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Shamim MA, Padhi BK, Satapathy P, Veeramachaneni SD, Chatterjee C, Tripathy S, Akhtar N, Pradhan A, Dwivedi P, Mohanty A, Rodriguez-Morales AJ, Sah R, Al-Tammemi AB, Al-Tawfiq JA, Nowrouzi-Kia B, Chattu VK. The use of antivirals in the treatment of human monkeypox outbreaks: a systematic review. Int J Infect Dis 2023; 127:150-161. [PMID: 36470502 PMCID: PMC9719850 DOI: 10.1016/j.ijid.2022.11.040] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/27/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Human monkeypox virus (MPXV) infection is a recently declared public health emergency of international concern by the World Health Organization. Besides, there is scant literature available on the use of antivirals in MPXV infection. This systematic review compiles all evidence of various antivirals used on their efficacy and safety and summarizes their mechanisms of action. METHODS A review was done of all original studies mentioning individual patient data on the use of antivirals in patients with MPXV infection. RESULTS Of the total 487 non-duplicate studies, 18 studies with 71 individuals were included. Tecovirimat was used in 61 individuals, followed by cidofovir in seven and brincidofovir (BCV) in three individuals. Topical trifluridine was used in four ophthalmic cases in addition to tecovirimat. Of the total, 59 (83.1%) were reported to have complete resolution of symptoms; one was experiencing waxing and waning of symptoms, only one (1.8%) had died, and the others were having a resolution of symptoms. The death was thought unrelated to tecovirimat. Elevated hepatic panels were reported among all individuals treated with BCV (leading to treatment discontinuation) and five treated with tecovirimat. CONCLUSION Tecovirimat is the most used and has proven beneficial in several aggravating cases. No major safety concerns were detected upon its use. Topical trifluridine was used as an adjuvant treatment option along with tecovirimat. BCV and cidofovir were seldom used, with the latter often being used due to the unavailability of tecovirimat. BCV was associated with treatment discontinuation due to adverse events.
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Affiliation(s)
| | - Bijaya Kumar Padhi
- Department of Community Medicine and School of Public Health, Postgraduate Institute of Medical Education and Research, Chandigarh, India,Corresponding authors
| | - Prakasini Satapathy
- Department of Virology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | | | - Snehasish Tripathy
- Department of Preventive Oncology, Homi Bhabha Cancer Hospital and Research Centre, Muzaffarpur, India
| | - Naushaba Akhtar
- Indian Council of Medical Research - Regional Medical Research Centre, Bhubaneswar, India
| | - Anindita Pradhan
- Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, India
| | - Pradeep Dwivedi
- Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, India,Centre of Excellence for Tribal Health, All India Institute of Medical Sciences, Jodhpur, India
| | - Aroop Mohanty
- All India Institute of Medical Sciences, Gorakhpur, India
| | - Alfonso J. Rodriguez-Morales
- Grupo de Investigación Biomedicina, Faculty of Medicine, Fundación Universitaria Autónoma de las Américas, Pereira, Colombia,Institución Universitaria Visión de las Américas, Pereira, Colombia,Clinical Epidemiology and Biostatistics, Universidad Cientifica del Sur, Lima, Peru
| | - Ranjit Sah
- Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal,Harvard Medical School, Boston, USA,Dr. D.Y. Patil Medical College, Hospital and Research Center, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India,Corresponding authors
| | - Ala'a B. Al-Tammemi
- Migration Health Division, International Organization for Migration (IOM), Amman, Jordan
| | - Jaffar A. Al-Tawfiq
- Infectious Diseases Division, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA,Infectious Disease Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA,Specialty Internal Medicine and Quality Department, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
| | - Behdin Nowrouzi-Kia
- ReSTORE Lab, Department of Occupational Science & Occupational Therapy, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Vijay Kumar Chattu
- ReSTORE Lab, Department of Occupational Science & Occupational Therapy, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada,Center for Transdisciplinary Research, Saveetha Institute of Medical and Technological Sciences, Saveetha University, Chennai, India,Department of Community Medicine, Faculty of Medicine, Datta Meghe Institute of Medical Sciences, Wardha, India,Corresponding authors
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Shamsian S, Saffaei A, Malek F, Khafafpour Z, Latifi A, Karamat M, Mirrahimi B. Intravesical alprostadil as a promising agent in BK virus-associated hemorrhagic cystitis: A report of a refractory case. Qatar Med J 2021; 2021:51. [PMID: 34692434 PMCID: PMC8502552 DOI: 10.5339/qmj.2021.51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 06/15/2021] [Indexed: 12/03/2022] Open
Abstract
Allogeneic stem cell transplant recipients are at risk of BK virus-associated hemorrhagic cystitis. This condition causes a significant morbidity and worsens clinical outcomes. The standard cares for BK virus-associated hemorrhagic cystitis are saline irrigation and forced diuresis. Notably, several beneficial roles are proposed for antiviral and anti-inflammatory agents against BK virus-associated hemorrhagic cystitis. However, cases who are at risk of cystectomy remain refractory. Herein, we present a 13-year-old boy with severe hematuria by passing two months from his allogeneic stem cell transplantation. The laboratory work up showed high BK viremia >1.1 × 108 copies/ml in this case's urine sample. The patient was treated with antiviral agents in combination with supportive care. Moreover, intravesical alum was administered, but no clinical benefits were achieved. Finally, intravesical alprostadil was prepared under the supervision of a pediatric clinical pharmacist. In this regard, an alprostadil solution was prepared by constitution of 250 μg alprostadil in 50 mL saline. After administrating the first dose of intravesical alprostadil, an acceptable clinical response was observed, and hematuria stopped. Of note, alprostadil induces platelet aggregation and vasoconstriction. Thus, bleeding can be controlled after the administration of intravesical alprostadil. This strategy may be associated with several side effects including bladder spasm. This study is the first report describing the special role of intravesical alprostadil in refractory cases of BK virus-associated hemorrhagic cystitis. In such refractory cases, clinicians can use intravesical alprostadil rather than invasive therapies in the treatment of BK virus-hemorrhagic cystitis.
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Affiliation(s)
- Shahin Shamsian
- Pediatric Congenital Hematologic Disorders Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran E-mail:
| | - Ali Saffaei
- Student Research Committee, Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Malek
- Pediatric Congenital Hematologic Disorders Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran E-mail:
| | - Zahra Khafafpour
- Pediatric Congenital Hematologic Disorders Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran E-mail:
| | - Abtin Latifi
- Pediatric Congenital Hematologic Disorders Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran E-mail:
| | - Mahdieh Karamat
- Student Research Committee, Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahador Mirrahimi
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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3
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Nepal P, Ojili V, Kumar S, Kumar D, Nagar A. Imaging spectrum of common and rare infections affecting the lower genitourinary tract. Abdom Radiol (NY) 2021; 46:2665-2682. [PMID: 33388810 DOI: 10.1007/s00261-020-02889-6] [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: 07/21/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 10/22/2022]
Abstract
In this review, we will discuss the imaging findings of common as well as uncommon lower genitourinary tract infections. For both clinicians and radiologists, it is imperative to understand etiopathogenesis, epidemiological information, clinical presentation, imaging findings and management options of such conditions. Knowledge of salient imaging features of these infections is of utmost importance because prompt recognition enables appropriate management.
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4
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Kwok M, Lin J, Routy JP. Concurrent BK polyomavirus, adenovirus and cytomegalovirus infections in a patient treated for chronic lymphocytic leukaemia. BMJ Case Rep 2021; 14:14/1/e235981. [PMID: 33402369 PMCID: PMC7786805 DOI: 10.1136/bcr-2020-235981] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
A 58-year-old woman with chronic lymphocytic leukaemia (CLL) presented with 2 weeks of fever and haematuria following chemo-immunotherapy. CT scan showed thickening of her left urethra and bladder, suggesting pyleo-ureteritis with cystitis. The patient was initially treated for suspected bacterial urinary tract infection although repeated blood and urine cultures remained negative. She then received multiple transfusions for chemotherapy-induced pancytopenia while her urinary symptoms did not improve. Due to her immunocompromised status, she was tested for viral infection, which revealed, BK polyomavirus, adenovirus and cytomegalovirus in serum and urine. Cidofovir was initially administered to treat these infections while ganciclovir was used with filgrastim due to neutropenia. The patient subsequently improved. This case represents a diagnostic and therapeutic challenge due to the multiple concurrent viral infections causing haematuria as well as the combined post-chemo-immunotherapy and antiviral myelotoxicity in a CLL patient.
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Affiliation(s)
- Michelle Kwok
- Division of Internal Medicine, McGill University Health Centre, Montréal, Quebec, Canada
| | - John Lin
- Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada
| | - Jean-Pierre Routy
- Infectious Disease and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada .,Division of Haematology, McGill University Health Centre, Montreal, Quebec, Canada
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Atilla E, Ateş C, Uslu A, Ataca Atilla P, Dolapçı I, Tekeli A, Topçuoğlu P. Prospective Analysis of Hemorrhagic Cystitis and BK Viremia in Allogeneic Hematopoietic Stem Cell Transplantation. Turk J Haematol 2020; 37:186-192. [PMID: 31852035 PMCID: PMC7463211 DOI: 10.4274/tjh.galenos.2019.2019.0296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023] Open
Abstract
Objective BK virus (BKV) infection has been shown to be related to hemorrhagic cystitis (HC) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). There are conflicting data regarding the association between BKV titers in plasma and clinical disease as well as the risk factors for BKV-related HC. Our aim is to study the risk factors and relationship with plasma BK viral load for development of HC in a prospective analysis. Materials and Methods We prospectively evaluated 59 patients who received allo-HSCT between 2014 and 2016 by quantitative BK virus polymerase chain reaction (PCR) (Altona Diagnostics, Germany) from blood samples at days 0, 30, 60, and 90 after allo-HSCT. The patients were monitored for signs and symptoms of HC. Results HC was diagnosed in 22 patients (37%) at a mean of 100 days (range: 0-367 days). In multivariate analysis, the usage of cyclophosphamide (sub-distribution hazard ratio [sdHR]: 7.82, confidence interval [CI]: 1.375-39.645, p=0.02), reactivated CMV (sdHR: 6.105, CI: 1.614-23.094, p=0.008), and positive BKV viremia (sdHR: 2.15, CI: 1.456-22.065, p=0.01) significantly increased the risk of developing HC. Patients with higher viral loads at day 30 and day 60 were diagnosed with more severe HC (p<0.001). Median BK viral loads of >101.5 copies/mL at day 0 (sensitivity 0.727, specificity 0.875), >98.5 copies/mL at day 30 (sensitivity 0.909, specificity 0.875), and >90.0 copies/mL at day 60 (sensitivity 0.909, specificity 0.875) were indicative of HC. Conclusion Our study showed that administration of cyclophosphamide, CMV reactivation, and BK virus positivity were associated with HC. Plasma BK virus PCR titers at days 0, 30, and 60 after transplant were sensitive tools for predicting clinically proven HC.
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Affiliation(s)
- Erden Atilla
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Can Ateş
- Van Yüzüncü Yıl University Faculty of Medicine, Department of Biostatistics, Van, Turkey
| | - Atilla Uslu
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Pınar Ataca Atilla
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Istar Dolapçı
- Ankara University Faculty of Medicine, Department of Microbiology, Ankara, Turkey
| | - Alper Tekeli
- Ankara University Faculty of Medicine, Department of Microbiology, Ankara, Turkey
| | - Pervin Topçuoğlu
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
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6
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Tooker GM, Stafford KA, Nishioka J, Badros AZ, Riedel DJ. Intravesicular Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis Following Hematopoietic Stem Cell Transplantation. Ann Pharmacother 2019; 54:547-553. [PMID: 31876431 DOI: 10.1177/1060028019897896] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: BK virus hemorrhagic cystitis (BKV-HC) is a common complication following hematopoietic stem cell transplant (HSCT); optimal management remains uncertain. Supportive care (bladder irrigation and blood transfusions) and intravenous and intravesicular cidofovir have all been used with varying success. Objective: The purpose of this study was to determine the safety and effectiveness of intravesicular cidofovir for BKV-HC following HSCT. Methods: A retrospective analysis of all HSCT patients with BKV-HC prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were treated for BKV-HC. The median age was 50 years (range 23-73), and 18 (55%) were male. The median HC symptom severity was 2, with a median BK urine viral load pretreatment of 100,000,000 IU/mL. Patients received a median of 2 intravesicular treatments (range 1-7) at a dosage of 5 mg/kg per instillation. In all, 19 (59%) patients demonstrated complete clinical resolution of symptoms; 9 (28%) had a partial response; and 4 (13%) had no change in symptoms. Patients with a high pretreatment BK viral load (>100 million) and high HC grade (2-4) had a lower frequency of complete remission. The main side effect of intravesicular instillation was severe bladder spasms in 4 patients (12%). Conclusion and Relevance: This is the largest study of intravesicular cidofovir treatment of BKV HC reported to date; 88% of patients with BVK-HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for this treatment for BKV-HC.
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Affiliation(s)
- Graham M Tooker
- University of Maryland Medical Center Midtown Campus, Baltimore, MD, USA
| | | | | | - Ashraf Z Badros
- University of Maryland School of Medicine, Baltimore, MD, USA
| | - David J Riedel
- University of Maryland School of Medicine, Baltimore, MD, USA
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7
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Nepal P, Ojili V, Sapire JM, Katkar A, Baxi A, Nagar A. Imaging of non-traumatic urinary bladder emergencies. Emerg Radiol 2019; 26:675-682. [PMID: 31280426 DOI: 10.1007/s10140-019-01703-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 06/28/2019] [Indexed: 12/17/2022]
Abstract
Non-traumatic urinary bladder emergencies are rare but critical diagnoses to make in an emergency setting. Acute urinary bladder pathologies require an accurate and timely diagnosis to ensure a favorable clinical outcome. Multidetector computed tomography (CT) is the imaging modality of choice for acute and emergent conditions affecting the urinary bladder. MRI is helpful as a problem-solving modality due to better soft tissue characterization and higher in-plane resolution. The purpose of this article is to illustrate the spectrum of urinary bladder emergencies, review the imaging findings, and briefly describe the role of imaging in the evaluation of such patients. Although there are a few cases of bladder emergencies been reported separately, the literature summarizing the spectrum is lacking. The objective of this article is to review the imaging of acute emergencies involving urinary bladder that will help us to think beyond non-specific conclusion in an emergency setting. For the sake of focused discussion, traumatic bladder emergencies will be excluded in this review. In the era of highly image reliant clinical practice, radiologists must be familiar with the diagnostic strategy to approach these entities.
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Affiliation(s)
- Pankaj Nepal
- Department of Radiology, St. Vincent's Medical Center, Bridgeport, CT, USA
| | - Vijayanadh Ojili
- Department of Radiology, University of Texas Health, San Antonio, TX, USA.
| | - Joshua M Sapire
- Department of Radiology, St. Vincent's Medical Center, Bridgeport, CT, USA
| | - Amol Katkar
- Department of Radiology, Brooke Army Medical Center, Fort Sam Houston, TX, USA
| | - Ameya Baxi
- Department of Radiology, University of Texas Health, San Antonio, TX, USA
| | - Arpit Nagar
- Department of Radiology, Ohio State University Wexner Medical Center, Columbus, OH, USA
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8
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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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9
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Abstract
Abstract
Background: BK virus infection is common but is usually asymptomatic. However, it can become life threatening as severe hemorrhagic cystitis (HC) or the polyomavirus-associated nephropathy (PVAN) particularly in immune compromised and transplant recipients. Some investigators have studied the pathophysiology and there are anecdotal and uncontrolled studies of therapy with few conclusions allowing treatment guidelines. Objectives: Summarize literature review of current knowledge concerning the nature, epidemiology, pathophysiology, diagnosis and treatment of this common virus infection. Results: HC is a not uncommon and often misdiagnosed infection from BK virus. It is usually self limited but can become life threatening in immune compromised patients. PVAN threatens survival of transplanted kidneys and is difficult to differentiate from rejection without sophisticated molecular diagnostic technology. We have sufficient information for making a diagnosis of BK virus disease by using clinical, serological and molecular technology. Studies using manipulation of immunosuppression and a variety of antiviral agents, including cidofovir, leflunomide, intravenous immunoglobulin, vidarabine, fluroquinolones, have been published but most were uncontrolled reports of few cases. Cidofovir offers some promise but more must be learned before there is hope for evidence-based treatment guidelines.
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Trofe J, Gordon J, Roy-Chaudhury P, Koralnik IJ, Atwood WJ, Alloway RR, Khalili K, Woodle ES. Polyomavirus Nephropathy in Kidney Transplantation. Prog Transplant 2016; 14:130-40; quiz 141-2. [PMID: 15264457 DOI: 10.1177/152692480401400207] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Polyomavirus nephropathy has become an important complication in kidney transplantation, with a prevalence of 1% to 8%. Unfortunately, the risk factors for polyomavirus nephropathy and renal allograft loss are not well defined. The definitive diagnosis is made through assessment of a kidney transplant biopsy. Recently, noninvasive urine and serum markers have been used to assist in polyomavirus nephropathy diagnosis and monitoring. Primary treatment is immunosuppression reduction, but must be balanced with the risks of rejection. No antiviral treatments for polyomavirus nephropathy have been approved by the Food and Drug Administration. Although cidofovir has shown in vitro activity against murine polyomaviruses, and has been effective in some patients, it is associated with significant nephrotoxicity. Graft loss due to polyomavirus nephropathy should not be a contraindication to retransplantation; however, experience is limited. This review presents potential risk factors, screening, diagnostic and monitoring methods, therapeutic management, and retransplantation experience for polyomavirus nephropathy.
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Affiliation(s)
- Jennifer Trofe
- University of Cincinnati, Division of Transplantation, Ohio, USA
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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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12
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Evans GL, Caller LG, Foster V, Crump CM. Anion homeostasis is important for non-lytic release of BK polyomavirus from infected cells. Open Biol 2016; 5:rsob.150041. [PMID: 26246492 PMCID: PMC4554916 DOI: 10.1098/rsob.150041] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BK polyomavirus (BKPyV) is a member of a family of potentially oncogenic viruses, whose reactivation can cause severe pathological conditions in transplant patients, leading to graft rejection. As with many non-enveloped viruses, it is assumed that virus release occurs through lysis of the host cell. We now show the first evidence for a non-lytic release pathway for BKPyV and that this pathway can be blocked by the anion channel inhibitor DIDS. Our data show a dose-dependent effect of DIDS on the release of BKPyV virions. We also observed an accumulation of viral capsids in large LAMP-1-positive acidic organelles within the cytoplasm of cells upon DIDS treatment, suggesting potential late endosome or lysosome-related compartments are involved in non-lytic BKPyV release. These data highlight a novel mechanism by which polyomaviruses can be released from infected cells in an active and non-lytic manner, and that anion homeostasis regulation is important in this pathway.
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Affiliation(s)
- Gareth L Evans
- Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
| | - Laura G Caller
- Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
| | - Victoria Foster
- Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
| | - Colin M Crump
- Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
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13
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Park YH, Lim JH, Yi HG, Lee MH, Kim CS. BK virus-hemorrhagic cystitis following allogeneic stem cell transplantation: Clinical characteristics and utility of leflunomide treatment. Turk J Haematol 2016; 33:223-230. [PMID: 27094950 PMCID: PMC5111468 DOI: 10.4274/tjh.2015.0131] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 12/21/2015] [Indexed: 12/01/2022] Open
Abstract
BK virus-hemorrhagic cystitis (BKV-HC) is a potential cause of morbidity and mortality in patients having undergone allogeneic stem cell transplantation (Allo-SCT). We analyzed the clinical features of BKV-HC following Allo-SCT and reported the utility of leflunomide therapy for BKV-HC. MATERIALS AND METHODS From January 2005 to June 2014, among the 69 patients underwent Allo-SCT in our institution, the patients who experienced BKV-HC were investigated retrospectively. RESULTS Hemorrhagic cystitis (HC) was observed in 30 patients (43.5%), and among them, 18 patients (26.1%) were identified as BKV-HC. The median age of the patients (12 males and 6 females) was 45 years (range, 13-63). Patients received Allo-SCT from acute myeloid leukemia (n=11), aplastic anemia (n=4), myelodysplastic syndrome (n=2), and non-Hodgkin lymphoma (n=1).The donor types were a HLA-matched sibling donor for 6 patients, HLA-matched unrelated donor for 9, and a haploidentical familial donor for 2. The median onset and duration of BKV-HC was on day 21 (range, 7-97) after transplantation and 22 days (range, 6-107). Eleven patients (62.1%) had grade I-II HC and seven patients (38.9%) had grade III-IV (high-grade) HC. Among the seven patients who had high-grade HC, one had complete response (CR), one partial response (PR), and five no response (NR). Among the five non-responders, one died of BKV-HC associated complications. The remaining four patients were treated with leflunomide, with achieving CR (n=2) and PR (n=2). The median duration from the start of leflunomide therapy to response was 13 days (range, 8-17 days). All patients tolerated the leflunomide treatment well, with three patients having mild gastrointestinal symptoms, including anorexia and abdominal bloating. CONCLUSION BKV-HC was commonly observed in patients with HC following Allo-SCT. In high-grade BKV-HC patients who fail supportive care, leflunomide may be a feasible option without significant toxicity.
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Affiliation(s)
- Young Hoon Park
- Inha University Faculty of Medicine and Hospital, Department of Hematology-Oncology, Incheon, Republic of Korea
| | - Joo Han Lim
- Inha University Faculty of Medicine and Hospital, Department of Hematology-Oncology, Incheon, Republic of Korea
| | - Hyeon Gyu Yi
- Inha University Faculty of Medicine and Hospital, Department of Hematology-Oncology, Incheon, Republic of Korea
| | - Moon Hee Lee
- Inha University Faculty of Medicine and Hospital, Department of Hematology-Oncology, Incheon, Republic of Korea
| | - Chul Soo Kim
- Inha University Faculty of Medicine and Hospital, Department of Hematology-Oncology, Incheon, Republic of Korea
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14
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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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15
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Abudayyeh A, Abdelrahim M. Current Strategies for Prevention and Management of Stem Cell Transplant-Related Urinary Tract and Voiding Dysfunction. CURRENT BLADDER DYSFUNCTION REPORTS 2015. [DOI: 10.1007/s11884-015-0289-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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16
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BK Virus and Its Role in Hematopoietic Stem Cell Transplantation: Evolution of a Pathogen. Curr Infect Dis Rep 2014; 16:417. [PMID: 24942378 DOI: 10.1007/s11908-014-0417-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
We reviewed the literature regarding disease induced by BK virus (BKV) in the hematopoietic stem cell transplant (HSCT) population, particularly hemorrhagic cystitis (HC) and nephritis. The association between BKV and HC has been reported over the past four decades. BKV has been clinically implicated and widely accepted as an etiologic agent of HC and nephritis in HSCT and nephropathy in renal transplant patients. We discuss the potential benefit of early initiation of therapy in patients who fail supportive care alone as well as the different treatment strategies for HC induced by BKV. Treatments that have been used such as cidofovir and leflunomide are accompanied by risks, and the benefits are not as concrete as with other viral illness in the HSCT population.
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17
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Rinaldo CH, Hirsch HH. Antivirals for the treatment of polyomavirus BK replication. Expert Rev Anti Infect Ther 2014; 5:105-15. [PMID: 17266458 DOI: 10.1586/14787210.5.1.105] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Antiviral drugs with specific activity against polyomavirus replication have not been developed in the past. This deficiency has become fully apparent with the emergence of polyomavirus-associated nephropathy in kidney-transplant recipients, with a prevalence rate of up to 10%. In most cases, high BK virus replication in tubular epithelial cells causes significant cytopathology, leading to permanently impaired renal allograft function and return to hemodialysis within 6-60 months. In 5-10% of allogenic bone marrow/hematopoietic stem cell transplant recipients, high-level BK virus replication in the ureter/bladder mucosa has been associated with postengraftment hemorrhagic cystitis, which appears to involve significant immunopathology. Thus, in view of the increasing clinical need, a number of drugs have been studied in small case series. We review the antiviral strategies explored to date and specifically discuss available in vivo and in vitro data on cidofovir, leflunomide, fluoroquinolones and intravenous immunoglobulins, regarding mechanism, administration, dosing and outcome and provide a perspective on future therapy options.
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Affiliation(s)
- Christine Hanssen Rinaldo
- University Hospital of North Norway, Department of Microbiology and Infection Control, PO Box 56, N-9038 Tromsø, Norway. christine.rinaldo@unn
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18
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Hsu JW, Wingard JR. Advances in the management of viral infections. Cancer Treat Res 2014; 161:157-180. [PMID: 24706224 DOI: 10.1007/978-3-319-04220-6_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Viral infections are common in cancer patients. The risk and severity of infection are influenced by patient, disease, treatment, and viral factors. Severe viral infections are more likely to occur in treatment regimens that are more immunosuppressive. Historically, the most frequent severe infections have been due to herpesviruses, but more recently, other pathogens, especially community respiratory and hepatitis viruses, have received increasing attention as major viral pathogens in cancer patients. Because of the new diagnostic assays and the introduction of better therapeutic options, knowledge of viral infections is important in optimizing antineoplastic therapies.
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Affiliation(s)
- Jack W Hsu
- Department of Medicine, University of Florida, 1600 SW Archer Road, PO Box 100277, Gainesville, FL, 32610, USA,
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19
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Han TT, Xu LP, Liu DH, Liu KY, Fu HX, Zhao XY, Zhao XS, Huang XJ. Cytomegalovirus is a potential risk factor for late-onset hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2014; 89:55-61. [PMID: 24009106 DOI: 10.1002/ajh.23584] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 08/21/2013] [Accepted: 08/24/2013] [Indexed: 11/07/2022]
Abstract
Late-onset hemorrhagic cystitis (LOHC) is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is primarily associated with viral infection. We prospectively quantified cytomegalovirus (CMV), BK virus (BKV), and adenovirus in urine and plasma using Q-RT-PCR in 50 consecutive patients to define the relationship between virus and LOHC. Of the 50 patients, 21 developed LOHC at a median of 29 days (range 4-64 days), with a cumulative incidence of 42% (±7.1%). The cumulative incidence of LOHC on day 100 in patients with and without CMV viremia (prior to or at the onset of LOHC) were 56.3% (±8.9%) and 16.7% (±9.1%) (P = 0.018), respectively, and it was 59.3% (±9.8%) and 21.7% (±8.8%) in patients with and without CMV viruria (prior to or at the onset of LOHC) (P = 0.021), respectively. The cumulative incidence of LOHC was also higher in patients with a plasma BKV load increased ≥3 log10 or with a urine BKV load increased ≥4 log10 than those without the increase (P < 0.001). Only one patient with LOHC was tested positive for ADV. Both the univariate and multivariate analyses showed that CMV viremia (HR = 3.461, 95% CI: 1.005-11.922, P = 0.049) and a plasma BKV load that was increased ≥3 log10 (HR = 10.705, 95%CI: 2.469-46.420, P = 0.002) were independent risk factors for the development of LOHC. We conclude that both CMV viremia and an increase of plasma BKV are independent risk factors for LOHC. And the role of CMV viremia was firstly demonstrated.
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Affiliation(s)
- Ting-Ting Han
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
| | - Lan-Ping Xu
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
| | - Dai-Hong Liu
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
| | - Kai-Yan Liu
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
| | - Hai-Xia Fu
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
| | - Xiang-Yu Zhao
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
| | - Xiao-Su Zhao
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
| | - Xiao-Jun Huang
- Peking University People's Hospital; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation; Beijing 100044 P.R. China
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20
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Rinaldo CH, Tylden GD, Sharma BN. The human polyomavirus BK (BKPyV): virological background and clinical implications. APMIS 2013; 121:728-45. [PMID: 23782063 DOI: 10.1111/apm.12134] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 04/27/2013] [Indexed: 12/13/2022]
Abstract
Polyomavirus BK (BKPyV) infects most people subclinically during childhood and establishes a lifelong infection in the renourinary tract. In most immunocompetent individuals, the infection is completely asymptomatic, despite frequent episodes of viral reactivation with shedding into the urine. In immunocompromised patients, reactivation followed by high-level viral replication can lead to severe disease: 1-10% of kidney transplant patients develop polyomavirus-associated nephropathy (PyVAN) and 5-15% of allogenic hematopoietic stem cell transplant patients develop polyomavirus-associated haemorrhagic cystitis (PyVHC). Other conditions such as ureteric stenosis, encephalitis, meningoencephalitis, pneumonia and vasculopathy have also been associated with BKPyV infection in immunocompromised individuals. Although BKPyV has been associated with cancer development, especially in the bladder, definitive evidence of a role in human malignancy is lacking. Diagnosis of PyVAN and PyVHC is mainly achieved by quantitative PCR of urine and plasma, but also by cytology, immunohistology and electron microscopy. Despite more than 40 years of research on BKPyV, there is still no effective antiviral therapy. The current treatment strategy for PyVAN is to allow reconstitution of immune function by reducing or changing the immunosuppressive medication. For PyVHC, treatment is purely supportive. Here, we present a summary of the accrued knowledge regarding BKPyV.
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Affiliation(s)
- Christine Hanssen Rinaldo
- Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway.
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21
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Late-onset hemorrhagic cystitis after haploidentical hematopoietic stem cell transplantation in patients with advanced leukemia: differences in ATG dosage are key. Int J Hematol 2013; 98:89-95. [DOI: 10.1007/s12185-013-1350-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2013] [Revised: 04/19/2013] [Accepted: 04/19/2013] [Indexed: 10/26/2022]
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Lee MC, Lu MC, Lai NS, Liu SC, Yu HC, Lin TY, Hung SP, Huang HB, Yin WY. Renal dysfunction by BK virus infection is correlated with activated T cell level in renal transplantation. J Surg Res 2012; 180:330-6. [PMID: 22658856 DOI: 10.1016/j.jss.2012.04.064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2012] [Revised: 04/05/2012] [Accepted: 04/26/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND BK virus (BKV) is known to be associated with nephropathy. Here, we investigated the relationships between BKV levels, T-cell activation, and kidney function in kidney transplant recipients. MATERIALS AND METHODS In renal transplant patients and controls, urine BKV levels were detected by quantitative real-time PCR, and the percentage of activated T lymphocytes in blood was determined by flow cytometry. The correlations between viral load, activated T cell percentage, and renal function were determined. RESULTS Urine BKV viral loads and the activated T cell percentage were significantly elevated in transplant recipients. Correlational analysis indicated that transplant recipients that had BKV levels of more than 10(6) copies/mL and an activated T lymphocyte percentage of less than 20% were likely to have poor renal function. CONCLUSIONS Urine BKV levels and the percentage of activated T lymphocytes can be used as clinical indices to optimize the dosage of immunosuppressive drugs.
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Affiliation(s)
- Ming-Che Lee
- Department of Surgery, Buddhist Hualien Tzu Chi General Hospital, Hualien, Taiwan; Tzu Chi University, Hualien, Taiwan
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23
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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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24
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Kinnaird AN, Anstead GM. Hemorrhagic cystitis and possible neurologic disease from BK virus infection in a patient with AIDS. Infection 2010; 38:124-7. [PMID: 20198406 PMCID: PMC7101561 DOI: 10.1007/s15010-009-9201-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2009] [Accepted: 09/21/2009] [Indexed: 12/16/2022]
Abstract
BK virus (BKV)-associated hemorrhagic cystitis occurs in bone marrow transplant recipients but is rare among other immunosuppressed patients. We present a rare case of BKV-associated hemorrhagic cystitis in a 48-year-old man with AIDS and previously diagnosed progressive multifocal leukoencephalopathy.
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Affiliation(s)
- A N Kinnaird
- Dept. of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
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25
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Lazarus HM, Laughlin MJ. Viral Infections in Hematopoietic Stem Cell Transplant Recipients. ALLOGENEIC STEM CELL TRANSPLANTATION 2010. [PMCID: PMC7120500 DOI: 10.1007/978-1-59745-478-0_29] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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26
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Decker DB, Karam JA, Wilcox DT. Pediatric hemorrhagic cystitis. J Pediatr Urol 2009; 5:254-64. [PMID: 19303365 DOI: 10.1016/j.jpurol.2009.02.199] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2008] [Accepted: 02/13/2009] [Indexed: 11/30/2022]
Abstract
PURPOSE To review the current literature as it pertains to hemorrhagic cystitis (HC) in the pediatric bone-marrow transplant (BMT) population. By reviewing the pathophysiology of the disease, preventive methods, and therapeutic options, urologists may be better equipped to manage this challenging clinical scenario. MATERIALS AND METHODS The HC literature was reviewed using a MEDLINE/PubMed literature search, specifically focusing on the pediatric BMT population as it pertains to the incidence, pathophysiology, prevention, and treatment of HC. RESULTS Conservative estimates of HC incidence in recent retrospective studies of pediatric BMT populations still approach 10-20%. Several high-volume pediatric BMT centers have reported contemporary data on their experience with HC providing increased insight into incidence and pathophysiology. Accumulating evidence linking BK virus to HC is a significant development warranting further investigation. Other contributing agents/risk factors need identification in the likely multifactorial etiology of HC. Preventive and therapeutic strategies have made modest advances, but certainly need further validation with prospective randomized studies. CONCLUSIONS Pediatric BMT patients are susceptible for HC development despite preventive measures and improved insight into the pathophysiology. Unfortunately, there are no evidence-based treatment guidelines for this difficult clinical issue that frequently requires prolonged care and multiple treatment modalities necessitating judicious patience in the application of more aggressive interventions.
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Affiliation(s)
- Daniel B Decker
- Children's Medical Center at Dallas, University of Texas Southwestern Medical Center, Department of Urology, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110, USA.
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27
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Hyperbaric oxygen therapy in BKV-associated hemorrhagic cystitis refractory to intravenous and intravesical cidofovir: Case report and review of literature. Leuk Res 2009; 33:556-60. [DOI: 10.1016/j.leukres.2008.06.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Revised: 06/16/2008] [Accepted: 06/17/2008] [Indexed: 11/22/2022]
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28
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Intravesicular Cidofovir for the Management of BK Virus-Associated Cystitis. Biol Blood Marrow Transplant 2009; 15:391-2. [DOI: 10.1016/j.bbmt.2008.12.490] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2008] [Accepted: 12/09/2008] [Indexed: 11/24/2022]
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Abstract
SUMMARY Human immunodeficiency virus (HIV)-infected patients may acquire new viral co-infections; they also may experience the reactivation or worsening of existing viral infections, including active, smoldering, or latent infections. HIV-infected patients may be predisposed to these viral infections owing to immunodeficiency or risk factors common to HIV and other viruses. A number of these affect the kidney, either by direct infection or by deposition of immune complexes. In this review we discuss the renal manifestations and treatment of hepatitis C virus, BK virus, adenovirus, cytomegalovirus, and parvovirus B19 in patients with HIV disease. We also discuss an approach to the identification of new viral renal pathogens, using a viral gene chip to identify viral DNA or RNA.
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Affiliation(s)
- Meryl Waldman
- Kidney Disease Section, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-1268, USA.
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30
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Kleinberg M. Viruses. MANAGING INFECTIONS IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES 2009. [PMCID: PMC7114983 DOI: 10.1007/978-1-59745-415-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Viral infections are an important and often unrecognized component of disease in immunocompromised patients. The diagnosis and management of viral infections have expanded largely because of new quantitative molecular diagnostic assays. Well-recognized pathogens such as herpes simplex virus (HSV), cytomegalovirus (CMV), and respiratory viruses have been joined by newly recognized pathogens such as BK virus, human herpesvirus-6 (HHV-6), and human metapneumovirus in this highly susceptible patient population. The role of Epstein-Barr virus (EBV) and Human herpesvirus-8 (HHV-8) in lymphoproliferative diseases also continue to be clarified. As a result, the management of viral infections in patients with hematologic malignancies continues to be a growing challenge for the clinician.
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Affiliation(s)
- Michael Kleinberg
- School of Medicine, University of Maryland, S. Greene St. 22, Baltimore, 21201 U.S.A
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31
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Jiang M, Abend JR, Johnson SF, Imperiale MJ. The role of polyomaviruses in human disease. Virology 2008; 384:266-73. [PMID: 18995875 DOI: 10.1016/j.virol.2008.09.027] [Citation(s) in RCA: 203] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2008] [Accepted: 09/30/2008] [Indexed: 12/31/2022]
Abstract
The human polyomaviruses, BK virus and JC virus, have long been associated with serious diseases including polyomavirus nephropathy and progressive multifocal leukoencephalopathy. Both viruses establish ubiquitous, persistent infections in healthy individuals. Reactivation can occur when the immune system is impaired, leading to disease progression. Recently, the human polyomavirus family has expanded with the identification of three new viruses (KI, WU and Merkel cell polyomavirus), all of which may prove to be involved in human disease. This review describes the general aspects of human polyomavirus infections and pathogenicity. Current topics of investigation and future directions in the field are also discussed.
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Affiliation(s)
- Mengxi Jiang
- Department of Microbiology and Immunology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, USA
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32
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Abstract
Lower urinary tract infections (UTIs) are common among the general population and are most often caused by bacterial pathogens. Viruses are an uncommon cause of UTIs in an immunocompetent host; however, viruses are increasingly recognized as the cause of lower UTI, especially hemorrhagic cystitis, among immunocompromised patients. BK virus, adenovirus, and cytomegalovirus are predominant pathogens involved in hemorrhagic cystitis after stem cell and solid organ transplantation, and their early diagnosis and treatment may prevent significant morbidity of hemorrhagic cystitis. The diagnosis of viral lower UTI is based on molecular techniques, and real-time polymerase chain reaction is often the method of choice because it allows for quantification of viral load. Cidofovir is becoming a drug of choice in viral UTIs because it is active against the most common viral pathogens. This review discusses the epidemiology, pitfalls in diagnosis, and current treatment of viral UTIs.
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33
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Harkensee C, Vasdev N, Gennery AR, Willetts IE, Taylor C. Prevention and management of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation--a systematic review and evidence-based guidance for clinical management. Br J Haematol 2008; 142:717-31. [PMID: 18540939 DOI: 10.1111/j.1365-2141.2008.07254.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Haemorrhagic cystitis (HC) is a common and, in its severe form, potentially life-threatening complication of Haematopoietic stem cell transplantation (HSCT) in children. Recent data indicate an important role of BK virus reactivation during the time of maximal post-transplant immune suppression in the pathogenesis of late-onset HC. Treatment of HC is mainly symptomatic and often frustrating. To give clinicians guidance on prevention and treatment options and their backing by scientific evidence, we have systematically assessed the available literature and devised evidence-based guidelines. Our comprehensive review demonstrates that evidence for the most commonly used interventions (such as cidofovir, oestrogen, hyperbaric oxygen, bladder instillation with formalin, alum salts or prostaglandin) is very limited. Some of these interventions also carry significant risks. Higher level evidence exists only for 2-mercaptoethane sodium (MESNA) and hyperhydration as a preventative intervention, and for systemic recombinant Factor VII as a treatment to stop acute haemorrhage. Further high-quality studies are required to establish effective and safe prevention and treatment options for HC.
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Affiliation(s)
- Christian Harkensee
- Supra-regional Children's Bone Marrow Transplant Unit (CBMTU), Newcastle General Hospital, Newcastle upon Tyne, UK.
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34
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Hassan Z, Remberger M, Svenberg P, Elbander M, Omazic B, Mattsson J, Conrad R, Svahn BM, Ahlgren A, Sairafi D, Aschan J, Le Blanc K, Barkholt L, Ringdén O. Hemorrhagic cystitis: a retrospective single-center survey. Clin Transplant 2007; 21:659-67. [PMID: 17845642 DOI: 10.1111/j.1399-0012.2007.00705.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Severe hemorrhagic cystitis (HC) may be a life-threatening complication in allogeneic stem cell transplantation (SCT). In order to improve the strategies for prophylaxis and treatment, we retrospectively analyzed data on patients who underwent SCT at our center from 1990 through 2005. Patients with HC were identified through our database and their medical charts were reviewed. Grades 2-5 and 3-5 HC developed in 109/834 patients (13.1%) and 27/834 patients (3.2%), respectively. The frequency of HC decreased over the time from 18.0% in 1990-1992 to 9.5% in 2002-2005 (p = 0.005). HC started on a median of 35 (0-166) days post-transplant and persisted for a median of 23 (2-270) days. Transplant-related mortality was 21% in patients without HC, 15% in those with HC of grade 2, 55% in those with grade 3, and 71% in patients with HC of grades 4-5 (p < 0.001). In multivariate analysis, the risk factors for HC were myeloablative conditioning, busulphan, cytomegalovirus infection, hematological malignancy, and acute graft-versus-host disease (aGVHD). With four risk factors, the risk of HC development was 31%. Risk factors for severe HC of grades 3-5 were aGVHD and bacteremia.
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Affiliation(s)
- Zuzana Hassan
- Center for Allogenic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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35
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Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant 2007; 41:11-8. [PMID: 17952131 DOI: 10.1038/sj.bmt.1705886] [Citation(s) in RCA: 148] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The association of BK virus infection with hemorrhagic cystitis in blood and marrow transplant (BMT) recipients was first demonstrated two decades ago. During this time, therapeutic interventions focused on supportive measures such as hyperhydration, continuous bladder irrigation and topical administration of agents that alter the mucosal surface of the bladder wall. In recent years, PCR amplification of viral DNA in the urine and plasma has solidified the association of BK virus infection with hemorrhagic cystitis, demonstrating that higher urine and plasma viral loads occur in the setting of disease. The evaluation of virus-specific therapy has lagged behind assessment of the viral load and theories of pathogenesis. Extrapolating from successes in the treatment of BK virus nephropathy in the renal transplant population, cidofovir and leflunomide are identified as potential effective agents for the treatment of BK virus-associated hemorrhagic cystitis. The fluoroquinolone antibiotics may prove to be effective as prophylactic agents. Given the manifestation of BK virus infection in organs outside of the urinary tract in an increasing immunocompromised patient population and the availability of potential antiviral agents, therapeutic trials need to progress beyond the small case series in order to improve the morbidity and mortality caused by BK virus-associated hemorrhagic cystitis in the BMT population.
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Affiliation(s)
- L K Dropulic
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
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36
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Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant 2007. [PMID: 17952131 DOI: 10.1038/j.bmt.1705886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The association of BK virus infection with hemorrhagic cystitis in blood and marrow transplant (BMT) recipients was first demonstrated two decades ago. During this time, therapeutic interventions focused on supportive measures such as hyperhydration, continuous bladder irrigation and topical administration of agents that alter the mucosal surface of the bladder wall. In recent years, PCR amplification of viral DNA in the urine and plasma has solidified the association of BK virus infection with hemorrhagic cystitis, demonstrating that higher urine and plasma viral loads occur in the setting of disease. The evaluation of virus-specific therapy has lagged behind assessment of the viral load and theories of pathogenesis. Extrapolating from successes in the treatment of BK virus nephropathy in the renal transplant population, cidofovir and leflunomide are identified as potential effective agents for the treatment of BK virus-associated hemorrhagic cystitis. The fluoroquinolone antibiotics may prove to be effective as prophylactic agents. Given the manifestation of BK virus infection in organs outside of the urinary tract in an increasing immunocompromised patient population and the availability of potential antiviral agents, therapeutic trials need to progress beyond the small case series in order to improve the morbidity and mortality caused by BK virus-associated hemorrhagic cystitis in the BMT population.
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Affiliation(s)
- L K Dropulic
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
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Pavlakis M, Haririan A, Klassen DK. BK virus infection after non-renal transplantation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 577:185-9. [PMID: 16626036 DOI: 10.1007/0-387-32957-9_13] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Infection with BK virus (BKV), a member of the Polyomavirus (PV) family, is ubiquitous, with the virus remaining in a latent form in the kidney and urinary tract. This infection is usually asymptomatic, but with impairment of the cellular immune system the virus can reactivate and lead to tissue damage. In recipients of bone marrow and solid organ transplants, PV reactivation can be associated with disease in urinary tract and kidneys. BKV was first discovered in 1971 from the urine of a kidney transplant recipient who had developed ureteral stenosis 4 months after transplantation. While much of the subsequent research focuses on patients after renal transplantation, we will review PV impact in patients after bone marrow transplant (BMT) and those with non-renal solid organ transplants.
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Ahsan N, Shah KV. Polyomaviruses and human diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 577:1-18. [PMID: 16626024 DOI: 10.1007/0-387-32957-9_1] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Polyomaviruses are small, nonenveloped DNA viruses, which are widespread in nature. In immunocompetent hosts, the viruses remain latent after primary infection. With few exceptions, illnesses associated with these viruses occur in times of immune compromise, especially in conditions that bring about T cell deficiency. The human polyomaviruses BKV and JCV are known to cause, respectively, hemorrhagic cystitis in recipients of bone marrow transplantation and progressive multifocal leukoencephalopathy in immunocompromised patients, for example, by HIV infection. Recently, transplant nephropathy due to BKV infection has been increasingly recognized as the cause for renal allograft failure. Quantitation of polyomavirus DNA in the blood, cerebrospinal fluid, and urine, identification of virus laden "decoy cells" in urine, and histopathologic demonstration of viral inclusions in the brain parenchyma and renal tubules are the applicable diagnostic methods. Genomic sequences of polyomaviruses have been reported to be associated with various neoplastic disorders and autoimmune conditions. While various antiviral agents have been tried to treat polyomavirus-related illnesses, current management aims at the modification and/or improvement in the hosts' immune status. In this chapter, we provide an overview of polyomaviruses and briefly introduce its association with human diseases, which will be covered extensively in other chapters by experts in the field.
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Affiliation(s)
- Nasimul Ahsan
- Mayo Clinic, College of Medicine, Mayo Clinic Transplant Center, Jacksonville, Florida, USA
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Savona MR, Newton D, Frame D, Levine JE, Mineishi S, Kaul DR. Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant. Bone Marrow Transplant 2007; 39:783-7. [PMID: 17438584 DOI: 10.1038/sj.bmt.1705678] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In recipients of hematopoietic stem cell transplants (HSCTs), BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC). In our institution, HSCT recipients with BKV-associated HC are treated with 1 mg/kg of cidofovir weekly. We identified HSCT recipients with BKV-associated HC, treated with weekly cidofovir. Microbiological response was defined as at least a one log reduction in urinary BKV viral load; clinical response was defined as improvement in symptoms and stability or reduction in the grade of cystitis. Nineteen allogeneic HSCT patients received a mean of 4.5 weekly doses of cidofovir. HC occurred at a mean of 68.7 days after transplant. A clinical response was detected in 16/19 (84%) patients, and 9/19 (47%) had a measurable microbiological response (8/10 nonresponders had a BKV viral load above the upper limit of the assay before treatment). Fourteen out of nineteen (74%) patients had no significant increase in serum creatinine. Five patients with renal dysfunction resolved after completion of the therapy and removal of other nephrotoxic agents. We conclude that weekly low-dose cidofovir appears to be a safe treatment option for BKV-associated HC. Although the efficacy of low-dose cidofovir is not proven, a prospective trial is warranted.
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Affiliation(s)
- M R Savona
- Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Kim SY, Lee JW, Lee KM, Cho BS, Eom KS, Kim YJ, Lee S, Min CK, Kim HJ, Cho SG, Kim DW, Min WS, Kim CC. Viruria in Adult Hemorrhagic Cystitis Patients Following Allogeneic Hematopoietic Stem Cell Transplantation and Implication of Antiviral Treatment. THE KOREAN JOURNAL OF HEMATOLOGY 2007. [DOI: 10.5045/kjh.2007.42.2.114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Sung-Yong Kim
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Jong-Wook Lee
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Kyu-Man Lee
- Department of Laboratory Medicine, Hallym University College of Medicine, Seoul, Korea
| | - Byung-Sik Cho
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Ki-Seong Eom
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Yoo-Jin Kim
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Seok Lee
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Chang-Ki Min
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Hee-Je Kim
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Seok-Goo Cho
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Dong-Wook Kim
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Woo-Sung Min
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Chun-Choo Kim
- Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
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41
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Paduch DA. Viral lower urinary tract infections. CURRENT PROSTATE REPORTS 2007; 5:40-50. [PMID: 32214913 PMCID: PMC7088526 DOI: 10.1007/s11918-007-0006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Lower urinary tract infections (UTIs) are common among the general population and are most often caused by bacterial pathogens. Viruses are an uncommon cause of UTIs in an immunocompetent host; however, viruses are increasingly recognized as the cause of lower UTI, especially hemorrhagic cystitis, among immunocompromised patients. BK virus, adenovirus, and cytomegalovirus are predominant pathogens involved in hemorrhagic cystitis after stem cell and solid organ transplantation, and their early diagnosis and treatment may prevent significant morbidity of hemorrhagic cystitis. The diagnosis of viral lower UTI is based on molecular techniques, and real-time polymerase chain reaction is often the method of choice because it allows for quantification of viral load. Cidofovir is becoming a drug of choice in viral UTIs because it is active against the most common viral pathogens. This review discusses the epidemiology, pitfalls in diagnosis, and current treatment of viral UTIs.
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Affiliation(s)
- Darius A Paduch
- Department of Urology, Weill Medical College of Cornell University, 525 East 68th Street, ST-924A, New York, NY 10021 USA
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Roskopf J, Trofe J, Stratta RJ, Ahsan N. Pharmacotherapeutic options for the management of human polyomaviruses. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 577:228-54. [PMID: 16626040 DOI: 10.1007/0-387-32957-9_17] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Polyomaviruses [BK virus (BKV), JC virus (JCV) and simian virus 40 (SV40)] have been known to be associated with diseases in humans for over thirty years. BKV-associated nephropathy and JCV-induced progressive multifocal leukoencephalopathy (PML) were for many years rare diseases occurring only in patients with underlying severe impaired immunity. Over the past decade, the use of more potent immunosuppression (IS) in transplantation, and the Acquired Immune Deficiency Syndrome (AIDS) epidemic, have coincided with a significant increase in the prevalence of these viral complications. Prophylactic and therapeutic interventions for human polyomavirus diseases are limited by our current understanding of polyomaviral pathogenesis. Clinical trials are limited by small numbers of patients affected with clinically significant diseases, lack of defined risk factors and disease definitions, no proven effective treatment and the overall significant morbidity and mortality associated with these diseases. This chapter will focus on a review of the current and future research related to therapeutic targets and interventions for polyomavirus-associated diseases.
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Affiliation(s)
- Julie Roskopf
- Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA
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Crew RJ, Markowitz G, Radhakrishnan J. Therapeutic options in BK virus-associated interstitial nephritis. Kidney Int 2006; 70:399-402. [PMID: 16775604 DOI: 10.1038/sj.ki.5001540] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- R J Crew
- Division of Nephrology, Columbia University, New York, New York, USA.
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Leung AYH, Yuen KY, Kwong YL. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant 2006; 36:929-37. [PMID: 16184185 DOI: 10.1038/sj.bmt.1705139] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Haemorrhagic cystitis (HC) is a distinct clinical disorder of multiple aetiologies. It is characterized by painful haematuria due to haemorrhagic inflammation of the urinary bladder mucosa. In allogeneic haematopoietic stem cell transplantation (HSCT), HC occurring before engraftment is mostly transient and self-limiting, whereas that after engraftment is severe and sometimes life-threatening. Pre- and post-engraftment HC represent distinct disorders with different aetiologies and treatment implications. Recent data suggest that reactivation of the polyoma BK virus (BKV) plays a pivotal role in post-engraftment HC. Urotoxicity of the conditioning regimen and alloimmune reaction accompanying graft-versus-host disease (GVHD) upon engraftment are also important pathogenetic factors. Based on data from BKV studies, we propose that HC may be divided into three phases. In the first phase, the conditioning regimen damages uroepithelial cells, providing a milieu for BKV replication. In the second phase, unchecked uroepithelial BKV replication leads to BK viruria. In the last phase after engraftment, alloimmunity against BKV-infected uroepithelial cells leads to HC. The quinolone antibiotics suppress BKV replication in vivo and in vitro, suggesting that their prophylactic use may prevent the occurrence of HC.
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Affiliation(s)
- A Y H Leung
- Department of Medicine, Faculty of Medicine, University of Hong Kong
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Josephson MA, Gillen D, Javaid B, Kadambi P, Meehan S, Foster P, Harland R, Thistlethwaite RJ, Garfinkel M, Atwood W, Jordan J, Sadhu M, Millis MJ, Williams J. Treatment of Renal Allograft Polyoma BK Virus Infection with Leflunomide. Transplantation 2006; 81:704-10. [PMID: 16534472 DOI: 10.1097/01.tp.0000181149.76113.50] [Citation(s) in RCA: 166] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals. METHODS We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy. RESULTS In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added. CONCLUSIONS Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.
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Hatakeyama N, Suzuki N, Yamamoto M, Kuroiwa Y, Hori T, Mizue N, Tsutsumi H. Detection of BK virus and adenovirus in the urine from children after allogeneic stem cell transplantation. Pediatr Infect Dis J 2006; 25:84-5. [PMID: 16395113 DOI: 10.1097/01.inf.0000195613.00368.df] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The development of hemorrhagic cystitis (HC) and urinary excretion of polyoma BK virus (BKV) and adenovirus (ADV) was investigated by polymerase chain reaction in 20 children undergoing allogeneic stem cell transplantation. Five children developed HC, and all of them excreted BKV; however, only 1 excreted ADV, suggesting that BKV is more significant cause of HC than ADV in children undergoing stem cell transplantation.
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Affiliation(s)
- Naoki Hatakeyama
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
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Toyoda M, Puliyanda DP, Amet N, Baden L, Cam V, Radha R, Pao A, Vo A, Bunnapradist S, Moudgil A, Jordan SC. Co-infection of Polyomavirus-BK and Cytomegalovirus in Renal Transplant Recipients. Transplantation 2005; 80:198-205. [PMID: 16041264 DOI: 10.1097/01.tp.0000165110.78397.93] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Polyomavirus-BK (BK) is a significant cause of allograft dysfunction in renal transplant recipients. Cytomegalovirus (CMV) and BK infection are thought to be possible risk factors for one another, but no supporting data are yet available. METHODS The authors monitored BK and CMV infection by quantitative polymerase chain reaction (PCR) in 69 renal transplant recipients with serum creatinine elevation to determine the prevalence of co-infection. In addition, 150 adult renal transplant recipients were also retrospectively analyzed for both infections. RESULTS Of 69 recipients, 12 were plasma BK-PCR-positive. Eight of the 12 showed high BK levels (>10 copies) and BK nephropathy. Six of the 12 were also CMV-PCR-positive compared with only 3 of 57 plasma BK-negative patients (50% vs. 5.3%, P=0.001). Comparatively, the incidence of Epstein-Barr virus infection was similar in both groups (1 of 12 [8.3%] vs. 2 of 57 [3.5%], P =not significant). In addition, retrospective analysis of CMV-PCR-positivity in 150 adult renal transplant recipients showed similar results (5 of 6 in BK-PCR-positive [83%] vs. 8 of 144 in BK-PCR-negative [5.6%], P=0.00001). More plasma BK-PCR-positive patients had concomitant CMV infection than CMV-PCR-positive patients with BK infection (5 of 6 [83%] vs. 4 of 13 [31%], P=0.05). CONCLUSIONS In conclusion, high plasma BK-positivity (>10) is significantly associated with BK nephropathy. Plasma BK-positivity is highly associated with co-infection of CMV, suggesting possible risk factors for one another. Therefore, detection of either infection strongly suggests the need to monitor for the other. This strategy may lead to the prevention of virus-induced complications by preemptive antiviral therapy in renal allografts.
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Affiliation(s)
- Mieko Toyoda
- Transplant Immunology Laboratory, Ahmanson Pediatric Center, Steven Spielberg Pediatric Research Laboratories, Cedars-Sinai Medical Center/University of California, Los Angeles, 90048, USA.
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Abstract
Viruses are among the most common causes of opportunistic infection after transplantation and the most important. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Viral infection, both symptomatic and asymptomatic, causes the "direct effects" of invasive disease and "indirect effects," including immune suppression predisposing to other opportunistic infections and oncogenesis. Rapid and sensitive microbiologic assays for many of the common viruses after transplantation have replaced, for the most part, serologic testing and in vitro cultures for the diagnosis of infection. Furthermore, quantitative molecular tests allow the individualization of antiviral therapies for prevention and treatment of infection. This advance is most prominent in the management of cytomegalovirus, Epstein-Barr, hepatitis B, and hepatitis C viruses. Diagnostic advances have not been accompanied by the development of specific and nontoxic anti-viral agents or effective antiviral vaccines. Vaccines, where available, should be given to patients as early as possible and well in advance of transplantation to optimize the immune response. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections.
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Affiliation(s)
- Camille N Kotton
- Transplant Infectious Disease and Compromised Host Service, Infectious Disease Division, Massachusetts General Hospital, 55 Fruit Street; GRJ 504, Boston, MA 02114, USA
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Palandri F, Bonifazi F, Rossi C, Falcioni S, Arpinati M, Giannini MB, Ansaloni F, Bandini G, Baccarani M. Successful treatment of severe hemorrhagic cystitis with selective vesical artery embolization. Bone Marrow Transplant 2005; 35:529-30. [PMID: 15665843 DOI: 10.1038/sj.bmt.1704818] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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50
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Singh N. Interactions between viruses in transplant recipients. Clin Infect Dis 2005; 40:430-6. [PMID: 15668868 DOI: 10.1086/427214] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2004] [Accepted: 09/24/2004] [Indexed: 01/31/2023] Open
Abstract
Viral coinfections may modulate disease expression, enhance pathogenicity, and lead to greater cumulative immunosuppression in the host. The pathophysiological basis of these may be direct virus-virus interactions, effect of cohabitating viruses on host cell function, or impaired host immune responses. The interrelationship between viral pathogens has become increasingly more relevant and its scope wider as new or previously unrecognized viruses continue to emerge as pathogens in transplant recipients. The pathways and mediators that modulate biological activity represent potential targets for immunomodulatory interventions as adjunctive therapies for transplant recipients.
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Affiliation(s)
- Nina Singh
- Veterans Affairs Medical Center and University of Pittsburgh, Pittsburgh, PA 15240, USA. nis5+@pitt.edu
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