The efficacy and safety of intravenous imatinib in invasively ventilated patients with COVID-19 related acute respiratory distress syndrome (InventCOVID): a multicentre, randomised, double-blinded, placebocontrolled, phase II clinical study

Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.

Phase 3 RCT of C5a-Specific Vilobelimab in Severe COVID-19 Pneumonia

Background: Blocking the C5a-C5aR axis in COVID-19 patients could improve outcomes by limiting myeloid cell infiltration in damaged organs and preventing excessive lung inflammation and endothelialitis. Aims and Objectives: Vilobelimab (VILO), an anti-C5a mAb that preserves the membrane attack complex (MAC), was tested in a Phase III adaptively designed multicenter, double-blind placebo (P)-controlled study for survival in critically ill COVID-19 patients. Method(s): COVID-19 pneumonia patients (N=369;VILO n=178, P n=191) within 48 hrs of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or P on top of standard of care. Primary outcome was 28-day allcause mortality. Result(s): 28-day all-cause mortality was 31.7% VILO vs 41.6% P (Kaplan-Meier estimates;Cox regression site stratified, HR 0.73;95%CI:0.50-1.06;P=0.094) with a 22.7% relative mortality reduction to Day 60. In predefined primary outcome analysis without site stratification, VILO significantly reduced 28-day mortality (HR 0.67;95%CI:0.48-0.96;P=0.027);needed to treat number, 10 to save 1. VILO significantly reduced 28-day mortality in severe patients with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95%CI:0.40-0.95;P=0.028) or severe ARDS/PaO2/FiO2<=100 mmHg (n=98, HR 0.55;95%CI:0.30-0.98;P=0.044) or eGFR<60 mL/min/1.73m2 (n=108, HR 0.55;95%CI:0.31-0.96;P=0.036). Treatment emergent AEs were 90.9% VILO vs 91.0% P. Infections were comparable;VILO (62.9%), P (59.3%). Serious AEs were 58.9% VILO, 63.5% P. Conclusion(s): VILO reduced mortality at 28 to 60 days in severe COVID-19 pneumonia patients with no increase in infections suggesting the importance of targeting C5a while preserving MAC.

Lung ultrasound to predict gas-exchange response to prone positioning in COVID-19 patients: A prospective study in pilot and confirmation cohorts.

PURPOSE: To examine whether lung ultrasound prior to prone positioning can predict the resulting gas-exchange response. MATERIALS AND METHODS: This is a prospective observational study on critically-ill COVID-19 patients with a pilot and confirmation cohort. Lung ultrasound examinations were performed before prone positioning and gas-exchange parameters were recorded before and after position change. RESULTS: A total of 79 patients, 36 in the pilot cohort and 43 in the confirmation cohort, were included. In the pilot cohort, a moderate correlation between pre-turn lung ultrasound score index (LUSI) and change in PaO2/FiO2 after prone positioning was found. These findings were corroborated and extended upon in the confirmation cohort. The confirmation cohort found that anterior LUSI had the strongest correlation with follow-up time-points 1, 6, 12, and 24 h after prone positioning, with strength of correlation gradually increasing up to 24 h. In a multivariate model anterior aeration loss (odds ratio 0.035; 95%CI 0.003-0.319 for anterior LUSI >50%) and higher pre-turn PaCO2 (odds ratio 0.479 95% CI 0.235-0.979) were negatively predictive of a PaO2/FiO2 increase ≥20 mmHg. CONCLUSIONS: Anterior LUSI, in addition to other clinical parameters, may be used to aid COVID-19 respiratory strategy and a clinician's decision to prone.

Randomized, Controlled Phase 3 Study of anti-C5a Vilobelimab's Effect on Mortality in Critically Ill COVID-19 Patients: A Therapy for Viral Pneumonia

Background. SARS-CoV-2 induces endothelial damage and activates the complement system. In severe COVID-19 patients, complement split factor C5a is highly elevated leading to inflammation that contributes to multiorgan failure. The anti-C5a monoclonal antibody, Vilobelimab (Vilo), which preserves the membrane attack complex (MAC), was investigated in an adaptively designed, randomized doubleblind, placebo (P)-controlled Phase 3 international multicenter study for survival in critically ill COVID-19 patients (pts). Methods. COVID-19 pneumonia pts (N=368;Vilo n=177, P n=191), mechanically ventilated within 48 hrs before treatment, received up to 6, 800 mg infusions of Vilo or P on top of standard of care. The primary and main secondary endpoints were 28-day (d) and 60-d all-cause mortality. Results. Pts enrolled in the study were on corticosteroids (97%) and anticoagulants (98%) as standard of care. A smaller proportion (20%) were either continuing or had taken immunomodulators such as tocilizumab and baricitinib prior to receiving Vilo. The 28-d all-cause mortality was 31.7% with Vilo vs 41.6% with P (Kaplan-Meier estimates;Cox regression site-stratified, HR 0.73;95% CI:0.50-1.06;P=0.094), representing a 23.8% relative mortality reduction. In predefined primary outcome analysis without site stratification, however, Vilo significantly reduced mortality at 28 (HR 0.67;95% CI:0.48-0.96;P=0.027) and 60 days (HR 0.67;95% CI:0.48-0.92;P=0.016). Vilo also significantly reduced 28-d mortality in more severe pts with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95% CI:0.40-0.95;P=0.028), severe ARDS/PaO2/FiO2 <= 100 mmHg (n=98, HR 0.55;95% CI:0.30-0.98;P=0.044) and eGFR < 60 mL/min/1.73m2 (n=108, HR 0.55;95% CI:0.31-0.96;P=0.036). Treatment-emergent AEs were 90.9% Vilo vs 91.0% P. Infections were comparable: Vilo 62.9%, P 59.3%. Infection incidence per 100 Pt days were equal. No meningococcal infections were reported. Serious AEs were 58.9% Vilo, 63.5% P. Conclusion. Vilo significantly reduced mortality at 28 and 60 days in critically ill COVID-19 pts with no increase in infections suggesting the importance of targeting C5a while preserving MAC. Vilo targets inflammation which may represent an approach to treat sepsis and ARDS caused by other respiratory viruses. (Figure Presented).

Multi-organ point-of-care ultrasound for detection of pulmonary embolism in critically ill COVID-19 patients - A diagnostic accuracy study.

PURPOSE: Critically ill COVID-19 patients have an increased risk of developing pulmonary embolism (PE). Diagnosis of PE by point-of-care ultrasound (POCUS) might reduce the need for computed tomography pulmonary angiography (CTPA), while decreasing time-to-diagnosis. MATERIALS & METHODS: This prospective, observational study included adult ICU patients with COVID-19. Multi-organ (lungs, deep vein, cardiac) POCUS was performed within 24 h of CTPA, looking for subpleural consolidations, deep venous thrombosis (DVT), and right ventricular strain (RVS). We reported the scan time, and calculated diagnostic accuracy measures for these signs separately and in combination. RESULTS: 70 consecutive patients were included. 23 patients (32.8%) had a PE. Median scan time was 14 min (IQR 11-17). Subpleural consolidations' diagnostic accuracy was: 42.9% (95%CI [34.1-52.0]). DVT's and RVS' diagnostic accuracy was: 75.6% (95%CI [67.1-82.9]) and 74.4% (95%CI [65.8-81.8]). Their sensitivity was: 24.0% (95%CI [9.4-45.1]), and 40.0% (95%CI [21.3-61.3]), while their specificity was: 88.8% (95%CI [80.8-94.3]), and: 83.0% (95%CI [74.2-89.8]), respectively. Multi-organ POCUS sensitivity was: 87.5% (95%CI [67.6-97.3]), and specificity was: 25% (95%CI [16.9-34.7]). CONCLUSIONS: Multi-organ rather than single-organ POCUS can be of aid in ruling out PE in critically ill COVID-19 and help select patients for CTPA. In addition, finding RVS can make PE more likely, while a DVT would preclude the need for a CTPA. REGISTRATION: www.trialregister.nl: NL8540.

Pre-admission anticoagulant therapy and mortality in hospitalized COVID-19 patients: A covid predict retrospectivecohort study

Background : A high incidence of venous thromboembolism (VTE) is observed in patients with COVID-19. Furthermore, several studies show that hypercoagulability is associated with mortality. Aims : To investigate whether pre-admission anticoagulant therapy is associated with a lower risk of all-cause mortality in hospitalized COVID-19 patients. Methods : Retrospective data from 1,851 consecutive patients with PCR-confirmed SARS-CoV-2 infection hospitalized in eight Dutch centres between February 27 th and August 1 st 2020 were used. During this period, Dutch guidelines recommended routine thromboprophylaxis for all hospitalized COVID-19 patients. After 1:1 propensity score nearest-neighbour matching based on age, sex, and 17 comorbidities, the association between pre-admission anticoagulant therapy for VTE, atrial fibrillation, or other indications (i.e. direct oral anticoagulants or vitamin K antagonists) and all-cause mortality and intensive care unit (ICU) admission was evaluated. A secondary analysis was performed with a broader definition of antithrombotic therapy including anticoagulants and antiplatelet drugs. Results : Mean age was 66.4 years (SD, 14.8) and 39% were women. Pre-admission, 678 patients (37%) were using anticoagulant and/or antiplatelet therapy of whom 287 (16%) used anticoagulant therapy only, 408 (22%) antiplatelet therapy only, and 17 both anticoagulant and antiplatelet therapy. 253 anticoagulant users and 253 patients not using therapeutic anticoagulation were matched. During a median follow-up of 21 days [IQR: 9.8-21.0], anticoagulant therapy was neither associated with all-cause mortality (hazard ratio [HR], 0.95;95%-CI, 0.70-1.27;Figure 1) nor with ICU admission (HR, 1.0;95%-CI, 0.59-1.70). Results did not materially change in the secondary analysis of anticoagulant and/or antiplatelet therapy (HR for mortality, 1.18 [95%-CI, 0.87-1.59] and HR for ICU admission, 2.98 [95%-CI, 0.60-1.39]). Conclusions : In this retrospective cohort study, pre-admission anticoagulant use was not associated with a lower risk of mortality or ICU admission in hospitalized COVID-19 patients. Further data from randomized controlled trials are needed to determine the riskbenefit ratio of initiating anticoagulant therapy during admission for COVID-19.

POCUS series: point-of-care lung ultrasound in patients with COVID-19

This article is part of the point-of-care ultrasound (POCUS) series. During the Coronavirus Disease 2019 (COVID-19) pandemic, we have been managing large numbers of infected patients whilst maintaining high-quality healthcare. In this article we aim to provide a short and practical description on how point-of-care lung ultrasound can be of use to facilitate diagnosis and treatment in critically ill patients diagnosed with COVID-19.