血浆EBV核酸载量对成人继发性噬血细胞综合征患者临床特征及预后的影响
Effect of Plasma Epstein-Barr Virus Nucleic Acid Loads on the Clinical Features and Prognosis in Adult Secondary Hemopha-gocytic Lymphohistiocytosis
段丽敏 1尹光丽 1田甜 1王菊娟 1高欣 1程婉莹 1房紫薇 1仇红霞 1许戟1
作者信息
- 1. 南京医科大学第一附属医院,江苏省人民医院老年血液科,江苏南京 210029
- 折叠
摘要
目的:探讨治疗前血浆EBV-DNA载量对初诊成人继发性噬血细胞综合征(sHLH)患者临床特点及预后的影响.方法:回顾性分析2017年6月至2022年1月江苏省人民医院收治的171例成人sHLH患者的临床特征、生存率及预后影响因素.根据血浆EBV-DNA载量将患者分为3组:EBV-DNA阴性组(＜5.0 × 102 copies/ml)、EBV-DNA 低拷贝数组(5.0 ×102-8.51 × 104 copies/ml)和 EBV-DNA 高拷贝数组(＞8.51 × 104 copies/ml).Cox 回归模型筛选预后因素,基于调整病因及治疗方案、EBV-DNA载量,通过列线图构建和实现成人sHLH生存预测模型.使用一致性指数(C-index)和校正曲线验证模型的预测和鉴别能力.结果:171例成人sHLH患者中,84例(49.1％)未合并EBV感染,87例(50.9％)合并EBV感染,其中EBV-DNA低拷贝数组48例、EBV-DNA高拷贝数组39例.随着EBV-DNA载量的不断升高,患者的转氨酶(ALT和AST)、乳酸脱氢酶、甘油三酯、β2-微球蛋白和铁蛋白水平均明显升高(P＜0.05),纤维蛋白原水平则更低(P＜0.001).中位随访时间为52(20-230)d,171例患者中123例死亡.生存分析结果显示,EBV感染组患者的OS较未感染EBV组更差(40vs118 d,P＜0.001).EBV-DNA 高拷贝数组、EBV-DNA低拷贝数组、EBV-DNA阴性组患者的中位OS分别为24、45和118 d,高拷贝数组患者的OS最短(P＜0.0001).多因素Cox比例风险回归分析显示,EBV-DNA高拷贝数(P=0.005)、纤维蛋白原≤1.5 g/L(P=0.012)、铁蛋白水平(P=0.041)、合并淋巴瘤(P=0.002)、接受抗肿瘤化学治疗(P=0.001)是影响患者OS的独立预后因素.列线图预测30、90和365 d生存率的C-index均＞0.8,校准图显示生存率的观测值和预测值之间有较好的一致性.亚组分析结果提示,在女性、铁蛋白＞5 000 µg/L、β2-微球蛋白＞7.4 mmol/L或无论年龄大小、不同病因、不同HScore积分的sHLH亚组中,合并EBV-DNA高拷贝数者预后更差.结论:血浆EBV-DNA病毒载量是成人sHLH患者强有力且影响生存的独立预后因素.基于EBV-DNA载量构建的列线图是可靠的,为评估成人sHLH预后提供了一个可视化工具.
Abstract
Objective:To investigate the effect of pre-treatment plasma Epstein-Barr virus(EBV)DNA copy number on the clinical features and prognosis of patients with adult secondary hemophagocytic lymphohistiocytosis(sHLH).Methods:The clinical characteristics,survival rate,and prognostic factors of 171 patients with adult sHLH treated at Jiangsu Province Hospital from June 2017 to January 2022 were retrospectively analyzed in this study.Patients were divided into three groups,including the EBV DNA-negative group(＜5.0 × 102 copies/ml),lower EBV-DNA loads group(5.0 × 102-8.51 × 104 copies/ml),and higher EBV-DNA loads group(＞8.51 × 104 copies/ml),according to pre-treatment plasma EBV-DNA copy number.Cox regression model was established for screening prognostic factors.Adult sHLH survival prediction model was constructed and realized through the nomogram based on EBV-DNA load after adjusted the factors affecting survival of etiology and treatment strategy.Concordance index(C-index)and calibration curves were calculated to verify model predictive and discriminatory capacity.Results:Among 171 adult sHLH patients,84 patients were not infected with EBV(EBV DNA-negative group),and 87 with EBV(EBV DNA-positive group,48 lower EBV-DNA loads group and 39 higher EBV-DNA loads group).Consistent elevations in the levels of liver enzymes(ALT and AST),LDH,TG,β2-microglobulin and ferritin across the increasing of EBV-DNA load(all P＜0.05),while the levels of fibrinogen decrease(P＜0.001).The median follow-up time was 52 days(range 20-230 days),and 123 patients died.The overall survival(OS)rate of patients in EBV DNA-positive group was lower than that in EBV DNA-negative group(median OS:40 days vs 118 days,P＜0.001).Higher EBV-DNA loads had worse OS(median OS:24 days vs 45 days vs 118 days,P＜0.0001 for trend)compared to lower EBV-DNA loads and EBV DNA-negative group.Multivariate Cox analysis revealed that higher EBV-DNA loads(P=0.005),fibrinogen≤ 1.5 g/L(P=0.012),ferritin(P=0.041),associated lymphoma(P=0.002),and anti-tumor based strategy(P=0.001)were independent prognostic factors for OS.The C-indexes of 30 day,90 days,365 days survival rate were all greater than 0.8 of the nomogram model and calibration curves provided credibility to their predictive capability.Subgroup analysis showed that patients with higher EBV-DNA loads had a significantly worse prognosis in adult sHLH who were women,ferritin＞5 000 µg/L,β2-microglobulin＞7.4 mmol/L and regardless of age,etiologies,HScore points.Conclusion:The EBV-DNA load is a strong and independent predictor for survival in patients with sHLH.The prognostic nomogram based on EBV-DNA loads was dependable and provides a visual tool for evaluating the survival of adult sHLH.
关键词
噬血细胞综合征/EB病毒感染/血浆/列线图/预后因素Key words
hemophagocytic lymphohistiocytosis/Epstein-Barr virus infection/plasma/nomogram/prognostic factors引用本文复制引用
基金项目
国家自然科学基金(82200209)
对外协作项目(TM140ES)
出版年
2024
NETL
NSTL
万方数据