Fulminant Adenoviral-Induced Hepatitis in Immunosuppressed Patients.

Human adenovirus (HAdV) can often lead to fulminant hepatitis in immunocompromised patients, mostly after reactivation of HAdV. Different risk factors, e.g., transplantation and chemotherapy, increase the risk of developing a HAdV hepatitis. We retrospectively analyzed three patients who showed the characteristics of a HAdV hepatitis observed in disseminated disease. In addition to PCR, diagnosis could be proven by pathology, CT scan, and markedly elevated transaminases. All patients had a hemato-oncologic underlying disease. Two had received a stem-cell transplant, and one was under chemotherapy including rituximab. Despite therapy with cidofovir, all patients died. As the incidence of HAdV hepatitis is low, diagnosis may be easily overlooked. No treatment approaches have yet been established. HAdV hepatitis should be considered as a differential diagnosis, especially when risk factors are present. To avoid dissemination, treatment should be initiated as soon as possible.

An extra priming dose of hepatitis A vaccine to adult patients with rheumatoid arthritis and drug induced immunosuppression - A prospective, open-label, multi-center study.

BACKGROUND: Previous studies have indicated that a pre-travel single dose of hepatitis A vaccine is not sufficient as protection against hepatitis A in immunocompromised travelers. We evaluated if an extra dose of hepatitis A vaccine given shortly prior to traveling ensures seroconversion. METHOD: Patients with rheumatoid arthritis (n = 69, median age = 55 years) treated with Tumor Necrosis Factor inhibitor(TNFi) and/or Methotrexate (MTX) were immunized with two doses of hepatitis A vaccine, either as double dose or four weeks apart, followed by a booster dose at six months. Furthermore, 48 healthy individuals, median age = 60 years were immunized with two doses, six months apart. Anti-hepatitis A antibodies were measured at 0, 1, 2, 6, 7 and 12 months. RESULTS: Two months after the initial vaccination, 88% of the RA patients had protective antibodies, compared to 85% of the healthy individuals. There was no significant difference between the two vaccine schedules. At twelve months, 99% of RA patients and 100% of healthy individuals had seroprotective antibodies. CONCLUSION: An extra priming dos of hepatitis A vaccine prior to traveling offered an acceptable protection in individuals treated with TNFi and/or MTX. This constitutes an attractive pre-travel solution to this vulnerable group of patients.

Single-Dose Hepatitis A Immunization: 7.5-Year Observational Pilot Study in Nicaraguan Children to Assess Protective Effectiveness and Humoral Immune Memory Response.

BACKGROUND: Universal 2-dose hepatitis A virus (HAV) vaccination of toddlers effectively controls hepatitis A. High vaccine costs, however, impede implementation in endemic countries. To test single-dose vaccination as a possible alternative, we initiated an observational, longitudinal study in Nicaragua, to assess protective effectiveness and-through challenge vaccination-humoral immune memory response. METHODS: After a 2003 serosurvey, 130 originally seronegative children received one dose of virosomal HAV vaccine in 2005, followed by yearly serological and clinical assessments until 2012. After 7.5 years, a vaccine booster was administered. Concurrent antibody screening of patients presenting with hepatitis symptoms documented persistent HAV circulation in the communities studied. RESULTS: Between serosurvey and vaccination, 25 children contracted hepatitis A subclinically (>8000 mIU/mL anti-HAV). In the remaining 105 children, immunization resulted in anti-HAV levels of 17-572 mIU/mL. Based on the ≥15% annual infection risk, an estimated 60% of children were exposed to HAV encounters during follow-up. No child presented with hepatitis symptoms. Serological breakthrough infection (7106 mIU/mL) was documented in 1 child, representing an estimated protective effectiveness of 98.3% (95% confidence interval, 87.9-99.8). Boosting elicited an average 29.7-fold increase of anti-HAV levels. CONCLUSIONS: In children living in hyperendemic settings, a single dose of virosomal HAV vaccine is sufficient to activate immune memory and may provide long-term protection.

Decreasing risk of hepatitis A infection in León, Nicaragua: evidence from cross-sectional and longitudinal seroepidemiology studies.

BACKGROUND AND OBJECTIVES: Nicaragua is highly endemic for hepatitis A. We aimed to provide an estimate of the change in the age-specific risk of hepatitis A virus (HAV) infection based on serological data from cross-sectional and longitudinal samples collected in León, Nicaragua, in 1995/96 (n = 979) and 2003 (n = 494). METHODS: The observed age-specific prevalence of anti-HAV antibodies was correlated to the age-specific risk of infection by calculating the probability of freedom from infection at a specific age. RESULTS: The proportion of seropositive children aged 1.5 to 6 years was 42% in 2003 compared to 67% in 1995/96. Estimated annual risk of infection for a 3-year old child was 30% (95% CI: 27.0%, 33.1%) in 1995 and 15.5% (95% CI: 12.4%, 19.0%) in 2003. There was good agreement between estimates based on cross-sectional and longitudinal data. The age-specific geometric mean of the quantified anti-HAV antibody levels assessed in 2003 was highest at age 4 and decreased steadily up to age 40. CONCLUSIONS: The substantially lower risk of HAV infection in 2003 than in 1995 for young children indicates a beginning transition from high to intermediate endemicity in León, Nicaragua. Consecutive age-stratified serosurveys are useful to assess changes in risk of infection following public health interventions. The decreasing age-specific GMC of anti-HAV antibodies during adulthood in a country with endemic HAV indirectly suggests that ongoing HAV exposure in the community has marginal boosting effect on antibody levels once protective immunity has been established by natural infection.

Immunogenicity and tolerability of a paediatric presentation of a virosomal hepatitis A vaccine in Chilean children aged 1-16 years.

We assessed the immunogenicity of the paediatric dose of Epaxal(®) (0.25 mL) and the degrees of seroprotection achieved with the standard dose (0.5 mL) of Epaxal(®) or a dose of Havrix(®) Junior, in children in an open, randomised, controlled, multi-centre, parallel-group study conducted at 2 Chilean study centres. 360 healthy children and adolescents 12 months to <17 years of age not previously vaccinated against hepatitis A were enrolled. Subjects were randomised 2:2:1 to be vaccinated with either Epaxal(®) 0.25 mL [n=146], Epaxal(®) 0.5 mL [n=142] or Havrix(®) Junior [n=72] intramuscularly on Day 1 and after 6 months (26 weeks±14 days). Primary end point was the proportion of subjects seroprotected (anti-HAV antibody concentration ≥10 mIU/mL) in the ATP population at Month 1. All vaccines elicited high seroprotection rates at Month 1: 95.7% with Epaxal(®) 0.25 mL, 99.3% with Epaxal(®) 0.5 mL and 94.0% with Havrix(®) Junior. After the booster vaccination, all subjects demonstrated 100% seroprotection with all vaccines. Antibody concentrations were similarly high in all age groups. The paediatric presentation achieved antibody concentrations similar to those achieved with the 0.5 mL dose across the entire age range, and there were no differences across the range of body weights from 9.0 kg to 82.7 kg. All study vaccines were well tolerated and there were no AEs leading to discontinuation. Thus, the paediatric 0.25 mL dose of Epaxal(®) fulfilled the primary objective of showing non-inferiority to the adult 0.5 mL dose and to Havrix(®) Junior, in terms of seroprotection rates achieved. The results show the paediatric dose of Epaxal(®) to be an attractive option when conducting childhood-vaccination programmes.

Successful memory response following a booster dose with a virosome-formulated hepatitis a vaccine delayed up to 11 years.

Boosting adult travelers with the virosome-formulated, aluminum-free hepatitis A vaccine Epaxal up to 128 months after a single primary dose confers full protection against hepatitis A, even in travelers aged 50 years and above. Delaying the booster dose did not influence the immune memory response to Epaxal.

Predicted 30-year protection after vaccination with an aluminum-free virosomal hepatitis A vaccine.

Few studies have examined the duration of protection following vaccination against hepatitis A virus (HAV) with currently licensed HAV vaccines. This study explored the long-term immunogenicity in individuals vaccinated with the virosomal hepatitis A virus, Epaxal. Adult volunteers (N = 130) previously enrolled into four different studies between 1992 and 1994 and who had completed a 0/12-month immunization regimen (primary and booster dose) were asked to participate in this follow-up study. Yearly anti-HAV titers up to 6 years following booster vaccination, and then once 9-11 years after booster were measured using two assays, Enzygnost and AxSYM HAVAB 2.0. Based on the Enzygnost assay, the seroprotection rate 9-11 years after booster was 100%, with a geometric mean concentration (GMC) of anti-HAV antibodies of 526 mIU/ml. Females had markedly higher GMCs than males (741 mIU/ml vs. 332 mIU/ml). Using an anti-HAV cut-off titer of >or=10 mIU/ml, a linear mixed mathematical model predicted a median duration of protection of 52.1 years. A duration of protection >or= 35.7 years was predicted for 95% of subjects. A more stringent cut-off of >or=20 mIU/ml shortened the median predicted duration of protection to 45.0 years. In conclusion, a two-dose Epaxal vaccination regimen confers in healthy adults a real-time protection of at least 9-11 years; this protection is predicted to last at least 30 years in over 95% of individuals. Further studies are necessary to assess the real duration of seroprotection and whether an additional booster is necessary later.

Isolated norovirus GII.7 strain within an extended GII.4 outbreak.

Noroviruses are a major cause of viral gastroenteritis and have been detected with increasing prevalence in recent years. Currently, two main genogroups GI and GII with an increasing number of subtypes are differentiated. Because of a high genetic variability new variants emerge constantly allowing epidemiological tracing of viruses from year to year and location to location. A 282 bp sequence at the 5'end of the capsid gene was analyzed in isolates originating from the University hospital, Technische Universität München. Phylogenetic analysis was based on 20 GII positive samples from an outbreak in March/April 2006 and 8 samples from the following winter season 2006-2008. In the initial outbreak two distinct genotypes were identified. The GII.4 strain 2006a found in the majority of outbreaks in 2006 worldwide was isolated from all but two patients. These two individuals were infected with a GII.7 strain clustering mainly with isolates from Asia. Of note, they excreted noroviral RNA for 81 and 27 days, respectively. Longitudinal analysis of an extended 1381 bp sequence revealed positive selection in the P2 domain. The variant was very similar to GII.7 strains isolated in 1990 and 1994 suggesting slow evolution with evidence of recombination according to the SimPlot analysis. Strains found in the following years 2006-2008 clustered around the isolate GII.4 2006b, characterized in the spring of 2006 and reaching a high prevalence in 2006-2007. The results provide an insight into norovirus evolution at a University hospital over 3 years and describe intraindividual evolution within a patient infected chronically.

Virosomal hepatitis a vaccine: comparing intradermal and subcutaneous with intramuscular administration.

BACKGROUND: Vaccination against hepatitis A virus (HAV) is unaffordable to many developing countries. Substantial reductions in cost occur when vaccines are administered intradermally at low doses. Aluminum-free HAV vaccines are considered more suitable for intradermal use than traditional vaccines which can cause long-lasting local reactions. Thus, we compared the immunogenicity and safety of an aluminum-free virosomal HAV vaccine (Epaxal) administered by different routes: intradermal (i.d.), subcutaneous (s.c.), and intramuscular (i.m.). METHODS: Two open pilot studies were conducted as sub-studies of a large lot consistency trial. Healthy subjects aged 18 to 45 were enrolled. Study 1 compared two i.d. regimens of a lower dose of Epaxal [0.1 mL (4.8 IU), one or two injection sites] with i.m. administration of the standard dose [0.5 mL (24 IU)]. Study 2 compared the s.c. with the i.m. administration of the standard dose. At month 12, subjects in study 1 received a booster dose of 0.1 mL i.d. or 0.5 mL i.m.; subjects in study 2 received 0.5 mL via the respective route (s.c. or i.m.). Serum was tested for antibodies at baseline, 2 weeks (study 1), and 1 and 6 months after the primary vaccination as well as prior and 1 month after the booster dose. Incidences of solicited and unsolicited adverse events were recorded. RESULTS: Seroprotection rates (anti-HAV geometric mean concentration of > or =20 mIU/mL) after 1 month ranged from 93.2% to 100% in all groups and remained high until month 12 (range 85.2&-90.2%). Complete (100%) seroprotection was achieved by all subjects in all groups after booster vaccination. All routes of administration were well tolerated. Local reactions were more common in subjects vaccinated i.d. and s.c. than i.m. CONCLUSIONS: The aluminum-free virosomal HAV vaccine Epaxal is highly immunogenic and well tolerated when administered either via i.d., s.c., or i.m. Vaccination via the i.d. route may confer significant cost savings over the conventional i.m. route.

Cell type-specific cleavage of nucleocapsid protein by effector caspases during SARS coronavirus infection.

The epidemic outbreak of severe acute respiratory syndrome (SARS) in 2003 was caused by a novel coronavirus (CoV), designated SARS-CoV. The RNA genome of SARS-CoV is complexed by the nucleocapsid protein (N) to form a helical nucleocapsid. Besides this primary function, N seems to be involved in apoptotic scenarios. We show that upon infection of Vero E6 cells with SARS-CoV, which elicits a pronounced cytopathic effect and a high viral titer, N is cleaved by caspases. In contrast, in SARS-CoV-infected Caco-2 cells, which show a moderate cytopathic effect and a low viral titer, this processing of N was not observed. To further verify these observations, we transiently expressed N in different cell lines. Caco-2 and N2a cells served as models for persistent SARS-CoV infection, whereas Vero E6 and A549 cells did as prototype cell lines lytically infected by SARS-CoV. The experiments revealed that N induces the intrinsic apoptotic pathway, resulting in processing of N at residues 400 and 403 by caspase-6 and/or caspase-3. Of note, caspase activation is highly cell type specific in SARS-CoV-infected as well as transiently transfected cells. In Caco-2 and N2a cells, almost no N-processing was detectable. In Vero E6 and A549 cells, a high proportion of N was cleaved by caspases. Moreover, we examined the subcellular localization of SARS-CoV N in these cell lines. In transfected Vero E6 and A549 cells, SARS-CoV N was localized both in the cytoplasm and nucleus, whereas in Caco-2 and N2a cells, nearly no nuclear localization was observed. In addition, our studies indicate that the nuclear localization of N is essential for its caspase-6-mediated cleavage. These data suggest a correlation among the replication cycle of SARS-CoV, subcellular localization of N, induction of apoptosis, and the subsequent activation of caspases leading to cleavage of N.

Prevalence and clinical role of GBV-C infection after cardiac surgery in childhood: a study on 414 patients.

OBJECTIVES: GB-virus C (GBV-C) and hepatitis C virus (HCV) share similar modes of transmission. We, therefore, examined the prevalence and clinical role of GBV-C and HCV in patients after cardiac surgery in childhood. METHODS: We analysed blood samples of 414 patients and compared them to 487 controls. Evidence of liver disease and risk factors for infection was analysed. RESULTS: Overall prevalence of GBV-C infection was 22.5% in the patients, compared to 6.2% in the controls (HCV infection 11.3 vs. 0.7%). GBV-C RNA was detected in 8.2% of the patients vs. 3.7% in the controls (HCV RNA in 6 and 0%, respectively). Eleven patients had detectable RNA of GBV-C and HCV. 63.4% of patients infected with GBV-C and 46.8% of patients infected with HCV cleared the virus from circulation. GBV-C infection was not associated with hepatitis. Liver disease was not more frequent in patients co-infected with HCV and GBV-C. CONCLUSIONS: before 1991 have a substantial risk for HCV and GBV-C infection. However, GBV-C infection seems not to be associated with a liver disease. Co-infection with GBV-C and HCV has no influence on long-term clinical outcome or viral clearance of HCV infection.

Efficacy of virosome hepatitis A vaccine in young children in Nicaragua: randomized placebo-controlled trial.

Immunization of young children could control hepatitis A virus (HAV) infection, but the efficacy of hepatitis A vaccines in early childhood is unknown. In a randomized, double-blind trial of a single dose of a virosome-formulated, aluminum-free inactivated HAV vaccine in Nicaragua, 274 children (age range, 1.5-6 years) received vaccine or placebo injections; 239 children seronegative for hepatitis A were included in the primary efficacy analysis. HAV infection documented by immunoglobulin M antibodies was the primary end point. Among children seronegative for hepatitis A, infection was diagnosed in 4 children in the vaccine group and 22 children in the placebo group (protective efficacy, 84.6%; 95% confidence interval, 54.7%-96.1%). All infections in children in the vaccine group occurred within 6 weeks. After 6 weeks, protective efficacy was 100% (79.8%-100%). In children in the placebo group, the incidence of HAV infection was 17.6 and that of icteric illness was 1.6 cases/100 person-years. Adverse effects were rare in both children in the vaccine group and children in the placebo group. A single dose of a hepatitis A virosome vaccine is safe and protects young children against HAV infection.

Prevalencia de anticuerpos anti-hepatitis A en escolares en la década actual / Prevalence of antibodies against hepatitis A virus in chilean school age children

Background: As sanitary conditions of a population improve, hepatitis A virus infection occurs at higher ages,thus decreasing the prevalence of antibodies against the virus. In the eighties, the prevalence of antibodies among children was 97 percent and depended on the socioeconomic level. Aim: To assess the prevalence of antibodies against hepatitis A virus in school age children living in Valdivia. Subjects and methods: Two thousand three hundred thirty three school age children were studied. Total antibodies against hepatitis A virus were detected using an ELISA kit from Abbott. Children were stratified in age groups and school were classified as private, subsidized, municipal or foster homes. Results: Antibodies were positive in 65 percent of children (59 percent in children aged 6 to 8 years old, 66 percent in children aged 9 to 11 years and 69 percent in children aged 12 to 15 years. In private schools, the prevalence was 26 percent, in subsidized schools the figure was 54 percent, in municipal schools 73 percent and in foster homes 91 percent. Conclusions: The general prevalence of antibodies against hepatitis A virus is higher in low socioeconomic level children. There is a global decrease in the prevalence of these antibodies in the last years

Prevalencia de anticuerpos del virus hepatitis E en donantes de bancos de sangre y otros grupos de población en la X región, Chile / Prevalence of hepatitis E virus antibodies in blood donors and other population groups at X region, Chile

Little is known about hepatitis E virus (HEV) prevalence in South American countries. AntiHEV was studied in 1,773 subjects from 1,360 blood donors of 3 cities in Chile, 72 in health care workers, 241 inmates in state jails and in 100 Araucarian indians. Anti-HEV was detected in 109 out of 1,360 (8.0 percent) total donors (6.3 percent, 6.1 percent and 18.8 percent from the cities of Valdivia, Osorno and Puerto Montt respectively); 9 out of 72 (12.5 percent) health care workers; 18 out of 241 (7.5 percent) inmates and 17 out of 100 (17 percent) Araucarian indians. Prevalence of anti-HEV was not related to age and sex. Hepatitis E is an endemic infection in some population groups of Southern Chile, associated to environmental pollution, crowding and low socioeconomic level