BK polyomavirus-associated hemorrhagic cystitis among pediatric allogeneic bone marrow transplant recipients: Treatment response and evidence for nosocomial transmission

Koskenvuo, Minna; Dumoulin, Alexis; Lautenschlager, Irmeli; Auvinen, Eeva; Mannonen, Laura; Anttila, Veli‐Jukka; Jahnukainen, Kirsi; Saarinen‐Pihkala, Ulla M.; Hirsch, Hans H.

doi:10.1016/j.jcv.2012.09.003

Cited by 65 publications

(67 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since orally administered BCV is preferentially distributed to the gastrointestinal tract, lung, liver, and spleen but not to the urinary tract in quantitative drug distribution studies in mice (52), for treatment of diagnosed PyVHC, intravesicular administration of BCV is likely to give better results than oral administration. Intravesicular treatment of PyVHC with CDV has been successfully used in some patients (reviewed in reference 23), but this has been questioned recently (53). Due to BCV's rapid transporter-independent absorption into all exposed cells, including urothelial cells as shown here, we speculate that intravesicular BCV is likely to be more efficient than intravesicular CDV.…”

Section: Discussionmentioning

confidence: 75%

Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

Tylden

Hirsch

Rinaldo

2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

e BK polyomavirus (BKPyV)-associated hemorrhagic cystitis (PyVHC) complicates 5 to 15% of allogeneic hematopoietic stem cell transplantations. Targeted antivirals are still unavailable. Brincidofovir (BCV; previously CMX001) has shown inhibitory activity against diverse viruses, including BKPyV in a primary human renal tubule cell culture model of polyomavirus-associated nephropathy. We investigated the effects of BCV in BKPyV-infected and uninfected primary human urothelial cells (HUCs), the target cells of BKPyV in PyVHC. The BCV concentrations causing 50 and 90% reductions (EC 50 and EC 90 ) in the number of intracellular BKPyV genome equivalents per cell (icBKPyV) were 0.27 M and 0.59 M, respectively. At 0.63 M, BCV reduced viral late gene expression by 90% and halted progeny release. Preinfection treatment for only 24 h reduced icBKPyV similarly to treatment from 2 to 72 h postinfection, while combined pre-and postinfection treatment suppressed icBKPyV completely. After investigating BCV's effects on HUC viability, mean selectivity indices at 50 and 90% inhibition (SI 50 and SI 90 ) calculated for cellular DNA replication were 2.7 and 2.9, respectively, those for mitochondrial activity were 8.9 and 10.4, those for total ATP were 8.6 and 8.2, and those for membrane integrity were 25.9 and 16.7. The antiviral and cytostatic effects, but less so the cytotoxic effects, were inversely related to cell density. The cytotoxic effects at concentrations of >10 M were rapid and likely related to BCV's lipid moiety. After carefully defining the antiviral, cytostatic, and cytotoxic properties of BCV in HUCs, we conclude that a preemptive or prophylactic approach in PyVHC is likely to give the best results.T he ubiquitous and usually quiescent BK polyomavirus (BKPyV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) following kidney and hematopoietic stem cell transplantation (HSCT), respectively (1).PyVHC afflicts 5 to 15% of HSCT patients after engraftment (2-5). The pathogenesis of PyVHC is incompletely characterized but is believed to involve initial iatrogenic damage to the bladder mucosa during pretransplantation conditioning, which is subsequently aggravated by lytic BKPyV replication in urothelial cells in the absence of immune surveillance. This leads to exposure of both viral and host epitopes to the foreign, engrafting lymphoid cells and may contribute to graft-versus-host disease (GVHD) (6-10). Inflammation and the resultant denudation of the urothelium cause hemorrhagic cystitis ranging from microhematuria to macrohematuria, clot-related urinary retention, and postrenal failure (reviewed in reference 5).PyVAN occurs in transplanted kidneys in 1 to 10% of recipients and often results in graft loss via a combination of lytic and inflammatory destruction of the renal parenchyma (2, 5). The initial reactivation signal is unknown, but mathematical modeling supports initial reactivation in the tubular epithelial compartment, followed by viral efflux with amplification in the uroth...

show abstract

Section: Discussionmentioning

confidence: 75%

Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

Tylden

Hirsch

Rinaldo

2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…While none of the BK virus-infected patients in our study responded to cidofovir therapy, all had severe symptoms and viral loads above the upper detectable limit at study entry. A case series from Finland reported responses in four of five pediatric patients receiving intravenous cidofovir: all patients were identified via surveillance rather than symptoms, suggesting that they were treated early in the disease course, and received both intravesicular and intravenous cidofovir (24). Other studies of adenovirus infection have similarly suggested that cidofovir is most effective when started early (18,21,25).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Brown

Cohen

Tong

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

fChildren undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.A utologous and allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant hematological and immunological disorders results in a variable period of compromised immunity (1). T-lymphocyte numbers and function are decreased by chemotherapeutic conditioning regimens, certain stem cell processing techniques, and immunosuppressive agents used to prevent or treat graft-versus-host disease (GVHD) in allogeneic HSCT recipients (1). In addition, the graft source, such as cord blood, peripheral blood stem cells, or marrow, impacts the pace and quality of immune reconstitution. Consequently, children undergoing HSCT are at profound risk for serious and potentially fatal viral infections. Viruses that commonly complicate HSCT include adenoviruses, cytomegalovirus (CMV), herpes simplex virus (HSV), human herpesvirus 6 (HHV-6), BK virus, and other community-acquired respiratory and gastrointestinal (GI) viruses (2-6). Furthermore, the need for protracted antiviral therapy due to impaired immune clearance increases the risk of antiviral resis...

show abstract

“…The use of ATG may be complicated by infections, as in the described case hemorrhagic cystitis caused by BKV and asymptomatic CMV reactivation were noted. BK virus-induced infections are frequently observed in patients after hematopoietic cell transplantation as well as the reactivation of herpes viruses [5,[11][12][13]. The availability of donor blood/bone marrow for posttransplant immunological manipulations played a crucial role in graft rejection prophylaxis and establishing sustained and stable donor chimerism.…”

Section: Discussionmentioning

confidence: 99%

Combined umbilical cord blood and bone marrow transplantation from a sibling in a patient with Fanconi anemia

Pawelec¹,

Boruczkowski²,

Ołdak³

et al. 2013

cejoi

View full text Add to dashboard Cite

show abstract

BK polyomavirus-associated hemorrhagic cystitis among pediatric allogeneic bone marrow transplant recipients: Treatment response and evidence for nosocomial transmission

Cited by 65 publications

References 28 publications

Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Combined umbilical cord blood and bone marrow transplantation from a sibling in a patient with Fanconi anemia

Contact Info

Product

Resources

About