Microvascular dysfunction in COVID-19: the MYSTIC study

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Abstract

Rationale

Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19.

Objectives

To comprehensively characterize and quantify microvascular alterations in patients with COVID-19.

Methods

Hospitalized adult patients with moderate-to-severe or critical COVID-19 ( n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity ( V _RBC), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay.

Measurements and main results

COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4–6 µm), and also significant reductions of V _RBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality.

Conclusions

Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.

Electronic supplementary material

The online version of this article (10.1007/s10456-020-09753-7) contains supplementary material, which is available to authorized users.

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Most cited references 29

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

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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Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Zunyou Wu, Jennifer M. McGoogan (2020)

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Author and article information

Contributors

Alexandros Rovas: alexandros.rovas@ukmuenster.de

Irina Osiaevi: irina.osiaevi@ukmuenster.de

Konrad Buscher: konrad.buscher@ukmuenster.de

Jan Sackarnd: jan.sackarnd@ukmuenster.de

Phil-Robin Tepasse: phil-robin.tepasse@ukmuenster.de

Manfred Fobker: manfred.fobker@ukmuenster.de

Joachim Kühn: joachim.kuehn@ukmuenster.de

Stephan Braune: stephan.braune@sfh-muenster.de

Ulrich Göbel: ulrich.goebel@sfh-muenster.de

Gerold Thölking: gerold.thoelking@ukmuenster.de

Andreas Gröschel: a.groeschel@alexianer.de

Hermann Pavenstädt: hermann.pavenstaedt@ukmuenster.de

Hans Vink: h.vink@maastrichtuniversity.nl

Philipp Kümpers:

ORCID: http://orcid.org/0000-0001-9929-0703

philipp.kuempers@ukmuenster.de

Journal

Journal ID (nlm-ta): Angiogenesis

Journal ID (iso-abbrev): Angiogenesis

Title: Angiogenesis

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0969-6970

ISSN (Electronic): 1573-7209

Publication date (Electronic): 14 October 2020

Publication date PMC-release: 14 October 2020

Pages: 1-13

Affiliations

[1 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, , University Hospital Münster, ; Albert-Schweitzer- Campus 1, 48149 Münster, Germany

[2 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Cardiology and Angiology, , University Hospital Münster, ; Albert- Schweitzer-Campus 1, 48149 Münster, Germany

[3 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Medicine B for Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology, , University Hospital Münster, ; Albert-Schweitzer-Campus 1, 48149 Münster, Germany

[4 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Center for Laboratory Medicine, , University Hospital Münster, ; Albert-Schweitzer- Campus 1, 48149 Münster, Germany

[5 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Institute of Virology, , University Hospital Münster, ; Albert-Schweitzer-Campus 1, 48149 Münster, Germany

[6 ]GRID grid.416655.5, Departmenf of medical internal intensive care and emergency medicine, , St. Franziskus-Hospital GmbH, ; 48145 Münster, Germany

[7 ]GRID grid.416655.5, Department of Anaesthesiology and Critical Care, , St. Franziskus-Hospital GmbH, ; 48145 Münster, Germany

[8 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Internal Medicine and Nephrology, , University Hospital Münster Marienhospital Steinfurt, ; 48565 Steinfurt, Germany

[9 ]GRID grid.500057.7, ISNI 0000 0004 0559 8961, Department of Pulmonology, , Clemenshospital, ; Münster, Germany

[10 ]GRID grid.5012.6, ISNI 0000 0001 0481 6099, Department of Physiology, Cardiovascular Research Institute Maastricht, , Maastricht University, ; Maastricht, The Netherlands

Author information

Philipp Kümpers http://orcid.org/0000-0001-9929-0703

Article

Publisher ID: 9753

DOI: 10.1007/s10456-020-09753-7

PMC ID: 7556767

PubMed ID: 33058027

SO-VID: 6c1ec315-07e4-47bc-9630-725fb6838336

License:

Open AccessThis 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

Date received : 16 September 2020

Date accepted : 28 September 2020

Funding

Funded by: Innovative Medical Research of the University of Münster Medical School

Award ID: RO221907

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: KFO342

Funded by: Universitätsklinikum Münster (8918)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

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