Non-infective Systemic Inflammatory Response Syndrome Research Articles

A gene network database for the identification of key genes for diagnosis, prognosis, and treatment in sepsis

Sepsis and sepsis-related diseases cause a high rate of mortality worldwide. The molecular and cellular mechanisms of sepsis are still unclear. We aim to identify key genes in sepsis and reveal potential disease mechanisms. Six sepsis-related blood transcriptome datasets were collected and analyzed by weighted gene co-expression network analysis (WGCNA). Functional annotation was performed in the gProfiler tool. DSigDB was used for drug signature enrichment analysis. The proportion of immune cells was estimated by the CIBERSORT tool. The relationships between modules, immune cells, and survival were identified by correlation analysis and survival analysis. A total of 37 stable co-expressed gene modules were identified. These modules were associated with the critical biology process in sepsis. Four modules can independently separate patients with long and short survival. Three modules can recurrently separate sepsis and normal patients with high accuracy. Some modules can separate bacterial pneumonia, influenza pneumonia, mixed bacterial and influenza A pneumonia, and non-infective systemic inflammatory response syndrome (SIRS). Drug signature analysis identified drugs associated with sepsis, such as testosterone, phytoestrogens, ibuprofen, urea, dichlorvos, potassium persulfate, and vitamin B12. Finally, a gene co-expression network database was constructed (https://liqs.shinyapps.io/sepsis/). The recurrent modules in sepsis may facilitate disease diagnosis, prognosis, and treatment.

Histidine-rich glycoprotein as a prognostic biomarker for sepsis

Various biomarkers have been proposed for sepsis; however, only a few become the standard. We previously reported that plasma histidine-rich glycoprotein (HRG) levels decreased in septic mice, and supplemental infusion of HRG improved survival in mice model of sepsis. Moreover, our previous clinical study demonstrated that HRG levels in septic patients were lower than those in noninfective systemic inflammatory response syndrome patients, and it could be a biomarker for sepsis. In this study, we focused on septic patients and assessed the differences in HRG levels between the non-survivors and survivors. We studied ICU patients newly diagnosed with sepsis. Blood samples were collected within 24 h of ICU admission, and HRG levels were determined using an enzyme-linked immunosorbent assay. Ninety-nine septic patients from 11 institutes in Japan were included. HRG levels were significantly lower in non-survivors (n = 16) than in survivors (n = 83) (median, 15.1 [interquartile ranges, 12.7–16.6] vs. 30.6 [22.1–39.6] µg/ml; p < 0.01). Survival analysis revealed that HRG levels were associated with mortality (hazard ratio 0.79, p < 0.01), and the Harrell C-index (predictive power) for HRG was 0.90. These results suggested that HRG could be a novel prognostic biomarker for sepsis.

Multiplexed Plasma Immune Mediator Signatures Can Differentiate Sepsis From NonInfective SIRS: American Surgical Association 2020 Annual Meeting Paper.

Sepsis and sterile both release "danger signals' that induce the systemic inflammatory response syndrome (SIRS). So differentiating infection from SIRS can be challenging. Precision diagnostic assays could limit unnecessary antibiotic use, improving outcomes. After surveying human leukocyte cytokine production responses to sterile damage-associated molecular patterns (DAMPs), bacterial pathogen-associated molecular patterns, and bacteria we created a multiplex assay for 31 cytokines. We then studied plasma from patients with bacteremia, septic shock, "severe sepsis," or trauma (ISS ≥15 with circulating DAMPs) as well as controls. Infections were adjudicated based on post-hospitalization review. Plasma was studied in infection and injury using univariate and multivariate means to determine how such multiplex assays could best distinguish infective from noninfective SIRS. Infected patients had high plasma interleukin (IL)-6, IL-1α, and triggering receptor expressed on myeloid cells-1 (TREM-1) compared to controls [false discovery rates (FDR) <0.01, <0.01, <0.0001]. Conversely, injury suppressed many mediators including MDC (FDR <0.0001), TREM-1 (FDR <0.001), IP-10 (FDR <0.01), MCP-3 (FDR <0.05), FLT3L (FDR <0.05), Tweak, (FDR <0.05), GRO-α (FDR <0.05), and ENA-78 (FDR <0.05). In univariate studies, analyte overlap between clinical groups prevented clinical relevance. Multivariate models discriminated injury and infection much better, with the 2-group random-forest model classifying 11/11 injury and 28/29 infection patients correctly in out-of-bag validation. Circulating cytokines in traumatic SIRS differ markedly from those in health or sepsis. Variability limits the accuracy of single-mediator assays but machine learning based on multiplexed plasma assays revealed distinct patterns in sepsis- and injury-related SIRS. Defining biomarker release patterns that distinguish specific SIRS populations might allow decreased antibiotic use in those clinical situations. Large prospective studies are needed to validate and operationalize this approach.

Histidine-Rich Glycoprotein As a Prognostic Biomarker for Sepsis: A Multicenter Prospective Observational Cohort Study

Background: Various biomarkers were used for sepsis; however, only a few become the standard. We reported that plasma histidine-rich glycoprotein (HRG) levels decreased in septic mice. Moreover, our clinical study on patients with systemic inflammatory response syndrome (SIRS) demonstrated that HRG levels in septic patients were lower than those in noninfective SIRS patients, and HRG could be a biomarker for sepsis within the SIRS population. In this study, we focused on septic patients and assessed the differences in HRG levels between the non-survivors and survivors. Methods: We studied intensive care unit (ICU) patients newly diagnosed with sepsis. Blood samples were collected within 24 h of ICU admission, and HRG levels were determined using an enzyme-linked immunosorbent assay. Findings: Ninety-nine septic patients from 11 institutes were included. HRG levels were significantly lower in non-survivors (n = 16) than in survivors (n = 83) (median, 15·1 [IQR, 12·7-16·6] vs. 30·6 [22·1-39·6] µg/ml; p < 0·01). Survival analysis revealed that the Harrell C-index (predictive power) for HRG was 0·90. Furthermore, when patients were divided into four subgroups according to quartiles of HRG level, the lowest HRG subgroup represented a significantly higher mortality. Interpretation: The initial HRG levels were found to be lower in non-survivors than in survivors. Decreased and classified HRG levels were also found to predict patient mortality. These results suggested that HRG could be a novel prognostic biomarker for sepsis. Trial Registration: UMIN Clinical Trials Registry (UMI17651). Funding Statement: This work was supported by grants from Japan Agency for Medical Research and Development (AMED) (AMED 15lk0201014h0003; AMED 18im0210109h0002), and from Secom Science and Technology Foundation to MN. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This was a multicenter, prospective, and observational investigation approved by the Institutional Review Board of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and of each institution.

Immature granulocytes as a sepsis predictor in patients undergoing cardiac surgery.

Usefulness of immature granulocyte percentage (IG%) to discriminate between postoperative non-infective systemic inflammatory response syndrome (SIRS) and sepsis was tested in cardiac surgical patients. A retrospective analysis of 124 patients who developed non-infective SIRS and sepsis after elective cardiac surgery was performed. Predictive ability of IG% to predict sepsis was compared to procalcitonin (PCT), white blood cell count, temperature and different biomarker combinations using receiver operating characteristic and logistic regression analysis. The optimal cut-off points, diagnosis sensitivity and specificity were calculated. There were 44 patients diagnosed with sepsis and 80 patients with non-infective SIRS. In receiver operating characteristic analysis, area under the curve was higher for IG% (0.71) and PCT (0.72) compared to white blood cell count (0.62) and temperature (0.58). The best cut-off value for IG% was 1.45% (sensitivity 70.5%, specificity 60%) and 1.43 µg/l for PCT (sensitivity 65.9%, specificity 75%). The combination of IG% and PCT provided the best sepsis prediction (area under the curve of 0.8, sensitivity 63.6% and specificity 88.8%). In cardiac surgical patients, IG% is a helpful marker with the moderate ability to discriminate between sepsis and non-infective SIRS, comparable to serum PCT. A combination of these parameters increased the test's overall predictive ability by improving its specificity.

Diagnostic effectiveness of soluble triggering receptor expressed on myeloid cells-1 in sepsis, severe sepsis and septic shock

IntroductionSensitivities and specificities of clinical signs and biochemical tests in sepsis diagnosis are not satisfactory. The aim of the study was to assess the diagnostic usefulness of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in sepsis, severe sepsis and septic shock against interleukin-6 (IL-6), C-reactive protein (CRP) and procalcitonin (PCT).Material and methodsA prospective, observational study was conducted in 85 adults with sepsis, severe sepsis or septic shock and 22 with non-infective systemic inflammatory response syndrome (NI-SIRS). Serum levels of sTREM-1, CRP, PCT and IL-6 were measured on admission.ResultsMedian serum sTREM-1 concentrations were higher in severe sepsis (540 pg/ml) and septic shock (536 pg/ml) in comparison with NI-SIRS patients (p < 0.05). There were no differences in sTREM-1 levels between NI-SIRS and sepsis. Similarly, CRP, PCT and IL-6 were significantly elevated in patients with severe sepsis and septic shock in comparison with NI-SIRS. The receiver operating characteristic curve analysis for diagnosis of severe sepsis showed higher discriminative value for CRP and IL-6 (AUC = 0.909, 95% CI: 0.829–0.99 and AUC = 0.854, 95% CI: 0.728–0.980, respectively) than sTREM-1 (AUC = 0.733, 95% CI: 0.596–0.870). In septic shock the highest AUC was found for CRP (AUC = 0.938, 95% CI: 0.872–1.0), lower for IL-6 (AUC = 0.869, 95% CI: 0.751–0.987), PCT (AUC = 0.828, 95% CI: 0.71–0.945) and sTREM-1 (AUC = 0.705, 95% CI: 0.553–0.856).ConclusionsSerum level of sTREM-1 has lower effectiveness as a diagnostic biomarker in severe sepsis and septic shock, in comparison with CRP and IL-6.

Decrease in Histidine-Rich Glycoprotein as a Novel Biomarker to Predict Sepsis Among Systemic Inflammatory Response Syndrome.

Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. Single-center, prospective, observational cohort study. ICU at an university-affiliated hospital. Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. None. We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53-66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74-41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26-51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72-15.74 µg/mL] vs 33.27 µg/mL [26.57-44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49-15.70 µg/mL] vs 31.78 µg/mL [18.57-42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively. Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin.

Severity of Systemic Inflammatory Response Syndrome Affects the Blood Levels of Circulating Inflammatory-Relevant MicroRNAs.

The systemic inflammatory response syndrome (SIRS) is a potentially lethal response triggered by diverse forms of tissue injury and infection. When systemic inflammation is triggered by infection, the term sepsis is used. Understanding how inflammation is mediated and regulated is of enormous medical importance. We previously demonstrated that circulating inflammatory-relevant microRNAs (CIR-miRNAs) are candidate biomarkers for differentiating sepsis from SIRS. Here, we set out to determine how CIR-miRNA levels reflect SIRS severity and whether they derive from activated immune cells. Clinical disease severity scores and markers of red blood cell (RBC) damage or immune cell activation were correlated with CIR-miRNA levels in patients with SIRS and sepsis. The release of CIR-miRNAs modulated during SIRS was assessed in immune cell cultures. We show that severity of non-infective SIRS, but not sepsis is reflected in the levels of miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. These CIR-miRNA levels positively correlate with levels of the redox biomarker, peroxiredoxin-1 (Prdx-1), which has previously been shown to be released by immune cells during inflammation. Furthermore, in vitro activated immune cells produce SIRS-associated miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. Our study furthers the understanding of the origin, role, and trafficking of CIR-miRNAs as potential regulators of inflammation.

Procalcitonin May Not Discriminate Between Sepsis and Non-Infective Systemic Inflammatory Response Syndrome (SIRS) in Heterogonous Critically Ill Patients

Background: In recent decades Procalcitonin (PCT) has been introduced to help physicians differentiate sepsis from SIRS. Its routine use in such specific settings as ICU, on the other hand, is very polemical owing to the variable results. Objectives: In this prospective observational study, we examined the accuracy of PCT levels in differentiating septic from SIRS in critically ill patients admitted to the general ICUs of two hospitals in Tabriz, Iran from September 2014 to May 2016. Further appraised was the effect of illness severity and organ failure on PCT value. We tried to answer this question that why there is controversial and wide range of findings pertaining to PCT in critical care settings. Methods: One hundred and thirty two SIRS (Systemic Inflammatory Response Syndrome) positive critically ill patients admitted to the ICU were enrolled in the present research. Patients were divided based on their positive cultures into infectious and SIRS positive groups, in both of which, PCT was measured, severity of illness and organ failure were recorded, and the PCT sensitivity and specificity for the detection of sepsis and its relationship with disease severity and mortality were evaluated. Results: The optimal cut-off point for the PCT, determined 0.25μg/L with a sensitivity and specificity of 73 % and 39 %, respectively. PCT level was not able to significantly diagnose septic patients from SIRS positive ones and was significantly correlated with Cr and BUN concentrations. Conclusions: These findings indicate that PCT may not differentiate between sepsis and SIRS in a heterogeneous population of critically ill patients admitted to the ICU; PCT measurements, nonetheless, can probably conduce to predicting the outcome of patients.

The significance of sTREM-1 as a diagnostic biomarker of sepsis in the context of Sepsis-3 definition

Aim. Sepsis remains the leading cause of mortality in spite of advanced diagnostics. The aim of the study was to test the diag-nostic value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the context of a new definition of sepsis. Methods. The study was conducted on 41 patients who were suspected of having sep-sis according to SIRS (Systemic Inflamma-tory Response Syndrome) criteria or sterile SIRS. 20 healthy volunteer blood donors were the control group (adult patients of both sexes). According to the latest sepsis criteria (Sepsis-3), patients were retrospec-tively divided into three subgroups: septic patients, patients with SIRS plus infection and patients with sterile SIRS (non-infec-tious SIRS). All subjects had concentrations of sTREM-1 determined by the ELISA meth-od (Abcam commercial test, Cambridge, MA, USA). Samples were collected upon admission to hospital and kept at -20°C until laboratory analysis was performed. Results. Concentrations of sTREM-1 were significantly increased in patients, com-pared to the healthy population (p=0.021), but there were no significant differences among subgroups of patients (SIRS plus infection vs. sepsis p=0.871, SIRS plus in-fection vs. sterile SIRS p=0.72, sepsis vs. sterile SIRS p=0.65).The value of 300pg/mL was determined to be the optimal cut-off. Concentrations of sTREM-1 were significantly higher in septic patients who did not develop Multiple Organ Dysfunction Syndrome (MODS) within the first 48 hours after admission than in those who did. Conclusion. According to our results, sTREM-1 failed to express significance as a diagnostic biomarker of sepsis, according to the new definition. Also, it seems not to be a valuable marker in differentiation of sepsis and non-infective SIRS.

Circulating Plasma microRNAs can differentiate Human Sepsis and Systemic Inflammatory Response Syndrome (SIRS).

Systemic inflammation in humans may be triggered by infection, termed sepsis, or non-infective processes, termed non-infective systemic inflammatory response syndrome (SIRS). MicroRNAs regulate cellular processes including inflammation and may be detected in blood. We aimed to establish definitive proof-of-principle that circulating microRNAs are differentially affected during sepsis and non-infective SIRS. Critically ill patients with severe (n = 21) or non-severe (n = 8) intra-abdominal sepsis; severe (n = 23) or non-severe (n = 21) non-infective SIRS; or no SIRS (n = 16) were studied. Next-generation sequencing and qRT-PCR were used to measure plasma microRNAs. Detectable blood miRNAs (n = 116) were generally up-regulated in SIRS compared to no-SIRS patients. Levels of these ‘circulating inflammation-related microRNAs’ (CIR-miRNAs) were 2.64 (IQR: 2.10–3.29) and 1.52 (IQR: 1.15–1.92) fold higher for non-infective SIRS and sepsis respectively (p < 0.0001), hence CIR-miRNAs appeared less abundant in sepsis than in SIRS. Six CIR-miRNAs (miR-30d-5p, miR-30a-5p, miR-192-5p, miR-26a-5p, miR-23a-5p, miR-191-5p) provided good-to-excellent discrimination of severe sepsis from severe SIRS (0.742–0.917 AUC of ROC curves). CIR-miRNA levels inversely correlated with pro-inflammatory cytokines (IL-1, IL-6 and others). Thus, among critically ill patients, sepsis and non-infective SIRS are associated with substantial, differential changes in CIR-miRNAs. CIR-miRNAs may be regulators of inflammation and warrant thorough evaluation as diagnostic and therapeutic targets.

Comparison of diagnostic and prognostic utility of lactate and procalcitonin for sepsis in adult cancer patients presenting to emergency department with systemic inflammatory response syndrome

ObjectivesDifferentiating sepsis from other noninfectious causes of systemic inflammatory response syndrome (SIRS) in cancer patients is often challenging. Although lactate and procalcitonin have been studied extensively regarding sepsis management, little is known about their utility in cancer patients.This study aimed to compare the diagnostic and prognostic utility of lactate and procalcitonin for sepsis in cancer patients. Material and methodsThis prospective case-control study was conducted with adult cancer patients presenting to emergency department (ED) with at least two SIRS criteria. The infection status of each patient was determined retrospectively.Main diagnostic variables were calculated for diagnostic and prognostic utilities of lactate and procalcitonin. ResultsAmong 86 patients, mean age was 61. Twenty-two (25.6%) were determined in the sepsis group.In the ROC analysis, a lactate value of 1 mmol/L predicted sepsis with 86.36% (95%CI: 65.1%–97.1%) sensitivity and 28.12% (95%CI: 17.6%–40.76%) specificity. A procalcitonin value of 0.8 ng/mL yielded a sensitivity of 63.64% (95%CI: 40.7%–82.8%) and 76.56% (95%CI: 63.4%–86.2%) specificity for differential diagnosis of sepsis in cancer patients.Lactate and procalcitonin showed similar abilities in differentiating sepsis from non-infective SIRS in cancer patients [AUROCs of 0.638 (95%CI:0.527–0.739) vs 0.637 (95%CI:0.527–0.738), respectively. p=0.994].They were also similar in predicting poor clinical outcome with AUROCs of 0.629 (95%CI:0.518–0.731) and 0.584 (95%CI: 0.473–0.69), respectively (p=0.577). ConclusionsThe results of this study indicated that, none of the lactate and procalcitonin can be recommended alone to differentiate sepsis from non-infectious SIRS and to predict the poor clinical outcomes in adult cancer patients with SIRS in the ED.

Clinical Epidemiology of SIRS and Sepsis in Newly Admitted Children.

To assess the clinical and demographic profile of Systemic Inflammatory Response Syndrome (SIRS) and sepsis, among newly admitted children in different age groups in a hospital in North India. This prospective study was conducted at a referral care centre in Northern India. All children, age group 0 to <18 y, admitted on days selected for study were screened and those with abnormal temperature and abnormal leukocyte count were included for further assessment. A total of twenty "24h" periods were randomly chosen during the study period. Patients were assessed according to age specific vital signs and laboratory values to diagnose Systemic Inflammatory Response Syndrome (SIRS) and sepsis and to gain clinical and demographic data. The criteria laid at International consensus conference, 2002, were used to define patients as SIRS, Sepsis, Severe sepsis and Septic shock. During the study period, a total of 865 patients were screened for SIRS. Prevalence of SIRS amongst hospitalised children was 23% (n = 201). Seventy nine percent (n = 159) of patients had infection associated SIRS and 21% (42) had non-infective SIRS. Sixty four percent (n = 129) SIRS patients had uncomplicated sepsis, 15% (n = 30) patients fulfilled criteria for severe sepsis. Out of the latter 30, 19 had septic shock. Organ dysfunction in SIRS was noted in 25% (n = 51). 37.25% (n = 19) had multiple organ dysfunction syndrome (MODS). The most common organism isolated was Staphylococcus aureus (n = 9). Focus of infection in majority was pulmonary (44%). Mean duration of antibiotic therapy and hospital stay in the SIRS group were 6.4 and 6.5 d respectively. In the group without SIRS, mean duration were 2.44 d and 3.07 d respectively The differences were statistically significant. In conclusion, the proportion of sepsis contributing to SIRS is high in a tertiary care hospital. Therefore rapid recognition of SIRS is essential. Goal directed treatment of sepsis is also important so that high mortality associated with severe sepsis and septic shock are prevented.

Procalcitonin in early rule-in/rule-out of sepsis in SIRS patients admitted to a medical ward.

A relevant amount of patients with clinical suspect of sepsis is admitted and treated in medical wards (MW). These patients have a better prognosis but are older and with more comorbidities compared to those admitted to intensive care units (ICU). Procalcitonin (PCT) is extensively used in emergency departments for the diagnosis of sepsis, but its accuracy in the setting of a MW has not been thoroughly investigated. Predicted low PCT levels also call for the comparison of immunomagnetic-chemiluminescent (L-PCT) and time-resolved amplified cryptate emission (TRACE, K-PCT) technologies, in PCT determination. In 80 patients with systemic inflammatory response syndrome (SIRS) diagnostic criteria and suspect of sepsis newly admitted to a MW, PCT was determined with L- and K-PCT method. Sixty patients were diagnosed as sepsis (20 microbiologically and 40 clinically proven) and 20 with non-infective SIRS. The sepsis group had significantly higher levels of both PCTs, with no differences between the clinically and microbiologically proven subgroups. The areas under ROC curves for L- and K-PCT were 0.72 and 0.78 (p<0.001 for each), respectively. Based on MW customized cut-off values of 0.150 (L-PCT) and 0.143 ng/mL (K-PCT), overall accuracies were 66.8 (95% CI 58.7-78.9) and 78.2% (69.8-87.2), respectively, compared to the 55% (44.2-66) of 0.5 ng/mL canonical cut-off. Neither PCT-L nor -K held prognostic value on survival. In MW patients, customized PCT cut-off levels provide better accuracy than customary levels adopted from ICU, and TRACE technology seems to offer a wider analysis range.

Differentiating sepsis from non-infective systemic inflammatory response syndrome: comparison between C-reactive protein and leptin

Differentiation of sepsis from non-infectious SIRS is important in improving sepsis outcome. We intended in this study to evaluate the role of serum leptin and to compare it with CRP in differentiating sepsis from non-infectious SIRS.

Heterogeneous models for an early discrimination between sepsis and non-infective SIRS in medical ward patients: a pilot study

The objective of the study was to determine the accuracy of phospholipase A2 group II (PLA2-II), interferon-gamma-inducible protein 10 (IP-10), angiopoietin-2 (Ang-2), and procalcitonin (PCT) plasma levels in early ruling in/out of sepsis among systemic inflammatory response syndrome (SIRS) patients. Biomarker levels were determined in 80 SIRS patients during the first 4 h of admission to the medical ward. The final diagnosis of sepsis or non-infective SIRS was issued according to good clinical practice. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for sepsis diagnosis were assessed. The optimal biomarker combinations with clinical variables were investigated by logistic regression and decision tree (CART). PLA2-II, IP-10 and PCT, but not Ang-2, were significantly higher in septic (n = 60) than in non-infective SIRS (n = 20) patients (P ≤ 0.001, 0.027, and 0.002, respectively). PLA2-II PPV and NPV were 88 and 86%, respectively. The corresponding figures were 100 and 31% for IP-10, and 93 and 35% for PCT. Binary logistic regression model had 100% PPV and NPV, while manual and software-generated CART reached an overall accuracy of 95 and 98%, respectively, both with 100% NPV. PLA2-II and IP-10 associated with clinical variables in regression or decision tree heterogeneous models may be valuable biomarkers for sepsis diagnosis in SIRS patients admitted to medical ward (MW). Further studies are needed to introduce them into clinical practice.

Differentiating sepsis from non-infective systemic inflammatory response syndrome: Comparison between C-reactive protein and Leptin

BackgroundDifferentiation of sepsis from non-infectious SIRS is important in improving sepsis outcome. We intended in this study to evaluate the role of serum Leptin and to compare it with CRP in differentiating sepsis from non-infectious SIRS. MethodsWe included 30 patients with SIRS. According to the presence or absence of infection, our patients were classified into SIRS group and sepsis group. Leptin and CRP were evaluated in all patients on admission, day 2 and day 4. ResultsOur patients had a mean age of 52.3 ± 18.6 year old, 10 males (33.3%). There were no significant differences regarding baseline demographic and clinical data apart from blood pressures which were lower in the sepsis group. Serum Leptin on Day 2 only was higher in the sepsis group (44.2 ± 17.7 μg/L vs. 31.1 ± 2.1 μg/L, P = 0.008) with no difference in days 0 and 4 of admission. We detected a serum Leptin level of 38.05 μg/L on day 2 to be 93% sensitive and 100% specific to diagnose sepsis. The three serum CRP levels were higher in sepsis compared to SIRS group (61.2 ± 9 mg/L vs. 48.9 ± 7.1 mg/L, P < 0.001 in day 0, 71.5 ± 9.6 mg/L and 196.8 ± 39.8 mg/L in sepsis group vs. 56.9 ± 8 mg/L and 73.7 ± 32.5 mg/L in SIRS group for days 2 and 4 respectively, P < 0.001 for both). We found a CRP of 67.5 mg/L on day 2 having 87% sensitivity and 93% specificity for the diagnosis of sepsis. ConclusionWe concluded that despite serum Leptin may not be beneficial in early differentiation between sepsis and non infectious SIRS on admission; it may be highly specific on second day.

Mitochondrial-derived N-formyl peptides: Novel links between trauma, vascular collapse and sepsis

Sepsis is a major cause of mortality and morbidity in trauma patients despite aggressive treatment. Traumatic injury may trigger infective or non-infective systemic inflammatory response syndrome (SIRS) and sepsis. Sepsis and SIRS are accompanied by an inability to regulate the inflammatory response but the cause of this perturbation is still unknown. The major pathophysiological characteristic of sepsis is the vascular collapse (i.e., loss of control of vascular tone); however, at the cellular level the final mediator of extreme vasodilatation has yet to be identified. After trauma, cellular injury releases endogenous damage-associated molecular patterns (DAMPs) that activate the innate immune system. Mitochondrial DAMPs express at least two molecular signatures, N-formyl peptides and mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptor 9, respectively. N-Formyl peptides are potent immunocyte activators and, once released in the circulation, they induce modulation of vascular tone by cellular mechanisms that are not completely understood. We have observed that N-formyl peptides from bacterial (FMLP) and mitochondrial (FMIT) sources induce FPR-mediated vasodilatation in resistance arteries. Accordingly, we propose that tissue and cellular trauma induces the release of N-formyl peptides from mitochondria triggering inflammation and vascular collapse via activation of FPR and contributing to the development of sepsis. The proposed hypothesis provides clinically significant information linking trauma, mitochondrial N-formyl peptides and inflammation to vascular collapse and sepsis. If our hypothesis is true, it may lead to new strategies in the management of sepsis that can help clinicians effectively manage non-infectious and infectious inflammatory responses.

PSP and NT-proCNP assessed for predisposition to infection

Gouel-Cheron and colleagues have recently published a pilot study [1] on which we would like to offer the following comments. As the paper currently appears, it is unclear whether in fact the study aimed at evaluating the predictive value of pancreatic stone protein/regenerating protein (PSP) and amino-terminal pro-C-type natriuretic peptide (NT-proCNP) for a predisposition to infection in non-infected systemic inflammatory response syndrome (SIRS) trauma patients under mechanical ventilation, or whether it rather aimed at evaluating the predictive value (that is, prognosis) of the biomarkers for sepsis development. Indeed, the authors omitted to mention that the assessment was carried out in patients exclusively before the occurrence of a hospital-acquired infection. This certainly explains why there are only 16 patients plotted in Figure 1 and not 21 (36% of 61 patients) as one would have otherwise expected. A non-equivocal use of 'prediction' is therefore essential. Providing these indications would have allowed to put the results into perspective with recent studies published in Critical Care on PSP ability to differentiate patients with sepsis from those with a non-infective SIRS [2] or on NT-proCNP ability to confirm sepsis and correlate with markers of bacterial infection [3]. Instead of analyzing the role of PSP and NT-proCNP in the prediction of sepsis, the authors seem to have actually predicted future hospital-acquired infection in the intensive care unit. Stating that the study assesses the prediction of sepsis is therefore clearly a misleading shortcut, since in fact the occurrence of infection, sometime later than the time-point of analysis of the biomarkers, will classify these SIRS patients as septic by definition.

A distinct influenza infection signature in the blood transcriptome of patients with severe community-acquired pneumonia

IntroductionDiagnosis of severe influenza pneumonia remains challenging because of a lack of correlation between the presence of influenza virus and clinical status. We conducted gene-expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure, such as bacterial pneumonia, and noninfective systemic inflammatory response syndrome.MethodsWhole-blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene-expression beadarrays. Differentially expressed genes were determined by linear mixed-model analysis and overrepresented biological pathways determined by using GeneGo MetaCore.ResultsThe gene-expression profile of H1N1 influenza A pneumonia was distinctly different from those of bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene-expression profile is characterized by upregulation of genes from cell-cycle regulation, apoptosis, and DNA-damage-response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene-expression profile of influenza infection persisted through 5 days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection in whom bacterial co-infection subsequently developed, the influenza gene-expression signature remained unaltered, despite the presence of a superimposed bacterial infection.ConclusionsThe whole-blood expression-profiling data indicate that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed the identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly.