Virus-associated Hemorrhagic Cystitis Research Articles

High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation

BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches.

BK virus-associated hemorrhagic cystitis after pediatric stem cell transplantation.

Hemorrhagic cystitis is a common stem cell transplantation-related complication. The incidence of early-onset hemorrhagic cystitis, which is related to the pretransplant conditioning regimen, has decreased with the concomitant use of mesna and hyperhydration. However, late-onset hemorrhagic cystitis, which is usually caused by the BK virus, continues to develop. Although the BK virus is the most common pathogenic microorganism of poststem cell transplantation late-onset hemorrhagic cystitis, pediatricians outside the hemato-oncology and nephrology specialties tend to be unfamiliar with hemorrhagic cystitis and the BK virus. Moreover, no standard guidelines for the early diagnosis and treatment of BK virus-associated hemorrhagic cystitis after stem cell transplantation have been established. Here, we briefly introduce poststem cell transplantation BK virus-associated hemorrhagic cystitis.

Efficacy and Safety of Leflunomide for the Treatment of BK Virus-Associated Hemorrhagic Cystitis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients

BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation. So far, no specific antiviral drug with proven efficacy has been approved for treating BKV-HC. Leflunomide is an immunosuppressive drug with antiviral activity and has been used in treating BKV-associated nephropathy after renal transplantation. This is the first report on the efficacy and safety of leflunomide in the treatment of BKV-HC. From January 2006 to January 2009, 89 patients received allogeneic hematopoietic stem cell transplantation, and among them, 18 patients were identified as having BKV-HC, with a 20% cumulative incidence. Fourteen patients were treated with oral leflunomide. Three days of 100 mg/day leflunomide was used as loading doses and followed by maintenance doses of 20 mg/day. The urinary BKV-DNA load was monitored weekly by real-time quantitative PCR. The efficacy was evaluated on day 20 after leflunomide treatment. Seven patients (50%) achieved complete remission, 5 patients (35.7%) achieved partial remission, and 2 patients (14.3%) had more than a 1-log reduction in urinary BKV-DNA loads after treatment. During the leflunomide treatment, the graft-versus-host disease of the patients did not progress, and the dosages of the immunosuppressant were reduced simultaneously. One patient discontinued treatment because of intolerable gastrointestinal symptoms. Neutropenia occurred in 2 cases. These preliminary data suggest that leflunomide may be a potentially effective medication for treating BKV-HC without significant toxicity, but evidence supporting its use requires randomized controlled trials.

BK Virus (BKV) Associated Haemorrhagic Cystitis Is Associated with Graft Versus Host Disease (GVHD) and Significant Morbidity Post Haematopoietic Stem Cell Transplant (HSCT).

AbstractAbstract 3040The Polyomavirus hominis 1 BK virus (BKV) is a non-encapsulated DNA virus, which infects up to 90% of the world's population, and may reactivate at times of severe immunosuppression, including post haematopoietic stem cell transplantation (HSCT).The significance of BK virus reactivation post Haematopoietic Stem Cell Transplant (HSCT) remains unclear. We collected retrospective data on viruria, viraemia, haemorrhagic cystitis (HC) and acute/chronic graft versus host disease (a/cGVHD) in patients at our institution over the period 2006 to 2011. We compared with a multivariate matched control group of 38, who did not reactivate BK. The groups were matched for age, sex, donor source and conditioning regimen including use of Alemtuzumab. Global BK reactivation incidence was 32% (38/118) of allogeneic HSCT during this period. 73% (28/38) of those who reactivated received volunteer unrelated donor (VUD) grafts, and 50% (18/38) received Alemtuzumab.Patients were sub-divided into those with high grade viraemia (HGV, VL >104 copies/ml), 47% (18/38) or low grade viraemia (LGV, VL<104 copies/ml), 53% (20/38). HGV was present in 57% of VUD transplants and 20% of sibling recipients, compared to LGV in 29% of VUDs and 70% of siblings. HGV influenced 1 year EFS; 18% versus 55% in LGV. Median OS was 173 days in HGV versus 345 days in LGV.Cumulative mortality rate in the BK group was 71% (27/38) as compared to 55% (21/38) in the control group (not significant). Relapse related mortality in the BK group was 22% (6/27) versus 57% (12/21) in the control group, at a median follow up of 229 days (p=0.088), indicating the high incidence of non-relapse causes of mortality in the BK group.79% (30/38) of patients reactivating BK developed aGVHD, including 83% (15/18) with HGV, compared to 57% (21/37) in the control group (p=0.039). The number of patients who developed grade II-IV aGVHD in the BK group was 30/38 (79%) and 11/37 (20%) in the control group (p <0.001), figure 1. In 33% of patients BK reactivation preceded aGVHD by a mean of 12 days. 84% (27/32) of patients developed cGVHD, compared to 30% (18/30) in control group (p=0.05). Moderate-severe (NIH grade) cGVHD was more prevalent in patients reactivating BK, compared to control group; 75% (24/32) versus 3% (1/30) (p<0.001), figure 2.This data suggests the association of BK with an increased incidence of acute and chronic GVHD, and significant morbidity. Notably 10 patients developed severe complications including grade 4 HC (5/10), obstructive hydronephrosis and bladder wall dysfunction requiring invasive intervention. 7/10 (70%) of these patients had HGV; 2 patients reactivated early, failed treatment, developed obstructive renal failure and died. These patients had an increased rate of mortality compared to the whole study group (p=0.005), and all failed to achieve an EFS of over 1 year. Of note, 8.5% of all allografts developed grade 4 HC and 90% of these subsequently died.BK reactivation strongly correlates with acute and chronic GVHD and an increase in non relapse mortality. Routine surveillance for BK with risk scoring may allow earlier detection and reduced morbidity of BK and GVHD. Further prospective studies are required to understand the impact of the reactivation of the virus. [Display omitted] p <0.001 [Display omitted] p <0.001 Disclosures:No relevant conflicts of interest to declare.

Development of BK Virus-Associated Hemorrhagic Cystitis (HC) Is Associated with Decreased Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

AbstractAbstract 1933 Introduction:Infection by BK virus in the allo-HSCT setting is associated with the development of HC, which is a major cause of morbidity. There are few studies evaluating the impact of BK virus-associated HC on survival post allo-HSCT. Objectives:To evaluate the incidence of HC by BK virus in patients after allo-HSCT and its impact on survival. Methods:We retrospectively reviewed the medical charts of 107 patients who underwent allo-HSCT at Hospital Israelita Albert Einstein from July 2007 until November 2011. HC was defined by the presence of any degree of unexplained hematuria and positivity for BK virus in a urine sample by quantitative polymerase chain reaction (PCR) assay. CMV reactivation was defined as positivity in the antigenemia assay or greater than 165 copies in a quantitative PCR assay. Three patients were excluded because PCR results for BK virus were inconclusive, with 104 patients being analyzed in the final cohort. Cumulative incidence (CI) of HC, CMV reactivation and acute graft-versus-host disease (GVHD) were estimated taking into account the competing risk of death. Overall survival (OS) was estimated by the Kaplan-Meier method. Gray model was used for regression analysis of factors associated with the development of HC. Hazard ratios (HRs) were estimated by a Cox multivariable proportional hazards model, considering HC, CMV reactivation and acute GVHD as discrete time-varying covariates. Results:Median age was 28 years (range 6 months–76 years), and 60.5% of patients were male. About 37% had high-risk disease (refractory leukemia/lymphoma or 2nd-transplantation). Source of HSCs included matched related donors (37%), 10/10 HLA-matched unrelated donors (24%) and cord blood/haploidentical donors in 39%. The conditioning regimen was myeloablative in 81% of cases. The median follow-up of the whole cohort was 450 days (range 9–1624 days). At 1 year, the cumulative incidence of HC was 30.5% (95% confidence interval [CI] 21.8%–39.7%). The 1-year incidence of CMV reactivation and acute GVHD (all grades) was 57.1% and 39.7%, respectively. In a multivariate analysis taking into account age, sex, risk of disease, source of HSCs, intensity of conditioning, CMV reactivation and acute GVHD, only receiving cells from cord blood/haploidentical donors was associated with an increased incidence of HC (subhazard ratio 4.04, 95% CI 1.31–12.49, p = 0.015). The 1 year-OS of the whole cohort was 55% (95% CI 44–62%). Patients who developed HC had an inferior OS (1 year: 18% vs. 70%; HR= 4.40, p <0.0001; 95% CI 2.37–8.14). In the multivariate Cox analysis for OS, after adjusting for age, sex, disease risk, source of HSCs, intensity of conditioning, CMV reactivation and development of acute GVHD, development of HC was associated with an increased mortality (table). Conclusion:In this cohort, the development of CH was associated with an inferior OS in patients undergoing allogeneic HSCT. Even after adjusting for several variables, including development of acute GVHD and CMV reactivation, HC still remained an important factor associated with decreased survrival. It is possible that HC is not the direct cause of the increased mortality, but is rather a surrogate marker of a state of severe immunosuppression and increased risk of dying in the post-transplant setting. Nonetheless, our results suggest that the development of BK virus-associated HC in allo-HSCT patients is associated with inferior survival and future studies should confirm this finding and seek strategies to prevent this complication.TableCox multivariable analysis for OSCovariateHR (95% CI)PAge1.00 (0.98-1.01)0.98Male sex (yes vs. no)0.65 (0.33-1.29)0.22Myeloablative conditioning (vs. reduced-intensity conditioning)3.61 (1.41-9.26)0.007Disease risk category• Intermediate (vs. Low)1.11 (0.38-3.18)0.84• High (vs. Low)2.06 (0.77-5.46)0.14Source of Stem Cells• Matched Unrelated Donor (vs. Matched Related Donor)0.46 (0.18-1.17)0.10• Cord Blood/Haploidentical Donor (vs. Matched Related Donor)1.15 (0.53-2.51)0.71Development of BK-virus associated Hemorrhagic Cystitis4.84 (2.51-9.34)<0.0001Development of CMV reactivation1.31 (0.66-2.62)0.41Development of acute GVHD1.74 (0.86-3.51)0.11 Disclosures:No relevant conflicts of interest to declare.

Infectious complications following allogeneic stem cell transplantation: reduced‐intensity vs. myeloablative conditioning regimens

In allogeneic stem cell transplantation (allo-SCT), reduced-intensity conditioning (RIC) is known for producing less regimen-related toxicity. However, whether or not RIC reduces the risk for infection and infection-related mortality (IRM) remains controversial. We retrospectively analyzed infectious episodes and IRMs after allo-SCTs by time period and by the intensity of the conditioning regimen (RIC [n = 81] vs. myeloablative conditioning, MAC [n = 150]). The cumulative incidence of any kind of infection was lower in the RIC group through the entire period (72% vs. 87%; P = 0.007). The onset of infections was deferred in the RIC group as compared with the MAC group (P = 0.012). Bacteremia occurred less frequently in the RIC group through the entire period (5% vs. 14%; P = 0.044). However, the incidences of cytomegalovirus reactivation and disease, herpes zoster, virus-associated hemorrhagic cystitis, and invasive fungal infection were not different between the two groups. Furthermore, there was no difference in relapse-free survival and IRM between the two conditioning regimens. Careful monitoring and appropriate preventive/therapeutic strategies for infectious complications, comparable to those for allo-SCT recipients with MAC, should also be applied to those with RIC, especially after engraftment.

Bk Virus-Associated Hemorrhagic Cystitis in Pediatric Hematopoietic Stem Cell Transplantation Recipients

Bk Virus-Associated Hemorrhagic Cystitis in Pediatric Hematopoietic Stem Cell Transplantation Recipients

Different Risk Factors Related to Adenovirus- or BK Virus-Associated Hemorrhagic Cystitis following Allogeneic Stem Cell Transplantation

Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC.

Efficacy and Safety of Ciprofloxacin for Prophylaxis of Polyomavirus BK Virus–Associated Hemorrhagic Cystitis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Polyoma virus BK-induced hemorrhagic cystitis is an important cause of morbidity after hematopoietic stem cell transplantation (HSCT). Fluoroquinolones have been shown in vitro to inhibit BK viral replication by direct inhibition of the BK-encoded DNA gyrase. We hypothesized that extended prophylaxis with ciprofloxacin may decrease the incidence of severe (grades 3 and 4) BK virus-associated hemorrhagic cystitis (sBKHC) after HSCT. We retrospectively collected patient and transplant data, as well as incidence of sBKHC, for all consecutive patients undergoing allogeneic HSCT between June 2006 and August 2010 at our institution. Prophylaxis for sBKHC with ciprofloxacin 500 mg orally twice daily from day 0 until day 60 had been instituted in March 2009, delimiting a group receiving ciprofloxacin prophylaxis (CP) or no prophylaxis (NP). We compared the cumulative incidence of sBKHC in CP and NP, including death in absence of sBKHC as a competing risk. Ninety-two consecutive patients were included in the analysis, 44 in CP and 48 in NP. Median age of patients was 50 years (range: 19-70), and 47% received a myeloablative conditioning regimen. The cumulative incidence of sBKHC was significantly reduced in CP (2.6% versus 20.9%, P=.01). Multivariate Cox regression analysis revealed that assignment to CP and concomitant acute graft-versus-host disease (GVHD) were the only factors independently associated with the occurrence of sBKHC. Patients in CP did not experience a higher risk of Clostridium difficile diarrhea and were less likely to develop episodes of bacteremia. Ciprofloxacin prophylaxis appears safe and effective in reducing the incidence of severe BKHC after allogeneic HSCT.

Extended Use of Ciprofloxacin Markedly Decreases the Incidence of Severe BK Virus-Associated Hemorrhagic Cystitis In Allogeneic HSCT Recipients

AbstractAbstract 2317 Introduction:The polyoma virus BK is present in the urothelial tract of the majority of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Urothelial damage by the conditioning regimen triggers early viral replication and subsequent immune mediated damage to the urothelium. Clinical manifestations of BK virus-associated hemorrhagic cystitis (BKHC), with typical onset in the first 100 days after HSCT, range from asymptomatic microscopic hematuria to massive life threatening blood loss and urinary obstruction. There is no standard prophylaxis or treatment for BKHC. The antibacterial fluoroquinolones have been shown in vitro to inhibit BK viral replication by direct inhibition of the BK encoded DNA gyrase. Therefore, we hypothesized that extended prophylaxis with the fluoroquinolone ciprofloxacin might decrease the incidence of severe BKHC after HSCT. Methods:In March 2009 we began prescribing prophylaxis for BKHC with ciprofloxacin 500 mg orally twice daily from day 0 until day 60 after transplantation in all allograft recipients (except patients allergic to ciprofloxacin). Patient and transplant variables, as well as incidence of severe BKHC, were collected retrospectively for all consecutive patients undergoing allogeneic HSCT between June 2006 and July 2010. Severe BKHC was defined as grades 3 or 4 hemorrhagic cystitis with evidence of urinary excretion of BK virus by polymerase chain reaction. We estimated the incidence of severe BKHC and the survival free of severe BKHC for patients receiving (ciprofloxacin group) or not (control group) prophylaxis. Additionally, we performed a multivariate analysis to assess the independent role of ciprofloxacin prophylaxis in preventing episodes of severe BKHC. Results:Eighty-one consecutive patients were included in the analysis, of which 33 received ciprofloxacin prophylaxis. Median age of patients was 50 years (range 19–70) and 37% were female. Overall 47% of patients received a myeloablative conditioning regimen and 60% had an alternative (not HLA-matched sibling) donor. Median follow up for patients in the ciprofloxacin and control groups were respectively 180 (range 33–504) and 515 days (range of 29–1645). There was no difference in overall survival between ciprofloxacin and control groups. Episodes of severe BKHC occurred after a median of 60 days (range 27–118) after transplantation and were less frequent in the ciprofloxacin than in the control group (2.9% vs. 22.9%, chi-square test P= 0.01). Survival free of severe BKHC was also significantly superior in the ciprofloxacin group (Log-rank test P=0.04; Figure). In a multivariate Cox-regression analysis including age, gender, intensity of the conditioning regimen, use of mesna during conditioning and alternative donor, only the use of ciprofloxacin prophylaxis was significantly associated with the endpoint survival free of severe BKHC (P=0.01). There were no complications associated with prolonged use of ciprofloxacin, in particular no increase in Clostridium difficile associated diarrhea. Conclusion:Ciprofloxacin prophylaxis appears safe and effective in reducing the incidence of severe BKHC after allogeneic HSCT. This finding requires confirmation with a prospective randomized trial. [Display omitted] Disclosures:Off Label Use: Ciprofloxacin- prevention of BK associated hemorragic cystitis.

BK virus-associated hemorrhagic cystitis presenting as mural nodules in the urinary bladder after hematopoietic stem cell transplantation

We report an unusual sonographic presentation of late-onset hemorrhagic cystitis caused by BK virus infection in an 8-year-old who had undergone hematopoietic stem cell transplantation for treatment of relapsed acute lymphoblastic leukemia. Sonography showed the presence of multiple bladder nodules in a background of diffuse bladder wall thickening. The dominant bladder nodule showed increase in size on serial sonograms and was vascularized on Doppler interrogation. Biopsy confirmed BK virus-associated cystitis. Recognition of this sonographic appearance in the appropriate clinical setting might obviate the need for biopsy in these children.

TLR4 Asp299Gly Variant Confers Strong Protection against BK Virus-Associated Hemorrhagic Cystitis After Hematopoietic Stem Cell Transplantation in Children.

Abstract 344▪▪This icon denotes an abstract that is clinically relevant.Hemorrhagic cystitis is a serious complication after hematopoietic stem cell transplantation (HSCT). The pathogenesis of hemorrhagic cystitis is not fully understood and is influenced by BK virus infection, type of transplant, conditioning regimen, stem cell source, and graft-versus-host disease. Nothing is known about human genetic factors and the development of BK virus-associated hemorrhagic cystitis in patients after HSCT. Toll-like receptors (TLR) are essential components of the innate immune system. TLR have been discovered as the most important class of pattern recognition receptors, involved in the host defense against bacteria, viruses, fungi, and protozoa. C3H/HeJ mice that lack functional TLR4 receptors did not develop cystitis after intravesical instillation of E. coli. Individuals with the Asp299Gly polymorphism of the TLR4 gene showed a diminished inflammatory responsiveness to endotoxin. Because of the requirement of TLR4 in inflammatory response we hypothesized that TLR4 Asp299Gly reduces the risk of BK virus-associated hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT). 166 children (median age, 13 years) with acute lymphoblastic leukemia (n=72), acute myeloid leukemia (n=38), myelodysplastic syndrome (n=21), chronic myeloid leukemia (n=12), genetic disease (n=12) or severe aplastic anemia (n=11) who underwent allogeneic bone marrow (n=105) or peripheral blood stem cell transplantation (n=61; T-cell depleted: n=31) in a single center and their respective donors were genotyped of TLR4 for rs4986790 (A896G, Asp299Gly) using TaqMan real-time polymerase chain reaction. The donor was HLA-matched unrelated in 57% of transplants or HLA-identical related in 33% of transplants. Conditioning regimen was myeloablative in all cases and based on total body irradiation in 48% of transplants or busulfan in 47% of transplants. Two forms of post-transplant immunosuppression predominated, cyclosporine A and methotrexate in 64% of transplants and cyclosporine A alone in 25% of transplants. The Asp299Gly variant was present in 21 of the 166 patients (12.6%) and in 24 of the 166 donors (14.4%). Interestingly, we found a significantly reduced incidence of BK virus-associated hemorrhagic cystitis in patients with the Asp299Gly variant (0% versus 22.8%, p=0.009). In addition, we observed a significantly reduced incidence of BK virus-associated hemorrhagic cystitis in patients who were transplanted from a donor with this specific variant (4.2% versus 22.5%; p=0.05). In ten of the donor-patient pairs the variant was present in both individuals and no hemorrhagic cystitis was observed. The occurrence of the TLR4 Asp299Gly variant, in either recipients or donors, had no significant impact on acute and chronic GVHD, relapse rate, bacterial and fungal infectious complications, transplant related mortality, and overall survival. In conclusion, the TLR4 Asp299Gly variant in the recipient and/or the donor confers strong protection against BK virus-associated hemorrhagic cystitis after HSCT in children. This study provides the first evidence that the innate immune system through TLR4 signaling pathway seems to play an important role in the pathogenesis of BK virus-associated hemorrhagic cystitis after HSCT. Disclosures:No relevant conflicts of interest to declare.

Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti‐thymocyte globulin

To evaluate the incidence of infectious complications after receiving alemtuzumab as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in Korean patients. From November 2004 to January 2006, 12 patients who received alemtuzumab-based conditioning regimens for allogeneic HSCT were evaluated retrospectively until death or until the end of the follow-up in July 2007; they were compared with 18 patients who received rabbit anti-thymocyte globulin (ATG)-containing conditioning regimens from January 2002 to January 2006. Post-engraftment infections occurred more frequently in the alemtuzumab recipients than in the ATG recipients; the mean number of infections, excluding cytomegalovirus (CMV) infections, per patient during the follow-up period was 2.6+/-1.4 vs. 1.0+/-0.8 (P=0.003), respectively. Although there was no statistical difference in the cumulative incidence of CMV infection between the 2 groups (91.7% vs. 55.6%, P=0.381), the alemtuzumab recipients had a higher incidence of CMV diseases (41.6% vs. 0%, P=0.0006) and a higher recurrence rate of CMV infection (90.0% vs. 27.3%, P=0.008) than did the ATG recipients, irrespective of the dose of alemtuzumab. Hemorrhagic cystitis (HC) (66.7% vs. 16.7%, P=0.009) and BK virus-associated HC (41.7% vs. 5.6%, P=0.026) developed more frequently in the alemtuzumab recipients. The all-cause mortality rate was not significantly different between the alemtuzumab and the ATG recipients (75% vs. 55.6%, P=0.28). Alemtuzumab recipients had a high incidence of CMV disease as well as BK virus-associated HC compared with the ATG recipients. The dose of alemtuzumab should be tailored to patients' risk; in addition, the implementation of the appropriate prophylaxis for CMV and early detection strategies for BK virus are recommended.

Cidofovir for BK Virus–Associated Hemorrhagic Cystitis: A Retrospective Study

BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation (HSCT), but antiviral treatment for this condition has not been evaluated. We conducted a retrospective survey on the safety and outcome of cidofovir treatment for patients with BKV-HC in centers affiliated with the European Group for Blood and Marrow Transplantation. From 1 April 2004 to 31 December 2007, 62 patients received a diagnosis of BKV-HC after a median interval of 35 days after HSCT (range, 3-577 days). Fifty-seven patients (92%) received intravenous cidofovir, whereas 5 patients received cidofovir intravesically. Complete response (CR) was recorded in 38 (67%) of 57 patients with HC treated with intravenous cidofovir, whereas partial response (PR) was documented in 7 patients (12%). CR was documented in 3 patients and PR in 1 patient with HC treated with intravesical cidofovir. A reduction of 1-3 logs in BKV load was documented in 8 of the 10 patients achieving CR. Mild-to-moderate toxic effects were recorded in 18 of 57 patients who received intravenous cidofovir administration. In a multivariate analysis, the factors significantly associated with response to cidofovir were the stem cell source (P = .01) and the use of total body irradiation (P = .03). After a median follow-up of 287 days, overall survival and total treatment-related mortality rates were 63% and 40% for patients achieving CR, compared with 14% and 72% for patients with PR or no response to cidofovir, respectively (P = .001 and P = .001, respectively). Cidofovir may be a potentially effective therapy for BKV-HC, but evidence supporting its use requires randomized controlled trials.

LOW DOSAGE CIDOFOVIR WITHOUT PROBENECID AS TREATMENT FOR BK VIRUS HAMORRHAGIC CYSTITIS AFTER HEMOPOIETIC STEM CELL TRANSPLANT

We describe a single-center pediatric experience with 1 mg/kg/wk cidofovir without probenecid in 7 children with BK virus-associated hemorrhagic cystitis. Clinical improvement was observed in all cases, without adverse events, although significant reduction of urinary viral load was observed 2 weeks after the end of cidofovir in 5 out of 6 patients who completed the treatment.

BK Virus in Hematopoietic Stem Cell Transplantation Recipients

BK virus has become a serious issue in hematopoietic stem cell transplantation recipients, commonly manifesting as hemorrhagic cystitis, which can last from a matter of days to months and, if severe enough, may result in death. Patients with BK virus-associated hemorrhagic cystitis often experience poor quality of life, severe pain and discomfort, and prolonged hospitalizations. Despite numerous advances in stem cell transplantation methods, BK virus-associated hemorrhagic cystitis is difficult to control and treatment options are few. This article provides an overview of BK virus along with risk factors, current treatment modalities, and nursing considerations.

Symptomatic Improvement Following Intravesicular Cidofovir for the Management of BK Virus Associated Cystitis.

BACKGROUND: Hemorrhagic cystitis (HC) is a complication of hematopoietic stem cell transplantation, occurring in 10 to 70% of transplant recipients. Factors that may contribute to the risk of developing HC include intensive preparative regimens, especially those including busulfan, high-dose cyclophosphamide or ifosfamide, transplantation from matched unrelated donors, infection with adenovirus, and the development of graft-versus-host disease. The reactivation of latent BK virus in the kidney is thought to lead to the development of late-onset HC in hematopoietic stem cell transplant patients. Early reports of cidofovir's efficacy in BK virus-associated HC used intravenous cidofovir, but treatment was often complicated or compromised by excessive toxicity, especially renal compromise. Based on small single patient reports of the use of intravesicular cidofovir in the management of other viral causes of cystitis, we evaluated the use of intravesicular cidofovir for the management of BK virus associated cystitis.METHODS: In patients undergoing stem cell transplant, BK viral loads were routinely monitored twice weekly. The presence of cystitis or hematuria in a patient with detectable BK viruria was considered the trigger for initiation of therapy. Patients were treated with cidofovir at a dose of 5 mg/kg. Drug was diluted with 60mL of normal saline and administered via foley catheter, which was clamped for one hour post administration. Weekly repeat dosing was allowed as long as symptoms persisted. In addition to symptom control, BK viral loads were measured before, during, and after treatment.RESULTS: Four patients were included in this initial evaluation. All were recipients of allogeneic stem cell transplants; three were recipients of matched unrelated donor transplants and one received a transplant from a matched sibling. Patients received between 1 and 4 doses of cidofovir for initial therapy. All 4 patients experienced complete resolution of symptoms. The range for symptom resolution ranged from 2 days to 3 weeks. Symptoms reappeared in only 1 patient after discontinuation of therapy. Monitoring of BK urine viral loads revealed that 3 of the 4 patients had a greater than 50% decrease in urine BK viral load with initial dosing of cidofovir, indicating presence of antiviral activity when the drug is administered by this novel route.CONCLUSION: Intravesicular cidofovir is safe, easy to administer, and associated with both elimination of symptoms and reduction in viral loads in patients with hemorrhagic cystitis following high dose therapy and allogeneic transplantation.

Polyomavirus BK infection in blood and marrow transplant recipients

The association of BK virus infection with hemorrhagic cystitis in blood and marrow transplant (BMT) recipients was first demonstrated two decades ago. During this time, therapeutic interventions focused on supportive measures such as hyperhydration, continuous bladder irrigation and topical administration of agents that alter the mucosal surface of the bladder wall. In recent years, PCR amplification of viral DNA in the urine and plasma has solidified the association of BK virus infection with hemorrhagic cystitis, demonstrating that higher urine and plasma viral loads occur in the setting of disease. The evaluation of virus-specific therapy has lagged behind assessment of the viral load and theories of pathogenesis. Extrapolating from successes in the treatment of BK virus nephropathy in the renal transplant population, cidofovir and leflunomide are identified as potential effective agents for the treatment of BK virus-associated hemorrhagic cystitis. The fluoroquinolone antibiotics may prove to be effective as prophylactic agents. Given the manifestation of BK virus infection in organs outside of the urinary tract in an increasing immunocompromised patient population and the availability of potential antiviral agents, therapeutic trials need to progress beyond the small case series in order to improve the morbidity and mortality caused by BK virus-associated hemorrhagic cystitis in the BMT population.

BK Virus-associated Hemorrhagic Cystitis in Pediatric Cancer Patients Receiving High-dose Cyclophosphamide

Hemorrhagic cystitis (HC) is a known complication of oxazophosphorine chemotherapy. BK virus (BKV) has been commonly found to be associated with hematuria in stem cell transplant patients; however, it has rarely been reported after cyclophosphamide chemotherapy alone. The authors present 3 cases of BK viruria with HC in nontransplant pediatric oncology patients. The 3 patients with BKV had more prolonged hematuria (14 to 16 wk) compared with 1 patient with BKV-negative HC (10 wk). The HC necessitated chemotherapy delays and also prolonged supportive care. One patient was treated with intravenous cidofovir with resolution of BK viruria and hematuria. BKV may have an association with the development of HC in nonstem cell transplant patients receiving high-dose oxazophosphorine chemotherapy. HC may present early and be more prolonged in patients with BK viruria. Patients with HC after cyclophosphamide or ifosfamide with negative bacterial cultures should be studied for BKV. Cidofovir may be beneficial in certain patients with BK viruria and HC; however, definitive data will require a clinical trial.

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.