Diagnostic and prognostic role of procalcitonin (PCT) and MR‐pro‐Adrenomedullin (MR‐proADM) in bacterial infections

Rapid diagnosis of bacterial infections is crucial for adequate antibiotic treatment. Serum molecules such as Procalcitonin (PCT) have been used as biomarkers of infection. Recently, the mid‐regional pro‐Adrenomedullin (MR‐proADM) has been evaluated in combination with PCT for sepsis diagnosis. The diagnostic role of PCT and MR‐proADM both in sepsis and in localized infections together with their contribution to effective antibiotic therapy has been evaluated. One hundred and eighty‐two patients with bacterial infection has been enrolled: PCT and MR‐proADM were measured at admission (T = 0), at 12–24 h (T = 1) and in the third or fifth day of antibiotic therapy (T = 3–5). ROC curve (receiver operating characteristic) and post‐test probability were calculated. MR‐proADM increased with the severity of the infection. PCT resulted significantly higher in sepsis than localized infection. After antibiotic therapy, PCT significantly decreased in localized respiratory infections and in sepsis, while MR‐proADM decreased significantly after antibiotic therapy only in patients with severe sepsis/septic shock. The threshold values of PCT and MR‐proADM were >0.1 ng/mL and >0.8 nmol/L, respectively. The combined use of PCT and MR‐proADM increased the post‐test probability of the diagnosis of bacterial infections compared to PCT alone. In conclusion, PCT and MR‐proADM combination improves the diagnosis of bacterial infection and contribute to prognosis and antibiotic therapy effectiveness.     

Farnesyltransferase inhibitor FTI‐277 inhibits PD‐L1 expression on septic spleen lymphocytes and promotes spleen lymphocyte activation

Farnesyltransferase inhibitors have been tested in clinical trials for the treatment of tumours. In sepsis, the binding of programmed death 1 (PD‐1) to programmed death ligand 1 (PD‐L1) promotes lymphocyte apoptosis and decreases cytokine expression, thus affecting survival rates. The PD‐1/PD‐L1 pathway plays an important role in chronic viral infection, bacterial infection and sepsis. However, the precise immunosuppressive and anti‐inflammatory functions of this pathway remain poorly understood. In our previous study, the induction of sepsis by caecal ligation and puncture (CLP) resulted in increased farnesyltransferase activity and farnesylated protein levels in the spleen relative to sham treatment. However, the effect of inhibition of farnesyltransferase activity on overall survival rates in patients with sepsis and the specific signalling pathway involved remain to be investigated. In this study, mice with CLP‐induced sepsis were treated with farnesyltransferase inhibitor (FTI‐277), and PD‐L1 expression on septic spleen lymphocytes was examined. Flow cytometric analysis revealed that PD‐L1 is expressed constitutively on lymphocytes and that PD‐L1 protein expression was up‐regulated strongly following CLP. FTI‐277 down‐regulated PD‐L1 mRNA and protein expression on septic spleen lymphocytes in a dose‐dependent manner. This effect was associated closely with nuclear factor kappa B (NF‐κB). In addition, the significant damping effect of FTI‐277 on the PD‐L1 signal promoted interferon (IFN)‐γ secretion, interleukin (IL)‐2 production and splenocyte proliferation in response to anti‐CD3⁺CD28⁺ antibodies in mice. Furthermore, FTI‐277 reduced spleen lymphocyte apoptosis in septic mice. Therefore, FTI‐277 regulates spleen lymphocyte activity via the PD‐L1 signalling pathway, with significant anti‐inflammatory effects attributable to suppression of the NF‐κB pathway. Farnesyltransferase represents a valuable therapeutic target for the treatment of sepsis.     

Increased Expression of Programmed Cell Death‐1 in Regulatory T Cells of Patients with Severe Sepsis and Septic Shock: An Observational Clinical Study

While regulatory T cells (Tregs) constitutively express programmed cell death‐1 (PD‐1), the role of PD‐1 expression in Tregs of patients with sepsis remains unclear. Thus, we determined PD‐1 expression in Tregs from the peripheral blood of patients with severe sepsis and septic shock. Seventy‐eight patients with severe sepsis and 40 with septic shock, as well as 21 healthy subjects, were enrolled in this study. The percentage of peripheral blood PD‐1⁺ Tregs, as well as absolute Treg counts, were compared between these three groups. PD‐1 expression in Tregs and absolute Treg counts were also compared between survivors and non‐survivors in patients with sepsis. PD‐1 expression in Tregs increased in patients with sepsis compared to healthy controls. Conversely, absolute Treg counts were significantly decreased in patients with sepsis compared to healthy controls; patients with septic shock had the lowest absolute Treg counts. Among patients with sepsis, survivors had lower levels of PD‐1 expression in Tregs, as well as higher absolute Treg counts, than non‐survivors. Additionally, the percentage of PD‐1⁺ Tregs correlated positively with lactate levels as well as the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in patients with sepsis. PD‐1 was upregulated in Tregs of patients with sepsis and may indicate a state of immune dysfunction. Overexpression of PD‐1 in Tregs was associated with more severe sepsis as well as poor outcomes.     

The use of the soluble adhesion molecules sE‐selectin,sICAM‐1, sVCAM‐1, sPECAM‐1 and their ligands CD11a and CD49d as diagnostic and prognostic biomarkers in septic and critically ill non‐septic ICU patients

Endothelial activation is pivotal in the development and escalation of sepsis. Central to endothelial activation is the endothelial up‐regulation of cellular adhesion molecules (CAMs) including E‐selectin, ICAM‐1, VCAM‐1, and PECAM‐1. Shed CAMs are also found in circulating soluble forms (sCAMs). We investigated whether sCAMs can be used as biomarkers for the differentiation between septic and non‐septic patients. Furthermore, we investigated lymphocyte and monocyte expression of LFA‐1 (CD11a/CD18) and VLA‐4 (CD49d/CD29) ligands for ICAM‐1 and VCAM‐1, respectively. Twenty‐one septic and 15 critically ill non‐septic patients were included. All patients had an APACHE II score above 13 at ICU admission. Fifteen healthy volunteers served as controls. Flow cytometry was used to estimate levels of sE‐selectin, sICAM‐1, sVCAM‐1, sPECAM‐1, and the cellular expression of CD11a and CD49d. Levels of sE‐selectin, sICAM‐1 and sPECAM‐1 were higher in the septic patients compared with the non‐septic patients and controls at admission and during the observation period. Lymphocyte and monocyte expression of CD11a and CD49d was suppressed or unaltered in the septic patients compared with the non‐septic patients and controls. Levels of sE‐selectin, sICAM‐1, and sPECAM‐1 were able to discriminate between septic and non‐septic patients, indicating that sCAMs may be potential diagnostic biomarkers of sepsis.     

血管外肺水指数与降钙素原对革兰氏阴性杆菌烧伤脓毒症病情严重程度的评估作用

目的探讨血管外肺水指数(EVLWI)、降钙素原(PCT)对革兰氏阴性杆菌烧伤脓毒症病情严重程度的评估作用。 方法选择2015年3月至2019年3月武汉大学同仁医院暨武汉市第三医院烧伤科收治的20例血培养为革兰氏阴性杆菌烧伤脓毒症患者(革兰氏阴性杆菌烧伤脓毒症组)及18例血培养为非革兰氏阴性杆菌烧伤脓毒症患者(非革兰氏阴性杆菌烧伤脓毒症组)。2组患者均行脉搏指示连续心输出量(PiCCO)监测,并分别在诊断为脓毒症与脓毒症休克时记录EVLWI的数值变化,连续测量3次,取其平均值;同时在确诊脓毒症与脓毒症休克时立即行静脉血的采集,采集非抗凝血3 mL,离心后留取血清并行PCT的检测,记录2组PCT值。比较2组确诊脓毒症与脓毒症休克时EVLWI及PCT,对数据行t检验并行Bonferroni校正。绘制EVLWI及血清PCT预测革兰氏阴性杆菌烧伤脓毒症与脓毒症休克患者的受试者工作特征(ROC)曲线,计算诊断革兰氏阴性杆菌烧伤脓毒症或脓毒症休克的95%的置信区间、约登指数、最佳临界值、灵敏度和特异度。 结果诊断为脓毒症时,革兰氏阴性杆菌烧伤脓毒症组患者的EVLWI、PCT水平分别为(10.6±1.6) mL/kg、(6.64±1.63) ng/mL,均高于非革兰氏阴性杆菌烧伤脓毒症组[(7.9±1.7) mL/kg、(4.60±1.31) ng/mL],差异均有统计学意义(t＝5.043、4.206,P值均小于0.05)。诊断为脓毒症休克时,革兰氏阴性杆菌烧伤脓毒症组患者的EVLWI、PCT水平分别为(15.0±1.3) mL/kg、(12.87±2.65) ng/mL,均高于非革兰氏阴性杆菌烧伤脓毒症组[(10.7±1.5) mL/kg、(6.29±1.79) ng/mL],差异均有统计学意义(t＝9.608、8.867,P值均小于0.05)。通过绘制ROC曲线可以得知,应用EVLWI及PCT判断革兰氏阴性杆菌烧伤脓毒症及非革兰氏阴性杆菌烧伤脓毒症的最佳临界值分别为10.5 mL/kg、5.9 ng/mL;约登指数分别为50%、59%,灵敏度分别为50%、70%,特异度分别为100%、89%。EVLWI及PCT判断革兰氏阴性杆菌烧伤脓毒症休克及非革兰氏阴性杆菌烧伤脓毒症休克的最佳临界值分别为13.5 mL/kg、9.2 ng/mL;约登指数分别为90%、95%,灵敏度分别为90%、95%,特异度均为100%。 结论EVLWI及PCT可作为革兰氏阴性杆菌烧伤脓毒症病情严重程度的有效评估指标,可进一步提高革兰氏阴性杆菌烧伤脓毒症危险预测性的准确度。     

The identification of up‐regulated ebv‐miR‐BHRF1‐2‐5p targeting MALT1 and ebv‐miR‐BHRF1‐3 in the circulation of patients with multiple sclerosis

Epstein–Barr virus (EBV) is a well‐documented aetiological factor for multiple sclerosis (MS). EBV encodes at least 44 microRNAs (miRNAs) that are readily detectable in the circulation of human. Previous studies have demonstrated that EBV‐encoded miRNAs regulate host immune response and may serve as biomarkers for EBV‐associated diseases. However, the roles of EBV miRNAs in MS are still unknown. To fill the gap, we conducted a comprehensive profiling of 44 mature EBV miRNAs in 30 relapsing–remitting MS (RRMS) patients at relapse and 30 matched healthy controls. Expression levels of ebv‐miR‐BHRF1‐2‐5p and ebv‐miR‐BHRF1‐3 were elevated significantly in the circulation and correlated positively with the expanded disability status scale (EDSS) scores of MS patients. Receiver operating characteristic (ROC) analyses confirmed that the expression of these two miRNAs distinguished MS patients clearly from healthy controls. Luciferase assays revealed that ebv‐miR‐BHRF1‐2‐5p may directly target MALT1 (mucosa‐associated lymphoid tissue lymphoma transport protein 1), a key regulator of immune homeostasis. In conclusion, we described the expression of EBV miRNAs in MS and preliminarily validated the potential target genes of significantly altered EBV miRNAs. The findings may pave the way for prospective study about the pathogenesis of MS.     

High Interleukin-10 Expression in Type 2 T Helper Cells in Septic Patients

Interleukin (IL)-10 response is associated with mortality in patients with sepsis. IL-10 is primarily produced by monocytes and type 2 T helper (Th2) cells. The aim of this study was to investigate differences in IL-10 production between monocytes and Th2 cells in patients with sepsis. Forty patients with sepsis and 35 healthy controls were enrolled. Cytokine expressions in peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry. The IL-10 expression in the Th2 cells of the septic patients was higher than in the healthy controls, but the expression of IL-10 in the monocytes of the septic patients was lower than in the healthy controls. After regression analysis, IL-10 expression in Th2 cells was positively associated with sepsis, but IL-10 expression in monocytes was not associated with sepsis or shock. In conclusion, the production of IL-10 in Th2 cells was higher in the patients with sepsis.     

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

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

IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

The implication of B lymphocytes in the immunopathology of multiple sclerosis (MS) is increasingly recognized. Here we investigated the response of B cells to IFN‐β, a first‐line therapy for relapsing‐remitting MS patients, upon stimulation with TLR. IFN‐β restored the frequency of TLR7‐induced IgM and IgG‐secreting cells in MS patients to the levels found in healthy donors, showing a specific deficiency in the TLR7 pathway. However, no difference was observed in the TLR9 response. Furthermore, in MS‐derived PBMCs, TLR7‐mediated production of IL‐6 and the ex vivo expression of B‐cell‐activating factor of the TNF family, two crucial cytokines for B‐cell differentiation and survival, were induced by IFN‐β. Depletion of monocytes, which are key producers of both IL‐6 and B‐cell‐activating factor of the TNF family, showed that TLR7‐mediated B‐cell differentiation into Ig‐secreting cells is strongly dependent on the cross‐talk between B cells and monocytes. Accordingly, impaired expression of TLR7 mRNA was observed in PBMCs and monocytes isolated from MS‐affected individuals as compared with those from healthy donors, which was rescued by IFN‐β therapy. Collectively, our data unveil a novel TLR7‐regulated mechanism in in vivo IFN‐β‐stimulated whole leukocytes that could be exploited to define new TLR7‐based strategies for the treatment of MS.     

Clinical outcome and predictors of mortality in children with sepsis,severe sepsis,and septic shock from Rohtak,Haryana: A prospective observational study

Background:

Information regarding early predictive factors for mortality and morbidity in sepsis is limited from developing countries.

Methods:

A prospective observational study was conducted to determine the clinical outcome and predictors of mortality in children with sepsis, severe sepsis, and septic shock. Children aged 1 month to 14 years admitted to a tertiary care pediatric intensive care unit (PICU) with a diagnosis of sepsis, severe sepsis, or septic shock were enrolled in the study. Hemodynamic and laboratory parameters which discriminate survivors from nonsurvivors were evaluated.

Results:

A total of 50 patients (30 [60%] males) were enrolled in the study, of whom 21 (42%) were discharged (survivors) and rest 29 (58%) expired (nonsurvivor). Median (interquartile range) age of enrolled patients were 18 (6, 60) months. Mortality was not significantly predicted individually by any factor including age (odds ratio [OR] [95% confidence interval [CI]]: 0.96 [0.91-1.01], P = 0.17), duration of PICU stay (OR [95% CI]: 1.18 [0.99-1.25], P = 0.054), time lag to PICU transfer (OR [95% CI]: 1.02 [0.93-1.12], P = 0.63), Pediatric Risk of Mortality (PRISM) score at admission (OR [95% CI]: 0.71 [0.47-1.04], P = 0.07) and number of organ dysfunction (OR [95% CI]: 0.03 [0.01-1.53], P = 0.08).

Conclusion:

Mortality among children with sepsis, severe sepsis, and septic shock were not predicted by any individual factors including the time lag to PICU transfer, duration of PICU stay, presence of multiorgan dysfunction, and PRISM score at admission.     

Endotoxin Binding and Elimination by Monocytes: Secretion of Soluble CD14 Represents an Inducible Mechanism Counteracting Reduced Expression of Membrane CD14 in Patients with Sepsis and in a Patient with Paroxysmal Nocturnal Hemoglobinuria

Little is known about the role of peripheral blood mononuclear cells (PBMCs) in lipopolysaccharide (LPS) elimination. We studied the endotoxin elimination capacities (EEC) of PBMCs of 15 healthy volunteers, 13 patients with sepsis, and 1 patient suffering from paroxysmal nocturnal hemoglobinuria (PNH). Although expression of CD14, the best-characterized receptor for LPS to date, was reduced from 93.6% ± 0.8% in healthy subjects to 50.5% ± 6.5% in patients with sepsis and was 0.3% in a patient with septic PNH, EEC were found to be unchanged. There was no difference in the amount of tumor necrosis factor alpha (TNF-α) released by PBMCs of healthy donors and patients with sepsis. Anti-CD14 antibodies (MEM-18) completely suppressed EEC, binding of fluorescein isothiocyanate-labeled LPS to monocytes as determined by FACScan analysis, and TNF-α release in all three groups studied. The concentrations of soluble CD14 (sCD14) secreted by endotoxin-stimulated PBMCs from healthy donors and patients with sepsis amounted to 4.5 ± 0.4 and 20.1 ± 1.8 ng/ml, respectively. Based on our results, we suggest that PBMCs eliminate LPS by at least two different mechanisms; in healthy subjects, the membrane CD14 (mCD14) receptor is the most important factor for LPS elimination, while in patients with sepsis (including the septic state of PNH), increased sCD14 participates in LPS elimination. Secretion of sCD14 is strongly enhanced under conditions of low expression of mCD14 in order to counteract the reduction of mCD14 and maintain the function of monocytes. This sCD14 may substitute the role of mCD14 in LPS elimination during sepsis. The elimination of LPS by PBMCs correlates with the binding reaction and the secretion of TNF-α.     

Expression of NK Cell and Monocyte Receptors in Critically Ill Patients – Potential Biomarkers of Sepsis

Sepsis is characterized by activation of both the innate and adaptive immune systems as a response to infection. During sepsis, the expression of surface receptors expressed on immune competent cells, such as NKG2D and NKp30 on NK cells and TLR4 and CD14 on monocytes, is partly regulated by pro‐ and anti‐inflammatory mediators. In this observational study, we aimed to explore whether the expression of these receptors could be used as diagnostic and/or prognostic biomarkers in sepsis. Patients with severe sepsis or septic shock (n = 21) were compared with critically ill non‐septic patients (n = 15). Healthy volunteers (n = 15) served as controls. To elucidate variations over time, all patients were followed for 4 days. Cell surface expression of NKG2D, NKp30, TLR4 and CD14 and serum levels of IL‐1β, IL‐6, IFN‐γ, TNF‐α, IL‐4 and IL‐10 was estimated by flow cytometry. We found that NK cell expression of NKG2D and monocyte expression of CD14 were lower in the septic patients compared with the non‐septic patients, both at ICU admission and during the observation period (P < 0.01 for all comparisons). Both at ICU admission, and during the observation period, levels of IL‐6 and IL‐10 were higher in the septic patients compared with the non‐septic patients (P < 0.001 for all comparisons). Conclusion: As both NKG2D and CD14 levels appear to distinguish between septic and non‐septic patients, both NKG2D and CD14 may be considered potential diagnostic biomarkers of severe sepsis and septic shock.     

Ultraviolet light converts propranolol,a nonselective β‐blocker and potential lupus‐inducing drug,into a proinflammatory AhR ligand

UV light and some medications are known to trigger lupus erythematosus (LE). A common mechanism underlying the immunopathologic effect, resulting from exposure to these two seemingly unrelated factors, remains unknown. The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of IL‐22 production in humans and can be activated by both xenobiotics and naturally occurring photoproducts. A significant expansion of Th17 and Th22 cells was observed in the peripheral blood of active systemic LE (SLE) patients, compared to inactive patients and controls. We also show that propranolol, a potential lupus‐inducing drug, induced stronger AhR activation in PBMCs of SLE patients than in those of controls. AhR agonist activity of propranolol was enhanced by UV light exposure. MS analysis of irradiated propranolol revealed the generation of a proinflammatory photoproduct. This compound behaves like the prototypic AhR ligand 6‐formylindolo[3,2‐b]carbazole, a cutaneous UV light‐induced tryptophan metabolite, both promoting IL‐22, IL‐8, and CCL2 secretion by T‐cells and macrophages. Finally, LE patients exhibit signs of cutaneous AhR activation that correlate with lesional expression of the same proinflammatory cytokines, suggesting a role for photometabolites in the induction of skin inflammation. The AhR might therefore represent a target for therapeutic intervention in LE.     

A metabonomic approach to early prognostic evaluation of experimental sepsis by 1H NMR and pattern recognition

This study proposes an NMR‐based metabonomic approach to early prognostic evaluation of sepsis. Forty septic rats receiving cecal ligation and puncture (CLP) were divided into the surviving group and nonsurviving group on day 6, while 20 sham‐operated rats served as the control group. Serum samples were collected from septic and sham‐operated rats at 12 h after surgery and analyzed using ¹H NMR spectroscopy. Orthogonal partial least squares (OPLS) were applied and showed clustering according to predefined groups, indicating that NMR‐based metabolic profiling could reveal pathologic characteristics in the serum of sham‐operated, surviving, and nonsurviving septic rats. In addition, six characteristic metabolites including lactate, alanine, acetate, acetoacetate, hydroxybutyrate, and formate, which are mainly involved in energy metabolism, changed markedly in septic rats, especially in the nonsurvivors. Using these metabolites, a predictive model for prognostic evaluation of sepsis was constructed using a radial basis function neural network (RBFNN) with a prediction accuracy of about 87% by test samples. The results indicated that the NMR‐based metabonomic approach is a potential technique for the early prognostic evaluation of sepsis. Copyright © 2009 John Wiley & Sons, Ltd.     

Performance Evaluation of Five Different Disseminated Intravascular Coagulation (DIC) Diagnostic Criteria for Predicting Mortality in Patients with Complicated Sepsis

Disseminated intravascular coagulation (DIC) is a major complication in sepsis patients. We compared the performance of five DIC diagnostic criteria, focusing on the prediction of mortality. One hundred patients with severe sepsis or septic shock admitted to intensive care unit (ICU) were enrolled. Routine DIC laboratory tests were performed over the first 4 days after admission. The overall ICU and 28-day mortality in DIC patients diagnosed from five criteria (International Society on Thrombosis and Haemostasis [ISTH], the Japanese Association for Acute Medicine [JAAM], the revised JAAM [R-JAAM], the Japanese Ministry of Health and Welfare [JMHW] and the Korean Society on Thrombosis and Hemostasis [KSTH]) were compared. Both KSTH and JMHW criteria showed superior performance than ISTH, JAAM and R-JAAM criteria in the prediction of overall ICU mortality in DIC patients (odds ratio 3.828 and 5.181, P = 0.018 and 0.006, 95% confidence interval 1.256–11.667 and 1.622–16.554, respectively) when applied at day 1 after admission, and survival analysis demonstrated significant prognostic impact of KSTH and JMHW criteria on the prediction of 28-day mortality (P = 0.007 and 0.049, respectively) when applied at day 1 after admission. In conclusion, both KSTH and JMHW criteria would be more useful than other three criteria in predicting prognosis in DIC patients with severe sepsis or septic shock.     

Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis.

Plasma levels of endothelin-1 (ET-1) and adrenomedullin (ADM), two opposingly acting peptides, correlate with mortality in endotoxemia, but their measurement is cumbersome. New sandwich assays have been introduced that measure more stable precursor fragments. The objective of this study was to investigate the counterplay of their precursor peptides in septic patients and to compare them with disease severity and other biomarkers. Blood samples of an observational study in 95 consecutive critically ill patients admitted to the intensive care unit (ICU) were analyzed. CT-proET-1 and MR-proADM concentrations on admission were measured using new sandwich immunoassays. Depending on the clinical severity of the infection, both CT-proET-1 and MR-proADM levels exhibited a gradual increase from Systemic Inflammatory Response Syndrome (SIRS) to sepsis and septic shock (p < .001). Compared to the group of survivors, the group of nonsurvivors had higher median values of MR-proADM (5.7 nmol/L [range 0.4 to 21.0] versus 1.9 nmol/L [range 0.3 to 17.1], p < .02) and similar CT-proET-1 levels (56.0pmol/L [range 0.5 to 271.0] versus 54.1pmol/L [range 1.0 to 506.0], p = .86). Receiver operating characteristics (ROC) curve analysis showed a higher prognostic accuracy of the calculated ratio of both counteracting substances as compared to CT-proET-1 (p = 0.001) and C-reactive protein (CRP) (p = .001) and in the range of MR-proADM (p = .51), procalcitonin (p = 0.22), and the APACHE II score (p = .61). Endothelin-1 and adrenomedullin precursor peptides gradually increase with increasing severities of infection in critically ill patients. The ratio of the two counteracting peptides correlates with mortality and shows a prognostic accuracy to predict adverse outcome comparable to the APACHE II score.     

Monocyte and lymphocyte surface molecules in severe sepsis and non‐septic critically ill Patients

The aim of the present study was to investigate whether expression of monocyte and lymphocyte surface molecules differs between patients with severe sepsis and non‐septic patients treated in the intensive care unit (ICU). The expression of monocyte CD14, CD40, CD80 and HLA‐DR, and lymphocyte CD69 were analyzed using quantitative flow cytometry on three consecutive days in 27 patients with severe sepsis and in 15 non‐septic patients. Receiver operating characteristic analyses were performed and each corresponding area under the curve (AUC) was determined. The results showed that the expression levels of CD40 on monocytes and CD69 on CD4+ T cells and on natural killer (NK) cells were highest in patients with severe sepsis (p < 0.05). Monocyte CD40 and NK cell CD69 expression levels were higher in patients with severe sepsis and positive blood culture compared with those with negative blood culture (p < 0.05). The highest values of AUC for severe sepsis detection were 0.836 for CD40, 0.872 for CD69 on NK cells, and 0.795 for CD69 on CD4+ T cells. These findings suggest that monocyte CD40 and CD69 on NK cells and CD4+ T cells could prove useful for new approaches in the identification of severe sepsis in the ICU.     

Inactivation of TMEM106A promotes lipopolysaccharide‐induced inflammation via the MAPK and NF‐κB signaling pathways in macrophages

Pattern recognition receptors, such as Toll‐like receptors (TLRs), play an important role in the host defense against invading microbial pathogens. Their activation must be precisely regulated, as inappropriate activation or overactivation of TLR signaling pathways may result in inflammatory disorders, such as septic shock or autoimmune diseases. TMEM106A is a type II transmembrane protein constitutively expressed in macrophages. Our current study demonstrated that TMEM106A levels were increased in macrophages upon lipopolysaccharide (LPS) stimulation, as well as in the peripheral monocytes of patients with sepsis. Tmem106a knockout mice were more sensitive to lipopolysaccharide (LPS)‐induced septic shock than wild‐type mice. Further experiments indicated that Tmem106a ablation enhanced the expression of CD80, CD86 and major histocompatibility complex (MHC)‐II in mouse macrophages upon LPS stimulation, accompanied with up‐regulation of tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, interferon (IFN)‐β and inducible nitric oxide synthase (iNOS), indicating the activation of macrophages and polarization towards the M1 inflammatory phenotype. Moreover, elevated mitogen‐activated protein kinase (MAPK) and nuclear factor kappa B (NF‐κB) signaling were found to be involved in the LPS‐induced inflammatory response in Tmem106a^?/? macrophages. However, this effect was largely abrogated by macrophage deletion in Tmem106a^?/? mice. Therefore, deficiency of Tmem106a in macrophages may enhance the M1 polarization in mice, resulting in inflammation. This suggests that TMEM106A plays an important regulatory role in maintaining macrophage homeostasis.     

Does C‐reactive protein independently predict mortality in adult community‐acquired bacteremia patients with known sepsis severity?

We evaluated whether sepsis severity and C‐reactive protein (CRP) level on admission prognostically corroborated or annulled each other in adult patients with incident community‐acquired bacteremia (Funen, Denmark, 2000–2008). We used logistic regression and area under the receiver operating characteristic curve (AUC) to evaluate 30‐day mortality in four models: (i) age, gender, comorbidity, bacteria, and ward. (ii) Model 1 and sepsis severity. (iii) Model 1 and CRP. (iv) Model 1, sepsis severity, and CRP. Altogether, 416 of 1999 patients died within 30 days. CRP independently predicted 30‐day mortality [Model 4, odds ratio (95% CIs) for 100 mg/L: 1.16 (1.06–1.27)], but it did not contribute to the AUC (Model 2 vs Model 4: p = 0.31). In the 963 non‐severe sepsis patients, CRP independently predicted 30‐day mortality [Model 4: 1.42 (1.20–1.69)] and it increased the AUC (Model 2 vs Model 4: p = 0.06), thus CRP contributed as much as sepsis severity to prognosis.     

Serum sPD‐L1, Upregulated in Sepsis,May Reflect Disease Severity and Clinical Outcomes in Septic Patients

We aimed to find the correlation between serum sPD‐L1 (soluble programmed cell death L‐1 ligand) and sepsis. Totally 91 consecutive patients with sepsis were performed in a 15‐bed medical intensive care unit (ICU) of the second affiliated hospital, Xi'an Jiaotong University in Xi'an, China, between February 2015 and May 2016. Healthy controls (HC) consisted of 29 healthy volunteer. Baseline demographic data were recorded. Blood samples were collected through an indwelling central venous or by peripheral venipuncture. Serum sPD‐L1 and sPD‐1 levels were determined with enzyme‐linked immunosorbent assay kits (Elabscience Biotechnology Co. Ltd, Wuhan, China). SPSS19.0 software (SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Kaplan–Meier survival analysis and Cox regression analysis were also performed. Serum sPD‐L1 levels and sPD‐1 levels were significantly increased in septic patients compared with HC (P = 0.000). Serum sPD‐L1 levels were significantly increased in non‐survivors compared with survivors (P < 0.05), but there was no statistically difference on serum sPD‐1 levels between non‐survivors and survivors (P > 0.05). Serum sPD‐L1 levels were correlated with absolute lymphocyte (ALC), platelets and SOFA scores. Serum sPD‐L1/sPD‐1 levels were negatively correlated with ALC and platelets, and SOFA scores. The prognostic accuracy of the sPD‐L1 level to predict 28‐day mortality was similar to that of the APACHE‐II scores and SOFA scores. Cox regression analysis showed that sPD‐L1 was an independent prognostic factor. Serum sPD‐L1 is upregulated in sepsis and may reflect disease severity and clinical outcomes in patients. Serum sPD‐L1 may be an independent prognostic factor for sepsis.