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Immune Monitoring for CMV in Transplantation

  • Transplant and Oncology (M Ison, N Theodoropoulos and S Pergam, Section Editors)
  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Immune monitoring to determine when and how the recovery of cytomegalovirus (CMV)-specific T-cells occurs post-transplantation may help clinicians to risk stratify individuals at risk of complications from CMV. We aimed to review all recent clinical studies using CMV immune monitoring in the pre- and post-transplant setting including the use of recently developed standardized assays (Quantiferon-CMV and the CMV ELISPOT) to better understand in whom, when, and how immune monitoring is best used.

Recent Findings

Pre-transplant assessment of CMV immunity in solid-organ transplant recipients where CMV seropositive recipients had undetectable cell-mediated responses despite past immunity has shown that they are at a much higher risk of developing CMV reactivation. Post-transplant CMV immune monitoring can guide (shorten or prolong) the duration of antiviral prophylaxis, identify recipients at risk of post-prophylaxis CMV disease, and predict recurrent CMV reactivation.

Summary

Thus, CMV immune monitoring, in addition to current clinical and DNA-based monitoring for CMV, has the potential to be incorporated into routine clinical care to better improve CMV management in both the stem and solid-organ transplant population.

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References

  1. Razonable RR, Humar A. Practice ASTIDCo. Cytomegalovirus in solid organ transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2013;13(Suppl 4):93–106.

    Article  CAS  Google Scholar 

  2. Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2010;10(5):1228–37.

    Article  CAS  Google Scholar 

  3. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2004;4(4):611–20.

    Article  CAS  Google Scholar 

  4. Matter-Walstra KW, Greiner M, Cusini A, Schiesser M, Ledergerber B, Fehr T, et al. Stringent adherence to a cytomegalovirus-prevention protocol is associated with reduced overall costs in the first 6 months after kidney transplantation. Transpl Infect Dis. 2015;17(3):342–9.

    Article  CAS  PubMed  Google Scholar 

  5. Manuel O, Kralidis G, Mueller NJ, Hirsch HH, Garzoni C, van Delden C, et al. Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2013;13(9):2402–10.

    Article  CAS  Google Scholar 

  6. Navarro D, San-Juan R, Manuel O, Gimenez E, Fernandez-Ruiz M, Hirsch HH, et al. Cytomegalovirus infection management in solid organ transplant recipients across European centers in the time of molecular diagnostics: an ESGICH survey. Transpl Infect Dis. 2017;19:e12773. https://doi.org/10.1111/tid.12773.

  7. Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D, Thymoglobulin Induction Study G. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355(19):1967–77.

    Article  CAS  PubMed  Google Scholar 

  8. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562–75.

    Article  CAS  PubMed  Google Scholar 

  9. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2013;96(4):333–60.

    Article  CAS  PubMed  Google Scholar 

  11. Martin-Gandul C, Perez-Romero P, Gonzalez-Roncero FM, Berdaguer S, Gomez MA, Lage E, et al. Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. J Inf Secur. 2014;69(5):500–6.

    Google Scholar 

  12. Manuel O. Clinical experience with immune monitoring for cytomegalovirus in solid-organ transplant recipients. Curr Infect Dis Rep. 2013;15:491–6.

    Article  Google Scholar 

  13. Kotton CN. Cytomegalovirus immunodiagnostics: getting closer to personalized cytomegalovirus prevention? Liver Transpl. 2015;21(12):1462–4.

    Article  PubMed  Google Scholar 

  14. Sester M, Leboeuf C, Schmidt T, Hirsch HH. The “ABC” of virus-specific T cell immunity in solid organ transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2016;16(6):1697–706.

    Article  CAS  Google Scholar 

  15. Yong MK, Cameron PU, Slavin M, Morrissey CO, Bergin K, Spencer A, et al. Identifying cytomegalovirus complications using the Quantiferon-CMV assay after allogeneic hematopoietic stem cell transplantation. J Infect Dis. 2017;215(11):1684–94.

    Article  PubMed  Google Scholar 

  16. Manuel O, Husain S, Kumar D, Zayas C, Mawhorter S, Levi ME, et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013;56(6):817–24.

    Article  CAS  Google Scholar 

  17. Giulieri S, Manuel O. QuantiFERON(R)-CMV assay for the assessment of cytomegalovirus cell-mediated immunity. Expert Rev Mol Diagn. 2011;11(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  18. Walker S, Fazou C, Crough T, Holdsworth R, Kiely P, Veale M, et al. Ex vivo monitoring of human cytomegalovirus-specific CD8+ T-cell responses using QuantiFERON-CMV. Transpl Infect Dis. 2007;9(2):165–70.

    Article  CAS  PubMed  Google Scholar 

  19. Avetisyan G, Aschan J, Hagglund H, Ringden O, Ljungman P. Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT. Bone Marrow Transplant. 2007;40(9):865–9.

    Article  CAS  PubMed  Google Scholar 

  20. Tey SK, Kennedy GA, Cromer D, Davenport MP, Walker S, Jones LI, et al. Clinical assessment of anti-viral CD8+ T cell immune monitoring using QuantiFERON-CMV(R) assay to identify high risk allogeneic hematopoietic stem cell transplant patients with CMV infection complications. PLoS One. 2013;8(10):e74744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yong MK, Cameron PU, Slavin MA, Cheng AC, Morrissey CO, Bergin K, et al. Low T-cell responses to mitogen stimulation predicts poor survival in recipients of allogeneic hematopoietic stem cell transplantation. Front Immunol. 2017;8:1506.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Abate D, Saldan A, Mengoli C, Fiscon M, Silvestre C, Fallico L, et al. Comparison of cytomegalovirus (CMV) enzyme-linked immunosorbent spot and CMV quantiferon gamma interferon-releasing assays in assessing risk of CMV infection in kidney transplant recipients. J Clin Microbiol. 2013;51(8):2501–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Banas B, Boger CA, Luckhoff G, Kruger B, Barabas S, Batzilla J, et al. Validation of T-track(R) CMV to assess the functionality of cytomegalovirus-reactive cell-mediated immunity in hemodialysis patients. BMC Immunol. 2017;18(1):15.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Barabas S, Spindler T, Kiener R, Tonar C, Lugner T, Batzilla J, et al. An optimized IFN-gamma ELISpot assay for the sensitive and standardized monitoring of CMV protein-reactive effector cells of cell-mediated immunity. BMC Immunol. 2017;18(1):14.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nesher L, Shah DP, Ariza-Heredia EJ, Azzi JM, Siddiqui HK, Ghantoji SS, et al. Utility of the enzyme-linked Immunospot interferon-gamma-release assay to predict the risk of cytomegalovirus infection in hematopoietic cell transplant recipients. J Infect Dis. 2016;213(11):1701–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Staats JS, Enzor JH, Sanchez AM, Rountree W, Chan C, Jaimes M, et al. Toward development of a comprehensive external quality assurance program for polyfunctional intracellular cytokine staining assays. J Immunol Methods. 2014;409:44–53.

    Article  CAS  PubMed  Google Scholar 

  27. Borchers S, Ogonek J, Varanasi PR, Tischer S, Bremm M, Eiz-Vesper B, et al. Multimer monitoring of CMV-specific T cells in research and in clinical applications. Diagn Microbiol Infect Dis. 2014;78(3):201–12.

    Article  CAS  PubMed  Google Scholar 

  28. Borchers S, Luther S, Lips U, Hahn N, Kontsendorn J, Stadler M, et al. Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2011;13(3):222–36.

    Article  CAS  PubMed  Google Scholar 

  29. Ogonek J, Verma K, Schultze-Florey C, Varanasi P, Luther S, Schweier P, et al. Characterization of high-avidity cytomegalovirus-specific T cells with differential tetramer binding Coappearing after allogeneic stem cell transplantation. J Immunol. 2017;199(2):792–805.

    Article  CAS  PubMed  Google Scholar 

  30. Cantisan S, Lara R, Montejo M, Redel J, Rodriguez-Benot A, Gutierrez-Aroca J, et al. Pretransplant interferon-gamma secretion by CMV-specific CD8+ T cells informs the risk of CMV replication after transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2013;13(3):738–45.

    Article  CAS  Google Scholar 

  31. Bestard O, Lucia M, Crespo E, Van Liempt B, Palacio D, Melilli E, et al. Pretransplant immediately early-1-specific T cell responses provide protection for CMV infection after kidney transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2013;13(7):1793–805.

    Article  CAS  Google Scholar 

  32. Lucia M, Crespo E, Melilli E, Cruzado JM, Luque S, Llaudo I, et al. Preformed frequencies of cytomegalovirus (CMV)-specific memory T and B cells identify protected CMV-sensitized individuals among seronegative kidney transplant recipients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014;59(11):1537–45.

    Article  CAS  Google Scholar 

  33. Schachtner T, Stein M, Reinke P. CMV-specific T cell monitoring offers superior risk stratification of CMV-seronegative kidney transplant recipients of a CMV-seropositive donor. Transplantation. 2017;101(10):e315-e25.

    Article  Google Scholar 

  34. San-Juan R, Navarro D, Garcia-Reyne A, Montejo M, Munoz P, Carratala J, et al. Effect of long-term prophylaxis in the development of cytomegalovirus-specific T-cell immunity in D+/R- solid organ transplant recipients. Transpl Infect Dis. 2015;17(5):637–46.

    Article  CAS  PubMed  Google Scholar 

  35. Westall GP, Cristiano Y, Peleg AY, Paraskeva M, Levvey B, Whitford H, et al. A study of QuantiFERON-CMV-directed CMV prophylaxis versus standard-of-care to reduce late CMV reactivation in patients undergoing lung transplantation. 37th International Society for Heart and Lung Transplantation Annual Meeting; San Diego, California 2017.

  36. Asberg A, Humar A, Jardine AG, Rollag H, Pescovitz MD, Mouas H, et al. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2009;9(5):1205–13.

    Article  CAS  Google Scholar 

  37. Muheim C, Vogel G, Seydoux C, Gillet M, Mosimann F, Von Segesser L, et al. Determinants of protracted cytomegalovirus infection in solid-organ transplant patients. Transplantation. 2002;74(2):226–36.

    Article  PubMed  Google Scholar 

  38. Couzi L, Pitard V, Moreau JF, Merville P, Dechanet-Merville J. Direct and indirect effects of cytomegalovirus-induced gammadelta T cells after kidney transplantation. Front Immunol. 2015;6:3.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kaminski H, Garrigue I, Couzi L, Taton B, Bachelet T, Moreau JF, et al. Surveillance of gammadelta T cells predicts cytomegalovirus infection resolution in kidney transplants. J Am Soc Nephrol. 2016;27(2):637–45.

    Article  CAS  PubMed  Google Scholar 

  40. Kumar D, Mian M, Singer L, An Interventional HA. Study using cell-mediated immunity to personalize therapy for cytomegalovirus infection after transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2017;17(9):2468–73.

    Article  CAS  Google Scholar 

  41. Mihm J, Leyking S, Dirks J, Smola S, Fliser D, Sester U, et al. Immune-based guidance of foscarnet treatment duration in a transplant recipient with ganciclovir-resistant cytomegalovirus infection. J Clin Virol. 2016;82:5–8.

    Article  CAS  PubMed  Google Scholar 

  42. Lisboa LF, Kumar D, Wilson LE, Humar A. Clinical utility of cytomegalovirus cell-mediated immunity in transplant recipients with cytomegalovirus viremia. Transplantation. 2012;93(2):195–200.

    Article  PubMed  Google Scholar 

  43. Mena-Romo JD, Perez Romero P, Martin-Gandul C, Gentil MA, Suarez-Artacho G, Lage E, et al. CMV-specific T-cell immunity in solid organ transplant recipients at low risk of CMV infection. Chronology and applicability in preemptive therapy. J Inf Secur. 2017;75(4):336–45.

    Google Scholar 

  44. Thursky K, Byrnes G, Grigg A, Szer J, Slavin M. Risk factors for post-engraftment invasive aspergillosis in allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;34(2):115–21.

    Article  CAS  PubMed  Google Scholar 

  45. Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD. Ganciclovir prophylaxis to prevent cytomegalovirus diseases after allogeneic marrow transplant. Ann Intern Med. 1993;118(3):173–8.

    Article  CAS  PubMed  Google Scholar 

  46. George B, Kerridge IH, Gilroy N, Huang G, Hertzberg MS, Bradstock KF, et al. A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group. Transpl Infect Dis. 2012;14(2):141–8.

    Article  CAS  PubMed  Google Scholar 

  47. Navarro D, Amat P, de la Camara R, Lopez J, Vazquez 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(2):ofw107.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lee SM, Kim YJ, Yoo KH, Sung KW, Koo HH, Kang ES. Clinical usefulness of monitoring cytomegalovirus-specific immunity by Quantiferon-CMV in pediatric allogeneic hematopoietic stem cell transplantation recipients. Ann Lab Med. 2017;37(3):277–81.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Borchers S, Bremm M, Lehrnbecher T, Dammann E, Pabst B, Wolk B, et al. Sequential anti-cytomegalovirus response monitoring may allow prediction of cytomegalovirus reactivation after allogeneic stem cell transplantation. PLoS One. 2012;7(12):e50248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Solano C, Benet I, Remigia MJ, de la Camara R, Munoz-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(4):e17–20.

    Article  PubMed  Google Scholar 

  51. Hoegh-Petersen M, Roa L, Liu Y, Zhou F, Ugarte-Torres A, Louie P, et al. Low cytomegalovirus-specific T-cell counts at reactivation are associated with progression to high-level viremia or disease in seropositive recipients of hematopoietic cell grafts from seropositive but not seronegative donors. Cytotherapy. 2012;14(2):194–204.

    Article  CAS  PubMed  Google Scholar 

  52. Lilleri D, Gerna G, Zelini P, Chiesa A, Rognoni V, Mastronuzzi A, et al. Monitoring of human cytomegalovirus and virus-specific T-cell response in young patients receiving allogeneic hematopoietic stem cell transplantation. PLoS One. 2012;7(7):e41648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Krol L, Stuchly J, Hubacek P, Keslova P, Sedlacek P, Stary J, et al. Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT. Bone Marrow Transplant. 2011;46(8):1089–98.

    Article  CAS  PubMed  Google Scholar 

  54. 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  PubMed  Google Scholar 

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Authors and Affiliations

  1. The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, 792 Elizabeth Street, Melbourne, VIC, 3000, Australia

    Michelle K. Yong & Sharon R. Lewin

  2. National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia

    Michelle K. Yong

  3. Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland

    Oriol Manuel

  4. Transplantation Center, Department of Anesthesiology and Surgery, University Hospital and University of Lausanne, Lausanne, Switzerland

    Oriol Manuel

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  1. Michelle K. Yong
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  2. Sharon R. Lewin
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Correspondence to Michelle K. Yong.

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Conflict of Interest

Dr. Manuel has received research grants from Lophius Biosciences GmbH and from Qiagen. Dr. Yong and Dr. Lewin declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Transplant and Oncology

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Yong, M.K., Lewin, S.R. & Manuel, O. Immune Monitoring for CMV in Transplantation. Curr Infect Dis Rep 20, 4 (2018). https://doi.org/10.1007/s11908-018-0610-4

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