Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV) (preprint)

BackgroundThe selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity in vitro, and observational and clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended in guidelines and their antiviral activity in vivo has not been characterised. MethodsPLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. We recruited low-risk adult outpatients aged 18-50 with early symptomatic COVID-19 (symptoms <4 days). Patients were assigned using block randomisation to one of eleven treatment arms including oral fluoxetine (40mg/day for 7 days), or no study drug. Uniform randomisation ratios were applied across the active treatment groups while the no study drug group comprised [≥]20% of patients at all times. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population (>2 days follow-up). The viral clearance rate was estimated under a Bayesian hierarchical linear model fitted to the log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over one week (18 measurements per patient). This ongoing trial is registered at ClinicalTrials.gov (NCT05041907). FindingsBetween 5 April 2022 and 8 May 2023 271 patients were concurrently randomised to either fluoxetine (n=120) or no study drug (n=151). Fluoxetine was well tolerated and accelerated the rate of viral clearance relative to the no study drug arm by 15% (95% credible interval (CrI): 2% to 34%). In a pooled meta-analysis including all unblinded patients the antiviral activity of fluoxetine was substantially less than ritonavir-boosted nirmatrelvir-85% increase in rate of viral clearance (95% CrI: 61 to 112%); and less than remdesivir 35% (14 to 59%), molnupiravir 37% (18 to 60%), and casirivimab/imdevimab 29% (10 to 48%). InterpretationFluoxetine has in vivo antiviral activity against SARS-CoV-2. Although the level of antiviral efficacy is substantially less than with other currently available antiviral drugs, fluoxetine might still be useful in prophylaxis where less antiviral effect is required. FundingWellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Evidence before this studyThe SSRIs fluoxetine and fluvoxamine have been proposed as COVID-19 therapeutics based initially on observational, randomised trial and in vitro evidence. The observational reports suggested that patients taking SSRIs had a reduced probability of developing severe COVID-19 and dying. We searched PubMed and EMBASE for studies in English up until the 30th November 2023 using the search terms "fluoxetine", "fluvoxamine" and "COVID-19" with the search restricted to randomised controlled trials (RCTs). Eight outpatient fluvoxamine RCTs were identified. There were no fluoxetine RCTs in outpatients. A meta-analysis of available RCTs is compatible with a moderate reduction in hospitalisation and death in COVID-19 patients with an estimated risk ratio of 0.80 (95% CI: 0.62,1.01). Added value of the studyWe showed that in early COVID-19 illness the SSRI fluoxetine has weak antiviral activity in vivo. This activity is substantially less than other available antivirals such as ritonavir-boosted nirmatrelvir and molnupiravir. The pharmacometric approach described here provides a quantitative measure of in vivo antiviral effects with tractable sample sizes. Implications of available evidenceFluoxetine has weak in vivo antiviral activity in early COVID-19. This is insufficient for treatment but, as less antiviral activity is required to prevent an infection, fluoxetine could still be beneficial in prophylaxis.

First confirmation of importation and transmission in Spain of the newly identified SARS-CoV-2 B.1.1.7 variant.

INTRODUCTION: A newly identified SARS-CoV-2 variant, VOC202012/01 originating lineage B.1.1.7, recently emerged in the United Kingdom. The rapid spread in the UK of this new variant has caused other countries to be vigilant. MATERIAL AND METHODS: We based our initial screening of B.1.1.7 on the dropout of the S gene signal in the TaqPath assay, caused by the 69/70 deletion. Subsequently, we confirmed the B.1.1.7 candidates by whole genome sequencing. RESULTS: We describe the first three imported cases of this variant from London to Madrid, subsequent post-arrival household transmission to three relatives, and the two first cases without epidemiological links to UK. One case required hospitalization. In all cases, drop-out of gene S was correctly associated to the B.1.1.7 variant, as all the corresponding sequences carried the 17 lineage-marker mutations. CONCLUSION: The first identifications of the SARS-CoV-2 B.1.1.7 variant in Spain indicate the role of independent introductions from the UK coexisting with post-arrival transmission in the community, since the early steps of this new variant in our country.

Acute coronavirus infection triggers a TNF-dependent osteoporotic phenotype in mice.

AIMS: Millions of people died during the COVID-19 pandemic, but the vast majority of infected individuals survived. Now, some consequences of the disease, known as long COVID, are been revealed. Although the respiratory system is the target of Sars-CoV-2, COVID-19 can influence other parts of the body, including bone. The aim of this work was to investigate the impact of acute coronavirus infection in bone metabolism. MAIN METHODS: We evaluated RANKL/OPG levels in serum samples of patients with and without acute COVID-19. In vitro, the effects of coronavirus in osteoclasts and osteoblasts were investigated. In vivo, we evaluated the bone phenotype in a BSL2 mouse model of SARS-like disease induced by murine coronavirus (MHV-3). KEY FINDINGS: Patients with acute COVID-19 presented decreased OPG and increased RANKL/OPG ratio in the serum versus healthy individuals. In vitro, MHV-3 infected macrophages and osteoclasts, increasing their differentiation and TNF release. Oppositely, osteoblasts were not infected. In vivo, MHV-3 lung infection triggered bone resorption in the femur of mice, increasing the number of osteoclasts at 3dpi and decreasing at 5dpi. Indeed, apoptotic-caspase-3+ cells have been detected in the femur after infection as well as viral RNA. RANKL/OPG ratio and TNF levels also increased in the femur after infection. Accordingly, the bone phenotype of TNFRp55-/- mice infected with MHV-3 showed no signs of bone resorption or increase in the number of osteoclasts. SIGNIFICANCE: Coronavirus induces an osteoporotic phenotype in mice dependent on TNF and on macrophage/osteoclast infection.

Wastewater Based Epidemiology, Phylogenetic Analysis and Machine Learning Approach to Describe the Evolution of SARS-CoV-2 in the South-East of Spain (preprint)

The COVID-19 pandemic has posed a significant global threat, leading to several initiatives for its control and management. One such initiative involves wastewater-based epidemiology, which has gained attention for its potential to provide early warning of virus outbreaks and real-time information on its spread. In this study, water samples from two wastewater treatment plants (WWTPs) located at the south east of Spain (Region of Murcia) namely Murcia, and Cartagena, were analyzed by RT-qPCR, Phylogenetic Analysis, and Machine Learning Approach. The aim was to determine whether SARS-CoV-2 detection in the WWTPs of these two cities could serve as a proxy for the virus's spread in the population. The results confirmed that the levels of SARS-CoV-2 in these wastewater samples changed concerning the number of SARS-CoV-2 cases detected in the population and variant occurrences were in line with clinical reported data. Additionally, the phylogenetic analysis showed that samples obtained in close sampling times exhibited a higher similarity than those obtained more distantly in time. A second analysis using a machine learning approach based on the mutations found in the SARS-CoV-2 spike protein was also conducted. Hierarchical Clustering (HC) was used as an efficient unsupervised approach for data analysis. Results indicated that samples obtained in October 2022 in Murcia and Cartagena were significantly different, which corresponded well with the different virus variants circulating in the two locations. The proposed methods in this study are adequate for comparing the Accumulated Natural Vector (ANV) of the SARS-CoV-2 sequences as a preliminary evaluation of potential changes in the variants that are circulating in a given population at a specific time point.

Comprehensive analysis of clinical data for COVID-19 outcome estimation with machine learning models

COVID-19 is a global threat for the healthcare systems due to the rapid spread of the pathogen that causes it. In such situation, the clinicians must take important decisions, in an environment where medical resources can be insufficient. In this task, the computer-aided diagnosis systems can be very useful not only in the task of supporting the clinical decisions but also to perform relevant analyses, allowing them to understand better the disease and the factors that can identify the high risk patients. For those purposes, in this work, we use several machine learning algorithms to estimate the outcome of COVID-19 patients given their clinical information. Particularly, we perform 2 different studies: the first one estimates whether the patient is at low or at high risk of death whereas the second estimates if the patient needs hospitalization or not. The results of the analyses of this work show the most relevant features for each studied scenario, as well as the classification performance of the considered machine learning models. In particular, the XGBoost algorithm is able to estimate the need for hospitalization of a patient with an AUC-ROC of Graphical abstract

Incidence of myocarditis among patients recovered from COVID-19 infection identified using cardiac magnetic resonance imaging

Introduction: Coronavirus disease 2019 (COVID-19) has caused significant morbidity and mortality worldwide and has been associated with several cardiac complications including myocarditis. COVID-19 patients with myocardial injury have worse clinical outcomes than those without cardiac involvement. Hence, early detection of myocardial involvement in those who have recovered would be helpful in risk stratification of these patients. Locally, there has been no literature regarding cardiac involvement detected by cardiac magnetic resonance (CMR) imaging among COVID-19 patients. This study aims to report the incidence of patients who developed myocarditis among those who recovered from COVID-19 infection and who underwent CMR imaging in our institution. Methodology: A single-center retrospective cohort study was performed in our institution. Consecutive patients from January 1, 2020, to December 31, 2021, who were initially referred for cardiac CMR examination due to cardiac symptoms and who met the following inclusion criteria 1) 19 years old and above;2) with a history of a previously confirmed diagnosis of COVID-19 using reverse transcription-polymerase chain reaction (RT-PCR) swab test;3) patients were considered recovered by the discharging criteria and 4) underwent CMR imaging for evaluation to rule out myocarditis in our institution. The primary outcome was determining the number of patients with positive and negative conventional MRI findings based on late gadolinium enhancement and edema. Result(s): Fifty-four percent (54%) of patients had positive conventional MRI findings indicative of myocarditis (myocardial edema or late gadolinium presence). The most common co-morbid condition remains to be Hypertension (55%), followed by Diabetes Mellitus (17%). Dyspnea, palpitations and chest discomfort were the most commonly reported symptoms in 29 (54%), 24 (44%) and 21 (39%) patients, respectively. Twenty-nine patients (54%) were observed with increased T2 signal or positive LGE. Myocardial edema was found in 9 (31%) patients. Among them, 8 (57%) patients were observed with positive LGE. There was no significant difference of LV and RV systolic function among patients with positive and negative conventional CMR findings. Conclusion(s): Myocarditis is one of the cardiovascular complications among patients who recovered from COVID-19, as demonstrated by our cardiac MRI study. Evaluation of the cardiac status of recovered COVID-19 patients needs to be closely monitored, and cardiac MRI may be a sensitive imaging tool to investigate any cardiac involvement further. This study provided local data on those with potential structural changes and cardiac complications aligned with the clinical history, which may be unique in our population after recovering from the disease. Further research with a larger sample size, risk factors, and the intervention to prevent disease progression may need more attention.

Comprehensive analysis of clinical data for COVID-19 outcome estimation with machine learning models.

COVID-19 is a global threat for the healthcare systems due to the rapid spread of the pathogen that causes it. In such situation, the clinicians must take important decisions, in an environment where medical resources can be insufficient. In this task, the computer-aided diagnosis systems can be very useful not only in the task of supporting the clinical decisions but also to perform relevant analyses, allowing them to understand better the disease and the factors that can identify the high risk patients. For those purposes, in this work, we use several machine learning algorithms to estimate the outcome of COVID-19 patients given their clinical information. Particularly, we perform 2 different studies: the first one estimates whether the patient is at low or at high risk of death whereas the second estimates if the patient needs hospitalization or not. The results of the analyses of this work show the most relevant features for each studied scenario, as well as the classification performance of the considered machine learning models. In particular, the XGBoost algorithm is able to estimate the need for hospitalization of a patient with an AUC-ROC of 0 . 8415 ± 0 . 0217 while it can also estimate the risk of death with an AUC-ROC of 0 . 7992 ± 0 . 0104 . Results have demonstrated the great potential of the proposal to determine those patients that need a greater amount of medical resources for being at a higher risk. This provides the healthcare services with a tool to better manage their resources.

SARS-CoV-2 superinfection and reinfection with three different strains.

We report a corona virus disease (COVID-19) case with unprecedented viral complexity. In the first severe episode, two different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains (superinfection) were identified within a week. Three months after discharge, the patient was readmitted and was infected in a nosocomial outbreak with a different strain, suffering a second milder COVID-19 episode.

Global Proportion of Disordered Eating in Children and Adolescents: A Systematic Review and Meta-analysis.

Importance: The 5-item Sick, Control, One, Fat, Food (SCOFF) questionnaire is the most widely used screening measure for eating disorders. However, no previous systematic review and meta-analysis determined the proportion of disordered eating among children and adolescents. Objective: To establish the proportion among children and adolescents of disordered eating as assessed with the SCOFF tool. Data Sources: Four databases were systematically searched (PubMed, Scopus, Web of Science, and the Cochrane Library) with date limits from January 1999 to November 2022. Study Selection: Studies were required to meet the following criteria: (1) participants: studies of community samples of children and adolescents aged 6 to 18 years and (2) outcome: disordered eating assessed by the SCOFF questionnaire. The exclusion criteria included (1) studies conducted with young people who had a diagnosis of physical or mental disorders; (2) studies that were published before 1999 because the SCOFF questionnaire was designed in that year; (3) studies in which data were collected during COVID-19 because they could introduce selection bias; (4) studies based on data from the same surveys/studies to avoid duplication; and (5) systematic reviews and/or meta-analyses and qualitative and case studies. Data Extraction and Synthesis: A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: Proportion of disordered eating among children and adolescents assessed with the SCOFF tool. Results: Thirty-two studies, including 63 181 participants, from 16 countries were included in this systematic review and meta-analysis. The overall proportion of children and adolescents with disordered eating was 22.36% (95% CI, 18.84%-26.09%; P < .001; n = 63 181) (I2 = 98.58%). Girls were significantly more likely to report disordered eating (30.03%; 95% CI, 25.61%-34.65%; n = 27 548) than boys (16.98%; 95% CI, 13.46%-20.81%; n = 26 170) (P < .001). Disordered eating became more elevated with increasing age (B, 0.03; 95% CI, 0-0.06; P = .049) and body mass index (B, 0.03; 95% CI, 0.01-0.05; P < .001). Conclusions and Relevance: In this systematic review and meta-analysis, the available evidence from 32 studies comprising large samples from 16 countries showed that 22% of children and adolescents showed disordered eating according to the SCOFF tool. Proportion of disordered eating was further elevated among girls, as well as with increasing age and body mass index. These high figures are concerning from a public health perspective and highlight the need to implement strategies for preventing eating disorders.

Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open- label, randomised, controlled adaptive platform trial (preprint)

Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. Methods: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome assessed in a modified intention-to-treat population (mITT) was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial is registered at ClinicalTrials.gov (NCT05041907). Results: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients administered favipiravir and patients receiving no study drug -1% (95% CI: -14 to 14% change). High dose favipiravir was well tolerated. Interpretation: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19.

Survival impact of previous statin therapy in patients hospitalized with COVID-19. / Impacto del tratamiento previo con estatinas sobre la supervivencia de los pacientes hospitalizados con COVID-19.

INTRODUCTION: Statin therapy might have a beneficial prognostic effect in patients with COVID-19, given its immunomodulative, anti-inflammatory and anti-atherosclerotic properties. Our purpose was to test this hypothesis by using the COVID-19 registry of a Spanish university hospital. METHODS: We conducted a single-center, observational and retrospective study in which hospitalized patients with COVID-19 diagnosed by PCR between March 2020 and October 2020 were included. By means of logistic regression, we designed a propensity score to estimate the likelihood that a patient would receive statin treatment prior to admission. We compared the survival of COVID-19 patients with and without statin treatment by means of Cox regression with inverse probability of treatment weighting (IPTW). The median follow-up was 406 days. RESULTS: We studied 1122 hospitalized patients with COVID-19, whose median age was 71years and of which 488 (43.5%) were women. 451 (40.2%) patients received statins before admission. In the IPTW survival analysis, prior statin treatment was associated with a significant reduction in mortality (HR: 0.76; 95%CI: 0.59-0.97). The greatest benefit of previous statin therapy was seen in subgroups of patients with coronary artery disease (HR: 0.32; 95%CI: 0.18-0.56) and extracardiac arterial disease (HR: 0.45; 95%CI: 0.28-0.73). CONCLUSIONS: Our study showed a significant association between previous treatment with statins and lower mortality in hospitalized patients with COVID-19. The observed prognostic benefit was greater in patients with previous coronary or extracardiac atherosclerotic disease.

Adherence to the Mediterranean Diet and Health-Related Quality of Life during the COVID-19 Lockdown: A Cross-Sectional Study including Preschoolers, Children, and Adolescents from Brazil and Spain.

Scientific literature has suggested positive associations between the Mediterranean diet (MD) and the health-related quality of life (HRQoL) in young populations. However, to our knowledge, this relationship is unexplored during a situation of social isolation (i.e., lockdown). The objective of the current study is to examine the relationship between the MD and HRQoL during the COVID-19 lockdown among preschoolers, children, and adolescents from Brazil and Spain. This cross-sectional study includes a sample of 1099 three- to seventeen-year-old participants (47.6% girls) who were recruited via social networks. The HRQoL was assessed with the EQ-5D-Y. The Quality Index for Children and Teenagers (KIDMED) questionnaire was applied to evaluate the relationship between the MD and HRQoL. The highest prevalence of reported problems was found for worried, sad, or unhappy participants (39.8%). Furthermore, the lowest proportion of HRQoL problems was observed for "mobility" (2.5%). The proportion of high adherence to the MD was 44.3%. Participants with greater MD adherence reported higher HRQoL mean scores when compared with those who did not adhere to the MD (83.7 ± 0.6 vs. 85.6 ± 0.7, respectively; p < 0.05). Adherence to the MD and especially daily fruit intake were related to higher HRQoL during the COVID-19 lockdown among Brazilian and Spanish young people aged three to seventeen years.

Survival impact of previous statin therapy in patients hospitalized with COVID-19 Impacto del tratamiento previo con estatinas sobre la supervivencia de los pacientes hospitalizados con COVID-19

Introduction Statin therapy might have a beneficial prognostic effect in patients with COVID-19, given its immunomodulative, anti-inflammatory and anti-atherosclerotic properties. Our purpose was to test this hypothesis by using the COVID-19 registry of a Spanish university hospital. Methods We conducted a single-center, observational and retrospective study in which hospitalized patients with COVID-19 diagnosed by PCR between March 2020 and October 2020 were included. By means of logistic regression, we designed a propensity score to estimate the likelihood that a patient would receive statin treatment prior to admission. We compared the survival of COVID-19 patients with and without statin treatment by means of Cox regression with inverse probability of treatment weighting (IPTW). The median follow-up was 406 days. Results We studied 1122 hospitalized patients with COVID-19, whose median age was 71 years and of which 488 (43.5%) were women. 451 (40.2%) patients received statins before admission. In the IPTW survival analysis, prior statin treatment was associated with a significant reduction in mortality (HR: 0.76;95% CI: 0.59-0.97). The greatest benefit of previous statin therapy was seen in subgroups of patients with coronary artery disease (HR: 0.32;95% CI: 0.18-0.56) and extracardiac arterial disease (HR: 0.45;95% CI: 0.28-0.73). Conclusions Our study showed a significant association between previous treatment with statins and lower mortality in hospitalized patients with COVID-19. The observed prognostic benefit was greater in patients with previous coronary or extracardiac atherosclerotic disease.

First confirmation of importation and transmission in Spain of the newly identified SARS-CoV-2 B.1.1.7 variant Primera confirmación de importación y transmisión en España de la variante B.1.1.7 del SARS-CoV-2 recientemente identificada

Introduction A newly identified SARS-CoV-2 variant, VOC202012/01 originating lineage B.1.1.7, recently emerged in the United Kingdom. The rapid spread in the UK of this new variant has caused other countries to be vigilant. Material and methods We based our initial screening of B.1.1.7 on the dropout of the S gene signal in the TaqPath assay, caused by the 69/70 deletion. Subsequently, we confirmed the B.1.1.7 candidates by whole genome sequencing. Results We describe the first three imported cases of this variant from London to Madrid, subsequent post-arrival household transmission to three relatives, and the two first cases without epidemiological links to UK. One case required hospitalization. In all cases, drop-out of gene S was correctly associated to the B.1.1.7 variant, as all the corresponding sequences carried the 17 lineage-marker mutations. Conclusion The first identifications of the SARS-CoV-2 B.1.1.7 variant in Spain indicate the role of independent introductions from the UK coexisting with post-arrival transmission in the community, since the early steps of this new variant in our country.

Survival impact of previous statin therapy in patients hospitalized with COVID-19.

Introduction: Statin therapy might have a beneficial prognostic effect in patients with COVID-19, given its immunomodulative, anti-inflammatory and anti-atherosclerotic properties. Our purpose was to test this hypothesis by using the COVID-19 registry of a Spanish university hospital. Methods: We conducted a single-center, observational and retrospective study in which hospitalized patients with COVID-19 diagnosed by PCR between March 2020 and October 2020 were included. By means of logistic regression, we designed a propensity score to estimate the likelihood that a patient would receive statin treatment prior to admission. We compared the survival of COVID-19 patients with and without statin treatment by means of Cox regression with inverse probability of treatment weighting (IPTW). The median follow-up was 406 days. Results: We studied 1122 hospitalized patients with COVID-19, whose median age was 71 years and of which 488 (43.5%) were women. 451 (40.2%) patients received statins before admission. In the IPTW survival analysis, prior statin treatment was associated with a significant reduction in mortality (HR: 0.76; 95% CI: 0.59-0.97). The greatest benefit of previous statin therapy was seen in subgroups of patients with coronary artery disease (HR: 0.32; 95% CI: 0.18-0.56) and extracardiac arterial disease (HR: 0.45; 95% CI: 0.28-0.73). Conclusions: Our study showed a significant association between previous treatment with statins and lower mortality in hospitalized patients with COVID-19. The observed prognostic benefit was greater in patients with previous coronary or extracardiac atherosclerotic disease.

Introducción: El tratamiento con estatinas podría presentar un efecto pronóstico beneficioso en pacientes con COVID-19, dadas sus propiedades inmunomoduladoras, antiinflamatorias y estabilizadoras de la placa de ateroma. Nuestro propósito fue analizar esta hipótesis tomando como base el registro de COVID-19 de un hospital universitario español. Métodos: Realizamos un estudio observacional y retrospectivo en el que se incluyeron los pacientes hospitalizados con COVID-19 diagnosticado mediante PCR entre marzo de 2020 y octubre de 2020 en un centro. Mediante regresión logística, diseñamos una puntuación de propensión para estimar la probabilidad de que un paciente recibiese tratamiento con estatinas antes del ingreso. Comparamos la supervivencia de los pacientes con y sin tratamiento con estatinas mediante la regresión de Cox ponderada por la inversa de la probabilidad de recibir el tratamiento (IPT). La mediana de seguimiento fue de 406 días. Resultados: Estudiamos 1.122 pacientes hospitalizados con COVID-19, cuya mediana de edad era de 71 años y de los cuales 488 (43,5%) eran mujeres. 451 (40,2%) pacientes recibían estatinas antes del ingreso. En el análisis de supervivencia ponderado por la IPT, el tratamiento previo con estatinas se asoció a una reducción significativa de la mortalidad (HR: 0,76; IC 95%: 0,59­0,97). El mayor beneficio del tratamiento previo con estatinas se observó en los subgrupos de pacientes con enfermedad arterial coronaria (HR: 0,32; IC 95%: 0,18­0,56) y enfermedad arterial extracardiaca (HR: 0,45; IC 95%: 0,28­0,73). Conclusiones: Nuestro estudio mostró una asociación significativa entre el tratamiento previo con estatinas y una menor mortalidad en pacientes hospitalizados con COVID-19. El beneficio pronóstico observado fue mayor en los pacientes con enfermedad aterosclerótica coronaria o extracardiaca previa.

First confirmation of importation and transmission in Spain of the newly identified SARS-CoV-2 B.1.1.7 variant.

INTRODUCTION: A newly identified SARS-CoV-2 variant, VOC202012/01 originating lineage B.1.1.7, recently emerged in the United Kingdom. The rapid spread in the UK of this new variant has caused other countries to be vigilant. MATERIAL AND METHODS: We based our initial screening of B.1.1.7 on the dropout of the S gene signal in the TaqPath assay, caused by the 69/70 deletion. Subsequently, we confirmed the B.1.1.7 candidates by whole genome sequencing. RESULTS: We describe the first three imported cases of this variant from London to Madrid, subsequent post-arrival household transmission to three relatives, and the two first cases without epidemiological links to UK. One case required hospitalization. In all cases, drop-out of gene S was correctly associated to the B.1.1.7 variant, as all the corresponding sequences carried the 17 lineage-marker mutations. CONCLUSION: The first identifications of the SARS-CoV-2 B.1.1.7 variant in Spain indicate the role of independent introductions from the UK coexisting with post-arrival transmission in the community, since the early steps of this new variant in our country.

Non-replicative antibiotic resistance-free DNA vaccine encoding S and N proteins induces full protection in mice against SARS-CoV-2.

SARS-CoV-2 vaccines currently in use have contributed to controlling the COVID-19 pandemic. Notwithstanding, the high mutation rate, fundamentally in the spike glycoprotein (S), is causing the emergence of new variants. Solely utilizing this antigen is a drawback that may reduce the efficacy of these vaccines. Herein we present a DNA vaccine candidate that contains the genes encoding the S and the nucleocapsid (N) proteins implemented into the non-replicative mammalian expression plasmid vector, pPAL. This plasmid lacks antibiotic resistance genes and contains an alternative selectable marker for production. The S gene sequence was modified to avoid furin cleavage (Sfs). Potent humoral and cellular immune responses were observed in C57BL/6J mice vaccinated with pPAL-Sfs + pPAL-N following a prime/boost regimen by the intramuscular route applying in vivo electroporation. The immunogen fully protected K18-hACE2 mice against a lethal dose (105 PFU) of SARS-CoV-2. Viral replication was completely controlled in the lungs, brain, and heart of vaccinated mice. Therefore, pPAL-Sfs + pPAL-N is a promising DNA vaccine candidate for protection from COVID-19.

Clinical antiviral efficacy of remdesivir and casirivimab/imdevimab against the SARS-CoV-2 Delta and Omicron variants (preprint)

BackgroundUncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absent in vitro activity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended. MethodsIn a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10 viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). ResultsAcceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In a post hoc subgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: -21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants. ConclusionsParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reduced in vitro activities, casirivimab/imdevimab retains in vivo antiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants. Brief summaryIn early symptomatic COVID-19 remdesivir accelerated viral clearance by 42% while the monoclonal antibody cocktail casirivimab/imdevimab accelerated clearance by approximately 60% in SARS-CoV-2 Delta variant infections, and by approximately 25% in infections with Omicron subvariants BA.2 and BA.5.

Protein-imprinted particles for coronavirus capture from solution.

Molecular imprinting is a promising strategy to selectively adsorb viruses, but it requires discerning and validating epitopes that serve as effective imprinting templates. In this work, glycoprotein-imprinted particles were synthesized for coronavirus capture. Adsorption was maximized at pH 6 (the glycoprotein isoelectric point) where the glycoprotein-imprinted particles outperformed non-imprinted particles, adsorbing 4.96 × 106  ± 3.33 × 103 versus 3.54 × 106  ± 1.39 × 106 median tissue culture infectious dose/mg of the target coronavirus, human coronavirus - organ culture 43, within the first 30 min (p = 0.012). During competitive adsorption, with pH adjustment (pH 6), the glycoprotein-imprinted particles adsorbed more target virus than non-target coronavirus (human coronavirus - Netherland 63) with 2.34 versus 1.94 log removal in 90 min (p < 0.01). In contrast, the non-imprinted particles showed no significant difference in target versus non-target virus removal. Electrostatic potential calculation shows that the human coronavirus - organ culture 43 glycoprotein has positively charged pockets at pH 6, which may facilitate adsorption at lower pH values. Therefore, tuning the target virus glycoprotein charge via pH adjustment enhanced adsorption by minimizing repulsive electrostatic interactions with the particles. Overall, these results highlight the effective use of glycoprotein-imprinted particles for coronavirus capture and discern the merits and limitations of glycoprotein imprinting for the capture of enveloped viruses.

Intranasal administration of a single dose of MVA-based vaccine candidates against COVID-19 induced local and systemic immune responses and protects mice from a lethal SARS-CoV-2 infection.

Current coronavirus disease-19 (COVID-19) vaccines are administered by the intramuscular route, but this vaccine administration failed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection in the upper respiratory tract, mainly due to the absence of virus-specific mucosal immune responses. It is hypothesized that intranasal (IN) vaccination could induce both mucosal and systemic immune responses that blocked SARS-CoV-2 transmission and COVID-19 progression. Here, we evaluated in mice IN administration of three modified vaccinia virus Ankara (MVA)-based vaccine candidates expressing the SARS-CoV-2 spike (S) protein, either the full-length native S or a prefusion-stabilized [S(3P)] protein; SARS-CoV-2-specific immune responses and efficacy were determined after a single IN vaccine application. Results showed that in C57BL/6 mice, MVA-based vaccine candidates elicited S-specific IgG and IgA antibodies in serum and bronchoalveolar lavages, respectively, and neutralizing antibodies against parental and SARS-CoV-2 variants of concern (VoC), with MVA-S(3P) being the most immunogenic vaccine candidate. IN vaccine administration also induced polyfunctional S-specific Th1-skewed CD4+ and cytotoxic CD8+ T-cell immune responses locally (in lungs and bronchoalveolar lymph nodes) or systemically (in spleen). Remarkably, a single IN vaccine dose protected susceptible K18-hACE2 transgenic mice from morbidity and mortality caused by SARS-CoV-2 infection, with MVA-S(3P) being the most effective candidate. Infectious SARS-CoV-2 viruses were undetectable in lungs and nasal washes, correlating with high titers of S-specific IgGs and neutralizing antibodies against parental SARS-CoV-2 and several VoC. Moreover, low histopathological lung lesions and low levels of pro-inflammatory cytokines in lungs and nasal washes were detected in vaccinated animals. These results demonstrated that a single IN inoculation of our MVA-based vaccine candidates induced potent immune responses, either locally or systemically, and protected animal models from COVID-19. These results also identified an effective vaccine administration route to induce mucosal immunity that should prevent SARS-CoV-2 host-to-host transmission.