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Pre-engraftment cytomegalovirus DNAemia in allogeneic hematopoietic stem cell transplant recipients: incidence, risk factors, and clinical outcomes

Bone Marrow Transplantation volume 54, pages 90–98 (2019)Cite this article

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Abstract

To gauge the risk of delaying initiation of prophylaxis with letermovir from the time of donor infusion to prevent CMV infection in allo-HSCT recipients we investigated the clinical outcomes of CMV DNAemia episodes occurring before engraftment, and compared to that of episodes developing after engraftment (up to day +365). A total of 197 consecutive adult patients were included. Plasma CMV DNA load was monitored by real-time PCR assays [limit of detection: 31 IU/ml]. A total of 150 out of 197 patients had CMV DNAemia (cumulative incidence of 77%; 95% CI, 73–81%), and 38 out of the 197 patients developed it before engraftment (cumulative incidence, 19%; 95% CI, 10–30.3%). Nine episodes of CMV DNAemia were detected prior to the time of donor progenitor cell infusion. A greater number of post-engraftment episodes required preemptive antiviral therapy compared with pre-engraftment episodes (62.5% vs 44.7%; P = 0.05). The cellular content of the donor progenitor cell infusion and transplant characteristics of patients did not differ between patients with pre-engraftment or post-engraftment CMV DNAemia. The cumulative incidence of overall mortality by days 100 and 365, aGvHD by day 100 and relapse by day 365 were not significantly different between patients with pre-engraftment or post-engraftment CMV DNAemia.

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References

  1. Pérez Romero P, Blanco P, Giménez E, Solano C, Navarro D. An update on the management and prevention of cytomegalovirus infection following allogeneic hematopoietic stem cell transplantation. Future Virol. 2015;10:113–34.

    Article  Google Scholar 

  2. Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016;3:e119–27.

    Article  Google Scholar 

  3. Solano C, Giménez E, Piñana JL, Albert E, Vinuesa V, Hernández-Boluda JC, et al. Impact of cytomegalovirus DNAemia on overall and non-relapse mortality in allogeneic stem cell transplant recipients. Transpl Infect Dis. 2017;19:e12717.

    Article  Google Scholar 

  4. Limaye AP, Bowden RA, Myerson D, Boeckh M. Cytomegalovirus disease occurring before engraftment in marrow transplant recipients. Clin Infect Dis. 1997;24:830–5.

    Article  CAS  Google Scholar 

  5. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017;377:2433–44.

    Article  Google Scholar 

  6. Clari MÁ, Bravo D, Costa E, Muñoz-Cobo B, Solano C, Remigia MJ, et al. Comparison of the new Abbott Real Time CMV assay and the Abbott CMV PCR Kit for the quantitation of plasma cytomegalovirus DNAemia. Diagn Microbiol Infect Dis. 2013;75:207–9.

    Article  CAS  Google Scholar 

  7. Solano C, Muñoz-Cobo B, Giménez E, Remigia MJ, Amat P, Clari MA, et al. Pre-emptive antiviral therapy for active CMV infection in adult allo-SCT patients guided by plasma CMV DNAemia quantitation using a real-time PCR assay: clinical experience at a single center. Bone Marrow Transplant. 2013;48:1010–2.

    Article  CAS  Google Scholar 

  8. Solano C, Giménez E, Piñana JL, Vinuesa V, Poujois S, Zaragoza S, et al. Preemptive antiviral therapy for CMV infection in allogeneic stem cell transplant recipients guided by the viral doubling time in the blood. Bone Marrow Transplant. 2016;51:718–21.

    Article  CAS  Google Scholar 

  9. Solano C, Benet I, Clari MA, Nieto J, de la Cámara R, López J, et al. Enumeration of cytomegalovirus-specific interferon gamma CD8+ and CD4+T cells early after allogeneic stem cell transplantation may identify patients at risk of active cytomegalovirus infection. Haematologica. 2008;93:1434–6.

    Article  CAS  Google Scholar 

  10. Tormo N, Solano C, Benet I, Clari MA, Nieto J, de la Cámara R, et al. Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNgamma CD8+ and CD4+T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2010;45:543–9.

    Article  CAS  Google Scholar 

  11. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017;64:87–9.

    Article  Google Scholar 

  12. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  Google Scholar 

  13. Cohen L, Yeshurun M, Shpilberg O, Ram R. Risk factors and prognostic scale for cytomegalovirus (CMV) infection in CMV-seropositive patients after allogeneic hematopoietic cell transplantation. Transpl Infect Dis. 2015;17:510–7.

    Article  CAS  Google Scholar 

  14. Mutter W, Reddehase MJ, Busch FW, Bühring HJ, Koszinowski UH. Failure in generating hemopoietic stem cells is the primary cause of death from cytomegalovirus disease in the immunocompromised host. J Exp Med. 1988;167:1645–58.

    Article  CAS  Google Scholar 

  15. Apperley JF, Dowding C, Hibbin J, Buiter J, Matutes E, Sissons PJ, et al. The effect of cytomegalovirus on hemopoiesis: in vitro evidence for selective infection of marrow stromal cells. Exp Hematol. 1989;17:38–45.

    CAS  PubMed  Google Scholar 

  16. Simmons P, Kaushansky K, Torok-Storb B. Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells. Proc Natl Acad Sci USA. 1990;87:1386–90.

    Article  CAS  Google Scholar 

  17. Sing GK, Ruscetti FW. Preferential suppression of myelopoiesis in normal human bone marrow cells after in vitro challenge with human cytomegalovirus. Blood. 1990;75:1965–73.

    CAS  PubMed  Google Scholar 

  18. Maciejewski JP, Bruening EE, Donahue RE, Mocarski ES, Young NS, St Jeor SC. Infection of hematopoietic progenitor cells by human cytomegalovirus. Blood. 1992;80:170–8.

    CAS  PubMed  Google Scholar 

  19. Kondo K, Kaneshima H, Mocarski ES. Human cytomegalovirus latent infection of granulocyte-macrophage progenitors. Proc Natl Acad Sci USA. 1994;91:11879–83.

    Article  CAS  Google Scholar 

  20. Reddehase MJ. Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation. Front Immunol. 2016;7:294.

    Article  Google Scholar 

  21. Sing GK, Ruscetti FW. The role of human cytomegalovirus in haematological diseases. Baillieres Clin Haematol. 1995;8:149–63.

    Article  CAS  Google Scholar 

  22. Apperley JF, Goldman JM. Cytomegalovirus: biology, clinical features and methods for diagnosis. Bone Marrow Transplant. 1988;3:253–64.

    CAS  PubMed  Google Scholar 

  23. Wingard JR, Chen DY, Burns WH, Fuller DJ, Braine HG, Yeager AM, et al. Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation. Blood. 1988;71:1432–7.

    CAS  PubMed  Google Scholar 

  24. Verdonck LF, de Gast GC, van Heugten HG, Nieuwenhuis HK, Dekker AW. Cytomegalovirus infection causes delayed platelet recovery after bone marrow transplantation. Blood. 1991;78:844–8.

    CAS  PubMed  Google Scholar 

  25. Bilgrami S, Almeida GD, Quinn JJ, Tuck D, Bergstrom S, Dainiak N, et al. Pancytopenia in allogeneic marrow transplant recipients: role of cytomegalovirus. Br J Haematol. 1994;87:357–62.

    Article  CAS  Google Scholar 

  26. Dominietto A1, Raiola AM, van Lint MT, Lamparelli T, Gualandi F, et al. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol. 2001;112:219–27.

    Article  CAS  Google Scholar 

  27. Torok-Storb B, Boeckh M, Hoy C, Leisenring W, Myerson D, Gooley T. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood. 1997;90:2097–102.

    CAS  PubMed  Google Scholar 

  28. Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, et al. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: a report from the Acute Leukemia Working Party of EBMT. Blood. 2013;122:3359–64.

    Article  CAS  Google Scholar 

  29. Hill JA, Mayer BT, Xie H, Leisenring WM, Huang ML, Stevens-Ayers T, et al. Kinetics of Double-Stranded DNA Viremia after Allogeneic Hematopoietic Cell Transplantation. Clin Infect Dis. 2018;66:368–75.

    Article  Google Scholar 

  30. Hill JA, Mayer BT, Xie H, Leisenring WM, Huang ML, Stevens-Ayers T, et al. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood. 2017;129:2316–25.

    Article  CAS  Google Scholar 

  31. Giménez E, Solano C, Vinuesa V, Hernández-Boluda JC, Albert E, Pérez A et al. Cytomegalovirus DNAemia Burden and Mortality Following Allogeneic Hematopoietic Stem Cell Transplantation: An Area Under a Curve-Based. Clin infect Dis 2018;https://doi.org/10.1093/cid/ciy138.

  32. Boeckh M, Geballe AP. Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest. 2011;121:1673–80.

    Article  CAS  Google Scholar 

  33. Elmaagacli AH, Koldehoff M. Cytomegalovirus replication reduces the relapse incidence in patients with acute myeloid leukemia. Blood. 2016;128:456–9.

    Article  CAS  Google Scholar 

  34. Litjens NHR, van der Wagen L, Kuball J, Kwekkeboom J. Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation. Front Immunol. 2018;9:389.

    Article  Google Scholar 

  35. Chemaly RF, Ullmann AJ, Stoelben S, Richard MP, Bornhäuser M, Groth C, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014;370:1781–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Estela Giménez holds a Río Hortega research contract from the Carlos III Health Institute (Ref. CM16/00200). This research was supported by grants (12/1992 and 15/0060) from FIS (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Spain).

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Author notes

  1. These authors contributed equally: Carlos Solano, Estela Giménez.

Authors and Affiliations

  1. Hematology Service, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain

    Carlos Solano, Montserrat Gómez, Rosa Goterris, Ariadna Pérez, Paula Amat, Juan Carlos Hernández-Boluda, Marc Poch & José Luis Piñana

  2. Department of Medicine, School of Medicine, University of Valencia, Valencia, Spain

    Carlos Solano

  3. Microbiology Service, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain

    Estela Giménez, Eliseo Albert & David Navarro

  4. Microbiology Department, School of Medicine, University of Valencia, Valencia, Spain

    Eva María Mateo & David Navarro

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  1. Carlos Solano
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Correspondence to David Navarro.

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Solano, C., Giménez, E., Albert, E. et al. Pre-engraftment cytomegalovirus DNAemia in allogeneic hematopoietic stem cell transplant recipients: incidence, risk factors, and clinical outcomes. Bone Marrow Transplant 54, 90–98 (2019). https://doi.org/10.1038/s41409-018-0251-0

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