Sepsis Subgroup Research Articles

Plasma Proteome, Metabolome Mendelian Randomization Identifies Sepsis Therapeutic Targets.

The interrelation between the plasma proteome and plasma metabolome with sepsis presents a multifaceted dynamic that necessitates further research to elucidate the underlying causal mechanisms. Our investigation used public genome-wide association study (GWAS) data to explore the relationships among the plasma proteome, metabolome, and sepsis, considering different sepsis subgroup. Initially, two-sample MR established causal connections between the plasma proteome and metabolome with sepsis. Subsequently, multivariate and iterative MR analyses were performed to understand the complex interactions in plasma during sepsis. The validity of these findings was supported by thorough sensitivity analyses. The study identified 25 plasma proteins that enhance risk and 34 that act as protective agents in sepsis. Post p-value adjustment (0.05/1306), ICAM5 emerged with a positive correlation to sepsis susceptibility (p-value = 2.14E-05, OR = 1.10, 95% CI = 1.05-1.15), with this significance preserved across three sepsis subgroup examined. Additionally, 29 plasma metabolites were recognized as risk factors, and 15 as protective factors for sepsis outcomes. Following p-value adjustment (0.05/997), elevated levels of 1,2,3-benzenetriol sulfate (2) was significantly associated with increased sepsis risk (p-value = 3.37E-05, OR = 1.18, 95% CI = 1.09-1.28). Further scrutiny revealed that this plasma metabolite notably augments the abundance of ICAM5 protein (p-value = 3.52E-04, OR = 1.11, 95% CI = 1.04-1.17), devoid of any detected heterogeneity, pleiotropy, or reverse causality. Mediated MR revealed ICAM5 mediated 11.9% of 1,2,3-benzenetriol sulfate (2)'s total effect on sepsis progression. This study details the causal link between the plasma proteome and metabolome with sepsis, highlighting the roles of ICAM5 and 1,2,3-benzenetriol sulfate (2) in sepsis progression, both independently and through crosstalk.

Mendelian randomization analysis reveals higher whole body water mass may increase risk of bacterial infections

Background and purposeThe association of water loading with several infections remains unclear. Observational studies are hard to investigate definitively due to potential confounders. In this study, we employed Mendelian randomization (MR) analysis to assess the association between genetically predicted whole body water mass (BWM) and several infections.MethodsBWM levels were predicted among 331,315 Europeans in UK Biobank using 418 SNPs associated with BWM. For outcomes, we used genome-wide association data from the UK Biobank and FinnGen consortium, including sepsis, pneumonia, intestinal infections, urinary tract infections (UTIs) and skin and soft tissue infections (SSTIs). Inverse-variance weighted MR analyses as well as a series of sensitivity analyses were conducted.ResultsGenetic prediction of BWM is associated with an increased risk of sepsis (OR 1.34; 95% CI 1.19 to 1.51; P = 1.57 × 10− 6), pneumonia (OR: 1.17; 95% CI 1.08 to 1.29; P = 3.53 × 10− 4), UTIs (OR: 1.26; 95% CI 1.16 to 1.37; P = 6.29 × 10− 8), and SSTIs (OR: 1.57; 95% CI 1.25 to 1.96; P = 7.35 × 10− 5). In the sepsis and pneumonia subgroup analyses, the relationship between BWM and infection was observed in bacterial but not in viral infections. Suggestive evidence suggests that BWM has an effect on viral intestinal infections (OR: 0.86; 95% CI 0.75 to 0.99; P = 0.03). There is limited evidence of an association between BWM levels and bacteria intestinal infections, and genitourinary tract infection (GUI) in pregnancy. In addition, MR analyses supported the risk of BWM for several edematous diseases. However, multivariable MR analysis shows that the associations of BWM with sepsis, pneumonia, UTIs and SSTIs remains unaffected when accounting for these traits.ConclusionsIn this study, the causal relationship between BWM and infectious diseases was systematically investigated. Further prospective studies are necessary to validate these findings.

Balanced Crystalloid Solution or Normal Saline in Fluid Resuscitation in Critically Ill Patients: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials

Background: Both balanced crystalloid solution and normal saline are commonly used for fluid therapy in critically ill patients. However, the association between the types of crystalloid solution and patient outcomes remains inconclusive. Materials and Methods: The authors performed a search using Pubmed, Embase, and Cochrane Central Register through January 2022. Randomized controlled trials (RCTs) comparing balanced crystalloids and normal saline in non-perioperative fluid resuscitation for critically ill adult patients were included. The primary outcome was 30-day mortality. A trial sequential analysis (TSA) was performed to assess the effect of each type of fluid on the outcomes. Secondary outcomes included the incidence of acute kidney injury (AKI), renal replacement therapy (RRT), and other pre-specified outcomes. Results: Ten RCTs were identified and included 36,233 participants. Between the balanced crystalloids and the normal saline group, there were no significant differences in mortality at 30 days (relative risk [RR] 0.95, 95% confidence interval [CI] 0.89 to 1.02, I²=0), the incidence of AKI (RR 0.95, 95% CI 0.90 to 1.01, I²=0), and RRT (RR 0.93, 95% CI 0.86 to 1.01, I²=13). However, patients receiving balanced crystalloids demonstrated a significantly lower serum chloride level than the patients receiving normal saline (MD –1.95, 95% CI –3.45 to –0.45, I²=99). There was also no mortality difference in the sepsis and traumatic brain injury subgroups. The TSA confirmed the absence of an effect on mortality at 30 days and the incidence of AKI. Conclusion: In critically ill patients, the use of balanced crystalloids does not decrease 30-day mortality or the incidence of AKI and RRT. However, data in specific subgroups of patients were underpowered and further studies are required. There were signals of benefit and risk of the balanced salt solution in the subgroups of sepsis and traumatic brain injury. Trial registration: The present study was registered in the PROSPERO database, CRD42021275796. Keywords: Balanced crystalloid; Normal saline; Critically ill patients; Mortality; Acute kidney injury

Elucidating common pathogenic transcriptional networks in infective endocarditis and sepsis: integrated insights from biomarker discovery and single-cell RNA sequencing.

Infective Endocarditis (IE) and Sepsis are two closely related infectious diseases, yet their shared pathogenic mechanisms at the transcriptional level remain unclear. This research gap poses a barrier to the development of refined therapeutic strategies and drug innovation. This study employed a collaborative approach using both microarray data and single-cell RNA sequencing (scRNA-seq) data to identify biomarkers for IE and Sepsis. It also offered an in-depth analysis of the roles and regulatory patterns of immune cells in these diseases. We successfully identified four key biomarkers correlated with IE and Sepsis, namely CD177, IRAK3, RNASE2, and S100A12. Further investigation revealed the central role of Th1 cells, B cells, T cells, and IL-10, among other immune cells and cytokines, in the pathogenesis of these conditions. Notably, the small molecule drug Matrine exhibited potential therapeutic effects by targeting IL-10. Additionally, we discovered two Sepsis subgroups with distinct inflammatory responses and therapeutic strategies, where CD177 demonstrated significant classification value. The reliability of CD177 as a biomarker was further validated through qRT-PCR experiments. This research not only paves the way for early diagnosis and treatment of IE and Sepsis but also underscores the importance of identifying shared pathogenic mechanisms and novel therapeutic targets at the transcriptional level. Despite limitations in data volume and experimental validation, these preliminary findings add new perspectives to our understanding of these complex diseases.

The value of right ventricular to pulmonary arterial coupling in the critically ill: a National Echocardiography Database of Australia (NEDA) substudy.

Right ventricular (RV) function is tightly coupled to afterload, yet echocardiographic indices of RV function are frequently assessed in isolation. Normalizing RV function for afterload (RV-PA coupling) using a simplified ratio of tricuspid annular plane systolic excursion (TAPSE)/ tricuspid regurgitant velocity (TRV) could help to identify RV decompensation and improve risk stratification in critically ill patients. This is the first study to explore the distribution of TAPSE/TRV ratio and its prognostic relevance in a large general critical care cohort. We undertook retrospective analysis of echocardiographic, clinical, and mortality data of intensive care unit (ICU) patients between January 2012 and May 2017. A total of 1077 patients were included and stratified into tertile groups based on TAPSE/TRV ratio: low (< 5.9mm.(m/s)-1), middle (≥ 5.9-8.02mm.(m/s)-1), and high (≥ 8.03mm.(m/s)-1). The distribution of the TAPSE/TRV ratio across ventricular function subtypes of normal, isolated left ventricular (LV), isolated RV, and biventricular dysfunction was explored. The overall prognostic relevance of the TAPSE/TRV ratio was tested, including distribution across septic, cardiovascular, respiratory, and neurological subgroups. Higher proportions of ventricular dysfunctions were seen in low TAPSE/TRV tertiles. TAPSE/TRV ratio is impacted by LV systolic function but to a lesser extent than RV dysfunction or biventricular dysfunction. There was a strong inverse relationship between TAPSE/TRV ratio and survival. After multivariate analysis, higher TAPSE/TRV ratios (indicating better RV-PA coupling) were independently associated with lower risk of death in ICU (HR 0.927 [0.872-0.985], p < 0.05). Kaplan-Meier analysis demonstrated higher overall survival in middle and high tertiles compared to low tertiles (log rank p < 0.0001). The prognostic relevance of TAPSE/TRV ratio was strongest in respiratory and sepsis subgroups. Patients with TAPSE/TRV < 5.9mm(m/s)-1 had a significantly worse prognosis than those with higher TAPSE/TRV ratios. The TAPSE/TRV ratio has prognostic relevance in critically ill patients. The prognostic power may be stronger in respiratory and septic subgroups. Larger prospective studies are needed to investigate the role of TAPSE/TRV in pre-specified subgroups including its role in clinical decision-making.

Routine diversion following delayed IPAA construction does not reduce the incidence of pouch-related sepsis or failure in patients with ulcerative colitis.

The aim of this study was to compare modified 2-stage and 3-stage IPAA construction techniques to evaluate the effect of diverting loop ileostomy following completion proctectomy and IPAA for ulcerative colitis. In addition, our overall institutional experience was reviewed to describe long-term outcomes and changes in staging trends over time. Our institutional database was searched to identify all cases of IPAA for ulcerative colitis between 1981 and 2018. Patient, pouch and outcome characteristics were abstracted. Primary study outcomes were the incidence of primary pouch failure and pouch-related sepsis. Failure was evaluated by Kaplan-Meier estimates of survival over time. The adjusted effect of pouch stage was evaluated using multivariable Cox and logistic regression models. Exploratory analysis evaluated the effect of stage on failure in the pouch related sepsis subgroup. A total of 2105 patients underwent primary IPAA over the study period. The 5, 10 and 20-year pouch survival probabilities were 95.2%, 92.7% and 86.6%. The incidence of pouch related sepsis was 12.3%. Adjusted analysis demonstrated no difference in pouch failure (HR = 0.64: 95% 0.39-1.07, p = 0.09) or post-operative sepsis (aOR = 0.79: 95% CI 0.53-1.17, p = 0.24) by stage of construction. Among patients experiencing pouch sepsis, there was no difference in Kaplan-Meier estimates of pouch survival by stage (p = 0.90). Pouch related sepsis and IPAA failure did not differ between modified 2-stage and 3-stage construction techniques. Among the sub-group of patients experiencing pouch related sepsis, there was no difference in failure between groups. The results suggest diverting ileostomy may be safely avoided following delayed pouch reconstruction in appropriately selected patients.

Determinants of fluid use and the association between volume of fluid used and effect of balanced solutions on mortality in critically ill patients: a secondary analysis of the BaSICS trial.

Fluid use could modulate the effect of balanced solutions (BS) on outcome of intensive care unit (ICU) patients. It is uncertain whether fluid use practices are driven more by patient features or local practices. It is also unclear whether a "dose-response" for the potential benefits of balanced solutions exists. The secondary analysis of the Balanced Solution in Intensive Care Study (BaSICS) compared 0.9% saline versus Plasma-Lyte 148® (BS) for fluid therapy in the ICU. The relative contribution of patient features and enrolling site (the random effect) on the volume of fluid used up to day 3 after admission was assessed using different methods, including a Bayesian regression, a frequentist mixed model, and a random forest, all adjusted for relevant patient confounders. Subsequently, a variety of methods were used to assess whether volume of fluid used modulated the effect of BS on 90-day mortality, including a traditional subgroup analysis for patients that remained alive and in the ICU up to 3 days, a Bayesian network accounting for competing risks, and an analysis based on site practices. 10,505 patients were analyzed. Median fluid use in the BS arm and in the 0.9% saline arm were 2500mL and 2488mL, respectively. The random effect in the Bayesian regression explained 0.32 (95% credible intervals (CrI) 0.24-0.41) of all model variance (0.33, 95% credible intervals from 0.32-0.35). Frequentist and random forest models produced similar results. In the analysis including only patients alive and in the ICU at 3 days, there was a strong suggestion of interaction between fluid use and the effect of BS, driven mostly by a lower mortality with BS compared to 0.9% saline as fluid use increased for patients with sepsis. These results were consistent in the Bayesian network analysis and in an analysis based on site practices, where septic patients enrolled to BS at high fluid use sites had a lower mortality (absolute risk reduction of -0.13 [95% credible interval -0.27 to -0.01]; 0.98 probability of benefit). Baseline patient characteristics collected in the BaSICS trial explain less of the variance of fluid use during the first 3 days than the enrolling site. Volume of fluid used and the effects of BS appear to interact, mostly in the sepsis subgroup where there was a strong association between fluid use after enrollment and the effect of BS on 90-day mortality.

Identification and validation of key biomarkers based on RNA methylation genes in sepsis.

RNA methylation is closely involved in immune regulation, but its role in sepsis remains unknown. Here, we aim to investigate the role of RNA methylation-associated genes (RMGs) in classifying and diagnosing of sepsis. Five types of RMGs (m1A, m5C, m6Am, m7G and Ψ) were used to identify sepsis subgroups based on gene expression profile data obtained from the GEO database (GSE57065, GSE65682, and GSE95233). Unsupervised clustering analysis was used to identify distinct RNA modification subtypes. The CIBERSORT, WGCNA, GO and KEGG analysis were performed to explore immune infiltration pattern and biological function of each cluster. RF, SVM, XGB, and GLM algorithm were applied to identify the diagnostic RMGs in sepsis. Finally, the expression levels of the five key RMGs were verified by collecting PBMCs from septic patients using qRT-PCR, and their diagnostic efficacy for sepsis was verified in combination with clinical data using ROC analysis. Sepsis was divided into three subtypes (cluster 1 to 3). Cluster 1 highly expressed NSUN7 and TRMT6, with the characteristic of neutrophil activation and upregulation of MAPK signaling pathways. Cluster 2 highly expressed NSUN3, and was featured by the regulation of mRNA stability and amino acid metabolism. NSUN5 and NSUN6 were upregulated in cluster 3 which was involved in ribonucleoprotein complex biogenesis and carbohydrate metabolism pathways. In addition, we identified that five RMGs (NSUN7, NOP2, PUS1, PUS3 and FTO) could function as biomarkers for clinic diagnose of sepsis. For validation, we determined that the relative expressions of NSUN7, NOP2, PUS1 and PUS3 were upregulated, while FTO was downregulated in septic patients. The area under the ROC curve (AUC) of NSUN7, NOP2, PUS1, PUS3 and FTO was 0.828, 0.707, 0.846, 0.834 and 0.976, respectively. Our study uncovered that dysregulation of RNA methylation genes (m1A, m5C, m6Am, m7G and Ψ) was closely involved in the pathogenesis of sepsis, providing new insights into the classification of sepsis endotypes. We also revealed that five hub RMGs could function as novel diagnostic biomarkers and potential targets for treatment.

Gut microbiota and sepsis: bidirectional Mendelian study and mediation analysis.

There is a growing body of evidence that suggests a connection between the composition of gut microbiota and sepsis. However, more research is needed to better understand the causal relationship between the two. To gain a deeper insight into the association between gut microbiota, C-reactive protein (CRP), and sepsis, we conducted several Mendelian randomization (MR) analyses. In this study, publicly available genome-wide association study (GWAS) summary statistics were examined to determine the correlation between gut microbiota and sepsis, including various sepsis subgroups (such as under 75, 28-day death, Critical Care Units (ICU), 28-day death in ICU). Initially, two-sample and reverse Mendelian randomization (MR) analyses were conducted to identify causality between gut microbiota and sepsis. Subsequently, multivariable and two-step MR analyses revealed that the relationship between microbiota and sepsis was mediated by CRP. The robustness of the findings was confirmed through several sensitivity analyses. In our study, we revealed positive correlations between 24 taxa and different sepsis outcomes, while 30 taxa demonstrated negative correlations with sepsis outcomes. Following the correction for multiple testing, we found that the Phylum Lentisphaerae (OR: 0.932, p = 2.64E-03), class Lentisphaeria, and order Victivallales (OR: 0.927, p = 1.42E-03) displayed a negative relationship with sepsis risk. In contrast, Phylum Tenericutes and class Mollicutes (OR: 1.274, p = 2.89E-03) were positively related to sepsis risk and death within 28 days. It is notable that Phylum Tenericutes and class Mollicutes (OR: 1.108, p = 1.72E-03) also indicated a positive relationship with sepsis risk in individuals under 75. From our analysis, it was shown that C-reactive protein (CRP) mediated 32.16% of the causal pathway from Phylum Tenericutes and class Mollicutes to sepsis for individuals under 75. Additionally, CRP was found to mediate 31.53% of the effect of the genus Gordonibacter on sepsis. Despite these findings, our reverse analysis did not indicate any influence of sepsis on the gut microbiota and CRP levels. The study showcased the connection between gut microbiota, CRP, and sepsis, which sheds new light on the potential role of CRP as a mediator in facilitating the impact of gut microbiota on sepsis.

Association Between the Neutrophil-Lymphocyte Ratio and Prognosis of Patients Admitted to the Intensive Care Unit With Chronic Heart Failure: A Retrospective Cohort Study.

The present study aimed to explore the association between the neutrophil-to-lymphocyte ratio (NLR) and prognosis of critically ill chronic heart failure patients. The records of 5298 patients who met the inclusion criteria were extracted from the Medical Information Mart for Intensive Care IV database. The primary outcome was 30-days all-cause mortality and the secondary outcome was 90-days all-cause mortality. Multivariable logistic regression analysis was performed to examine the relationship between NLR and 30-days mortality. Subgroup analysis was carried out to identify whether the association between NLR and 30-days mortality differed across various subgroups. For 30-days mortality, after adjusting for multiple confounders, the odds ratio (OR) (95% confidence interval [CI]) for the second (NLR 4.0-8.4) and the third (NLR ≥8.4) tertiles were 1.52 (1.13-2.03) and 2.53 (1.92-3.34), respectively, compared with the first tertile (NLR <4.0). As for 90-days mortality, the OR for the second (NLR 4.0-8.4) was 1.34 (1.07-1.67) and 2.23 (1.81-2.76) for the third (NLR ≥8.4) tertiles compared with the reference (NLR<4.0). The interactions between the sepsis subgroup and 30-days mortality were significant. Our study concluded that the NLR was an independent predictor of 30- and 90-days mortality for critically ill patients with chronic heart failure.

Hospital-onset sepsis and community-onset sepsis in critical care units in Japan: a retrospective cohort study based on a Japanese administrative claims database

BackgroundHospital- and community-onset sepsis are significant sepsis subgroups. Japanese data comparing these subgroups are limited. This study aimed to describe the epidemiology of hospital- and community-onset sepsis in critical care units in Japan.MethodsWe performed a retrospective cohort study using the Japanese Diagnosis and Procedure Combination database. Adult patients admitted to critical care units with sepsis from April 2010 to March 2020 were included. Sepsis cases were identified based on ICD-10 codes for infectious diseases, procedure codes for blood culture tests, and medication codes for antimicrobials. Patients’ characteristics, in-hospital mortality, and resource utilization were assessed. The in-hospital mortality between groups was compared using the Poisson regression generalized linear mixed-effect model.ResultsOf 516,124 patients, 52,183 (10.1%) had hospital-onset sepsis and 463,940 (89.9%) had community-onset sepsis. Hospital-onset sepsis was characterized by younger age, infrequent emergency hospitalization, frequent surgery under general anesthesia, and frequent organ support upon critical care unit admission compared to community-onset sepsis. In-hospital mortality was higher for hospital-onset than for community-onset sepsis (35.5% versus 19.2%; unadjusted mean difference, 16.3% [95% confidence interval (CI) 15.9–16.7]; adjusted mean difference, 15.6% [95% CI 14.9–16.2]). Mean hospital length of stay was longer for hospital-onset than for community-onset sepsis (47 days versus 30 days; unadjusted mean difference, 17 days [95% CI 16–17]; adjusted mean difference, 13 days [95% CI 12–14]).ConclusionPatients with hospital-onset sepsis admitted to critical care units in Japan had a poorer prognosis and more resource utilization including organ support rate, number of days with critical care unit surcharge codes, and hospital length of stay than those with community-onset sepsis.

Vitamin C for\u2009\u2265\u20095\xa0days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study

BackgroundPrevious randomized trials of vitamin C, hydrocortisone, and thiamine on sepsis were limited by short-term vitamin C administration, heterogeneous populations, and the failure to evaluate each component’s effect. The purpose of this study was to determine whether vitamin C alone for ≥ 5 days or in combination with corticosteroids and/or thiamine was associated with decreased mortality across the sepsis population and subpopulation.MethodsNationwide population-based study conducted using the Korean National Health Insurance Service database. A total of 384,282 adult patients with sepsis who were admitted to the intensive care unit were enrolled from January 2017 to December 2019. The primary outcome was hospital mortality, while the key secondary outcome was 90-day mortality.ResultsThe mean [standard deviation] age was 69.0 [15.4] years; 57% were male; and 36,327 (9%) and 347,955 did and did not receive vitamin C, respectively. After propensity score matching, each group involved 36,327 patients. The hospital mortality was lower by − 0.9% in the treatment group (17.1% vs 18.0%; 95% confidence interval, − 1.3 to − 0.5%; p < 0.001), a significant but extremely small difference. However, mortality decreased greater in patients who received vitamin C for ≥ 5 days (vs 1–2 or 3–4 days) (15.8% vs 18.8% vs 18.3%; p < 0.001). Further, vitamin C was associated with a lower hospital mortality in patients with older age, multiple comorbidities, pneumonia, genitourinary infection, septic shock, and mechanical ventilation. Consistent findings were found for 90-day mortality. Moreover, vitamin C alone or in combination with thiamine was significantly associated with decreased hospital mortality.ConclusionsIntravenous vitamin C of ≥ 5 days was significantly associated with decreased hospital and 90-day mortality in sepsis patients. Vitamin C combined with corticosteroids and/or thiamine in specific sepsis subgroups warrants further study.

Hypoxia in Liver Cirrhosis (Liver Specific and Systemic Causes)

Background: During this covid pandemic hypoxia was one of the initial mode of screening diagnosis and follow-up. Hypoxia in liver cirrhosis patients is also not uncommon especially in late stages. Hypoxia can have varied causes either liver specific or systemic conditions. Aim: aim of our observational study was to find etiology, incidence, severity and hypoxia related mortality in patients with liver cirrhosis. Methods: we conducted an observational study over a period of two months a total of n=64 patients with liver cirrhosis with hypoxia were included in the study. Further follow up data was collected from their clinical work up. Mortality data was collected for their mean follow up periods from their inclusion in the study. Results: ACLF was found to be the most common cause of hypoxia in cirrhosis patients with n=24 (37.5%) with a mean spo2 of 86.4% Mortality in ACLF was 70.8%, second most common cause was covid pneumonitis n=17 (26.6%) with a mean spo2 of 82.6% and a mortality of 23.5%, Followed by sepsis n=10 (15.6%) with an average spo2 of 88% and mortality of 60%. Hepato-pulmonary syndrome was seen in n=8 (12.5%) average spo2 of 91% and mortality of 25% followed by hepatic and hydrothorax n=4 (6.25%) average spo2 of 92.5% with 25% mortality and one patient with porto- pulmonary syndrome with an spo2 of 93% no mortality. Conclusion: Novel corona virus induced hypoxia was second most common causes for hypoxia in the current pandemic era after ACLF. Though hypoxia in COVID pneumonitis was more severe than ACLF and sepsis but the mortality was higher in ACLF and sepsis subgroup. Prognosis and mortality in hypoxic cirrhosis depends on the etiology and does not directly corelate with the severity of spo2 directly.

Circulating dipeptidyl peptidase 3 on intensive care unit admission is a predictor of organ dysfunction and mortality

BackgroundOur aim was to investigate the prognostic potential of circulating dipeptidyl peptidase 3 (cDPP3) to predict mortality and development of organ dysfunction in a mixed intensive care unit (ICU) population, and for this reason, we analysed prospectively collected admission blood samples from adult ICU patients at four Swedish hospitals. Blood samples were stored in a biobank for later batch analysis. The association of cDPP3 levels with 30-day mortality and Sequential Organ Failure Assessment (SOFA) scores on day two was investigated before and after adjustment for the simplified acute physiology score III (SAPS-3), using multivariable (ordinal) logistic regression. The predictive power of cDPP3 was assessed using the area under the receiver operating characteristic curve (AUROC).ResultsOf 1978 included consecutive patients in 1 year (2016), 632 fulfilled the sepsis 3-criteria, 190 were admitted after cardiac arrest, and 157 because of trauma. Admission cDPP3 was independently (of SAPS-3) associated with 30-day mortality with odds ratios of 1.45 (95% confidence interval (CI) 1.28–1.64) in the entire ICU population, 1.30 (95% CI 1.08–1.57) in the sepsis subgroup and 2.28 (95% CI 1.50–3.62) in cardiac arrest. For trauma, there was no clear association. Circulating DPP3 alone was a moderate predictor of 30-day mortality with AUROCs of 0.68, 0.62, and 0.72 in the entire group, the sepsis subgroup, and the cardiac arrest subgroup, respectively. By adding cDPP3 to SAPS-3, AUROC improved for the entire group, the sepsis subgroup, and the cardiac arrest subgroup (p = 0.023).ConclusionCirculating DPP3 on admission is a SAPS-3 independent prognostic factor of day-two organ dysfunction and 30-day mortality in a mixed ICU population and needs further evaluation.

Plasma proenkephalin A 119\u2013159 on intensive care unit admission is a predictor of organ failure and 30-day mortality

BackgroundProenkephalin A 119-159 (penKid) has been suggested as a marker of renal failure and poor outcome. We aimed to investigate the association of penKid on ICU admission with organ dysfunction and mortality in a mixed ICU population. In this retrospective, observational study, admission penKid levels from prospectively collected blood samples of consecutive patients admitted to four Swedish ICUs were analysed. The association of penKid with day-two sequential organ failure assessment (SOFA) scores and 30-day mortality was investigated using (ordinal) logistic regression. The predictive power of penKid for 30-day mortality and dialysis was assessed using the area under the receiver operating characteristic curve (AUC).ResultsOf 1978 included patients, 632 fulfilled the sepsis 3-criteria, 190 had a cardiac arrest, and 157 had experienced trauma. Admission penKid was positively associated with 30-day mortality with an odds ratio of 1.95 (95% confidence interval 1.75–2.18, p < 0.001), and predicted 30-day mortality in the entire ICU population with an AUC of 0.71 (95% confidence interval 0.68–0.73) as well as in the sepsis, cardiac arrest and trauma subgroups (AUCs of 0.61–0.84). Correction for admission plasma creatinine revealed that penKid correlated with neurological dysfunction.ConclusionPlasma penKid on ICU admission is associated with day-two organ dysfunction and predictive of 30-day mortality in a mixed ICU-population, as well as in sepsis, cardiac arrest and trauma subgroups. In addition to being a marker of renal dysfunction, plasma penKid is associated with neurologic dysfunction in the entire ICU population, and cardiovascular dysfunction in sepsis.

Independent Validation of Sepsis Index for Sepsis Screening in the Emergency Department.

(1) Background: The early detection of sepsis is still challenging, and there is an urgent need for biomarkers that could identify patients at a high risk of developing it. We recently developed an index, namely the Sepsis Index (SI), based on the combination of two CBC parameters: monocyte distribution width (MDW) and mean monocyte volume (MMV). In this study, we sought to independently validate the performance of SI as a tool for the early detection of patients at a high risk of sepsis in the Emergency Department (ED). (2) Methods: We enrolled all consecutive patients attending the ED with a request of the CBC. MDW and MMV were measured on samples collected in K3-EDTA tubes on the UniCel DxH 900 haematology analyser. SI was calculated based on the MDW and MMV. (3) Results: We enrolled a total of 703 patients stratified into four subgroups according to the Sepsis-2 criteria: control (498), infection (105), SIRS (52) and sepsis (48). The sepsis subgroup displayed the highest MDW (median 27.5, IQR 24.6–32.9) and SI (median 1.15, IQR 1.05–1.29) values. The ROC curve analysis for the prediction of sepsis showed a good and comparable diagnostic accuracy of the MDW and SI. However, the SI displayed an increased specificity, positive predictive value and positive likelihood ratio in comparison to MDW alone. (4) Conclusions: SI improves the diagnostic accuracy of MDW for sepsis screening.

A gain-of-function NLRP3 3\u2032-UTR polymorphism causes miR-146a-mediated suppression of NLRP3 expression and confers protection against sepsis progression

Nucleotide-binding domain and leucine-rich repeat (LRR)-containing family protein 3 (NLRP3) regulated the maturation of inflammation-related cytokines by forming NLRP3 inflammasome, which plays pivotal roles in sepsis pathogenesis. In this study, we evaluated the genetic association of NLRP3 polymorphisms with sepsis (640 patients and 769 controls) and characterized the impact of NLRP3 polymorphisms on NLRP3 expression and inflammatory responses. No significant differences were observed in genotype/allelic frequencies of NLRP3 29940G>C between sepsis cases and controls. The G allele was significantly overrepresented in patients with septic shock than those in sepsis subgroup, and the GC/GG genetypes were related to the 28-day mortality of sepsis. Lipopolysaccharide challenge to peripheral blood mononuclear cells showed a significant suppression of NLRP3 mRNA expression and release of IL-1β and TNF-α in CC compared with the GC/GG genotype category. Functional experiments with luciferase reporter vectors containing the NLRP3 3′-UTR with the 29940 G-to-C variation in HUVECs and THP-1 cells showed a potential suppressive effect of miR-146a on NLRP3 transcription in the presence of the C allele. Taken together, these results demonstrated that the 29940 G-to-C mutation within the NLRP3 3′-UTR was a gain-of-function alteration that caused the suppression of NLRP3 expression and downstream inflammatory cytokine production via binding with miR-146a, which ultimately protected patients against susceptibility to sepsis progression and poor clinical outcome.

Association of blood culture with carbapenem use in pyogenic liver abscess: a two-center retrospective study

BackgroundHighly empiric use of carbapenem in pyogenic liver abscess (PLA) is widespread problem. However, few studies have examined the association between blood culture and carbapenem use in patients with PLA in China. Thus, we conducted this observational study.MethodsThe data of patients diagnosed with PLA at two comprehensive tertiary care centers from 2014 to 2020 were retrospectively collected. Demographic and clinical data were analyzed, and univariate and multivariate analyses were performed to investigate the association between blood culture and carbapenem use. Subgroup analysis was conducted to explore whether the effect is different in sepsis.ResultsBlood culture was performed in 110 (46.0%) patients, of whom 44 (40.0%) patients had positive results for bacterial culture. Extended-spectrum beta-lactamase (ESBL)-positive blood culture isolates were detected in 8 (7.3%) patients. The positivity rate of blood culture in sepsis was higher than in non-sepsis (58.1% vs. 32.9%, P = 0.015). Fewer patients who had a blood culture received carbapenem treatment in comparison to patients without blood culture (19.1% vs. 31.8%, P = 0.026). Multivariate analysis showed that blood culture was independently associated with less carbapenem exposure (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI]: 0.16–0.68, P = 0.003), and this effect remained significant in the sepsis subgroup (adjusted OR = 0.17, 95% CI: 0.05–0.53, P = 0.002).ConclusionBlood culture had a high positivity rate and was associated with less carbapenem use in PLA, especially those who developed sepsis. More attention should be paid to performing early blood culture and less carbapenem use in PLA.

Diagnostic Value of Neutrophil CD64 in Burn Patients With Infection in Chinese Population: A Systematic Review and Meta-analysis.

Infection is one of the leading causes of death in burn patients. Many researchers regard neutrophil CD64 (nCD64) as a biomarker in the early diagnosis of burn patients with infection. Nevertheless, the conclusions are controversial. A comprehensive analysis of the diagnostic value of nCD64 for burn infection was performed in China using a meta-analysis method. Pubmed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and China Wanfang databases were searched for studies on nCD64 as a diagnostic biomarker of burn patients with infection from the establishment of the databases to September 29, 2020. The data were analyzed by Stata 15.0 software. Six studies were identified. The results showed that the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.92 (95% confidence interval [CI]: 0.88~0.95), 0.82 (95% CI: 0.76~0.87), 5.10 (95% CI: 3.90~6.80), 0.10 (95% CI: 0.06~0.15), and 52 (95% CI: 29~94), respectively. The area under the curve was 0.94 (95% CI: 0.92~0.94). According to the analysis of the sepsis subgroup, it showed that nCD64 had good diagnostic value in the patients with burn sepsis in Chinese population. Neutrophil CD64 is highly efficient to diagnose burn infection in Chinese population. Therefore, nCD64 could be regarded as a valuable biomarker for the early diagnosis of burn infection in China, especially in patients with burn sepsis. Combined with other diagnostic indexes, nCD64 can be clinically used in the early diagnosis of burn infection to improve the sensitivity and specificity.

Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway.

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.