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      The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19)

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          Abstract

          The novel coronavirus SARS-CoV-2 causes COVID-19, a highly pathogenic viral infection threatening millions. The majority of the individuals infected are asymptomatic or mildly symptomatic showing typical clinical signs of common cold. However, approximately 20% of the patients can progress to acute respiratory distress syndrome (ARDS), evolving to death in about 5% of cases. Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for virus entry into host target cells. The upregulation of ACE2 in patients with comorbidities may represent a propensity for increased viral load and spreading of infection to extrapulmonary tissues. This systemic infection is associated with higher neutrophil to lymphocyte ratio in infected tissues and high levels of pro-inflammatory cytokines leading to an extensive microthrombus formation with multiorgan failure. Herein we investigated whether SARS-CoV-2 can stimulate extracellular neutrophils traps (NETs) in a process called NETosis. We demonstrated for the first time that SARS-CoV-2 in fact is able to activate NETosis in human neutrophils. Our findings indicated that this process is associated with increased levels of intracellular Reactive Oxygen Species (ROS) in neutrophils. The ROS-NET pathway plays a role in thrombosis formation and our study suggest the importance of this target for therapy approaches against disease.

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          Incidence of thrombotic complications in critically ill ICU patients with COVID-19

          Introduction COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available. Methods We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital. Results We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications. Conclusion The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.
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            The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

            Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Based on the large number of infected people that were exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or reduce transmission should be applied in susceptible populations including children, health care providers, and elderly people. In this review, we highlights the symptoms, epidemiology, transmission, pathogenesis, phylogenetic analysis and future directions to control the spread of this fatal disease.
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              Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

              Background A relatively high mortality of severe coronavirus disease 2019 (COVID‐19) is worrying, and the application of heparin in COVID‐19 has been recommended by some expert consensus because of the risk of disseminated intravascular coagulation and venous thromboembolism. However, its efficacy remains to be validated. Methods Coagulation results, medications, and outcomes of consecutive patients being classified as having severe COVID‐19 in Tongji hospital were retrospectively analyzed. The 28‐day mortality between heparin users and nonusers were compared, as was a different risk of coagulopathy, which was stratified by the sepsis‐induced coagulopathy (SIC) score or D‐dimer result. Results There were 449 patients with severe COVID‐19 enrolled into the study, 99 of them received heparin (mainly with low molecular weight heparin) for 7 days or longer. D‐dimer, prothrombin time, and age were positively, and platelet count was negatively, correlated with 28‐day mortality in multivariate analysis. No difference in 28‐day mortality was found between heparin users and nonusers (30.3% vs 29.7%, P  = .910). But the 28‐day mortality of heparin users was lower than nonusers in patients with SIC score ≥4 (40.0% vs 64.2%, P  = .029), or D‐dimer >6‐fold of upper limit of normal (32.8% vs 52.4%, P  = .017). Conclusions Anticoagulant therapy mainly with low molecular weight heparin appears to be associated with better prognosis in severe COVID‐19 patients meeting SIC criteria or with markedly elevated D‐dimer.
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                Author and article information

                Contributors
                alexandre.morrot@ioc.fiocruz.br
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                12 November 2020
                12 November 2020
                2020
                : 10
                : 19630
                Affiliations
                [1 ]GRID grid.8536.8, ISNI 0000 0001 2294 473X, Medical Biochemistry Institute, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil
                [2 ]GRID grid.8536.8, ISNI 0000 0001 2294 473X, Carlos Chagas Filho Biophysics Institute, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil
                [3 ]GRID grid.8536.8, ISNI 0000 0001 2294 473X, Tuberculosis Research Laboratory, Faculty of Medicine, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil
                [4 ]Molecular Biology Laboratory, Institute of Biomedical Research, Marcílio Dias Naval Hospital, Navy of Brazil, Rio de Janeiro, Brazil
                [5 ]Parasitic Diseases Division, Marcílio Dias Naval Hospital, Navy of Brazil, Rio de Janeiro, Brazil
                [6 ]GRID grid.8536.8, ISNI 0000 0001 2294 473X, Microbiology Institute, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil
                [7 ]GRID grid.412391.c, ISNI 0000 0001 1523 2582, Veterinary Institute, , Federal Rural University of Rio de Janeiro, ; Rio de Janeiro, Brazil
                [8 ]GRID grid.418068.3, ISNI 0000 0001 0723 0931, Immunoparasitology Laboratory, Oswaldo Cruz Foundation, , Oswaldo Cruz Institute/FIOCRUZ, ; Bld. Leônidas and Maria Deane/Room 406C, Av. Brazil 4365, Manguinhos, Rio de Janeiro, RJ Brazil
                [9 ]GRID grid.418068.3, ISNI 0000 0001 0723 0931, Laboratory on Thymus Research, Oswaldo Cruz Institute, , Oswaldo Cruz Foundation, ; Rio de Janeiro, Rio de Janeiro Brazil
                [10 ]GRID grid.418068.3, ISNI 0000 0001 0723 0931, National Institute of Science and Technology on Neuroimmunomodulation—INCT-NIM, Oswaldo Cruz Institute, , Oswaldo Cruz Foundation, ; Rio de Janeiro, Rio de Janeiro Brazil
                [11 ]GRID grid.418068.3, ISNI 0000 0001 0723 0931, Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, , Oswaldo Cruz Foundation, ; Rio de Janeiro, Rio de Janeiro Brazil
                Article
                76781
                10.1038/s41598-020-76781-0
                7665044
                33184506
                4e2c2b14-c15d-4a12-8d1d-3d05f2c51f0f
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 3 July 2020
                : 3 November 2020
                Categories
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                © The Author(s) 2020

                Uncategorized
                infection,sars-cov-2
                Uncategorized
                infection, sars-cov-2

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