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EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335386


Background: Kidney failure is the second most frequent condition after acute respiratory distress syndrome (ARDS) in critically ill patients with severe COVID-19 and is strongly associated with mortality. The aim of this multicentric study was to assess the impact of the specific treatments of COVID-19 and ARDS on the risk of severe acute kidney injury (AKI) in critically ill COVID-19 patients.MethodsIn this cohort study, data from consecutive patients hospitalized in 6 ICUs for COVID-19 were retrospectively collected. The incidence and severity of AKI were monitored during the entire ICU stay. Patients older than 18 years admitted to the ICU for COVID-19-related ARDS requiring invasive mechanical ventilation were included.Results164 patients were included in the final analysis, 97 (59.1%) displayed AKI, of which 39 (23.8%) severe stage 3 AKI and 21 (12.8%) requiring renal replacement therapy (RRT). In univariate analysis, severe AKI was associated with Angiotensin Converting Enzyme inhibitors (ACEI) exposure (p=0.016), arterial hypertension (p=0.029), APACHE-II score (p=0.004) and mortality at D28 (p=0.008), D60 (p<0.001) and D90 (p<0.001). In multivariate analysis, the factors associated with the onset of stage 3 AKI were: exposure to ACEI (OR: 4.238 (1.307-13.736), p=0.016), APACHE II score (without age) (OR: 1.138 (1.044-1.241), p=0.003) and iNO (OR: 5.694 (1.953-16.606), p=0.001). Protective factors were prone positioning (OR: 0.234 (0.057-0.967), p=0.045) and dexamethasone (OR: 0.194 (0.053-0.713), p=0.014).ConclusionsDexamethasone was associated with a prevention of the risk of severe AKI and RRT, and iNO was associated with severe AKI and RRT in critically ill patients with COVID-19. iNO should be used with caution in COVID-19 related ARDS.

Preprint in English | SSRN | ID: ppcovidwho-325830


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.

J Clin Med ; 10(23)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1542625


OBJECTIVES: To describe clinical characteristics and management of intensive care units (ICU) patients with laboratory-confirmed COVID-19 and to determine 90-day mortality after ICU admission and associated risk factors. METHODS: This observational retrospective study was conducted in six intensive care units (ICUs) in three university hospitals in Marseille, France. Between 10 March and 10 May 2020, all adult patients admitted in ICU with laboratory-confirmed SARS-CoV-2 and respiratory failure were eligible for inclusion. The statistical analysis was focused on the mechanically ventilated patients. The primary outcome was the 90-day mortality after ICU admission. RESULTS: Included in the study were 172 patients with COVID-19 related respiratory failure, 117 of whom (67%) received invasive mechanical ventilation. 90-day mortality of the invasively ventilated patients was 27.4%. Median duration of ventilation and median length of stay in ICU for these patients were 20 (9-33) days and 29 (17-46) days. Mortality increased with the severity of ARDS at ICU admission. After multivariable analysis was carried out, risk factors associated with 90-day mortality were age, elevated Charlson comorbidity index, chronic statins intake and occurrence of an arterial thrombosis. CONCLUSION: In this cohort, age and number of comorbidities were the main predictors of mortality in invasively ventilated patients. The only modifiable factor associated with mortality in multivariate analysis was arterial thrombosis.

Med Sci (Paris) ; 37(4): 333-341, 2021 Apr.
Article in French | MEDLINE | ID: covidwho-1174712


The complement system is an essential component of the innate immune system. Its excessive activation during COVID-19 contributes to cytokine storm, disease-specific endothelial inflammation (endotheliitis) and thrombosis that comes with the disease. Targeted therapies of complement inhibition in COVID-19, in particular blocking the C5a-C5aR1 axis have to be taken into account in the establishment of potential biomarkers and development of therapeutic strategies in the most severe forms of the disease.

TITLE: Implication de la cascade du complément dans les formes sévères de COVID-19. ABSTRACT: Le système du complément est un composant essentiel du système immunitaire inné. Son activation excessive au cours de la COVID-19 participe à l'orage cytokinique, à l'inflammation endothéliale (endothélite) et aux thromboses qui accompagnent la maladie. Bloquer le complément, notamment l'axe C5a-C5aR1, par des thérapies spécifiques représente un espoir thérapeutique dans les formes les plus sévères de la maladie.

COVID-19/immunology , COVID-19/pathology , Complement Activation/physiology , Complement System Proteins/physiology , Animals , COVID-19/metabolism , Complement C5a/immunology , Complement C5a/metabolism , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Inflammation/complications , Inflammation/immunology , Inflammation/pathology , SARS-CoV-2/immunology , Severity of Illness Index , Signal Transduction/immunology
Eur J Immunol ; 51(7): 1652-1659, 2021 07.
Article in English | MEDLINE | ID: covidwho-1141308


The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.

COVID-19/pathology , Complement C5a/antagonists & inhibitors , Cytokine Release Syndrome/pathology , Cytokines/immunology , Immunotherapy/methods , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , COVID-19/drug therapy , COVID-19/immunology , Complement Activation/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/immunology , Signal Transduction/immunology , Thrombosis/immunology , Thrombosis/pathology
Nature ; 588(7836): 146-150, 2020 12.
Article in English | MEDLINE | ID: covidwho-690324


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.

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
Proc Natl Acad Sci U S A ; 117(32): 18951-18953, 2020 08 11.
Article in English | MEDLINE | ID: covidwho-662427


Around the tenth day after diagnosis, ∼20% of patients with coronavirus disease 2019 (COVID-19)-associated pneumonia evolve toward severe oxygen dependence (stage 2b) and acute respiratory distress syndrome (stage 3) associated with systemic inflammation often termed a "cytokine storm." Because interleukin-1 (IL-1) blocks the production of IL-6 and other proinflammatory cytokines, we treated COVID-19 patients early in the disease with the IL-1 receptor antagonist, anakinra. We retrospectively compared 22 patients from three different centers in France with stages 2b and 3 COVID-19-associated pneumonia presenting with acute severe respiratory failure and systemic inflammation who received either standard-of-care treatment alone (10 patients) or combined with intravenous anakinra (12 patients). Treatment started at 300 mg⋅d-1 for 5 d, then tapered with lower dosing over 3 d. Both populations were comparable for age, comorbidities, clinical stage, and elevated biomarkers of systemic inflammation. All of the patients treated with anakinra improved clinically (P < 0.01), with no deaths, significant decreases in oxygen requirements (P < 0.05), and more days without invasive mechanical ventilation (P < 0.06), compared with the control group. The effect of anakinra was rapid, as judged by significant decrease of fever and C-reactive protein at day 3. A mean total dose of 1,950 mg was infused with no adverse side effects or bacterial infection. We conclude that early blockade of the IL-1 receptor is therapeutic in acute hyperinflammatory respiratory failure in COVID-19 patients.

Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory Insufficiency/drug therapy , Aged , Anti-Inflammatory Agents/administration & dosage , COVID-19 , Case-Control Studies , Coronavirus Infections/complications , Female , Humans , Immunologic Factors/administration & dosage , Injections, Intravenous , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/etiology , Respiratory Insufficiency/etiology
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Article in English | MEDLINE | ID: covidwho-625131

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