The onset of late severe lung impairment in COVID-19 is associated with high inflammation markers at admission and metabolic syndrome markers (preprint)

Background: COVID-19 severity is mainly related to lung impairment. However, preexisting patient characteristics and biomarkers at admission associated with this event are not precisely known. Methods. We report 205 patients admitted for a proven COVID-19 in our institution between March 7 and April 22, 2020, particularly their comorbidities, respiratory severity, immune profile, and metabolic profile. Findings. Median age was 70 years [interquartile range (IQR) 25-75: 60;79]; 115 (56.1%) patients were men. Oxygen supplementation of >2L/min was required in 107 patients (52.2%) after a median time of 8 days [IQR: 6;10] after the first symptoms; 67 (32.7%) patients were admitted to the intensive care unit (ICU), almost exclusively due to severe hypoxia. Patients requiring >2L/min oxygen therapy and/or ICU admission were older and more frequently males, with a significantly higher body mass index (BMI), a significantly higher total cholesterol (TC) / HDL cholesterol ratio, and higher triglycerides. They also had higher plasma levels of C-reactive protein (CRP) and interleukin 6 (IL-6); IL-6 >20 ng/L and CRP >70 mg/L were significantly associated with ICU admission and/or (for patients with a decision of limitation of life-support therapy) death. Higher BMI and TC/HDL-c ratio were associated with higher CRP and IL-6 levels. Steroid therapy was performed in 61 patients; while its clinical impact was inconclusive due to heterogeneous situations, IL-6 levels decreased significantly more in these patients. Interpretation. Severe COVID-19 mostly relates to late-onset pneumonia associated with preexisting metabolic syndrome markers and a surge in inflammatory markers, allowing the early identification of at-risk patients.

Impact of vaccination on the presence and severity of symptoms of hospitalised patients with an infection by the Omicron variant (B.1.1.529) of the SARS-CoV-2 (subvariant BA.1). (preprint)

Objectives: The emergence of SARS-CoV-2 variants raised questions over the extent to which vaccines designed in 2020 have remained effective. We aimed to assess whether vaccine status was associated with the severity of Omicron SARS-CoV-2 infection in hospitalised patients. Methods: We conducted an international, multicentric, retrospective study in 14 centres (Bulgaria, Croatia, France, Turkey). We collected data on patients hospitalised [≥]24 hours between 01/12/2021 and 03/03/2022, with PCR-confirmed infection at a time of exclusive Omicron circulation, with hospitalisation related or not to the infection. Patients who had received prophylaxis by monoclonal antibodies were excluded. Patients were considered fully vaccinated if they had received at least 2 injections of either mRNA and/or ChAdOx1-S, or 1 injection of Ad26.CoV2-S vaccines. Results: Among the 1215 patients (median [IQR] age 73.0 [57.0; 84.0]; 51.3% males), 746 (61.4%) were fully vaccinated. In multivariate analysis, being vaccinated was associated with lower 28-day mortality (RR=0.50 [0.32-0.77]), ICU admission (R=0.40 [0.26-0.62], and oxygen requirement (RR=0.34 [0.25-0.46]), independently of age and comorbidities. When co-analysing these Omicron patients with 948 Delta patients from a study we recently conducted, Omicron infection was associated with lower 28-day mortality (RR=0.53 [0.37-0.76]), ICU admission (R=0.19 [0.12-0.28], and oxygen requirements (RR=0.50 [0.38-0.67]), independently of age, comorbidities and vaccination status. Conclusions: mRNA- and adenovirus-based vaccines have remained effective on severity of Omicron SARS-CoV-2 infection. Omicron is associated with a lower risk of severe forms, independently of vaccination and patient characteristics.

COVID-19 mass vaccination - an illustration of the impact of syringe choice on the effectiveness of mass vaccination campaigns.

In order to optimise the operational implementation of mass vaccination policies, it is critical to consider not only the supply of vaccines as well as each element of the vaccination process. This study, which was conducted in a vaccination center clearly shows how the choice of a syringe reference used during the COVID-19 vaccination campaign influences the number of vaccine doses available. The results appear to be closely related to the type of vaccine used (COMIRNATY® and SPIKEVAX®). In this context, the choice of the right reference of syringe has major economic and organisational consequences on a global scale.

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

Objectives We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-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. Methods We 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. Results The intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-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-β-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. Conclusion In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

Symptoms and severity in vaccinated and unvaccinated patients hospitalised with SARS-CoV-2 delta (B.1.617.2) variant infection (preprint)

Background: The diffusion of the SARS-CoV-2 delta (B.1.617.2) variant and the waning of immune response after primary Covid-19 vaccination favoured the breakthrough SARS-CoV-2 infections in vaccinated subjects. To assess the impact of vaccination, we determined the severity of infection in hospitalised patients according to vaccine status. Methods: We retrospectively analysed data from patients hospitalised in 10 centres with a SARS-CoV-2 infection (delta variant) from July to November 2021: i) all patients who had completed their primary vaccination at least 14 days before hospital admission; and ii) the same number of completely unvaccinated patients. We assessed the impact of vaccination and other risk factors through logistic regression. Findings: We included 955 patients (474 vaccinated and 481 unvaccinated). Vaccinated patients were significantly older, more frequently males, and with more comorbidities. They were less often admitted for Covid-19 (59.3% vs. 75.1%, p<0.001), showed fewer lung lesions, and required oxygen less frequently (57.5% vs. 73.0%, p<0.001), at a lower flow (3.0 vs. 6.0 L/min, p<0.001), and for a shorter duration (3 vs. 6 days, p<0.001). They less frequently required intensive care unit admission (16.2 % vs. 36.0 %, p<0.001). Mortality at day 28 was not different between the two groups (16.7% vs. 12.2%, p=0.075), but multivariate logistic regression showed that vaccination significantly decreased the risk of negative outcomes, including mortality, even when considering older patients, and those with comorbidities. Conclusions: Among patients hospitalised with a delta variant SARS-CoV-2 infection, vaccination was associated with less severe forms, even in the presence of comorbidities.

Fine analysis of lymphocyte subpopulations in SARS-CoV-2 infected patients: toward a differential profiling of patients with severe outcome (preprint)

COVID-19 is caused by the human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in widespread morbidity and mortality. CD4+ T cells, CD8+ T cells and neutralizing antibodies all contribute to control SARS-CoV-2 infection. However, heterogeneity is a major factor in disease severity and in immune innate and adaptive responses to SARS-CoV-2. We performed a deep analysis by flow cytometry of lymphocyte populations of 125 hospitalized SARS-CoV-2 infected patients on the day of hospital admission. Five clusters of patients were identified using hierarchical classification on the basis of their immunophenotypic profile, with different mortality outcomes. Some characteristics were observed in all the clusters of patients, such as lymphopenia and an elevated level of effector CD8+CCR7- T cells. However, low levels of T cell activation are associated to a better disease outcome; on the other hand, profound CD8+ T-cell lymphopenia, a high level of CD4+ and CD8+ T-cell activation and a high level of CD8+ T-cell senescence are associated with a higher mortality outcome. Furthermore, a cluster of patient was characterized by high B-cell responses with an extremely high level of plasmablasts. Our study points out the prognostic value of lymphocyte parameters such as T-cell activation and senescence and strengthen the interest in treating the patients early in course of the disease with targeted immunomodulatory therapies based on the type of adaptive response of each patient.

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

Background: Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective: To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design: Open-label, randomized, adaptive, controlled trial. Setting: Multi-center trial with patients from France. Participants: 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention: Standard 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 micrograms 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). Measurements: 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 and safety analyses. Results: Adjusted 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. Limitations: Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion: No 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. Registration: NCT04315948. Funding: PHRC 2020, Dim OneHealth, REACTing