The diagnostic accuracy of lung ultrasound to determine PiCCO-derived extravascular lung water in invasively ventilated patients with COVID-19 ARDS (preprint)

Background: Lung ultrasound (LUS) is a non-invasive method to detect and quantify pulmonary edema. However, it remains uncertain how components of the LUS examination should be aggregated into a score for quantifying pulmonary edema. We examined the diagnostic accuracy of various LUS scores with the extravascular lung water index (EVLWi) assessed with PiCCO in patients with moderate-to-severe COVID-19 ARDS. Methods: In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were included within 48h after intubation and underwent LUS and EVLWi measurement at two time points (first and fourth study day). EVLWi and ∆EVLWi were used as reference standard. Two 12-region scores (global LUS and LUS-ARDS), an 8-region anterior-lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi>15mL/kg) was calculated. Results: 26 of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 of 29 patients (83%) at time point 2. The global LUS (r=0.54), LUS-ARDS (r=0.58) and anterior-lateral score (r=0.54) were significantly correlated with EVLWi, while the B-line score was not (r=0.32). ∆global LUS (r=0.49) and ∆anterior-lateral LUS (r=0.52) were significantly correlated with ∆EVLWi, while correlation of ∆LUS-ARDS (r=0.43) and ∆B-lines (r=0.32) did not reach statistical significance. AUROCC for EVLWi>15ml/kg was 0.73 for the global LUS, 0.79 for the anterior-lateral and 0.85 for the LUS-ARDS score. Conclusions: The global LUS, LUS-ARDS and antero-lateral score can quantify PiCCO-derived pulmonary edema measurements in COVID-19 ARDS. The LUS-ARDS score showed the highest diagnostic accuracy for severe pulmonary edema. Trial registration: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020-005447-23.

Modeling the Opening SARS-CoV-2 Spike: an Investigation of its Dynamic Electro-Geometric Properties (preprint)

The recent COVID-19 pandemic has brought about a surge of crowd-sourced initiatives aimed at simulating the proteins of the SARS-CoV-2 virus. A bottleneck currently exists in translating these simulations into tangible predictions that can be leveraged for pharmacological studies. Here we report on extensive electrostatic calculations done on an exascale simulation of the opening of the SARS-CoV-2 spike protein, performed by the Folding@home initiative. We compute the electric potential as the solution of the non-linear Poisson-Boltzmann equation using a parallel sharp numerical solver. The inherent multiple length scales present in the geometry and solution are reproduced using highly adaptive Octree grids. We analyze our results focusing on the electro-geometric properties of the receptor-binding domain and its vicinity. This work paves the way for a new class of hybrid computational and data-enabled approaches, where molecular dynamics simulations are combined with continuum modeling to produce high-fidelity computational measurements serving as a basis for protein bio-mechanism investigations.

Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID 19 (preprint)

Our understanding of the coronavirus disease-19 (COVID-19) immune response is almost exclusively derived from studies that examined blood. To gain insight in the pulmonary immune response we analysed BALF samples and paired blood samples from 17 severe COVID-19 patients. Macrophages and T cells were the most abundant cells in BALF. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells and expressed higher levels of the exhaustion marker PD-1 than in peripheral blood. Prolonged ICU stay associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. In conclusion, the bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood. SummaryThe bronchoalveolar immune response in severe COVID-19 strongly differs from the peripheral blood immune profile. Fatal COVID-19 associated with T cell activation blood, but not in BALF.

Anti-C5a Antibody (IFX-1) Treatment of Severe COVID-19: An Exploratory Phase 2 Randomized Controlled Trial (preprint)

Background: Severe coronavirus disease 2019 (Covid-19) is characterized by inflammation and coagulation in the presence of complement activation. Methods: We conducted an explorative phase 2 randomized, open label first part of an adaptive phase 2/3 trial of intravenous IFX-1, a monoclonal antibody selectively blocking the anaphylatoxin C5a, in adults with severe Covid-19. Patients were randomized between IFX-1 plus best supportive care (BSC) or BSC only. Results: 30 patients underwent randomization: 15 assigned to IFX-1 and 15 to BSC. PaO2/FiO2 ratio improvement on day 5, chosen as primary outcome parameter, did not show significant differences between groups. However, IFX-1 treatment was associated with consistent trends of improvement as evidenced by lower mortality rate, reduction in renal impairment, normalization of lymphocyte counts, and lowering of plasma lactate dehydrogenase concentrations. Kaplan-Meier estimates of mortality by 28 days were 13% for IFX-1 and 27% for BSC (HR for death, 0.56; 95%CI 0.09-3.74). Serious adverse events rates were comparable between groups but the rate of pulmonary embolisms was three-fold lower in the IFX-1 group (13%) compared to BSC group (40%). IFX-1 treatment was associated with significant increase of D-dimer levels suggesting a potential pro-fibrinolytic activity of anti-C5a treatment. Conclusion: In this exploratory part of the study, C5a inhibition with IFX-1 was shown to be safe in severe Covid-19. PaO2/FiO2 ratio at day five was comparable between groups, but consistent signals of benefit including a lower 28-day all-cause mortality rate, lower rate in impaired kidney function and a lower rate of pulmonary embolism warrant investigating C5a-inhibition with IFX-1 within a phase 3 trial.Trial Registration: This trial has been registered with the NIH, U.S. National Library of Medicine at ClinicalTrials.gov (NCT04333420). Funding Statement: The trial is funded by InflaRx GmbH.Declaration of Interests: NR and RG are founders, active officers and executive directors of InflaRx (InflaRx GmbH, InflaRx Pharmaceuticals Inc. and InflaRx N.V.) and hold shares and stock options in InflaRx. KP is Global Head of Clinical Development of InflaRx and holds stock options in InflaRx. SR is employee at Metronomia, a contracted statistical service provider for InflaRx. MW is supported by grants from the German Research Foundation, SFB-TR84 C6 and C9 and by the German Ministry of Education and Research in the framework of the CAPSyS (01ZX1304B) and the PROVID project (FKZ 01KI20160A). DvdB reports receiving departmental honoraria for serving on a scientific advisory board for InflaRx in 2017, paid to Amsterdam UMC. All other authors have no Conflict of Interest. Ethics Approval Statement: The study protocol was approved by the institutional review board of the Academic Medical Center, part of Amsterdam UMC, Amsterdam, the Netherlands (IRB: 2020_067#B2020179). If direct informed consent of patients was not feasible, patients could be included with a deferred consent procedure. All patients or their legally authorized representatives gave written informed consent for the study.