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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324582

ABSTRACT

Background: Microvascular thrombosis, as well as arterial and venous thrombotic events, have been largely described during severe Coronavirus disease 19 (COVID-19). Therapeutic anticoagulation has been proposed in critical patients, however mechanisms underlying hemostasis dysregulation remain unclear. Methods: : We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes. Results: : We found that elevated soluble (s) P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67, p = 0.028 and AUC = 0.74, p = 0.0047, respectively). An optimal cutoff value of 150 NC (normalized concentration) was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. Next, an unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to primary hemostasis. Hierarchical clustering identified ITG2AB , GP1BB , PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of mechanical ventilation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both markers). An optimal cutoff value for PBPP was predictive of mechanical ventilation with 100% NPV and 45% PPV, and for SELPLG was predictive of mechanical ventilation with 100% NPV and 50% PPV. Conclusion: We provide evidence that platelets contribute to disease severity with the identification of sP-selectin as a biomarker for poor outcome. Transcriptional analysis identified PPBP and SELPLG RNA count as biomarkers for mechanical ventilation. These findings provide rationale for novel therapeutic approaches with antiplatelet agents.

2.
Arthritis Rheumatol ; 73(11): 1976-1985, 2021 11.
Article in English | MEDLINE | ID: covidwho-1432359

ABSTRACT

OBJECTIVE: The clinical relevance of antiphospholipid antibodies (aPLs) in COVID-19 is controversial. This study was undertaken to investigate the prevalence and prognostic value of conventional and nonconventional aPLs in patients with COVID-19. METHODS: This was a multicenter, prospective observational study in a French cohort of patients hospitalized with suspected COVID-19. RESULTS: Two hundred forty-nine patients were hospitalized with suspected COVID-19, in whom COVID-19 was confirmed in 154 and not confirmed in 95. We found a significant increase in lupus anticoagulant (LAC) positivity among patients with COVID-19 compared to patients without COVID-19 (60.9% versus 23.7%; P < 0.001), while prevalence of conventional aPLs (IgG and IgM anti-ß2 -glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti-ß2 -glycoprotein I, IgG and IgM isotypes of anti-phosphatidylserine/prothrombin, and IgG and IgM isotypes of antiprothrombin) was low in both groups. Patients with COVID-19 who were positive for LAC, as compared to patients with COVID-19 who were negative for LAC, had higher levels of fibrinogen (median 6.0 gm/liter [interquartile range 5.0-7.0] versus 5.3 gm/liter [interquartile range 4.3-6.4]; P = 0.028) and C-reactive protein (CRP) (median 115.5 mg/liter [interquartile range 66.0-204.8] versus 91.8 mg/liter [interquartile range 27.0-155.1]; P = 0.019). Univariate analysis did not show any association between LAC positivity and higher risks of venous thromboembolism (VTE) (odds ratio 1.02 [95% confidence interval 0.44-2.43], P = 0.95) or in-hospital mortality (odds ratio 1.80 [95% confidence interval 0.70-5.05], P = 0.24). With and without adjustment for CRP level, age, and sex, Kaplan-Meier survival curves according to LAC positivity confirmed the absence of an association with VTE or in-hospital mortality (unadjusted P = 0.64 and P = 0.26, respectively; adjusted hazard ratio 1.13 [95% confidence interval 0.48-2.60] and 1.80 [95% confidence interval 0.67-5.01], respectively). CONCLUSION: Patients with COVID-19 have an increased prevalence of LAC positivity associated with biologic markers of inflammation. However, LAC positivity at the time of hospital admission is not associated with VTE risk and/or in-hospital mortality.


Subject(s)
COVID-19/complications , Lupus Coagulation Inhibitor/blood , Venous Thromboembolism/etiology , Aged , Aged, 80 and over , COVID-19/blood , COVID-19/mortality , Female , Hospital Mortality , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Risk Factors , Survival Rate , Venous Thromboembolism/blood
4.
Ann Intensive Care ; 11(1): 113, 2021 Jul 17.
Article in English | MEDLINE | ID: covidwho-1315865

ABSTRACT

BACKGROUND: Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). However, mechanisms underlying hemostasis dysregulation remain unclear. METHODS: We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes. RESULTS: We found that elevated soluble (s)P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67, p = 0.028 and AUC = 0.74, p = 0.0047, respectively). An optimal cutoff value was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. An unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to platelet activation. Hierarchical clustering identified ITG2AB, GP1BB, PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both). An optimal cutoff value for PBPP was predictive of intubation with 100% NPV and 45% PPV, and for SELPLG with 100% NPV and 50% PPV. CONCLUSION: We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified PPBP/CXCL7 and SELPLG as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required.

5.
Int J Mol Sci ; 22(14)2021 Jul 12.
Article in English | MEDLINE | ID: covidwho-1308362

ABSTRACT

OBJECTIVE: We aimed to investigate the prognostic performances of oxidative stress (OS), inflammatory and cell activation biomarkers measured at admission in COVID-19 patients. DESIGN: retrospective monocentric study. SETTING: patients with suspected SARS-CoV-2 infection (COVID-19) admitted to the hospital. PATIENTS: One hundred and sixty documented and unselected COVID-19-patients. Disease severity (from mild to critical) was scored according to NIH's classification. INTERVENTIONS: none. MEASUREMENTS AND MAIN RESULTS: We measured OS biomarkers (thiol, advanced oxidation protein products (AOPP), ischemia-modified albumin (IMA)), inflammation biomarkers (interleukin-6 (IL-6), presepsin) and cellular activation biomarkers (calprotectin) in plasma at admission. Thiol concentrations decreased while IMA, IL-6, calprotectin and PSEP increased with disease severity in COVID-19 patients and were associated with increased O2 needs and ICU admission. The best area under the receiver-operating-characteristics curve (AUC) for the prediction of ICU admission was for thiol (AUC = 0.762). A thiol concentration <154 µmol/L was predictive for ICU admission (79.7% sensitivity, 64.6% specificity, 58.8% positive predictive value, 78.9% negative predictive value). In a stepwise logistic regression, we found that being overweight, having dyspnoea, and thiol and IL-6 plasmatic concentrations were independently associated with ICU admission. In contrast, calprotectin was the best biomarker to predict mortality (AUC = 0.792), with an optimal threshold at 24.1 mg/L (94.1% sensitivity, 64.9% specificity, 97.1% positive predictive value and 98.9% negative predictive value), and survival curves indicated that high IL-6 and calprotectin concentrations were associated with a significantly increased risk of mortality. CONCLUSIONS: Thiol measurement at admission is a promising tool to predict ICU admission in COVID-19-patients, whereas IL-6 and calprotectin measurements effectively predict mortality.


Subject(s)
Biomarkers/metabolism , COVID-19/epidemiology , Hospitalization/statistics & numerical data , Inflammation/diagnosis , Oxidative Stress , SARS-CoV-2/isolation & purification , Severity of Illness Index , Adult , Aged , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Critical Care , Female , Humans , Inflammation/metabolism , Inflammation/virology , Intensive Care Units , Male , Middle Aged , Prognosis , ROC Curve , Retrospective Studies
6.
Eur J Haematol ; 107(2): 190-201, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1223481

ABSTRACT

BACKGROUND: A high prevalence of pulmonary embolism (PE) has been described during COVID-19. Our aim was to identify predictive factors of PE in non-ICU hospitalized COVID-19 patients. METHODS: Data and outcomes were collected upon admission during a French multicenter retrospective study, including patients hospitalized for COVID-19, with a CT pulmonary angiography (CTPA) performed in the emergency department for suspected PE. Predictive factors significantly associated with PE were identified through a multivariate regression model. RESULTS: A total of 88 patients (median [IQR] age of 68 years [60-78]) were analyzed. Based on CTPA, 47 (53.4%) patients were diagnosed with PE, and 41 were not. D-dimer ≥3000 ng/mL (OR 8.2 [95% CI] 1.3-74.2, sensitivity (Se) 0.84, specificity (Sp) 0.78, P = .03), white blood count (WBC) ≥12.0 G/L (29.5 [2.3-1221.2], Se 0.47, Sp 0.92, P = .02), and ferritin ≥480 µg/L (17.0 [1.7-553.3], Se 0.96, Sp 0.44, P = .03) were independently associated with the PE diagnosis. The presence of the double criterion D-dimer ≥3000 ng/mL and WBC ≥12.0 G/L was greatly associated with PE (OR 21.4 [4.0-397.9], P = .004). CONCLUSION: The white blood count, the D-dimer and ferritin levels could be used as an indication for CTPA to confirm PE on admission in non-ICU COVID-19 patients.


Subject(s)
COVID-19/complications , Ferritins/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Leukocyte Count , Pulmonary Embolism/blood , Pulmonary Embolism/complications , COVID-19/virology , France , Humans , Patient Admission , Retrospective Studies , SARS-CoV-2/isolation & purification
7.
Viruses ; 13(5)2021 04 26.
Article in English | MEDLINE | ID: covidwho-1201364

ABSTRACT

The incidence of pulmonary embolism (PE) is high during severe Coronavirus Disease 2019 (COVID-19). We aimed to identify predictive and prognostic factors of PE in non-ICU hospitalized COVID-19 patients. In the retrospective multicenter observational CLOTVID cohort, we enrolled patients with confirmed RT-PCR COVID-19 who were hospitalized in a medicine ward and also underwent a CT pulmonary angiography for a PE suspicion. Baseline data, laboratory biomarkers, treatments, and outcomes were collected. Predictive and prognostics factors of PE were identified by using logistic multivariate and by Cox regression models, respectively. A total of 174 patients were enrolled, among whom 86 (median [IQR] age of 66 years [55-77]) had post-admission PE suspicion, with 30/86 (34.9%) PE being confirmed. PE occurrence was independently associated with the lack of long-term anticoagulation or thromboprophylaxis (OR [95%CI], 72.3 [3.6-4384.8]) D-dimers ≥ 2000 ng/mL (26.3 [4.1-537.8]) and neutrophils ≥ 7.0 G/L (5.8 [1.4-29.5]). The presence of these two biomarkers was associated with a higher risk of PE (p = 0.0002) and death or ICU transfer (HR [95%CI], 12.9 [2.5-67.8], p < 0.01). In hospitalized non-ICU severe COVID-19 patients with clinical PE suspicion, the lack of anticoagulation, D-dimers ≥ 2000 ng/mL, neutrophils ≥ 7.0 G/L, and these two biomarkers combined might be useful predictive markers of PE and prognosis, respectively.


Subject(s)
COVID-19/pathology , Fibrin Fibrinogen Degradation Products/metabolism , Neutrophils/pathology , Pulmonary Embolism/virology , Aged , COVID-19/blood , Computed Tomography Angiography , Female , Humans , Logistic Models , Male , Middle Aged , Prognosis , Pulmonary Embolism/blood , Pulmonary Embolism/pathology , Retrospective Studies , Risk Factors , SARS-CoV-2/genetics , Venous Thromboembolism/blood , Venous Thromboembolism/pathology , Venous Thromboembolism/virology
8.
J Thromb Haemost ; 19(7): 1823-1830, 2021 07.
Article in English | MEDLINE | ID: covidwho-1172713

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with vascular inflammation and endothelial injury. OBJECTIVES: To correlate circulating angiogenic markers vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), and fibroblast growth factor 2 (FGF-2) to in-hospital mortality in COVID-19 adult patients. METHODS: Consecutive ambulatory and hospitalized patients with COVID-19 infection were enrolled. VEGF-A, PlGF, and FGF-2 were measured in each patient ≤48 h following admission. RESULTS: The study enrolled 237 patients with suspected COVID-19: 208 patients had a positive diagnostic for COVID-19, of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF-A, PlGF, and FGF-2 significantly increase with the severity of the disease (P < .001). Using a logistic regression model, we found a significant association between the increase of FGF-2 or PlGF and mortality (odds ratio [OR] 1.11, 95% confidence interval [CI; 1.07-1.16], P < .001 for FGF-2 and OR 1.07 95% CI [1.04-1.10], P < .001 for PlGF) while no association were found for VEGF-A levels. Receiver operating characteristic curve analysis was performed and we identified PlGF above 30 pg/ml as the best predictor of in-hospital mortality in COVID-19 patients. Survival analysis for PlGF confirmed its interest for in-hospital mortality prediction, by using a Kaplan-Meier survival curve (P = .001) and a Cox proportional hazard model adjusted to age, body mass index, D-dimer, and C-reactive protein (3.23 95% CI [1.29-8.11], P = .001). CONCLUSION: Angiogenic factor PlGF is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID-19.


Subject(s)
COVID-19 , Vascular Endothelial Growth Factor A , Adult , Biomarkers , Female , Hospital Mortality , Humans , Placenta Growth Factor , SARS-CoV-2
10.
Angiogenesis ; 24(3): 505-517, 2021 08.
Article in English | MEDLINE | ID: covidwho-1032491

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis. OBJECTIVES: To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients. METHODS: Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission. RESULTS: Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and D-dimer levels. CONCLUSION: VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.


Subject(s)
COVID-19/blood , COVID-19/mortality , Pandemics , SARS-CoV-2 , von Willebrand Factor/metabolism , Adult , Aged , Biomarkers/blood , Biomarkers/chemistry , COVID-19/physiopathology , Cross-Sectional Studies , Endothelium, Vascular/physiopathology , Female , Hospital Mortality , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Molecular Weight , Paris/epidemiology , Proportional Hazards Models , Protein Multimerization , Severity of Illness Index , Thrombosis/blood , Thrombosis/etiology , von Willebrand Factor/chemistry
11.
Stem Cell Rev Rep ; 17(1): 296-299, 2021 02.
Article in English | MEDLINE | ID: covidwho-1009200

ABSTRACT

We report the case of an HIV-1-infected patient, treated with anti-CD20 monoclonal antibody for a B-cell lymphoma previously treated by autologous stem cell transplant. He suffered from chronic COVID19 and we monitored by plasma SARS-CoV-2 RNA by highly sensitive droplet-based digital PCR technology (ddPCR). Under tocilizumab therapy and despite a first clinical improvement biologically associated with decreasing inflammatory markers, a slight increase of SARS-CoV-2 RNAaemia quantified by ddPCR was highlighted, confirming the absence of viral efficacy of this treatment and predicting the subsequent observed deterioration. As expected, his complete recovery, finally achieved after COVID-19 convalescent plasmatherapy, strictly paralleled plasma SARS-CoV-2 RNA clearance. With these results, we confirmed the interest of SARS-CoV-2 RNAaemia monitoring by ddPCR in COVID-19 patients, particularly during treatment, and firstly showed that this new and specific biomarker could be helpful to select eligible patient for anti-IL6 receptors therapy considering the variable levels of efficacy recently observed with such therapy.


Subject(s)
COVID-19/blood , HIV Infections/blood , Lymphoma, B-Cell/drug therapy , RNA, Viral/blood , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , COVID-19/genetics , COVID-19/virology , HIV Infections/genetics , HIV Infections/therapy , HIV Infections/virology , HIV-1/pathogenicity , Humans , Lymphocytes/virology , Lymphoma, B-Cell/complications , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/virology , RNA, Viral/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Viral Load/drug effects
12.
Blood ; 136(20): 2290-2295, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-950941

ABSTRACT

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/pathology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Immune Sera/administration & dosage , Lymphopenia/therapy , Pneumonia, Viral/immunology , Adult , Aged , B-Lymphocytes/immunology , Blood Component Transfusion , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/therapy , Coronavirus Infections/virology , Female , France , Hematologic Neoplasms/complications , Humans , Immunization, Passive , Lymphopenia/etiology , Lymphopenia/pathology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS-CoV-2
13.
Cell ; 182(6): 1401-1418.e18, 2020 09 17.
Article in English | MEDLINE | ID: covidwho-694669

ABSTRACT

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14LowCD16High monocytes, accumulation of HLA-DRLow classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10LowCD101-CXCR4+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.


Subject(s)
Coronavirus Infections , Coronavirus , Pandemics , Pneumonia, Viral , Betacoronavirus , COVID-19 , Flow Cytometry , Humans , Leukocyte L1 Antigen Complex , Monocytes , Myeloid Cells , Prospective Studies , SARS-CoV-2
14.
Science ; 369(6504): 718-724, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-641396

ABSTRACT

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-ß and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Interferon alpha-2/metabolism , Interferon-alpha/metabolism , Interferon-beta/metabolism , Pneumonia, Viral/immunology , Adult , Aged , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/virology , Critical Illness , Cross-Sectional Studies , Female , Gene Expression Profiling , Humans , Immunity, Innate , Inflammation , Interleukin-6/metabolism , Male , Middle Aged , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor-alpha/metabolism , Viral Load
15.
BMJ ; 369: m1844, 2020 May 14.
Article in English | MEDLINE | ID: covidwho-260539

ABSTRACT

OBJECTIVE: To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen. DESIGN: Comparative observational study using data collected from routine care. SETTING: Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020. PARTICIPANTS: 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care. INTERVENTIONS: Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group). MAIN OUTCOME MEASURES: The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting. RESULTS: In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment. CONCLUSIONS: Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Female , Humans , Male , Middle Aged , Oxygen Inhalation Therapy , Pandemics , Young Adult
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