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1
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Mendoza MA, Imlay H. Polyomaviruses After Allogeneic Hematopoietic Stem Cell Transplantation. Viruses 2025; 17:403. [PMID: 40143330 PMCID: PMC11946477 DOI: 10.3390/v17030403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 02/28/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Polyomaviruses (PyVs) are non-enveloped double-stranded DNA viruses that can cause significant morbidity in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, particularly BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV). BKPyV is primarily associated with hemorrhagic cystitis (HC), while JCPyV causes progressive multifocal leukoencephalopathy (PML). The pathogenesis of these diseases involves viral reactivation under immunosuppressive conditions, leading to replication in tissues such as the kidney, bladder, and central nervous system. BKPyV-HC presents as hematuria and urinary symptoms, graded by severity. PML, though rare after allo-HSCT, manifests as neurological deficits due to JCPyV replication in glial cells. Diagnosis relies on nucleic acid amplification testing for DNAuria or DNAemia as well as clinical criteria. Management primarily involves supportive care, as no antiviral treatments have proven consistently effective for either virus and need further research. This review highlights the virology, clinical presentations, and management challenges of PyV-associated diseases post-allo-HSCT, emphasizing the need for improved diagnostic tools and therapeutic approaches to mitigate morbidity and mortality in this vulnerable population.
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Affiliation(s)
| | - Hannah Imlay
- Division of Infectious Diseases, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA;
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2
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Riggsbee DL, Alali M, Kussin ML. Cidofovir for Viral Infections in Immunocompromised Children: Guidance on Dosing, Safety, Efficacy, and a Review of the Literature. Ann Pharmacother 2024; 58:286-304. [PMID: 37272472 DOI: 10.1177/10600280231176135] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023] Open
Abstract
OBJECTIVE To describe the use of cidofovir (CDV) for viral infections in immunocompromised children (IC) and provide guidance on dosing and supportive care. DATA SOURCES A PubMed search was conducted for literature published between 1997 and January 2022 using the following terms: cidofovir, plus children or pediatrics. STUDY SELECTION AND DATA EXTRACTION Limits were set to include human subjects less than 24 years of age receiving intravenous (IV) or intrabladder CDV for treatment of infections due to adenovirus, polyomavirus-BK (BKV), herpesviruses, or cytomegalovirus. DATA SYNTHESIS Data were heterogeneous, with largely uncontrolled studies. Conventional dosing (CDV 5 mg/kg/dose weekly) was commonly used in 60% (31/52) of studies and modified dosing (CDV 1 mg/kg/dose 3 times/week) was used in 17% (9/52) of studies, despite being off-label. Nephrotoxicity reported across studies totaled 16% (65/403 patients), which was higher for conventional dosing 29 of 196 patients (15%) than modified dosing 1 of 27 patients (4%). Saline hyperhydration and concomitant probenecid remain the cornerstones of supportive care, while some regimens omitting probenecid are emerging to target BKV. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE To our knowledge, this is the first comprehensive review of CDV use (indications, dosing, supportive care, response, and nephrotoxicity) in pediatric IC. CONCLUSIONS Effective utilization of CDV in IC remains challenging. Further prospective studies are needed to determine the optimal CDV dosing; however, less aggressive dosing regimens such as modified thrice weekly dosing or low dosing once weekly omitting probenecid to enhance urinary penetration may be reasonable alternatives to conventional dosing in some IC.
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Affiliation(s)
- Daniel L Riggsbee
- Department of Pharmacy, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA
| | - Muayad Alali
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University, Indianapolis, IN, USA
| | - Michelle L Kussin
- Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University, Indianapolis, IN, USA
- Department of Pharmacy, Riley Hospital for Children, Indiana University Health, Indianapolis, IN, USA
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3
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O'Brien A, Boan P. Cidofovir-induced anterior uveitis in an allogeneic stem cell transplant recipient. Transpl Infect Dis 2022; 24:e13974. [PMID: 36306187 DOI: 10.1111/tid.13974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 09/16/2022] [Indexed: 12/24/2022]
Abstract
Anterior uveitis is a reported complication of intravenous cidofovir, almost exclusively described in human immunodeficiency virus (HIV) infected patients treated for cytomegalovirus retinitis. In this study, we report the case of an allogeneic stem cell transplant recipient with significant visual impairment and hypotony following administration of high-dose intravenous cidofovir for hemorrhagic cystitis due to BK virus.
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Affiliation(s)
- Aine O'Brien
- Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Western Australia
| | - Peter Boan
- Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Western Australia
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4
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Beyond antivirals: virus-specific T-cell immunotherapy for BK virus haemorrhagic cystitis and JC virus progressive multifocal leukoencephalopathy. Curr Opin Infect Dis 2021; 34:627-634. [PMID: 34751182 DOI: 10.1097/qco.0000000000000794] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW The clinical manifestations of the polyomaviruses BK and JC in immunocompromised patients include BK virus (BKV) induced haemorrhagic cystitis and nephropathy, and JC virus (JCV) associated progressive multifocal leukoencephalopathy (PML) and are typically a consequence of impaired adaptive immunity in the host. To date, little clinical success has been achieved with antiviral agents or other drug therapies to treat these conditions. Here we review the methods and outcomes of the most recent clinical studies utilising adoptive immunotherapy with BK and/or JC virus-specific T-cells (VST) as either prophylaxis or treatment alternatives. RECENT FINDINGS In the last 12-18 months, several clinical trials have been published in the post-haemopoietic stem cell transplant (HSCT) setting showing good clinical success with the use of VST for treatment of BK viremia ± haemorrhagic cystitis. Between 82 and 100% clinical response has been observed in haemorrhagic cystitis using either third-party or donor-derived VST. The therapy was well tolerated with few cases of graft versus host disease in HSCT recipients, but immune mediated renal allograft loss was observed in one renal transplant recipient. Studies using BKV/JCV VST to treat PML are hindered by few patients who are sufficiently stable to receive VST. In a condition that otherwise carries such poor prognosis, VST were associated with clearance of JC virus, clinical and radiological improvement in some patients. Immune reconstitution inflammatory syndrome was a noted adverse event. SUMMARY Restoration of BK and JC virus immunity using VST immunotherapy has shown good clinical outcomes in BKV associated infections. Further evaluation with the administration of VST earlier in the course of disease is warranted for the treatment of BKV associated nephropathy in renal allograft and in JCV PML. In both indications, larger cohorts and standardisation of dosing and outcome measures would be of benefit.
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Li N, Huang XJ, Wang Y, Suo P, Xu LP, Liu KY, Zhang XH, Yan CH, Wang FR, Kong J, Cheng YF. [BK virus encephalitis in children with hematopoietic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:823-827. [PMID: 34788921 PMCID: PMC8607018 DOI: 10.3760/cma.j.issn.0253-2727.2021.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
目的 探讨异基因造血干细胞移植患儿中BK病毒（BKV）脑炎的发病率、病死率、中位发病时间、临床表现、诊治及转归等，以提高临床医师对本病的认识。 方法 回顾性分析2015年1月1日至2020年12月31日在北京大学人民医院接受单倍型造血干细胞移植治疗的709例儿童患者，其中14例诊断为BKV脑炎，分析其临床特征、治疗过程及转归。 结果 BKV脑炎发生率为1.97％（14例）。患儿多为男性（12例），中位年龄为11岁，中位发病时间为移植后第55天。最常见的临床表现为意识障碍、抽搐发作（7例）。14例患儿予阿昔洛韦、更昔洛韦单用，或联合丙种球蛋白治疗，9例患儿痊愈，1例患儿死于病毒性脑炎，4例患儿死于其他疾病，病死率为35.7％。 结论 BKV脑炎主要表现为脑炎或脑膜炎。虽然确诊BKV脑炎后积极予药物治疗，但许多患者仍死于多器官衰竭或其他并发症。当异基因造血干细胞移植患者出现神经系统症状、出血性膀胱炎时，必须高度警惕BKV脑炎，尽早施救，从而改善患者的生存率及生活质量。
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Affiliation(s)
- N Li
- Peking University People's Hospital,Beijing 100044,China Xingtai People's Hospital, Xingtai 054000, China
| | - X J Huang
- Peking University People's Hospital,Beijing 100044,China
| | - Y Wang
- Peking University People's Hospital,Beijing 100044,China
| | - P Suo
- Peking University People's Hospital,Beijing 100044,China
| | - L P Xu
- Peking University People's Hospital,Beijing 100044,China
| | - K Y Liu
- Peking University People's Hospital,Beijing 100044,China
| | - X H Zhang
- Peking University People's Hospital,Beijing 100044,China
| | - C H Yan
- Peking University People's Hospital,Beijing 100044,China
| | - F R Wang
- Peking University People's Hospital,Beijing 100044,China
| | - J Kong
- Peking University People's Hospital,Beijing 100044,China
| | - Y F Cheng
- Peking University People's Hospital,Beijing 100044,China
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6
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Palacio D, Prakash K, Riedel DJ. Review of Intravesicular Cidofovir for BK Virus Hemorrhagic Cystitis. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2021. [DOI: 10.1007/s40506-021-00251-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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7
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Wu Z, Graf FE, Hirsch HH. Antivirals against human polyomaviruses: Leaving no stone unturned. Rev Med Virol 2021; 31:e2220. [PMID: 33729628 DOI: 10.1002/rmv.2220] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 12/20/2022]
Abstract
Human polyomaviruses (HPyVs) encompass more than 10 species infecting 30%-90% of the human population without significant illness. Proven HPyV diseases with documented histopathology affect primarily immunocompromised hosts with manifestations in brain, skin and renourinary tract such as polyomavirus-associated nephropathy (PyVAN), polyomavirus-associated haemorrhagic cystitis (PyVHC), polyomavirus-associated urothelial cancer (PyVUC), progressive multifocal leukoencephalopathy (PML), Merkel cell carcinoma (MCC), Trichodysplasia spinulosa (TS) and pruritic hyperproliferative keratinopathy. Although virus-specific immune control is the eventual goal of therapy and lasting cure, antiviral treatments are urgently needed in order to reduce or prevent HPyV diseases and thereby bridging the time needed to establish virus-specific immunity. However, the small dsDNA genome of only 5 kb of the non-enveloped HPyVs only encodes 5-7 viral proteins. Thus, HPyV replication relies heavily on host cell factors, thereby limiting both, number and type of specific virus-encoded antiviral targets. Lack of cost-effective high-throughput screening systems and relevant small animal models complicates the preclinical development. Current clinical studies are limited by small case numbers, poorly efficacious compounds and absence of proper randomized trial design. Here, we review preclinical and clinical studies that evaluated small molecules with presumed antiviral activity against HPyVs and provide an outlook regarding potential new antiviral strategies.
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Affiliation(s)
- Zongsong Wu
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - Fabrice E Graf
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland.,Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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8
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Alkoxylalkyl Esters of Nucleotide Analogs Inhibit Polyomavirus DNA Replication and Large T Antigen Activities. Antimicrob Agents Chemother 2021; 65:AAC.01641-20. [PMID: 33288638 DOI: 10.1128/aac.01641-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/23/2020] [Indexed: 12/21/2022] Open
Abstract
Polyomavirus infections occur commonly in humans and are normally nonfatal. However, in immunocompromised individuals, they are intractable and frequently fatal. Due to a lack of approved drugs to treat polyomavirus infections, cidofovir, a phosphonate nucleotide analog approved to treat cytomegalovirus infections, has been repurposed as an antipolyomavirus agent. Cidofovir has been modified in various ways to improve its efficacies as a broad-spectrum antiviral agent. However, the actual mechanisms and targets of cidofovir and its modified derivatives as antipolyomavirus agents are still under research. Here, polyomavirus large tumor antigen (Tag) activities were identified as the viral target of cidofovir derivatives. The alkoxyalkyl ester derivatives of cidofovir efficiently inhibit polyomavirus DNA replication in cell-free human extracts and a viral in vitro replication system utilizing only purified proteins. We present evidence that DNA helicase and DNA binding activities of polyomavirus Tags are diminished in the presence of low concentrations of alkoxyalkyl ester derivatives of cidofovir, suggesting that the inhibition of viral DNA replication is at least in part mediated by inhibiting single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) binding activities of Tags. These findings show that the alkoxyalkyl ester derivatives of cidofovir are effective in vitro without undergoing further conversions, and we conclude that the inhibitory mechanisms of nucleotide analog-based drugs are more complex than previously believed.
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9
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Schneidewind L, Neumann T, Dräger DL, Kranz J, Hakenberg OW. Leflunomide in the treatment of BK polyomavirus associated nephropathy in kidney transplanted patients - A systematic review. Transplant Rev (Orlando) 2020; 34:100565. [PMID: 32611496 DOI: 10.1016/j.trre.2020.100565] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/09/2020] [Accepted: 06/15/2020] [Indexed: 12/25/2022]
Abstract
BK polyomavirus (BKPyV) associated nephropathy (BKVAN) is seen in about 5% of renal transplant patients and can lead to chronic graft failure or graft loss. No effective therapy is available. Leflunomide has shown promising results in BKVAN. We performed a systematic review about the use of leflunomide for the treatment of BKVAN. The recommendations of the Cochrane Handbook of systematic Reviews were followed. Due to different study designs and endpoints no meta-analysis was performed. The literature search for primary studies yielded 274 results. Finally, twelve studies were included with a total of 267 patients. Clearance of BKPyV viremia was reported in 33.3% to 92.3% of cases and 27 graft losses (10.1%). The included studies were very heterogeneous, especially in terms of leflunomide dosing. Pharmacokinetics seem to have an important impact on the efficacy of leflunomide in BKVAN. There was no correlation between leflunomide serum levels and virus reduction. New adverse events of leflunomide have been described, e.g. haemolytic anaemia and thrombotic microangiopathy. Overall, the risk of bias in the studies was assessed as high and the quality of evidence was rated low. The role of leflunomide in BKVAN remains unclear, but further studies seem reasonable and should address pharmacokinetic aspects.
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Affiliation(s)
| | - Thomas Neumann
- University Hospital Greifswald, Dept. Haematology/Oncology, Greifswald, Germany
| | | | - Jennifer Kranz
- St. Antonius Hospital Eschweiler, Dept. of Urology, Eschweiler, Germany; Department of Urology and Kidney Transplantation, Martin-Luther-University, Halle (Saale), Germany
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10
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Ito Y, Hino T, Honda A, Kurokawa M. Fluoroquinolones for BK viral complication after transplantation: Meta-analysis. Transpl Infect Dis 2020; 22:e13433. [PMID: 32744404 DOI: 10.1111/tid.13433] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVES BK polyomavirus (BKV) causes two distinct complications after transplantation, hemorrhagic cystitis (BKV-HC) after hematopoietic stem cell transplantation (HSCT), and BKV-associated nephropathy (BKVAN) after kidney transplantation (KT). Although fluoroquinolones show efficacy against BKV proliferation in vitro, the clinical effect remains uncertain; thus, we performed meta-analysis to assess its efficacy in the prophylaxis. METHODS Articles published before March 2020 were searched from PubMed, the Cochrane Library, ISRCTN registry, and ClinicalTrials.gov. Primary outcomes were BKV-HC after HSCT and BKVAN after KT. Secondary outcomes were BK viremia, viruria after KT, and fluoroquinolone-related adverse events. RESULTS Three trials with 281 patients post-HSCT and 11 trials with 1882 patients post KT were included as for prophylaxis. Fluoroquinolone prophylaxis did not show effects on BKV-HC (OR 0.54, 95% CI 0.13-2.25), BKVAN (OR 0.74, 95% CI 0.35-1.55), and BK viremia (OR 0.79, 95% CI 0.49-1.28), but significantly decreased BK viruria (OR 0.64, 95% CI 0.45-0.91). Fluoroquinolone prophylaxis was associated with the higher percentage of fluoroquinolone-resistant infection among identified bacteria (OR 2.38, 95% CI 1.16-4.88), but the incidence of fluoroquinolone-resistant infection was similar (OR 1.15, 95% CI 0.71-1.86), due to the decrease of infection itself (OR 0.52, 95% CI 0.34-0.81). CONCLUSIONS This meta-analysis showed that fluoroquinolones did not prevent BKV-HC after HSCT or BKVAN after KT, although the effect against BKV-HC should be further investigated by randomized controlled trials. Fluoroquinolones could reduce the rate of BK viruria to some extent but may not have clinically sufficient effects.
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Affiliation(s)
- Yusuke Ito
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan
| | - Toshiya Hino
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan
| | - Akira Honda
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan
| | - Mineo Kurokawa
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo City, Japan.,Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Bunkyo City, Japan
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11
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Saade A, Styczynski J, Cesaro S. BK virus infection in allogeneic hematopoietic cell transplantation: An update on pathogenesis, immune responses, diagnosis and treatments. J Infect 2020; 81:372-382. [PMID: 32526327 DOI: 10.1016/j.jinf.2020.06.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 06/01/2020] [Accepted: 06/05/2020] [Indexed: 12/15/2022]
Abstract
In hematopoietic cell transplantation (HCT) patients, BK polyomavirus (BKPyV) infection results in significant morbidity mainly due to hemorrhagic cystitis (HC). Despite increased knowledge acquired over recent decades, no treatment has shown effectiveness in the management of organ damage in HCT allografts. This review summarizes the current knowledge on BKPyV, from the virus constitution to the pathophysiology and immune-related mechanisms. We next focus on BKPyV-induced HC in HCT to discuss the benefit of monitoring BKPyV viruria and viremia in the management of patients. At last, we review currently used therapeutics, along with future promising therapies to propose clinical and practical guidelines and further interesting research areas.
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Affiliation(s)
- Anastasia Saade
- Department of Hematology, Ponchaillou, Centre Hospitalier Universitaire de Rennes, France.
| | - Jan Styczynski
- Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland
| | - Simone Cesaro
- Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata Verona, Italy
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12
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Visintini C, Venturini M, Palese A. Haemorrhagic cystitis, preventive and treatment interventions in patients undergoing haematopoietic stem cell transplantation: A scoping review. Eur J Oncol Nurs 2019; 42:50-62. [PMID: 31446264 DOI: 10.1016/j.ejon.2019.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 07/03/2019] [Accepted: 07/11/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE to map (a) methodological features, (b) Haemorrhagic Cystitis (HC) preventive and treatment interventions scrutinized to date, (c) outcomes measured, and (d) trends in effectiveness as documented among Haematopoietic Stem Cell Transplanted (HSCT) adults. METHODS A scoping review was performed in 2018. Medline, CINAHL, and Cochrane Systematic Reviews databases were researched using "haemorrhagic cystitis", "prevention", "treatment", "prevent*" and "treat*" as search terms. Handsearching was also performed. Clinical trials, randomized controlled trials, comparative and observational studies, reviews, systematic reviews and meta-analyses published in English and concerning adults were all included. RESULTS Fifteen primary studies, mainly monocentric, retrospective and with a sample size <200, were identified. Seven focused on preventive (mainly continuous bladder irrigation and mesna) and eight on treatment interventions (mainly intravenous and intravesical cidofovir). The onset of micro and macrohaematuria and the clinical resolution of HC were the main measured outcomes. Positive effectiveness trends were apparent for mesna and cidofovir. CONCLUSIONS In HC prevention and treatment, published primary studies are sparse and further research is required with larger, multicenter, and longitudinal designs conducted at international levels, with standardized methods, interventions, outcome measures, and reported data.
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Affiliation(s)
| | | | - Alvisa Palese
- Department of Medical Sciences, Udine University, Italy.
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13
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Nursing Management of Haemorrhagic Cystitis in Patients Undergoing Haematopoietic Stem Cell Transplantation: a Multicentre Italian Survey. Mediterr J Hematol Infect Dis 2019; 11:e2019051. [PMID: 31528317 PMCID: PMC6736169 DOI: 10.4084/mjhid.2019.051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 08/08/2019] [Indexed: 02/07/2023] Open
Abstract
Background Haemorrhagic cystitis (HC) is a severe complication occurring after haematopoietic stem cell transplantation (HSCT) in 13–40% of patients, caused by infectious and/or non-infectious factors that increase the in-hospital length of stay and the risk of mortality of transplanted recipients. Although different management interventions have been suggested in the literature, available knowledge on interventions performed by Italian nurses in their daily practices has not been documented to date. Aim of the study The aim of this study is to describe HC preventive and treatment interventions in patients undergoing HSCT as performed by Italian nurses in their daily practice. Material and methods A multicentre survey was conducted in 2018 by inviting all 110 Italian HSCT centres belonging to the Italian Group for Bone Marrow Transplantation (GITMO). Data collection was performed with an online questionnaire submitted to GITMO reference nurses working in each HSCT centre. Descriptive statistics were performed. Results A total of 38 Italian centres participated. The preventive intervention most applied in daily care was the mesna administration (n=37; 97.4%), followed by intravenous hyperhydration (n=33; 86.8%) and forced diuresis with furosemide (n=24; 63.1%). Preventive continuous bladder irrigation (CBI) was performed in 13 centres (34.2%). Transfusions of blood products (n=32; 84.2%), CBI (n=31; 81.6%) and intravenous hydration (n=28; 73.7%) were the most applied treatments, beyond the administration of analgesics (n=38; 100.0%) and antispasmodics (n=26; 68.4%). Conclusion A great variability both in the HC prevention and treatment interventions applied in daily practice across centres have emerged suggesting that no strong recommendations in the field are available to date. Therefore, there is a need to increase the evidence available in the field by providing methodological studies of higher quality, multicentre and prospective.
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Obeid KM. Infections with DNA Viruses, Adenovirus, Polyomaviruses, and Parvovirus B19 in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancies. Infect Dis Clin North Am 2019; 33:501-521. [PMID: 30940465 DOI: 10.1016/j.idc.2019.02.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Infections due to adenovirus, polyomaviruses (BK and JC viruses), and parvovirus B19 may not be as common as infections due to other DNA viruses, such as cytomegalovirus in patients with hematological malignancies and the recipients of hematopoietic stem cell transplantation. However, these infections may result in life-threatening diseases that significantly impact patients' recovery, morbidity, and mortality. Treating physicians should be aware of the diseases associated with these viruses, the patient populations at increased risk for complications due to these infections, and the available diagnostic and therapeutic approaches.
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Affiliation(s)
- Karam M Obeid
- Division of Infectious Diseases and International Medicine, University of Minnesota, 420 Delaware Street SE, MMC250, Minneapolis, MN 55455, USA.
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15
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Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat Biotechnol 2019; 37:303-313. [PMID: 30833775 DOI: 10.1038/s41587-019-0048-8] [Citation(s) in RCA: 281] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 01/23/2019] [Indexed: 01/10/2023]
Abstract
Adult stem cell-derived organoids are three-dimensional epithelial structures that recapitulate fundamental aspects of their organ of origin. We describe conditions for the long-term growth of primary kidney tubular epithelial organoids, or 'tubuloids'. The cultures are established from human and mouse kidney tissue and can be expanded for at least 20 passages (>6 months) while retaining a normal number of chromosomes. In addition, cultures can be established from human urine. Human tubuloids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. We apply tubuloids to model infectious, malignant and hereditary kidney diseases in a personalized fashion. BK virus infection of tubuloids recapitulates in vivo phenomena. Tubuloids are established from Wilms tumors. Kidney tubuloids derived from the urine of a subject with cystic fibrosis allow ex vivo assessment of treatment efficacy. Finally, tubuloids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active (trans-)epithelial transport function.
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16
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Al Zein S, Price H, Chen G, Kaur G. Native kidney BK nephropathy: A case report. Clin Case Rep 2019; 7:353-356. [PMID: 30847205 PMCID: PMC6389493 DOI: 10.1002/ccr3.1982] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 11/20/2018] [Accepted: 11/27/2018] [Indexed: 11/11/2022] Open
Abstract
BK virus nephropathy (BKN) is uncommonly reported in native kidneys; mostly reported in bone marrow transplant patients. This case report represents an interesting clinical scenario of biopsy-proven BKN in native kidneys, in the presence of more than one million copies/mL of BK virus in serum.
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Affiliation(s)
- Said Al Zein
- Penn State Health Milton S. Hershey Medical CenterHersheyPennsylvania
| | - Hayley Price
- Penn State Health Milton S. Hershey Medical CenterHersheyPennsylvania
| | - Guoli Chen
- Penn State Health Milton S. Hershey Medical CenterHersheyPennsylvania
| | - Gurwant Kaur
- Penn State Health Milton S. Hershey Medical CenterHersheyPennsylvania
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17
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Aldiwani M, Tharakan T, Al-Hassani A, Gibbons N, Pavlu J, Hrouda D. BK Virus Associated Haemorrhagic Cystitis. A systematic review of current prevention and treatment strategies. Int J Surg 2019; 63:34-42. [PMID: 30711618 DOI: 10.1016/j.ijsu.2019.01.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 01/29/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND BK virus is a major cause of late onset haemorrhagic cystitis in patients undergoing Haematopoietic Cell Transplantation (HCT). The evidence for the management of BK Virus Associated Haemorrhagic Cystitis (BKV-HC) is limited. Much of the published data consists of non-randomised case series and case reports. To our knowledge this is the first systematic review for the management of BKV-HC in both paediatric and adult populations. Our primary outcome was to examine the evidence for strategies of 1) prevention and 2) cessation of haematuria associated with BKV. Secondary outcomes were to assess the toxicity of treatment strategies and devise management recommendations for clinicians. MATERIALS AND METHODS We performed a systematic review of the PubMed and Central databases to evaluate the current evidence. A search protocol was prepared and registered with the PROSPERO database (CRD42017082442). The review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement and AMSTAR (Assessing the methodological quality of systematic reviews) guidelines. Results were classified by treatment type. Qualitative analysis of included articles was performed, and grades of recommendations were devised for each treatment. RESULTS Of 896 titles screened, 44 articles were included for qualitative analysis. The overall quality of evidence was low. There is insufficient evidence to recommend prophylactic quinolones. 40 studies evaluated treatments for established BKV-HC. There are no high-quality comparative studies. Cidofovir is the most studied treatment but quality of evidence is low, and grade of recommendation is weak. Hyperbaric oxygen therapy, Fibrin glue, Leflunomide, Sodium Pentosan Polysulfate, Intravesical Alum and Radiological embolisation have all been described but the effectiveness of these treatments is unclear. CONCLUSION There remains no clear specific treatment for BKV-HC. An effective multi-disciplinary approach leading to early recognition and initiation of treatment is encouraged. The development of novel therapies followed by well-designed clinical studies are urgently needed.
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Affiliation(s)
- M Aldiwani
- Dept of Urology, Imperial College NHS Trust, UK.
| | - T Tharakan
- Dept of Urology, Imperial College NHS Trust, UK
| | - A Al-Hassani
- Dept of Haematology, University College London, UK
| | - N Gibbons
- Dept of Urology, Imperial College NHS Trust, UK
| | - J Pavlu
- Centre for Haematology, Imperial College London, UK
| | - D Hrouda
- Dept of Urology, Imperial College NHS Trust, UK
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18
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Cesaro S, Dalianis T, Hanssen Rinaldo C, Koskenvuo M, Pegoraro A, Einsele H, Cordonnier C, Hirsch HH. ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother 2018; 73:12-21. [PMID: 29190347 DOI: 10.1093/jac/dkx324] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objectives To define guidelines for BK polyomavirus (BKPyV)-associated haemorrhagic cystitis (BKPyV-HC) after paediatric and adult HSCT. Methods Review of English literature and evidence-based recommendations by expert consensus. Results BKPyV-HC occurs in 8%-25% of paediatric and 7%-54% of adult recipients undergoing allogeneic HSCT. Diagnosis requires the triad of cystitis, macro-haematuria and high urine BKPyV loads >7 log10 copies/mL, and exclusion of other relevant aetiologies. BKPyV viraemia is frequent and may serve as a more specific semiquantitative follow-up marker. No randomized controlled trials are available to inform antiviral prophylaxis or treatment. However, hyper-hydration and/or bladder irrigation showed limited prophylactic value. Fluoroquinolones are not effective for prophylaxis or treatment, but rather increase antibiotic resistance. Hyperbaric oxygen or fibrin glue is marginally effective based on small case series from correspondingly equipped centres. Although cidofovir has been reported to improve and/or reduce BKPyV viraemia or viruria, the current data do not support its regular use. Conclusions BKPyV-HC remains a disabling unmet clinical need in HSCT that requires novel approaches supported by proper clinical trials.
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Affiliation(s)
- Simone Cesaro
- Pediatric Hematology-Oncology, Azienda Ospedaliera Universitaria Integrata Verona, Italy
| | - Tina Dalianis
- Department of Oncology Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Christine Hanssen Rinaldo
- Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway.,Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
| | - Minna Koskenvuo
- Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Finland
| | - Anna Pegoraro
- Pediatric Hematology-Oncology, Azienda Ospedaliera Universitaria Integrata Verona, Italy
| | - Hermann Einsele
- Department of Internal Medicine II, University Hospital Würzburg, Julius Maximilians University Würzburg, Germany
| | - Catherine Cordonnier
- Assistance Publique-Hôpitaux de Paris, Henri Mondor Teaching Hospital, Department of Hematology, 94000 Créteil, Paris-Est Créteil (UPEC) University, Créteil
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10; CH-4009 Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
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19
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Schneidewind L, Neumann T, Schmidt CA, Krüger W. Comparison of intravenous or intravesical cidofovir in the treatment of BK polyomavirus-associated hemorrhagic cystitis following adult allogeneic stem cell transplantation-A systematic review. Transpl Infect Dis 2018; 20:e12914. [PMID: 29797613 DOI: 10.1111/tid.12914] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/29/2018] [Accepted: 04/13/2018] [Indexed: 01/14/2023]
Abstract
INTRODUCTION BK polyomavirus can lead to hemorrhagic cystitis (BKPyV-HC) in allogeneic stem cell transplantation and therefore to increased morbidity. No causal therapy has been established yet. Cidofovir (CDV) is a nucleotide analog of cytosine that is active against various DNA viruses and it has been described for therapy of BKPyV-HC using 2 admission routes: intravenous and intravesical. METHODS We performed a systematic review regarding the comparison of intravenous or intravesical cidofovir in the treatment of BKPyV-HC following adult allogeneic stem cell transplantation. Since there is a lack of randomized controlled trials, we considered all kinds of studies for this review. Due to heterogeneity of the data, we were not able to perform a meta-analysis, so the results are shown descriptively. RESULTS The literature search for primary studies yielded 232 results. Finally, 9 studies where considered which included a total of 189 adult patients with BKPyV-HC after allogeneic stem cell transplantation. We could only identify retrospective studies for this review. A total of 172 patients received intravenous CDV, 17 patients received intravesical CDV, and 2 patients received CDV in both admission routes. In 68.0% of the cases, a complete response for intravenous CDV was documented and in 88.2% for intravesical CDV. Interestingly, no kidney toxicity was mentioned in intravesical CDV. 9.3% of the intravenously treated patients had renal failure. CONCLUSION There is only weak evidence for the use of CDV. The intravesical admission route should be further investigated because of a good toxicity profile.
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Affiliation(s)
- Laila Schneidewind
- Department of Haematology/Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Thomas Neumann
- Department of Haematology/Oncology, University Medicine Greifswald, Greifswald, Germany
| | | | - William Krüger
- Department of Haematology/Oncology, University Medicine Greifswald, Greifswald, Germany
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20
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Foster JH, Cheng WS, Nguyen NY, Krance R, Martinez C. Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant. Pediatr Transplant 2018; 22:e13141. [PMID: 29388318 DOI: 10.1111/petr.13141] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/28/2017] [Indexed: 12/11/2022]
Abstract
BK virus hemorrhagic cystitis is a complication of HCST. Response to IV cidofovir is unpredictable, and treatment carries risk of toxicity. We report the largest series of pediatric patients with BKHC after HSCT successfully treated with intravesicular cidofovir. There was no significant decrease in urine or plasma BK PCR. There was significant decrease in pain score on days 3 and 7, with associated decrease in morphine use. No patients experienced toxicities associated with IV cidofovir. Intravesicular cidofovir appears to be safe and effective for symptomatic treatment of BKHC in pediatric patients after HSCT.
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Affiliation(s)
- Jennifer H Foster
- Baylor College of Medicine, Houston, TX, USA.,Texas Children's Hospital, Houston, TX, USA
| | | | | | - Robert Krance
- Baylor College of Medicine, Houston, TX, USA.,Texas Children's Hospital, Houston, TX, USA
| | - Caridad Martinez
- Baylor College of Medicine, Houston, TX, USA.,Texas Children's Hospital, Houston, TX, USA
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21
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Coomes EA, Wolfe Jacques A, Michelis FV, Kim DDH, Thyagu S, Viswabandya A, Lipton JH, Messner HA, Deotare U. Efficacy of Cidofovir in Treatment of BK Virus-Induced Hemorrhagic Cystitis in Allogeneic Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant 2018; 24:1901-1905. [PMID: 29679772 DOI: 10.1016/j.bbmt.2018.04.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 04/10/2018] [Indexed: 11/19/2022]
Abstract
BK virus-associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with incidences up to 70%. Cidofovir is an antiviral agent with growing evidence as a therapeutic intervention. To assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC, a retrospective study was undertaken of the allo-HCT cohort who received cidofovir for symptomatic BK-HC (hematuria with BK viruria or viremia) from January 2010 until March 2017 in a single transplant center in Ontario, Canada. The primary outcome measure was a reduction in BK-HC severity (graded from 1 to 4); secondary outcomes included overall survival, BK virus titers, and the onset of acute kidney injury. Twelve allo-HCT patients received cidofovir for BK-HC, with pretreatment clinical severity of 3 (50%) or 4 (50%). Cidofovir was administered via intravenous (33%), intravesical (58%), or both modalities (8%). After a median cumulative dose of 10 mg/kg (range, 1 to 37), mean BK-HC grade decreased significantly by 1.8 (3.5 precidofovir, 1.7 postcidofovir, P < .01). Sixty-six percent of patients had at least partial response to cidofovir, with similar response rates between intravenous (66%) and intravesical (62%) administration. Sixty-seven percent of patients died, and 33% of patients experienced renal toxicity, including 2 patients receiving intravesical therapy. In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration; most patients achieved at least partial response after cidofovir administration. Even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. Although cidofovir may be an efficacious therapy for BK-HC, albeit with potential demonstrated toxicities, further prospective trials are needed.
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Affiliation(s)
- Eric A Coomes
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Amanda Wolfe Jacques
- Department of Pharmacy, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Fotios V Michelis
- Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Dennis Dong Hwan Kim
- Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Santhosh Thyagu
- Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Auro Viswabandya
- Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jeffrey H Lipton
- Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Hans A Messner
- Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Uday Deotare
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, Ontario, Canada
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22
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Cho SY, Lee HJ, Lee DG. Infectious complications after hematopoietic stem cell transplantation: current status and future perspectives in Korea. Korean J Intern Med 2018; 33:256-276. [PMID: 29506345 PMCID: PMC5840605 DOI: 10.3904/kjim.2018.036] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 02/18/2018] [Indexed: 12/28/2022] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is a treatment for hematologic malignancies, immune deficiencies, or genetic diseases, ect. Recently, the number of HSCTs performed in Korea has increased and the outcomes have improved. However, infectious complications account for most of the morbidity and mortality after HSCT. Post-HSCT infectious complications are usually classified according to the time after HSCT: pre-engraftment, immediate post-engraftment, and late post-engraftment period. In addition, the types and risk factors of infectious complications differ according to the stem cell source, donor type, conditioning intensity, region, prophylaxis strategy, and comorbidities, such as graft-versushost disease and invasive fungal infection. In this review, we summarize infectious complications after HSCT, focusing on the Korean perspectives.
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Affiliation(s)
- Sung-Yeon Cho
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyeon-Jeong Lee
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dong-Gun Lee
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Correspondence to Dong-Gun Lee, M.D. Division of Infectious Diseases, Department of Internal Medicine, The Catholic Blood and Marrow Transplantation Centre, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2-2258-6003 Fax: +82-2-535-2494 E-mail:
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23
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Ariza-Heredia EJ, El Chaer F, Chemaly RF. Antiviral Treatment and Prophylaxis in Immunocompromised Hosts. MANAGEMENT OF INFECTIONS IN THE IMMUNOCOMPROMISED HOST 2018:317-337. [DOI: 10.1007/978-3-319-77674-3_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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24
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Apiwattanakul N, Hongeng S, Anurathapan U, Pakakasama S, Srisala S, Techasaensiri C, Andersson BS. Viral-specific T-cell response in hemorrhagic cystitis after haploidentical donor stem cell transplantation. Transpl Infect Dis 2017; 19. [PMID: 28865164 DOI: 10.1111/tid.12775] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/07/2017] [Accepted: 06/11/2017] [Indexed: 01/08/2023]
Abstract
Viral hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) can be devastating. Standard treatment modalities have not been well established, but immune reconstitution may be necessary for sustained viral clearance. We studied five pediatric patients who developed viral HC after haplo-identical HSCT. All patients developed virus-specific CD4- and CD8-positive T cells, and the emergence of these viral-specific T cells was temporally associated with successful viral clearance.
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Affiliation(s)
- Nopporn Apiwattanakul
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suradej Hongeng
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Usanarat Anurathapan
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Samart Pakakasama
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Supanart Srisala
- Section for Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chonnamet Techasaensiri
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Borje S Andersson
- Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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25
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Bourlon C, Alamoudi S, Kumar D, Viswabandya A, Thyagu S, Michelis FV, Kim DDH, Lipton JH, Messner HA, Deotare U. A short tale of blood, kidney and brain: BK virus encephalitis in an allogeneic stem cell transplant recipient. Bone Marrow Transplant 2017; 52:907-909. [PMID: 28218753 DOI: 10.1038/bmt.2017.18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- C Bourlon
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - S Alamoudi
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - D Kumar
- Transplant Infectious Diseases, University Health Network, Toronto, Canada
| | - A Viswabandya
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - S Thyagu
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - F V Michelis
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - D D-H Kim
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - J H Lipton
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - H A Messner
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
| | - U Deotare
- Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada
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26
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Vigil D, Konstantinov NK, Barry M, Harford AM, Servilla KS, Kim YH, Sun Y, Ganta K, Tzamaloukas AH. BK nephropathy in the native kidneys of patients with organ transplants: Clinical spectrum of BK infection. World J Transplant 2016; 6:472-504. [PMID: 27683628 PMCID: PMC5036119 DOI: 10.5500/wjt.v6.i3.472] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/25/2016] [Accepted: 09/08/2016] [Indexed: 02/05/2023] Open
Abstract
Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research.
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27
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Pérez-Huertas P, Cueto-Sola M, Escobar-Cava P, Fernández-Navarro JM, Borrell-García C, Albert-Marí A, López-Briz E, Poveda-Andrés JL. BK Virus-Associated Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation in the Pediatric Population. J Pediatr Oncol Nurs 2016; 34:13-19. [PMID: 26902502 DOI: 10.1177/1043454216631952] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE To study the incidence, risk factors, and treatment of hemorrhagic cystitis secondary to BK-virus reactivation (HC-BKV) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the pediatric population. METHODS Case-control study in which all pediatric patients (0-18 years) who underwent allo-HSCT from September 2009 to January 2014 were followed. RESULTS Twenty-nine patients underwent an allo-HSCT. The median age was 9 years (range = 6 months to 15 years), 61% male. The primary diagnosis was acute lymphoblastic leukemia (72.4%). Six (20.7%) developed HC-BKV. In a multivariate analysis of risk factors, it was observed that the reactivation of BK virus was associated with age more than 10 years ( P = .098) and those with positive serology for Epstein-Barr virus ( P = .06). Five of the 6 patients with HC-BKV received cidofovir (CDV) at doses of 3 to 5 mg/kg/week. The treatment lasted a median of 3 cycles (range = 2-5). One of the patients (20%) developed nephrotoxicity. Of the 5 patients treated with CDV, 3 (60%) had a complete response, 1 (20%) partial response, and 1 (20%) no response. CONCLUSION We conclude that HC-BKV is a frequent complication after allo-HSCT. CDV therapy can be effective but controlled clinical trials are needed.
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28
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Philippe M, Ranchon F, Gilis L, Schwiertz V, Vantard N, Ader F, Labussiere-Wallet H, Thomas X, Nicolini FE, Wattel E, Ducastelle-Leprêtre S, Barraco F, Lebras L, Salles G, Michallet M, Rioufol C. Cidofovir in the Treatment of BK Virus–Associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2016; 22:723-730. [DOI: 10.1016/j.bbmt.2015.12.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 12/15/2015] [Indexed: 12/16/2022]
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Abstract
PURPOSE OF REVIEW This article describes recent advances in the diagnosis and management of encephalitis in immunocompromised individuals. RECENT FINDINGS Herpes simplex virus (HSV) and varicella zoster virus (VZV) are common causes of encephalitis in immunocompromised individuals, although clinical manifestations may be atypical, and thus challenging to recognize. Recently, an increased incidence of HSV and VZV central nervous system infections has been reported in association with novel immunosuppressive and immunomodulatory treatments. The free-living ameba Balamuthia mandrillaris causes granulomatous encephalitis predominantly in immunocompromised individuals and is associated with nearly uniform fatality. In the setting of organ transplantation, the recipient's immunocompromised state along with the potential for donor-transmitted infections can result in a unique epidemiology of encephalitis, including infection by human herpes virus-6 and BK virus. Recent studies utilizing next-generation sequencing techniques have identified several pathogens, including Leptospira santarosai and a neurotropic astrovirus, as causes of encephalitis in immunocompromised individuals. SUMMARY Diagnosis and management of encephalitis is challenging in immunocompromised individuals, in part because of atypical clinical presentations and the presence of uncommon or novel infectious agents. Unbiased techniques for pathogen discovery are likely to play an increasing role in the diagnosis of central nervous system infections in immunocompromised individuals.
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Successful treatment with intravesical cidofovir for virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: A case report and a review of the literature. J Infect Chemother 2016; 22:495-500. [PMID: 26898668 DOI: 10.1016/j.jiac.2016.01.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 01/16/2016] [Accepted: 01/19/2016] [Indexed: 11/20/2022]
Abstract
Virus-associated hemorrhagic cystitis (VAHC) is a formidable complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The standard management of severe VAHC after allo-HSCT has not been established. Intravenous administration of cidofovir (CDV), an acyclic nucleoside analogue with broad-spectrum activity against DNA viruses, has been reported to be effective for VAHC, but it can cause severe renal toxicity. Here we report four cases who achieved clinical responses with intravesical instillation of CDV for severe VAHC after allo-HSCT. Median age was 57 years (40-63), and all were male. The underlying diseases were hematological malignancies. Three had received bone marrow transplantation, and one received cord blood transplantation twice. Conditioning regimen was myeloablative for one, and reduced-intensity for three. The viral types were BK virus and/or adenovirus. Two patients had received CDV intravenously prior to the intravesical therapy. A dose of intravesical CDV was 2-5 mg/kg. In all cases, symptoms of cystitis improved dramatically within a few days without showing any systemic adverse effects. The virological response was observed in two cases. This local therapy was effective even in the cases refractory to the intravenous CDV and a case with severe renal failure. Along with the review of literature, we propose that the intravesical instillation of CDV can be a therapeutic option for severe VAHC after allo-HSCT.
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Aitken SL, Zhou J, Ghantoji SS, Kontoyiannis DP, Jones RB, Tam VH, Chemaly RF. Pharmacokinetics and safety of intravesicular cidofovir in allogeneic HSCT recipients. J Antimicrob Chemother 2015; 71:727-30. [PMID: 26612873 DOI: 10.1093/jac/dkv393] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 10/21/2015] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVES The objective of this study was to evaluate the pharmacokinetics and safety of cidofovir administered via the intravesicular route to patients with haemorrhagic cystitis following allogeneic HSCT (allo-HSCT). METHODS Patients with gross haematuria and confirmed BK or adenovirus viruria following allo-HSCT were prospectively enrolled in an open-label pharmacokinetic study (ClinicalTrials.gov registration: NCT01816646). Three hours after an oral probenecid dose (2 g), cidofovir (2.5-5 mg/kg in 50-100 mL of normal saline) was given via a transurethral catheter for up to 2 h of dwell time. Serial plasma samples were obtained over 24 h and assayed for cidofovir concentrations using LC-MS/MS. A custom pharmacokinetic model with a time-limited absorption compartment was fitted to the concentration-time profile of each patient. Systemic drug exposure was expressed as AUC0-24, by integrating the best-fit profile with respect to time. RESULTS Six subjects (mean ± SD age = 38 ± 21 years) with baseline serum creatinine <1.4 mg/dL were enrolled. Mean values for volume of distribution, clearance and elimination half-life were 19.5 L, 5.6 L/h and 2.8 h, respectively. Compared with the reported AUC0-24 for an equivalent intravenous dose, intravesicular instillation of cidofovir resulted in 1%-74% of the corresponding systemic exposure. Owing to primarily lower abdominal pain, only two patients were able to tolerate a 2 h dwell time. One patient developed a >50% increase in serum creatinine within 7 days of administration. CONCLUSIONS Intravesicular administration of cidofovir resulted in highly variable systemic exposures. The safety and efficacy of intravesicular cidofovir should be further evaluated before routine use.
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Affiliation(s)
- Samuel L Aitken
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0090, Houston, TX 77030, USA Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX 77030, USA
| | - Jian Zhou
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX 77030, USA
| | - Shashank S Ghantoji
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1460, Houston, TX 77030, USA
| | - Dimitrios P Kontoyiannis
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1460, Houston, TX 77030, USA
| | - Roy B Jones
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0423, Houston, TX 77030, USA
| | - Vincent H Tam
- Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX 77030, USA
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1460, Houston, TX 77030, USA
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Lee SS, Ahn JS, Jung SH, Ahn SY, Kim JY, Jang HC, Kang SJ, Jang MO, Yang DH, Kim YK, Lee JJ, Kim HJ. Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation. Korean J Intern Med 2015; 30:212-8. [PMID: 25750563 PMCID: PMC4351328 DOI: 10.3904/kjim.2015.30.2.212] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 04/22/2014] [Accepted: 07/07/2014] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS BK 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. METHODS Allogeneic 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. RESULTS Eight 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. CONCLUSIONS Weekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC.
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Affiliation(s)
- Seung-Shin Lee
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Jae-Sook Ahn
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Sung-Hoon Jung
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Seo-Yeon Ahn
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Jae-Yong Kim
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Hee-Chang Jang
- Department of Infectious Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Seung-Ji Kang
- Department of Infectious Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Mi-Ok Jang
- Department of Infectious Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Deok-Hwan Yang
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Yeo-Kyeoung Kim
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Je-Jung Lee
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Hyeoung-Joon Kim
- Department of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
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Andrei G, Topalis D, De Schutter T, Snoeck R. Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia. Antiviral Res 2014; 114:21-46. [PMID: 25446403 DOI: 10.1016/j.antiviral.2014.10.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 09/22/2014] [Accepted: 10/21/2014] [Indexed: 12/30/2022]
Abstract
Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.
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Affiliation(s)
- G Andrei
- Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Belgium.
| | - D Topalis
- Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Belgium
| | - T De Schutter
- Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Belgium
| | - R Snoeck
- Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Belgium
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Chittick P, Williamson JC, Ohl CA. BK virus encephalitis: case report, review of the literature, and description of a novel treatment modality. Ann Pharmacother 2014; 47:1229-33. [PMID: 24259742 DOI: 10.1177/1060028013500646] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE To describe a case of BK virus encephalitis with attempted direct antiviral therapy, review the reported cases of BK virus in the central nervous system, and report the novel use of intravenous cimetidine in place of oral probenecid to minimize the toxicities of intravenous cidofovir. CASE SUMMARY A 36-year-old male with acute myelomonocytic leukemia and subsequent myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplant. His course was complicated by severe graft-versus-host disease involving his skin and gastrointestinal tract. Five weeks after transplantation, he developed fever and confusion. Magnetic resonance imaging was suggestive of limbic encephalitis and cerebrospinal fluid tested positive for BK virus. Therapy with intravenous cidofovir was thought to be indicated. Although probenecid is commonly used to minimize the toxicities of cidofovir, the patient's severe graft-versus-host disease raised concerns about absorption of oral medications. Based on animal models and pharmacokinetic data, intravenous cimetidine was used in place of oral probenecid. Despite these therapies, the patient's mental status did not improve. He developed progressive organ system failure, and care was ultimately withdrawn. DISCUSSION BK virus is increasingly described as a cause of encephalitis. The majority of reported cases have occurred in immunocompromised patients and have generally had a poor outcome. This case describes attempted antiviral therapy using cidofovir, the antiviral agent used most frequently in other syndromes due to BK virus. Intravenous cimetidine is a novel modality used to minimize ocular and renal toxicities frequently seen with cidofovir, and we believe this warrants further investigation. CONCLUSIONS BK virus may be a cause of encephalitis in immunocompromised hosts, and cidofovir represents a possible treatment option. Intravenous cimetidine can be considered to minimize toxicities associated with cidofovir use in patients unable to tolerate or absorb oral probenecid.
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Satyanarayana G, Marty FM, Tan CS. The polyomavirus puzzle: is host immune response beneficial in controlling BK virus after adult hematopoietic cell transplantion? Transpl Infect Dis 2014; 16:521-31. [PMID: 24834968 DOI: 10.1111/tid.12233] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 01/22/2014] [Accepted: 02/08/2014] [Indexed: 12/14/2022]
Abstract
BK virus (BKV), a ubiquitous human polyomavirus, usually does not cause disease in healthy individuals. BKV reactivation and disease can occur in immunosuppressed individuals, such as those who have undergone renal transplantation or hematopoietic cell transplantation (HCT). Clinical manifestations of BKV disease include graft dysfunction and failure in renal transplant recipients; HCT recipients frequently experience hematuria, cystitis, hemorrhagic cystitis (HC), and renal dysfunction. Studies of HCT patients have identified several risk factors for the development of BKV disease including myeloablative conditioning, acute graft-versus-host disease, and undergoing an umbilical cord blood (uCB) HCT. Although these risk factors indicate that alterations in the immune system are necessary for BKV pathogenesis in HCT patients, few studies have examined the interactions between host immune responses and viral reactivation in BKV disease. Specifically, having BKV immunoglobulin-G before HCT does not protect against BKV infection and disease after HCT. A limited number of studies have demonstrated BKV-specific cytotoxic T cells in healthy adults as well as in post-HCT patients who had experienced HC. New areas of research are required for a better understanding of this emerging infectious disease post HCT, including prospective studies examining BK viruria, viremia, and their relationship with clinical disease, a detailed analysis of urothelial histopathology, and laboratory evaluation of systemic and local cellular and humoral immune responses to BKV in patients receiving HCT from different sources, including uCB and haploidentical donors.
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Affiliation(s)
- G Satyanarayana
- Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Division of Infectious Disease, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2014; 49:664-70. [PMID: 24488049 DOI: 10.1038/bmt.2013.235] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 09/26/2013] [Accepted: 11/23/2013] [Indexed: 11/08/2022]
Abstract
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.
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Kwon HJ, Kang JH, Lee JW, Chung NG, Kim HK, Cho B. Treatment of BK virus-associated hemorrhagic cystitis in pediatric hematopoietic stem cell transplant recipients with cidofovir: a single-center experience. Transpl Infect Dis 2013; 15:569-74. [PMID: 24028353 DOI: 10.1111/tid.12136] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 01/08/2013] [Accepted: 03/24/2013] [Indexed: 01/07/2023]
Abstract
BACKGROUND BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is a severe complication after hematopoietic stem cell transplantation (HSCT). Cidofovir (CDV) has emerged as an effective agent for the treatment of BKV nephropathy, but its use for BKV-HC in pediatric HSCT recipients has not yet been established as a standard therapy. PATIENT AND METHODS We retrospectively investigated the efficacy and safety of CDV therapy for patients with BKV-HC at a single institution and analyzed the clinical management outcomes. RESULTS From April 2009 to July 2011, 12 patients developed BKV-HC at a median of 37 days after transplant (range 15-59 days). The cumulative incidence was 9% and the median peak of the urine BKV load was 2.5 × 10(10) copies/mL (range 1.4 × 10(9) -1.2 × 10(11) copies/mL). Eleven patients received intravenous CDV (5 mg/kg/dose, with probenecid), whereas 1 patient received CDV (5 mg/kg/dose, without probenecid) intravesically. The median duration of therapy was 25 days (range 9-73 days), and a median of 2 doses was given (range 1-4). A reduction of ≥ 1 log in the BKV load was found in 11 patients, while 1 patient did not have any significant change in BKV load. Clinical improvement was observed in all cases, and no HC-related death was observed. CDV-related toxicity occurred in 1 patient (8%) and spontaneously resolved. CONCLUSIONS CDV appears to be an effective and safe treatment for BKV-HC in pediatric HSCT recipients, but prospective trials are warranted to support its use.
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Affiliation(s)
- H J Kwon
- Division of Infectious Diseases, Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Akazawa Y, Terada Y, Yamane T, Tanaka S, Aimoto M, Koh H, Nakane T, Koh KR, Nakamae H, Ohsawa M, Wakasa K, Hino M. Fatal BK virus pneumonia following stem cell transplantation. Transpl Infect Dis 2012; 14:E142-6. [PMID: 22998078 DOI: 10.1111/tid.12011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 05/14/2012] [Accepted: 06/14/2012] [Indexed: 12/16/2022]
Abstract
We report the case of a 39-year-old male patient who died of severe BK virus (BKV) pneumonia 168 days after hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. After suffering from BKV-associated late-onset hemorrhagic cystitis (HC) with long-term sustained BKV viremia, he died of rapidly progressive pneumonia. On autopsy, numerous viral intranuclear inclusions were seen in his lungs and bladder. An immunohistochemical examination of his lungs was positive for simian virus 40. Based on these pathological results and the high sustained BKV viral load in his blood, we reached a diagnosis of BKV pneumonia. Viral infection can occasionally become life threatening among HSCT recipients. It is widely known that BKV can cause late-onset HC, but BKV-associated pneumonia is rare. Because of its rapid progression and poor prognosis, it is difficult to make an antemortem diagnosis of BKV pneumonia. A treatment strategy for BKV pneumonia also needs to be formulated. Similar to other viral pathogens, BKV can cause pneumonia and the clinician should therefore be aware of it in immunocompromised patients.
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Affiliation(s)
- Y Akazawa
- Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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Breuer S, Rauch M, Matthes-Martin S, Lion T. Molecular diagnosis and management of viral infections in hematopoietic stem cell transplant recipients. Mol Diagn Ther 2012; 16:63-77. [PMID: 22497528 DOI: 10.1007/bf03256431] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Viral infections after allogeneic hematopoietic stem cell transplantation (HSCT) are important complications associated with high morbidity and mortality. In this setting, reactivations of persisting latent viral pathogens from donor and/or recipient cells play a central role whereas the sterile environment of transplant units renders new infections less likely. The viruses currently regarded as most relevant in the HSCT setting include particularly the herpes virus family--specifically cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6)--as well as human adenoviruses (AdVs) and the polyoma virus BK (BKV). Timely detection and monitoring of virus copy numbers are prerequisites for successful preemptive treatment approaches. Pre- and post-transplant surveillance by sensitive and quantitative molecular methods has therefore become an essential part of the diagnostic routine. In this review, we discuss diagnostic aspects and the clinical management of the most important viral infections in HSCT recipients, with a focus on pediatric patients.
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Affiliation(s)
- Sabine Breuer
- Department of Pediatric Stem Cell Transplantation, St. Anna Childrens Hospital, Medical University of Vienna, Vienna, Austria
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Mackey MC. Intravesicular cidofovir for the treatment of polyomavirus-associated hemorrhagic cystitis. Ann Pharmacother 2012; 46:442-6. [PMID: 22395246 DOI: 10.1345/aph.1q430] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To review the literature regarding the use of intravesicular cidofovir in the treatment of polyomavirus-associated hemorrhagic cystitis. DATA SOURCES Searches of PubMed were conducted, with key search terms including intravesicular cidofovir, polyomavirus, BK virus, JC virus, and hemorrhagic cystitis. Limits were set to include human subjects. STUDY SELECTION AND DATA EXTRACTION All articles identified were evaluated, and one was excluded due to being published only in the German language. All case studies/case series were included if patients received at least 1 dose of intravesicular cidofovir for treatment of cystitis. DATA SYNTHESIS Polyomavirus-associated hemorrhagic cystitis is more common in immunocompromised patients, particularly those who have undergone stem cell transplantation. Early-onset cystitis is often due to chemotherapy agents, while cystitis that develops 10-14 days into therapy is often associated with infection with polyomavirus, such as BK virus. There is no standard of therapy for polyomavirus-associated cystitis other than hyperhydration and continuous bladder irrigation, and many different therapeutic agents have been used in this setting, with mixed results. One such agent, intravenous cidofovir, provides clinical improvement but carries a risk of renal failure. Intravesicular cidofovir has been reported in case reports/series to provide positive symptomatic improvement; however, it has not been universally found to decrease urine viral load. CONCLUSIONS At this time, it appears that intravesicular cidofovir may be used as an option to provide symptomatic relief in patients with polyomavirus-associated hemorrhagic cystitis. However, it is not definitively known whether its use significantly decreases urine virus load in these patients. Larger clinical trials need to be conducted to fully understand the role of intravesicular cidofovir in this setting.
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Affiliation(s)
- Melissa C Mackey
- Department of Pharmacy, Duke University Hospital, Durham, NC, USA.
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41
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Current world literature. Curr Opin Organ Transplant 2011; 16:650-60. [PMID: 22068023 DOI: 10.1097/mot.0b013e32834dd969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Silva RLD. Polyoma BK virus: an emerging opportunistic infectious agent of the human central nervous system. Braz J Infect Dis 2011; 15:276-84. [DOI: 10.1016/s1413-8670(11)70189-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Accepted: 01/15/2011] [Indexed: 01/19/2023] Open
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Haines HL, Laskin BL, Goebel J, Davies SM, Yin HJ, Lawrence J, Mehta PA, Bleesing JJ, Filipovich AH, Marsh RA, Jodele S. Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17:1512-9. [PMID: 21385622 DOI: 10.1016/j.bbmt.2011.02.012] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 02/16/2011] [Indexed: 12/16/2022]
Abstract
BK virus is a significant cause of hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT). However, its role in nephropathy post-HSCT is less studied. We retrospectively evaluated clinical outcomes in pediatric HSCT patients with hemorrhagic cystitis. Although most of these patients had very high urine BK viral loads (viruria), patients with higher BK plasma loads (viremia) had significant renal dysfunction, a worse clinical course, and decreased survival. Patients with a peak plasma BK viral load of >10,000 copies/mL (high viremia) were more likely to need dialysis and aggressive treatment for hemorrhagic cystitis compared to patients with ≤ 10,000 copies/mL (low viremia). Conversely, most patients with low viremia had only transient elevations in creatinine, and less severe hemorrhagic cystitis that resolved with supportive therapy. Overall survival (OS) at 1 year post-HSCT was 89% in the low viremia group and 48% in the high viremia group. We conclude that the degree of BK viremia, and not viruria, may predict renal, urologic, and overall outcome in the post-HSCT population.
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Affiliation(s)
- Hilary L Haines
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
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Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant 2010; 17:1176-81. [PMID: 21185389 DOI: 10.1016/j.bbmt.2010.12.700] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Accepted: 12/13/2010] [Indexed: 11/23/2022]
Abstract
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.
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