Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS).

INTRODUCTION: Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking. METHODS: We conducted a multi-center, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. PRIMARY OUTCOME: reduction in 28-day mortality. SECONDARY OUTCOMES: mechanical ventilation-free days at 28 days, need for ICU referral, length of hospitalisation, need for tracheostomy, changes in PaO2:FiO2 ratio, C-reactive protein levels and WHO clinical progression scale at days 3, 7, and 14. RESULTS: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35[10.4%] versus 41[12.1%]; p=0.49), nor in the median mechanical ventilation-free days (23[14] versus 24[16]; p=0.49). ICU referral was necessary in 41[12.2%] versus 45[13.2%]; p=0.68 and tracheostomy in 8[2.4%] versus 9[2.6%]; p=0.82. Survivors in the methylprednisolone group required a longer median hospitalisation (15[11] versus 14[11] days; p=0.005) and experienced an improvement in C-reactive protein levels, but not in PaO2:FiO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified timepoints. CONCLUSION: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared to conventional dexamethasone in COVID-19 pneumonia.

Long pentraxin 3 (PTX3) levels predict death, intubation and thrombotic events among hospitalized patients with COVID-19.

Background: PTX3 is an important mediator of inflammation and innate immunity. We aimed at assessing its prognostic value in a large cohort of patients hospitalized with COVID-19. Methods: Levels of PTX3 were measured in 152 patients hospitalized with COVID-19 at San Gerardo Hospital (Monza, Italy) since March 2020. Cox regression was used to identify predictors of time from admission to in-hospital death or mechanical ventilation. Crude incidences of death were compared between patients with PTX3 levels higher or lower than the best cut-off estimated with the Maximally Selected Rank Statistics Method. Results: Upon admission, 22% of the patients required no oxygen, 46% low-flow oxygen, 30% high-flow nasal cannula or CPAP-helmet and 3% MV. Median level of PTX3 was 21.7 (IQR: 13.5-58.23) ng/ml. In-hospital mortality was 25% (38 deaths); 13 patients (8.6%) underwent MV. PTX3 was associated with risk of death (per 10 ng/ml, HR 1.08; 95%CI 1.04-1.11; P<0.001) and death/MV (HR 1.04; 95%CI 1.01-1.07; P=0.011), independently of other predictors of in-hospital mortality, including age, Charlson Comorbidity Index, D-dimer and C-reactive protein (CRP). Patients with PTX3 levels above the optimal cut-off of 39.32 ng/ml had significantly higher mortality than the others (55% vs 8%, P<0.001). Higher PTX3 plasma levels were found in 14 patients with subsequent thrombotic complications (median [IQR]: 51.4 [24.6-94.4] versus 21 [13.4-55.2]; P=0.049). Conclusions: High PTX3 levels in patients hospitalized with COVID-19 are associated with a worse outcome. The evaluation of this marker could be useful in prognostic stratification and identification of patients who could benefit from immunomodulant therapy.

COVID-19 Infection Among Incarcerated Individuals and Prison Staff in Lombardy, Italy, March 2020 to February 2021.

Importance: Owing to infrastructural and population characteristics, the prison setting is at increased risk for transmission of SARS-CoV-2 and for severe clinical outcomes. Because of structural and operational reasons, research in prison settings is challenging and available studies are often monocentric and have limited temporal coverage; broader-based research is necessary. Objectives: To assess the extent and dynamics of the COVID-19 pandemic within the prison system of a large Italian region, Lombardy, and report the infection prevention and control measures implemented. Design, Setting, and Participants: This repeated cross-sectional study was carried out from March 1, 2020, through February 28, 2021 (first wave, March-June 2020; second wave, October 2020-February 2021) in the prison system of Lombardy, which includes 18 detention facilities for adults. All incarcerated persons and the prison staff of the penitentiary system of the Lombardy region participated in the study. Exposures: The main exposures of interest were the weekly average number of incarcerated individuals placed in quarantine in single or shared isolation rooms, the rate of sick leave by symptomatic and asymptomatic prison staff reported to the prison occupational medicine department on a weekly basis, and the level of overcrowding. Main Outcomes and Measures: The primary outcome measures were weekly COVID-19 crude case rates, weekly test positivity rate, and the relative risk of acquiring the infection for prison staff, incarcerated persons, and the general population. Results: The study population comprised a mean of 7599 incarcerated individuals and 4591 prison staff. Approximately 5.1% of the prison population were women; demographic characteristics of the prison staff were not available. During the study, COVID-19 occurred in 1564 incarcerated individuals and 661 prison staff. Most of these cases were reported during the second wave (1474 in incarcerated individuals, 529 in prison staff), when stringent measures previously enforced were relaxed. During both epidemic waves, incarcerated individuals and prison staff had a higher relative risk for COVID-19 infection than the general population during both the first wave (incarcerated individuals: 1.30; 95% CI, 1.06-1.58; prison staff: 3.23; 95% CI, 2.74-3.84) and the second wave (incarcerated individuals: 3.91; 95% CI, 3.73-4.09; prison staff: 2.61; 95% CI, 2.41-2.82). Conclusions and Relevance: The findings of this study suggest that the prison setting was an element of fragility during COVID-19 pandemic, with a high burden of COVID-19 cases among both the incarcerated individuals and prison staff. The prison setting and prison population need to be included and possibly prioritized in the response during epidemic events.

Compassionate Use of Remdesivir in Children With Severe COVID-19.

OBJECTIVES: Remdesivir shortens time to recovery in adults with severe coronavirus disease 2019 (COVID-19), but its efficacy and safety in children are unknown. We describe outcomes in children with severe COVID-19 treated with remdesivir. METHODS: Seventy-seven hospitalized patients <18 years old with confirmed severe acute respiratory syndrome coronavirus 2 infection received remdesivir through a compassionate-use program between March 21 and April 22, 2020. The intended remdesivir treatment course was 10 days (200 mg on day 1 and 100 mg daily subsequently for children ≥40 kg and 5 mg/kg on day 1 and 2.5 mg/kg daily subsequently for children <40 kg, given intravenously). Clinical data through 28 days of follow-up were collected. RESULTS: Median age was 14 years (interquartile range 7-16, range <2 months to 17 years). Seventy-nine percent of patients had ≥1 comorbid condition. At baseline, 90% of children required supplemental oxygen and 51% required invasive ventilation. By day 28 of follow-up, 88% of patients had a decreased oxygen-support requirement, 83% recovered, and 73% were discharged. Among children requiring invasive ventilation at baseline, 90% were extubated, 80% recovered, and 67% were discharged. There were 4 deaths, of which 3 were attributed to COVID-19. Remdesivir was well tolerated, with a low incidence of serious adverse events (16%). Most adverse events were related to COVID-19 or comorbid conditions. Laboratory abnormalities, including elevations in transaminase levels, were common; 61% were grades 1 or 2. CONCLUSIONS: Among 77 children treated with remdesivir for severe COVID-19, most recovered and the rate of serious adverse events was low.

The high volume of patients admitted during the SARS-CoV-2 pandemic has an independent harmful impact on in-hospital mortality from COVID-19.

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, advanced health systems have come under pressure by the unprecedented high volume of patients needing urgent care. The impact on mortality of this "patients' burden" has not been determined. METHODS AND FINDINGS: Through retrieval of administrative data from a large referral hospital of Northern Italy, we determined Aalen-Johansen cumulative incidence curves to describe the in-hospital mortality, stratified by fixed covariates. Age- and sex-adjusted Cox models were used to quantify the effect on mortality of variables deemed to reflect the stress on the hospital system, namely the time-dependent number of daily admissions and of total hospitalized patients, and the calendar period. Of the 1225 subjects hospitalized for COVID-19 between February 20 and May 13, 283 died (30-day mortality rate 24%) after a median follow-up of 14 days (interquartile range 5-19). Hospitalizations increased progressively until a peak of 465 subjects on March 26, then declined. The risk of death, adjusted for age and sex, increased for a higher number of daily admissions (adjusted hazard ratio [AHR] per an incremental daily admission of 10 patients: 1.13, 95% Confidence Intervals [CI] 1.05-1.22, p = 0.0014), and for a higher total number of hospitalized patients (AHR per an increase of 50 patients in the total number of hospitalized subjects: 1.11, 95%CI 1.04-1.17, p = 0.0004), while was lower for the calendar period after the peak (AHR 0.56, 95%CI 0.43-0.72, p<0.0001). A validation was conducted on a dataset from another hospital where 500 subjects were hospitalized for COVID-19 in the same period. Figures were consistent in terms of impact of daily admissions, daily census, and calendar period on in-hospital mortality. CONCLUSIONS: The pressure of a high volume of severely ill patients suffering from COVID-19 has a measurable independent impact on in-hospital mortality.

Remdesivir Use in Patients Requiring Mechanical Ventilation due to COVID-19.

BACKGROUND: Remdesivir has been associated with accelerated recovery of severe coronavirus disease 2019 (COVID-19). However, whether it is also beneficial in patients requiring mechanical ventilation is uncertain. METHODS: All consecutive intensive care unit (ICU) patients requiring mechanical ventilation due to COVID-19 were enrolled. Univariate and multivariable Cox models were used to explore the possible association between in-hospital death or hospital discharge, considered competing-risk events, and baseline or treatment-related factors, including the use of remdesivir. The rate of extubation and the number of ventilator-free days were also calculated and compared between treatment groups. RESULTS: One hundred thirteen patients requiring mechanical ventilation were observed for a median of 31 days of follow-up; 32% died, 69% were extubated, and 66% were discharged alive from the hospital. Among 33 treated with remdesivir (RDV), lower mortality (15.2% vs 38.8%) and higher rates of extubation (88% vs 60%), ventilator-free days (median [interquartile range], 11 [0-16] vs 5 [0-14.5]), and hospital discharge (85% vs 59%) were observed. Using multivariable analysis, RDV was significantly associated with hospital discharge (hazard ratio [HR], 2.25; 95% CI, 1.27-3.97; P = .005) and with a nonsignificantly lower mortality (HR, 0.73; 95% CI, 0.26-2.1; P = .560). RDV was also independently associated with extubation (HR, 2.10; 95% CI, 1.19-3.73; P = .011), which was considered a competing risk to death in the ICU in an additional survival model. CONCLUSIONS: In our cohort of mechanically ventilated patients, RDV was not associated with a significant reduction of mortality, but it was consistently associated with shorter duration of mechanical ventilation and higher probability of hospital discharge, independent of other risk factors.

Corticosteroid therapy for critically ill patients with COVID-19: A structured summary of a study protocol for a prospective meta-analysis of randomized trials.

OBJECTIVES: Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events. STUDY DESIGN: Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible. PARTICIPANTS: Hospitalised, critically ill patients with suspected or confirmed COVID-19. INTERVENTION AND COMPARATOR: Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo. MAIN OUTCOME: All-cause mortality up to 28 days after randomization. SEARCH METHODS: Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials. RISK OF BIAS ASSESSMENTS: These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. We will use GRADE to assess the certainty of the evidence. STATISTICAL ANALYSES: Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung-Knapp adjustment) meta-analyses. We will quantify inconsistency in effects between trials using I2 statistics. Evidence for subgroup effects will be quantified by ratios of odds ratios comparing effects in the subgroups, and corresponding interaction p-values. Comparisons between subgroups defined by trial characteristics will be made using random-effects meta-regression. Comparisons between subgroups defined by patient characteristics will be made by estimating trial-specific ratios of odds ratios comparing intervention effects between subgroups then combining these using random-effects meta-analysis. Steroid interventions will be classified as high or low dose according to whether the dose is greater or less than or equal to 400 mg hydrocortisone per day or equivalent. We will use network meta-analysis methods to make comparisons between the effects of high and low dose steroid interventions (because one trial randomized participants to both low and high dose steroid arms). PROSPERO REGISTRATION NUMBER: CRD42020197242 FULL PROTOCOL: The full protocol for this prospective meta-analysis is attached as an additional file, accessible from the Trials website (Additional file 1). To expedite dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol for the systematic review.

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).