Epstein–Barr virus reactivation after allogeneic stem cell transplantation without lymph node enlargement

Abstract

Epstein–Barr virus-associated disease is a rare complication after allogeneic bone marrow transplantation (BMT) with a cumulative incidence of 1% at 10 years using nonmanipulated grafts [1]. T-cell depletion increases the incidence significantly [2]. Most cases occur during the 1st year after transplantation with the incidence highest at 2–3 months after BMT [3]. Epstein–Barr virus (EBV) disease after stem cell transplantation is always a reactivation of latent infection and mainly derives from donor B lymphocytes. It presents usually as a disseminated disease with fever, lymph node enlargement, respiratory disease, and features of hepatitis [1, 3, 4]. The common lymphadenopathy usually leads to diagnosis; however, cases diagnosed only at autopsy have been published [5, 6]. A 62-year-old male patient was allografted for stage IIIB light chain multiple myeloma, which had relapsed after tandem high-dose melphalan therapy combined with autologous peripheral blood stem cell transplantation 2 years ago. Conditioning therapy for allografting consisted of treosulfan 36 g/m, fludarabine 75 mg/m (50% dose reduced for renal impairment), and antithymocyte globulin (ATG) 90 mg/m [7]. The patient was grafted with 11×10 CD34 cells per kilogram body weight mobilized with granulocyte colony-stimulating factor (G-CSF) from an HLA-matched, unrelated male donor. Donor and recipient were both seronegative for cytomegalovirus (CMV) and positive for EBV. Cyclosporin A and short-course methotrexate were given for graft-versus-host disease (GVHD) prophylaxis. Regimen-related toxicity was moderate with Bearman grade I for liver and mucosa [8]. Fever of unknown origin was treated with broad-spectrum antibiotics and acyclovir was given for local herpes simplex virus reactivation. The patient engrafted with 1000 leukocytes/μl on day +13 and with 20,000 thrombocytes/μl on day +18 and was discharged on day +28 without signs of GVHD or infection. The patient was readmitted on day +48 because of fever up to 39.0°C and malaise. Broad antimicrobial therapy including antibiotics, systemic fungistatics and virostatics was initiated immediately without success despite several modifications during therapy. Clinical presentation and results of comprehensive radiological, computed tomography (CT) scan and ultrasound diagnostics remained noncharacteristic. Bilirubin rose to the approximately 20fold upper normal value and transaminases increased only slightly. There were no signs of cutaneous or enteric GVHD. The patient developed renal and pulmonary failure and died on day +63 from multiorgan failure on the intensive care unit. Neither bacterial nor fungal pathogens could be isolated from blood, urine, and bronchoalveolar lavage. Tests for fungal antigens scored even negative. Screening for viral pathogens was done by polymerase chain reaction (PCR) amplification. The tests scored consistently negative for CMV, human herpesvirus (HHV)-6, HHV-7, varicellazoster virus, parvovirus B19, adenovirus, enterovirus, respiratory syncytial virus, and influenza virus type A and B. EBV DNA could not be amplified from a first blood sample obtained at day +51. However, since day +54 blood samples had scored consistently positive for EBV DNA. Additionally, EBV DNAwas amplified by conventional PCR from bone marrow aspiration, bronchoalveolar lavage, duodenal secretion, and urine. Examination of a liver biopsy obtained by transjugular puncture a few days prior to death led to the diagnosis of a lymphohistiocytic hepatitis and to exclusion of GVHD. W. H. Kruger (*) . F. Schuler . C. Lotze . C. Busemann . G. Dolken Internal Medicine C (Haematology and Oncology, Transplant Centre), Ernst-Moritz-Arndt-University, Ferdinand-Sauerbruch-Strase, 17487 Greifswald, Germany e-mail: william.krueger@uni-greifswald.de Tel.: +49-3834-8622007 Fax: +49-3834-8622012