Five-year follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D.

BACKGROUND & AIMS: Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown. METHODS: In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 µg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 µg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy). RESULTS: Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p = .179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p = .04) and hepatic decompensation (p = .009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p > .999) but was associated with a higher chance of HDV-RNA suppression (p = .024, odds ratio 3.9 [1.3-12]). CONCLUSIONS: Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment. CLINICAL TRIAL REGISTRATION: NCT00932971.

Quality-of-life scores improve after 96 weeks of PEG-IFNa-2a treatment of hepatitis D: An analysis of the HIDIT-II trial.

BACKGROUND & AIMS: Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient-reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta. METHODS: Here, we investigated quality of life (QOL) as assessed by the Short Form 36 Health Survey (SF-36) in patients undergoing antiviral therapy with pegylated interferon alfa (PEG-IFNa-2a)-based treatment in the HIDIT-II trial. HIDIT-II was a randomized prospective trial exploring PEG-IFNa-2a with tenofovir disoproxil (TDF) or placebo for 96 weeks in patients with compensated hepatitis delta. Surveys completed by 83 study participants before, during, and after treatments were available. RESULTS: Overall, we observed a reduced QOL of HDV patients compared with a reference population, both in physical as well as mental scores. Interestingly, PEG-IFNa-2a treatment showed only minor impairment of the QOL during therapy. Moreover, HDV-RNA clearance was not associated with relevant changes in physical or social SF-36 scores, whereas an improvement of fibrosis during treatment was associated with increased QOL. Overall, slight improvements of the QOL scores were observed 24 weeks after the end of treatment as compared with baseline. TDF co-treatment had no influence on QOL. CONCLUSIONS: Overall, our findings suggest that PEG-IFNa-2a was reasonably tolerated even over a period of 96 weeks by hepatitis D patients reporting SF-36 questionnaires. Of note, several patients may benefit from PEG-IFNa-2a-based therapies with off-treatment improvements in quality of life.

Eradication of Chronic HCV Infection: Improvement of Dysbiosis Only in Patients Without Liver Cirrhosis.

BACKGROUND AND AIMS: It is well accepted that liver diseases and their outcomes are associated with intestinal microbiota, but causality is difficult to establish. The intestinal microbiota are altered in patients with hepatitis C. As chronic HCV infection can now be cured in almost all patients, it is an ideal model to study the influence of liver disease on the microbiota. APPROACH AND RESULTS: We aimed to prospectively analyze the changes in the gut microbiome in patients who received direct-acting antivirals (DAA) and achieved sustained virological response (SVR). Amplicon sequencing of the V1-V2 region in the 16S ribosomal RNA gene was performed in stool samples of patients with chronic hepatitis C. Patients in the treatment group received DAA (n = 65), whereas in the control group, no DAA were given (n = 33). Only patients achieving SVR were included. The alpha diversity increased numerically but not significantly from baseline to SVR at week 24 or 48 (SVR24/48; 2.784 ± 0.248 vs. 2.846 ± 0.224; P = 0.057). When stratifying for the presence of liver cirrhosis, a significant increase in diversity was only seen in patients without cirrhosis. Differences in the microbial community structure induced by the achievement of SVR were only observed in patients without liver cirrhosis. In patients with liver cirrhosis and in the control group, no significant differences were observed. CONCLUSIONS: In conclusion, the achievement of SVR24/48 in patients with chronic HCV was associated with changes in the intestinal microbiota. However, these changes were only seen in patients without liver cirrhosis. A major role of liver remodeling on the intestinal microbiota is indicated by the dynamics of the intestinal microbial community structure depending on the stage of fibrosis in patients resolving chronic hepatitis C.

The biliary microbiome in ischaemic-type biliary lesions can be shaped by stenting but is resilient to antibiotic treatment.

This study aims to characterize the biliary microbiome as neglected factor in patients with ischaemic-type biliary lesions (ITBL) after liver transplantation. Therefore, the V1-V2 region of the 16S rRNA gene was sequenced in 175 bile samples. Samples from patients with anastomotic strictures (AS) served as controls. Multivariate analysis and in silico metagenomics were applied cross-sectionally and longitudinally. The microbial community differed significantly between ITBL and AS in terms of alpha and beta diversity. Both, antibiotic treatment and stenting were associated independently with differences in the microbial community structure. In contrast to AS, in ITBL stenting was associated with pronounced differences in the biliary microbiome, whereas no differences associated with antibiotic treatment could be observed in ITBL contrasting the pronounced differences found in AS. Bacterial pathways involved in the production of antibacterial metabolites were increased in ITBL with antibiotic treatment. After liver transplantation, the biliary tract harbours a complex microbial community with significant differences between ITBL and AS. Fundamental changes in the microbial community in ITBL can be achieved with biliary stenting. However, the effect of antibiotic treatment in ITBL was minimal. Therefore, antibiotics should be administered wisely in order to reduce emerging resistance of the biliary microbiome towards external antibiotics.

Out of sight for the endoscopist? Gastrointestinal bleeding after aortic repair.

BACKGROUND AND STUDY AIM: Secondary Aortoenteric Fistulas (sAEF) are difficult to diagnose and usually result in fatal gastrointestinal (GI) bleeding following aortic repair. Outcomes are largely dependent on a timely diagnosis, but AEFs remain challenging to identify endoscopically and are usually diagnosed on computed tomography (CT) scans. The aim of our study was optimize diagnosis of AEF by identifying patients developing GI bleeding after aortic repair, investigate their clinical course and identify factors specific to different bleeding sources. METHODS: A retrospective, single-center study capturing all patients developing upper or lower GI bleeding after aortic surgery between January 2009 and March 2020 was performed. Electronic health records were screened for diagnostic codes of the relevant procedures. Bleeding was classified into three groups: AEF with demonstrable fistula, ischemic - macroscopic ulceration plus histological confirmation or imaging and "other" due to other recognized conventional cause, such as peptic ulcer disease. RESULTS: 47 GI bleeding episodes in 39 patients were identified. Of these, 10 episodes (21%) were caused by AEF, 16 (34%) by ischemic ulceration and 21 (45%) due to other causes. Patients with AEF exhibited more frequent hemodynamic instability requiring vasopressors and had higher mortality, while ischemic ulcerations were associated with more recent operation or hypotensive episode. CONCLUSIONS: GI bleeding complications are uncommon following aortic surgery. AEF and ischemic ulceration are however frequent bleeding causes in this cohort. In patients presenting with fulminant bleeding, primary CT-scanning should be considered.

Endoscopic vacuum assisted closure (E-VAC) of upper gastrointestinal leakages.

OBJECTIVES: Endoscopic vacuum-assisted closure (E-VAC) of leaks of the upper gastrointestinal tract is an increasingly applied endoscopic technique. Data on indication, clinical success, complications and prognostic factors are still sparse. METHODS: Patients treated with E-VAC between 2012 and 2019 at a tertiary referral center have been retrospectively analyzed. RESULTS: Overall, 116 patients treated with E-VAC were identified. Indication for E-VAC placement was postoperative leakage in 94/116 (81%), iatrogenic perforations 7/116 (6%) and others 15/116 (13%). In 92/116 (79%) of the patients E-VAC therapy showed successful wound closure. The first E-VAC after detection of insufficiency was significantly more often placed intracavitary in patients with E-VAC failure (p = .031). There was a trend for longer intensive care unit treatment for patients with E-VAC failure (p = .069). Complications occurred significantly more often in patients with E-VAC failure (p = .009). Platelet count was significantly higher in patients with E-VAC success at day of insufficiency detection (257/Thsd/µL (interquartile range [IQR], 185-362) vs. 195 (IQR, 117-309); p = .039). Platelet count (375 Thsd/µL (IQR, 256-484) vs. 190 (IQR, 129-292)), hemoglobin (9.5 g/dL (IQR, 8.8-10.1) vs. 8.7 g/dL (IQR, 8.15-9.35)) and C-reactive protein level (79 mg/L (IQR, 39.7-121.9) vs. 152 mg/L (IQR, 73.7-231)) at day 14 differed significantly. The 30 days mortality rate was 33.3% (8/24) in E-VAC failure compared with 2.2% in patients with E-VAC success (p = .001). CONCLUSIONS: E-VAC is an emerging highly effective interventional endoscopic technique for gastrointestinal wound closure even in highly selected patients.

Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta.

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG-interferon alpha-2a (PEG-IFNα-2a) is the only effective treatment but its long-term clinical impact is unclear. The aim of this study was to investigate the long-term outcome after 48 weeks of pegylated interferon alpha-2a therapy. We performed a retrospective follow-up study of the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-I trial). Patients had received 48 weeks of treatment with either PEG-IFNα-2a plus adefovir dipivoxil (ADV) (Group I), PEG-IFNα-2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver-related complications were defined as liver-related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child-Pugh scores B or C or an increase in Model for End-stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG-IFNα-2a. Follow-up data (at least 1 visit beyond post-treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow-up was 8.9 (1.6 - 13.4) years. 19 patients were retreated with IFN-based therapy: 42% (n = 8) in PEG-IFNα-2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long-term follow-up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. The annual event-free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long-term follow-up of a large randomized clinical trial suggests that off-treatment HDV RNA response to PEG-IFNα-2a treatment leads to improved clinical long-term outcome.

The impact of proton pump inhibitors on the intestinal microbiota in chronic hepatitis C patients.

Objectives: Proton pump inhibitors (PPI), a class of drugs commonly used, are known to be associated with changes in the intestinal microbiota. Published studies were done in heterogeneous cohorts which could hamper conclusions drawn as effects of diseases were not taken into consideration. We aimed to elucidate differences in the intestinal microbiota being associated to the use of PPI in a cohort study of patients with chronic hepatitis C. Material and Methods: The 16S rDNA gene was analyzed in stool samples of patients with and without PPI use. Patients with concomitant medication influencing the microbiota were excluded. Results were compared with the clinical course of hepatitis C patients with decompensated liver cirrhosis. Results: No differences in alpha diversity could be observed, while the microbial community structure differed significantly, especially in patients with liver cirrhosis. The relative abundance of Streptococcus spp., Enterobacter spp. and Haemophilus spp. was significantly increased in patients with PPI use irrespectively of the stage of liver disease. Finally, in patients with decompensated liver cirrhosis due to chronic HCV infection only in these using PPI bacterial phylotypes were isolated. Conclusions: PPI use was associated with significant alterations in the microbial community in patients with chronic hepatitis C, which were even pronounced in patients with liver cirrhosis. In patients with decompensated liver cirrhosis due to chronic HCV infection, the use of PPI may promote infections either directly or indirectly through changes in the microbial community structure. Future studies should further investigate long-term impact on the microbiota and the clinical outcome.

Antiviral treatment and liver-related complications in hepatitis delta.

Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG-IFNα) is effective in only 25%-30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long-term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti-HDV-positive patients who were followed for at least 6 months in a retrospective single-center cohort (mean time of follow-up, 5.2 years; range, 0.6-18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty-nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNα)-based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver-related death developed in 55 patients (40%). Patients who received IFNα-based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi-square and Kaplan-Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long-term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07-0.9). Loss of HDV RNA during follow-up was more frequent in IFNα-treated patients and strongly linked with a lower likelihood to experience liver-related complications. CONCLUSION: IFNα-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414-425).

Intestinal microbiota in patients with chronic hepatitis C with and without cirrhosis compared with healthy controls.

BACKGROUND & AIMS: The importance of the intestinal microbiota for the onset and clinical course of many diseases, including liver diseases like non-alcoholic steatohepatitis and cirrhosis, is increasingly recognized. However, the role of intestinal microbiota in chronic hepatitis C virus (HCV) infection remains unclear. METHODS: In a cross-sectional approach, the intestinal microbiota of 95 patients chronically infected with HCV (n=57 without cirrhosis [NO-CIR]; n=38 with cirrhosis [CIR]) and 50 healthy controls (HC) without documented liver diseases was analysed. RESULTS: Alpha diversity, measured by number of phylotypes (S) and Shannon diversity index (H'), decreased significantly from HC to NO-CIR to CIR. S and H' correlated negatively with liver elastography. Analysis of similarities revealed highly statistically significant differences in the microbial communities between HC, NO-CIR and CIR (R=.090; P<1.0×10-6 ). Stratifying for HCV genotypes even increased the differences. In addition, we observed distinct patterns in the relative abundance of genera being either positive or negative correlated with diseases status. CONCLUSIONS: This study shows that not only the stage of liver disease but also HCV infection is associated with a reduced alpha diversity and different microbial community patterns. These differences might be caused by direct interactions between HCV and the microbiota or indirect interactions facilitated by the immune system.

Clinical characteristics of patients with liver cirrhosis and spontaneous portosystemic shunts detected by ultrasound in a tertiary care and transplantation centre.

OBJECTIVES: The clinical relevance of spontaneous portosystemic shunts detected by ultrasound is insufficiently investigated. The aim of this retrospective study was to assess the frequency and clinical relevance of spontaneous portosystemic shunts in patients with liver cirrhosis. METHODS: We evaluated portosystemic shunts, liver cirrhosis and spleen size by ultrasound in 982 patients with liver cirrhosis and correlated these with laboratory results, clinical data and the incidence of clinical endpoint deaths, liver transplantation and the development of HCC during the follow-up period (mean 1.26 ± 1.53 years [range 0-7.2 years]). RESULTS: Portosystemic shunts were detected in 34% of the patients. These patients had a higher rate of alcohol-related cirrhosis (37% vs. 30%, p = .003), a higher MELD score (p < .001) and Child-Pugh grade (p < .001), as well as more frequent hepatic encephalopathy (p < .001) and oesophageal varices (p < .003). The most frequent portosystemic shunt in this cohort was an umbilical vein shunt (69%) followed by splenorenal (16%), mesenteric (7%) and combined/other shunts (8%). Patients with umbilical vein shunts had a higher rate of alcohol-related cirrhosis (p = .041) and suffered more frequently from Child B/C stages (p = .03), hepatorenal syndrome (p = .03), massive ascites (p = .001) and spontaneous bacterial peritonitis (p = .011). CONCLUSIONS: Patients with portosystemic shunts that are detected by ultrasound should be monitored carefully as these patients are associated with advanced liver disease and multiple clinical risk factors.

Non-invasive fibrosis score for hepatitis delta.

BACKGROUND & AIMS: Identifying advanced fibrosis in chronic hepatitis delta patients and thus in need of urgent treatment is crucial. To avoid liver biopsy, non-invasive fibrosis scores may be helpful but have not been evaluated for chronic hepatitis delta yet. METHODS: We evaluated eight non-invasive fibrosis scores in 100 HDV RNA-positive patients with available central histological reading. New cut-off values were calculated by using Receiver Operating Characteristics and Youden indexes. Predictors for the presence of ISHAK F3-6 were revealed by t-tests or Mann-Whitney tests. RESULTS: None of the tested scores had an area under the curve (AUROC) > 0.8 and performed according to our predefined requirements of a sensitivity of >80% and a positive predictive value (PPV) >90% - even after adaption. However, the ELF score was able to identify advanced fibrosis with a high sensitivity (93%) and PPV (81%), but relies on expensive extracellular matrix markers with bad availability in many endemic regions of HDV. Thus, we developed a novel non-invasive approach and identified low cholinesterase (P=.002), low albumin (P=.041), higher gamma glutamyl transferase, as well as older age (P<.001) as predictors of fibrosis resulting in the Delta Fibrosis Score (DFS). The DFS performed with a sensitivity of 85% and PPV of 93% with an AUROC of 0.87. CONCLUSIONS: Existing non-invasive fibrosis scores are either impracticable or do not perform well in chronic hepatitis delta patients. However, the new Delta Fibrosis Score is the first non-invasive fibrosis score specifically developed for chronic hepatitis delta and requires only standard parameters.

Association Between Level of Hepatitis D Virus RNA at Week 24 of Pegylated Interferon Therapy and Outcome.

BACKGROUND & AIMS: Interferon is the only effective treatment for chronic hepatitis D virus (HDV) infection. No rules have been set for stopping treatment based on viral kinetics. We analyzed data from an international study of hepatitis D treatment to identify factors associated with outcomes of pegylated interferon treatment, with and without adefovir. METHODS: We analyzed data from the Hep-Net-International Delta Hepatitis Intervention Trial on 50 patients with compensated liver disease who tested positive for anti-HDV and HDV RNA. Subjects received pegylated interferon α 2a, with adefovir or placebo, or only adefovir, for 48 weeks. Twenty-four weeks after treatment ended, 41 patients were evaluated for levels of HDV RNA and DNA, liver enzymes, and hepatitis B surface antigen (HBsAg); liver biopsy specimens were analyzed for fibrosis. Response to therapy was defined as end-of-treatment response or post-treatment week 24 virologic response. In both cases virologic response was associated with undetectable HDV RNA levels. Patients with less than a 1 log decrease in HDV RNA at the end of treatment were considered null responders. RESULTS: Based on univariate and multivariate analysis, the level of HDV RNA at week 24 of treatment was associated more strongly with response to therapy than other factors analyzed. The level of HBsAg at week 24 of treatment was associated with a response to therapy only in univariate analysis. Lack of HDV RNA at week 24 of treatment, or end of treatment, identified responders with positive predicted values of 71% and 100%, respectively. At 24 weeks after treatment, a decrease in HDV RNA level of less than 1 log, combined with no decrease in HBsAg level, identified null responders with a positive predictive value of 83%. A decrease in HDV RNA level of more than 2 log at week 24 of treatment identified null responders with a negative predictive value of 95%. CONCLUSIONS: Based on an analysis of data from a large clinical trial, the level of HDV RNA at week 24 of treatment with pegylated interferon, with or without adefovir for 48 weeks, can identify patients who will test negative for HDV RNA 24 weeks after the end of treatment. This information can be used to help physicians manage patients receiving therapy for chronic hepatitis D.

Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta.

UNLABELLED: Interferon alpha is the only treatment option for hepatitis delta virus (HDV). Trials investigating the efficacy of pegylated interferon alpha (PEG-IFNa) showed HDV RNA negativity rates of 25-30% 24 weeks after therapy. However, the clinical and virological long-term outcome of HDV-infected patients treated with PEG-IFNa is unknown. We performed a retrospective-prospective follow-up of 77 patients treated for 48 weeks with either PEG-alfa-2a and adefovir (ADV) or either drug alone in the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-1) trial. Long-term follow-up data were available for 58 out of 77 patients (75%) with a median time of follow-up of 4.5 (0.5-5.5) years and a median 3 visits per patient. Patients treated with ADV alone received retreatment with PEG-IFNa (48% versus 19%; P = 0.02) more often. Hepatitis B virus surface antigen (HBsAg) became negative in six PEG-IFNa-treated patients until the end of long-term follow-up (10%). Sixteen patients tested HDV RNA-negative 6 months after PEG-IFNa treatment who were entered in the long-term follow-up study. Out of these, nine individuals tested HDV RNA-positive at least once during further long-term follow-up, with seven patients being HDV RNA-positive at the most recent visit. Clinical endpoints (liver-related death, liver transplantation, hepatic decompensation, hepatocellular carcinoma) were observed in three PEG-IFNa-treated (8%) and three ADV-treated (14%) patients during posttreatment long-term follow-up with an overall annual event rate of 2.5% (4.9% in cirrhosis). Sequencing confirmed the reappearance of pretreatment virus strains in all cases. CONCLUSION: Late HDV RNA relapses may occur after PEG-IFNa therapy of hepatitis delta and thus the term sustained virological response should be avoided in HDV infection. The annual posttreatment rate of clinical events in hepatitis delta patients eligible for PEG-IFNa therapy is about 2.5% and 4.9% in patients with cirrhosis.

Next Generation Sequencing Outperforms Cultivation-Based Methods for Detection of Bacterial Genera in Bile After Liver Transplantation.

Background and aims: Bacterial cholangitis is a common complication in patients with ischemic type biliary lesions and/or anastomotic strictures after liver transplantation (LTX). Patients frequently need antibiotics and endoscopic retrograde cholangiography (ERC) to improve the bile flow. Antibiotic treatment is based on findings in standard microbiological cultivation (SMC) of bile. However, the cultivation techniques are limited to a subset of bacteria easy-to-cultivate. Therefore, the aim of our study was to evaluate the value of next generation sequencing as an additional diagnostic tool to SMC in ischemic type biliary lesions and/or anastomotic strictures. Methods: We sequenced the V1-V2 region of the 16S rRNA gene in 242 stored bile samples in patients after LTX and compared the results with findings of SMC. SMC was performed in n = 135 (56%) fresh bile samples in addition to NGS. SMC was part of the clinical routine in these patients. Results: NGS detected bacterial genera in bile samples more often than SMC (P = 5.42 × 10-74). SMC showed insufficient discovery of bacterial genera compared to NGS with better performance in patients receiving antibiotics prior to ERC. SMC missed many bacterial genera detected by NGS. Conclusions: NGS was more sensitive in detecting bacteria in bile than SMC, no clinical parameters could be used to improve discovery rates in SMC and many genera were missed by SMC. Therefore, NGS should be used in a combined approach with SMC for improved diagnostics to achieve more specific and targeted antibiotic treatments.

Prevention of peri-interventional hypothermia during endoscopic retrograde cholangiopancreatography using a forced-air heating system.

Background and study aims Perioperative hypothermia is associated with significant complications and can be prevented with forced-air heating systems (FAHS). Whether hypothermia occurs during prolonged endoscopic sedation is unclear and prevention measures are not addressed in endoscopic sedation guidelines. We hypothesized that hypothermia also occurs in a significant proportion of patients undergoing endoscopic interventions associated with longer sedation times such as endoscopic retrograde cholangiopancreaticography (ERCP), and that FAHS may prevent it. Patients and methods In this observational study, each patient received two consecutive ERCPs, the first ERCP following current standard of care without FAHS (SOC group) and a consecutive ERCP with FAHS (FAHS group). The primary endpoint was maximum body temperature difference during sedation. Results Twenty-four patients were included. Median (interquartile range) maximum body temperature difference was -0.9°C (-1.2; -0.4) in the SOC and -0.1°C (-0.2; 0) in the FAHS group ( P < 0.001). Median body temperature was lower in the SOC compared with the FAHS group after 20, 30, 40, and 50 minutes of sedation. A reduction in body temperature of > 1°C ( P < 0.001) and a reduction below 36°C ( P = 0.01) occurred more often in the SOC than in the FAHS group. FAHS was independently associated with reduced risk of hypothermia ( P = 0.006). More patients experienced freezing in the SOC group ( P = 0.004). Hemodynmaic and respiratory stability were comparable in both groups. Conclusions Hypothermia occurred in the majority of patients undergoing prolonged endoscopic sedation without active temperature control. FAHS was associated with higher temperature stability during sedation and better patient comfort.

Percutaneous transhepatic ultrasound-guided gallbladder aspiration: Still a safe option for gallbladder decompression in patients at high surgical risk.

AIMS: Cholecystitis generally warrants immediate cholecystectomy; however, high-risk patients require non-surgical options for gallbladder decompression. The continuous evolution of endoscopic techniques makes it difficult for clinicians tochoose the best technique for high-risk patients. Here we aimed to show that percutaneous transhepatic gallbladder aspiration, a technique that has fallen into disuse, is a safe and rapid method for gallbladder decompression. MATERIALS AND METHODS: In our local database, we identified 48 patients who had undergone transhepatic punctures of the biliary system,34 of whom were excluded because they had received bile duct punctures. The remaining 14 patients had received gallbladder punctures, of whom 9 were considered eligible for analysis. Cases were retrospectively analyzed for technical success, complications, and individual outcomes. RESULTS: Our analysis included 9 patients (3 female, 6 male; median age, 51 years; range, 32-84 years). Underlying malignancy was found in 5 patients, while 4 were in a palliative situation. Underlying infection was found in 8 cases. All punctures were technically successful without complications. In all patients, individual therapy goals were met,including clinical stabilization in palliative situations, stabilization before liver surgery, exclusion of gallbladder empyema and infection in gallbladder hydrops, and avoidance of gallbladder rupture. The white blood cell counts at the day of punction were significantly reduced one week after the puncture (p=0.023). CONCLUSIONS: When selecting an appropriate technique for high-risk patients, clinicians should remember that gallbladder aspiration is a feasible and successful bedside procedure in patients at high surgical risk, which does not require an experienced endoscopist.

Cultivation-based characterization of biliary microbiota in bile samples collected during routine endoscopic retrograde cholangiography: 10 years of experience at a tertiary center.

INTRODUCTION: Bile has long been considered sterile. Recent studies show that bacteria can frequently be detected in bile and certain bacterial species are associated with bile duct-associated liver disease. OBJECTIVES: To detect bacterial species and antibiotic resistance in bile in bile duct-associated liver disease. METHODOLOGY: To evaluate microbiological findings of bile samples obtained during ERCP at a tertiary center from 2009 to 2019. RESULTS: There were 1885 bile samples from 992 patients examined by cultural microbiological analysis. Germs were detected in 91% of the samples. Most bile samples (n) were obtained from patients who had undergone liver transplantation (LTX; n = 556), followed by patients with primary sclerosing cholangitis (PSC; n = 287). Enterococci were detected in 67% of samples, followed by E. coli (32.2%) and Klebsiella (28.2%). Of 1151 enterococci detected, 13.1% were vancomycin (VRE)s and of 216 staphylococci detected, 10% were ORSA. The proportion of VRE increased with the number of tests performed during ERCPs ( P  < 0.01; chi-square) and increased 2.5-fold over 10 years, whereas the detection of ORSA remained stable. Patients with cholecystolithiasis were significantly more likely to have evidence of VRE in bile compared to LTX and PSC patients ( P  = 0.02, P  < 0.01; chi-square). The most abundant bacterial genera showed highly statistically significant differences in their levels of liver enzymes and c-reactive protein ( P  < 0.001). CONCLUSION: Knowledge of the bacterial composition of bile in various bile duct-associated liver diseases may allow more targeted antibiotic use in the future.

Daily Low-Volume Paracentesis and Clinical Complications in Patients With Refractory Ascites.

Importance: The potential association of low-volume paracentesis of less than 5 L with complications in patients with ascites remains unclear, and individuals with cirrhosis and refractory ascites (RA) treated with devices like Alfapump or tunneled-intraperitoneal catheters perform daily low-volume drainage without albumin substitution. Studies indicate marked differences regarding the daily drainage volume between patients; however, it is currently unknown if this alters the clinical course. Objective: To determine whether the incidence of complications, such as hyponatremia or acute kidney injury (AKI), is associated with the daily drainage volume in patients with devices. Design, Setting, and Participants: This retrospective cohort study of patients with liver cirrhosis, RA, and a contraindication for a transjugular intrahepatic portosystemic shunt who received either device implantation or standard of care (SOC; ie, repeated large-volume paracentesis with albumin infusion), and were hospitalized between 2012 and 2020 were included. Data were analyzed from April to October 2022. Interventions: Daily ascites volume removed. Main outcomes and Measures: The primary end points were 90-day incidence of hyponatremia and AKI. Propensity score matching was performed to match and compare patients with devices and higher or lower drainage volumes to those who received SOC. Results: Overall, 250 patients with RA receiving either device implantation (179 [72%] patients; 125 [70%] male; 54 [30%] female; mean [SD] age, 59 [11] years) or SOC (71 [28%] patients; 41 [67%] male; 20 [33%] female; mean [SD] age, 54 [8]) were included in this study. A cutoff of 1.5 L/d or more was identified to estimate hyponatremia and AKI in the included patients with devices. Drainage of 1.5 L/d or more was associated with hyponatremia and AKI, even after adjusting for various confounders (hazard ratio [HR], 2.17 [95% CI, 1.24-3.78]; P = .006; HR, 1.43 [95% CI, 1.01-2.16]; P = .04, respectively). Moreover, patients with taps of 1.5 L/d or more and less than 1.5 L/d were matched with patients receiving SOC. Those with taps of 1.5 L/d or more had a higher risk of hyponatremia and AKI compared with those receiving SOC (HR, 1.67 [95% CI, 1.06-2.68]; P = .02 and HR, 1.51 [95% CI, 1.04-2.18]; P = .03), while patients with drainage of less than 1.5 L/d did not show an increased rate of complications compared with those receiving SOC. Conclusions and Relevance: In this cohort study, clinical complications in patients with RA performing low-volume drainage without albumin infusion were associated with the daily volume drained. Based on this analysis, physicians should be cautious in patients performing drainage of 1.5 L/d or more without albumin infusion.

Clinical long-term outcome of hepatitis D compared to hepatitis B monoinfection.

BACKGROUND AND AIMS: Hepatitis D virus (HDV) infection causes the most severe form of chronic viral hepatitis. However, it is still unclear to what extent the underlying cirrhosis may contribute to disease progression. The aim of this study was to compare the long-term outcome of HDV infection with HBV monoinfection in a single-center cohort of both non-cirrhotic and cirrhotic patients. METHOD: We retrospectively studied 175 patients with chronic hepatitis D (CHD) who were followed for at least 6 months (median of 6.3 (0.6-23.6) years). In addition, we selected 175 patients with HBV monoinfection (CHB) who were matched for gender, age, region of origin, HBeAg status, and bilirubin. Liver-related clinical end points were defined as hepatic decompensation (ascites, encephalopathy, variceal bleeding), liver transplantation, HCC, or liver-related death. RESULTS: Clinical complications developed earlier (4.6 vs. 6.2 years) and more frequently (35.4% vs. 12.6%, p < 0.01) in CHD patients. In a multivariate Cox regression, HDV infection was independently associated with the development of end points (p < 0.01; HR: 3.0; 95% CI 1.4-6.4). However, in cirrhotic patients there were no significant differences between HBV and HDV in the development of end points. Besides, CHB patients with cirrhosis developed more frequently HCC (35.5%) than CHD patients with cirrhosis (18.5%). CONCLUSION: Our results confirmed that HDV leads to a faster progression to cirrhosis compared to HBV. However, once cirrhosis is present, not HDV but the underlying cirrhosis is the dominate intrinsic risk factor for the development of liver-related end points and for the progression to HCC.