Hepatitis E Virus Genotype 4 Outbreak, Italy, 2011
AbstractDuring 2011, 5 persons in the area of Lazio, Italy were infected with a monophyletic strain of hepatitis Evirus that showed high sequence homology with isolates from swine in China. Detection of this genotype in Italy parallels findings in other countries in Europe, signaling the possible spread of strains new to western countries.
HEV genotype 4 is endemic among humans in China, Japan, India, and Indonesia (4) and was detected during 2008 from swine fecal samples in Belgium (5). Human infections with imported strains of this genotype that later became endemic have subsequently been described in Germany (6) and northern France (7). Recently, multiple cases of HEV infection have been described in southern France (8,9).
In different areas of Italy, HEV seroprevalence estimates range from 1% to 6% (10); prevalence is 2.9% in the Lazio region and 2.5% in the province of Rome (11). However, the number of acute hepatitis cases caused by HEV reported in Italy is relatively low compared with surrounding European countries and is probably underestimated; most cases are travel-related and caused by genotype 1, but sporadic cases spread within Italy have been caused by genotype 3 (12). We report an outbreak of HEV genotype 4 infection among persons living in Lazio, an administrative region of Italy that encompasses Rome.
The similarity of the strain from this outbreak to strains from recent autochthonous HEV genotype 4 infections in Europe was relatively low: 73.5% in the overlapping 37–172-nt ORF1 region of the isolate from Germany (GenBank accession no. EU879120) (6), 85.7% in the overlapping 31–373-nt ORF2 region of the isolate from northern France (accession no. GU982294) (7), and 84.7%–84.8% in the 329-nt overlapping ORF2 region of 5 isolates from southern France (9). Consistent with these data, 85.1% and 85.3% identity was observed in the 537-nt ORF2 region of 2 of the isolates from southern France (accession nos. JF900631 and JF900632) (8), (Technical Appendix [PDF - 93 KB - 2 pages]).
Three patients had IgG against hepatitis A virus (HAV); no information on HAV vaccination status was available. However, the presence of these antibodies does not necessarily imply higher than average levels of exposure to enterically transmitted viruses; a HAV seroprevalence >60% has been reported in persons in the birth cohorts of the 5 case-patients in central Italy (14).
Consumption of contaminated food (i.e., pork or wild animal meat, bivalve mollusks, or shellfish) is considered the most likely source of infection with HEV genotype 3 in Europe (8,12). For genotype 4, uncooked deer meat was indicated as a source of human infection in Japan (15), and undercooked pork meat was the probable source of infection in southern France (8,9). The isolates from this study had the highest genetic similarity to subgenotype 4d strains of swine origin from China (Figure 2), which suggests a possible zoonotic origin through either direct (e.g., ingestion of raw or undercooked pork products) or indirect (e.g., by water contaminated with animal excreta) transmission.
Possible sources of infection with this HEV strain that cannot be ruled out include contaminated food from abroad and direct introduction through infected immigrants from China or other countries in Asia. However, the proportion of immigrants from Asia in this area of Italy, 0.77%, is lower than the national average (1.26%; www.comuni-italiani.it/statistiche/stranieri.html). Available data do not support correlations between immigration from China and spread of this HEV genotype in Lazio.
Strong sequence similarity (>96%) was observed between HEV isolates from human cases in northern and southern France and the strain isolated from swine in Belgium (5), classified as subgenotype 4b. Human infection with HEV genotype 4 reported in Germany in 2008 (6) was attributed to a different subgenotype (4f). The strain involved in the outbreak in Italy showed relatively poor genetic resemblance with any of these strains, which indicates that different HEV genotype 4 strains have been recently introduced in Europe.
In summary, this outbreak of HEV genotype 4 infection in Italy was not linked to infection by imported foods or persons traveling from endemic areas, which suggests the possibility that newly imported strains might spread this virus to new areas. Molecular characterization of HEV outbreaks in Europe is needed to implement epidemiologic mapping of infection with introduced strains of HEV and subsequent circulation.
The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 278433-PREDEMICS and from the Italian Ministry of Health, grants “Ricerca Corrente.”
Dr Garbuglia is a senior scientist at the virology laboratory of the Lazzaro Spallanzani National Institute for Infectious Diseases in Rome. Her primary research interests include virus evolution analysis and host-pathogen interaction.
We thank Philippe Colson for providing the sequences of HEV genotype 4 from southern France.
- Drexler JF, Seelen A, Corman VM, Fumie Tateno A, Cottontail V, Melim Zerbinati R, Bats worldwide carry hepatitis E virus-related viruses that form a putative novel genus within the family Hepeviridae. J Virol. 2012;86:9134–47.
- Lu L, Li C, Hagedorn CH. Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis. Rev Med Virol. 2006;16:5–36.
- Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J, Hepatitis E. Lancet. 2012;379:2477–88.
- Hu GD, Ma X. Detection and sequences analysis of bovine hepatitis E virus RNA in Xinjiang autonomous region. Bing Du Xue Bao. 2010;26:27–32.
- Hakze-van der Honing RW, van Coillie E, Antonis AF, van der Poel WH. First isolation of hepatitis E virus genotype 4 in Europe through swine surveillance in the Netherlands and Belgium. PLoS ONE. 2011;6:e22673.
- Wichmann O, Schimanski S, Koch J, Kohler M, Rothe C, Plentz A, Phylogenetic and case-control study on hepatitis E virus infection in Germany. J Infect Dis. 2008;198:1732–41.
- Tessé S, Lioure B, Fornecker L, Wendling MJ, Stoll-Keller F, Bigaillon C, Circulation of genotype 4 hepatitis E virus in Europe: First autochthonous hepatitis E infection in France. J Clin Virol. 2012;54:197–200.
- Colson P, Romanet P, Moal V, Borentain P, Purgus R, Benezech A, Autochthonous infections with hepatitis E virus genotype 4, France. Emerg Infect Dis. 2012;18:1361–4.
- Colson P, Swiader L, Motte A, Ferretti A, Borentain P, Gerolami R. Circulation of almost genetically identical hepatitis E virus of genotype 4 in France. J Clin Virol. 2012;55:181–3. Epub 2012 Jul 25.
- Romanò L, Paladini S, Tagliacarne C, Canuti M, Bianchi S, Zanetti AR. Hepatitis E in Italy: a long-term prospective study. J Hepatol. 2011;54:34–40.
- Vulcano A, Angelucci M, Candelori E, Martini V, Patti AM, Mancini C, HEV prevalence in the general population and among workers at zoonotic risk in Latium Region. Ann Ig. 2007;19:181–6.
- La Rosa G, Muscillo M, Vennarucci VS, Garbuglia AR, La Scala P, Capobianchi MR. Hepatitis E virus in Italy: molecular analysis of travel-related and autochthonous cases. J Gen Virol. 2011;92:1617–26.
- Mizuo H, Suzuki K, Takikawa Y, Sugai Y, Tokita H, Akahane Y, Polyphyletic strains of hepatitis E virus are responsible for sporadic cases of acute hepatitis in Japan. J Clin Microbiol. 2002;40:3209–18.
- Ansaldi F, Bruzzone B, Rota MC, Bella A. Ciofi degli Atti M, Durando P, Gasparini R, Icardi G; Serologic Study Group. Hepatitis A incidence and hospital-based seroprevalence in Italy: a nation-wide study. Eur J Epidemiol. 2008;23:45–53.
- Nishizawa T, Takahashi M, Mizuo H, Miyajima H, Gotanda Y, Okamoto H. Characterization of Japanese swine and human hepatitis E virus isolates of genotype IV with 99% identity over the entire genome. J Gen Virol. 2003;84:1245–51.