Who Is the Patient at Risk of CMV Recurrence: A Review of the Current Scientific Evidence with a Focus on Hematopoietic Cell Transplantation

Jan Styczynski, Jan Styczynski

Abstract

Cytomegalovirus (CMV) is an agent of global infection, and its acquisition in a population is characterized by an age-dependent rise in seropositivity. After primary infection, CMV remains in the host cells in latent form, and it can reactivate in the case of immune suppression. The risk of CMV recurrence is dependent on the level of incompetency of the immune system, manifested as an impairment of T-cell immunity, including the presence and function of CMV-specific cytotoxic T lymphocytes. This article presents data on the incidence of CMV recurrence in groups of immunocompromised patients, including allogeneic hematopoietic stem cell transplantation (HSCT) patients and other groups of patients, based on a summary of reported data. The median rate of CMV recurrence in HSCT recipients was estimated as 37% after allogeneic transplant and 12% after autologous transplant, 5% in patients with nontransplant hematological malignancies, 14% in recipients of anti-CD52 therapy, 30% in solid organ transplant recipients, 21% in patients with primary immunodeficiencies, 20% during active replication in HIV-positive patients and 3.3% during antiretroviral therapy, 7% in patients with chronic kidney disease, 0.6% in patients with congenital infection, and 0.6% in neonates with primary infection. The highest risk of CMV recurrence and CMV disease is reported for HSCT CMV-seropositive recipients, regardless of donor serostatus. The odds ratio (OR) for CMV recurrence is higher for recipient-positive versus recipient-negative CMV serostatus transplants (OR 8.0), donor-negative/recipient-positive versus donor-positive/recipient-positive CMV serostatus transplants (OR 1.2), unrelated/mismatched versus matched-family donor transplants (OR 1.6), and acute graft-versus-host-disease versus other diseases (OR 3.2). Other risk factors have minor significance.

Keywords: Cytomegalovirus; Cytomegalovirus disease; Cytomegalovirus recurrence; Hematopoietic stem cell transplantation; Population; Risk factors; Risk group.

Figures

Fig. 1
Fig. 1
Groups potentially at risk of CMV infection and the rate of CMV infection. allo-HSCT allogeneic hematopoietic stem cell transplantation, auto-HSCT autologous hematopoietic stem cell transplantation, HAART highly active antiretroviral therapy, ICU intensive care unit, VLBW very low birth weight
Fig. 2
Fig. 2
Posttransplant phases with risk factors and infections in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. ADV adenovirus, CARV community-acquired respiratory viruses, CMV, EBV Epstein–Barr virus, GN gram-negative, GP gram-positive, GVHD graft-versus-host disease, HSV herpes simplex virus, PCP pneumocystis pneumonia, VOD veno-occlusive disease, VZV varicella–zoster virus
Fig. 3
Fig. 3
Estimated time-dependent cumulative incidence of CMV reactivation and CMV infection after allogeneic hematopoietic stem cell transplantation (HSCT)
Fig. 4
Fig. 4
Risk factors for CMV reactivation in allogeneic hematopoietic stem cell transplantation patients
Fig. 5
Fig. 5
Major risk factors for CMV reactivation and CMV disease in allogeneic hematopoietic stem cell transplantation patients according to number of studies indicating statistical significance in multivariate analysis. D- donor negative, GVHD graft-versus-host disease, MMD mismatched donor, R+ recipient positive, UD unrelated donor

References

    1. Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013;26(1):86–102. doi: 10.1128/CMR.00062-12.
    1. Ljungman P, Brandan R. Factors influencing cytomegalovirus seropositivity in stem cell transplant patients and donors. Haematologica. 2007;92(8):1139–1142. doi: 10.3324/haematol.11061.
    1. Ljungman P, de la Camara R, Cordonnier C, et al. Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transpl. 2008;42(4):227–240. doi: 10.1038/bmt.2008.162.
    1. Styczynski J. Managing post-transplant lymphoproliferative disorder. Expert Opin Orphan Drugs. 2017;5(1):19–35. doi: 10.1080/21678707.2017.1262256.
    1. Styczynski J, Reusser P, Einsele H. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transpl. 2009;43(10):757–770. doi: 10.1038/bmt.2008.386.
    1. Cannon MJ. Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol. 2009;46(Suppl 4):S6–S10. doi: 10.1016/j.jcv.2009.09.002.
    1. Hyde TB, Schmid DS, Cannon MJ. Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Rev Med Virol. 2010;20(5):311–326. doi: 10.1002/rmv.659.
    1. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20(4):202–213. doi: 10.1002/rmv.655.
    1. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am. 2011;25(1):151–169. doi: 10.1016/j.hoc.2010.11.011.
    1. 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(5):1373–1380.
    1. Boeckh M, Leisenring W, Riddell SR, 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(2):407–414. doi: 10.1182/blood-2002-03-0993.
    1. Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64(1):87–91. doi: 10.1093/cid/ciw668.
    1. Arav-Boger R. Strain variation and disease severity in congenital cytomegalovirus infection. in search of a viral marker. Infect Dis Clin North Am. 2015;29(3):401–414. doi: 10.1016/j.idc.2015.05.009.
    1. Renzette N, Pokalyuk C, Gibson L, et al. Limits and patterns of cytomegalovirus genomic diversity in humans. Proc Natl Acad Sci USA. 2015;112(30):E4120–E4128. doi: 10.1073/pnas.1501880112.
    1. Styczynski J, Czyzewski K, Wysocki M, et al. Increased risk of infections and infection-related mortality in children undergoing haematopoietic stem cell transplantation compared to conventional anticancer therapy: a multicentre nationwide study. Clin Microbiol Infect. 2016;22(2):179.e1–179.e10. doi: 10.1016/j.cmi.2015.10.017.
    1. Schmidt-Hieber M, Labopin M, Beelen D, et al. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: a report from the Acute Leukemia Working Party of EBMT. Blood. 2013;122(19):3359–3364. doi: 10.1182/blood-2013-05-499830.
    1. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427–2438. doi: 10.1182/blood-2015-11-679639.
    1. Nakamae H, Kirby KA, Sandmaier BM, et al. Effect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2009;15(6):694–703. doi: 10.1016/j.bbmt.2009.02.009.
    1. Green ML, Leisenring W, Xie H, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016;3(3):e119–e127. doi: 10.1016/S2352-3026(15)00289-6.
    1. Schuster MG, Cleveland AA, Dubberke ER, et al. Infections in hematopoietic cell transplant recipients: results from the organ transplant infection project, a multicenter, prospective, cohort study. Open Forum Infect Dis. 2017;4(2):ofx050. doi: 10.1093/ofid/ofx050.
    1. Ljungman P, Perez-Bercoff L, Jonsson J, et al. Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. Haematologica. 2006;91(1):78–83.
    1. Han XY. Epidemiologic analysis of reactivated cytomegalovirus antigenemia in patients with cancer. J Clin Microbiol. 2007;45(4):1126–1132. doi: 10.1128/JCM.01670-06.
    1. Inazawa N, Hori T, Nojima M, et al. Virus reactivations after autologous hematopoietic stem cell transplantation detected by multiplex PCR assay. J Med Virol. 2017;89(2):358–362. doi: 10.1002/jmv.24621.
    1. Jain T, John J, Kotecha A, et al. Cytomegalovirus infection in autologous stem cell transplant recipients in the era of rituximab. Ann Hematol. 2016;95(8):1323–1327. doi: 10.1007/s00277-016-2700-4.
    1. Marchesi F, Pimpinelli F, Ensoli F, Mengarelli A. Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant. Hematol Oncol. 2017
    1. Piukovics K, Terhes G, Gurbity-Palfi T, et al. Cytomegalovirus infection in patients with haematological diseases and after autologous stem cell transplantation as consolidation: a single-centre study. Ann Hematol. 2017;96(1):125–131. doi: 10.1007/s00277-016-2831-7.
    1. Mengarelli A, Annibali O, Pimpinelli F, et al. Prospective surveillance vs clinically driven approach for CMV reactivation after autologous stem cell transplant. J Infect. 2016;72(2):265–268. doi: 10.1016/j.jinf.2015.11.005.
    1. Marchesi F, Pimpinelli F, Gumenyuk S, et al. Cytomegalovirus reactivation after autologous stem cell transplantation in myeloma and lymphoma patients: a single-center study. World J Transpl. 2015;5(3):129–136. doi: 10.5500/wjt.v5.i3.129.
    1. Jain R, Trehan A, Mishra B, Singh R, Saud B, Bansal D. Cytomegalovirus disease in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2016;33(4):239–247. doi: 10.3109/08880018.2016.1173147.
    1. Skoetz N, Bauer K, Elter T et al. Alemtuzumab for patients with chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012;(2):CD008078.
    1. Hilal T, Slone S, Peterson S, Bodine C, Gul Z. Cytomegalovirus reactivation is associated with a lower rate of early relapse in myeloid malignancies independent of in vivo T cell depletion strategy. Leuk Res. 2017;57:37–44. doi: 10.1016/j.leukres.2017.02.009.
    1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013;45(3):260–271. doi: 10.3947/ic.2013.45.3.260.
    1. Natori Y, Humar A, Husain S, et al. Recurrence of CMV infection and the effect of prolonged antivirals in organ transplant recipients. Transplantation. 2017;101(6):1449–1454. doi: 10.1097/TP.0000000000001338.
    1. Nagai S, Mangus RS, Anderson E, et al. Cytomegalovirus infection after intestinal/multivisceral transplantation: a single-center experience with 210 cases. Transplantation. 2016;100(2):451–460. doi: 10.1097/TP.0000000000000832.
    1. Selvey LA, Lim WH, Boan P, et al. Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience. BMC Infect Dis. 2017;17(1):501. doi: 10.1186/s12879-017-2599-y.
    1. Kamar N, Mengelle C, Esposito L, et al. Predictive factors for cytomegalovirus reactivation in cytomegalovirus-seropositive kidney-transplant patients. J Med Virol. 2008;80(6):1012–1017. doi: 10.1002/jmv.21176.
    1. Cipe FE, Dogu F, Aytekin C, et al. HLA-haploidentical transplantations for primary immunodeficiencies: a single-center experience. Pediatr Transpl. 2012;16(5):451–457. doi: 10.1111/j.1399-3046.2012.01703.x.
    1. Al-Herz W, Zainal ME, Alenezi HM, Husain K, Alshemmari SH. Performance status and deaths among children registered in Kuwait National Primary ImmunoDeficiency Disorders Registry. Asian Pac J Allergy Immunol. 2010;28(2–3):141–146.
    1. Al-Herz W, Moussa MA. Survival and predictors of death among primary immunodeficient patients: a registry-based study. J Clin Immunol. 2012;32(3):467–473. doi: 10.1007/s10875-011-9636-1.
    1. Durier N, Ananworanich J, Apornpong T, et al. Cytomegalovirus viremia in Thai HIV-infected patients on antiretroviral therapy: prevalence and associated mortality. Clin Infect Dis. 2013;57(1):147–155. doi: 10.1093/cid/cit173.
    1. Brantsaeter AB, Holberg-Petersen M, Jeansson S, Goplen AK, Bruun JN. CMV quantitative PCR in the diagnosis of CMV disease in patients with HIV-infection—a retrospective autopsy based study. BMC Infect Dis. 2007;7:127. doi: 10.1186/1471-2334-7-127.
    1. Reitter A, Buxmann H, Haberl AE, et al. Incidence of CMV co-infection in HIV-positive women and their neonates in a tertiary referral centre: a cohort study. Med Microbiol Immunol. 2016;205(1):63–71. doi: 10.1007/s00430-015-0427-9.
    1. Fielding K, Koba A, Grant AD, et al. Cytomegalovirus viremia as a risk factor for mortality prior to antiretroviral therapy among HIV-infected gold miners in South Africa. PLoS One. 2011;6(10):e25571. doi: 10.1371/journal.pone.0025571.
    1. Luo B, Sun J, Cai R, et al. Spectrum of opportunistic infections and risk factors for in-hospital mortality of admitted AIDS patients in Shanghai. Medicine (Baltimore) 2016;95(21):e3802. doi: 10.1097/MD.0000000000003802.
    1. Xiao J, Gao G, Li Y, et al. Spectrums of opportunistic infections and malignancies in HIV-infected patients in tertiary care hospital, China. PLoS One. 2013;8(10):e75915. doi: 10.1371/journal.pone.0075915.
    1. Varo R, Buck WC, Kazembe PN, Phiri S, Andrianarimanana D, Weigel R. Seroprevalence of CMV, HSV-2 and HBV among HIV-infected malawian children: a cross-sectional survey. J Trop Pediatr. 2016;62(3):220–226. doi: 10.1093/tropej/fmv105.
    1. Ford N, Shubber Z, Saranchuk P, et al. Burden of HIV-related cytomegalovirus retinitis in resource-limited settings: a systematic review. Clin Infect Dis. 2013;57(9):1351–1361. doi: 10.1093/cid/cit494.
    1. Chiotan C, Radu L, Serban R, Cornacel C, Cioboata M, Anghel A. Cytomegalovirus retinitis in HIV/AIDS patients. J Med Life. 2014;7(2):237–240.
    1. Sepehrvand N, Khameneh ZR, Eslamloo HR. Survey the seroprevalence of CMV among hemodialysis patients in Urmia, Iran. Saudi J Kidney Dis Transpl. 2010;21(2):363–367.
    1. Vilibic-Cavlek T, Kolaric B, Beader N, Vrtar I, Tabain I, Mlinaric-Galinovic G. Seroepidemiology of cytomegalovirus infections in Croatia. Wien Klin Wochenschr. 2017;129(3–4):129–135. doi: 10.1007/s00508-016-1069-7.
    1. Pliquett RU, Klein C, Grunewald T, Ruf BR, Beige J. Lack of evidence for systemic cytomegalovirus reactivation in maintenance hemodialysis patients. Eur J Clin Microbiol Infect Dis. 2011;30(12):1557–1560. doi: 10.1007/s10096-011-1260-8.
    1. Wang S, Wang T, Zhang W, et al. Cohort study on maternal cytomegalovirus seroprevalence and prevalence and clinical manifestations of congenital infection in China. Medicine (Baltimore) 2017;96(5):e6007. doi: 10.1097/MD.0000000000006007.
    1. Bialas KM, Swamy GK, Permar SR. Perinatal cytomegalovirus and varicella zoster virus infections: epidemiology, prevention, and treatment. Clin Perinatol. 2015;42(1):61–75. doi: 10.1016/j.clp.2014.10.006.
    1. Kelly MS, Benjamin DK, Puopolo KM, et al. Postnatal cytomegalovirus infection and the risk for bronchopulmonary dysplasia. JAMA Pediatr. 2015;169(12):e153785. doi: 10.1001/jamapediatrics.2015.3785.
    1. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253–276. doi: 10.1002/rmv.535.
    1. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–363. doi: 10.1002/rmv.544.
    1. Karimian P, Yaghini O, Nasr Azadani H, et al. Prevalence, characteristics, and one-year follow-up of congenital cytomegalovirus infection in Isfahan City, Iran. Interdiscip Perspect Infect Dis. 2016;2016:7812106. doi: 10.1155/2016/7812106.
    1. Pokorska-Spiewak M, Niezgoda A, Golkowska M, et al. Recommendations for the diagnosis and treatment of CMV infections. Polish Society of Epidemiology and Infectious Diseases. Przegl Epidemiol. 2016;70(2):297–310.
    1. Ogonek J, Kralj Juric M, Ghimire S, et al. Immune reconstitution after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2016;7:507. doi: 10.3389/fimmu.2016.00507.
    1. Ganepola S, Gentilini C, Hilbers U, et al. Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation. Bone Marrow Transpl. 2007;39(5):293–299. doi: 10.1038/sj.bmt.1705585.
    1. Ljungman P, Brand R, Hoek J, et al. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European Group for Blood and Marrow Transplantation. Clin Infect Dis. 2014;59(4):473–481. doi: 10.1093/cid/ciu364.
    1. Zhou W, Longmate J, Lacey SF, et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood. 2009;113(25):6465–6476. doi: 10.1182/blood-2009-02-203307.
    1. Takenaka K, Nishida T, Asano-Mori Y, et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: the Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group. Biol Blood Marrow Transpl. 2015;21(11):2008–2016. doi: 10.1016/j.bbmt.2015.07.019.
    1. Ozdemir E, Saliba RM, Champlin RE, et al. Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies. Bone Marrow Transpl. 2007;40(2):125–136. doi: 10.1038/sj.bmt.1705699.
    1. 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(3):273–282. doi: 10.1086/338624.
    1. Walker CM, van Burik JA, De For TE, Weisdorf DJ. Cytomegalovirus infection after allogeneic transplantation: comparison of cord blood with peripheral blood and marrow graft sources. Biol Blood Marrow Transpl. 2007;13(9):1106–1115. doi: 10.1016/j.bbmt.2007.06.006.
    1. Marty FM, Bryar J, Browne SK, et al. 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. doi: 10.1182/blood-2007-01-069294.
    1. Nichols WG, Corey L, Gooley T, et al. 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. doi: 10.1182/blood.V97.4.867.
    1. Ljungman P, Aschan J, Lewensohn-Fuchs I, et al. Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients. Transplantation. 1998;66(10):1330–1334. doi: 10.1097/00007890-199811270-00012.
    1. Mise J, Dembitz V, Banfic H, Visnjic D. Combined inhibition of PI3K and mTOR exerts synergistic antiproliferative effect, but diminishes differentiative properties of rapamycin in acute myeloid leukemia cells. Pathol Oncol Res. 2011;17(3):645–656. doi: 10.1007/s12253-011-9365-z.
    1. Kudchodkar SB, Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes. Proc Natl Acad Sci U S A. 2006;103(38):14182–14187. doi: 10.1073/pnas.0605825103.
    1. Reddehase MJ, Balthesen M, Rapp M, Jonjic S, Pavic I, Koszinowski UH. The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease. J Exp Med. 1994;179(1):185–193. doi: 10.1084/jem.179.1.185.
    1. Lin TS, Zahrieh D, Weller E, Alyea EP, Antin JH, Soiffer RJ. Risk factors for cytomegalovirus reactivation after CD6+ T-cell-depleted allogeneic bone marrow transplantation. Transplantation. 2002;74(1):49–54. doi: 10.1097/00007890-200207150-00009.
    1. Passweg JR, Baldomero H, Bader P, et al. Impact of drug development on the use of stem cell transplantation: a report by the European Society for Blood and Marrow Transplantation (EBMT) Bone Marrow Transpl. 2017;52(2):191–196. doi: 10.1038/bmt.2016.258.
    1. Styczynski J, Tridello G, Gil L, et al. Impact of donor Epstein-Barr virus serostatus on the incidence of graft-versus-host disease in patients with acute leukemia after hematopoietic stem-cell transplantation: a study from the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation. J Clin Oncol. 2016;34(19):2212–2220. doi: 10.1200/JCO.2015.64.2405.
    1. Emery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet. 2000;355(9220):2032–2036. doi: 10.1016/S0140-6736(00)02350-3.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner