Non-infectious Systemic Inflammatory Response Syndrome Research Articles

Accuracy of procalcitonin for diagnosing sepsis in adult patients admitted to the emergency department: a systematic review and meta-analysis.

Differentiating sepsis from non-infectious systemic inflammatory response syndrome (SIRS) is challenging. Biomarkers like procalcitonin (PCT) aid early risk assessment and guide antibiotic use. This study aims to ascertain PCT's accuracy as a sepsis biomarker among adult emergency department admissions. The PRISMA guidelines were followed to search for relevant articles in five electronic databases between April 14th and August 4th, 2023: PubMed, Cochrane Library, ProQuest, EMBASEs, and ScienceDirect. Studies had to be published in English to avoid directly translating scientific terms. Besides, the inclusion criteria were based on the diagnosis of sepsis in adult patients admitted to an emergency department. QUADAS-2 tool provided by the Review Manager version 5.4.1 was utilized to assess the risk of bias in included studies. STATA (v. 16) software was used to perform the meta-analysis. Ten of 2457 studies were included. We sampled 2980 adult sepsis patients for the under-investigated role of PCT in ED sepsis diagnosis. PCT emerged as the primary early diagnostic biomarker with high levels (29.3 ± 85.3ng/mL) in sepsis patients. Heterogeneity in outcomes, possibly due to bias in cohort and observational studies, was observed. PCT tests offer moderate accuracy in diagnosing sepsis and stand out for rapidly and precisely distinguishing between viral and bacterial inflammations.

Independent predictors of systemic inflammatory response syndrome for intramedullary nailing of femoral shaft fractures: Analysis of national inpatient sample database

BackgroundThe systemic inflammatory response syndrome (SIRS) is a clinical reaction that can occur due to a variety of stimuli. Reamed intramedullary femoral nailing is a common orthopedic surgery that has been shown to induce SIRS. To date, no nationwide analyses have been performed to evaluate the incidence, risk factors, and economic burdens of SIRS following intramedullary femoral nailing for femoral shaft fractures. The objective of this study is to investigate the independent predictors, incidence, post-operative, and economic burden of SIRS among patients treated with intramedullary nailing for femoral shaft fractures. MethodsWe utilized the 2016–2019 National Inpatient Sample (NIS) to identify patients who underwent intramedullary femoral nailing and were diagnosed with non-infectious SIRS (NI-SIRS) based on ICD-10-CM coding. Identified patients who underwent intramedullary femoral nailing were dichotomized into SIRS and Non-SIRS groups to assess independent predictors of SIRS development, and to compare post-operative complications and costs. ResultsA total of 65,240 patients with femur shaft fractures underwent IMFN, of which 665 (1.0 %) developed NI-SIRS. Patients with NI-SIRS had a higher incidence of laparotomy (OR = 13.97, p < 0.001), initial treatment with external fixation (OR = 1.845, p < 0.001), and late application of external fixation (OR = 4.884, p = 0.005). Routine discharge (OR = 0.491, p < 0.001) was less likely in patients with NI-SIRS. Length of stay (12.38 days vs 7.16 days, p < 0.001) and total charges ($278, 590 vs $145,118, p < 0.001) were both increased in patients with NI-SIRS. ConclusionNI-SIRS is associated with increasing injury severity and post-operative complications. Those that developed NI-SIRS experienced higher healthcare resource utilization. Risk factors associated with development of NI-SIRS warrant further investigation.

C-Reactive Protein, Procalcitonin, and a Novel Pathogenesis and Therapeutic Target of Thrombocytopenia in Sepsis.

Objective The aim of the study is to analyze the clinical characteristics, pathogen distribution, and drug sensitivity information of adult sepsis, and to provide reference for empirical clinical use; to explore the relationship between C-reactive protein (CRP) and calcitonin (PCT) The clinical value in the diagnosis of adult sepsis. Methods We collected 455 cases of hospitalized patients with positive blood culture, including 352 cases with sepsis and 103 cases without sepsis; 1609 cases of hospitalized patients with suspected infection and negative blood culture, including 287 cases of sepsis, and 518 cases of non-infectious systemic inflammatory response syndrome (SIRS) and 804 cases of local infection. Age, gender, route of admission, admission status, CRP, PCT, and white blood cell (WBC) levels were collected from the patients. The differences between the factors were statistically analyzed, and the receiver operating characteristic curve (ROC curve) was plotted to obtain the optimal cut-off values of CRP and PCT and their area under the curve (AUC), and to compare the CRP, PCT and PCT, and the CRP + PCT tandem to diagnose sepsis sensitivity and specificity. Results (1) 387 pathogenic strains were isolated from blood cultures of patients with sepsis, 71.06% Gram-negative, 26.87% Gram-positive and 2.07% fungi. (2) Among Gram-positive bacteria, Staphylococcus aureus was 87.5% resistant to penicillin and sensitive to vancomycin, milantropine, and teicoplanin; among Gram-negative bacteria, Escherichia coli was resistant to piracillin The resistance rate was 73.1%, fully susceptible to viraemia (100%) and resistant to imipenem, amikacin, and lacillin/tazole. (3) Among patients with positive blood cultures, CRP and PCT levels were higher in patients with sepsis than in those without sepsis. Pairwise comparison of ROC curves showed that the diagnostic value of PCT was greater than that of CRP (P=0.016). Conclusion CRP and PCT have a good reference value for diagnosis of sepsis patients and determination of the degree of infection in septic patients, especially PCT is more valuable for diagnosis of sepsis.

Circulating Myeloid Cell-derived Extracellular Vesicles as Mediators of Indirect Acute Lung Injury.

Blood-borne myeloid cells, neutrophils and monocytes, play a central role in the development of indirect acute lung injury (ALI) during sepsis and noninfectious systemic inflammatory response syndrome. By contrast, the contribution of circulating myeloid cell-derived extracellular vesicles (EVs) to ALI is unknown, despite acute increases in their numbers during sepsis and systemic inflammatory response syndrome. Here, we investigated the direct role of circulating myeloid-EVs in ALI using a mouse isolated perfused lung system and a human cell coculture model of pulmonary vascular inflammation consisting of lung microvascular endothelial cells and peripheral blood mononuclear cells. Total and immunoaffinity-isolated myeloid (CD11b+) and platelet (CD41+) EVs were prepared from the plasma of intravenous LPS-injected endotoxemic donor mice and transferred directly into recipient lungs. Two-hour perfusion of lungs with unfractionated EVs from a single donor induced pulmonary edema formation and increased perfusate concentrations of RAGE (receptor for advanced glycation end products), consistent with lung injury. These responses were abolished in the lungs of monocyte-depleted mice. The isolated myeloid- but not platelet-EVs produced a similar injury response and the acute intravascular release of proinflammatory cytokines and endothelial injury markers. In the invitro human coculture model, human myeloid- (CD11b+) but not platelet- (CD61+) EVs isolated from LPS-stimulated whole blood induced acute proinflammatory cytokine production and endothelial activation. These findings implicate circulating myeloid-EVs as acute mediators of pulmonary vascular inflammation and edema, suggesting an alternative therapeutic target for attenuation of indirect ALI.

Towards Remote Continuous Monitoring of Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is a noninfec-tious systemic inflammatory response syndrome condition and a principle severe adverse event common in oncology patients treated with immunotherapies. Accurate monitoring and timely prediction of CRS severity remain a challenge. This study presents an XGBoost-based machine learning algorithm for forecasting CRS severity (no CRS, mild- and severe-CRS classes) in the 24 hours following the time of prediction utilizing the common vital signs and Glasgow coma scale (GCS) questionnaire inputs. The CRS algorithm was developed and evaluated on a cohort of patients (n=1,139) surgically treated for neoplasm with no ICD9 codes for infection or sepsis during a collective 9,892 patient-days of monitoring in ICU settings. Different models were trained with unique feature sets to mimic practical monitoring environments where different types of data availability will exist. The CRS models that incorporated all time series features up to the prediction time showcased a micro-average area under curve (AUC) statistic for the receiver operating characteristic curve (ROC) of 0.94 for the 3 classes of CRS grades. Models developed on a second cohort requiring data within the 24 hours preceding prediction time showcased a relatively lower 0.88 micro-average AUROC as these models did not benefit from implicit information in the data availability. Systematic removal of blood pressure and/or GCS inputs revealed significant decreases (p<0.05) in model performances that confirm the importance of such features for CRS prediction. Accurate CRS prediction and timely intervention can reverse CRS adverse events and maximize the benefit of immunotherapies in oncology patients.

Evaluation of quick sequential organ failure scores in dogs with severe sepsis and septic shock.

To evaluate the prognostic utility of the quick sequential organ failure assessment score indogs with severe sepsis and septic shock presenting to an emergency service, and evaluate the clinical value of the quick sequential organ failure assessment score to predict severe sepsis and septic shock. The quick sequential organ failure assessment score was calculated by evaluating respiratory rate (&gt;22 breaths per minute), arterial systolic blood pressure (≤100 mmHg) and altered mentation. The quick sequential organ failure assessment scores with respiratory rate cut-offs of greater than 22, greater than 30 and greater than 40 were compared. Cases were defined as dogs presented to the emergency room and met at least 2 systemic inflammatory response syndrome criteria, had documented infection, and at least one organ dysfunction. A control population of dogs included animals with non-infectious systemic inflammatory response syndrome. Forty-five dogs with severe sepsis and septic shock and 45 dogs with non-infectious systemic inflammatory response syndrome were included in the final analysis. The quick sequential organ failure assessment provided poor discrimination between survivors and non-survivors for severe sepsis and septic shock (area under receiving operating characteristic curve, 0.51; 95% confidence interval, 0.35 to 0.67). Discrimination remained poor when quick sequential organ failure assessment greater than 30 and quick sequential organ failure assessment greater than 40 scores were calculated (area under receiving operating characteristic curve, 0.56; 95% confidence interval, 0.39 to 0.72, and 0.54; 95% confidence interval, 0.36 to 0.71). The quick sequential organ failure assessment of at least 2, quick sequential organ failure assessment greater than 30 of at least 2 and quick sequential organ failure assessment greater than 40 of at least 2 produced sensitivity and specificity to detect severe sepsis and septic shock of 66.7% and 64.5%, 62.2% and 71.1%, 44.4% and 80%, respectively. Scoring systems utilised in emergency rooms should have high sensitivity to reduce missed sepsis cases and treatment delays. The use of the quick sequential organ failure assessment for severe sepsis and septic shock demonstrated poor mortality prediction and low sensitivity to detect canine patients with severe sepsis and septic shock and should not be used alone when screening for sepsis.

Progressive endothelial cell damage in correlation with sepsis severity. Defibrotide as a contender

BackgroundThe vascular endothelium plays a key role in sepsis pathophysiology and the associated organ dysfunction. MethodsWe evaluated endothelial function in an experimental in vitro model of sepsis, using endothelial cells grown in the presence of serum from patients with septic syndromes (sepsis, severe sepsis, and septic shock), noninfectious systemic inflammatory response syndrome (NI‐SIRS) and healthy volunteers. Experiments were performed in the absence and presence of defibrotide (DF) (100 µg/ml) to evaluate its potential protective effect. ResultsAfter exposure to patients' sera, there was a progressive endothelial cell activation in correlation with sepsis severity, with a proinflammatory and prothrombotic phenotype, exhibiting significantly increased expression of adhesion receptors at the surface (intercellular adhesion molecule‐1, p< .05 and vascular cell adhesion molecule‐1, p< .05); higher production and release to the extracellular matrix (ECM) of von Willebrand factor (p< .001); augmented thrombogenicity of the ECM toward platelets (p< .001); and increased phosphorylation of intracellular p38MAPK. DF prevented these changes in all groups. ConclusionsMarkers of endothelial damage increased progressively in association with the severity of septic syndromes. The endothelium is therefore an important therapeutic target to prevent complications of sepsis. DF shows promising potential to modulate the endothelial damage associated with sepsis and may constitute a pharmacological tool to decrease its sequelae including multiorgan failure.

Circulating Biomarkers of COVID-19-Triggered Endotheliopathy: From Conjecture to Certainty

Background: Clinical and analytical data on patients suffering from coronavirus disease-2019 (COVID-19) indicate that endothelial damage plays a key role in the pathophysiology of the disease and is responsible for the pulmonary complications and the thrombotic microangiopathy affecting multiple organs, which contribute directly to mortality (Ackerman et al. N Engl J Med 2020). Detection of biomarkers of endothelial injury in circulating blood may provide critical diagnostic and prognostic information on the disease course (Goshua et al. Lancet Haematology 2020). Endothelial injury is also a cornerstone of pathobiology in other septic and potentially life-threatening inflammatory syndromes.Objectives: To identify circulating markers of endothelial damage in COVID-19 patients, and compare their levels with those observed in other septic syndromes.Methods: Plasma samples from non-critically ill patients with confirmed COVID-19 pneumonia (positive nasopharyngeal swab and confirmatory radiological chest imaging) requiring admission (n=42) were collected during the first 36h of hospitalization. Endothelial damage was evaluated by measuring in plasma: i) markers of endothelial function and activation (sVCAM-1, VWF, ADAMTS-13 activity, Protein C and α2-antiplasmin as a marker of fibrinolysis); ii) heparan sulfate (HS) levels, as indicators of endothelial glycocalyx degradation and loss of endothelial barrier function; and iii) C5b9 deposits on endothelial cells in culture, and soluble C5b9 (sC5b9) levels, to measure complement activation. Circulating dsDNA was analyzed as an indicator of the presence of neutrophil extracellular traps (NETs). ELISA tests were used for sVCAM-1, Protein C, HS, and sC5b9 levels. ADAMTS-13 activity was evaluated by FRETS. VWF, Protein C, and α2-antiplasmin were measured at the Atellica COAG 360 (Siemens Healthineers). C5b9 deposits were assessed by immunofluorescence and dsDNA levels by Quant-iT PicoGreen assay kit. Results were compared with those obtained in healthy donors (controls, n=45), and patients with non-infectious systemic inflammatory response syndrome (NI-SIRS, n=8) and septic shock (SS, n=8).Results: Levels of sVCAM-1 were significantly higher in COVID-19 patients vs. controls, NI-SIRS and SS (159±12 vs. 79±4, 57±8 and 80±10 ng/mL, respectively, p<0.005) (Mean±SDM). VWF was elevated in COVID-19 patients vs. controls (240±26 vs. 96±5%, p<0.001), with similar values in NI-SIRS (271±40%), and significantly reduced vs. SS (476±43%, p<0.001). HS levels in COVID-19 patients were twice those detected in controls (1669±174 vs. 839±36 ng/mL, p=0.001), but they did not differ from those in NI-SIRS (1372±368 ng/mL), and were significantly lower than in SS (3677±880 ng/mL, p<0.001 vs COVID-19). Regarding complement activation, deposits of C5b9 on endothelial cells were significantly increased vs. controls (2-fold, p<0.01), with no notable differences vs. NI-SIRS (3±1-fold) and significantly lower than in SS (8±2-fold, p<0.001). Remarkably, sC5b9 levels were much more elevated in COVID-19 patients (1064±120 vs. 204±11 ng/mL, p<0.001), and no significant differences were observed vs. NI-SIRS (902±160 ng/mL) or SS (958±180 ng/mL). Also of note, presence of NETs was significantly elevated in the plasma of COVID-19 patients vs. controls (16±1.3 vs. 2±0.3 ng/ml, p<0.001), but similar to NI-SIRS (19±5 ng/mL) and clearly inferior to SS (33±6 ng/mL, p<0.001) (Figure). Importantly and in contrast, ADAMTS-13 activity, Protein C, and α2-antiplasmin values were within the normal range in COVID-19 patients.Conclusions: Our data clearly demonstrate the presence of endothelial stress products in the circulating blood of non-critically ill COVID-19 patients. These biomarkers of endothelial injury are suggestive indicators of different aspects of the disease: specifically, release of acute phase reactants, degradation of the endothelial cell glycocalyx, and activation of the complement system. Furthermore, this profile of biomarkers in COVID-19 appears specific, with a differential behavior in comparison with septic shock, in which endothelial damage is also known to be critical. Additional studies are needed to validate these biomarkers as diagnostic and prognostic tools of the endothelial complications in COVID-19 patients, both in early disease and later, as well as supporting specific forms of therapeutic intervention.FigureDisclosuresCarreras:Jazz Pharmaceuticals: Research Funding, Speakers Bureau; German Jose´ Carreras Leukaemia Foundation: Research Funding. Carlo-Stella:Boehringer Ingelheim and Sanofi: Consultancy; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Moraleda:Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel Expenses. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Diaz-Ricart:German Jose Carreras Leukaemia Foundation: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding.

Diagnosis and mortality prediction of sepsis via lysophosphatidylcholine 16:0 measured by MALDI-TOF MS

Sepsis remains a critical problem with high mortality worldwide, but there is still a lack of reliable biomarkers. We aimed to evaluate the serum lysophosphatidylcholine (LPC) 16:0 as a biomarker of sepsis using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Patients admitted to intensive care unit at Severance Hospital from March 2017 through June 2018 were prospectively enrolled. The inclusion criteria were the fulfillment of at least two criteria of systemic inflammatory response syndrome (SIRS) or the presence of sepsis. Of the 127 patients, 14 had non-infectious SIRS, 41 had sepsis, and 72 had septic shock. The mean serum LPC 16:0 concentration (µmol/L) in non-infectious SIRS was significantly higher than in patients with sepsis and septic shock (101.1 vs. 48.92, p < 0.05; 101.1 vs. 25.88, p < 0.001, respectively). The area under the curve (AUC) predicting 28-day mortality using ΔLPC16:0 (D1-D0) levels was 0.7, which was comparable with the APACHE II score (AUC 0.692) and SOFA score (AUC 0.67). Mechanical ventilation, CRRT, lactate, Δ LPC16:0 (D1-D0) less than the cut-off value were significantly associated with 28-day mortality in multivariable analysis. Our results suggest that LPC16:0 could be a useful biomarker for sepsis diagnosis and mortality prediction in ICU patients.

Diagnostic Value of miR-103 in Patients with Sepsis and Noninfectious SIRS and Its Regulatory Role in LPS-Induced Inflammatory Response by Targeting TLR4.

Background Sepsis is a life-threatening condition and a systemic inflammatory response syndrome (SIRS) driven by infection. This study aimed at investigating the expression of microRNA-103 (miR-103) in sepsis patients, evaluating its diagnostic value, and exploring the regulatory effect of miR-103 on LPS-induced inflammation in monocytes. Methods Expression of miR-103 was measured using quantitative real-time PCR. A receiver operating characteristics curve was plotted to evaluate the diagnostic vale of miR-103. Serum and cell supernatant levels of proinflammatory cytokines were analyzed using ELISA. The interaction between miR-103 and Toll-like receptors 4 (TLR4) was analyzed using luciferase reporter assay. The effect of miR-103 on inflammation was examined in LPS-treated monocytes. Results Serum expression of miR-103 was decreased in noninfectious SIRS and sepsis patients compared with healthy controls, and the lowest expression value was observed in sepsis patients (all P < 0.05). Serum levels of miR-103 have considerable diagnostic accuracy in distinguishing sepsis patients from SIRS patients and healthy controls. A negative correlation was found between miR-103 and inflammatory responses in sepsis patients. TLR4 was demonstrated to be a direct target of miR-103 and was negatively regulated by miR-103 in monocytes. The promoted inflammatory responses by LPS in monocytes were reversed by the overexpression of miR-103. Conclusion All the data revealed that serum decreased miR-103 in sepsis patients serves as a promising noninvasive diagnostic biomarker and may be involved in the pathogenesis of sepsis by regulating inflammatory responses via targeting TLR4.

Procalcitonin and Interleukin-6 for predicting culturenegative and culture positive bacterial sepsis in critically ill patients with systemic inflammatory response syndrome

Introduction: Differentiation between culture-negative bacterial sepsis (BS), culturepositive BS and non-infectious systemic inflammatory response syndrome (SIRS) among critically ill patients remains a diagnostic challenge to the intensive care unit (ICU) physicians. This study aimed to evaluate the role of procalcitonin (PCT) and interleukin-6 (IL-6) in predicting non-infectious SIRS, culture-negative BS and culture-positive BS in the ICU. Methods: This prospective observational study was conducted in a tertiary ICU in Pahang. The patients were divided into sepsis and non-infectious SIRS based on clinical assessment with or without positive cultures. Patients with positive cultures were further divided into bacteraemia and positive other culture. The PCT and IL-6 were measured daily over the first 3 days. Results: Two hundred and thirty nine consecutive patients diagnosed with SIRS were recruited, of whom 164 (69%) had sepsis. Among sepsis patients, there were 62 (37.8%) culture positive and 102 (62.2%) culture negative. Of these, 27 (16.5%) develop bacteraemia. The most common site of infection was respiratory (34.4%). Post-LSD analyses showed significant difference in the PCT between culture negative sepsis and SIRS (p=0.01); and positive other culture and SIRS (p=0.04). On the other hand IL-6 cannot differentiate between SIRS and negative culture sepsis (p=0.06). Both PCT and IL-6 predicted bacteraemia with an AUC of 0.70 (0.57 to 0.82) and 0.68 (0.53 to 0.70). IL-6 is independently associated with bacteraemia and other culture after adjusting for age, sex, hypertension, SAPS II score and day 1 PCT. Conclusions: Procalcitonin but not Interleukin-6 is able to differentiate SIRS from culture-negative BS. However, IL-6 is independently associated with bacteraemia and other culture.

The usefulness of neutrophil/lymphocyte count ratio in the diagnosis and prognosis of bacterial sepsis – An old parameter with new implications

Abstract Aims: To analyze the diagnostic role of neutrophil/lymphocyte count ratio (NLCR) in sepsis and to evaluate its usefulness in appreciating the prognosis of septic patients. Methods : A prospective analysis of patients diagnosed with sepsis between October 2015 and July 2017 was performed. A control group of patients with systemic inflammatory response syndrome (SIRS) with noninfectious causes was recruited. The sensitivity, specificity and AUC of NCLR for sepsis diagnosis were comparatively assessed with other biomarkers including fibrinogen (FIB), C-reactive protein (CRP) and procalcitonin (PCT). The baseline levels of NLCR were correlated with APACHE IV, APS and SOFA scores of severity. Results : We enrolled 105 patients with sepsis and 37 patients with noninfectious SIRS. NLCR had significantly higher levels in the first group (p---lt---0.05). For an optimal cut-off value of 8.18, the sensitivity, specificity and AUC of NLCR for sepsis diagnosis were 70.5%, 72.2% and 0.766, respectively. A cut-off value of 12.0 led to moderate sensitivity (58.7%) and moderate-to-high specificity (89%). For patients with SOFA score over 2 points, the characteristics did not significantly improve. The correlations between baseline NCLR and the severity scores were not statistically significant. Conclusion : NLCR levels were significantly higher in sepsis group compared to noninfectious SIRS group. NLCR had moderate sensitivity and specificity regarding sepsis diagnosis. Baseline levels of NLCR did not correlate with the severity scores, so its usefulness in sepsis prognosis was limited.

Rapid and Digital Detection of Inflammatory Biomarkers Enabled by a Novel Portable Nanoplasmonic Imager.

New point-of-care diagnostic devices are urgently needed for rapid and accurate diagnosis, particularly in the management of life-threatening infections and sepsis, where immediate treatment is key. Sepsis is a critical condition caused by systemic response to infection, with chances of survival drastically decreasing every hour. A novel portable biosensor based on nanoparticle-enhanced digital plasmonic imaging is reported for rapid and sensitive detection of two sepsis-related inflammatory biomarkers, procalcitonin (PCT) and C-reactive protein (CRP) directly from blood serum. The device achieves outstanding limit of detection of 21.3 pg mL-1 for PCT and 36 pg mL-1 for CRP, and dynamic range of at least three orders of magnitude. The portable device is deployed at Vall d'Hebron University Hospital in Spain and tested with a wide range of patient samples with sepsis, noninfectious systemic inflammatory response syndrome (SIRS), and healthy subjects. The results are validated against ultimate clinical diagnosis and currently used immunoassays, and show that the device provides accurate and robust performance equivalent to gold-standard laboratory tests. Importantly, the plasmonic imager can enable identification of PCT levels typical of sepsis and SIRS patients in less than 15 min. The compact and low-cost device is a promising solution for assisting rapid and accurate on-site sepsis diagnosis.

Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis

BackgroundSepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is not well understood but is known to involve epigenetic and transcriptional dysregulation.MethodsBead arrays were used to compare global DNA methylation changes in patients with sepsis, non-infectious systemic inflammatory response syndrome, and healthy controls. Bioinformatic analyses were performed to dissect functional reprogramming and signaling pathways related to the acquisition of these specific DNA methylation alterations. Finally, in vitro experiments using human monocytes were performed to test the induction of similar DNA methylation reprogramming.ResultsHere, we focused on DNA methylation changes associated with sepsis, given their potential role in stabilizing altered phenotypes. Tolerized monocytes from patients with sepsis display changes in their DNA methylomes with respect to those from healthy controls, affecting critical monocyte-related genes. DNA methylation profiles correlate with IL-10 and IL-6 levels, significantly increased in monocytes in sepsis, as well as with the Sequential Organ Failure Assessment score; the observed changes associate with TFs and pathways downstream to toll-like receptors and inflammatory cytokines. In fact, in vitro stimulation of toll-like receptors in monocytes results in similar gains and losses of methylation together with the acquisition of tolerance.ConclusionWe have identified a DNA methylation signature associated with sepsis that is downstream to the response of monocytes to inflammatory signals associated with the acquisition of a tolerized phenotype and organic dysfunction.

Evaluation of the host cytokine response in dogs with sepsis and noninfectious systemic inflammatory response syndrome.

To quantify plasma cytokine concentrations in dogs with sepsis and noninfectious systemic inflammation and to evaluate the association between plasma cytokines and outcome in dogs with sepsis. Prospective, observational cohort study. University teaching hospital. Forty-five dogs with sepsis, 10 dogs with noninfectious systemic inflammation (nSIRS), and 15 healthy controls were consecutively enrolled from June 2015 to February 2016 and followed to hospital discharge. Dogs with sepsis satisfied ≥2 SIRS criteria and had a documented or highly suspected bacterial infection. Dogs with nSIRS satisfied ≥2 SIRS criteria but had no evidence of infection. Dogs<3kg and those with documented coagulopathy were excluded. Measurement of inflammatory cytokines and high-mobility group box-1 (HMGB-1) was performed on each group. High-mobility group box-1 concentrations were analyzed by ELISA. Plasma concentrations of 13 cytokines were measured in singlet using multiplex magnetic bead assays. Kruskal-Wallis with Dunn's multiple comparison tests were used to compare biomarker concentrations between groups. Mann-Whitney U-tests were used to compare biomarker concentrations between survivors and nonsurvivors. Associations between biomarkers were evaluated using Spearman's correlation coefficients. Independent outcome predictors were identified using multivariable logistic regression. Alpha was set at 0.05. Concentrations of interleukin (IL)-6, C-X-C motif chemokine (CXCL)-8, keratinocyte-derived chemokine (KC)-like, C-C motif chemokine ligand 2 (CCL2), and HMGB-1 were significantly greater in dogs with sepsis versus healthy controls (all P≤0.034). In dogs with sepsis, only CCL2 was independently associated with survival (odds ratio [OR] 0.996, 95% CI 0.993-0.999, P=0.004). A cut-off of 385 pg/mL for CCL2 was 80% sensitive and 91.4% specific for nonsurvival (area under the ROC curve [AUROC] 0.866). Dogs with sepsis have significantly increased concentrations of HMGB-1 and inflammatory cytokines, including IL-6, CXCL8, and KC-like. Increased CCL2 concentration is a negative prognostic indicator in dogs with sepsis. These findings should be confirmed using duplicate analyses in larger, distinct populations of dogs with sepsis before applying them to clinical patients.

AKIRIN1: A Potential New Reference Gene in Human Natural Killer Cells and Granulocytes in Sepsis.

Timely and reliable distinction of sepsis from non-infectious systemic inflammatory response syndrome (SIRS) supports adequate antimicrobial therapy and saves lives but is clinically challenging. Blood transcriptional profiling promises to deliver insights into the pathomechanisms of SIRS and sepsis and to accelerate the discovery of urgently sought sepsis biomarkers. However, suitable reference genes for normalizing gene expression in these disease conditions are lacking. In addition, variability in blood leukocyte subtype composition complicates gene profile interpretation. Here, we aimed to identify potential reference genes in natural killer (NK) cells and granulocytes from patients with SIRS and sepsis on intensive care unit (ICU) admission. Discovery by a two-step probabilistic selection from microarray data followed by validation through branched DNA assays in independent patients revealed several candidate reference genes in NK cells including AKIRIN1, PPP6R3, TAX1BP1, and ADRBK1. Initially, no candidate genes could be validated in patient granulocytes. However, we determined highly similar AKIRIN1 expression also in SIRS and sepsis granulocytes and no change by in vitro LPS challenge in granulocytes from healthy donors. Inspection of external neutrophil transcriptome datasets further support unchanged AKIRIN1 expression in human systemic inflammation. As a potential new reference gene in NK cells and granulocytes in infectious and inflammatory diseases, AKIRIN1 may improve our pathomechanistic understanding of SIRS and sepsis and help identifying new sepsis biomarkers.

Vitamin D deficiency - a potential risk factor for sepsis development, correlation with inflammatory markers, SOFA score and higher early mortality risk in sepsis.

Sepsis is a life-threatening organ dysfunction generated due to the dysregulation of the immune response to infection. The aim of this study was to highlight the role of vitamin D in sepsis and non-infectious SIRS (systemic inflammatory response syndrome) and to find correlation of vitamin D levels with inflammatory markers, severity of the disease, and association with the 7th and 28th survival rate of patients. We investigated 32 patients (21 men, 11 women) admitted to an intensive care unit with both SIRS and sepsis. Blood was taken within 24 hours after admission. Plasma levels of 25(OH)D, sTREM-1, CRP, presepsin and procalcitonin were investigated. Patients with sepsis had lower levels of 25(OH)D (n = 25) than SIRS patients (n = 7; p = 0.0032). Significantly lower levels of 25(OH)D were found also in patients, who did not survive the 7th (p = 0.0076) and 28th day (p = 0.0338) of hospital care compared to 7th, resp. 28th day survivors. We revealed a negative correlation between the levels of 25(OH)D and inflammatory markers CRP (p = 0.0003), presepsin (p = 0.0032) and sTREM-1 (p = 0.0065) in all SIRS/sepsis patients and clinical condition (SOFA score; p = 0.0385). Our results showed that vitamin D deficiency predisposed to the development of sepsis, negatively correlated with CRP, presepsin, sTREM-1 and SOFA score and their levels associates with both 7th and 28th days survival of patients (Tab. 5, Ref. 64).

Evaluating the discriminating capacity of cell death (apoptotic) biomarkers in sepsis

BackgroundSepsis biomarker panels that provide diagnostic and prognostic discrimination in sepsis patients would be transformative to patient care. We assessed the mortality prediction and diagnostic discriminatory accuracy of two biomarkers reflective of cell death (apoptosis), circulating cell-free DNA (cfDNA), and nucleosomes.MethodsThe cfDNA and nucleosome levels were assayed in plasma samples acquired in patients admitted from four emergency departments with suspected sepsis. Subjects with non-infectious systemic inflammatory response syndrome (SIRS) served as controls. Samples were acquired at enrollment (T0) and 24 h later (T24). We assessed diagnostic (differentiating SIRS from sepsis) and prognostic (28-day mortality) predictive power. Models incorporating procalcitonin (diagnostic prediction) and APACHE II scores (mortality prediction) were generated.ResultsTwo hundred three subjects were included (107 provided procalcitonin measurements). Four subjects exhibited uncomplicated sepsis, 127 severe sepsis, 35 septic shock, and 24 had non-infectious SIRS. There were 190-survivors and 13 non-survivors. Mortality prediction models using cfDNA, nucleosomes, or APACHEII yielded AUC values of 0.61, 0.75, and 0.81, respectively. A model combining nucleosomes with the APACHE II score improved the AUC to 0.84. Diagnostic models distinguishing sepsis from SIRS using procalcitonin, cfDNA(T0), or nucleosomes(T0) yielded AUC values of 0.64, 0.65, and 0.63, respectively. The three parameter model yielded an AUC of 0.74.ConclusionsTo our knowledge, this is the first head-to-head comparison of cfDNA and nucleosomes in diagnosing sepsis and predicting sepsis-related mortality. Both cfDNA and nucleosome concentrations demonstrated a modest ability to distinguish sepsis survivors and non-survivors and provided additive diagnostic predictive accuracy in differentiating sepsis from non-infectious SIRS when integrated into a diagnostic prediction model including PCT and APACHE II. A sepsis biomarker strategy incorporating measures of the apoptotic pathway may serve as an important component of a sepsis diagnostic and mortality prediction tool.

Derivation and Validation of a Biomarker-Based Clinical Algorithm to Rule Out Sepsis From Noninfectious Systemic Inflammatory Response Syndrome at Emergency Department Admission: A Multicenter Prospective Study.

To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. Multicenter prospective study. At emergency department admission in five University hospitals. Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. None. A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholipase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholipase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome.

Urinary miR-26b as a potential biomarker for patients with sepsis-associated acute kidney injury: a Chinese population-based study.

Acute kidney injury (AKI) is common in critically ill patients, and sepsis patients with AKI had a higher mortality rate. The aim of the present study was to determine the potential value of urinary miR-26b in the diagnosis of sepsis-associated AKI. Urinary samples were collected from a cohort of 155 sepsis patients (68 AKI patients and 87 non-AKI patients) and 57 patients with non-infectious systemic inflammatory response syndrome (SIRS). The expression levels of urinary miR-26b were measured by RT-qPCR analysis. ROC curve analysis was performed to determine the diagnostic value. Pearson correlation analysis was performed to assess the levels of urinary miR-26b and several clinical parameters. Kaplan-Meier curves were plotted to show the impact of urinary miR-26b on the 28-day survival. Significantly increased urinary miR-26b levels were found in patients with sepsis-associated AKI. Urinary miR-26b had a sensitivity of 90.8% and specificity of 75.0% for distinguishing between AKI sepsis and non-AKI sepsis. Urinary miR-26b levels were closely correlated with clinical parameters reflecting the severity of the disease. Kaplan-Meier analysis revealed that sepsis patients with high urinary miR-26b levels had an elevated mortality rate. Taken together, these findings suggested that urinary miR-26b might be utilized as a potential biomarker for sepsis-associated AKI.