Foreword

Hepatitis E virus (HEV) infection may well be the most common cause of acute hepatitis and jaundice in the world today. Hepatitis E, identified as a novel clinical entity three decades ago, has been attracting increasing research interest due to the complexity of its clinical presentations, its multifaceted epidemiology, and many unanswered issues concerning HEV biology. Outbreaks and sporadic cases of hepatitis E, presenting as an acute viral infection, have been observed in several countries of the Indian subcontinent, in Asia, and Africa. More recently, however, sporadic cases of hepatitis E were reported from the Western world, including Europe and the United States, where HEV infection causes not only acute illness, but also presents clinical and pathologic features of chronic hepatitis. Epidemiology and clinical presentations of HEV infection seem to be linked somehow to the molecular structure of the virus; HEV genotypes 1 and 2 are associated with epidemic outbreaks in disease-endemic geographic areas and associated with unexplained mortality among infected pregnant women. HEV genotypes 3 and 4 are zoonotic; genotype 3 is uniquely associated with autochthonous hepatitis E reported from the Western world, and with almost all cases of the acute infection with extrahepatic manifestations.

The puzzling nature of HEV infection and its magnitude as a public health problem explain the challenge and excitement throughout my planning for this issue of Seminars in Liver Disease, the first one in the journal's 33-year history devoted specifically to this pathogen. We sought in this issue to present a comprehensive review of recent advances in our understanding of multiple important facets of HEV infection.

In the first article, Shahid Jameel and collaborators from the International Centre for Genetic Engineering and Biotechnology in New Delhi, India, review our current knowledge of the molecular virology of HEV, the causative agent of hepatitis E disease. The review summarizes current knowledge of the viral genome and its constituent proteins. Their report stresses the significance of the recent development of the replicon methodology critical for the study of HEV molecular virology and emphasizes further progress in establishing HEV in vitro infection systems to study HEV entry, cellular replication, and egress—essential elements of the viral life cycle.

Alain Labrique and coauthors from the Department of International Health, Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, were invited to review the epidemiology of the disease occurring in countries where HEV infection is endemic. Their historical summary of the epidemics on the Indian subcontinent, in Asia, and Africa is complemented by extensive demographic analysis and serology data indicating the spread of the infection in low and middle income countries. The review reminds us of the unresolved epidemiologic and pathogenetic puzzles of the low prevalence of hepatitis E clinical illness among children and the high case fatality rate in pregnant women.

Rakesh Aggarwal from the Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow, India, reviews clinical characteristics of hepatitis E caused by HEV genotype 1 as a range of presentations that include asymptomatic infections, fully developed self-limited acute hepatitis and frequently fatal fulminant hepatic failure. A very important part of the contribution is a critical review of the various diagnostic methods used for identification of HEV infection. The excellent analysis of various currently used immunologic and molecular assays emphasizes the need for a better standardization of diagnostic tools for identification of HEV infection to strengthen the significance of epidemiologic studies performed in laboratories in various geographic locations.

Three subsequent contributions in this issue of Seminars describe HEV genotype 3 (and 4) infection in animals and its causative association with hepatitis E in humans occurring in developed countries as sporadic and cluster cases.

X-J Meng from the Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, was the first to identify HEV genotype 3 infecting pigs in 1997, and in a series of publications that followed the discovery established its zoonotic characteristics and its ability to cause cross-species infection. His review in this issue of Seminars highlights the significance of animal reservoirs of the virus as sources of infection in humans. The discovery of HEV in pigs broadened the host range and diversity of HEV and raised public health concerns for zoonosis and food safety associated with genotypes 3 and 4 HEV infections.

Harry Dalton and coauthors from the Royal Cornwall Hospital Trust, University of Exeter Medical School in Truro, Cornwall, United Kingdom, for several years observed local cases of viral hepatitis connecting them etiologically to HEV genotype 3 infection (autochthonous hepatitis E). They reviewed autochthonous hepatitis E in developed countries and made a case for zoonotic origin of the infection (infected domestic or wild pigs) transmitted through direct contact, consumption of products from infected animals, or through ingestion of water contaminated with feces from infected animals. Intriguingly, the authors propose that sporadic cases of hepatitis E in European countries are historically related to infections that occurred much earlier in the same geographic region. Equally interesting are the authors' observations and comments on HEV infection in human immunodeficiency virus (HIV)-infected individuals and transfusion-related HEV infections.

Nassim Kamar and coauthors from Université Paul Sabatier in Toulouse, France, focus their review on chronic hepatitis E cases reported in Western European patients receiving solid-organ transplants, those with hematologic diseases, and those who are HIV-positive. Their contribution summarizes existing data on the incidence and natural history of HEV genotype 3 infections in immunosuppressed patients and available information on rare cases of extrahepatic manifestations seemingly associated with HEV infection (neurologic symptoms, kidney injuries, and hematological disorders).The authors also review the effectiveness of antiviral therapies (pegylated interferon, ribavirin) for HEV infection and conclude that in the absence of spontaneous clearance of HEV, the use of ribavirin can lead to viral clearance without reactivation of the infection.

Heiner Wedemeyer and Sven Pischke from the Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule in Hannover, Germany were joined by Jolanta Rybczynska from the Department of Pathology, Medical University of Warsaw, Poland, and I in reviewing pathogenetic mechanisms that lead to liver injury during HEV infection. We conclude that the host immune response to the virus is central and essential in a cascade of innate and adaptive immune events ensuing after the infection. Although detailed mechanisms leading to different clinical outcomes of HEV infection are only partially understood, we suggest that both host and viral factors such as HEV genotype and the dose of the infectious inoculum may be of critical significance for the clinical course and pathologic presentation of the infection. As HEV does not seem to induce a direct cytopathic effect on target cells, recent studies summarized in our review provide compelling evidence for association of T-cell responses, activation of the interferon-system, and viral evolution with severity of acute hepatitis and/or the development of chronic infection.

The final hepatitis E report in the issue, by Jim WaiKuo Shih, Ning-Shao Xia, Jun Zhang, and coauthors from the National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, P.R. China, reviews efforts that focus on the successful development of an HEV vaccine. Several groups of investigators have designed candidate hepatitis E vaccines and tested their efficacy in animal models, of which two vaccines were successfully tested in clinical trials. One of the two (HEV239 protein), developed in the authors' laboratory, has been shown to be fully protective against hepatitis E in a large clinical trial; it is registered and marketed in their country.

In closing, I am grateful to the authors who contributed to this issue of Seminars in Liver Disease for sharing their deep knowledge of the subject with our readers, and for their valuable contributions and commitment to improving our understanding of the complicated issues of hepatitis E virus infection.

I hope that readers will enjoy this issue as much as I enjoyed planning for it.