Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Management of cytomegalovirus infection in solid organ transplantation

Nature Reviews Nephrology volume 6, pages 711–721 (2010)Cite this article

Subjects

Abstract

Cytomegalovirus (CMV) infections are among the most common infections that occur following solid organ transplantation. CMV disease ranges from asymptomatic viremia, to CMV syndrome, to tissue-invasive disease. As CMV prophylaxis, treatment, diagnostics, and overall awareness have improved, the general trend has been towards earlier diagnosis of CMV disease and more mild clinical presentations in solid organ transplant recipients. Major stumbling blocks remain in the areas of duration of prophylaxis for the individual recipient, in the identification of which patients might need secondary prophylaxis, in the treatment of resistant virus, and in the possible use of the adoptive transfer of CMV-specific T cells. Several guidelines have been published during the past few years regarding the management of CMV in solid organ transplant recipients. This Review covers CMV diagnostics, methods for the prevention of CMV infection, treatment of both regular and drug-resistant CMV, as well as future directions for CMV management and research.

Key Points

  • Cytomegalovirus (CMV) infections are the most common infections following solid organ transplantation; active CMV disease significantly increases morbidity and mortality, and decreases graft survival

  • The main prevention methods for CMV infection are universal prophylaxis and pre-emptive therapy

  • Guidelines exist regarding the optimal management of CMV infection, but as all methods have benefits and risks, individual transplant centers must decide on the most appropriate method

  • Treatment of CMV has evolved over the years as data from new studies has enabled the increased use of oral therapy for mild to moderate disease

  • Immunologic assays are an emerging technology that will hopefully provide individualized information for patients regarding risk of CMV infection

  • Individualized information would enable tailoring of prophylaxis and treatment, with reduction in concomitant drug toxicities and costs, and will hopefully optimize transplant outcomes

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kotton, C. N. et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 89, 779–795 (2010).

    Article  PubMed  Google Scholar 

  2. [No authors listed] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am. J. Transplant. 9 (Suppl. 3), S1–S155 (2009).

  3. Humar, A. & Snydman, D. Cytomegalovirus in solid organ transplant recipients. Am. J. Transplant. 9 (Suppl. 4), S78–S86 (2009).

    Article  PubMed  Google Scholar 

  4. Fishman, J. A. Infection in solid-organ transplant recipients. N. Engl. J. Med. 357, 2601–2614 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Ho, M. Epidemiology of cytomegalovirus infections. Rev. Infect. Dis. 12 (Suppl. 7), S701–S710 (1990).

    Article  PubMed  Google Scholar 

  6. Kanter, J. et al. Cytomegalovirus infection renal transplant recipients: risk factors and outcome. Transplant. Proc. 41, 2156–2158 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Doron, S., Ruthazer, R., Werner, B. G., Rabson, A. & Snydman, D. R. Hypogammaglobulinemia in liver transplant recipients: incidence, timing, risk factors, and outcomes. Transplantation 81, 697–703 (2006).

    Article  PubMed  Google Scholar 

  8. Corales, R. et al. Significant post-transplant hypogammaglobulinemia in six heart transplant recipients: an emerging clinical phenomenon? Transpl. Infect. Dis. 2, 133–139 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Goldfarb, N. S. et al. Hypogammaglobulinemia in lung transplant recipients. Transplantation 71, 242–246 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Hoffmann, T. W. et al. Association between a polymorphism in the human programmed death-1 (PD-1) gene and cytomegalovirus infection after kidney transplantation. J. Med. Genet. 47, 54–58 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Lowance, D. et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N. Engl. J. Med. 340, 1462–1470 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Gane, E. et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group [corrected]. Lancet 350, 1729–1733 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. San Juan, R. et al. Impact of current transplantation management on the development of cytomegalovirus disease after renal transplantation. Clin. Infect. Dis. 47, 875–882 (2008).

    Article  PubMed  Google Scholar 

  14. Ettinger, N. A. et al. Cytomegalovirus infection and pneumonitis. Impact after isolated lung transplantation. Washington University Lung Transplant Group. Am. Rev. Respir. Dis. 147, 1017–1023 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Duncan, A. J. et al. Cytomegalovirus infection and survival in lung transplant recipients. J. Heart Lung Transplant. 10, 638–644 (1991).

    CAS  PubMed  Google Scholar 

  16. Pescovitz, M. D. Benefits of cytomegalovirus prophylaxis in solid organ transplantation. Transplantation 82, S4–S8 (2006).

    Article  PubMed  Google Scholar 

  17. Falagas, M. E. et al. Clinical and epidemiological predictors of recurrent cytomegalovirus disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group. Clin. Infect. Dis. 25, 314–317 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Sagedal, S. et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int. 66, 329–337 (2004).

    Article  PubMed  Google Scholar 

  19. Streblow, D. N., Orloff, S. L. & Nelson, J. A. Acceleration of allograft failure by cytomegalovirus. Curr. Opin. Immunol. 19, 577–582 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kliem, V. et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am. J. Transplant. 8, 975–983 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Reischig, T. et al. Effect of cytomegalovirus viremia on subclinical rejection or interstitial fibrosis and tubular atrophy in protocol biopsy at 3 months in renal allograft recipients managed by preemptive therapy or antiviral prophylaxis. Transplantation 87, 436–444 (2009).

    Article  PubMed  Google Scholar 

  22. Razonable, R. R. et al. Allograft rejection predicts the occurrence of late-onset cytomegalovirus (CMV) disease among CMV-mismatched solid organ transplant patients receiving prophylaxis with oral ganciclovir. J. Infect. Dis. 184, 1461–1464 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Sagedal, S. et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am. J. Transplant. 2, 850–856 (2002).

    Article  PubMed  Google Scholar 

  24. Dmitrienko, S., Balshaw, R., Machnicki, G., Shapiro, R. J. & Keown, P. A. Probabilistic modeling of cytomegalovirus infection under consensus clinical management guidelines. Transplantation 87, 570–577 (2009).

    Article  PubMed  Google Scholar 

  25. Johnson, R. J., Clatworthy, M. R., Birch, R., Hammad, A. & Bradley, J. A. CMV mismatch does not affect patient and graft survival in UK renal transplant recipients. Transplantation 88, 77–82 (2009).

    Article  PubMed  Google Scholar 

  26. Freeman, R. B. Jr. The 'indirect' effects of cytomegalovirus infection. Am. J. Transplant. 9, 2453–2458 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Lautenschlager, I. CMV infection, diagnosis and antiviral strategies after liver transplantation. Transpl. Int. 22, 1031–1040 (2009).

    Article  PubMed  Google Scholar 

  28. Weber, B., Fall, E. M., Berger, A. & Doerr, H. W. Screening of blood donors for human cytomegalovirus (HCMV) IgG antibody with an enzyme immunoassay using recombinant antigens. J. Clin. Virol. 14, 173–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Seed, C. R. et al. Validation of an automated immunoglobulin G-only cytomegalovirus (CMV) antibody screening assay and an assessment of the risk of transfusion transmitted CMV from seronegative blood. Transfusion 49, 134–145 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Lazzarotto, T., Brojanac, S., Maine, G. T. & Landini, M. P. Search for cytomegalovirus-specific immunoglobulin M: comparison between a new western blot, conventional western blot, and nine commercially available assays. Clin. Diagn. Lab. Immunol. 4, 483–486 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Humar, A. et al. Clinical utility of cytomegalovirus (CMV) serology testing in high-risk CMV D+/R- transplant recipients. Am. J. Transplant. 5, 1065–1070 (2005).

    Article  PubMed  Google Scholar 

  32. Rayes, N. et al. Monitoring of human cytomegalovirus, HHV-6 and HHV-7 infection in kidney transplant recipients by molecular methods to predict HCMV disease after transplantation: a prospective study. Ann. Transplant. 10, 23–28 (2005).

    PubMed  Google Scholar 

  33. Schröeder, R. et al. Antigenemia for cytomegalovirus in renal transplantation: choosing a cutoff for the diagnosis criteria in cytomegalovirus disease. Transplant. Proc. 37, 2781–2783 (2005).

    Article  PubMed  Google Scholar 

  34. Baldanti, F., Lilleri, D. & Gerna, G. Monitoring human cytomegalovirus infection in transplant recipients. J. Clin. Virol. 41, 237–241 (2008).

    Article  PubMed  Google Scholar 

  35. Gerna, G. et al. Human cytomegalovirus pp67 mRNAemia versus pp65 antigenemia for guiding preemptive therapy in heart and lung transplant recipients: a prospective, randomized, controlled, open-label trial. Transplantation 75, 1012–1019 (2003).

    Article  PubMed  Google Scholar 

  36. Villa, M. et al. Preemptive therapy for the prevention of cytomegalovirus disease following heart transplantation directed by PP65 antigenemia. Transplant. Proc. 35, 732–734 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Caliendo, A. M. et al. Distinguishing cytomegalovirus (CMV) infection and disease with CMV nucleic acid assays. J. Clin. Microbiol. 40, 1581–1586 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lao, W. C. et al. Use of polymerase chain reaction to provide prognostic information on human cytomegalovirus disease after liver transplantation. J. Med. Virol. 51, 152–158 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Razonable, R. R. et al. Dynamics of cytomegalovirus replication during preemptive therapy with oral ganciclovir. J. Infect. Dis. 187, 1801–1808 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Rollag, H. et al. Cytomegalovirus DNA concentration in plasma predicts development of cytomegalovirus disease in kidney transplant recipients. Clin. Microbiol. Infect. 8, 431–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Emery, V. C. et al. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 355, 2032–2036 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Humar, A. et al. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients. Transplantation 68, 1305–1311 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Humar, A., Kumar, D., Boivin, G. & Caliendo, A. M. Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease. J. Infect. Dis. 186, 829–833 (2002).

    Article  PubMed  Google Scholar 

  44. Razonable, R. R. et al. The clinical use of various blood compartments for cytomegalovirus (CMV) DNA quantitation in transplant recipients with CMV disease. Transplantation 73, 968–973 (2002).

    Article  PubMed  Google Scholar 

  45. Tang, W., Elmore, S. H., Fan, H., Thorne, L. B. & Gulley, M. L. Cytomegalovirus DNA measurement in blood and plasma using Roche LightCycler CMV quantification reagents. Diagn. Mol. Pathol. 17, 166–173 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Hamprecht, K., Steinmassl, M., Einsele, H. & Jahn, G. Discordant detection of human cytomegalovirus DNA from peripheral blood mononuclear cells, granulocytes and plasma: correlation to viremia and HCMV infection. J. Clin. Virol. 11, 125–136 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Koidl, C., Bozic, M., Marth, E. & Kessler, H. H. Detection of CMV DNA: is EDTA whole blood superior to EDTA plasma? J. Virol. Methods 154, 210–212 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Pang, X. L. et al. Interlaboratory comparison of cytomegalovirus viral load assays. Am. J. Transplant. 9, 258–268 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Caliendo, A. M. et al. Comparison of quantitative cytomegalovirus (CMV) PCR in plasma and CMV antigenemia assay: clinical utility of the prototype AMPLICOR CMV MONITOR test in transplant recipients. J. Clin. Microbiol. 38, 2122–2127 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Piiparinen, H., Höckerstedt, K., Grönhagen-Riska, C. & Lautenschlager, I. Comparison of two quantitative CMV PCR tests, Cobas Amplicor CMV Monitor and TaqMan assay, and pp65-antigenemia assay in the determination of viral loads from peripheral blood of organ transplant patients. J. Clin. Virol. 30, 258–266 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Riise, G. C. et al. Quantification of cytomegalovirus DNA in BAL fluid: a longitudinal study in lung transplant recipients. Chest 118, 1653–1660 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Westall, G. P., Michaelides, A., Williams, T. J., Snell, G. I. & Kotsimbos, T. C. Human cytomegalovirus load in plasma and bronchoalveolar lavage fluid: a longitudinal study of lung transplant recipients. J. Infect. Dis. 190, 1076–1083 (2004).

    Article  PubMed  Google Scholar 

  53. Chemaly, R. F. et al. Correlation between viral loads of cytomegalovirus in blood and bronchoalveolar lavage specimens from lung transplant recipients determined by histology and immunohistochemistry. J. Clin. Microbiol. 42, 2168–2172 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Gerna, G. et al. Preemptive therapy for systemic and pulmonary human cytomegalovirus infection in lung transplant recipients. Am. J. Transplant. 9, 1142–1150 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Solans, E. P., Yong, S., Husain, A. N., Eichorst, M. & Gattuso, P. Bronchioloalveolar lavage in the diagnosis of CMV pneumonitis in lung transplant recipients: an immunocytochemical study. Diagn. Cytopathol. 16, 350–352 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Ljungman, P., Griffiths, P. & Paya, C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin. Infect. Dis. 34, 1094–1097 (2002).

    Article  PubMed  Google Scholar 

  57. Lautenschlager, I., Halme, L., Höckerstedt, K., Krogerus, L. & Taskinen, E. Cytomegalovirus infection of the liver transplant: virological, histological, immunological, and clinical observations. Transpl. Infect. Dis. 8, 21–30 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Halme, L. et al. High frequency of gastroduodenal cytomegalovirus infection in liver transplant patients. APMIS 116, 99–106 (2008).

    Article  PubMed  Google Scholar 

  59. Pillay, D. et al. The prognostic significance of positive CMV cultures during surveillance of renal transplant recipients. Transplantation 56, 103–108 (1993).

    Article  CAS  PubMed  Google Scholar 

  60. Sester, M. et al. Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation 71, 1287–1294 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Gerna, G. et al. Monitoring of human cytomegalovirus-specific CD4 and CD8 T-cell immunity in patients receiving solid organ transplantation. Am. J. Transplant. 6, 2356–2364 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Kumar, D. et al. Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients. Am. J. Transplant. 9, 1214–1222 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Radha, R. et al. Cellular immune responses to cytomegalovirus in renal transplant recipients. Am. J. Transplant. 5, 110–117 (2005).

    Article  PubMed  Google Scholar 

  64. Sester, U. et al. Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am. J. Transplant. 5, 1483–1489 (2005).

    Article  PubMed  Google Scholar 

  65. Sester, U. et al. PD-1 expression and IL-2 loss of cytomegalovirus-specific T cells correlates with viremia and reversible functional anergy. Am. J. Transplant. 8, 1486–1497 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Harari, A., Vallelian, F., Meylan, P. R. & Pantaleo, G. Functional heterogeneity of memory CD4 T cell responses in different conditions of antigen exposure and persistence. J. Immunol. 174, 1037–1045 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Crough, T. & Khanna, R. Immunobiology of human cytomegalovirus: from bench to bedside. Clin. Microbiol. Rev. 22, 76–98 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sester, M., Gärtner, B. C. & Sester, U. Monitoring of CMV-specific T-cell levels after organ transplantation. J. Lab. Med. 32, 121–130 (2008).

    CAS  Google Scholar 

  69. Gandhi, M. K. & Khanna, R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect. Dis. 4, 725–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Einsele, H. et al. Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 99, 3916–3922 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Brestrich, G. et al. Adoptive T-cell therapy of a lung transplanted patient with severe CMV disease and resistance to antiviral therapy. Am. J. Transplant. 9, 1679–1684 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Plotkin, S. A. et al. Effect of Towne live virus vaccine on cytomegalovirus disease after renal transplant. A controlled trial. Ann. Intern. Med. 114, 525–531 (1991).

    Article  CAS  PubMed  Google Scholar 

  74. Pass, R. F. et al. Vaccine prevention of maternal cytomegalovirus infection. N. Engl. J. Med. 360, 1191–1199 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Clinical Trials. CMV Glycoprotein B Vaccine in Allograft Recipients [online],.

  76. Wloch, M. K. et al. Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects. J. Infect. Dis. 197, 1634–1642 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Schleiss, M. R. VCL-CB01, an injectable bivalent plasmid DNA vaccine for potential protection against CMV disease and infection. Curr. Opin. Mol. Ther. 11, 572–578 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Bernstein, D. I. et al. Effect of previous or simultaneous immunization with canarypox expressing cytomegalovirus (CMV) glycoprotein B (gB) on response to subunit gB vaccine plus MF59 in healthy CMV-seronegative adults. J. Infect. Dis. 185, 686–690 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Berencsi, K. et al. A canarypox vector-expressing cytomegalovirus (CMV) phosphoprotein 65 induces long-lasting cytotoxic T cell responses in human CMV-seronegative subjects. J. Infect. Dis. 183, 1171–1179 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Reap, E. A. et al. Development and preclinical evaluation of an alphavirus replicon particle vaccine for cytomegalovirus. Vaccine 25, 7441–7449 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhong, J., Rist, M., Cooper, L., Smith, C. & Khanna, R. Induction of pluripotent protective immunity following immunisation with a chimeric vaccine against human cytomegalovirus. PLoS ONE 3, e3256 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Paya, C. et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am. J. Transplant. 4, 611–620 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Humar, A. et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am. J. Transplant. 10, 1228–1237 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Luan, F. L. et al. Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection. J. Am. Soc. Nephrol. 20, 2449–2458 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Razonable, R. R. et al. Herpesvirus infections in solid organ transplant patients at high risk of primary cytomegalovirus disease. J. Infect. Dis. 192, 1331–1339 (2005).

    Article  PubMed  Google Scholar 

  86. Hodson, E. M. et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet 365, 2105–2115 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Arthurs, S. K. et al. Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation. Clin. Infect. Dis. 46, 840–846 (2008).

    Article  PubMed  Google Scholar 

  88. Scemla, A., Kreis, H. & Legendre, C. Less pessimistic long-term results for patients with cytomegalovirus disease. Clin. Infect. Dis. 47, 1360–1361 (2008).

    Article  PubMed  Google Scholar 

  89. Limaye, A. P. et al. Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis. Transplantation 81, 1645–1652 (2006).

    Article  PubMed  Google Scholar 

  90. Khoury, J. A. et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am. J. Transplant. 6, 2134–2143 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Reischig, T. et al. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am. J. Transplant. 8, 69–77 (2008).

    CAS  PubMed  Google Scholar 

  92. Kalil, A. C., Levitsky, J., Lyden, E., Stoner, J. & Freifeld, A. G. Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann. Intern. Med. 143, 870–880 (2005).

    Article  PubMed  Google Scholar 

  93. Small, L. N., Lau, J. & Snydman, D. R. Preventing post-organ transplantation cytomegalovirus disease with ganciclovir: a meta-analysis comparing prophylactic and preemptive therapies. Clin. Infect. Dis. 43, 869–880 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Levitsky, J. et al. A survey of CMV prevention strategies after liver transplantation. Am. J. Transplant. 8, 158–161 (2008).

    CAS  PubMed  Google Scholar 

  95. Shiley, K. T. et al. Increased incidence of cytomegalovirus infection in high-risk liver transplant recipients receiving valganciclovir prophylaxis versus ganciclovir prophylaxis. Liver Transpl. 15, 963–967 (2009).

    Article  PubMed  Google Scholar 

  96. Arthurs, S. K. et al. Delayed-onset primary cytomegalovirus disease after liver transplantation. Liver Transpl. 13, 1703–1709 (2007).

    Article  PubMed  Google Scholar 

  97. Ranganathan, K. et al. Cytomegalovirus immunoglobulin decreases the risk of cytomegalovirus infection but not disease after pediatric lung transplantation. J. Heart Lung Transplant. 28, 1050–1056 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Chamberlain, C. E. et al. Pharmacokinetics of low and maintenance dose valganciclovir in kidney transplant recipients. Am. J. Transplant. 8, 1297–1302 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Brumble, L. M. et al. Prevention of cytomegalovirus infection and disease after lung transplantation: results using a unique regimen employing delayed ganciclovir. Chest 121, 407–414 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. San Juan, R. et al. A new strategy of delayed long-term prophylaxis could prevent cytomegalovirus disease in (D+/R-) solid organ transplant recipients. Clin. Transplant. 23, 666–671 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Asberg, A. et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am. J. Transplant. 7, 2106–2113 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. McGavin, J. K. & Goa, K. L. Ganciclovir: an update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs 61, 1153–1183 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Emery, V. C. & Griffiths, P. D. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc. Natl Acad. Sci. USA 97, 8039–8044 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Chou, S. W. Cytomegalovirus drug resistance and clinical implications. Transpl. Infect. Dis. 3 (Suppl. 2), 20–24 (2001).

    Article  PubMed  Google Scholar 

  105. Sia, I. G. et al. Cytomegalovirus (CMV) DNA load predicts relapsing CMV infection after solid organ transplantation. J. Infect. Dis. 181, 717–720 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Asberg, A. et al. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am. J. Transplant. 9, 1205–1213 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Humar, A. et al. Cytomegalovirus disease recurrence after ganciclovir treatment in kidney and kidney-pancreas transplant recipients. Transplantation 67, 94–97 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. Shanahan, A., Malani, P. N. & Kaul, D. R. Relapsing cytomegalovirus infection in solid organ transplant recipients. Transpl. Infect. Dis. 11, 513–518 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Eid, A. J., Arthurs, S. K., Deziel, P. J., Wilhelm, M. P. & Razonable, R. R. Clinical predictors of relapse after treatment of primary gastrointestinal cytomegalovirus disease in solid organ transplant recipients. Am. J. Transplant. 10, 157–161 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Boeckh, M. & Nichols, W. G. Immunosuppressive effects of beta-herpesviruses. Herpes 10, 12–16 (2003).

    PubMed  Google Scholar 

  111. Boivin, G., Goyette, N., Gilbert, C., Humar, A. & Covington, E. Clinical impact of ganciclovir-resistant cytomegalovirus infections in solid organ transplant patients. Transplant. Infect. Dis. 7, 166–170 (2005).

    Article  CAS  Google Scholar 

  112. Limaye, A. P., Corey, L., Koelle, D. M., Davis, C. L. & Boeckh, M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 356, 645–649 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Marfori, J. E., Exner, M. M., Marousek, G. I., Chou, S. & Drew, W. L. Development of new cytomegalovirus UL97 and DNA polymerase mutations conferring drug resistance after valganciclovir therapy in allogeneic stem cell recipients. J. Clin. Virol. 38, 120–125 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Li, F. et al. Incidence and clinical features of ganciclovir-resistant cytomegalovirus disease in heart transplant recipients. Clin. Infect. Dis. 45, 439–447 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Limaye, A. P. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin. Infect. Dis. 35, 866–872 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Gilbert, C., Bestman-Smith, J. & Boivin, G. Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resist. Updat. 5, 88–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Chou, S. Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. Rev. Med. Virol. 18, 233–246 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Chou, S., Lurain, N. S., Thompson, K. D., Miner, R. C. & Drew, W. L. Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. J. Infect. Dis. 188, 32–39 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Gilbert, C. & Boivin, G. Human cytomegalovirus resistance to antiviral drugs. Antimicrob. Agents Chemother. 49, 873–883 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Boivin, G., Goyette, N., Gilbert, C. & Covington, E. Analysis of cytomegalovirus DNA polymerase (UL54) mutations in solid organ transplant patients receiving valganciclovir or ganciclovir prophylaxis. J. Med. Virol. 77, 425–429 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Chou, S., Marousek, G. I., Van Wechel, L. C., Li, S. & Weinberg, A. Growth and drug resistance phenotypes resulting from cytomegalovirus DNA polymerase region III mutations observed in clinical specimens. Antimicrob. Agents Chemother. 51, 4160–4162 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Smith, I. L. et al. High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. J. Infect. Dis. 176, 69–77 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Mylonakis, E., Kallas, W. M. & Fishman, J. A. Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. Clin. Infect. Dis. 34, 1337–1341 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Ljungman, P. et al. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients. The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 97, 388–392 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Biron, K. K. et al. Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob. Agents Chemother. 46, 2365–2372 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pescovitz, M. D. Maribavir: a new oral anti-cytomegalovirus drug. Future Virol. 3, 435–443 (2008).

    Article  CAS  Google Scholar 

  127. Winston, D. J. et al. 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, 5403–5410 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ozaki, K. S. et al. The use of sirolimus in ganciclovir-resistant cytomegalovirus infections in renal transplant recipients. Clin. Transplant. 21, 675–680 (2007).

    Article  PubMed  Google Scholar 

  129. Shapira, M. Y. et al. Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation. Clin. Infect. Dis. 46, 1455–1457 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Avery, R. K. Update in management of ganciclovir-resistant cytomegalovirus infection. Curr. Opin. Infect. Dis. 21, 433–437 (2008).

    Article  PubMed  Google Scholar 

  131. Levi, M. E., Mandava, N., Chan, L. K., Weinberg, A. & Olson, J. L. Treatment of multidrug-resistant cytomegalovirus retinitis with systemically administered leflunomide. Transpl. Infect. Dis. 8, 38–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Battiwalla, M. et al. Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation. Transpl. Infect. Dis. 9, 28–32 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Mossad, S. B. & Avery, R. K. Second look at leflunomide “failure” to control cytomegalovirus infection in the setting of renal failure. Transpl. Infect. Dis. 9, 260 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Spivey, J. F. et al. Safety and efficacy of prolonged cytomegalovirus prophylaxis with intravenous ganciclovir in pediatric and young adult lung transplant recipients. Pediatr. Transplant. 11, 312–318 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Genentech Valcyte—Full Prescribing Information [online], (2010).

  136. Vaudry, W. et al. Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients. Am. J. Transplant. 9, 636–643 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Genentech. CYTOVENE®-IV (Ganciclovir Sodium for Injection) [online], (2010).

  138. Drugs Information. Ganciclovir (Systemic) [online], (2010).

Download references

Acknowledgements

The author appreciates the education, collegiality, philosophy, and overall experience of the members of The Transplantation Society International CMV Consensus Group. The technical expertise of Karen Manning is also greatly appreciated. L. Barclay, freelance writer and reviewer, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

  1. Infectious Diseases Division, Massachusetts General Hospital, 55 Fruit Street, Cox 5, Boston, 02114, MA, USA

    Camille N. Kotton

Authors
  1. Camille N. Kotton
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author has served as a continuing medical education speaker on the topic of CMV for Genentech and Viropharma. She led The Transplantation Society International CMV Consensus Group with an investigator-initiated independent grant from Roche (now Genentech).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kotton, C. Management of cytomegalovirus infection in solid organ transplantation. Nat Rev Nephrol 6, 711–721 (2010). https://doi.org/10.1038/nrneph.2010.141

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2010.141

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing