Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034). Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Cardiorespiratory Fitness and Neuromuscular Function of Mechanically Ventilated ICU COVID-19 Patients.

OBJECTIVES: The aim of the current study was to investigate the level of cardiorespiratory fitness and neuromuscular function of ICU survivors after COVID-19 and to examine whether these outcomes are related to ICU stay/mechanical ventilation duration. DESIGN: Prospective nonrandomized study. SETTING: Patients hospitalized in ICU for COVID-19 infection. PATIENTS: Sixty patients hospitalized in ICU (mean duration: 31.9 ± 18.2 d) were recruited 4-8 weeks post discharge from ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients visited the laboratory on two separate occasions. The first visit was dedicated to quality of life questionnaire, cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function were performed in the second visit. Maximal oxygen uptake (V o2 max) was 18.3 ± 4.5 mL·min -1 ·kg -1 , representing 49% ± 12% of predicted value, and was significantly correlated with ICU stay/mechanical ventilation (MV) duration ( R = -0.337 to -0.446; p < 0.01 to 0.001), as were maximal voluntary contraction and electrically evoked peak twitch. V o2 max (either predicted or in mL· min -1 ·kg -1 ) was also significantly correlated with key indices of pulmonary function such as predicted forced vital capacity or predicted forced expiratory volume in 1 second ( R = 0.430-0.465; p ≤ 0.001) and neuromuscular function. Both cardiorespiratory fitness and neuromuscular function were correlated with self-reported physical functioning and general health status. CONCLUSIONS: V o2 max was on average only slightly above the 18 mL·min -1 ·kg -1 , that is, the cut-off value known to induce difficulty in performing daily tasks. Overall, although low physical capacities at admission in ICU COVID-19 patients cannot be ruled out to explain the association between V o2 max or neuromuscular function and ICU stay/MV duration, altered cardiorespiratory fitness and neuromuscular function observed in the present study may not be specific to COVID-19 disease but seem applicable to all ICU/MV patients of similar duration.

Association of COVID-19 Acute Respiratory Distress Syndrome With Symptoms of Posttraumatic Stress Disorder in Family Members After ICU Discharge.

IMPORTANCE: Persistent physical and mental disorders are frequent in survivors of COVID-19-related acute respiratory distress syndrome (ARDS). However, data on these disorders among family members are scarce. OBJECTIVE: To determine the association between patient hospitalization for COVID-19 ARDS vs ARDS from other causes and the risk of posttraumatic stress disorder (PTSD)-related symptoms in family members. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study in 23 intensive care units (ICUs) in France (January 2020 to June 2020 with final follow-up ending in October 2020). ARDS survivors and family members (1 family member per patient) were enrolled. EXPOSURES: Family members of patients hospitalized for ARDS due to COVID-19 vs ARDS due to other causes. MAIN OUTCOMES AND MEASURES: The primary outcome was family member symptoms of PTSD at 90 days after ICU discharge, measured by the Impact of Events Scale-Revised (score range, 0 [best] to 88 [worst]; presence of PTSD symptoms defined by score >22). Secondary outcomes were family member symptoms of anxiety and depression at 90 days assessed by the Hospital Anxiety and Depression Scale (score range, 0 [best] to 42 [worst]; presence of anxiety or depression symptoms defined by subscale scores ≥7). Multivariable logistic regression models were used to determine the association between COVID-19 status and outcomes. RESULTS: Among 602 family members and 307 patients prospectively enrolled, 517 (86%) family members (median [IQR] age, 51 [40-63] years; 72% women; 48% spouses; 26% bereaved because of the study patient's death; 303 [50%] family members of COVID-19 patients) and 273 (89%) patients (median [IQR] age, 61 [50-69] years; 34% women; 181 [59%] with COVID-19) completed the day-90 assessment. Compared with non-COVID-19 ARDS, family members of patients with COVID-19 ARDS had a significantly higher prevalence of symptoms of PTSD (35% [103/293] vs 19% [40/211]; difference, 16% [95% CI, 8%-24%]; P < .001), symptoms of anxiety (41% [121/294] vs 34% [70/207]; difference, 8% [95% CI, 0%-16%]; P= .05), and symptoms of depression (31% [91/291] vs 18% [37/209]; difference, 13% [95% CI, 6%-21%]; P< .001). In multivariable models adjusting for age, sex, and level of social support, COVID-19 ARDS was significantly associated with increased risk of PTSD-related symptoms in family members (odds ratio, 2.05 [95% CI, 1.30 to 3.23]). CONCLUSIONS AND RELEVANCE: Among family members of patients hospitalized in the ICU with ARDS, COVID-19 disease, as compared with other causes of ARDS, was significantly associated with increased risk of symptoms of PTSD at 90 days after ICU discharge. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04341519.

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.

Live virus neutralization testing in convalescent patients and subjects vaccinated against 19A, 20B, 20I/501Y.V1 and 20H/501Y.V2 isolates of SARS-CoV-2.

SARS-CoV-2 mutations appeared recently and can lead to conformational changes in the spike protein and probably induce modifications in antigenicity. We assessed the neutralizing capacity of antibodies to prevent cell infection, using a live virus neutralization test with different strains [19A (initial one), 20B (B.1.1.241 lineage), 20I/501Y.V1 (B.1.1.7 lineage), and 20H/501Y.V2 (B.1.351 lineage)] in serum samples collected from different populations: two-dose vaccinated COVID-19-naive healthcare workers (HCWs; Pfizer-BioNTech BNT161b2), 6-months post mild COVID-19 HCWs, and critical COVID-19 patients. No significant difference was observed between the 20B and 19A isolates for HCWs with mild COVID-19 and critical patients. However, a significant decrease in neutralization ability was found for 20I/501Y.V1 in comparison with 19A isolate for critical patients and HCWs 6-months post infection. Concerning 20H/501Y.V2, all populations had a significant reduction in neutralizing antibody titers in comparison with the 19A isolate. Interestingly, a significant difference in neutralization capacity was observed for vaccinated HCWs between the two variants but not in the convalescent groups.

A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity.

Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and, thus, for public health policy and vaccine development for COVID-19. In this study, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections, including patients with mild symptoms and also more severe forms, including those that required intensive care. We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers; conversely, patients with milder disease symptoms had heterogeneous nAb titers, and asymptomatic or exclusive outpatient-care patients had no or low nAbs. We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses. Moreover, we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2. Finally, we found that the D614G mutation in the spike protein, which has recently been identified as the current major variant in Europe, does not allow neutralization escape. Altogether, our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease, and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.