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EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309270


Background: A cytokine-storm-induced coagulopathy has been described in both critical COVID-19 and septic shock. Improving the understanding of the critical COVID-19 pathophysiology could help in finding new therapeutic targets already explored in the treatment of septic shock. Methods: This prospective observational was conducted between February 1, 2019, and June 1, 2020. Consecutive adult patients admitted to ICU for critical COVID-19 with acute respiratory distress syndrome (ARDS) (n=22), septic shock (n=48) and matched control patients (n=48) were enrolled. A between-group comparison of lung histopathology, clinical characteristics and outcomes and key plasmatic soluble biomarkers of inflammation and coagulopathy was performed. Findings: The histopathological findings showed microthrombi with NETosis in both COVID-19- and septic shock-related ARDS. In the prospective cohort, the critical COVID-19 patients exhibited a prolonged ICU length-of-stay, less organ failure, no sepsis-induced coagulopathy, a higher level of soluble tissue factor (106±57 versus 60±28pg/mL for septic shock, p<0·0001), reduced tissue plasminogen activator release (12537±5942 versus 25974±23020pg/mL for septic shock, p=0·020), marginal elevation of platelet activation biomarkers, similar NETosis and a distinct inflammatory reaction characterized by a lymphocytic response (interleukin-7 68±16 versus 36·3±17·5pg/mL for septic shock and soluble CD40L 276±132 versus 95± 58pg/mL for septic shock, p<0·0001). Interpretation: Critical COVID-19 exhibits a prolonged disease course but less organ failure compared to septic shock. At ICU admission, COVID-19 is characterized by a lymphocytic immune response and distinct coagulopathy with less platelet or coagulation factor consumption, and fibrinolysis alterations. Clinical Trial Registration Details: NCT04107402.Funding Information: Fondation Saint-Luc (Brussels, Belgium) and QUALIblood s.a.Declaration of Interests: The Division of Cardiology at Cliniques universitaires Saint-Luc, Belgium, has received unrestricted research grants from AstraZeneca (Belgium). J.D. is the CEO and founder of QUALIblood s.a., a Belgian Contract Research Organization. The remaining authors declare no competing interests.Ethics Approval Statement: The ethics committee approved the study protocol, and all patients signed their informed consent (B403201938590, NCT04107402). Protocol amendment was done to include COVID-19 patients in the ongoing study.

Frontiers in medicine ; 8, 2021.
Article in English | EuropePMC | ID: covidwho-1661044


Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1β and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients.

Am J Respir Crit Care Med ; 204(9): 1024-1034, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1495777


Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.

Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/physiopathology , Case-Control Studies , Female , Humans , Immunohistochemistry , Logistic Models , Male , Middle Aged , Proportional Hazards Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/virology , Retrospective Studies , Severity of Illness Index , Up-Regulation