424例地中海贫血患儿异基因造血干细胞移植后继发侵袭性真菌病临床分析

doi:10.12372/jcp.2025.24e0023

Abstract

Abstract:

Objective This study aims to investigate the clinical characteristics and risk factors of invasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with transfusion-dependent thalassemia (TDT). Methods The clinical data of 424 children with TDT who received allo-HSCT from January 2021 to December 2022 were retrospectively analyzed, and the influencing factors of IFD after allo-HSCT were analyzed. Results A total of 424 TDT children undergoing allo-HSCT were included, 261 (61.6%) boys and 163(38.4%) girls, with a median age of 8.0 (5.0-11.0) years. Among them, there were 278 cases of haploidentical transplantation, 116 cases of matched or well matched related transplantation, and 30 cases of matched or well matched unrelated transplantation. All transplant patients received primary antifungal prophylaxis. A total of 30 patients (7.1%, 20 boys and 10 girls) had IFD, 25 patients (83.3%) were probable IFD and 5 (16.7%) were proven IFD. The median occurrence time of IFD was 39.0 (23.5-85.8) days after transplantation. The lung was the most common site of infection (24 cases, 80.0%). Cough (15 cases, 50.0%) and fever (10 cases, 33.3%) were the main symptoms. The pulmonary imaging findings were atypical (14 cases, 46.7%). The main fungal pathogen was Aspergillus (19 cases, 63.3%). Co-infection was detected in 17 cases (56.7%), and co-virus infection was most common. The median follow-up time was 16.0 (9.0-21.8) months, and the overall survival (OS) rate was (99.3±0.01) %. The OS rates of non-IFD group and IFD group were (99.7±0.003) % and (93.3±0.06)%, respectively, and the difference between the two groups was statistically significant (P<0.001). The results of binary logistic regression analysis indicated that poor graft function or graft failure, acute graft-versus-host disease (aGVHD) and antifungal prophylaxis of non-posaconazole were independent risk factors for development of IFD after allo-HSCT (P<0.05). Conclusions TDT children undergoing allo-HSCT and receiving primary fungal prophylaxis exhibited a low incidence of IFD, and IFD was associated with higher risk of death. Patients with a history of poor graft function/ graft failure, aGVHD or those receiving non-posaconazole prophylaxis faced a greater risk of developing IFD.

Key words: invasive fungal disease, thalassemia, allogeneic hematopoietic stem cell transplantation, child

LUO Mingjing, YU Jiaming, WANG Xiaodong, ZHANG Xiaoling, YU Yue, ZHANG Yu, WEN Feiqiu, LIU Sixi. Clinical analysis of invasive fungal disease secondary to allogeneic hematopoietic stem cell transplantation in 424 children with thalassemia[J].Journal of Clinical Pediatrics, 2025, 43(1): 21-28.

Figures/Tables 3

Table 1

Table 2

Figure 1

References 43

[1]	Ayoub PG, Kohn DB. β-thalassemia: all about that base, no cutting[J]. Blood, 2023, 141(10): 1098-1099. doi: 10.1182/blood.2022019350 pmid: 36893006
[2]	Kattamis A, Kwiatkowski JL, Aydinok Y. Thalassaemia[J]. Lancet, 2022, 399(10343): 2310-2324. doi: 10.1016/S0140-6736(22)00536-0 pmid: 35691301
[3]	Hazar V, Karasu GT, Uygun V, et al. Risks and outcomes of invasive fungal infections in pediatric allogeneic hematopoietic stem cell transplant recipients receiving fluconazole prophylaxis: a multicenter cohort study by the Turkish Pediatric Bone Marrow Transplantation Study Group[J]. Med Mycol, 2019, 57(2): 161-170. doi: 10.1093/mmy/myy015 pmid: 29608706
[4]	Styczyński J, Tridello G, Koster L, et al. Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors[J]. Bone Marrow Transplant, 2020, 55(1): 126-136.
[5]	中华医学会血液学分会红细胞疾病(贫血)学组. 中国输血依赖型β地中海贫血诊断与治疗指南(2022年版)[J]. 中华血液学杂志, 2022, 43(11): 889-896.
	Red Blood Cell Diseases (Anemia) Group. Chinese Society of Hematology, Chinese Medical Association. Chinese guideline for diagnosis and treatment of transfusion dependent β-thalassemia (2022)[J]. Zhonghua Xueyexue Zazhi, 2022, 43(11): 889-896.
[6]	广东省地中海贫血防治协会, 《中国实用儿科杂志》编辑委员会. 造血干细胞移植治疗重型β地中海贫血儿科专家共识[J]. 中国实用儿科杂志, 2018, 33(12): 935-939.
	Thalassaemia Association of Guangdong Province, Editorial Board of Chinese Journal of Practical Pediatrics. Pediatric expert consensus on hematopoietic stem cell transplantation for the treatment of severe βthalassemia[J]. Zhonghua shiyong Erke Zazhi, 2018, 33(12): 935-939.
[7]	Döring M, Müller C, Johann PD, et al. Analysis of posaconazole as oral antifungal prophylaxis in pediatric patients under 12 years of age following allogeneic stem cell transplantation[J]. BMC Infect Dis, 2012, 12: 263. doi: 10.1186/1471-2334-12-263 pmid: 23082876
[8]	Groll AH, Pana D, Lanternier F, et al. 8^th European Conference on Infections in Leukaemia: 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation[J]. Lancet Oncol, 2021, 22(6): e254-e269.
[9]	泊沙康唑临床应用专家组. 泊沙康唑临床应用专家共识[J]. 国际呼吸杂志, 2020, 40(4): 241-261.
	Working Group of Expert Consensus on Clinical Use of Posaconazole. Expert consensus on clinical use of posaconazole[J]. Guoji Huxi Zazhi, 2020, 40(4): 241-261.
[10]	中国医师协会血液科医师分会, 中国侵袭性真菌感染工作组. 血液病/恶性肿瘤患者侵袭性真菌病的诊断标准与治疗原则(第六次修订版)[J]. 中华内科杂志, 2020, 59(10): 754-763.
	Chinese Association Hematologists, Chinese Invasive Fungal Infection Working Group. The Chinese guidelines for the diagnosis and treatment of invasive fungal disease in patients with hematological disorders and cancers (the 6^th revision)[J]. Zhonghua Neike Zazhi, 2020, 59(10): 754-763.
[11]	Lehrnbecher T, Robinson PD, Ammann RA, et al. Guideline for the management of fever and neutropenia in pediatric patients with cancer and hematopoietic cell transplantation recipients: 2023 update[J]. J Clin Oncol, 2023, 41(9): 1774-1785.
[12]	Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health. Common terminology criteria for adverse events v5.0 (CTCAE)[EB/OL]. [2024-06-22]. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf.
[13]	Lehrnbecher T, Fisher BT, Phillips B, et al. Clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation recipients[J]. J Clin Oncol, 2020, 38(27): 3205-3216. doi: 10.1200/JCO.20.00158 pmid: 32459599
[14]	Cesaro S, Tridello G, Castagnola E, et al. Retrospective study on the incidence and outcome of proven and probable invasive fungal infections in high-risk pediatric onco-hematological patients[J]. Eur J Haematol, 2017, 99(3): 240-248. doi: 10.1111/ejh.12910 pmid: 28556426
[15]	Kobayashi R, Hori D, Sano H, et al. Risk factors for invasive fungal infection in children and adolescents with hematologic and malignant diseases: a 10-year analysis in a single institute in Japan[J]. Pediatr Infect Dis J, 2018, 37(12): 1282-1285. doi: 10.1097/INF.0000000000002010 pmid: 30408007
[16]	Czyżewski K, Gałązka P, Frączkiewicz J, et al. Epidemiology and outcome of invasive fungal disease in children after hematopoietic cell transplantation or treated for malignancy: impact of national programme of antifungal prophylaxis[J]. Mycoses, 2019, 62(11): 990-998. doi: 10.1111/myc.12990 pmid: 31429997
[17]	Gomez S, Fynn AB, Fernanda S, et al. Early bacterial and fungal infection in children receiving allogeneic stem cell transplantation for acute lymphoblastic leukemia in Argentina[J]. Pediatr Transplant, 2018, 22(1). doi: 10.1111/petr.13070.
[18]	Lehrnbecher T, Schöning S, Poyer F, et al. Incidence and outcome of invasive fungal diseases in children with hematological malignancies and/or allogeneic hematopoietic stem cell transplantation: results of a prospective multicenter study[J]. Front Microbiol, 2019, 10: 681. doi: 10.3389/fmicb.2019.00681 pmid: 31040830
[19]	Olivier-Gougenheim L, Rama N, Dupont D, et al. Invasive fungal infections in immunocompromised children: novel insight following a national study[J]. J Pediatr, 2021, 236: 204-210.
[20]	Simms-Waldrip T, Rosen G, Nielsen-Saines K, et al. Invasive fungal infections in pediatric hematopoietic stem cell transplant patients[J]. Infect Dis (Lond), 2015, 47(4): 218-224.
[21]	Viens AL, Timmer KD, Alexander NJ, et al. TLR signaling rescues fungicidal activity in syk-deficient neutrophils[J]. J Immunol, 2022, 208(7): 1664-1674. doi: 10.4049/jimmunol.2100599 pmid: 35277418
[22]	Yoo DG, Paracatu LC, Xu E, et al. NADPH oxidase limits collaborative pattern-recognition receptor signaling to regulate neutrophil cytokine production in response to fungal pathogen-associated molecular patterns[J]. J Immunol, 2021, 207(3): 923-937.
[23]	Feldman MB, Vyas JM, Mansour MK. It takes a village: Phagocytes play a central role in fungal immunity[J]. Semin Cell Dev Biol, 2019, 89: 16-23. doi: S1084-9521(17)30174-X pmid: 29727727
[24]	Zhou Z, Liu X, Zhang X, et al. Impact of early natural killer cell reconstitution on the outcomes of T cell-replete allogeneic hematopoietic stem cell transplantation[J]. J Inflamm Res, 2023, 16: 2993-3008. doi: 10.2147/JIR.S416708 pmid: 37489148
[25]	Sun Y, Meng F, Han M, et al. Epidemiology, management, and outcome of invasive fungal disease in patients undergoing hematopoietic stem cell transplantation in China: a multicenter prospective observational study[J]. 2015, 21(6): 1117-1126.
[26]	Zhang X, Zhang L, Li Y, et al. Clinical performance of metagenomic next-generation sequencing for diagnosis of invasive fungal disease after hematopoietic cell transplant[J]. Front Cell Infect Microbiol, 2024, 14: 1210857.
[27]	Piñana JL, Gómez MD, Montoro J, et al. Incidence, risk factors, and outcome of pulmonary invasive fungal disease after respiratory virus infection in allogeneic hematopoietic stem cell transplantation recipients[J]. Transpl Infect Dis, 2019, 21(5): e13158.
[28]	Kontoyiannis DP. Antifungal prophylaxis in hematopoietic stem cell transplant recipients: the unfinished tale of imperfect success[J]. Bone Marrow Transplant, 2011, 46(2): 165-173.
[29]	Srinivasan A, Wang C, Srivastava DK, et al. Timeline, epidemiology, and risk factors for bacterial, fungal, and viral infections in children and adolescents after allogeneic hematopoietic stem cell transplantation[J]. Biol Blood Marrow Transplant, 2013, 19(1): 94-101.
[30]	Ricard N, Zebali L, Renard C, et al. New perspectives on primary prophylaxis of invasive fungal infection in children undergoing hematopoietic stem cell transplantation: a 10-year retrospective cohort study[J]. Cancers (Basel), 2023, 15(7): 2107.
[31]	Chuleerarux N, Nematollahi S, Thongkam A, et al. The association of cytomegalovirus infection and cytomegalovirus serostatus with invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients: a systematic review and meta-analysis[J]. Clin Microbiol Infect, 2022, 28(3): 332-344.
[32]	中华医学会儿科学分会, 中华儿科杂志编辑委员会. 儿童侵袭性肺部真菌感染临床实践专家共识(2022版)[J]. 中华儿科杂志, 2022, 60(4): 274-282.
	Society of Pediatrics, Chinese Medical Association; Editorial Board, Chinese Journal of Pediatrics. Expert consensus on clinical practice of invasive pulmonary fungal infections in children (2022)[J]. Zhonghua Erke Zazhi, 2022, 60(4): 274-282.
[33]	Saffioti C, Mesini A, Bandettini R, et al. Diagnosis of invasive fungal disease in children: a narrative review[J]. Expert Rev Anti Infect Ther, 2019, 17(11): 895-909.
[34]	Burgos A, Zaoutis TE, Dvorak CC, et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases[J]. Pediatrics, 2008, 121(5): e1286-e1294.
[35]	Tao Y, Yan H, Liu Y, et al. Diagnostic performance of metagenomic next-generation sequencing in pediatric patients: a retrospective study in a large children's medical center[J]. 2022, 68(8): 1031-1041.
[36]	Danion F, Duval C, Séverac F, et al. Factors associated with coinfections in invasive aspergillosis: a retrospective cohort study[J]. Clin Microbiol Infect, 2021, 27(11): 1644-1651.
[37]	Rotte LGY, Loeffen YGT, Bierings MB, et al. Allogenic hematopoietic stem cell transplantation is feasible in pediatric patients with an active or recently diagnosed invasive fungal infection[J]. Transplant Cell Ther, 2021, 27(9): 781.e1-781.e5.
[38]	Linke C, Ehlert K, Ahlmann M, et al. Epidemiology, utilisation of healthcare resources and outcome of invasive fungal diseases following paediatric allogeneic haematopoietic stem cell transplantation[J]. Mycoses, 2020, 63(2): 172-180. doi: 10.1111/myc.13029 pmid: 31661569
[39]	彭英楠, 边志磊, 曹伟杰, 等. 泊沙康唑与伏立康唑预防异基因造血干细胞移植后侵袭性真菌感染的疗效和安全性[J]. 实用医学杂志, 2023, 39(6): 742-746.
	Peng YN, Bian ZL, Cao WJ, et al. Efficacy and safety study of posaconazole and voriconazole for the prevention of invasive fungal infections after allogeneic hematopoietic stem cell transplantation[J]. Shiyong Yixue Zazhi, 2023, 39(6): 742-746.
[40]	陆婧媛, 洪秀理, 陈亚玫, 等. 泊沙康唑预防性抗真菌治疗在重型地中海贫血儿童干细胞移植中的应用[J]. 中国感染与化疗杂志, 2020, 20(2): 125-130. doi: 10.16718/j.1009-7708.2020.02.003
	Lu JY, Hong XL, Chen YM, et al. Oral posaconazole as antifungal prophylaxis in the pediatric patients with major thalassemia following allogeneic stem cell transplantation[J]. Zhongguo Ganran Yu Hualiao Zahi, 2020, 20(2): 125-130.
[41]	潘静, 凌卓君, 王晶晶, 等. 泊沙康唑预防高危儿童肺部侵袭性真菌感染的效果与安全性评估[J]. 中华医院感染学杂志, 2016, 26(14): 3310-3312.
	Pan J, Ling ZQ, Wang JJ, et al. Effect and safety of posaconazole in prevention of pulmonary invasive fungal infections in children[J]. Zhonghua Yiyuan Ganranxue Zazhi, 2016, 26(14): 3310-3312.
[42]	Döring M, Blume O, Haufe S, et al. Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation[J]. Eur J Clin Microbiol Infect Dis, 2014, 33(4): 629-638.
[43]	泊沙康唑临床应用专家组. 泊沙康唑临床应用专家共识(2022年版)[J]. 中华临床感染病杂志, 2022, 15(5): 321-332.
	Working Group of Expert Consensus on Clinical Use of Posaconazole. Expert consensus on clinical use of posaconazole (2022 edition)[J]. Zhonghua Linchuang Ganranbing Zazhi, 2022, 15(5): 321-332.

项目	非IFD组(n=394)	IFD组(n=30)	统计量	P
年龄[n(%)]			χ²=0.03	0.855
≤12岁	343(87.1)	27(90.0)
>12岁	51(12.9)	3(10.0)
男性[n(%)]	241(61.2)	20(66.7)	χ²=0.36	0.551
移植方案[n(%)]			χ²=3.23	0.199
亲缘全/良好相合	111(28.2)	5(16.7)
无关全/良好相合	26(6.6)	4(13.3)
亲缘单倍体	257(65.2)	21(70.0)
造血干细胞类型[n(%)]			－	0.378¹⁾
外周血	253(64.2)	23(76.7)
外周血+骨髓	126(32.0)	7(23.3)
外周血+脐血	15(3.8)	0(0)
GVHD预防方案[n(%)]			χ²=2.74	0.098
PT-CY+FK506+MMF	329(83.5)	29(96.7)
MTX+CSA+MMF	65(16.5)	1(3.3)
植入情况[M(P₂₅~P₇₅)]/d
中性粒细胞植活	17.0(15.0~20.0)	17.5(15.8~21.0)	Z=1.38	0.168
红细胞植活	15.0(12.0~18.0)	15.5(14.0~20.8)	Z=1.91	0.056
血小板植活	13.0(12.0~16.0)	13.0(12.0~19.5)	Z=1.09	0.277
急性GVHD[n(%)]	21(5.3)	5(16.7)	χ²=4.41	0.036
植入不良/失败[n(%)]	15(3.8)	4(13.3)	χ²=3.89	0.048
病毒感染[n(%)]
CMV	99(25.1)	14(46.7)	χ²=6.62	0.010
EBV	41(10.4)	3(10.0)	χ²=0.00	1.000
初级真菌预防[n(%)]			χ²=6.34	0.012
泊沙康唑	355(90.1)	22(73.3)
非泊沙康唑	39(9.9)	8(26.7)
随访时间[M(P₂₅~P₇₅)]/月	16.0(9.0~22.0)	17.0(9.8~21.3)	Z=0.20	0.842

变量	偏回归系数	标准误	χ²值	P	OR(95%CI)
植入不良/失败	1.29	0.61	4.44	0.035	3.64(1.09~12.11)
不含泊沙康唑	1.13	0.46	6.12	0.013	3.08(1.26~7.53)
急性GVHD	1.15	0.55	4.31	0.038	3.16(1.07~9.33)
常量	－2.98	0.24	149.14	<0.001	－

Clinical analysis of invasive fungal disease secondary to allogeneic hematopoietic stem cell transplantation in 424 children with thalassemia

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 3

References 43

Related Articles 15

Metrics

Comments

Recommended 0

[1]	HAO Chuangli, JIANG Wujun. Influence of COVID-19 epidemic on the epidemiology of pathogens causing respiratory tract infections in children [J]. Journal of Clinical Pediatrics, 2025, 43(3): 163-167.
[2]	XU Xuena, LI Jiaoyang, CHEN Suqing, ZHANG Yizhu, JIANG Wujun, HAO Chuangli. Analysis of RSV prevalence dynamics and mixed positivity for other pathogens among children in Suzhou before, during and after the COVID-19 pandemic [J]. Journal of Clinical Pediatrics, 2025, 43(3): 168-176.
[3]	LI Shanshan, HU Dandan. Analysis of risk factors for death from influenza A (H1N1)-associated encephalopathy in children [J]. Journal of Clinical Pediatrics, 2025, 43(3): 177-183.
[4]	ZHAI Yu, DUAN Suxia, JIA Fanping, JIA Yongping, ZHANG Jingjing, GUO Yinghui. Analysis of epidemiological characteristics of respiratory tract Boca virus infection in children: a single-center retrospective study [J]. Journal of Clinical Pediatrics, 2025, 43(3): 184-190.
[5]	ZHAO Peiwei, ZHANG Lei, MENG Qingjie, HE Xuelian. Clinical and genetic features of seven patients with neurodegeneration with brain iron accumulation [J]. Journal of Clinical Pediatrics, 2025, 43(3): 199-203.
[6]	JIA Shuangzhen, KONG Yan, LIU Qian-chao, ZHU Ailin, WU Jie. Application of precision therapy in pediatric inflammatory bowel disease [J]. Journal of Clinical Pediatrics, 2025, 43(3): 226-232.
[7]	LI Zhaofei, WANG Lingchao, ZHAO Dean. Research progress in clinical diagnosis and treatment of pediatric esophageal corrosive injury [J]. Journal of Clinical Pediatrics, 2025, 43(3): 237-242.
[8]	YANG Fan, LI Juan, ZHANG Wanglin, CHANG Guoying, LI Xin, LI Yunyun, SHE Jiaxiao, LIN Kana, LI Hao, WANG Xiumin. Clinical analysis of burosumab in the treatment of X-linked hypophosphatemic rickets [J]. Journal of Clinical Pediatrics, 2025, 43(2): 105-111.
[9]	LE Huijuan, WU Jin. Examination of peripheral blood MDSCs quantitative variations and biological properties in infants with necrotizing enterocolitis: utilizing GEO database insights [J]. Journal of Clinical Pediatrics, 2025, 43(2): 112-119.
[10]	HUANG Liufang, WU Bo, WANG Ying. An analysis of predictive markers for surgical treatment of ulcerative colitis in children [J]. Journal of Clinical Pediatrics, 2025, 43(2): 120-127.
[11]	LIN Lihua, ZHANG Ning, CHEN Qihong, CHEN Lili, CHEN Lixian, YANG Yungang. Bronchial dieulafoy's disease in children: a case report and review of literature [J]. Journal of Clinical Pediatrics, 2025, 43(2): 135-140.
[12]	ZHANG Shuo, ZHAO Xuemin, SHEN Xiuhua. The effect of vegetarian diet on children and adolescents [J]. Journal of Clinical Pediatrics, 2025, 43(2): 157-162.
[13]	GUO Fang, KANG Lei, WU Xiaoyuan, JIA Yanhong, DI Yanan, JIA Li, XU Meixian. Analysis of children with severe pertussis complicated with Pneumocystis jirovecii pneumonia [J]. Journal of Clinical Pediatrics, 2025, 43(2): 99-104.
[14]	LIU Dongxia, JIN Rong, LIN Rongjun. Risk factors analysis of severe refractory Mycoplasma pneumoniae pneumonia complicated with bronchitis obliterans in children [J]. Journal of Clinical Pediatrics, 2025, 43(1): 29-34.
[15]	ZHONG Jinhong, WANG Can, CHEN Fang. Progress in the research of infantile fiberoptic bronchoscopy sedation [J]. Journal of Clinical Pediatrics, 2025, 43(1): 50-55.