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      Targeting potential drivers of COVID-19: Neutrophil extracellular traps

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          Abstract

          In this Perspective, autopsy results and literature are presented supporting the hypothesis that neutrophil extracellular traps (NETs) may contribute to organ damage and mortality in COVID-19. If correct, existing drugs that target NETs, although unspecific, may benefit COVID-19 patients.

          Abstract

          Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

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

          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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            Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

            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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              Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

              In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: Data curationRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Project administrationRole: Writing - review & editing
                Role: Project administrationRole: Resources
                Role: InvestigationRole: Project administrationRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Project administrationRole: Resources
                Role: ConceptualizationRole: InvestigationRole: Writing - original draftRole: Writing - review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: Project administrationRole: Resources
                Role: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: InvestigationRole: ResourcesRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                Rockefeller University Press
                0022-1007
                1540-9538
                01 June 2020
                16 April 2020
                16 April 2020
                : 217
                : 6
                : e20200652
                Affiliations
                [1 ]Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research & Departments of Molecular Medicine and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
                [2 ]Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
                [3 ]Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
                [4 ]Division of Thoracic and Upper GI Surgery, Department of Surgery, Montreal, Canada
                [5 ]Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, East Garden City, NY
                [6 ]Centre Hospitalier Universitaire de Nancy, Nancy, France
                [7 ]Goodman Cancer Research Centre, McGill University, Montreal, Canada
                [8 ]Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
                [9 ]Department of Medicine, University of California, San Francisco, San Francisco, CA
                [10 ]Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX
                [11 ]Department of Medicine, McGill University & The Research Institute of the McGill University Health Centre, Montreal, Canada
                [12 ]Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY
                [13 ]Department of Pediatrics, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT
                [14 ]Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Northwell Health, Manhasset, NY
                Author notes
                Correspondence to Mikala Egeblad: egeblad@ 123456cshl.edu

                Disclosures: M.R. Looney reported "other" from Neutrolis outside the submitted work. R.E. Schwartz is a Sponsored Advisory Board Member for Miromatrix Inc. J.D. Spicer reported personal fees from Bristol Myers Squibb, personal fees from Astra Zeneca, personal fees from Merck, personal fees from Trans-Hit Bio, and non-financial support from Astra Zeneca outside the submitted work. C.C. Yost reports a grant from PEEL Therapeutics, Inc. during the conduct of the study; in addition, C.C. Yost authors a US patent (patent no. 10,232,023 B2) held by the University of Utah for the use of NET-inhibitory peptides for "treatment of and prophylaxis against inflammatory disorders." PEEL Therapeutics, Inc. has exclusive licensing rights. M. Egeblad reported "other" from Santhera during the conduct of the study; and consulted for CytomX in 2019. No other disclosures were reported.

                Author information
                https://orcid.org/0000-0001-6807-8064
                https://orcid.org/0000-0002-8581-1093
                https://orcid.org/0000-0003-2101-8966
                https://orcid.org/0000-0003-0995-9771
                https://orcid.org/0000-0003-0241-9190
                https://orcid.org/0000-0001-7508-020X
                https://orcid.org/0000-0002-8773-575X
                https://orcid.org/0000-0001-7237-2696
                https://orcid.org/0000-0002-5417-5995
                https://orcid.org/0000-0003-2708-1309
                https://orcid.org/0000-0001-9800-3709
                https://orcid.org/0000-0002-3371-1445
                Article
                jem.20200652
                10.1084/jem.20200652
                7161085
                32302401
                4ba1694a-a299-4c89-b312-74b0bf86dd0e
                © 2020 Barnes et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 07 April 2020
                : 09 April 2020
                : 13 April 2020
                Page count
                Pages: 7
                Categories
                Perspective
                Infectious Disease and Host Defense

                Medicine
                Medicine

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