Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.

BACKGROUND: Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. METHODS: We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794. FINDINGS: From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events. INTERPRETATION: In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. FUNDING: Italian Medicine Agency.

Assessment of neutrophil gelatinase-associated lipocalin and lactate dehydrogenase in peritoneal fluids for the screening of bacterial peritonitis.

BACKGROUND: Manual microscopy remains the gold standard for enumeration and classification of nucleated cells in peritoneal fluids, especially for diagnosing bacterial peritonitis. However, this approach carries several drawbacks, so that the use of simple and automated tests may be a viable option for initial screening of peritoneal fluids. MATERIALS AND METHODS: Neutrophil gelatinase-associated lipocalin (NGAL), lactate dehydrogenase (LDH), proteins and glucose were assessed in peritoneal fluids from patients with new onset nonmalignant ascites, along with nucleated cell count and differentiation. RESULTS: One hundred and eleven specimens were analyzed, 26 of which (23%) with polymorphonuclear leukocyte (PMN) count≥250/µL, thus compatible with bacterial peritonitis. The median concentration of LDH and NGAL was 3.4 and 3.7-fold higher in samples with ≥250 PMN/µL. The concentration of proteins was also higher in samples with ≥250 PMN/µL, whereas that of glucose was lower. The PMN count significantly correlated with peritoneal fluid values of LDH (r=0.859), NGAL (r=0.774) and proteins (r=0.268), but not with glucose (r=-0.069). The area under ROC curve was 0.88 for LDH, 0.89 for NGAL and 0.94 for their combination (both tests positive), whereas that of proteins and glucose was 0.80 and 0.71, respectively. Sensitivities and specificities were 0.81 and 0.87 for LDH≥227 U/L, 0.96 and 0.75 for NGAL≥120 ng/mL, 0.77 and 0.95 for their combination. The agreement with PMN count was 0.86 for LDH, 0.80 for NGAL, and 0.91 for their combination. CONCLUSIONS: These results suggest that assessment of NGAL in peritoneal fluids, especially in combination with LDH, may be a reliable approach for screening of bacterial peritonitis in patients with new onset nonmalignant ascites.

Virus-specific CD8+ lymphocytes share the same effector-memory phenotype but exhibit functional differences in acute hepatitis B and C.

Hepatitis B and hepatitis C viruses (HBV and HCV) are both noncytopathic and can cause acute and chronic infections of the liver. Although they share tropism for the same organ, development of chronic hepatitis is much more frequent following HCV infection, suggesting different mechanisms of viral persistence. In this study, we show that circulating HBV- and HCV-specific tetramer-positive CD8 cells during the acute phase of hepatitis B and C belong almost entirely to an effector-memory subset (CCR7(-) CD45RA(-)). Despite this phenotypic similarity, HBV- and HCV-specific CD8 cells show striking functional differences. HBV-specific tetramer-positive CD8 cells express high perforin content ex vivo, expand vigorously, and display efficient cytotoxic activity and gamma interferon (IFN-gamma) production upon peptide stimulation. A comparable degree of functional efficiency is maintained after the resolution of hepatitis B. In contrast, HCV-specific CD8 cells in the acute phase of hepatitis C express significantly lower levels of perforin molecules ex vivo and show depressed CD8 function in terms of proliferation, lytic activity, and IFN-gamma production, irrespective of the final outcome of the disease. This defect is transient, because HCV-specific CD8 cells can progressively improve their function in patients with self-limited hepatitis C, while the CD8 function remains persistently depressed in subjects with a chronic evolution.

Intrahepatic and circulating HLA class II-restricted, hepatitis C virus-specific T cells: functional characterization in patients with chronic hepatitis C.

To compare the functional features of circulating and intrahepatic hepatitis C virus (HCV)-specific CD4+ T cells in chronic HCV infection, peripheral blood and liver-infiltrating lymphocytes from 29 patients with chronic hepatitis C were stimulated with structural and nonstructural HCV proteins to produce antigen-specific T-cell lines and clones. Antigen specificity, fine specificity, phenotype, cytokine production, and T-cell receptor (TCR)-vbeta chain expression were analyzed. The results indicate a hierarchy of stimulatory capacity by the different HCV proteins, core being the antigen most frequently recognized by CD4+ intrahepatic lymphocytes, followed by NS4 and NS5. The CD4 response was directed simultaneously against different HCV proteins in individual patients, but fine-specificity analysis indicated that the response was generally focused on a limited number of immunodominant epitopes. Although the narrowly focused nature of this response may favor the emergence of escape mutations, this event was not observed by following-up over time the sequence of 2 epitopes strongly immunodominant for intrahepatic CD4 cells of a patient with chronic HCV infection. In conclusion, simultaneous analysis of peripheral blood and intrahepatic CD4 cells in the same patients indicated a predominant Th1 profile of HCV-specific CD4 cells and suggests a specific compartmentalization of virus-specific T cells into the liver.