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Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients

Abstract

Hepatitis E virus (HEV) can cause chronic infection and liver cirrhosis in immunocompromised individuals. The frequency and clinical importance of HEV was studied retrospectively in a cohort of 236 Swedish allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In blood samples collected at 6 months after HSCT, HEV RNA was identified in 8/236 (3.4%) patients, and 11/236 (4.7%) patients had detectable anti-HEV IgG and/or IgM, eight of whom were HEV RNA negative. Two of the patients with positive HEV RNA died with ongoing signs of hepatitis: one of acute liver and multiple organ failure, the other of unrelated causes. The remaining six patients with HEV RNA had cleared the infection at 7–24 (median 8.5) months after HSCT. HEV infection was associated with elevated alanine aminotransferase at 6 months after HSCT (OR 15, 1.3–174, p = 0.03). Active graft-versus-host disease of the liver at 6 months after HSCT was present in 3/8 (38%) patients with HEV RNA, but was not significantly associated with HEV infection. In conclusion, HEV infection is an important differential diagnosis in patients with elevated liver enzymes after HSCT. Although spontaneous clearance was common, the clinical course may be severe.

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Fig. 1: The course of HEV infection in the three patients with persistent viremia (patients 1, 2, and 3).
Fig. 2: Phylogenetic tree based on 325 nucleotides of partial ORF1 for 348 HEV genotype 3 strains.

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References

  1. Kamar N, Izopet J, Pavio N, Aggarwal R, Labrique A, Wedemeyer H, et al. Hepatitis E virus infection. Nat Rev Dis Prim. 2017;3:17086. https://doi.org/10.1038/nrdp.2017.86.

    Article  PubMed  Google Scholar 

  2. Hewitt PE, Ijaz S, Brailsford SR, Brett R, Dicks S, Haywood B, et al. Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet. 2014;384:1766–73. https://doi.org/10.1016/s0140-6736(14)61034-5.

    Article  PubMed  Google Scholar 

  3. Koenecke C, Pischke S, Beutel G, Ritter U, Ganser A, Wedemeyer H, et al. Hepatitis E virus infection in a hematopoietic stem cell donor. Bone Marrow Transplant. 2014;49:159–60. https://doi.org/10.1038/bmt.2013.148.

    Article  CAS  PubMed  Google Scholar 

  4. Schlosser B, Stein A, Neuhaus R, Pahl S, Ramez B, Kruger DH, et al. Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient. J Hepatol. 2012;56:500–2. https://doi.org/10.1016/j.jhep.2011.06.021.

    Article  CAS  PubMed  Google Scholar 

  5. Guillois 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;62:351–7. https://doi.org/10.1093/cid/civ862.

    Article  PubMed  Google Scholar 

  6. Kamar N, Selves J, Mansuy JM, Ouezzani L, Peron JM, Guitard J, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med. 2008;358:811–7. https://doi.org/10.1056/NEJMoa0706992.

    Article  CAS  PubMed  Google Scholar 

  7. Dalton HR, Bendall RP, Keane FE, Tedder RS, Ijaz S. Persistent carriage of hepatitis E virus in patients with HIV infection. N Engl J Med. 2009;361:1025–7. https://doi.org/10.1056/NEJMc0903778.

    Article  CAS  PubMed  Google Scholar 

  8. Ollier L, Tieulie N, Sanderson F, Heudier P, Giordanengo V, Fuzibet JG, et al. Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab. Ann Intern Med. 2009;150:430–1.

    Article  Google Scholar 

  9. Versluis J, Pas SD, Agteresch HJ, de Man RA, Maaskant J, Schipper ME, et al. Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Blood. 2013;122:1079–86. https://doi.org/10.1182/blood-2013-03-492363.

    Article  CAS  PubMed  Google Scholar 

  10. Koenecke C, Pischke S, Heim A, Raggub L, Bremer B, Raupach R, et al. Chronic hepatitis E in hematopoietic stem cell transplant patients in a low-endemic country? Transpl Infect Dis. 2012;14:103–6. https://doi.org/10.1111/j.1399-3062.2011.00702.x.

    Article  CAS  PubMed  Google Scholar 

  11. Remberger M, Ackefors M, Berglund S, Blennow O, Dahllof G, Dlugosz A, et al. Improved survival after allogeneic hematopoietic stem cell transplantation in recent years. A single-center study. Biol Blood Marrow Transpl. 2011;17:1688–97. https://doi.org/10.1016/j.bbmt.2011.05.001.

    Article  Google Scholar 

  12. Torlen J, Ringden O, Garming-Legert K, Ljungman P, Winiarski J, Remes K, et al. A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation. Haematologica. 2016;101:1417–25. https://doi.org/10.3324/haematol.2016.149294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

    CAS  PubMed  Google Scholar 

  14. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56. https://doi.org/10.1016/j.bbmt.2005.09.004.

    Article  PubMed  Google Scholar 

  15. Norder H, Karlsson M, Mellgren A, Konar J, Sandberg E, Lasson A, et al. Diagnostic performance of five assays for anti-hepatitis E virus IgG and IgM in a large cohort study. J Clin Microbiol. 2016;54:549–55. https://doi.org/10.1128/jcm.02343-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Roth A, Lin J, Magnius L, Karlsson M, Belak S, Widen F, et al. Markers for ongoing or previous hepatitis E virus infection are as common in wild ungulates as in humans in Sweden. Viruses. 2016;8. https://doi.org/10.3390/v8090259.

  17. Pagano M, Gauvreau K. Principles of Biostatistics, 2nd edition. Pacific Grove, CA: Duxbury; 2000.

  18. Sheskin DJ. Handbook of parametric and nonparametric statistical procedures, 4th edition. Boca Raton, FL: Chapman & Hall/ CRC; 2004.

  19. Willemse SB, Bezuur DL, Blom P, Kneppers E, Verheij J, Zaaijer HL, et al. Hepatitis E virus infection and hepatic GvHD in allogeneic hematopoietic stem cell transplantation recipients. Bone Marrow Transplant. 2017;52:622–4. https://doi.org/10.1038/bmt.2016.327.

    Article  CAS  PubMed  Google Scholar 

  20. Tang FF, Mo XD, Wang Y, Yan CH, Chen YH, Chen H, et al. Hepatitis E virus infection after haploidentical haematopoietic stem cell transplantation: incidence and clinical course. Br J Haematol. 2019;184:788–96. https://doi.org/10.1111/bjh.15672.

    Article  CAS  PubMed  Google Scholar 

  21. Abravanel F, Mansuy JM, Huynh A, Kamar N, Alric L, Peron JM, et al. Low risk of hepatitis E virus reactivation after haematopoietic stem cell transplantation. J Clin Virol. 2012;54:152–5. https://doi.org/10.1016/j.jcv.2012.02.015.

    Article  PubMed  Google Scholar 

  22. Reekie I, Irish D, Ijaz S, Fox T, Bharucha T, Griffiths P, et al. Hepatitis E infection in stem cell and solid organ transplantpatients: a cross-sectional study: the importance of HEV RNA screening in peri-transplant period. J Clin Virol. 2018;107:1–5. https://doi.org/10.1016/j.jcv.2018.07.011.

    Article  PubMed  Google Scholar 

  23. Carre 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;52:643–5. https://doi.org/10.1038/bmt.2016.337.

    Article  CAS  PubMed  Google Scholar 

  24. von Felden J, Alric L, Pischke S, Aitken C, Schlabe S, Spengler U, et al. The burden of hepatitis E among patients with haematological malignancies: a retrospective European cohort study. J Hepatol. 2019;71:465–72. https://doi.org/10.1016/j.jhep.2019.04.022.

    Article  Google Scholar 

  25. Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012;18:1851–60. https://doi.org/10.3748/wjg.v18.i16.1851.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Donnelly MC, Scobie L, Crossan CL, Dalton H, Hayes PC, Simpson KJ. Review article: hepatitis E—a concise review of virology, epidemiology, clinical presentation and therapy. Aliment Pharmacol Ther. 2017;46:126–41. https://doi.org/10.1111/apt.14109.

    Article  CAS  PubMed  Google Scholar 

  27. Wahren B, Gahrton G, Linde A, Ljungman P, Lonnqvist B, Ringden O, et al. Transfer and persistence of viral antibody-producing cells in bone marrow transplantation. J Infect Dis. 1984;150:358–65. https://doi.org/10.1093/infdis/150.3.358.

    Article  CAS  PubMed  Google Scholar 

  28. Baylis SA, Gartner T, Nick S, Ovemyr J, Blumel J. Occurrence of hepatitis E virus RNA in plasma donations from Sweden, Germany and the United States. Vox Sang. 2012;103:89–90. https://doi.org/10.1111/j.1423-0410.2011.01583.x.

    Article  CAS  PubMed  Google Scholar 

  29. Thom K, Gilhooly P, McGowan K, Malloy K, Jarvis LM, Crossan C, et al. Hepatitis E virus (HEV) in Scotland: evidence of recent increase in viral circulation in humans. Euro Surveill: Bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2018;23. https://doi.org/10.2807/1560-7917.Es.2018.23.12.17-00174.

  30. Boland F, Martinez A, Pomeroy L, O’Flaherty N. Blood donor screening for hepatitis E virus in the European Union. Transfus Med Hemother. 2019;46:95–103. https://doi.org/10.1159/000499121.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Norder H, Galli C, Magnil E, Sikora P, Ekvarn E, Nystrom K, et al. Hepatitis E virus genotype 3 genomes from RNA-positive but serologically negative plasma donors have CUG as the Start Codon for ORF3. Intervirology. 2018;61:96–103. https://doi.org/10.1159/000491926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Norder H, Sundqvist L, Magnusson L, Ostergaard Breum S, Lofdahl M, Larsen LE, et al. Endemic hepatitis E in two Nordic countries. Euro Surveill: bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2009;14:pii: 19211.

  33. Boxman ILA, Jansen CCC, Hagele G, Zwartkruis-Nahuis A, Tijsma ASL, Vennema H. Monitoring of pork liver and meat products on the Dutch market for the presence of HEV RNA. Int J Food Microbiol. 2019;296:58–64. https://doi.org/10.1016/j.ijfoodmicro.2019.02.018.

    Article  CAS  PubMed  Google Scholar 

  34. Wang H, Castillo-Contreras R, Saguti F, Lopez-Olvera JR, Karlsson M, Mentaberre G, et al. Genetically similar hepatitis E virus strains infect both humans and wild boars in the Barcelona area, Spain, and Sweden. Transbound Emerg Dis. 2019;66:978–85. https://doi.org/10.1111/tbed.13115.

    Article  CAS  PubMed  Google Scholar 

  35. Agency EM. Reflection paper on viral safety of plasma-derived medicinal products with respect to hepatitis E virus. London: European Medicines Agency; 2016.

    Google Scholar 

  36. EASL. Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018;68:1256–71. https://doi.org/10.1016/j.jhep.2018.03.005.

    Article  Google Scholar 

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Acknowledgements

We thank Stephan Mielke for critically reading the paper and giving valuable comments.

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Swartling, L., Nordén, R., Samuelsson, E. et al. Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 55, 1255–1263 (2020). https://doi.org/10.1038/s41409-020-0823-7

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