A Low Incidence of Cytomegalo Virus Infection Following Allogeneic Hematopoietic Stem Cell Transplantation Despite a High Seroprevalence

  • Anup J. Devasia
  • Shoba Mammen
  • Anu Korula
  • Aby Abraham
  • N. A. Fouzia
  • Kavitha M. Lakshmi
  • Asha Mary Abraham
  • Alok Srivastava
  • Vikram Mathews
  • Biju George
Original Article
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Abstract

Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality following allogeneic stem cell transplantation (SCT). We wanted to study if the high sero-prevalence seen in our population translated into a high incidence of CMV infection following SCT. This is a retrospective analysis of patients who underwent allogeneic SCT between January 2008 and December 2012 at our centre. 475 patients underwent allogeneic SCT for malignant (46.5%) and non-malignant (53.5%) haematological disorders. 463 (97.4%) SCT recipients and 403 (84.8%) SCT donors were IgG seropositive for CMV. CMV reactivation within 100 days post SCT was seen in 174 (36.6%) at a median of 41 days (range 10–100) post SCT. Ganciclovir was used in 166 patients (95.4%) for a mean duration of 16 days (range 5–32). 157 patients (90%) responded to therapy. Sixty-six patients (42.3%) had secondary reactivation of the virus. Use of a male donor (p = 0.000), donor and recipient age > 15 (p = 0.005 and 0.000), unrelated donor (p = 0.000), degree of HLA mismatch (p = 0.000), occurrence of acute GVHD (p = 0.000) and steroid refractory acute GVHD (p = 0.026) were identified as risk factors for CMV reactivation while early neutrophil recovery (< 15 days) was found to be protective (p = 0.004). On multivariate analysis, male donor (p = 0.042), degree of HLA mismatch (p = 0.006), the occurrence of acute GVHD (p = 0.000) and steroid refractory acute GVHD (p = 0.031) continued to remain significant. 5-year overall survival was significantly better in patients without CMV reactivation compared to those who developed reactivation of CMV (68.9 ± 3.7 vs 58.2 ± 4.9% p = 0.004). The incidence of CMV infection does not seem to be higher despite a high sero-prevalence of CMV. However, patients who developed CMV infection post SCT had inferior outcomes.

Keywords

Cytomegalo virus Stem cell transplantation Seroprevalence 

Notes

Acknowledgements

AJD performed the clinical data accrual, analyzed the data, and wrote the paper. SM and AMA performed the laboratory tests, analyzed the data and wrote the paper. KML performed the statistical analysis and wrote the paper. AK, AA, FNA, AS, and VM analyzed the data and wrote the paper. BG designed the study, analyzed the data, and wrote the paper.

Compliance with Ethical Standards

Conflict of interest

The authors have no conflicts of interest to declare.

Informed Consent

Informed consent was obtained from all human participants involved in this study. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

References

  1. 1.
    Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL (1996) The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84(5):769–779CrossRefPubMedGoogle Scholar
  2. 2.
    Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G et al (2017) Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis Off Publ Infect Dis Soc Am 64(1):87–91CrossRefGoogle Scholar
  3. 3.
    Ljungman P, Hakki M, Boeckh M (2011) Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am 25(1):151–169CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Gerna G, Lilleri D, Caldera D, Furione M, Zenone Bragotti L, Alessandrino EP (2008) Validation of a DNAemia cutoff for preemptive therapy of cytomegalovirus infection in adult hematopoietic stem cell transplant recipients. Bone Marrow Transplant 41(10):873–879CrossRefPubMedGoogle Scholar
  5. 5.
    Lilleri D, Gerna G, Furione M, Bernardo ME, Giorgiani G, Telli S et al (2007) Use of a DNAemia cut-off for monitoring human cytomegalovirus infection reduces the number of preemptively treated children and young adults receiving hematopoietic stem-cell transplantation compared with qualitative pp65 antigenemia. Blood 110(7):2757–2760CrossRefPubMedGoogle Scholar
  6. 6.
    Ozdemir E, Saliba RM, Champlin RE, Couriel DR, Giralt SA, de Lima M et al (2007) Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies. Bone Marrow Transplant 40(2):125–136CrossRefPubMedGoogle Scholar
  7. 7.
    Pietersma FL, van Dorp S, Minnema MC, Kuball J, Meijer E, Schuurman R et al (2011) Influence of donor cytomegalovirus (CMV) status on severity of viral reactivation after allogeneic stem cell transplantation in CMV-seropositive recipients. Clin Infect Dis Off Publ Infect Dis Soc Am. 52(7):e144–e148CrossRefGoogle Scholar
  8. 8.
    Miller W, Flynn P, McCullough J, Balfour HH, Goldman A, Haake R et al (1986) Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease. Blood 67(4):1162–1167PubMedGoogle Scholar
  9. 9.
    Kothari A, Ramachandran VG, Gupta P, Singh B, Talwar V (2002) Seroprevalence of cytomegalovirus among voluntary blood donors in Delhi, India. J Health Popul Nutr 20(4):348–351PubMedGoogle Scholar
  10. 10.
    Das B, Kaur G, Basu S (2014) Seroprevalence of cytomegalovirus antibodies among blood donors and multitransfused recipients—a study from north India. Transfus Apheresis Sci Off J World Apheresis Assoc Off J Eur Soc Haemapheresis 50(3):438–442Google Scholar
  11. 11.
    Cannon MJ, Schmid DS, Hyde TB (2010) Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 20(4):202–213CrossRefPubMedGoogle Scholar
  12. 12.
    Sachithanandham J, Kannangai R, Pulimood SA, Desai A, Abraham AM, Abraham OC et al (2014) Significance of epstein-barr virus (HHV-4) and CMV (HHV-5) infection among subtype-C human immunodeficiency virus-infected individuals. Indian J Med Microbiol 32(3):261CrossRefPubMedGoogle Scholar
  13. 13.
    Kim DH, Kim JG, Lee NY, Sung WJ, Sohn SK, Suh JS et al (2004) Risk factors for late cytomegalovirus infection after allogeneic stem cell transplantation using HLA-matched sibling donor: donor lymphocyte infusion and previous history of early CMV infection. Bone Marrow Transplant 34(1):21–27CrossRefPubMedGoogle Scholar
  14. 14.
    Ljungman P, Perez-Bercoff L, Jonsson J, Avetisyan G, Sparrelid E, Aschan J et al (2006) Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. Haematologica 91(1):78–83PubMedGoogle Scholar
  15. 15.
    Sharma SK, Kumar S, Agrawal N, Singh L, Mukherjee A, Seth T et al (2013) Cytomegalovirus reactivation following hematopoietic stem cell transplantation. J Infect Dev Ctries 7(12). [cited 2018 Apr 5]. http://www.jidc.org/index.php/journal/article/view/2947
  16. 16.
    Boeckh M, Nichols WG (2004) The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103(6):2003–2008CrossRefPubMedGoogle Scholar
  17. 17.
    Zhou W, Longmate J, Lacey SF, Palmer JM, Gallez-Hawkins G, Thao L et al (2009) Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood 113(25):6465–6476CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C (2003) Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood 102(13):4255–4260CrossRefPubMedGoogle Scholar
  19. 19.
    Beck JC, Wagner JE, DeFor TE, Brunstein CG, Schleiss MR, Young J-A et al (2010) Impact of cytomegalovirus (CMV) reactivation after umbilical cord blood transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 16(2):215–222CrossRefGoogle Scholar
  20. 20.
    George B, Pati N, Gilroy N, Ratnamohan M, Huang G, Kerridge I et al (2010) Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis Off J Transplant Soc 12(4):322–329CrossRefGoogle Scholar
  21. 21.
    Cummins NW, Deziel PJ, Abraham RS, Razonable RR (2009) Deficiency of cytomegalovirus (CMV)-specific CD8 + T cells in patients presenting with late-onset CMV disease several years after transplantation. Transpl Infect Dis Off J Transplant Soc 11(1):20–27CrossRefGoogle Scholar
  22. 22.
    Ariza-Heredia EJ, Nesher L, Chemaly RF (2014) Cytomegalovirus diseases after hematopoietic stem cell transplantation: a mini-review. Cancer Lett 342(1):1–8CrossRefPubMedGoogle Scholar
  23. 23.
    Vij R, Khoury H, Brown R, Goodnough LT, Devine SM, Blum W et al (2003) Low-dose short-course intravenous ganciclovir as pre-emptive therapy for CMV viremia post allo-PBSC transplantation. Bone Marrow Transplant 32(7):703–707CrossRefPubMedGoogle Scholar
  24. 24.
    Salzberger B, Bowden RA, Hackman RC, Davis C, Boeckh M (1997) Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood 90(6):2502–2508PubMedGoogle Scholar
  25. 25.
    Winston DJ, Young J-AH, Pullarkat V, Papanicolaou GA, Vij R, Vance E et al (2008) Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood 111(11):5403–5410CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Clancy LE, Blyth E, Simms RM, Micklethwaite KP, Ma C-KK, Burgess JS et al (2013) Cytomegalovirus-specific cytotoxic T lymphocytes can be efficiently expanded from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell products ex vivo and safely transferred to stem cell transplantation recipients to facilitate immune reconstitution. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 19(5):725–734CrossRefGoogle Scholar
  27. 27.
    Einsele H, Kapp M, Grigoleit GU (2008) CMV-specific T cell therapy. Blood Cells Mol Dis 40(1):71–75CrossRefPubMedGoogle Scholar

Copyright information

© Indian Society of Hematology and Blood Transfusion 2018

Authors and Affiliations

  • Anup J. Devasia
    • 1
  • Shoba Mammen
    • 2
  • Anu Korula
    • 1
  • Aby Abraham
    • 1
  • N. A. Fouzia
    • 1
  • Kavitha M. Lakshmi
    • 1
  • Asha Mary Abraham
    • 2
  • Alok Srivastava
    • 1
  • Vikram Mathews
    • 1
  • Biju George
    • 1
  1. 1.Department of Clinical HematologyChristian Medical CollegeVelloreIndia
  2. 2.Department of Clinical VirologyChristian Medical CollegeVelloreIndia

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