Cardiac Adverse Events and Remdesivir in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19): A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial.

BACKGROUND: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) receiving remdesivir plus standard of care (SoC) compared to SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. METHODS: This post-hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19 (NCT04315948). Any first AE occurring between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves and Kaplan-Meier estimates were calculated for event rates. RESULTS: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (HR 1.0, 95% CI 0.7-1.5, p = 0.98), even when evaluating serious and non-serious cardiac AEs separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between remdesivir and control groups in the occurrence of different cardiac AE subclasses, including arrhythmic events (HR 1.1, 95% CI: 0.7-1.7, p = 0.68). CONCLUSIONS: Remdesivir treatment was not associated with an increased risk of cardiac AEs, whether serious or not, and regardless of AE severity, compared to control, in patients hospitalized with moderate or severe COVID-19. This is consistent with the results of other randomized controlled trials and meta-analyses.

Critically Ill Patients with Visceral Nocardia Infection, France and Belgium, 2004-2023.

We studied 50 patients with invasive nocardiosis treated during 2004-2023 in intensive care centers in France and Belgium. Most (65%) died in the intensive care unit or in the year after admission. Nocardia infections should be included in the differential diagnoses for patients in the intensive care setting.

Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death.

BACKGROUND: We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. METHODS: We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. FINDINGS: We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. INTERPRETATION: Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups. FUNDING: European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR).

Association between SARS-CoV-2 viral kinetics and clinical score evolution in hospitalized patients.

The role of antiviral treatment in coronavirus disease 2019 hospitalized patients is controversial. To address this question, we analyzed simultaneously nasopharyngeal viral load and the National Early Warning Score 2 (NEWS-2) using an effect compartment model to relate viral dynamics and the evolution of clinical severity. The model is applied to 664 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23) randomly assigned to either standard of care (SoC) or SoC + remdesivir. Then we use the model to simulate the impact of antiviral treatments on the time to clinical improvement, defined by a NEWS-2 score lower than 3 (in patients with NEWS-2 <7 at hospitalization) or 5 (in patients with NEWS-2 ≥7 at hospitalization), distinguishing between patients with low or high viral load at hospitalization. The model can fit well the different observed patients trajectories, showing that clinical evolution is associated with viral dynamics, albeit with large interindividual variability. Remdesivir antiviral activity was 22% and 78% in patients with low or high viral loads, respectively, which is not sufficient to generate a meaningful effect on NEWS-2. However, simulations predicted that antiviral activity greater than 99% could reduce by 2 days the time to clinical improvement in patients with high viral load, irrespective of the NEWS-2 score at hospitalization, whereas no meaningful effect was predicted in patients with low viral loads. Our results demonstrate that time to clinical improvement is associated with time to viral clearance and that highly effective antiviral drugs could hasten clinical improvement in hospitalized patients with high viral loads.

Pneumocystis jirovecii pneumonia in intensive care units: a multicenter study by ESGCIP and EFISG.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. MATERIALS AND METHODS: The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. RESULTS: Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13-9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23-11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07-33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76-10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01-4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42-1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. CONCLUSION: PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.

Rationale and evidence for the use of new beta-lactam/beta-lactamase inhibitor combinations and cefiderocol in critically ill patients.

BACKGROUND: Healthcare-associated infections involving Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) phenotype are associated with impaired patient-centered outcomes and poses daily therapeutic challenges in most of intensive care units worldwide. Over the recent years, four innovative ß-lactam/ß-lactamase inhibitor (BL/BLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam) and a new siderophore cephalosporin (cefiderocol) have been approved for the treatment of certain DTR-GNB infections. The literature addressing their microbiological spectrum, pharmacokinetics, clinical efficacy and safety was exhaustively audited by our group to support the recent guidelines of the French Intensive Care Society on their utilization in critically ill patients. This narrative review summarizes the available evidence and unanswered questions on these issues. METHODS: A systematic search for English-language publications in PUBMED and the Cochrane Library database from inception to November 15, 2022. RESULTS: These drugs have demonstrated relevant clinical success rates and a reduced renal risk in most of severe infections for whom polymyxin- and/or aminoglycoside-based regimen were historically used as last-resort strategies-namely, ceftazidime-avibactam for infections due to Klebsiella pneumoniae carbapenemase (KPC)- or OXA-48-like-producing Enterobacterales, meropenem-vaborbactam for KPC-producing Enterobacterales, ceftazidime-avibactam/aztreonam combination or cefiderocol for metallo-ß-lactamase (MBL)-producing Enterobacterales, and ceftolozane-tazobactam, ceftazidime-avibactam and imipenem-relebactam for non-MBL-producing DTR Pseudomonas aeruginosa. However, limited clinical evidence exists in critically ill patients. Extended-infusion scheme (except for imipenem-relebactam) may be indicated for DTR-GNB with high minimal inhibitory concentrations and/or in case of augmented renal clearance. The potential benefit of combining these agents with other antimicrobials remains under-investigated, notably for the most severe presentations. Other important knowledge gaps include pharmacokinetic information in particular situations (e.g., pneumonia, other deep-seated infections, and renal replacement therapy), the hazard of treatment-emergent resistance and possible preventive measures, the safety of high-dose regimen, the potential usefulness of rapid molecular diagnostic tools to rationalize their empirical utilization, and optimal treatment durations. Comparative clinical, ecological, and medico-economic data are needed for infections in whom two or more of these agents exhibit in vitro activity against the causative pathogen. CONCLUSIONS: New BL/BLI combinations and cefiderocol represent long-awaited options for improving the management of DTR-GNB infections. Several research axes must be explored to better define the positioning and appropriate administration scheme of these drugs in critically ill patients.

Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial.

The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-ß1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities.

Development of a Decision Support Tool for Anticoagulation in Critically Ill Patients Admitted for SARS-CoV-2 Infection: The CALT Protocol.

Severe COVID-19 infections are at high risk of causing thromboembolic events (TEEs). However, the usual exams may be unavailable or unreliable in predicting the risk of TEEs at admission or during hospitalization. We performed a retrospective analysis of two centers (n = 124 patients) including severe COVID-19 patients to determine the specific risk factors of TEEs in SARS-CoV-2 infection at admission and during stays at the intensive care unit (ICU). We used stepwise regression to create two composite scores in order to predict TEEs in the first 48 h (H0-H48) and during the first 15 days (D1-D15) in ICU. We then evaluated the performance of our scores in our cohort. During the period H0-H48, patients with a TEE diagnosis had higher D-Dimers and ferritin values at day 1 (D1) and day 3 (D3) and a greater drop in fibrinogen between D1 and D3 compared with patients without TEEs. Over the period D1-D15, patients with a diagnosis of a TEE showed a more marked drop in fibrinogen and had higher D-Dimers and lactate dehydrogenase (LDH) values at D1 and D3. Based on ROC analysis, the COVID-related acute lung and deep vein thrombosis (CALT) 1 score, calculated at D1, had a diagnostic performance for TEEs at H0-H48, estimated using an area under the curve (AUC) of 0.85 (CI95%: 0.76-0.93, p < 10-3). The CALT 2 score, calculated at D3, predicted the occurrence of TEEs over the period D1-D15 with an estimated AUC of 0.85 (CI95%: 0.77-0.93, p < 10-3). These two scores were used as the basis for the development of the CALT protocol, a tool to assist in the decision to use anticoagulation during severe SARS-CoV-2 infections. The CALT scores showed good performances in predicting the risk of TEEs in severe COVID-19 patients at admission and during ICU stays. They could, therefore, be used as a decision support protocol on whether or not to initiate therapeutic anticoagulation.

Impact of corticosteroids use on midterm sequelae in survivors of COVID-19 admitted to hospital: A prospective cohort study.

An understanding of the midterm sequelae in COVID-19 and their association with corticosteroids use are needed. Between March and July 2020, we evaluated 1227 survivors of COVID-19, 3 months posthospitalization, of whom 213 had received corticosteroids within 7 days of admission. Main outcome was any midterm sequelae (oxygen therapy, shortness of breath, one major clinical sign, two minor clinical signs or three minor symptoms). Association between corticosteroids use and midterm sequelae was assessed using inverse propensity-score weighting models. Our sample included 753 (61%) male patients, and 512 (42%) were older than 65 years. We found a higher rate of sequelae among users than nonusers of corticosteroids (42% vs. 35%, odds ratio [OR] 1.40 [1.16-1.69]). Midterm sequelae were more frequent in users of low-dose corticosteroids than nonusers (64% vs. 51%, OR 1.60 [1.10-2.32]), whereas no association between higher doses (≥20 mg/day equivalent of dexamethasone) and sequelae was evidenced (OR 0.95 [0.56-1.61]). Higher risk of sequelae with corticosteroids use was observed among subjects with propensity score below the 90th percentile. Our study suggest that corticosteroids use during hospitalization for COVID-19 is associated with higher risk of midterm sequelae.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Prevalence of post-acute coronavirus disease 2019 symptoms twelve months after hospitalization in participants retained in follow-up: analyses stratified by gender from a large prospective cohort.

OBJECTIVES: Persistent post-acute coronavirus disease 2019 (COVID-19) symptoms (PACSs) have been reported up to 6 months after hospital discharge. Herein we assessed the symptoms that persisted 12 months (M12) after admission for COVID-19 in the longitudinal prospective national French coronavirus disease cohort. METHODS: Hospitalized patients with a confirmed virological diagnosis of COVID-19 were enrolled. Follow-up was planned until M12 after admission. Associations between persistence of ≥3 PACSs at M12 and clinical characteristics at admission were assessed through logistic regression according to gender. RESULTS: We focused on participants enrolled between 24 January 2020 and 15 July 2020, to allow M12 follow-up. The M12 data were available for 737 participants. Median age was 61 years, 475 (64%) were men and 242/647 (37%) were admitted to intensive care units during the acute phase. At M12, 27% (194/710) of the participants had ≥3 persistent PACS, mostly fatigue, dyspnoea and joint pain. Among those who had a professional occupation before the acute phase, 91 out of 339 (27%) were still on sick leave at M12. Presence of ≥3 persistent PACS was associated with female gender, both anxiety and depression, impaired health-related quality of life and Medical Muscle Research Council Scale <57. Compared with men, women more often reported presence of ≥3 persistent PACSs (98/253, 39% vs. 96/457, 21%), depression and anxiety (18/152, 12% vs. 17/268, 6% and 33/156, 21% vs. 26/264, 10%, respectively), impaired physical health-related quality of life (76/141, 54% vs. 120/261, 46%). Women had less often returned to work than men (77/116, 66% vs. 171/223, 77%). CONCLUSIONS: One fourth of the individuals admitted to hospital for COVID-19 still had ≥3 persistent PACSs at M12 post-discharge. Women reported more often ≥3 persistent PACSs, suffered more from anxiety and depression and had less often returned to work than men.

Effects of high oxygen tension on healthy volunteer microcirculation.

INTRODUCTION: Previous studies have highlighted hyperoxia-induced microcirculation modifications, but few have focused on hyperbaric oxygen (HBO) effects. Our primary objective was to explore hyperbaric hyperoxia effects on the microcirculation of healthy volunteers and investigate whether these modifications are adaptative or not. METHODS: This single centre, open-label study included 15 healthy volunteers. Measurements were performed under five conditions: T0) baseline value (normobaric normoxia); T1) hyperbaric normoxia; T2) hyperbaric hyperoxia; T3) normobaric hyperoxia; T4) return to normobaric normoxia. Microcirculatory data were gathered via laser Doppler, near-infrared spectroscopy and transcutaneous oximetry (PtcO2). Vascular-occlusion tests were performed at each step. We used transthoracic echocardiography and standard monitoring for haemodynamic investigation. RESULTS: Maximal alterations were observed under hyperbaric hyperoxia which led, in comparison with baseline, to arterial hypertension (mean arterial pressure 105 (SD 12) mmHg vs 95 (11), P < 0.001) and bradycardia (55 (7) beats·min⁻¹ vs 66 (8), P < 0.001) while cardiac output remained unchanged. Hyperbaric hyperoxia also led to microcirculatory vasoconstriction (rest flow 63 (74) vs 143 (73) perfusion units, P < 0.05) in response to increased PtcO2 (104.0 (45.9) kPa vs 6.3 (2.4), P < 0.0001); and a decrease in laser Doppler parameters indicating vascular reserve (peak flow 125 (89) vs 233 (79) perfusion units, P < 0.05). Microvascular reactivity was preserved in every condition. CONCLUSIONS: Hyperoxia significantly modifies healthy volunteer microcirculation especially during HBO exposure. The rise in PtcO2 promotes an adaptative vasoconstrictive response to protect cellular integrity. Microvascular reactivity remains unaltered and vascular reserve is mobilised in proportion to the extent of the ischaemic stimulus.

The Changing Landscape of Invasive Fungal Infections in ICUs: A Need for Risk Stratification to Better Target Antifungal Drugs and the Threat of Resistance.

The landscape of invasive candidiasis and invasive aspergillosis has changed dramatically in intensive care units over the past two decades. Today, we are faced with new risk factors such as the emergence of resistance, but are also equipped with new therapeutic strategies and diagnostic tools which are changing epidemiological data and diagnostic algorithms. Some common points need to be addressed: (i) the best way to use microbiological tools and to integrate their results in decisional algorithms; (ii) the need to find the optimum balance between under-diagnosis and overtreatment; (iii) and the need to decipher pathophysiology. In this short review, we will try to illustrate these points.

Κey Role of Early Source Control in Candidemic Patients With Sepsis or Septic Shock.

Background: Despite advances in diagnostic and therapeutic approaches, candidemia remains associated with high mortality rates. This study aimed at identifying predictors of mortality among patients with candidemia, with a focus on early interventions that can improve prognosis. Methods: This was a single-center retrospective study including all adult patients with at least 1 positive blood culture for Candida species from 2014 to 2021. Results: A total of 222 episodes of candidemia were included. Most candidemias were of unknown origin (36%) or vascular catheter related (29%). Septic shock developed in 29% episodes. Overall, 14-day mortality rate was 23%. In univariate analyses, septic shock was associated with higher 14-day mortality, whereas catheter-related candidemia and early (<72 hours) interventions, such as appropriate antifungal therapy, source control, and infectious diseases consultation, were associated with improved survival. In a Cox multivariate regression model, septic shock (odds ratio [OR], 3.62 [95% confidence interval {CI}, 2.05-6.38]) was associated with higher mortality. While the impact of early antifungal therapy did not reach statistical significance, early (<72 hours) infectious diseases consultation (OR, 0.46 [95% CI, .23-.91]) and early source control (OR, 0.15 [95% CI, .08-.31]) were associated with better survival. Subanalyses showed that the benefits of early source control, specifically catheter removal, were significant among patients with sepsis or septic shock, but not among those without sepsis. These associations remained significant after exclusion of patients who died prematurely or were in palliative care. Conclusions: Early source control, in particular catheter removal, was a key determinant of outcome among candidemic patients with sepsis or septic shock.

High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial.

Importance: The benefit of high-dose dexamethasone and oxygenation strategies vs standard of care for patients with severe acute hypoxemic respiratory failure (AHRF) caused by COVID-19 pneumonia is debated. Objectives: To assess the benefit of high-dose dexamethasone compared with standard of care dexamethasone, and to assess the benefit of high-flow nasal oxygen (HFNo2) or continuous positive airway pressure (CPAP) compared with oxygen support standard of care (o2SC). Design, Setting, and Participants: This multicenter, placebo-controlled randomized clinical trial was conducted in 19 intensive care units (ICUs) in France from April 2020 to January 2021. Eligible patients were consecutive ICU-admitted adults with COVID-19 AHRF. Randomization used a 2 × 3 factorial design for dexamethasone and oxygenation strategies; patients not eligible for at least 1 oxygenation strategy and/or already receiving invasive mechanical ventilation (IMV) were only randomized for dexamethasone. All patients were followed-up for 60 days. Data were analyzed from May 26 to July 31, 2021. Interventions: Patients received standard dexamethasone (dexamethasone-phosphate 6 mg/d for 10 days [or placebo prior to RECOVERY trial results communication]) or high-dose dexamethasone (dexamethasone-phosphate 20 mg/d on days 1-5 then 10 mg/d on days 6-10). Those not requiring IMV were additionally randomized to o2SC, CPAP, or HFNo2. Main Outcomes and Measures: The main outcomes were time to all-cause mortality, assessed at day 60, for the dexamethasone interventions, and time to IMV requirement, assessed at day 28, for the oxygenation interventions. Differences between intervention groups were calculated using proportional Cox models and expressed as hazard ratios (HRs). Results: Among 841 screened patients, 546 patients (median [IQR] age, 67.4 [59.3-73.1] years; 414 [75.8%] men) were randomized between standard dexamethasone (276 patients, including 37 patients who received placebo) or high-dose dexamethasone (270 patients). Of these, 333 patients were randomized among o2SC (109 patients, including 56 receiving standard dexamethasone), CPAP (109 patients, including 57 receiving standard dexamethasone), and HFNo2 (115 patients, including 56 receiving standard dexamethasone). There was no difference in 60-day mortality between standard and high-dose dexamethasone groups (HR, 0.96 [95% CI, 0.69-1.33]; P = .79). There was no significant difference for the cumulative incidence of IMV criteria at day 28 among o2 support groups (o2SC vs CPAP: HR, 1.08 [95% CI, 0.71-1.63]; o2SC vs HFNo2: HR, 1.04 [95% CI, 0.69-1.55]) or 60-day mortality (o2SC vs CPAP: HR, 0.97 [95% CI, 0.58-1.61; o2SC vs HFNo2: HR, 0.89 [95% CI, 0.53-1.47]). Interactions between interventions were not significant. Conclusions and Relevance: In this randomized clinical trial among ICU patients with COVID-19-related AHRF, high-dose dexamethasone did not significantly improve 60-day survival. The oxygenation strategies in patients who were not initially receiving IMV did not significantly modify 28-day risk of IMV requirement. Trial Registration: ClinicalTrials.gov Identifier: NCT04344730; EudraCT: 2020-001457-43.