Endothelial cell infection and endotheliitis in COVID-19
Authors: Zsuzsanna Varga, Andreas J Flammer, Peter Steiger, Martina Haberecker, Rea Andermatt, Annelies S Zinkernagel, Mandeep R Mehra, Reto A Schuepbach, Frank Ruschitzka, Holger Moch
Journal: The Lancet (2020)

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.1Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Summary Full Text Full Text PDF PubMed Scopus (18730) Google Scholar, 2Horton R Offline: COVID-19—bewilderment and candour.Lancet. 2020; 3951178Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar 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.3Ferrario CM Jessup J Chappell MC et al.Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.Circulation. 2005; 111: 2605-2610Crossref PubMed Scopus (1278) Google Scholar 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.4Monteil V KH Prado P Hagelkrüys A et al.Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell. 2020; (published online in press.)https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdfDate accessed: April 17, 2020Summary Full Text Full Text PDF PubMed Scopus (1597) Google Scholar 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. 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.3Ferrario CM Jessup J Chappell MC et al.Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.Circulation. 2005; 111: 2605-2610Crossref PubMed Scopus (1278) Google Scholar 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.5Flammer AJ Anderson T Celermajer DS et al.The assessment of endothelial function: from research into clinical practice.Circulation. 2012; 126: 753-767Crossref PubMed Scopus (910) Google Scholar 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.6Bonetti PO Lerman LO Lerman A Endothelial dysfunction - a marker of atherosclerotic risk.Arterioscl Throm Vas. 2003; 23: 168-175Crossref PubMed Scopus (1923) Google Scholar 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.7Anderson TJ Meredith IT Yeung AC Frei B Selwyn AP Ganz P The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.N Engl J Med. 1995; 332: 488-493Crossref PubMed Scopus (1111) Google Scholar, 8Taddei S Virdis A Ghiadoni L Mattei P Salvetti A Effects of angiotensin converting enzyme inhibition on endothelium-dependent vasodilatation in essential hypertensive patients.J Hypertens. 1998; 16: 447-456Crossref PubMed Scopus (105) Google Scholar, 9Flammer AJ Sudano I Hermann F et al.Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.Circulation. 2008; 117: 2262-2269Crossref PubMed Scopus (104) Google Scholar, 10Hurlimann D Forster A Noll G et al.Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.Circulation. 2002; 106: 2184-2187Crossref PubMed Scopus (550) Google Scholar, 11Feldmann M Maini RN Woody JN et al.Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed.Lancet. 2020; (published online April 9.)https://doi.org/10.1016/S0140-6736(20)30858-8Summary Full Text Full Text PDF PubMed Scopus (442) Google Scholar 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. ZV and AJF contributed equally as first authors, and RAS, FR, and HM contributed equally as last authors. AJF reports fees from Alnylam, Amgen, AstraZeneca, Fresenius, Imedos Systems, Novartis, Pfizer, Roche, Vifor, and Zoll, unrelated to this Correspondence. MRM reports consulting relationships with Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV, FineHeart, Leviticus, Baim Institute for Clinical Research, Riovant, and Triple Gene, unrelated to this Correspondence. FR has been paid for the time spent as a committee member for clinical trials, advisory boards, other forms of consulting and lectures or presentations. These payments were made directly to the University of Zurich and no personal payments were received in relation to these trials or other activities. All other authors declare no competing interests. Download .pdf (1.83 MB) Help with pdf files Supplementary appendix Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort studyThe 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. Full-Text PDF Electron microscopy of SARS-CoV-2: a challenging task – Authors' replyWe thank Cynthia Goldsmith and colleagues for their interest in our recent Correspondence.1 We described autopsy findings from patients who had died from COVID-19 and showed a systemic endotheliitis with evidence of loss of integrity of the endothelial monolayer.1 Full-Text PDF Electron microscopy of SARS-CoV-2: a challenging taskWe read with interest the Correspondence by Zsuzsanna Varga and colleagues1 on the possible infection of endothelial cells by SARS-CoV-2 using electron microscopic (EM) images as evidence. However, we believe the EM images in the Correspondence do not show coronavirus particles but instead show cross-sections of the rough endoplasmic reticulum (RER). These spherical structures are surrounded by dark dots, which might have been interpreted as spikes on coronavirus particles but are instead ribosomes. Full-Text PDF