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61: The effectiveness of the first dose of BNT162 b 2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real-world evidence
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Posted 29 Jan 2021

The effectiveness of the first dose of BNT162 b 2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real-world evidence
36,524 downloads medRxiv infectious diseases

Gabriel Chodcik, Lilac Tene, Tal Patalon, Sivan Gazit, Amir Ben-Tov, Dani Cohen, Khitam Muhsen

Background BNT162b2 vaccines showed high efficacy against COVID-19 in a randomized controlled phase-III trial. A vaccine effectiveness evaluation in real life settings is urgently needed, especially given the global disease surge. Hence, we assessed the short-term effectiveness of the first dose of BNT162b2-vaccine against SARS-CoV-2 infection. Given the BNT162b2 Phase-III results, we hypothesized that the cumulative incidence of SARS-CoV-2 infection among vaccinees will decline after 12 days following immunization compared to the incidence during the preceding days. Methods We conducted a retrospective cohort study using data from 2.6 million-member state-mandated health provider in Israel. Study population consisted of all members aged 16 or above years who were vaccinated with BNT162b2-vaccine between December/19/2020 and January/15/2021. We collected information regarding medical history and positive SARS-CoV-2 polymerase chain reaction test from days after first dose to January/17/2021. Daily and cumulative infection rates in days 13-24 were compared to days 1-12 after first dose using Kaplan-Meier survival analysis and generalized linear models. Findings Data of 503,875 individuals (mean age 59.7 years SD=14.7, 47.8% males) were analyzed, of whom 351,897 had 13-24 days of follow-up. The cumulative incidence of SARS-CoV-2 infection was 0.57% (n=2484) during days 1-12 and 0.27% (n=614) in days 13-24. A 51.4% relative risk reduction (RRR) was calculated in weighted-average daily incidence of SARS-CoV-2 infection from 43.41-per-100,000(SE=12.07) in days 1-12 to 21.08-per-100,000(SE=6.16) in days 13-24 following immunization. The decrement in incidence was evident from day 18 after first dose. Similar RRRs were calculated in individuals aged 60 or above (44.5%), younger individuals (50.2%), females (50.0%) and males (52.1%). Findings were similar in sub-populations and patients with various comorbidities. Conclusions We demonstrated an effectiveness of 51% of BNT162b2 vaccine against SARS-CoV-2 infection 13-24 days after immunization with the first dose. Immunization with the second dose should be continued to attain the anticipated protection.

62: COVID-19 seropositivity changes in asymptomatic individuals during the second and third waves of COVID-19 in Tokyo.
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Posted 23 Sep 2020

COVID-19 seropositivity changes in asymptomatic individuals during the second and third waves of COVID-19 in Tokyo.
36,027 downloads medRxiv infectious diseases

Sawako Hibino, Kazutaka Hayashida, Andrew C. Ahn, Yasutaka Hayashida

Importance: The decline of anti-SARS-COV-2 antibody titers has been documented. It is not clear whether the antibodies are persistent in infected individuals who had no symptoms. Serial serological tests on the same individuals can provide insights into the population-level prevalence and dynamic patterns of seropositivity against COVID-19 infection. Objective: To assess changes in COVID-19 seroprevalence and the persistence among the asymptomatic working population in Tokyo from May 2020 to December 2020, spanning from the second wave to the third wave of COVID19 through serial testing on the same individuals. Design: We conducted a cohort observational study about SARS-COV-2 seropositivity on the same individuals with no COVID-19 symptoms from May 26 to December 15, 2020. Six hundred fifteen healthy volunteers (mean + SD 40.8 + 10.0, range 19 - 69; 45.7 % female) from 1877 office workers were initially enrolled from 11 disparate locations across Tokyo. Participants having fever, cough, or shortness of breath at the time of testing were excluded. Fingertip blood was applied onto the cassette of a COVID19 IgM/IgG rapid test kit to detect antibodies. We compared two test results with the same kits approximately one month apart for the self-reference to validate the positive test results. Initial two tests were performed weekly from May 26 to August 25. Those who had positive test results either at the first or second test were offered the follow-up test on Dec 8 or 15, 2020. An outside ethical committee reviewed and approved the protocol. Participants: Healthy office workers from 11 disparate locations (1877 employees in total) across Tokyo volunteered to the study. Participants having fever, cough, or shortness of breath at the time of testing were excluded. Main Outcome(s) and Measure(s): Seropositivity rate (SPR) was calculated by pooled data from each two-week window from May 26 to August 25. Either IgM or IgG positivity was defined as seropositive. Changes in immunological status against SARS-CoV-2 were determined by comparing results between two tests a month apart obtained from the same individual. A Follow-up test was offered to the seropositive individuals on December 8 or 15. Results: Six hundred fifteen healthy volunteers (mean + SD 40.8 + 10.0; range 19 - 69; 45.7 % female) received at least one test. Seropositivity rate (SPR) increased from 5.8 % to 46.8 % during the second wave. The most dramatic increase in SPR occurred in late June and early July, paralleling the rise in daily confirmed cases within Tokyo, which peaked on August 4. Out of the 350 individuals (mean + SD 42.5 + 10.0; range 19 - 69; 46.0 % female) who completed the initial two tests, 152 participants were found to be seropositive at either the first or second test. Out of 152 seropositive individuals, 74 participants (52%: women, median age: 44 years, range: 23-69 years) underwent the third test. The interval between the initial positive results and the third test was approximately four months (mean + S.D. 120 + 17 days). Thirty participants (40.5 %) became seronegative at the third test on December 8 or 15. Conclusions and Relevance: COVID-19 infection may have spread widely across the general population of Tokyo despite the quite low fatality rate during the second wave. Given the temporal correlation between the rise in seropositivity and peaking in reported COVID-19 cases that occurred without a shut-down, Tokyo might achieve herd immunity temporally at the second wave. Substantial reduction of the seropositivity among asymptomatic individuals in four months in December may explain why Tokyo had the third wave, the resurgence of COVID19 is occurring every 3 to 4 months, and the herd immunity strategy has not succeeded.

63: Safety and immunogenicity of the Ad26.COV2.S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial
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Posted 25 Sep 2020

Safety and immunogenicity of the Ad26.COV2.S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial
35,743 downloads medRxiv infectious diseases

Jerry Sadoff, Mathieu Le Gars, Georgi Shukarev, Dirk Heerwegh, Carla Truyers, Anna Marit de Groot, Jeroen Stoop, Sarah Tete, Wim Van Damme, Isabel Leroux-Roels, Pieter-Jan Berghmans, Murray Kimmel, Pierre Van Damme, Jan De Hoon, William Smith, Kathryn Stephenson, Dan Barouch, Stephen De Rosa, Kristen Cohen, Juliana McElrath, Emmanuel Cormier, Gert Scheper, Jenny Hendriks, Frank Struyf, Macaya Douoguih, Johan Van Hoof, Hanneke Schuitemaker

BACKGROUND The ongoing coronavirus disease (COVID)-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be controlled by an efficacious vaccine. Multiple vaccines are in development, but no efficacious vaccine is currently available. METHODS We designed a multi-center phase 1/2a randomized, double-blinded, placebo-controlled clinical study to assesses the safety, reactogenicity and immunogenicity of Ad26.COV2.S, a non-replicating adenovirus 26 based vector expressing the stabilized pre-fusion spike (S) protein of SARS-CoV-2. Ad26.COV2.S was administered at a dose level of 5x1010 or 1x1011 viral particles (vp) per vaccination, either as a single dose or as a two-dose schedule spaced by 56 days in healthy adults (18-55 years old; cohort 1a & 1b; n= 402 and healthy elderly >65 years old; cohort 3; n=394). Vaccine elicited S specific antibody levels were measured by ELISA and neutralizing titers were measured in a wild-type virus neutralization assay (wtVNA). CD4+ T-helper (Th)1 and Th2, and CD8+ immune responses were assessed by intracellular cytokine staining (ICS). RESULTS We here report interim analyses after the first dose of blinded safety data from cohorts 1a, 1b and 3 and group unblinded immunogenicity data from cohort 1a and 3. In cohorts 1 and 3 solicited local adverse events were observed in 58% and 27% of participants, respectively. Solicited systemic adverse events were reported in 64% and 36% of participants, respectively. Fevers occurred in both cohorts 1 and 3 in 19% (5% grade 3) and 4% (0% grade 3), respectively, were mostly mild or moderate, and resolved within 1 to 2 days after vaccination. The most frequent local adverse event (AE) was injection site pain and the most frequent solicited AEs were fatigue, headache and myalgia. After only a single dose, seroconversion rate in wtVNA (50% inhibitory concentration - IC50) at day 29 after immunization in cohort 1a already reached 92% with GMTs of 214 (95% CI: 177; 259) and 92% with GMTs of 243 (95% CI: 200; 295) for the 5x1010 and 1x1011vp dose levels, respectively. A similar immunogenicity profile was observed in the first 15 participants in cohort 3, where 100% seroconversion (6/6) (GMTs of 196 [95%CI: 69; 560]) and 83% seroconversion (5/6) (GMTs of 127 [95% CI: <58; 327]) were observed for the 5x1010 or 1x1011 vp dose level, respectively. Seroconversion for S antibodies as measured by ELISA (ELISA Units/mL) was observed in 99% of cohort 1a participants (GMTs of 528 [95% CI: 442; 630) and 695 (95% CI: 596; 810]), for the 5x1010 or 1x1011 vp dose level, respectively, and in 100% (6/6 for both dose levels) of cohort 3 with GMTs of 507 (95% CI: 181; 1418) and 248 (95% CI: 122; 506), respectively. On day 14 post immunization, Th1 cytokine producing S-specific CD4+ T cell responses were measured in 80% and 83% of a subset of participants in cohort 1a and 3, respectively, with no or very low Th2 responses, indicative of a Th1-skewed phenotype in both cohorts. CD8+ T cell responses were also robust in both cohort 1a and 3, for both dose levels. CONCLUSIONS The safety profile and immunogenicity after only a single dose are supportive for further clinical development of Ad26.COV2.S at a dose level of 5x1010 vp, as a potentially protective vaccine against COVID-19. Trial registration number: NCT04436276

64: Temporal dynamics in viral shedding and transmissibility of COVID-19
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Posted 18 Mar 2020

Temporal dynamics in viral shedding and transmissibility of COVID-19
34,801 downloads medRxiv infectious diseases

Xi He, Eric Lau, Peng Wu, Xilong Deng, Jian Wang, Xinxin Hao, Yiu Chung Lau, Jessica Y Wong, Yujuan Guan, Xinghua Tan, Xiaoneng Mo, Yanqing Chen, Baolin Liao, Weilie Chen, Fengyu Hu, Qing Zhang, Mingqiu Zhong, Yanrong Wu, Lingzhai Zhao, Fuchun Zhang, Benjamin J Cowling, Fang Li, Gabriel M Leung

We report temporal patterns of viral shedding in 94 laboratory-confirmed COVID-19 patients and modelled COVID-19 infectiousness profile from a separate sample of 77 infector-infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% of transmission could occur before first symptoms of the index. Disease control measures should be adjusted to account for probable substantial pre-symptomatic transmission.

65: Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region
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Posted 05 May 2020

Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region
34,360 downloads medRxiv infectious diseases

Ania Wajnberg, Mayce Mansour, Emily Leven, Nicole M. Bouvier, Gopi Patel, Adolfo Firpo, Rao Mendu, Jeffrey Jhang, Suzanne Arinsburg, Melissa Gitman, Jane Houldsworth, Ian Baine, Viviana Simon, Judith Aberg, Florian Krammer, David Reich, Carlos Cordon-Cardo

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The percentage of infected individuals who seroconvert is still an open question. In addition, it has been shown in some individuals that viral genome can still be detected at considerable time post symptom resolution. Here we investigated both seroconversion and PCR-positivity in a large cohort of convalescent serum donors in New York City. Methods: Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via enzyme-linked immunosorbent assay for presence of anti SARS-CoV-2 spike antibodies. Results: All but three confirmed SARS-CoV-2 patients seroconverted to the SARS-CoV-2 spike while only 37.4% of suspected SARS-CoV-2 patients seroconverted. PCR-positivity was detected up to 28 days from symptom resolution. Conclusions: Here we show that the vast majority of confirmed COVID19 patients seroconvert, potentially providing immunity to reinfection. We also report that in a large proportion of individuals, viral genome can be detected via PCR in the upper respiratory tract for weeks post symptom resolution, but it is unclear if this signal represents infectious virus.

66: Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis
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Posted 30 Sep 2020

Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis
34,056 downloads medRxiv infectious diseases

Joseph A. Ladapo, John E. McKinnon, Peter A. McCullough, Harvey Risch

Objective--To determine if hydroxychloroquine (HCQ) reduces the incidence of new illness, hospitalization or death among outpatients at risk for or infected with SARS-CoV-2 (COVID-19). Design--Systematic review and meta-analysis of randomized clinical trials. Data sources--Search of MEDLINE, EMBASE, PubMed, medRxiv, PROSPERO, and the Cochrane Central Register of Controlled Trials. Also review of reference lists from recent meta-analyses. Study selection--Randomized clinical trials in which participants were treated with HCQ or placebo/standard-of-care for pre-exposure prophylaxis, post-exposure prophylaxis, or outpatient therapy for COVID-19. Methods--Two investigators independently extracted data on trial design and outcomes. Medication side effects and adverse reactions were also assessed. The primary outcome was COVID-19 hospitalization or death. When unavailable, new COVID-19 infection was used. We calculated random effects meta-analysis according to the method of DerSimonian and Laird. Heterogeneity between the studies was evaluated by calculation of Cochran Q and I2 parameters. An Egger funnel plot was drawn to investigate publication bias. We also calculated the fixed effects meta-analysis summary of the five studies. All calculations were done in Excel, and results were considered to be statistically significant at a two-sided threshold of P=.05. Results--Five randomized controlled clinical trials enrolling 5,577 patients were included. HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization or death, P=.025 (RR, 0.76 [95% CI, 0.59 to 0.97]). No serious adverse cardiac events were reported. The most common side effects were gastrointestinal. Conclusion--Hydroxychloroquine use in outpatients reduces the incidence of the composite outcome of COVID-19 infection, hospitalization, and death. Serious adverse events were not reported and cardiac arrhythmia was rare. Systematic review registration--This review was not registered.

67: Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis
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Posted 20 Mar 2020

Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis
33,951 downloads medRxiv infectious diseases

Chaoqun Ma, Jiawei Gu, Pan Hou, Liang Zhang, Yuan Bai, Zhifu Guo, Hong Wu, Bili Zhang, Pan Li, Xianxian Zhao

BackgroundRecently, Coronavirus Disease 2019 (COVID-19) outbreak started in Wuhan, China. Although the clinical features of COVID-19 have been reported previously, data regarding the risk factors associated with the clinical outcomes are lacking. ObjectivesTo summary and analyze the clinical characteristics and identify the predictors of disease severity and mortality. MethodsThe PubMed, Web of Science Core Collection, Embase, Cochrane and MedRxiv databases were searched through February 25, 2020. Meta-analysis of Observational Studies in Epidemiology (MOOSE) recommendations were followed. We extracted and pooled data using random-e{square}ects meta-analysis to summary the clinical feature of the confirmed COVID-19 patients, and further identify risk factors for disease severity and death. Heterogeneity was evaluated using the I2 method and explained with subgroup analysis and meta-regression. ResultsA total of 30 studies including 53000 patients with COVID-19 were included in this study, the mean age was 49.8 years (95% CI, 47.5-52.2 yrs) and 55.5% were male. The pooled incidence of severity and mortality were 20.2% (95% CI, 15.1-25.2%) and 3.1% (95% CI, 1.9-4.2%), respectively. The predictor for disease severity included old age ([&ge;] 50 yrs, odds ratio [OR] = 2.61; 95% CI, 2.29-2.98), male (OR =1.348, 95% CI, 1.195-1.521), smoking (OR =1.734, 95% CI, 1.146-2.626) and any comorbidity (OR = 2.635, 95% CI, 2.098-3.309), especially chronic kidney disease (CKD, OR = 6.017; 95% CI, 2.192-16.514), chronic obstructive pulmonary disease (COPD, OR = 5.323; 95% CI, 2.613-10.847) and cerebrovascular disease (OR = 3.219; 95% CI, 1.486-6.972). In terms of laboratory results, increased lactate dehydrogenase (LDH), C-reactive protein (CRP) and D-dimer and decreased blood platelet and lymphocytes count were highly associated with severe COVID-19 (all for P < 0.001). Meanwhile, old age ([&ge;] 60 yrs, RR = 9.45; 95% CI, 8.09-11.04), followed by cardiovascular disease (RR = 6.75; 95% CI, 5.40-8.43) hypertension (RR = 4.48; 95% CI, 3.69-5.45) and diabetes (RR = 4.43; 95% CI, 3.49-5.61) were found to be independent prognostic factors for the COVID-19 related death. ConclusionsTo our knowledge, this is the first evidence-based medicine research to explore the risk factors of prognosis in patients with COVID-19, which is helpful to identify early-stage patients with poor prognosis and adapt effective treatment.

68: Human coronavirus reinfection dynamics: lessons for SARS-CoV-2
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Posted 18 May 2020

Human coronavirus reinfection dynamics: lessons for SARS-CoV-2
33,837 downloads medRxiv infectious diseases

Arthur WD Edridge, Joanna M Kaczorowska, Alexis CR Hoste, Margreet Bakker, Michelle Klein, Maarten F Jebbink, Amy Matser, Cormac Kinsella, Paloma Rueda, Maria Prins, Patricia Sastre, Martin Deijs, Lia van der Hoek

In the current COVID-19 pandemic a key unsolved question is the duration of acquired immunity in recovered individuals. The recent emergence of SARS-CoV-2 precludes a direct study on this virus, but the four seasonal human coronaviruses may reveal common characteristics applicable to all human coronaviruses. We monitored healthy subjects over a time span of 35 years (1985-2020), providing a total of 2473 follow up person-months, and determined a) the time to reinfection by the same seasonal coronavirus and b) the dynamics of coronavirus antibody depletion post-infection. An alarmingly short duration of protective immunity to coronaviruses was found. Reinfections occurred frequently at 12 months post-infection and there was for each virus a substantial reduction in antibody levels as soon as 6 months post-infection.

69: Laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections
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Posted 12 Feb 2020

Laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections
33,807 downloads medRxiv infectious diseases

Yang Yang, Minghui Yang, Chenguang Shen, Fuxiang Wang, Jing Yuan, Jinxiu Li, Mingxia Zhang, Zhaoqin Wang, Li Xing, Jinli Wei, Ling Peng, Gary Wong, Haixia Zheng, Weibo Wu, Mingfeng Liao, Kai Feng, Jianming Li, Qianting Yang, Juanjuan Zhao, Zheng Zhang, Lei Liu, Yingxia Liu

BackgroundThe outbreak of novel coronavirus pneumonia (NCP) caused by 2019-nCoV spread rapidly, and elucidating the diagnostic accuracy of different respiratory specimens is crucial for the control and treatment of this disease. MethodsRespiratory samples including nasal swabs, throat swabs, sputum and bronchoalveolar lavage fluid (BALF) were collected from Guangdong CDC confirmed NCP patients, and viral RNAs were detected using a CFDA approved detection kit. Results were analyzed in combination with sample collection date and clinical information. FindingsExcept for BALF, the sputum possessed the highest positive rate (74.4%[~]88.9%), followed by nasal swabs (53.6%[~]73.3%) for both severe and mild cases during the first 14 days after illness onset (d.a.o). For samples collected [&ge;] 15 d.a.o, sputum and nasal swabs still possessed a high positive rate ranging from 42.9%[~]61.1%. The positive rate of throat swabs collected [&ge;] 8 d.a.o was low, especially in samples from mild cases. Viral RNAs could be detected in all the lower respiratory tract of severe cases, but not the mild cases. CT scan of cases 02, 07 and 13 showed typical viral pneumonia with ground-glass opacity, while no viral RNAs were detected in first three or all the upper respiratory samples. InterpretationSputum is most accurate for laboratory diagnosis of NCP, followed by nasal swabs. Detection of viral RNAs in BLAF is necessary for diagnosis and monitoring of viruses in severe cases. CT scan could serve as an important make up for the diagnosis of NCP. FundingNational Science and Technology Major Project, Sanming Project of Medicine and China Postdoctoral Science Foundation.

70: The link between vitamin D deficiency and Covid-19 in a large population
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Posted 07 Sep 2020

The link between vitamin D deficiency and Covid-19 in a large population
33,754 downloads medRxiv infectious diseases

Ariel Israel, Assi Cicurel, Ilan Feldhamer, Yosef Dror, Shmuel M Giveon, David Gillis, David Strich, Gil Lavie

BACKGROUND Recent studies suggest a link between vitamin D deficiency and Covid-19 infection. In our population we observe major differences in Covid-19 incidence in ethnic groups and genders in each group. METHODS We carried out a population-based study among 4.6 million members of Clalit Health Services (CHS). We collected results from vitamin D tests performed between 2010 and 2019 and used weighted linear regression to assess the relationship between prevalence of vitamin D deficiency and Covid-19 incidence in 200 localities. Additionally, we matched 52,405 infected patients with 524,050 control individuals of the same sex, age, geographical region and used conditional logistic regression to assess the relationship between baseline vitamin D levels, acquisition of vitamin D supplements in the last 4 months, and positive Covid-19. RESULTS We observe a highly significant correlation between prevalence of vitamin D deficiency and Covid-19 incidence, and between female-to-male ratio for severe vitamin D deficiency and female-to-male ratio for Covid-19 incidence in localities (P<0.001). In the matched cohort, we found a significant association between low vitamin D levels and the risk of Covid-19, with the highest risk observed for severe vitamin D deficiency. A significant protective effect was observed for members who acquired liquid vitamin D formulations (drops) in the last 4 months. CONCLUSION In this large observational population study, we show a strong association between vitamin D deficiency and Covid-19 occurrence. After adjustment for baseline characteristics and prior vitamin D levels, acquisition of liquid vitamin D formulations is associated with decreased risk for Covid-19 infection.

71: Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
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Posted 27 Mar 2020

Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
33,017 downloads medRxiv infectious diseases

Bin Lou, Ting-Dong Li, Shu-Fa Zheng, Ying-Ying Su, Zhi-Yong Li, Wei Liu, Fei Yu, Sheng-Xiang Ge, Qian-Da Zou, Quan Yuan, Sha Lin, Cong-Ming Hong, Xiang-Yang Yao, Xue-Jie Zhang, Ding-Hui Wu, Guo-Liang Zhou, Wang-Heng Hou, Ting-Ting Li, Ya-Li Zhang, Shi-Yin Zhang, Jian Fan, Jun Zhang, Ning-Shao Xia, Yu Chen

BackgroundTimely diagnosis of SARS-CoV-2 infection is the prerequisite for treatment and preventive quarantine. The serology characteristics and complement diagnosis value of antibody test to RNA test needs to be demonstrated. MethodA patient cohort study was conducted at the first affiliated hospital of Zhejiang University, China. Serial plasma of COVID-19 patients and were collected and total antibody (Ab), IgM and IgG antibody against SARS-CoV-2 were detected. The antibody dynamics during the infection were described. ResultsThe seroconversion rate for Ab, IgM and IgG in COVID-19 patients was 98.8% (79/80), 93.8% (75/80) and 93.8% (75/80), respectively. The first detectible serology marker is total antibody and followed by IgM and IgG, with a median seroconversion time of 15, 18 and 20 day post exposure (d.p.e) or 9, 10 and 12 days post onset, separately. The antibody levels increased rapidly since 6 d.p.o and accompanied with the decline of viral load. For patients in the early stage of illness (0-7d.p.o),Ab showed the highest sensitivity (64.1%) compared to the IgM and IgG (33.3% for both, p<0.001). The sensitivities of Ab, IgM and IgG detection increased to 100%, 96.7% and 93.3% two weeks later, respectively. ConclusionsTypical acute antibody response is induced during the SARS-CoV-2 infection. The serology testing provides important complementation to RNA test for pathogenic specific diagnosis and helpful information to evaluate the adapted immunity status of patient. It should be strongly recommended to apply well-validated antibody tests in the clinical management and public health practice to improve the control of COVID-19 infection. Take-Home MessageAntibody responses are induced after SARS-CoV-2 infection and complement diagnosis value of antibody test to RNA test was observed. Antibody tests are critical tools in clinical management and control of SARS-CoV-2 infection and COVID-19.

72: Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy
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Posted 22 Apr 2020

Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy
32,857 downloads medRxiv infectious diseases

Luca Carsana, Aurelio Sonzogni, Ahmed Nasr, Roberta Rossi, Alessandro Pellegrinelli, Pietro Zerbi, Roberto Rech, Riccardo Colombo, Spinello Antinori, Mario Corbellino, Massimo Galli, Emanuele Catena, Antonella Tosoni, Andrea Gianatti, Manuela Nebuloni

Importance. The analysis of lung tissues of patients with COVID-19 may help understand pathogenesis and clinical outcomes in this life-threatening respiratory illness. Objective. To determine the histological patterns in lung tissue of patients with severe COVID-19. Design and participants. Lungs tissues of 38 cases who died for COVID-19 in two hospital of Northern Italy were systematically analysed. Hematoxylin-eosin staining, immunohistochemistry for the inflammatory infiltrate and cellular components, electron microscopy were performed. Results. The features of the exudative and proliferative phases of Diffuse Alveolar Disease (DAD) were found: capillary congestion, necrosis of pneumocytes, hyaline membrane, interstitial oedema, pneumocyte hyperplasia and reactive atypia, platelet-fibrin thrombi. The inflammatory infiltrate was composed by macrophages in alveolar lumens and lymphocytes mainly in the interstitium. Electron microscopy revealed viral particles within cytoplasmic vacuoles of pneumocytes. Conclusions and relevance. The predominant pattern of lung lesions in COVID-19 patients is DAD, as described for the other two coronavirus that infect humans, SARS-CoV and MERS-CoV. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequently found. The main relevant finding is the presence of platelet-fibrin thrombi in small arterial vessels; this important observation fits into the clinical context of coagulopathy which dominates in these patients and which is one of the main targets of therapy.

73: Treatment Response to Hydroxychloroquine, Lopinavir/Ritonavir, and Antibiotics for Moderate COVID 19: A First Report on the Pharmacological Outcomes from South Korea
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Posted 18 May 2020

Treatment Response to Hydroxychloroquine, Lopinavir/Ritonavir, and Antibiotics for Moderate COVID 19: A First Report on the Pharmacological Outcomes from South Korea
32,343 downloads medRxiv infectious diseases

Min Seo Kim, Soon-Woo Jang, Yu-Kyung Park, Bong-ok Kim, Tae-Ho Hwang, Seok Ho Kang, Won Jun Kim, Hea-Woon Park, Wonjong Yang, Joonyoung Jang, Min Ho An

The authors have withdrawn this manuscript because of the controversy about hydroxychloroquine and potential changes in results after peer-review, the authors intend to share their results in formal publication. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

74: Estimation of SARS-CoV-2 infection fatality rate by real-time antibody screening of blood donors
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Posted 28 Apr 2020

Estimation of SARS-CoV-2 infection fatality rate by real-time antibody screening of blood donors
31,140 downloads medRxiv infectious diseases

Christian Erikstrup, Christoffer Egeberg Hother, Ole Birger Vestager Pedersen, Kåre Mølbak, Robert Leo Skov, Dorte Kinggaard Holm, Susanne Sækmose, Anna Christine Nilsson, Patrick Terrence Brooks, Jens Kjaergaard Boldsen, Christina Mikkelsen, Mikkel Gybel-Brask, Erik Sørensen, Khoa Manh Dinh, Susan Mikkelsen, Bjarne Kuno Møller, Thure Haunstrup, Lene Holm Harritshoej, Bitten Aagaard Jensen, Henrik Hjalgrim, Søren Thue Lillevang, Henrik Ullum

Background: The pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has tremendous consequences for our societies. Knowledge of the seroprevalence of SARS-CoV-2 is needed to accurately monitor the spread of the epidemic and also to calculate the infection fatality rate (IFR). These measures may help the authorities to make informed decisions and adjust the current societal interventions. Blood donors comprise approximately 4.7% of the similarly aged population of Denmark and blood is donated in all areas of the country. The objective of this study was to perform real-time seroprevalence surveying among blood donors as a tool to estimate previous SARS-CoV-2 infections and the population based IFR. Methods: All Danish blood donors aged 17-69 years giving blood April 6 to 17 were tested for SARS-CoV-2 immunoglobulin M and G antibodies using a commercial lateral flow test. Antibody status was compared between areas and an estimate of the IFR was calculated. The seroprevalence was adjusted for assay sensitivity and specificity taking the uncertainties of the test validation into account when reporting the 95% confidence intervals (CI). Results: The first 9,496 blood donors were tested and a combined adjusted seroprevalence of 1.7% (CI: 0.9-2.3) was calculated. The seroprevalence differed across areas. Using available data on fatalities and population numbers a combined IFR in patients younger than 70 is estimated at 82 per 100,000 (CI: 59-154) infections. Conclusions: The IFR was estimated to be slightly lower than previously reported from other countries not using seroprevalence data. The IFR, including only individuals with no comorbidity, is likely several fold lower than the current estimate. This may have implications for risk mitigation. We have initiated real-time nationwide anti-SARS-CoV-2 seroprevalence surveying of blood donations as a tool in monitoring the epidemic.

75: A deep learning algorithm using CT images to screen for Corona Virus Disease (COVID-19)
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Posted 17 Feb 2020

A deep learning algorithm using CT images to screen for Corona Virus Disease (COVID-19)
30,835 downloads medRxiv infectious diseases

Shuai Wang, Bo Kang, Jinlu Ma, Xianjun Zeng, Mingming Xiao, Jia Guo, Mengjiao Cai, Jingyi Yang, Yaodong Li, Xiangfei Meng, Bo Xu

BackgroundTo control the spread of Corona Virus Disease (COVID-19), screening large numbers of suspected cases for appropriate quarantine and treatment is a priority. Pathogenic laboratory testing is the diagnostic gold standard but it is time consuming with significant false negative results. Fast and accurate diagnostic methods are urgently needed to combat the disease. Based on COVID-19 radiographical changes in CT images, we aimed to develop a deep learning method that could extract COVID-19s graphical features in order to provide a clinical diagnosis ahead of the pathogenic test, thus saving critical time for disease control. Methods and FindingsWe collected 1,065CT images of pathogen-confirmed COVID-19 cases (325 images) along with those previously diagnosed with typical viral pneumonia (740 images). We modified the Inception transfer-learning model to establish the algorithm, followed by internal and external validation. The internal validation achieved a total accuracy of 89.5% with specificity of 0.88 and sensitivity of 0.87. The external testing dataset showed a total accuracy of 79.3% with specificity of 0.83 and sensitivity of 0.67. In addition, in 54 COVID-19 images that first two nucleic acid test results were negative, 46 were predicted as COVID-19 positive by the algorithm, with the accuracy of 85.2%. ConclusionThese results demonstrate the proof-of-principle for using artificial intelligence to extract radiological features for timely and accurate COVID-19 diagnosis.

76: Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App
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Posted 21 Oct 2020

Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App
30,168 downloads medRxiv infectious diseases

Carole H Sudre, Benjamin Murray, Thomas Varsavsky, Mark S Graham, Rose S. Penfold, Ruth C. Bowyer, Joan Capdevila Pujol, Kerstin Klaser, Michela Antonelli, Liane S. Canas, Erika Molteni, Marc Modat, M. Jorge Cardoso, Anna May, Sajaysurya Ganesh, Richard Davies, Long H Nguyen, David A. Drew, Christina M. Astley, Amit D. Joshi, Jordi Merino, Neli Tsereteli, Tove Fall, Maria F Gomez, Emma L Duncan, Cristina Menni, Frances MK Williams, Paul W Franks, Andrew T Chan, Jonathan Wolf, Sebastien Ourselin, Tim Spector, Claire J Steves

Reports of "Long-COVID", are rising but little is known about prevalence, risk factors, or whether it is possible to predict a protracted course early in the disease. We analysed data from 4182 incident cases of COVID-19 who logged their symptoms prospectively in the COVID Symptom Study app. 558 (13.3%) had symptoms lasting >=28 days, 189 (4.5%) for >=8 weeks and 95 (2.3%) for >=12 weeks. Long-COVID was characterised by symptoms of fatigue, headache, dyspnoea and anosmia and was more likely with increasing age, BMI and female sex. Experiencing more than five symptoms during the first week of illness was associated with Long-COVID, OR=3.53 [2.76;4.50]. A simple model to distinguish between short and long-COVID at 7 days, which gained a ROC-AUC of 76%, was replicated in an independent sample of 2472 antibody positive individuals. This model could be used to identify individuals for clinical trials to reduce long-term symptoms and target education and rehabilitation services.

77: The Infectious Nature of Patient-Generated SARS-CoV-2 Aerosol
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Posted 20 Jul 2020

The Infectious Nature of Patient-Generated SARS-CoV-2 Aerosol
29,931 downloads medRxiv infectious diseases

Joshua L Santarpia, Vicki L Herrera, Danielle N Rivera, Shanna Ratnesar-Shumate, St Patrick Reid, Paul W. Denton, Jacob W.S. Martens, Ying Fang, Nicholas Conoan, Michael V Callahan, James V. Lawler, David M Brett-Major, John J. Lowe

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission causing coronavirus disease 2019 (COVID-19) may occur through multiple routes. We collected aerosol samples around six patients admitted into mixed acuity wards in April of 2020 to identify the risk of airborne SARS-CoV-2. Measurements were made to characterize the size distribution of aerosol particles, and size-fractionated, aerosol samples were collected to assess the presence of infectious virus in particles sizes of >4.1 m, 1-4 m, and <1 m in the patient environment. Samples were analyzed by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), cell culture, western blot, and transmission electron microscopy (TEM). SARS-CoV-2 RNA was detected in all six rooms in all particle size fractions (>4.1 m, 1-4 m, and <1 m). Increases in viral RNA during cell culture of the virus from recovered aerosol samples demonstrated the presence of infectious, replicating virions in three <1 m aerosol samples (P<0.05). Viral replication of aerosol was also observed in the 1-4 m stage but did not reach statistical significance (0.05<P<0.10). Western blot and TEM analysis of these samples also showed evidence of viral proteins and intact virions. The infectious nature of aerosol collected in this study further suggests that airborne transmission of COVID-19 is possible, and that aerosol prevention measures are necessary to effectively stem the spread of SARS-CoV-2.

78: SARS-CoV-2 titers in wastewater are higher than expected from clinically confirmed cases
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Posted 07 Apr 2020

SARS-CoV-2 titers in wastewater are higher than expected from clinically confirmed cases
29,843 downloads medRxiv infectious diseases

FQ Wu, A Xiao, JB Zhang, XQ Gu, WL Lee, K Kauffman, WP Hanage, M Matus, N Ghaeli, N Endo, C Duvallet, K Moniz, TB Erickson, PR Chai, J Thompson, EJ Alm

Wastewater surveillance may represent a complementary approach to measure the presence and even prevalence of infectious diseases when the capacity for clinical testing is limited. Moreover, aggregate, population-wide data can help inform modeling efforts. We tested wastewater collected at a major urban treatment facility in Massachusetts and found the presence of SARS-CoV-2 at high titers in the period from March 18 - 25 using RT-qPCR. We then confirmed the identity of the PCR product by direct DNA sequencing. Viral titers observed were significantly higher than expected based on clinically confirmed cases in Massachusetts as of March 25. The reason for the discrepancy is not yet clear, and until further experiments are complete, these data do not necessarily indicate that clinical estimates are incorrect. Our approach is scalable and may be useful in modeling the SARS-CoV-2 pandemic and future outbreaks.

79: Cluster of COVID-19 in northern France: A retrospective closed cohort study
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Posted 23 Apr 2020

Cluster of COVID-19 in northern France: A retrospective closed cohort study
29,714 downloads medRxiv infectious diseases

Arnaud Fontanet, Laura Tondeur, Yoann Madec, Rebecca Grant, Camille Besombes, Nathalie Jolly, Sandrine Fernandes Pellerin, Marie-Noëlle Ungeheuer, Isabelle Cailleau, Lucie Kuhmel, Sarah Temmam, Christele Huon, Kuang-Yu Chen, Bernadette Crescenzo, Sandie Munier, Caroline Demeret, Ludivine Grzelak, Isabelle Staropoli, Timothee Bruel, Pierre Gallian, Simon Cauchemez, Sylvie van der Werf, Olivier Schwartz, Marc Eloit, Bruno Hoen

Background: The Oise department in France has been heavily affected by COVID-19 in early 2020. Methods: Between 30 March and 4 April 2020, we conducted a retrospective closed cohort study among pupils, their parents and siblings, as well as teachers and non-teaching staff of a high-school located in Oise. Participants completed a questionnaire that covered history of fever and/or respiratory symptoms since 13 January 2020 and had blood tested for the presence of anti-SARS-CoV-2 antibodies. The infection attack rate (IAR) was defined as the proportion of participants with confirmed SARS-CoV-2 infection based on antibody detection. Blood samples from two blood donor centres collected between 23 and 27 March 2020 in the Oise department were also tested for presence of anti-SARS-CoV-2 antibodies. Findings: Of the 661 participants (median age: 37 years), 171 participants had anti-SARS-CoV-2 antibodies. The overall IAR was 25.9% (95% confidence interval (CI) = 22.6-29.4), and the infection fatality rate was 0% (one-sided 97.5% CI = 0-2.1). Nine of the ten participants hospitalised since mid-January were in the infected group, giving a hospitalisation rate of 5.3% (95% CI = 2.4-9.8). Anosmia and ageusia had high positive predictive values for SARS-CoV-2 infection (84.7% and 88.1%, respectively). Smokers had a lower IAR compared to non-smokers (7.2% versus 28.0%, P <0.001). The proportion of infected individuals who had no symptoms during the study period was 17.0% (95% CI = 11.2-23.4). The proportion of donors with anti-SARS-CoV-2 antibodies in two nearby blood banks of the Oise department was 3.0% (95% CI = 1.1-6.4). Interpretation: The relatively low IAR observed in an area where SARS-CoV-2 actively circulated weeks before confinement measures indicates that establishing herd immunity will take time, and that lifting these measures in France will be long and complex.

80: Handyfuge-LAMP: low-cost and electricity-free centrifugation forisothermal SARS-CoV-2 detection in saliva.
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Posted 01 Jul 2020

Handyfuge-LAMP: low-cost and electricity-free centrifugation forisothermal SARS-CoV-2 detection in saliva.
29,424 downloads medRxiv infectious diseases

Ethan Li, Adam Larson, Anestha Kothari, Manu Prakash

Point of care diagnostics for COVID-19 detection are vital to assess infection quickly and at the source so appropriate measures can be taken. The loop-mediated isothermal amplification (LAMP) assay has proven to be a reliable and simple protocol that can detect small amounts of viral RNA in patient samples (<10 genomes per L) (Nagamine, Hase, and Notomi 2002) Recently, Rabe and Cepko at Harvard published a sensitive and simple protocol for COVID-19 RNA detection in saliva using an optimized LAMP assay (Rabe and Cepko, 2020). This LAMP protocol has the benefits of being simple, requiring no specialized equipment; rapid, requiring less than an hour from sample collection to readout; and cheap, costing around $1 per reaction using commercial reagents. The pH based colorimetric readout also leaves little ambiguity and is intuitive. However, a shortfall in many nucleic acid-based methods for detection in saliva samples has been the variability in output due to the presence of inhibitory substances in saliva. Centrifugation to separate the reaction inhibitors from inactivated sample was shown to be an effective way to ensure reliable LAMP amplification. However, a centrifuge capable of safely achieving the necessary speeds of 2000 RPM for several minutes often costs hundreds of dollars and requires a power supply. We present here an open hardware solution- Handyfuge - that can be assembled with readily available components for the cost of <5 dollars a unit and could be used together with the LAMP assay for point of care detection of COVID-19 RNA from saliva. The device is then validated using the LAMP protocol from Rabe and Cepko. With the use of insulated coolers for reagent supply chain and delivery, the assay presented can be completed without the need for electricity or any laboratory scale infrastructure.

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