Nucleotide sequences from a total of 421 HEV isolates were retrieved from Genbank and analysed. Phylogenetically, HEV was classified into four major genotypes. Genotype 1 was more conserved and classified into five subtypes. The number of genotype 2 sequences was limited but can be classified into two subtypes. Genotypes 3 and 4 were extremely diverse and can be subdivided into ten and seven subtypes. Geographically, genotype 1 was isolated from tropical and several subtropical countries in Asia and Africa, and genotype 2 was from Mexico, Nigeria, and Chad; whereas genotype 3 was identified almost worldwide including Asia, Europe, Oceania, North and South America. In contrast, genotype 4 was found exclusively in Asia. It is speculated that genotype 3 originated in the western hemisphere and was imported to several Asian countries such as Japan, Korea and Taiwan, while genotype 4 has been indigenous and likely restricted to Asia. Genotypes 3 and 4 were not only identified in swine but also in wild animals such as boar and a deer. Furthermore, in most areas where genotypes 3 and 4 were characterised, sequences from both humans and animals were highly conserved, indicating they originated from the same infectious sources. Based upon nucleotide differences from five phylogenies, it is proposed that five, two, ten and seven subtypes for HEV genotypes 1, 2, 3 and 4 be designated alphabetised subtypes. Accordingly, a total of 24 subtypes (1a, 1b, 1c, 1d, 1e, 2a, 2b, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 4a, 4b, 4c, 4d, 4e, 4f and 4g) were given.

Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis.

Hepatitis E is endemic in many developing countries where it causes substantial morbidity. In industrialised countries, it is considered rare, and largely confined to travellers returning from endemic areas. However, there is now a growing body of evidence that challenges this notion. Autochthonous hepatitis E in developed countries is far more common than previously recognised, and might be more common than hepatitis A. Hepatitis E has a predilection for older men in whom it causes substantial morbidity and mortality. The disease has a poor prognosis in the context of pre-existing chronic liver disease, and is frequently misdiagnosed as drug-induced liver injury. The source and route of infection remain uncertain, but it might be a porcine zoonosis. Patients with unexplained hepatitis should be tested for hepatitis E, whatever their age or travel history.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(08)70255-X.pdf

Hepatitis E: an emerging infection in developed countries

Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries.

Hepatitis E Virus Infection

Genetic variability and evolution of hepatitis E virus.

Hepatitis E virus (HEV) is responsible for enterically-transmitted acute hepatitis in humans with two distinct epidemiological patterns. In endemic regions, large waterborne epidemics with thousands of people affected have been observed, and, in contrast, in non-endemic regions, sporadic cases have been described. Although contaminated water has been well documented as the source of infection in endemic regions, the modes of transmission in non-endemic regions are much less known. HEV is a single-strand, positive-sense RNA virus which is classified in the Hepeviridae family with at least four known main genotypes (1-4) of mammalian HEV and one avian HEV. HEV is unique among the known hepatitis viruses, in which it has an animal reservoir. In contrast to humans, swine and other mammalian animal species infected by HEV generally remain asymptomatic, whereas chickens infected by avian HEV may develop a disease known as Hepatitis-Splenomegaly syndrome. HEV genotypes 1 and 2 are found exclusively in humans while genotypes 3 and 4 are found both in humans and other mammals. Several lines of evidence indicate that, in some cases involving HEV genotypes 3 and 4, animal to human transmissions occur. Furthermore, individuals with direct contact with animals are at higher risk of HEV infection. Cross-species infections with HEV genotypes 3 and 4 have been demonstrated experimentally. However, not all sources of human infections have been identified thus far and in many cases, the origin of HEV infection in humans remains unknown.

/pdf/zoonotic-hepatitis-e-animal-reservoirs-and-emerging-risks-2bwouagmml.pdf

Zoonotic hepatitis E: animal reservoirs and emerging risks.

The objectives of the present study were to establish the presence of hepatitis E virus (HEV) in New Zealand pigs, first by testing for HEV antibody in pig herds throughout New Zealand to measure the herd prevalence, then by attempting to amplify HEV genomic sequences by PCR. Antibody was measured by two independently designed ELISA serology tests. HEV RNA fragments were amplified by RT-PCR of nucleic acid extracted from faeces of 10-12-week-old piglets using primers targeting ORF1, ORF2, and ORF2/3. PCR products were subject to phylogenetic analysis. Antibody to HEV was found throughout New Zealand pig herds as well as in the different age groups within the herds. Twenty herds from 22 tested were positive for HEV antibody (91% herd prevalence). Phylogenetic analysis of the amplified sequences placed this New Zealand strain of HEV closest to the human European strain It-1 (AF 110390) and U.S. swine strain (AF 082843) with 88% and 83% similarity respectively in ORF1. It was concluded that HEV is widely distributed in the New Zealand pig population. Phylogenetic analysis shows that this is a new HEV strain, grouping most closely with the United States/European cluster, which includes HEV strains of both human and swine origin.

Detection and characterisation of swine hepatitis E virus in New Zealand.

Background and Aim:  Locally acquired hepatitis E virus (HEV) infection has been described in a number of developed countries and is thought to be zoonotic from pigs. Little is known about hepatitis E in humans in New Zealand (NZ) but 90% of NZ pigs show evidence of HEV infection. The aim of this study was to investigate the epidemiology of hepatitis E infection in NZ by documenting HEV immunoglobulin (Ig) G seroprevalence in NZ blood donors, testing patients with unexplained hepatitis for HEV, and comparing genetic sequences of human HEV with local porcine isolates.



Methods:  In total, 265 blood donors were tested for HEV IgG and 77 patients with unexplained hepatitis were tested for HEV. Viral sequences were compared with known HEV isolates including those from NZ pigs.



Results:  The HEV IgG seroprevalence was 4%. HEV genotype 3 was isolated in four patients with unexplained hepatitis. Clinical and sequencing data suggest that two cases were acquired in Europe and two in NZ. All cases were in elderly patients, one of whom was asymptomatic and initially misdiagnosed as a drug reaction. The NZ-acquired cases were most similar to HEV from Japan, and bore little sequence homology to HEV isolated from NZ pigs.



Conclusions:  Hepatitis E does occur in NZ in patients who have not traveled to endemic areas and seems to affect the elderly. The seroprevalence data suggest that subclinical/unrecognized infection is common. Sequencing data suggest that some reservoir other than pigs could be the source of HEV in NZ. It is recommend that all patients with unexplained hepatitis, whatever their age or travel history, are tested for HEV.

Hepatitis E in new zealand.

TT-virus (TTV, patient initials: T.T.), a novel DNA virus, was first isolated in Japan in 1997 from serum of a patient with post-transfusion hepatitis of unknown aetiology. To date, the contribution of TTV to liver disease remains doubtful. The potential for transmission via blood and blood products makes it essential to establish the prevalence of TTV viraemia in the blood donor population. 413 blood donor serum samples were chosen randomly, the DNA was extracted and TTV-specific DNA amplified by nested polymerase chain reaction (PCR). TTV infection was present in 13 out of 413 (3.15%) blood donors in the Auckland region of New Zealand using a set of primers targeting open reading frame (ORF) 1. These 13 amplification products (264 bp) were sequenced and TTV genotypes determined. Alignment with published TTV sequences showed that seven (53.8%) of the thirteen positive serum samples belonged to genotype 1, five (38.5%) belonged to genotype 2 and one (7.7%) could not be classified as either genotype 1 or 2. One hundred twenty-seven blood donor serum samples were retested with a second set of primers targeting the 5' region of the TTV genome in a single round PCR. Forty-three samples were positive for TTV DNA with these primers resulting in a prevalence of 37%. The data demonstrate that TTV is present among New Zealand blood donors and support the need for further investigation into the natural history of TTV infection.

Prevalence and phylogenetic characterisation of TT-virus in the blood donor population of Auckland, New Zealand.

Eradication of allograft HBV infection with lamivudine/low dose HBIG prophylaxis: a precursor to safe HBIG withdrawal?

http://journal.chestnet.org/article/S001236922300034X/pdf

A 40-Year-Old Man With Multiple Pulmonary Nodules and Mediastinal Lymphadenopathy With Positive Anti-Neutrophil Cytoplasmic Antibody Reveals an Unexpected Diagnosis.

Bryan Schroeder

Papers

Detection and characterisation of swine hepatitis E virus in New Zealand.

Hepatitis E in new zealand.

Prevalence and phylogenetic characterisation of TT-virus in the blood donor population of Auckland, New Zealand.

Eradication of allograft HBV infection with lamivudine/low dose HBIG prophylaxis: a precursor to safe HBIG withdrawal?

A 40-Year-Old Man With Multiple Pulmonary Nodules and Mediastinal Lymphadenopathy With Positive Anti-Neutrophil Cytoplasmic Antibody Reveals an Unexpected Diagnosis.