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Infectious Complications

High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 49, pages 664–670 (2014)Cite this article

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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 €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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References

  1. Cesaro S, Facchin C, Tridello G, Messina C, Calore E, Biasolo MA et al. A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 363–370.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Chesters PM, Heritage J, McCance DJ . Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis 1983; 147: 676–684.

    Article  CAS  PubMed  Google Scholar 

  4. Dolei A, Pietropaolo V, Gomes E, Taranto CDi, Ziccheddu M, Spanu MA 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  PubMed  Google Scholar 

  5. Knowles WA, Pipkin P, Andrews N, Vyse A, Minor P, Brown DWG et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 2003; 71: 115–123.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Randhawa PS, Demetris AJ . Nephropathy due to polyomavirus type BK. N Engl J Med 2000; 342: 1361–1363.

    Article  CAS  PubMed  Google Scholar 

  8. Arthur RR, Shah KV, Baust SJ, Santos GW, Saral R . Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med 1986; 315: 230–234.

    Article  CAS  PubMed  Google Scholar 

  9. Leung AYH, Chan M, Cheng VCC, Lie AKW, Yuen K-Y, Kwong Y-L . Polyoma BK viruria in patients undergoing autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2005; 35: 1029–1030.

    Article  CAS  PubMed  Google Scholar 

  10. Silva L, de P, Patah PA, Saliba RM, Szewczyk NA, Gilman L et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. Haematologica 2010; 95: 1183–1190.

    Article  Google Scholar 

  11. Giraud G, Bogdanovic G, Priftakis P, Remberger M, Svahn B-M, Barkholt L et al. The incidence of hemorrhagic cystitis and BK-viruria in allogeneic hematopoietic stem cell recipients according to intensity of the conditioning regimen. Haematologica 2006; 91: 401–404.

    PubMed  Google Scholar 

  12. Bogdanovic G, Priftakis P, Giraud G, Dalianis T . A related donor and reduced intensity conditioning reduces the risk of development of BK virus-positive haemorrhagic cystitis in allogeneic haematopoetic stem cell-transplanted patients. Anticancer Res 2006; 26: 1311–1318.

    CAS  PubMed  Google Scholar 

  13. Megged O, Stein J, Ben-Meir D, Shulman LM, Yaniv I, Shalit I et al. BK-virus-associated hemorrhagic cystitis in children after hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 2011; 33: 190–193.

    Article  PubMed  Google Scholar 

  14. Wong ASY, Chan K-H, Cheng VCC, Yuen K-Y, Kwong Y-L, Leung AYH . Relationship of pretransplantation polyoma BK virus serologic findings and BK viral reactivation after hematopoietic stem cell transplantation. Clin Infect Dis 2007; 44: 830–837.

    Article  PubMed  Google Scholar 

  15. Giraud G, Priftakis P, Bogdanovic G, Remberger M, Dubrulle M, Hau A et al. BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts. Bone Marrow Transplant 2008; 41: 737–742.

    Article  CAS  PubMed  Google Scholar 

  16. Xie Y, Han Y, Wu D-P . The role of BK polyomavirus in the development of hemorrhagic cystitis after hematopoietic stem cell transplantation. Zhonghua Nei Ke Za Zhi 2008; 47: 746–749.

    CAS  PubMed  Google Scholar 

  17. Bedi A, Miller CB, Hanson JL, Goodman S, Ambinder RF, Charache P 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  PubMed  Google Scholar 

  18. Bogdanovic G, Priftakis P, Giraud G, Kuzniar M, Ferraldeschi R, Kokhaei P et al. Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation. J Clin Microbiol 2004; 42: 5394–5396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Leung AY, Suen CK, Lie AK, Liang RH, Yuen KY, Kwong YL . Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. Blood 2001; 98: 1971–1978.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  21. Harkensee C, Vasdev N, Gennery AR, Willetts IE, Taylor C . Prevention and management of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation—a systematic review and evidence-based guidance for clinical management. Br J Haematol 2008; 142: 717–731.

    Article  PubMed  Google Scholar 

  22. El-Zimaity M, Saliba R, Chan K, Shahjahan M, Carrasco A, Khorshid O et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. Blood 2004; 103: 4674–4680.

    Article  CAS  PubMed  Google Scholar 

  23. Dalianis T, Ljungman P . Full myeloablative conditioning and an unrelated HLA mismatched donor increase the risk for BK virus-positive hemorrhagic cystitis in allogeneic hematopoetic stem cell transplanted patients. Anticancer Res 2011; 31: 939–944.

    PubMed  Google Scholar 

  24. Erard V, Kim HW, Corey L, Limaye A, Huang M-L, Myerson D et al. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood 2005; 106: 1130–1132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Leung AYH, Mak R, Lie AKW, Yuen KY, Cheng VCC, Liang R et al. Clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation. Bone Marrow Transplant 2002; 29: 509–513.

    Article  CAS  PubMed  Google Scholar 

  26. Seber A, Shu XO, Defor T, Sencer S, Ramsay N . Risk factors for severe hemorrhagic cystitis following BMT. Bone Marrow Transplant 1999; 23: 35–40.

    Article  CAS  PubMed  Google Scholar 

  27. Mori Y, Miyamoto T, Kato K, Kamezaki K, Kuriyama T, Oku S et al. Different risk factors related to adenovirus- or BK virus-associated hemorrhagic cystitis following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2012; 18: 458–465.

    Article  PubMed  Google Scholar 

  28. Azzi A, Fanci R, Bosi A, Ciappi S, Zakrzewska K, de Santis R et al. Monitoring of polyomavirus BK viruria in bone marrow transplantation patients by DNA hybridization assay and by polymerase chain reaction: an approach to assess the relationship between BK viruria and hemorrhagic cystitis. Bone Marrow Transplant 1994; 14: 235–240.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Leung AYH, Chan MTL, Yuen K-Y, Cheng VCC, Chan K-H, Wong CLP et al. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2005; 40: 528–537.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  32. Leung AYH, Yuen K-Y, Kwong Y-L . Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant 2005; 36: 929–937.

    Article  CAS  PubMed  Google Scholar 

  33. Erard V, Storer B, Corey L, Nollkamper J, Huang M-L, Limaye A et al. BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors, and association with postengraftment hemorrhagic cystitis. Clin Infect Dis 2004; 39: 1861–1865.

    Article  PubMed  Google Scholar 

  34. Haines HL, Laskin BL, Goebel J, Davies SM, Yin HJ, Lawrence J et al. Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: 1512–1519.

    Article  PubMed  Google Scholar 

  35. Ost L, Lönnqvist B, Eriksson L, Ljungman P, Ringdén O . Hemorrhagic cystitis—a manifestation of graft versus host disease? Bone Marrow Transplant 1987; 2: 19–25.

    CAS  PubMed  Google Scholar 

  36. Cesaro S, Brugiolo A, Faraci M, Uderzo C, Rondelli R, Favre C et al. Incidence and treatment of hemorrhagic cystitis in children given hematopoietic stem cell transplantation: a survey from the Italian association of pediatric hematology oncology-bone marrow transplantation group. Bone Marrow Transplant 2003; 32: 925–931.

    Article  CAS  PubMed  Google Scholar 

  37. Faraci M, Cuzzubbo D, Lanino E, Marco EDi, Cirillo C, Dallorso S et al. Low dosage cidofovir without probenecid as treatment for BK virus hamorrhagic cystitis after hemopoietic stem cell transplant. Pediatr Infect Dis J 2009; 28: 55–57.

    Article  PubMed  Google Scholar 

  38. Ganguly N, Clough LA, Dubois LK, Mcguirk JP, Abhyankar S, Aljitawi OS et al. 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 2010; 12: 406–411.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank the RCP HEMINF physician group for challenging collaborative work.

Author information

Author notes

  1. L Gilis, S Morisset, G Billaud, S Ducastelle-Leprêtre, H Labussière-Wallet, F-E Nicolini, F Barraco, M Detrait, X Thomas, N Tedone, M Sobh, C Chidiac, T Ferry, G Salles, M Michallet and F Ader: See Appendix.

Authors and Affiliations

  1. Hematology Department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France

    L Gilis, S Morisset, S Ducastelle-Leprêtre, H Labussière-Wallet, F-E Nicolini, F Barraco, M Detrait, X Thomas, N Tedone, M Sobh, G Salles & M Michallet

  2. Virology Laboratory, Laboratoire de Virologie Est, Hospices Civils de Lyon, Bron, France

    G Billaud

  3. Infectious Diseases Department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France

    C Chidiac, T Ferry & F Ader

  4. Inserm U1111 CIRI, Claude Bernard Lyon I University, Lyon, France

    T Ferry & F Ader

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  1. L Gilis
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on behalf of the Lyon BK virus Study group

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Correspondence to F Ader.

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Author contributions

LG and FA designed the study and wrote the manuscript. LG, FA, GB and NT collected the data. SM and MS analyzed the data. HLW, SDL, FB, MD, FEN, XT and MM recruited the patients. CC, TF, GS and MM reviewed the manuscript.

Appendix

Appendix

Lyon BK virus Study group: F Ader, P André, F. Barraco, G Billaud, F Biron, A Boibieux, A Bouaziz, V Bozzoli, C Chidiac, L Cotte, M Detrait, S Ducastelle-Lepretre, V Escuret, T Ferry, E Frobert, L Gilis, V Icard, H Labussière-Wallet, L Lebras, B Lina, P Miailhes, M Michallet, F Morfin-Sherpa, FE Nicolini, T Perpoint, D Peyramond, G Salles, A Sénéchal, M Sobh, N Tedone, X Thomas, E Wattel.

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Gilis, L., Morisset, S., Billaud, G. et al. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 49, 664–670 (2014). https://doi.org/10.1038/bmt.2013.235

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