Cytomegalovirus (CMV) is a frequently encountered infection following hematopoietic cell transplantation, and tissue invasive pneumonia is a dreaded complication of the virus in this population. In this review of CMV pneumonia, we address epidemiology, pathogenesis, diagnostics, current therapy, and strategies to prevent the development of CMV. We also review emerging treatment and prevention options for this challenging disease.
KonoplevSChamplinREGiraltS. Cytomegalovirus pneumonia in adult autologous blood and marrow transplant recipients. Bone Marrow Transplant. 2001;27(8):877–881.
2.
LjungmanP. CMV infections after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008;42(suppl 1):S70–S72.
3.
BoeckhMNicholsWGPapanicolaouGRubinRWingardJRZaiaJ. Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003;9(9):543–558.
4.
GooleyTAChienJWPergamSA. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091–2101.
5.
GreenMLLeisenringWStachelD. Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18(11):1687–1699.
6.
MilanoFPergamSAXieH. Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients. Blood. 2011;118(20):5689–5696.
7.
IsonMGFishmanJA. Cytomegalovirus pneumonia in transplant recipients. Clin Chest Med. 2005;26(4):691–705.
8.
KotloffRMAhyaVNCrawfordSW. Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2004;170(1):22–48.
9.
BoeckhMLjungmanP. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711–5719.
10.
BoeckhMLeisenringWRiddellSR. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood. 2003;101(2):407–414.
11.
HakkiMRiddellSRStorekJ. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood. 2003;102(8):3060–3067.
12.
OzdemirESalibaRMChamplinRE. Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies. Bone Marrow Transplant. 2007;40(2):125–136.
JunghanssCStorbRMarisMB. Impact of unrelated donor status on the incidence and outcome of cytomegalovirus infections after non-myeloablative allogeneic stem cell transplantation. Br J Haematol. 2003;123(4):662–670.
15.
van BurikJACarterSLFreifeldAG. Higher risk of cytomegalovirus and aspergillus infections in recipients of T cell-depleted unrelated bone marrow: analysis of infectious complications in patients treated with T cell depletion versus immunosuppressive therapy to prevent graft-versus-host disease. Biol Blood Marrow Transplant. 2007;13(12):1487–1498.
16.
AlexanderBTHladnikLMAugustinKM. Use of cytomegalovirus intravenous immune globulin for the adjunctive treatment of cytomegalovirus in hematopoietic stem cell transplant recipients. Pharmacotherapy. 2010;30(6):554–561.
17.
GeorgeBPatiNGilroyN. Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis. 2010;12(4):322–329.
18.
BuyckHCPrenticeHGGriffithsPDEmeryVC. The risk of early and late CMV DNAemia associated with Campath use in stem cell transplant recipients. Bone Marrow Transplant. 2010;45(7):1212–1219.
19.
TomonariATakahashiSOoiJ. Impact of cytomegalovirus serostatus on outcome of unrelated cord blood transplantation for adults: a single-institute experience in Japan. Eur J Haematol. 2008;80(3):251–257.
20.
PergamSAXieHSandhuR. Efficiency and risk factors for CMV transmission in seronegative hematopoietic stem cell recipients. Biol Blood Marrow Transplant. 2012;18(9):1391–1400.
21.
KollmanCHoweCWAnasettiC. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98(7):2043–2051.
22.
LjungmanPBrandREinseleHFrassoniFNiederwieserDCordonnierC. Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood. 2003;102(13):4255–4260.
23.
BoeckhMNicholsWG. 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(6):2003–2008.
24.
NicholsWGCoreyLGooleyTDavisCBoeckhM. 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(3):273–282.
25.
LjungmanPHakkiMBoeckhM. Cytomegalovirus in hematopoietic stem cell transplant recipients. Infect Dis Clin North Am. 2010;24(2):319–337.
26.
TrenschelRRossSHusingJ. Reduced risk of persisting cytomegalovirus pp65 antigenemia and cytomegalovirus interstitial pneumonia following allogeneic PBSCT. Bone Marrow Transplant. 2000;25(6):665–672.
27.
BrunsteinCGBarkerJNWeisdorfDJ. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110(8):3064–3070.
28.
CornettaKLaughlinMCarterS. Umbilical cord blood transplantation in adults: results of the prospective cord blood transplantation (COBLT). Biol Blood Marrow Transplant. 2005;11(2):149–160.
29.
BaronFStorerBMarisMB. Unrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning. Biol Blood Marrow Transplant. 2006;12(11):1176–1187.
30.
PinanaJLMartinoRBarbaP. Cytomegalovirus infection and disease after reduced intensity conditioning allogeneic stem cell transplantation: single-centre experience. Bone Marrow Transplant. 2010;45(3):534–542.
31.
NakamaeHKirbyKASandmaierBM. Effect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15(6):694–703.
32.
TakenakaKGondoHTanimotoK. Increased incidence of cytomegalovirus (CMV) infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors. The Fukuoka bone marrow transplantation group. Bone Marrow Transplant. 1997;19(3):241–248.
33.
DoderoACarrabbaMMilaniR. Reduced-intensity conditioning containing low-dose alemtuzumab before allogeneic peripheral blood stem cell transplantation: graft-versus-host disease is decreased but T-cell reconstitution is delayed. Exp Hematol. 2005;33(8):920–927.
34.
HolmbergLABoeckhMHooperH. Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation. Blood. 1999;94(12):4029–4035.
35.
OrlandiEMBaldantiFCitroAPochintestaLGattiMLazzarinoM. Monitoring for cytomegalovirus and Epstein-Barr virus infection in chronic lymphocytic leukemia patients receiving i.v. fludarabine-cyclophosphamide combination and alemtuzumab as consolidation therapy. Haematologica. 2008;93(11):1758–1760.
36.
Schmidt-HieberMSchwarckSStrouxA. Immune reconstitution and cytomegalovirus infection after allogeneic stem cell transplantation: the important impact of in vivo T cell depletion. Int J Hematol. 2010;91(5):877–885.
37.
SchaenmanJMShashidharSRheeC. Early CMV viremia is associated with impaired viral control following nonmyeloablative hematopoietic cell transplantation with a total lymphoid irradiation and antithymocyte globulin preparative regimen. Biol Blood Marrow Transplant. 2011;17(5):693–702.
38.
YoonHSLeeJHChoiES. Cytomegalovirus infection in children who underwent hematopoietic stem cell transplantation at a single center: a retrospective study of the risk factors. Pediatr Transplant. 2009;13(7):898–905.
39.
Asano-MoriYKandaYOshimaK. Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation. Int J Hematol. 2008;87(3):310–318.
40.
GeorgeBKerridgeIHGilroyN. 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):141–148.
41.
OlkinuoraHvon WillebrandEKanteleJM. The impact of early viral infections and graft-versus-host disease on immune reconstitution following paediatric stem cell transplantation. Scand J Immunol. 2011;73(6):586–593.
42.
MillerWFlynnPMcCulloughJ. Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease. Blood. 1986;67(4):1162–1167.
43.
OsarogiagbonRUDeforTEWeisdorfMAEriceAWeisdorfDJ. CMV antigenemia following bone marrow transplantation: risk factors and outcomes. Biol Blood Marrow Transplant. 2000;6(3):280–288.
44.
LjungmanPPerez-BercoffLJonssonJ. Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. Haematologica. 2006;91(1):78–83.
45.
OnishiCOhashiKSawadaT. A high risk of life-threatening infectious complications in mycophenolate mofetil treatment for acute or chronic graft-versus-host disease. Int J Hematol. 2010;91(3):464–470.
46.
KasperCSayerHGMuggeLO. Combined standard graft-versus-host disease (GvHD) prophylaxis with mycophenolate mofetil (MMF) in allogeneic peripheral blood stem cell transplantation from unrelated donors. Bone Marrow Transplant. 2004;33(1):65–69.
47.
HambachLStadlerMDammannEGanserAHertensteinB. Increased risk of complicated CMV infection with the use of mycophenolate mofetil in allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;29(11):903–906.
48.
MartyFMBryarJBrowneSK. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood. 2007;110(2):490–500.
49.
RuellJBarnesCMuttonK. Active CMV disease does not always correlate with viral load detection. Bone Marrow Transplant. 2007;40(1):55–61.
50.
JangJEHyunSYKimYD. Risk factors for progression from cytomegalovirus viremia to cytomegalovirus disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(6):881–886.
51.
EmeryVCSabinCACopeAVGorDHassan-WalkerAFGriffithsPD. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet. 2000;355(9220):2032–2036.
52.
Soderberg-NauclerC. Human cytomegalovirus persists in its host and attacks and avoids elimination by the immune system. Crit Rev Immunol. 2006;26(3):231–264.
53.
ChamplinRESchmitzNHorowitzMM. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR histocompatibility and stem cell sources working committee and the European group for blood and marrow transplantation (EBMT). Blood. 2000;95(12):3702–3709.
54.
HahnGJoresRMocarskiES. Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc Natl Acad Sci U S A. 1998;95(7):3937–3942.
55.
KondoKKaneshimaHMocarskiES. Human cytomegalovirus latent infection of granulocyte-macrophage progenitors. Proc Natl Acad Sci U S A. 1994;91(25):11879–11883.
56.
KondoKMocarskiES. Cytomegalovirus latency and latency-specific transcription in hematopoietic progenitors. Scand J Infect Dis Suppl. 1995;99:63–67.
57.
KondoKXuJMocarskiES. Human cytomegalovirus latent gene expression in granulocyte-macrophage progenitors in culture and in seropositive individuals. Proc Natl Acad Sci U S A. 1996;93(20):11137–11142.
58.
Taylor-WiedemanJSissonsJGBorysiewiczLKSinclairJH. Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991;72(pt 9):2059–2064.
59.
KoffronAJHummelMPattersonBK. Cellular localization of latent murine cytomegalovirus. J Virol. 1998;72(1):95–103.
60.
KurzSKRappMSteffensHPGrzimekNKSchmalzSReddehaseMJ. Focal transcriptional activity of murine cytomegalovirus during latency in the lungs. J Virol. 1999;73(1):482–494.
61.
ToorkeyCBCarriganDR. Immunohistochemical detection of an immediate early antigen of human cytomegalovirus in normal tissues. J Infect Dis. 1989;160(5):741–751.
62.
Soderberg-NauclerCFishKNNelsonJA. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997;91(1):119–126.
63.
de MaarEFVerschuurenEAHarmsenMCTheTHvan SonWJ. Pulmonary involvement during cytomegalovirus infection in immunosuppressed patients. Transpl Infect Dis. 2003;5(3):112–120.
64.
BarrySMJohnsonMAJanossyG. Cytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisited. Bone Marrow Transplant. 2000;26(6):591–597.
65.
RiddellSR. Pathogenesis of cytomegalovirus pneumonia in immunocompromised hosts. Semin Respir Infect. 1995;10(4):199–208.
66.
GrundyJEShanleyJDGriffithsPD. Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathological condition?Lancet. 1987;2(8566):996–999.
67.
SquireSBLipmanMCBagdadesEK. Severe cytomegalovirus pneumonitis in HIV infected patients with higher than average CD4 counts. Thorax. 1992;47(4):301–304.
68.
ShanleyJDThrallRSFormanSJ. Murine cytomegalovirus replication in the lungs of athymic BALB/c nude mice. J Infect Dis. 1997;175(2):309–315.
69.
SteffensHPKurzSHoltappelsRReddehaseMJ. Preemptive CD8 T-cell immunotherapy of acute cytomegalovirus infection prevents lethal disease, limits the burden of latent viral genomes, and reduces the risk of virus recurrence. J Virol. 1998;72(3):1797–1804.
70.
RazonableRR. Immune-based therapies for cytomegalovirus infection. Immunotherapy. 2010;2(1):117–130.
71.
PergamSBoeckhMHsuK. Donor KIR3DS1 is Associated with Less CMV Disease Following Unrelated Hematopoietic Cell Transplantation in High Risk Subjects. ICAAC 49th Annual Meeting. San Francisco, CA. September 2009(Abstract 2351).
72.
ZaiaJASunJYGallez-HawkinsGM. The effect of single and combined activating killer immunoglobulin-like receptor genotypes on cytomegalovirus infection and immunity after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15(3):315–325.
73.
CookMBriggsDCraddockC. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood. 2006;107(3):1230–1232.
74.
EscudierEFleuryJCordonnierCVernantJPBernaudinJF. Large granular lymphocytes in bronchoalveolar lavage fluids from immunocompromised patients with cytomegalovirus pneumonitis. Am J Clin Pathol. 1986;86(5):641–645.
75.
BironCAByronKSSullivanJL. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med. 1989;320(26):1731–1735.
76.
PersoonsMCStalsFSvan dam MierasMCBruggemanCA. Multiple organ involvement during experimental cytomegalovirus infection is associated with disseminated vascular pathology. J Pathol. 1998;184(1):103–109.
77.
GrefteABlomNvan der GiessenMvan SonWTheTH. Ultrastructural analysis of circulating cytomegalic cells in patients with active cytomegalovirus infection: evidence for virus production and endothelial origin. J Infect Dis. 1993;168(5):1110–1118.
78.
GrefteAvan der GiessenMvan SonWTheTH. Circulating cytomegalovirus (CMV)-infected endothelial cells in patients with an active CMV infection. J Infect Dis. 1993;167(2):270–277.
79.
LjungmanPGriffithsPPayaC. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002;34(8):1094–1097.
80.
CrumpackerCSZhangJL.Cytomegalovirus. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone; 1971–1987.
81.
FranquetTLeeKSMullerNL. Thin-section CT findings in 32 immunocompromised patients with cytomegalovirus pneumonia who do not have AIDS. AJR Am J Roentgenol. 2003;181(4):1059–1063.
GasparettoELOnoSEEscuissatoD. Cytomegalovirus pneumonia after bone marrow transplantation: high resolution CT findings. Br J Radiol. 2004;77(921):724–727.
ShimadaAKogaTShimadaM. Cytomegalovirus pneumonitis presenting small nodular opacities. Intern Med. 2004;43(12):1198–1200.
86.
TammMTraenklePGrilliB. Pulmonary cytomegalovirus infection in immunocompromised patients. Chest. 2001;119(3):838–843.
87.
CrawfordSWBowdenRAHackmanRCGleavesCAMeyersJDClarkJG. Rapid detection of cytomegalovirus pulmonary infection by bronchoalveolar lavage and centrifugation culture. Ann Intern Med. 1988;108(2):180–185.
88.
GleavesCAMeyersJD. Rapid detection of cytomegalovirus in bronchoalveolar lavage specimens from marrow transplant patients: evaluation of a direct fluorescein-conjugated monoclonal antibody reagent. J Virol Methods. 1989;26(3):345–349.
89.
ErikssonBMBryttingMZweygberg-WirgartBHillerdalGOlding-StenkvistELindeA.Diagnosis of cytomegalovirus in bronchoalveolar lavage by polymerase chain reaction, in comparison with virus isolation and detection of viral antigen. Scand J Infect Dis. 1993;25(4):421–427.
90.
CathomasGMorrisPPekleKCunninghamIEmanuelD. Rapid diagnosis of cytomegalovirus pneumonia in marrow transplant recipients by bronchoalveolar lavage using the polymerase chain reaction, virus culture, and the direct immunostaining of alveolar cells. Blood. 1993;81(7):1909–1914.
91.
RuutuPRuutuTVolinLTukiainenPUkkonenPHoviT. Cytomegalovirus is frequently isolated in bronchoalveolar lavage fluid of bone marrow transplant recipients without pneumonia. Ann Intern Med. 1990;112(12):913–916.
92.
TangYWJohnsonJEBrowningPJ. Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol. 2003;41(6):2633–2640.
93.
CrawfordSWHackmanRCClarkJG. Open lung biopsy diagnosis of diffuse pulmonary infiltrates after marrow transplantation. Chest. 1988;94(5):949–953.
94.
MyersonDHackmanRCNelsonJAWardDCMcDougallJK. Widespread presence of histologically occult cytomegalovirus. Hum Pathol. 1984;15(5):430–439.
95.
RenaudCCampbellAP. Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients. Curr Opin Infect Dis. 2011;24(4):333–343.
96.
GasparettoELEscuissatoDLInoueCMarchioriEMullerNL. Herpes simplex virus type 2 pneumonia after bone marrow transplantation: high-resolution CT findings in 3 patients. J Thorac Imaging. 2005;20(2):71–73.
97.
HanCSMillerWHaakeRWeisdorfD. Varicella zoster infection after bone marrow transplantation: incidence, risk factors and complications. Bone Marrow Transplant. 1994;13(3):277–283.
98.
MariotteESchnellDScieuxC. Significance of herpesvirus 6 in BAL fluid of hematology patients with acute respiratory failure. Infection. 2011;39(3):225–230.
99.
DuleryRSalleronJDewildeA. Early human herpesvirus type 6 reactivation after allogeneic stem cell transplantation: a large-scale clinical study. Biol Blood Marrow Transplant. 2012;18(7):1080–1089.
100.
ConeRW. Human herpesvirus 6 as a possible cause of pneumonia. Semin Respir Infect. 1995;10(4):254–258.
101.
ConeRWHackmanRCHuangML. Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation. N Engl J Med. 1993;329(3):156–161.
102.
IsonMG. Adenovirus infections in transplant recipients. Clin Infect Dis. 2006;43(3):331–339.
103.
Panoskaltsis-MortariAGrieseMMadtesDK. An official American thoracic society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome. Am J Respir Crit Care Med. 2011;183(9):1262–1279.
104.
JintaMOhashiKOhtaT. Clinical features of allogeneic hematopoietic stem cell transplantation-associated organizing pneumonia. Bone Marrow Transplant. 2007;40(5):465–472.
105.
YoshiharaSYanikGCookeKRMineishiS. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(7):749–759.
106.
BarberNAGantiAK. Pulmonary toxicities from targeted therapies: a review. Target Oncol. 2011;6(4):235–243.
107.
PatelAVHahnTBognerPN. Fatal diffuse alveolar hemorrhage associated with sirolimus after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2010;45(8):1363–1364.
108.
MachadoCMDulleyFLBoasLS. CMV pneumonia in allogeneic BMT recipients undergoing early treatment of pre-emptive ganciclovir therapy. Bone Marrow Transplant. 2000;26(4):413–417.
109.
SheppDHDandlikerPSde MirandaP. Activity of 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine in the treatment of cytomegalovirus pneumonia. Ann Intern Med. 1985;103(3):368–373.
110.
BironKK. Antiviral drugs for cytomegalovirus diseases. Antiviral Res. 2006;71(2-3):154–163.
111.
LjungmanPDeliliersGLPlatzbeckerU. 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. 2001;97(2):388–392.
112.
HakkiMChouS. The biology of cytomegalovirus drug resistance. Curr Opin Infect Dis. 2011;24(6):605–611.
113.
BironKKHarveyRJChamberlainSC. Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents Chemother. 2002;46(8):2365–2372.
114.
AveryRKMartyFMStrasfeldL. Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients. Transpl Infect Dis. 2010;12(6):489–496.
115.
Maribavir for Treatment of Resistant or Refractory CMV Infections in Transplant Recipients. ClinicalTrials.gov Identifier NCT01611974. ClinicalTrials.gov. Accessed June 2012.
116.
PriceNBPrichardMN. Progress in the development of new therapies for herpesvirus infections. Curr Opin Virol. 2011;1(6):548–554.
117.
GoldnerTHewlettGEttischerNRuebsamen-SchaeffHZimmermannHLischkaP. The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011;85(20):10884–10893.
118.
KaulDRStoelbenSCoberE. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am J Transplant. 2011;11(5):1079–1084.
119.
WaldmanWJKnightDALurainNS. Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation. 1999;68(6):814–825.
120.
AveryRKBolwellBJYen-LiebermanB. Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection. Bone Marrow Transplant. 2004;34(12):1071–1075.
121.
BattiwallaMPaplhamPAlmyroudisNG. Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation. Transpl Infect Dis. 2007;9(1):28–32.
122.
SnydmanDR. Cytomegalovirus immunoglobulins in the prevention and treatment of cytomegalovirus disease. Rev Infect Dis. 1990;12(suppl 7):S839–S848.
123.
SchmidtGMKovacsAZaiaJA. Ganciclovir/immunoglobulin combination therapy for the treatment of human cytomegalovirus-associated interstitial pneumonia in bone marrow allograft recipients. Transplantation. 1988;46(6):905–907.
124.
ReedECBowdenRADandlikerPSLillebyKEMeyersJD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med. 1988;109(10):783–788.
125.
EmanuelDCunninghamIJules-ElyseeK. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med. 1988;109(10):777–782.
126.
ErardVGuthrieKSmithJ. Cytomegalovirus pneumonia after hematopoietic cell transplantation: outcomes and factors associated with mortality. Paper presented at: the Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL: September 2007. Abstract V-1379.
127.
LjungmanPEngelhardDLinkH. 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(4):831–835.
128.
LjungmanPCordonnierCEinseleH. 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(5):473–476.
129.
GerdemannUVeraJFRooneyCMLeenAM.Generation of multivirus-specific T cells to prevent/treat viral infections after allogeneic hematopoietic stem cell transplant. J. Vis. Exp. 2011;(51):e2736.
130.
HanleyPJCruzCRSavoldoB. Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood. 2009;114(9):1958–1967.
131.
BaoLDunhamKStamerMMulieriKMLucasKG. Expansion of cytomegalovirus pp65 and IE-1 specific cytotoxic T lymphocytes for cytomegalovirus-specific immunotherapy following allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008;14(10):1156–1162.
132.
O'ReillyRJDoubrovinaETrivediDHasanAKollenWKoehneG. Adoptive transfer of antigen-specific T-cells of donor type for immunotherapy of viral infections following allogeneic hematopoietic cell transplants. Immunol Res. 2007;38(1-3):237–250.
133.
AtkinsonKDownsKGoleniaM. Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection. Br J Haematol. 1991;79(1):57–62.
134.
WinstonDJHoWGBartoniK. 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(3):179–184.
135.
SalzbergerBBowdenRAHackmanRCDavisCBoeckhM. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood. 1997;90(6):2502–2508.
136.
BurnsLJMillerWKandaswamyC. Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation. Bone Marrow Transplant. 2002;30(12):945–951.
137.
LiCRGreenbergPDGilbertMJGoodrichJMRiddellSR. 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(7):1971–1979.
138.
BoeckhM. Current antiviral strategies for controlling cytomegalovirus in hematopoietic stem cell transplant recipients: prevention and therapy. Transpl Infect Dis. 1999;1(3):165–178.
139.
LjungmanPde La CamaraRMilpiedN. Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood. 2002;99(8):3050–3056.
140.
WinstonDJYeagerAMChandrasekarPHSnydmanDRPetersenFBTerritoMC. Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation. Clin Infect Dis. 2003;36(6):749–758.
141.
WinstonDJYoungJAPullarkatV. 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(11):5403–5410.
142.
MartyFMLjungmanPPapanicolaouGA. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011;11(4):284–292.
143.
MartyFMWinstonDRowleySDBoeckhM. CMX001 for Prevention and Control of CMV Infection in CMV-Seropositive Allogeneic Stem-Cell Transplant Recipients: A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial of Safety, Tolerability and Antiviral Activity. ASBMT Tandem Meeting. San Diego, CA. February 2012. (Abstract S203).
144.
ZimmermannH and the AIC246 Study Team. Letermovir (AIC246) for prevention of HCMV infections in patients after human blood precursor cell transplantation: a randomised, double-blind, placebocontrolled trial to evaluate the safety, tolerability and antiviral activity of 12 weeks treatment. 23rd European Congress of Clinical Microbiology and Infectious Diseases. London, England. April 2012. (Abstract LB2815).
145.
PollackMHeugelJXieH. An international comparison of current strategies to prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2011;17(5):664–673.
146.
BoeckhMGooleyTAMyersonDCunninghamTSchochGBowdenRA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood. 1996;88(10):4063–4071.
147.
de GastGCBolandGJVliegerAM. Abortive human cytomegalovirus infection in patients after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1992;9(4):221–225.
148.
RaananiPGafter-GviliAPaulMBen-BassatILeiboviciLShpilbergO. Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol. 2009;27(5):770–781.
149.
Kharfan-DabajaMABoeckhMWilckMB. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2012;12(4):290–299.
150.
GriffithsPDStantonAMcCarrellE. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011;377(9773):1256–1263.
151.
La RosaCLongmateJLaceySF. Clinical evaluation of safety and immunogenicity of PADRE-cytomegalovirus (CMV) and tetanus-CMV fusion peptide vaccines with or without PF03512676 adjuvant. J Infect Dis. 2012;205(8):1294–1304.
152.
BacigalupoATedoneESannaMA. CMV infections following allogeneic BMT: risk factors, early treatment and correlation with transplant related mortality. Haematologica. 1992;77(6):507–513.
153.
Matthes-MartinSLionTAberleSW. Pre-emptive treatment of CMV DNAemia in paediatric stem cell transplantation: the impact of recipient and donor CMV serostatus on the incidence of CMV disease and CMV-related mortality. Bone Marrow Transplant. 2003;31(9):803–808.
154.
LjungmanPAschanJLewensohn-FuchsI. Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients. Transplantation. 1998;66(10):1330–1334.
155.
JaskulaEDlubekDSedzimirskaMDudaDTarnowskaALangeA. Reactivations of cytomegalovirus, human herpes virus 6, and Epstein-Barr virus differ with respect to risk factors and clinical outcome after hematopoietic stem cell transplantation. Transplant Proc. 2010;42(8):3273–3276.
156.
BachanovaVBrunsteinCGBurnsLJ. Fewer infections and lower infection-related mortality following non-myeloablative versus myeloablative conditioning for allotransplantation of patients with lymphoma. Bone Marrow Transplant. 2009;43(3):237–244.
157.
ScheteligJOswaldOSteuerN. Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia. Bone Marrow Transplant. 2003;32(7):695–701.
158.
NicholsWGCoreyLGooleyT. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes. Blood. 2001;97(4):867–874.
159.
LonnqvistBRingdenOWahrenBGahrtonGLundgrenG. Cytomegalovirus infection associated with and preceding chronic graft-versus-host disease. Transplantation. 1984;38(5):465–468.
160.
RembergerMAschanJBarkholtLTollemarJRingdenO. Treatment of severe acute graft-versus-host disease with anti-thymocyte globulin. Clin Transplant. 2001;15(3):147–153.
