After allogenic bone marrow transplantation agent of hemorrhagic cystitis: BK virus

doi:10.4236/crcm.2013.25080

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Vol.2, No.5, 298-301 (2013) Case Reports in Clinical Medicine

http://dx.doi.org/10.4236/crcm.2013.25080

After allogenic bone marrow transplantation agent of

hemorrhagic cystitis: BK virus*

Berber Ilhami1#, Koroglu Mustafa1, Erkurt Mehmet Ali1, Oguz Fatih2, Altint as Ramazan2,

Kaya Emin1, Kuku Irfan1, Ulutas Ozkan3

1Department of Hematology, Faculty of Medicine, Inonu University, Malatya, Turkey;

#Corresponding Author: [email protected]

2Department of Urology, Faculty of Medicine, Inonu University, Malatya, Turkey

3Department of Nephrology, Faculty of Medicine, Inonu University, Malatya, Turkey

Received 5 June 2013; revised 11 July 2013; accepted 20 July 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Hemorrhagic cystitis is a common and in its

severe form potentially life threatening compli-

cation of hematopoietic stem cell transplanta-

tion. Hemorrhagic cystitis is defined as a diffuse

inflammatory condition of the urinary bladder

due to an infectious or noninfectious etiology

resulting in bleeding from the bladder mucosa.

Hemorrhagic cystitis is characterized by lower

urinary tract symptoms including dy suria, hema-

turia and h emorrhag e. The mos t common cause is

a bacterial infection that usuall y responds prom-

ptly to treatment. But chronic and recurrent he-

morrhagic cystitis often arises from anticancer

chemotherapy or radiotherapy for the treatment

of pelvic malignancies. Infectious etiologies are

less common causes of chronic hemorrhagic

cystitis except in immunocompromised hosts

like bone marrow transplant recipients. Hemor-

rhagic cystitis is a significant complication of

bone marrow transplantation which influences

economic and survival outcome. Hemorrhagic

cystitis can be divided into two classes accord-

ing to onset time; early and late onset time. Early-

onset hemorrhagic cystitis is commonly asso-

ciated used with chemo-radiotherapy protocols

in some of the preparatory regimens. More than

one factor is accused in the etiology of late

onset hemorrhagic cystitis. Here, we present a

patient whose hematuria started after 54 days

from allogeneic stem cell transplantation.

Keywords: Allogenic Bone Marrow Transplantation;

Hemorrhagic Cysti tis; BK V irus

1. INTRODUCTION

Hemorrhagic cystitis is described as a diffuse in-

flammatory condition of the urinary bladder due to an

infectious or noninfectious etiology resulting in bleeding

from the bladder mucosa. Hemorrhagic cystitis is diffe-

rentiated into two types according to onset time; early

and late onset hemorrhagic cystitis [1].

Early-onset hemorrhagic cystitis commonly associates

with chemo-radiotherapy used in the preparation regi-

mens. Especially, hemorrhagic cystitis emerges as a re-

sult of high dose cyclophosphamide an d ifosfamide treat-

ments. The dose of cyclophosphamide is associated with

the risk of hemorrhagic cystitis. If prophylaxis is not

used for hemorrhagic cystitis in cases with hematopoietic

stem cell transplantation, the risk of hemorrhagic cystitis

has increased. Hematuria is the most frequently occurred

after two weeks of preparation regimen. On the other

hand, hemorrhagic cystitis can start immediately or three

months later after application of cyclophosphamide. Risk

is increased in patients who had pelvic irradiation and

busulfan treatment. Allogeneic transplant patients and

elderly patients have an additional risk in terms of hem-

orrhagic cystitis [2].

Multiple factors are accused in the etiology of late-

onset hemorrhagic cystitis. Generally, this type of hem-

orrhagic cystitis occurs after weeks or months from trans-

plantation. A history of hemorrhagic cystitis attack is the

most important risk factor for another attack. Viruses and

graft versus host disease (GVHD) are also accused in the

etiology of hemorrhagic cystitis. The BK polyoma virus,

adenovirus, cytomegalovirus (CMV), JC virus, Epstein

Barr virus (EBV) and herpes virus have been implicated

in the etiology of hemorrhagic cystitis. Suitable hosts for

*The authors declare that they have no competing i nt e rests.

B. Ilhami et al. / Case Reports in Clinical Medicine 2 (2013) 298-301 299

these viruses are immunosuppressed patients. GVHD and

hemorrhagic cystitis are another issue discussed in the

literature [1].

The BK virus is a member of the polyoma virus family.

BK virus is highly prevalent in the population and is

thought to remain dormant and asymptomatic in the kid-

ney and other organs after the initial infection. Wh en the

immune system is compromised, as in persons undergo-

ing chemotherapy after bone marrow, stem cell and solid

organ transplantation, the virus gets reactivated leading

to cystitis. BK virus has been reported to cause hemorr-

hagic cystitis in 5.7% to 7.7% of bone marrow transplant

recipients. Early diagnosis and treatment of viral cystitis

may prevent significant morbidity of hemorrhagic cysti-

tis. The diagnosis is based on molecular techniques and

real-time polymerase chain reaction (PCR), which allows

quantification of viral load is often the method of choice

[3]. Although no drug is yet licensed fo r use in BK virus

infection, cidofovir is becoming the drug of choice in

viral hemorrhagic cystitis in immunosupressed patients

because it is active against the most common viral patho-

gens. Leflunomide has been shown to significantly re-

duce BK viral load in blood an d urine in renal transplant

patients with biopsy proven BK nephropathy [4]. Cipro-

floxacin may have a prophylactic role in preventing BK

viral cystitis in bone marrow transplant patients [5]. Hy-

perbaric oxygen in the treatment of refractory hemor-

rhagic cystitis can be used successfully in patients [6].

Here, we present a case of hemorrhagic cystitis due to

BK virus infection in an acute myeloid leukemia patient

was treated with allogeneic stem cell transplantation.

2. CASE PRESENTATION

A 40 years old female patient was diagnosed acute

myeloid leukemia and idarubicine 1 × 12 mg/m2/day (3

days), cytarabine 1 × 100 mg/m2/day (7 days) therapies

as induction and 3 cycles of high-dose cytarabine (2 × 3

g/m2/day) therapy for consolidation were given success-

fully. After these treatments, the patient was applied

seamlessly allogeneic stem cell transplantation from

HLA matched siblings with BU-CY (busulfan-cyclo-

phosphamide) protocol (busulfan 4 × 0.8 mg/kg/day (4

days), cyclophosphamide 60 mg/kg/day (2 days), mesna

90 mg/kg/day (2 days) in bone marrow transplantation

unit. Although the patient did not have hematuria before

he experienced a gross hematuria episode in fifty second

day of transplantation. Physical examination revealed

marked suprapubic tenderness. A complete blood count

revealed hemoglobin 8.8 g/dL, leukocyte 2.100/microL,

neutrophil 1.500/microL, lymphocyte 500/microL, and

platelets 22.000/microL. Peripheral blood smear was com-

patible with blood count. International normalized ratio

(INR), Activated Partial Thromboplastin Time (APTT),

and serum creatinine levels were normal. C-reactive pro-

tein concentration was moderately elevated as 3.2 mg/dL.

The red color of urine was seen only in the sediment (and

the supernatant was not red). Bacterial or fungi infection

were not seen in the cytobacteriological examination of

urine samples. Nephrolithiasis, or other bladder patholo-

gies causing of hematuria were not seen in radiographic

examinations including ult rasonography, non-cont rast com -

puted tomography of abdomen and pelvis. Medication

usage history in terms of hemorrhagic cystitis was nega-

tive. Hemocultures and urine cultu res were negative. The

patient was not using drugs like anticoagulants at this

time and patient was using treatments like cyclosporine

(2 × 150 mg/day/i.v), methyl prednisolone (1 × 120 mg/

day/i.v) and intravenous immune globulin (5 gr/day/i.v

once a weak to 100th day) for GVHD and infection pre-

vention. After excluding other causes of hematuria, urine

analysis with polymerase PCR analysis revealed positiv e

BK virus. Real-time PCR for adenoviruses was negative.

We could not analyze the other viruses. Platelet suspen-

sion was given and then platelet counts was detected

72.000/microL, but gross hematuria persisted. Erythro-

cyte suspension was transfused intermittent ly as support-

ing treatment. We stopped methyl prednisolone and re-

duced dose of cyclosporine (2 × 50 mg/day/i.v). We gave

ciprofloxacin (2 × 400 mg/day/i.v for 14 days) treatments.

Continious bladder irrigation was performed with three

way foley urethral catheter. Cystoscopy was applied and

hemorrhagic foci was cauterized by consulting with the

department of urology and nephrology clinics (Figure 1).

After one month of mentioned treatments above blood in

the urine decreased slowly. We applied control cysto-

scopy, revealing recovery of hemorrhagic foci (Figure 2),

and blood in the urin e stopped without need of an y other

treatments. Control BK virus PCR result was negative.

3. DISCUSSION

Hemorrhagic cystitis after allogeneic stem cell trans-

Figure 1. Cystoscopic view of

the bladder showing the wide-

spread bleeding areas on the

bladder mucosa.

B. Ilhami et al. / Case Reports in Clinical Medicine 2 (2013) 298-301

300

Figure 2. Cystoscopic image af-

ter one month of treatment mi-

nimal local hemorrhagic area on

the bladder mucosa.

plantation is one of the most common causes of morbi-

dity and mortality in patient with stem cell transplan-

tation. Hemorrhagic cystitis can be emerged in the early

or late phase of stem cell transplantation [1]. In our pa-

tient, hemorrhagic cystitis was seen in fifty second day

after allogeneic stem cell transplantation. The patient was

eveluated w ith X-ray, ultr asonography and n on-spiral CT

of urinary tract, urine analysis, urine culture for diag-

nosis of hemorrhagic cystitis. Thus, among the main causes

of hematuria like stone, simple infections were elimi-

nated and the patient was diagnosed late onset hemor-

rhagic cystitis.

A grading system for severity of hemorrhagic cystitis

has been proposed by Droller et al. for hemorrhagic cys-

titis [7]. We accepted our patient. Stage III (macroscopic

hematuria with small clots) hemorrhagic cystitis and we

searched for causes of late onset hemorrhagic cystitis.

A history of hemorrhagic cystitis episode is a main

risk factor for late onset hemorrhagic cystitis. In addition,

viruses (BK virus, adenovirus, and CMV) and GVHD

are accused for hemorrhagic cystitis. Our patient did not

has a history of hemorrhagic cystitis. There was no signs

like skin rash, diarrhea, and ab normal liver function tests

which could support a diagnosis of acute GVHD. We

eveluated the urine analysis with PCR method for CMV,

adenovirus and BK virus. PCR result for BK virus was

positive. The cornerstone of therapy for hemorrhagic

cystitis due to BK virus is reduction of immunosuppres-

sion. Studies showed that overall immunosupressive load

is more important than a single immunosuppressive

agent use in terms of BK virus infections [8]. In our pa-

tient we thought the cause of BK virus infection as im-

munosuppressive load and dose of cyclosporine treat-

ment was reduced to 2 × 50 mg/day/i.v.

In the literature, a large bore three-way foley urethral

catheter insertion to decompress the bladder and saline

solution irrigation of bladder is recommended as a first

step treatment. This maneuver may slow or stop the

bleeding. In some instances cystoscopic clot evacuation

may be necessary [1]. Continuous irrigation was applied

for 30 days by consulting with th e department of urology

and nephrology clinics. Cystoscopy was performed to

treat hematuria and hemorrhage foci were cauterized by

urology clinic.

Other therapeutic options include cidofovir, leflu-

nomide, intravenous immunoglobulin, and fluoroquino-

lones for BK virus infection. Cidofovir is a nucleotide

analogue of cytosine that is active against various DNA

viruses. Cidofovir may have activity against BK virus [9].

Leflunomide reduces BK viral load in blood and urine in

renal transplant patients with BK nephropathy [4]. Lim-

ited data is available concerning the efficacy of intrave-

nous immune globulin in patients with BK nephropathy

[10]. The efficacy of ciprofloxacin, was best reported in a

study of 68 hematopoietic stem cell transplantation pa-

tients. These informations support a role for ciproflox-

acin in the prevention of BK viremia [5]. Hyperbaric

oxygen in the treatment of refractory hemorrhagic cysti-

tis is used succesfully [6]. Our patient responded to re-

duce dose of immunosuppressive, ciprofloxacin treat-

ment, intravenous immune globulin, continuous irriga-

tion and cauterization.

4. CONCLUSION

BK virus infection must be kept when an allogeneic

stem cell transplantation patient admitted with gross he-

maturia.

5. AUTHORS’ CONTRIBUTIONS

This report reflects the opinion of the authors and does

not represent the official position of any institution or

sponsor. IB was responsible for reviewing previous re-

search, journal hand searching, and drafting the report.

FO and RA were responsible for provision of published

trial bibliographies, and preparing photographs. MK,

MAE and OU contributed to the final draft of the manu-

script and analysis of relevant data. IK and EK was re-

sponsible for project coordination. All authors read and

approved the final manuscript.

6. CONSENT

Written informed consent was obtained from the pa-

tient’s next of kin for publication of this manuscript and

accompanying images. A copy of the written consent is

available for review by the Editor-in-Chief of this jour-

nal.

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ABBREVIATIONS

GVHD: Graft Versus Host Disease

CMV: Cytomegalovirus

EBV: Epstein Barr Virus

PCR: Polymerase Chain Reaction

BU-CY: Busulfan-Cyclophosphamide

INR: International Normalized Ratio

APTT: Acti vated Partial Thro mbopl astin Time