Competing interest statement
Conflict of interest: the authors declare no potential conflict of interest.
BK virus is a human polyoma virus that is acquired in childhood. It remains latent in the genitourinary system for whole life.1 It could cause more frequent and higher grade viraemia in immunosuppressed patients.2 The use of specific immunosuppressive agents and the intensity of immunosuppression could effect the risk of BK virus replication and the the progression of clinical disease in transplant recipients.3 BK virus could cause hemorrhagic cystitis in allogeneic stem cell transplant (ASCT) recipients.4 Hemorrhagic cystitis could cause morbidity and long term hospital stay.5 Acute hemorrhagic cystitis following engraftment in hematopoietic stem cell transplant recipients could be associated with BK virus.6 Clinical diagnosis could be put by detecting BK virus DNA by quantitative or real-time (polymerase chain reaction) PCR in plasma or serum and less frequently in urine.7 In this article, we present three allogeneic stem cell transplanted patients with hemorrhagic cystitis associated BK virus.
Case Report #1
A 43-year-old female patient with the diagnosis of acute myeloid leukemia-M6 (AML-M6) was admitted to the hematology inpatient 3 + 7 (standard dose cytosine, arabinoside and idarubicin) chemotherapy was given to the patient. She went into complete remission and after that she received 1 course of HIDAC (high dose cytarabine) chemotherapy. ASCT was done after 3 months. Graft-versus-host disease (GVHD) was developed in the patient. Methylprednisolone, cyclosporine and mycophenolate mofetil therapy were started. Macroscopic hematuria was developed in the patient after three months of the stem cell transplantation. Hemoglobin (Hb): 11.8 gr/dL, hematocrit (Htc): 33.8%, white blood cell (WBC): 1930/μL (neutrophil: 450/μL), platelet: 52,000/μL, creatinine: 1.21 mg/dL, blood urea nitrogen (BUN): 18 mg/dL, uric acid: 4.4 mg/dL and C-reactive protein (CRP): 4.7 mg/dL (0-5) in laboratory tests. Because of the febrile neutropenic attack, piperacillin-tazobactam 3x4.5 mg intravenous (IV) was started empirically. Blood and urine cultures were taken in patient with high fever. The urine culture, gram staining, tuberculosis culture, ARB (acid resistant bacteria) staining, BK virus PCR and adenovirus PCR tests were taken for differential diagnosis. BK virus PCR: 20.763.373 copies/mL was detected. Other tests were negative. The bladder irrigation and reduction of immunosuppressive treatment decreased hematuria. BK virus PCR: 3.760.719.465 copies/mL were detected in the control. Creatinine level increased to 3.34 mg/dL and nephritis was considered as secondary to BK virus. However, biopsy could not be performed due to low platelet counts. Hemodialysis was initiated to the patient. Leflunomide 3x100 mg tb, levofloxacin 1×500 mg IV and 0.5 g/kg intravenous immunoglobulin G (IVIG) were started to patient. The patient was admitted to the intensive care unit due to the clinical regression. The patient died due to refractory AML and severe GVHD after 4th day of leflunamide and levofloxacin treatments.
Case Report #2
A 64-year-old male patient with AML secondary to myelofibrosis was admitted to the Bone Marrow Transplantation Service (BMTS) for ASCT. The hematuria was developed in the patient at 33th day after transplantation. Hb: 7.6 gr/dL, Htc: 22.7%, WBC: 590/μL (neutrophil: 54/μL), platelets: 28,000/μL, creatinine: 1.13 mg/dL, BUN: 30 mg/dL, uric acid: 5.7 mg/dL, CRP: 27.65 mg/dL in laboratory tests. A 10 mm diameter cortical cyst was detected in the right kidney in the abdomen USG. Bladder irrigation was started with 12 liters isotonic per day. The hematuria decreased. BK virus PCR: 163,000,000 copies/mL were detected. Other tests were negative. Because of hemorrhagic cystitis, IVIG 0.5 g/kg and levofloxacin 1×750 mg IV were started to the patient. Clots were detected in the bladder in control abdomen USG. The patient underwent cystoscopy and the clots were evacuated. BK virus PCR: 580.800.000 copies/ml were detected. The patient’s immunosuppressive treatment was reduced. Cidofovir treatment was started at 5 mg/kg once in a week for two weeks, continued after then every two weeks. After 1 month, BK virus PCR: 46.120 copies/mL were detected and treatment continued. The hematuria decreased. One month later BK virus PCR: 17.080 copies/mL was detected again. The patient’s treatment continued. Symptoms of the patient improved. The treatment of the patient was completed after 3 months. The BK virus PCR was detected as negative for control purposes.
Case Report #3
A 20-year-old AML-M6 male patient with remission was admitted to the BMTS for ASTC. The patient was gone into ASCT. Acute GVHD developed after the transplant. Methylprednisolone, cyclosporine and mycophenolate mofetil treatment were started. Hematuria developed in the patient after the 30th day of transplantation. Hb: 5.7 gr/dL, Htc: 16%, WBC: 5.860/μL (Neutrophil: 5.370 /μL), platelets: 55.000 μL, creatinine: 1.28 mg/dL, BUN: 52 mg/dL, uric acid: 6.8 mg/dL in laboratory tests. 28 leukocytes and 328 erythrocytes were detected in the urine microscopy. The bladder irrigation was started with 12 liters of isotonic per day. Hematuria complaints of the patient increased. BK virus PCR: 905.080.070 copies/mL were detected. IVIG 0.5g/kg IV and levofloxacin 1×750 mg IV were started. But hematuria did not decrease. Cidofovir therapy is scheduled to be given at 5 mg/kg once a week for two weeks followed by once in two week period. However, the patient’s general condition went worse and the patient was admitted to the intensive care unit. The patient died because of refractory AML and severe GVHD before cidovofir treatment.
Discussion and Conclusions
BK virus could cause hemorrhagic cystitis in allogeneic stem cell transplantation patients.4 Hemorrhagic cystitis is a serious complication of hematopoietic stem cell transplantation. It could cause to morbidity and long term hospital stay.5 In a study conducted by Arthur et al. BK virus was detected in 53 hematopoietic stem cell transplant recipients.6 ASCT were performed in three of our cases. Hemorrhagic cystitis developed after 3th month of transplantation in the first case and hemorrhagic cystitis developed after approximately 1 months after transplantation in the other 2 cases. BK virus was detected as the cause of hemorrhagic cystitis. The use of quantitative or real-time PCR to detect BK virus DNA has been shown to be useful in plasma or serum, less frequently in urine in following renal transplant recipients.7 In all of the three cases, BK virus was detected in urine by real-time PCR test.
The reduction of immunosuppression was known to be effective in the treatment of BK virus infection. The reduction of immunosuppression was found to be successful in elimination of viremia in a single-center study with 24 patients.8 Several agents with anti-BK virus activity were demonstrated.9 The cidofovir is cytosine nucleotide analogue and it is an active agent against various DNA viruses including poliomyelitis viruses.10 In a retrospective nonrandomized study, 8 of 21 patients were treated with weekly low-dose cidofovir administration and immunosuppression reduction, only 13 patients were treated with reduced immunosuppressive therapy.11 In another study, clinical response was obtained in all adult patients treated with cidofovir (16/19, 84%); but only 9 of 19 patients (47%) were detected reduction greater than 1 log in the BK virus load in urine.12 In a study conducted by Cesaro et al.,14 (81%) of 27 patients had a complete clearance of BK virus associated hemorrhagic cystitis after the introduction of cidofovir on the average 37 days.13 Cidofovir treatment and the reduction of immunosuppressive treatment was started to the patient. 1 log decreased in BK virus load after 1st month of cidofovir treatment. Hematuria was regressed in case 2.
Leflunomide is a prodrug. Anti-metabolite of leflunomide is A77 1726. Both have immunosuppressive and antiviral activities.15 The mechanism of action against BK virus is unknown.16 In the case series, leflunomide improved in 23 of 26 patients with BK virus nephropathy.17 Leflunomide treatment was started in one of our cases; but the patient died because of refractory AML and severe GVHD after 4 days. IVIG contain antibodies against to BK and JC (John Cunningham) viruses. Three of the our patients received IVIG. Quinolone antibiotics have anti-BK virus activities.18 Levofloxacin was given as a treatment or as a prophylactic agent in the treatment of active BK viremia in two randomized trials.19 BK virus was detected as the cause of hemorrhagic cystitis in our cases. The cidofovir treatment and the reduction of immunosuppressive treatment caused to improve symptoms and findings. They caused to decrease in the BK virus load.
Intravenous immunoglobulin G contain antibodies against JC and BK virus. These viruses are ubiquitous in the general population. But, these antibodies not be neutralizing.20,21 Other studies indicate that the anti-BK antibodies are not protective and these antibodies indicate an augmented humoral response to an inadequate cellular immune response.22 IVIG 0.5 g/kg IV was started in case 2 and case 3. But hematuria did not decrease in these cases.
In this article, it is aimed to emphasize that cidofovir treatment with reducing immunosuppressive treatment is a good alternative in the treatment of hemorrhagic cystitis associated with BK virus in the allogeneic stem cell transplant recipients.