Epidemiology and Outcome of Early-Onset Acute Kidney Injury and Recovery in Critically Ill COVID-19 Patients: A Retrospective Analysis.

BACKGROUND: The clinical significance of early-onset acute kidney injury (EO-AKI) and recovery in severe COVID-19 intensive care unit (ICU) patients is poorly documented. OBJECTIVE: The aim of the study was to assess the epidemiology and outcome of EO-AKI and recovery in ICU patients admitted for SARS-CoV-2 pneumonia. DESIGN: This was a retrospective single-centre study. SETTING: The study was carried out at the medical ICU of the university hospital of Clermont-Ferrand, France. PATIENTS: All consecutive adult patients aged ≥18 years admitted between 20 March 2020 and 31 August 2021 for SARS-CoV-2 pneumonia were enrolled. Patients with chronic kidney disease, referred from another ICU, and with an ICU length of stay (LOS) ≤72 h were excluded. INTERVENTIONS: EO-AKI was defined on the basis of serum creatinine levels according to the Kidney Disease Improving Global Outcomes criteria, developing ≤7 days. Depending on renal recovery, defined by the normalization of serum creatinine levels, EO-AKI was transient (recovery within 48 h), persistent (recovery between 3 and 7 days) or AKD (no recovery within 7 days after EO-AKI onset). MEASUREMENTS: Uni- and multivariate analyses were performed to determine factors associated with EO-AKI and EO-AKI recovery. MAIN RESULTS: EO-AKI occurred in 84/266 (31.5%) study patients, of whom 42 (50%), 17 (20.2%) and 25 (29.7%) had EO-AKI stages 1, 2 and 3, respectively. EO-AKI was classified as transient, persistent and AKD in 40 (47.6%), 15 (17.8%) and 29 (34.6%) patients, respectively. The 90-day mortality was 87/244 (35.6%) and increased with EO-AKI occurrence and severity: no EO-AKI, 38/168 (22.6%); EO-AKI stage 1, 22/39 (56.4%); stage 2, 9/15 (60%); and stage 3, 18/22 (81.8%) (p < 0.01). The 90-day mortality in patients with transient or persistent AKI and AKD was 20/36 (55.6%), 8/14 (57.1%) and 21/26 (80.8%), respectively (p < 0.01). MAKE-90 occurred in 42.6% of all patients. CONCLUSIONS: In ICU patients admitted for SARS-CoV-2 pneumonia, the development of EO-AKI and time to recovery beyond day 7 of onset were associated with poor outcome.

‘Which severe COVID-19 patients could benefit from High dose dexamethasone? A Bayesian reanalysis of a randomized clinical trial (preprint)

Background: The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching opposite conclusions. In the COVIDICUS trial, we argued against any additional benefit of high-dose dexamethasone (DXM20). We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care dose of DXM (DXMSoC). Methods: We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXM6 or DXM20 in the COVIDICUS trial. The primary outcome was the 60-day mortality rate of DXM20 over DXMSoC, with the treatment effect measured on the posterior mean of relative risk (RR) estimated using a beta-binomial model with 95% credibility intervals (95% CrI). Bayesian measures of interaction quantified the probability of interaction (Pr Interact) that the RR of 60-day death differed across the subsets by 20%. Results: Overall, the posterior mean RR of Day 60 mortality was 1.06 with a 95% credible confidence interval (0.77 to 1.44) and a posterior probability of benefit and harm of 27.0% and 50.5%, respectively. There was some evidence of treatment by subset interaction according to age, with the benefit increasing in patients aged below 70 years (RR=0.74, 95% CrI 0.41-1.22) compared to those aged above 70 (RR=1.12, 95% CrI 0.77 to 1.60) (Pr Interact, 77%), when the time since symptoms onset was lower than 7 days (RR=0.66, 95% CrI 0. 36 to 1.09) compared to 7 days or more (RR=1.15, 95% CrI 0.76 to 1.67) (Pr Interact, 90%) and in patients receiving remdesivir (RR=0.62, 95% CrI 0.29 to 1.14) compared to those who did not (RR=1.12, 95% CrI 0.78 to 1.58) (Pr Interact, 88%). Conclusions: In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings. Trial registration: NCT04344730, date of registration April 14, 2020 (https://clinicaltrials.gov/ct2/show/NCT04344730?term=NCT04344730&draw=2&rank=1); EudraCT: 2020-001457-43 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001457-43).

Ventilator-Associated Pneumonia in COVID-19 Patients Admitted in Intensive Care Units: Relapse, Therapeutic Failure and Attributable Mortality-A Multicentric Observational Study from the OutcomeRea Network.

Introduction: Ventilator-associated pneumonia (VAP) incidence is high among critically ill COVID-19 patients. Its attributable mortality remains underestimated, especially for unresolved episodes. Indeed, the impact of therapeutic failures and the determinants that potentially affect mortality are poorly evaluated. We assessed the prognosis of VAP in severe COVID-19 cases and the impact of relapse, superinfection, and treatment failure on 60-day mortality. Methods: We evaluated the incidence of VAP in a multicenter prospective cohort that included adult patients with severe COVID-19, who required mechanical ventilation for ≥48 h between March 2020 and June 2021. We investigated the risk factors for 30-day and 60-day mortality, and the factors associated with relapse, superinfection, and treatment failure. Results: Among 1424 patients admitted to eleven centers, 540 were invasively ventilated for 48 h or more, and 231 had VAP episodes, which were caused by Enterobacterales (49.8%), P. aeruginosa (24.8%), and S. aureus (22%). The VAP incidence rate was 45.6/1000 ventilator days, and the cumulative incidence at Day 30 was 60%. VAP increased the duration of mechanical ventilation without modifying the crude 60-day death rate (47.6% vs. 44.7% without VAP) and resulted in a 36% increase in death hazard. Late-onset pneumonia represented 179 episodes (78.2%) and was responsible for a 56% increase in death hazard. The cumulative incidence rates of relapse and superinfection were 45% and 39.5%, respectively, but did not impact death hazard. Superinfection was more frequently related to ECMO and first episode of VAP caused by non-fermenting bacteria. The risk factors for treatment failure were an absence of highly susceptible microorganisms and vasopressor need at VAP onset. Conclusions: The incidence of VAP, mainly late-onset episodes, is high in COVID-19 patients and associated with an increased risk of death, similar to that observed in other mechanically ventilated patients. The high rate of VAP due to difficult-to-treat microorganisms, pharmacokinetic alterations induced by renal replacement therapy, shock, and ECMO likely explains the high cumulative risk of relapse, superinfection, and treatment failure.

Hypercoagulability in critically ill patients with COVID 19, an observational prospective study.

OBJECTIVE: COVID 19 is often associated with hypercoagulability and thromboembolic (TE) events. The aim of this study was to assess the characteristics of hypercoagulability and its relationship with new-onset TE events and the composite outcome of need for intubation and/or death in intensive care unit (ICU) patients admitted for COVID. DESIGN: Prospective observational study. SETTING: Monocentric, intensive care, University Hospital of Clermont Ferrand, France. PATIENTS: Patients admitted to intensive care from January 2020 to May 2021 for COVID-19 pneumonia. INTERVENTIONS: Standard hemostatic tests and rotational thromboelastometry (ROTEM) were performed on admission and on day 4. Hypercoagulability was defined by at least one of the following criteria: D-dimers > 3000 µg/dL, fibrinogen > 8 g/L, EXTEM CFT below the normal range, EXTEM A5, MCF, Li 60 above the normal range, and EXTEM G-score ((5000 x MCF) / (100-MCF)) ≥ 11 dyne/cm2. MEASUREMENTS AND MAIN RESULTS: Of the 133 patients included, 17 (12.7%) developed new-onset TE events, and 59 (44.3%) required intubation and/or died in the ICU. ROTEM was performed in 133 patients on day 1 and in 67 on day 4. Hypercoagulability was present on day 1 in 115 (86.4%) patients. None of the hypercoagulability indices were associated with subsequent new-onset TE events on days 1 and 4 nor with the need for intubation and/or ICU death. Hyperfibrinogenemia > 8g/dL, higher D-dimers and higher EXTEM Li 60 on day 4 were predictive of need for intubation and/or of ICU death. CONCLUSIONS: Our study confirmed that most COVID-19 ICU patients have hypercoagulability on admission and almost all on day 4. Hyperfibrinogenemia or fibrinolysis shutdown on day 4 were associated with unfavorable outcome.

Bacterial Pulmonary Co-Infections on ICU Admission: Comparison in Patients with SARS-CoV-2 and Influenza Acute Respiratory Failure: A Multicentre Cohort Study.

BACKGROUND: Few data are available on the impact of bacterial pulmonary co-infection (RespCoBact) during COVID-19 (CovRespCoBact). The aim of this study was to compare the prognosis of patients admitted to an ICU for influenza pneumonia and for SARS-CoV-2 pneumonia with and without RespCoBact. METHODS: This was a multicentre (n = 11) observational study using the Outcomerea© database. Since 2008, all patients admitted with influenza pneumonia or SARS-CoV-2 pneumonia and discharged before 30 June 2021 were included. Risk factors for day-60 death and for ventilator-associated-pneumonia (VAP) in patients with influenza pneumonia or SARS-CoV-2 pneumonia with or without RespCoBact were determined. RESULTS: Of the 1349 patients included, 157 were admitted for influenza and 1192 for SARS-CoV-2. Compared with the influenza patients, those with SARS-CoV-2 had lower severity scores, were more often under high-flow nasal cannula, were less often under invasive mechanical ventilation, and had less RespCoBact (8.2% for SARS-CoV-2 versus 24.8% for influenza). Day-60 death was significantly higher in patients with SARS-CoV-2 pneumonia with no increased risk of mortality with RespCoBact. Patients with influenza pneumonia and those with SARS-CoV-2 pneumonia had no increased risk of VAP with RespCoBact. CONCLUSIONS: SARS-CoV-2 pneumonia was associated with an increased risk of mortality compared with Influenza pneumonia. Bacterial pulmonary co-infections on admission were not associated with patient survival rates nor with an increased risk of VAP.

Fluid balance neutralization secured by hemodynamic monitoring versus protocolized standard of care in critically ill patients requiring continuous renal replacement therapy: study protocol of the GO NEUTRAL randomized controlled trial.

BACKGROUND: Fluid overload is associated with worse outcome in critically ill patients requiring continuous renal replacement therapy (CRRT). Net ultrafiltration (UFNET) allows precise control of the fluid removal but is frequently ceased due to hemodynamic instability episodes. However, approximately 50% of the hemodynamic instability episodes in ICU patients treated with CRRT are not associated with preload dependence (i.e., are not related to a decrease in cardiac preload), suggesting that volume removal is not responsible for these episodes of hemodynamic impairment. The use of advanced hemodynamic monitoring, comprising continuous cardiac output monitoring to repeatedly assess preload dependency, could allow securing UFNET to allow fluid balance control and prevent fluid overload. METHODS: The GO NEUTRAL trial is a multicenter, open-labeled, randomized, controlled, superiority trial with parallel groups and balanced randomization with a 1:1 ratio. The trial will enroll adult patients with acute circulatory failure treated with vasopressors and severe acute kidney injury requiring CRRT who already have been equipped with a continuous cardiac output monitoring device. After informed consent, patients will be randomized into two groups. The control group will receive protocolized fluid removal with an UFNET rate set to 0-25 ml h-1 between inclusion and H72 of inclusion. The intervention group will be treated with an UFNET rate set on the CRRT of at least 100 ml h-1 between inclusion and H72 of inclusion if hemodynamically tolerated based on a protocolized hemodynamic protocol aiming to adjust UFNET based on cardiac output, arterial lactate concentration, and preload dependence assessment by postural maneuvers, performed regularly during nursing rounds, and in case of a hemodynamic instability episode. The primary outcome of the study will be the cumulative fluid balance between inclusion and H72 of inclusion. Randomization will be generated using random block sizes and stratified based on fluid overload status at inclusion. The main outcome will be analyzed in the modified intention-to-treat population, defined as all alive patients at H72 of inclusion, based on their initial allocation group. DISCUSSION: We present in the present protocol all study procedures in regard to the achievement of the GO NEUTRAL trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial result report. Enrollment of patients in the GO NEUTRAL trial has started on June 31, 2021, and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04801784. Registered on March 12, 2021, before the start of inclusion.

Augmented renal clearance in the ICU: estimation, incidence, risk factors and consequences-a retrospective observational study.

BACKGROUND: Augmented renal clearance (ARC) remains poorly evaluated in ICU. The objective of this study is to provide a full description of ARC in ICU including prevalence, evolution profile, risk factors and outcomes. METHODS: This was a retrospective, single-center, observational study. All the patients older than 18 years admitted for the first time in Medical ICU, Bichat, University Hospital, APHP, France, between January 1, 2017, and November 31, 2020 and included into the Outcomerea database with an ICU length of stay longer than 72 h were included. Patients with chronic kidney disease were excluded. Glomerular filtration rate was estimated each day during ICU stay using the measured creatinine renal clearance (CrCl). Augmented renal clearance (ARC) was defined as a 24 h CrCl greater than 130 ml/min/m2. RESULTS: 312 patients were included, with a median age of 62.7 years [51.4; 71.8], 106(31.9%) had chronic cardiovascular disease. The main reason for admission was acute respiratory failure (184(59%)) and 196(62.8%) patients had SARS-COV2. The median value for SAPS II score was 32[24; 42.5]; 146(44%) and 154(46.4%) patients were under vasopressors and invasive mechanical ventilation, respectively. The overall prevalence of ARC was 24.6% with a peak prevalence on Day 5 of ICU stay. The risk factors for the occurrence of ARC were young age and absence of cardiovascular comorbidities. The persistence of ARC during more than 10% of the time spent in ICU was significantly associated with a lower risk of death at Day 30. CONCLUSION: ARC is a frequent phenomenon in the ICU with an increased incidence during the first week of ICU stay. Further studies are needed to assess its impact on patient prognosis.

Association of nitrogen balance trajectories with clinical outcomes in critically ill COVID-19 patients: A retrospective cohort study.

BACKGROUND & AIMS: The intensity and duration of the catabolic phase in COVID-19 patients can differ between survivors and non-survivors. The purpose of the study was to assess the determinants of, and association between, nitrogen balance trajectories and outcome in critically ill COVID-19 patients. METHODS: This retrospective monocentric observational study involved patients admitted to the intensive care unit (ICU) of the University Hospital of Clermont Ferrand, France, from January 2020 to May 2021 for COVID-19 pneumonia. Patients were excluded if referred from another ICU, if their ICU length of stay was <72 h, or if they were treated with renal replacement therapy during the first seven days after ICU admission. Data were collected prospectively at admission and during ICU stay. Death was recorded at the end of ICU stay. Comparisons of the time course of nitrogen balance according to outcome were analyzed using two-way ANOVA. At days 3, 5, 7, 10 and 14, uni- and multivariate logistic regression analyses were performed to assess the impact of a non-negative nitrogen-balance on ICU death. To investigate the relationships between nitrogen balance, inflammatory markers and protein intake, linear and non-nonlinear models were run at days 3, 5 and 7, and the amount of protein intake necessary to reach a neutral nitrogen balance was calculated. Subgroup analyses were carried out according to BMI, age, and sex. RESULTS: 99 patients were included. At day 3, a similar negative nitrogen balance was observed in survivors and non-survivors: -16.4 g/d [-26.5, -3.3] and -17.3 g/d [-22.2, -3.8] (p = 0.54). The trajectories of nitrogen balance over time thus differed between survivors and non-survivors (p = 0.01). In survivors, nitrogen balance increased over time, but decreased from day 2 to day 6 in non-survivors, and thereafter increased slowly up to day 14. At days 5 and 7, a non-negative nitrogen-balance was protective from death. Administering higher protein amounts was associated with higher nitrogen balance. CONCLUSION: We report a prolonged catabolic state in COVID patients that seemed more pronounced in non-survivors than in survivors. Our study underlines the need for monitoring urinary nitrogen excretion to guide the amount of protein intake required by COVID-19 patients.

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.

Severe COVID-19 is characterized by the co-occurrence of moderate cytokine inflammation and severe monocyte dysregulation.

BACKGROUND: SARS-CoV-2 has been responsible for considerable mortality worldwide, owing in particular to pulmonary failures such as ARDS, but also to other visceral failures and secondary infections. Recent progress in the characterization of the immunological mechanisms that result in severe organ injury led to the emergence of two successive hypotheses simultaneously tested here: hyperinflammation with cytokine storm syndrome or dysregulation of protective immunity resulting in immunosuppression and unrestrained viral dissemination. METHODS: In a prospective observational monocentric study of 134 patients, we analysed a panel of plasma inflammatory and anti-inflammatory cytokines and measured monocyte dysregulation via their membrane expression of HLA-DR. We first compared the results of patients with moderate forms hospitalized in an infectious disease unit with those of patients with severe forms hospitalized in an intensive care unit. In the latter group of patients, we then analysed the differences between the surviving and non-surviving groups and between the groups with or without secondary infections. FINDINGS: Higher blood IL-6 levels, lower quantitative expression of HLA-DR on blood monocytes and higher IL-6/mHLA-DR ratios were statistically associated with the risk of severe forms of the disease and among the latter with death and the early onset of secondary infections. INTERPRETATION: The unique immunological profile in patients with severe COVID-19 corresponds to a moderate cytokine inflammation associated with severe monocyte dysregulation. Individuals with major CSS were rare in our cohort of hospitalized patients, especially since the use of corticosteroids, but formed a very severe subgroup of the disease. FUNDING: None.

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.

Impact of early corticosteroids on 60-day mortality in critically ill patients with COVID-19: A multicenter cohort study of the OUTCOMEREA network.

OBJECTIVES: In severe COVID-19 pneumonia, the appropriate timing and dosing of corticosteroids (CS) is not known. Patient subgroups for which CS could be more beneficial also need appraisal. The aim of this study was to assess the effect of early CS in COVID-19 pneumonia patients admitted to the ICU on the occurrence of 60-day mortality, ICU-acquired-bloodstream infections(ICU-BSI), and hospital-acquired pneumonia and ventilator-associated pneumonia(HAP-VAP). METHODS: We included patients with COVID-19 pneumonia admitted to 11 ICUs belonging to the French OutcomeReaTM network from January to May 2020. We used survival models with ponderation with inverse probability of treatment weighting (IPTW). RESULTS: The study population comprised 303 patients having a median age of 61.6 (53-70) years of whom 78.8% were male and 58.6% had at least one comorbidity. The median SAPS II was 33 (25-44). Invasive mechanical ventilation was required in 34.8% of the patients. Sixty-six (21.8%) patients were in the Early-C subgroup. Overall, 60-day mortality was 29.4%. The risks of 60-day mortality (IPTWHR = 0.86;95% CI 0.54 to 1.35, p = 0.51), ICU-BSI and HAP-VAP were similar in the two groups. Importantly, early CS treatment was associated with a lower mortality rate in patients aged 60 years or more (IPTWHR, 0.53;95% CI, 0.3-0.93; p = 0.03). In contrast, CS was associated with an increased risk of death in patients younger than 60 years without inflammation on admission (IPTWHR = 5.01;95% CI, 1.05, 23.88; p = 0.04). CONCLUSION: For patients with COVID-19 pneumonia, early CS treatment was not associated with patient survival. Interestingly, inflammation and age can significantly influence the effect of CS.

Multistate Modeling of COVID-19 Patients Using a Large Multicentric Prospective Cohort of Critically Ill Patients.

The mortality of COVID-19 patients in the intensive care unit (ICU) is influenced by their state at admission. We aimed to model COVID-19 acute respiratory distress syndrome state transitions from ICU admission to day 60 outcome and to evaluate possible prognostic factors. We analyzed a prospective French database that includes critically ill COVID-19 patients. A six-state multistate model was built and 17 transitions were analyzed either using a non-parametric approach or a Cox proportional hazard model. Corticosteroids and IL-antagonists (tocilizumab and anakinra) effects were evaluated using G-computation. We included 382 patients in the analysis: 243 patients were admitted to the ICU with non-invasive ventilation, 116 with invasive mechanical ventilation, and 23 with extracorporeal membrane oxygenation. The predicted 60-day mortality was 25.9% (95% CI: 21.8%-30.0%), 44.7% (95% CI: 48.8%-50.6%), and 59.2% (95% CI: 49.4%-69.0%) for a patient admitted in these three states, respectively. Corticosteroids decreased the risk of being invasively ventilated (hazard ratio (HR) 0.59, 95% CI: 0.39-0.90) and IL-antagonists increased the probability of being successfully extubated (HR 1.8, 95% CI: 1.02-3.17). Antiviral drugs did not impact any transition. In conclusion, we observed that the day-60 outcome in COVID-19 patients is highly dependent on the first ventilation state upon ICU admission. Moreover, we illustrated that corticosteroid and IL-antagonists may influence the intubation duration.

Association Between Early Invasive Mechanical Ventilation and Day-60 Mortality in Acute Hypoxemic Respiratory Failure Related to Coronavirus Disease-2019 Pneumonia.

OBJECTIVES: About 5% of patients with coronavirus disease-2019 are admitted to the ICU for acute hypoxemic respiratory failure. Opinions differ on whether invasive mechanical ventilation should be used as first-line therapy over noninvasive oxygen support. The aim of the study was to assess the effect of early invasive mechanical ventilation in coronavirus disease-2019 with acute hypoxemic respiratory failure on day-60 mortality. DESIGN: Multicenter prospective French observational study. SETTING: Eleven ICUs of the French OutcomeRea network. PATIENTS: Coronavirus disease-2019 patients with acute hypoxemic respiratory failure (Pao2/Fio2 ≤ 300 mm Hg), without shock or neurologic failure on ICU admission, and not referred from another ICU or intermediate care unit were included. INTERVENTION: We compared day-60 mortality in patients who were on invasive mechanical ventilation within the first 2 calendar days of the ICU stay (early invasive mechanical ventilation group) and those who were not (nonearly invasive mechanical ventilation group). We used a Cox proportional-hazard model weighted by inverse probability of early invasive mechanical ventilation to determine the risk of death at day 60. MEASUREMENT AND MAIN RESULTS: The 245 patients included had a median (interquartile range) age of 61 years (52-69 yr), a Simplified Acute Physiology Score II score of 34 mm Hg (26-44 mm Hg), and a Pao2/Fio2 of 121 mm Hg (90-174 mm Hg). The rates of ICU-acquired pneumonia, bacteremia, and the ICU length of stay were significantly higher in the early (n = 117 [48%]) than in the nonearly invasive mechanical ventilation group (n = 128 [52%]), p < 0.01. Day-60 mortality was 42.7% and 21.9% in the early and nonearly invasive mechanical ventilation groups, respectively. The weighted model showed that early invasive mechanical ventilation increased the risk for day-60 mortality (weighted hazard ratio =1.74; 95% CI, 1.07-2.83, p=0.03). CONCLUSIONS: In ICU patients admitted with coronavirus disease-2019-induced acute hypoxemic respiratory failure, early invasive mechanical ventilation was associated with an increased risk of day-60 mortality. This result needs to be confirmed.

COVID-19 increased the risk of ICU-acquired bloodstream infections: a case-cohort study from the multicentric OUTCOMEREA network.

PURPOSE: The primary objective of this study was to investigate the risk of ICU bloodstream infection (BSI) in critically ill COVID-19 patients compared to non-COVID-19 patients. Subsequently, we performed secondary analyses in order to explain the observed results. METHODS: We conducted a matched case-cohort study, based on prospectively collected data from a large ICU cohort in France. Critically ill COVID-19 patients were matched with similar non-COVID-19 patients. ICU-BSI was defined by an infection onset occurring > 48 h after ICU admission. We estimated the effect of COVID-19 on the probability to develop an ICU-BSI using proportional subdistribution hazards models. RESULTS: We identified 321 COVID-19 patients and 1029 eligible controls in 6 ICUs. Finally, 235 COVID-19 patients were matched with 235 non-COVID-19 patients. We observed 43 ICU-BSIs, 35 (14.9%) in the COVID-19 group and 8 (3.4%) in the non-COVID-19 group (p ≤ 0.0001), respectively. ICU-BSIs of COVID-19 patients were more frequently of unknown source (47.4%). COVID-19 patients had an increased probability to develop ICU-BSI, especially after 7 days of ICU admission. Using proportional subdistribution hazards models, COVID-19 increased the daily risk to develop ICU-BSI (sHR 4.50, 95% CI 1.82-11.16, p = 0.0012). Among COVID-19 patients (n = 235), a significantly increased risk for ICU-BSI was detected in patients who received tocilizumab or anakinra (sHR 3.20, 95% CI 1.31-7.81, p = 0.011) but not corticosteroids. CONCLUSIONS: Using prospectively collected multicentric data, we showed that the ICU-BSI risk was higher for COVID-19 than non-COVID-19 critically ill patients after seven days of ICU stay. Clinicians should be particularly careful on late ICU-BSIs in COVID-19 patients. Tocilizumab or anakinra may increase the ICU-BSI risk.

A Longitudinal Study of Immune Cells in Severe COVID-19 Patients.

Little is known about the time-dependent immune responses in severe COVID-19. Data of 15 consecutive patients were sequentially recorded from intensive care unit admission. Lymphocyte subsets and total monocyte and subsets counts were monitored as well as the expression of HLA-DR. For 5 patients, SARS-CoV-2-specific T-cell polyfunctionality was assessed against Spike and Nucleoprotein SARS-CoV-2 peptides. Non-specific inflammation markers were increased in all patients. Median monocyte HLA-DR expression was below the 8,000 AB/C threshold defining acquired immunodepression. A "V" trend curve for lymphopenia, monocyte numbers, and HLA-DR expression was observed with a nadir between days 11 and 14 after symptoms' onset. Intermediate CD14++CD16+ monocytes increased early with a reduction in classic CD14++CD16- monocytes. Polyfunctional SARS-Cov-2-specific CD4 T-cells were present and functional, whereas virus-specific CD8 T-cells were less frequent and not efficient. We report a temporal variation of both innate and adaptive immunity in severe COVID-19 patients, helpful in guiding therapeutic decisions (e.g. anti-inflammatory vs. immunostimulatory ones). We describe a defect in virus-specific CD8 T-cells, a potential biomarker of clinical severity. These combined data also provide helpful knowledge for vaccine design. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT04386395.