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1.
Front Immunol ; 13: 851497, 2022.
Article in English | MEDLINE | ID: covidwho-1775682

ABSTRACT

Introduction: Coronavirus disease 2019 (COVID-19) can cause life-threatening acute respiratory distress syndrome (ARDS). Recent data suggest a role for neutrophil extracellular traps (NETs) in COVID-19-related lung damage partly due to microthrombus formation. Besides, pulmonary embolism (PE) is frequent in severe COVID-19 patients, suggesting that immunothrombosis could also be responsible for increased PE occurrence in these patients. Here, we evaluate whether plasma levels of NET markers measured shorty after admission of hospitalized COVID-19 patients are associated with clinical outcomes in terms of clinical worsening, survival, and PE occurrence. Patients and Methods: Ninety-six hospitalized COVID-19 patients were included, 50 with ARDS (severe disease) and 46 with moderate disease. We collected plasma early after admission and measured 3 NET markers: total DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. Comparisons between survivors and non-survivors and patients developing PE and those not developing PE were assessed by Mann-Whitney test. Results: Analysis in the whole population of hospitalized COVID-19 patients revealed increased circulating biomarkers of NETs in patients who will die from COVID-19 and in patients who will subsequently develop PE. Restriction of our analysis in the most severe patients, i.e., the ones who enter the hospital for COVID-19-related ARDS, confirmed the link between NET biomarker levels and survival but not PE occurrence. Conclusion: Our results strongly reinforce the hypothesis that NETosis is an attractive therapeutic target to prevent COVID-19 progression but that it does not seem to be linked to PE occurrence in patients hospitalized with COVID-19.


Subject(s)
COVID-19 , Extracellular Traps , Pulmonary Embolism , Respiratory Distress Syndrome , Biomarkers , COVID-19/complications , Humans , Pulmonary Embolism/etiology , Respiratory Distress Syndrome/etiology
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330837

ABSTRACT

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is ongoing. The pathophysiology of SARS-CoV-2 infection is beginning to be elucidated but the role of microRNAs (miRNAs), small non-coding RNAs that regulate gene expression, remains incompletely understood. They play a role in the pathophysiology of viral infections with potential use as biomarkers. The objective of this study was to identify miRNAs as biomarkers of severe COVID-19 and to analyze their role in the pathophysiology of SARS-CoV-2 infection. Methods miRNA expression was measured in nasopharyngeal swabs from 20 patients with severe COVID-19, 21 patients with non-severe COVID-19 and 20 controls. Promising miRNAs to differentiate non-severe from severe COVID-19 patients were identified by differential expression analysis and sparse Partial Least Squares-Discriminant Analysis (sPLS-DA). ROC analysis, target prediction, GO enrichment and pathway analysis were used to analyze the role and the pertinence of these miRNAs in severe COVID-19. Results The number of expressed miRNAs was lower in severe COVID-19 patients compared to non-severe COVID-19 patients and controls. Among the differentially expressed miRNAs between severe COVID-19 and controls, 5 miRNAs were also differentially expressed between severe and non-severe COVID-19. sPLS-DA analysis highlighted 8 miRNAs, that allowed to discriminate the severe and non-severe COVID-19 cases. Target and functional analysis revealed enrichment for genes involved in viral infections and the cellular response to infection as well as one miRNA, hsa-miR-15b-5p, that targeted the SARS-CoV-2 RNA. The comparison of results of differential expression analysis and discriminant analysis revealed three miRNAs, namely hsa-miR-125a-5p, hsa-miR-491-5p and hsa-miR-200b-3p. These discriminated severe from non-severe cases with areas under the curve ranging from 0.76 to 0.80. Conclusions Our analysis of miRNA expression in nasopharyngeal swabs revealed several miRNAs of interest to discriminate severe and non-severe COVID-19. These miRNAs represent promising biomarkers and possibly targets for antiviral or anti-inflammatory treatment strategies.

4.
Thromb Res ; 205: 120-127, 2021 09.
Article in English | MEDLINE | ID: covidwho-1324320

ABSTRACT

BACKGROUND: In intensive-care unit (ICU) patients, pathophysiological changes may affect the pharmacokinetics of enoxaparin and result in underdosing. OBJECTIVES: To develop a pharmacokinetic model of enoxaparin to predict the time-exposure profiles of various thromboprophylactic regimens in COVID-19 ICU-patients. METHODS: This was a retrospective study in ICUs of two French hospitals. Anti-Xa activities from consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated with enoxaparin for the prevention or the treatment of venous thrombosis were used to develop a population pharmacokinetic model using non-linear mixed effects techniques. Monte Carlo simulations were then performed to predict enoxaparin exposure at steady-state after three days of administration. RESULTS: A total of 391 anti-Xa samples were measured in 95 patients. A one-compartment model with first-order kinetics best fitted the data. The covariate analysis showed that enoxaparin clearance (typical value 1.1 L.h-1) was related to renal function estimated by the CKD-EPI formula and volume of distribution (typical value 17.9 L) to actual body weight. Simulation of anti-Xa activities with enoxaparin 40 mg qd indicated that 64% of the patients had peak levels within the range 0.2 to 0.5 IU.mL-1 and 75% had 12-hour levels above 0.1 IU.mL-1. Administration of a total daily dose of at least 60 mg per day improved the probability of target attainment. CONCLUSION: In ICU COVID-19 patients, exposure to enoxaparin is reduced due to an increase in the volume of distribution and clearance. Consequently, enoxaparin 40 mg qd is suboptimal to attain thromboprophylactic anti-Xa levels.


Subject(s)
COVID-19 , Enoxaparin , Anticoagulants , Critical Illness , Enoxaparin/therapeutic use , Humans , Retrospective Studies , SARS-CoV-2
5.
Diagnostics (Basel) ; 11(3)2021 03 03.
Article in English | MEDLINE | ID: covidwho-1125803

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an ongoing pandemic. Reverse transcription polymerase chain reaction (RT-PCR) is the gold standard for the detection of SARS-CoV-2 and has been applied to different specimen types. Understanding the virus load and virus detection frequency in different specimen types is important to improve diagnosis and estimate the duration of potential infectivity. We conducted a retrospective single-center cohort study on hospitalized and outpatients with SARS-CoV-2 infection. We analyzed the frequency of virus detection, virus load, and duration of the virus excretion in upper and lower respiratory specimens as well as stool and plasma. We found that the frequency of SARS-CoV-2 detection, the virus load, and duration of virus excretion was higher in lower respiratory tract (LRT) than in upper respiratory tract (URT) specimens. The duration of virus excretion was longer in patients requiring intensive care unit (ICU) admission. In conclusion, LRT specimens are the most appropriate specimen type for the detection and follow-up of SARS-CoV-2 infection. Duration of virus excretion is longer in severe cases of SARS-CoV-2 infection.

8.
ASAIO J ; 67(2): 125-131, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1054373

ABSTRACT

No study has compared patients with COVID-19-related refractory ARDS requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO) to a relevant and homogenous control population. We aimed to compare the outcomes, the clinical characteristics, and the adverse effects of COVID-19 patients to a retrospective cohort of influenza patients. This retrospective case-control study was conducted in the ICUs of Lille and Rouen University Hospitals between January 2014 and May 2020. Two independent cohorts of patients with ARDS requiring V-V ECMO infected with either COVID-19 (n = 30) or influenza (n = 22) were compared. A 3-month follow-up was completed for all patients. Median age of COVID-19 and influenza patients was similar (57 vs. 55 years; p = 0.62). The 28-day mortality rate did not significantly differ between COVID-19 (43.3%) and influenza patients (50%, p = 0.63). There was no significant difference considering the cumulative incidence of ECMO weaning, hospital discharge, and 3-month survival. COVID-19 patients had a lower SAPS II score (58 [37-64] vs. 68 [52-83]; p = 0.039), a higher body mass index (33 [29-38] vs. 30 [26-34] kg/m2; p = 0.05), and were cannulated later (median delay between mechanical support and V-V ECMO 6 vs. 3 days, p = 0.004) compared with influenza patients. No difference in overall adverse events was observed between COVID-19 and influenza patients (70% vs. 95.5% respectively; p = 0.23). Despite differences in clinical presentation before V-V ECMO implantation, 28-day and 3-month mortality rate did not differ between COVID-19 and influenza patients. Considering the lack of specific treatment for COVID-19, V-V ECMO should be considered as a relevant rescue organ support.


Subject(s)
COVID-19/complications , Extracorporeal Membrane Oxygenation , Influenza, Human/complications , Respiratory Distress Syndrome/therapy , Extracorporeal Membrane Oxygenation/adverse effects , Female , Humans , Intensive Care Units , Male , Middle Aged , Respiratory Distress Syndrome/etiology , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
9.
Crit Care Med ; 49(2): e191-e198, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-889603

ABSTRACT

OBJECTIVES: Treating acute respiratory failure in patients with coronavirus disease 2019 is challenging due to the lack of knowledge of the underlying pathophysiology. Hypoxemia may be explained in part by the loss of hypoxic pulmonary vasoconstriction. The present study assessed the effect of almitrine, a selective pulmonary vasoconstrictor, on arterial oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome. DESIGN: Single-center retrospective observational study. SETTING: ICU of Lille Teaching Hospital, France, from February 27, 2020, to April 14, 2020. PATIENTS: Patients with coronavirus disease 2019 pneumonia confirmed by positive reverse transcriptase-polymerase chain reaction for severe acute respiratory syndrome-coronavirus 2 and acute respiratory distress syndrome according to Berlin definition. Data focused on clinicobiological features, ventilator settings, therapeutics, outcomes, and almitrine-related adverse events. INTERVENTIONS: Almitrine was considered in patients with severe hypoxemia (Pao2/Fio2 ratio < 150 mm Hg) in addition to the recommended therapies, at an hourly IV delivery of 10 µg/kg/min. Comparative blood gases were done before starting almitrine trial and immediately after the end of the infusion. A positive response to almitrine was defined by an increase of Pao2/Fio2 ratio greater than or equal to 20% at the end of the infusion. MEASUREMENTS AND MAIN RESULTS: A total of 169 patients were enrolled. Thirty-two patients with acute respiratory distress syndrome received an almitrine infusion trial. In most cases, almitrine was infused in combination with inhaled nitric oxide (75%). Twenty-one patients (66%) were responders. The median Pao2/Fio2 ratio improvement was 39% (9-93%) and differs significantly between the responders and nonresponders (67% [39-131%] vs 6% [9-16%], respectively; p < 0.0001). The 28-day mortality rates were 47.6% and 63.6% (p = 0.39) for the responders and nonresponders, respectively. Hemodynamic parameters remained similar before and after the trial, not suggesting acute cor pulmonale. CONCLUSIONS: Almitrine infusion improved oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome without adverse effects. In a multistep clinical approach to manage severe hypoxemia in this population, almitrine could be an interesting therapeutic option to counteract the loss of hypoxic pulmonary vasoconstriction and redistribute blood flow away from shunting zones.


Subject(s)
Almitrine/therapeutic use , COVID-19/drug therapy , Respiratory Distress Syndrome/drug therapy , Respiratory System Agents/therapeutic use , COVID-19/complications , Critical Care/methods , Dose-Response Relationship, Drug , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Pulmonary Gas Exchange/drug effects , Respiratory Distress Syndrome/etiology , Retrospective Studies
10.
J Thromb Haemost ; 18(11): 2942-2953, 2020 11.
Article in English | MEDLINE | ID: covidwho-717319

ABSTRACT

BACKGROUND: Hypercoagulability seems to contribute to SARS-CoV-2 pneumonia pathogenesis. However, age and metabolic syndrome are potential confounders when assessing the value of coagulation biomarkers' prediction of COVID-19 outcomes. We assessed whether coagulation biomarkers, including factor VIII (FVIII) and von Willebrand factor (VWF) levels, measured at time of admission, were predictive of COVID-19 adverse outcomes irrespective of age and major comorbidities associated with metabolic syndrome. METHODS: Blood was sampled at admission in 243 adult COVID-19 patients for analysis of coagulation biomarkers including FVIII and VWF on platelet-poor plasma. The association between baseline C-reactive protein (CRP), activated partial thromboplastin time ratio, prothrombin time ratio, D-dimers, fibrinogen, FVIII, VWF antigen (VWF:Ag), and FVIII/VWF:Ag ratio levels and adverse outcomes (increased oxygen requirements, thrombosis, and death at day 30) was assessed by regression analysis after adjustment on age, sex, body mass index (BMI), diabetes, and hypertension. RESULTS: In univariable regression analysis increased CRP (subdistribution hazard ratio [SHR], 1.68; 95% confidence interval [CI], 1.26-2.23), increased fibrinogen (SHR, 1.32; 95% CI, 1.04-1.68), and decreased FVIII/VWF:Ag ratio (SHR, 0.70; 95% CI, 0.52-0.96) levels at admission were significantly associated with the risk of increased oxygen requirement during follow-up. Leucocytes (SHR, 1.36; 95% CI, 1.04-1.76), platelets (SHR,1.71; 95% CI, 1.11-2.62), D-dimers (SHR, 2.48; 95% CI, 1.66-3.78), and FVIII (SHR, 1.78; 95% CI, 1.17-2.68) were associated with early onset of thrombosis after admission. After adjustment for age, sex, BMI, hypertension, and diabetes, these associations were not modified. CONCLUSION: Coagulation biomarkers are early and independent predictors of increased oxygen requirement in COVID-19 patients.


Subject(s)
Blood Coagulation , COVID-19/therapy , Factor VIII/analysis , Oxygen Inhalation Therapy , Thrombosis/blood , Venous Thromboembolism/blood , von Willebrand Factor/analysis , Age Factors , Anticoagulants/therapeutic use , Biomarkers/blood , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , Comorbidity , Female , France/epidemiology , Humans , Male , Middle Aged , Patient Admission , Prevalence , Prospective Studies , Risk Assessment , Risk Factors , Sex Factors , Thrombosis/diagnosis , Thrombosis/epidemiology , Thrombosis/prevention & control , Treatment Outcome , Venous Thromboembolism/diagnosis , Venous Thromboembolism/epidemiology , Venous Thromboembolism/prevention & control
11.
Cancers (Basel) ; 12(7)2020 Jul 21.
Article in English | MEDLINE | ID: covidwho-670257

ABSTRACT

Advanced age or preexisting comorbidities have been characterized as risk factors for severe coronavirus disease 2019 (COVID-19) cases requiring hospitalization and intensive care. In recent years, clonal hematopoiesis (CH) of indeterminate potential (CHIP) has emerged as a risk factor for chronic inflammatory background and subsequent aging-associated diseases. The purpose of this study was to identify biological factors (particularly leukocyte subtypes and inflammatory markers) associated with a risk of clinical deterioration (i.e., orotracheal intubation (OTI)) and to determine whether CH was likely to influence clinical and biological behavior in patients with severe COVID-19 requiring hospitalization. Here, we describe clinical and biological features, including the screening of CHIP mutants in a well-annotated cohort of 122 hospitalized patients with a laboratory-confirmed diagnosis of COVID-19 (55% requiring OTI). We showed that elevated white blood cell counts, especially neutrophils and high C-reactive protein (CRP) levels at admission, were associated with an increased requirement of OTI. We noticed a high prevalence of CH (25%, 38%, 56%, and 82% of patients aged <60 years, 60-70 years, 70-80 years, and >80 years) compared to a retrospective cohort of patients free of hematological malignancy explored with the same pipelines (10%, 21%, 37%, and 44%). However, the existence of CH did not significantly impact clinical outcome, including OTI or death, and did not correlate with other laboratory findings.

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