Body composition and short-term mortality in patients critically ill with acute-on-chronic liver failure.

Background & Aims: Body composition is sex dependent and associated with an increased mortality risk in patients with cirrhosis. We evaluated whether it was also associated with short-term mortality in patients critically ill with acute-on-chronic liver failure (ACLF). Patients and methods: We retrospectively included all patients with cirrhosis and ACLF hospitalised in the intensive care unit (ICU) of Lausanne University Hospital between 2010 and 2019 for whom an abdominal computed tomography (CT) scan performed ±7 days from admission was available. Patients from the ICU of Paul Brousse University Hospital admitted between 2017 and 2020 served as an external cohort. All body composition parameters at the third lumbar vertebral level (L3) were quantified using a deep learning-based method. Results: In total, 192 patients from Lausanne were included. Median age was 62 years and 28-day survival rate was 58.2%. In males, variables independently associated with 28-day mortality on days 1 and 3 were Chronic Liver Failure Consortium (CLIF-C) ACLF-lactate and sarcopenia. In females, CLIF-C ACLF-lactate on days 1 and 3 was the only predictor of 28-day survival. We derived two scores combining sarcopenia and the CLIF-C ACLF-lactate score on days 1 and 3, with area under the receiver operating characteristic outperforming the CLIF-C ACLF-lactate score alone in male but not in female patients. Comparable results were found in the external cohort of 58 patients and supported the sex specificity of the performance of the model. Patients with sarcopenia had increased risks of invasive fungal infection and renal replacement therapy. Conclusion: Sarcopenia was associated with 28-day mortality in male but not in female patients critically ill with ACLF. Although screening for sarcopenia could impact the management of male patients, further studies are needed in female cohorts to investigate whether other body composition parameters are associated with outcomes. Impact and implications: Body composition, easily assessed by CT, is altered in patients with cirrhosis and associated with outcome; it has never been investigated in patients critically ill with ACLF. The results of the present study, underlining the benefit of sarcopenia evaluation to improve prognosis prediction in males critically ill with ACLF, are of importance for physicians managing such patients to optimise the decision-making process toward continued treatment, liver transplantation, or limitation of care. In a wider sense, besides the number and course of organ failures, the results recall the weight of the general condition of males with ACLF at admission to ICU. In females critically ill with ACLF, in analyses limited by the sample size, none of the body composition parameters was associated with short-term mortality independently of organ failures; this suggests that the number and course of organ failures are the main determinant of mortality in these patients.

Assessing the Functional Heterogeneity of Monocytes in Human Septic Shock: a Proof-of-Concept Microfluidic Assay of TNFα Secretion.

Objective: The development of advanced single-cell technologies to decipher inter-cellular heterogeneity has enabled the dynamic assessment of individual cells behavior over time, overcoming the limitation of traditional assays. Here, we evaluated the feasibility of an advanced microfluidic assay combined to fluorescence microscopy to address the behavior of circulating monocytes from septic shock patients. Methods: Seven septic shock patients and ten healthy volunteers were enrolled in the study. Using the proposed microfluidic assay we investigated the production over time of LPS-elicited TNFα by single monocytes encapsulated within droplets. Cellular endocytic activity was assessed by internalization of magnetic nanoparticles. Besides, we assessed HLA-DR membrane expression and LPS-induced TNFα production in monocytes through classical flow cytometry assays. Results: Consistent with the flow cytometry results, the total number of TNFα molecules secreted by encapsulated single monocytes was significantly decreased in septic shock patients compared to healthy donors. TNFα production was dampened as soon as 30 and 60 minutes after LPS stimulation in monocytes from septic patients. Furthermore, the microfluidic assay revealed heterogeneous individual behavior of monocytes from septic shock patients. Of note, monocytes from both healthy donors and patients exhibited similar phagocytic activities over time. Conclusion: The microfluidic assay highlights the functional heterogeneity of monocytes, and provides in-depth resolution in assessing the hallmark monocyte deactivation encountered in post-septic immunosuppression.

Sepsis and Cancer: An Interplay of Friends and Foes.

Sepsis and cancer share a number of pathophysiological features, and both result from the inability of the host's immune system to cope with the initial insult (tissue invasion by pathogens and malignant cell transformation, respectively). The common coexistence of both disorders and the profound related alterations in immune homeostasis raise the question of their mutual impact on each other's course. This translational review aims to discuss the interactions between cancer and sepsis supported by clinical data and the translation to experimental models. The dramatic improvement in cancer has come at a cost of increased risks of life-threatening infectious complications. Investigating the long-term outcomes of sepsis survivors has revealed an unexpected susceptibility to cancer long after discharge from the ICU. Nonetheless, it is noteworthy that an acute septic episode may harbor antitumoral properties under particular circumstances. Relevant double-hit animal models have provided clues to whether and how bacterial sepsis may impact malignant tumor growth. In sequential sepsis-then-cancer models, postseptic mice exhibited accelerated tumor growth. When using reverse cancer-then-sepsis models, bacterial sepsis applied to mice with cancer conversely resulted in inhibition or even regression of tumor growth. Experimental models thus highlight dual effects of sepsis on tumor growth, mostly depending on the sequence of insults, and allow deciphering the immune mechanisms and their relation with microorganisms.

Post-transfusion platelet responses in critically ill cancer patients with hypoproliferative thrombocytopenia.

BACKGROUND: Platelet transfusion is aimed at increasing platelet counts to prevent or treat bleeding. Critically ill cancer patients with hypoproliferative thrombocytopenia are high consumers of blood products. We herein described their post-transfusion platelet responses in the intensive care unit (ICU) and analyzed the determinants of poor post-transfusion increments. STUDY DESIGN AND METHODS: This was a single-center 9-year (2009-2017) retrospective observational study. Patients with malignancies and presumed or proven hypoproliferative thrombocytopenia who had received at least one platelet transfusion in the ICU were included. Poor post-transfusion platelet increments were defined as body surface-adjusted corrected count increment (CCI) <7, or alternatively as weight-adjusted platelet transfusion recovery (PTR) <0.2. Patients were deemed refractory to platelet transfusions when two consecutive ABO-compatible transfusions resulted in poor platelet increments. RESULTS: A total of 1470 platelet transfusions received by 326 patients were analyzed. Indications for platelet transfusions were distributed into prophylactic (44.5%), peri-procedural (18.1%) and therapeutic (37.4%). Regardless of indications, 54.6% and 55.4% of transfusion episodes were associated with a CCI <7 or a PTR <0.2. Factors independently associated with poor post-transfusion increments were lower body mass index, spleen enlargement, concurrent severity of clinical condition, fever ≥39°C, antibiotic therapy and increased storage duration of platelet concentrates. Eventually, 48 patients developed refractoriness to platelet transfusion, which was associated increased incidence of bleeding events. CONCLUSION: Platelet transfusions are often associated with poor increments in critically ill cancer patients with hypoproliferative thrombocytopenia. The findings suggest amenable interventions to improve the platelet transfusion practices in this setting.

Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced Natural Killer cell activity.

Sepsis-induced immune dysfunctions are likely to impact on malignant tumor growth. Sequential sepsis-then-cancer models of tumor transplantation in mice recovering from sepsis have shown that the post-septic immunosuppressive environment was able to promote tumor growth. We herein addressed the impact of sepsis on pre-established malignancy in a reverse cancer-then sepsis experimental model. Mice previously inoculated with MCA205 fibrosarcoma cells were subjected to septic challenges by polymicrobial peritonitis induced by cecal ligation and puncture or endotoxinic shock. The anti-tumoral immune response was assessed through the distribution of tumor-infiltrating immune cells, as well as the functions of cytotoxic cells. As compared to sham surgery, polymicrobial sepsis dampened malignant tumor growth in wild-type (WT) mice, but neither in Toll-like receptor 4 (Tlr4)-/- nor in Myd88-/- mice. Similar tumor growth inhibition was observed following a LPS challenge in WT mice, suggesting a regulatory role of Tlr4 in this setting. The low expression of MHC class 1 onto MCA205 cells suggested the involvement of Natural Killer (NK) cells in sepsis-induced tumor inhibition. Septic insults applied to mice with cancer promoted the main anti-tumoral NK functions of IFNγ production and degranulation. The anti-tumoral properties of NK cells obtained from septic mice were exacerbated when cultured with MHC1low MCA205 or YAC-1 cells. These results suggest that sepsis may harbor dual effects on tumor growth depending on the sequential experimental model. When applied in mice with cancer, sepsis prevents tumor growth in a Tlr4-dependent manner by enhancing the anti-tumoral functions of NK cells.

Value of EEG reactivity for prediction of neurologic outcome after cardiac arrest: Insights from the Parisian registry.

PURPOSE: To evaluate the predictive value of EEG reactivity assessment and confounders for neurological outcome after cardiac arrest. METHODS: All consecutive patients admitted in a tertiary cardiac arrest center between 2007 and 2016 still alive 48 h after admission with at least one EEG recorded during coma. EEG reactivity was defined as a reproducible waveform change in amplitude or frequency following standardized stimulation. Each EEG was classified based on American Clinical Neurophysiology Society nomenclatures and classified in highly malignant (including status epilepticus), malignant, or benign EEG. We assessed the predictive values of EEG reactivity and sedation effect for neurologic outcome at ICU discharge using the Cerebral Performance Category scale (with CPC 1-2 assumed as favorable outcome and CPC 3-4-5 considered as poor outcome). RESULTS: Among 428 patients, a poor outcome was observed in 80% patients. The median time to EEG recording was 3 (1-4) days and 51% patients had a non-reactive EEG. The positive predictive value (PPV) of a non-reactive EEG to predict an unfavorable outcome was 97.1% (IC95% 93.6-98.9), increasing to 98.3% (IC95 94.1-99.8) when the EEG had been performed without sedation. In multivariate analysis, a non-reactive EEG was associated with poor outcome (OR 12.6 IC95% 4.7-33.6; p < 0.001). In multivariate analysis, concomitant sedation was not statistically associated with EEG non-reactivity. The PPV of a benign EEG to predict favorable outcome was 49.7% (IC95% 41.5-57.9), increasing to 66.2% (IC95% 54.3-76.8) when EEG was recorded earlier, with ongoing sedation. CONCLUSIONS: After cardiac arrest, absence of EEG reactivity was predictive of unfavorable outcome. By contrast, a benign EEG was slightly predictive of a favorable outcome. Reactivity assessment may have important implications in the neuroprognostication process after cardiac arrest and could be influenced by sedation.

Early High-Dose Erythropoietin Therapy After Out-of-Hospital Cardiac Arrest: A Multicenter, Randomized Controlled Trial.

BACKGROUND: Preliminary data suggested a clinical benefit in treating out-of-hospital cardiac arrest (OHCA) patients with a high dose of erythropoietin (Epo) analogs. OBJECTIVES: The authors aimed to evaluate the efficacy of epoetin alfa treatment on the outcome of OHCA patients in a phase 3 trial. METHODS: The authors performed a multicenter, single-blind, randomized controlled trial. Patients still comatose after a witnessed OHCA of presumed cardiac origin were eligible. In the intervention group, patients received 5 intravenous injections spaced 12 h apart during the first 48 h (40,000 units each, resulting in a maximal dose of 200,000 total units), started as soon as possible after resuscitation. In the control group, patients received standard care without Epo. The main endpoint was the proportion of patients in each group reaching level 1 on the Cerebral Performance Category (CPC) scale (survival with no or minor neurological sequelae) at day 60. Secondary endpoints included all-cause mortality rate, distribution of patients in CPC levels at different time points, and side effects. RESULTS: In total, 476 patients were included in the primary analysis. Baseline characteristics were similar in the 2 groups. At day 60, 32.4% of patients (76 of 234) in the intervention group reached a CPC 1 level, as compared with 32.1% of patients (78 of 242) in the control group (odds ratio: 1.01; 95% confidence interval: 0.68 to 1.48). The mortality rate and proportion of patients in each CPC level did not differ at any time points. Serious adverse events were more frequent in Epo-treated patients as compared with controls (22.6% vs. 14.9%; p = 0.03), particularly thrombotic complications (12.4% vs. 5.8%; p = 0.01). CONCLUSIONS: In patients resuscitated from an OHCA of presumed cardiac cause, early administration of erythropoietin plus standard therapy did not confer a benefit, and was associated with a higher complication rate. (High Dose of Erythropoietin Analogue After Cardiac Arrest [Epo-ACR-02]; NCT00999583).

Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4.

Severe sepsis remains a frequent and dreaded complication in cancer patients. Beyond the often fatal short-term outcome, the long-term sequelae of severe sepsis may also impact directly on the prognosis of the underlying malignancy in survivors. The immune system is involved in all stages of tumour development, in the detection of transforming and dying cells and in the prevention of tumour growth and dissemination. In fact, the profound and sustained immune defects induced by sepsis may constitute a privileged environment likely to favour tumour growth. We investigated the impact of sepsis on malignant tumour growth in a double-hit animal model of polymicrobial peritonitis, followed by subcutaneous inoculation of MCA205 fibrosarcoma cells. As compared to their sham-operated counterparts, post-septic mice exhibited accelerated tumour growth. This was associated with intratumoural accumulation of CD11b(+) Ly6G(high) polymorphonuclear cells (PMNs) that could be characterized as granulocytic myeloid-derived suppressor cells (G-MDSCs). Depletion of granulocytic cells in post-septic mice inhibited the sepsis-enhanced tumour growth. Toll-like receptor (TLR)-4 (Tlr4) and Myd88 deficiencies prevented sepsis-induced expansion of G-MDSCs and tumour growth. Our results demonstrate that the myelosuppressive environment induced by severe bacterial infections promotes malignant tumour growth, and highlight a critical role of CD11b(+) Ly6G(high) G-MDSCs under the control of TLR-dependent signalling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a multicenter, multinational, 14-day inception cohort study.

PURPOSE: In this prospective, multicenter, 14-day inception cohort study, we investigated the epidemiology, patterns of infections, and outcome in patients admitted to the intensive care unit (ICU) as a result of severe acute respiratory infections (SARIs). METHODS: All patients admitted to one of 206 participating ICUs during two study weeks, one in November 2013 and the other in January 2014, were screened. SARI was defined as possible, probable, or microbiologically confirmed respiratory tract infection with recent onset dyspnea and/or fever. The primary outcome parameter was in-hospital mortality within 60 days of admission to the ICU. RESULTS: Among the 5550 patients admitted during the study periods, 663 (11.9 %) had SARI. On admission to the ICU, Gram-positive and Gram-negative bacteria were found in 29.6 and 26.2 % of SARI patients but rarely atypical bacteria (1.0 %); viruses were present in 7.7 % of patients. Organ failure occurred in 74.7 % of patients in the ICU, mostly respiratory (53.8 %), cardiovascular (44.5 %), and renal (44.6 %). ICU and in-hospital mortality rates in patients with SARI were 20.2 and 27.2 %, respectively. In multivariable analysis, older age, greater severity scores at ICU admission, and hematologic malignancy or liver disease were independently associated with an increased risk of in-hospital death, whereas influenza vaccination prior to ICU admission and adequate antibiotic administration on ICU admission were associated with a lower risk. CONCLUSIONS: Admission to the ICU for SARI is common and associated with high morbidity and mortality rates. We identified several risk factors for in-hospital death that may be useful for risk stratification in these patients.

Platelet transfusions in cancer patients with hypoproliferative thrombocytopenia in the intensive care unit.

BACKGROUND: Thrombocytopenia is a frequent finding in critically ill cancer patients for whom indications of platelet transfusions are unclear. We herein addressed the current practices in platelet transfusion and the risk of bleeding in cancer patients with hypoproliferative thrombocytopenia in the intensive care unit (ICU). METHODS: A retrospective monocenter study over a 7-year period was conducted in a medical ICU. Adult patients with malignancies and hypoproliferative thrombocytopenia, and who received at least one platelet concentrate during their ICU stay, were included. RESULTS: 296 patients were included and received a total of 904 platelet transfusions, for prophylactic indications in 300 (33.2 %) episodes, for securing an invasive procedure in 257 (28.4 %), and for treatment of minor to major bleeding manifestations in 347 (38.4 %). Most prophylactic transfusions (80 %) were performed at platelet count thresholds below 10-20 × 10(9)/L. Platelet increments were generally low in all three indications, 10 (interquartile range 2-25), 11 (2-25), and 8 (0-21) × 10(9)/L, respectively. A total of 97 major ICU-acquired bleeding events occurred in 40 patients. About half of those bleeding episodes (54.7 %) occurred at platelet counts below 20 × 10(9)/L. However, neither low admission platelet count nor low nadir platelet counts were predictive of ICU-acquired bleeding. The in-ICU mortality rate tended to be higher in patients with severe ICU-acquired bleeding events (50 vs. 36 %). CONCLUSIONS: Most prophylactic platelet transfusions were given using thresholds of 10-20 × 10(9)/L in critically ill thrombocytopenic cancer patients. The individual risk of ICU-acquired severe bleeding appears hardly predictable with the depth of thrombocytopenia.

Timing and causes of death in septic shock.

BACKGROUND: Most studies about septic shock report a crude mortality rate that neither distinguishes between early and late deaths nor addresses the direct causes of death. We herein aimed to determine the modalities of death in septic shock. METHODS: This was a 6-year (2008-2013) monocenter retrospective study. All consecutive patients diagnosed for septic shock within the first 48 h of intensive care unit (ICU) admission were included. Early and late deaths were defined as occurring within or after 3 days following ICU admission, respectively. The main cause of death in the ICU was determined from medical files. A multinomial logistic regression analysis using the status alive as the reference category was performed to identify the prognostic factors associated with early and late deaths. RESULTS: Five hundred forty-three patients were included, with a mean age of 66 ± 15 years and a high proportion (67 %) of comorbidities. The in-ICU and in-hospital mortality rates were 37.2 and 45 %, respectively. Deaths occurred early for 78 (32 %) and later on for 166 (68 %) patients in the ICU (n = 124) or in the hospital (n = 42). Early deaths were mainly attributable to intractable multiple organ failure related to the primary infection (82 %) and to mesenteric ischemia (6.4 %). In-ICU late deaths were directly related to end-of-life decisions in 29 % of patients and otherwise mostly related to ICU-acquired complications, including nosocomial infections (20.4 %) and mesenteric ischemia (16.6 %). Independent determinants of early death were age, malignancy, diabetes mellitus, no pathogen identification, and initial severity. Among 3-day survivors, independent risk factors for late death were age, cirrhosis, no pathogen identification, and previous corticosteroid treatment. CONCLUSIONS: Our study provides a comprehensive assessment of septic shock-related deaths. Identification of risk factors of early and late deaths may determine differential prognostic patterns.

Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort.

INTRODUCTION: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. METHODS: We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint. RESULTS: Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P < 0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P < 0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes in respiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis. CONCLUSIONS: Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study.

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust.

Toll-like receptor 2 deficiency increases resistance to Pseudomonas aeruginosa pneumonia in the setting of sepsis-induced immune dysfunction.

BACKGROUND: Sepsis is characterized by a dysregulated inflammatory response followed by immunosuppression that favors the development of secondary infections. Toll-like receptors (TLRs) are major regulators of the host's response to infections. How variability in TLR signaling may impact the development of sepsis-induced immune dysfunction has not been established. We sought to establish the role of TLR2, TLR4, and TLR5 in postseptic mice with Pseudomonas aeruginosa pneumonia. METHODS: We used an experimental model of sublethal polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wild-type, tlr2(-/-), tlr4(-/-), tlr5(-/-), tlr2 4(-/-) mice that underwent CLP were secondarily subjected to P. aeruginosa pulmonary infection. RESULTS: Postseptic wild-type and tlr4(-/-) and tlr5(-/-) mice displayed high susceptibility to P. aeruginosa pneumonia. In contrast, TLR2-deficient mice, either tlr2(-/-)or tlr2 4(-/-), that underwent CLP were resistant to the secondary pulmonary infection. As compared to wild-type mice, tlr2(-/-) mice displayed improvement in bacterial clearance, decreased bacteremic dissemination, and attenuated lung damage. Furthermore, tlr2(-/-) mice exhibited a pulmonary proinflammatory cytokine balance, with increased production of tumor necrosis factor α and decreased release of interleukin 10. CONCLUSIONS: In a model of secondary P. aeruginosa pneumonia in postseptic mice, TLR2 deficiency improves survival by promoting efficient bacterial clearance and restoring a proinflammatory cytokine balance in the lung.

Combined loss of cRel/p50 subunits of NF-κB leads to impaired innate host response in sepsis.

NF-κB, which comprises homo- and hetero-dimers of the five members of the Rel family, plays a crucial role in immunity to infection. The cRel and p50 subunits have been implicated in the development and function of the immune cells, but their in vivo importance remains poorly explored in sepsis. We aimed to study the impact of the combined loss of these two subunits on the innate response to infection in a cecal ligation and puncture model of sepsis. We have explored the possible defects in host defense, including pathogen clearance, bacterial phagocytosis and cytokine plasma release. We also performed gene profiling of cRel(-/-)p50(-/-) and wild-type LPS-stimulated peritoneal macrophages. Deficiency of cRel and p50 led to enhanced mortality to sepsis that was associated with defective macrophages phagocytosis, decreased bacterial clearance and moderate cytokine response. Transcription profile analysis revealed a common inflammatory response but a significant down-regulated transcription of genes encoding for pathogen recognition receptors and antimicrobial molecules, supporting the in vivo findings in mice. In conclusion, the cRel and p50 subunits of NF-κB play an important combined role in the innate response and are crucial for survival and pathogen clearance in polymicrobial sepsis.

IMPDHII protein inhibits Toll-like receptor 2-mediated activation of NF-kappaB.

Toll-like receptor 2 (TLR2) plays an essential role in innate immunity by the recognition of a large variety of pathogen-associated molecular patterns. It induces its recruitment to lipid rafts induces the formation of a membranous activation cluster necessary to enhance, amplify, and control downstream signaling. However, the exact composition of the TLR2-mediated molecular complex is unknown. We performed a proteomic analysis in lipopeptide-stimulated THP1 and found IMPDHII protein rapidly recruited to lipid raft. Whereas IMPDHII is essential for lymphocyte proliferation, its biologic function within innate immune signal pathways has not been established yet. We report here that IMPDHII plays an important role in the negative regulation of TLR2 signaling by modulating PI3K activity. Indeed, IMPDHII increases the phosphatase activity of SHP1, which participates to the inactivation of PI3K.

Critical role of cRel subunit of NF-κB in sepsis survival.

NF-κB is a critical regulator of gene expression during severe infections. NF-κB comprises homo- and heterodimers of proteins from the Rel family. Among them, p50 and p65 have been clearly implicated in the pathophysiology of sepsis. In contrast, the role of cRel in sepsis is still controversial and has been poorly studied in single-pathogen infections. We aimed to investigate the consequences of cRel deficiency in a cecal ligation and puncture (CLP) model of sepsis. We have approached the underlying mechanisms of host defense by analyzing bacterial clearance, systemic inflammation, and the distribution of spleen dendritic cell subsets. Moreover, by using a genome-wide technology, we have also analyzed the CLP-induced modifications in gene expression profiles both in wild-type (wt) and in rel(-/-) mice. The absence of cRel enhances mortality due to polymicrobial sepsis. Despite normal pathogen clearance, cRel deficiency leads to an altered systemic inflammatory response associated with a sustained loss of the spleen lymphoid dendritic cells. Furthermore, a whole-blood microarray study reveals that the differential outcome between wt and rel(-/-) mice during sepsis is preceded by remarkable changes in the expression of hundreds of genes involved in aspects of host-pathogen interaction, such as host survival and lipid metabolism. In conclusion, cRel is a key NF-κB member required for host antimicrobial defenses and a regulatory transcription subunit that controls the inflammatory and immune responses in severe infection.

Study of human RIG-I polymorphisms identifies two variants with an opposite impact on the antiviral immune response.

BACKGROUND: RIG-I is a pivotal receptor that detects numerous RNA and DNA viruses. Thus, its defectiveness may strongly impair the host antiviral immunity. Remarkably, very little information is available on RIG-I single-nucleotide polymorphisms (SNPs) presenting a functional impact on the host response. METHODOLOGY/PRINCIPAL FINDINGS: Here, we studied all non-synonymous SNPs of RIG-I using biochemical and structural modeling approaches. We identified two important variants: (i) a frameshift mutation (P(229)fs) that generates a truncated, constitutively active receptor and (ii) a serine to isoleucine mutation (S(183)I), which drastically inhibits antiviral signaling and exerts a down-regulatory effect, due to unintended stable complexes of RIG-I with itself and with MAVS, a key downstream adapter protein. CONCLUSIONS/SIGNIFICANCE: Hence, this study characterized P(229)fs and S(183)I SNPs as major functional RIG-I variants and potential genetic determinants of viral susceptibility. This work also demonstrated that serine 183 is a residue that critically regulates RIG-I-induced antiviral signaling.

Comparison between Flotrac-Vigileo and Bioreactance, a totally noninvasive method for cardiac output monitoring.

INTRODUCTION: This study was designed to compare the clinical acceptability of two cardiac output (CO) monitoring systems: a pulse wave contour-based system (FloTrac-Vigileo) and a bioreactance-based system (NICOM), using continuous thermodilution (PAC-CCO) as a reference method. METHODS: Consecutive patients, requiring PAC-CCO monitoring following cardiac surgery, were also monitored by the two other devices. CO values obtained simultaneously by the three systems were recorded continuously on a minute-by-minute basis. RESULTS: Continuous recording was performed on 29 patients, providing 12,099 simultaneous measurements for each device (417 +/- 107 per patient). In stable conditions, correlations of NICOM and Vigileo with PAC-CCO were 0.77 and 0.69, respectively. The bias was -0.01 +/- 0.84 for NICOM and -0.01 +/- 0.81 for Vigileo (NS). NICOM relative error was less than 30% in 94% of the patients and less than 20% in 79% vs. 91% and 79% for the Vigileo, respectively (NS). The variability of measurements around the trend line (precision) was not different between the three methods: 8 +/- 3%, 8 +/- 4% and 8 +/- 3% for PAC-CCO, NICOM and Vigileo, respectively. CO changes were 7.2 minutes faster with Vigileo and 6.9 minutes faster with NICOM (P < 0.05 both systems vs. PAC-CCO, NS). Amplitude of changes was not significantly different than thermodilution. Finally, the sensitivity and specificity for predicting significant CO changes were 0.91 and 0.95 respectively for the NICOM and 0.86 and 0.92 respectively for the Vigileo. CONCLUSION: This study showed that the NICOM and Vigileo devices have similar monitoring capabilities in post-operative cardiac surgery patients.

Dendritic cells modulate lung response to Pseudomonas aeruginosa in a murine model of sepsis-induced immune dysfunction.

Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a murine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 x 10(6) CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-alpha and restored an adequate Il-12p70/IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.