Abstract
We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.
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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: 543–558.
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: 4063–4071.
Maschke M, Katsrup O, Diener HC . CNS manifestations of cytomegalovirus infections. Diagnosis and treatment. CNS Drugs 2002; 16: 303–315.
Ljungman P, Griffiths P, Paya C . Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34: 1094–1097.
Seo SK, Regan A, Cihlar T, Lin DC, Boulad F, George D et al. Cytomegalovirus ventriculoencephalitis in a bone marrow transplant recipient receiving antiviral maintenance: clinical and molecular evidence of drug resistance. Clin Infect Dis 2001; 33: e105–e108.
Julin JE, van Burik JH, Krivit W, Webb C, Holman CJ, Clark HB et al. Ganciclovir-resistant cytomegalovirus encephalitis in a bone marrow transplant recipient. Transpl Infect Dis 2002; 4: 201–206.
Hamprecht K, Eckle T, Prix L, Faul C, Einsele H, Jahn G . Ganciclovir-resistant cytomegalovirus disease after allogeneic stem cell transplantation: pitfalls of phenotypic diagnosis by in vitro selection of an UL97 mutant strain. J Infect Dis 2003; 187: 139–143.
Wolf DG, Lurain NS, Zuckerman T, Hoffman R, Satinger J, Honigman A et al. Emergence of late cytomegalovirus central nervous system disease in hematopoietic stem cell transplant recipients. Blood 2003; 101: 463–465.
Zeiser R, Grullich C, Bertz H, Pantazis G, Hufert FT, Bley TA et al. Late cytomegalovirus polyradiculopathy following haploidentical CD34+ selected hematopoietic stem cell transplantation. Bone Marrow transplant 2004; 33: 243–245.
Battiwalla M, Paplham P, Almyroudis NG, McCarthy A, Abdelhalim A, Elefante A et al. Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation. Transpl Infect Dis 2006; 9: 28–32.
Miller GG, Boivin G, Dummer JS, McConnell T, Becher MW, Kassim A . Cytomegalovirus ventriculoencephalitis in a peripheral blood stem cell transplant recipient. Clin Infect Dis 2006; 42: e26–e29.
Hubacek P, Keslova P, Formankova R, Pochop P, Cinek O, Zajac M et al. Cytomegalovirus encephalitis/retinitis in allogeneic haematopoietic stem cell transplant recipient treated successfully with combination of cidofovir and foscarnet. Pediatr Transplant 2009; 13: 919–922.
Griffiths P . Cytomegalovirus infection of the central nervous system. Herpes 2004; 11 (Suppl 2): 95a–104a.
Quinnan GV, Kirmani N, Rook AH, Manischewitz JF, Jackson L, Moreschi G et al. Cytotoxic T cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N Engl J Med 1982; 307: 7–13.
Reusser P, Riddell SR, Meyers JD, Greenberg PD . Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 1991; 78: 1373–1380.
Brown JA, Boussiotis VA . Umbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution. Clin Immunol 2008; 127: 286–297.
Fletcher C, Sawchuk R, Chinnock B, de Miranda P, Balfour HH . Human pharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther 1986; 40: 281–286.
Raffi F, Taburet AM, Ghaleh B, Huart A, Singlas E . Penetration of foscarnet into cerebrospinal fluid of AIDS patients. Antimicrob Agents Chemother 1993; 37: 1777–1780.
Mylonakis E, Kallas WM, Fishman JA . Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. Clin Infect Dis 2002; 34: 1337–1341.
Boeckh M, Nichols W, Chemaly R, Papanicolaou G, Wingard J, Kirby KA et al. Prevention of late CMV disease after HCT: a randomized double-blind multicenter trial of valganciclovir prophylaxis versus PCR-guided GCV/VGCV preemptive therapy. Biol Blood Marrow Transplant 2008; 14: 30 (abstract 75).
Winston DJ, Young JH, Pullarkat V, Papanicolaou GA, Vij R, Vance E 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 2008; 111: 5403–5410.
Bidanset DJ, Beadle JR, Wan WB, Hostetler KY, Kern ER . Oral activity of ether lipid ester prodrugs of cidofovir against experimental human cytomegalovirus infection. J Infect Dis 2004; 190: 499–503.
Leen AM, Heslop HE . Cytotoxic T lymphocytes as immune-therapy in haematological practice. Br J Haematol 2008; 143: 169–179.
Wloch MK, Smith LR, Boutsaboualoy S, Reyes L, Han C, Kehler J et al. Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects. J Infect Dis 2008; 197: 1634–1642.
Go V, Pollard RB . A cytomegalovirus vaccine for transplantation: are we closer? J Infect Dis 2008; 197: 1631–1633.
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The work was carried out at UCLA Medical Center, Los Angeles, CA, USA.
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Reddy, S., Winston, D., Territo, M. et al. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant 45, 979–984 (2010). https://doi.org/10.1038/bmt.2010.35
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DOI: https://doi.org/10.1038/bmt.2010.35
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