Standardized monitoring of cytomegalovirus-specific immunity can improve risk stratification of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation
Eva Wagner-Drouet, Daniel Teschner, Christine Wolschke, Dietlinde Janson, Kerstin Schäfer-Eckart, Johannes Gärtner, Stephan Mielke, Martin Schreder, Guido Kobbe, Mustafa Kondakci, Inken Hilgendorf, Marie von Lilienfeld-Toal, Stefan Klein, Daniela Heidenreich, Sebastian Kreil, Mareike Verbeek, Sandra Grass, Markus Ditschkowski, Tanja Gromke, Martina Koch, Monika Lindemann, Thomas Hünig, Traudel Schmidt, Anne Rascle, Harald Guldan, Sascha Barabas, Ludwig Deml, Ralf Wagner, Daniel Wolff, Eva Wagner-Drouet, Daniel Teschner, Christine Wolschke, Dietlinde Janson, Kerstin Schäfer-Eckart, Johannes Gärtner, Stephan Mielke, Martin Schreder, Guido Kobbe, Mustafa Kondakci, Inken Hilgendorf, Marie von Lilienfeld-Toal, Stefan Klein, Daniela Heidenreich, Sebastian Kreil, Mareike Verbeek, Sandra Grass, Markus Ditschkowski, Tanja Gromke, Martina Koch, Monika Lindemann, Thomas Hünig, Traudel Schmidt, Anne Rascle, Harald Guldan, Sascha Barabas, Ludwig Deml, Ralf Wagner, Daniel Wolff
Abstract
Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
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References
- Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am. 2011;25(1):151-169.
- Azevedo LS, Pierrotti LC, Abdala E, et al. Cytomegalovirus infection in transplant recipients. Clinics. 2015;70(7):515-523.
- de la Cámara R. CMV in Hematopoietic stem cell transplantation. Mediterr J Hematol Infect Dis. 2016;8(1):e2016031.
- 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 Transplant. 2008;42(4):227-240.
- Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Preface. Bone Marrow Transplant. 2009;44(8):453-455.
- Emery V, Zuckerman M, Jackson G, et al. Management of cytomegalovirus infection in haemopoietic stem cell transplantation. Br J Haematol. 2013;162(1):25-39.
- 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.
- Lilleri D, Gerna G. Strategies to control human cytomegalovirus infection in adult hematopoietic stem cell transplant recipients. Immunotherapy. 2016;8(9):1135-1149.
- Ljungman P, de la Camara R, Robin C, et al. 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. 2019;19(8):e260-e272.
- Krause H, Hebart H, Jahn G, Müller CA, Einsele H. Screening for CMV-specific T cell proliferation to identify patients at risk of developing late onset CMV disease. Bone Marrow Transplant. 1997;19(11):1111-1116.
- 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.
- Lamba R, Carrum G, Myers GD, et al. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with alemtuzumab. Bone Marrow Transplant. 2005;36(9):797-802.
- 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 Transplant. 2007;40(2):125-136.
- Yong MK, Lewin SR, Manuel O. Immune monitoring for CMV in transplantation. Curr Infect Dis Rep. 2018;20(4):4.
- Ciáurriz M, Zabalza A, Beloki L, et al. The immune response to cytomegalovirus in allogeneic hematopoietic stem cell transplant recipients. Cell Mol Life Sci. 2015;72(21):4049-4062.
- Avetisyan G, Aschan J, Hägglund H, Ringdén O, Ljungman P. Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT. Bone Marrow Transplant. 2007;40(9):865-869.
- Moins-Teisserenc H, Busson M, Scieux C, et al. Patterns of cytomegalovirus reactivation are associated with distinct evolutive profiles of immune reconstitution after allogeneic hematopoietic stem cell transplantation. J Infect Dis. 2008;198(6):818-826.
- Gratama JW, Brooimans RA, van der Holt B, et al. Monitoring cytomegalovirus IE-1 and pp65-specific CD4+ and CD8+ T-cell responses after allogeneic stem cell transplantation may identify patients at risk for recurrent CMV reactivations. Cytometry B Clin Cytom. 2008;74(4):211-220.
- Gratama JW, Boeckh M, Nakamura R, et al. Immune monitoring with iTAg MHC tetramers for prediction of recurrent or persistent cytomegalovirus infection or disease in allogeneic hematopoietic stem cell transplant recipients: a prospective multicenter study. Blood. 2010;116(10):1655-1662.
- Fleming T, Dunne J, Crowley B. Ex vivo monitoring of human cytomegalovirus-specific CD8(+) T-cell responses using the QuantiFERON-CMV assay in allogeneic hematopoietic stem cell transplant recipients attending an Irish hospital. J Med Virol. 2010;82(3):433-440.
- Borchers S, Luther S, Lips U, et al. Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2011;13(3): 222-236.
- Borchers S, Bremm M, Lehrnbecher T, et al. Sequential anti-cytomegalovirus response monitoring may allow prediction of cytomegalovirus reactivation after allogeneic stem cell transplantation. PloS One. 2012;7(12):e50248.
- Tey S-K, Kennedy GA, Cromer D, et al. Clinical assessment of anti-viral CD8+ T cell immune monitoring using QuantiFERONCMV ® assay to identify high risk allogeneic hematopoietic stem cell transplant patients with CMV infection complications. PloS One. 2013;8(10):e74744.
- Lee SM, Kim YJ, Yoo KH, et al. Clinical usefulness of monitoring cytomegalovirus-specific immunity by Quantiferon-CMV in pediatric allogeneic hematopoietic stem cell transplantation recipients. Ann Lab Med. 2017;37(3):277-281.
- Yong MK, Cameron PU, Slavin M, et al. Identifying cytomegalovirus complications using the quantiferon-CMV assay after allogeneic hematopoietic stem cell transplantation. J Infect Dis. 2017;215(11): 1684-1694.
- Barabas S, Spindler T, Kiener R, et al. An optimized IFN-γ ELISpot assay for the sensitive and standardized monitoring of CMV protein-reactive effector cells of cell-mediated immunity. BMC Immunol. 2017;18(1):14.
- Banas B, Böger CA, Lückhoff G, et al. Validation of T-Track® CMV to assess the functionality of cytomegalovirus-reactive cell-mediated immunity in hemodialysis patients. BMC Immunol. 2017;18(1):15.
- Barabas S, Gary R, Bauer T, et al. Urea-mediated cross-presentation of soluble Epstein- Barr virus BZLF1 protein. PLoS Pathog. 2008;4(11):e1000198.
- Nesher L, Shah DP, Ariza-Heredia EJ, et al. Utility of the enzyme-linked immunospot interferon-γ-release assay to predict the risk of cytomegalovirus infection in hematopoietic cell transplant recipients. J Infect Dis. 2016;213(11):1701-1707.
- Banas B, Steubl D, Renders L, et al. Clinical validation of a novel ELISpot-based in vitro diagnostic assay to monitor CMV-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study. Transpl Int. 2018;31(4):436-450.
- 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.
- Hakki M, Riddell SR, Storek J, et al. 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.
- Bae S, Jung J, Kim S-M, et al. The detailed kinetics of cytomegalovirus-specific T cell responses after hematopoietic stem cell transplantation: 1 Year Follow-up Data. Immune Netw. 2018;18(2):e2.
- Meesing A, Razonable RR. Absolute lymphocyte count thresholds: a simple, readily available tool to predict the risk of cytomegalovirus infection after transplantation. Open Forum Infect. Dis. 2018;5(10):ofy230.
- Watanabe M, Kanda J, Hishizawa M, et al. Lymphocyte area under the curve as a predictive factor for viral infection after allogenic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(3):587-593.
- Gutiérrez A, Muñoz I, Solano C, et al. Reconstitution of lymphocyte populations and cytomegalovirus viremia or disease after allogeneic peripheral blood stem cell transplantation. J Med Virol. 2003;70(3):399-403.
- Rénard C, Barlogis V, Mialou V, et al. Lymphocyte subset reconstitution after unrelated cord blood or bone marrow transplantation in children. Br J Haematol. 2011;152(3):322-330.
- Chakrabarti S, Mackinnon S, Chopra R, et al. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood. 2002;99(12):4357-4363.
- Hiwarkar P, Gajdosova E, Qasim W, et al. Frequent occurrence of cytomegalovirus retinitis during immune reconstitution warrants regular ophthalmic screening in highrisk pediatric allogeneic hematopoietic stem cell transplant recipients. Clin Infect Dis. 2014;58(12):1700-1706.
- Ogonek J, Kralj Juric M, Ghimire S, et al. Immune reconstitution after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2016;7:507.
- Stemberger C, Graef P, Odendahl M, et al. Lowest numbers of primary CD8(+) T cells can reconstitute protective immunity upon adoptive immunotherapy. Blood. 2014;124(4):628-637.
- Gabanti E, Lilleri D, Ripamonti F, et al. Reconstitution of human cytomegalovirusspecific CD4+ T cells is critical for control of virus reactivation in hematopoietic stem cell transplant recipients but does not prevent organ infection. Biol Blood Marrow Transplant. 2015;21(12):2192-2202.
- Shams El-Din AA, El-Desoukey NA, Amin Tawadrous DG, et al. The potential association of CMV-specific CD8+ T lymphocyte reconstitution with the risk of CMV reactivation and persistency in post allogeneic stem cell transplant patients. Hematol Amst Neth. 2018;23(8):463-469.
- Barron MA, Gao D, Springer KL, et al. Relationship of reconstituted adaptive and innate cytomegalovirus (CMV)-specific immune responses with CMV viremia in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2009;49(12):1777-1783.
- Drylewicz J, Schellens IMM, Gaiser R, et al. Rapid reconstitution of CD4 T cells and NK cells protects against CMV-reactivation after allogeneic stem cell transplantation. J Transl Med. 2016;14(1):230.
- Foster AE, Gottlieb DJ, Sartor M, Hertzberg MS, Bradstock KF. Cytomegalovirus-specific CD4+ and CD8+ T-cells follow a similar reconstitution pattern after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2002;8(9):501-511.
- Pourgheysari B, Piper KP, McLarnon A, et al. Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT. Bone Marrow Transplant. 2009;43(11):853-861.
- Lilleri D, Gerna G, Fornara C, et al. Prospective simultaneous quantification of human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplants. Blood. 2006;108(4):1406-1412.
- Widmann T, Sester U, Schmidt T, et al. Rapid reconstitution of CMV-specific T-cells after stem-cell transplantation. Eur J Haematol. 2018;101(1):38-47.
- Lilleri D, Fornara C, Chiesa A, et al. Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection. Haematologica. 2008;93(2):248-256.
- Ozdemir E, St John LS, Gillespie G, et al. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen- specific CD8+ T cells. Blood. 2002;100(10):3690-3697.
- Jung J, Lee H-J, Kim S-M, et al. Diagnostic usefulness of dynamic changes of CMV-specific T-cell responses in predicting CMV infections in HCT recipients. J Clin Virol. 2017;87:5-11.
- Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433-2444.
- Lindemann M, Eiz-Vesper B, Steckel NK, et al. Adoptive transfer of cellular immunity against cytomegalovirus by virus-specific lymphocytes from a third-party family donor. Bone Marrow Transplant. 2018;53(10):1351-1355.
- Chemaly RF, Chou S, Einsele H, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019;68(8):1420-1426.
Source: PubMed