"Inhibitory immune checkpoints predict 7-day, in-hospital and 1-year mortality of internal medicine patients admitted with bacterial sepsis".

BACKGROUND: Sepsis is a life-threatening syndrome with complex pathophysiology and great clinical heterogeneity which complicates the delivery of personalized therapies. Our goals were to demonstrate that some biomarkers identified as regulatory immune checkpoints in preclinical studies could 1)improve sepsis prognostication based on clinical variables and 2)guide the stratification of septic patients in subgroups with shared characteristics of immune response or survival outcomes. METHODS: We assayed the soluble counterparts of 12 biomarkers of immune response in 113 internal medicine patients with bacterial sepsis. RESULTS: IL-1 receptor-associated kinase M (IRAK-M) exhibited the highest hazard ratios (HRs) for increased 7-day (1.94 [1.17-3.20]) and 30-day mortality (1.61 [1.14-2.28]). HRs of IRAK-M and Galectin-1 for predicting 1-year mortality were 1.52 (1.20-1.92) and 1.64 (1.13-2.36), respectively. A prognostic model including IRAK-M, Galectin-1, and clinical variables (Charlson Comorbidty Index, multiple source of sepsis, and SOFA score) had high discrimination for death at 7 days and 30 days (area under the curve 0.90 [0.82-0.99]) and 0.86 [0.79-0.94], respectively). Patients with elevated serum levels of IRAK-M and Galectin-1 had clinical traits of immune suppression and low survival rates. None of the 12 biomarkers were independent predictors of 2-year mortality. CONCLUSIONS: Two inhibitory immune checkpoint biomarkers (IRAK-M and Galectin-1) helped identify 3 distinct sepsis phenotypes with distinct prognoses. These biomarkers shed light on the interplay between immune dysfunction and prognosis in patients with bacterial sepsis and may prove to be useful prognostic markers, therapeutic targets, and biochemical markers for targeted enrollment in targeted therapeutic trials.

Transcriptomic profiling of osteoarthritis synovial macrophages reveals a tolerized phenotype compounded by a weak corticosteroid response.

OBJECTIVES: It is well-known that long-term osteoarthritis prognosis is not improved by corticosteroid treatments. Here we investigate what could underlie this phenomenon by measuring the short term corticosteroid response of OA-Mf. METHODS: We determined the genome-wide transcriptomic response to corticosteroids of end-stage osteoarthritic joint synovial macrophages (OA-Mf). This was compared with LPS-tolerized and ß-glucan-trained circulating blood monocyte-derived macrophage models. RESULTS: Upon corticosteroid stimulation, the trained and tolerized macrophages significantly alter the abundance of 201 and 257 RNA transcripts, respectively. By contrast, by the same criteria, OA-Mf have a very restricted corticosteroid response of only 12 RNA transcripts. Furthermore, while metalloproteinases 1, -2, -3 and -10 expression clearly distinguish OA-Mf from both the tolerized and trained macrophage models, OA-Mf Interleukin 1 (IL1), chemokine (CXCL) and cytokine (CCL) family member profiles resemble the tolerized macrophage model, with the exception that OA-Mf show high levels of CCL20. CONCLUSION: Terminal osteoarthritis joints therefore harbor macrophages with an inflammatory state that closely resembles the tolerized macrophage state and this is compounded by a weak corticosteroid response capacity that may explain the lack of positive long-term effects of corticosteroid treatment for osteoarthritis patients.

Role of dexmedetomidine in modifying immune paralysis in patients with septic shock: randomized controlled trial.

BACKGROUND: Immune paralysis can be defined as a hypoinflammatory state associated with the incapacity of the immune system to release proinflammatory mediators despite the clearance of pathogens by antimicrobials. Persistent immune paralysis leads to failure to eradicate primary infections with a substantial increase in the risk of multiorgan dysfunction and mortality. The state of immune paralysis is caused mainly by the diminished ability of monocytes to release proinflammatory cytokines in response to endotoxin. This phenomenon is known as endotoxin tolerance. This study aimed to assess the role of dexmedetomidine in modifying immune paralysis in septic shock patients. METHODS: Twenty-four patients with septic shock were randomized into two groups of 12 patients. A continuous intravenous infusion of dexmedetomidine started at 0.15 µg kg-1 hr-1 and adjusted by 0.15 µg kg-1 h-1 to a maximum of 0.75 µg kg-1 h-1 (10 ml h-1), while midazolam was started at 1 mg h-1 (2 mL hr-1) and adjusted by 1 mg h-1 to a maximum of 5 mg h-1 (10 mL h-1). All infusions were adjusted by increments of 2 mL/hr-1 to maintain blinding. Serum levels of CD42a+/CD14+, HLADR+/CD14+, CRP, IL-6, IL-10 and TNF-α were measured at baseline (T1), 12 h (T2), and 24 h (T3). RESULTS: Treatment with dexmedetomidine yielded no significant difference in CD42a+/CD14+, HLADR+/CD14, CD24b-MFI, HLADR-MFI, IL6 and TREM1 at all time points when compared with midazolam treatment. There was no significant difference in TLR levels between the two groups. Cardiac output in the dexmedetomidine group showed a significant decrease at 6, 12 and 24 h (P = 0.033, 0.021, and 0.005, respectively) compared with that in the midazolam group. CONCLUSION: Our results indicated that dexmedetomidine did not affect CD42a+/CD14+ and HLA-DR+/CD14+ expression in septic patients. Furthermore, cytokine production and inflammatory biomarkers did not change with dexmedetomidine infusion. Trial registration Clinical trial.gov registry (NCT03989609) on June 14, 2019, https://register. CLINICALTRIALS: gov .

Amphipathic Liponecrosis Impairs Bacterial Clearance and Causes Infection During Sterile Inflammation.

BACKGROUND & AIMS: Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition. METHODS: Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry. RESULTS: Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered ß-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid. CONCLUSIONS: Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.

The Effects of Mitochondrial Transplantation on Sepsis Depend on the Type of Cell from Which They Are Isolated.

Previously, we have shown that mitochondrial transplantation in the sepsis model has immune modulatory effects. The mitochondrial function could have different characteristics dependent on cell types. Here, we investigated whether the effects of mitochondrial transplantation on the sepsis model could be different depending on the cell type, from which mitochondria were isolated. We isolated mitochondria from L6 muscle cells, clone 9 liver cells and mesenchymal stem cells (MSC). We tested the effects of mitochondrial transplantation using in vitro and in vivo sepsis models. We used the LPS stimulation of THP-1 cell, a monocyte cell line, as an in vitro model. First, we observed changes in mitochondrial function in the mitochondria-transplanted cells. Second, we compared the anti-inflammatory effects of mitochondrial transplantation. Third, we investigated the immune-enhancing effects using the endotoxin tolerance model. In the in vivo polymicrobial fecal slurry sepsis model, we examined the survival and biochemical effects of each type of mitochondrial transplantation. In the in vitro LPS model, mitochondrial transplantation with each cell type improved mitochondrial function, as measured by oxygen consumption. Among the three cell types, L6-mitochondrial transplantation significantly enhanced mitochondrial function. Mitochondrial transplantation with each cell type reduced hyper-inflammation in the acute phase of in vitro LPS model. It also enhanced immune function during the late immune suppression phase, as shown by endotoxin tolerance. These functions were not significantly different between the three cell types of origin for mitochondrial transplantation. However, only L6-mitochondrial transplantation significantly improved survival compared to the control in the polymicrobial intraabdominal sepsis model. The effects of mitochondria transplantation on both in vitro and in vivo sepsis models differed depending on the cell types of origin for mitochondria. L6-mitochondrial transplantation might be more beneficial in the sepsis model.

Liver cirrhosis and immune dysfunction.

Cirrhosis is end-stage liver disease resulting from various etiologies and is a common cause of death worldwide. The progression from compensated to decompensated cirrhosis to acute-on-chronic liver failure (ACLF) is due to multiple factors, including continuation of alcohol use or continued exposure to other toxins, an imbalance of the gut microbiota (dysbiosis), increased gut permeability and a disrupted immune response. This disrupted immune response is also named cirrhosis-associated immune dysfunction, which is characterized by worsening systemic inflammation with concomitant immune paralysis, as liver disease deteriorates. This review highlights central immunologic events during the exacerbation of cirrhosis and characterizes the different immune cell populations involved therein.

Beneficial Immune Regulation by Biological Response Modifier Glucans in COVID-19 and Their Envisaged Potentials in the Management of Sepsis.

Sepsis is a life-threatening condition caused by an abnormal immune response induced by infection with no approved or specific therapeutic options. We present our perspectives for the therapeutic management of sepsis through a four-way approach: (1) infection control through immune enhancement; (2) immune suppression during the initial hyper-inflammatory phase; (3) balanced immune-modulation to counter the later immune-paralysis phase; and (4) advantageous effects on metabolic and coagulation parameters throughout. COVID-19 is a virus-triggered, accelerated sepsis-like reaction that is associated with the rapid progress of an inflammatory cascade involving a cytokine storm and multiorgan failure. Here, we discuss the potential of the biological response modifiers, ß-glucans (BRMGs), in the management of sepsis based on their beneficial effects on inflammatory-immune events in COVID-19 clinical studies. In COVID-19 patients, apart from metabolic regulation, BRMGs, derived from a black yeast, Aureobasidium pullulans strain AFO-202, have been reported to stimulate immune responses. BRMGs, produced by another strain (N-163) of A. pullulans, have been implicated in the beneficial regulation of inflammatory markers and immunity, namely IL-6, C-reactive protein (CRP), D-Dimer, ferritin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCR), leucocyte-to-C-reactive protein ratio (LeCR), and leukocyte-to-IL-6 ratio (LeIR). Agents such as these ß-glucans, which are safe as they have been widely consumed by humans for decades, have potential as adjuncts for the prevention and management of sepsis as they exert their beneficial effects across the spectrum of processes and factors involved in sepsis pathology, including, but not limited to, metabolism, infection, inflammation, immune modulation, immune enhancement, and gut microbiota.

Challenging molecular dogmas in human sepsis using mathematical reasoning.

Sepsis is defined as a dysregulated host-response to infection, across all ages and pathogens. What defines a dysregulated state remains intensively researched but incompletely understood. Here, we dissect the meaning of this definition and its importance for the diagnosis and management of sepsis. We deliberate on pathophysiological features and dogmas that range from cytokine storms and immune paralysis to dormancy and altered homeostasis setpoints. Mathematical reasoning, used to test for plausibility, reveals three interlinked cardinal rules governing host-response trajectories in sepsis. Rule one highlights that the amplitude of the immune response while important is not sufficient and is strictly dependent on rule two, specifying bioenergetic capacity and are together dynamically driven by rule three, delineating stability and alterations in setpoints. We consider these rules and associated pathophysiological parameters for guiding data-science and artificial intelligence mining of multi-omics and big-data for improving the precision of diagnostic and therapeutic approaches to sepsis. FUNDING: PG funded by the European Regional Development Fund and Welsh Government (Ser Cymru programme - Project Sepsis).

Chloride intercellular channel 3 suppression-mediated macrophage polarization: a potential indicator of poor prognosis of hepatitis B virus-related acute-on-chronic liver failure.

Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are important mediators of immune responses can be subclassified into two main phenotypes: classically activated and alternatively activated. However, few studies have investigated changes to macrophage polarization in HBV-related liver diseases. Therefore, we investigated the functional status of monocyte-derived macrophages (MDMs) from patients with mild chronic hepatitis B (n = 226), HBV-related compensated cirrhosis (n = 36), HBV-related decompensated cirrhosis (n = 40), HBV-ACLF (n = 62) and healthy controls (n = 10), as well as Kupffer cells (KCs) from patients with HBV-ACLF (n = 3). We found that during the progression of HBV-related liver diseases, the percentage of CD163+ CD206+ macrophages increased, while the percentage of CD80+ human leukocyte antigen-DR+ macrophages decreased significantly. MDMs and KCs mainly exhibited high CD163+ CD206+ expression in patients with HBV-ACLF, which predicted poor clinical outcome and higher liver transplantation rate. Transcriptome sequencing analysis revealed that chloride intracellular channel-3 (CLIC3) was reduced in patients with HBV-ACLF, indicating a poor prognosis. To further study the effect of CLIC3 on macrophage polarization, human monocytic THP-1 cell-derived macrophages were used. We found that classical and alternative macrophage activation occurred through nuclear factor kappa B (NF-κB) and phosphoinositide 3-kinase/protein kinase B pathways, respectively. CLIC3 suppression inhibited NF-κB activation and promoted the alternative activation. In conclusion, macrophage polarization gradually changed from classically activated to alternatively activated as HBV-related liver diseases progressed. Both CLIC3 suppression and increased alternatively activated macrophage percentage were potential indicators of the poor prognosis of patients with HBV-ACLF.

A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling.

Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

Human Leukocyte Antigen-DR Isotype Expression in Monocytes and T Cells Interferon-Gamma Release Assay in Septic Patients and Correlation With Clinical Outcome.

BACKGROUND: Sepsis is a life-threatening dysregulated host response to infection responsible of multiple organs dysfunction (Sepsis-3 International Consensus Definition), during which clinical outcome is a balance between inflammation and immune suppression. Monocytes and lymphocytes may play an important role in immune paralysis, and their impaired functional activity can decrease overall immune system efficiency. We evaluated sepsis-induced changes in monocytes human leukocyte antigen-DR isotype (HLA-DR) expression and T cell capacity of interferon (IFN)-γ production in relation with patient's clinical outcome. METHODS: Analysis of HLA-DR expression on blood monocytes (mHLA-DR) was performed in 55 patients with high procalcitonin (hPCT, > 0.5 ng/mL,) and suspected/confirmed sepsis, and 20 controls. HLA-DR absolute quantification and IFN-γ release assay were monitored in 16 septic patients for 4 weeks following sepsis confirmation. RESULTS: Cytofluorimetric analysis revealed a significant decrease of mHLA-DR percentage in septic patients with adverse outcome compared to patients with better clinical outcome (88.4% vs. 98.6% with P < 0.05), in combination with a significant decrease of absolute number of HLA-DR molecules per monocyte (P < 0.05, starting at 1 week of follow-up). Lymphocytes stimulation with phytohemagglutinin (PHA), Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) showed a severe declining of IFN-γ release related to fatal clinical outcome of patients. CONCLUSIONS: This immunologic anergy of innate and adaptative immunity showed an early immune paralysis during sepsis which appears correlated with the impairment of clinical outcome.

Acute Decompensation and Acute-on-Chronic Liver Failure.

Liver cirrhosis is a major healthcare problem. Acute decompensation, and in particular its interplay with dysfunction of other organs, is responsible for the majority of deaths in patients with cirrhosis. Acute decompensation has different courses, from stable decompensated cirrhosis over unstable decompensated cirrhosis to pre-acute-on-chronic liver failure and finally acute-on-chronic liver failure, a syndrome with high short-term mortality. This review focuses on the recent developments in the field of acute decompensation and acute-on-chronic liver failure.

The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat.

BACKGROUND: Sepsis has a high mortality rate, but no specific drug has been proven effective, prompting the development of new drugs. Immunologically, sepsis can involve hyperinflammation, immune paralysis, or both, which might pose challenges during drug development. Recently, mitochondrial transplantation has emerged as a treatment modality for various diseases involving mitochondrial dysfunction, but it has never been tested for sepsis. METHODS: We isolated mitochondria from L6 muscle cells and umbilical cord mesenchymal stem cells and tested the quality of the isolated mitochondria. We conducted both in vivo and in vitro sepsis studies. We investigated the effects of intravenous mitochondrial transplantation on cecal slurry model in rats in terms of survival rate, bacterial clearance rate, and the immune response. Furthermore, we observed the effects of mitochondrial transplantation on the immune reaction regarding both hyperinflammation and immune paralysis. To do this, we studied early- and late-phase cytokine production in spleens from cecal slurry model in rats. We also used a lipopolysaccharide (LPS)-stimulated human PBMC monocyte model to confirm the immunological effects of mitochondrial transplantation. Apoptosis and the intrinsic apoptotic pathway were investigated in septic spleens. RESULTS: Mitochondrial transplantation improved survival and bacterial clearance. It also mitigated mitochondrial dysfunction and apoptosis in septic spleens and attenuated both hyperinflammation and immune paralysis in the spleens of cecal slurry model in rats. This effect was confirmed with an LPS-stimulated human PBMC study. CONCLUSIONS: In rat polymicrobial cecal slurry model, the outcome is improved by mitochondrial transplantation, which might have an immunomodulatory effect.

Flow Cytometric Analysis of Monocytes Polarization and Reprogramming From Inflammatory to Immunosuppressive Phase During Sepsis.

Sepsis outcome is determined by a balance between inflammation and immune suppression. We aimed to evaluate monocytes polarization and reprogramming during these processes. We analyzed 93 patients with procalcitonin level >0.5 ng/mL (hPCT) and suspected/confirmed sepsis, and 84 controls by analysis of CD14, CD16 and HLA-DR expression on blood monocytes using fluorescent labeled monoclonal antibodies and BD FACS CANTO II. Complete blood cell count, procalcitonin and other biochemical markers were evaluated. Intermediate monocytes CD14++CD16+ increased in hPCT patients (including both positive and negative culture) compared to controls (13.6% ± 0.8 vs 6.2% ± 0.3, p<0.001), while classical monocytes CD14++CD16-were significantly reduced (72.5% ± 1.6 vs 82.6% ± 0.7, p<0.001). Among hPCT patients having positive microbial culture, the percentage of intermediate monocytes was significantly higher in septic compared with non-septic/localized-infection patients (17.4% vs 11.5%; p<0.05) whilst the percentage of classical monocytes was lower (68.0% vs 74.5%). Three-four days following the diagnosis of sepsis, HLA-DR expression on monocyte (mHLA-DR) was lower (94.3%) compared to controls (99.4%) (p<0.05). Septic patients with the worst clinical conditions showed higher incidence of secondary infections, longtime hospitalization and lower HLA-DR+ monocytes compared to septic patients with better clinical outcome (88.4% vs 98.6%, p=0.05). The dynamic nature of sepsis correlates with monocytes functional polarization and reprogramming from a pro-inflammatory CD14++CD16+ phenotype in non-septic hPCT patients to a decrease of HLA-DR surface expression in hPCT patients with confirmed sepsis, making HLA-DR reduction a marker of immune-paralysis and sepsis outcome. Analysis of monocytes plasticity opens to new mechanisms responsible for pro/anti-inflammatory responses during sepsis, and new immunotherapies.

Dysfunctional Immune Response in Acute-on-Chronic Liver Failure: It Takes Two to Tango.

Acute-on-chronic liver failure (ACLF) is characterized by the acute decompensation of cirrhosis associated with organ failure and high short-term mortality. The key event in the pathogenesis is a dysfunctional immune response arising from exacerbation of the two main immunological alterations already present in cirrhosis: systemic inflammation and immune cell paralysis. High-grade systemic inflammation due to predominant activation and dysregulation of the innate immune response leads to the massive release of cytokines. Recognition of acutely increased pathogen and damage-associated molecular patterns by specific receptors underlies its pathogenesis and contributes to tissue damage and organ failure. In addition, an inappropriate compensatory anti-inflammatory response over the course of ACLF, along with the exhaustion and dysfunction of both the innate and adaptive immune systems, leads to functional immune cell paralysis. This entails a high risk of infection and contributes to a poor prognosis. Therapeutic approaches seeking to counteract the immune alterations present in ACLF are currently under investigation.

Immune Response in Bacterial and Candida Sepsis.

Sepsis leads to a systemic immune response, and despite the progress of modern medicine, it is still responsible for a high mortality rate. The immune response to sepsis is dependent on the innate and adaptive immune systems. The first line is the innate system, which requires complex and multiple pathways in order to eliminate the invading threats. The adaptive responses start after the innate response. The cell-mediated arm of CD4+ and CD8+ T and B cells is the main responsible for this response. A coordinated cytokine response is essential for the host immune response. A dysregulated response can lead to a hyperinflammatory condition (cytokine storm). This hyperinflammation leads to neutrophils activation and may also lead to organ dysfunction. An imbalance of this response can increase the anti-inflammatory response, leading to compensatory anti-inflammatory response syndrome (CARS), persistent inflammation-immunsupression, catabolism syndrome (PICS), and, above all, an immune paralysis stat. This immune paralysis leads to opportunistic infections, Candida species being one of the emerging microorganisms involved. The host immune response is different for bacterial or Candida sepsis. Immune responses for bacterial and Candida sepsis are described in this paper.

[A 64-year-old male with recurrence of herpes simplex encephalitis after suffering from severe pneumonia and sepsis].

The case is a 64-year-old male who had a past history of herpes simplex virus encephalitis (HSE) two years prior to his admission. He was admitted to our hospital due to severe pneumonia and sepsis. Several days later, he developed HSE again. It has been known that immunosuppressive state called immune paralysis occurs in the patient with sepsis due to the amplification of anti-inflammatory responses after the initial hyper-inflammatory phase, which increases the susceptibility to various latent viruses including herpes simplex virus. In the present case, we consider that the severe infection may trigger the recurrence of HSE through the viral reactivation due to immune paralysis. When we see a patient suffering from severe infection who had a past history of HSE, we should keep in mind that such a patient may have a risk of the recurrence of HSE.

Immunosenescence in neurocritical care.

BACKGROUND: Several advanced and developing countries are now entering a superaged society, in which the percentage of elderly people exceeds 20% of the total population. In such an aging society, the number of age-related diseases such as malignant tumors, diabetes, and severe infections including sepsis is increasing, and patients with such disorders often find themselves in the ICU. MAIN BODY: Age-related diseases are closely related to age-induced immune dysfunction, by which reductions in the efficiency and specificity of the immune system are collectively termed "immunosenescence." The most noticeable is a decline in the antigen-specific acquired immune response. The exhaustion of T cells in elderly sepsis is related to an increase in nosocomial infections after septicemia, and even death over subacute periods. Another characteristic is that senescent cells that accumulate in body tissues over time cause chronic inflammation through the secretion of proinflammatory cytokines, termed senescence-associated secretory phenotype. Chronic inflammation associated with aging has been called "inflammaging," and similar age-related diseases are becoming an urgent social problem. CONCLUSION: In neuro ICUs, several neuro-related diseases including stroke and sepsis-associated encephalopathy are related to immunosenescence and neuroinflammation in the elderly. Several advanced countries with superaged societies face the new challenge of improving the long-term prognosis of neurocritical patients.

Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.

Elevated serum prostaglandin E2 predicts the risk of infection in hepatitis B virus-related acute-on-chronic liver failure patients.

OBJECTIVE: To evaluate the serum Prostaglandin E2 (PGE2) level in Acute-on-chronic liver failure (ACLF) and determine its predicative value for infection. METHODS: From April 2014 to April 2015, ninety-one patients with hepatitis B virus and ACLF but without infection were enrolled into this prospective study that was carried out at our Hospital. Twenty patients with stable chronic hepatitis B were enrolled from the outpatient department and twenty healthy control subjects without any disease were enrolled from hospital staff. Serum PGE2 levels were determined using ELISA at enrollment. Clinical and laboratory parameters were collected. Receiver operating characteristic (ROC) curves were used to determine optimal cut-off values to predict infection. RESULTS: Significantly higher PGE2 levels were found in patients with ACLF in comparison with healthy controls and patients with stable CHB (P < 0.0001). In ACLF patients, PGE2 levels were significantly higher in patients that eventually developed infection than those without this complication (P < 0.0001). ROC analysis showed that serum PGE2 (area under the ROC curve, 0.83) could predict infection in patients with ACLF with sensitivity of 78.4% and specificity of 81.5% using a threshold of 141 pg/mL. CONCLUSIONS: Serum PGE2 is associated with the susceptibility to secondary infections for patients with ACLF. Increased PGE2 serum levels may serve as a potential biomarker for developing infections in ACLF patients.