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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
356,397 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
281,206 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
248,900 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
197,258 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
192,870 downloads medRxiv epidemiology

John 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.
160,227 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 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
135,520 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
130,141 downloads medRxiv epidemiology

Jordan Peccia, Alessandro Zulli, Doug E. Brackney, Nathan D. Grubaugh, Edward H Kaplan, Arnau Cassanovas-Massana, Albert Ko, Amyn A Malik, Dennis Wang, Mike Wang, Joshua L Warren, Daniel M. 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: Correlation of SARS-CoV-2 Breakthrough Infections to Time-from-vaccine; Preliminary Study
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Posted 31 Jul 2021

Correlation of SARS-CoV-2 Breakthrough Infections to Time-from-vaccine; Preliminary Study
116,235 downloads medRxiv epidemiology

Roni Lotan, Sivan Gazit, Gabriel Chodik, Tal Patalon, Galit Perez, Amir Ben Tov, barak mizrahi, Nir Kalkstein, Asaf Peretz

The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine was widely demonstrated. However, long term effectiveness is still unknown. A nationwide vaccination campaign was initiated early in Israel, allowing for a real-world evaluation of the interaction between protection and time-from-vaccine. The Delta (B.1.617.2) variant became the dominant strain in Israel in June 2021, as Israel is currently experiencing a new surge of cases. Leveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we assessed the correlation between time-from-vaccine and incidence of breakthrough infection. We found that the risk for infection was significantly higher for early vaccinees compared to those vaccinated later. This preliminary finding should prompt further investigagions into long-term protection against different strains, and prospective clinical trials to examine the effect of a booster vaccine against breakthrough infection.

10: 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
115,967 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.

11: Mask mandate and use efficacy for COVID-19 containment in US States
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Posted 25 May 2021

Mask mandate and use efficacy for COVID-19 containment in US States
113,651 downloads medRxiv epidemiology

Damian Guerra, Daniel J Guerra

Background: COVID-19 pandemic mitigation requires evidence-based strategies. Because COVID-19 can spread via respired droplets, most US states mandated mask use in public settings. Randomized control trials have not clearly demonstrated mask efficacy against respiratory viruses, and observational studies conflict on whether mask use predicts lower infection rates. We hypothesized that statewide mask mandates and mask use were 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: Earlier mask mandates were not associated with lower total cases or lower maximum growth rates. Earlier mandates were weakly associated with lower minimum COVID-19 growth rates. Mask use predicted lower minimum but not lower maximum growth rates. Growth rates and total growth were comparable between US states in the first and last mask use quintiles during the Fall-Winter wave. These observations persisted for both natural logarithmic and fold growth models and when adjusting for differences in US state population density. Conclusions: We did not observe association between mask mandates or use and reduced COVID-19 spread in US states. COVID-19 mitigation requires further research and use of existing efficacious strategies, most notably vaccination.

12: 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
107,257 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.

13: 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
91,647 downloads medRxiv epidemiology

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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began to spread in late 2019, gradually depleting susceptible populations and causing the incidence of new infections to decline over time. Variation in individual susceptibility or exposure to infection exacerbated this effect. Individuals who were more susceptible or more exposed tended to be infected earlier, depleting the susceptible subpopulation of those who were at higher risk of infection. This selective depletion of susceptibles intensified the deceleration in incidence irrespectively of vaccination programmes. In a theoretical scenario of acquired immunity being long-lasting, susceptible numbers would eventually become low enough to prevent epidemic growth or, in other words, the herd immunity threshold (HIT) would be naturally reached. Early in the coronavirus disease (COVID-19) pandemic, simple calculations, relying on homogeneity assumptions, suggested that herd immunity would require 60-80% of the population to become immune. Here we build, into the underlying models, individual variation in susceptibility or in exposure to infection and demonstrate how that lowers the HIT. Based on data from a variety of sources and early parameter estimates these basic models suggest the HIT associated with natural infection to be in the order of 10-30% for SARS-CoV-2. We discuss how a structure accounting for unobserved selectable variation can be a core feature of infectious disease modelling embedded in model development as reality evolves and complexity is incremented. The goal is to enhance accuracy and enable trade-offs to be adequately addressed in the design of optimal policies.

14: 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)
90,401 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.

15: Protection of previous SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: A three-month nationwide experience from Israel
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Posted 24 Apr 2021

Protection of previous SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: A three-month nationwide experience from Israel
89,872 downloads medRxiv epidemiology

Yair Goldberg, Micha Mandel, Yonatan Woodbridge, Ronen Fluss, Ilya Novikov, Rami Yaari, Arnona Ziv, Laurence Freedman, Amit Huppert

Worldwide shortage of vaccination against SARS-CoV-2 infection while the pandemic is still uncontrolled leads many states to the dilemma whether or not to vaccinate previously infected persons. Understanding the level of protection of previous infection compared to that of vaccination is critical for policy making. We analyze an updated individual-level database of the entire population of Israel to assess the protection efficacy of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Vaccination was highly effective with overall estimated efficacy for documented infection of 92.8% (CI: [92.6, 93.0]); hospitalization 94.2% (CI: [93.6, 94.7]); severe illness 94.4% (CI: [93.6, 95.0]); and death 93.7% (CI: [92.5, 94.7]). Similarly, the overall estimated level of protection from prior SARS-CoV-2 infection for documented infection is 94.8% (CI: [94.4, 95.1]); hospitalization 94.1% (CI: [91.9, 95.7]); and severe illness 96.4% (CI: [92.5, 98.3]). Our results question the need to vaccinate previously-infected individuals.

16: 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
82,773 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, IƱaki 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.

17: 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
81,103 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.

18: 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.
74,606 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.

19: SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis
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Posted 08 Sep 2021

SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis
74,052 downloads medRxiv epidemiology

Tracy Beth Hoeg, Allison Krug, Josh Stevenson, John Mandrola

Objectives: Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic. Design, Setting and Participants: Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words myocarditis, pericarditis, and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic. Main outcome measures: 1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk. Results: A total of 257 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 94.0 (ages 16-17); among females, rates were 13.0 and 13.4 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 3.7-6.1 times higher than their 120-day COVID-19 hospitalization risk as of August 21, 2021 (7-day hospitalizations 1.5/100k population) and 2.6-4.3-fold higher at times of high weekly hospitalization risk (2.1/100k), such as during January 2021. For boys 16-17 without medical comorbidities, the rate of CAE is currently 2.1-3.5 times higher than their 120-day COVID-19 hospitalization risk, and 1.5-2.5 times higher at times of high weekly COVID-19 hospitalization. Conclusions: Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.

20: 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
72,959 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.

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