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TREATMENT OF EPSTEIN-BARR VIRUS-INDUCED POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER WITH FOSCARNET ALONE IN AN ADULT AFTER SIMULTANEOUS HEART AND RENAL TRANSPLANTATION

Oertel, Stephan H. K.1,4; Ruhnke, Markus S.1; Anagnostopoulos, Ioannis2; Kahl, Andreas A. A. H.1; Frewer, Andreas F. W.1; Bechstein, Wolf O.1; Hummel, Manfred W.3; Riess, Hanno B.1

Brief Communications: Clinical Transplantation
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Background. The kind and intensity of immunosuppression as well as Epstein-Barr virus, a transforming herpes virus that selectively infects B lymphocytes and causes infectious mononucleosis, have been implicated in the development of posttransplantation lymphproliferative disorders (PT-LPD), a life-threatening complication of solid organ transplantation. The morphologic spectrum of PT-LPD ranges from polymorphous hyperplasia to monomorphous B-non-Hodgkin lymphomas. Among different modalities of treatment, reduction of immunosuppression with or without coadministration of antiviral agents may result in PT-LPD regression especially in mononucleosis-like disease.

Methods. Nonmononucleosis-like PT-LPD in a simultaneous heart and renal recipient was treated with Foscarnet, a potent inhibitor of different herpes viruses with a low profile of toxicity, although intensive immunosuppression therapy was maintained.

Results and conclusions. A 4-week course of Foscarnet resulted in relapse-free complete remission (follow-up 10+ months). Thus, antiviral treatment with Foscarnet, may induce prolonged remission in non-mononucleosis-like PT-LPD without reduction of immunosuppression.

Department of Haematology and Oncology, Charite-Campus Virchow, Medizinische Fakultät der Humboldt Unversität, Augustenburger Platz 1, 13353 Berlin; Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin; and Institut of Pathology, Benjamin Franklin Clinic, Free University, Hindenburg Damm 30, 12200 Berlin, Germany

1 Department of Haematology and Oncology, Charite-Campus Virchow, Medizinische Fakultät der Humboldt Unversität.

2 Institut of Pathology, Benjamin Franklin Clinic, Free University.

3 Deutsches Herzzentrum Berlin.

4 Address correspondence to: Stephan Oertel, Charite-Campus Virchow, Hämatologie und Onkologie, Hämatologische Ambulanz, Augustenburger Platz 1, 13353 Berlin, Germany.

Received 21 July 1998.

Accepted 14 October 1998.

Posttransplantation lymphoproliferative disorders (PT-LPD*) are a life-threatening complication after transplantation of solid organs with an incidence of 1-10% (1). It encompasses a spectrum of disorders that vary from polymorphous to monomorphous proliferation of EBV-transformed B cells (2). Treatments used have included reduction of immunosuppression alone, additional administration of antiviral agents, infusion of anti-B-cell immunoglobulin, surgical resection, and cytotoxic chemotherapy (3-5). Foscarnet is a potent inhibitor of different herpes viruses such as EBV. Foscarnet inhibits the EBV-associated DNA-polymerase, even in the presence of cyclosporin A. In long-term cultures of EBV-immortalized lymphoblastoid cell lines the number of copies of the viral genome per cell is reduced by Foscarnet. In bone marrow and heart transplant recipients with CMV-infections foscarnet has been used without clinical adverse events (6).

A 47-year-old man received a simultaneous heart and renal transplantation in December 1994 for end stage congestive heart failure and end stage renal failure due to mesangioproliferative glomerulonephritis. For the first 7 days after transplantation, immunosuppressive induction consisted of anti-T lymphocyte globulin (ATG) in addition to a long-term immunosuppressive triple-regime with cyclosporine A, azathioprin, and prednisolone. The patient did not receive OKT3 at any time. The patient's recovery was uncomplicated from discharge in January 1995 until August 1997 when he was admitted with a serum creatinine level having increased from 1.8 to 3.5 mg/dl. A renal biopsy (August 12, 1997) was interpreted as tubulotoxicity and mild acute rejection (grade 0-1). The patient was treated with a 3-day course of intravenous methylprednisolone (500 mg/day), whereby the dosages of cyclosporine A (100 mg twice a day) were maintained and azathioprin was switched to mycophenolatmofetil (1.5 g/day). The serum creatinine level decreased to 1.7 mg/dl. A routinely (August 15, 1997) performed chest x-ray revealed a new hilar infiltrate in the right lung and a CT scan demonstrated two distinct infiltrates measuring 2×3 cm and 1×1 cm in segments 9/10 of the right lung. Physical examination showed normal vital signs, no B symptoms, and no evidence of lymphadenopathy. Lactat-dehydrogenase level was 321 U/L (normal range <240 U/L), β2 microglobulin 6.22 mg/L (normal range 0.7-3.4 mg/l); further laboratory studies including liver function tests and levels of serum immunoglobulins were normal. No atypical lymphocytes were seen in a peripheral-blood smear and in flow cytometry. CD4+CD3+ lymphocyte counts was 43%=460/μl and "CD4/CD8" - ratio was 1,1. EBV serology showed evidence of a previous infection, e.g., EBV IgM=negative, EBV IgG=positive, EBV-encoded nuclear antigen (EBNA)=positive. Alkaline phosphatase-anti-alkaline phosphatase for immediate cytomegalovirus (CMV) early antigen was negative. Polymerase chain reaction (PCR) did not reveal CMV-DNA or human-herpes virus 8 (HHV8)-DNA in peripheral blood at any time. The minute tissue cylinder, which was obtained bronchoscopically, showed an area of recent tissue necrosis in half of the sample. In the remaining sample a polymorphous lymphoid infiltrate was observed in the pulmonary interstitium. Immunohistology disclosed that the predominant population consisted of small CD3+ T cells. The majority of the T cells belonged to the subgroup expressing CD8. Between these cells a low number of lymphoid B blasts expressing the CD20 and CD 79a antigens were identified. Expression of the EBNA2 as an indication of EBV infection of these B cells was also found. Immunostaining for virally encoded latent membrane protein 1 led to demarcation of some blasts and also of shadows of necrotic cells expressing this antigen. The patterns of expression of the EBV-specific proteins observed led to the diagnosis of an EBV-induced B cell lymphoproliferation. Because only a small amount of paraffin-embedded material was available an investigation of clonality unfortunately could not be performed. With the acute rejection period in mind, a reduction of the baseline immunosuppressive regime was not performed and application of cyclosporine was maintained at a monoclonal level of 180-200 ng/ml plasma. A chest x-ray control (5.9.1997) did not reveal progression of the tumor. Intravenous foscarnet therapy with 2×200 mg daily and i.v. hydration was started on the same day. Apart from transient hypocalcemia and hypomagnesemia that was corrected by oral calcium and magnesium no other adverse events related to therapy were observed. The chest x-ray control on days 7 and 14 demonstrated stable disease and beginning regression, respectively. Because of a rising serum creatinine level (2.2 mg/dl) on day 14 the foscarnet dose was reduced to 2×125 mg daily and a second 3-day course of methylprednisolone (500 mg/day) was initiated. Renal biopsy did not reveal acute rejection but cyclosporine-induced vascular toxicity. X-ray control on day 21 showed further regression so that the patient received 1 more week of therapy with foscarnet, for a total of 28 days. X-ray and thoracic CT scan on day 29 showed no evidence of pulmonary involvement. During the next months all investigations confirmed persisting complete remission. (Figures 1-4)

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Figure 2

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Figure 4

Figure 4

PT-LPD are a life-threatening complication of solid organ transplantation. The rare occurence of PT-LPD makes therapeutical recommendations difficult. In general, immunosuppression is reduced and without further interventions PT-LPD may regress in some patients (3). The presumed role of EBV in the pathogenesis of PT-LPD suggests that antiviral agents such as acyclovir might be of value (4, 7). Foscarnet, is another, more potent anti EBV drug acting by inhibition of viral DNA polymerase but has no effect on cell multiplication or on the synthesis of human cellular DNA, RNA, and protein (6).

Antiviral therapy with acyclovir in addition to reduction of immunosuppressive drugs, first described by Hanto et al. in 1982, resulted in prolonged regression of PT-LPD in patients with mononucleosis-like disease, but not in PT-LPD which switched from poly- to monoclonal and not in primary monoclonal PT-LPD.

Our patient had two distinct pulmonary infitrates without fever, lymphadenitis, malaise, or any other mononucleosislike symptoms. Nevertheless, in contrast to available data on antiviral therapy of PT-LPD (4, 7) the patient experienced a complete remission (follow-up: 10+ months) after a 4-week course of Foscarnet.

As reduction of immunosuppression with or without antiviral therapy may result in regression of PT-LPD, the role of antiviral treatment in PT-LPD is not definitely determined. In our case report, antiviral treatment with Foscarnet resulted for the first time in persisting complete remission of parenchymatous, localized PT-LPD tumours in the presence of a continous high level of immunosuppressive drugs. This case report supports the hypothesis of the pathoetiologic role of EBV in PT-LPD as well as a causal role of Foscarnet in the treatment of PT-LPD. Which subgroup of patients with PT-LPD will have long-term benefits from this therapy, however, must be evaluated in prospective multicenter trials (8).

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