Objective: Whether endotheliopathy only mirrors coronavirus disease 2019 (COVID-19) severity or plays an intrinsic role in microvascular thrombosis and organ failure remains unanswered. We assessed whether markers of endothelial damage and immune dysregulation were associated with organ failure, thrombus formation, and death. Approach and Results: Markers of endothelial damage (VWF:Ag [von Willebrand factor antigen], PAI-1 [plasminogen activator inhibitor-1], syndecan-1, TFPI [tissue factor pathway inhibitor], and soluble thrombomodulin), complement activation (C5a and C5b-9), cytokines (IL [interleukin]-6, TNF [tumor necrosis factor]-α, and IL-2R), and neutrophil extracellular traps (cell-free DNA, nucleosomes, and myeloperoxidase-DNA) were measured at intensive care unit admission in 82 patients with COVID-19. We also analyzed the histological composition of thrombi collected in critically ill living patients successfully weaned from extracorporeal membrane oxygenation. Beside respiratory failure, VWF:Ag, PAI-1, TFPI, and syndecan-1 were independently associated with liver injury and multiorgan failure development, underlining the direct role of endotheliopathy in organ failure. Nucleosomes were also associated with liver injury, multiorgan failure, and death which occurred in 38%, 60%, and 27% of patients, respectively. Moreover, dysregulated immune response including cytokines, complement, and neutrophil extracellular traps was associated with markers of endothelial damage, respiratory failure, and liver injury. COVID-19 thrombi retrieved from extracorporeal membrane oxygenation circuitry contained accumulation of neutrophils, VWF, and significantly higher amount of neutrophil extracellular traps when compared with non-COVID-19 thrombi. Conclusions: We provide new associative data supporting that endotheliopathy and dysregulated immune responses are involved in respiratory and liver failure through microvascular damage in patients with severe COVID-19.

The collapsibility index of the inferior vena cava (cIVC) has potential for predicting fluid responsiveness in spontaneously breathing patients, but a standardized approach for measuring the inferior vena cava diameter has yet to be established. The aim was to test the accuracy of different measurement sites of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with sepsis-related circulatory failure and examine the influence of a standardized breathing manoeuvre. Among the 81 patients included in the study, the median Simplified Acute Physiologic Score II was 34 (24; 42). Sepsis was of pulmonary origin in 49 patients (60%). Median volume expansion during the 24 h prior to study inclusion was 1000 mL (0; 2000). Patients were not severely ill: none were intubated, only 20% were on vasopressors, and all were apparently able to perform a standardized breathing exercise. Forty-one (51%) patients were responders to volume expansion (i.e. a ≥ 10% stroke volume index increase). The cIVC was calculated during non-standardized (cIVC-ns) and standardized breathing (cIVC-st) conditions. The accuracy with which both cIVC-ns and cIVC-st predicted fluid responsiveness differed significantly by measurement site (interaction p < 0.001 and < 0.0001, respectively). Measuring inferior vena cava diameters 4 cm caudal to the right atrium predicted fluid responsiveness with the best accuracy. At this site, a standardized breathing manoeuvre also significantly improved predictive power: areas under ROC curves [mean and (95% CI)] for cIVC-ns = 0.85 [0.78–0.94] versus cIVC-st = 0.98 [0.97–1.0], p < 0.001. When cIVC-ns is superior or equal to 33%, fluid responsiveness is predicted with a sensitivity of 66% and a specificity of 92%. When cIVC-st is superior or equal to 44%, fluid responsiveness is predicted with a sensitivity of 93% and a specificity of 98%. The accuracy with which cIVC measurements predict fluid responsiveness in spontaneously breathing patients depends on both the measurement site of inferior vena cava diameters and the breathing regime. Measuring inferior vena cava diameters during a standardized inhalation manoeuvre at 4 cm caudal to the right atrium seems to be the method by which to obtain cIVC measurements best-able to predict patients’ response to volume expansion.

Advanced age or preexisting comorbidities have been characterized as risk factors for severe coronavirus disease 2019 (COVID-19) cases requiring hospitalization and intensive care. In recent years, clonal hematopoiesis (CH) of indeterminate potential (CHIP) has emerged as a risk factor for chronic inflammatory background and subsequent aging-associated diseases. The purpose of this study was to identify biological factors (particularly leukocyte subtypes and inflammatory markers) associated with a risk of clinical deterioration (i.e., orotracheal intubation (OTI)) and to determine whether CH was likely to influence clinical and biological behavior in patients with severe COVID-19 requiring hospitalization. Here, we describe clinical and biological features, including the screening of CHIP mutants in a well-annotated cohort of 122 hospitalized patients with a laboratory-confirmed diagnosis of COVID-19 (55% requiring OTI). We showed that elevated white blood cell counts, especially neutrophils and high C-reactive protein (CRP) levels at admission, were associated with an increased requirement of OTI. We noticed a high prevalence of CH (25%, 38%, 56%, and 82% of patients aged 80 years) compared to a retrospective cohort of patients free of hematological malignancy explored with the same pipelines (10%, 21%, 37%, and 44%). However, the existence of CH did not significantly impact clinical outcome, including OTI or death, and did not correlate with other laboratory findings.