2021, Number 1
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Rev Cubana Hematol Inmunol Hemoter 2021; 37 (1)
Cytomegalovirus in hematopoietic stem cell transplant recipients
Jaime FJC, Roque GW, Castellanos HL
Language: Spanish
References: 76
Page: 1-25
PDF size: 391.20 Kb.
ABSTRACT
Introduction:
Cytomegalovirus infection is very common in patients undergoing hematopoietic progenitor transplantation, due to myeloablative conditioning treatments, genetic disparity, and immunosuppressive treatment, and occurs mainly after the engrafment.
Objective:
A review and update of the diagnosis and management of cytomegalovirus is made in hematopoietic transplant recipients.
Method:
A bibliographic review was carried out in Spanish and English, using the search engines of Pubmed, Scholar Google and Scielo about the diagnosis and management of cytomegalovirus in hematopoietic transplant recipients.
Development:
The information obtained was collected and organized chronologically about the emergence of techniques for diagnosis and the appearance of new drugs in recent years. Recent articles by experts in prestigious journals were reviewed and the importance of early diagnosis and initiation of treatment is evidenced.
Conclusions:
There are currently new forms of diagnosis and novel medications, but mortality can be high, if the patient is not treated before the symptoms of the disease appear and even despite treatment, sometimes it is not possible to eradicate the virus, leading to major complications and death. Cytomegalic disease continues to be a frequent complication in these patients despite measures to prevent virus reactivation.
REFERENCES
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 Jan;101(2):407-14.
Locatelli F, Crotta A, Ruggeri A, Eapen M, Wagner JE, Macmillan ML, et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood. 2013 Sep;122(12):2135-41.
Raffucci fl. Cytomegalovirus infection. Br Med J. Sep 1965;2(5463):663-4.
Zuhair M, Smit GSA, Wallis G, Jabbar F, Smith C, Devleesschauwer B, Griffiths P. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol. 2019 May;29(3):e2034.
Hill JA, Mayer BT, Xie H, Leisenring WM, Huang ML, Stevens-Ayers T, et al. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood. 2017 Apr;129(16):2316-25.
Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P, et al. Acute and Chronic Leukemia Working Parties; Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005 Nov;36(9):757-69.
Li G, Kamil JP. Viral Regulation of Cell Tropism in Human Cytomegalovirus. J Virol. 2015 Nov;90(2):626-9.
Sousa H, Boutolleau D, Ribeiro J, Teixeira AL, Pinho Vaz C, Campilho F, et al. Cytomegalovirus infection in patients who underwent allogeneic hematopoietic stem cell transplantation in Portugal: a five-year retrospective review. Biol Blood Marrow Transplant. 2014 Dec;20(12):1958-67.
Morayta-Ramírez A, Bonilla-Reyna MA, Martínez-Bustamante ME, Ordoñez-Ortega J, Miranda-Madrazo R, Gutiérrez-Hernández S. Infección por citomegalovirus en el paciente sometido a trasplante de progenitores hematopoyéticos: Reporte de caso y revisión de la literatura. Rev Latin Infect Pediatr. Abr-Jun 2018;31(2):76-9.
Rowe RG, Guo D, Lee M, Margossian S, London WB, Lehmann L. Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation: Risk Factors for Primary Infection and Cases of Recurrent and Late Infection at a Single Center. Biol Blood Marrow Transplant. 2016 Jul;22(7):1275-83.
Broers AE, van Der Holt R, van Esser JW, Gratama JW, Henzen-Logmans S, Kuenen-Boumeester V, et al. Cornelissen JJ. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. Blood. Apr 2000;95(7):2240-5.
Peric Z, Wilson J, Durakovic N, Ostojic A, Desnica L, Vranjes VR, et al. Early human cytomegalovirus reactivation is associated with lower incidence of relapse of myeloproliferative disorders after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018 Nov;53(11):1450-56.
Della Chiesa M, Falco M, Podestà M, Locatelli F, Moretta L, Frassoni F, et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood. 2012 Jan;119(2):399-410.
Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005 Sep;202(5):673-85.
Boeckh M, Geballe AP. Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest. 2011 May;121(5):1673-80.
Król L, Stuchlý J, Hubácek P, Keslová P, Sedlácek P, Starý J, et al. Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT. Bone Marrow Transplant. Aug 2011;46(8):1089-98.
Komanduri KV, Wieder ED, Benjamin CL, Levy RB. The evolving art of hematopoietic stem cell transplantation: translational research in post-transplant immune reconstitution and immunosuppression. Immunol Res. 2013 Dec;57(1-3):140-50.
Krol L, Stuchly J, Hubacek P, Keslova P, Sedlacek P, Stary J, et al. Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT. 2011 Aug;46(8):1089-98
Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017 Dec;10(4):233-238.
Crough T, Khanna R. Immunobiology of human cytomegalovirus: from bench to bedside. Clin Microbiol Rev. 2009 Jan;22(1):76-98
Gillespie GM, Wills MR, Appay V, O'Callaghan C, Murphy M, Smith N, et al. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J Virol. 2000 Sep;74(17):8140-50.
de la Cámara R. CMV in Hematopoietic Stem Cell Transplantation. Mediterr J Hematol Infect Dis. Jun 2016;8(1):e2016031.
Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, et al. Maribavir 1263-300 Clinical Study Group. 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 Apr;11(4):284-92.
Marty FM, Winston DJ, Rowley SD, Vance E, Papanicolaou GA, Mullane KM, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013 Sep;369(13):1227-36.
Chemaly RF, Ullmann AJ, Stoelben S, Richard MP, Bornhäuser M, Groth C, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014 May;370(19):1781-9.
Boeckh M, Nichols WG, Chemaly RF, Papanicolaou GA, Wingard JR, Xie H, et al. Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial. Ann Intern Med. 2015 Jan;162(1):1-10.
Lin CH, Su YJ, Hsu CY, Wang PN, Teng CJ. Haploidentical allogeneic hematopoietic stem cell transplantation increases the risk of cytomegalovirus infection in adult patients with acute leukemia. Transpl Infect Dis. 2019 Aug;21(4):e13096.
Styczynski J. Who Is the Patient at Risk of CMV Recurrence: A Review of the Current Scientific Evidence with a Focus on Hematopoietic Cell Transplantation. Infect Dis Ther. 2018 Mar;7(1):1-16.
Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec;377(25):2433-44.
Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan;64(1):87-91.
Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, et al; 2017 European Conference on Infections in Leukaemia group. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. Aug 2019;19(8):e260-e272.
Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002 Apr;34(8):1094-7.
Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, et al. Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019 Apr;68(8):1420-14.
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 Apr;324(15):1005-11.
Chetty R, Roskell DE. Cytomegalovirus infection in the gastrointestinal tract. J Clin Pathol. 1994 Nov;47(11):968-72.
Dioverti MV, Razonable RR. Cytomegalovirus. Microbiol Spectr. Aug 2016;4(4). DOI: https://10.1128/microbiolspec.DMIH2-0022-2015
Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-31.
Hodinka R. 2015. Human Cytomegalovirus, p 1718-1737. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. DOI: https://10.1128/9781555817381.ch100
Martín Peinador, Y. (Internet) Grupo de Patología Infecciosa AEPap. Aproximación diagnóstica a la infección por citomegalovirus. Jun 2014;.[acceso 08/03/2020] [acceso 08/03/2020] https://aepap.org/grupos/grupo-de-patologia-infecciosa/contenido/documentos-del-gpi .
Caliendo AM. The long road toward standardization of viral load testing for cytomegalovirus. Clin Infect Dis. 2013 Feb;56(3):374-5.
Fryer JF, Heath AB, Minor PD; Collaborative Study Group. A collaborative study to establish the 1st WHO International Standard for human cytomegalovirus for nucleic acid amplification technology. Biologicals. Jul 2016;44(4):242-51.
Abdul-Ali D, Kraft CS, Ingersoll J, Frempong M, Caliendo AM. Cytomegalovirus DNA stability in EDTA anti-coagulated whole blood and plasma samples. J Clin Virol. 2011 Nov;52(3):222-4.
Kraft CS, Armstrong WS, Caliendo AM. Interpreting quantitative cytomegalovirus DNA testing: understanding the laboratory perspective. Clin Infect Dis. 2012 Jun;54(12):1793-7.
Babady NE, Cheng C, Cumberbatch E, Stiles J, Papanicolaou G, Tang YW. Monitoring of cytomegalovirus viral loads by two molecular assays in whole-blood and plasma samples from hematopoietic stem cell transplant recipients. J Clin Microbiol. 2015 Apr;53(4):1252-7.
Dioverti MV, Lahr BD, Germer JJ, Yao JD, Gartner ML, Razonable RR. Comparison of Standardized Cytomegalovirus (CMV) Viral Load Thresholds in Whole Blood and Plasma of Solid Organ and Hematopoietic Stem Cell Transplant Recipients with CMV Infection and Disease. Open Forum Infect Dis. Jul 2017;4(3):ofx143.
Caliendo AM, St George K, Kao SY, Allega J, Tan BH, LaFontaine R, 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. 2000 Jun;38(6):2122-7.
Wreghitt TG, Teare EL, Sule O, Devi R, Rice P. Cytomegalovirus infection in immunocompetent patients. Clin Infect Dis. 2003 Dec;37(12):1603-6.
Martin SH. Citomegalovirus infection. En: Harrison TR, ed. Principles of internal medicine. Singapore: Mc Graw-Hill, 1994:794-6.
Giménez E, Torres I, Albert E, Piñana JL, Hernández-Boluda JC, Solano C, et al. Cytomegalovirus (CMV) infection and risk of mortality in allogeneic hematopoietic stem cell transplantation (Allo-HSCT): A systematic review, meta-analysis, and meta-regression analysis. Am J Transplant. 2019 Sep;19(9):2479-94.
Marty FM, Winston DJ, Rowley SD, Vance E, Papanicolaou GA, Mullane KM, et al. CMX001-201 Clinical Study Group. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013 Sep;369(13):1227-36.
Chemaly RF, Ullmann AJ, Stoelben S, Richard MP, Bornhäuser M, Groth C, et al. Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation. N Engl J Med. 2014 May;370(19):1781-9.
Lodding IP, Schultz HH, Jensen JU, Kirkby N, Perch M, Andersen C, et al. Cytomegalovirus Viral Load in Bronchoalveolar Lavage to Diagnose Lung Transplant Associated CMV Pneumonia. Transplantation. 2018 Feb;102(2):326-32.
Rubin RH. Preemptive therapy in immunocompromised hosts. N Engl J Med. 1991 Apr;324(15):1057-9.
Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med. 1991 Dec;325(23):1601-7.
Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, 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 Mar;3(3):e119-27.
Tan SK, Waggoner JJ, Pinsky BA. Cytomegalovirus load at treatment initiation is predictive of time to resolution of viremia and duration of therapy in hematopoietic cell transplant recipients. J Clin Virol. 2017 Aug;69:179-83.
Giménez E, Muñoz-Cobo B, Solano C, Amat P, Navarro D. Early kinetics of plasma cytomegalovirus DNA load in allogeneic stem cell transplant recipients in the era of highly sensitive real-time PCR assays: does it have any clinical value? J Clin Microbiol. 2014 Feb;52(2):654-6.
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 Aug;26(4):413-7.
Young PG, Rubin J, Angarone M, Flaherty J, Penugonda S, Stosor V, et al. Ganciclovir-resistant cytomegalovirus infection in solid organ transplant recipients: a single-center retrospective cohort study. Transpl Infect Dis. 2016 Jun;18(3):390-5.
Avery RK, Arav-Boger R, Marr KA, Kraus E, Shoham S, Lees L, et al. Outcomes in Transplant Recipients Treated with Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation. 2016 Oct;100(10):e74-80.
Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, et al. Maribavir 1263-300 Clinical Study Group. 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 Apr;11(4):284-92.
European Medicines Agency (EMA). European Public Assessment Report (EPAR): Prevymis(r) (letermovir). [Internet]. Londres: EMA; Nov 2017. Procedure number: EMEA/H/C/004536/0000. (acceso 19/06/2020). Disponible en: Disponible en: http://www.ema.europa.eu/ema/index.jsp?curl=/pages/medicines/human/medicines/004536/human_med_002200.jsp&mid=WC0b01ac058001d124 .
AEMPS. Ficha técnica o resumen de las características del producto: Prevymis(r) (letermovir). [Internet]. Madrid: AEMPS. [acceso 19/06/2020]. Disponible en: Disponible en: https://ec.europa.eu/health/documents/community-register/2018/20180108139609/anx_139609_es.pdf .
Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-44.
Lin A, Maloy M, Su Y, Bhatt V, De Respiris L, Griffin M, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real-world experience. Transpl Infect Dis. Dec 2019;21(6):e13187.
Turner N, Strand A, Grewal DS, Cox G, Arif S, Baker AW, et al. Use of Letermovir as Salvage Therapy for Drug-Resistant Cytomegalovirus Retinitis. Antimicrob Agents Chemother. Feb 2019;63(3):e02337-18.
Papanicolaou GA, Silveira FP, Langston AA, Pereira MR, Avery RK, Uknis M, et al. Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study. Clin Infect Dis. 2019 Apr;68(8):1255-64.
Chou S. Foscarnet resistance mutations mapping to atypical domains of the cytomegalovirus DNA polymerase gene. Antiviral Res. 2017 Feb; 138:57-60.
Chou S, Ercolani RJ, Derakhchan K. Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus. Antiviral Res. 2018 Sep; 157:128-33.
Krawczyk A, Ackermann J, Goitowski B, Trenschel R, Ditschkowski M, Timm J, et al. Assessing the risk of CMV reactivation and reconstitution of antiviral immune response post bone marrow transplantation by the QuantiFERON-CMV-assay and real time PCR. J Clin Virol. Feb-Mar 2018;99-100:61-6.
Yong MK, Cameron PU, Slavin M, Morrissey CO, Bergin K, Spencer A, et al. Identifying Cytomegalovirus Complications Using the Quantiferon-CMV Assay After Allogeneic Hematopoietic Stem Cell Transplantation. J Infect Dis. 2017 Jun;215(11):1684-94.
Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016 May;127(20):2427-38.
Ogonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, et al. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2016 Nov;7:507.
Ogonek J, Varanasi P, Luther S, Schweier P, Kühnau W, Göhring G, et al. Possible Impact of Cytomegalovirus-Specific CD8+ T Cells on Immune Reconstitution and Conversion to Complete Donor Chimerism after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. Jul 2017;23(7):1046-53.
La Rosa C, Longmate J, Lacey SF, Kaltcheva T, Sharan R, Marsano D, et al. 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 Apr;205(8):1294-304.
Nakamura R, La Rosa C, Longmate J, Drake J, Slape C, Zhou Q, et al. Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol. 2016 Feb;3(2):e87-98.