BK Virus-associated Hemorrhagic Cystitis Research Articles

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.

Brazil: Votorantim — ZnO

Therapy for BK virus (BKV)–associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (P = .018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P = .037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P = .0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.

Bk virus: a clinical review.

We present a review of the clinically oriented literature about BK virus, a relative of JC virus, which is the etiologic agent of progressive multifocal leukoencephalopathy (PML). The kidney, lung, eye, liver, and brain have been proposed as sites of BK virus-associated disease, both primary and reactivated. BK virus has also been detected in tissue specimens from a variety of neoplasms. We believe that BK virus is most often permissively present in sites of disease in immunosuppressed patients, rather than being an etiologic agent that causes symptoms or pathologic findings. There is, however, strong evidence for BK virus-associated hemorrhagic cystitis and nephritis, especially in recipients of solid organ or bone marrow transplants. Now that BK virus can be identified by use of specific and sensitive techniques, careful evaluation of the clinical and pathologic presentations of patients with BK virus will allow us to form a clearer picture of viral-associated pathophysiology in many organ systems.