Carla S. Coffin

A population-based study of pyogenic liver abscesses in the United States: incidence, mortality, and temporal trends.

OBJECTIVES:Few population-based studies have evaluated pyogenic liver abscess (PLA) in North America. We assessed the incidence of PLA and evaluated predictors of mortality.METHODS:We used the Nationwide Inpatient Sample to identify all patients with discharges for PLA (ICD-9 572.0) between 1994 and 2005. Multivariable logistic regression analysis was performed to determine whether mortality was associated with patient and hospital characteristics including comorbidities, interventions, and bacterial cultures. We determined the annual incidence for PLA in the US population and assessed for temporal changes using generalized linear regression models.RESULTS:We identified 17,787 PLA discharges for an overall incidence of PLA of 3.6 (95% confidence interval (CI): 3.5–3.7) per 100,000 population. From 1994 to 2005, the annual average percent increase in incidence was 4.1% (95% CI: 3.4–4.8; P<0.0001). In-hospital mortality was 5.6% (95% CI: 5.3–6.0). Mortality was associated with older age (65–84 vs. 18–34: odds ratio (OR)=2.28 (1.48–3.51)); Medicaid (OR=1.74 (1.36–2.23)) and Medicare (OR=1.48 (1.18–1.85) vs. private insurance; and comorbidities such as cirrhosis (OR=2.48 (1.85–3.31)), chronic renal failure (OR=1.99 (1.28–3.09)), and cancer (OR=2.32 (1.97–2.73)). Patients who underwent percutaneous liver aspiration (OR=0.45 (0.39–0.52)) had lower mortality, whereas surgical drainage (OR=0.87 (0.68–1.10)) and endoscopic retrograde cholangiopancreatography (OR=0.73 (0.52–1.03)) were not associated with mortality. The most commonly recorded bacterial infections were Streptococcus species (29.5%) and Escherichia coli (18.1%). Patients with bacteremia or septicemia (OR=3.88 (3.36–4.48)) had an increased risk of death.CONCLUSIONS:The incidence of PLA is increasing and is associated with significant mortality that is attributable to several modifiable risk factors.

Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease.

Background  Anti‐Tumour necrosis factor (TNF) therapy is now well established in the treatment of inflammatory bowel disease and the risk of opportunistic infection is recognized. However, specific considerations regarding screening, detection, prevention and treatment of chronic viral infections in the context of anti‐TNF therapy in inflammatory bowel disease are not widely adopted in practice.

The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection

BACKGROUND & AIMS GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B. METHODS In two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha. RESULTS Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point. CONCLUSIONS Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.

PERSISTENCE OF INFECTIOUS HEPADNAVIRUS IN THE OFFSPRING OF WOODCHUCK MOTHERS RECOVERED FROM VIRAL HEPATITIS

Mother-to-child transmission is an important route for hepatitis B virus (HBV) dissemination. It has been established that HBV traces persist for years after complete clinical recovery from hepatitis B. Similarly, resolution of hepatitis caused by HBV-related woodchuck hepatitis virus (WHV) is followed by occult lifelong carriage of pathogenic virus. In this study, we documented that WHV persisting after termination of acute hepatitis is transmittable to newborns as an asymptomatic long-term infection. All 11 offspring from 4 dams studied carried transcriptionally active WHV genomes for 3.5 years after birth without immunovirological markers of infection. WHV genomes and mRNA were detected both in the liver and lymphoid tissue in the majority of offspring; WHV covalently closed circular DNA was detected in some samples. In 4 offspring, however, the virus was restricted to the lymphatic system. In the circulation, WHV DNA-reactive particles were DNase resistant and of comparable size and density to complete virions. Importantly, the virus in offspring with or without hepatic WHV DNA expression was infectious to WHV-naive woodchucks. Finally, offspring challenged with WHV were not protected against reinfection. These findings show that mothers with occult hepadnaviral carriage transmit pathogenic virus to their offspring, inducing a persistent infection invariably within the lymphatic system but not always in the liver.

Low Doses of Hepadnavirus Induce Infection of the Lymphatic System That Does Not Engage the Liver

ABSTRACT Woodchuck hepatitis virus (WHV), which is closely related to human hepatitis B virus and is considered to be principally hepatotropic, invades the hosts lymphatic system and persists in lymphoid cells independently of whether the infection is symptomatic and serologically evident or concealed. In this study, we show, with the woodchuck model of hepatitis B, that hepadnavirus can establish an infection that engages the lymphatic system, but not the liver, and persists in the absence of virus serological markers, including antiviral antibodies. This primary occult infection is caused by wild-type virus invading the host at a quantity usually not greater than 103 virions. It is characterized by trace virus replication progressing in lymphatic organs and peripheral lymphoid cells that, with time, may also spread to the liver. The infection is transmissible to virus-naive hosts as an asymptomatic, indefinitely long, occult carriage of small amounts of biologically competent virus. In contrast to residual silent WHV persistence, which normally endures after the resolution of viral hepatitis and involves the liver, primary occult infection restricted to the lymphatic system does not protect against reinfection with a large, liver-pathogenic WHV dose; however, the occult infection is associated with a swift recovery from hepatitis caused by the superinfection. Our study documents that the lymphatic system is the primary target of WHV infection when small quantities of virions invade a susceptible host.

Hydrogen sulphide synthesis in the rat and mouse gastrointestinal tract

AIMS Hydrogen sulphide (H2S) exerts several anti-inflammatory effects, accelerates the healing of experimental gastric ulcers, and can stimulate intestinal secretion. Little is known about H2S synthesis in the gastrointestinal tract. The aim of this study was to characterize H2S synthesis throughout the gastrointestinal tract. METHODS H2S synthesis in various gastrointestinal tissues of rats and mice was determined. The effects and selectivity of inhibitors of two key enzymes for H2S synthesis, cystathionine-gamma-lyase and cystathionine-beta-synthase, were examined. Cystathionine-gamma-lyase and cystathionine-beta-synthase expression was evaluated by Western blotting and immunohistochemistry. Cystathionine-gamma-lyase and cystathionine-beta-synthase expression in biopsies of human colon was also examined. RESULTS H2S synthesis was variable throughout the gastrointestinal tract in parallel with variations in cystathionine-gamma-lyase and cystathionine-beta-synthase expression. The efficacy of cystathionine-beta-synthase and cystathionine-gamma-lyase inhibitors to reduce H2S synthesis in these tissues was also variable. Cystathionine-beta-synthase is the predominant source of H2S synthesis in the colon of rodents. Cystathionine-gamma-lyase and cystathionine-beta-synthase were also expressed in healthy human colon biopsies. CONCLUSIONS The capacity for H2S synthesis varies throughout the rodent gastrointestinal tract, as does the distribution and contribution of the two key enzymes. Investigation of additional enzymatic sources of H2S and the development of more selective inhibitors are suggested.

Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy

BACKGROUND Although most patients with autoimmune hepatitis (AIH) respond to treatment with prednisone and⁄or azathioprine, some patients are intolerant or refractory to standard therapy. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells and has demonstrated efficacy in other autoimmune conditions. AIMS To evaluate the safety and efficacy of rituximab in patients with refractory AIH in an open-label, single-centre pilot study. METHODS Six patients with definite, biopsy-proven AIH who failed prednisone and azathioprine treatment received two infusions of rituximab 1000 mg two weeks apart and were followed for 72 weeks. RESULTS Rituximab was well tolerated with no serious adverse events. By week 24, mean (± SD) aspartate aminotransferase (AST) levels had significantly improved (90.0±23.3 U⁄L versus 31.3±4.2 U⁄L; P=0.03) and mean immunoglobulin G levels had fallen (16.4±2.0 g⁄L versus 11.5±1.1 g⁄L; P=0.056). The prednisone dose was weaned in three of four subjects, with one subject flaring after steroid withdrawal. Inflammation grade improved in all four subjects who underwent repeat liver biopsy at week 48. Regulatory T cell levels examined by FoxP3 immunohistochemistry paralleled inflammatory activity and did not increase on follow-up biopsies. There was no significant change in serum chemokine or cytokine levels from baseline to week 24 (n=5), although interferon-gamma-induced protein 10 levels improved in three of five subjects. CONCLUSIONS Rituximab was safe, well tolerated and resulted in biochemical improvement in subjects with refractory AIH. These results support further investigation of rituximab as a treatment for AIH.

Management of hepatitis B in liver transplant recipients.

Summary.  Advances in hepatitis B virus (HBV) antiviral prophylaxis have dramatically improved graft and patient survival for patients undergoing liver transplantation for hepatitis B related end‐stage liver disease. In particular, the availability of hepatitis B immune globulin (HBIg) in combination with nucleos(t)ide analogues such as lamivudine and adefovir, have transformed outcomes. The availability of newer antivirals such as adefovir, tenofovir and entecavir either as monotherapy or in combination offer an increasing number of antiviral options. Despite these advances, significant challenges remain. Factors that affect the efficacy of anti‐viral therapy include detectable HBV viraemia at the time of transplant and emergence of HBV mutants (especially in patients with prior exposure to lamivudine). HBV prophylaxis protocols are expensive especially with use of high‐dose HBIg and newer nucleos(t)ide analogues. This review summarizes current HBV prophylaxis protocols and management of recurrent disease post‐transplantation. There is an increasing need for individualization of therapy based on prior drug exposures, level of HBV DNA at time of transplantation and type of prophylaxis used.

Pregnancy outcomes among liver transplant recipients in the United States: A nationwide case‐control analysis

Liver transplant recipients and their infants may have an increased risk of obstetric complications. Our objective was to describe pregnancy outcomes in women with a prior transplant from a population‐based perspective. We analyzed the 1993–2005 US Nationwide Inpatient Sample database to identify obstetric hospitalizations among transplant recipients (n = 206) and controls matched by age, hospital, and year (n = 4060). The effect of prior transplantation on maternal and fetal outcomes was evaluated with regression models with adjustments for patient and hospital factors, including admission to a transplant center. Between 1993 and 2005, 146 delivery admissions among liver transplant recipients were identified. Cesarean deliveries were more common among transplant recipients (38% versus 24%; P = 0.0001); however, this difference was not significant after multivariate adjustment [OR (odds ratio) = 0.87; 95% confidence interval (CI) = 0.60–1.27]. Maternal mortality was similar among cases and controls (0% versus 0.02%; P = 1.00), but transplant patients had higher rates of fetal mortality (6.3% versus 2.0%; P = 0.0006), antepartum admission (OR = 2.27; 95% CI = 1.59–3.25), and maternal (OR = 2.63; 95% CI = 1.82–3.80) and fetal complications (OR = 2.49; 95% CI = 1.68–3.70). Gestational hypertension (30% versus 9%; P < 0.0001) and postpartum hemorrhage (8% versus 3%; P = 0.009) were more common among transplant recipients; their infants had higher rates of prematurity (27% versus 11%; P < 0.0001), distress (10% versus 5%; P = 0.005), and growth restriction (5% versus 2%; P = 0.05) but not congenital anomalies. Hospitalization in a transplant center (∼50%) was associated with similar obstetric outcomes. In conclusion, although most pregnancy outcomes are favorable, liver transplant recipients and their infants have an increased risk of obstetric complications. Additional studies evaluating mechanisms aimed at reducing these complications are necessary. Liver Transpl 16:56–63, 2010.

Liver Stiffness by Transient Elastography Predicts Liver-Related Complications and Mortality in Patients with Chronic Liver Disease

Background Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. Methods In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic. Results Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0–23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10–19.9, 20–39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03–1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75–0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%). Conclusions Liver stiffness by TE accurately predicts the risk of death or hepatic complications in patients with chronic liver disease. TE may facilitate the estimation of prognosis and guide management of these patients.