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Clinical utility of measuring Epstein–Barr virus-specific cell-mediated immunity after HSCT in addition to virological monitoring: results from a prospective study

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Abstract

Lack of virus-specific cell-mediated immunity (CMI) is associated with worse viral infection outcome in hematopoietic stem cell transplantation (HSCT). We aimed to evaluate the role of immunological monitoring of Epstein–Barr virus (EBV) infection in addition to virological one in 33 adult and 18 pediatric allogeneic HSCT recipients. Virological monitoring of infection was performed on whole blood samples by a quantitative real-time PCR assay. Immunological monitoring was performed by Enzyme-linked ImmunoSPOT assay, evaluating EBV-specific CMI, at fixed time-points and when EBV DNAemia was ≥ 10,000 copies/mL. Fifty-one percent of patients developed a post-transplant EBV infection and reduced-intensity conditioning regimen was the only factor associated to infection (P = 0.023). Lack of EBV-specific CMI during active EBV infection was associated with a greater severity of infection. Patients without EBV-specific CMI showed higher median peak level of EBV DNAemia than patients with EBV-specific CMI (P = 0.014), and consequently received more frequently, at EBV DNAemia peak, anti-CD20 therapy (0 versus 54.5%, P = 0.002). No patients with EBV-specific CMI versus 27.2% without EBV-specific CMI developed EBV-related complications (P = 0.063), including two lethal EBV-related post-transplant lymphoproliferative disorders. Combined immunological and virological measurements could improve EBV infection management in HSCT, anticipating the beginning of preemptive treatment from the EBV DNAemia peak to the finding of the lack of EBV-specific CMI.

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References

  1. Styczynski J, van der Velden W, Fox CP, Engelhard D, de la Camara R, Cordonnier C et al (2016) Management of Epstein–Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica 101:803–811

    Article  CAS  Google Scholar 

  2. Gärtner BC, Schäfer H, Marggraff K, Eisele G, Schäfer M, Dilloo D et al (2002) Evaluation of use of Epstein–Barr viral load in patients after allogeneic stem cell transplantation to diagnose and monitor posttransplant lymphoproliferative disease. J Clin Microbiol 40:351–358

    Article  Google Scholar 

  3. van Esser JW, van der Holt B, Meijer E, Niesters HG, Trenschel R, Thijsen SF et al (2001) Epstein–Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT. Blood 98:972–978

    Article  Google Scholar 

  4. Kinch A, Oberg G, Arvidson J, Falk KI, Linde A, Pauksens K (2007) Post-transplant lymphoproliferative disease and other Epstein–Barr virus diseases in allogeneic haematopoietic stem cell transplantation after introduction of monitoring of viral load by polymerase chain reaction. Scand J Infect Dis 39:235–244

    Article  CAS  Google Scholar 

  5. Baldanti F, Gatti M, Furione M, Paolucci S, Tinelli C, Comoli P et al (2008) Kinetics of Epstein–Barr virus DNA load in different blood compartments of pediatric recipients of T-cell-depleted HLA-haploidentical stem cell transplantation. J Clin Microbiol 46:3672–3677

    Article  CAS  Google Scholar 

  6. Chiereghin A, Prete A, Belotti T, Gibertoni D, Piccirilli G, Gabrielli L et al (2016) Prospective Epstein–Barr virus-related post-transplant lymphoproliferative disorder prevention program in pediatric allogeneic hematopoietic stem cell transplant: virological monitoring and first-line treatment. Transpl Infect Dis 18:44–54

    Article  CAS  Google Scholar 

  7. Lazzarotto T, Chiereghin A, Piralla A, Piccirilli G, Girello A, Campanini G et al (2018) Cytomegalovirus and Epstein–Barr virus DNA kinetics in whole blood and plasma of allogeneic hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant 24:1699–1706

    Article  CAS  Google Scholar 

  8. Calarota SA, Aberle JH, Puchhammer-Stöckl E, Baldanti F (2015) Approaches for monitoring of non virus-specific and virus-specific T-cell response in solid organ transplantation and their clinical applications. J Clin Virol 70:109–119

    Article  CAS  Google Scholar 

  9. Remakus S, Sigal LJ (2013) Memory CD8(+) T cell protection. Adv Exp Med Biol 785:77–86

    Article  CAS  Google Scholar 

  10. Sant AJ, McMichael A (2012) Revealing the role of CD4(+) T cells in viral immunity. J Exp Med 209:1391–1395

    Article  CAS  Google Scholar 

  11. Patriarca F, Medeot M, Isola M, Battista ML, Sperotto A, Pipan C et al (2013) Prognostic factors and outcome of Epstein–Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab. Transpl Infect Dis 15:259–267

    Article  CAS  Google Scholar 

  12. Uhlin M, Wikell H, Sundin M, Blennow O, Maeurer M, Ringden O et al (2014) Risk factors for Epstein–Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica 99:346–352

    Article  Google Scholar 

  13. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al (2008) WHO classification of tumours of haematopietic and lymphoid tissues. Revised 4th edn. Volume 2

  14. Chiereghin A, Bertuzzi C, Piccirilli G, Gabrielli L, Squarzoni D, Turello G et al (2016) Successful management of EBV-PTLD in allogeneic bone marrow transplant recipient by virological-immunological monitoring of EBV infection, prompt diagnosis and early treatment. Transpl Immunol 34:60–64

    Article  Google Scholar 

  15. Chiereghin A, Gabrielli L, Zanfi C, Petrisli E, Lauro A, Piccirilli G et al (2010) Monitoring cytomegalovirus T-cell immunity in small bowel/multivisceral transplant recipients. Transplant Proc 42:69–73

    Article  CAS  Google Scholar 

  16. Simon RM, Subramanian J, Li MC, Menezes S (2011) Using cross-validation to evaluate predictive accuracy of survival risk classifiers based on high-dimensional data. Brief Bioinform 12:203–214

    Article  Google Scholar 

  17. Styczynski J, Gil L, Tridello G, Ljungman P, Donnelly JP, van der Velden W et al (2013) Response to rituximab-based therapy and risk factor analysis in Epstein Barr virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 57:794–802

    Article  CAS  Google Scholar 

  18. Carpenter B, Haque T, Dimopoulou M, Atkinson C, Roughton M, Grace S et al (2010) Incidence and dynamics of Epstein–Barr virus reactivation after alemtuzumab based conditioning for allogeneic hematopoietic stem cell transplantation. Transplantation 90:564–570

    Article  CAS  Google Scholar 

  19. Cesaro S, Pegoraro A, Tridello G, Calore E, Pillon M, Varotto S et al (2010) A prospective study on modulation of immunosuppression for Epstein–Barr virus reactivation in pediatric patients who underwent unrelated hematopoietic stem cell transplantation. Transplantation 89:1533–1540

    Article  CAS  Google Scholar 

  20. Finke J, Schmoor C, Bethge WA, Ottinger H, StelljesM Volin L et al (2017) Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol 4:e293–e301

    Article  Google Scholar 

  21. Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M et al (2016) Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med 374:43–53

    Article  Google Scholar 

  22. Locatelli F, Bernardo ME, Bertaina A, Rognoni C, Comoli P, Rovelli A et al (2017) Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 18:1126–1136

    Article  CAS  Google Scholar 

  23. Admiraal R, Nierkens S, de Witte MA, Petersen EJ, Fleurke GJ, Verrest L et al (2017) Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a retrospective, pharmacodynamic cohort analysis. Lancet Haematol 4:e183–e191

    Article  Google Scholar 

  24. Bonifazi F, Olivieri J, Sessa M, Dan E, Sinigaglia B, Rizzi S et al (2018) Low-dose anti-T lymphoglobulin as prophylaxis for graft-versus-host disease in unrelated donor transplantations for acute leukemias and myelodysplastic syndromes. Biol Blood Marrow Transplant 24:2450–2458

    Article  CAS  Google Scholar 

  25. Styczynski J, Einsele H, Gil L, Ljungman P (2009) Outcome of treatment of Epstein–Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases. Transpl Infect Dis 11:383–392

    Article  CAS  Google Scholar 

  26. Rouce RH, Louis CU, Heslop HE (2014) EBV lymphoproliferative disease after hematopoietic stem cell transplant. Curr Opin Hematol 21:476–481

    Article  CAS  Google Scholar 

  27. Gasiorowski R, Gibson J, Watson G, Trotman J, Larsen S (2013) Rapidly fatal post-allogeneic stem cell transplant lymphoproliferative disorder presenting with skin and bone marrow involvement. Pathology 45:81–83

    Article  Google Scholar 

  28. Wróblewska M, Gil LA, Komarnicki MA (2015) Successful treatment of Epstein–Barr virus-related post-transplant lymphoproliferative disease with central nervous system involvement following allogeneic haematopoietic stem cell transplantation—a case study. Cent Eur J Immunol 40:122–125

    Article  Google Scholar 

  29. Czyzewski K, Styczynski J, Krenska A, Debski R, Zajac-Spychala O, Wachowiak J et al (2013) Intrathecal therapy with rituximab in central nervous system involvement of post-transplant lymphoproliferative disorder. Leuk Lymphoma 54:503–506

    Article  CAS  Google Scholar 

  30. Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P et al (2012) Immune reconstitution after antithymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 14:1258–1275

    Article  CAS  Google Scholar 

  31. Gaballa A, Sundin M, Stikvoort A, Abumaree M, Uzunel M, Sairafi D et al (2016) T cell receptor excision circle (TREC) monitoring after allogeneic stem cell transplantation; a predictive marker for complications and clinical outcome. Int J Mol Sci 17:1705

    Article  Google Scholar 

  32. D’Aveni M, Aïssi-Rothé L, Venard V, Salmon A, Falenga A, Decot V et al (2011) The clinical value of concomitant Epstein Barr virus (EBV)-DNA load and specific immune reconstitution monitoring after allogeneic hematopoietic stem cell transplantation. Transpl Immunol 24:224–232

    Article  Google Scholar 

  33. Vogl BA, Fagin U, Nerbas L, Schlenke P, Lamprecht P, Jabs WJ (2012) Longitudinal analysis of frequency and reactivity of Epstein–Barr virus-specific T lymphocytes and their association with intermittent viral reactivation. J Med Virol 84:119–131

    Article  CAS  Google Scholar 

  34. Hislop AD, Taylor GS, Sauce D, Rickinson AB (2007) Cellular responses to viral infection in humans: lessons from Epstein–Barr virus. Annu Rev Immunol 25:587–617

    Article  CAS  Google Scholar 

  35. Calarota SA, Chiesa A, Zelini P, Comolli G, Minoli L, Baldanti F (2013) Detection of Epstein–Barr virus-specific memory CD4+ T cells using a peptide-based cultured enzyme-linked immunospot assay. Immunology 139:533–544

    Article  CAS  Google Scholar 

  36. Annels NE, Kalpoe JS, Bredius RG, Claas EC, Kroes AC, Hislop AD et al (2006) Management of Epstein–Barr virus (EBV) reactivation after allogeneic stem cell transplantation by simultaneous analysis of EBV DNA load and EBV-specific T cell reconstitution. Clin Infect Dis 42:1743–1748

    Article  CAS  Google Scholar 

  37. Peric Z, Cahu X, Chevallier P, Brissot E, Malard F, Guillaume T et al (2011) Features of Epstein–Barr virus reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia 25:932–938

    Article  CAS  Google Scholar 

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Acknowledgements

This work is based on the PhD thesis of Dr. Angela Chiereghin, available at http://amsdottorato.unibo.it/7611/1/Chiereghin_Angela_Tesi.pdf. The authors thank the Linguistic Consultant, Lucy Scioscia, for editing the English language text.

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Author notes

  1. Francesca Bonifazi and Tiziana Lazzarotto contributed equally to this work.

Authors and Affiliations

  1. Department of Specialized, Experimental, and Diagnostic Medicine, Operative Unit of Clinical Microbiology, St. Orsola-Malpighi Polyclinic, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy

    Angela Chiereghin, Giulia Piccirilli, Gabriele Turello, Eva Caterina Borgatti & Tiziana Lazzarotto

  2. Unit of Pediatric Oncology and Hematology, Department of Pediatrics, St. Orsola-Malpighi Polyclinic, Via Massarenti 9, 40138, Bologna, Italy

    Tamara Belotti & Arcangelo Prete

  3. Department of Specialized, Experimental, and Diagnostic Medicine, Hematopathology Section, St. Orsola-Malpighi Polyclinic, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy

    Clara Bertuzzi

  4. Department of Biomedical and Neuromotor Sciences, Unit of Hygiene and Biostatistics, University of Bologna, Via San Giacomo 12, 40126, Bologna, Italy

    Dino Gibertoni

  5. Operative Unit of Clinical Microbiology, St. Orsola-Malpighi Polyclinic, Via Massarenti 9, 40138, Bologna, Italy

    Liliana Gabrielli

  6. Institute of Hematology “L. and A. Seràgnoli”, St. Orsola-Malpighi Polyclinic, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy

    Francesco Barbato, Mariarosaria Sessa, Mario Arpinati & Francesca Bonifazi

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  1. Angela Chiereghin
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  2. Giulia Piccirilli
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Correspondence to Tiziana Lazzarotto.

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Ethical standards

The study was approved by the Independent Hospital Ethics Committee of St. Orsola-Malpighi Polyclinic, University of Bologna and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual adult participants included in the study, as well as from the parents of the pediatric participants.

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Edited by Matthias J. Reddehase.

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Chiereghin, A., Piccirilli, G., Belotti, T. et al. Clinical utility of measuring Epstein–Barr virus-specific cell-mediated immunity after HSCT in addition to virological monitoring: results from a prospective study. Med Microbiol Immunol 208, 825–834 (2019). https://doi.org/10.1007/s00430-019-00629-2

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