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Sepsis is a critical condition that disrupts metabolic, physiological, and immune functions, often resulting in severe complications such as multi-organ failure and increased mortality. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a promising biomarker for infection and inflammation, offering potential advantages for early mortality prediction. This study compared the predictive value of serum NGAL levels with pediatric risk of mortality III (PRISM III) scores in critically ill pediatric patients with sepsis. A prospective cohort study was conducted at a tertiary hospital from September 2022 to March 2023, involving 75 pediatric patients diagnosed with sepsis, septic shock, or multi-organ dysfunction syndrome (MODS), along with 25 healthy controls. Serum NGAL levels were measured within the first hour of PICU admission and analyzed alongside PRISM III scores to evaluate their correlation with mortality and sepsis severity. The results demonstrated that serum NGAL levels were significantly elevated in septic patients compared to controls, with the highest levels observed in those with MODS. NGAL showed greater sensitivity and specificity for predicting mortality than PRISM III scores, with ROC curve analysis revealing that NGAL levels > 599 mg/ml were strongly associated with increased mortality risk (sensitivity 70.4% and specificity 50%). Multivariate analysis confirmed NGAL as an independent predictor of mortality, outperforming PRISM III scores in identifying severe cases., Conclusion: Serum NGAL is a valuable biomarker for early prediction of mortality and sepsis severity in pediatric patients, providing faster and more accurate assessments than PRISM III scores. Its integration into clinical practice may enhance decision-making in pediatric critical care settings, allowing for timely interventions and improved patient outcomes., What Is Known: • Pediatric risk of mortality III (Prism III) scores is widely used to predict sepsis severity and mortality in pediatric intensive care units, but requiring 12-24 hours to complete. Neutrophil is an established biomarker for inflammation and infection with a potentially anti-pathological value in the neutrophil gelatinus-lipocalin (NGAL) sepsis., What Is New: • Serum NGAL levels, PICU is measured within the first hour of entry, prism III score in pediatric patients in predicting mortality and severity of sepsis. > An NGAL cutoff of 599 mg/mL is significantly associated with mortality risk, which provides a rapid, independent and more immediate immunity tool for important care decision making., Competing Interests: Declarations. Consent to participate and ethics approval: The investigation was approved by the Institutional Review Board (IRB) of the Faculty of Medicine before data collection. The permission number is 388:2022. Authorization for publication.: Parents/legal guardians provided written informed consent. Conflicting interests: The authors declare no competing interests., (© 2025. The Author(s).)

The study aimed to investigate the relationship between the respiratory quotient (RQ), measured by the central venous-arterial carbon dioxide partial pressure difference/arterial-venous oxygenation difference ratio, and the early remission of multi-organ failure (MOF) in sepsis patients with hyperlactatemia. The study observed 49 septic patients with hyperlactatemia in the ICU, obtaining blood samples before and after resuscitation, and dividing the patients into two groups depending on whether the modified Sequential Organ Failure Assessment score improved after 24 hours of treatment. Results showed that lactate clearance was faster and the rate of change in RQ was higher in the improved group than in the unimproved group. Further analysis showed that an RQ ≤0.198 mmHg/mL/L or a change of ≥30.71% in RQ after 24 hours of resuscitation was associated with early improvement in MOF. In conclusion, changes in RQ were associated with early improvement in MOF in septic patients with hyperlactatemia, suggesting that RQ could be used as a potential marker for predicting early remission and guiding clinical interventions.

Sepsis, a severe and life-threatening condition arising from a dysfunctional host response to infection, presents considerable challenges to the health care system and is characterized by high mortality rates and substantial economic costs. Exosomes have garnered attention as potential diagnostic markers because of their capacity to mirror the pathophysiological milieu of sepsis. This discourse reviews the progression of sepsis classification from Sepsis 1.0 to Sepsis 3.0, highlighting the imperative for sensitive and specific biomarkers to facilitate timely diagnosis and optimize patient outcomes. Existing biomarkers, such as procalcitonin (PCT) and C-reactive protein (CRP), exhibit certain limitations, thereby prompting the quest for more dependable diagnostic indicators. Exosomal cargoes, which encompass proteins and miRNAs, present a trove of biomarker candidates, attributable to their stability, pervasive presence, and indicative nature of the disease status. The potential of exosomal biomarkers in the identification of sepsis-induced organ damage, including cardiomyopathy, acute kidney injury, and acute lung injury, is emphasized, as they provide real-time insights into cardiac and renal impairments. Despite promising prospects, hurdles persist in the standardization of exosome extraction and the need for extensive clinical trials to validate their efficacy. The combination of biomarker development and sophisticated exosome detection techniques represents a pioneering strategy in the realm of sepsis diagnosis and management, underscoring the significance of further research and clinical validation., Competing Interests: Declarations. Ethics approval and consent to participate: Human Ethics and Consent to participate declarations: Not applicable. Consent for publication: Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: The peripheral perfusion index (PI) reflects microcirculatory blood flow perfusion and indicates the severity and prognosis of sepsis. Method: The cohort comprised 208 patients admitted to the intensive care unit (ICU) with infection, among which 117 had sepsis. Demographics, medication history, ICU variables, and laboratory indexes were collected. Primary endpoints were in-hospital mortality and 28-day mortality. Secondary endpoints included organ function variables (coagulation function, liver function, renal function, and myocardial injury), lactate concentration, mechanical ventilation time, and length of ICU stay. Univariate and multivariate analyses were conducted to assess the associations between the PI and clinical outcomes. Sensitivity analyses were performed to explore the associations between the PI and organ functions in the sepsis and nonsepsis groups. Result: The PI was negatively associated with in-hospital mortality (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.15 to 0.55), but was not associated with 28-day mortality. The PI was negatively associated with the coagulation markers prothrombin time (PT) (β -0.36, 95% CI -0.59 to 0.13) and activated partial thromboplastin time (APTT) (β -1.08, 95% CI -1.86 to 0.31), and the myocardial injury marker cardiac troponin I (cTnI) (β -2085.48, 95% CI -3892.35 to 278.61) in univariate analysis, and with the PT (β -0.36, 95% CI -0.60 to 0.13) in multivariate analysis. The PI was negatively associated with the lactate concentration (β -0.57, 95% CI -0.95 to 0.19), mechanical ventilation time (β -23.11, 95% CI -36.54 to 9.69), and length of ICU stay (β -1.28, 95% CI -2.01 to 0.55). Sensitivity analyses showed that the PI was significantly associated with coagulation markers (PT and APTT) and a myocardial injury marker (cTnI) in patients with sepsis, suggesting that the associations between the PI and organ function were stronger in the sepsis group than the nonsepsis group. Conclusion: The PI provides new insights for assessing the disease severity, short-term prognosis, and organ function damage in ICU patients with sepsis, laying a theoretical foundation for future research., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Cell division cycle 42 (CDC42) modulates inflammation and multiple organ dysfunction by regulating T-cell differentiation and macrophage polarization. This research intended to explore the association of blood CDC42 expression with septic risk, multi-organ dysfunctions, and mortality., Methods: 145 sepsis patients and 50 health controls were recruited, then CDC42 expression in peripheral blood mononuclear cell (PBMC) from them was measured by RT-qPCR., Results: CDC42 was decreased in sepsis patients versus health controls ( P <0.001); meanwhile, the receiver operating characteristic (ROC) curve showed that CDC42 had a certain value to predict sepsis risk with an area under the curve (AUC) (95% confidence interval (CI): 0.797 (0.725-0.869). Furthermore, CDC42 was negatively correlated with C-reactive protein ( P <0.001), tumor necrosis factor-alpha ( P <0.001) and interleukin-17A ( P <0.001) but less with interleukin-6 ( P =0.056). Moreover, CDC42 was negatively related to the SOFA score ( P <0.001) and its several subscales (respiratory system, liver, cardiovascular, and renal system) ( P <0.05). Furthermore, CDC42 was lower in septic deaths versus survivors ( P <0.001); meanwhile, the ROC curve exhibited a certain ability of CDC42 in estimating 28-day mortality with an AUC (95%CI) of 0.766 (0.676-0.855)., Conclusion: Circulating CDC42 exhibits potency to be a prognostic biomarker reflecting multi-organ dysfunctions and higher mortality risk in sepsis., (© 2024 by the Association of Clinical Scientists, Inc.)

Objectives: Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool., Design: In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission., Setting: Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin)., Patients: One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1., Interventions: None., Measurements and Main Results: The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively., Conclusions: Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission., Competing Interests: Drs. Bolanaki’s, Winning’s, Slagman’s, Kiehntopf’s, Stacke’s, and Möckel’s institutions received funding from the Federal Ministry of Education and Research (Germany) (Bundesministerium für Bildung und Forschung [BMBF]). Dr. Slagman reports research funds from the German Research Council (Deutsche Forschungsgemeinschaft), the Innovation Fonds (Gemeinsamer Bundesausschuss), Roche Diagnostics, and ThermoFisher BRAHMS. Dr. Bolanaki reports funds from the Roche Diagnostics and ThermoFisher BRAHMS. Dr. Reinhart reported research grants from the Innovation Fonds (Gemeinsamer Bundesausschuss) and holds shares of the InflaRx NV, Jena, Germany. Dr. Bauer participated in advisory boards of BRAHMS/ThermoFisher and Roche Diagnostics regarding the use of biomarkers to diagnose sepsis. Dr. Winning disclosed he is an employee of the Jena University Hospital (JUH) and at the Ernst-Abbe-Hochschule in Jena. Drs. Kiehntopf’s and Bauer’s institutions received funding from the BMBF (Grant No. 03ZZ0810B). Dr. Kiehntopf disclosed they are inventor of a patent covering a method for quantification of C-terminal peptides of α1-antitrypsin (applicant: JUH; EP22154836.5; status: application), and the inventor of other patents covering C-terminal AAT peptides in inflammation (applicant: JUH: Method for determining the origin of an infection; EP17719610.2 [application]; EP3239712 [granted]) and Diagnosis of Sepsis and Systemic Inflammatory Response Syndrome (CN104204808B, EP2592421, EP2780719, US10712350B2, JP6308946B2 [all granted]). Dr. Möckel’s institution received funding from Roche Molecular Diagnostics German Innovation Funds; he received funding from ThermoFisher BRAHMS GmbH, AstraZeneca, Abbott, Medtronic, Radiometer, and Sanofi; and he disclosed he is Editor-in-Chief of Biomarkers. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: Sepsis, a complex condition characterized by dysregulated immune response and organ dysfunction, is a leading cause of mortality in ICU patients. Current diagnostic and prognostic approaches primarily rely on non-specific biomarkers and illness severity scores, despite early endothelial activation being a key feature of sepsis. This study aimed to evaluate the levels of soluble thrombomodulin and soluble endoglin in seriously ill surgical septic patients and explore their association with organ dysfunction and disease severity., Methodology: A case control study was conducted from March 2022 to November 2022, involving seriously ill septic surgical patients. Baseline clinical and laboratory data were collected within 24 h of admission to the Surgical Intensive Care Unit. This included information such as age, sex, hemodynamic parameters, blood chemistry, SOFA score, qSOFA score, and APACHE-II score. A proforma was filled out to record these details. The outcome of each patient was noted at the time of discharge., Results: The study found significantly elevated levels of soluble thrombomodulin and soluble endoglin in seriously ill surgical septic patients. The RTqPCR analysis revealed a positive correlation between soluble thrombomodulin and soluble endoglin levels with the qSOFA score, as well as, there was a positive association between RTqPCR soluble thrombomodulin and the SOFA score. These findings indicate a correlation between these biomarkers and organ dysfunction and disease severity., Conclusion: The study concludes that elevated levels of soluble thrombomodulin and soluble endoglin can serve as endothelial biomarkers for early diagnosis and prognostication in seriously ill surgical septic patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (<150/nL, p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients.

Critical illness and sepsis may cause organ failure and are recognized as mortality drivers in hospitalized patients. Neuropilin-1 (NRP-1) is a multifaceted transmembrane protein involved in the primary immune response and is expressed in immune cells such as T and dendritic cells. The soluble form of NRP-1 (sNRP-1) acts as an antagonist to NRP-1 by scavenging its ligands. The aim of this study was to determine the value of sNRP-1 as a biomarker in critical illness and sepsis. We enrolled 180 critically ill patients admitted to a medical intensive care unit and measured serum sNRP-1 concentrations at admission, comparing them to 48 healthy individuals. Critically ill and septic patients showed higher levels of sNRP-1 compared to healthy controls (median of 2.47 vs. 1.70 nmol/L, p < 0.001). Moreover, sNRP-1 was also elevated in patients with sepsis compared to other critical illness (2.60 vs. 2.13 nmol/L, p = 0.01), irrespective of disease severity or organ failure. In critically ill patients, sNRP-1 is positively correlated with markers of kidney and hepatic dysfunction. Most notably, critically ill patients not surviving in the long term (one year after admission) showed higher concentrations of sNRP-1 at the time of ICU admission ( p = 0.036), with this association being dependent on the presence of organ failure. Critically ill and septic patients exhibit higher serum concentrations of circulating sNRP-1, which correlates to organ failure, particularly hepatic and kidney dysfunction.

Objective: Sepsis is a host response with life-threatening organ dysfunction caused by an infection. Although the overall mortality rate has increased from 30% to 37% by the surviving sepsis campaign, it is still not acceptable. Early identification, accurate stratification and appropriate intervention can improve the prognosis. In this study we assessed the risk stratification and prognostic value of serum neutrophil gelatinase-associated lipocalin (sNGAL) as a biomarker in sepsis patients., Methods: A total of 112 sepsis patients (38 patients with sepsis, 41 patients with severe sepsis, 33 patients with septic shock) and 25 healthy controls were enrolled in this study. Serum samples of all patients were collected and frozen before testing. Basic patient information was collected, including age, gender, primary infection, complications, and so on. Results of serum calcitonin, lactic acid, and SOFA score were followed up for 28 days., Results: Levels of serum procalcitonin (PCT), serum lactate, Sequential Organ Failure Assessment (SOFA) score and sNGAL of sepsis patients were significantly higher (p<0.05) than those of controls. The sNGAL level in sepsis patients who were alive on the 28th day of follow-up was significantly lower (p<0.05) than that of sepsis patients who had died before the 28th day of follow-up. Multiple logistic regression analysis showed that sNGAL-0h and lactates were independent risk factors of death due to sepsis within 28 days. At cut-off value of 250 ng/mL, the sensitivity and specificity sNGAL-0h predicting the 28-day mortality in septic patients were 0.838 and 0.827, respectively. The sNGAL level in sepsis patients with acute kidney injury (AKI) was significantly higher (p<0.05) than in sepsis patients without AKI., Conclusion: Serum NGAL may contribute to the assessment of the severity of sepsis. Serum NGAL and lactate can be independent risk factors for 28-day mortality in sepsis patients. Serum NGAL has potential of predicting septic-AKI.

Background: Long non-coding RNA potassium voltage-gated channel subfamily Q member 1 opposite strand 1 (lnc-KCNQ1OT1) represses inflammation and multiple organ dysfunction, whereas its clinical value in sepsis is unclear. Thus, this study aimed to explore this issue., Methods: Lnc-KCNQ1OT1 from peripheral blood mononuclear cells were detected by RT-qPCR in 116 sepsis patients and 60 healthy controls (HCs). Moreover, sepsis patients were followed-up until death or up to 28 days., Results: Lnc-KCNQ1OT1 decreased in patients with sepsis than in HCs (p < 0.001). In sepsis patients, lnc-KCNQ1OT1 was negatively correlated with sequential organ failure assessment (SOFA) scores (r = -0.344, p < 0.001) and several SOFA subscale scores (including respiratory system, coagulation, liver, and renal systems) (all r < 0, p < 0.05). Furthermore, lnc-KCNQ1OT1 was negatively correlated with CRP (r = -0.386, p < 0.001), TNF-α (r = -0.332, p < 0.001), IL-1β (r = -0.319, p < 0.001), and IL-6 (r = -0.255, p = 0.006). Additionally, lnc-KCNQ1OT1 levels were lower in sepsis deaths than in sepsis survivors (p < 0.001), and the receiver operating characteristic curve showed that lnc-KCNQ1OT1 had an acceptable ability to predict 28-day mortality (area under the curve: 0.780, 95% confidence interval: 0.678-0.882). Meanwhile, its ability to predict 28-day mortality risk was higher than that of CRP, TNF-α, IL-1β, and IL-6, but slightly lower than the SOFA score and acute physiology and chronic health evaluation II score., Conclusion: Lnc-KCNQ1OT1 serves as a potential biomarker for monitoring disease severity and prognosis in patients with sepsis., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: To investigate the feasibility and the value of using mitochondrial quality control (MQC)-related proteins as biomarkers in septic patients., Methods: The enrolled subjects were divided into four groups: healthy control group (n = 30), intensive care unit (ICU) control group (n = 62), septic nonshock group (n = 40), and septic shock group (n = 94). Serum levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), fission protein 1 (Fis1), mitofusin2 (Mfn2), and Parkin were measured by enzyme-linked immunosorbent assay at the time of enrollment for all groups. Clinical parameters and laboratory test results were also collected., Results: The levels of MQC-related biomarkers between any two of the four groups were significantly different (P < 0.001 for all). The serum levels of PGC-1α, Mfn2, and Parkin were lowest in healthy individuals; the levels were dramatically higher in the ICU control group compared with the others, and they decreased progressively from the septic nonshock group to the septic shock group. However, the pattern for Fis1 was inverse; the more severe the condition was, the higher the level of Fis1. Moreover, there was moderate correlation between MQC-related biomarkers and the SOFA score (PGC-1α, r = -0.662; Fis1, r = 0.609; Mfn2, r = -0.677; Parkin, r = 0.-0.674, P < 0.001 for all)., Conclusions: The serum levels of PGC-1α, Fis1, Mfn2, and Parkin were significantly correlated with organ dysfunction and reflected the disease progression and severity. The dynamic surveillance of these four biomarkers could be beneficial to predict outcome and guide treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Sepsis is a life-threatening complication of infection closely associated with coagulation abnormalities. Heat shock factor 1 (HSF1) is an important transcription factor involved in many biological processes, but its regulatory role in blood coagulation remained unclear. We generated a sepsis model in HSF1-knockout mice to evaluate the role of HSF1 in microthrombosis and multiple organ dysfunction. Compared with septic wild-type mice, septic HSF1-knockout mice exhibited a greater degree of lung, liver, and kidney tissue damage, increased fibrin/: fibrinogen deposition in the lungs and kidneys, and increased coagulation activity. RNA-seq analysis revealed that tissue-type plasminogen activator (t-PA) was upregulated in the lung tissues of septic mice, and the level of t-PA was significantly lower in HSF1-knockout mice than in wild-type mice in sepsis. The effects of HSF1 on t-PA expression were further validated in HSF1-knockout mice with sepsis and in vitro in mouse brain microvascular endothelial cells using HSF1 RNA interference or overexpression under lipopolysaccharide stimulation. Bioinformatics analysis, combined with electromobility shift and luciferase reporter assays, indicated that HSF1 directly upregulated t-PA at the transcriptional level. Our results reveal, for the first time, that HSF1 suppresses coagulation activity and microthrombosis by directly upregulating t-PA , thereby exerting protective effects against multiple organ dysfunction in sepsis., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients., Methods: The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later., Results: Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality., Conclusions: Admission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The present investigation aimed to evaluate the protective effect of Zingerone (ZIN) against lipopolysaccharide-induced oxidative stress, DNA damage, and cytokine storm in rats. For survival study the rats were divided into four groups (n = 10). The control group was treated with normal saline; Group II received an intraperitoneal (i.p) injection (10 mg/kg) of LPS as disease control. Rats in Group III were treated with ZIN 150 mg/kg (p.o) 2 h before LPS challenge and rats in Group IV were given ZIN only. Survival of the rats was monitored up to 96 h post LPS treatment. In another set, the animals were divided into four groups of six rats. Animals in Group I served as normal control and were treated with normal saline. Animals in Group II were treated with lipopolysaccharide (LPS) and served as disease control. Group III animals were treated with ZIN 2 h before LPS challenge. Group IV served as positive control and were treated with ZIN (150 mg/kg orally). The blood samples were collected and used for the analysis of biochemical parameters like alanine transaminase (ALT), alkaline phosphatase (ALP), aspartate transaminase (AST), blood urea nitrogen (BUN), Cr, Urea, lactate dehydrogenase (LDH), albumin, bilirubin (BIL), and total protein. Oxidative stress markers malondialdehyde (MDA), glutathione peroxidase (GSH), myeloperoxidase (MPO), and (DNA damage marker) 8-OHdG levels were measured in different organs. Level of nitric oxide (NO) and inflammatory markers like TNF-α, IL-1ß, IL-1α, IL-2, IL-6, and IL-10 were also quantified in plasma. Procalcitonin (PCT), a sepsis biomarker, was also measured. ZIN treatment had shown significant ( p < 0.5) restoration of plasma enzymes, antioxidant markers and attenuated plasma proinflammatory cytokines and sepsis biomarker (PCT), thereby preventing the multi-organ and tissue damage in LPS-induced rats also confirmed by histopathological studies of different organs. The protective effect of ZIN may be due to its potent antioxidant potential. Thus ZIN can prevent LPS-induced oxidative stress as well as inflammatory and multi-organ damage in rats when administered to the LPS treated animals.

Objective: Fractalkine, CX3CL1, is involved in the directional movement of chemokine cells, immune response, inflammatory response, tissue repair, and other processes. However, its role in sepsis is not well known., Methods: We measured circulating Fractalkine in adult patients with sepsis. Effects of Fractalkine on the survival, inflammation, tissue injury, and bacterial clearance were assessed using the WT or CX3CL -/- murine model of cecal ligation and puncture (CLP)-induced sepsis., Results: Serum Fractalkine concentrations were significantly elevated in adult patients with sepsis compared to healthy adults. Increased Fractalkine correlated positively with the number of blood leukocytes and the level of inflammatory cytokines, including IL-6, IL-1β, IL-17A, IFN-γ, and TNF-α, and correlated negatively with IL-10 in clinical sepsis. Recombinant Fractalkine impaired survival whereas Fractalkine gene knockout or anti-Fractalkine antibody improved survival in the murine model of CLP-induced sepsis. Fractalkine administration increased inflammatory response, evident by higher levels of cytokines (TNF-α, IL-1β, IL-17A, IFN-γ, and IL-6 but not IL-10), and tissue damage (lung, liver, and kidney) in CLP-induced sepsis. Fractalkine reduced bacterial clearance in CLP-induced polymicrobial sepsis by reducing macrophage or neutrophil phagocytosis and intracellular elimination of E. coli., Conclusions: Fractalkine aggravates sepsis by increasing inflammation and decreasing bacterial clearance, and is a potential tool for anti-sepsis therapy., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Sepsis is a severe state of infection with high mortality. Pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) initiate dysregulated systemic inflammation upon binding to pattern recognition receptors. Exosomes are endosome-derived vesicles, which carry proteins, lipids and nucleic acids, and facilitate intercellular communications. Studies have shown altered contents and function of exosomes during sepsis. In sepsis, exosomes carry increased levels of cytokines and DAMPs to induce inflammation. Exosomal DAMPs include, but are not limited to, high mobility group box 1, heat shock proteins, histones, adenosine triphosphate, and extracellular RNA. Exosomes released during sepsis have impact on multiple organs, including the lungs, kidneys, liver, cardiovascular system, and central nervous system. Here, we review the mechanisms of inflammation caused by exosomes, and their contribution to multiple organ dysfunction in sepsis., (Copyright © 2020 Murao, Brenner, Aziz and Wang.)

Current sepsis biomarkers may be helpful in determining organ failure and evaluating patient clinical course; however, direct molecular biomarkers to predict subsequent organ failure have not yet been discovered. Exosomes, a small population of extracellular vesicles, play an important role in the inflammatory response, coagulation process and cardiac dysfunction in sepsis. Nonetheless, the association of plasma exosome with severity and mortality of sepsis is not well known. Therefore, the overall levels of plasma exosome in sepsis patients were assessed and whether exosome levels were associated with organ failure and mortality was evaluated in the present study. Plasma level of exosomes was measured by ELISA. Among 220 patients with sepsis, 145 (66%) patients were diagnosed with septic shock. A trend of increased exosome levels in control, sepsis and septic shock groups was observed (204 µg/mL vs 525 µg/mL vs 802 µg/mL, P < 0.001). A positive linear relationship was observed between overall exosome levels and Sequential Organ Failure Assessment (SOFA) score in the study cohorts (r value = 0.47). When patients were divided into two groups according to best cut-off level, a statistical difference in 28- and 90-day mortality between patients with high and low plasma exosomes was observed. Elevated levels of plasma exosomes were associated with severity of organ failure and predictive of mortality in critically ill patients with sepsis., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Sepsis is a highly complex and lethal syndrome with highly heterogeneous clinical manifestations that makes it difficult to detect and treat. It is also one of the major and most urgent global public health challenges. More than 30 million people are diagnosed with sepsis each year, with 5 million attributable deaths and long-term sequalae among survivors. The current international consensus defines sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Over the past decades substantial research has increased the understanding of its pathophysiology. The immune response induces a severe macro and microcirculatory dysfunction that leads to a profound global hypoperfusion, injuring multiple organs. Consequently, patients with sepsis might present dysfunction of virtually any system, regardless of the site of infection. The organs more frequently affected are kidneys, liver, lungs, heart, central nervous system, and hematologic system. This multiple organ failure is the hallmark of sepsis and determines patients' course from infection to recovery or death. There are tools to assess the severity of the disease that can also help to guide treatment, like the Sequential Organ Failure Assessment (SOFA) score. However, sepsis disease process is vastly heterogeneous, which could explain why interventions targeted to directly intervene its mechanisms have shown unsuccessful results and predicting outcomes with accuracy is still elusive. Thus, it is required to implement strong public health strategies and leverage novel technologies in research to improve outcomes and mitigate the burden of sepsis and septic shock worldwide., (Copyright ©2019, Yale Journal of Biology and Medicine.)

Background: Sepsis is a leading cause of death worldwide and a major challenge for physicians to predict and manage. Proenkephalin A 119-159 (penKid) is a reliable surrogate marker for the more unstable endogenous opioid peptide enkephalin, which has previously been shown to predict both acute and chronic kidney disease. The aim of this prospective observational study was to assess penKid as a predictor of acute kidney injury (AKI), multi-organ failure and mortality in sepsis among unselected sepsis patients presenting to the emergency department (ED)., Method: We enrolled 644 patients consecutively during office-hours (6 AM-6 PM) between December 1, 2013 and February 1, 2015. Fifty-six patients were excluded due to incomplete data. We measured penKid in 588 adult patients (patients under 18 years of age were excluded) with sepsis (≥2SIRS criteria + suspected infection) upon admission to the ED at Skåne University Hospital, Malmö, Sweden. Logistic regression analysis was used to relate levels of penKid at presentation to AKI, multi-organ failure, 28-day mortality and progression of renal SOFA subscore. Odds ratios are presented as the number of standard deviations from the mean of log-transformed penKid., Results: In age and sex adjusted models, penKid predicted AKI within 48 h and 7 days, but these associations were attenuated after additional adjustment for estimated creatinine-based glomerular filtration rate (eGFR). In models adjusted for age, sex and eGFR, penKid significantly predicted progression from rSOFA = 0 and ≤ 1 to higher rSOFA scores as well as multi-organ failure and mortality. In contrast, eGFR did not predict 28-day mortality., Conclusion: PenKid is an effective predictor of renal injury, severe multi-organ failure and mortality in unselected sepsis patients presenting to the emergency department.

Background: Sepsis profoundly alters immune homeostasis. Cytokine release after whole blood lipopolysaccharide (LPS)-stimulation reflects cell function across multiple immune cell classes and represents the immune response to LPS. The main goal of this study was to evaluate the prognostic value of ex vivo stimulation of whole blood with LPS in sepsis., Methods: Blood was drawn on day 1 and day 7 after admission, and stimulated ex vivo with LPS. Tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10 were measured with and without stimulation. Our primary outcome measure was the persistence of at least one organ dysfunction at day 7. Organ dysfunction was defined according to the SOFA components by a score ≥ 2., Results: Forty-nine patients with sepsis from a 21-bed intensive care unit, and 23 healthy volunteers were enrolled. The blood of septic patients was less responsive to ex vivo stimulation with LPS than that of healthy controls at day 1 and 7, as demonstrated by lower TNF-α, IL-1β, IL-6 and IL-10 release. Persistent organ dysfunction was more frequent in patients with lower IL-10 release at day 1 but such an association was not found for pro-inflammatory cytokines. A persistent low IL-10 release at day 7 was also associated with persistent organ dysfunction., Conclusion: These data suggest that the capacity to produce IL-10 in response to whole blood ex vivo stimulation early in sepsis, as well as persistent low IL-10 response over time, may help in prognostication and patient stratification. These results will need to be confirmed in future studies., (Copyright © 2019 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis., Design: Prospective observational study SETTING:: Single academic PICU., Patients: One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction., Interventions: None., Measurements and Main Results: Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1-2, 3-5, and 8-14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1-2 maximal uncoupled respiration (9.7 ± 7.7 vs 13.7 ± 4.1 pmol O2/s/10 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2 ± 4.3 vs 9.6 ± 3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1-2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1-2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3-5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61-0.84) and trended toward fewer organ failure-free days although day 28 (β coefficient, -0.64; 95% CI, -1.35 to 0.06; p = 0.08)., Conclusions: Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction.

Objectives: Multiple organ dysfunction syndrome is characterized by simultaneous multiple organ failure, which is the leading cause of death in acute critically ill patients. However, what mediates multiple organ dysfunction syndrome is not fully understood. The discovery of toxic effects by extracellular histones on different individual organs strongly suggests their involvement in multiple organ dysfunction syndrome. In this study, we investigate whether circulating histones are major mediators of multiple organ dysfunction syndrome in acute critical illnesses., Design: Combination of retrospective clinical studies and animal models with intervention., Setting: ICU in a tertiary hospital and research laboratories., Patients: Four hundred and twenty ICU patients, including sepsis (140), severe trauma (63), severe pancreatitis (89), and other admission diagnoses (128)., Laboratory Investigation: Cells from major organs are treated with calf thymus histones or histone-containing sera. Animal models for sepsis, trauma, and acute pancreatitis are treated with antihistone reagents., Intervention: Antihistone reagents in in vitro, ex vivo, and animal models., Measurement and Main Results: Retrospective analysis of a prospectively recruited ICU cohort demonstrated a strong correlation between circulating histones and organ injury markers and Sequential Organ Failure Assessment scores. Ex vivo experiments showed that patient sera containing high histone levels were toxic to cultured cells from different origins, suggesting their universal toxicity to multiple organs. Animal models of sepsis, trauma, and pancreatitis further demonstrated a temporal correlation between histone levels and disease severity and multiple organ injury. Importantly, antihistone reagents, that is, antihistone single-chain variable fragment and nonanticoagulant heparin, could dramatically reduce multiple organ injury, particularly of the heart and lungs, and improve survival in mouse models., Conclusions: High levels of circulating histones are major mediators of multiple organ dysfunction syndrome. Our results indicate that monitoring upon ICU admission could inform on disease severity and developing antihistone therapy holds great potential of reducing multiple organ dysfunction syndrome and improving survival of critically ill patients.

Purpose: Sepsis stimulates pro- and anti-inflammatory immune responses. The innate immune response is critical to organ injury repair. We tested for an association between innate immune function and organ function recovery in a prospective cohort of immune-competent adults with sepsis., Methods: We conducted a prospective observational cohort study enrolling immune-competent adults with sepsis. We tested innate immune function by quantification of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) α production capacity in whole blood samples on hospital days 1, 4, and 6. The primary outcome was organ function recovery on day 4 defined as a 4-point decrease in the composite cardiovascular and respiratory Sequential Organ Failure Assessment (SOFA) score components or a SOFA score ≤2., Results: Patients with sepsis who recovered organ function by day 4 (n = 11) had similar baseline characteristics when compared to those with ongoing organ failure (n = 13). Tumor necrosis factor α production capacity was similar between the 2 groups on hospital days 1 and 4 but significantly different on day 6. Patients who regained organ function recovery had significantly higher TNF-α production capacity on day 6 ( P = .01), which persisted after adjustment for age, Acute Physiology and Chronic Health Evaluation III score, and steroid administration ( P = .03). There was no difference in TNF-α production capacity over time in those who survived to hospital discharge versus nonsurvivors., Conclusion: Increasing TNF-α production capacity is associated with improved organ failure recovery. Further studies are needed to evaluate a causal association between innate immune suppression and organ failure recovery as well as predictive accuracy for hospital survival. Impaired TNF-α production as a marker of sepsis-associated innate immune dysfunction may be a feasible target for immune stimulation to decrease time to organ failure recovery.

Background: In patients with sepsis, an inflammatory response can lead to destruction of the glycocalyx. These alterations cause the progression of organ dysfunction. Destruction of the glycocalyx can also occur in chronic hyperglycemia. Glycated hemoglobin (HbA1c) is a reliable marker of premorbid hyperglycemia. We investigated the association between HbA1c level at admission and the degree of organ dysfunction progression 72 hours after admission and ICU mortality., Methods and Findings: This study was a retrospective observational study. Logistic regression and correlation analyses were performed to evaluate the association between the HbA1c level and the degree of organ dysfunction progression 72 hours after ICU admission. We applied survival analysis to examine the association between HbA1c level and ICU mortality. A total of 90 patients were included in this study. The association between HbA1c level and degree of organ dysfunction progression was significant (r = 0.320; P = 0.002). Multivariable logistic regression analysis showed that high HbA1c level (≥6.5%) (OR, 2.98; 95% CI, 1.033-8.567; P = 0.043) were significant, independent predictors of severe organ dysfunction progression. Patients with an HbA1c level ≥6.5% exhibited significantly greater liver and kidney dysfunction progression 72 hours after ICU admission compared with those with an HbA1c level <6.5%. Kaplan-Meier analysis showed that the survival period was significantly shorter in patients with an HbA1c level ≥6.5% than in those with an HbA1c level <6.5% (P < 0.001). Multivariable Cox proportional hazard analysis showed that HbA1c level ≥6.5% (HR, 3.49; 95% CI, 1.802-6.760; P <0.001) were significant, independent predictors of ICU mortality., Conclusions: In patients with sepsis, the HbA1c level at ICU admission is associated with progression of organ dysfunction 72 hours later and with ICU mortality. It may be important to assess HbA1c level at ICU admission because it may be a predictor of ICU outcome. For patients with a high HbA1c level (≥6.5%), greater attention should be paid to the possibility of organ dysfunction progression., Competing Interests: The authors have declared that no competing interests exist.

Background: In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored the relationship between TRAIL and RIPK3., Methods: We performed an observational study of critically ill adults admitted to intensive care units at 3 academic medical centers across 2 continents, using 1 as derivation and the other 2 as validation cohorts. Levels of TRAIL were measured in the plasma of 570 subjects by ELISA., Results: In all cohorts, lower (<28.5 pg/ml) versus higher levels of TRAIL were associated with increased organ dysfunction (P ≤ 0.002) and septic shock (P ≤ 0.004). Lower TRAIL levels were associated with in-hospital mortality in 2 of 3 cohorts (Weill Cornell-Biobank of Critical Illness, P = 0.012; Brigham and Women's Hospital Registry of Critical Illness, P = 0.011; Asan Medical Center, P = 0.369). Lower TRAIL was also associated with increased RIPK3 (P ≤ 0.001)., Conclusion: Lower levels of TRAIL were associated with septic shock and organ dysfunction in 3 independent ICU cohorts. TRAIL was inversely associated with RIPK3 in all cohorts., Funding: NIH (R01-HL055330 and KL2-TR002385).

Patients who survive the acute phase of sepsis can progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Although sepsis is characterized by early hypercoagulability and delayed hypocoagulability, coagulopathy during chronic critical illness is not fully understood. The objective of this study was to determine whether sepsis-induced PICS is associated with coagulation abnormalities. Using our previously described murine PICS model, outbred mice underwent cecal ligation and puncture, and coagulability was characterized after 8 days. We found that during PICS the spleen became markedly enlarged with increased splenocytes and splenic megakaryocytes without a concomitant increase in circulating platelets. Microscopy revealed a nearly sevenfold increase in pulmonary microvascular thrombi in PICS mice, along with significantly decreased pulmonary tidal volumes and inspiratory times and with significantly increased respiratory rates. Thromboelastometry showed that PICS mice had significantly delayed clot initiation time but increased clot firmness. Finally, PICS mice displayed delayed thrombin production and decreased overall thrombin concentrations. All together, these data demonstrate a general dysregulation of coagulation resulting in microthrombus formation and compromised lung function. On the basis of these findings, we propose that consumptive coagulopathy constitutes another cardinal feature of PICS and may contribute to the ongoing tissue damage and multiple organ failure that can occur in chronic critical illness.

Objective: Mitochondrial dysfunction has been implicated as a key cellular event leading to organ dysfunction in sepsis. Our objective is to measure changes in mitochondrial bioenergetics in subjects with early presentation of sepsis to provide insight into the incompletely understood pathophysiology of the dysregulated host response in sepsis., Design: Prospective observational study., Setting: Single site tertiary academic emergency department., Subjects: We enrolled a total of 48 subjects in the study, 10 with sepsis or septic shock, 10 with infection without sepsis, 14 older and 14 younger healthy controls., Interventions: Peripheral blood mononuclear cells were measured with high-resolution respirometry (OROBOROS O2K)., Measurements and Main Results: The median age in patients with sepsis, infection only, older control and younger controls were 63, 34, 61, and 29 years old, respectively. In the Sepsis group, the median 1st 24-h SOFA score was 8, and the initial median lactate was 4.2 mmol/dL, compared with 1.1 in the Infection Group. The 30-day mortality of the sepsis/septic shock group was 50%, with a median length of stay of 7-days. The Sepsis Group had significantly lower routine and Max respiration when compared with the other groups as well as uncoupled Complex I respiration. There was also a significant decrease in ATP-linked respiration along with the Spare Reserve Capacity in the Sepsis Group when compared with the other group. There were no age-related differences in respiration between the Older and Younger control group., Conclusions: Bedside measurement of mitochondrial respiration can be minimally invasive and performed in a timely manner. Mitochondrial dysfunction, detected by decreased oxygen consumption utilized for energy production and depleted cellular bioenergetics reserve.

Purpose of Review: Sepsis is a common syndrome of multiorgan system dysfunction caused by a dysregulated inflammatory response to an infection and is associated with high rates of mortality. Plasma lipid and lipoprotein levels and composition change profoundly during sepsis and have emerged as both biomarkers and potential therapeutic targets for this condition. The purpose of this article is to review recent progress in the understanding of the molecular regulation of lipid metabolism during sepsis., Recent Findings: Patients who experience greater declines in high-density lipoprotein during sepsis are at much greater risk of succumbing to organ failure and death. Although the causality of these findings remains unclear, all lipoprotein classes can sequester and prevent the excessive inflammation caused by pathogen-associated lipids during severe infections such as sepsis. This primordial innate immune function has been best characterized for high-density lipoproteins. Most importantly, results from human genetics and preclinical animal studies have suggested that several lipid treatment strategies, initially designed for atherosclerosis, may hold promise as therapies for sepsis., Summary: Lipid and lipoprotein metabolism undergoes significant changes during sepsis. An improved understanding of the molecular regulation of these changes may lead to new opportunities for the treatment of sepsis.

Objectives: Recent metabolomic studies of sepsis showed that increased circulatory acylcarnitines were associated with worse survival. However, it is unknown whether plasma carnitine and acylcarnitines can reflect the severity of sepsis, and the role of specific acylcarnitines in prognostic assessment need further confirmation. This study aimed to clarify these questions., Design: Prospective multicenter cohort studies with derivation and validation cohort design., Setting: ICUs at two medical centers and three regional hospitals in Taiwan., Patients: Patients with sepsis and acute organ dysfunction were enrolled. Recruitment of the derivation (n = 90) and validation cohorts (n = 120) occurred from October 2010 through March 2012 and January 2013 through November 2014, respectively., Interventions: Plasma samples were collected immediately after admission, and the levels of carnitine and acylcarnitines were measured by ultra-high performance liquid chromatography-mass spectrometry., Measurements and Main Results: In the derivation cohort, increased plasma levels of short- and medium-chain acylcarnitines were significantly associated with hepatobiliary dysfunction, renal dysfunction, thrombocytopenia, and hyperlactatemia. However, acetylcarnitine is the only acylcarnitine significantly correlating with various plasma cytokine concentrations and also associated with blood culture positivity and 28-day mortality risk. The association between plasma acetylcarnitine and multiple organ dysfunction severity, blood culture positivity, and 28-day mortality, was confirmed in the validation cohort. Patients with high plasma acetylcarnitine (≥ 6,000 ng/mL) had significantly increased 28-day mortality compared with those with plasma acetylcarnitine less than 6,000 ng/mL (52.6% vs 13.9%; hazard ratio, 5.293; 95% CI, 2.340-11.975; p < 0.001 by Cox proportional hazard model)., Conclusions: We confirm that plasma acetylcarnitine can reflect the severity of organ dysfunction, inflammation, and infection in sepsis and can serve as a prognostic biomarker for mortality prediction.

Objective: An imbalance in oxidant-antioxidant status may impact the severity of sepsis. We hypothesised links between nitrosative stress and pro-inflammatory cytokines and their correlation with the severity of sepsis and associated organ dysfunction., Methods: The hypothesis was tested in 110 patients with sepsis (in whom a disease severity score (APACHE II) and assessment of organ failure score (SOFA) were determined) and 55 healthy volunteers. Neutrophil inducible nitric oxide synthase (iNOS) expressions at mRNA and protein levels were estimated by real-time PCR and immuno-precipitation followed by Western blotting, respectively. Nitric oxide (NO) content was assessed in neutrophils by confocal microscopy, plasma nitrite by the Griess reaction and inflammatory cytokines (TNF-α, IFN-γ and IL-8) by ELISA (in plasma) and real-time PCR (in neutrophils). Serum bilirubin and creatinine were determined by routine methods and lung function by the PaO 2 /FiO 2 ratio., Results: Increased neutrophil iNOS expression and NO content, plasma total nitrite content and pro-inflammatory cytokines were present in sepsis patients (all P < 0.001). Plasma nitrite correlated with cytokines, APACHE II, SOFA, PaO 2 /FiO 2 ratio, serum bilirubin and creatinine clearance (all r 2 0.63-0.85, P < 0.001). Cytokines correlated with nitrite, APACHE II, SOFA, PaO 2 /FiO 2 ratio, serum bilirubin and creatinine clearance (all r 2 0.35-0.85, P < 0.001)., Conclusion: Neutrophils iNOS expression, NO content, plasma nitrite and cytokines have a role in the assessment of the severity of sepsis and organ toxicity.

Background: Sepsis, defined as life-threatening organ failure caused by a dysregulated host response to infection, is a major cause of morbidity and mortality in hospitalized patients. Understanding the features that distinguish sepsis from bloodstream infections (and other types of infection) can help clinicians appropriately and efficiently target their diagnostic workup and therapeutic interventions, especially early in the disease course., Content: In this review, sepsis and bloodstream infections are both defined, with a focus on recent changes in the sepsis definition. The molecular and cellular pathways involved in sepsis pathogenesis are described, including cytokines, the coagulation cascade, apoptosis, and mitochondrial dysfunction. Laboratory tests that have been evaluated for their utility in sepsis diagnosis are discussed., Summary: Sepsis is defined not only by the presence of an infection, but also by organ dysfunction from a dysregulated host response to that infection. Numerous pathways, including proinflammatory and antiinflammatory cytokines, the coagulation cascade, apoptosis, and mitochondrial dysfunction, help determine if a bloodstream infection (or any other infection) progresses to sepsis. Many biomarkers, including C-reactive protein, procalcitonin, and lactic acid have been evaluated for use in sepsis diagnosis, although none are routinely recommended for that purpose in current clinical practice. While some laboratory tests can help distinguish the 2, the presence of organ dysfunction is what separates sepsis from routine infections., (© 2018 American Association for Clinical Chemistry.)

Although the role of B cells in sepsis immunoregulation has become an interesting topic, there is lack of data on the role of B cell function regulators in prediction of multiorgan dysfunction syndrome (MODS). The aim of this study was to evaluate the prognostic value of A Proliferation Inducing Ligand (APRIL) and soluble Transmembrane Activator and CAML Interactor Protein (sTACI), the main B cell function regulators, in prediction of MODS development within the first 48 h after admission to intensive care unit, among septic patients. We included 112 patients with sepsis, treated at Clinic for Infectious Diseases and Emergency Center, Clinical Center of Vojvodina, Novi Sad, Serbia. Plasma concentrations of APRIL and sTACI were determined at the admission and potential development of MODS was confirmed in the first 48 h. Concentrations of APRIL (p = 0.003) and sTACI (p<0.001) were higher in patients who developed MODS (n = 30). ROC curve analysis showed that AUC for sTACI (AUC = 0.764) was greater than that for procalcitonin (AUC = 0.719) and APRIL (AUC = 0.673) in MODS development prediction. Multivariate regression analysis showed that sTACI, as an anti-inflammatory biomarker stimulating the apoptosis of B cells, was the only independent predictor of MODS, beside SOFA score. Elevated level of sTACI could be the alarm for the increased B cell apoptosis and development of immune paralysis. Including these biomarkers into predictive scores specific for septic patients may potentially improve their sensitivity and specificity. Measurement of their concentrations dynamics could contribute to better assessment of sepsis evolution and timely introduction of immunomodulatory therapy.

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial., Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock., Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8)., Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial., Trial Registration: ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

Objective: High density lipoprotein (HDL) is important for defense against sepsis but becomes dysfunctional (Dys-HDL) during inflammation. We hypothesize that Dys-HDL correlates with organ dysfunction (sequential organ failure assessment (SOFA) score) early sepsis., Methods: A prospective cohort study of adult ED sepsis patients enrolled within 24 hours., Results: Eighty eight patients were analyzed. Dys-HDL (expressed as HDL inflammatory index (HII)) correlated with SOFA at enrollment (r = 0.23, p = 0.024) and at 48 hours (r = 0.24, p = 0.026) but HII change over the first 48 hours did not correlate with change in SOFA (r = 0.06, p = 0.56). Enrollment HII was significantly different in patients with most severe organ failure (2.31, IQR 1.33-5.2) compared to less severe organ failure (1.81, IQR 1.23-2.64, p = 0.043). Change in HII over 48 hours was significantly different for in-hospital non-survivors (-0.45, IQR-2.6, -0.14 p = 0.015) and for 28-day non-survivors (-1.12, IQR -1.52, 0.12, p = 0.044). In a multivariable linear regression equation (R2 = 0.13), for each unit HII increase, 48-hour SOFA increased by 0.72 (p = 0.009)., Conclusion: HII correlated with SOFA and predicted 48-hour SOFA score in early sepsis. Future studies are needed to delineate potential mechanisms., Trial Registration: NCT02370186. Registered February 24, 2015., Competing Interests: The authors have declared that no competing interests exist.

Thrombocytopenia-associated multiple-organ failure (TAMOF) is an increasingly fatal phenomenon that may be associated with sepsis. TAMOF results from immune dysregulation and impaired activity of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif, member 13. Early recognition of this premorbid condition and specific management results in a significantly improved outcome. Herein, we report the presentation and management of a 2-year-old child with TAMOF who was successfully treated with plasma exchange and recovered without long-term sequelae., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Biomarkers are widely used to confirm the presence of infection. However, it would be of the greatest importance to predict in advance the occurrence or worsening of organ dysfunction in infected patients allowing timely antibiotic escalation. This study investigates the ability of procalcitonin (PCT) and MR-proADM to predict the transition to sepsis in infected patients. The study was conducted in a neurointensive care unit over a three-month period. We included both patients with and without infection to investigate the specificity of organ dysfunction prediction in infected patients. Daily measurement of PCT and MR-proADM, SOFA, Pitt, and CPIS were performed. To measure the correlation between each biomarker and each severity score, linear mixed-effects models were developed. For each biomarker-score combination we tested the correlation of the score with the biomarker measured one and two days before, the same day, and the day after. Sixty-four critically ill patients, 31 with infection, were enrolled. The statistically significant biomarker-score combinations were PCT-SOFA, MR-proADM-SOFA, MR-proADM-Pitt, and MR-proADM-CPIS. The MR-proADM models predicting Pitt and CPIS variations with 24-hour anticipation showed the best fit. The scores increased by 0.6 ± 0.3 and 0.4 ± 0.2 for each unitary biomarker increase, respectively. The MR-proADM-SOFA combinations were equivalent when the biomarker was measured the day before or the same day (score increases were 1.5 ± 0.4 and 1.9 ± 0.4, respectively). The PCT-SOFA model had the best fit when PCT was measured the same day of the score. There was no difference in the predictive ability of the biomarker in infected and non-infected patients. This was a pivotal study conducted in a single neurointensive centre on a limited number of patients, and as such it does not provide definitive conclusions. PR-proADM predicted occurrence and worsening of organ failure in critically ill patients with and without infection. The combination with infection diagnostic biomarkers such as PCT would allow predicting evolution to sepsis in infected patients., Competing Interests: In the last two years Bruno Viaggi has received honoraria for speaking at symposia from ABBOTT - ACCELERATE DIAGNOSTICS - ADA - ALIFAX - BECTON & DICKINSON - BELLCO - MERCK SHARP & DOHME - PFIZER - THERMOFISCHER SCIENTIFIC. Stefano Finazzi has been supported by Fondazione Cariplo through grant no. 2014-1962. The study was supported unconditionally by THERMOFISCHER SCIENTIFIC, which provided the immunoassays and the use of the analyser. THERMOFISCHER SCIENTIFIC that will pay the fee to Plos One for the article publication. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Objective- Nbeal2 -/- mice, a model of human gray platelet syndrome, have reduced neutrophil granularity and impaired host defense against systemic Staphylococcus aureus infection. We here aimed to study the role of Nbeal2 deficiency in both leukocytes and platelets during gram-negative pneumonia and sepsis. Approach and Results- We studied the role of Nbeal2 in platelets and leukocytes during murine pneumonia and sepsis by Klebsiella pneumoniae. Apart from platelet α-granule deficiency and reduced neutrophil granularity, also monocyte granularity was reduced in Nbeal2 -/- mice, whereas plasma levels of MPO (myeloperoxidase), elastase, NGAL (neutrophil gelatinase-associated lipocalin), and MMP-9 (matrix metalloproteinase 9), and leukocyte CD11b expression were increased. Nbeal2 -/- leukocytes showed unaltered in vitro antibacterial response and phagocytosis capacity against Klebsiella, and unchanged reactive nitrogen species and cytokine production. Also during Klebsiella pneumonia and sepsis, Nbeal2 -/- mice had similar bacterial growth in lung and distant body sites, with enhanced leukocyte migration to the bronchoalveolar space. Despite similar infection-induced inflammation, organ damage was increased in Nbeal2 -/- mice, which was also seen during endotoxemia. Platelet-specific Nbeal2 deficiency did not influence leukocyte functions, indicating that Nbeal2 directly modifies leukocytes. Transfusion of Nbeal2 -/- but not of Nbeal2 +/+ platelets into thrombocytopenic mice was associated with bleeding in the lung but similar host defense, pointing at a role for platelet α-granules in maintaining vascular integrity but not host defense during Klebsiella pneumosepsis. Conclusions- These data show that Nbeal2 deficiency-resulting in gray platelet syndrome-affects platelets, neutrophils, and monocytes, with intact host defense but increased organ damage during gram-negative pneumosepsis.

Objective: To investigate the plasma concentration of endogenous morphine and the value of endogenous morphine in predicting shock, death, and multiple organ dysfunction syndrome (MODS) in children with sepsis., Methods: A total of 31 children with sepsis who met the diagnostic criteria were enrolled. According to the presence or absence of shock, they were divided into non-shock group with 19 children and shock group with 12 children. According to the outcome, they were divided into survival group with 22 children and death group with 9 children. According to the presence or absence of MODS, they were divided into non-MODS group with 13 children and MODS group with 18 children. In addition, 16 children with common infection and 31 who underwent physical examination were enrolled as controls. High-performance liquid chromatography-mass spectrometry was used to measure the plasma concentration of endogenous morphine. The receiver operating characteristic (ROC) curve was used to evaluate the value of endogenous morphine in predicting shock, death, and MODS in children with sepsis., Results: No endogenous morphine was detected in the healthy control group. Endogenous morphine was detected in 3 children from the common infection group and in all of 31 children with sepsis. The shock group had a significantly higher plasma concentration of endogenous morphine than the non-shock group (P<0.05). The death group had a significantly higher plasma concentration of endogenous morphine than the survival group (P<0.05). The MODS group had a significantly higher plasma concentration of endogenous morphine than the non-MODS group (P<0.05). The ROC curve showed that endogenous morphine had certain value in predicting shock, death, and MODS in children with sepsis (P<0.05)., Conclusions: There is a significant increase in the plasma concentration of endogenous morphine in children with sepsis, and endogenous morphine has a good value in predicting the risk of shock, death, and MODS.

Objective: To determine the validity of plasma lactate in the emergency department for the early detection of tissue hypoperfusion in septic patients., Materials and Methods: Longitudinal descriptive study. Non probabilistic sampling for convenience. Plasma lactate levels were determined in patients admitted to the emergency department with systemic inflammatory response data and clinical suspicion or documented infection. Follow-up was seven days. Complications were considered if the patients presented septic shock, severe sepsis, entry to intensive care or death., Results: Ninety patients were included. The mean age was 57.4±20.31. Fifty five percent (n=49) were women. 25% (n=22) of the patients showed complications. Plasma lactate levels were 1.55mmol/L in uncomplicated patients and 3.72mmol/L for complicated patients (p<0.001). The area under the ROC curve was 0.72 (95% CI, 0.575-0.829). The cutoff point that best described the relationship with the probability of complications was that set at 4.2mmol/L. The variables studied that showed a significant association with the probability of complications were edema (p=0.004), and infections of the respiratory tract (p=0.037). A model that included lactate levels, using as adjustment variables edema and the presence of low respiratory tract infection explained between 0.234 and 0.349 of the dependent variant, correctly classifying 80% of the cases., Conclusion: Plasma lactate is useful in emergency departments as a predictive test for the early detection of patients with tissue hypoperfusion that evolve to severe sepsis, septic shock or death., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rationale: Late immune suppression is associated with nosocomial infection and mortality in adults and children with sepsis. Relationships between early immune suppression and outcomes in children with sepsis remain unclear., Objectives: Prospective observational study to test the hypothesis that early innate and adaptive immune suppression are associated with longer duration of organ dysfunction in children with severe sepsis or septic shock., Methods: Children younger than 18 years of age meeting consensus criteria for severe sepsis or septic shock were sampled within 48 hours of sepsis onset. Healthy control subjects were sampled once. Innate immune function was quantified by whole blood ex vivo LPS-induced TNF-α (tumor necrosis factor-α) production capacity. Adaptive immune function was quantified by ex vivo phytohemagglutinin-induced IFN-γ production capacity., Measurements and Main Results: One hundred two children with sepsis and 35 healthy children were enrolled. Compared with healthy children, children with sepsis demonstrated lower LPS-induced TNF-α production (P < 0.0001) and lower phytohemagglutinin-induced IFN-γ production (P < 0.0001). Among children with sepsis, early innate and adaptive immune suppression were associated with greater number of days with multiple organ dysfunction syndrome and greater number of days with any organ dysfunction. On multivariable analyses, early innate immune suppression remained independently associated with increased multiple organ dysfunction syndrome days (adjusted relative risk, 1.2; 95% confidence interval, 1.03-1.5) and organ dysfunction days (adjusted relative risk, 1.2; 95% confidence interval, 1.1-1.3)., Conclusions: Critically ill children with severe sepsis or septic shock demonstrate early innate and adaptive immune suppression. Early innate and adaptive immune suppression are associated with longer durations of organ dysfunction and may be useful markers to help guide future investigations of immunomodulatory therapies in children with sepsis.

Objective: The aim of the study was to investigate the expression and clinical correlations of costimulatory molecules on peripheral T-cell subsets of severe sepsis (SS) patients., Methods: Blood samples of patients with community-acquired pneumonia-associated SS and healthy controls (HCs) were analyzed. SS patients were followed up for 28 days. Costimulatory molecule expression on T-cell subsets was determined by flow cytometry analysis. The clinical correlations of these parameters were examined., Results: A total of 92 SS patients and 29 HCs were recruited. Higher frequency of CD28, CD27, OX40 on CD4+ T cells, OX40 on CD4+CD27-CD28- T cells and lower frequency of CD4+CD27-CD28- T cells in the SS group compared with the HC group and in the nonsurvived SS group compared with the survived SS subgroup were observed. The SS group and the nonsurvived SS subgroup exhibited lower frequency of 4-1BB on either CD8+ or CD4+ T cells. The frequency of regulatory T cells (Tregs), OX40+ Tregs and 4-1BB+ conventional T cells (Tconvs) were higher in the SS group. The frequency of CD4+CD27+ T cells, CD4+CD28+ T cells, and OX40+ on CD4+CD27-CD28- T cells were positively correlated with the sequential organ failure assessment (SOFA) score. The frequency of CD4+CD27+ T cells and OX40+ on CD4+CD27-CD28- T cells independently predicted 28-day mortality., Conclusions: Early-stage SS patients exhibited an activated T-cell phenotype. Imbalanced OX40 and 4-1BB expression presented on Tregs and Tconvs may contribute to a functional imbalance of Tregs/Tconvs. The frequency of CD4+CD27+ T cells and OX40+ on CD4+CD27-CD28- T cells predicted 28-day mortality of SS.

Background: Procalcitonin (PCT) is a valuable prognostic biomarker in human sepsis that is predictive of organ dysfunction, septic shock and mortality. Data on PCT in dogs is limited. This study aimed to investigate the prognostic value of baseline and serial PCT measurements in dogs with sepsis and to determine the association between PCT and sepsis severity and the presence of organ dysfunction. PCT concentrations were measured in citrated plasma samples collected from 53 dogs with sepsis at the time of admission (T0, n = 53) and at 24 h (T1, n = 35) and 48 h (T2, n = 30) post-admission using a commercial ELISA. Dogs were classified by sepsis severity (sepsis without organ dysfunction; severe sepsis; septic shock) and outcome (survivors; non-survivors). Organ dysfunctions were recorded at T0 and during hospitalization, and the APPLE fast score calculated at T0. Healthy dogs (n = 12) were used as controls., Results: There were 18 septic dogs without organ dysfunction, 24 dogs with severe sepsis and 11 with septic shock. Baseline PCT concentrations were significantly greater in dogs with sepsis compared to healthy controls (P < 0.0001), and in dogs with septic shock compared to dogs without cardiovascular compromise (P = 0.01). Baseline PCT was significantly correlated with organ dysfunction (P = 0.003). Declining PCT concentrations were documented in survivors at T1 and T2 compared to PCT at T0 (P = 0.0006), and PCT clearance at 24 h was significantly higher in survivors (n = 38) compared to non-survivors (n = 15) (P = 0.037). Canine APPLE fast score was not predictive of sepsis severity, the development of MODS or outcome., Conclusion: In dogs with sepsis, PCT concentrations at hospital admissions are predictive of organ dysfunction and septic shock. Serial procalcitonin monitoring may offer valuable prognostic information in canine sepsis, wherein early decreases in PCT concentrations are associated with survival.

Background: We assessed the Th17 (T-helper cell)/Treg (Regulatory T cell) imbalance in sepsis patients with multiple organ dysfunction syndrome (MODS) and the clinical benefits of continuous high-volume hemofiltration (HVHF)., Methods: 48 sepsis patients, including 22 patients with MODS (MODS group, n = 22) and 26 without (non-MODS group, n = 26), and 20 healthy volunteer controls were enrolled. The patients in MODS group were randomly divided into the continuous blood purification (CBP) group (n = 11) receiving conventional comprehensive treatment plus high-volume hemofiltration and the non-CBP group (n = 11) receiving conventional comprehensive treatment only. At day 28, all 48 patients were divided into the survival group (n = 36) and the non-survival group (n = 12). Venous blood samples, collected at 0, 6, 12 and 24 hours during hemofiltration (or equivalent times in the non-CBP group), were assessed by flow cytometry to detect the Th17 and Treg cells in peripheral blood. Serum cytokines (such as IL-6, IL-17, IL-23, IL-10 and TGF-β1) were detected by enzyme-linked immune sorbent assay (ELISA)., Results: Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL-23, IL-10 and TGF-β1 were significantly higher in MODS and non-MODS group than in the health control (p<0.05), while Th17%, Treg%, Th17/Treg and measured cytokines were significantly higher in the MODS group compared to the non-MODS group (p<0.05). After HVHF treatment, Th17%, Treg%, Th17/Treg, IL-6, IL-17, and IL-10 were significantly reduced (p<0.05), while there were no significant changes in the non-CBP group (p>0.05). In addition, APACHE II and SOFA scores decreased markedly after HVHF treatment. Baseline Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL-23, IL-10 and TGF-β1 were significantly higher in the non-survival group compared to the survival group. Both Th17% and Th17/Treg were positivity correlated with concentration of IL-6 and APACHE II score (p<0.01)., Conclusions: The level of Th17/Treg imbalance in sepsis is related to the occurrence and prognosis of MODS. High-volume hemofiltration can attenuate the Th17/Treg imbalance in sepsis patients, possibly by removing inflammatory mediators.

Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models., Competing Interests: The authors declare no conflict of interest.

Introduction: The purpose of this study was to investigate the value of N-terminal pro brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and procalcitonin (PCT) in predicting mortality in septic patients during hospitalization with mortality risk<10% evaluated by Sepsis-related Organ Failure Assessment (SOFA)., Material and Methods: Prospective, observational study performed in sepsis patients with SOFA risk<10%. We obtained levels of biomarkers in the first 72h after admission in hospital. All patients were monitored during hospitalization or until death. We used ROC curves to determine area under curve (AUC) and identify the best cutoff concentrations to predict mortality., Results: A total of 174 patients were analyzed. Seventeen (9.8%) patients died during hospitalization. The AUC of NT-proBNP was 0.793 (95% CI 0.686-0.9; P<.0005) compared to AUC of CRP (0.728; 95% CI 0.617-0.839; P=.004) and AUC of PCT (0.684; 95% CI 0.557-0.811; P=.019). Factors independently associated with in-hospital mortality were NT-proBNP>1,330pg/ml (OR=23.23; 95% CI 2.92-182.25; P=.003) and to have predisposing factors (OR=3.05; 95% CI 1.3-9.3; P=.044) CONCLUSIONS: In patients with low mortality risk according to SOFA score, NT-proBNP obtained in the first 72h after admission prove to be a powerful predictor of mortality. Their implementations in clinical practice would improve the predictive ability of clinical severity scores., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

Introduction: Although recent studies have reported the efficacy of antithrombin (AT) supplementation for sepsis-associated disseminated intravascular coagulation (DIC), the factors that influence AT's effect have not been sufficiently studied. The purpose of this survey was to identify factors that modulate the effects and the adverse effects of AT., Methods: We performed a multi-institutional survey. The data from 159 patients with septic DIC with AT ≤70% and who had undergone AT supplementation were analyzed. The patients' demographic characteristics, including the infection site, baseline sepsis-related organ failure assessment (SOFA) score, baseline DIC score, and baseline AT activity, were analyzed in relation to the 28-day mortality. Bleeding-related adverse events were also examined., Results: Overall, 116 patients survived and 43 did not (28-day mortality: 27.0%). A logistic regression analysis revealed that the baseline SOFA score (odds ratio [OR]: 0.816, P = .001), coadministration of recombinant thrombomodulin (rTM; OR: 3.989, P = .006), and respiratory tract infection (OR: 0.129, P = .000) were significantly associated with the survival. Survivors exhibited a higher peak AT activity than nonsurvivors (85.1% vs 65.0%, P = .027). Bleeding events were observed in 4.13% (major bleeding: 1.65%) of the patients, and the coadministration of rTM did not increase the risk of bleeding (with rTM: 4.11% vs without rTM: 4.17%). Heparin was concomitantly used in 22 (18.2%) cases, and its use nonsignificantly increased the bleeding risk (with heparins: 9.09% vs without heparins: 3.03%; P = .224)., Conclusion: The coadministration of rTM may improve survival without increasing the risk of bleeding in patients with sepsis-associated DIC treated with AT.

Infectious diseases remain a major health problem, and sepsis and other severe infectious diseases are common causes of morbidity and mortality. There is a need for clinical and laboratory tools to identify patients with severe infections early and to distinguish between bacterial and nonbacterial conditions. Heparin-binding protein (HBP), also known as azurocidin or cationic antimicrobial protein of 37 KDa, is a promising biomarker to distinguish between patients with these conditions. It is biologically plausible that HBP is an early and predictive biomarker because it is prefabricated and rapidly mobilized from migrating neutrophils in response to bacterial infections. HBP induces vascular leakage and oedema formation and has a pro-inflammatory effect on a variety of white blood cells and epithelial cells. The dysregulation of vascular barrier function and cellular inflammatory responses can then lead to organ dysfunction. Indeed, it has been shown that patients with sepsis express elevated levels of HBP in plasma several hours before they develop hypotension or organ dysfunction. HBP has a major role in the pathophysiology of severe bacterial infections and thus represents a potential diagnostic marker and a target for the treatment of sepsis., (© 2017 The Association for the Publication of the Journal of Internal Medicine.)