Efficacy and safety of convalescent plasma to treat hospitalised COVID-19 patients with or without underlying immunodeficiency: a randomized clinical trial

Efficacy of COVID-19 convalescent plasma (CCP) in COVID-19 pneumonia is uncertain. The CORIPLASM study was an open-label, Bayesian randomised clinical trial evaluating the efficacy of CCP in patients with moderate COVID-19, including immunocompromised patients. Patients hospitalised with COVID-19 and less than 9 days since symptoms onset were assigned to receive 4 units of plasma over 2 days ({approx} 840 ml)(CCP) or usual care alone (UC). Primary outcomes were the proportion of patients with a WHO-Clinical Progression Score (CPS) [≥]6 on the 10-point scale on day (d) 4 and survival without ventilation or additional immunomodulatory treatment by d14. A total of 120 patients were recruited and assigned to CCP (n=60) or UC (n=60), including 22 (CCP) and 27 (UC) immunocompromised patients. Thirteen (22%) patients with CCP had a WHO-CPS [≥]6 at d4 versus 8 (13%) with UC, adjusted odds ratio (aOR) 1.88 [95%CI 0.71 to 5.24]. By d14, 19 (31.6%) patients with CCP and 20 (33.3%) patients with UC had ventilation, additional immunomodulatory treatment or had died. Cumulative incidence of death was 3 (5%) with CCP and 8 (13%) with UC at d14 (aHR 0.40 [95%CI 0{middle dot}10 -1{middle dot}53]), and 7 (12%) with CCP and 12 (20%) with UC at d28 (aHR 0.51 [95%CI 0.20-1.32]). Subgroup analysis indicated that CCP might be associated with a lower mortality in immunocompromised patients (HR 0.37 [95%CI 0.14-0.97]). CCP treatment did not improve early outcomes in patients with moderate COVID-19 but was associated with reduced mortality in the subgroup of immunocompromised patients.

An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19 - Final results from the DisCoVeRy trial

ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-{beta}-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. MethodsWe conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely. ResultsThe intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-{beta}-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-{beta}-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-{beta}-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

High seroconversion rate and SARS-CoV-2 Delta neutralization in PLWHIV vaccinated with BNT162b2

ObjectivesTo assess the humoral and cellular responses against SARS-CoV-2 Delta variant after BNT162b2 vaccination in PLWHIV. DesignMulticenter cohort study of PLWHIV, with a CD4 cell count <500/mm3 and a viral load <50 copies/ml on stable antiretroviral therapy for at least 3 months. MethodsAnti-SARS-CoV-2 Receptor Binding Domain IgG antibodies (anti-RBD IgG) were quantified and their neutralization capacity was evaluated using an ELISA (GenScript) and a virus neutralization test (VNT), against historical strain, Beta and Delta variants before vaccination (day 0) and one month after a complete vaccination schedule (M1). Results97 patients were enrolled in the study: 85 received 2 vaccine doses (11 previous COVID-19 and 1 premature exit). The seroconversion rate in anti-RBD IgG was 97% CI95[90%; 100%] at M1. Median (IQR) anti-RBD IgG titer was 0.97 (0.97-5.3) BAU/ml at D0 and 1219 (602-1929) at M1. Neutralizing antibodies (NAbs) capacity improved between D0 (15% CI95[8%; 23%]) and M1 (94% CI95[87%; 98%]) with the GenScript assay (p<0.0001). At M1, NAbs against historical strain, Beta and Delta variants were present in 82%, 77% and 84% patients respectively. The seroconversion rate and median anti-RBD IgG were 91% and 852 BAU/ml in patients with CD4<250/mm3 (n=13) and 98% and 1270 BAU/ml in patients with CD4>250/mm3 (n=64) (p=0.3994). 73% of patients with CD4<250 had NAbs and 97% of those with CD4>250 (p=0.0130). The NAbs against Beta variant was elicited in 50% in CD4<250 and in 81% in CD4>250 (p=0.0292). No change in CD4+ or CD8+ T cells count was observed while a decrease of CD19+ B cells count was observed (208 {+/-}124 cells/mm3 at D0 vs 188 {+/-}112 cells/mm3 at M1, p<0.01). No notable adverse effects or COVID-19 were reported. ConclusionsThese results show a high seroconversion rate with a Delta neutralization in PLWHIV patients after a complete BNT162b2 vaccination schedule.

Cumulative incidence of SARS-CoV-2 infection and associated risk factors among frontline health care workers in Paris, France: the SEROCOV prospective cohort study

BackgroundWith the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern. MethodsIn this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression. ResultsAmong 1,062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95%CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); active smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3. ConclusionThe rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk. Key messagesO_LIDuring the first epidemic wave, 14.6% of 1,062 first-line Health Care Workers had a positive serology and/or RT-PCR test for SARS-CoV-2. C_LIO_LIMost infections occurred early C_LIO_LIRisk was increased by working in infectious diseases (OR 4.22, 95% confidence interval [0.92; 18.28]), emergency (3.91 [0.83; 18.43]) and intensive care units (1.80, [0.38; 8.58]) C_LIO_LIBeing an active smoker was protective (0.36 [0.21; 0.3]). C_LI

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-{beta}-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-{beta}-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. DesignOpen-label, randomized, adaptive, controlled trial. SettingMulti-center trial with patients from France. Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory support InterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-{beta}-1a (44 g of subcutaneous IFN-{beta}-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). MeasurementsThe primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses. ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-{beta}-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. LimitationsNot a placebo-controlled, no anti-inflammatory agents tested. ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. RegistrationNCT04315948. FundingPHRC 2020, Dim OneHealth, REACTing

LOX-1+ immature neutrophils predict severe COVID-19 patients at risk of thrombotic complications

RationalLymphopenia and neutrophil/lymphocyte ratio may have prognostic value in coronavirus disease 2019 (COVID-19) severity. ObjectiveWe sought to investigate the representation of neutrophil subsets in severe and critical COVID-19 patients based on Intensive Care Units (ICU) and non-ICU admission. MethodsWe developed a multi-parametric neutrophil profiling strategy based on known neutrophil markers to distinguish COVID-19 phenotypes in critical and severe patients. ResultsOur results showed that 80% of ICU patients develop strong myelemia with CD10-CD64+ immature neutrophils. Cellular profiling revealed two distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or the Interleukin-3 receptor alpha (CD123), both significantly overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1-expressing immature neutrophils positively correlated with clinical severity, with the cytokine storm (IL-1{beta}, IL-6, IL-8, TNF), and with intravascular coagulation. Importantly, high proportions of LOX-1+-immature neutrophils are associated with high risks of severe thrombosis. ConclusionsTogether these data suggest that point of care enumeration of LOX-1-immature neutrophils might help distinguish patients at risk of thrombosis complication and most likely to benefit from intensified anticoagulant therapy.