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      Complement C3 inhibition in severe COVID-19 using compstatin AMY-101

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          Abstract

          Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 ( n = 16) or placebo ( n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101–treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug’s inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

          Abstract

          Abstract

          C3 inhibitor AMY-101 exerts broad effects on COVID-19 thromboinflammation and reveals noncanonical routes of C3 activation.

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          Most cited references53

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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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              Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

              There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19).
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                Author and article information

                Contributors
                Role: ConceptualizationRole: MethodologyRole: Project administrationRole: Writing - original draft
                Role: ConceptualizationRole: Data curationRole: Project administrationRole: ResourcesRole: ValidationRole: Visualization
                Role: ConceptualizationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: ValidationRole: Visualization
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Resources
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing - original draft
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Visualization
                Role: InvestigationRole: Resources
                Role: Investigation
                Role: InvestigationRole: ResourcesRole: Writing - review & editing
                Role: Investigation
                Role: InvestigationRole: Visualization
                Role: InvestigationRole: MethodologyRole: Resources
                Role: Formal analysisRole: InvestigationRole: Resources
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: MethodologyRole: Resources
                Role: Formal analysisRole: MethodologyRole: Validation
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation
                Role: ConceptualizationRole: MethodologyRole: Writing - review & editing
                Role: MethodologyRole: Writing - review & editing
                Role: Formal analysisRole: Validation
                Role: ConceptualizationRole: Methodology
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing - original draft
                Role: ConceptualizationRole: Funding acquisitionRole: Methodology
                Role: ConceptualizationRole: MethodologyRole: Project administration
                Role: ConceptualizationRole: SupervisionRole: Validation
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                August 2022
                17 August 2022
                : 8
                : 33
                : eabo2341
                Affiliations
                [ 1 ]First Department of Internal Medicine and Laboratory of Molecular Hematology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
                [ 2 ]First Department of Internal Medicine, AHEPA University Hospital, and Basic and Translational Research Unit, Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
                [ 3 ]National Center for Scientific Research “Demokritos”, Athens, Greece.
                [ 4 ]Department of Medicine and Research Laboratory of Internal Medicine, National and European Expertise Center of Greece in Autoimmune Liver Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece.
                [ 5 ]Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
                [ 6 ]R&D Department, Hycult Biotechnology, Uden, Netherlands.
                [ 7 ]Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden.
                [ 8 ]Department of Neurological Surgery, Columbia University, New York, NY, USA.
                [ 9 ]Department of Biology, University of Rome Tor Vergata, Rome, Italy.
                [ 10 ]Department of Medical Imaging, Hematology and Oncology, University of São Paulo, School of Medicine, Ribeirão Preto, Brazil.
                [ 11 ]Institute for Clinical and Experimental Trauma-Immunology, Ulm University Hospital, Ulm, Germany.
                [ 12 ]AORN Moscati Avellino, Italy and Federico II University of Naples, Naples, Italy.
                [ 13 ]Amyndas Pharmaceuticals, Glyfada, Greece.
                [ 14 ]Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
                Author notes
                [* ]Corresponding author. Email: lambris@ 123456pennmedicine.upenn.edu
                Author information
                https://orcid.org/0000-0003-0456-7015
                https://orcid.org/0000-0001-7985-3118
                https://orcid.org/0000-0002-6634-3271
                https://orcid.org/0000-0001-7391-6851
                https://orcid.org/0000-0002-1591-9760
                https://orcid.org/0000-0002-4962-790X
                https://orcid.org/0000-0002-0361-0846
                https://orcid.org/0000-0002-2505-7076
                https://orcid.org/0000-0002-3964-5944
                https://orcid.org/0000-0003-2652-4120
                https://orcid.org/0000-0002-7618-4243
                https://orcid.org/0000-0002-8614-6742
                https://orcid.org/0000-0002-3715-8640
                https://orcid.org/0000-0001-6207-496X
                https://orcid.org/0000-0003-3958-2266
                https://orcid.org/0000-0001-7075-8464
                https://orcid.org/0000-0002-6746-7372
                https://orcid.org/0000-0002-4188-9518
                https://orcid.org/0000-0002-7966-6029
                https://orcid.org/0000-0003-2359-6516
                https://orcid.org/0000-0002-9370-5776
                Article
                abo2341
                10.1126/sciadv.abo2341
                9385148
                35977025
                5a362f29-e451-42ee-b693-396cff89db09
                Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 21 January 2022
                : 01 July 2022
                Categories
                Research Article
                Biomedicine and Life Sciences
                SciAdv r-articles
                Coronavirus
                Custom metadata
                Kyle Solis

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