Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm

Bone Marrow Transplantation volume 36, pages 929–937 (2005)Cite this article

Summary:

Haemorrhagic cystitis (HC) is a distinct clinical disorder of multiple aetiologies. It is characterized by painful haematuria due to haemorrhagic inflammation of the urinary bladder mucosa. In allogeneic haematopoietic stem cell transplantation (HSCT), HC occurring before engraftment is mostly transient and self-limiting, whereas that after engraftment is severe and sometimes life-threatening. Pre- and post-engraftment HC represent distinct disorders with different aetiologies and treatment implications. Recent data suggest that reactivation of the polyoma BK virus (BKV) plays a pivotal role in post-engraftment HC. Urotoxicity of the conditioning regimen and alloimmune reaction accompanying graft-versus-host disease (GVHD) upon engraftment are also important pathogenetic factors. Based on data from BKV studies, we propose that HC may be divided into three phases. In the first phase, the conditioning regimen damages uroepithelial cells, providing a milieu for BKV replication. In the second phase, unchecked uroepithelial BKV replication leads to BK viruria. In the last phase after engraftment, alloimmunity against BKV-infected uroepithelial cells leads to HC. The quinolone antibiotics suppress BKV replication in vivo and in vitro, suggesting that their prophylactic use may prevent the occurrence of HC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. DeVries CR, Freiha FS . Haemorrhagic cystitis: a review. J Urol 1990; 143: 1–9.

    Article  CAS  Google Scholar 

  2. Bedi A, Miller CB, Hanson JL et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13: 1103–1109.

    Article  CAS  Google Scholar 

  3. McCarville MB, Hoffer FA, Gingrich JR, Jenkins II JJ . Imaging findings of haemorrhagic cystitis in pediatric oncology patients. Pediatr Radiol 2000; 30: 131–138.

    Article  CAS  Google Scholar 

  4. Leung AY, Mak R, Lie AK et al. Clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation. Bone Marrow Transplantation 2002; 29: 509–513.

    Article  CAS  Google Scholar 

  5. Shepherd JD, Pringle LE, Barnett MJ et al. Mesna versus hyperhydration for the prevention of cyclophosphamide-induced haemorrhagic cystitis in bone marrow transplantation. J Clin Oncol 1991; 9: 2016–2020.

    Article  CAS  Google Scholar 

  6. Tsuboi K, Kishi K, Ohmachi K et al. Multivariate analysis of risk factors for haemorrhagic cystitis after hematopoietic stem cell transplantation. Bone Marrow Transplantation 2003; 32: 903–907.

    Article  CAS  Google Scholar 

  7. Sell A, Bertelsen K, Andersen JE et al. Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer. Gynecol Oncol 1990; 37: 367–373.

    Article  CAS  Google Scholar 

  8. Seber A, Shu XO, Defor T et al. Risk factors for severe haemorrhagic cystitis following BMT. Bone Marrow Transplantation 1999; 23: 35–40.

    Article  CAS  Google Scholar 

  9. Yamamoto R, Kusumi E, Kami M et al. Late haemorrhagic cystitis after reduced-intensity hematopoietic stem cell transplantation (RIST). Bone Marrow Transplantation 2003; 32: 1089–1095.

    Article  CAS  Google Scholar 

  10. Cesaro S, Brugiolo A, Faraci M et al. Incidence and treatment of haemorrhagic cystitis in children given hematopoietic stem cell transplantation: a survey from the Italian association of pediatric hematology oncology – bone marrow transplantation group. Bone Marrow Transplantation 2003; 32: 925–931.

    Article  CAS  Google Scholar 

  11. El-Zimaity M, Saliba R, Chan K et al. Haemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. Blood 2004; 103: 4674–4680.

    Article  CAS  Google Scholar 

  12. Gardner SD, Field AM, Coleman DV, Hulme B . New human papovavirus (BK) isolated from urine after renal transplantation. Lancet 1971; 1: 1253–1257.

    Article  CAS  Google Scholar 

  13. Hirsch HH, Steiger J . Polyomavirus BK. Lancet Infect Dis 2003; 3: 611–623.

    Article  Google Scholar 

  14. Reploeg MD, Storch GA, Clifford DB . BK virus: a clinical review. Clin Infect Dis 2001; 33: 191–202.

    Article  CAS  Google Scholar 

  15. Binet I, Nickeleit V, Hirsch HH . Polyomavirus infections in transplant recipients. Curr Opin Organ Transplant 2000; 5: 210–216.

    Article  Google Scholar 

  16. Tognon M, Corallini A, Martini F et al. Oncogenic transformation by BK virus and association with human tumors. Oncogene 2003; 22: 5192–5200.

    Article  CAS  Google Scholar 

  17. Cubukcu-Dimopulo O, Greco A, Kumar A et al. BK virus infection in AIDS. Am J Surg Pathol 2000; 24: 145–149.

    Article  CAS  Google Scholar 

  18. Nickeleit V, Klimkait T, Binet IF et al. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 2000; 342: 1309–1315.

    Article  CAS  Google Scholar 

  19. Kwak EJ, Vilchez RA, Randhawa P et al. Pathogenesis and management of polyomavirus infection in transplant recipients. Clin Infect Dis 2002; 35: 1081–1087.

    Article  Google Scholar 

  20. Tavis JE, Walker DL, Gardner SD, Frisque RJ . Nucleotide sequence of the human polyomavirus AS virus, an antigenic variant of BK virus. J Virol 1989; 63: 901–911.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chatterjee M, Weyandt TB, Frisque RJ . Identification of archetype and rearranged forms of BK virus in leukocytes from healthy individuals. J Med Virol 2000; 60: 353–362.

    Article  CAS  Google Scholar 

  22. Priftakis P, Bogdanovic G, Kalantari M, Dalianis T . Overrepresentation of point mutations in the Sp1 site of the non-coding control region of BK virus in bone marrow transplanted patients with haemorrhagic cystitis. J Clin Virol 2001; 21: 1–7.

    Article  CAS  Google Scholar 

  23. Leung AY, Chan MT, Kwong YL . Genotyping of the non-coding control region of BK virus in patients with haemorrhagic cystitis after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplantation 2005; 35: 531–532.

    Article  CAS  Google Scholar 

  24. Negrini M, Sabbioni S, Arthur RR et al. Prevalence of the archetypal regulatory region and sequence polymorphisms in nonpassaged BK virus variants. J Virol 1991; 65: 5092–5095.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Dolei A, Pietropaolo V, Gomes E et al. Polyomavirus persistence in lymphocytes: prevalence in lymphocytes from blood donors and healthy personnel of a blood transfusion centre. J Gen Virol 2000; 81: 1967–1973.

    Article  CAS  Google Scholar 

  26. Azzi A, Cesaro S, Laszlo D et al. Human polyomavirus BK (BKV) load and haemorrhagic cystitis in bone marrow transplantation patients. J Clin Virol 1999; 14: 79–86.

    Article  CAS  Google Scholar 

  27. Leung AY, Suen CK, Lie AK et al. Quantification of polyoma BK viruria in haemorrhagic cystitis complicating bone marrow transplantation. Blood 2001; 98: 1971–1978.

    Article  CAS  Google Scholar 

  28. Erard V, Kim HW, Corey L et al. BK DNA viral load in plasma: evidence for an association with haemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood 2005 April 21 [epub ahead of print].

  29. Leung AY, Chan MT, Yuen KY et al. Ciprofloxacin decreased polyoma BK viruria in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2005; 40: 528–537.

    Article  CAS  Google Scholar 

  30. Erard V, Storer B, Corey L et al. BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors and association with postengraftment haemorrhagic cystitis. Clin Infect Dis 2004; 39: 1861–1865.

    Article  Google Scholar 

  31. Ferrazzi E, Peracchi M, Biasolo MA et al. Antiviral activity of gyrase inhibitors norfloxacin, coumermycin A1 and nalidixic acid. Biochem Pharm 1988; 37: 1885–1886.

    Article  CAS  Google Scholar 

  32. Portolani M, Pietrosemoli P, Cermelli C et al. Suppression of BK virus replication and cytopathic effect by inhibitors of prokaryotic DNA gyrase. Antiviral Res 1988; 9: 205–218.

    Article  CAS  Google Scholar 

  33. Ost L, Lonnqvist B, Eriksson L et al. Haemorrhagic cystitis – a manifestation of graft versus host disease? Bone Marrow Transplantation 1987; 2: 19–25.

    CAS  PubMed  Google Scholar 

  34. Gluck TA, Knowles WA, Johnson MA et al. BK virus-associated haemorrhagic cystitis in an HIV-infected man. AIDS 1994; 8: 391–392.

    Article  CAS  Google Scholar 

  35. Barouch DH, Faquin WC, Chen Y et al. BK virus-associated haemorrhagic cystitis in a human immunodeficiency virus-infected patient. Clin Infect Dis 2002; 35: 326–329.

    Article  Google Scholar 

  36. Leung AY, Chan M, Chen VC et al. Polyoma BK viruria in patients undergoing autologous hematopoietic stem cell transplantation. Bone Marrow Transplantation 2005; 35: 1029–1030.

    Article  CAS  Google Scholar 

  37. Drummond JE, Shah KV, Saral R et al. BK virus specific humoral and cell mediated immunity in allogeneic bone marrow transplant (BMT) recipients. J Med Virol 1987; 23: 331–344.

    Article  CAS  Google Scholar 

  38. Drummond JE, Shah KV, Donnenberg AD . Cell-mediated immune responses to BK virus in normal individuals. J Med Virol 1985; 17: 237–247.

    Article  CAS  Google Scholar 

  39. Cheng VC, Yuen KY, Chan WM et al. Immunorestitution disease involving the innate and adaptive response. Clin Infect Dis 2000; 30: 882–892.

    Article  CAS  Google Scholar 

  40. Akiyama H, Kurosu T, Sakashita C et al. Adenovirus is a key pathogen in haemorrhagic cystitis associated with bone marrow transplantation. Clin Infect Dis 2001; 32: 1325–1330.

    Article  CAS  Google Scholar 

  41. Miyamura K, Takeyama K, Kojima S et al. Haemorrhagic cystitis associated with urinary excretion of adenovirus type 11 following allogeneic bone marrow transplantation. Bone Marrow Transplantation 1989; 4: 533–535.

    CAS  PubMed  Google Scholar 

  42. Tutuncuoglu SO, Yanovich S, Ozdemirli M . CMV-induced haemorrhagic cystitis as a complication of peripheral blood stem cell transplantation: case report. Bone Marrow Transplantation 2005 June 6.

  43. Spach DH, Bauwens JE, Myerson D et al. Cytomegalovirus-induced haemorrhagic cystitis following bone marrow transplantation. Clin Infect Dis 1993; 16: 142–144.

    Article  CAS  Google Scholar 

  44. Kristoffersen AK, Johnsen JI, Seternes OM et al. The human Polyomavirus BK T antigen induces gene expression in human cytomegalovirus. Virus Res 1997; 52: 61–71.

    Article  CAS  Google Scholar 

  45. Ordemann R, Naumann R, Geissler G et al. Encouraging results in the treatment of haemorrhagic cystitis with estrogen-report of 10 cases and review of the literature. Bone Marrow Transplantation 2000; 25: 981–985.

    Article  CAS  Google Scholar 

  46. Choong SK, Walkden M, Kirby R . The management of intractable haematuria. Br J Urol 2000; 86: 951–959.

    Article  CAS  Google Scholar 

  47. Gine E, Rovira M, Real I et al. Successful treatment of severe haemorrhagic cystitis after hemopoietic cell transplantation by selective embolization of the vesical arteries. Bone Marrow Transplantation 2003; 31: 923–925.

    Article  CAS  Google Scholar 

  48. Palandri F, Bonifazi F, Rossi C et al. Successful treatment of severe haemorrhagic cystitis with selective vesical artery embolization. Bone Marrow Transplantation 2005; 35: 529–530.

    Article  CAS  Google Scholar 

  49. Sebe P, Garderet L, Traxer O et al. Subtotal cystectomy with ileocystoplasty for severe haemorrhagic cystitis after bone marrow transplantation. Urology 2001; 57: 168.

    Article  CAS  Google Scholar 

  50. Garderet L, Bittencourt H, Sebe P et al. Cystectomy for severe hemorrhagic cystitis in allogeneic stem cell transplant recipients. Transplantation 2000; 70: 1807–1811.

    Article  CAS  Google Scholar 

  51. Capelli-Schellpfeffer M, Gerber GS . The use of hyperbaric oxygen in urology. J Urol 1999; 162 (Part 1): 647–654.

    Article  CAS  Google Scholar 

  52. Nagafuji K, Aoki K, Henzan H et al. Cidofovir for treating adenoviral haemorrhagic cystitis in hematopoietic stem cell transplant recipients. Bone Marrow Transplantation 2004; 34: 909–914.

    Article  CAS  Google Scholar 

  53. Held TK, Biel SS, Nitsche A et al. Treatment of BK virus-associated haemorrhagic cystitis and simultaneous CMV reactivation with cidofovir. Bone Marrow Transplantation 2000; 26: 347–350.

    Article  CAS  Google Scholar 

  54. Studemeister A . Cytomegalovirus-induced haemorrhagic cystitis in AIDS patient treated successfully with valganciclovir. AIDS 2002; 16: 1437–1438.

    Article  Google Scholar 

  55. Blatt J, Gold SH, Wiley JM et al. Off-label use of recombinant factor VIIa in patients following bone marrow transplantation. Bone Marrow Transplantation 2001; 28: 405–407.

    Article  CAS  Google Scholar 

  56. Karimi M, Zakerinia M, Khojasteh HN et al. Successful treatment of cyclophosphamide induced intractable haemorrhagic cystitis with recombinant FVIIa (NovoSeven) after allogeneic bone marrow transplantation. J Thromb Haemost 2004; 2: 1853–1855.

    Article  CAS  Google Scholar 

  57. Demesmay K, Tissot E, Bulabois CE et al. Factor XIII replacement in stem-cell transplant recipients with severe haemorrhagic cystitis: a report of four cases. Transplantation 2002; 74: 1190–1192.

    Article  CAS  Google Scholar 

  58. Fanourgiakis P, Georgala A, Vekemans M et al. Intravesical instillation of cidofovir in the treatment of haemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient. Clin Infect Dis 2005; 40: 199–201.

    Article  Google Scholar 

  59. Ouwenga MK, Langston MD, Campbell SC . Use of fibrin sealant in recalcitrant haemorrhagic cystitis. J Urol 2004; 172: 1348.

    Article  Google Scholar 

  60. Tunuguntla HS, Bhandari M, Srivastava A et al. Endoscopic injection sclerotherapy control of intractable Haematuria following radiation-induced haemorrhagic cystitis. A novel approach. Arch Esp Urol 2000; 53: 396–402.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the Kadoorie Charitable Foundation.

Author information

Authors and Affiliations

  1. Department of Medicine, Faculty of Medicine, University of Hong Kong, Hong Kong

    A Y H Leung & Y-L Kwong

  2. Department of Microbiology, Faculty of Medicine, University of Hong Kong, Hong Kong

    K-Y Yuen

Authors
  1. A Y H Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K-Y Yuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y-L Kwong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y-L Kwong.

Additional information

Permission to publish: Permission to reproduce Figures 1 and 2 has been obtained from Blood, Journal of the American Society of Hematology. Permission to reproduce Figure 3 has been obtained from Clinical Infectious Diseases, University of Chicago Press and the Infectious Diseases Society of America.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leung, A., Yuen, KY. & Kwong, YL. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant 36, 929–937 (2005). https://doi.org/10.1038/sj.bmt.1705139

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705139

Keywords

This article is cited by

Search

Advanced search

Quick links