For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
9
views
41
references
 Top references
cited by
138
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
2 collections
    0
    shares
      102
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.

          Highlights

          • •

            Deregulated complement activation underpins the pathophysiology of severe COVID-19

          • •

            Complement inhibition abrogates COVID-19 hyper-inflammation leading to resolution of SARS-CoV-2-associated ARDS

          • •

            Divergent profiles of C3 vs C5 inhibition point to a broader impact of C3 inhibition on NET-driven thromboinflammation

          Related collections

          Most cited references41

          • Record: found
          • Abstract: found
          • Article: not found

          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.
          Article 0 comments Cited 21792 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found

            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)
            Article 0 comments Cited 8349 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

              Mark Peters (2020)
              Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)
              Article 0 comments Cited 4832 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): Clin Immunol
                Journal ID (iso-abbrev): Clin. Immunol
                Title: Clinical Immunology (Orlando, Fla.)
                Publisher: Elsevier Inc.
                ISSN (Print): 1521-6616
                ISSN (Electronic): 1521-7035
                Publication date PMC-release: 19 September 2020
                Publication date (Print): November 2020
                Publication date (Electronic): 19 September 2020
                Volume: 220
                Page: 108598
                Affiliations
                [a ]National Center for Scientific Research ‘Demokritos’, Aghia Paraskevi, Athens, Greece
                [b ]Department of Medical Imaging, Hematology and Clinical Oncology, University of São Paulo, Ribeirão Preto, School of Medicine, Brazil
                [c ]Department of Internal Medicine, University of São Paulo, Ribeirão Preto School of Medicine, Brazil
                [d ]Intensive Care Unit, University Hospital, University of São Paulo, Ribeirão Preto School of Medicine, Brazil
                [e ]Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
                [f ]Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
                [g ]Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, University Hospital of Ulm, Ulm, Germany
                [h ]First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
                [i ]AORN San Giuseppe Moscati, Hematology and Hematopoietic Stem Cell Transplantation Unit, Avellino, Italy
                [j ]Department of Biology, University of Rome Tor Vergata, Rome, Italy
                [k ]Institute for Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
                [l ]Division of Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden
                [m ]Amyndas Pharmaceuticals, Glyfada, Greece
                [n ]Department of Neurological Surgery, Columbia University, New York, NY, USA
                [o ]Humanitas University, Pieve Emanuele, Milan, Italy
                [p ]University Vita Salute San Raffaele, Milan, Italy
                [q ]Federico II University of Naples, Naples, Italy
                [r ]Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
                Author notes
                [* ]Corresponding author at: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
                [1]

                these authors contributed equally

                [2]

                shared supervision of the study

                Article
                Publisher ID: S1521-6616(20)30758-0 Publisher ID: 108598
                DOI: 10.1016/j.clim.2020.108598
                PMC ID: 7501834
                PubMed ID: 32961333
                SO-VID: 42d6488f-e7f9-4770-87e1-cdfb166e169d
                Copyright © © 2020 Elsevier Inc. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 5 September 2020
                Date revision received : 16 September 2020
                Date accepted : 16 September 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Keywords: covid-19,thromboinflammation,c3 inhibition,c5 blockade,amy-101,eculizumab,drug efficacy,biomarkers
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: covid-19, thromboinflammation, c3 inhibition, c5 blockade, amy-101, eculizumab, drug efficacy, biomarkers

                Comments

                Comment on this article

                scite_

                Similar content102

                See all similar

                Cited by132

                See all cited by

                Most referenced authors5,677

                See all reference authors