Vidarabine Therapy for Virus-Associated Cystitis After Allogeneic Bone Marrow Transplantation
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Bone Marrow Transplantation, (1997) 20, 485–490 1997 Stockton Press All rights reserved 0268–3369/97 $12.00 Vidarabine therapy for virus-associated cystitis after allogeneic bone marrow transplantation M Kawakami, S Ueda, T Maeda, T Karasuno, H Teshima, A Hiraoka, H Nakamura, K Tanaka and T Masaoka The Fifth Department of Internal Medicine and Department of Structure Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Summary: so, against double-stranded DNA viruses including human adenovirus and rodent polyomavirus in vitro.9,10 Vidarabine We describe a method of diagnosing virus-associated has been reported to be effective for hemorrhagic cystitis cystitis after allogeneic bone marrow transplantation caused by adenovirus and polyomavirus in a few cases after (BMT) and treatment with vidarabine therapy. At 7–10 BMT.11,12 However, clinical efficacy of this agent still days post-BMT when cystitis was suspected, we remains unclear for hemorrhagic cystitis and related con- observed urinary sediments by the Papanicolaou stain ditions caused by adenovirus or polyomavirus after BMT. to detect virus inclusion bodies. When positive, we In this report, we describe our experience of vidarabine examined urinary sediments by transmission electron therapy for these conditions after BMT. microscope and measured the diameter of viral particles to determine the families. This process needed only 4 days. Among 16 consecutive cases, adenovirus and poly- Patients and methods omavirus were each detected in three. Adenovirus caused hemorrhagic cystitis in two cases and cystitis Patients without macroscopic hematuria in one case. Polyoma- virus caused cystitis without macroscopic hematuria in Among 16 consecutive patients who received BMT one case. Polyomavirus was also detected in two cases between November 1994 and October 1995 in our institute, without any symptoms. Vidarabine (10 mg/kg/day i.v.) a total of six patients suffered from virus-associated was administered for 5 days as one course. Soon after hemorrhagic cystitis, virus-associated cystitis or viruria. one course of vidarabine, most symptoms subsided and Patient characteristics are shown in Table 1. Two virus inclusion bodies disappeared in all cases except patients received BMT from HLA-matched unrelated for one with severe hemorrhagic cystitis. From these donors and others from HLA-matched sibling donors. Four experiences, vidarabine reduces excretion of adenovirus patients had a transplant for chronic myeloid leukemia in and polyomavirus in the urine of BMT recipients and chronic phase, one for myelodysplastic syndrome improves clinical symptoms in some cases of cystitis (FAB:RA), and one for acute myelogenous leukemia associated with these viruses. (FAB:M2 in 1st CR). All patients were conditioned with Keywords: vidarabine; hemorrhagic cystitis; adenovirus; high-dose cyclophosphamide (120 mg/kg) and total body polyomavirus; BMT; transmission electron microscope irradiation (12 Gy). MCNU (150 mg/body) and splenic irradiation (8 Gy) were added for CML patients. To avoid acrolein-induced hemorrhagic cystitis, infusion of mesna, alkalinization of urine and forced diuresis were performed Virus-associated hemorrhagic cystitis is one of the intrac- during the administration of cyclophosphamide. No urinary table complications after allogeneic bone marrow transplan- symptoms or hematuria occurred during and immediately tation (BMT), and is commonly caused by adenovirus or after administration of cyclophosphamide. Cyclosporine A polyomavirus.1–7 (6 mg/kg p.o. from day 21) and methotrexate (10 mg i.v. Adenovirus and polyomavirus are double-stranded DNA on days 1 and 3) were used for GVHD prophylaxis in all viruses, the diameters of which are about 80 and 42 nm, six patients. respectively.8 We have reported the use of transmission electron microscopy (TEM) on urinary sediments for differ- ential diagnosis of hemorrhagic cystitis caused by these Diagnosis 8 viruses as opposed to other causes. Every 7 to 10 days after BMT or when cystitis was sus- Vidarabine has been reported to be active, though weakly pected from symptoms, we performed urine cultures for bacteria and fungi and observed urinary sediments by Papanicolaou stain to detect virus inclusion bodies in the Correspondence: Dr A Hiraoka, 3-Nakamichi, 1-chome, Higashinari-ku, Osaka 537, Osaka Medical Center for Cancer and Cardiovascular Dis- nuclei and/or cytoplasm. When inclusion bodies were eases, Japan detected, we examined viral particles in urinary sediments Received 18 October 1996; accepted 29 May 1997 by TEM and speculated the family of the virus by measur- Vidarabine for cystitis after BMT M Kawakami et al 486 Table 1 Characteristics of patients Case No. (UPN) Age Sex Diagnosis Transplant type Conditioning regimen 1 (143) 25 F CML-CP R MCNU 1 SI 1 CY 1 TBI 2 (142) 46 M CML-CP U MCNU 1 SI 1 CY 1 TBI 3 (152) 36 F CML-CP U MCNU 1 SI 1 CY 1 TBI 4 (137) 23 M AML (M2) 1st CR R CY 1 TBI 5 (139) 44 M MDS (RA) U CY 1 TBI 6 (141) 30 F CML-CP U MCNU 1 SI 1 CY 1 TBI R = HLA matched sibling donor; MCNU = ranimustine; CY = cyclophosphamide; U = HLA matched unrelated donor; SI = splenic irradiation; TBI = total body irradiation. ing the diameter of particles, as we reported previously.8 teria and fungus were negative or when they were positive, Urine samples were centrifuged at 1800 r.p.m. for 5 min, and antibiotics and antifungal agents did not improve the and supernatants discarded. Buffy coats layered onto red symptoms even after bacteria and fungus had cleared. blood cells were fixed in Saccommano solution, smeared ‘Viruria’ was diagnosed when no urinary symptoms nor on the slide, and stained by the Papanicolaou method.13 For hematuria occurred but viral particles were detected in TEM, buffy coats were resuspended in 2% glutaraldehyde urinary sediments. at pH 7.4 and fixed for 45 min at 4°C. They were postfixed in 1% osmium tetroxide, dehydrated in ethanol and embed- Treatment ded in epon. Sections were cut with a glass knife on a LKB microtome (LKB, Bromma, Sweden) and stained with ura- Patients with urinary symptoms were treated with forced nyl acetate and lead nitrate. A minimum of 100 cells per alkaline diuresis. Analgesics and antibiotics were used as sample selected at random from two epon blocks was necessary. In cases with macroscopic hematuria we perfor- examined. Photographs were taken by Jeol electron micro- med continuous bladder irrigation with prostaglandin E1 scope (Jeol-100CX; Jeol, Tokyo, Japan).8 bladder instillation,15 in addition to forced alkaline diuresis. The diameters of adenovirus and polyomavirus particles All six cases were given vidarabine at a dose of 10 mg/kg are 80 and 42 nm, respectively. When adenovirus infection per day for 5 days as a 2–3-h intravenous infusion, as one was suspected from TEM examination, we performed viral course. Another course was given when necessary. culture to confirm the diagnosis. Polyomavirus is difficult to isolate by the conventional culture method. We pre- viously reported a case of hemorrhagic cystitis after Results alloBMT in which TEM examination of urinary sediments revealed many viral particles of 42 nm diameter, and urine Diagnosis culture with human embryonal kidney (HEK) cells pro- duced polyomavirus BK. Immunocytochemistry of urinary The diagnosis and clinical features of each case are summa- sediments using a polyclonal antibody against simian virus rized in Table 2. Adenovirus was detected in three cases 40 (SV40) virion raised in rabbits was found to react (cases 1–3) and polyomavirus in the remaining three (cases mainly with the major coat protein (VP1) of SV40 and was 4–6). In the former three cases, viral cultures of the urine confirmed to crossreact with both human polyomaviruses also produced adenovirus. Cases 1 and 2 were diagnosed BK and JC by immunofluorescence which detected many to have hemorrhagic cystitis, cases 3 and 4 cystitis, and VP1-positive cells with staining in the nuclei.14 In this cases 5 and 6 viruria. Urine cultures for bacteria and fungus study we considered viral particles of 42 nm diameter as were negative in all cases except case 2. In case 2, cultures polyomaviruses without viral culture and immunocytoch- of urine produced E. coli and urinalysis showed an increase emistry because HEK cells and the antibody against SV40 of leukocytes, indicating the co-incident presence of bac- virion were not routinely available.8 Figure 1 shows terial cystitis. As severe hematuria with blood clot forma- electron micrographs of these viral particles in urinary tion continued even after the administration of antibiotics, sediments. a diagnosis of virus-associated hemorrhagic cystitis was made. Definition Treatment with vidarabine In this report, virus-associated hemorrhagic cystitis and related conditions are defined as follows. ‘Virus-associated Case 1 (Figure 2): Micturition pain and macroscopic hem- hemorrhagic cystitis’ was diagnosed when viral particles aturia developed on days 26 and 28 after BMT, respect- were detected in urinary sediments and macroscopic hemat- ively. The diagnosis of adenovirus-associated hemorrhagic uria with urinary symptoms were present. ‘Virus-associated cystitis was made after TEM examination of urinary sedi- cystitis’ was diagnosed when viral particles were detected ments. Continuous bladder irrigation and urine alkaliniz- in urinary sediments and urinary symptoms developed, but ation, and bladder instillation of prostaglandin E1 at a dose no macroscopic hematuria occurred. The diagnosis of these of 500 mg per day for 7 days were instigated but the symp- two conditions was made only when urine cultures for bac- toms did not resolve. On day 34 vidarabine therapy was Vidarabine for cystitis after BMT M Kawakami et al 487 Figure 1 Electron micrographs of urinary sediments. Many viral particles are observed in the nucleus of the urotherial cell. (a) The diameter of viral particles is about 80 nm, corresponding to adenovirus. (b) The diameter of viral particles is about 42 nm, corresponding to polyomavirus.