Ann Hematol (2015) 94:359–360 DOI 10.1007/s00277-014-2163-4


Chronic hepatitis E virus infection following allogeneic hematopoietic stem cell transplantation: an important differential diagnosis for graft versus host disease Dominik Bettinger & Elisabeth Schorb & Daniela Huzly & Marcus Panning & Annette Schmitt-Graeff & Philipp Kurz & Hartmut Bertz & Jürgen Finke & Volker Brass & Robert Thimme & Peter Hasselblatt

Received: 28 May 2014 / Accepted: 4 July 2014 / Published online: 13 July 2014 # Springer-Verlag Berlin Heidelberg 2014

Dear Editor, Hepatitis E virus (HEV) infection is increasingly recognized as an important cause of chronic liver disease in immunocompromised patients, in particular following organ transplantation [1]. Chronic HEV infection can be controlled in most cases by reducing immunosuppressive therapies and/or antiviral therapy with ribavirin [2]. Diagnosis and clinical management are particularly challenging in patients with preexisting liver disease such as hepatic graft versus host disease (GvHD). Here, we report on a 47-year-old patient, who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) for mantle cell lymphoma in October 2011. Subsequent relapses were treated with immunochemotherapy and donor lymphocyte infusions, and complete remission was achieved in May 2013. Grade IV gastrointestinal and cutaneous GvHD was controlled by corticosteroids. In November 2013, he was hospitalized for gastrointestinal bleeding from colonic ulcerations of unknown origin that ceased

Dominik Bettinger and Elisabeth Schorb equally contributed in this study. D. Bettinger : V. Brass : R. Thimme : P. Hasselblatt (*) Department of Medicine II, University Hospital Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany e-mail: [email protected] E. Schorb : H. Bertz : J. Finke Department of Medicine I, University Hospital Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany D. Huzly : M. Panning Institute of Virology, University Hospital Freiburg, Hermann-Herder-Str. 11, 79104 Freiburg, Germany A. Schmitt-Graeff : P. Kurz Institute of Pathology, University Hospital Freiburg, Breisacher Str. 114a, 79106 Freiburg, Germany

spontaneously. However, jaundice and progressive cholestatic liver disease were noted. Infection with hepatitis A, B, and C virus was excluded, and immunosuppressive therapy with corticosteroids was intensified for suspected hepatic GvHD. However, liver function deteriorated (bilirubin 39.8 mg/dl). Liver histology revealed mild and rather inactive GvHD, while pronounced periportal hepatitis suggested a toxic origin. In the meantime, chronic HEV infection was diagnosed based on serology and detection of HEV RNA in the patients’ peripheral blood and stool. Retrospective analyses of several blood samples revealed ongoing viremia since July 2013. Immunosuppressive therapy was tapered, and antiviral therapy with ribavirin (800 mg/day) was initiated. Although HEV reverse transcription PCR (RT-PCR) became negative within 6 weeks, liver dysfunction and hyperbilirubinemia persisted (Fig. 1). Another liver biopsy suggested progression of hepatic GvHD, and corticosteroid therapy was reinitiated. However, the patient eventually died from hepatic and renal failure in March 2014. Retrospective analysis revealed that HEV genotype 3f had been transmitted by platelet transfusions in July 2013 from an asymptomatic donor (see [3] for virological details). Interestingly, the donor was seronegative, and the virus could only be detected by RT-PCR reminiscent of a similar case of transfusion-associated chronic hepatitis E [4]. A retrospective cohort study comprising 328 patients revealed that de novo HEV infection may occur in up to 2.4 % of patients after allo-HSCT, which is frequently misdiagnosed as GvHD and associated with high mortality rates [5]. HEV may also be reactivated in seropositive patients due to the severe immunosuppression related to allo-HSCT [5], although this risk appears to be low [6, 7]. The implications of this case are several-fold. To our knowledge, this is the first case of proven transfusion-


Ann Hematol (2015) 94:359–360

serum bilirubin [mg/dl]


HEV-RNA positive (plasma)

References Ribavirin

40 30 20



1st liver biopsy

2nd liver biopsy

0 0 1 2 3 4





months after HEV infection by platelet transfusion

Fig. 1 Time course of liver dysfunction as determined by serum bilirubin concentrations in a patient with chronic HEV infection and concomitant hepatic GvHD

associated HEV infection in Germany. In addition to HSC donors [8], suitable screening guidelines for blood products need to be discussed, which would be particularly important for patients undergoing allo-HSCT with regard to the pronounced immunosuppression and need for repetitive transfusions. Since liver dysfunction related to GvHD is common in patients following allo-HSCT [9], chronic HEV infection should be ruled out in these patients, especially since GvHD and viral hepatitis are treated by opposing therapeutic strategies. However, clinical management remains particularly challenging in patients with concomitant chronic HEV infection and hepatic GvHD, as in this patient. Informed consent was obtained from this patient. Conflict of interest The authors declare that they have no conflict of interest.

1. Hoofnagle JH, Nelson KE, Purcell RH (2012) Hepatitis E. N Engl J Med 367(13):1237–1244 2. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, Radenne S, Coilly A, Garrigue V, D’Alteroche L, Buchler M, Couzi L, Lebray P, Dharancy S, Minello A, Hourmant M, Roque-Afonso AM, Abravanel F, Pol S, Rostaing L, Mallet V (2014) Ribavirin for chronic hepatitis E virus infection in transplant recipients. N Engl J Med 370(12):1111–1120 3. Huzly D, Umhau M, Bettinger D, Cathomen T, Emmerich F, Hasselblatt P, Hengel H, Herzog R, Kappert O, Maassen S, Schorb E, Schulz-Huotari C, Thimme R, Unmussig R, Wenzel J, Panning M (2014) Transfusion-transmitted hepatitis E in Germany, 2013. Euro surveillance: bulletin Europeen sur les maladies transmissibles= European Communicable Disease Bulletin 19 (21) 4. Haim-Boukobza S, Ferey MP, Vetillard AL, Jeblaoui A, Pelissier E, Pelletier G, Teillet L, Roque-Afonso AM (2012) Transfusiontransmitted hepatitis E in a misleading context of autoimmunity and drug-induced toxicity. J Hepatol 57(6):1374–1378 5. Versluis J, Pas SD, Agteresch HJ, de Man RA, Maaskant J, Schipper ME, Osterhaus AD, Cornelissen JJ, van der Eijk AA (2013) Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Blood 122(6): 1079–1086 6. Abravanel F, Mansuy JM, Huynh A, Kamar N, Alric L, Peron JM, Recher C, Izopet J (2012) Low risk of hepatitis E virus reactivation after haematopoietic stem cell transplantation. J Clin Virol 54(2):152– 155 7. Koenecke C, Pischke S, Heim A, Raggub L, Bremer B, Raupach R, Buchholz S, Schulz T, Manns MP, Ganser A, Wedemeyer H (2012) Chronic hepatitis E in hematopoietic stem cell transplant patients in a low-endemic country? Transpl Infect Dis 14(1):103–106 8. Koenecke C, Pischke S, Beutel G, Ritter U, Ganser A, Wedemeyer H, Eder M (2014) Hepatitis E virus infection in a hematopoietic stem cell donor. Bone Marrow Transplant 49(1):159–160 9. Tuncer HH, Rana N, Milani C, Darko A (2012) Al-Homsi SA Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol 18(16):1851–1860

Chronic hepatitis E virus infection following allogeneic hematopoietic stem cell transplantation: an important differential diagnosis for graft versus host disease.

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