Hepatitis E in Italy: a long-term prospective study.

BACKGROUND & AIMS: In developed countries, hepatitis E is usually associated with travelling to endemic areas, but a growing number of sporadic cases are also seen in patients with no travel history. The aim of this study was to assess the impact and the molecular epidemiology of hepatitis E in Italy. METHODS: Between January 1994 and October 2009, we analyzed 651 patients with acute non-A-C hepatitis. Diagnosis of hepatitis E was based on the presence of IgM anti-HEV and/or the detection of HEV RNA by RT-PCR. Viral isolates were sequenced and phylogenetically characterized. RESULTS: A total of 134 out of 651 (20.6%) patients tested had acute hepatitis E. All were anti-HEV IgM and IgG positive and 96 (71.6%) were also positive for HEV RNA. Moreover, 39 (6%) patients were anti-HEV IgG positive but negative for both IgM anti-HEV and HEV RNA. A total of 109 (81.3%) patients developed hepatitis E travelling to endemic areas, 3 (2.3%) acquired intra-familial infection from relatives who developed travel-related disease, while 22 (16.4%) patients denied having travelled abroad. In all patients, acute disease had a self-limited course with ALT normalization within 3-6 weeks. Phylogenetic analysis of 39 isolates from patients with a travel-related disease showed that they belonged to genotype 1, while sequences from five patients with autochthonous hepatitis E belonged to genotype 3. CONCLUSIONS: In Italy, most cases of hepatitis E are travel related, caused by viral genotype 1, while autochthonous cases are caused by genotype 3. The prevalence of genotype 3 among pigs and boars suggests that HEV infection may have zoonotic origins in non-endemic countries.

Epidemiological and clinical features of rotavirus among children younger than 5 years of age hospitalized with acute gastroenteritis in Northern Italy.

BACKGROUND: Rotavirus is the major cause of acute gastroenteritis and severe dehydrating diarrhea in young children. METHODS: To estimate the proportion of hospital admissions for rotavirus acute gastroenteritis and identify the circulating G and P genotypes among children under five years of age, we conducted a prospective observational study from January to December 2008, recruiting children consecutively admitted to six hospitals in Milan and nearby towns in northern Italy. Typing was done on stool samples by reverse transcriptase polymerase chain reaction amplification. RESULTS: Of the 521 stool samples from children with acute gastroenteritis, 34.9% (95%CI, 30.8 to 39.2%) were rotavirus-positive. Two thirds (67.6%) were under two years of age, and 13.2% were under six months. The predominant G type was G1 (40.7%), followed by G9 (22.5%), G2 (13.2%), G3 (5.5%), G4 (3.8%) and G10 (1.6%). Twenty-one (11.7%) mixed-G infections were identified: G1+G10 (8.8%); G1+G9 (1.6%); and G2+G10 (1.2%). Only P[8] (67.6%) and P[4] (12.6%) types were P genotyped. The predominant single G/P combination was G1P[8] (39.7%), followed by G9P[8] (25.3%), G2P[4] (14.3%), and G3P[8] (4.1%). All G-mixed types combined with P[8]. CONCLUSIONS: These findings show an high prevalence of rotavirus infections among children admitted to hospital for acute gastroenteritis caused by different rotavirus strains circulating in the area studied.

Hepatitis B vaccination.

Hepatitis B virus is a worldwide leading cause of acute and chronic liver disease including cirrhosis and hepatocellular carcinoma. Effective vaccines have been available since the early '80s and vaccination has proved highly successful in reducing the disease burden, the development of the carrier state and the HB-related morbidity and mortality in the countries where vaccination has been implemented.   Neutralizing (protective) antibodies (anti-HBs) induced by vaccination are targeted largely towards the amino acid hydrophilic region, referred to as the common a determinant which is present on the outer protein coat or surface antigen (HBsAg), spanning amino acids 124-149. This provides protection against all HBV genotypes (from A to H) and is responsible for the broad immunity afforded by hepatitis B vaccination. Thus, alterations of residues within this region of the surface antigen may determine conformational changes that can allow replication of the mutated HBV in vaccinated people. An important mutation in the surface antigen region was identified in Italy some 25 years ago in infants born to HBsAg carrier mothers who developed breakthrough infections despite having received HBIG and vaccine at birth. This virus had a point mutation from guanosine to adenosine at nucleotide position 587, resulting in aa substitution from glycine (G) to arginine (R) at position 145 in the a determinant. Since the G145R substitution alters the projecting loop (aa 139-147) of the a determinant, the neutralizing antibodies induced by vaccination are no longer able to recognize the mutated epitope. Beside G145R, other S-gene mutations potentially able to evade neutralizing anti-HBs and infect vaccinated people have been described worldwide. In addition, the emergence of Pol mutants associated with resistance to treatment with nucleos(t)ide analogues can select viruses with crucial changes in the overlapping S-gene, potentially able to alter the S protein immunoreactivity. Thus such mutants have the potential to infect both naïve and immunized people, negatively affecting the efficacy of both the antiviral treatment and the vaccination programs. Despite concern, at present the overall impact of vaccine escapes mutants seems to be low and they do not pose a public health threat or a need to modify the established hepatitis B vaccination programs. The development of novel NAs with a high barrier to resistance is warranted.

Phylogeography and phylodynamics of European genotype 3 hepatitis E virus.

Hepatitis E virus is classified into four genotypes that have different geographical and host distributions. The main cause of sporadic autochthonous type E acute hepatitis in developed countries is genotype 3, which has a worldwide distribution and widely infects pigs. The aim of this study was to make hypotheses concerning the origin and global dispersion routes of this genotype by reconstructing the spatial and temporal dynamics of 208 HEV genotype 3 ORF-2 sequences (retrieved from public databases) isolated in different geographical areas. The evolutionary rates, time of the most recent common ancestors (tMRCAs), epidemic growth and phylogeography of HEV-3 were co-estimated using a MCMC Bayesian method. The maximum clade credibility tree showed the existence of two distinct main clades: clade A, which consists of only European subtypes (HEV-3e and 3f), and clade B, which consists of European subtype 3c and all of the Asian subtypes (3a, 3b and 3d) sharing a common ancestor, which most probably existed in Asia in 1920s. All of the North American isolates belonged to Asian subtype 3a. On the basis of our time-scaled phylogeographical reconstruction, we hypothesise that after originating in the early 1800s in Europe, HEV reached Asia in the first decades of 1900, and then moved to America probably in the 1970s-1980s. Analysis of the skyline plot showed a sharp increase of the number of infections between the 1980s and 2005, thus suggesting the intervention of new and highly efficient routes of transmission possibly related to changes in the pig industry.

Twenty years of universal vaccination against hepatitis B in Italy: achievements and challenges.

UNLABELLED: Viral hepatitis B is a vaccine-preventable disease. Vaccination has proved to be safe and highly effective in reducing the incidence, the carrier rate and HBV-related mortality on a global scale. In Italy, universal vaccination against hepatitis B started in 1991 in infants as well as in adolescents, providing an outstanding record of safety and effectiveness. Within a few years, over 95% coverage was consistently reported. Today, some 17 million people are immune against hepatitis B and their immunity has been shown to be long-lasting. At present, no booster is required in healthy vaccinated people to sustain protection. Surveillance data from Italy have shown a clear overall decline in hepatitis B among successfully vaccinated individuals. Furthermore, a generation of children and young people (at present cohorts ranging from 0 to 32 years) is emerging with practically no markers of HBV infection. Italy's vaccination programme has resulted in substantial progress towards the prevention and control of hepatitis B. The vaccination programme must continue. Maintaining mandatory vaccination of infants and increasing HBV vaccination coverage in high-risk groups, including households of HBsAg carriers as well as immigrants, remain a priority for the future. ACKNOWLEDGMENTS: Data reported in this paper were presented at a national Meeting, Towards the elimination of hepatitis B: celebrating 20 years of vaccination in Italy, held in Milano (19 November 2011) under the high patronage of the President of the Italian Republic. Distinguished figures from the world of Italian Public Health as well as international experts participated and paid tribute to the work of those who had contributed to the saving of lives, prevention of suffering, and the savings made to the State.

The worldwide impact of vaccination on the control and protection of viral hepatitis B.

Viral hepatitis B is a leading cause of acute and chronic liver disease worldwide, including cirrhosis and hepatocellular carcinoma. Vaccination is the most effective measure for controlling and preventing hepatitis B and its severe long-term sequelae. According to the World Health Organization (WHO), by the end of 2008 177 countries had introduced hepatitis B vaccination into their national routine neonatal, infant and/or adolescent immunisation programmes, and Italy was one of the first countries to implement a universal strategy of hepatitis B vaccination. The implementation of such vaccination programmes has globally resulted in a marked decrease in disease burden, in the carrier rate and in hepatitis B-related morbidity and mortality. Despite this success, work remains to be done to fully achieve the WHO goal of control of hepatitis B and HBV-related diseases on a global scale.

The changing face of the epidemiology of type A, B, and D viral hepatitis in Italy, following the implementation of vaccination.

The morbidity and mortality rates of viral hepatitis A, B and Delta have dramatically dropped in Italy during the last decades. Thanks to the general improvements in hygiene and sanitation, hepatitis A has shifted from a high to an intermediate/low endemicity status. Vaccination against hepatitis A is recommended to people at increased risk, including travellers to endemic areas, military personnel and individuals at occupational risk. The implementation of universal anti-hepatitis B vaccination of infants and adolescents has resulted in a dramatic decline in disease burden and in the carrier rate. An additional benefit of hepatitis B vaccination is that hepatitis Delta has also substantially declined.