Endotoxin Activity Levels Research Articles

Hemoglobin and Endotoxin Levels Predict Sarcopenia Occurrence in Patients with Alcoholic Cirrhosis

Alcohol is a major risk factor of liver cirrhosis (LC). This study aimed to elucidate a surrogate marker of sarcopenia in patients with LC of different etiology. Out of 775 patients with LC, 451 were assessed for handgrip strength and skeletal muscle mass (by computed tomography). They were then divided into two groups: alcoholic cirrhosis (AC; n = 149) and nonalcoholic cirrhosis (NAC; n = 302). Endotoxin activity (EA) levels were measured with an EA assay. Group AC showed significantly higher platelet counts (p = 0.027) and lower blood urea nitrogen levels and fibrosis-4 index than group NAC (p = 0.0020 and p = 0.038, respectively). The risk factors of sarcopenia were age ≥ 65 years, female sex, CP-C LC, Hb levels < 12 g/dL, and EA level > 0.4 in all patients with LC; hemoglobin (Hb) levels < 12 g/dL and EA level > 0.4 in group AC; and age ≥ 65 years, CP-C LC, and Hb levels < 12 g/dL in group NAC. The prediction accuracy of Hb for sarcopenia in group AC, group NAC, and all patients was 83.6%, 75.9%, and 78.1% (sensitivity: 92.0%, 69.0%, and 80.2%; specificity: 66.4%, 71.0%, and 64.0%), respectively. Although not significant, the predictive performance was better when using the combination of Hb and EA measurements than when using Hb alone in group AC but was comparable in all patients. Hb levels can predict sarcopenia in patients with LC, but in those with AC, the combination of Hb and EA improves the prediction performance.

Evaluating clinical utility of subgingival and salivary endotoxin activity levels as periodontal biomarkers.

The use of periodontal biomarkers for identification and monitoring of unique patient populations could foster better stratification of at-risk groups, increase access to treatment for those most in need, facilitate preventive measures and improve personalised care plans. The aim of this study was to examine the diagnostic and prognostic utility of oral lipopolysaccharides as bacterially-derived periodontal biomarkers. Periodontal parameters were recorded, and saliva and subgingival plaque samples were collected at the beginning of the study from periodontally healthy volunteers and periodontitis patients, and three months after completion of conventional periodontal treatment in the periodontitis group. Endotoxin activity in the samples was measured using the recombinant factor C assay. Associations between clinical periodontal parameters and subgingival and salivary endotoxin activities were analysed using a multivariate regression model, while the ROC curve was applied to estimate the sensitivity, specificity and c-statistics for salivary and subgingival endotoxin activities as diagnostic biomarkers for periodontitis. Significant correlations were found between subgingival endotoxin activities, probing pocket depth and periodontal diagnosis, which were independent from patients' age, gender and smoking status. In addition, subgingival endotoxin levels had high specificity and sensitivity in detecting periodontal health and disease (0.91 and 0.85 respectively). Salivary endotoxin activity was positively associated with periodontal diagnosis, mean probing pocket depth, percentages of sites over 4 mm and full mouth bleeding score. However, it was inferior in discriminating patients with stable periodontium from those with periodontitis (sensitivity = 0.69, specificity = 0.61) compared to subgingival endotoxin activity. Subgingival endotoxin activity has good diagnostic and prognostic values as a site-specific periodontal biomarker and is not influenced by the patient's age, gender or smoking status. In contrast, salivary endotoxin activity, as a patient-level biomarker, is dependent on patient's age, has poorer diagnostic and prognostic capability, but shows good correlations with disease susceptibility and both its extent and severity.

Increased Endotoxin Activity in COVID-19 Patients Admitted to the Intensive Care Unit.

Endotoxin is a component of Gram-negative bacteria and can be measured in blood using the endotoxin activity assay (EAA). Endotoxin exposure initiates an inflammatory cascade that may contribute to organ dysfunction. Endotoxemia has been reported in previous viral pandemics and we investigated the extent of endotoxemia and its relationship to outcomes in critically ill patients with COVID-19. We conducted a Prospective Cohort Study of 96 critically-ill COVID-19 patients admitted to the George Washington University Hospital ICU from 25 Mar-6 Jun 2020. EAA and inflammatory markers (ferritin, d dimer, IL-6, CRP) were measured on ICU admission and at the discretion of the clinical team. Clinical outcomes (mortality, LOS, need for renal replacement therapy (RRT), intubation) were measured. Statistical analysis was conducted using descriptive statistics and effect estimates with 95% confidence intervals. Comparisons were made using chi-square tests for categorical variables, and T-tests for continuous variables. A majority of patients (68.8%) had high EAA [≥ 0.60], levels seen in septic shock. Only 3 patients had positive bacterial cultures. EAA levels did not correlate with mortality, higher levels were associated with greater organ failure (cardiovascular, renal) and longer ICU LOS. Among 14 patients receiving RRT for severe AKI, one had EAA < 0.6 (p = 0.043). EAA levels did not directly correlate with other inflammatory markers. High levels of endotoxin activity were found in a majority of critically-ill COVID-19 patients admitted to the ICU and were associated with greater risk for cardiovascular and renal failure. Further investigation is needed to determine if endotoxin reducing strategies are useful in treating severe COVID-19 infection.

Endotoxin Activity Reflects an Increase in Body Temperature in Cirrhotic Patients With Ascites Undergoing Cell-free and Concentrated Ascites Reinfusion Therapy.

Ascites commonly complicates cirrhosis and is refractory to the vasopressin-2 antagonist tolvaptan and fluid restriction in approximately 60% of patients. We aimed to identify risk factors associated with adverse events following cell-free and concentrated ascites reinfusion therapy (CART) in patients with cirrhosis and ascites. We evaluated the efficacy and tolerability to the CART system in 18 patients with decompensated liver cirrhosis and ascites. We determined serum endotoxin activity using endotoxin activity (EA) assays and serum and ascitic fluid concentrations of interleukin 6 (IL6) and tumor necrosis factor-α (TNFα) before and after the CART procedures. Body weight and waist circumference significantly decreased after CART (both p<0.001). Body temperature (BT) increased significantly at an average rate of 1.1°C during CART (p<0.001). The change in BT was correlated with EA and not interleukin IL6 or TNFα. The rise in BT was positively correlated with serum EA levels at baseline. The increase in BT was significantly higher in the group with high EA (≥0.37) than in the low EAA group (<0.37) (p=0.02). TNFα and serum IL6 levels in ascites were significantly increased during CART (both p<0.001). However, no significant differences in the EA, serum TNFα or IL6 levels were found in ascitic fluid before and after the CART procedures. Although this discovery warrants further study, EA assay can indicate an increase in BT during effective CART in patients with cirrhosis and ascites.

Impact of polymyxin B hemoperfusion therapy on high endotoxin activity level patients after successful infection source control: a prospective cohort study

We sought to evaluate the clinical implication of endotoxin levels in gram-negative bacilli (GNB)-induced abdominal septic shock patients with polymyxin B-hemoperfusion (PMX-HP) treatment. A prospective cohort of 60 patients who received surgical infectious source control for abdominal sepsis from January 2019 to December 2020 was included in the study. Endotoxin activity (EA) levels and Sequential Organ Failure Assessment (SOFA) scores were assessed immediately after surgery (baseline), 24, and 48 h post baseline. With receiver operating characteristic curves, the patients were stratified into two groups by the EA cut-off value (high-risk group vs low-risk group) and the clinical outcomes were compared. Logistic regression was performed to identify the clinical impact of PMX-HP on in-hospital death. Among the 31 high-risk patients (EA level ≥ 0.54), 16 patients (51.6%) received PMX-HP treatment and showed significant decreases in EA levels compared to patients who underwent conventional treatment only (− 0.34 vs − 0.12, p = 0.01). SOFA scores also showed significant improvement with PMX-HP treatment (12.8–8.9, p = 0.007). Fourteen in-hospital deaths occurred (45.2%), and PMX-HP treatment had a protective effect on in-hospital death (odds ratio (OR) 0.04, p = 0.03). In 29 low-risk patients (EA level < 0.54), seven patients (24.1%) received PMX-HP treatment and showed significant decreases in EA levels (0.46–0.16, p = 0.018). However, SOFA scores and in-hospital deaths were not improved by PMX-HP treatment. EA level significantly decreased after PMX-HP treatment and it may represent a therapeutic option to improve organ impairment and in-hospital death in septic shock patients with EA levels exceeding 0.54.

The association between sarcopenia and endotoxin in patients with alcoholic cirrhosis.

We aimed to prospectively identify the risk factors of sarcopenia in patients with cirrhosis.Patients (n = 193) included in a discovery cohort (January 2011 and December 2014) were categorized into alcoholic (A1; n = 55) and non-alcoholic cirrhosis (NA; n = 138) groups, and those (n = 235) in a validation cohort (January 2015 to December 2019) were categorized into alcoholic (n = 92), non-alcoholic steatohepatitis-related (n = 27), and hepatitis C virus-related cirrhosis groups (n = 116). Skeletal muscle mass index (SMI) was determined using computed tomography (SMI-CT) and bioelectrical impedance analysis (SMI-BIA). Endotoxin activity (EA) was measured with an EA assay.SMI-CT correlated with grip strength in all the groups but significantly correlated with SMI-BIA of the men in group A1 (R = 0.64, P < .0001) and both sexes in group NA (male: R = 0.44, P = .0001; female: R = 0.35, P = .003). SMI-CT inversely correlated with the EA levels of the men in group A1 (R = −0.67, P < .0001) and myostatin levels in group NA (R = −0.53, P < .0001). Lower extremity SMI had a strong negative correlation with the EA levels of the men in group A1 (R = −0.58, P < .001), whereas upper extremity SMI showed an inverse trend with EA levels (R = −0.28, P = .08). SMI-CT also inversely correlated with the EA levels in groups A2 (R = −0.52, P = .003) and N (R = −0.67, P < .0001) and myostatin levels in group C (R = −0.65, P < .0001). Moreover, SMI-CT correlated with nutritional factors, including cholinesterase (R = 0.50, P = .005), zinc (R = 0.45, P = .01), branched amino acid-to-tyrosine ratio (R = 0.39, P = .02), and triglyceride (R = 0.33, P = .03) in group N.Sarcopenia risk factors differ among cirrhosis etiologies. Alcohol-induced, intestine-mediated peripheral endotoxemia could participate in sarcopenia development in patients with alcoholic cirrhosis.

Endotoxemia in Critically Ill Patients with COVID-19

Introduction: Mechanism(s) mediating critical illness in coronavirus disease 2019 (COVID-19) remain unclear. Previous reports demonstrate the existence of endotoxemia in viral infections without superimposed gram-negative bacteremia, but the rate and severity of endotoxemia in critically ill patients with COVID-19 requires further exploration. Materials and Methods: This is a single-center cross-sectional study of 92 intensive care unit patients diagnosed with COVID-19 pneumonia. Endotoxin activity (EA) was measured in patients that met the following criteria: (1) age ≥18 years and (2) multi-organ dysfunction score >9 from March 24, 2020, to June 20, 2020. Results: A total of 32 patients met the inclusion/exclusion criteria for measurement of EA. The median age of the study cohort was 60 years with a majority male (21/32, 65%) with hypertension (50%). A significant proportion of the patients exhibited either elevated EA in the intermediate range (0.40–0.59 EA units) (10/32, 31%) or high range (≥0.60 EA units) (14/32, 44%) or were nonresponders (NRs, low neutrophil response) to EA (6/32, 19%), with the presence of gram-negative bacteremia only in 2/32 (6%) patients. Low EA was reported in 2/32 patients. NRs (5/6, 83%) and patients with high EA (7/14, 50%) exhibited higher acute kidney injury (AKI) as compared to patients with low/intermediate EA level (1/12, 8.3%). Discussion/Conclusion: Elevated EA was observed in a large majority of critically ill patients with COVID-19 and multi-organ dysfunction despite a low incidence of concurrent gram-negative bacteremia. While we observed that elevated EA and nonresponsiveness to EA were associated with AKI in critically ill patients with COVID-19, these findings require further validation in larger longitudinal cohorts.

Rifaximin Alleviates Endotoxemia with Decreased Serum Levels of Soluble CD163 and Mannose Receptor and Partial Modification of Gut Microbiota in Cirrhotic Patients.

Rifaximin is a poorly absorbable antibiotic against hepatic encephalopathy (HE). This observational study aimed to elucidate the effect of rifaximin on intestinal permeability and gut microbiota in patients with decompensated cirrhosis. Thirty patients with decompensated cirrhosis were assessed by ammonia level, neuropsychological testing, endotoxin activity (EA), and serum proinflammatory cytokines at baseline and after four weeks of rifaximin treatment (1200 mg/day). Intestinal permeability was indicated by serum soluble CD163 (sCD163), mannose receptor (sMR), and zonulin levels. To evaluate the gut microbiome, 16S ribosomal RNA gene sequencing was applied. Rifaximin ameliorated hyperammonemia and cognitive dysfunction, although it did not change the serum proinflammatory cytokine levels. It decreased EA levels as well as serum levels of sCD163 and sMR, but not zonulin, and both decreases in sCD163 and sMR showed positive correlations with EA decrease (ΔsCD163: Correlation coefficient (R) = 0.680, p = 0.023; ΔsMR: R = 0.613, p = 0.014, vs. ΔEA). Gut microbial analysis revealed that the richness and complexity of species were unchanged while the abundance of the Streptococcus genus was reduced after treatment with rifaximin. Collectively, rifaximin alleviated HE and endotoxemia with improved intestinal hyperpermeability in patients with decompensated cirrhosis, and this effect is partially involved in a gut microbial change.

Utility Of An Automatic Limulus Amebocyte Lysate Kinetic Turbidimetric Test For Endotoxin Screening Of Dialysate Samples.

BackgroundEndotoxin contamination of dialysate has serious adverse effects on patients undergoing hemodialysis. Therefore, endotoxin activity in dialysate is closely monitored. Limulus amebocyte lysate (LAL) has been used as a reagent to measure endotoxin activity. Here, we investigated the efficacy of an automatic LAL kinetic turbidimetric test (Toxinometer ET-mini) for screening endotoxin activity in dialysate.MethodsIn total, endotoxin activity was measured in 110 dialysate samples obtained from several sites within hemodialysis circuits between June 2012 and March 2018. The results were compared with those from a conventional chromogenic substrate LAL test conducted by a clinical examination laboratory.ResultsBoth the automatic LAL test and the chromogenic substrate LAL test had a minimum detection level of 0.001 endotoxin units (EU)/mL. Endotoxin activity levels measured via the automatic LAL test showed a strongly positive correlation (concordance correlation coefficient: 0.9933; 95% CI: 0.9902–0.9954) and good agreement (mean difference: 0.00±0.01 EU/mL) with those obtained using the chromogenic substrate LAL test.ConclusionThe results suggest that the automatic LAL test may be useful for endotoxin activity screening in hemodialysis facilities.

Association between endotoxemia and enterocyte injury and clinical course in patients with gram-positive septic shock: A posthoc analysis of a prospective observational study.

Endotoxemia often occurs in patients with gram-positive infections. The possible mechanism is thought to be bacterial translocation after enterocyte hypoperfusion injury. However, the association between endotoxemia and enterocyte injury among patients with gram-positive septic shock has never been assessed. The aim of this study was to evaluate the association between endotoxemia and enterocyte injury in gram-positive septic shock patients and to evaluate the association among endotoxemia, subsequent clinical course, and other related factors.This was a posthoc analysis of a prospective observational study that evaluated the capability of intestinal fatty acid-binding protein (I-FABP), an indicator of enterocyte injury, to predict mortality. Among 57 patients in septic shock, those whose causative microorganisms were gram positive were included. The correlation between endotoxin activity (EA), which indicates endotoxemia, and I-FABP levels upon admission to the intensive care unit (ICU), the clinical course, and other related factors were evaluated.A total of 21 patients were examined. One-third of the patients presented with high EA levels at the time of ICU admission. However, there was no significant correlation between EA and I-FABP levels (Spearman ρ = 0.002, P = .993). Additionally, high EA levels were not associated with abdominal complications after ICU admission or mortality. Similarly, high EA levels were not associated with severity scores, inotropic scores, or lactate levels upon ICU admission, which were previously reported to be factors related to high EA levels.In this posthoc analysis, no correlation was observed between endotoxemia and enterocyte injury among patients in gram-positive septic shock. Additionally, high EA levels were not associated with the clinical course and reported factors related to endotoxemia. Although our results need to be validated in a large prospective cohort study, hypoperfusion enterocyte injury might not be a cause of endotoxemia in these patients. Thus, if there is no correlation between EA and I-FABP levels, other mechanisms that induce high EA levels among patients with gram-positive septic shock should be elucidated.

Comparative Evaluation of Endotoxin Activity Level and Various Biomarkers for Infection and Outcome of ICU-Admitted Patients.

Here, we concurrently measured the endotoxin activity (EA) level and levels of multiple biomarkers in patient blood obtained within 24 h after being admitted into the intensive care unit (ICU) and analyzed whether there were links between these markers and their associations with patient conditions and outcomes. The EA levels highly correlated with disease severity and patient survival, and showed a significant positive association with levels of lactate, procalcitonin, presepsin, and interleukin-6. Notably, the EA level was the marker that most highly correlated with the results of blood culture, and the presepsin level was the marker most highly correlated with the survival outcome at 28 days. Thus, the optimal biomarker should be selected based on whether it will be used to discriminate the presence of an infection or to predict survival.

Subgingival lipid A profile and endotoxin activity in periodontal health and disease

Regulation of lipopolysaccharide (LPS) chemical composition, particularly its lipid A domain, is an important, naturally occurring mechanism that drives bacteria-host immune system interactions into either a symbiotic or pathogenic relationship. Members of the subgingival oral microbiota can critically modulate host immuno-inflammatory responses by synthesizing different LPS isoforms. The objectives of this study were to analyze subgingival lipid A profiles and endotoxin activities in periodontal health and disease and to evaluate the use of the recombinant factor C assay as a new, lipid A-based biosensor for personalized, point-of-care periodontal therapy. Subgingival plaque samples were collected from healthy individuals and chronic periodontitis patients before and after periodontal therapy. Chemical composition of subgingival lipid A moieties was determined by ESI-Mass Spectrometry. Endotoxin activity of subgingival LPS extracts was assessed using the recombinant factor C assay, and their inflammatory potential was examined in THP-1-derived macrophages by measuring TNF-α and IL-8 production. Characteristic lipid A molecular signatures, corresponding to over-acylated, bi-phosphorylated lipid A isoforms, were observed in diseased samples. Healthy and post-treatment samples were characterized by lower m/z peaks, related to under-acylated, hypo-phosphorylated lipid A structures. Endotoxin activity levels and inflammatory potentials of subgingival LPS extracts from periodontitis patients were significantly higher compared to healthy and post-treatment samples. This is the first study to consider structure-function-clinical implications of different lipid A isoforms present in the subgingival niche and sheds new light on molecular pathogenic mechanisms of subgingival biofilm communities. Subgingival endotoxin activity (determined by lipid A chemical composition) could be a reliable, bacterially derived biomarker and a risk assessment tool for personalized periodontal care.

Proton pump inhibitor therapy does not increase serum endotoxin activity in patients with cirrhosis

Proton pump inhibitors (PPIs) are frequently prescribed in patients with cirrhosis, but this therapy entails potential complications. We aimed to investigate the influence of PPI use on intestinal permeability in patients with cirrhosis. We recruited 228 patients with cirrhosis and divided them into four groups. Group (Gp)1 comprised patients receiving a PPI with concurrent neomycin (NEO) (PPI-NEO group, n = 14 [6.1%]), Gp2 and Gp3 comprised those receiving either PPI or NEO (PPI group, n = 91 [39.9%]; and NEO group, n = 11 [4.4%]), and Gp4 comprised those receiving neither of these medications (control group; n = 112 [49.1%]). We assessed the intestinal permeability by measuring endotoxin activity (EA) using a luminol chemiluminescence method. Endotoxin activity levels were significantly higher in patients with Child B cirrhosis than in those with Child A cirrhosis, but we found no significant differences in EA levels between patients with Child C cirrhosis and those with either Child A or B cirrhosis. We observed no significant differences in EA levels among groups 1-4. Patients without antibiotic exposure (n = 203), comprising 91 patients on PPI therapy (Gp2) and 112 no-PPI-therapy controls (Gp4), were subdivided according to Child-Pugh (CP) classification. We found no significant differences in EA levels between Gp2 and Gp4 in either CP class. Our results suggest that PPI usage does not have a significant impact on serum levels of gut-derived endotoxins, which are already elevated because of the increased intestinal permeability in patients with cirrhosis.

Occurrence and fate of endotoxin activity at drinking water purification plants and healthcare facilities in Japan

Occurrence of residual endotoxin activity (ET) in dialysis water and also tap water as its source is a matter of great concern to medical professionals conducting dialysis therapy at healthcare facilities (HCFs). The present study was performed to determine the occurrence and fate of the ET at selected Japanese drinking water purification plants and HCFs between 2014 and 2016. Chemical coagulation and sedimentation, rapid sand filtration, and membrane filtration were highly effective to decrease both ET dissolved in water (free-ET) and ET bound to cells/particles (bound-ET). Moderate decreases in bound-ET and limited decreases in free-ET were observed by chlorination and ozonation. Bacterial activated carbon filtration was a major cause of significant increases in endotoxin activity during the course of drinking water purification process. Levels of residual ET in water supplied to HCFs were strongly affected by their source waters and the configurations of water purification processes served. Microbial regrowth on the premises, from water tanks to faucets at HCFs could also contribute to ET increases in tap water.

Constipation-Predominant Irritable Bowel Syndrome Females Have Normal Colonic Barrier and Secretory Function.

The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function. A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g 13C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression. There were no differences in the in vivo measurements of barrier function between IBS-C patients and healthy controls: cumulative excretion of 13C mannitol (0-2 h mean (s.e.m.); IBS-C: 12.1 (0.9) mg vs. healthy: 13.2 (0.8) mg) and lactulose (8-24 h; IBS-C: 0.9 (0.5) mg vs. healthy: 0.5 (0.2) mg); duodenal impedance IBS-C: 729 (65) Ω vs. healthy: 706 (43) Ω; plasma mean endotoxin activity level IBS-C: 0.36 (0.03) vs. healthy: 0.35 (0.02); and in colonic mRNA expression of occludin, zonula occludens (ZO) 1-3, and claudins 1-12 and 14-19. The ex vivo findings were consistent, with no group differences: duodenal TMR (IBS-C: 28.2 (1.9) Ω cm2 vs. healthy: 29.8 (1.9) Ω cm2) and colonic TMR (IBS-C: 19.1 (1.1) Ω cm2 vs. healthy: 17.6 (1.7) Ω cm2); fluorescein isothiocyanate (FITC)-dextran (4 kDa) and E. coli Bio-Particle flux. Colonic basal Isc was similar, but duodenal basal Isc was lower in IBS-C (43.5 (4.5) μA cm-2) vs. healthy (56.9 (4.9) μA cm-2), P=0.05. Ach-evoked ΔIsc was similar. Females with IBS-C have normal colonic barrier and secretory function. Basal duodenal secretion is decreased in IBS-C.

Serum Endotoxin Activity Measured with Endotoxin Activity Assay Is Associated with Serum Interleukin-6 Levels in Patients on Chronic Hemodialysis

Background: This study aims to evaluate, in patients on chronic hemodialysis (PHD), the levels of endotoxin through a chemiluminescent bioassay based on the oxidative burst reaction of activated neutrophils to complement coated LPS-IgM immune complexes and define the variables possibly correlated. Methods: In 61 PHD, we measured serum endotoxin activity (EA) with the Endotoxin Activity Assay (EAA™) and we defined the possible association with demographic, clinical and laboratory variables. Results: Mean serum EA was 0.43 ± 0.26 UI. EA was low (<0.40) in 29 patients (47.5%), intermediate (0.40-0.60) in 14 (23%) and high (>0.60) in 18 (29.5%). A significant exponential relationship was detected between EA and serum interleukin-6 (IL-6) levels (r = 0.871). At the multiple regression analysis, intermediate-high EA was directly associated only with serum IL-6 levels. In a second model of multiple regression analysis without the variable serum IL-6 levels, intermediate-high EA was directly associated with constipation and serum troponin levels and inversely associated with serum albumin and the monthly number of sevelamer tablets. Conclusions: A high percentage of PHD has intermediate or high EA. Intermediate-high EA is significantly associated with serum IL-6 levels.

IgM-Enriched Immunoglobulin Attenuates Systemic Endotoxin Activity in Early Severe Sepsis: A Before-After Cohort Study.

IntroductionSepsis remains associated with a high mortality rate. Endotoxin has been shown to influence viscoelastic coagulation parameters, thus suggesting a link between endotoxin levels and the altered coagulation phenotype in septic patients. This study evaluated the effects of systemic polyspecific IgM-enriched immunoglobulin (IgM-IVIg) (Pentaglobin® [Biotest, Dreieich, Germany]) on endotoxin activity (EA), inflammatory markers, viscoelastic and conventional coagulation parameters.MethodsPatients with severe sepsis were identified by daily screening in a tertiary, academic, surgical ICU. After the inclusion of 15 patients, the application of IgM-IVIg (5 mg/kg/d over three days) was integrated into the unit’s standard operation procedure (SOP) to treat patients with severe sepsis, thereby generating “control” and “IgM-IVIg” groups. EA assays, thrombelastometry (ROTEM®) and impedance aggregometry (Multiplate®) were performed on whole blood. Furthermore, routine laboratory parameters were determined according to unit’s standards.ResultsData from 26 patients were included. On day 1, EA was significantly decreased in the IgM-IVIg group following 6 and 12 hours of treatment (0.51 ±0.06 vs. 0.26 ±0.07, p<0.05 and 0.51 ±0.06 vs. 0.25 ±0.04, p<0.05) and differed significantly compared with the control group following 6 hours of treatment (0.26 ±0.07 vs. 0.43 ±0.07, p<0.05). The platelet count was significantly higher in the IgM-IVIg group following four days of IgM-IVIg treatment (200/nl ±43 vs. 87/nl ±20, p<0.05). The fibrinogen concentration was significantly lower in the control group on day 2 (311 mg/dl ±37 vs. 475 mg/dl ±47 (p = 0.015)) and day 4 (307 mg/dl ±35 vs. 420 mg/dl ±16 (p = 0.017)). No differences in thrombelastometric or aggregometric measurements, or inflammatory markers (interleukin-6 (IL-6), leukocyte, lipopolysaccharide binding protein (LBP)) were observed.ConclusionTreatment with IgM-enriched immunoglobulin attenuates the EA levels in patients with severe sepsis and might have an effect on septic thrombocytopenia and fibrinogen depletion. Viscoelastic, aggregometric or inflammatory parameters were not influenced.Trial Registrationclinicaltrials.gov NCT02444871

Cardiorenal Syndrome Type 5 in Sepsis: Role of Endotoxin in Cell Death Pathways and Inflammation

Background/Aims: Cardiorenal Syndrome Type 5 (CRS Type 5) is characterized by concomitant cardiac and renal dysfunction in the setting of different systemic disorders, such as sepsis. In this study, we investigated the possible relationship between endotoxin levels, renal cell death and inflammation in septic patients with CRS Type 5. Methods: We enrolled 11 patients with CRS Type 5. CRS Type 5 was defined according to the current classification system. AKI was defined by Acute Kidney Injury Network (AKIN) criteria. Acute cardiac dysfunction was documented by echocardiography as acute left and/or right ventricular dysfunction leading to decreased ejection fraction. Endotoxin activity was measured by the Endotoxin Activity Assay (EAA). Plasma from CRS Type 5 patients was incubated with renal tubular cells (RTCs) and cell death levels were evaluated. Plasma cytokines levels were measured as well. Results: Accordingly to EAA levels, patients were divided into two groups: 45.4% of patients had low endotoxin activity level (negative EAA), while 54.5% of patients showed high endotoxin activity (positive EAA). RTCs incubated with plasma from EAA positive patients showed significantly higher apoptosis levels and higher caspase-3 activation compared to cells incubated with plasma from EAA negative patients, and a significant positive correlation was observed between EAA levels and RTC apoptosis levels. Furthermore, IL-6 and IFN-γ levels were significantly higher in CRS Type 5 patients with positive EAA. Conclusion: Our data suggest a possible relationship between endotoxin levels and renal cell death in septic patients with CRS Type 5. Furthermore, this study highlights the presence of renal apoptosis, the immune deregulation and the strong inflammation in CRS Type 5 patients, especially in those with high endotoxin activity.

TEMPORAL LINKS BETWEEN ENDOTOXIN ACTIVITY LEVELS AND INTERLEUKIN 6 CONCENTRATIONS IN ABDOMINAL SEPSIS.

In severe human peritonitis, the precise pathophysiological importance of endotoxin is controversial. Prognostic and therapeutic studies have yielded conflicting results. The current study wanted to investigate qualitative, quantitative, and temporal associations between blood endotoxin activity (EA) levels and acute inflammatory reactions. We conducted a prospective observational study in 30 patients with intra-abdominal infections who had undergone specific focus therapies (surgical/radiological/pharmaceutical interventions) and who required intensive care therapy. We performed sequential postinterventional measurements of blood EA levels and plasma interleukin 6 (IL-6) concentrations until recurrence or cure. There was no association between daily EA levels and IL-6 concentrations, or daily EA levels and changes in IL-6 concentrations on subsequent days. We found, however, a significant association between EA levels and IL-6 concentrations, when newly changing EA levels were referred to subsequent changes in IL-6 concentrations (P < 0.05). Increasing EA levels were followed by a 90% increase of subsequent IL-6 concentrations during the next 24 to 48 h, whereas decreasing/stable EA levels were associated with slightly decreasing IL-6 concentrations (P < 0.05). Our findings suggest an altered response of the innate immune system because postinterventional EA levels did not vary with concomitant or subsequent inflammatory reactions and because inflammatory responses to newly increasing EA levels were delayed and comparatively small. Still, our results support the concept that endotoxin is a trigger of inflammatory reactions in human peritonitis.

Prevalence and clinical significance of early endotoxin activity in septic shock patients

The endotoxin activity (EA) assay is a useful test to risk stratify critically ill patients and assess for Gram-negative (GN) infection. However, the prevalence and significance of early high levels of EA in patients with septic shock (SS) has yet to be elucidated.