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Peras M, Bilić E, Mareković I. Recent Insights into the Pathogenesis, Diagnostics, and Treatment of BK Virus Infections in Children After Hematopoietic Stem Cell Transplantation. Pathogens 2025; 14:236. [PMID: 40137721 PMCID: PMC11944647 DOI: 10.3390/pathogens14030236] [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: 02/09/2025] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/29/2025] Open
Abstract
BK polyomavirus (BKPyV) is a pathogen responsible for infectious complications in hematopoietic stem cell transplant (HSCT) recipients. This review aims to give an insight into recent data about the structure and genomic organization, epidemiology, clinical manifestations, diagnosis, and current treatment options of BKPyV infections in children after HSCT. News regarding viral replication and pathogenesis include the generation of miRNA, new mechanisms of viral shedding by releasing infectious particles via extracellular vesicles, and human bladder microvascular endothelial cells probably acting as viral reservoirs enabling low-level viral replication and persistence. In studies conducted over the past five years, BKPyV hemorrhagic cystitis (BKPyV-HC) has a prevalence rate of 4 to 27% in children undergoing HSCT. Diagnostics still has unsolved dilemmas like whole blood or plasma samples as well as the standardization of molecular methods to allow for reporting in international units. In terms of treatment, new approaches have been used in the past five years, including the use of mesenchymal stem cells (MSCs), virus-specific T cells (VSTs), and recombinant human keratinocyte growth factor (rH-KGF), although the efficacy of some of these treatments has only been documented in isolated studies. This complication continues to pose a substantial clinical challenge, characterized by an absence of effective preventive and therapeutic measures.
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Affiliation(s)
- Mislav Peras
- Department of Microbiology, Institute of Public Health Zagreb County, 10 000 Zagreb, Croatia
| | - Ernest Bilić
- Department of Pediatrics, University Hospital Centre Zagreb, 10 000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia
| | - Ivana Mareković
- School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia
- Department of Clinical Microbiology, Infection and Prevention Control, 10 000 Zagreb, Croatia
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Wei A, Jing Y, Zhu G, Wang B, Yang J, Jia C, Luo Y, Yan Y, Zheng J, Zhou X, Qin M, Wang T. Analysis of BK Virus Infection in Children After Hematopoietic Cell Transplantation: A Retrospective Single-center Study. J Pediatr Hematol Oncol 2024; 46:e487-e492. [PMID: 39008534 DOI: 10.1097/mph.0000000000002922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 06/24/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND BK virus (BKV) is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation (HSCT). Viruses can be found in urine and serum of immunocompromised patients. OBJECTIVE This study aimed to evaluate the incidence, clinical course, and risk factors for BKV infection in children undergoing HSCT. METHODS Retrospectively analyzed children who underwent HSCT at Beijing Children's Hospital, Capital Medical University from June 2020 to June 2022. Data related to the clinical manifestations, engraftment, and prognosis were extracted from medical records. Patients were divided into the case group and the control group, according to the BKV infection or not after HSCT. RESULTS A total of 149 patients were enrolled in this study, and 61 (40.9%) patients developed BKV infection after HSCT. Among the 61 patients, BKV load was detected in all patients in urine samples and 22 patients in blood samples. The median value of BKV DNA copies in urine and plasma were 9.50×10 7 (5.37×10 2 to 6.84×10 9 ) copies/mL and 2.97×10 3 (9.96×10 2 to 3.58×10 8 ) copies/mL, respectively. The median time from beginning of the conditioning regimen to BKV infection was 23 (0 to 273) days, and the first positive time of urinary BKV was earlier than that of blood (13.5 d [0.0 to 123.0 d] vs. 30.5 d [7.0 to 165.0 d], P =0.003). Among the patients with BKV infection, 36 (59.0%) patients met the diagnosis of hemorrhagic cystitis (HC), and the incidence was higher than that in the control group ( P <0.001). Similarly, 15 (24.6%) patients developed renal function damage in the case group and the proportion was higher than that in the control group. The median follow-up was 5.67 (0.03 to 24.90) months, and there was no significant difference in 1-year overall survival rate between the case group and the control group (84.2%±5.7% vs. 95.3%±2.3%, P =0.688), but the incidence of TA-TMA/VOD (31.1%) and diffuse alveolar hemorrhage (9.8%) in the case group was higher than that in the control group ( P =0.002 and 0.038, respectively). Multivariate analysis showed that age above 5 years old (OR=9.039, 95% CI: 3.561-24.333, P <0.001) and use of MMF (OR=2.708, 95% CI: 1.041-7.044, P <0.05) were independent risk factors for BKV infection after HSCT. CONCLUSION Among children after HSCT, the incidence of BKV infection was high and BKV infection was associated with an increased incidence of TA-TMA/VOD and diffuse alveolar hemorrhage. Patients older than 5 years of age at the time of HSCT and treated with MMF were more likely to develop BKV infection.
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Affiliation(s)
- Ang Wei
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Yuanfang Jing
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Guanghua Zhu
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Bin Wang
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Jun Yang
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Chenguang Jia
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Yanhui Luo
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Yan Yan
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Jie Zheng
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Xuan Zhou
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Maoquan Qin
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
| | - Tianyou Wang
- Beijing Key Laboratory of Pediatric Hematology Oncology
- National Key Discipline of Pediatrics
- Department of Stem cell Transplantation, Beijing Children's Hospital, Capital Medical University
- Key Laboratory of Major Diseases in Children, Ministry of Education
- National Center for Children's Health, Beijing, China
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Umezawa Y, Yoshifuji K, Tanaka K, Nogami A, Nagano K, Tsuji A, Nagao T, Yamamoto M, Kajiwara M, Tohda S, Mori T. Impact of BK polyomavirus viremia on the outcomes of allogeneic hematopoietic stem cell transplantation. Ann Hematol 2024; 103:1737-1744. [PMID: 38509389 DOI: 10.1007/s00277-024-05707-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
Although it is known that BK polyomavirus (BKPyV) causes hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of BKPyV viremia has not been fully evaluated. We retrospectively analyzed the results of quantitative polymerase chain reaction (PCR) evaluations for detecting BKPyV in the whole blood samples of patients undergoing allogeneic HSCT during the period from January 2010 to June 2020 at a single institute, Tokyo Medical and Dental University. BKPyV was detected in the blood of 28 of the 107 evaluated patients, and the cumulative incidence of was 27.9% (95%CI: 20.2-37.9%). HC due to BKPyV developed in four of the 28 patients with BKPyV viremia (14.3%) and in two of the 79 patients without it (2.5%; P < 0.05). BKPyV viremia itself did not affect the patients' post-transplant estimated glomerular filtration rate (eGFR), but BKPyV viremia with a high viral load was significantly associated with decreased eGFR values (P < 0.05). BKPyV viremia was also associated with significantly lower progression-free survival at 3 years (35.1% [95%CI: 17.8-53.1%] vs. 60.4% [95%CI: 48.4-70.5], P < 0.05). Our findings demonstrated that BKPyV viremia was associated with onset of HC, an early decline of renal function, and poorer survival after allogeneic HSCT. Further studies are needed to test these results and elucidate the mechanisms of renal dysfunction associated with BKPyV viremia.
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Affiliation(s)
- Yoshihiro Umezawa
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan.
| | - Kota Yoshifuji
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Keisuke Tanaka
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Ayako Nogami
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
- Department of Laboratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Katsutoshi Nagano
- Department of Clinical Laboratory, Tokyo Medical and Dental University (TMDU) Hospital, Tokyo, Japan
| | - Ayako Tsuji
- Center for Transfusion Medicine and Cell Therapy, Tokyo Medical and Dental University (TMDU) Hospital, Tokyo, Japan
| | - Toshikage Nagao
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Masahide Yamamoto
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Michiko Kajiwara
- Center for Transfusion Medicine and Cell Therapy, Tokyo Medical and Dental University (TMDU) Hospital, Tokyo, Japan
| | - Shuji Tohda
- Department of Laboratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Takehiko Mori
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
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Dequirez PL, Magro L, Alsuliman T, Ceballos P, Desbrosses Y, Yakoub-Agha I, Guillaume T. [Haemorrhagic cystitis following hematopoietic stem cell transplantation: Prophylaxis, diagnosis, and treatment. Guidelines from the SFGM-TC]. Bull Cancer 2023; 110:S48-S55. [PMID: 35181061 DOI: 10.1016/j.bulcan.2022.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 10/19/2022]
Abstract
Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic cell transplantation (allo-HCT). Its manifestations range from microscopic hematuria without urinary symptoms to extensive and prolonged macroscopic hemorrhage requiring invasive interventions that can often prolong the duration of hospitalization and result in significant morbidity. The early onset of HC is related to allo-HCT conditioning regimen, whereas the late onset form is secondary to viral infection, most commonly due to BK virus. In the framework of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) practice harmonization workshops held in Lille in September 2021, the prophylaxis, the diagnostic approach and the treatments of HC following allografting were reviewed after analysis of published studies.
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Affiliation(s)
- Pierre-Luc Dequirez
- CHU de Lille, service d'urologie, 2, rue Michel-Polonowski, 59000 Lille, France
| | - Leonardo Magro
- CHU de Lille, service des maladies du sang, 2, rue Michel-Polonowski, 59000 Lille, France
| | - Tamim Alsuliman
- AP-HP, Sorbonne université, service d'hématologie et de thérapie cellulaire, hôpital Saint-Antoine, 184, rue Faubourg St-Honoré, 75012 Paris, France
| | - Patrice Ceballos
- CHU Saint-Éloi, service d'hématologie clinique, 80, avenue Bertin-Sans, 34080 Montpellier cedex 8, France
| | - Yohan Desbrosses
- CHRU Jean-Minjoz, service d'hématologie, 3, boulevard Fleming, 25030 Besançon cedex, France
| | - Ibrahim Yakoub-Agha
- CHU de Lille, université de Lille, service d'hématologie, Infinite, Inserm U1286, 59000 Lille, France
| | - Thierry Guillaume
- CHU de Nantes, Hôtel-Dieu, service d'hématologie, 1, place Ricordeau, 44000 Nantes, France.
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Yuan H, Chen G, Qu J, Yang R, Muhashi M, Aizezi G, Jiang M. Clinical study of late-onset hemorrhagic cystitis after allo-HSCT without in vitro T-cell depletion. Medicine (Baltimore) 2022; 101:e32130. [PMID: 36550833 PMCID: PMC9771304 DOI: 10.1097/md.0000000000032130] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
This study is to investigate the hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) without in vitro T-cell depletion. Patients receiving allo-HSCT in 2019 were enrolled. The occurrence and clinical characteristics of HC after HLA-identical HSCT and haploidentical HSCT were retrospectively analyzed. BK, JC, cytomegalovirus, and other viruses were monitored when HC occurred. Conventional HC treatment was performed. Additionally, 5 cases of severe refractory HC were treated with adipose-derived mesenchymal stem cell (ADSC) besides conventional HC treatment. Totally, 54 patients with allo-HSCT were enrolled, including 12 cases with HLA-identical HSCT and 42 cases with haploidentical HSCT. Among them, 17 developed late-onset HC (LOHC). There was no early-onset HC. The median onset time was 33.5 (9-189) days, with a median duration of 19 (5-143) days. There were 8 cases of grade III HC and 2 cases of grade IV HC. The cumulative incidence of LOHC in 54 patients was 29.6%, and the cumulative incidence of LOHC in 42 patients with haploidentical HSCT was 40.5%. The 1-year expected progression-free survival (PFS) of 26 patients without HC was 86.6%, and the 1-year expected PFS of 16 HC patients was 74.5%. However, there was no statistically significant difference (P = .326). The urine BK virus of 14 patients was positive, with the lowest of 1.98 × 105 copies/mL, and the highest of 8.96 × 105 copies/mL. For the 5 patients with severe refractory HC, the lowest infusion dose of ADSC was 0.9 × 106/kg and the highest was 1.4 × 106/kg. All 5 patients were cured. The incidence of LOHC is higher after haploidentical HSCT. LOHC is positively correlated with urine BK virus. LOHC has no obvious effect on the overall PFS of patients. ADSC infusion has a good therapeutic effect on severe and prolonged LOHC.
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Affiliation(s)
- Hailong Yuan
- Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Gang Chen
- Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Jianhua Qu
- Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Ruixue Yang
- Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Maria Muhashi
- Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Gulibadanmu Aizezi
- Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Ming Jiang
- Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi, Xinjiang Uygur Autonomous Region, China
- * Correspondence: Ming Jiang, Hematology Center, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, No.137, Liyushan South Road, Urumqi 830054, Xinjiang Uygur Autonomous Region, China (e-mail: )
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Yuan H, Chen G, Xu J, Yang R, Muhashi M, Aizezi G, Jiang M. Incidence of late-onset hemorrhagic cystitis and its effect on PFS in acute leukemia patients after haplo-PBSCT: The 5-year single-center data. Front Oncol 2022; 12:913802. [PMID: 35912244 PMCID: PMC9334683 DOI: 10.3389/fonc.2022.913802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/28/2022] [Indexed: 12/02/2022] Open
Abstract
We conducted a single-center 5-year retrospective study on the occurrence of hemorrhagic cystitis (HC) and its effect on survival after haploid high-dose peripheral blood stem cell transplantation (haplo-PBSCT) in patients with acute leukemia. We retrospectively analyzed 153 patients with acute leukemia who were treated with non-in vitro T-cell depleted haplo-PBSCT and myeloablative conditioning regimen. All patients were followed up for more than 180 days after transplantation. HC occurrence and its effect on long-term progression free survival (PFS) were retrospectively analyzed. Totally, 64 out of 153 patients had late onset HC (LOHC). No early onset HC occurred. The median onset time was 38.5 (17-163) days after transplantation. The cumulative incidence of LOHC was 41.8%. The cumulative incidence of LOHC in patients under 27 years old (50.0%) and in ALL patients (54.1%) was significantly higher than that in patients over 27 years old (34.5%) and in AML patients (36.9%), respectively. The cumulative incidence of mild LOHC was 44.2% and that of severe LOHC was 28.6%. However, urine copies of BK virus were not related to LOHC duration. There was no significant difference in 3-year expected PFS between AML and ALL patients with and without LOHC, or between LOHC duration more than and less than 38.5 days (P>0.05). Conclusively, LOHC incidence is higher in patients under 27 years old and in ALL patients. LOHC occurrence is related to urine BK virus copy, but not blood BK virus load. LOHC duration and severity has no significant effect on PFS.
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Incidence, risk factors and outcome of BK virus hemorrhagic cystitis following allogenic hematopoietic cell transplantation: a retrospective cohort study. Bone Marrow Transplant 2022; 57:1287-1294. [PMID: 35596063 DOI: 10.1038/s41409-022-01665-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 11/08/2022]
Abstract
BK polyomavirus (BKPyV) can cause hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (allo-HCT). Recent evaluation of BKPyV HC (BKHC) incidence and risk factors are scarce. We conducted a retrospective single-center study on a recent allo-HCT cohort over 3 years in a referral academic hospital for hematological malignancies. Primary objective was to determine BKHC incidence using competitive risk analysis. Secondary objectives were the identification of HC risk factors using Fine and Gray models and the evaluation of mortality. Among 409 allo-HCT recipients (median age 47 years), 41 developed BKHC after a median delay of 41 [32-55] days. Incidence density of BKHC was 2.4 [1.8-3.1] events per 100 days post-allo-HCT. The proportion of BKHC after adjustment for time-dependent competing risk was 9.5 [9.5-9.6]% at 100 days. BK viremia was detected in 63 versus 20% in tested patients with and without BKHC, respectively. After adjustment for confounders, myeloablative conditioning regimen with and without cyclophosphamide and CMV seropositivity were independently associated with BKHC. Post-transplantation cyclophosphamide was not associated with BKHC. BKHC resolved in 90% of the patients. No difference in mortality was found between patients with or without BKHC. In parallel to the recent evolution of allo-HCT protocols, BKHC remains a frequent complication following allo-HCT.
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Yuan H, Chen G, Qu J, Yang R, Muhashi M, Aizezi G, Jiang M. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT. Open Med (Wars) 2021; 16:1493-1502. [PMID: 34703902 PMCID: PMC8494146 DOI: 10.1515/med-2021-0368] [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] [Received: 03/18/2021] [Revised: 08/12/2021] [Accepted: 09/02/2021] [Indexed: 01/17/2023] Open
Abstract
Introduction This study is to investigate the effect of late-onset hemorrhagic cystitis (LOHC) on progression-free survival (PFS) of patients after haploidentical peripheral blood hematopoietic stem cell transplantation (haplo-PBSCT). Methods This retrospective study enrolled 74 patients with hematological malignancies treated with a myeloablative conditioning regimen and haplo-PBSCT. The effect of LOHC on PFS was studied in terms of HC occurrence, grade, disease type, duration, onset time, gender, and age. Results There were 28 patients with LOHC, and no case was with early-onset HC. The cumulative incidence of LOHC was 37.8% (95% CI: 26.9–48.7%). The 2-year expected PFS of 74 patients and 34 AML patients was not significantly different between LOHC patients and patients without HC (P > 0.05). Among 27 ALL patients, the 2-year expected PFS of LOHC patients was 75%, significantly higher than patients without HC (54.2%) (P < 0.05). The 2-year expected PFSs of patients with mild LOHC and severe LOHC were 69.8 and 77.8%, respectively (P > 0.05). Similarly, the onset time, duration, age, and gender of LOHC patients did not show significant effects on PFS (P > 0.05). Conclusions After haplo-PBSCT, LOHC has a significant effect on the PFS of ALL patients. The HC grade, duration, onset time, gender, and age have no significant effect on PFS.
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Affiliation(s)
- Hailong Yuan
- Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi 830054, China
| | - Gang Chen
- Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi 830054, China
| | - Jianhua Qu
- Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi 830054, China
| | - Ruixue Yang
- Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi 830054, China
| | - Maria Muhashi
- Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi 830054, China
| | - Gulibadanmu Aizezi
- Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, Urumqi 830054, China
| | - Ming Jiang
- Hematology Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Institute of Hematology, No. 137 Liyushan South Road, Urumqi 830054, China
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Pretransplant BK Virus-Specific T-Cell-Mediated Immunity and Serotype Specific Antibodies May Have Utility in Identifying Patients at Risk of BK Virus-Associated Haemorrhagic Cystitis after Allogeneic HSCT. Vaccines (Basel) 2021; 9:vaccines9111226. [PMID: 34835157 PMCID: PMC8625163 DOI: 10.3390/vaccines9111226] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 11/17/2022] Open
Abstract
BK polyomavirus (BKPyV) persists lifelong in renal and urothelial cells with asymptomatic urinary shedding in healthy individuals. In some immunocompromised persons after transplantation of hematopoietic stem cells (HSCT), the BKPyV high-rate replication is associated with haemorrhagic cystitis (HC). We tested whether the status of BKPyV immunity prior to HSCT could provide evidence for the BKPyV tendency to reactivate. We have shown that measurement of pretransplant anti-BKPyV 1 and 4 IgG levels can be used to evaluate the HC risk. Patients with anti-BKPyV IgG in the range of the 1st-2nd quartile of positive values and with positive clinical risk markers have a significantly increased HC risk, in comparison to the reference group of patients with "non-reactive" anti-BKPyV IgG levels and with low clinical risk (LCR) (p = 0.0009). The predictive value of pretransplant BKPyV-specific IgG was confirmed by determination of genotypes of the shed virus. A positive predictive value was also found for pretransplant T-cell immunity to the BKPyV antigen VP1 because the magnitude of IFN-γ T-cell response inversely correlated with posttransplant DNAuria and with HC. Our novel data suggest that specific T-cells control BKPyV latency before HSCT, and in this way may influence BKPyV reactivation after HSCT. Our study has shown that prediction using a combination of clinical and immunological pretransplant risk factors can help early identification of HSCT recipients at high risk of BKPyV disease.
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Hosoi H, Murata S, Suzuki T, Li TC, Hatanaka K, Tanaka-Taya K, Mushino T, Kuriyama K, Tamura S, Hanaoka N, Sonoki T. A cluster of BK polyomavirus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2021; 23:e13736. [PMID: 34546601 DOI: 10.1111/tid.13736] [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: 06/22/2021] [Revised: 09/01/2021] [Accepted: 09/08/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND BK polyomavirus (BKV) can cause hemorrhagic cystitis (HC) in immunocompromised patients after hematopoietic stem cell transplantation (HSCT). It remains unclear whether nosocomial BKV infections occur. During a 9-month period, an increase in BKV-associated HC (BKV-HC) cases was observed at our institution. AIM The BKV-HC cluster population was compared with populations of HSCT patients from before and after the BKV-HC cluster to evaluate whether nosocomial BKV transmission had occurred. METHODS A retrospective analysis was carried out to assess the risk of patients developing BKV-HC after HSCT. The background data of the cluster patients were compared with those of the patients who underwent HSCT before or after the cluster, and the collected BKV isolates were serotyped. RESULTS BKV-HC involving grade ≥2 hematuria occurred in six of 15 HSCT recipients during a 9-month period. The incidence of BKV-HC was significantly higher in this period than in the other periods (p = 0.0014). There were no significant differences in the patients' background data between the cluster and non-cluster periods, including in terms of risk factors for BKV-HC. Serotype analyses of BKV revealed that the BKV detected in the urine samples from four of the six BKV-HC patients belonged to subtype Ic. The gene sequences of these four BKV exhibited >99.5% homology. CONCLUSION Our study suggests that nosocomial BKV infections may occur after HSCT. Although many cases of BKV-HC are caused by the reactivation of a latent virus, it is necessary to employ appropriate hygiene measures when cases of BKV-HC occur.
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Affiliation(s)
- Hiroki Hosoi
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Shogo Murata
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Disease, Tokyo, Japan
| | - Kazuo Hatanaka
- Department of Hematology, Sakai City Medical Center, Osaka, Japan
| | - Keiko Tanaka-Taya
- Center for Surveillance, Immunization, and Epidemiologic Research, National Institute of Infectious Disease, Tokyo, Japan
| | - Toshiki Mushino
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Kodai Kuriyama
- Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Shinobu Tamura
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Nobuyoshi Hanaoka
- Department of General Medicine, National Hospital Organization Kumamotominami National Hospital, Kumamoto, Japan
| | - Takashi Sonoki
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
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11
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Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, Lutzko C, Zhu X, Blackard JT, Jodele S, Lane A, Wallace G, Dandoy CE, Lake K, Duell A, Litts B, Seif AE, Olson T, Bunin N, Davies SM. The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation. Clin Infect Dis 2021; 71:3044-3054. [PMID: 31851312 DOI: 10.1093/cid/ciz1194] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function. METHODS In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1-4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use. RESULTS We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1-4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure. CONCLUSIONS Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.
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Affiliation(s)
- Benjamin L Laskin
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michelle R Denburg
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Susan L Furth
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Taylor Moatz
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | | | | | - Carolyn Lutzko
- Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Xiang Zhu
- Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jason T Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Sonata Jodele
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Adam Lane
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Gregory Wallace
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Christopher E Dandoy
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Kelly Lake
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Alexandra Duell
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Bridget Litts
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Alix E Seif
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Timothy Olson
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Nancy Bunin
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Stella M Davies
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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12
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Prospective analysis of BKV hemorrhagic cystitis in children and adolescents undergoing hematopoietic cell transplantation. Ann Hematol 2021; 100:1283-1293. [PMID: 33661334 PMCID: PMC8043890 DOI: 10.1007/s00277-021-04454-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 02/07/2021] [Indexed: 12/11/2022]
Abstract
BK virus is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic cell transplantation (HCT). Viruses can be found in urine and serum samples of immunocompromised patients. Malignant diseases, age, cell source, day of granulocyte reconstitution, conditioning regimen, or use of total body irradiation may play an important role in BKV epidemiology, development of hemorrhagic cystitis course, and outcome. The aim of this study was to evaluate the incidence, clinical course, and risk factors for BKV-HC in children undergoing HCT. A total number of 133 patients who were prospectively tested for BKV colonization/infection were enrolled into this multicenter analysis. Episodes of BKV-HC occurred in 36/133 (27%) enrolled subjects. In a univariate analysis for BKV-HC incidence, the following factors were significant: age >5 years, peripheral blood transplantation, matched unrelated donor (MUD) transplantation, busulfan-cyclophosphamide-melphalan conditioning regimen, and acute myeloblastic leukemia (AML) diagnosis. Presence of acute graft-versus-host disease (aGVHD) in liver and gut GVHD was a significant risk factor of BKV-HC. No BKV-attributed deaths were reported. In multivariate analysis, the incidence of HC was significantly higher in patients with AML, age >5 years, MUD transplants, and children with GVHD. HC is a frequent complication after HCT among children causes prolonged hospitalization but rarely contributes to death. We identified risk factors of BKV-HC development in children, with focus on aGVHD: we concluded that excessive immune reaction connected with GVHD and immunosuppression drugs might play a pivotal role in the development of BKV-HC.
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13
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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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14
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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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15
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Santos CAQ, Rhee Y, Czapka MT, Kazi AS, Proia LA. Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients. J Clin Med 2020; 9:jcm9030865. [PMID: 32245201 PMCID: PMC7141503 DOI: 10.3390/jcm9030865] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/11/2020] [Indexed: 12/11/2022] Open
Abstract
Hematopoietic stem cell transplant recipients are at increased risk of infection and immune dysregulation due to reception of cytotoxic chemotherapy; development of graft versus host disease, which necessitates treatment with immunosuppressive medications; and placement of invasive catheters. The prevention and management of infections in these vulnerable hosts is of utmost importance and a key “safety net” in stem cell transplantation. In this review, we provide updates on the prevention and management of CMV infection; invasive fungal infections; bacterial infections; Clostridium difficile infection; and EBV, HHV-6, adenovirus and BK infections. We discuss novel drugs, such as letermovir, isavuconazole, meropenem-vaborbactam and bezlotoxumab; weigh the pros and cons of using fluoroquinolone prophylaxis during neutropenia after stem cell transplantation; and provide updates on important viral infections after hematopoietic stem cell transplant (HSCT). Optimizing the prevention and management of infectious diseases by using the best available evidence will contribute to better outcomes for stem cell transplant recipients, and provide the best possible “safety net” for these immunocompromised hosts.
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16
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Hussain I, Tasneem F, Gilani US, Arshad MI, Farhan Ul Haque M, Abbas Z, Umer M, Shahzad N. Human BK and JC polyomaviruses: Molecular insights and prevalence in Asia. Virus Res 2020; 278:197860. [PMID: 31911182 DOI: 10.1016/j.virusres.2020.197860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/31/2019] [Accepted: 01/02/2020] [Indexed: 12/11/2022]
Abstract
Polyomaviridae family consists of small circular dsDNA viruses. Out of the 14 human polyomaviruses described so far, BKPyV and JCPyV have been studied extensively since their discovery in 1971. Reportedly, both BKPyV and JCPyV are widely distributed across the globe with the frequency of 80-90 % in different populations. The primary infection of these viruses is usually asymptomatic and latent which is activated as a consequence of immunosuppression. Activated BKPyV and JCPyV viruses lead to the development of BK Virus Associated Nephropathy and Progressive Multifocal Leukoencephalopathy, respectively. Immense progress has been made during the last few decades regarding the molecular understanding of polyomaviruses. Epidemiology of polyomaviruses has also been studied extensively. However, most of the epidemiological studies have focused on European and American populations. Therefore, limited data is available regarding the geographical distribution of these potentially oncogenic viruses in Asian countries. In this article, we have presented a compendium of latest advances in the molecular understanding of polyomaviruses and their pathobiology. We also present a comprehensive review of published literature regarding the epidemiology and prevalence of BKPyV and JCPyV in Asian regions. For this purpose, a thorough search of available online resources was performed. As a result, we retrieved 24 studies for BKPyV and 22 studies for JCPyV, that describe their prevalence in Asia. These studies unanimously report high occurrence of both BKPyV and JCPyV in Asian populations. The available data from these studies was categorized into two groups: on the basis of prevalence (low, medium and high) and disease development (healthy and diseased). Altogether, Korean population hasbeen evidenced to possess highest frequency of BKPyV (66.7 %), while JCPyV was found to be most prevalent in Taiwan (88 %). Due to high and ubiquitous distribution of these viruses, frequent studies are required to develop a better understanding regarding the epidemiology and pathobiology of these viruses in Asia.
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Affiliation(s)
- Iqra Hussain
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Fareeda Tasneem
- Department of Zoology, University of the Punjab, Lahore, Pakistan
| | - Usman Shah Gilani
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | | | | | - Zaigham Abbas
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Muhammed Umer
- Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, Nathan, QLD, 4111, Australia
| | - Naveed Shahzad
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
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17
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Kerbauy LN, Kerbauy MN, Bautzer V, Chapchap EC, de Mattos VRP, da Rocha JDA, Esteves I, Kutner JM, Kerbauy FR, Ribeiro AAF, Machado CM, Hamerschlak N, Santos FPDS. Severe hemorrhagic cystitis caused by the BK polyomavirus is associated with decreased survival post‐allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2019; 21:e13101. [DOI: 10.1111/tid.13101] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/21/2019] [Accepted: 04/06/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Lucila Nassif Kerbauy
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Mariana Nassif Kerbauy
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Vivien Bautzer
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Eduardo Cerello Chapchap
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Vinicius Renan Pinto de Mattos
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Juliana Dall’ Agnol da Rocha
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Iracema Esteves
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Jose Mauro Kutner
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Fabio Rodrigues Kerbauy
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Andreza Alice Feitosa Ribeiro
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Clarisse Martins Machado
- Instituto Israelita de Ensino e Pesquisa – IIEP Hospital Israelita Albert Einstein São Paulo Brazil
- Virology Laboratory, Institute of Tropical Medicine University of São Paulo São Paulo Brazil
| | - Nelson Hamerschlak
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
| | - Fabio Pires de Souza Santos
- Department of Hematology and Stem Cell Transplantation, Centro de Hematologia e Oncologia Família Dayan‐Daycoval Hospital Israelita Albert Einstein São Paulo Brazil
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Favi E, Puliatti C, Sivaprakasam R, Ferraresso M, Ambrogi F, Delbue S, Gervasi F, Salzillo I, Raison N, Cacciola R. Incidence, risk factors, and outcome of BK polyomavirus infection after kidney transplantation. World J Clin Cases 2019; 7:270-290. [PMID: 30746369 PMCID: PMC6369392 DOI: 10.12998/wjcc.v7.i3.270] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/08/2018] [Accepted: 12/12/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Polyomavirus-associated nephropathy is a leading cause of kidney allograft failure. Therapeutic options are limited and prompt reduction of the net state of immunosuppression represents the mainstay of treatment. More recent application of aggressive screening and management protocols for BK-virus infection after renal transplantation has shown encouraging results. Nevertheless, long-term outcome for patients with BK-viremia and nephropathy remains obscure. Risk factors for BK-virus infection are also unclear. AIM To investigate incidence, risk factors, and outcome of BK-virus infection after kidney transplantation. METHODS This single-centre observational study with a median follow up of 57 (31-80) mo comprises 629 consecutive adult patients who underwent kidney transplantation between 2007 and 2013. Data were prospectively recorded and annually reviewed until 2016. Recipients were periodically screened for BK-virus by plasma quantitative polymerized chain reaction. Patients with BK viral load ≥ 1000 copies/mL were diagnosed BK-viremia and underwent histological assessment to rule out nephropathy. In case of BK-viremia, immunosuppression was minimized according to a prespecified protocol. The following outcomes were evaluated: patient survival, overall graft survival, graft failure considering death as a competing risk, 30-d-event-censored graft failure, response to treatment, rejection, renal function, urologic complications, opportunistic infections, new-onset diabetes after transplantation, and malignancies. We used a multivariable model to analyse risk factors for BK-viremia and nephropathy. RESULTS BK-viremia was detected in 9.5% recipients. Initial viral load was high (≥ 10000 copies/mL) in 66.7% and low (< 10000 copies/mL) in 33.3% of these patients. Polyomavirus-associated nephropathy was diagnosed in 6.5% of the study population. Patients with high initial viral load were more likely to experience sustained viremia (95% vs 25%, P < 0.00001), nephropathy (92.5% vs 15%, P < 0.00001), and polyomavirus-related graft loss (27.5% vs 0%, P = 0.0108) than recipients with low initial viral load. Comparison between recipients with or without BK-viremia showed that the proportion of patients with Afro-Caribbean ethnicity (33.3% vs 16.5%, P = 0.0024), panel-reactive antibody ≥ 50% (30% vs 14.6%, P = 0.0047), human leukocyte antigen (HLA) mismatching > 4 (26.7% vs 13.4%, P = 0.0110), and rejection within thirty days of transplant (21.7% vs 9.5%; P = 0.0073) was higher in the viremic group. Five-year patient and overall graft survival rates for patients with or without BK-viremia were similar. However, viremic recipients showed higher 5-year crude cumulative (22.5% vs 12.2%, P = 0.0270) and 30-d-event-censored (22.5% vs 7.1%, P = 0.001) incidences of graft failure than control. In the viremic group we also observed higher proportions of recipients with 5-year estimated glomerular filtration rate < 30 mL/min than the group without viremia: 45% vs 27% (P = 0.0064). Urologic complications were comparable between the two groups. Response to treatment was complete in 55%, partial in 26.7%, and absent in 18.3% patients. The nephropathy group showed higher 5-year crude cumulative and 30-d-event-censored incidences of graft failure than control: 29.1% vs 12.1% (P = 0.008) and 29.1% vs 7.2% (P < 0.001), respectively. Our multivariable model demonstrated that Afro-Caribbean ethnicity, panel-reactive antibody > 50%, HLA mismatching > 4, and rejection were independent risk factors for BK-virus viremia whereas cytomegalovirus prophylaxis was protective. CONCLUSION Current treatment of BK-virus infection offers sub-optimal results. Initial viremia is a valuable parameter to detect patients at increased risk of nephropathy. Panel-reactive antibody > 50% and Afro-Caribbean ethnicity are independent predictors of BK-virus infection whereas cytomegalovirus prophylaxis has a protective effect.
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Affiliation(s)
- Evaldo Favi
- Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
| | - Carmelo Puliatti
- Renal Transplantation, Barts Health NHS Trust, Royal London Hospital, London E1 1BB, United Kingdom
| | - Rajesh Sivaprakasam
- Renal Transplantation, Barts Health NHS Trust, Royal London Hospital, London E1 1BB, United Kingdom
| | - Mariano Ferraresso
- Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy
| | - Federico Ambrogi
- Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy
| | - Serena Delbue
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan 20100, Italy
| | - Federico Gervasi
- Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy
| | - Ilaria Salzillo
- Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
| | - Nicholas Raison
- MRC Centre for Transplantation, King’s College London, London WC2R 2LS, United Kingdom
| | - Roberto Cacciola
- Renal Transplantation, Barts Health NHS Trust, Royal London Hospital, London E1 1BB, United Kingdom
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Impacts and Challenges of Advanced Diagnostic Assays for Transplant Infectious Diseases. PRINCIPLES AND PRACTICE OF TRANSPLANT INFECTIOUS DISEASES 2019. [PMCID: PMC7121269 DOI: 10.1007/978-1-4939-9034-4_47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The advanced technologies described in this chapter should allow for full inventories to be made of bacterial genes, their time- and place-dependent expression, and the resulting proteins as well as their outcome metabolites. The evolution of these molecular technologies will continue, not only in the microbial pathogens but also in the context of host-pathogen interactions targeting human genomics and transcriptomics. Their performance characteristics and limitations must be clearly understood by both laboratory personnel and clinicians to ensure proper utilization and interpretation.
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20
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Donor lymphocyte infusion for BK virus hemorrhagic cystitis and nephropathy: a case report. Bone Marrow Transplant 2018; 54:772-774. [PMID: 30518978 DOI: 10.1038/s41409-018-0402-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/17/2018] [Accepted: 11/04/2018] [Indexed: 02/02/2023]
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21
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Sirohi D, Vaske C, Sanborn Z, Smith SC, Don MD, Lindsey KG, Federman S, Vankalakunti M, Koo J, Bose S, Peralta-Venturina MD, Ziffle JV, Grenert JP, Miller S, Chiu C, Amin MB, Simko JP, Stohr BA, Luthringer DJ. Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study. Mod Pathol 2018; 31:1429-1441. [PMID: 29765141 DOI: 10.1038/s41379-018-0065-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 03/29/2018] [Accepted: 03/30/2018] [Indexed: 12/11/2022]
Abstract
In recent years, there has been increased interest in carcinomas of the urologic tract, that demonstrate association with the polyoma virus BK arising in immunosuppressed individuals, though the nature of this association is uncertain. To begin to understand this phenomenon, we reviewed the clinical, morphological, and immunohistochemical features of 11 carcinomas of the urologic tract, mainly urothelial (N = 9) and collecting duct carcinomas (N = 2), occurring during immunosuppression, and expressing polyoma virus T-antigen by immunohistochemistry. These were compared to a control group of carcinomas (N = 8), also arising during immunosuppression, but without T-antigen expression. A subset of both groups were also studied by hybrid capture-based DNA sequencing, probing not only for 479 cancer-related human genes, but also for polyoma and other viral sequences. Polyoma T-antigen-expressing tumors arose in 7 males and 4 females, at a median age of 66, and were aggressive, high-grade tumors with more than 1 variant morphologic pattern identified in 81% of cases, and a majority (73%) presenting at high stage category (>pT3). Diffuse polyoma T-antigen staining was seen in 91% of cases, with co-localization of aberrant p53 staining in 89%. Sequencing detected a lower number of deleterious mutations among T-antigen-expressing cases (average 1.62; 1/8 with TP53 mutation) compared to control cases (average 3.5, 2/4 with TP53 mutation). Only BK virus was detected with clonal integration and breakpoints randomly distributed across the human and viral genomes in 5/5 of the polyoma T-antigen-expressing carcinomas, and in none of the controls (0/4). In summary, these findings identify aggressive clinicopathologic features of polyoma T-antigen-expressing carcinomas, document BK as the strain involved, and associate BK viral integration with T-antigen expression and p53 aberrancy. While the apparent randomness of viral insertion sites is functionally unclear, the differing rates of mutations between T-antigen-expressing and control cases is intriguing.
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Affiliation(s)
- Deepika Sirohi
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA.
| | | | | | - Steven C Smith
- Departments of Pathology and Urology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Michelle D Don
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Scot Federman
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Mahesha Vankalakunti
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jamie Koo
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Shikha Bose
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Jessica van Ziffle
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - James P Grenert
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Steve Miller
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Charles Chiu
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Mahul B Amin
- Department of Pathology and Laboratory Medicine and Urology, University of Tennessee Health Science, Memphis, TN, USA
| | - Jeffry P Simko
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Bradley A Stohr
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Daniel J Luthringer
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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22
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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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23
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Abstract
BK polyomavirus (BKV) causes frequent infections during childhood and establishes persistent infections within renal tubular cells and the uroepithelium, with minimal clinical implications. However, reactivation of BKV in immunocompromised individuals following renal or hematopoietic stem cell transplantation may cause serious complications, including BKV-associated nephropathy (BKVAN), ureteric stenosis, or hemorrhagic cystitis. Implementation of more potent immunosuppression and increased posttransplant surveillance has resulted in a higher incidence of BKVAN. Antiviral immunity plays a crucial role in controlling BKV replication, and our increasing knowledge about host-virus interactions has led to the development of improved diagnostic tools and clinical management strategies. Currently, there are no effective antiviral agents for BKV infection, and the mainstay of managing reactivation is reduction of immunosuppression. Development of immune-based therapies to combat BKV may provide new and exciting opportunities for the successful treatment of BKV-associated complications.
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24
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Kato J, Mori T, Suzuki T, Ito M, Li TC, Sakurai M, Yamane Y, Yamazaki R, Koda Y, Toyama T, Hasegawa N, Okamoto S. Nosocomial BK Polyomavirus Infection Causing Hemorrhagic Cystitis Among Patients With Hematological Malignancies After Hematopoietic Stem Cell Transplantation. Am J Transplant 2017; 17:2428-2433. [PMID: 28295968 DOI: 10.1111/ajt.14271] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/10/2017] [Accepted: 03/01/2017] [Indexed: 01/25/2023]
Abstract
BK polyomavirus (BKPyV) is recognized as a pathogen that causes diseases such as hemorrhagic cystitis and nephritis after allogeneic hematopoietic stem cell transplantation (HSCT) or renal transplantation. BKPyV-associated disease is thought to occur through reactivation under immunosuppression. However, the possibility of its nosocomial transmission and the clinical significance of such transmission have not been elucidated. During a 6-month period, nine adult patients (median age: 47 years) who had hematological disorders and who were treated with HSCT (n = 7) or chemotherapy (n = 2) in a single hematology department developed hemorrhagic cystitis due to BKPyV infection. The polymerase chain reaction products of BKPyV DNA obtained from each patient were sequenced. Of the nine patients, six had subtype I, 2 had subtype IV, and 1 had subtype II or III. In the alignment of sequences, four and two of the six subtype I strains were completely homologous (100%). These results strongly suggest that BKPyV has the potential to cause nosocomial infection within a medical facility, especially among recipients of HSCT. Further studies are clearly warranted to elucidate the route(s) of BKPyV transmission in order to establish optimal infection control.
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Affiliation(s)
- J Kato
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
| | - T Mori
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan.,Center for Infectious Diseases and Infection Control, Keio University Hospital, Tokyo, Japan
| | - T Suzuki
- Department of Infectious Diseases, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - M Ito
- Department of Infectious Diseases, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - T C Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - M Sakurai
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
| | - Y Yamane
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
| | - R Yamazaki
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
| | - Y Koda
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
| | - T Toyama
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
| | - N Hasegawa
- Center for Infectious Diseases and Infection Control, Keio University Hospital, Tokyo, Japan
| | - S Okamoto
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
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25
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Abstract
Similarly to the general population, genitourinary tract infections are common conditions in theimmunocompromised host. They can be furthermore divided into infections of the urinary tract and genital tract infections. Transplant recipients are more likely to have infections of the urinary tract infections while persons with human immunodeficiency virus (HIV) are at higher risk for the second group of infections, especially sexually transmitted infections (STIs). Manifestations of these diseases can be associated with more complications and can be more severe. We provide an overview of manifestations, diagnosis, and management of these disorders.
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26
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Marr KA. Infections in Hematopoietic Stem Cell Transplant Recipients. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00080-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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27
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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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28
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Rahiala J, Koskenvuo M, Sadeghi M, Waris M, Vuorinen T, Lappalainen M, Saarinen-Pihkala U, Allander T, Söderlund-Venermo M, Hedman K, Ruuskanen O, Vettenranta K. Polyomaviruses BK, JC, KI, WU, MC, and TS in children with allogeneic hematopoietic stem cell transplantation. Pediatr Transplant 2016; 20:424-31. [PMID: 27038301 DOI: 10.1111/petr.12659] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/19/2015] [Indexed: 11/29/2022]
Abstract
Timely and reliable detection of viruses is of key importance in early diagnosis of infection(s) following allogeneic HSCT. Among the immunocompetent, infections with BKPyV and JCPyV are mostly subclinical, while post-HSCT, the former may cause HC and the latter PML. The epidemiology and clinical impact of the newly identified KIPyV, WUPyV, MCPyV, and TSPyV in this context remain to be defined. To assess the incidence and clinical impact of BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, and TSPyV infections, we performed longitudinal molecular surveillance for DNAemias of these HPyVs among 53 pediatric HSCT recipients. Surveillance pre-HSCT and for three months post-HSCT revealed BKPyV DNAemia in 20 (38%) patients. Our data demonstrate frequent BKPyV DNAemia among pediatric patients with HSCT and the confinement of clinical symptoms to high copy numbers alone. MCPyV and JCPyV viremias occurred at low and TSPyV viremia at very low prevalences. KIPyV or WUPyV viremias were not demonstrable in this group of immunocompromised patients.
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Affiliation(s)
- Jaana Rahiala
- Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki, Helsinki, Finland.,Department of Pediatrics, Porvoo Hospital, Porvoo, Finland
| | - Minna Koskenvuo
- Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki, Helsinki, Finland.,Department of Pediatrics, Turku University Hospital, Turku, Finland
| | | | - Matti Waris
- Division of Microbiology and Genetics, Department of Clinical Virology, Turku University Hospital, Turku, Finland.,Department of Virology, University of Turku, Turku, Finland
| | - Tytti Vuorinen
- Division of Microbiology and Genetics, Department of Clinical Virology, Turku University Hospital, Turku, Finland.,Department of Virology, University of Turku, Turku, Finland
| | - Maija Lappalainen
- Department of Virology and Immunology, Helsinki University Hospital Laboratory Services (HUSLAB), Helsinki, Finland
| | - Ulla Saarinen-Pihkala
- Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki, Helsinki, Finland
| | - Tobias Allander
- Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | | | - Klaus Hedman
- Department of Virology, University of Helsinki, Helsinki, Finland.,Department of Virology and Immunology, Helsinki University Hospital Laboratory Services (HUSLAB), Helsinki, Finland
| | - Olli Ruuskanen
- Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - Kim Vettenranta
- Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki, Helsinki, Finland
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29
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Peterson L, Ostermann H, Fiegl M, Tischer J, Jaeger G, Rieger CT. Reactivation of polyomavirus in the genitourinary tract is significantly associated with severe GvHD and oral mucositis following allogeneic stem cell transplantation. Infection 2016; 44:483-90. [PMID: 26792012 DOI: 10.1007/s15010-016-0872-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 01/04/2016] [Indexed: 12/16/2022]
Abstract
PURPOSE BK-virus and JC-virus are the most common polyomaviridae associated with hemorrhagic cystitis in the allogeneic transplant setting. Hemorrhagic cystitis and symptomatic viruria caused by these viruses are a major cause of morbidity in patients undergoing allogeneic stem cell transplantation. METHODS We performed a retrospective evaluation on a highly uniform study population of 73 patients receiving allogeneic stem cell transplantation. Patients were treated according to the FLAMSA-RIC-protocol, and were examined for the incidence of BK-/JC-viruria and late-onset BK-positive hemorrhagic cystitis within a two-year period. RESULTS The occurrence of BK-viruria was correlated with published risk factors (acute GvHD, oral mucositis, donor type, conditioning, age, gender). Thirty patients (41 %) were found to excrete either BK-virus (n = 17), JC-virus (n = 3) or both (n = 10), of whom 18 patients (60 %) developed higher-grade hemorrhagic cystitis as opposed to none in the virus-negative control group. Higher grade GvHD (grade B-D) was more common in patients with viruria (p = 0.013) and also more common in patients with manifest hemorrhagic cystitis (p = 0.048). Similarly, oral mucositis was associated both with viruria (p = 0.014) and hemorrhagic cystitis (p = 0.005). Manifest cystitis but not viruria was significantly associated with male gender (p = 0.016). No significant correlation was found with age, conditioning with busulfane vs total body irradiation or related vs unrelated donor. CONCLUSIONS Severe GvHD and oral mucositis are significantly associated with reactivation of polyomaviridae in the genitourinary-tract already at the level of asymptomatic viruria.
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Affiliation(s)
- Lisa Peterson
- Department of Internal Medicine III, University of Munich, Munich, Germany
| | - Helmut Ostermann
- Department of Internal Medicine III, University of Munich, Munich, Germany
| | - Michael Fiegl
- Department of Internal Medicine III, University of Munich, Munich, Germany
| | - Johanna Tischer
- Department of Internal Medicine III, University of Munich, Munich, Germany
| | - Gundula Jaeger
- Max-von-Pettenkofer-Institut, University of Munich, Munich, Germany
| | - Christina T Rieger
- Department of Internal Medicine III, University of Munich, Munich, Germany. .,Internistische Lehrpraxis der LMU Germering, Ludwig-Maximilians-University Munich, Munich, Germany.
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30
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Laskin BL, Sullivan KE, Hester J, Goebel J, Davies SM, Jodele S. Antibodies to BK virus in children prior to allogeneic hematopoietic cell transplant. Pediatr Blood Cancer 2015; 62:1670-3. [PMID: 25833296 PMCID: PMC4515143 DOI: 10.1002/pbc.25536] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/05/2015] [Indexed: 01/08/2023]
Abstract
BK virus (BKV) is associated with kidney and bladder disease after hematopoietic cell transplantation (HCT) but less is known about the seroprevalence of pre-transplant antibodies to BKV in children. We measured BKV IgG antibody titers in 36 children before HCT. BKV IgG antibodies were detected in all 36 patients, with 28/36 (77.8%) developing BK viremia in the first 100 days. Pre-HCT BKV IgG antibody titers >1:40,960 were protective against later BK viremia ≥10,000 copies/ml. The seroprevalence of antibodies to BKV is high in children undergoing HCT and post-transplant BK viremia, which is associated with bladder and kidney injury, is common.
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Affiliation(s)
- Benjamin L Laskin
- Division of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Kathleen E Sullivan
- Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jeff Hester
- Viracor-IBT Laboratories, Lee’s Summit, Missouri
| | - Jens Goebel
- Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Stella M Davies
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Sonata Jodele
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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31
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Cesaro S, Tridello G, Pillon M, Calore E, Abate D, Tumino M, Carucci N, Varotto S, Cannata E, Pegoraro A, Barzon L, Palù G, Messina C. A Prospective Study on the Predictive Value of Plasma BK Virus-DNA Load for Hemorrhagic Cystitis in Pediatric Patients After Stem Cell Transplantation. J Pediatric Infect Dis Soc 2015; 4:134-42. [PMID: 26407413 DOI: 10.1093/jpids/piu043] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 03/11/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND In hematopoietic stem cell transplantation (HSCT), late hemorrhagic cystitis (HC) has been associated with BK virus (BKV) infection. We assessed the value of plasma BKV load in predicting HC. METHODS Plasma and urine BKV-DNA load were assessed prospectively in 107 pediatric patients. RESULTS Twenty patients developed grade II and III HC, with 100-day cumulative incidence of 18.8%. At diagnosis of HC, the median load of BKV DNA was 2.3 × 10(3) copies/mL. A plasma BKV-DNA load of 10(3) copies/mL had a sensitivity of 100% and a specificity of 86% with a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 39% for HC. A urine BKV-DNA load of >10(7) copies/mL had a sensitivity of 86% and a specificity of 60% with a NPV of 98% and a PPV of 14% for HC. A BKV load of 10(3) copies/mL on plasma was significantly associated with HC in multivariate analysis (hazard ratio [HR], 6.1; P = .0006). Patients with HC had a significantly higher risk of mortality than patients who did not have HC (HR, 2.6; P = .018). CONCLUSIONS The above values were used to monitor plasma BKV-DNA load, and they provided a better prediction of patients at risk of HC than urine BKV-DNA load.
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Affiliation(s)
- Simone Cesaro
- Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy Pediatric Hematology Oncology, Department of Pediatrics
| | - Gloria Tridello
- Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy Pediatric Hematology Oncology, Department of Pediatrics
| | - Marta Pillon
- Pediatric Hematology Oncology, Department of Pediatrics
| | | | - Davide Abate
- Department of Molecular Medicine, University of Padova, Italy
| | | | | | | | - Elisa Cannata
- Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Anna Pegoraro
- Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Luisa Barzon
- Department of Molecular Medicine, University of Padova, Italy
| | - Giorgio Palù
- Department of Molecular Medicine, University of Padova, Italy
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32
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The risk of polyomavirus BK-associated hemorrhagic cystitis after allogeneic hematopoietic SCT is associated with myeloablative conditioning, CMV viremia and severe acute GVHD. Bone Marrow Transplant 2014; 49:1528-34. [PMID: 25111517 DOI: 10.1038/bmt.2014.181] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 06/16/2014] [Accepted: 06/18/2014] [Indexed: 01/13/2023]
Abstract
Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic SCT (allo-HSCT). Several risk factors have been suggested including BU-containing myeloablative conditioning, unrelated donors and GVHD, but these have not been consistently reported. We conducted a retrospective study including 339 allo-HSCT recipients between 2009 and 2012. Of 339 patients, 79 (23.3%) developed HC with 2-year cumulative incidence of 24.0% (95% confidence interval, 19.4-28.9). The median onset time was 45 days (range, 16-430) after allo-HSCT. Sixty-two patients (84%) out of 74 evaluated for urine BK virus PCR testing showed a positive result (mean 2.0 × 10(10) copies of DNA per mL). In univariate analysis, myeloablative conditioning, HLA-mismatched donor, CMV viremia and acute GVHD (aGVHD) grade 3-4 were significantly associated with the risk of HC. Multivariate analysis confirmed all associating factors identified in univariate analysis except for HLA-mismatched donor: myeloablative conditioning (hazard ratio (HR) 2.63, P=0.003), CMV viremia (HR 1.88, P=0.014) and aGVHD grade 3-4 (HR 1.71, P=0.029). HC did not affect OS or non-relapse mortality. Symptomatic HC is a frequent complication following allo-HSCT, with a 2-year cumulative incidence of 24.0%. Three clinical factors associated with HC were identified including myeloablative conditioning, CMV viremia and severe aGVHD.
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33
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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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34
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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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Relationship of BK polyoma virus (BKV) in the urine with hemorrhagic cystitis and renal function in recipients of T Cell-depleted peripheral blood and cord blood stem cell transplantations. Biol Blood Marrow Transplant 2014; 20:1204-10. [PMID: 24769326 DOI: 10.1016/j.bbmt.2014.04.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 04/15/2014] [Indexed: 02/07/2023]
Abstract
Hematopoietic stem cell transplant (HSCT) recipients are at significant risk for BK virus (BKV) reactivation, hemorrhagic cystitis (HC), and renal dysfunction. We prospectively monitored 98 patients who had received HSCT by serial BKV PCR in the urine through day (D) +100 to analyze the relationship between BK viruria and HC, serum creatinine (Cr), and creatinine clearance (CrCl) through D +180 or death. Patients, median age 52 years (range, 20 to 73), received T cell-depleted (50%) or cord blood allografts (21%). Median pre-HSCT BKV IgG titers were 1:10,240. Incremental increase in BKV IgG titers correlated with developing BK viruria ≥ 10(7) copies/mL. By D +100, 53 (54%) patients had BK viruria. BKV load in the urine increased at engraftment and persisted throughout D +100. HC developed in 10 patients (10%); 7 of 10 with BK viruria. In competing risk analyses, BK viruria ≥ 10(7) copies/mL, older age, cytomegalovirus reactivation, and foscarnet use were risk factors for HC. Cr and CrCl at 2, 3, and 6 months after HSCT were similar between patients with and without BK viruria.
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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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BK virus disease after allogeneic stem cell transplantation: a cohort analysis. Biol Blood Marrow Transplant 2014; 20:564-70. [PMID: 24462984 DOI: 10.1016/j.bbmt.2014.01.014] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 01/15/2014] [Indexed: 11/21/2022]
Abstract
The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.
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Abstract
Polyomaviruses are ubiquitous, species-specific viruses belonging to the family Papovaviridae. The two most commonly known human polyomaviruses, BK virus and JC virus were first described in the 1970s. Newer human polyomaviruses, namely KI polyoma virus, WU polyoma virus and Merkel cell polyoma virus were identified in the last five years. Most humans encounter BK and JC virus during childhood, causing mild illness. However, when reactivated or acquired in the immunocompromised host, BK and JC virus have been implicated in a number of human clinical disease states. BK is most commonly associated with renal involvement, such as ureteral stenosis, hemorrhagic cystitis and nephropathy. Less commonly, it is associated with pneumonitis, retinitis, liver disease and meningoencephalitis. JC virus is most well known for its association with progressive multifocal leukoencephalopathy, and is possibly implicated in the development of various human neoplasms. The following chapter will outline the basic virology, epidemiology and clinical manifestations of BK and JC virus and discuss relevant diagnostic and treatment options.
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Affiliation(s)
- Michelle Pinto
- Division of Infectious and Immunological Diseases, Department of Pediatrics, BC Children's Hospital, Vancouver, Canada.
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Laskin BL, Denburg M, Furth S, Diorio D, Goebel J, Davies SM, Jodele S. BK viremia precedes hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19:1175-82. [PMID: 23665115 PMCID: PMC3774139 DOI: 10.1016/j.bbmt.2013.05.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 05/02/2013] [Indexed: 01/01/2023]
Abstract
BK virus is associated with hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT), although evidence supporting a causal relationship remains limited. Although BK viruria is common after HSCT, BK viremia may better predict clinically significant cystitis, similar to its predictive value for nephropathy after kidney transplantation. We hypothesized that BK viremia would precede hemorrhagic cystitis in a cohort of 88 consecutive children prospectively enrolled to originally study thrombotic microangiopathy in the first 100 days after allogeneic HSCT. Cox regression models with time-varying covariates assessed the association between different BK viremia cutoffs and the development of hemorrhagic cystitis, defined as at least macroscopic hematuria. Subjects with a peak plasma BK viral load 1 to 9999 copies/mL had an adjusted hazard ratio of 4.2 (95% confidence interval (CI), 1.3 to 13.7) for the development of hemorrhagic cystitis. Those with peak BK viremia >100,000 copies/mL had an adjusted hazard ratio of 116.8 (95% CI, 12 to 1136) for cystitis. Other independent risk factors for hemorrhagic cystitis included age >7 years and HHV-6 viremia. Neither graft-versus-host disease nor achieving engraftment increased the risk for cystitis. If therapeutic strategies are found to be effective, these observations may support screening for BK viremia after HSCT, as currently recommended for other DNA viruses.
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Affiliation(s)
- Benjamin L Laskin
- Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
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Human polyomavirus reactivation: disease pathogenesis and treatment approaches. Clin Dev Immunol 2013; 2013:373579. [PMID: 23737811 PMCID: PMC3659475 DOI: 10.1155/2013/373579] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 03/27/2013] [Accepted: 03/27/2013] [Indexed: 02/07/2023]
Abstract
JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct, immunocompromised patient cohorts. The recent discoveries of eight new members of the Polyomaviridae family that are capable of infecting humans suggest that there are more to be discovered and raise the possibility that they may play a more significant role in human disease than previously understood. In spite of this, there remains a dearth of specific therapeutic options for human polyomavirus infections and an incomplete understanding of the relationship between the virus and the host immune system. This review summarises the human polyomaviruses with particular emphasis on pathogenesis in those directly implicated in disease aetiology and the therapeutic options available for treatment in the immunocompromised host.
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Hwang YY, Sim J, Leung AYH, Lie AKW, Kwong YL. BK virus-associated bilateral ureteric stenosis after haematopoietic SCT: viral kinetics and successful treatment. Bone Marrow Transplant 2012; 48:745-6. [PMID: 23128571 DOI: 10.1038/bmt.2012.215] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Bennett SM, Broekema NM, Imperiale MJ. BK polyomavirus: emerging pathogen. Microbes Infect 2012; 14:672-83. [PMID: 22402031 PMCID: PMC3568954 DOI: 10.1016/j.micinf.2012.02.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Revised: 02/03/2012] [Accepted: 02/07/2012] [Indexed: 02/07/2023]
Abstract
BK polyomavirus (BKPyV) is a small double-stranded DNA virus that is an emerging pathogen in immunocompromised individuals. BKPyV is widespread in the general population, but primarily causes disease when immune suppression leads to reactivation of latent virus. Polyomavirus-associated nephropathy and hemorrhagic cystitis in renal and bone marrow transplant patients, respectively, are the most common diseases associated with BKPyV reactivation and lytic infection. In this review, we discuss the clinical relevance, effects on the host, virus life cycle, and current treatment protocols.
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Affiliation(s)
- Shauna M. Bennett
- Program in Cellular and Molecular Biology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
| | - Nicole M. Broekema
- Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
| | - Michael J. Imperiale
- Program in Cellular and Molecular Biology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
- Comprehensive Cancer Center University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
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Mori Y, Miyamoto T, Kato K, Kamezaki K, Kuriyama T, Oku S, Takenaka K, Iwasaki H, Harada N, Shiratsuchi M, Abe Y, Nagafuji K, Teshima T, Akashi K. Different risk factors related to adenovirus- or BK virus-associated hemorrhagic cystitis following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2011; 18:458-65. [PMID: 21810401 DOI: 10.1016/j.bbmt.2011.07.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2011] [Accepted: 07/27/2011] [Indexed: 10/17/2022]
Abstract
Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC.
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Affiliation(s)
- Yasuo Mori
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Ganguly N, Clough LA, Dubois LK, Mcguirk JP, Abhyankar S, Aljitawi OS, O'Neal N, Divine CL, Ganguly S. Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach. Transpl Infect Dis 2011; 12:406-11. [PMID: 20487411 DOI: 10.1111/j.1399-3062.2010.00513.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BK virus (BKV) reactivation occurs in 50% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Standardized antiviral management of BKV infection has not been established. In order to develop a uniform guideline, a treatment algorithm for the management of symptomatic BKV replication was implemented for our allo-HSCT population. This is a retrospective analysis of patients treated according to the protocol between January 2008 and January 2009. Eighteen patients developed symptomatic BKV replication a median of 43 days after allo-HSCT. All patients had BK viruria and 12 patients had BK viremia in addition to viruria. Patients with isolated viruria were treated with intravenous (IV) low-dose cidofovir (0.5-1mg/kg IV weekly) until symptom resolution. In patients with BK viremia, therapy was continued until virological clearance was achieved in the blood. Four patients also received intravesical instillation of cidofovir per physician discretion. Thirteen of 18 (72%) patients with viruria and 8 of 12 (75%) patients with viremia responded to treatment. Three patients developed transient renal dysfunction. Low-dose cidofovir is safe and effective in allo-HSCT recipients. In absence of randomized prospective data, an institutional algorithmic protocol removes variance in practice pattern and derives data that may be used for research and improved patient care.
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Affiliation(s)
- N Ganguly
- Department of Pharmacy, University of Kansas Medical Center, Kansas City, Kansas, USA.
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45
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Lonergan RM, Carr MJ, De Gascun CF, Costelloe LF, Waters A, Coughlan S, Duggan M, Doyle K, Jordan S, Hutchinson MW, Hall WW, Tubridy NJ. Reactivation of BK polyomavirus in patients with multiple sclerosis receiving natalizumab therapy. J Neurovirol 2010; 15:351-9. [PMID: 19670070 DOI: 10.3109/13550280903131923] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Natalizumab therapy in multiple sclerosis has been associated with JC polyomavirus-induced progressive multifocal leucoencephalopathy. We hypothesized that natalizumab may also lead to reactivation of BK, a related human polyomavirus capable of causing morbidity in immunosuppressed groups. Patients with relapsing remitting multiple sclerosis treated with natalizumab were prospectively monitored for reactivation of BK virus in blood and urine samples, and for evidence of associated renal dysfunction. In this cohort, JC and BK DNA in blood and urine; cytomegalovirus (CMV) DNA in blood and urine; CD4 and CD8 T-lymphocyte counts and ratios in peripheral blood; and renal function were monitored at regular intervals. BK subtyping and noncoding control region sequencing was performed on samples demonstrating reactivation. Prior to commencement of natalizumab therapy, 3 of 36 patients with multiple sclerosis (8.3%) had BK viruria and BK reactivation occurred in 12 of 54 patients (22.2%). BK viruria was transient in 7, continuous in 2 patients, and persistent viruria was associated with transient viremia. Concomitant JC and CMV viral loads were undetectable. CD4:CD8 ratios fluctuated, but absolute CD4 counts did not fall below normal limits. In four of seven patients with BK virus reactivation, transient reductions in CD4 counts were observed at onset of BK viruria: these resolved in three of four patients on resuppression of BK replication. No renal dysfunction was observed in the cohort. BK virus reactivation can occur during natalizumab therapy; however, the significance in the absence of renal dysfunction is unclear. We propose regular monitoring for BK reactivation or at least for evidence of renal dysfunction in patients receiving natalizumab.
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Affiliation(s)
- Roisin M Lonergan
- Department of Neurology, St Vincent's University Hospital, Elm Park, Dublin, Ireland.
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Chatzidimitriou D, Gavriilaki E, Sakellari I, Diza E. Hematopoietic cell transplantation and emerging viral infections. J Med Virol 2010; 82:528-38. [PMID: 20087928 PMCID: PMC7166846 DOI: 10.1002/jmv.21696] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2009] [Indexed: 12/11/2022]
Abstract
Viral infections remain important causes of morbidity and mortality in hematopoietic cell transplant recipients. More recent developments in preparative regimens and graft manipulations, as well as the control of well-recognized post-transplant infections by the introduction of prophylaxis and preemptive strategies, have influenced the timing and the epidemiology of infections. As new pathogens, such as human metapneumovirus (HMPV), human bocavirus, human coronaviruses HCoV-NL63 and HCoV-HKU1, human herpesviruses HHV-6 and HHV-7, and polyomaviruses, have emerged, it is fundamental to determine the significance of the newly discovered viruses and their role in the transplantation field. This article summarizes recent data on epidemiology and laboratory diagnosis of new pathogens, as well as clinical features and management of the associated infectious complications. J. Med. Virol. 82:528-538, 2010. (c) 2010 Wiley-Liss, Inc.
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Affiliation(s)
- D Chatzidimitriou
- 2nd Department of Microbiology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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47
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Marr KA. Infections in hematopoietic stem cell transplant recipients. Infect Dis (Lond) 2010. [DOI: 10.1016/b978-0-323-04579-7.00074-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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48
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Erard V, Hirsch HH. BK virus replication and disease in transplant patients. Infect Dis (Lond) 2010. [DOI: 10.1016/b978-0-323-04579-7.00243-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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49
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Gaziev J, Paba P, Miano R, Germani S, Sodani P, Bove P, Perno CF, Marziali M, Gallucci C, Isgrò A, Paciaroni K, Roveda A, Simone MD, De Angelis G, Alfieri C, Lucarelli G. Late-onset hemorrhagic cystitis in children after hematopoietic stem cell transplantation for thalassemia and sickle cell anemia: a prospective evaluation of polyoma (BK) virus infection and treatment with cidofovir. Biol Blood Marrow Transplant 2009; 16:662-71. [PMID: 20026413 DOI: 10.1016/j.bbmt.2009.12.009] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Accepted: 12/12/2009] [Indexed: 01/31/2023]
Abstract
Little is known about late-onset hemorrhagic cystitis (HC) in children, its relationship to BK virus, and treatment with cidofovir (CDV) following hematopoietic stem cell transplantation (HSCT). We prospectively investigated BK virus reactivation in children who underwent HSCT from a matched related donor for thalassemia or sickle cell anemia following busulfan-cyclophosphamide-based conditioning regimens and analyzed risk factors for development of HC and its treatment with CDV. Grade 2-4 HC occurred in 30 patients with a cumulative incidence of 26% (95% confidence interval [CI] = 18%-34%). The cumulative incidences of BK viruria and viremia were 81% (95% CI = 69%-89%) and 28% (95% CI = 18%-40%), respectively. Multivariate analysis revealed that use of antithymocyte globulin (ATG) (hazard ratio [HR] = 10.5; P = .001), peak BK viruria >100,000 copies/mL (HR = 6.2; P = .004), and grade II-IV acute graft-versus-host disease (HR = 5.3; P = .007) were predictive factors for HC. Nineteen patients with HC were given CDV at 1.5 mg/kg/day 3 times a week, or 5 mg/kg/week. The median duration of therapy was 27 days (range, 21-180 days), and a median of 9 doses were given (range, 6-22). All patients had a complete clinical response (CCR), and 69% had a microbiological response at 4 weeks. Eleven patients with BK virus-related HC receiving supportive care also had CCR. The median duration of HC in these patients was similar to that in patients treated with CDV. None of the patients with HC cleared BK viruria when CCR was achieved. We conclude that late-onset HC is more prevalent in children with sustained high BK viruria who are treated with ATG or who develop graft-versus-host disease. Randomized clinical trials are urgently needed to better define the role of CDV in treating BK virus-related HC.
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Affiliation(s)
- Javid Gaziev
- International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.
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50
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Park S, Choi SM, Lee DG, Choi JH, Yoo JH, Kim SH, Kim HJ, Cho SG, Eom KS, Lee JW, Min WS, Shin WS, Kim CC. Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti-thymocyte globulin. Transpl Infect Dis 2009; 11:413-23. [DOI: 10.1111/j.1399-3062.2009.00414.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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