Brief Report

LATE-ONSET HEMORRHAGIC CYSTITIS FOLLOWING BONE MARROW TRANSPLANTATION: A Case Report

Andrea C. Goddard, MRCP, and Vaskar Saha, PhD Academic Department of Pediatric Oncology, St Bartholomew's Hospital, London, UK

A 7year-old child developed BK virus-induced hemorrhagic cystitis on day I6 after a n allogeneic bone mawow transplant. Contraly to previous repmts, intravesical instillation of prostaglandin E2 was associated with considerable discomfort and failed to alleviate symptoms. Supportive treatment thereafter consisted of adequate hydration until the spontaneous resolution of symptoms on day 52.

Keywords BK virus, bone marrow transplant, hemorrhagic cystitis

Hemorrhagic cystitis (HC) occurs in 10-70% of recipients of allogeneic bone marrow transplants (BMTs) [ 11. It is distressing and occasionally life threatening [2]. Early-onset HC occurswithin 48 hours of cyclophosphamide administration and is probably due to the direct toxic effect of cyclophospha- mide (CY) metabolites on the bladder mucosa [3]. Preventive and therapeu- tic measures include intravenous (IV) hydration and/or mesna [4]. The etiology of late-onset HC, occurring more than 48 hours after CY administra- tion [3], remains uncertain, although BK virus-induced cystitis has been increasingly implicated [ 5 ] . Although the rationale for the management and prevention of early-onset HC is clear, there are no established methods of treatment of late-onset HC. Strategies proposed have included vidarabine [6], bacterial DNA-gyrase inhibitors (which have been shown to possess in vitro activity against the BK virus) [ l ] and the intravesical instillation of formalin, silver nitrate, or aluminum [ 71. Recently, intravesical instillation of prostaglandin E2 (PGE:,) has been used successfully for the symptomatic treatment of adult patients with late-onset HC, with few side effects "71. The mechanism of action of PGE2 in controlling HC is unknown. BK virus is associated with diffuse mucosal bleeding and it is possible that PGEp decreases bleeding by causing smooth muscle contractions in mucosal and

Received 5 August 1996; accepted 20 September 1996. Address correspondence to Dr. Vaskar Saha, Department of Pediatric Oncology, St. Bartholomew's

Hospital, London, EClA 7BE, UK. E-mail: v.saha@icrf.icnet.uk

Pediatrir Hematology and Oncology, 14:273-275, I997 CDpyright 0 1997 Taylor LY Francis 0888-0018/97 $12.00 -I .00

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274 A. C. CODDARD AND V. SAHA

submucosal blood vessels [8]. We report our experience with PGE2 in a child with late-onset HC.

CASE REPORT

A 7-year-old Cypriot boy received an allogeneic BMT while in second remission of acute lymphoblastic leukemia. Prior to transplantation he was noted to have decreased creatinine clearance (69 mL/min/m2) and dimin- ished left ventricular function (ejection fraction 42%). These abnormalities were attributed to prior chemotherapy. Serological evidence of prior infec- tion with cytomegalovirus (CMV) was noted. CY with total body irradiation and a testicular boost was used as the conditioning regimen according to the Medical Research Council UKALL XI protocol, which incorporates mesna and hydration as uroprotective measures. Cyclosporine and metho- trexate were used as graft-versus-host disease (GVHD) prophylaxis. The patient received prophylactic fluconazole and acyclovir from day -7 and weekly N immunoglobulin from day - 1. A febrile episode that developed on day 6 was treated with ceftazidime and ciprofloxacin-vancomycin with resolution on day 14. The rationale for this empirical antibiotic regimen was to avoid the use of aminoglycosides because of the presence of renal insufficiency. Blood product support (irradiated and CMV negative) was given throughout the aplastic period to maintain hemoglobin greater than 8 g/dL and platelets greater than 15 X 109/L. Engraftment was evident from day 14, at which time he developed transient grade I1 GVHD.

On day 16 he developed persistent grade 3-4 hematuria [l]. This did not improve with fluid diuresis, platelet support, or the use of a bacterial DNA-gyrase inhibitor (ciprofloxacin) . Electron microscopy of a urine sample on day 21 revealed the presence of a polyoma virus, confirmed as the BK virus by the polymerase chain reaction [9]. Subsequent analysis of pretrans- plantation serum was positive for anti-BK virus antibody. Urine culture was persistently negative for bacteria, CMV, and adenovirus. PGE2 was instilled intravesically on three occasions at a dose of 500 p g in 100 mL of normal saline left for 1 hour on two occasions and 750 pg for 4 hours on the third occasion. Despite N sedation and narcotic analgesia, instillation was not tolerated. There was abdominal discomfort during and cramps after the procedure. Apart from a transient decrease in the degree of hematuria following the first instillation, there was no improvement in the severity of dysuria or hematuria. PGE2 treatment was abandoned and he was supported with hydration alone until his HC resolved spontaneously on day 52.

DISCUSSION

Subclinical infection with the BK polyoma virus occurs in nearly all children [3], following which the virus is thought to remain latent in the

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PGE, A N D POSTTRANSPLANTATION HEMORRHAGIC CYSTITIS 275

cells of the uroepithelium [ 5 ] . Reactivation, symptomatic or asymptomatic, and excretion in the urine may occur in pregnancy and during periods of immune suppression [ 5 ] . There is a strong temporal correlation between BKviruria and late-onset HC [ 5 ] , although prior damage to the uroepithel- ium by acrolein and the increased immune suppression associated with GVHD (or its prophylaxis) may be additional contributing factors [ 3 ] . We graded hematuria as previously reported [ 11 : grade 0, no hematuria; grade 1, microscopic hematuria; grade 2, macroscopic; grade 3, macroscopic with clots; and grade 4, associated with clots and elevated creatinine. Only grades 2 to 4 are considered to be HC as grade 1 hematuria is not unusual in bone marrow recipients. In the absence of specific therapy, treatment of grade 3-4 HC is supportive: to relieve pain and avoid the complications of mechanical obstruction of the urinary tract. This is achieved by blood product support and hyperhydration. Bladder irrigation with normal saline and urological intervention may be required in severe cases. In this child, in contrast to previously reported cases, intravesical instillation of PGEp was ineffective. It was unpleasant for the patient and exposed him to the potential complica- tions of instrumentation of the urinary tract and the risks associated with IV narcotic analgesia and sedation.

REFERENCES 1. Bedi A, Miller CB, Haiison JL, et al. Association of BK virus with failure of prophylaxis against

hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995;13: 1103-1 109. 2. Brugiercs I,, Hartmann 0, Travagli JP, et al. Hemorrhagic cystitis following highdose chemotherapy

and bone marrow transplantation in children with malignancies: incidence, clinical course, and outcome. J Clin Onrol. 1989;7:194-199.

3. Russell SJ, Vowels MR, Vale T. Hemorrhagic cystitis in pediatric hone marrow transplant patients: an association with infective agentr, GVHD and prior cyclophosphamide. Bone Marrow Transplant.

4. Shepherd JD, Pringle LE, Barrictt MJ, Klingemann HG, Reece DE, Phillips GL. Mesna versus hyper- hydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in hone marrow transplantation. ,I Clin Oncol. 1991;9:2016-2020.

5. Arthur RR, Shah KV, Baust SJ, Santos GW, Sara1 R. Association of BKviruria with hemorrhagic cystitis in recipients of hone marrow transplants. N EnglJ Med. 1986;315:230-234.

6. Kitabayashi A, Hirokawa M, Kuroki J, Nishinari T, Niitsu H, Miura AB. Successful vidarahine therapy for adenovirus type 1 I-associated acute hemorrhagic cystitis after allogeneic bone marrow transplanta- tion. Bone Marrow Transplant. 1994;14:853-854.

7. Laszlo D, Bosi A, Guidi S, et al. Prostaglandin E2 bladder instillation for the treatment of hemorrhagic cystitis after allogeneic bone marrow transplantation. Huematologzca. 1995;80:421-425.

8. Laurence A, Levine MD, Kranc DM. Evaluation of carboprostromethamine in the treatment of cyclophosphamide-induced haemorrhagic cystitis. Cancer. 1990;66:242-245.

9. Azzi A, Fanci R, Bosi A, et al. Monitoring of polyomavirus BKviruria in bone marrow transplantation patients by DNA hybridization assay and by polymerase chain reaction: an approach to assess the relationship between BK viruria and hemorrhagic cystitis. Bone Marrow Transplant. 1994; 14:235-240.

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