Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: failure of intravenous ribavirin therapy

Abstract

Summary:Fulminant hepatic failure due to adenovirus infection is a rare complication following stem cell transplantation. We report this complication in an unrelated bone marrow transplant recipient 30 weeks post-transplant. Treatment with intravenous ribavirin was started within 36 h of admission, but he succumbed to unusually fulminant hepatic failure. Adenovirus type 2 was isolated from stool surveillance samples and from post-mortem liver samples. Adenovirus DNA was detected by PCR in blood and sputum samples at admission and was identified in post-mortem liver tissue by electron microscopy. Implications of the failure of ribavirin therapy are discussed. Keywords: adenovirus; bone marrow transplantation; liver failure; ribavirin Adenovirus infections have been increasingly reported in marrow transplant recipients over the past few years. [1][2][3] This is probably attributable to the increase in intensity of immunosuppression and the use of T cell depletion in unrelated donor transplants. Although effective treatment strategies have evolved for cytomegalovirus infection in stem cell transplant recipients, little progress has been made in the treatment of adenovirus infection. Ribavirin, a broad spectrum antiviral agent has often been used in adenovirus disease in stem cell transplant recipients with variable results. [4][5][6][7] We report an uncommon presentation of adenovirus infection in an unrelated bone marrow transplant recipient with failure of ribavirin therapy and briefly discuss its implications. Case reportA 44-year-old male with chronic myeloid leukaemia in chronic phase underwent bone marrow transplantation from an unrelated HLA-matched donor in August 1997. He received cyclophosphamide (120 mg/kg) and total body Correspondence: Dr DW Milligan, Clinical Haematology, Birmingham Heartlands Hospital, Birmingham, B9 5SS, UK Received 4 November 1998; accepted 17 January 1999 irradiation (1440 cGy) as the conditioning regimen, together with Campath-1G antibody (10 mg/day) from day −5 to day +4. GVHD prophylaxis was cyclosporin A and short course methotrexate. The patient also received prophylactic aciclovir, fluconazole and ciprofloxacin. He had evidence of neutrophil engraftment by day +19. Grade 2-3 acute GVHD of the skin developed and was treated with intravenous methylprednisolone (5 mg/kg) followed by oral prednisolone (100 mg/day). At his discharge on day +28 he was on tapering doses of prednisolone. During this period he had stomatitis related to herpes simplex virus which responded to valaciclovir and also an episode of respiratory illness of unproven aetiology. After initial good engraftment, there was a fall in neutrophil and platelet counts. This was associated with normal marrow cellularity. The pancytopenia was thought to be autoimmune or related to GVHD. This was treated with prednisolone, intravenous immunoglobulin, azathioprine and G-CSF with little success. Parvovirus B19 and human herpesvirus-6 infections were excluded. Recurrent herpes simplex stomatitis unresponsive to valaciclovir...

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

“…42 In some cases therapy was successful, [43][44][45][46][47][48] but many patients died despite RBV treatment. [49][50][51][52][53][54][55][56] Furthermore, cidofovir (CDV), an acyclic nucleoside phosphonate that has activity against virtually all DNA viruses including adenovirus, 57,58 has been evaluated for disseminated adenovirus disease with limited success. [59][60][61] Reports of successful alternative strategies are less common and include an apparent beneficial effect of donor leukocyte infusion, 53,54 intravenous immunoglobulin, 62 and ganciclovir(GCV) treatment.…”

Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery

“…4,5,8,9 The outcome of disseminated or fulminant infections has remained dismal despite antiviral therapy. 8,9,12 Although large retrospective studies have been performed, it remains unclear why some patients develop severe disease and succumb to it, whereas others have a more benign course. Because of the retrospective nature of these studies, the natural history of infections in the posttransplantation period remains largely unexplored.…”

Adenovirus Fulminant Hepatic Failure: Disseminated Adenovirus Disease after Unrelated Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia

“…Intravenous or aerosolized ribavirin (1,7,19,38,45,47), vidarabine (7), and cidofovir (7,36,(45)(46)(47) are included in antiviral agents, and the intravenous administration of immunoglobulin (12), the discontinuation of antibiotics (36), donor lymphocyte infusion (7) (38). Although limited, however, early diagnosis and preemptive therapy might be the best hope (39,43 …”

“…In terms of diagnosis, liver biopsy was performed in only one case (5) (11,19), one case with donor lymphocyte infusion (20), and the others without. All of the patients died.…”