Pathogenic mechanisms and current epidemiological status of HEV infection in asymptomatic blood donors and patients with chronic diseases

  • L. Albano
  • Maria VascoEmail author
  • G. Benincasa
  • L. Sommese
  • R. Alfano
  • C. Napoli


In recent years, the seroprevalence of anti-hepatitis E virus immunoglobulins (HEV) has increased in European countries with significant variability among the different geographical areas. HEV infection is spread in a wide range of animal species of which domestic pigs and wild boar represent the main reservoirs of genotype 3 and 4 (the genotypes present also in Europe). European citizens are incidental hosts, mainly infected by direct contact or consumption of foods derived from undercooked or insufficient hygiene handling infected pork products or wild boar meat. Epidemiologically, the HEV incidence is low in humans but serological data show a high proportion of subclinical infection caused by genotypes 3 or 4. In the general population, asymptomatic infection represents a high potential risk in particular subjects such as blood component recipients or occupationally exposed workers. This review offers a landscape of the current epidemiological status of HEV infection (genotypes 1, 2, 3, 4, 7) both in European asymptomatic subjects, patients with chronic diseases, and domestic pig impact on humans. We also underline advantages/disadvantages of high sensitivity and specificity tests using for detecting viral RNA or anti-HEV antibodies.


HEV Epidemiology European populations Patients qRT-PCR ELISA 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Khuroo MS, Khuroo MS (2016) Hepatitis E: an emerging global disease—from discovery towards control and cure. J Viral Hepat 23(2):68–79. CrossRefGoogle Scholar
  2. 2.
    Balayan MS, Andjaparidze AG, Savinskaya SS, Ketiladze ES, Braginsky DM, Savinov AP, Poleschuk VF (1983) Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 20(1):23–31CrossRefGoogle Scholar
  3. 3.
    Arends JE, Ghisetti V, Irving W, Dalton HR, Izopet J, Hoepelman AI, Salmon D (2014) Hepatitis E: an emerging infection in high income countries. J Clin Virol 59(2):81–88. CrossRefGoogle Scholar
  4. 4.
    Smith DB, Simmonds P, International Committee on Taxonomy of Viruses Hepeviridae Study Group, Jameel S, Emerson SU, Harrison TJ, Meng XJ, Okamoto H, Van der Poel WH, Purdy MA (2014) Consensus proposals for classification of the family Hepeviridae. J Gen Virol 95(Pt 10):2223–2232. CrossRefGoogle Scholar
  5. 5.
    Smith DB, Purdy MA, Simmonds P (2013) Genetic variability and the classification of hepatitis E virus. J Virol 87(8):4161–4169. CrossRefGoogle Scholar
  6. 6.
    Kamar N, Dalton HR, Abravanel F, Izopet J (2014) Hepatitis E virus infection. Clin Microbiol Rev 27(1):116–138. CrossRefGoogle Scholar
  7. 7.
    Dalton HR, Bendall R, Ijaz S, Banks M (2008) Hepatitis E: an emerging infection in developed countries. Lancet Infect Dis 8(11):698–709. CrossRefGoogle Scholar
  8. 8.
    Aggarwal R (2013) Diagnosis of hepatitis E. Nat Rev Gastroenterol Hepatol 10(1):24–33. CrossRefGoogle Scholar
  9. 9.
    Teshale EH, Hu DJ, Holmberg SD (2010) The two faces of hepatitis E virus. Clin Infect Dis 51(3):328–334. CrossRefGoogle Scholar
  10. 10.
    Lopez-Lopez P, Risalde MLA, Frias M, García-Bocanegra I, Brieva T, Caballero-Gomez J, Camacho A, Fernández-Molera V, Machuca I, Gomez-Villamandos JC, Rivero A, Rivero-Juarez A (2018) Risk factors associated with hepatitis E virus in pigs from different production systems. Vet Microbiol 224:88–92. CrossRefGoogle Scholar
  11. 11.
    Di Bartolo I, Diez-Valcarce M, Vasickova P, Kralik P, Hernandez M, Angeloni G, Ostanello F, Bouwknegt M, Rodríguez-Lázaro D, Pavlik I, Ruggeri FM (2012 Aug) Hepatitis E virus in pork production chain in Czech Republic, Italy, and Spain, 2010. Emerg Infect Dis 18(8):1282–1289. CrossRefGoogle Scholar
  12. 12.
    Marano G, Vaglio S, Pupella S, Facco G, Bianchi M, Calizzani G, Candura F, Catalano L, Farina B, Lanzoni M, Piccinini V, Liumbruno GM, Grazzini G (2015 Jan) Hepatitis E: an old infection with new implications. Blood Transfus 13(1):6–17. Google Scholar
  13. 13.
    Frias M, López-López P, Rivero A, Rivero-Juarez A (2018) Role of hepatitis E virus infection in acute-on-chronic liver failure. Biomed Res Int 2018:9098535. Google Scholar
  14. 14.
    Marcantonio C, Pezzotti P, Bruni R, Taliani G, Chionne P, Madonna E, Villano U, Pisani G, Equestre M, Dell'Orso L, Ragone K, Ciccaglione AR, Spada E (2018) Incidence of hepatitis E virus infection among blood donors in a high endemic area of Central Italy. J Viral Hepat.
  15. 15.
    Murrison LB, Sherman KE (2017) The enigma of hepatitis E virus. Gastroenterol Hepatol (N Y) (8):484–491Google Scholar
  16. 16.
    Dalton HR, Kamar N, van Eijk JJ, Mclean BN, Cintas P, Bendall RP, Jacobs BC (2016) Hepatitis E virus and neurological injury. Nat Rev Neurol 12(2):77–85. CrossRefGoogle Scholar
  17. 17.
    Pavio N, Meng XJ, Renou C (2010) Zoonotic hepatitis E: animal reservoirs and emerging risks. Vet Res 41(6):46. CrossRefGoogle Scholar
  18. 18.
    Berto A, Backer JA, Mesquita JR, Nascimento MS, Banks M, Martelli F, Ostanello F, Angeloni G, Di Bartolo I, Ruggeri FM, Vasickova P, Diez-Valcarce M, Hernandez M, Rodriguez-Lazaro D, van der Poel WH (2012) Prevalence and transmission of hepatitis E virus in domestic swine populations in different European countries. BMC Res Notes 5:190. CrossRefGoogle Scholar
  19. 19.
    De Schryver A, De Schrijver K, François G, Hambach R, van Sprundel M, Tabibi R, Colosio C (2015) Hepatitis E virus infection: an emerging occupational risk? Occup Med (Lond) 65(8):667–672. CrossRefGoogle Scholar
  20. 20.
    Dremsek P, Joel S, Baechlein C, Pavio N, Schielke A, Ziller M, Dürrwald R, Renner C, Groschup MH, Johne R, Krumbholz A, Ulrich RG (2013) Hepatitis E virus seroprevalence of domestic pigs in Germany determined by a novel in-house and two reference ELISAs. J Virol Methods 190(1–2):11–16. CrossRefGoogle Scholar
  21. 21.
    Walachowski S, Dorenlor V, Lefevre J, Lunazzi A, Eono F, Merbah T, Eveno E, Pavio N, Rose N (2014) Risk factors associated with the presence of hepatitis E virus in livers and seroprevalence in slaughter-age pigs: a retrospective study of 90 swine farms in France. Epidemiol Infect 142(9):1934–1944. CrossRefGoogle Scholar
  22. 22.
    Martinelli N, Luppi A, Cordioli P, Lombardi G, Lavazza A (2011) Prevalence of hepatitis E virus antibodies in pigs in northern Italy. Infect Ecol Epidemiol 1.
  23. 23.
    Martelli F, Caprioli A, Zengarini M, Marata A, Fiegna C, Di Bartolo I, Ruggeri FM, Delogu M, Ostanello F (2008) Detection of hepatitis E virus (HEV) in a demographic managed wild boar (Sus scrofa scrofa) population in Italy. Vet Microbiol 126(1–3):74–81CrossRefGoogle Scholar
  24. 24.
    Fernández-Barredo S, Galiana C, García A, Vega S, Gómez MT, Pérez-Gracia MT (2006) Detection of hepatitis E virus shedding in feces of pigs at different stages of production using reverse transcription-polymerase chain reaction. J Vet Diagn Investig 18(5):462–465CrossRefGoogle Scholar
  25. 25.
    Kantala T, Kinnunen PM, Oristo S, Jokelainen P, Vapalahti O, Maunula L (2017) Hepatitis E virus antibodies in Finnish veterinarians. Zoonoses Public Health 64(3):232–238. CrossRefGoogle Scholar
  26. 26.
    Sommerkorn FM, Schauer B, Schreiner T, Fickenscher H, Krumbholz A (2017) Performance of hepatitis E virus (HEV)-antibody tests: a comparative analysis based on samples from individuals with direct contact to domestic pigs or wild boar in Germany. Med Microbiol Immunol 206(3):277–286. CrossRefGoogle Scholar
  27. 27.
    Mughini-Gras L, Angeloni G, Salata C, Vonesch N, D'Amico W, Campagna G, Natale A, Zuliani F, Ceglie L, Monne I, Vascellari M, Capello K, DI Martino G, Inglese N, Palù G, Tomao P, Bonfanti L (2017) Hepatitis E virus infection in North Italy: high seroprevalence in swine herds and increased risk for swine workers. Epidemiol Infect 145(16):3375–3384. CrossRefGoogle Scholar
  28. 28.
    Dalton HR, Hazeldine S, Banks M, Ijaz S, Bendall R (2007) Locally acquired hepatitis E in chronic liver disease. Lancet 369(9569):1260. CrossRefGoogle Scholar
  29. 29.
    Lapa D, Capobianchi MR, Garbuglia AR (2015) Epidemiology of hepatitis E virus in European countries. Int J Mol Sci 16(10):25711–25743. CrossRefGoogle Scholar
  30. 30.
    Riveiro-Barciela M, Buti M, Homs M, Campos-Varela I, Cantarell C, Crespo M, Castells L, Tabernero D, Quer J, Esteban R, Rodriguez-Frías F (2014) Cirrhosis, liver transplantation and HIV infection are risk factors associated with hepatitis E virus infection. PLoS One 9(7):e103028. CrossRefGoogle Scholar
  31. 31.
    Hamid SS, Atiq M, Shehzad F, Yasmeen A, Nissa T, Salam A, Siddiqui A, Jafri W (2002) Hepatitis E virus superinfection in patients with chronic liver disease. Hepatology 36(2):474–478CrossRefGoogle Scholar
  32. 32.
    Goyal R, Kumar A, Panda SK, Paul SB, Acharya SK (2012) Ribavirin therapy for hepatitis E virus-induced acute on chronic liver failure: a preliminary report. Antivir Ther 17(6):1091–1096. CrossRefGoogle Scholar
  33. 33.
    Ramachandran J, Eapen CE, Kang G, Abraham P, Hubert DD, Kurian G, Hephzibah J, Mukhopadhya A, Chandy GM (2004) Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease. J Gastroenterol Hepatol 19(2):134–138CrossRefGoogle Scholar
  34. 34.
    Kondili LA, Chionne P, Porcaro A, Madonna E, Taffon S, Resuli B, Taliani G, Rapicetta M (2006) Seroprevalence of hepatitis E virus (HEV) antibody and the possible association with chronic liver disease: a case-control study in Albania. Epidemiol Infect 134(1):95–101CrossRefGoogle Scholar
  35. 35.
    Vollmer T, Diekmann J, Knabbe C, Dreier J (2019) Hepatitis E virus blood donor NAT screening: as much as possible or as much as needed? Transfusion 59(2):612–622. CrossRefGoogle Scholar
  36. 36.
    Rivero-Juarez A, Jarilla-Fernandez M, Frias M, Madrigal-Sanchez E, López-López P, Andújar-Troncoso G, Machuca I, Camacho A, Muñoz-Valbuena P, Rivero A (2019) Hepatitis E virus in Spanish donors and the necessity for screening. J Viral Hepat.
  37. 37.
    Al-Absi ES, Al-Sadeq DW, Younis MH, Yassine HM, Abdalla OM, Mesleh AG, Hadwan TA, Amimo JO, Thalib L, Nasrallah GK (2018) Performance evaluation of five commercial assays in assessing seroprevalence of HEV antibodies among blood donors. J Med Microbiol 67(9):1302–1309. CrossRefGoogle Scholar
  38. 38.
    Ankcorn MJ, Tedder RS (2017) Hepatitis E: the current state of play. Transfus Med 27(2):84–95. CrossRefGoogle Scholar
  39. 39.
    Boxall E, Herborn A, Kochethu G, Pratt G, Adams D, Ijaz S, Teo CG (2006) Transfusion-transmitted hepatitis E in a ‘nonhyperendemic’ country. Transfus Med 16(2):79–83CrossRefGoogle Scholar
  40. 40.
    Bihl F, Castelli D, Marincola F, Dodd RY, Brander C (2007) Transfusion-transmitted infections. J Transl Med 5:25CrossRefGoogle Scholar
  41. 41.
    Wallace SJ, Webb GW, Madden RG, Dalton HC, Palmer J, Dalton RT, Pollard A, Martin R, Panayi V, Bennett G, Bendall RP, Dalton HR (2017) Investigation of liver dysfunction: who should we test for hepatitis E? Eur J Gastroenterol Hepatol 29(2):215–220. CrossRefGoogle Scholar
  42. 42.
    Juhl D, Baylis SA, Blümel J, Görg S, Hennig H (2014) Seroprevalence and incidence of hepatitis E virus infection in German blood donors. Transfusion 54(1):49–56. CrossRefGoogle Scholar
  43. 43.
    Mansuy JM, Gallian P, Dimeglio C, Saune K, Arnaud C, Pelletier B, Morel P, Legrand D, Tiberghien P, Izopet J (2016) A nationwide survey of hepatitis E viral infection in French blood donors. Hepatology 63(4):1145–1154. CrossRefGoogle Scholar
  44. 44.
    Slot E, Hogema BM, Riezebos-Brilman A, Kok TM, Molier M, Zaaijer HL (2013) Silent hepatitis E virus infection in Dutch blood donors, 2011 to 2012. Euro Surveill 18(31)Google Scholar
  45. 45.
    Sauleda S, Ong E, Bes M, Janssen A, Cory R, Babizki M, Shin T, Lindquist A, Hoang A, Vang L, Piron M, Casamitjana N, Koppelman M, Danzig L, Linnen JM (2015) Seroprevalence of hepatitis E virus (HEV) and detection of HEV RNA with a transcription-mediated amplification assay in blood donors from Catalonia (Spain). Transfusion 55(5):972–979. CrossRefGoogle Scholar
  46. 46.
    Domanović D, Tedder R, Blümel J, Zaaijer H, Gallian P, Niederhauser C, Sauleda Oliveras S, O'Riordan J, Boland F, Harritshøj L, Nascimento MSJ, Ciccaglione AR, Politis C, Adlhoch C, Flan B, Oualikene-Gonin W, Rautmann G, Strengers P, Hewitt P (2017) Hepatitis E and blood donation safety in selected European countries: a shift to screening? Euro Surveill 22(16).
  47. 47.
    Féray C, Pawlotsky JM, Roque-Afonso AM, Samuel D, Dhumeaux D (2014) Should we screen blood products for hepatitis E virus RNA? Lancet 383(9913):218. CrossRefGoogle Scholar
  48. 48.
    Purcell RH, Emerson SU (2008) Hepatitis E: an emerging awareness of an old disease. J Hepatol 48(3):494–503. CrossRefGoogle Scholar
  49. 49.
    Al-Sadeq DW, Majdalawieh AF, Mesleh AG, Abdalla OM, Nasrallah GK (2018) Laboratory challenges in the diagnosis of hepatitis E virus. J Med Microbiol 67(4):466–480. CrossRefGoogle Scholar
  50. 50.
    Trémeaux P, Lhomme S, Chapuy-Regaud S, Peron JM, Alric L, Kamar N, Izopet J, Abravanel F (2016) Performance of an antigen assay for diagnosing acute hepatitis E virus genotype 3 infection. J Clin Virol 79:1–5. CrossRefGoogle Scholar
  51. 51.
    Vollmer N, Trombini F, Hely M, Bellon S, Mercier K, Cazeneuve C (2014) Methodology to study polymers interaction by surface plasmon resonance imaging. MethodsX 2:14–18. eCollection 2015CrossRefGoogle Scholar
  52. 52.
    Zhang F, Li X, Li Z, Harrison TJ, Chong H, Qiao S, Huang W, Zhang H, Zhuang H, Wang Y (2006) Detection of HEV antigen as a novel marker for the diagnosis of hepatitis E. J Med Virol 78(11):1441–1448CrossRefGoogle Scholar
  53. 53.
    Pas SD, de Man RA, Mulders C, Balk AH, van Hal PT, Weimar W, Koopmans MP, Osterhaus AD, van der Eijk AA (2012) Hepatitis E virus infection among solid organ transplant recipients, the Netherlands. Emerg Infect Dis 18(5):869–872. CrossRefGoogle Scholar
  54. 54.
    Baylis SA, Blümel J, Mizusawa S, Matsubayashi K, Sakata H, Okada Y, Nübling CM, Hanschmann KM (2013) HEV collaborative study group. World Health Organization International Standard to harmonize assays for detection of hepatitis E virus RNA. Emerg Infect Dis 19(5):729–735. CrossRefGoogle Scholar
  55. 55.
    Sommese L, Paolillo R, Cacciatore F, Grimaldi V, Sabia C, Esposito A, Sorriento A, Iannone C, Rupealta N, Sarno G, Santangelo M, De Rosa P, Nicoletti G, Napoli C (2018) HLA-G and anti-HCV in patients on the waiting list for kidney transplantation. Adv Med Sci 63(2):317–322. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Experimental MedicineUniversity of Campania “Luigi Vanvitelli”NaplesItaly
  2. 2.U.O.C. Division of Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant ImmunologyUniversity of Campania “Luigi Vanvitelli”NaplesItaly
  3. 3.University Department of Advanced Medical and Surgical Sciences, Clinical Department of Internal Medicine and Specialistic Units (DAI)University of Campania “Luigi Vanvitelli”NaplesItaly

Personalised recommendations