Prevention of legionella infections from toilet flushing cisterns.

INTRODUCTION: Immunocompromised patients are at an increased risk of severe legionella infections. We present the results of an outbreak investigation initiated following a fatal case of hospital-acquired legionellosis linked to contaminated water from a toilet-flushing cistern. Additionally, we provide experimental data on the growth of Legionella spp. in flushing cisterns and propose a straightforward protocol for prevention. METHODS: We monitored the growth of Legionella spp. in the building's hot- and cold-water systems using quantitative bacterial culture on selective agar. Molecular typing of Legionella pneumophila isolates from the infected patient and the water system was conducted through core-genome multi-locus sequence typing (cgMLST). RESULTS: Legionella contamination in the hospital building's cold-water system was significantly higher than in the hot-water system and significantly higher in toilet flushing cistern's water compared with cold water from bathroom sinks and showers. Isolates from the patient and from the flushing cistern of the patient's bathroom were identical by cgMLST. In an experimental setting, daily toilet flushing for a period of 21 days resulted in a 67% reduction in the growth of Legionella spp. in the water of toilet flushing cisterns. Moreover, a one-time disinfection of cisterns with peracetic acid, followed by daily flushing, decreased legionella growth to less than 1% over a period of at least seven weeks in these setting. CONCLUSIONS: One-time disinfection of highly contaminated cisterns with peracetic acid and daily toilet flushing as short-term measure can significantly reduce legionella contamination in flushing cisterns. These measures may aid in preventing legionella infection among immunocompromised patients.

Outcomes of influenza and COVID-19 inpatients in different phases of the SARS-CoV-2 pandemic: a single-centre retrospective case-control study.

BACKGROUND: The virulence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) changed during the pandemic. In order to provide a rationale for treatment priorities of respiratory infections and the adaption of in-house infection control strategies, this study evaluated treatment on an intensive care unit (ICU), requirement for mechanical ventilation (MV), requirement for extracorporeal membrane oxygenation (ECMO) and death for inpatients infected with the influenza virus or SARS-CoV-2 during the wild-type, Alpha, Delta, Omicron BA.1/2 and Omicron BA.5 waves of the pandemic. DESIGN: Single-centre retrospective case-control study. SETTING: Tertiary hospital in Germany. PARTICIPANTS: One thousand three hundred and sixteen adult inpatients infected with SARS-CoV-2 and 218 adult inpatients infected with influenza virus. METHODS: Demographic data, outcome parameters and underlying comorbidities of patients were obtained from the hospital information system. Multi-variate regression analysis was performed for the assessment of significant associations between risk factors and outcome variables. RESULTS: Compared with inpatients infected with influenza virus, patients infected with SARS-CoV-2 showed significantly higher rates for in-hospital mortality, admission to ICU and requirement for MV in the wild-type, Alpha and Delta waves, and a significantly higher rate for requirement for ECMO in the wild-type wave. In the Omicron BA.1/BA.2 and Omicron BA.5 waves, patients infected with SARS-CoV-2 did not show significantly higher risk of in-hospital mortality, admission to ICU, or requirement for MV or ECMO compared with patients infected with influenza virus. The length of hospital stay of patients infected with SARS-CoV-2 decreased from 10.8 to 6.2 days, which was less than that of patients infected with influenza virus (8.3 days). CONCLUSIONS: Treatment capacities should be shared equally between SARS-CoV-2 and influenza virus infections. Similar levels of infection control could be applied, at least regarding the severity of infection.

Gender and gut microbiota composition determine hepatic bile acid, metabolic and inflammatory response to a single fast-food meal in healthy adults.

BACKGROUND & AIMS: Regular consumption of fast-food (FF) as a form of typical Western style diet is associated with obesity and the metabolic syndrome, including its hepatic manifestation nonalcoholic fatty liver disease. Currently, it remains unclear how intermittent excess FF consumption may influence liver metabolism. The study aimed to characterize the effects of a single FF binge on hepatic steatosis, inflammation, bile acid (BA), glucose and lipid metabolism. METHODS: Twenty-five healthy individuals received a FF meal and were asked to continue eating either for a two-hour period or until fully saturated. Serum levels of transaminases, fasting BA, lipid profile, glucose and cytokine levels as well as transient elastography and controlled attenuation parameter (CAP; to assess hepatic steatosis) were analyzed before (day 0) and the day after FF binge (day 1). Feces was collected prior and after the FF challenge for microbiota analysis. RESULTS: The FF meal induced a modest increase in CAP, which was accompanied by a robust increase of fasting serum BA levels. Surprisingly, levels of cholesterol and bilirubin were significantly lower after the FF meal. Differentiating individuals with a relevant delta BA (>1 µmol/l) increase vs. individuals without (delta BA ≤1 µmol/l), identified several gut microbiota, as well as gender to be associated with the BA increase and the observed alterations in liver function, metabolism and inflammation. CONCLUSION: A single binge FF meal leads to a robust increase in serum BA levels and alterations in parameters of liver injury and metabolism, indicating a novel metabolic aspect of the gut-liver axis.

Metaproteomics of fecal samples of Crohn's disease and Ulcerative Colitis.

Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic inflammatory bowel diseases (IBD) of the gastrointestinal tract. This study used non-invasive LC-MS/MS to find disease specific microbial and human proteins which might be used later for an easier diagnosis. Therefore, 17 healthy controls, 11 CD patients and 14 UC patients but also 13 Irritable Bowel Disease (IBS) patients, 8 Colon Adenoma (CA) patients, and 8 Gastric Carcinoma (GCA) patients were investigated. The proteins were extracted from the fecal samples with liquid phenol in a ball mill. Subsequently, the proteins were digested tryptically to peptides and analyzed by an Orbitrap LC-MS/MS. For protein identification and interpretation of taxonomic and functional results, the MetaProteomeAnalyzer software was used. Cluster analysis and non-parametric test (analysis of similarities) separated healthy controls from patients with CD and UC as well as from patients with GCA. Among others, CD and UC correlated with an increase of neutrophil extracellular traps and immune globulins G (IgG). In addition, a decrease of human IgA and the transcriptional regulatory protein RprY from Bacillus fragilis was found for CD and UC. A specific marker in feces for CD was an increased amount of the human enzyme sucrose-isomaltase. SIGNIFICANCE: Crohn's Disease and Ulcerative Colitis are chronic inflammatory diseases of the gastrointestinal tract, whose diagnosis required comprehensive medical examinations including colonoscopy. The impact of the microbial communities in the gut on the pathogenesis of these diseases is poorly understood. Therefore, this study investigated the impact of gut microbiome on these diseases by a metaproteome approach, revealing several disease specific marker proteins. Overall, this indicated that fecal metaproteomics has the potential to be useful as non-invasive tool for a better and easier diagnosis of both diseases.

Patients with ultrasound diagnosis of hepatic steatosis are at high metabolic risk.

Background and aims: Hepatic steatosis is the basis of non-alcoholic fatty liver disease (NALFD). Mere fat accumulation within hepatocytes is considered the mild form of NAFLD, but can progress in some patients to advanced steatohepatitis (NASH), which may lead to fibrosis, cirrhosis or hepatocellular carcinoma. However, even hepatic steatosis alone may be a risk factor for cardiovascular disease (CVD). Patients and methods: In the present real life study 106 patients from the outpatient clinic of the Department for Gastroenterology and Hepatology with either NAFLD (n = 60) or other typical diagnoses (n = 46) were included. Ultrasound examination identified 77 patients with hepatic steatosis. Liver enzymes, lipid profile, surrogate cell death markers, and adiponectin were determined. Transient elastography (Fibroscan®) and bioelectrical impedance analysis (BIA) were performed. Results: Mean patient age was 46 years (23 - 62) for non-NAFLD and 53 years (18 - 71) for the NAFLD group. ALT and AST did not differ significantly between the two groups. Adiponectin and HDL were significantly lower in NAFLD (p < 0.05) and BIA profiles showed higher fat and fat free mass. Non-NAFLD patients with steatosis also exhibited an adverse metabolic profile. Overall steatosis was associated with factors of metabolic syndrome (MS) and CVD. Prevalence of CVD and factors of MS hint to steatosis as an early event for these conditions. Conclusion: Patients with steatosis are at higher cardiovascular and metabolic risk without differences in transaminases levels compared to those without steatosis. Steatosis diagnosed by ultrasound needs to rise attention for further metabolic alterations including CVD.

Treatment of fulminant acute Hepatitis B with nucles(t)id analogues is safe and does not lead to secondary chronification of Hepatitis B.

Background: Acute hepatitis B virus (HBV) infection is still a major cause of acute liver failure (ALF), necessitating a high rate of emergency liver transplantation (LTx). Acute infection is followed by high viral replication rates leading to hepatocyte death and, ultimately, ALF. The objective of treating HBV-induced ALF thus is to eliminate, or significantly suppress, HBV replication and therefore reduce cell death and support regeneration. Objective: In this retrospective study, we want to evaluate the timing, the safety, and the long-term virological outcome of this approach. Methods/results: In this study, we included 32 patients (16 female and 16 males; median age 39.5 years) with ALF due to hepatitis B, who were transferred to the university hospital Essen, Germany between January 2009 and December 2013. Before treatment, transaminases were highly elevated, bilirubin was increased, and elevated international normalized ratio (INR) revealed impaired liver function. HBV-DNA and HBsAg were positive. All 32 patients received oral antiviral treatment (3 lamivudine, 21 entecavir, and 8 tenofovir) between 1 day and 4 months after diagnosis of acute hepatitis B. One patient died, 2 were transplanted, one died shortly after LTx the other patient survived after LTx. These 3 patients received treatment in a state of advanced liver failure, and 1 patient 4 months after initial diagnosis of hepatitis B. Twenty-nine patients survived without LTx. Five patients were discharged without further follow-up. All 24 remaining patients became HBV-DNA negative in median of 100 days. Twenty-two patients were followed further, and all patients lost their HBsAg in median of 108 days. Sixteen of the 22 patients experienced a seroconversion to anti-HBs in median of 137 days. Four patients who were followed for 1 more year after HBsAg did not develop anti-HBs. None of the patients developed chronic hepatitis B. Conclusion: Immediate treatment of HBV-induced ALF with nucleos(t)id-analogues (NUCs) appears save and prevents LTx and death, and there is no indication for increased chronicity.

[Hepatic steatosis : Differential diagnostics and current aspects]. / Hepatische Steatosen : Differenzialdiagnostik und aktuelle Aspekte.

The frequency of non-alcoholic fatty liver disease (NAFLD) has continously increased over the last few decades in parallel with the increasing prevalence of metabolic syndrome. With the increasing frequency of obesity and type 2 diabetes an increase in non-alcoholic steatohepatitis (NASH) is also to be expected. The NASH-associated liver cirrhosis and primary hepatocellular carcinoma (HCC) are indications for liver transplantation (LTX), which is gaining importance in Germany. In contrast, liver cirrhosis as a result of alcoholic steatohepatitis (ASH) is already the leading cause for LTX in Germany. A significant number of patients with ASH cirrhosis develop HCC. Less common causes of hepatic steatosis are secondary and include chemotherapy-associated steatohepatitis (CASH). In this article the causes, diagnostics and novel therapeutic approaches for the various forms of steatosis are discussed.

Corticosteroid receptor expression and in vivo glucocorticoid sensitivity in multiple sclerosis.

To estimate the efficiency of glucocorticoid signaling in multiple sclerosis in vivo, we measured mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and four genes regulated by GR and implicated in immune function, in whole blood. GR expression and MR expression were significantly lower in 52 patients than in 18 controls. In contrast, expression of GR regulated genes was increased (significantly for glucocorticoid induced leucine zipper, GILZ), especially in mildly impaired patients. Reduced GR expression appears to be compensated, either by hyperactive hypothalamo-pituitary-adrenal axis or by intracellular adaptations.

[Drug-induced liver injury as predominant cause of acute liver failure in a monocenter study]. / Medikamentös-toxische Schädigung als wichtigste Ätiologie des akuten Leberversagens.

BACKGROUND AND AIM: Clinical course and mortality of acute liver failure (ALF) are determined by its causes. Traditionally, fulminant hepatitis B infection (HBV) was thought to be the predominant etiology of ALF in Germany. However, recent studies, conducted in American and European cohorts pointed to drug-induced liver injury (DILI) as the major cause. Aim of this study was to identify currently predominant etiologies of ALF in a monocenter study at a leading transplant center in Germany. PATIENTS AND METHODS: The data of 161 patients admitted with ALF from 1/2002 to 12/2012 were analyzed retrospectively. All patients fulfilled the criteria of the "Acute Liver Failure Study Group Germany" (international normalized ratio (INR) ≥ 1.5, hepatic encephalopathy ≥ stage 1). RESULTS: DILI was the leading cause of ALF in this cohort. About 20 % of ALF patients with DILI died or received liver transplantats. Mortality rate was highest in ALF patients with unknown etiology and those without specific therapy available. CONCLUSIONS: In Europe ALF etiologies exhibit a North-South divide. In Germany the most common cause for ALF is idiosyncratic pharmacological intoxication followed by acute hepatitis B.

Non-alcoholic steatohepatitis occurs in celiac disease and is associated with cellular stress.

BACKGROUND AND AIMS: Liver and gut not only share alimentary but also immunological features. Major histocompatibility complex class I-related chains A and B (MIC A/B) function as indicators for cellular stress. These so called stress-induced ligands are suggested to play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) and are a prominent feature of celiac disease (CD). PATIENTS AND METHODS: In the present study, 24 patients with celiac disease and 20 patients with non-alcoholic steatohepatitis (NASH) were included. Liver enzymes, serum cell death markers (M30, M65), MIC B and expression of adiponectin were determined. RESULTS: Mean patient age was 42 years (18 - 69) for CD and 49 years (33 - 68) for the NASH group. ALT and AST values were lower in CD compared to NASH patients. While serum cell death markers were higher in NASH, the predominant type of cell death in CD was apoptosis. Also, expression of MIC B was significantly up-regulated in CD patients as compared to NASH patients. Adiponectin values were significantly lower in NASH compared to CD patients. CONCLUSION: Stress-induced ligands and apoptosis are induced in CD. Prospective studies need to determine the exact role of cellular stress and apoptosis in the gut-liver axis and the clinical implications to screen for NAFLD in CD patients.

Acute management of refractory variceal bleeding in liver cirrhosis by self-expanding metal stents.

BACKGROUND AND AIMS: Current treatment strategies of variceal bleeding (VB) include banding and sclerotherapy. However, up to 10% of bleeding events remain refractory to standard therapy with high mortality. With this study, we aimed to evaluate the implantation of self-expanding metal stents (SEMS) for the management of therapy-refractory variceal bleeding. PATIENTS AND METHODS: Eight cirrhotic patients who presented to our unit with a total of 9 refractory bleeding events were treated by SEMS placement. RESULTS: Stenting resulted in immediate hemostasis in all cases without recurrent bleeding with SEMS in situ. After stabilization, 1 patient was treated by transjugular intrahepatic portosystemic shunt (TIPS) and after the second bleeding episode by TIPS dilation. One patient underwent orthotopic liver transplantation (OLT). The remaining patients were treated with standard drug regimens to reduce portal pressure. The SEMS were removed after a median of 11 days. No acute hemorrhage was noted on stent retrieval. While no early rebleeding occurred in the patients after TIPS implant, TIPS dilation or OLT, 3 out of 5 patients on conservative treatment experienced recurrence of VB within 9 days after SEMS removal. CONCLUSIONS: SEMS placement sufficiently stops hemorrhage in refractory VB. Due to the high rebleeding rate after conservative treatment alone following SEMS removal, this procedure may be utilized as a mere bridging method. Additional interventional and/or surgical methods to effectively reduce portal pressure (i.e. TIPS, OLT) should be considered. Further studies to evaluate the optimum treatment algorithm of refractory esophageal VB are warranted.

Hepatocyte apoptotic bodies encasing nonstructural HCV proteins amplify hepatic stellate cell activation: implications for chronic hepatitis C.

Chronic hepatitis C infection leads to increased hepatocyte apoptosis. Because engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) is profibrogenic, we compared the effects of ABs derived from hepatitis C virus (HCV)-negative vs HCV-infected (Con1+) Huh7 hepatoblastoma cells on fibrogenic and activation-related mRNA expression by a human HSC line (LX2). Uptake of Huh7(Con1+) ABs by LX2 cells dose dependently upregulated profibrotic genes (COL1A1, TGFB1; TIMP1; TIMP2). When normalized to the apoptotic cytokeratin-18 M30 neoepitope, HCV(+) ABs exhibited a more pronounced effect than HCV(-) ABs. In contrast, neither noningested ABs nor nucleic acids obtained from Huh7, Huh7(Con1+) or HepG2 cells triggered those AB-dependent effects. Both the engulfment of Huh7(Con1+) ABs and their effects were partially blocked by masking of phosphatidylserine with annexin V and completely inhibited by the class-A scavenger receptor ligand, polyinosinic acid. Our findings demonstrate that AB uptake stimulates HSCs and indicate that HCV infection leads to amplified fibrogenic mRNA expression and enhanced HSC activation.

A Rare Case of Propofol-Induced Acute Liver Failure and Literature Review.

The incidence of drug-induced acute liver failure is increasing. A number of drugs can inhibit mitochondrial functions, alter ß-oxidation and cause accumulation of free fatty acids within the hepatocytes. This may result in hepatic steatosis, cell death and liver injury. In our case, propofol, an anesthetic drug commonly used in adults and children, is suspected to have induced disturbance of the mitochondrial respiratory chain, which in consequence led to insufficient energy supply and finally liver failure. We report the case of a 35-year-old Caucasian woman with acute liver failure after anesthesia for stripping of varicose veins. Liver histology, imaging and laboratory data indicate drug-induced acute liver failure, presumably due to propofol. Hepatocyte death and microvesicular fatty degeneration of 90% of the liver parenchyma were observed before treatment with steroids. Six months later, a second biopsy was performed, which revealed only minimal steatosis and minimal periportal hepatitis. We suggest that propofol led to impaired fatty acid oxidation possibly due to a genetic susceptibility. This caused free fatty acid accumulation within hepatocytes, which presented as hepatocellular fatty degeneration and cell death. Large scale hepatocyte death was followed by impaired liver function and, consecutively, progressed to acute liver failure.

Acute liver failure in a metropolitan area in Germany: a retrospective study (2002 - 2008).

OBJECTIVES: To determine current etiologies of acute liver failure (ALF) and clinical and laboratory parameters associated with the outcome upon ALF, so as to identify the frequency of present causes of ALF in Germany as well as potential new prognostic parameters. PATIENTS: 134 adult patients (63 % females / 37 % males) aged 41 +/- 16 years (median: 38 years) with established ALF criteria. DESIGN AND SETTING: A retrospective study (1 / 2002 - 4 / 2008) on ALF patients from the Ruhr Area, the largest urban region located in northwestern Germany. Clinical and laboratory data were collected for a period of four weeks after study admission. RESULTS: Etiologies of ALF were identified as drug toxicity (39.6 % of the cases); combined viral hepatitides (23.1 %); or miscellaneous (16.4 %). In 20.9 % of the cases, the etiology remained indeterminate. Overall patient survival at four weeks was 81.3 %. While 89 patients (66.4 %) recovered under best supportive therapy, 26 patients (19.4 %) had to undergo liver transplantation. Increased body mass indices were significantly (p < 0.003) associated with a poor outcome. Intriguingly, high levels of cholestatic enzymes significantly (p < 0.01) correlated with a positive outcome. CONCLUSIONS: In providing first data on current ALF etiologies Germany, this study reveals that drug toxicity - in particular due to acetaminophen - has replaced viral hepatitis as the most single frequent cause of ALF in a densely populated urban area; this correlates with similar findings in the USA, the UK and Scandinavia. Lower body mass indices and elevated cholestatic enzyme levels had statistically significant prognostic power.

Gallbladder endometriosis as a cause of occult bleeding.

A 17-year-old girl with colicky abdominal pain and chronic anemia presented to the gastrointestinal service of the University Hospital of Essen. In the routine workup, there were no pathological findings despite the anemia. Because of the fluctuation of symptoms with a climax at the time of menstruation, consecutive ultrasound studies were performed revealing a visible mass inside the gallbladder. This finding was confirmed by a magnetic resonance imaging (MRI) study performed at the same time. Because of the severe anemia by that time, a cholecystectomy was performed, and histology reconfirmed the diagnosis of isolated gallbladder endometriosis. The patient recovered well and has had no recurrence of the disease to date.

Lipid metabolism in the liver.

As a key metabolic organ, the liver is central to the imbalance of high-caloric diets, and particularly dietary fat consumption, in the industrialized countries and their association with the increasing prevalence of morbid obesity. By interacting with the intestinal tract and adipose tissue, the liver plays a key role in various aspects of lipid metabolism. Increasing activation of transcription factors, such as carbohydrate responsive element binding protein (ChREBP), sterol response element binding protein-1c (SREBP-1c), or forkhead box 01 (Fox01), may contribute to fatty acid synthesis. Their translocation occurs via fatty acid transporters such as fatty acid transport proteins (FATP), fatty acid translocase (FAT/CD36), caveolin-1 and fatty acid binding protein (FABP) . Eventually, the accumulation of fat in the form of lipid droplets within the hepatocytes results in hepatic steatosis which, indeed, is a hallmark of liver diseases such as non-alcoholic fatty liver disease, alcoholic fatty liver, acute fatty liver in pregnancy, and hepatitis C. In contrast, lipid accumulation within hepatocytes during liver regeneration is essential. It is thus now becoming clear that steatosis is not only a mere consequence of metabolic imbalance, but that it is also a result of discrete alterations in the beta-oxidation, transport mechanisms, and signaling pathways involved in the synthesis, systemic traffic modalities, and cellular effects of fatty acids. Such a novel insight offers potential options for improved treatment.

Crohn's disease-induced non-alcoholic fatty liver disease (NAFLD) sensitizes for severe acute hepatitis B infection and liver failure.

Non-alcoholic fatty liver disease (NAFLD) commonly is associated with chronic inflammatory bowel disease (CIBD) and usually is considered to be stable and benign. However, NAFLD -- and in particular its subset, non-alcoholic steatohepatitis (NASH) -- may lead to progressive liver disease. Moreover, NAFLD sensitizes the liver to injury and increases the risk of developing acute-on-chronic liver failure following a "third hit". We here present one patient with NASH, as probably induced by long-standing Crohn's disease in the absence of ethanol consumption or abuse. The patient acquired an acute HBV infection and died from complications. As based on the clinical and histological findings, Crohn's disease appears to be a risk factor for developing NAFLD and thus to contribute to the progression into NASH. In conclusion, we suggest that Crohn's disease-related NAFLD may increase the vulnerability of the liver, which indicates that patients with a known history of CIBD merit special attention.