Contribution of genetics and lifestyle to the risk of major cardiovascular and thromboembolic complications following COVID-19

Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.

Venous Thromboembolism in Ambulatory Covid-19 patients: Clinical and Genetic Determinants

BackgroundSubstantial evidence suggests that severe Covid-19 leads to an increased risk of Venous Thromboembolism (VTE). We aimed to quantify the risk of VTE associated with ambulatory Covid-19, study the potential protective role of vaccination, and establish key clinical and genetic determinants of post-Covid VTE. MethodsWe analyzed a cohort of ambulatory Covid-19 patients from UK Biobank, and compared their 30-day VTE risk with propensity-score-matched non-infected participants. We fitted multivariable models to study the associations between age, sex, ethnicity, socio-economic status, obesity, vaccination status and inherited thrombophilia with post-Covid VTE. ResultsOverall, VTE risk was nearly 20-fold higher in Covid-19 vs matched non-infected participants (hazard ratio [HR] 19.49, 95% confidence interval [CI] 11.50 to 33.05). However, the risk was substantially attenuated amongst the vaccinated (HR: 2.79, 95% CI 0.82 to 9.54). Older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 2.00 (1.61 to 2.47) per 10 years, 1.66 (1.28 to 2.15), and 1.85 (1.29 to 2.64), respectively. Further, inherited thrombophilia led to an HR 2.05, 95% CI 1.15 to 3.66. ConclusionsAmbulatory Covid-19 was associated with a striking 20-fold increase in incident VTE, but no elevated risk after breakthrough infection in the fully vaccinated. Older age, male sex, and obesity were clinical determinants of Covid-19-related VTE. Additionally, inherited thrombophilia doubled risk further, comparable to the effect of 10-year ageing. These findings reinforce the need for vaccination, and call for targeted strategies to prevent VTE during outpatient care of Covid-19.

Remdesivir for the treatment of patients hospitalized with COVID-19 receiving supplemental oxygen: a targeted literature review and meta-analysis

This network meta-analysis (NMA) assessed the efficacy of remdesivir in hospitalized patients with COVID-19 requiring supplemental oxygen. Randomized controlled trials of hospitalized patients with COVID-19, where patients were receiving supplemental oxygen at baseline and at least one arm received treatment with remdesivir, were identified. Outcomes included mortality, recovery, and no longer requiring supplemental oxygen. NMAs were performed for low-flow oxygen (LFO2); high-flow oxygen (HFO2), including NIV; or oxygen at any flow (AnyO2) at early (day 14/15) and late (day 28/29) time points. Six studies were included (N=5,245 patients) in the NMA. Remdesivir lowered early and late mortality among AnyO2 patients (risk ratio (RR) 0.52, 95% credible interval (CrI) 0.34-0.79; RR 0.81, 95%CrI 0.69-0.95) and LFO2 patients (RR 0.21, 95%CI 0.09-0.46; RR 0.24, 95%CI 0.11-0.48); no improvement was observed among HFO2 patients. Improved early and late recovery was observed among LFO2 patients (RR 1.22, 95%CrI 1.09-1.38; RR 1.17, 95%CrI 1.09-1.28). Remdesivir also lowered the requirement for oxygen support among all patient subgroups. Among hospitalized patients with COVID-19 requiring supplemental oxygen at baseline, use of remdesivir compared to best supportive care is likely to improve the risk of mortality, recovery and need for oxygen support in AnyO2 and LFO2 patients.

Unraveling the antiviral activity of plitidepsin by subcellular and morphological analysis

The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation factor 1 alpha 1) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin completely blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work.

Clinical course impacts early kinetics and long-term magnitude and amplitude of SARS-CoV-2 neutralizing antibodies beyond one year after infection

BackgroundUnderstanding the determinants of long-term immune responses to SARS-CoV-2 and the concurrent impact of vaccination and emerging variants of concern will guide optimal strategies to achieve global protection against the COVID-19 pandemic. MethodsA prospective cohort of 332 COVID-19 patients was followed beyond one year. Plasma neutralizing activity was evaluated using HIV-based reporter pseudoviruses expressing different SARS-CoV-2 spikes and was longitudinally analyzed using mixed-effects models. FindingsLong-term neutralizing activity was stable beyond one year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short- and long-lived memory B cells, while outpatient responses were dominated by long-lived B cells. In both groups, vaccination boosted responses to natural infection, although viral variants, mainly B.1.351, reduced the efficacy of neutralization. Importantly, despite showing higher neutralization titers, hospitalized patients showed lower cross-neutralization of B.1.351 variant compared to outpatients. Multivariate analysis identified severity of primary infection as the factor that independently determines both the magnitude and the inferior cross-neutralization activity of long-term neutralizing responses. ConclusionsNeutralizing response induced by SARS-CoV-2 is heterogeneous in magnitude but stable beyond one year after infection. Vaccination boosts these long-lasting natural neutralizing responses, counteracting the significant resistance to neutralization of new viral variants. Severity of primary infection determines higher magnitude but poorer quality of long-term neutralizing responses.

Characterization of long-term patient-reported symptoms of COVID-19: an analysis of social media data

As the SARS-CoV-2 virus (COVID-19) continues to affect people across the globe, there is limited understanding of the long term implications for infected patients1-3. While some of these patients have documented follow-ups on clinical records, or participate in longitudinal surveys, these datasets are usually designed by clinicians, and not granular enough to understand the natural history or patient experiences of long COVID. In order to get a complete picture, there is a need to use patient generated data to track the long-term impact of COVID-19 on recovered patients in real time. There is a growing need to meticulously characterize these patients experiences, from infection to months post-infection, and with highly granular patient generated data rather than clinician narratives. In this work, we present a longitudinal characterization of post-COVID-19 symptoms using social media data from Twitter. Using a combination of machine learning, natural language processing techniques, and clinician reviews, we mined 296,154 tweets to characterize the post-acute infection course of the disease, creating detailed timelines of symptoms and conditions, and analyzing their symptomatology during a period of over 150 days.

Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization.

Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19. One-Sentence SummaryPlitidepsin, an inhibitor of SARS-Cov-2 in vitro, is safe and positively influences the outcome of patients hospitalized with COVID-19.

Siglec-1 on dendritic cells mediates SARS-CoV-2 trans-infection of target cells while on macrophages triggers proinflammatory responses

COVID-19 pandemic is not yet under control by vaccination, and effective antivirals are critical for preparedness. Here we report that macrophages and dendritic cells, key antigen presenting myeloid cells (APCs), are largely resistant to SARS-CoV-2 infection. APCs effectively captured viruses within cellular compartments that lead to antigen degradation. Macrophages sense SARS-CoV-2 and released higher levels of cytokines, including those related to cytokine storm in severe COVID-19. The sialic acid-binding Ig-like lectin 1 (Siglec-1/CD169) present on APCs, which interacts with sialylated gangliosides on membranes of retroviruses or filoviruses, also binds SARS-CoV-2 via GM1. Blockage of Siglec-1 receptors by monoclonal antibodies reduces SARS-CoV-2 uptake and transfer to susceptible target cells. APCs expressing Siglec-1 and carrying SARS-CoV-2 are found in pulmonary tissues of non-human primates. Single cell analysis reveals the in vivo induction of cytokines in those macrophages. Targeting Siglec-1 could offer cross-protection against SARS-CoV-2 and other enveloped viruses that exploit APCs for viral dissemination, including those yet to come in future outbreaks.

Highly functional Cellular Immunity in SARS-CoV-2 Non-Seroconvertors is associated with immune protection

The role of T cells in the control of SARS-CoV-2 infection has been underestimated in favor of neutralizing antibodies. However, cellular immunity is essential for long-term viral control and protection from disease severity. To understand T-cell immunity in the absence of antibody generation we focused on a group of SARS-CoV-2 Non-Seroconvertors (NSC) recovered from infection. We performed an immune comparative analysis of SARS-CoV-2 infected individuals stratified by the absence or presence of seroconversion and disease severity. We report high levels of total naive and low effector CD8+ T cells in NSC. Moreover, polyfunctional Nucleocapsid (NP)-specific CD8+ T-cell responses, as well as reduced levels of T-cell activation monitored by PD-1 and activation-induced markers, were distinctive immunological traits in NSC. Longitudinal data support the stability of the NSC phenotype over three months. Our results implicate highly functional SARS-CoV-2 Spike and NP T-cell responses with low immune activation in protection from disease severity in the absence of seroconversion. SUMMARYTo understand SARS-CoV-2 specific T-cell immunity in the absence of seroconversion, we characterized immunological features of Non-Seroconvertors recovered from infection. Highly functional specific T-cell responses and low immune activation were determinants of immune protection from severe disease.

Previous SARS-CoV-2 infection increases B.1.1.7 cross-neutralization by vaccinated individuals.

To assess the potential impact of predominant circulating SARS-CoV-2 variants on neutralizing activity of infected and/or vaccinated individuals, we analyzed neutralization of pseudoviruses expressing the spike of the original Wuhan strain, the D614G and B.1.1.7 variants. Our data show that parameters of natural infection (time from infection and infecting variant) determined cross-neutralization. Importantly, upon vaccination, previously infected individuals developed equivalent B.1.1.7 and Wuhan neutralizing responses. In contrast, uninfected vaccinees showed reduced neutralization against B.1.1.7. FundingThis study was funded by Grifols, the Departament de Salut of the Generalitat de Catalunya, the Spanish Health Institute Carlos III, CERCA Programme/Generalitat de Catalunya, and the crowdfunding initiatives #joemcorono, BonPreu/Esclat and Correos.

Stable neutralizing antibody levels six months after mild and severe COVID-19 episode

Understanding mid-term kinetics of immunity to SARS-CoV-2 is the cornerstone for public health control of the pandemic and vaccine development. However, current evidence is rather based on limited measurements, thus losing sight of the temporal pattern of these changes1-6. In this longitudinal analysis, conducted on a prospective cohort of COVID-19 patients followed up to 242 days, we found that individuals with mild or asymptomatic infection experienced an insignificant decay in neutralizing activity that persisted six months after symptom onset or diagnosis. Hospitalized individuals showed higher neutralizing titers, which decreased following a two-phase pattern, with an initial rapid decline that significantly slowed after day 80. Despite this initial decay, neutralizing activity at six months remained higher among hospitalized individuals. The slow decline in neutralizing activity at mid-term contrasted with the steep slope of antibody titers change, reinforcing the hypothesis that the quality of immune response evolves over the post-convalescent stage4,5.

Using Real World Data to Understand HIV and COVID-19 in the U.S.A. and Spain: Characterizing Co-Infected Patients Across the Care Cascade

ObjectiveMost patients severely affected by COVID-19 have been elderly and patients with underlying chronic disease such as diabetes, cardiovascular disease, or respiratory disease. People living with HIV (PLHIV) may have greater risk of contracting or developing severe COVID-19 due to the underlying HIV infection or higher prevalence of comorbidities. DesignThis is a cohort study, including PLHIV diagnosed, hospitalized, or requiring intensive services for COVID-19. MethodsData sources include routine electronic medical record or claims data from the U.S. and Spain. Patient demographics, comorbidities, and medication history are described. ResultFour data sources had a population of HIV/COVID-19 coinfected patients ranging from 288 to 4606 lives. PLHIV diagnosed with COVID-19 were younger than HIV-negative patients diagnosed with COVID-19. PLHIV diagnosed with COVID-19 diagnosis had similar comorbidities as HIV-negative COVID-19 patients with higher prevalence of those comorbidities and history of severe disease. Treatment regimens were similar between PLHIV diagnosed with COVID-19 or PLHIV requiring intensive services. ConclusionsOur study uses routine practice data to explore HIV impact on COVID-19, providing insight into patient history prior to COVID-19. We found that HIV and COVID-19 coinfected patients have higher prevalence of underlying comorbidities such as cardiovascular and respiratory disease as compared to HIV-negative COVID-19 infected patients. We also found that, across the care cascade, co-infected patients who received intensive services were more likely to have more serious underlying disease or a history of more serious events as compared to PLHIV who were diagnosed with COVID-19.

Design and implementation of the multi-arm, multi-stage Therapeutics for Inpatients with COVID-19 (TICO) platform master protocol: An Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative

BackgroundSafe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership initiated the Therapeutics for Inpatients with COVID-19 (TICO). TICO is a multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. Four agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. Protocol Design and ImplementationThree clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. TICO utilizes a MAMS design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo as well as the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and DSMB schedule was developed for the study of agents with limited in-human data. ChallengesChallenges included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff, and obtaining regulatory approvals across a global network of sites. ConclusionThrough a robust multi-network partnership, the TICO protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required.

Ethnicity, comorbidity, socioeconomic status, and their associations with COVID-19 infection in England: a cohort analysis of UK Biobank data

ObjectivesRecent data suggest higher COVID-19 rates and severity in Black, Asian, and minority ethnic (BAME) communities. The mechanisms underlying such associations remain unclear. We aimed to study the association between ethnicity and risk of COVID-19 infection and disentangle any correlation with socioeconomic deprivation or previous comorbidity. DesignProspective cohort. SettingUK Biobank linked to Hospital Episode Statistics (HES) and COVID-19 tests until 14 April 2020. ParticipantsUK Biobank participants from England, excluding drop-outs and deaths. Main measuresCOVID-19 infection based on a positive PCR test. Ethnicity was self-reported and classified using Office of National Statistics groups. Socioeconomic status was based on index of multiple deprivation quintiles. Comorbidities were self-reported and completed from HES. AnalysesMultivariable Poisson analysis to estimate incidence rate ratios of COVID-19 infection according to ethnicity, adjusted for socioeconomic status, alcohol drinking, smoking, body mass index, age, sex, and comorbidity. Results415,582 participants were included, with 1,416 tested and 651 positive for COVID-19. The incidence of COVID-19 was 0.61% (95% CI: 0.46%-0.82%) in Black/Black British participants, 0.32% (0.19%-0.56%) in other ethnicities, 0.32% (0.23%-0.47%) in Asian/Asian British, 0.30% (0.11%-0.80%) in Chinese, 0.16% (0.06%-0.41%) in mixed, and 0.14% (0.13%-0.15%) in White. Compared with White participants, Black/Black British participants had an adjusted relative risk (RR) of 3.30 (2.39-4.55), Chinese participants 3.00 (1.11-8.06), Asian/Asian British participants 2.04 (1.36-3.07), other ethnicities 1.93 (1.08-3.45), and mixed ethnicities 1.07 (0.40-2.86). Socioeconomic status (adjusted RR 1.93 (1.51-2.46) for the most deprived), obesity (adjusted RR 1.04 (1.02-1.05) per kg/m2) and comorbid hypertension, chronic obstructive pulmonary disease, asthma, and specific renal diseases were also associated with increased risk of COVID-19. ConclusionsCOVID-19 rates in the UK are higher in BAME communities, those living in deprived areas, obese patients, and patients with previous comorbidity. Public health strategies are needed to reduce COVID-19 infections among the most susceptible groups.

Search for SARS-CoV-2 inhibitors in currently approved drugs to tackle COVID-19 pandemia

There is an urgent need to identify therapeutics for the treatment of Coronavirus diseases 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18% had an IC50 below 25 M or 102 IU/mL. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.