21 February, 2021

International risk of the new variant COVID-19 importations originating in the United Kingdom -

A fast-spreading SARS-CoV-2 variant identified in the United Kingdom in December 2020 has raised international alarm. We estimate that, in 16 out of 19 countries analyzed, there is at least a 50% chance the variant was imported by travelers from the United Kingdom by December 7th.

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Exhaled SARS-CoV-2 quantified by face-mask sampling in hospitalised patients with covid-19 -

Background Human to human transmission of SARS-CoV-2 is driven by the respiratory route but little is known about the pattern and quantity of virus output from exhaled breath. We have previously shown that face-mask sampling (FMS) can detect exhaled tubercle bacilli and have adapted its use to quantify exhaled SARS-CoV-2 RNA in patients admitted to hospital with covid-19. Methods Between May and December 2020, we took two concomitant FMS and nasopharyngeal samples (NPS) over two days, starting within 24 hours of a routine virus positive NPS in patients hospitalised with covid-19, at University Hospitals of Leicester NHS Trust, UK. Participants were asked to wear a modified duckbilled facemask for 30 minutes, followed by a nasopharyngeal swab. Demographic, clinical, and radiological data, as well as International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) mortality and deterioration scores were obtained. Exposed masks were processed by removal, dissolution and analysis of sampling matrix strips fixed within the mask by RT-qPCR. Viral genome copy numbers were determined and results classified as Negative; Low: less than or equal to 999 copies; Medium: 1,000-99,999 copies and High 100,000 or more copies per strip for FMS or per 100microlitres for NPS. Results 102 FMS and NPS were collected from 66 routinely positive patients; median age: 61 (IQR 49 - 77), of which FMS was positive in 37% of individuals and concomitant NPS was positive in 50%. Positive FMS viral loads varied over five orders of magnitude (<10-3.3 x 106 genome copies/strip); 21 (32%) patients were asymptomatic at the time of sampling. High FMS viral load was associated with respiratory symptoms at time of sampling and shorter interval between sampling and symptom onset (FMS High: median (IQR) 2 days (2-3) vs FMS Negative: 7 days (7-10), p=0.002). On multivariable linear regression analysis, higher FMS viral loads were associated with higher ISARIC mortality (Medium FMS vs Negative FMS gave an adjusted coefficient of 15.7, 95% CI 3.7-27.7, p=0.01) and deterioration scores (High FMS vs Negative FMS gave an adjusted coefficient of 37.6, 95% CI 14.0 to 61.3, p=0.002), while NPS viral loads showed no significant association. Conclusion We demonstrate a simple and effective method for detecting and quantifying exhaled SARS-CoV-2 in hospitalised patients with covid-19. Higher FMS viral loads were more likely to be associated with developing severe disease compared to NPS viral loads. Similar to NPS, FMS viral load was highest in early disease and in those with active respiratory symptoms, highlighting the potential role of FMS in understanding infectivity.

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Evaluation of sampling frequency and normalization of SARS-CoV-2 wastewater concentrations for capturing COVID-19 burdens in the community -

Wastewater surveillance for SARS-CoV-2 provides an approach for assessing the infection burden across a city. For these data to be useful for public health, measurement variability and the relationship to case data need to be established. We measured SARS-CoV-2 RNA concentrations in the influent of twelve wastewater treatment plants from August 2020 to January 2021. Replicate samples demonstrated that N1 gene target concentrations varied by 21% RSD between technical replicate filters and by 14% RSD between duplicate assays. COVID-19 cases were correlated significantly (rho≥0.70) to wastewater SARS-CoV-2 RNA concentrations for seven plants, including large and small cities. SARS-CoV-2 data normalized to flow improved correlations to reported COVID-19 cases for some plants but normalizing to a spiked recovery control (BCoV) or a fecal marker (PMMoV or HF183) generally reduced correlations. High frequency sampling demonstrated that a minimum of two samples collected per week was needed to maintain accuracy in trend analysis. We found a significantly different ratio of COVID-19 cases to SARS-CoV-2 loads in one of three large communities, suggesting a higher rate of undiagnosed cases. These data demonstrate that SARS-CoV-2 wastewater surveillance can provide a useful community-wide metric to assess the course of the COVID-19 pandemic.

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Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines -

Aim and Background: We aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses per dose in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young. Methods: Based on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established ′one dose fits all′ approach with tailored strategies: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, amplifying the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates similar to Europe in late January 2021 is used. Results: When the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100′000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30′000. Conclusion: Protecting the vulnerable, minimizing overall deaths and stopping the pandemic is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose, in this model parameterized to European demographics, coronavirus transmission observations and vaccine characteristics.

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Encephalopathies associated with severe COVID-19 present specific neurovascular unit alterations without evidence of strong neuroinflammation -

Objective: Coronavirus disease (COVID-19) has been associated with a large variety of neurological disorders. However the mechanisms underlying these neurological complications remain elusive. In this study we aimed at determining whether neurological symptoms were caused by SARS-CoV-2 direct infection or by either systemic or local pro-inflammatory mediators. Methods: We checked for SARS-CoV-2 RNA by RT-qPCR, SARS-CoV-2-specific antibodies and for 49 cytokines/chemokines/growth factors (by Luminex) in the cerebrospinal fluids (CSF) +/- sera of a cohort of 22 COVID-19 patients with neurological presentation and 55 neurological control patients (inflammatory [IND], non-inflammatory [NIND], multiple sclerosis [MS]). Results: We detected SARS-CoV-2 RNA and virus-specific antibodies in the CSF of 0/22 and 10/21 COVID-19 patients, respectively. Of the four categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines and growth factors. In contrast, COVID-19 patients did not present overall upregulation of inflammatory mediators in the CSF. However, the CSF of patients with severe COVID-19 (ICU patients) exhibited higher concentrations of CCL2, CXCL8, and VEGF-A in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated barrier index and correlated to the increase of peripheral inflammation (serum HGF and CXCL10). Conclusion: Our results point at an absence of massive SARS-CoV-2 infection or inflammation of the central nervous system, but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.

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The Mean Unfulfilled Lifespan (MUL): A New Indicator of the Impact of Mortality Shocks on the Individual Lifespan -

Declines in period life expectancy at birth (PLEB) provide intuitive indicators of the impact of a cause of death on the individual lifespan. Derived under the assumption that future mortality conditions will remain indefinitely those observed during a reference period, however, the intuitive interpretation of a PLEB becomes problematic when that period conditions reflect a temporary mortality shock, resulting from a natural disaster or the diffusion of a new epidemic in the population for instance. Rather than to make assumptions about future mortality, I propose measuring the difference between a period average age at death and the average expected age at death of the same individuals (death cohort): the Mean Unfulfilled Lifespan (MUL). For fine-grained tracking of the mortality impact of an epidemic, I also provide an empirical shortcut to MUL estimation for small areas or short periods. For illustration, quarterly MUL values in 2020 are derived from estimates of COVID-19 deaths in 159 national populations and 122 sub-national populations in Italy, Mexico, Spain and the US. The highest quarterly values in national populations are obtained for Ecuador (5.12 years, second quarter) and Peru (4.56 years, third quarter) and, in sub-national populations, for New York (5.52 years), New Jersey (5.56 years, second quarter) and Baja California (5.19 years, fourth quarter). Using a seven-day rolling window, the empirical shortcut suggests the MUL peaked at 9.12 years in Madrid, 9.20 years in New York, and 9.15 years in Baja California, and in Guayas (Ecuador) it even reached 12.6 years for the entire month of April. Based on reported COVID-19 deaths that might substantially underestimate overall mortality change in affected populations, these results nonetheless illustrate how the MUL tracks the mortality impact of the pandemic, or any mortality shock, retaining the intuitive metric of differences in PLEB, without their problematic underlying assumptions.

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A Multiscale Multicellular Spatiotemporal Model of Local Influenza Infection and Immune Response -

Respiratory viral infections pose a serious public health concern, from mild seasonal influenza to pandemics like those of SARS-CoV-2. Spatiotemporal dynamics of viral infection impact nearly all aspects of the progression of a viral infection, like the dependence of viral replication rates on the type of cell and pathogen, the strength of the immune response and localization of infection. Mathematical modeling is often used to describe respiratory viral infections and the immune response to them using ordinary differential equation (ODE) models. However, ODE models neglect spatially-resolved biophysical mechanisms like lesion shape and the details of viral transport, and so cannot model spatial effects of a viral infection and immune response. In this work, we develop a multiscale, multicellular spatiotemporal model of influenza infection and immune response by combining non-spatial ODE modeling and spatial, cell-based modeling. We employ cellularization, a recently developed method for generating spatial, cell-based, stochastic models from non-spatial ODE models, to generate much of our model from a calibrated ODE model that describes infection, death and recovery of susceptible cells and innate and adaptive responses during influenza infection, and develop models of cell migration and other mechanisms not explicitly described by the ODE model. We determine new model parameters to generate agreement between the spatial and original ODE models under certain conditions, where simulation replicas using our model serve as microconfigurations of the ODE model, and compare results between the models to investigate the nature of viral exposure and impact of heterogeneous infection on the time-evolution of the viral infection. We found that using spatially homogeneous initial exposure conditions consistently with those employed during calibration of the ODE model generates far less severe infection, and that local exposure to virus must be multiple orders of magnitude greater than a uniformly applied exposure to all available susceptible cells. This strongly suggests a prominent role of localization of exposure in influenza A infection. We propose that the particularities of the microenvironment to which a virus is introduced plays a dominant role in disease onset and progression, and that spatially resolved models like ours may be important to better understand and more reliably predict future health states based on susceptibility of potential lesion sites using spatially resolved patient data of the state of an infection. We can readily integrate the immune response components of our model into other modeling and simulation frameworks of viral infection dynamics that do detailed modeling of other mechanisms like viral internalization and intracellular viral replication dynamics, which are not explicitly represented in the ODE model. We can also combine our model with available experimental data and modeling of exposure scenarios and spatiotemporal aspects of mechanisms like mucociliary clearance that are only implicitly described by the ODE model, which would significantly improve the ability of our model to present spatially resolved predictions about the progression of influenza infection and immune response.

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Preprints in motion: tracking changes between posting and journal publication -

Amidst the COVID-19 pandemic, preprints in the biomedical sciences are being posted and accessed at unprecedented rates, drawing widespread attention from the general public, press and policymakers for the first time. This phenomenon has sharpened longstanding questions about the reliability of information shared prior to journal peer review. Does the information shared in preprints typically withstand the scrutiny of peer review, or are conclusions likely to change in the version of record? We assessed preprints that had been posted and subsequently published in a journal between 1st January and 30th April 2020, representing the initial phase of the pandemic response. We utilised a combination of automatic and manual annotations to quantify how an article changed between the preprinted and published version. We found that the total number of figure panels and tables changed little between preprint and published articles. Moreover, the conclusions of 6% of non-COVID-19-related and 15% of COVID-19-related abstracts undergo a discrete change by the time of publication, but the majority of these changes do not reverse the main message of the paper.

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KLF2 is a therapeutic target for COVID-19 induced endothelial dysfunction -

Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its mechanism being incompletely understood. Emerging evidence has demonstrated that the endothelium represents the Achilles’ heel in COVID-19 patients and that endothelial dysfunction precipitates COVID-19 and accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. Primary human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) were treated with serum from control subjects or COVID-19 patients. Downstream monocyte adhesion and associated gene/protein expression was evaluated in endothelial cells exposed to COVID-19 patient serum in the presence of KLF2 activator (Atorvastatin) or KLF2 overexpression by an adenoviral vector. Here, we demonstrate that the expression of KLF2 was significantly reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1{beta} and TNF-, two cytokines observed in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis and reduced angiogenesis). Treatment of HPMECs with atorvastatin or KLF2 adenovirus ameliorate COVID-19 serum-induced increase in endothelial inflammation and monocyte adhesion by increasing KLF2 expression. Altogether, the present study demonstrates that genetic and pharmacological activation of KLF2 represses COVID-19 associated endothelial dysfunction, heralding a potentially new direction to treat endothelialitis accompanying COVID-19.

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Knowledge, attitudes and perceptions towards COVID-19 vaccinations: a cross-sectional community survey in Bangladesh -

Background: Several vaccines have been approved against coronavirus disease (COVID-19) and distributed globally in different regions. However, general community knowledge, attitudes and perceptions towards COVID-19 vaccinations are poorly understood. Thus, the study aimed to investigate community knowledge, attitudes and perceptions towards COVID-19 vaccinations in Bangladesh. Methods: An exploratory and anonymous population-based e-survey was conducted among 1658 general individuals (55.6% male; mean age=23.17±6.05 years; age range=18-65 years). The survey was conducted using a semi-structured and self-reported questionnaire containing informed consent along with four sections (i.e., socio-demographics, knowledge, attitudes, and perceptions). Multiple linear regression was performed to determine the variables predicting knowledge, and attitudes towards COVID-19 vaccinations. Results: The mean scores of knowledge and attitudes were 2.83±1.48 (out of 5) and 9.34±2.39 (out of 12) respectively. About a quarter of participants thought that the COVID-19 vaccination available in Bangladesh is safe, only 60% will have the vaccination and about two-thirds will recommend it to family and friends. In the multiple regression model, higher SES, having university/ higher levels of education, holding nuclear families and having previous history of essential vaccines uptake were associated with knowledge; whilst attitudes were significantly associated with being female and having previous history of essential vaccines uptake. Just over half of the participants thought that everyone should be vaccinated and 61% responded that health workers should be vaccinated first on priority basis. 95% vaccine should be administered free of charge in Bangladesh and almost 90% believed that the COVID-19 vaccine used in Bangladesh may have side effects. Conclusions: The findings reflect inadequate knowledge but more positive attitudes towards COVID-19 vaccine among the general population in Bangladesh. In order to improve knowledge, immediate health education programs need to be initiated before mass vaccination schedule.

🖺 Full Text HTML: Knowledge, attitudes and perceptions towards COVID-19 vaccinations: a cross-sectional community survey in Bangladesh

Statewide Impact of COVID-19 on Social Determinants of Health - A First Look: Findings from the Survey of the Health of Wisconsin -

There is an urgent need to track the early and ongoing impact of the COVID-19 pandemic on population health from local to global scales. At the same time, there is an overall lack of U.S. state-specific surveillance data tracking social determinants of health (SDOH) and associations with population well-being, individual mitigation and coping strategies, family dynamics and other economic shocks of the pandemic in populations. Statewide data can offer important insights into how SDOH shape the long-term effects of COVID-19 in the population since implementation of many policies and programs varied widely early on in the pandemic. In May of 2020, the Survey of the Health of Wisconsin (SHOW) program launched a statewide online/phone survey of early and ongoing impacts of COVID-19 on health and well-being across diverse communities and families. The goal of this study is to provide descriptive data including perceived COVID-19 risks, access to and results of COVID-19 antigen testing, individual mitigation and coping strategies, family dynamics and other economic shocks of the pandemic on health and mental health in populations. Key findings include higher rates of testing and perceived past infection from COVID-19 among non-white respondents. Higher economic shifts and job changes in female vs male respondents. Families with children reported overall higher levels of stress, and stress from the pandemic. There were urban and rural differences in changes to access to care. Rural regions, which had a lower prevalence of infections early in the pandemic as compared to urban areas, also reported fewer delays or missed appointments due to COVID-19. Key findings show that SDOH are shaping impacts of health and well-being early on in the pandemic and future longitudinal follow-up will be important to shape policies and programs well into the future.

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The unexpected dynamics of COVID-19 in Manaus, Brazil: Herd immunity versus interventions -

The arrival of SARS-COV-2 in late March 2020 in the state of Amazonas, Brazil, captured worldwide attention and concern. The rapid growth of the epidemic, a health system that had collapsed, and mass gravesites for coping with growing numbers of dead, were broadcast by the media around the world. Moreover, a majority of the local Amazonian indigenous communities were physically distant from appropriate medical services, to the point where warnings of genocide were issued. In a recent Science paper (December 2020), Buss et al. reported that some 76% of the residents of the city of Manaus, the capital of Amazonas, had been infected by October 2020. This estimate of the COVID-19 attack rate was based on a seroprevalence analysis of blood donor data, which despite its shortcomings was thought to be a sufficiently reliable proxy of the larger population. An attack rate of this magnitude (76%) implied that herd immunity had already been reached and the community was relatively protected from further infection. Yet in December 2020, a harsh second wave of COVID-19 struck Manaus, and currently appears to be even larger than the first wave. Here we use mathematical modelling of mortality data in Manaus, and in various states of Brazil, to understand why a second wave appeared against all expectations. Our analysis is based on estimating a “flexible” reproductive number R_0 (t) from the mortality data, as it changes in time over the epidemic.

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In depth analysis of patients with severe SARS-CoV-2 in sub-Saharan Africa demonstrates distinct clinical and immunological profiles -

Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we comprehensively characterise patients hospitalised with suspected or confirmed COVID-19, and healthy community controls. PCR-confirmed COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-/IgG+ and PCR-/IgG- participants. PCR-/IgG+ participants exhibited a nasal and systemic cytokine signature analogous to PCR-confirmed COVID-19 participants, but increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. We did not find evidence that HIV co-infection in COVID-19 participants was associated with mortality or altered cytokine responses. The nasal immune signature in PCR-/IgG+ and PCR-confirmed COVID-19 participants was distinct and predominated by chemokines and neutrophils. In addition, PCR-/IgG+ individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies.

🖺 Full Text HTML: In depth analysis of patients with severe SARS-CoV-2 in sub-Saharan Africa demonstrates distinct clinical and immunological profiles

Evaluation of a Commercial Culture-free Neutralization Antibody Detection Kit for Severe Acute Respiratory Syndrome-Related Coronavirus-2 and Comparison with an Anti-RBD ELISA Assay -

Background: SARS-CoV-2 surrogate neutralization assays that obviate the need for viral culture offer substantial advantages regarding throughput and cost. The cPass SARS-CoV-2 Neutralization Antibody Detection Kit (Genscript) is the first such commercially available assay, detecting antibodies that block RBD/ACE-2 interaction. We aimed to evaluate cPass to inform its use and assess its added value compared to anti-RBD ELISA assays. Methods: Serum reference panels comprising 205 specimens were used to compare cPass to plaque-reduction neutralization test (PRNT) and a pseudotyped lentiviral neutralization (PLV) assay for detection of neutralizing antibodies. We assessed the correlation of cPass with an ELISA detecting anti-RBD IgG, IgM, and IgA antibodies at a single timepoint and across intervals from onset of symptoms of SARS-CoV-2 infection. Results: Compared to PRNT-50, cPass sensitivity ranged from 77% - 100% and specificity was 95% - 100%. Sensitivity was also high compared to the pseudotyped lentiviral neutralization assay (93% [95%CI 85-97]), but specificity was lower (58% [95%CI 48-67]). Highest agreement between cPass and ELISA was for anti-RBD IgG (r=0.823). Against the pseudotyped lentiviral neutralization assay, anti-RBD IgG sensitivity (99% [95%CI 94-100]) was very similar to that of cPass, but overall specificity was lower (37% [95%CI 28-47]). Against PRNT-50, results of cPass and anti-RBD IgG were nearly identical. Conclusions: The added value of cPass compared to an IgG anti-RBD ELISA was modest.

🖺 Full Text HTML: Evaluation of a Commercial Culture-free Neutralization Antibody Detection Kit for Severe Acute Respiratory Syndrome-Related Coronavirus-2 and Comparison with an Anti-RBD ELISA Assay

Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis of the UK Biobank -

Objectives To assess whether gout and / or rheumatoid arthritis (RA) are risk factors for coronavirus disease 19 (COVID-19) diagnosis. To assess whether gout and / or RA are risk factors for death with COVID-19. Methods We used data from the UK Biobank. Multivariable-adjusted logistic regression was employed in the following analyses: Analysis A, to test for association between gout or RA and COVID-19 diagnosis (n=473,139); Analysis B, to test for association between gout or RA and death with COVID-19 in a case-control cohort of people who died or survived with COVID-19 (n=2,059); Analysis C, to test for association with gout or RA and death with COVID-19 in the entire UK Biobank cohort (n=473,139) Results RA, but not gout, associated with COVID-19 diagnosis in analysis A. Neither RA nor gout associated with risk of death in the COVID-19-diagnosed group in analysis B. However RA associated with risk of death related to COVID-19 using the UK Biobank cohort in analysis C independent of comorbidities and other measured risk factors (OR=1.9 [95% CI 1.2 ; 3.0]). Gout was not associated with death related to COVID-19 in the same UK Biobank analysis (OR=1.2 [95% CI 0.8 ; 1.7]). Conclusion Rheumatoid arthritis is a risk factor for death with COVID-19 using the UK Biobank cohort. These findings require replication in larger data sets that also allow inclusion of a wider range of factors.

🖺 Full Text HTML: Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis of the UK Biobank

Covid-19 Sentry

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