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PurposeThe 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.MethodsWe 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.ResultsWe 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.ConclusionsUsing 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.

Background The sepsis-induced immunodepression contributes to impaired clinical outcomes of various stress conditions. This syndrome is well documented and characterized by attenuated function of innate and adaptive immune cells. Several pharmacological interventions aimed to restore the immune response are emerging of which interferon-gamma (IFNγ) is one. It is of paramount relevance to obtain clinical information on optimal timing of the IFNγ-treatment, −tolerance, −effectiveness and outcome before performing a RCT. We describe the effects of IFNγ in a cohort of 18 adult and 2 pediatric sepsis patients. Methods In this open-label prospective multi-center case-series, IFNγ treatment was initiated in patients selected on clinical and immunological criteria early (< 4 days) or late (> 7 days) following the onset of sepsis. The data collected in 18 adults and 2 liver transplanted pediatric patients were: clinical scores, monocyte expression of HLA-DR (flow cytometry), lymphocyte immune-phenotyping (flow cytometry), IL-6 and IL-10 plasma levels (ELISA), bacterial cultures, disease severity, and mortality. Results In 15 out of 18 patients IFNγ treatment was associated with an increase of median HLA-DR expression from 2666 [IQ 1547; 4991] to 12,451 [IQ 4166; 19,707], while the absolute number of lymphocyte subpopulations were not affected, except for the decrease number of NK cells 94.5 [23; 136] to 32.5 [13; 90.8] (0.0625)]. Plasma levels of IL-6 464 [201–770] to 108 (89–140) ng/mL ( p  = 0.04) and IL-10 from IL-10 from 29 [12–59] to 9 [1–15] pg/mL decreased significantly. Three patients who received IFNγ early after ICU admission (<4 days) died. The other patients had a rapid clinical improvement assessed by the SOFA score and bacterial cultures that were repeatedly positive became negative. The 2 pediatric cases improved rapidly, but 1 died for hemorrhagic complication. Conclusion Guided by clinical and immunological monitoring, adjunctive immunotherapy with IFNγ appears well-tolerated in our cases and improves immune host defense in sepsis induced immuno suppression. Randomized clinical studies to assess its potential clinical benefit are warranted.

The aims of our study were to assess the correlations between sarcopenia and myosteatosis assessed by CT-scan at T4 and/or L3 levels and inflammation in critically ill COVID patients on ICU admission, and their respective prognostic value on day 90 death (D90-death). It is a retrospective monocentric study. Sarcopenia was defined by skeletal muscle cross sectional surface area (CSA) and myosteatosis by skeletal muscle density (SMD) at L3 and T4 levels. Inflammatory biomarkers were collected on ICU admission. Of the 239 patients, 74 died by D90; 66.6% get sarcopenia on ICU admission. CSA at T4 level was an independent risk factor for D90-death (1.66[1.03; 2.66]; p  = 0.04), as were procalcitonin (2.03[1.2; 3.43]; p  = 0.01) and IL-6 levels (1.56[0.96; 2.54]; p  = 0.07). In addition, we found correlation factors of 0.79 ( p  < 0.01) between SMD at T4 and L3 levels, and a correlation factor of 0.64 ( p  < 0.01) between CSA at T4 and L3 levels.These results indicate a poorer prognosis following a decrease in muscle surface area, a decrease in density, and an increase in inflammatory biomarkers such as Il6. It also suggests that incorporating indices of sarcopenia with inflammatory biomarkers may improve prognostic accuracy.

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 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. https://clinicaltrials.gov/, identifier NCT04386395.

CT-scan and inflammatory and coagulation biomarkers could help in prognostication of COVID-19 in patients on ICU admission. The objectives of this study were to measure the prognostic value of the extent of lung parenchymal lesions on computed tomography (CT) and of several coagulation and inflammatory biomarkers, and to explore the characteristics of the patients depending on the extent of lung parenchymal lesions. Retrospective monocentric observational study achieved on a dataset collected prospectively. Medical ICU of the university hospital of Clermont-Ferrand, France. All consecutive adult patients aged ≥18 years admitted between 20 March, 2020 and 31 August, 2021 for COVID-19 pneumonia. Characteristics at baseline and during ICU stay, and outcomes at day 60 were recorded. The extent of lung parenchyma lesions observed on the chest CT performed on admission was established by artificial intelligence software. Several clinical characteristics and laboratory features were collected on admission including plasma interleukin-6, HLA-DR monocytic-expression rate (mHLA-DR), and the extent of lung parenchymal lesions. Factors associated with day-60 mortality were investigated by uni- and multivariate survival analyses. 270 patients were included. Inflammation biomarkers including the levels of neutrophils, CRP, ferritin and Il10 were the indices the most associated with the severity of the extent of the lung lesions. Patients with more extensive lung parenchymal lesions (≥ 75%) on admission had higher CRP serum levels. The extent of lung parenchymal lesions was associated with a decrease in the PaO2/FiO2 ratio(p<0.01), fewer ventilatory-free days (p = 0.03), and a higher death rate at day 60(p = 0.01). Extent of the lesion of more than 75% was independently associated with day-60 mortality (aHR = 1.72[1.06; 2.78], p = 0.03). The prediction of death at day 60 was improved when considering simultaneously biological and radiological markers obtained on ICU admission (AUC = 0.78). The extent of lung parenchyma lesions on CT was associated with inflammation, and the combination of coagulation and inflammatory biomarkers and the extent of the lesions predicted the poorest outcomes.

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). We included patients with COVID-19 pneumonia admitted to 11 ICUs belonging to the French OutcomeRea.sup.TM network from January to May 2020. We used survival models with ponderation with inverse probability of treatment weighting (IPTW). 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 (.sub.IPTW HR = 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 (.sub.IPTW HR, 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 (.sub.IPTW HR = 5.01;95% CI, 1.05, 23.88; p = 0.04). 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.

Purpose Despite antiviral therapy (ART), 800,000 deaths still occur yearly and globally due to HIV infection. In parallel with the good virological control and the aging of this population, multiple comorbidities [HIV-associated-non-AIDS (HANA) conditions] may now be observed. Methods HIV adult patients hospitalized in intensive care unit (ICU) from all the French region from university and non-university hospital who participate to the OutcomeRea™ database on a voluntary basis over a 24-year period. Results Of the 24,298 stays registered, 630 (2.6%) were a first ICU stay for HIV patients. Over time, the mean age and number of comorbidities (diabetes, renal and respiratory history, solid neoplasia) of patients increased. The proportion of HIV diagnosed on ICU admission decreased significantly, while the median duration of HIV disease as well as the percentage of ART-treated patients increased. The distribution of main reasons for admission remained stable over time (acute respiratory distress > shock > coma). We observed a significant drop in the rate of active opportunistic infection on admission, while the rate of active hemopathy (newly diagnosed or relapsed within the last 6 months prior to admission to ICU) qualifying for AIDS increased—nonsignificantly—with a significant increase in the anticancer chemotherapy administration in ICU. Admissions for HANA or non-HIV reasons were stable over time. In multivariate analysis, predictors of 60-day mortality were advanced age, chronic liver disease, past chemotherapy, sepsis-related organ failure assessment score > 4 at admission, hospitalization duration before ICU admission > 24 h, AIDS status, but not the period of admission. Conclusion Whereas the profile of ICU-admitted HIV patients has evolved over time (HIV better controlled but more associated comorbidities), mortality risk factors remain stable, including AIDS status.

Background Community-acquired pneumonia (CAP), especially pneumococcal CAP (P-CAP), is associated with a heavy burden of illness as evidenced by high rates of intensive care unit (ICU) admission, mortality, and costs. Although well-defined acutely, determinants influencing long-term burden are less known. This study assessed determinants of 28-day and 1-year mortality and costs among P-CAP patients admitted in ICUs. Methods Data regarding all hospital and ICU stays in France in 2014 were extracted from the French healthcare administrative database. All patients admitted in the ICU with a pneumonia diagnosis were included, except those hospitalized for pneumonia within the previous 3 months. The pneumococcal etiology and comorbidities were captured. All hospital stays were included in the cost analysis. Comorbidities and other factors effect on the 28-day and 1-year mortality were assessed using a Cox regression model. Factors associated with increased costs were identified using log-linear regression models. Results Among 182,858 patients hospitalized for CAP in France for 1 year, 10,587 (5.8%) had a P-CAP, among whom 1665 (15.7%) required ICU admission. The in-hospital mortality reached 22.8% at day 28 and 32.3% at 1 year. The mortality risk increased with age > 54 years, malignancies (hazard ratio (HR) 1.54, 95% CI [1.23–1.94], p  = 0.0002), liver diseases (HR 2.08, 95% CI [1.61–2.69], p  < 0.0001), and the illness severity at ICU admission. Compared with non-ICU-admitted patients, ICU survivors remained at higher risk of 1-year mortality. Within the following year, 38.2% (516/1350) of the 28-day survivors required at least another hospital stay, mostly for respiratory diseases. The mean cost of the initial stay was €19,008 for all patients and €11,637 for subsequent hospital stays within 1 year. One-year costs were influenced by age (lower in patients > 75 years old, p = 0.008), chronic cardiac (+ 11% [0.02–0.19], p  = 0.019), and respiratory diseases (+ 11% [0.03–0.18], p = 0.006). Conclusions P-CAP in ICU-admitted patients was associated with a heavy burden of mortality and costs at one year. Older age was associated with both early and 1-year increased mortality. Malignant and chronic liver diseases were associated with increased mortality, whereas chronic cardiac failure and chronic respiratory disease with increased costs. Trial registration N/A (study on existing database)

The high mortality rate in septic shock patients is likely due to environmental and genetic factors, which influence the host response to infection. Two genome-wide association studies (GWAS) on 832 septic shock patients were performed. We used integrative bioinformatic approaches to annotate and prioritize the sepsis-associated single nucleotide polymorphisms (SNPs). An association of 139 SNPs with death based on a false discovery rate of 5% was detected. The most significant SNPs were within the CISH gene involved in cytokine regulation. Among the 139 SNPs associated with death and the 1311 SNPs in strong linkage disequilibrium with them, we investigated 1439 SNPs within non-coding regions to identify regulatory variants. The highest integrative weighted score (IW-score) was obtained for rs143356980, indicating that this SNP is a robust regulatory candidate. The rs143356980 region is located in a non-coding region close to the CISH gene. A CRISPR-Cas9-mediated deletion of this region and specific luciferase assays in K562 cells showed that rs143356980 modulates the enhancer activity in K562 cells. These analyses allowed us to identify several genes associated with death in patients with septic shock. They suggest that genetic variations in key genes, such as CISH, perturb relevant pathways, increasing the risk of death in sepsis patients.

To determine the prevalence of functional, respiratory and renal impairments and of post-intensive-care-syndrome (PICS) among patients who had attended a post-ICU multidisciplinary consultation (post-ICU-MC) around 3 months after ICU discharge, we performed a retrospective, monocentric observational study, at Clermont Ferrand University hospital, France. We included patients who had attended a post-ICU-MC. Their characteristics during ICU stay and at the post-ICU-MC were collected. Functional status was assessed by the 6-min-walking test, handgrip test and peak inspiratory pressure, respiratory function by exploratory functional outcomes, mental status by SF-36 score, and quality of life by SF-36 score and European Quality of Life 5 Dimensions questionnaire. Overall, we enrolled 67 patients, of whom 70%, 74%, and 68% had functional, respiratory, and renal impairments, respectively, at the post-ICU-MC. Additionally, 40%, 28%, 19%, and 2.5% had three, two, one, and none of these impairments, respectively. All patients experienced mental disorders and a decline in quality of life. Functional impairment correlated with frailty score and sex, and respiratory function with age. To conclude, the prevalence of PICS in our cohort was high, as was that of functional, respiratory and renal failure.