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1.
SSRN;
Preprint in English | SSRN | ID: ppcovidwho-325830

ABSTRACT

Background: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. Methods: FORCE was a double-blind, placebo-controlled study. Patients receiving oxygen support ≥5 L/min to maintain SpO2 > 93% (WHO scale ≥ 5) were randomly assigned, in a 1:1 ratio to the avdoralimab and placebo arms. Avdoralimab (500 mg loading dose followed by a 200 mg maintenance dose) or placebo (normal saline) was administered intravenously every 48 h until oxygen therapy was no longer needed, and for a maximum of 14 days. Patients received conventional oxygen therapy or high-flow oxygen (HFO)/non-invasive ventilation (NIV) in cohort 1;HFO, NIV or invasive mechanical ventilation (IMV) in cohort 2 and IMV in cohort 3. The primary outcome was clinical status on the WHO ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. Findings: Between May 2020 and January 2021, we randomized 207 patients: 99 in cohort 1, 49 in cohort 2 and 59 in cohort 3. Glucocorticoids were administered to 95% of patients during hospitalization. Avdoralimab did not improve WHO clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7, p =0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2, p =0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7, p =0.96), or secondary outcomes in any cohort. No subgroup of interest was identified. Interpretation: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 or 28.

2.
Nature ; 588(7836): 146-150, 2020 12.
Article in English | MEDLINE | ID: covidwho-690324

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic1. The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes1. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.


Subject(s)
COVID-19/complications , COVID-19/immunology , Complement C5a/immunology , Inflammation/complications , Inflammation/immunology , Receptor, Anaphylatoxin C5a/immunology , Acute Lung Injury/drug therapy , Acute Lung Injury/immunology , Acute Lung Injury/prevention & control , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , CD11b Antigen/immunology , CD11b Antigen/metabolism , COVID-19/blood , COVID-19/pathology , Complement C5a/antagonists & inhibitors , Complement C5a/biosynthesis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Disease Models, Animal , Female , Humans , Inflammation/drug therapy , Inflammation/pathology , Lung/drug effects , Lung/immunology , Lung/pathology , Mice , Mice, Inbred C57BL , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/pathology , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Receptor, Anaphylatoxin C5a/blood , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
4.
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Article in English | MEDLINE | ID: covidwho-625131

Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Molecular Targeted Therapy/methods , Pneumonia, Viral/immunology , Pneumonia/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Apyrase/antagonists & inhibitors , Apyrase/genetics , Apyrase/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Betacoronavirus/immunology , COVID-19 , Case-Control Studies , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Coronavirus Infections/virology , Gene Expression/drug effects , Humans , Immunologic Factors/therapeutic use , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , NK Cell Lectin-Like Receptor Subfamily C/antagonists & inhibitors , NK Cell Lectin-Like Receptor Subfamily C/genetics , NK Cell Lectin-Like Receptor Subfamily C/immunology , Pandemics , Pneumonia/drug therapy , Pneumonia/genetics , Pneumonia/virology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology
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