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Autochthonous hepatitis E: a common and fatal but neglected emerging disease in France

2017; Elsevier BV; Volume: 23; Issue: 12 Linguagem: Inglês

10.1016/j.cmi.2017.06.027

1469-0691

Philippe Colson, Didier Raoult,

Viral gastroenteritis research and epidemiology

During the summer of 2016, a feature article entitled 'Europe's new hepatitis problem' was published in Science and focused on the emergence, risk factors and clinical concern about autochthonous hepatitis E in European countries, particularly in France [[1]Kupferschmidt K. Europe's new hepatitis problem.Science. 2016; 353: 862-863Crossref PubMed Scopus (28) Google Scholar]. However, in France itself, hepatitis E is deeply neglected. Hepatitis E virus (HEV), discovered in 1983, is the leading cause of acute hepatitis in developing countries, mostly in Asia and sub-Saharan Africa, and is responsible for an estimated 20 million infections, 3 million symptomatic cases and 70 000 deaths per year [[2]Rein D.B. Stevens G.A. Theaker J. Wittenborn J.S. Wiersma S.T. The global burden of hepatitis E virus genotypes 1 and 2 in 2005.Hepatology. 2012; 55: 988-997Crossref PubMed Scopus (511) Google Scholar]. In these geographical areas, the HEV involved are mostly of genotypes 1 and 2 and transmitted through the faecal–oral route [[2]Rein D.B. Stevens G.A. Theaker J. Wittenborn J.S. Wiersma S.T. The global burden of hepatitis E virus genotypes 1 and 2 in 2005.Hepatology. 2012; 55: 988-997Crossref PubMed Scopus (511) Google Scholar]. In France, as in other developed countries in Western Europe and worldwide, HEV infections were considered until 2006 as acquired only while travelling abroad. However, this paradigm changed during the last decade as it was revealed that the majority of these infections were autochthonous, involved viruses of genotype 3, mostly, or 4, and were linked to a porcine viral reservoir and often related to consumption of uncooked pig liver sausages [1Kupferschmidt K. Europe's new hepatitis problem.Science. 2016; 353: 862-863Crossref PubMed Scopus (28) Google Scholar, 3Colson P. Borentain P. Queyriaux B. Kaba M. Moal V. Gallian P. et al.Pig liver sausage as a source of hepatitis E virus transmission to humans.J Infect Dis. 2010; 202: 825-834Crossref PubMed Scopus (543) Google Scholar, 4Guillois Y. Abravanel F. Miura T. Pavio N. Vaillant V. Lhomme S. et al.High proportion of asymptomatic infections in an outbreak of hepatitis E associated with a spit-roasted piglet, France, 2013.Clin Infect Dis. 2016; 62: 351-357Crossref PubMed Scopus (80) Google Scholar, 5Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar]. Some HEV transmissions might occur through drinking water or eating shellfish. HEV RNA can be detected for 5 weeks in faeces, and for a longer duration in immunocompromised people [5Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar, 6Hewitt P.E. Ijaz S. Brailsford S.R. Brett R. Dicks S. Haywood B. et al.Hepatitis E virus in blood components: a prevalence and transmission study in southeast England.Lancet. 2014; 384: 1766-1773Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar]. Concomitantly, it was shown that acute autochthonous HEV infection could lead to liver transplantation and death [7Aherfi S. Borentain P. Raissouni F. Le Goffic A. Guisset M. Renou C. et al.Liver transplantation for acute liver failure related to autochthonous genotype 3 hepatitis E virus infection.Clin Res Hepatol Gastroenterol. 2014; 38: 24-31Crossref PubMed Scopus (23) Google Scholar, 8Carre M. Thiebaut-Bertrand A. Larrat S. Leroy V. Pouzol P. Sturm N. et al.Fatal autochthonous fulminant hepatitis E early after allogeneic stem cell transplantation.Bone Marrow Transplant. 2017; 52: 643-645Crossref PubMed Scopus (9) Google Scholar, 9Doudier B. Verrot D. Serratrice C. Poucel C. Auguste R. Colson P. Fatal outcome of autochthonous hepatitis E in a patient with B cell lymphoma in Southeastern France.J Clin Microbiol. 2015; 53: 339-342Crossref PubMed Scopus (12) Google Scholar]. It can also evolve towards chronic hepatitis, in severely immunocompromised people, particularly solid organ transplant recipients, and can cause cirrhosis as soon as 2 years post-infection in such patients [[5]Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar]. Moreover, HEV is also increasingly described as a causative agent of neurological disorders that occur in ≈6%–8% of infections and include most commonly Guillain–Barré syndrome, Parsonage–Turner syndrome and encephalitis/myelitis [[5]Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar]. Ribavirin was shown to be efficient to clear HEV infection in most chronically infected patients, although some experience virological rebound [[5]Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar]. In addition, efficient recombinant vaccines were developed, one being used in China, which might open the door to control, especially as only one serotype has been recognized for HEV and the available HEV genotype 1-based vaccine showed cross-protective efficacy against different genotypes [[5]Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar]. Unfortunately, in the absence of a mandatory report for hepatitis E in France, there is currently no robust estimation of the HEV incidence, and there is no accounting of the number of individuals with chronic hepatitis or subsequent cirrhosis, liver transplantations or deaths due to HEV. A total of 1851 HEV infections were reported by the French reference centre in 2013, 99.8% being autochthonous and 555 being confirmed by PCR (http://www.cnrvha-vhe.org/wp-content/uploads/2012/03/2014-Rap-Act-VHE-VHA.pdf). However, this number probably only reflects a small proportion of cases. In southern France, the incidence of HEV diagnoses was found to range between 0.7 and 2.7/100 person-years among kidney transplant recipients [[10]Moal V. Legris T. Burtey S. Morange S. Purgus R. Dussol B. et al.Infection with hepatitis E virus in kidney transplant recipients in southeastern France.J Med Virol. 2013; 85: 462-471Crossref PubMed Scopus (57) Google Scholar]. We have described that HEV was, in Marseille public hospitals, southeastern France, the first cause in 2008 of autochthonous acute hepatitis among adults, accounting for 51% of the 34 cases. In addition, from 2006 to 2010, HEV was the first infectious cause with hepatitis B of liver transplantation, being involved in two of the ten cases, and two other HEV-infected individuals died while on the waiting list [[7]Aherfi S. Borentain P. Raissouni F. Le Goffic A. Guisset M. Renou C. et al.Liver transplantation for acute liver failure related to autochthonous genotype 3 hepatitis E virus infection.Clin Res Hepatol Gastroenterol. 2014; 38: 24-31Crossref PubMed Scopus (23) Google Scholar]. Overall, between 2006 and 2015, we have reported five fatal HEV infections [7Aherfi S. Borentain P. Raissouni F. Le Goffic A. Guisset M. Renou C. et al.Liver transplantation for acute liver failure related to autochthonous genotype 3 hepatitis E virus infection.Clin Res Hepatol Gastroenterol. 2014; 38: 24-31Crossref PubMed Scopus (23) Google Scholar, 9Doudier B. Verrot D. Serratrice C. Poucel C. Auguste R. Colson P. Fatal outcome of autochthonous hepatitis E in a patient with B cell lymphoma in Southeastern France.J Clin Microbiol. 2015; 53: 339-342Crossref PubMed Scopus (12) Google Scholar]. It is also worthy to note that HEV infection is reported to be asymptomatic in 63%–88% of immunocompetent or immunosuppressed people [4Guillois Y. Abravanel F. Miura T. Pavio N. Vaillant V. Lhomme S. et al.High proportion of asymptomatic infections in an outbreak of hepatitis E associated with a spit-roasted piglet, France, 2013.Clin Infect Dis. 2016; 62: 351-357Crossref PubMed Scopus (80) Google Scholar, 10Moal V. Legris T. Burtey S. Morange S. Purgus R. Dussol B. et al.Infection with hepatitis E virus in kidney transplant recipients in southeastern France.J Med Virol. 2013; 85: 462-471Crossref PubMed Scopus (57) Google Scholar] and may lead silently to chronic liver diseases in immunocompromised hosts. At the country scale, IgG and IgM prevalence among blood donors was determined to be 22% and 1%, respectively, and for southern France, prevalence exceeded 50% for IgG and reached 3.2%–4.6% for IgM [[11]Mansuy J.M. Gallian P. Dimeglio C. Saune K. Arnaud C. Pelletier B. et al.A nationwide survey of hepatitis E viral infection in French blood donors.Hepatology. 2016; 63: 1145-1154Crossref PubMed Scopus (178) Google Scholar]. Hence, seroprevalence varied greatly according to the geographical area. In this study, the same serological assays were used for all blood samples, which is relevant because the performance of serological tests can vary considerably [[5]Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar]. Moreover, HEV RNA was detected in France in one out of 2300 (0.4‰) blood donations, and this rate was of 0.7‰–0.9‰ in southern France [[11]Mansuy J.M. Gallian P. Dimeglio C. Saune K. Arnaud C. Pelletier B. et al.A nationwide survey of hepatitis E viral infection in French blood donors.Hepatology. 2016; 63: 1145-1154Crossref PubMed Scopus (178) Google Scholar]. Human infections with HEV of genotype 3 are widespread in Western Europe, with differences in incidence and immunoglobulin prevalence according to the country [5Kamar N. Dalton H.R. Abravanel F. Izopet J. Hepatitis E virus infection.Clin Microbiol Rev. 2014; 27: 116-138Crossref PubMed Scopus (449) Google Scholar, 11Mansuy J.M. Gallian P. Dimeglio C. Saune K. Arnaud C. Pelletier B. et al.A nationwide survey of hepatitis E viral infection in French blood donors.Hepatology. 2016; 63: 1145-1154Crossref PubMed Scopus (178) Google Scholar]. In England, it was estimated, based on a similar HEV prevalence for blood donations (1/2848) as found in France and a similar population size, for a duration of viraemia of 8 weeks, that ≈80 000–100 000 acute HEV infections may occur yearly across the country [[6]Hewitt P.E. Ijaz S. Brailsford S.R. Brett R. Dicks S. Haywood B. et al.Hepatitis E virus in blood components: a prevalence and transmission study in southeast England.Lancet. 2014; 384: 1766-1773Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar]. Data are also lacking in France on the incidence and clinical outcome of transfusion-transmitted HEV infections, which would be useful to consider the relevance of systematic HEV RNA testing of blood products [11Mansuy J.M. Gallian P. Dimeglio C. Saune K. Arnaud C. Pelletier B. et al.A nationwide survey of hepatitis E viral infection in French blood donors.Hepatology. 2016; 63: 1145-1154Crossref PubMed Scopus (178) Google Scholar, 12Feray C. Pawlotsky J.M. Roque-Afonso A.M. Samuel D. Dhumeaux D. Should we screen blood products for hepatitis E virus RNA.Lancet. 2014; 383: 218Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]; currently, only a fraction of the solvent/detergent-treated plasma is tested. At least 13 transfusion-transmitted hepatitis E infections occurred between 2012 and 2014 in France, with various types of blood products (http://ansm.sante.fr/var/ansm_site/storage/original/application/4ee5a6f35365ab8b2ab1ad5eaccb5bd6.pdf). Registered cases most commonly involved immunocompromised patients, and five individuals with chronic hepatitis E required ribavirin therapy [[12]Feray C. Pawlotsky J.M. Roque-Afonso A.M. Samuel D. Dhumeaux D. Should we screen blood products for hepatitis E virus RNA.Lancet. 2014; 383: 218Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. Based on these data, it is puzzling that HEV infection has remained neglected in France. In public health, other targets whose clinical impact has been very limited in metropolitan France were favoured (http://invs.santepubliquefrance.fr/). Among these infectious agents are Chikungunya virus with 509 cases between 2006 and 2016 including only 13 autochthonous and none fatal; SARS-coronavirus with four cases in 2003 including one fatal; Middle East respiratory syndrome-coronavirus with two cases between 2012 and 2016 including one fatal (in 2013); and avian influenza virus with no case since 2004. With respect to the observed clinical burden of HEV infection in metropolitan France, greater efforts are warranted for its surveillance and prevention. This should include improving the epidemiological surveillance of HEV-related morbidity and mortality, as well as enhancing the awareness of clinicians and people about the sources and routes of HEV transmission, particularly in the case of individuals who are immunocompromised or have underlying liver diseases and are therefore at higher risk of severe outcomes. The authors report no conflicts of interest relevant to this article. No external funding was received for this article.