Philipp A. Reuken

NOD2 gene variants are a risk factor for culture-positive spontaneous bacterial peritonitis and monomicrobial bacterascites in cirrhosis.

Background: Spontaneous bacterial peritonitis (SBP) is considered as result of bacterial translocation from the gastrointestinal lumen to the mesenteric lymph nodes and subsequent circulation. Variants of the NOD2 gene contribute to bacterial translocation and were associated with SBP in a recent study.

Emergence of spontaneous bacterial peritonitis due to enterococci – risk factors and outcome in a 12-year retrospective study

Third‐generation cephalosporins (TGC) constitute the empirical first‐line therapy for spontaneous bacterial peritonitis (SBP). Hospitalisation, invasive procedures and use of antibiotics may challenge this concept due to an increase in enterococci and other TGC‐resistant microorganisms.

Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short-term mortality

Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis.

ADAMTS13 activity is decreased in a septic porcine model. Significance for glomerular thrombus deposition.

During sepsis, the balance between abundantly secreted von Willebrand factor (VWF) and the activity of its size regulating protease ADAMTS13 is assumed to be involved in coagulation abnormalities. We aimed to establish a porcine model with haemorrhagic shock with consecutive sepsis and hypothesised that a decreased ADAMTS13-activity as well as an altered VWF multimer pattern is associated with renal failure. Animals (n=21) were subjected to haemorrhagic shock. After volume replacement, intraperitoneal Escherichia coli sepsis was induced. Blood samples were drawn at baseline, after haemorrhage and sepsis induction. Directly postmortem we examined renal tissue by JONES-silver, CD61, VWF and fibrin staining for characterisation of thrombi. Renal failure was analysed by scoring PAS-stained sections for acute tubular damage. Glomerular microthrombi were observed in six of 21 septic animals. Porcine ADAMTS13 activity declined significantly during sepsis, accompanied by a drop-off in platelet count. At 12 hours after sepsis induction, ADAMTS13 activity was significantly diminished compared to sham controls, and an elevated acute tubular damage score was associated with an increased proportion of high-molecular-weight VWF multimers. Compared to baseline the proportion of high-molecular-weight VWF multimers increased significantly in septic animals. Similar to human sepsis, diminished ADAMTS13 activity was observed in a septic porcine model associated with a shift to rather thrombogenic VWF multimers and deposition of microthrombi. Therefore, this porcine model seems to be appropriate for performing functional and therapeutic studies in sepsis-associated ADAMTS13 deficiency.

The prognostic significance of bacterial DNA in patients with decompensated cirrhosis and suspected infection.

Circulating and peritoneal fragments of microbial DNA (bactDNA) are evidence for bacterial translocation in decompensated cirrhosis and may serve as a rational approach for antibiotic therapy when infection is suspected.

Mortality after urinary tract infections in patients with advanced cirrhosis - Relevance of acute kidney injury and comorbidities.

Bacterial infections increase mortality four‐fold in patients with decompensated cirrhosis. However, specific mortality associated with urinary tract infections (UTI) in cirrhosis is not known.

Further evidence for the relevance of TLR2 gene variants in spontaneous bacterial peritonitis

Editor: ad with interest the recent study on the association n Toll-like receptor (TLR) 2 gene polymorphisms and neous bacterial peritonitis (SBP) by Hans Dieter Nischalke lleagues published in the Journal of Hepatology [1]. As a ane-bound pattern recognition receptor that is expressed riety of immune cells, TLR2 can either act as a homodimer heterodimers with TLR1 or TLR6 to recognize an ed spectrum of microbial lipopeptides from Gram-positive am-negative bacteria [2]. Nischalke et al. reported a higher SBP in patients with increasing numbers of tandem GT in intron 2 of the TLR2 gene, which correlated with the ygous TLR2 promoter variant 16934A>T (rs4696480). y, they also observed a trend toward increased risk of presence of the TLR2 Arg753Gln variant (rs5743708) that t reach statistical significance (p = 0.089). Despite its low frequency in Caucasian subjects (3%) [1], the TLR2 Gln polymorphism has recently been found to be involved riety of infectious diseases, including endocarditis [3], uriact infections and recurrent bacterial infections in children reexisting infections in critically ill patients admitted to ensive care unit [6], and infection recurrence in patients ram-positive bacterial infections after liver transplantation

Risk Factors for Multi-Drug Resistant Pathogens and Failure of Empiric First-Line Therapy in Acute Cholangitis.

Background Acute cholangitis (AC) requires the immediate initiation of antibiotic therapy in addition to treatment for biliary obstruction. Against a background of an increasing prevalence of multi-drug resistant (MDR) bacteria, the risk factors for the failure of empiric therapy must be defined. Methods Using a pathogen-based approach, 1764 isolates from positive bile duct cultures were retrospectively analyzed to characterize the respective pathogen spectra in two German tertiary centers. Using a patient-based approach, the clinical and laboratory data for 83 patients with AC were assessed to identify risk factors for AC with pathogens resistant to the applied empiric therapy. Results Bile cultures were predominantly polymicrobial, and empiric antibiotic therapies did not cover the full biliary pathogen spectrum in 78% of cases. MDR bacteria were isolated from the bile of 24/83 (29%) patients. The univariate risk factors for biliary MDR bacteria were male sex, nosocomial AC, prior antibiotic exposure and prior biliary stenting, of which biliary stenting was the only independent risk factor according to multivariate analysis (OR = 3.8; 95% CI 1.3–11.0, P = 0.013). Although there were no significant differences in survival or hospital stay in AC patients with and without detected biliary MDR pathogens, the former more often had a concomitant bloodstream infection (58% vs. 24%; P = 0.019), including those involving MDR pathogens or fungi (21% vs. 2%; P = 0.007). Conclusion Patients with biliary stents who develop AC should receive empiric therapy covering enterococci and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. These patients are at an increased risk for bloodstream infections by MDR pathogens or fungi.

Mid-regional pro-adrenomedullin (MR-proADM): An even better prognostic biomarker than C-reactive protein to predict short-term survival in patients with decompensated cirrhosis at risk of infection?

and inflammatory biomarkers to predict shortand long-term survival in community-acquired pneumonia: results from the German Competence Network, CAPNETZ. Am J Respir Crit Care Med 2010;182:1426–1434. [4] Hoeboer SH, Alberts E, van den Hul I, Tacx AN, Debets-Ossenkopp YJ, Groeneveld ABJ. Old and new biomarkers for predicting high and low risk microbial infection in critically ill patients with new onset fever: a case for procalcitonin. J Infection 2012;64:484–493. [5] Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 2005;51:1823–1829. [6] Eto T, Kato J, Kitamura K. Regulation of production and secretion of adrenomedullin in the cardiovascular system. Regul Pept 2003;112:61–69. [7] Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 2000;21:138–167. [8] Fabrega E, Casafont F, Crespo J, de la Pena J, San Miguel G, de las Heras G, et al. Plasma adrenomedullin levels in patients with hepatic cirrhosis. Am J Gastroenterol 1997;92:1901–1904. [9] Guevara M, Gines P, Jimenez W, Sort P, Fernandez-Esparrach G, Escorsell A, et al. Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems. Gastroenterology 1998;114:336–343. [10] Kojima H, Tsujimoto T, Uemura M, Takaya A, Okamoto S, Ueda S, et al. Significance of increased plasma adrenomedullin concentration in patients with cirrhosis. J Hepatol 1998;28:840–846. Philipp A. Reuken Division of Gastroenterology, Hepatology, and Infectious Diseases, Department of Internal Medicine II, Jena University Hospital, Jena, Germany The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena, Germany

Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C.

In sepsis, the severity-dependent decrease of von Willebrand factor (VWF)-inactivating protease, a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), results in platelet aggregation and consumption, leading to sepsis-associated thrombotic microangiopathy (TMA) and organ failure. Previous reports assessing its functional deficiency have pinpointed involvement of autoantibodies or mutations to propagate thrombotic thrombocytopenic purpura (TTP). However, mechanisms of acquired ADAMTS13 deficiency during host response remain unclear. To enhance understanding of ADAMTS13 deficiency in sepsis, we evaluated changes in expression of mRNA coding ADAMTS13 during septic conditions using primary cellular sources of the protease. We hypothesized that proinflammatory cytokines and constituents of serum from septic patients affect the transcriptional level of ADAMTS13 in vitro, and previously recommended therapeutic agents as adjunctive therapy for sepsis interact therewith. Cultured hepatic stellate cells (HSCs), endothelial cells (HMEC) and human precision-cut liver slices as an ex vivo model were stimulated with sepsis prototypic cytokines, bacterial endotoxin and pooled serum obtained from septic patients. Stimulation resulted in a significant decrease in ADAMTS13 mRNA between 10% and 80% of basal transcriptional rates. Costimulation of selenite or recombinant activated protein C (APC) with serum prevented ADAMTS13 decrease in HSCs and increased ADAMTS13 transcripts in HMEC. In archived clinical samples, the activity of ADAMTS13 in septic patients treated with APC (n = 5) increased with an accompanying decrease in VWF propeptide as surrogate for improved endothelial function. In conclusion, proinflammatory conditions of sepsis repress mRNA coding ADAMTS13 and the ameliorating effect by selenite and APC may support the concept for identification of beneficial mechanisms triggered by these drugs at a molecular level.