儿童异基因造血干细胞移植后巨细胞病毒感染的治疗进展
Treatment Advances for Cytomegalovirus Infection after Pediatric Allogeneic Hematopoietic Stem Cell Transplantation
DOI: 10.12677/acm.2026.1631088, PDF,   
作者: 张继源, 张志勇*：重庆医科大学附属儿童医院临床研究科，儿童少年健康与疾病国家临床医学研究中心，儿童发育疾病研究教育部重点实验室，儿童感染与免疫罕见病重庆市重点实验室，重庆
关键词: 异基因造血干细胞移植；巨细胞病毒；来特莫韦；马立巴韦；Allogeneic Hematopoietic Stem Cell Transplantation； Cytomegalovirus； Letermovir； Maribavir
摘要: 异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT)是儿童多种血液系统疾病、免疫出生缺陷等疾病的根治手段。预处理方案、移植物抗宿主病的防治及免疫功能重建延迟等多种因素导致的免疫抑制，使巨细胞病毒(cytomegalovirus, CMV)感染风险显著升高，严重影响患儿预后。本文综述了儿童allo-HSCT后CMV感染的治疗进展。更昔洛韦、膦甲酸钠等传统抗病毒药物仍是临床基础治疗选择，随着来特莫韦获批用于儿童群体，推动CMV管理从“抢先治疗”为主转向“预防联合抢先治疗”的综合模式；马立巴韦为难治性、耐药性CMV感染提供了更多治疗选择。未来需进一步积累新型药物的儿科临床数据，探索免疫监测在治疗策略指导中的应用，进一步改善患儿长期预后。
Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for various hematological diseases, inborn errors of immunity (IEI), and other disorders in children. Immunosuppression resulting from conditioning regimens, graft-versus-host disease (GVHD) prophylaxis and treatment, and delayed immune reconstitution significantly increases the risk of cytomegalovirus (CMV) infection, severely impairing outcomes in pediatric patients. This article reviews recent advances in the treatment of CMV infection following allo-HSCT in children. Conventional antiviral agents such as ganciclovir and foscarnet remain the fundamental therapeutic options. The recent approval of letermovir for pediatric use has shifted CMV management from preemptive therapy-based strategies to a comprehensive approach combining prophylaxis and preemptive treatment. Maribavir provides additional therapeutic options for refractory and drug-resistant CMV infections. Future efforts should focus on accumulating pediatric clinical data for novel agents and exploring the application of immune monitoring in guiding therapeutic strategies, aiming to further improve long-term outcomes in this population.
文章引用：张继源, 张志勇. 儿童异基因造血干细胞移植后巨细胞病毒感染的治疗进展[J]. 临床医学进展, 2026, 16(3): 2860-2868. https://doi.org/10.12677/acm.2026.1631088

参考文献

[1] Zuhair, M., Smit, G.S.A., Wallis, G., et al. (2019) Estimation of the Worldwide Seroprevalence of Cytomegalovirus: A Systematic Review and Meta-Analysis. Reviews in Medical Virology, 29, e2034.
[2] Verdeguer, A., de Heredia, C.D., González, M., Martínez, A.M., Fernández-Navarro, J.M., Pérez-Hurtado, J.M., et al. (2010) Observational Prospective Study of Viral Infections in Children Undergoing Allogeneic Hematopoietic Cell Transplantation: A 3-Year GETMON Experience. Bone Marrow Transplantation, 46, 119-124. [Google Scholar] [CrossRef] [PubMed]
[3] Wu, J., Ma, H., Lu, C., Chen, J., Lee, P., Jou, S., et al. (2017) Risk Factors and Outcomes of Cytomegalovirus Viremia in Pediatric Hematopoietic Stem Cell Transplantation Patients. Journal of Microbiology, Immunology and Infection, 50, 307-313. [Google Scholar] [CrossRef] [PubMed]
[4] Lin, R., Wu, J. and Liu, Q. (2025) Epidemiology, Clinical Outcomes, and Treatment Patterns of Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Scoping Review and Meta-Analysis. Frontiers in Microbiology, 16, Article ID: 1518275. [Google Scholar] [CrossRef] [PubMed]
[5] Jaing, T., Chang, T., Chen, S., Wen, Y., Yu, T., Lee, C., et al. (2019) Factors Associated with Cytomegalovirus Infection in Children Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation. Medicine, 98, e14172. [Google Scholar] [CrossRef] [PubMed]
[6] Heston, S.M., Young, R.R., Tanaka, J.S., Jenkins, K., Vinesett, R., Saccoccio, F.M., et al. (2021) Risk Factors for CMV Viremia and Treatment-Associated Adverse Events among Pediatric Hematopoietic Stem Cell Transplant Recipients. Open Forum Infectious Diseases, 9, ofab639. [Google Scholar] [CrossRef] [PubMed]
[7] Wen, Y., Wang, Y., Chang, T., Hsiao, Y., Yang, Y., Chen, S., et al. (2024) Comparison of Cytomegalovirus Reactivation in Children after Allogeneic Hematopoietic Cell Transplantation in 2 Transplant Eras. Transplantation Proceedings, 56, 1878-1884. [Google Scholar] [CrossRef] [PubMed]
[8] Ferrando, G., Bagnasco, F., Giardino, S., Pierri, F., Pestarino, S., Di Marco, E., et al. (2024) Monitoring and Management of Cytomegalovirus Reactivations after Allogeneic Hematopoietic Stem Cell Transplantation in Children: Experience from a Single Pediatric Center. Diagnostics (Basel, Switzerland), 14, Article No. 2461. [Google Scholar] [CrossRef] [PubMed]
[9] 中华医学会血液学分会干细胞应用学组. 异基因造血干细胞移植患者巨细胞病毒感染管理中国专家共识(2022年版) [J]. 中华血液学杂志, 2022, 43(8): 617-623.
[10] Teira, P., Battiwalla, M., Ramanathan, M., Barrett, A.J., Ahn, K.W., Chen, M., et al. (2016) Early Cytomegalovirus Reactivation Remains Associated with Increased Transplant-Related Mortality in the Current Era: A CIBMTR Analysis. Blood, 127, 2427-2438. [Google Scholar] [CrossRef] [PubMed]
[11] Hakki, M., Aitken, S.L., Danziger-Isakov, L., Michaels, M.G., Carpenter, P.A., Chemaly, R.F., et al. (2021) American Society for Transplantation and Cellular Therapy Series: #3—Prevention of Cytomegalovirus Infection and Disease after Hematopoietic Cell Transplantation. Transplantation and Cellular Therapy, 27, 707-719. [Google Scholar] [CrossRef] [PubMed]
[12] Ljungman, P., de la Camara, R., Robin, C., Crocchiolo, R., Einsele, H., Hill, J.A., et al. (2019) 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). The Lancet Infectious Diseases, 19, e260-e272. [Google Scholar] [CrossRef] [PubMed]
[13] Portillo, V., Masouridi-Levrat, S., Royston, L., Yerly, S., Schibler, M., Mappoura, M., et al. (2023) Revisiting Cytomegalovirus Serology in Allogeneic Hematopoietic Cell Transplant Recipients. Clinical Infectious Diseases, 78, 423-429. [Google Scholar] [CrossRef] [PubMed]
[14] Sayyed, A., Wilson, L., Stavi, V., Chen, S., Chen, C., Mattsson, J., et al. (2024) Impact of Cytomegalovirus (cmv) Seroconversion Pre‐Allogeneic Hematopoietic Cell Transplantation on Posttransplant Outcomes. European Journal of Haematology, 113, 441-453. [Google Scholar] [CrossRef] [PubMed]
[15] Morton, S., Danby, R., Rocha, V., Peniket, A. and Murphy, M.F. (2015) Transfusion of CMV‐Unselected Blood Components May Lead to Inappropriate Donor Selection for Patients Subsequently Undergoing Allogeneic Stem Cell Transplant. Transfusion Medicine, 25, 411-413. [Google Scholar] [CrossRef] [PubMed]
[16] Ljungman, P., Alain, S., Chemaly, R.F., Einsele, H., Galaverna, F., Hirsch, H.H., et al. (2025) Recommendations from the 10th European Conference on Infections in Leukaemia for the Management of Cytomegalovirus in Patients after Allogeneic Haematopoietic Cell Transplantation and Other T-Cell-Engaging Therapies. The Lancet Infectious Diseases, 25, e451-e462. [Google Scholar] [CrossRef] [PubMed]
[17] Solano, C., Giménez, E., Piñana, J.L., Vinuesa, V., Poujois, S., Zaragoza, S., et al. (2015) Preemptive Antiviral Therapy for CMV Infection in Allogeneic Stem Cell Transplant Recipients Guided by the Viral Doubling Time in the Blood. Bone Marrow Transplantation, 51, 718-721. [Google Scholar] [CrossRef] [PubMed]
[18] Giménez, E., Muñoz-Cobo, B., Solano, C., Amat, P. and Navarro, D. (2014) 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? Journal of Clinical Microbiology, 52, 654-656. [Google Scholar] [CrossRef] [PubMed]
[19] Lilleri, D., Gerna, G., Zelini, P., Chiesa, A., Rognoni, V., Mastronuzzi, A., et al. (2012) Monitoring of Human Cytomegalovirus and Virus-Specific T-Cell Response in Young Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation. PLOS ONE, 7, e41648. [Google Scholar] [CrossRef] [PubMed]
[20] Lee, S., Kim, Y., Yoo, K.H., Sung, K.W., Koo, H.H. and Kang, E. (2017) Clinical Usefulness of Monitoring Cytomegalovirus-Specific Immunity by Quantiferon-CMV in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients. Annals of Laboratory Medicine, 37, 277-281. [Google Scholar] [CrossRef] [PubMed]
[21] Seo, E., et al. (2023) Immunologic Monitoring of Cytomegalovirus (CMV) Enzyme-Linked Immune Absorbent Spot (ELISPOT) for Controlling Clinically Significant CMV Infection in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients. PLOS ONE, 18, e0294486. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246191 [Google Scholar] [CrossRef] [PubMed]
[22] Gagelmann, N., Ljungman, P., Styczynski, J. and Kröger, N. (2018) Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis. Biology of Blood and Marrow Transplantation, 24, 2101-2109. [Google Scholar] [CrossRef] [PubMed]
[23] César, T., Le, M.P., Klifa, R., Castelle, M., Fournier, B., Lévy, R., et al. (2023) Letermovir for CMV Prophylaxis in Very High-Risk Pediatric Hematopoietic Stem Cell Transplantation Recipients for Inborn Errors of Immunity. Journal of Clinical Immunology, 44, Article No. 6. [Google Scholar] [CrossRef] [PubMed]
[24] Galaverna, F., Baccelli, F., Zama, D., Tridello, G., Masetti, R., Soncini, E., et al. (2024) Letermovir for Cytomegalovirus Infection in Pediatric Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation: A Real-Life Study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP). Bone Marrow Transplantation, 59, 505-512. [Google Scholar] [CrossRef] [PubMed]
[25] Kuhn, A., Puttkammer, J., Madigan, T., Dinnes, L., Khan, S., Ferdjallah, A., et al. (2023) Letermovir as Cytomegalovirus Prophylaxis in a Pediatric Cohort: A Retrospective Analysis. Transplantation and Cellular Therapy, 29, 62.e1-62.e4. [Google Scholar] [CrossRef] [PubMed]
[26] Gutierrez, V., Stanek, J., Ardura, M.I. and Song, E. (2024) Cytomegalovirus Viral Load at Initiation of Pre‐Emptive Antiviral Therapy Impacts Cytomegalovirus Dynamics in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients. Transplant Infectious Disease, 26, e14358. [Google Scholar] [CrossRef] [PubMed]
[27] Ljungman, P., Chemaly, R.F., Khawaya, F., Alain, S., Avery, R., Badshah, C., et al. (2024) Consensus Definitions of Cytomegalovirus (CMV) Infection and Disease in Transplant Patients Including Resistant and Refractory CMV for Use in Clinical Trials: 2024 Update from the Transplant Associated Virus Infections Forum. Clinical Infectious Diseases, 79, 787-794. [Google Scholar] [CrossRef] [PubMed]
[28] Chou, S., Waldemer, R.H., Senters, A.E., Michels, K.S., Kemble, G.W., Miner, R.C., et al. (2002) Cytomegalovirus UL97 Phosphotransferase Mutations That Affect Susceptibility to Ganciclovir. The Journal of Infectious Diseases, 185, 162-169. [Google Scholar] [CrossRef] [PubMed]
[29] Chou, S. (2015) Rapid in Vitro Evolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance. Antimicrobial Agents and Chemotherapy, 59, 6588-6593. [Google Scholar] [CrossRef] [PubMed]
[30] Khawaja, F., Zamora, D., Yong, M.K., Hakki, M., Goscicki, B.K., Danziger-Isakov, L., et al. (2025) American Society for Transplantation and Cellular Therapy Series #11: Updated Cytomegalovirus Guidelines in Hematopoietic Cell Transplant and Cellular Therapy Recipients. Transplantation and Cellular Therapy, 31, 727-741. [Google Scholar] [CrossRef] [PubMed]
[31] Cassaniti, I., Colombo, A.A., Bernasconi, P., Malagola, M., Russo, D., Iori, A.P., et al. (2021) Positive HCMV Dnaemia in Stem Cell Recipients Undergoing Letermovir Prophylaxis Is Expression of Abortive Infection. American Journal of Transplantation, 21, 1622-1628. [Google Scholar] [CrossRef] [PubMed]
[32] Groll, A.H., Danziger-Isakov, L., Gefen, A., Fraser, C.J., Schulte, J.H., Bielorai, B., et al. (2025) Cytomegalovirus Prophylaxis with Letermovir in Pediatric (Birth to < 18 Years of Age) Hematopoietic Cell Transplant Recipients: Pharmacokinetics, Efficacy, and Safety Results of a Phase 2b Study. Antimicrobial Agents and Chemotherapy, 69, e0042025. [Google Scholar] [CrossRef] [PubMed]
[33] Zhu, Y., Wang, L., Xiang, Y., Wang, Y., Zhang, A., Wang, Y., et al. (2025) Efficacy and Safety of Letermovir for Cytomegalovirus Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients. Drug Design, Development and Therapy, 19, 5059-5069. [Google Scholar] [CrossRef] [PubMed]
[34] Song, E. (2024) Case Report: Approaches for Managing Resistant Cytomegalovirus in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients. Frontiers in Pediatrics, 12, Article ID: 1394006. [Google Scholar] [CrossRef] [PubMed]
[35] Sun, K., Hayes, S., Farrell, C. and Song, I.H. (2023) Population Pharmacokinetic Modeling and Simulation of Maribavir to Support Dose Selection and Regulatory Approval in Adolescents with Posttransplant Refractory Cytomegalovirus. CPT: Pharmacometrics & Systems Pharmacology, 12, 719-723. [Google Scholar] [CrossRef] [PubMed]
[36] Luque-Paz, D., et al. (2024) Absence of Maribavir Penetration into the Central Nervous System: Confirmation by Multiple Cerebrospinal Fluid Dosages in a Solid Organ Transplant Recipient. Journal of Antimicrobial Chemotherapy, 79, 1462-1463.
[37] Blyth, E., Clancy, L., Simms, R., Ma, C.K.K., Burgess, J., Deo, S., et al. (2013) Donor-Derived CMV-Specific T Cells Reduce the Requirement for CMV-Directed Pharmacotherapy after Allogeneic Stem Cell Transplantation. Blood, 121, 3745-3758. [Google Scholar] [CrossRef] [PubMed]
[38] Pei, X., Liu, X., Zhao, X., Lv, M., Mo, X., Chang, Y., et al. (2022) Comparable Anti-CMV Responses of Transplant Donor and Third-Party CMV-Specific T Cells for Treatment of CMV Infection after Allogeneic Stem Cell Transplantation. Cellular & Molecular Immunology, 19, 482-491. [Google Scholar] [CrossRef] [PubMed]
[39] Leen, A.M., Bollard, C.M., Mendizabal, A.M., Shpall, E.J., Szabolcs, P., Antin, J.H., et al. (2013) Multicenter Study of Banked Third-Party Virus-Specific T Cells to Treat Severe Viral Infections after Hematopoietic Stem Cell Transplantation. Blood, 121, 5113-5123. [Google Scholar] [CrossRef] [PubMed]
[40] Keller, M.D., Hanley, P.J., Chi, Y., Aguayo-Hiraldo, P., Dvorak, C.C., Verneris, M.R., et al. (2024) Antiviral Cellular Therapy for Enhancing T-Cell Reconstitution before or after Hematopoietic Stem Cell Transplantation (ACES): A Two-Arm, Open Label Phase II Interventional Trial of Pediatric Patients with Risk Factor Assessment. Nature Communications, 15, Article No. 3258. [Google Scholar] [CrossRef] [PubMed]
[41] Neuenhahn, M., Albrecht, J., Odendahl, M., Schlott, F., Dössinger, G., Schiemann, M., et al. (2017) Transfer of Minimally Manipulated CMV-Specific T Cells from Stem Cell or Third-Party Donors to Treat CMV Infection after Allo-HSCT. Leukemia, 31, 2161-2171. [Google Scholar] [CrossRef] [PubMed]

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