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      Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

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          Abstract

          Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

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          Most cited references 120

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

              Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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                Author and article information

                Contributors
                mdiaz@clinic.cat
                Journal
                Cardiovasc Drugs Ther
                Cardiovasc Drugs Ther
                Cardiovascular Drugs and Therapy
                Springer US (New York )
                0920-3206
                1573-7241
                7 June 2021
                : 1-14
                Affiliations
                [1 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Medical Intensive Care Unit, , Hospital Clinic, ; Barcelona, Spain
                [2 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, School of Medicine, , University of Barcelona, ; Barcelona, Spain
                [3 ]GRID grid.10403.36, IDIBAPS, ; Barcelona, Spain
                [4 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona, ; Barcelona, Spain
                [5 ]Barcelona Endothelium Team, Barcelona, Spain
                [6 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Hematopathology, Pathology Department, , CDB, Hospital Clinic, ; Villarroel 170, 08036 Barcelona, Spain
                [7 ]Arrels Centre Dental, Badalona, Spain
                [8 ]GRID grid.262285.9, ISNI 0000 0000 8800 2297, Frank H. Netter M.D. School of Medicine At, Quinnipiac University, ; North Haven, CT USA
                [9 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Surgery, , Yale University School of Medicine, ; New Haven, CT USA
                [10 ]GRID grid.65499.37, ISNI 0000 0001 2106 9910, Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, , Dana-Farber Cancer Institute, Harvard Medical School, ; Boston, MA USA
                [11 ]GRID grid.416167.3, Cardiology Department, , Cardiovascular Institute, Mount Sinai Hospital, ; New York, NY USA
                [12 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, AtheroThrombosis Research Unit, , Cardiovascular Institute, Icahn School of Medicine At Mount Sinai, ; New York, NY USA
                Article
                7207
                10.1007/s10557-021-07207-w
                8181544
                34097193
                © Springer Science+Business Media, LLC, part of Springer Nature 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                Funding
                Funded by: Fundació Clínic
                Award ID: HCB/2020/0401
                Funded by: FundRef http://dx.doi.org/10.13039/100011096, Jazz Pharmaceuticals;
                Award ID: IST-16-10355
                Funded by: FundRef http://dx.doi.org/10.13039/501100005677, José Carreras Leukämie-Stiftung;
                Award ID: 03R/2019
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: PI19/00888
                Funded by: FundRef http://dx.doi.org/10.13039/100008666, Fundació la Marató de TV3;
                Award ID: 202026-10
                Funded by: FundRef http://dx.doi.org/10.13039/100002491, Bristol-Myers Squibb;
                Award ID: ERISTA15
                Funded by: FundRef http://dx.doi.org/10.13039/501100002809, Generalitat de Catalunya;
                Award ID: 2017-SGR671
                Funded by: CERCA Program
                Categories
                Review Article

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