BKV-associated Hemorrhagic Cystitis Research Articles

A Novel Prediction Model for BK Virus Associated Hemorrhagic Cystitis in Acute Leukemia Patients Following Allogenic Hematopoietic Cell Transplantation: A Retrospective Cohort Study

Introduction BK polyomavirus (BKV) has been associated with hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (HSCT). BK virus hemorrhagic cystitis (BKHC) is associated with high morbidity and higher mortality. Previous studies have identified several risk factors associated with BKHC (Biol Blood Marrow Transplant, 2022). However, these results are contradictory among studies, and the potential mechanisms of BKHC are still unclear. Therefore, an accurate systematic evaluation method for screening high-risk populations before the onset of BKHC is highly necessary. This study was designed to establish an efficient prediction model for BKHC in acute leukemia patients following HSCT, thereby facilitating identification and early intervention in patients at high risk of BKHC. Methods In our retrospective study, a cohort of 789 acute leukemia patients following allogenic hematopoietic cell transplantation in 2019 was included and further divided into a BKHC group and a non-BKHC group. Among these patients, 80% were assigned to the derivation cohort, and 20% were assigned to the validation cohort. We first calculated the univariate association of each variable with the occurrence of BKHC. Second, the variables with p values less than 0.05 in the univariate analysis were further included as candidate predictors in the multivariate analysis using a backward stepwise logistic regression model. The variables that remained in the final model based on the outcomes of the multivariate analysis in the derivation cohort were identified as independent risk factors. The discrimination power of the model was assessed in both derivation and validation cohorts through ROC curve (AUC), calibration curve and decision curve analyses. Results Among 789 acute leukemia patients following allogenic hematopoietic cell transplantation, 171 patients were diagnosed with BKHC 14 days post transplantation according to the European Conference on Infections in Leukemia (ECIL) definition of BKHC. Patients with early-onset HC occurring within 14 days post transplantation were excluded from the BKHC group. The incidence rate of developing BKHC after allo-HSCT was 21.7%. The median time from transplantation to BKHC development was 30 days. Using multivariable logistic regression methods with stepwise variable selection, four highly significant independent risk factors for developing BKHC were identified: use of ATG during the transplantation regimen (p=0.048; odds ratio [OR], 2.32; 95% confidence interval [CI], 0.025-1.71), use of bone marrow blood and peripheral blood as sources of stem cells (p<0.001; odds ratio [OR], 0.25; 95% confidence interval [CI], 0.025-1.71), age less than 30 years old (p=0.02; odds ratio [OR], 1.74; 95% confidence interval [CI], 0.089-1.021) and absolute lymphocyte count at 14 days post-transplantation less than 0.035×10 9/L (p=0.02; odds ratio [OR], 2.59; 95% confidence interval [CI], 0.31-1.62). The area under the ROC curve (AUC) was 0.741 (95% confidence interval [CI], 0.694-0.789). According to the calibration plots, the model-predicted probabilities showed a good correlation with actual observed frequencies in both the derivation and validation cohorts. Decision curve analysis indicated that the clinical implementation of this model could benefit BKHC patients. A BKV-associated HC Risk Index (BHRI) was constructed according to the regression coefficients. The patient cohort was divided into a high-risk group and a low-risk group according to risk scores. Kaplan‒Meier estimations of the probabilities of BKHC were significantly different between the two risk groups. Conclusions Patients with BKHC after allo-HSCT usually have high morbidity and higher mortality. A novel prediction model, BHRI, was developed and validated, and this is the first straightforward scoring system designed to evaluate the probability of patients developing BKHC after receiving allo-HSCT to treat hematological malignancies. This model can be effectively utilized to help improve the prognosis of BKHC patients by accelerating the early identification of patients at a high risk of developing BKHC and contributing to the appropriate implementation of timely medical support.

A cluster of BK polyomavirus‐associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

BK polyomavirus (BKV) can cause hemorrhagic cystitis (HC) in immunocompromised patients after hematopoietic stem cell transplantation (HSCT). It remains unclear whether nosocomial BKV infections occur. During a 9-month period, an increase in BKV-associated HC (BKV-HC) cases was observed at our institution. The BKV-HC cluster population was compared with populations of HSCT patients from before and after the BKV-HC cluster to evaluate whether nosocomial BKV transmission had occurred. A retrospective analysis was carried out to assess the risk of patients developing BKV-HC after HSCT. The background data of the cluster patients were compared with those of the patients who underwent HSCT before or after the cluster, and the collected BKV isolates were serotyped. BKV-HC involving grade ≥2 hematuria occurred in six of 15 HSCT recipients during a 9-month period. The incidence of BKV-HC was significantly higher in this period than in the other periods (p = 0.0014). There were no significant differences in the patients' background data between the cluster and non-cluster periods, including in terms of risk factors for BKV-HC. Serotype analyses of BKV revealed that the BKV detected in the urine samples from four of the six BKV-HC patients belonged to subtype Ic. The gene sequences of these four BKV exhibited >99.5% homology. Our study suggests that nosocomial BKV infections may occur after HSCT. Although many cases of BKV-HC are caused by the reactivation of a latent virus, it is necessary to employ appropriate hygiene measures when cases of BKV-HC occur.

Research Advances on BK Virus Associated Hemorrhagic Cystitis after HSCT-Review

BK virus（BKV）associated hemorrhagic cystitis is one of the most common complications after hematopoietic stem cell transplantation（HSCT）, which can increase the suffering, become time consuming and even life threatening. However, BKV infection has not attracted enough attention in clinical practice. Accurate BKV monitoring and effective clinical treatments are still in urgent need. In recent years, BKV-DNA monitoring has shown a significant clinical value in BKV-associated hemorrhagic cystitis after HSCT. As for clinical treatments, traditional antivirus agent cidofovir is still to show promising effects, in the meantime, the virus-specific lymphocytes and other new therapies are continuously appearing. Here, the most recent advances on pathogenesis, treatment, virus monstoring and so on for BKV associated hemorrhagic cystitis after HSCT are reviwed.

Administration of Most Closely HLA-Matched Multivirus-Specific T Cells for the Treatment of EBV, CMV, AdV, HHV6, and BKV Post Allogeneic Hematopoietic Stem Cell Transplant

▪Viral infections remain a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Adoptive immunotherapy with donor-derived virus-specific T cells (VSTs) has proven safe and effective for the prophylaxis and treatment of EBV, CMV, AdV, BKV and HHV-6 infections post-HSCT. However, broader application is restricted by the time taken to prepare patient-specific products and the lack of virus-specific T cell precursors in cord blood and seronegative donors. Thus, to assess whether 3rd party multivirus-directed VSTs could produce clinical benefit when administered as an "off the shelf" product to allogeneic HSCT recipients with refractory BKV, EBV, CMV, AdV and/or HHV-6 infections we initiated a Phase II clinical trial and now report interim results for 22 patients infused to date. We prepared a bank of 58 VST lines from individuals with common HLA polymorphisms by exposing donor PBMCs (3x107) to overlapping peptide libraries spanning AdV (Hexon, Penton), EBV (LMP2, EBNA1, BZLF1), CMV (pp65, IE1), BKV (Large T, VP1) and HHV-6 (U11, U14, U90) antigens followed by a 9-11 day expansion phase in a G-Rex device in the presence of IL4 and IL7. This produced a mean of 4.2±1x108 VSTs that were polyclonal, comprising both CD4+ (61±2.4%) and CD8+ (34±2.1%) cells that expressed central (CD45RO+/CD62L+/CCR7+ - 43±3.9%) and effector memory markers (CD45RO+/CD62L- - 10±1%). 56/58 lines had activity against AdV, 50/58 against EBV, 35/58 against BKV, 34/58 against HHV-6, and 33/58 against CMV.To date, 62 HSCT recipients have been screened for study participation and a potential line, based on target virus specificity through a shared allele and overall HLA match, was identified for 58. Of these, 22 patients with infections that were unresponsive to at least 2 lines of antiviral treatment have been infused (fixed dose level - 2x107 VSTs/m2) with VST lines matched at 1 to 6 HLA antigens. Seventeen received just 1 infusion, while 5 patients required 2 or more infusions for sustained benefit. Eight patients received VSTs for CMV infections, including 3 cases of CMV colitis, 8 for BKV (6 for cystitis, 2 for nephritis), 1 for HHV-6, 1 for EBV-PTLD, 1 for AdV, 1 for BKV and EBV, 1 for CMV and AdV and 1 for CMV and BKV infections. There were no immediate adverse effects related to infusion. Based on viral load measurements by quantitative PCR a single VST infusion successfully controlled active infections in 19/21 evaluable patients: CMV (4 CR, 5 PR, 1NR); EBV (2 CR); AdV (1 CR, 1 NR); BKV (1 CR, 7 PR); and HHV-6 (1 PR). Of note, all 6 patients with BK hemorrhagic cystitis and 2/3 patients with CMV colitis had marked improvement/resolution of symptoms following VST treatment. In 8 subjects who responded to VST therapy we saw an increase in virus-specific T cells post-infusion. These expanded cells were confirmed to be of 3rd party VST origin in 3 patients and persisted for up to 6 weeks post-infusion. Finally, despite the HLA disparity of VSTs and recipients, de novo GvHD occurred in only one subject, who developed Grade I skin GVHD 1 week post-infusion, which resolved with the administration of topical steroids. One additional patient had a flare of chronic skin GVHD coincident with tapering of immunosuppression and 1 patient developed a transient fever 5 hours post-infusion, which spontaneously resolved. These results demonstrate the feasibility and safety of 3rd party multivirus-directed VSTs, generated by direct stimulation of PBMCs with synthetic peptides and administered as an "off the shelf" product. The infused cells were capable of in vivo expansion in allogeneic HSCT recipients and proved clinically effective against refractory EBV, CMV and AdV infections and also controlled HHV-6 reactivation and BKV-associated hemorrhagic cystitis. DisclosuresOff Label Use: Adoptively transferred T cells administered under an IND. Brenner:Bluebird Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Collaborative Research Agreement; Cell Medica: Other: Licensing Agreement. Rooney:Celgene: Other: Collaborative research agreement; Cell Medica: Other: Licensing Agreement. Heslop:Celgene: Other: Collaborative research agreement; Cell Medica: Other: Licensing Agreement.

Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation.

Background/AimsBK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses.MethodsAllogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade.ResultsEight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment.ConclusionsWeekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC.

Levofloxacin for the treatment of severe refractory BK virus-associated hemorrhagic cystitis in hematopoietic stem cell transplantation recipients: A report of three cases.

BK-virus (BKV) is an important etiological agent for late-onset hemorrhagic cystitis (HC) in patients undergoing hematopoietic stem cell transplantation. Late-onset HC causes significant morbidity among these patients. Therapeutic approaches remain predominantly symptomatic. Several treatment options have been used with variable success rates. Cidofovir has the highest specificity against BKV; however, its lack of availability in the majority of countries, high costs and potential nephrotoxic effects limit its use. The present study reports three cases of severe and prolonged BKV-associated HC (BKHC). HC was resolved in all three of the patients using oral levofloxacin. Thus, levofloxacin may be an effective treatment modality for achieving complete clinical and molecular response in patients with refractory, severe BKHC.

Unusual presentations of BK virus infections in pediatric renal transplant recipients

BKV has emerged as a significant pathogen in the field of transplantation, predominantly causing BKV nephropathy in renal transplant recipients and hemorrhagic cystitis in HSCT recipients. However, case reports describe more diverse complications, and we too present three unusual cases of BKV infections in pediatric renal transplant recipients. First, we describe a case of biopsy-proven renal damage secondary to BKV prior to the onset of viremia, demonstrating that BKV nephropathy can occur without preceding viremia. We also present two renal transplant recipients with persistent BK viruria, one with BKV-associated hemorrhagic cystitis and the other with microscopic hematuria. Therefore, we conclude that BKV manifestations may be more diverse than previously thought and suggest clinical utility in urine BKV qPCR testing in specific transplant recipients.

Evaluation of Human Polyomavirus (BKV)–Specific T Cell Immune Reconstitution in Allogeneic Haematopoietic Stem Cell Transplant Recipients,

Abstract 3223AbstractThe human polyomavirus type 1, better known as “BK virus” (BKV), persists in a latent state in more than 90% of the world's population. It is infamous as a pathogen in kidney transplant recipients by causing BKV-associated nephropathy (BKVN) often resulting in allograft dysfunction and loss. BKV has also been associated with hemorrhagic cystitis (HC) in haematopoietic stem cell transplant (HSCT) recipients. However, treatment for this condition remains challenging, as the mechanism through which BKV reactivation causes HC in HSCT recipients is not known. In addition, there is currently little data about the reconstitution of BKV-specific immunity after HSCT and its relationship to HC. It is still unclear whether the BKV-specific T cell response helps to prevent and bring about the resolution of HC, or if HC is an immunopathology and the BKV specific immunity damages the bladder mucosa in the process of attacking BKV-infected urothelial cells.We hypothesized that BKV-associated HC is initiated by an imbalance between immune surveillance and BKV reactivation, followed by eventual rebound of BKV- specific T immunity causing an immunopathological reaction towards BKV-infected urothelial cells that ultimately lead to cystitis after HSCT. We aim to correlate BKV titre levels in the urine and blood with BKV- specific T cells. This is a novel prospective study that describes the immune reconstitution of BKV specific T cells immunity after allogeneic HSCT and uses the clinical manifestation of HC as a maker to analyze reconstitution of the immune system post HSCT.This study was approved by the institutional review board. Ten patients undergoing allogeneic HSCT were recruited over a 1 year period. The clinical data collected included conditioning regime, indication for transplant, presence of GVHD and development of HC. Patient's blood samples were collected prior to conditioning and at 4 weekly intervals for 24 weeks. Peripheral blood mononuclear cells (PBMCs) isolated from these whole blood samples were then stimulated with overlapping peptide mixes of BK LT and VP1. Quantification of BKV-specific T cells were accomplished by flow cytometry.Results revealed higher levels of CD3+IL-17+BKV specific T cells (p<0.05) in subjects who developed HC compared to those who did not. Peak levels of CD3+IL-17+BKV specific T cells were observed just before or just after the presentation of HC. Both CD4+IL-17+ (p<0.01) and CD8+IL-17+ (p=0.05) BKV specific T cells were significantly higher in patients who developed HC compared to those who did not. This increment of IL-17+ BKV-specific T immune cells coincided with high levels of BKV detected in the urine.These preliminary results strongly suggest that BKV-associated HC is an immunopathology caused by IL-17 secreting BKV-specific T cells. Though our cohort of patients is small however in view of the promising results; we plan to extend the study to a larger cohort of patient. The demonstration of an immunological basis of HC will provide a theoretical framework for the development of potential immunotherapeutic interventions in the prevention and treatment of HC. Disclosures:No relevant conflicts of interest to declare.

Polyomavirus BK-specific CD8+ T cell responses in patients after allogeneic stem cell transplant

Polyomavirus BK (BKV) is known as an important etiologic agent in the development of hemorrhagic cystitis (HC) after allogeneic stem cell transplant (SCT). To define T cell epitopes of the BKV proteins VP1 and sT, eight potential HLA-A2-binding peptides were synthesized based on computer algorithms. These peptides were co-incubated with CD8 + T cells from the peripheral blood (PB) of 25 healthy volunteers and seven patients suffering from HC after allogeneic SCT in a mixed-lymphocyte peptide culture (MLPC), which were subsequently screened by enzyme-linked immunospot (ELISPOT) assays and fluorescence-activated cell sorting (FACS) analysis. We found that CD8 + T cells from five of seven (71%) patients with HC presensitized with the BKV peptide VP1 p108 (LLMWEAVTV) specifically recognized T2 cells pulsed with VP1 p108. In contrast, only seven of 25 (28%) healthy volunteers had CD8 + T cells reactive with VP1 p108-pulsed T2 cells. The presence of VP1 p108-specific T cells could be confirmed by FACS analysis. The BKV peptide VP1 p108 seems to play an important role as an immunodominant peptide in the pathogenesis of HC in patients after allogeneic SCT, and might be a promising target for immunotherapies or even strategies to prevent the development of BKV-associated HC.

Hemorrhagic Cystitis and Possible Neurologic Disease from BK Virus Infection in a Patient with AIDS

BK virus (BKV)-associated hemorrhagic cystitis occurs in bone marrow transplant recipients but is rare among other immunosuppressed patients. We present a rare case of BKVassociated hemorrhagic cystitis in a 48-year-old man with AIDS and previously diagnosed progressive multifocal leukoencephalopathy.

Hyperbaric oxygen therapy in BKV-associated hemorrhagic cystitis refractory to intravenous and intravesical cidofovir: Case report and review of literature

Hemorrhagic cystitis is a common complication in hematopoietic stem cell transplant recipients. We report here a case of severe BKV-associated hemorrhagic cystitis who did not respond to intravenous cidofovir. Overt hematuria successfully resolved after a few days on hyperbaric oxygen and intravesical instillations of cidofovir, while BK viruria dropped after a few weeks and remained low. We review the literature for therapeutic options in hemorrhagic cystitis and try to explain how hyperbaric oxygen stimulates mucosal repair in the urinary bladder.

Risk Factors for BK Viruria and Hemorrhagic Cystitis in Hematopoietic Stem Cell Transplant (HSCT) Recipients.

Polyomavirus BK associated hemorrhagic cystitis (HC) is becoming an increasingly recognized complication of HSCT. The pathogenesis of BK-associated HC is not fully understood, and it is not possible to predict the clinical course of BK reactivation in patients following HSCT. Multiple co-factors could play a role in the development of HC after HSCT in patients (pts) with BK viruria (BKV) including the type of transplant autologous (auto) vs. allogeneic (allo), conditioning regimen, development of Graft-Versus-Host Disease (GVHD), conditioning intensity and source of donor stem cells (Matched unrelated [MUD] vs. HLA-identical sibling [SIB]).We retrospectively analyzed the incidence, risk factors and outcome of BK reactivation and HC in pts who had HSCT at the Univ. of Pittsburgh Cancer Institute during the last 2 years. BKV was determined using a quantitative real-time PCR assay considered positive for titers higher than 10 copies. In total, 247 pts were studied, 63% (155/247) received an auto and 37% (92/247) an allo HSCT. BKV was observed in 20% (49/247) of pts. 3% (5/155) of pts undergoing auto and 48% of pts undergoing allo HSCT (44/92) developed BKV. 18% of pts (9/49) developed HC, 1 in the auto and 8 in the allo group. Three pts died from complications related to HC. Of the allo HSCT pts, 50% (46/92) received Sib and MUD HSCT. Non-myeloablative conditioning regimens (Flu/TBI, Flu/Cy, Flu/Bu/ATG, TLI/ATG, Flu/Csa/MMF) were used in 39% pts (36/92) and whereas 61% (56/92) of pts underwent myeloablative conditioning (BuCy, TBI/Cy). In pts undergoing allo HSCT with myeloablative regimen, 52% (29/56) had BKV with 28% (8/29) having HC, while 42% (16/35) of pts after nonmyeloablative conditioning had BKV with no pt developing HC. Of the allo HSCT pts, GVHD data was available for 67 pts, 69% (46/67) had grade 1-4 acute GVHD whereas 31% (21/67) had no evidence of GVHD. In pts with no GVHD, BKV was seen in 38% (8/21) with no pt developing HC while 52% (24/46) pts with GVHD had BKV with 13% (3/24) developing HC. In patients undergoing MUD HSCT, BKV and HC were present in 43% (20/46) and 5% (1/20) respectively, whereas in the SIB group, BKV and HC developed in 52% (24/46) and 29% (7/24), respectively. As calculated by Fisher exact test BKV was significantly associated with allo HSCT (p< 0.001) and Cyclophosphamide-containing non-myeloablative conditioning in allo HSCT recipients (p=0.03). In contrast we did not observe a significant impact of ATG vs. non-ATG-containing regimen, non-ablative vs. myeloablative conditioning or presence vs. absence of GVHD in our cohort of allo-HSCT patients. However, development of BK-induced HC in BKV+ allogeneic HSCT patients was significantly associated with the presence of myeloablative conditioning (p=0.03). Based on these findings we conclude that 1. Development of BKV occurs predominantly following allogeneic HSCT. 2. Conditioning intensity is an important risk factor for the development of HC in patients with BKV. 3. Cyclophosphamide is an important co-factor for the development of BKV in patients undergoing non-myeloablative conditioning. We hypothesize that cyclophosphamide-induced bladder damage might not only contribute to BKV-associated HC, but also to BK reactivation. Therefore, prospective trials addressing the value of prophylactic or pre-emptive therapy for BKV should focus on patients undergoing myeloablative allogeneic HSCT.

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant

In recipients of hematopoietic stem cell transplants (HSCTs), BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC). In our institution, HSCT recipients with BKV-associated HC are treated with 1 mg/kg of cidofovir weekly. We identified HSCT recipients with BKV-associated HC, treated with weekly cidofovir. Microbiological response was defined as at least a one log reduction in urinary BKV viral load; clinical response was defined as improvement in symptoms and stability or reduction in the grade of cystitis. Nineteen allogeneic HSCT patients received a mean of 4.5 weekly doses of cidofovir. HC occurred at a mean of 68.7 days after transplant. A clinical response was detected in 16/19 (84%) patients, and 9/19 (47%) had a measurable microbiological response (8/10 nonresponders had a BKV viral load above the upper limit of the assay before treatment). Fourteen out of nineteen (74%) patients had no significant increase in serum creatinine. Five patients with renal dysfunction resolved after completion of the therapy and removal of other nephrotoxic agents. We conclude that weekly low-dose cidofovir appears to be a safe treatment option for BKV-associated HC. Although the efficacy of low-dose cidofovir is not proven, a prospective trial is warranted.

Weekly High-Dose Cidofovir Is an Effective Treatment for Symptomatic BK Virus (BKV)-Associated Hemorrhagic Cystitis (HC) after Allogeneic Stem Cell Transplantation (Allo-SCT).

A proportion of cases of HC after allo-SCT are associated with infection from BKV. Supportive treatment is not sufficient for the relief of symptoms in many patients with BKV-associated HC. Cidofovir is an antiviral agent active against BKV. Its use is limited, however, due to the reported risk of renal failure in patients with cytomegalovirus (CMV) infection. The experience with cidofovir in BKV-associated HC is anecdotal, and the optimal dose schedule of the drug has not been determined. We administered weekly high-dose cidofovir in 5 patients for the treatment of 6 episodes of symptomatic BKV-associated HC, which were refractory to first-line therapy with hydration and continuous bladder irrigation. One patient was treated twice with cidofovir for 2 temporally separated episodes of HC, combined with papillary necrosis and ureteritis respectively. All 5 patients were males, aged 21–44 years, and had received grafts from matched related (n=2), matched unrelated (n=1) or haploidentical (n=1) donors. The median time from transplantation to diagnosis of HC was 61.5 (range, 26–303) days. In all cases, the development of HC was associated with severe immunosuppression due to profound lymphopenia or treatment with steroids or antithymocyte globulin for GVHD. BKV-associated HC was confirmed by detection of BKV in the urine by real-time PCR (1.5 × 107–5.5 × 109 copies/ml). In 2 of the 6 episodes, the patients also developed BKV viremia (5.0–9.9 × 103 copies/ml). The median time from the manifestation of symptoms to initiation of cidofovir was 12 (range, 4–53) days. Cidofovir was started at a dose of 2.5 mg/kg/week intravenously over 1 hour. If renal function remained stable, subsequent doses of 5 mg/kg were given at weekly intervals for a total of 4–6 doses. Oral probenecid and intravenous hydration were administered in combination with cidofovir. No patient developed renal toxicity (a rise in serum creatinine of at least 1.5 × baseline or proteinuria). In 5 of the 6 cases, clinical improvement of patients was observed, with a median time to response of 5 (range, 3–8) days after the first dose of cidofovir. Complete resolution of symptoms of HC was achieved in these 5 cases after 4 to 6 doses of cidofovir. BKV viral load was monitored weekly in urine (and blood) during therapy. Clinical responses did not correlate with a reduction in viral load in urine. However, in the 2 cases with BKV viremia, real-time PCR became negative after treatment with cidofovir. Concomitant CMV infection was detected in 5 of the 6 episodes of BKV-associated HC, and in all but one, complete suppression of CMV reactivation was achieved by cidofovir. Four of the 5 patients are currently alive and free of symptoms of HC. In conclusion, treatment of BKV-associated HC with cidofovir at the dose of 5 mg/kg/week seems to be safe and may result in prompt and sustained relief of the debilitating symptoms of this condition. Additional manifestations of BKV-associated disease (papillary necrosis and ureteritis) and concurrent CMV infection can be managed successfully with this dose schedule. To our knowledge, these 6 cases comprise the largest reported experience of treatment of BKV-associated HC with cidofovir, albeit the encouraging results need to be substantiated by further trials.

BK VIRUS-ASSOCIATED FATAL RENAL FAILURE FOLLOWING LATE-ONSET HEMORRHAGIC CYSTITIS IN AN UNRELATED BONE MARROW TRANSPLANTATION

The human polyomavirus BK (BKV)-associated hemorrhagic cystitis (HC) has been a frequent and seldom life-threatening complication after bone marrow transplantation (BMT). The authors report a male with myelodysplastic syndrome, who developed BKV-associated late-onset HC 12 days after HLA-matched unrelated BMT. His urine contained epithelial cells with intranuclear inclusion bodies suggestive of BKV infection and was positive for BKV in polymerase chain reaction. He did not respond to any treatment for HC. In addition, he developed BKV-associated acute renal failure on day 26, followed by hepatic veno-occlusive disease on day 42. This is the first case in which BKV may be associated with fatal progressive renal failure.