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      Vascular occlusion by neutrophil extracellular traps in COVID-19

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          Abstract

          Background

          Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood.

          Methods

          Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry.

          Patient findings

          Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage.

          Interpretation

          These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage.

          Funding

          Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung

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          Most cited references39

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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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            A Novel Coronavirus from Patients with Pneumonia in China, 2019

            Na Zhu, Dingyu Zhang, Wenling Wang … (2020)
            Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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              A pneumonia outbreak associated with a new coronavirus of probable bat origin

              Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)
              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.
              Article 0 comments Cited 10097 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Moritz Leppkes
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 31 July 2020
                Publication date Collection: August 2020
                Publication date (Electronic): 31 July 2020
                Volume: 58
                Electronic Location Identifier: 102925
                Affiliations
                [a ]Department of Internal Medicine 1, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
                [b ]Department of Internal Medicine 3, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
                [c ]Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
                [d ]Department of Internal Medicine 5, Hematology and Oncology, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
                [e ]Department of Nephropathology, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
                [f ]Institute of Pathology, University Medical Center Regensburg, Germany
                [g ]Institut of Pathology, Klinikum Bayreuth, Germany
                [h ]Department of Anaesthesiology, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
                [i ]Institute of Pathology, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
                [j ]Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
                Author notes
                [* ]Corresponding author at: Department of Internal Medicine 1, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. moritz.leppkes@ 123456uk-erlangen.de
                [1]

                ML and JK equally contributed

                Article
                Publisher ID: S2352-3964(20)30300-5 Publisher ID: 102925
                DOI: 10.1016/j.ebiom.2020.102925
                PMC ID: 7397705
                PubMed ID: 32745993
                SO-VID: 8f19b0bc-3a13-4fa4-b3a7-3150cfc28d89
                Copyright © © 2020 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 19 June 2020
                Date revision received : 7 July 2020
                Date accepted : 13 July 2020
                Categories
                Subject: Research paper

                Keywords: sars-cov-2,endothelialitis,immunothrombosis,aggregated neutrophil extracellular traps,coagulopathy
                Data availability:
                Keywords: sars-cov-2, endothelialitis, immunothrombosis, aggregated neutrophil extracellular traps, coagulopathy

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