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      Endotheliitis bei COVID-19 Translated title: Endotheliitis in COVID-19

      review-article
      Der Pathologe
      Springer Medizin
      COVID-19, SARS-CoV-2, Endotheliitis, Diffuser Organbefall, COVID-19, SARS-CoV-2, Endotheliitis, Diffuse organ affection

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          Abstract

          Bei COVID-19-Infektion liegt eine systemische virale Reaktion gefolgt von einer entzündlichen Krankheitsphase vor. Die erste Phase verläuft meist mild/asymptomatisch. Nur ein Teil der Patienten entwickelt die entzündliche Phase mit hoher Mortalität. Patienten mit vorbestehenden kardiovaskulären Erkrankungen und kardiovaskulären Risikofaktoren haben ein höheres Risiko, schwer an COVID-19 zu erkranken. COVID-19 betrifft nicht nur das Lungenparenchym durch die ACE2-Rezeptoren. COVID-19 betrifft nicht nur das Lungenparenchym durch die ACE2-Rezeptoren, sondern kann auch im Gesamtkörper eine generalisierte endotheliale Schädigung und Entzündung im Sinne einer sog. Endotheliitis zur Folge haben. Die Morphologie der Endotheliitis stellt eine Akkumulation von Lymphozyten, Plasmazellen und Makrophagen im und unterhalb der endothelialen Zellen dar. Eine Endotheliitis kann eine Vasokonstriktion mit konsekutiver Organischämie, Entzündung und Gewebeödem sowie thrombotische Mikrozirkulationsstörung zur Folge haben. Patienten mit vorbestehender kardiovaskulärer Dysfunktion (Hypertonus, Diabetes mellitus, Übergewicht und weitere kardiovaskuläre Erkrankungen, männliches Geschlecht) haben ein erhöhtes Risiko für schwere Verläufe einer COVID-19-Infektion. Insbesondere endothelstabilisierende Ansätze kommen aus diesen Gründen zum Einsatz. Die Erkenntnisse wurden seit dem Pandemieausbruch mehrheitlich von Autopsien gewonnen.

          Translated abstract

          COVID-19 disease is a systemic inflammatory viral reaction starting with the viral phase followed by the inflammatory phase. The first phase is rather mild and asymptomatic with only a small subset of infected patients turning into the inflammatory phase with high mortality. Patients with pre-existing cardiovascular diseases and cardiovascular risk factors pose a considerably higher risk to develop severe or lethal COVID-19 disease course. COVID-19 affects not only the epithelial cells of the lung parenchyma via ACE2, but also endothelial cells across the whole body thus leading to generalized endothelial damage and inflammation, so-called endotheliitis. The histological morphology of endotheliitis comprises the accumulation of lymphocytes, plasma cells and macrophages beneath the endothelial cells and within the perivascular spaces. Endothelial cells play an important role in the regulation of vascular tone and the maintenance of vascular homeostasis. Endotheliitis thus can shift the vascular equilibrium towards more pronounced vasoconstriction with subsequent organ ischemia, inflammation with associated tissue edema and a procoagulant state. Patients with pre-existing endothelial dysfunction (male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease) are particularly vulnerable and have adverse outcomes in COVID-19. This is a rationale for approaches to stabilize the endothelium. Most of these findings have been established from autopsies since the outbreak of the pandemic.

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

            There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19).
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              Endothelial cell infection and endotheliitis in COVID-19

              Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.1, 2 SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells. 3 Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro. 4 Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix). Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient's condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8. Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B ). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested. Figure Pathology of endothelial cell dysfunction in COVID-19 (A, B) Electron microscopy of kidney tissue shows viral inclusion bodies in a peritubular space and viral particles in endothelial cells of the glomerular capillary loops. Aggregates of viral particles (arrow) appear with dense circular surface and lucid centre. The asterisk in panel B marks peritubular space consistent with capillary containing viral particles. The inset in panel B shows the glomerular basement membrane with endothelial cell and a viral particle (arrow; about 150 nm in diameter). (C) Small bowel resection specimen of patient 3, stained with haematoxylin and eosin. Arrows point to dominant mononuclear cell infiltrates within the intima along the lumen of many vessels. The inset of panel C shows an immunohistochemical staining of caspase 3 in small bowel specimens from serial section of tissue described in panel D. Staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections, indicating that apoptosis is induced in a substantial proportion of these cells. (D) Post-mortem lung specimen stained with haematoxylin and eosin showed thickened lung septa, including a large arterial vessel with mononuclear and neutrophilic infiltration (arrow in upper inset). The lower inset shows an immunohistochemical staining of caspase 3 on the same lung specimen; these staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections. COVID-19=coronavirus disease 2019. Patient 2 was a woman, aged 58 years, with diabetes, arterial hypertension, and obesity. She developed progressive respiratory failure due to COVID-19 and subsequently developed multi-organ failure and needed renal replacement therapy. On day 16, mesenteric ischaemia prompted removal of necrotic small intestine. Circulatory failure occurred in the setting of right heart failure consequent to an ST-segment elevation myocardial infarction, and cardiac arrest resulted in death. Post-mortem histology revealed lymphocytic endotheliitis in lung, heart, kidney, and liver as well as liver cell necrosis. We found histological evidence of myocardial infarction but no sign of lymphocytic myocarditis. Histology of the small intestine showed endotheliitis (endothelialitis) of the submucosal vessels. Patient 3 was a man, aged 69 years, with hypertension who developed respiratory failure as a result of COVID-19 and required mechanical ventilation. Echocardiography showed reduced left ventricular ejection fraction. Circulatory collapse ensued with mesenteric ischaemia, and small intestine resection was performed, but the patient survived. Histology of the small intestine resection revealed prominent endotheliitis of the submucosal vessels and apoptotic bodies (figure C). We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs. 3 Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D). The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis. 5 Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state. 6 Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.
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                Author and article information

                Contributors
                zsuzsanna.varga@usz.ch
                Journal
                Pathologe
                Pathologe
                Der Pathologe
                Springer Medizin (Heidelberg )
                0172-8113
                1432-1963
                11 December 2020
                11 December 2020
                : 1-4
                Affiliations
                GRID grid.412004.3, ISNI 0000 0004 0478 9977, Institut für Pathologie und Molekularpathologie, , Universitätsspital Zürich, ; Schmelzbergstraße 12, CH-8091 Zürich, Schweiz
                Article
                875
                10.1007/s00292-020-00875-9
                7731145
                33306138
                86345d43-d7a7-42d6-a948-2caf1025f6ce
                © The Author(s) 2020

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                Funding
                Funded by: University of Zurich
                Categories
                Hauptreferate: Hauptprogramm der DGP

                covid-19,sars-cov-2,endotheliitis,diffuser organbefall,diffuse organ affection

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