Low Percentage of Perforin-Expressing NK Cells during Severe SARS-CoV-2 Infection: Consumption Rather than Primary Deficiency.

Genetic defects in the ability to deliver effective perforin have been reported in patients with hemophagocytic lymphohistiocytosis. We tested the hypothesis that a primary perforin deficiency might also be causal in severe SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to intensive care units or non-intensive care units and age- and sex-matched healthy controls. Compared with healthy controls, the percentage of perforin-expressing CD3-CD56+ NK cells quantified by flow cytometry was low in COVID-19 patients (69.9 ± 17.7 versus 78.6 ± 14.6%, p = 0.026). There was no correlation between the proportions of perforin-positive NK cells and T8 lymphocytes. Moreover, the frequency of NK cells producing perforin was neither linked to disease severity nor predictive of death. Although IL-6 is known to downregulate perforin production in NK cells, we did not find any link between perforin expression and IL-6 plasma level. However, we unveiled a negative correlation between the degranulation marker CD107a and perforin expression in NK cells (r = -0.488, p = 10-4). PRF1 gene expression and the frequency of NK cells harboring perforin were normal in patients 1 y after acute SARS-CoV-2 infection. A primary perforin defect does not seem to be a driver of COVID-19 because NK perforin expression is 1) linked neither to T8 perforin expression nor to disease severity, 2) inversely correlated with NK degranulation, and 3) normalized at distance from acute infection. Thus, the cause of low frequency of perforin-positive NK cells appears, rather, to be consumption.

Occurrences of post-traumatic stress disorder, anxiety, depression, and burnout syndrome in ICU staff workers after two-year of the COVID-19 pandemic: the international PSY-CO in ICU study.

PURPOSE: The present study aimed at assessing the prevalences of post-traumatic stress disorder (PTSD) (main objective), anxiety, depression, and burnout syndrome (BOS) and their associated factors in intensive care unit (ICU) staff workers in the second year of the COVID-19 pandemic. MATERIALS AND METHODS: An international cross-sectional multicenter ICU-based online survey was carried out among the ICU staff workers in 20 ICUs across 3 continents. ICUs staff workers (both caregivers and non-caregivers) were invited to complete PCL-5, HADS, and MBI questionnaires for assessing PTSD, anxiety, depression, and the different components of BOS, respectively. A personal questionnaire was used to isolate independent associated factors with these disorders. RESULTS: PCL-5, HADS, and MBI questionnaires were completed by 585, 570, and 539 responders, respectively (525 completed all questionnaires). PTSD was diagnosed in 98/585 responders (16.8%). Changing familial environment, being a non-caregiver staff worker, having not being involved in a COVID-19 patient admission, having not been provided with COVID-19-related information were associated with PTSD. Anxiety was reported in 130/570 responders (22.8%). Working in a public hospital, being a woman, being financially impacted, being a non-clinical healthcare staff member, having no theoretical or practical training on individual preventive measures, and fear of managing COVID-19 patients were associated with anxiety. Depression was reported in 50/570 responders (8.8%). Comorbidity at risk of severe COVID-19, working in a public hospital, looking after a child, being a non-caregiver staff member, having no information, and a request for moving from the unit were associated with depression. Having received no information and no adequate training for COVID-19 patient management were associated with all 3 dimensions of BOS. CONCLUSION: The present study confirmed that ICU staff workers, whether they treated COVID-19 patients or not, have a substantial prevalence of psychological disorders.

Epidemiologic features and outcomes associated with caustic ingestion among adults admitted in intensive care unit from 2013 to 2019: a French national observational study.

PURPOSE: Caustic ingestion is a potential life-threatening condition associated with high morbidity and mortality. Data on patients admitted to Intensive Care Unit (ICU) for severe caustic ingestion are lacking. We aimed to describing epidemiological features and outcomes of patients admitted to ICU for caustic ingestion in France. METHODS: In a retrospective, observational, and multicenter study, data from the national French Programme de Médicalisation des Systèmes d'Informations (PMSI) database were analysed from 2013 to 2019. In-hospital mortality rate (primary outcome) and in-ICU complications (secondary outcomes) were reported and analysed. RESULTS: 569 patients (289 males (50.8%), with median age of 49 years [interquartile (26-62)] were admitted in 65 French ICU for severe caustic ingestion. Five hundred and thirteen patients (90%) were admitted for intentional caustic ingestion. The median length of stay in ICU was 14.0 [4.0-31.0] days. In-hospital mortality occurred in 56 patients (9.8%). In multivariate analysis, age and simplified acute physiology score II were associated with in-hospital mortality age of 40-59 years [OR = 15.3 (2.0-115.3)], age of 60-79 years [OR = 23.6 (3.1-182.5)], and age > 80 years [OR = 37.0 (4.2-328.6)] and SAPS 2 score [OR = 1.0018 (1.003-1.033), p < 0.001]. During ICU stay, 423 complications (74%) were reported in 505 patients (89%). Infectious (244 (42.9%)), respiratory (207 (36.4%)), surgical 62 (10.9%), haemorrhagic (64 (11.2%)) and thrombo-embolic and (35 (6.2%)) complications were the most frequently reported during ICU stay. CONCLUSION: ICU admission for severe caustic ingestion is associated with 9.8% mortality and 74% complications. Age > 40 years and SAPS 2 score were independently associated with mortality.

A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive Care Units: The SAFE-ICU study.

Objective: To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity. Design setting and participants: This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected. Main outcome measures: The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured. Results and conclusions: This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.

Repetitive mRNA vaccination is required to improve the quality of broad-spectrum anti-SARS-CoV-2 antibodies in the absence of CXCL13.

Since the initial spread of severe acute respiratory syndrome coronavirus 2 infection, several viral variants have emerged and represent a major challenge for immune control, particularly in the context of vaccination. We evaluated the quantity, quality, and persistence of immunoglobulin G (IgG) and IgA in individuals who received two or three doses of messenger RNA (mRNA) vaccines, compared with previously infected vaccinated individuals. We show that three doses of mRNA vaccine were required to match the humoral responses of preinfected vaccinees. Given the importance of antibody-dependent cell-mediated immunity against viral infections, we also measured the capacity of IgG to recognize spike variants expressed on the cell surface and found that cross-reactivity was also strongly improved by repeated vaccination. Last, we report low levels of CXCL13, a surrogate marker of germinal center activation and formation, in vaccinees both after two and three doses compared with preinfected individuals, providing a potential explanation for the short duration and low quality of Ig induced.

Post-traumatic stress disorder, anxiety, depression and burnout in nursing home staff in South France during the COVID-19 pandemic.

The high mortality rate in nursing homes during the COVID-19 pandemic may be linked to psychological disorders in staff. Hence, we assessed the prevalence and associated factors of probable post-traumatic stress disorder (PTSD), anxiety, depression, and burnout of nursing home staff during the COVID-19 pandemic in a cross-sectional study including 66 randomly selected nursing homes in southern France. 537 of the contacted 3 821 nursing home workers (14.0%) responded between April and October 2021. We collected information on center organization, severity of COVID-19 exposure, and socio-demographic information in an online survey. The prevalence of probable PTSD (PCL-5), anxiety and depressive disorders (Hospital Anxiety Depression Scale) and the sub-scores of burnout syndrome (Maslach Burnout Inventory Human Services Survey for Medical Personnel) were assessed. Probable PTSD was reported in 115/537 responders (21.4% (95% CI [18.0%-24.9%])). After adjustment, low-level exposure to COVID-19 in nursing home residents (AOR, 0.5; 95% CI [0.3-0.9]), fear of managing COVID-19 residents (AOR, 3.5; 95% CI [1.9-6.4]), conflicts with residents (AOR, 2.3; 95% CI, [1.2-4.4]), conflicts with colleagues (AOR, 3.6; 95% CI [1.7-8.6]), cancellation of leave (AOR, 4.8; 95% CI [2.0-11.7]) and temporary worker employment (AOR, 3.4; 95% CI [1.7-6.9]) were associated with higher prevalence of probable PTSD. The prevalence of probable anxiety and depression were 28.8% (95% CI [24.9%-32.7%]) and 10.4% (95% CI [7.8%-13.1%]), respectively. Psychological disorders were observed in nearly one third of nursing home workers during the COVID-19 pandemic. Hence, continuous surveys and preventive measures are needed in this particularly at-risk population.

Association between combination antibiotic therapy as opposed as monotherapy and outcomes of ICU patients with Pseudomonas aeruginosa ventilator-associated pneumonia: an ancillary study of the iDIAPASON trial.

BACKGROUND: The optimal treatment duration and the nature of regimen of antibiotics (monotherapy or combination therapy) for Pseudomonas aeruginosa ventilator­associated pneumonia (PA-VAP) remain debated. The aim of this study was to evaluate whether a combination antibiotic therapy is superior to a monotherapy in patients with PA-VAP in terms of reduction in recurrence and death, based on the 186 patients included in the iDIAPASON trial, a multicenter, randomized controlled trial comparing 8 versus 15 days of antibiotic therapy for PA-VAP. METHODS: Patients with PA-VAP randomized in the iDIAPASON trial (short-duration-8 days vs. long-duration-15 days) and who received appropriate antibiotic therapy were eligible in the present study. The main objective is to compare mortality at day 90 according to the antibiotic therapy received by the patient: monotherapy versus combination therapy. The primary outcome was the mortality rate at day 90. The primary outcome was compared between groups using a Chi-square test. Time from appropriate antibiotic therapy to death in ICU or to censure at day 90 was represented using Kaplan-Meier survival curves and compared between groups using a Log-rank test. RESULTS: A total of 169 patients were included in the analysis. The median duration of appropriate antibiotic therapy was 14 days. At day 90, among 37 patients (21.9%) who died, 17 received monotherapy and 20 received a combination therapy (P = 0.180). Monotherapy and combination antibiotic therapy were similar for the recurrence rate of VAP, the number of extra pulmonary infections, or the acquisition of multidrug-resistant (MDR) bacteria during the ICU stay. Patients in combination therapy were exposed to mechanical ventilation for 28 ± 12 days, as compared with 23 ± 11 days for those receiving monotherapy (P = 0.0243). Results remain similar after adjustment for randomization arm of iDIAPASON trial and SOFA score at ICU admission. CONCLUSIONS: Except longer durations of antibiotic therapy and mechanical ventilation, potentially related to increased difficulty in achieving clinical cure, the patients in the combination therapy group had similar outcomes to those in the monotherapy group. TRIAL REGISTRATION: NCT02634411 , Registered 15 December 2015.

How to improve the efficiency and the safety of real-time ultrasound-guided central venous catheterization in 2023: a narrative review.

Central venous catheterization (CVC) is a frequent procedure, practiced by intensivists, anesthesiologists and advanced practice nurses in intensive care units and operative rooms. To reduce CVC-associated morbidity, it is essential to strive for best practices, based on the latest evidence. This narrative review aims to synthesize current knowledge on evidence-based best practices for CVC that improve the use and feasibility of real-time ultrasound-guided insertion procedures. Optimization of the vein puncture technique and the development of new technologies are discussed to reinforce the use of the subclavian vein catheterization as first choice. The search for alternative site of insertions, without increasing infectious and thrombotic risks, deserves further research.

Intensive Care Unit activity in France from the national database between 2013 and 2019: More critically ill patients, shorter stay and lower mortality rate.

BACKGROUND: Knowledge of the occurrence and outcome of admissions to Intensive Care Units (ICU) over time is important to inform healthcare services planning. This observational study aims at describing the activity of French ICUs between 2013 and 2019. METHODS: Patient admission characteristics, organ dysfunction scores, therapies, ICU and hospital lengths of stay and case fatality were collected from the French National Hospital Database (population-based cohort). Logistic regression models were developed to investigate the association between age, sex, SAPS II, organ failure, and year of care on in-ICU case fatality. FINDINGS: Among 1,594,801 ICU admissions, the yearly ICU admission increased from 3.3 to 3.5 per year per 1000 inhabitants (bed occupancy rate between 83.4 and 84.3%). The mean admission SAPS II was 42 ± 22, with a gradual annual increase. The median lengths of stay in ICU and in hospital were 3 (interquartile range (IQR) = [1-7]) and 11 days (IQR = [6-21]), respectively, with a progressive decrease over time. The in-ICU and hospital mortality case fatalities decreased from 18.0% to 17.1% and from 21.1% to 19.9% between 2013 and 2019, respectively. Male sex, age, SAPS II score, and the occurrence of any organ failure were associated with a higher case fatality rate. After adjustment on age, sex, SAPS II and organ failure, in-ICU case fatality decreased in 2019 as compared to 2013 (adjusted Odds Ratio = 0.87 [95% confidence interval, 0.85-0.89]). INTERPRETATION: During the study, an increasing incidence of ICU admission was associated with higher severity of illness but lower in-ICU case fatality.

Echocardiographic hemodynamic assessment in decompensated cirrhosis: comparison between Intensivists and Gastroenterologists.

BACKGROUND & AIMS: Ascites is a frequent complication of cirrhosis. In intensive care units, initial hemodynamic assessment is frequently performed by echocardiography. This study evaluated the feasibility and usefulness of early hemodynamic assessment in the gastroenterology ward. METHODS: This observational cohort study prospectively included all patients admitted to a teaching hospital's gastroenterology unit for decompensated cirrhosis. A gastroenterologist with minimal training and an intensivist both performed an echocardiography exam. The primary outcome was inter-rater agreement and reliability for three echocardiography parameters: visual LVEF (Left Ventricular Ejection Fraction), subaortic VTI (velocity time integral) and E wave velocity. Secondary outcomes were agreement for presence of pleural effusion, description of 3 hemodynamics profiles (hypovolemic, hyperkinetic and intermediate), and 28-day mortality. RESULTS: From March 2018 to March 2020, 53 patients were included. The median age was 62 years and 81% were men. Patients presented mostly advanced liver disease, with 43% Child-Pugh C and median MELD score of 15.2. The limits of agreement between intensivists and gastroenterologists for subaortic VTI were - 6.6 to 7.2 cm, and ranged from - 0.6 to 0.37 m.s-1 for E wave velocity. Clinically significant differences between intensivists and gastroenterologists were found in 22% for subaortic VTI and 24.5% for E wave velocity. Reliability was good for subaortic VTI (ICC: 0.79, 95% CI [0.58; 0.9;]) and moderate for E wave velocity (0.53, 95% CI [0.19; 0.74]). The three hemodynamics profiles had different prognosis, with a 28-day mortality for Hypovolemic, Intermediate and Hyperkinetic group of 31, 18, and 4%, respectively. CONCLUSION: Reliability of hemodynamic assessment by gastroenterologists was good, while agreement was unsatisfactory, advocating for further training. Transthoracic echocardiography can differentiate hypovolemia from hyperkinetic states. The role of transthoracic echocardiography in managing decompensated cirrhosis requires further study. CLINICAL TRIAL NUMBER: NCT03650660.

Prognostic value of an automated thrombin generation assay in COVID-19 patients entering hospital: A multicentric, prospective observational study.

INTRODUCTION: The prognostic significance of the thrombin generation assay (TGA) with a thrombomodulin (TM) challenge in patients entering hospital with severe COVID-19 is uncertain. METHODS: We prospectively evaluated an automated TGA (aTGA) using the ST-ThromboScreen® assay and ST-Genesia® analyser in 179 patients with severe COVID-19 during their admission to 2 university hospitals. The primary outcome was early survival at Day 28 (D28). Secondary outcomes were late survival at Day 90 (D90), later transfer to an intensive care unit (ICU), and occurrence of any thrombotic complications during hospitalisation. RESULTS: Among the 174 patients, 50 were initially admitted to ICUs. Forty-two were transferred to ICUs before D28. Fourteen patients, all in ICUs, died before D28, and 20 before D90, all but 1 in ICUs. None of the aTGA-derived results were associated with vital status either at D28 or D90. Nine patients had a thrombotic event with no association with the aTGA results. Later transfer to the ICU was associated with higher velocity index, thrombin peak height and endogenous thrombin potential (ETP) values of the aTGA performed with TM, and mainly with a lower TM-induced decrease in ETP (odds ratio 15.5 (2.15-132), p = 0.009). CONCLUSIONS: aTGA, a global assay supposed to evidence coagulopathy, could predict neither early or late survival, nor thrombotic events, in hospitalised COVID-19 patients. Its clinical justification in that setting is thus unlikely. A relative resistance of the ETP to TM was associated with later transfer to the ICU and deserves further investigation.

High success rates of ultrasound-guided distal internal jugular vein and axillary vein approaches for central venous catheterization: A randomized controlled open-label pilot trial.

BACKGROUND: Ultrasound (US)-guided axillary vein (AV) catheterization has been considered as the preferred site of insertion to minimize catheter-related infections. Given its difficulty of realization, internal jugular vein (IJV) access remains, thus, the first choice of catheter insertion site. This descriptive study was aimed to assess the success and complication rates of in-plane short axis approach of IJV in the lower neck and the AV approach under US-guidance. METHODS: In a prospective randomized controlled open-label pilot trial, all patients requiring central venous catheterization (CVC) in intensive care unit or operating room were randomly assigned to low IJV or AV groups. The primary objective was to estimate the overall success rate of both approaches. The secondary objectives were immediate complication rates, procedure durations, success rate after the first puncture, late complication rates (i.e., thrombosis, catheter colonization, and catheter-related infections), and nurse satisfaction regarding insertion site dressings. RESULTS: One hundred and seventy-three out of two hundred and ten included patients were fully analyzed (90 and 83 in the IJV and AV approach groups, respectively). Overall success rates for IJV and AV sites were 96% (95% confidence interval (CI) [90-99]) and 89% (95% CI [81-94]) respectively. First puncture success rates were 90% and 80% respectively. The median overall procedure duration from US pre-procedural screening to guidewire insertion was 8 and 10 min in IJV and AV groups. Overall immediate complications rates for IJV and AV sites were 11.6% and 14.6%, respectively. Incidence of catheter colonization were 7.9% and 6.8% and catheter-related infection rate were 2.6% and 0%, respectively. CONCLUSION: In this pilot study, US-guided low IJV and AV approaches are safe and efficient techniques for CVC insertion associated with high success and low complications rates. Duration for guidewire insertion seemed to be shorter in the short axis in-plane IJV approach. It provides the basis for a future randomized trial comparing these two approaches.

Axillary vein catheterization using ultrasound guidance: A prospective randomized cross-over controlled simulation comparing standard ultrasound and new needle-pilot device.

BACKGROUND: Real-time ultrasound (US) guidance facilitates central venous catheterization in intensive care unit (ICU). New magnetic needle-pilot devices could improve efficiency and safety of central venous catheterization. This simulation trial was aimed at comparing venipuncture with a new needle-pilot device to conventional US technique. METHODS: In a prospective, randomized, simulation trial, 51 ICU physicians and residents cannulated the right axillary vein of a human torso mannequin with standard US guidance and with a needle-pilot system, in a randomized order. The primary outcome was the time from skin puncture to successful venous cannulation. The secondary outcomes were the number of skin punctures, the number of posterior wall puncture of the axillary vein, the number of arterial punctures, the number of needle redirections, the failure rate, and the operator comfort. RESULTS: Time to successful cannulation was shorter with needle-pilot US-guided technique (22 s (interquartile range (IQR) = 16-42) vs 25 s (IQR = 19-128); median of difference (MOD) = -9 s (95%-confidence interval (CI) -5, -22), p < 0.001). The rates of skin punctures, posterior wall puncture of axillary vein, and needle redirections were also lower (p < 0.01). Comfort was higher in needle-pilot US-guided group on a 11-points numeric scale (8 (IQR = 8-9) vs 6 (IQR = 6-8), p < 0.001). CONCLUSIONS: In a simulation model, US-guided axillary vein catheterization with a needle-pilot device was associated with a shorter time of successful cannulation and a decrease in numbers of skin punctures and complications. The results plea for investigating clinical performance of this new device.

T4 apoptosis in the acute phase of SARS-CoV-2 infection predicts long COVID.

Background: As about 10% of patients with COVID-19 present sequelae, it is important to better understand the physiopathology of so-called long COVID. Method: To this aim, we recruited 29 patients hospitalized for SARS-CoV-2 infection and, by Luminex®, quantified 19 soluble factors in their plasma and in the supernatant of their peripheral blood mononuclear cells, including inflammatory and anti-inflammatory cytokines and chemokines, Th1/Th2/Th17 cytokines, and endothelium activation markers. We also measured their T4, T8 and NK differentiation, activation, exhaustion and senescence, T cell apoptosis, and monocyte subpopulations by flow cytometry. We compared these markers between participants who developed long COVID or not one year later. Results: None of these markers was predictive for sequelae, except programmed T4 cell death. T4 lymphocytes from participants who later presented long COVID were more apoptotic in culture than those of sequelae-free participants at Month 12 (36.9 ± 14.7 vs. 24.2 ± 9.0%, p = 0.016). Conclusions: Our observation raises the hypothesis that T4 cell death during the acute phase of SARS-CoV-2 infection might pave the way for long COVID. Mechanistically, T4 lymphopenia might favor phenomena that could cause sequelae, including SARS-CoV-2 persistence, reactivation of other viruses, autoimmunity and immune dysregulation. In this scenario, inhibiting T cell apoptosis, for instance, by caspase inhibitors, could prevent long COVID.