Cytomegalovirus infection/disease after hematopoietic stem cell transplantation
Progress in Hematology Infectious complications after hematopoietic stem cell transplantation
First Online: 23 April 2010 Received: 10 August 2009 Revised: 07 April 2010 Accepted: 07 April 2010 DOI:
Cite this article as: Mori, T. & Kato, J. Int J Hematol (2010) 91: 588. doi:10.1007/s12185-010-0569-x Abstract
Cytomegalovirus (CMV) disease has historically been a main cause of death after allogeneic hematopoietic stem cell transplantation (HSCT). Since the introduction of prophylactic or preemptive therapy against CMV, the incidence of CMV disease has been successfully reduced. However, breakthrough CMV disease, particularly CMV gastrointestinal disease, remains one of the major infectious complications. Administration of an antiviral agent, ganciclovir, is often associated with myelotoxicity in HSCT recipients, and delayed immune reconstitution against CMV. Delayed immune reconstitution is a possible cause of the increasing incidence of late (more than 3 months after transplant) CMV disease after HSCT in this era of preemptive therapy. Foscarnet and valganciclovir are the available alternatives to intravenous ganciclovir. Foscarnet is not myelotoxic and has a toxicity profile different from ganciclovir. Valganciclovir, a prodrug of ganciclovir, has a higher bioavailability than oral ganciclovir and could be of clinical use, particularly in the outpatient setting or for patients requiring long-term antiviral therapy. Recent technological developments have enabled the visualization and isolation of CMV-specific T cells. Using these techniques, an individualized approach could be conducted based on each patient’s immune reconstitution against CMV. In this review, we summarize the recent progress and current knowledge of CMV infection and disease after allogeneic HSCT.
Keywords Cytomegalovirus Hematopoietic stem cell transplantation CMV antigenemia Preemptive therapy Prophylactic therapy Real-time PCR Ganciclovir Foscarnet Immunotherapy References
Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003;9:543–58.
Avery RK, Adal KA, Longworth DL, Bolwell BJ. A survey of allogeneic bone marrow transplant programs in the United States regarding cytomegalovirus prophylaxis and pre-emptive therapy. Bone Marrow Transplant. 2000;26:763–7.
Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood. 2004;103:2003–8.
Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C. Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood. 2003;102:4255–60.
Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis. 2002;185:273–82.
Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113:5711–9.
Bowden RA, Slichter SJ, Sayers M, Weisdorf D, Cays M, Schoch G, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood. 1995;86:3598–603.
Nichols WG, Price TH, Gooley T, Corey L, Boeckh M. Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood. 2003;101:4195–200.
Vamvakas EC. Is white blood cell reduction equivalent to antibody screening in preventing transmission of cytomegalovirus by transfusion? A review of the literature and meta-analysis. Transfus Med Rev. 2005;19:181–99.
Bowden RA, Fisher LD, Rogers K, Cays M, Meyers JD. Cytomegalovirus (CMV)-specific intravenous immunoglobulin for the prevention of primary CMV infection and disease after marrow transplant. J Infect Dis. 1991;164:483–7.
Ruutu T, Ljungman P, Brinch L, Lenhoff S, Lönnqvist B, Ringdén O, Ruutu P, et al. No prevention of cytomegalovirus infection by anti-cytomegalovirus hyperimmune globulin in seronegative bone marrow transplant recipients. The Nordic BMT Group. Bone Marrow Transplant. 1997;19:233–6.
Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol. 2009;27:770–81.
Gluckman E, Lotsberg J, Devergie A, Zhao XM, Melo R, Gomez-Morales M, Nebout T, Mazeron MC, Perol Y. Prophylaxis of herpes infections after bone-marrow transplantation by oral acyclovir. Lancet. 1983;2:706–8.
Meyers JD, Reed EC, Shepp DH, Thornquist M, Dandliker PS, Vicary CA, et al. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. N Engl J Med. 1988;318:70–5.
Selby PJ, Powles RL, Easton D, Perren TJ, Stolle K, Jameson B, et al. The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation. Br J Cancer. 1989;59:434–8.
Prentice HG, Gluckman E, Powles RL, Ljungman P, Milpied N, Fernandez Rañada JM, et al. Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group. Lancet. 1994;343:749–53.
Prentice HG, Gluckman E, Powles RL, Ljungman P, Milpied NJ, Camara R, et al. Long-term survival in allogeneic bone marrow transplant recipients following acyclovir prophylaxis for CMV infection. The European Acyclovir for CMV Prophylaxis Study Group. Bone Marrow Transplant. 1997;19:129–33.
Talarico CL, Burnette TC, Miller WH, Smith SL, Davis MG, Stanat SC, et al. Acyclovir is phosphorylated by the human cytomegalovirus UL97 protein. Antimicrob Agents Chemother. 1999;43:1941–6.
Ljungman P, de La Camara R, Milpied N, Volin L, Russell CA, Crisp A, et al. Valacyclovir International Bone Marrow Transplant Study Group. Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood. 2002;99:3050–6.
Winston DJ, Yeager AM, Chandrasekar PH, Snydman DR, Petersen FB, Territo MC. Valacyclovir Cytomegalovirus Study Group. Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation. Clin Infect Dis. 2003;36:749–58.
Mori T, Aisa Y, Shimizu T, Nakazato T, Yamazaki R, Ikeda Y, et al. Prevention of cytomegalovirus infection by valaciclovir after allogeneic bone marrow transplantation from an unrelated donor. Int J Hematol. 2006;83:266–70.
Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med. 1993;118:173–8.
Winston DJ, Ho WG, Bartoni K, Du Mond C, Ebeling DF, Buhles WC, et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial. Ann Intern Med. 1993;118:179–84.
Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood. 1996;88:4063–71.
O’Brien S, Ravandi F, Riehl T, Wierda W, Huang X, Tarrand J, et al. Valganciclovir prevents cytomegalovirus reactivation in patients receiving alemtuzumab-based therapy. Blood. 2008;111:1816–9.
Schmidt GM, Horak DA, Niland JC, Duncan SR, Forman SJ, Zaia JA. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants; The City of Hope-Stanford-Syntex CMV Study Group. N Engl J Med. 1991;324:1005–11.
Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF, Buhles WC, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med. 1991;325:1601–7.
Einsele H, Ehninger G, Hebart H, Wittkowski KM, Schuler U, Jahn G, Mackes P, et al. Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood. 1995;86:2815–20.
Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood. 1994;83:1971–9.
Mori T, Mori S, Kanda Y, Yakushiji K, Mineishi S, Takaue YG, et al. Clinical significance of cytomegalovirus (CMV) antigenemia in the prediction and diagnosis of CMV gastrointestinal disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2004;33:431–4.
Kanda Y, Mineishi S, Saito T, Seo S, Saito A, Suenaga KO, et al. Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan. Bone Marrow Transplant. 2001;27:437–44.
Mori T, Okamoto S, Matsuoka S, Yajima T, Wakui M, Watanabe R, et al. Risk-adapted pre-emptive therapy for cytomegalovirus disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant. 2000;25:765–9.
Mori T, Okamoto S, Watanabe R, Yajima T, Iwao Y, Yamazaki R, et al. Dose-adjusted preemptive therapy for cytomegalovirus disease based on real-time polymerase chain reaction after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29:777–82.
Choi SM, Lee DG, Choi JH, Yoo JH, Kim YJ, Park SH, et al. Risk-adapted preemptive therapy for cytomegalovirus disease after allogeneic stem cell transplantation: a single-center experience in Korea. Int J Hematol. 2005;81:69–74.
Mori T, Okamoto S, Watanabe R, Yamazaki R, Tsukada Y, Nagayama H, et al. Incidence of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell recipients at low risk of CMV infection. Bone Marrow Transplant. 2002;29:1005–6.
Moretti S, Zikos P, Van Lint MT, Tedone E, Occhini D, Gualandi F, et al. Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after allogeneic hemopoietic stem cell transplantation (HSCT): a randomised study. Bone Marrow Transplant. 1998;22:175–80.
Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, et al. Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood. 2002;99:1159–64.
Ayala E, Greene J, Sandin R, Perkins J, Field T, Tate C, et al. Valganciclovir is safe and effective as pre-emptive therapy for CMV infection in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2006;37:851–6.
Busca A, de Fabritiis P, Ghisetti V, Allice T, Mirabile M, Gentile G, et al. Oral valganciclovir as preemptive therapy for cytomegalovirus infection post allogeneic stem cell transplantation. Transpl Infect Dis. 2007;9:102–7.
Candoni A, Simeone E, Tiribelli M, Pipan C, Fanin R. What is the optimal dosage of valganciclovir as preemptive therapy for CMV infection in allogeneic hematopoietic SCT? Bone Marrow Transplant. 2008;42:207–8.
Takenaka K, Eto T, Nagafuji K, Kamezaki K, Matsuo Y, Yoshimoto G, et al. Fukuoka Blood and Marrow Transplant Group (FBMTG). Oral valganciclovir as preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients. Int J Hematol. 2009;89:231–7.
Einsele H, Reusser P, Bornhäuser M, Kalhs P, Ehninger G, Hebart H, et al. Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation. Blood. 2006;107:3002–8.
van der Meer JT, Drew WL, Bowden RA, Galasso GJ, Griffiths PD, Jabs DA, et al. Summary of the international consensus symposium on advances in the diagnosis, treatment and prophylaxis and cytomegalovirus infection. Antiviral Res. 1996;32:119–40.
Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002;34:1094–7.
Ando Y, Terao K, Narita M, Oguchi Y, Sata T, Iwasaki T. Quantitative analyses of cytomegalovirus genome in aqueous humor of patients with cytomegalovirus retinitis. Jpn J Ophthalmol. 2002;46:254–60.
Emanuel D, Cunningham I, Jules EK, Brochstein JA, Kernan NA, Laver J, et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med. 1988;109:777–82.
Ljungman P, Engelhard D, Link H, Biron P, Brandt L, Brunet S, et al. Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous immune globulin: experience of European Bone Marrow Transplant Group. Clin Infect Dis. 1992;14:831–5.
Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med. 1988;109:783–8.
Schmidt GM, Kovacs A, Zaia JA, Horak DA, Blume KG, Nademanee AP, et al. Ganciclovir/immunoglobulin combination therapy for the treatment of human cytomegalovirus-associated interstitial pneumonia in bone marrow allograft recipients. Transplantation. 1988;46:905–7.
Machado CM, Dulley FL, Boas LS, Castelli JB, Macedo MC, Silva RL, et al. CMV pneumonia in allogeneic BMT recipients undergoing early treatment of pre-emptive ganciclovir therapy. Bone Marrow Transplant. 2000;26:413–7.
Ljungman P, Cordonnier C, Einsele H, Bender-Götze C, Bosi A, Dekker A, et al. Use of intravenous immune globulin in addition to antiviral therapy in the treatment of CMV gastrointestinal disease in allogeneic bone marrow transplant patients: a report from the European Group for Blood and Marrow Transplantation (EBMT). Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant. 1998;21:473–6.
Keenan RD, Ainsworth J, Khan N, Bruton R, Cobbold M, Assenmacher M, et al. Purification of cytomegalovirus-specific CD8 T cells from peripheral blood using HLA-peptide tetramers. Br J Haematol. 2001;115:428–34.
Cwynarski K, Ainsworth J, Cobbold M, Wagner S, Mahendra P, Apperley J, et al. Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. Blood. 2001;97:1232–40.
Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333:1038–44.
Einsele H, Roosnek E, Rufer N, Sinzger C, Riegler S, Löffler J, et al. Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood. 2002;99:3916–22.
Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet. 2003;362:1375–7.
Rauser G, Einsele H, Sinzger C, Wernet D, Kuntz G, Assenmacher M, et al. Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood. 2004;103:3565–72.
Boeckh M, Leisenring W, Riddell SR, Bowden RA, Huang ML, Myerson D, et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood. 2003;101:407–14.
CrossRef PubMed Copyright information
© The Japanese Society of Hematology 2010