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      Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy

      research-article
      Author(s): , MD 1 , 5 , * , , , BA 1 , 5 , * , , cand med 1 , , MD 1 , 5 , , MD 1 , 5 , , MD 2 , , MD 6 , 8 , , MD 3 , 9 , , MD 7 , , MD 7 , , MD 1 , 5 , , MD 7 , , MD 4 , , MD, , MD 6 , 8 , , MD 2 , , MD 4 , , MD 3 , 9 , , MD 1 , 5 , , MD 1 , 5 , , MD 1 , 5 , † , , , MD 1 , 5 , †
      Publication date (Electronic):
      Journal: Circulation
      Publisher: Lippincott Williams & Wilkins
      Keywords: blood platelets, COVID-19, disseminated intravascular coagulation, neutrophils, respiratory insufficiency, severe acute respiratory syndrome coronavirus 2, thrombosis

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          Background:

          Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19.

          Methods:

          A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction–confirmed COVID-19 and n=24 non–COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker–based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well.

          Results:

          We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non–COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability.

          Conclusions:

          Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.

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          Most cited references38

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)
          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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            Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

            Fei Zhou, Ting Yu, Ronghui Du … (2020)
            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 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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                Author and article information

                Journal
                Journal ID (nlm-ta): Circulation
                Journal ID (iso-abbrev): Circulation
                Journal ID (publisher-id): CIR
                Title: Circulation
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0009-7322
                ISSN (Electronic): 1524-4539
                Publication date (Electronic): 28 July 2020
                Publication date (Print): 22 September 2020
                Publication date PMC-release: 28 July 2020
                Volume: 142
                Issue: 12
                Pages: 1176-1189
                Affiliations
                [1 ]Medizinische Klinik und Poliklinik I (L.N., A.L., S.B., R.K., T.W., C.S., S.K., S.M., K.P., K.S.), University Hospital Ludwig-Maximilian University Munich, Germany.
                [2 ]Institute of Laboratory Medicine (M.W., D.T.), University Hospital Ludwig-Maximilian University Munich, Germany.
                [3 ]Medizinische Klinik und Poliklinik III (J.C.H., M.v.B.-B.), University Hospital Ludwig-Maximilian University Munich, Germany.
                [4 ]Department of Anesthesiology (M.Z., B.Z.), University Hospital Ludwig-Maximilian University Munich, Germany.
                [5 ]DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (L.N., A.L., R.K., T.W., C.S., S.K., S.M., K.P., K.S.).
                [6 ]Virology, Max von Pettenkofer Institute (M.M., O.K.), Ludwig-Maximilian University Munich, Germany.
                [7 ]Institute of Pathology (S.L., H.S., M.R.), Ludwig-Maximilian University Munich, Germany.
                [8 ]German Center for Infection Research (DZIF), Partner Site Munich (M.M., O.K.).
                [9 ]German Cancer Consortium (DKTK), Munich (J.C.H., M.v.B.-B.).
                Author notes
                Leo Nicolai, MD, Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian-University Munich, Marchioninistr. 15 81377, Munich, Germany. Email leo.nicolai@ 123456med.uni-muenchen.de
                Kami Pekayvaz, MD, Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian-University Munich, Marchioninistr. 15 81377, Munich, Germany. Email kami.pekayvaz@ 123456med.uni-muenchen.de
                Article
                Accession ID: 00007
                DOI: 10.1161/CIRCULATIONAHA.120.048488
                PMC ID: 7497892
                PubMed ID: 32755393
                SO-VID: 366b7a2e-1f70-408d-8853-0c4b1ba1c913
                Copyright © © 2020 The Authors.
                License:

                Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                Date received : 6 May 2020
                Date accepted : 17 July 2020
                Categories
                Subject: 10030
                Subject: 10041
                Subject: 10042
                Subject: 10053
                Subject: 10054
                Subject: Original Research Articles
                Custom metadata
                SDC T
                OPEN-ACCESS TRUE

                Keywords: blood platelets,covid-19,disseminated intravascular coagulation,neutrophils,respiratory insufficiency,severe acute respiratory syndrome coronavirus 2,thrombosis
                Data availability:
                Keywords: blood platelets, covid-19, disseminated intravascular coagulation, neutrophils, respiratory insufficiency, severe acute respiratory syndrome coronavirus 2, thrombosis

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