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The kinetics of torque teno virus plasma DNA load shortly after engraftment predicts the risk of high-level CMV DNAemia in allogeneic hematopoietic stem cell transplant recipients

Abstract

Monitoring Torque teno virus (TTV) DNA load helps to estimate the risk of opportunistic infections in solid organ transplant recipients. We investigated whether the early kinetic pattern of plasma TTV DNA load after allogeneic hematopoietic stem cell transplantation (allo-HSCT) associates with subsequent CMV and EBV DNAemia. This study included 71 allo-HSCT patients. We found that the area under the curve (AUC) for log10 TTV DNA loads quantified by days 20 and 30 after transplantation (TTV DNA load AUC20-30), was significantly lower (P=0.036) in patients who subsequently developed CMV DNAemia requiring preemptive antiviral therapy (n=17) than in those who did not (n=8) or had no CMV DNAemia (n=19). Patients displaying TTV DNA load AUC20-302.8 copies × days × mL−1 were more likely to have high-level CMV DNAemia. A trend towards a direct correlation between TTV DNA AUC20-30 and CMV-specific interferon-γ CD8+ T-cell counts by day +30 was noted (P=0.095). However, this dynamic parameter was not useful for anticipating the occurrence of either CMV recurrences (n=12) or EBV DNAemia (n=34). In summary, it may be possible to identify a subset of allo-HSCT patients at a high risk of developing high-level CMV DNAemia by analyzing the kinetics of plasma TTV DNA load early after engraftment.

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References

  1. Okamoto H . History of discoveries and pathogenicity of TT viruses. Curr Top Microbiol Immunol 2009; 331: 1–20.

    CAS  PubMed  Google Scholar 

  2. Focosi D, Antonelli G, Pistello M, Maggi F . Torquetenovirus: the human virome from bench to bedside. Clin Microbiol Infect 2016; 22: 589–593.

    Article  CAS  Google Scholar 

  3. De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 2013; 155: 1178–1187.

    Article  CAS  Google Scholar 

  4. Gorzer I, Jaksch P, Kundi M, Seitz T, Klepetko W, Puchhammer-Stockl E . Pre-transplant plasma Torque Teno virus load and increase dynamics after lung transplantation. PLoS ONE 2015; 10: e0122975.

    Article  Google Scholar 

  5. Beland K, Dore-Nguyen M, Gagne MJ, Patey N, Brassard J, Alvarez F et al. Torque Teno Virus in children who underwent orthotopic liver transplantation: new insights about a common pathogen. J Infect Dis 2014; 209: 247–254.

    Article  CAS  Google Scholar 

  6. Focosi D, Macera L, Pistello M, Maggi F . Torquetenovirus (TTV) viremia correlates with intensity of maintenance immunosuppression in adult orthotopic liver transplantation. J Infect Dis 2014; 210: 667–668.

    Article  Google Scholar 

  7. Gorzer I, Haloschan M, Jaksch P, Klepetko W, Puchhammer-Stockl E . Plasma DNA levels of Torque teno virus and immunosuppression after lung transplantation. J Heart Lung Transpl 2014; 33: 320–328.

    Article  Google Scholar 

  8. Schiemann M, Puchhammer-Stöckl E, Eskandary F, Kohlbeck P, Rasoul-Rockenschaub S, Heilos A et al. Torque Teno virus load-inverse association with antibody-mediated rejection after kidney transplantation. Transplantation 2017; 101: 360–367.

    Article  Google Scholar 

  9. Simonetta F, Pradier A, Masouridi-Levrat S, van Delden C, Giostra E, Morard I et al. Torque Teno Virus load and acute rejection after orthotopic liver transplantation. Transplantation 2017; 101: e219–e221.

    Article  Google Scholar 

  10. Kanda Y, Tanaka Y, Kami M, Saito T, Asai T, Izutsu K et al. TT virus in bone marrow transplant recipients. Blood 1999; 93: 2485–2490.

    CAS  PubMed  Google Scholar 

  11. Maggi F, Focosi D, Albani M, Lanini L, Vatteroni ML, Petrini M et al. Role of hematopoietic cells in the maintenance of chronic human torquetenovirus plasma viremia. J Virol 2010; 84: 6891–6893.

    Article  CAS  Google Scholar 

  12. Masouridi-Levrat S, Pradier A, Simonetta F, Kaiser L, Chalandon Y, Roosnek E . Torque teno virus in patients undergoing allogeneic hematopoietic stem cell transplantation for hematological malignancies. Bone Marrow Transplant 2016; 51: 440–442.

    Article  CAS  Google Scholar 

  13. Albert E, Solano C, Pascual T, Torres I, Macera L, Focosi D et al. Dynamics of Torque Teno virus plasma DNAemia in allogeneic stem cell transplant recipients. J Clin Virol 2017; 94: 22–28.

    Article  CAS  Google Scholar 

  14. Maggi F, Fornai C, Zaccaro L,, Morrica A, Vatteroni ML, Isola P et al. TT virus (TTV) loads associated with different peripheral blood cell types and evidence for TTV replication in activated mononuclear cells. J Med Virol 2001; 64: 190–194.

    Article  CAS  Google Scholar 

  15. Mariscal LF, López-Alcorocho JM, Rodríguez-Iñigo E, Ortiz-Movilla N, de Lucas S, Bartolomé J et al. TT virus replicates in stimulated but not in nonstimulated peripheral blood mononuclear cells. Virology 2002; 301: 121–129.

    Article  CAS  Google Scholar 

  16. Focosi D, Macera L, Boggi U, Ceccherini Nelli L, Maggi F . Short-term kinetics of torque teno virus viraemia after induction immunosuppression confirm T lymphocytes as the main replication-competent cells. J Gen Virol 2015; 96: 115–117.

    Article  CAS  Google Scholar 

  17. 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: 113–134.

    Article  Google Scholar 

  18. Landgren O, Gilbert ES, Rizzo JD, Socié G, Banks PM, Sobocinski KA et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood 2009; 113: 4992–5001.

    Article  CAS  Google Scholar 

  19. 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: 207–209.

    Article  CAS  Google Scholar 

  20. 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: 1010–1012.

    Article  CAS  Google Scholar 

  21. Giménez E, Muñoz-Cobo B, Solano C, Amat P, Navarro D . Early kinetics of plasma cytomegalovirus DNA load in allogeneic stem cell transplant recipients in the era of highly sensitive real-time PCR assays: does it have any clinical value? J Clin Microbiol 2014; 52: 654–656.

    Article  Google Scholar 

  22. 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: 718–721.

    Article  CAS  Google Scholar 

  23. Vinuesa V, Solano C, Giménez E, Navarro D . Comparison of the artus Epstein-Barr virus (EBV) PCR kit and the Abbott RealTime EBV assay for measuring plasma EBV DNA loads in allogeneic stem cell transplant recipients. Diagn Microbiol Infect Dis 2017; 88: 36–38.

    Article  CAS  Google Scholar 

  24. Solano C, Benet I, Clari MA, Nieto J, de la Cámara R, López J et al. Enumeration of cytomegalovirus-specific interferongamma CD8+ and CD4+ T cells early after allogeneic stem cell transplantation may identify patients at risk of active cytomegalovirus infection. Haematologica 2008; 93: 1434–1436.

    Article  CAS  Google Scholar 

  25. Tormo N, Solano C, Benet I, Nieto J, de la Cámara R, López J et al. Reconstitution of CMV pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T-cell responses affording protection from CMV DNAemia following allogeneic hematopoietic SCT. Bone Marrow Transplant 2011; 46: 1437–1443.

    Article  CAS  Google Scholar 

  26. 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 

  27. Torres A, Sánchez J, Lakomsky D, Serrano J, Alvarez MA, Martín C et al. Assessment of hematologic progenitor engraftment by complete reticulocyte maturation parameters after autologous and allogeneic hematopoietic stem cell transplantation. Haematologica 2001; 86: 24–29.

    CAS  PubMed  Google Scholar 

  28. 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: doi: 10.1111/tid.12717.

    Article  Google Scholar 

  29. 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–e127.

    Article  Google Scholar 

  30. 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: 543–549.

    Article  CAS  Google Scholar 

  31. Solano C, Benet I, Remigia MJ, de la Cámara R, Muñoz-Cobo B, Costa E et al. Immunological monitoring for guidance of preemptive antiviral therapy for active cytomegalovirus infection in allogeneic stem-cell transplant recipients: a pilot experience. Transplantation 2011; 92: e17–e20.

    Article  Google Scholar 

  32. Navarro D, Amat P, de la Cámara R, López J, Vázquez L, Serrano D et al. Efficacy and safety of a preemptive antiviral therapy strategy based on combined virological and immunological monitoring for active cytomegalovirus infection in allogeneic stem cell transplant recipients. Open Forum Infect Dis 2016; 3: ofw107.

    Article  Google Scholar 

  33. Marshall NA, Howe JG, Formica R, Krause D, Wagner JE, Berliner N et al. Rapid reconstitution of Epstein-Barr virus-specific T lymphocytes following allogeneic stem cell transplantation. Blood 2000; 96: 2814–2821.

    CAS  PubMed  Google Scholar 

  34. Meij P, van Esser JW, Niesters HG, van Baarle D, Miedema F, Blake N et al. Impaired recovery of Epstein-Barr virus (EBV)—specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease. Blood 2003; 101: 4290–4297.

    Article  CAS  Google Scholar 

  35. Gilles R, Herling M, Holtick U, Heger E, Awerkiew S, Fish I et al. Dynamics of Torque Teno virus viremia could predict risk of complications after allogeneic hematopoietic stem cell transplantation. Med Microbiol Immunol 2017; doi: 10.1007/s00430-017-0511-4.

    Article  CAS  Google Scholar 

  36. Haloschan M, Bettesch R, Görzer I, Weseslindtner L, Kundi M, Puchhammer-Stöckl E . TTV DNA plasma load and its association with age, gender, and HCMV IgG serostatus in healthy adults. Age (Dordr) 2014; 36: 9716.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Juan Manuel Moya Serrano for his technical assistance. Estela Giménez holds a Río-Hortega Contract from the Carlos III Health Institute (ISCIII) (Ref. CM16/00200). This work was presented, in part, at the European Congress of Clinical Virology in Lisbon, 2016.

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Correspondence to D Navarro.

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Albert, E., Solano, C., Giménez, E. et al. The kinetics of torque teno virus plasma DNA load shortly after engraftment predicts the risk of high-level CMV DNAemia in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 53, 180–187 (2018). https://doi.org/10.1038/bmt.2017.235

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