individual case reports and estimated key epidemiology parameters, including the incubation period. Integrating these estimates and high-resolution real-time human travel and infection data with mathematical models, we estimated that the number of infected individuals during early epidemic double every 2.4 days, and the R0 value is likely to be between 4.7 and 6.6. We further show that quarantine and contact tracing of symptomatic individuals alone may not be effective and early, strong control measures are needed to stop transmission of the virus. One-sentence summaryBy collecting and analyzing spatiotemporal data, we estimated the transmission potential for 2019-nCoV.

8: SARS-CoV-2 RNA concentrations in primary municipal sewage sludge as a leading indicator of COVID-19 outbreak dynamics
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Posted 22 May 2020

SARS-CoV-2 RNA concentrations in primary municipal sewage sludge as a leading indicator of COVID-19 outbreak dynamics
128,836 downloads medRxiv epidemiology

Jordan Peccia, Alessandro Zulli, Doug E. Brackney, Nathan D. Grubaugh, Edward H Kaplan, Arnau Cassanovas-Massana, Albert I. Ko, Amyn A Malik, Dennis Wang, Mike Wang, Joshua L Warren, Daniel Weinberger, Saad B Omer

We report a time course of SARS-CoV-2 RNA concentrations in primary sewage sludge during the Spring COVID-19 outbreak in a northeastern U.S. metropolitan area. SARS-CoV-2 RNA was detected in all environmental samples, and when adjusted for the time lag, the virus RNA concentrations tracked the COVID-19 epidemiological curve. SARS-CoV-2 RNA concentrations were a leading indicator of community infection ahead of compiled COVID-19 testing data and local hospital admissions. Decisions to implement or relax public health measures and restrictions require timely information on outbreak dynamics in a community.

9: Adjusted age-specific case fatality ratio during the COVID-19 epidemic in Hubei, China, January and February 2020
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Posted 06 Mar 2020

Adjusted age-specific case fatality ratio during the COVID-19 epidemic in Hubei, China, January and February 2020
115,401 downloads medRxiv epidemiology

Anthony Hauser, Michel J Counotte, Charles C Margossian, Konstantinoudis Garyfallos, Nicola Low, Christian L Althaus, Julien Riou

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSThe epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that originated in Wuhan, China in late 2019 is now pandemic. Reliable estimates of death from coronavirus disease 2019 (COVID-19) are essential to guide control efforts and to plan health care system requirements. The objectives of this study are to: 1) simulate the transmission dynamics of SARS-CoV-2 using publicly available surveillance data; 2) give estimates of SARS-CoV-2 mortality adjusted for bias in the two regions with the worlds highest numbers of confirmed Covid-19 deaths: Hubei province, China and northern Italy. Method and FindingsWe developed an age-stratified susceptible-exposed-infected-removed (SEIR) compartmental model describing the dynamics of transmission and mortality during the SARS-CoV-2 epidemic. Our model accounts for two biases; preferential ascertainment of severe cases and delayed mortality (right-censoring). We fitted our transmission model to surveillance data from Hubei province (1 January to 11 February 2020) and northern Italy (8 February to 3 March 2020). Overall mortality among all symptomatic and asymptomatic infections was estimated to be 3.0% (95% credible interval: 2.6-3.4%) in Hubei province and 3.3% (2.0-4.7%) in northern Italy. Mortality increased with age; we estimate that among 80+ year olds, 39.0% (95%CrI: 31.1-48.9%) in Hubei province and 89.0% (95%CrI: 56.2-99.6%) in northern Italy dies or will die. Limitations are that the model requires data recorded by date of onset and that sex-disaggregated mortality was not available. ConclusionsWe developed a mechanistic approach to correct the crude CFR for bias due to right-censoring and preferential ascertainment and provide adjusted estimates of mortality due to SARS-CoV-2 infection by age group. While specific to the situation in Hubei, China and northern Italy during these periods, these findings will help the mitigation efforts and planning of resources as other regions prepare for SARS-CoV-2 epidemics.

10: False positives in reverse transcription PCR testing for SARS-CoV-2
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Posted 01 May 2020

False positives in reverse transcription PCR testing for SARS-CoV-2
101,932 downloads medRxiv epidemiology

Andrew N Cohen, Bruce Kessel, Michael G Milgroom

Contrary to the practice during previous epidemics, with COVID-19 health authorities have treated a single positive result from a PCR-based test as confirmation of infection, irrespective of signs, symptoms and exposure. This is based on a widespread belief that positive results in these tests are highly reliable. However, evidence from external quality assessments and real-world data indicate enough a high enough false positive rate to make positive results highly unreliable over a broad range of scenarios. This has clinical and case management implications, and affects an array of epidemiological statistics, including the asymptomatic ratio, prevalence, and hospitalization and death rates, as well as epidemiologic models. Steps should be taken to raise awareness of false positives and reduce their frequency. The most important immediate action is to check positive results with additional tests, at least when prevalence is low.

11: Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold
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Posted 02 May 2020

Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold
90,107 downloads medRxiv epidemiology

M. Gabriela M. Gomes, Rodrigo M. Corder, Jessica G. King, Kate E Langwig, Caetano Souto-Maior, Jorge Carneiro, Guilherme Goncalves, Carlos Penha-Goncalves, Marcelo U Ferreira, Ricardo Aguas

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, the susceptible subpopulation is depleted causing the incidence of new cases to decline. Variation in individual susceptibility or exposure to infection exacerbates this effect. Individuals that are more susceptible or more exposed tend to be infected earlier, depleting the susceptible subpopulation of those who are at higher risk of infection. This selective depletion of susceptibles intensifies the deceleration in incidence. Eventually, susceptible numbers become low enough to prevent epidemic growth or, in other words, the herd immunity threshold (HIT) is reached. Although estimates vary, simple calculations suggest that herd immunity to SARS-CoV-2 requires 60-70% of the population to be immune. By fitting epidemiological models that allow for heterogeneity to SARS-CoV-2 outbreaks across the globe, we show that variation in susceptibility or exposure to infection reduces these estimates. Accurate measurements of heterogeneity are therefore of paramount importance in controlling the COVID-19 pandemic.

12: Mask mandate and use efficacy in state-level COVID-19 containment
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Posted 25 May 2021

Mask mandate and use efficacy in state-level COVID-19 containment
90,006 downloads medRxiv epidemiology

Damian Guerra, Daniel J Guerra

Background: Containment of the COVID-19 pandemic requires evidence-based strategies to reduce transmission. Because COVID-19 can spread via respired droplets, many states have mandated mask use in public settings. Randomized control trials have not clearly demonstrated mask efficacy against respiratory viruses, but observational studies suggest greater mask compliance may be associated with lower infection rates. We hypothesized that statewide mask mandates and mask use are associated with lower COVID-19 case growth rates in the United States. Methods: We calculated total COVID-19 case growth and mask use for the continental United States with data from the Centers for Disease Control and Prevention and Institute for Health Metrics and Evaluation. We estimated post-mask mandate case growth in non-mandate states using median issuance dates of neighboring states with mandates. Results: Case growth was not significantly different between mandate and non-mandate states at low or high transmission rates, and surges were equivocal. Mask use predicted lower case growth at low, but not high transmission rates. Growth rates were comparable between states in the top and bottom mask use quintiles adjusted for normalized total cases early in the pandemic and unadjusted after peak Fall-Winter infections. Mask use did not predict Summer 2020 case growth for non-Northeast states or Fall-Winter 2020 growth for all states. Conclusions: Mask mandates and use are not associated with slower state-level COVID-19 spread during COVID-19 growth surges. COVID-19 containment requires future research and implementation of existing efficacious strategies.

13: Closed environments facilitate secondary transmission of coronavirus disease 2019 (COVID-19)
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Posted 03 Mar 2020

Closed environments facilitate secondary transmission of coronavirus disease 2019 (COVID-19)
89,015 downloads medRxiv epidemiology

Hiroshi Nishiura, Hitoshi Oshitani, Tetsuro Kobayashi, Tomoya Saito, Tomimasa Sunagawa, Tamano Matsui, Takaji Wakita, MHLW COVID-19 Response Team, Motoi Suzuki

ObjectiveTo identify common features of cases with novel coronavirus disease (COVID-19) so as to better understand what factors promote secondary transmission including superspreading events. MethodsA total of 110 cases were examined among eleven clusters and sporadic cases, and investigated who acquired infection from whom. The clusters included four in Tokyo and one each in Aichi, Fukuoka, Hokkaido, Ishikawa, Kanagawa and Wakayama prefectures. The number of secondary cases generated by each primary case was calculated using contact tracing data. ResultsOf the 110 cases examined, 27 (24.6%) were primary cases who generated secondary cases. The odds that a primary case transmitted COVID-19 in a closed environment was 18.7 times greater compared to an open-air environment (95% confidence interval [CI]: 6.0, 57.9). ConclusionsIt is plausible that closed environments contribute to secondary transmission of COVID-19 and promote superspreading events. Our findings are also consistent with the declining incidence of COVID-19 cases in China, as gathering in closed environments was prohibited in the wake of the rapid spread of the disease.

14: Emergence and spread of a SARS-CoV-2 variant through Europe in the summer of 2020
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Posted 28 Oct 2020

Emergence and spread of a SARS-CoV-2 variant through Europe in the summer of 2020
81,302 downloads medRxiv epidemiology

Emma B Hodcroft, Moira Zuber, Sarah Ann Nadeau, Timothy G Vaughan, Katharine HD Crawford, Christian L Althaus, Martina Reichmuth, John E Bowen, Alexandra C Walls, Davide Corti, Jesse D Bloom, David Veesler, David Mateo, Alberto Hernando de Castro, Iñaki Comas, Fernando Gonzalez Candelas, SeqCOVID-SPAIN consortium, Tanja Stadler, Richard A Neher

Following its emergence in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic resulting in unprecedented efforts to reduce transmission and develop therapies and vaccines (WHO Emergency Committee, 2020; Zhu et al., 2020). Rapidly generated viral genome sequences have allowed the spread of the virus to be tracked via phylogenetic analysis (Worobey et al., 2020; Hadfield et al., 2018; Pybus et al., 2020). While the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced, allowing continent-specific variants to emerge. However, within Europe travel resumed in the summer of 2020, and the impact of this travel on the epidemic is not well understood. Here we report on a novel SARS-CoV-2 variant, 20E (EU1), that emerged in Spain in early summer, and subsequently spread to multiple locations in Europe. We find no evidence of increased transmissibility of this variant, but instead demonstrate how rising incidence in Spain, resumption of travel across Europe, and lack of effective screening and containment may explain the variant's success. Despite travel restrictions and quarantine requirements, we estimate 20E (EU1) was introduced hundreds of times to countries across Europe by summertime travellers, likely undermining local efforts to keep SARS-CoV-2 cases low. Our results demonstrate how a variant can rapidly become dominant even in absence of a substantial transmission advantage in favorable epidemiological settings. Genomic surveillance is critical to understanding how travel can impact SARS-CoV-2 transmission, and thus for informing future containment strategies as travel resumes.

15: Viral cultures for COVID-19 infectivity assessment. Systematic review
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Posted 04 Aug 2020

Viral cultures for COVID-19 infectivity assessment. Systematic review
78,171 downloads medRxiv epidemiology

Tom Jefferson, Elizabeth A Spencer, Jon Brassey, Carl Heneghan

Objective To review the evidence from studies comparing SARS-CoV-2 culture, with the results of reverse transcriptase polymerase chain reaction (RT-PCR). Methods We searched LitCovid, medRxiv, Google Scholar and the WHO Covid-19 database for Covid-19 using the terms viral culture or viral replication and associated synonyms up to 10 September 2020. We carried out citation matching and included studies reporting attempts to culture or observe SARS-CoV-2 matching with cutoffs for RT-PCR positivity. One reviewer extracted data for each study and a second reviewer checked end edited the extraction and summarised the narratively by sample: fecal, respiratory, environment, blood or mixed. Where necessary we wrote to corresponding authors of the included or background papers for additional information. We assessed quality using a modified QUADAS 2 risk of bias tool. This is the fourth version of this review that was first published on the 4th of August and updated on the 21t of August, on the 3rd and 10th of September. Results We included 29 studies reporting culturing or observing tissue invasion by SARS-CoV in sputum, naso or oropharyngeal, urine, stool, blood and environmental samples from patients diagnosed with Covid-19. The data are suggestive of a relation between the time from collection of a specimen to test, cycle threshold and symptom severity. The quality of the studies was moderate with lack of standardised reporting. Twelve studies reported that Ct values were significantly lower and log copies higher in samples producing live virus culture. Five studies reported no growth in samples based on a Ct cut-off value. These values ranged from CT > 24 for no growth to Ct > 34 or more. Two studies report a strong relationship between Ct value and ability to recover infectious virus and that the odds of live virus culture reduced by 33% for every one unit increase in Ct. A cut-off RT-PCR Ct > 30 was associated with non-infectious samples. One study that analysed the NSP, N and E gene fragments of the PCR result reported different cut-off thresholds depending on the gene fragment analysed. The duration of RNA shedding detected by PCR was far longer compared to detection of live culture. Six out of eight studies reported RNA shedding for longer than 14 days. Yet, infectivity declines after day 8 even among cases with ongoing high viral loads. A very small proportion of people re-testing positive after hospital discharge or with high Ct are likely to be infectious. Conclusion Prospective routine testing of reference and culture specimens are necessary for each country involved in the pandemic to establish the usefulness and reliability of PCR for Covid-19 and its relation to patient factors. Infectivity is related to the date of onset of symptoms and cycle threshold level. A binary Yes / No approach to the interpretation RT-PCR unvalidated against viral culture will result in false positives with possible segregation of large numbers of people who are no longer infectious and hence not a threat to public health.

16: Full lockdown policies in Western Europe countries have no evident impacts on the COVID-19 epidemic.
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Posted 01 May 2020

Full lockdown policies in Western Europe countries have no evident impacts on the COVID-19 epidemic.
74,000 downloads medRxiv epidemiology

Thomas A. J. Meunier

This phenomenological study assesses the impacts of full lockdown strategies applied in Italy, France, Spain and United Kingdom, on the slowdown of the 2020 COVID-19 outbreak. Comparing the trajectory of the epidemic before and after the lockdown, we find no evidence of any discontinuity in the growth rate, doubling time, and reproduction number trends. Extrapolating pre-lockdown growth rate trends, we provide estimates of the death toll in the absence of any lockdown policies, and show that these strategies might not have saved any life in western Europe. We also show that neighboring countries applying less restrictive social distancing measures (as opposed to police-enforced home containment) experience a very similar time evolution of the epidemic.

17: Viable SARS-CoV-2 in the air of a hospital room with COVID-19 patients
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Posted 04 Aug 2020

Viable SARS-CoV-2 in the air of a hospital room with COVID-19 patients
71,791 downloads medRxiv epidemiology

John A Lednicky, Michael Lauzardo, Z. Hugh Fan, Antarpreet S Jutla, Trevor B Tilly, Mayank Gangwar, Moiz Usmani, Sripriya N Shankar, Karim Mohamed, Arantza Eiguren-Fernandez, Caroline J. Stephenson, Md. Mahbubul Alam, Maha A Elbadry, Julia C Loeb, Kuttichantran Subramaniam, Thomas B Waltzek, Kartikeya Cherabuddi, John Glenn Morris, Chang-Yu Wu

Background - There currently is substantial controversy about the role played by SARS-CoV-2 in aerosols in disease transmission, due in part to detections of viral RNA but failures to isolate viable virus from clinically generated aerosols. Methods - Air samples were collected in the room of two COVID-19 patients, one of whom had an active respiratory infection with a nasopharyngeal (NP) swab positive for SARS-CoV-2 by RT-qPCR. By using VIVAS air samplers that operate on a gentle water-vapor condensation principle, material was collected from room air and subjected to RT-qPCR and virus culture. The genomes of the SARS-CoV-2 collected from the air and of virus isolated in cell culture from air sampling and from a NP swab from a newly admitted patient in the room were sequenced. Findings - Viable virus was isolated from air samples collected 2 to 4.8m away from the patients. The genome sequence of the SARS-CoV-2 strain isolated from the material collected by the air samplers was identical to that isolated from the NP swab from the patient with an active infection. Estimates of viable viral concentrations ranged from 6 to 74 TCID50 units/L of air. Interpretation - Patients with respiratory manifestations of COVID-19 produce aerosols in the absence of aerosol-generating procedures that contain viable SARS-CoV-2, and these aerosols may serve as a source of transmission of the virus.

18: Predicting the Trajectory of Any COVID19 Epidemic From the Best Straight Line
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Posted 28 Jun 2020

Predicting the Trajectory of Any COVID19 Epidemic From the Best Straight Line
69,520 downloads medRxiv epidemiology

Michael Levitt, Andrea Scaiewicz, Francesco Zonta

A pipeline involving data acquisition, curation, carefully chosen graphs and mathematical models, allows analysis of COVID-19 outbreaks at 3,546 locations world-wide (all countries plus smaller administrative divisions with data available). Comparison of locations with over 50 deaths shows all outbreaks have a common feature: H(t) defined as loge(X(t)/X(t 1)) decreases linearly on a log scale, where X(t) is the total number of Cases or Deaths on day, t (we use ln for loge). The downward slopes vary by about a factor of three with time constants (1/slope) of between 1 and 3 weeks; this suggests it may be possible to predict when an outbreak will end. Is it possible to go beyond this and perform early prediction of the outcome in terms of the eventual plateau number of total confirmed cases or deaths? We test this hypothesis by showing that the trajectory of cases or deaths in any outbreak can be converted into a straight line. Specifically , is a straight line for the correct plateau value N, which is determined by a new method, Best-Line Fitting (BLF). BLF involves a straight-line facilitation extrapolation needed for prediction; it is blindingly fast and amenable to optimization. We find that in some locations that entire trajectory can be predicted early, whereas others take longer to follow this simple functional form. Fortunately, BLF distinguishes predictions that are likely to be correct in that they show a stable plateau of total cases or death (N value). We apply BLF to locations that seem close to a stable predicted N value and then forecast the outcome at some locations that are still growing wildly. Our accompanying web-site will be updated frequently and provide all graphs and data described here.

19: Sentinel surveillance of SARS-CoV-2 in wastewater anticipates the occurrence of COVID-19 cases
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Posted 13 Jun 2020

Sentinel surveillance of SARS-CoV-2 in wastewater anticipates the occurrence of COVID-19 cases
67,005 downloads medRxiv epidemiology

Gemma Chavarria-Miró, Eduard Anfruns-Estrada, Susana Guix, Miquel Paraira, Belén Galofré, Gloria Sáanchez, Rosa Pinto, Albert Bosch

SARS-CoV-2 was detected in Barcelona sewage long before the declaration of the first COVID-19 case, indicating that the infection was present in the population before the first imported case was reported. Sentinel surveillance of SARS-CoV-2 in wastewater would enable adoption of immediate measures in the event of future COVID-19 waves.

20: Suppression of COVID-19 outbreak in the municipality of Vo, Italy
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Posted 18 Apr 2020

Suppression of COVID-19 outbreak in the municipality of Vo, Italy
63,128 downloads medRxiv epidemiology

Enrico Lavezzo, Elisa Franchin, Constanze Ciavarella, Gina Cuomo-Dannenburg, Luisa Barzon, Claudia Del Vecchio, Lucia Rossi, Riccardo Manganelli, Arianna Loregian, Nicolò Navarin, Davide Abate, Manuela Sciro, Stefano Merigliano, Ettore Decanale, Maria Cristina Vanuzzo, Francesca Saluzzo, Francesco Onelia, Monia Pacenti, Saverio Parisi, Giovanni Carretta, Daniele Donato, Luciano Flor, Silvia Cocchio, Giulia Masi, Alessandro Sperduti, Lorenzo Cattarino, Renato Salvador, Katy A.M. Gaythorpe, Imperial College London COVID-19 Response Team, Alessandra R. Brazzale, Stefano Toppo, Marta Trevisan, Vincenzo Baldo, Christl A Donnelly, Neil M Ferguson, Ilaria Dorigatti, Andrea Crisanti

On the 21st of February 2020 a resident of the municipality of Vo, a small town near Padua, died of pneumonia due to SARS-CoV-2 infection. This was the first COVID-19 death detected in Italy since the emergence of SARS-CoV-2 in the Chinese city of Wuhan, Hubei province. In response, the regional authorities imposed the lockdown of the whole municipality for 14 days. We collected information on the demography, clinical presentation, hospitalization, contact network and presence of SARS-CoV-2 infection in nasopharyngeal swabs for 85.9% and 71.5% of the population of Vo at two consecutive time points. On the first survey, which was conducted around the time the town lockdown started, we found a prevalence of infection of 2.6% (95% confidence interval (CI) 2.1-3.3%). On the second survey, which was conducted at the end of the lockdown, we found a prevalence of 1.2% (95% CI 0.8-1.8%). Notably, 43.2% (95% CI 32.2-54.7%) of the confirmed SARS-CoV-2 infections detected across the two surveys were asymptomatic. The mean serial interval was 6.9 days (95% CI 2.6-13.4). We found no statistically significant difference in the viral load (as measured by genome equivalents inferred from cycle threshold data) of symptomatic versus asymptomatic infections (p-values 0.6 and 0.2 for E and RdRp genes, respectively, Exact Wilcoxon-Mann-Whitney test). Contact tracing of the newly infected cases and transmission chain reconstruction revealed that most new infections in the second survey were infected in the community before the lockdown or from asymptomatic infections living in the same household. This study sheds new light on the frequency of asymptomatic SARS-CoV-2 infection and their infectivity (as measured by the viral load) and provides new insights into its transmission dynamics, the duration of viral load detectability and the efficacy of the implemented control measures.

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