Dexamethasone Modulates the Cytokine Response but Not COVID-19-Induced Coagulopathy in Critically Ill.

Severe forms of coronavirus 2019 (COVID-19) disease are caused by an exaggerated systemic inflammatory response and subsequent inflammation-related coagulopathy. Anti-inflammatory treatment with low dose dexamethasone has been shown to reduce mortality in COVID-19 patients requiring oxygen therapy. However, the mechanisms of action of corticosteroids have not been extensively studied in critically ill patients in the context of COVID-19. Plasma biomarkers of inflammatory and immune responses, endothelial and platelet activation, neutrophil extracellular trap formation, and coagulopathy were compared between patients treated or not by systemic dexamethasone for severe forms of COVID-19. Dexamethasone treatment significantly reduced the inflammatory and lymphoid immune response in critical COVID-19 patients but had little effect on the myeloid immune response and no effect on endothelial activation, platelet activation, neutrophil extracellular trap formation, and coagulopathy. The benefits of low dose dexamethasone on outcome in critical COVID-19 can be partially explained by a modulation of the inflammatory response but not by reduction of coagulopathy. Future studies should explore the impact of combining dexamethasone with other immunomodulatory or anticoagulant drugs in severe COVID-19.

Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study.

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)-1ß 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.

NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study.

Background: Neutrophil extracellular traps' (NETs') formation is a mechanism of defense that neutrophils deploy as an alternative to phagocytosis, to constrain the spread of microorganisms. Aim: The aim was to evaluate biomarkers of NETs' formation in a patient cohort admitted to intensive care unit (ICU) due to infection. Methods: Forty-six septic shock patients, 22 critical COVID-19 patients and 48 matched control subjects were recruited. Intact nucleosomes containing histone 3.1 (Nu.H3.1), or citrullinated histone H3R8 (Nu.Cit-H3R8), free citrullinated histone (Cit-H3), neutrophil elastase (NE) and myeloperoxidase (MPO) were measured. Results: Significant differences in Nu.H3.1 and NE levels were observed between septic shock and critical COVID-19 subjects as well as with controls (p-values < 0.05). The normalization of nucleosome levels according to the neutrophil count improved the discrimination between septic shock and critical COVID-19 patients. The ratio of Nu.Cit-H3R8 to Nu.H3.1 allowed the determination of nucleosome citrullination degree, presumably by PAD4. Conclusions: H3.1 and Cit-H3R8 nucleosomes appear to be interesting markers of global cell death and neutrophil activation when combined. Nu.H3.1 permits the evaluation of disease severity and differs between septic shock and critical COVID-19 patients, reflecting two distinct potential pathological processes in these conditions.

Development of SARS-CoV2 humoral response including neutralizing antibodies is not sufficient to protect patients against fatal infection.

More than a year after the start of the pandemic, COVID-19 remains a global health emergency. Although the immune response against SARS-CoV-2 has been extensively studied, some points remain controversial. One is the role of antibodies in viral clearance and modulation of disease severity. While passive transfer of neutralizing antibodies protects against SARS-CoV-2 infection in animal models, titers of anti-SARS-CoV-2 antibodies have been reported to be higher in patients suffering from more severe forms of the disease. A second key question for pandemic management and vaccine design is the persistence of the humoral response. Here, we characterized the antibody response in 187 COVID-19 patients, ranging from asymptomatic individuals to patients who died from COVID-19, and including patients who recovered. We developed in-house ELISAs to measure titers of IgG, IgM and IgA directed against the RBD or N regions in patient serum or plasma, and a spike-pseudotyped neutralization assay to analyse seroneutralization. Higher titers of virus-specific antibodies were detected in patients with severe COVID-19, including deceased patients, compared to asymptomatic patients. This demonstrates that fatal infection is not associated with defective humoral response. Finally, most of recovered patients still had anti-SARS-CoV-2 IgG more than 3 months after infection.

Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients.

BACKGROUND: SARS-CoV-2 targets endothelial cells through the angiotensin-converting enzyme 2 receptor. The resulting endothelial injury induces widespread thrombosis and microangiopathy. Nevertheless, early specific markers of endothelial dysfunction and vascular redox status in COVID-19 patients are currently missing. METHODS: Observational study including ICU and non-ICU adult COVID-19 patients admitted in hospital for acute respiratory failure, compared with control subjects matched for cardiovascular risk factors similar to ICU COVID-19 patients, and ICU septic shock patients unrelated to COVID-19. FINDINGS: Early SARS-CoV-2 infection was associated with an imbalance between an exacerbated oxidative stress (plasma peroxides levels in ICU patients vs. controls: 1456.0 ± 400.2 vs 436 ± 272.1 mmol/L; P < 0.05) and a reduced nitric oxide bioavailability proportional to disease severity (5-α-nitrosyl-hemoglobin, HbNO in ICU patients vs. controls: 116.1 ± 62.1 vs. 163.3 ± 46.7 nmol/L; P < 0.05). HbNO levels correlated with oxygenation parameters (PaO2/FiO2 ratio) in COVID-19 patients (R2 = 0.13; P < 0.05). Plasma levels of angiotensin II, aldosterone, renin or serum level of TREM-1 ruled out any hyper-activation of the renin-angiotensin-aldosterone system or leucocyte respiratory burst in ICU COVID-19 patients, contrary to septic patients. INTERPRETATION: Endothelial oxidative stress with ensuing decreased NO bioavailability appears as a likely pathogenic factor of endothelial dysfunction in ICU COVID-19 patients. A correlation between NO bioavailability and oxygenation parameters is observed in hospitalized COVID-19 patients. These results highlight an urgent need for oriented research leading to a better understanding of the specific endothelial oxidative stress that occurs during SARS-CoV-2. FUNDING: Stated in the acknowledgments section.

Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study

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.

COVID-19: an 'extraterrestrial' disease?

BACKGROUND: Since the beginning of the pandemic, COVID-19 has been regarded as an exceptional disease. Control measures have exclusively focused on 'the virus', while failing to account for other biological and social factors that determine severe forms of the disease. AIM: We argue that although COVID-19 was initially considered a new challenge, justifying extraordinary response measures, this situation has changed - and so should our response. MAIN ARGUMENTS: We now know that COVID-19 shares many features of common infectious respiratory diseases, and can now ascertain that SARS-CoV-2 has not suddenly presented new problems. Instead, it has exposed and exacerbated existing problems in health systems and the underlying health of the population. COVID-19 is evidently not an 'extraterrestrial' disease. It is a complex zoonotic disease, and it needs to be managed as such, following long-proven principles of medicine and public health. CONCLUSION: A complex disease cannot be solved through a simple, magic-bullet cure or vaccine. The heterogeneity of population profiles susceptible to developing a severe form of COVID-19 suggests the need to adopt varying, targeted measures that are able to address risk profiles in an appropriate way. The critical role of comorbidities in disease severity calls for short-term, virus-targeted interventions to be complemented with medium-term policies aimed at reducing the burden of comorbidities, as well as mitigating the risk of transition from infection to disease. Strategies required include upstream prevention, early treatment, and consolidation of the health system.