Herpes Virus Reactivation in Lymphoma Patients During and After Autologous Hematopoietic Stem Cell Transplantation

Aim. To assess the detection rate of human herpes virus DNA (of cytomegalovirus, herpes simplex virus types 1 and 2 [HSV-1/2], human herpes virus type 6 [HHV-6], and Epstein-Barr virus) in different biological environments at different stages of autologous hematopoietic stem cell transplantation (auto-HSCT) as well as the effect of immune factors on reactivation of viruses under study.

Materials & Methods. From 2019 to 2021 the study enrolled 87 lymphoma patients during and after auto-HSCT. Virological monitoring was performed on biological fluids (blood, saliva, urine, etc.) on therapeutic grounds prior to conditioning regimen on Day 0 as well as on Day +5 and Day +10 after auto-HSCT. On these days (Day 0, Day +5, and Day +10) the immune factors (IgM, IgG, and IgA levels and pattern of lymphocyte subpopulation in peripheral blood) in 15 % (14/87) of patients were assessed in terms of their effect on herpes virus reactivation.

Results. The overall rate of viral DNA detection increased from 26 % (26/87) to 42 % (37/87) of cases in the period of granulocytopoietic recovery. The most frequent were HHV-6 and HSV-1/2 reactivations reported in 23 % (20/87) and 16 % (14/87) of cases, respectively. The median B-lymphocyte proportion in peripheral blood of patients with herpes virus reactivation was 0.26 %, whereas in patients without reactivation it was 6.7 % (p = 0.019). The median absolute B-lymphocyte count in the cohort of patients with detected viral DNAs was 0.001 × 10⁹/L, whereas in patients without them it was 0.098 × 10⁹/L (p = 0.026).

Conclusion. A high rate of herpes virus DNA detection in lymphoma patients after auto-HSCT affected neither transplant engraftment nor transplantation mortality. Immune predictors of virus infection reactivation were the decreasing proportion of B-cells in the total lymphocyte count and the absolute B-lymphocyte count in the peripheral blood prior to auto-HSCT.

• Yana Konstantinovna Mangasarova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• Yu.O. Davydova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• D.S. Tikhomirov National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• O.V. Margolin National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• L.G. Gorenkova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• E.S. Nesterova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• F.E. Babaeva National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• A.E. Misyurina National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• M.O. Bagova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• E.A. Fastova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• A.U. Magomedova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• I.V. Galtseva National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• T.A. Tupoleva National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• S.K. Kravchenko National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167

1. Roizman B, Zhou G. The 3 facets of regulation of herpes simplex virus gene expression: A critical inquiry. Virology. 2015;479–480:562–7. doi: 10.1016/j.virol.2015.02.036. DOI: https://doi.org/10.1016/j.virol.2015.02.036
2. Викулов Г.Х. Иммунологические аспекты герпесвирусных инфекций. Клиническая дерматология и венерология. 2015;5:104–14.
3. [Vikulov GKh. Immunological aspects of herpes virus infections. Klinicheskaya dermatologiya i venerologiya. 2015;5:104–14. (In Russ)]
4. Zuhair M, Smit G, Wallis G, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: a systematic review and meta-analysis. Rev Med Virol. 2019;29(3):e2034. doi: 10.1002/rmv.2034. DOI: https://doi.org/10.1002/rmv.2034
5. Deayton JR, Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viremia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet. 2004;363(9427):2116–21. doi: 10.1016/S0140-6736(04)16500-8. DOI: https://doi.org/10.1016/S0140-6736(04)16500-8
6. Verschuuren EAM. Balance between Herpes Viruses and Immunosuppression after Lung Transplantation. University of Groningen; 2006.
7. Falcone EL, Adegbulugbe AA, Sheikh V, et al. Cerebrospinal fluid HIV-1 compartmentalization in a patient with AIDS and acute varicella-zoster virus meningomyeloradiculitis. Clin Infect Dis. 2013;57(5):e135–е142. doi: 10.1093/cid/cit356. DOI: https://doi.org/10.1093/cid/cit356
8. Jain NA, Lu K, Ito S, et al. The clinical and financial burden of pre-emptive management of cytomegalovirus disease after allogeneic stem cell transplantation-implications for preventative treatment approaches. Cytotherapy. 2014;16(7):927–33. doi: 10.1016/j.jcyt.2014.02.010. DOI: https://doi.org/10.1016/j.jcyt.2014.02.010
9. Тeira 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):2427–38. doi: 10.1182/blood-2015-11-679639. DOI: https://doi.org/10.1182/blood-2015-11-679639
10. Webb BJ, Harrington R, Schwartz J, et al. The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation. Transpl Infect Dis. 2018;20(5):e12961. doi: 10.1111/tid.12961. DOI: https://doi.org/10.1111/tid.12961
11. Schmitz N, Buske C, Gisselbrecht C. Autologous stem cell transplantation in lymphoma. Semin Hematol. 2007;44(4):234–45. doi: 10.1053/j.seminhematol.2007.08.007. DOI: https://doi.org/10.1053/j.seminhematol.2007.08.007
12. Ljungman P. The role of cytomegalovirus serostatus on outcome of hematopoietic stem cell transplantation. Curr Opin Hematol. 2014;21(6):466–9. doi: 10.1097/MOH.0000000000000085. DOI: https://doi.org/10.1097/MOH.0000000000000085
13. Boeckh M, Nichols W. 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):2003–8. doi: 10.1182/blood-2003-10-3616. DOI: https://doi.org/10.1182/blood-2003-10-3616
14. Inazawa AN, Hori T. Virus Reactivations after autologous hematopoietic stem cell transplantation detected by multiplex PCR assay. J Med Virol. 2017;89(2):358–62. doi: 10.1002/jmv.24621. DOI: https://doi.org/10.1002/jmv.24621
15. Chapenko S, Troikas I, Donina S, et al. Relationship between beta-herpesviruses reactivation and development of complications after autologous peripheral blood stem cell transplantation. J Med Virol. 2012;84(12):1953–60. doi: 10.1002/jmv.23412. DOI: https://doi.org/10.1002/jmv.23412
16. Duver F, Weissbrich B, Eyrich M, et al. Viral reactivations following hematopoietic stem cell transplantation in pediatric patients – A single center 11-year analysis. PLoS One. 2020;15(2):e0228451. doi: 10.1371/journal.pone.0228451. DOI: https://doi.org/10.1371/journal.pone.0228451
17. Хайдуков С.В., Байдун Л.В. Современные подходы к оценке клеточной составляющей иммунного статуса. Медицинский алфавит. 2015;2(8):44–51.
18. [Khaidukov SV, Baidun LV. Modern approaches to assessing the cellular component of the immune status. Meditsinskii alfavit. 2015;2(8):44–51. (In Russ)]
19. Hoppe RT, Advani RH, Ai WZ, et al. Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2012;10(5):589–97. doi: 10.6004/jnccn.2012.0061. DOI: https://doi.org/10.6004/jnccn.2012.0061
20. Eichenauer DA, Engert A, Dreyling M, ESMO Guidelines Working Group. Hodgkin’s lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl 6):vi55–8. doi: 10.1093/annonc/mdr378. DOI: https://doi.org/10.1093/annonc/mdr378
21. Martelli M, Gherlinzoni F, De Renzo A, et al. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin’s lymphoma: an Italian multicenter randomized trial. J Clin Oncol. 2003;21(7):1255–62. doi: 10.1200/JCO.2003.01.117. DOI: https://doi.org/10.1200/JCO.2003.01.117
22. Verdonck LF, van Putten WLJ, Hagenbeek A, et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1995;332(16):1045–51. doi: 10.1056/NEJM199504203321601. DOI: https://doi.org/10.1056/NEJM199504203321601
23. Celebi H, Akan H, Akcaglayan E, et al. Febrile neutropenia in allogeneic and autologous peripheral blood stem cell transplantation and conventional chemotherapy for malignancies. Bone Marrow Transplant. 2000;26(2):211–4. doi: 10.1038/sj.bmt.1702503. DOI: https://doi.org/10.1038/sj.bmt.1702503
24. 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):3359–64. doi: 10.1182/blood-2013-05-499830. DOI: https://doi.org/10.1182/blood-2013-05-499830
25. Drokov M, Davydova J, Kuzmina L, et al. Level of granzyme B-positive T-regulatory cells is a strong predictor biomarker of acute graft-versus-host disease after day +30 after allo-HSCT. Leuk Res. 2017;54:25–9. doi: 10.1016/j.leukres.2017.01.014. DOI: https://doi.org/10.1016/j.leukres.2017.01.014
26. Williams K, Gress R. Immune reconstitution and implications for immunotherapy following haematopoietic stem cell transplantation. Best Pract Res Clin Haematol. 2008;21(3):579–96. doi: 10.1016/j.beha.2008.06.003. DOI: https://doi.org/10.1016/j.beha.2008.06.003