Buket ŞEFLEK, Hale GÜMÜŞ, Mehmet ÇİMENTEPE, Serhan KÜPELİ, Fügen YARKIN

Hematopoetik kök hücre transplant alıcılarında cytomegalovirus, Epstein-Barr virus ve adenovirus enfeksiyonlarının izlenmesi

Amaç: İyatrojenik immünsüpresyonu olan hematopoetik kök hücre transplant (HKHT) alıcıları viral enfeksiyonlar için yüksek riskli hastalardır. Bu çalışmanın amacı, HKHT alıcılarında cytomegalovirus (CMV), Epstein-Barr virus (EBV) ve adenovirus (ADV) enfeksiyonlarının insidansını araştırmaktır. Gereç ve Yöntem: Yaşları 0-17 arasında allojenik (n=30) ve otolog (n=5) HKHT'si olan 35 hasta prospektif olarak CMV, EBV ve ADV için kantitatif gerçek zamanlı polimeraz zincir reaksiyonu testleri ile izlendi. Monitorizasyon, HKHT'den bir hafta önce başladı ve HKHT'den sonra ilk 100 gün için haftalık, bir yıla kadar ayda bir yapıldı. Ek olarak, virüsler için seropozitiflik, transplantasyondan bir hafta önce Enzyme-Linked Immunosorbent Assay ile analiz edildi. Bulgular: Transplantasyon öncesi HKHT yapılan 35 (%100) hastanın tamamı CMV IgG pozitif, 30 (%85.7- 95% CI: 74.1%-97.3%) HKHT alıcısı EBV IgG pozitif bulundu. Allojenik HKHT hastalarının 24'ünde (%80 - 95% CI: 65.7%-94.3%) CMV enfeksiyonu, 11'inde (%36.7 - 95% CI: 19.4%-53.9%) ADV enfeksiyonu ve 8'inde (%26.7) EBV enfeksiyonu bulundu. Bu grupta biri (%3.3) EBV DNA ve biri (%3.3) ADV DNA ile koenfekte olan 8 hastada (%26.7) CMV DNA viral yükü preemptif tedavi için gerekli olan 1000 kopya/mL üzerindeydi. Otolog 5 HKHT alıcısından CMV DNA 2 hastada, EBV DNA 5 hastada ve ADV DNA 2 hastada tespit edildi. Preemptif tedavi 35 hastanın 11'ine (%31.4 - 95% CI: 16%-46.8%; 6 CMV, 2 EBV, 1 ADV, 1 CMV-EBV ve 1 CMV-ADV enfeksiyonu) verildi. Böylece 7 (%63.6 - 95% CI: 35.2%-92.1%) hastada viral hastalık gelişimi engellendi. Toplam 35 hastadan sadece 2'si (%5.7 - 95% CI: 0.0%-13.4%)) viral enfeksiyon nedeniyle kaybedildi. Sonuç: HKHT hastalarında viral yüklerin prospektif olarak izlenmesi ile viral enfeksiyonların erken tanısı, preemptif tedavinin zamanında başlatılmasını sağlayarak morbidite ve mortaliteyi önlemede etkili olacaktır.

Anahtar Kelimeler:

CMV, EBV, ADV, hematopoetik kök hücre transplantasyonu

Monitoring of cytomegalovirus, Epstein-Barr virus and adenovirus infections in hematopoietic stem cell transplant recipients

Purpose: Haematopoietic stem cell transplant (HSCT) recipients with iatrogenic immunosuppression are high-risk patients for viral infections. The aim of this study was to investigate the incidence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (ADV) infections in HSCT recipients. Materials and Methods: We prospectively monitored 35 patients aged 0-17 years who had allogeneic (n=30) and autologous (n=5) HSCT by quantitative real-time polymerase chain reaction tests for CMV, EBV, and ADV. The monitoring was performed one week before HSCT and weekly for the first 100 days, once a month up to one year after HSCT. In addition, seropositivity for viruses was analysed by Enzyme-Linked Immuno Sorbent Assay a week before transplantation. Results: Before transplantation, all 35 (100%) patients who underwent HSCT were CMV IgG positive, 30 (85.7% - 95% CI: 74.1%-97.3%) HSCT recipients were found to be EBV IgG positive. CMV infection was found in 24 (80% - 95% CI: 65.7%-94.3%), ADV infection in 11 (36.7% - 95% CI: 19.4%-53.9%) and EBV infection in 8 (26.7% - 95% CI: 10.8%-42.5%) allogeneic HSCT patients. In this group, CMV DNA viral load in 8 (26.7%) patients, of which one (3.3%) coinfected with EBV DNA and one (3.3%) with ADV DNA, was higher than 1000 copies/mL which was required for pre-emptive treatment. Among 5 autologous HSCT recipients, CMV DNA was detected in 2 patients, EBV DNA in 5 and ADV DNA in 2. Pre-emptive treatment was given to 11 (%31.4 - 95% CI: 16%-46.8%; 6 CMV, 2 EBV, 1 ADV, 1 CMV-EBV and 1 CMV-ADV infection) of 35 patients. Thus, the development of viral disease was prevented in 7 (63.6% - 95% CI: 35.2%-92.1%). Of the total 35 patients, only 2 (5.7% - 95% CI: 0.0%-13.4%) died due to viral infection. Conclusion: Early diagnosis of viral infections by prospective monitoring of viral loads in HSCT patients would be effective in preventing morbidity and mortality by ensuring timely initiation of pre-emptive therapy.

Keywords:

CMV, EBV, ADV, hematopoietic stem cell transplantation,

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Wölfl M, Qayed M, Benitez Carabante MI, Sykora T, Bonig H, Lawitschka A et al. Current prophylaxis and treatment approaches for acute graft-versus-host disease in haematopoietic stem cell transplantation for children with acute lymphoblastic leukaemia. Front Pediatr. 2022;9:784377.
Annaloro C, Serpenti F, Saporiti G, Galassi G, Cavallaro F, Grifoni F etal. Viral infections in HSCT: detection, monitoring, clinical management, and immunologic implications. Front Immunol. 2021;11:569381.
Xuan L, Huang F, Fan Z, Zhou H, Zhang X, Yu G et al. Effects of intensified conditioning on Epstein-Barr virus and cytomegalovirus infections in allogeneic hematopoietic stem cell transplantation for hematological malignancies. J Hematol Oncol. 2012;5:46.
Rojas-Rechy MH, Gaytán-Morales F, Sánchez-Ponce Y, Castorena-Villa I, López-Martínez B, Parra-Ortega I et al Herpesvirus screening in childhood hematopoietic transplant reveals high systemic inflammation in episodes of multiple viral detection and an EBV association with elevated IL-1β, IL-8 and Graft-Versus-Host Disease. Microorganisms. 2022;10:1685.
Ukonmaanaho EM, Alexandersson A, Mannonen L, Lautenschlager I, Taskinen M, Koskenvuo M. Respiratory viruses after paediatric allogenic haematopoietic stem cell transplantation. Infect Dis. 2021;53:214˗7.
Wang X, Patel SA, Haddadin M, Cerny J. Post-allogeneic hematopoietic stem cell transplantation viral reactivations and viremias: a focused review on human herpesvirus-6, BK virus and adenovirus. Ther Adv Infect Dis. 2021;24:20499361211018027.
Griffiths P, Reeves M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol. 2021;19:759–73.
Zajac-Spychala O, Kampmeier S, Lehrnbecher T, Groll AH. Infectious complications in paediatric haematopoietic cell transplantation for Acute Lymphoblastic Leukaemia: Current Status. Front Pediatr. 2022;9:782530.
Burrell CJ, Howard CR, Murphy FA. Laboratory Diagnosis of virus diseases. Fenner and White's Med Virol. 2017;135˗54.
Düver F, Weißbrich B, Eyrich M, Wölfl M, Schlegel PG, Wiegering V. Viral reactivations following hematopoietic stem cell transplantation in pediatric patients - a single center 11-year analysis. PLoS One. 2020;15:e02284511–17.
Diop NS, Enok Bonong PR, Buteau C, Duval M, Lacroix J, Laporte L et al. Association between antiviral prophylaxis and cytomegalovirus and Epstein-Barr virus DNAemia in pediatric recipients of allogeneic hematopoietic stem cell transplant. Vaccines. 2021;9:610.
Sahin DG, Gunduz E, Kasifoglu N, Akay OM, Us T, Gulbas Z. Cytomegalovirus DNAemia detected with real-time polymerase chain reaction in hematopoietic stem cell transplant patients. Adv Ther. 2013;30:784-91.
Goldstein G, Rutenberg TF, Mendelovich SL, Hutt D, Oikawa MT, Toren A et al. The role of immunoglobulin prophylaxis for prevention of cytomegalovirus infection in pediatric hematopoietic stem cell transplantation recipients. Pediatr Blood Cancer. 2017;64: doi: 10.1002/pbc.26420.
Wu JL, Ma HY, Lu CY, Chen JM, Lee PI, Jou ST et al. Risk factors and outcomes of cytomegalovirus viremia in pediatric hematopoietic stem cell transplantation patients. J Microbiol Immunol Infect. 2017;50:307-13.
Tsoumakas K, Giamaiou K, Goussetis E, Graphakos S, Kossyvakis A, Horefti E et al. Epidemiology of viral infections among children undergoing hematopoietic stem cell transplant: a prospective single-center study. Transpl Infect Dis. 2019;21:e13095.
Pereira MR, Pouch SM, Scully B. Infections in allogeneic stem cell transplantation. in principles and practice of transplant infectious diseases, (Eds. A. Safdar):209-26. New York, Springer. 2018.
Feghoul L, Chevret S, Cuinet A, Dalle JH, Ouachee M, Yacouben K et al. Adenovirus infection and disease in paediatric haematopoietic stem cell transplant patients: clues for antiviral pre-emptive treatment. Clin Microbiol Infect. 2015;21:701-9.
Mynarek M, Ganzenmueller T, Mueller-Heine A, Mielke C, Gonnermann A, Beier R et al. Patient, virus, and treatment-related risk factors in pediatric adenovirus infection after stem cell transplantation: results of a routine monitoring program. Biol Blood Marrow Transplant. 2014;20:250-6.
Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000;49(RR-10):1-CE7.
Hayashi RJ. Considerations in preparative regimen selection to minimize rejection in pediatric hematopoietic transplantation in non-malignant diseases. Front Immunol. 2020;11:567423.
Ustun C, Kim S, Chen M, Beitinjaneh AM, Brown VI, Dahi PB et al. Increased overall and bacterial infections following myeloablative allogeneic HCT for patients with AML in CR1. Blood Adv. 2019;3:2525˗36.
Sperotto A, Candoni A, Gottardi M, Facchin G, Stella R, De Marchi R et al. Cytomegalovirus prophylaxis versus pre-emptive strategy: different CD4+ and CD8+ T cell reconstitution after allogeneic hematopoietic stem cell transplantation. Transplant Cell Ther. 2021;27:518.e1-4.