Corrigendum: XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants.

[This corrects the article DOI: 10.3389/fimmu.2021.761250.].

Monoclonal Antibodies in Hospitalised Patients with COVID-19: The Role of SARS-COV-2 Serostatus in an Evolving Pandemic.

Appropriately selected neutralising monoclonal antibodies (nmAbs) are an effective treatment for patients with mild or moderate coronavirus disease 2019 (COVID-19) who are at high risk of progression to severe disease. In contrast, the efficacy of nmAbs in patients hospitalised with COVID-19 has been mixed, and clinical benefit has largely been restricted to seronegative patients [i.e. those lacking endogenous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies] in the trials with positive outcomes. This review summarises the major clinical trial data investigating nmAb treatment for hospitalised patients with COVID-19, and explores current definitions of seropositivity, what they mean in a late-pandemic context and discusses the current late-pandemic challenges associated with defining 'seroprotection' in a clinically meaningful way. We conclude that following widespread vaccination, increasing numbers of prior infections and emerging viral variants, seropositivity now reflects a range of immune coverage rather than a binary tool with which to aid decision-making on a clinically actionable timescale. Treatment decisions with nmAbs in a late-pandemic context would therefore likely best rely on information regarding clinical status, time since symptom onset, underlying patient condition(s) and the dominant circulating variant, should they be approved for future use in hospitalised patients with COVID-19.

Virus-Associated Nephropathies: A Narrative Review.

While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient's underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.

Tocilizumab plus dexamethasone versus dexamethasone in patients with moderate-to-severe COVID-19 pneumonia: A randomised clinical trial from the CORIMUNO-19 study group.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals;however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population. Type I IFN auto-Abs are found in 20% of hypoxemic, mRNA vaccinated COVID-19 patients despite SARS-CoV-2 neutralizing antibodies. Description

Public health impact of COVID-19 in French ambulatory patients with at least one risk factor for severe disease.

Background: Quantification of COVID-19 burden may be useful to support the future allocation of resources. Objective: To evaluate the public health impact of COVID-19 in French ambulatory patients with at least one risk factor for severe disease. Study design: A Markov model was used to estimate life years, costs, number of hospitalisations, number of deaths and long/prolonged COVID forms over a time horizon of 2 years. The hospitalisation probabilities were derived from an early access cohort, and the hospitalisation stay characteristics were derived from the French national hospital discharge database. Several scenario analyses were conducted. Results: The number of hospitalisations reached 256 per 1,000 patients over the acute phase (first month of simulation), and 382 per 1,000 patients over 2 years. The number of deaths was 37 per 1,000 patients, and the number of long/prolonged COVID forms reached 407 per 1,000 patients. These translated into a reduction of 0.7 days of life per patient in the first month, with an associated cost of €1,578, and a reduction of 27 days of life over the time horizon, with an associated cost of €4,280. The highest burden was observed for patients over 80 years old, and those not vaccinated. The scenarios with a less severe situation or new treatments available showed a non-negligible burden reduction. Conclusion: This study allowed us to quantify the considerable burden related to COVID-19 in infected patients, with at least one risk factor for severe form. Strategies with the ability to substantially reduce this burden in France are urgently required.

Clinical Outcomes of Hospitalized COVID-19 Patients Treated with Remdesivir-NEAT ID 909REM Study

Background There are few real-world data on the use of remdesivir (RDV) looking at timing of initiation in relation to symptom onset and severity of presenting disease. Methods We conducted multi-country retrospective study of clinical practice and use of RDV in COVID-19 patients. De-identified medical records data were entered into an e-CRF. Primary endpoints were all-cause mortality at day 28 and hospitalization duration. We assessed time from symptom onset to RDV start and re-admission. We included adults with PCR-confirmed symptomatic COVID-19 who were hospitalized after Aug 31, 2020 and received at least 1 dose of RDV. Descriptive analyses were conducted. Kaplan-Meier methods were used to calculate the mortality rate, LogRank test to compare groups defined by severity of disease. Competing risk regression with discharge and death as competing events was used to estimate duration of hospitalization, and Gray’s test to compare the groups. Results 448 patients in 5 countries (12 sites) were included. Demographics are summarized (table) by 3 disease severity groups at baseline: no supplemental oxygen (NSO), low flow oxygen ≤6 L/min (LFO), and high-flow oxygen > 6L/min (HFO). No demographic differences were found between groups except for the higher percentage of cancer/chemotherapy patients in NSO group. Corticosteroids use was HFO 73.6%, LFO 62.7%, NSO 58.0%. Mortality rate was significantly lower in NSO, and LFO groups compared with HFO (6.2%, 10.2%, 23.6%, respectively;Fig1). Median duration of hospitalization was 9 (95%CI 8-10), 9 (8-9), 13 (10-15) days, respectively (Fig2). Median time from first symptom to RDV start was 7 days in all 3 groups. Patients started RDV on day 1 of hospitalization in HFO and LFO and day 2 on NSO groups. And received a 5 day course (median). Readmission within 28-days of discharge was < 5% and similar across all 3 groups. Table 1. Patients baseline characteristics and primary and secondary outcomes Figure 1. Kaplan-Meier estimates of mortality Figure 2. Competing-risks regression of discharge from hospital Conclusion In this real-world cohort of COVID-19 positive hospitalized patients, RDV use was consistent across countries. RDV was started within a median of 7 days from symptom within 2 days of admission and given for a median of 5 days. Higher mortality rate and duration of hospitalization was seen in the HFO group and similar rates seen in the LFO and NSO groups. Readmission was consistently low across all 3 groups. Disclosures François Raffi, MD, PhD, Gilead Sciences (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Consultant)MSD (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member)Roche (Consultant)Theratechnologies (Advisor or Review Panel member)ViiV (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member) Nadir Arber, MD, MSc, MHA, Check cap (Consultant)Coved cd 24 (Board Member)Israel Innovation Authority (Research Grant or Support)Nucleix (Advisor or Review Panel member)Zion Pharmaceuticals (Advisor or Review Panel member) Casper Rokx, MD PhD, Gilead Sciences (Grant/Research Support, Advisor or Review Panel member, Research Grant or Support)Merck (Grant/Research Support, Research Grant or Support)ViiV (Grant/Research Support, Advisor or Review Panel member, Research Grant or Support) Ameet Bakhai, MBBS, MD, FRCP, FESC, Bayer AG (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Boehringer Ingelheim (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Bristol-Myers Squibb (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Daiichi-Sankyo Europe (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator)Janssen (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Johnson & Johnson (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)MSD (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Novartis (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Pfizer (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Roche (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Sanofi (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor) Alex Soriano, MD, Angelini (Speaker's Bureau)Gilead Sciences (Research Grant or Support, Speaker's Bureau)Menarini (Speaker's Bureau)MSD (Research Grant or Support, Speaker's Bureau)Pfizer (Research Grant or Support, Speaker's Bureau)Shionogi (Speaker's Bureau) Carlos Lumbreras, MD, PhD, Gilead Sciences (Grant/Research Support)MSD (Consultant) Vicente Estrada, MD, PhD, Gilead Sciences (Consultant, Grant/Research Support)Janssen (Advisor or Review Panel member)MSD (Consultant, Grant/Research Support)Theratechnologies (Consultant)ViiV (Consultant) Adrian Curran, MD, PhD, Gilead Sciences (Advisor or Review Panel member, Research Grant or Support)Janssen (Advisor or Review Panel member, Research Grant or Support)MSD (Advisor or Review Panel member, Research Grant or Support)ViiV (Advisor or Review Panel member, Research Grant or Support) Essy Mozaffari, PharmD, MPH, MBA, Gilead Sciences (Employee, Shareholder) Richard Haubrich, MD, Gilead Sciences (Employee, Shareholder) Paul Hodgkins, PhD, MSc, Gilead Sciences (Employee, Shareholder) Anton Pozniak, MD, FRCP, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)Janssen (Grant/Research Support, Research Grant or Support)Merck (Advisor or Review Panel member)Theratec (Grant/Research Support, Advisor or Review Panel member, Research Grant or Support)ViiV (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)

XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants.

Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.

Pharmacokinetics and Safety of XAV-19, a Swine Glyco-humanized Polyclonal Anti-SARS-CoV-2 Antibody, for COVID-19-Related Moderate Pneumonia: a Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study.

We assessed the pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in coronavirus disease 2019 (COVID-19)-related moderate pneumonia. The objective was to evaluate the optimal dose and safety of XAV-19 during this first administration to patients with COVID-19-related moderate pneumonia. In this phase IIa trial, adults with COVID-19-related moderate pneumonia with a duration of ≤10 days were randomized to receive an infusion of XAV-19 at 0.5 mg/kg of body weight at day 1 and day 5 (group 1), 2 mg/kg at day 1 and day 5 (group 2), or 2 mg/kg at day 1 (group 3) or placebo. Eighteen patients (n = 7 for group 1, n = 1 for group 2, n = 5 for group 3, and n = 5 for placebo) were enrolled. Baseline characteristics were similar across groups; median XAV-19 serum concentrations (ranges) at the time of the maximum serum concentration of the drug (Cmax) and at day 8 were 9.1 (5.2 to 18.1) and 6.4 (2.8 to 11.9) µg/ml, 71.5 and 47.2 µg/ml, and 50.4 (29.1 to 55.0) and 20.3 (12.0 to 22.7) µg/ml for groups 1, 2, and 3, respectively (P = 0.012). The median terminal half-life (range) was estimated at 11.4 (5.5 to 13.9) days for 2 mg/kg of XAV-19 at day 1. Serum XAV-19 concentrations were above the target concentration of 10 µg/ml (2-fold the in vitro 100% inhibitory concentration [IC100]) from the end of perfusion to more than 8 days for XAV-19 at 2 mg/kg at day 1. No hypersensitivity or infusion-related reactions were reported during treatment, and there were no discontinuations for adverse events and no serious adverse events related to the study drug. A single intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability. (This study has been registered at ClinicalTrials.gov under identifier NCT04453384.).

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-ß-1a and hydroxychloroquine in hospitalized patients with COVID-19.

OBJECTIVES: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-ß-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. METHODS: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. RESULTS: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-ß-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-ß-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. CONCLUSION: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial.

BACKGROUND: Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2. METHODS: Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population. DISCUSSION: This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis. TRIAL REGISTRATION: ClinicalTrials.gov NCT04453384 , registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.

Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort.

The characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics in hospitalized patients and its association with mortality is unknown. We analyzed death and nasopharyngeal viral kinetics in 655 hospitalized patients from the prospective French COVID cohort. The model predicted a median peak viral load that coincided with symptom onset. Patients with age ≥65 y had a smaller loss rate of infected cells, leading to a delayed median time to viral clearance occurring 16 d after symptom onset as compared to 13 d in younger patients (P < 10-4). In multivariate analysis, the risk factors associated with mortality were age ≥65 y, male gender, and presence of chronic pulmonary disease (hazard ratio [HR] > 2.0). Using a joint model, viral dynamics after hospital admission was an independent predictor of mortality (HR = 1.31, P < 10-3). Finally, we used our model to simulate the effects of effective pharmacological interventions on time to viral clearance and mortality. A treatment able to reduce viral production by 90% upon hospital admission would shorten the time to viral clearance by 2.0 and 2.9 d in patients of age <65 y and ≥65 y, respectively. Assuming that the association between viral dynamics and mortality would remain similar to that observed in our population, this could translate into a reduction of mortality from 19 to 14% in patients of age ≥65 y with risk factors. Our results show that viral dynamics is associated with mortality in hospitalized patients. Strategies aiming to reduce viral load could have an effect on mortality rate in this population.

Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors.

Coagulopathy in COVID-19 is a burning issue and strategies to prevent thromboembolic events are debated and highly heterogeneous. The objective was to determine incidence and risk factors of venous thromboembolism (VTE) in COVID-19 inpatients receiving thromboprophylaxis. In this retrospective French cohort study, patients hospitalized in medical wards non-ICU with confirmed COVID-19 and adequate thromboprophylaxis were included. A systematic low limb venous duplex ultrasonography was performed at hospital discharge or earlier if deep venous thrombosis (DVT) was clinically suspected. Chest angio-CT scan was performed when pulmonary embolism (PE) was suspected. Of 71 patients, 16 developed VTE (22.5%) and 7 PE (10%) despite adequate thromboprophylaxis. D-dimers at baseline were significantly higher in patients with DVT (p < 0.001). Demographics, comorbidities, disease manifestations, severity score, and other biological parameters, including inflammatory markers, were similar in patients with and without VTE. The negative predictive value of a baseline D-dimer level < 1.0 µg/ml was 90% for VTE and 98% for PE. The positive predictive value for VTE was 44% and 67% for D-dimer level ≥ 1.0 µg/ml and ≥ 3 µg/ml, respectively. The association between D-dimer level and VTE risk increased by taking into account the latest available D-dimer level prior to venous duplex ultrasonography for the patients with monitoring of D-dimer. Despite thromboprophylaxis, the risk of VTE is high in COVID-19 non-ICU inpatients. Increased D-dimer concentrations of more than 1.0 µg/ml predict the risk of venous thromboembolism. D-dimer level-guided aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.