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Background Critical care admissions due to breakthrough COVID-19 in fully vaccinated patients remain rare. There is limited data on their characteristics and outcomes compared to non- or partially vaccinated patients, and no studies have evaluated the impact of variants of concern. Method This study used the COMETE-19 (COVID-19 patients in the intensive care unit [ICU]) near real-time prospective registry, a tool launched on March 1, 2020, to track patient and disease characteristics as well as the disease course of critically ill COVID-19 patients in two French ICUs. Fully vaccinated patients were compared with non- or partially vaccinated patients. The primary outcome was a composite criterion of severity, including invasive mechanical ventilation (IMV), other organ assistance, or death. Differences between the vaccinated and control groups regarding other outcomes, patient variables, management, and SARS-CoV-2 variants were explored using univariate analysis. Factors associated with high disease severity in both groups were examined using logistic regression analysis. Results A total of 805 patients (median age, 65 years [IQR 56–71], 67% male) were enrolled. Of these, 41 (5%) were fully vaccinated. Fully vaccinated patients required less frequent IMV (27% vs. 51%, p  = 0.003) and had lower mortality (15% vs. 26%, p  = 0.026). Full vaccination status was associated with lower disease severity (OR 0.30; CI95% [0.11–0.74]; p  = 0.011) and tended to prevent ICU mortality (OR 0.39, CI95% [0.13–1.04], p  = 0.072). Variants-of-concern did not associate with outcomes. Conclusion Among critically ill COVID-19 patients, full vaccination was associated with less severe disease progression compared to partial or no vaccination. Trial Registration Clinical Trial: NCT04430322

The clinical outcomes of the Beta (B.1.351) variant of concern (VOC) of the SARS-CoV-2 virus remain poorly understood. In early 2021, northeastern France experienced an outbreak of Beta that was not observed elsewhere. This outbreak slightly preceded and then overlapped with a second outbreak of the better understood VOC Alpha (B.1.1.7) in the region. This situation allowed us to contemporaneously compare Alpha and Beta in terms of the characteristics, management, and outcomes of critically ill patients. A multicenter prospective cohort study was conducted on all consecutive adult patients who had laboratory confirmed SARS CoV-2 infection, underwent variant screening, and were admitted to one of four intensive care units (ICU) for acute respiratory failure between January 9th and May 15th, 2021. Primary outcome was 60-day mortality. Differences between Alpha and Beta in terms of other outcomes, patient variables, management, and vaccination characteristics were also explored by univariate analysis. The factors that associated with 60-day death in Alpha- and Beta-infected patients were examined with logistic regression analysis. In total, 333 patients (median age, 63 years; 68% male) were enrolled. Of these, 174 and 159 had Alpha and Beta, respectively. The two groups did not differ significantly in terms of 60-day mortality (19 vs. 23%), 28-day mortality (17 vs. 20%), need for mechanical ventilation (60 vs. 61%), mechanical ventilation duration (14 vs. 15 days), other management variables, patient demographic variables, comorbidities, or clinical variables on ICU admission. The vast majority of patients were unvaccinated (94%). The remaining 18 patients had received a partial vaccine course and 2 were fully vaccinated. The vaccinated patients were equally likely to have Alpha and Beta. Beta did not differ from Alpha in terms of patient characteristics, management, or outcomes in critically ill patients. ClinicalTrials.gov, identifier: NCT04906850.

The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. For the French translation of the abstract see Supplementary Materials section.

A previously healthy 46-year-old woman presented to emergency room with sudden asthenia, fever and diarrhea. Onset of a septic shock with multiple organ failure quickly led to intensive care unit management.

Rational To evaluate the respective impact of standard oxygen, high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) on oxygenation failure rate and mortality in COVID-19 patients admitted to intensive care units (ICUs). Methods Multicenter, prospective cohort study (COVID-ICU) in 137 hospitals in France, Belgium, and Switzerland. Demographic, clinical, respiratory support, oxygenation failure, and survival data were collected. Oxygenation failure was defined as either intubation or death in the ICU without intubation. Variables independently associated with oxygenation failure and Day-90 mortality were assessed using multivariate logistic regression. Results From February 25 to May 4, 2020, 4754 patients were admitted in ICU. Of these, 1491 patients were not intubated on the day of ICU admission and received standard oxygen therapy (51%), HFNC (38%), or NIV (11%) ( P  < 0.001). Oxygenation failure occurred in 739 (50%) patients (678 intubation and 61 death). For standard oxygen, HFNC, and NIV, oxygenation failure rate was 49%, 48%, and 60% ( P  < 0.001). By multivariate analysis, HFNC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.36–0.99, P  = 0.013) but not NIV (OR 1.57, 95% CI 0.78–3.21) was associated with a reduction in oxygenation failure). Overall 90-day mortality was 21%. By multivariable analysis, HFNC was not associated with a change in mortality (OR 0.90, 95% CI 0.61–1.33), while NIV was associated with increased mortality (OR 2.75, 95% CI 1.79–4.21, P  < 0.001). Conclusion In patients with COVID-19, HFNC was associated with a reduction in oxygenation failure without improvement in 90-day mortality, whereas NIV was associated with a higher mortality in these patients. Randomized controlled trials are needed.

Eligible participants were adults (aged ≥18 years) who were admitted to hospital with a positive PCR test for SARS-CoV-2 (<72 h before randomisation) and also had pulmonary rales or crackles with a peripheral oxygen saturation of 94% or less or required supplemental oxygen. Similar to findings from preliminary analyses, participants from the remdesivir group who were not on mechanical ventilation or ECMO when they were randomly assigned to a treatment group (n=692) had a significantly longer time to the composite endpoint of new mechanical ventilation, ECMO, or death in the 29 days following randomisation than did the control group (cumulative incidence in the remdesivir group was 58 [17%] of 343 participants vs 88 [25%] of 349 in the control group; adjusted hazard ratio [HR] 0·63 [95% CI 0·45–0·88]; p=0·010). In non-prespecified analyses, this effect was significant in participants with severe disease when they were randomly assigned to a treatment group (cumulative incidence in the remdesivir group 25 [29%] of 87 vs 47 [50%] of 94 in the control group; unadjusted HR 0·49 [95% CI 0·30–0·80]; p=0·0040) but not in those with moderate disease (33 (13%) of 256 vs 41 (16%) of 255; 0·79 [0·50–1·25]; p=0·31).

Background Limitations of life-sustaining therapies (LST) practices are frequent and vary among intensive care units (ICUs). However, scarce data were available during the COVID-19 pandemic when ICUs were under intense pressure. We aimed to investigate the prevalence, cumulative incidence, timing, modalities, and factors associated with LST decisions in critically ill COVID-19 patients. Methods We did an ancillary analysis of the European multicentre COVID-ICU study, which collected data from 163 ICUs in France, Belgium and Switzerland. ICU load, a parameter reflecting stress on ICU capacities, was calculated at the patient level using daily ICU bed occupancy data from official country epidemiological reports. Mixed effects logistic regression was used to assess the association of variables with LST limitation decisions. Results Among 4671 severe COVID-19 patients admitted from February 25 to May 4, 2020, the prevalence of in-ICU LST limitations was 14.5%, with a nearly six-fold variability between centres. Overall 28-day cumulative incidence of LST limitations was 12.4%, which occurred at a median of 8 days (3–21). Median ICU load at the patient level was 126%. Age, clinical frailty scale score, and respiratory severity were associated with LST limitations, while ICU load was not. In-ICU death occurred in 74% and 95% of patients, respectively, after LST withholding and withdrawal, while median survival time was 3 days (1–11) after LST limitations. Conclusions In this study, LST limitations frequently preceded death, with a major impact on time of death. In contrast to ICU load, older age, frailty, and the severity of respiratory failure during the first 24 h were the main factors associated with decisions of LST limitations.

Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring mechanical ventilation suffer from a high incidence of ventilator associated pneumonia (VAP), mainly related to Enterobacterales. Data regarding extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) VAP are scarce. We aimed to investigate risk factors and outcomes of ESBL-E related VAP among critically ill coronavirus infectious disease-19 (COVID-19) patients who developed Enterobacterales related VAP. Patients and methods We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU) that included 4929 COVID-19 critically ill patients. For the present analysis, only patients with complete data regarding resistance status of the first episode of Enterobacterales related VAP (ESBL-E and/or carbapenem-resistant Enterobacterales, CRE) and outcome were included. Results We included 591 patients with Enterobacterales related VAP. The main causative species were Enterobacter sp (n = 224) , E. coli (n = 111) and K. pneumoniae (n = 104). One hundred and fifteen patients (19%), developed a first ESBL-E related VAP, mostly related to Enterobacter sp (n = 40), K. pneumoniae (n = 36), and E. coli (n = 31). Eight patients (1%) developed CRE related VAP. In a multivariable analysis, African origin (North Africa or Sub-Saharan Africa) (OR 1.7 [1.07–2.71], p  = 0.02), time between intubation and VAP (OR 1.06 [1.02–1.09], p  = 0.002), PaO 2 /FiO 2 ratio on the day of VAP (OR 0.997 [0.994–0.999], p  = 0.04) and trimethoprim-sulfamethoxazole exposure (OR 3.77 [1.15–12.4], p  = 0.03) were associated with ESBL-E related VAP. Weaning from mechanical ventilation and mortality did not significantly differ between ESBL-E and non ESBL-E VAP. Conclusion ESBL-related VAP in COVID-19 critically-ill patients was not infrequent. Several risk factors were identified, among which some are modifiable and deserve further investigation. There was no impact of resistance of the first Enterobacterales related episode of VAP on outcome.

We investigated whether baseline levels of biomarkers related to endotheliopathy, thromboinflammation, and fibrosis were associated with clinical outcomes in hospitalized COVID-19 patients. We analyzed the associations between baseline levels of 21 biomarkers and time to hospital discharge and change in NEWS-2 score in patients from DisCoVeRy trial. We fitted multivariate models adjusted for baseline ISARIC 4C score, disease severity, D-dimer values, and treatment regimen. Between March 22 and June 29, 2020, 603 participants were randomized; 454 had a sample collected at baseline and analyzed. The backward selection of multivariate models showed that higher baseline levels of soluble suppressor of tumorigenicity 2 (sST2) and nucleosomes were statistically associated with a lower chance of hospital discharge before day 29 (sST2: aHR 0.24, 95% CI [0.15–0.38], p  < 10 −9 ; nucleosomes: aHR 0.62, 95% CI [0.48–0.81], p  < 10 −3 ). Likewise, higher levels of baseline sST2 were statistically associated with lower changes in the NEWS-2 score between baseline and day 15 (adjusted beta 4.47, 95% CI [2.65–6.28], p  < 10 −5 ). Moreover, we evaluated sST2 involvement in a confirmation cohort (SARCODO study, 103 patients) and found that elevated baseline sST2 levels were significantly associated with lower rates of hospital discharge before day 29 and a higher model performance (AUC at day 29 of 92%) compared to models without sST2. sST2 emerged as an independent predictor of clinical outcomes in two large cohort of hospitalized COVID-19 patients, warranting further investigation to elucidate its role in disease progression and potential as a therapeutic target.