儿童造血细胞移植后免疫重建时的病毒激活及其相关结局。

Viral reactivations and associated outcomes in the context of immune reconstitution after pediatric hematopoietic cell transplantation.

机构信息

Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands; Pediatric Blood and Marrow Transplantation Program, University Medical Centre Utrecht, Utrecht, The Netherlands.

Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.

出版信息

J Allergy Clin Immunol. 2017 Dec;140(6):1643-1650.e9. doi: 10.1016/j.jaci.2016.12.992. Epub 2017 Apr 7.

DOI:10.1016/j.jaci.2016.12.992

PMID:28392330

Abstract

BACKGROUND

Viral reactivations (VRs) after hematopoietic cell transplantation (HCT) contribute to significant morbidity and mortality. Timely immune reconstitution (IR) is suggested to prevent VR.

OBJECTIVES

We studied the relation between IR (as a continuous predictor over time) and VR (as a time-varying predictor) and the relation between VR and other clinical outcomes.

METHODS

In this retrospective analysis all patients receiving a first HCT between January 2004 and September 2014 were included. IR (CD3/CD4/CD8 T, natural killer, and B cells) was measured biweekly until 12 weeks and monthly thereafter. Main outcomes of interest were VR of adenovirus, EBV, human herpesvirus 6 (HHV6), cytomegalovirus (CMV), and BK virus screened weekly. Clinical outcomes included overall survival (OS), event-free-survival, nonrelapse mortality (NRM), and graft-versus-host disease. Cox proportional hazard and Fine and Gray competing risk models were used.

RESULTS

Two hundred seventy-three patients (age, 0.1-22.7 years; median follow-up, 58 months) were included. Delayed CD4 reconstitution predicted reactivation of adenovirus (hazard ratio [HR], 0.995; P = .022), EBV (HR, 0.994; P = .029), and HHV6 (HR, 0.991; P = .012) but not CMV (P = .31) and BK virus (P = .27). Duration of adenovirus reactivation was shorter with timely CD4 reconstitution, which was defined as 50 × 10 cells/L or greater within 100 days. Adenovirus reactivation predicted lower OS (HR, 2.17; P = .0039) and higher NRM (HR, 2.96; P = .0008). Concomitant CD4 reconstitution abolished this negative effect of adenovirus reactivation (OS, P = .67; NRM, P = .64). EBV and HHV6 reactivations were predictors for the occurrence of graft-versus-host disease, whereas CMV and BK virus reactivation did not predict clinical outcomes.

CONCLUSION

These results stress the importance of timely CD4 reconstitution. Strategies to improve CD4 reconstitution can improve HCT outcomes, including survival, and reduce the need for toxic antiviral therapies.

摘要

背景

造血细胞移植（HCT）后病毒再激活（VR）会导致显著的发病率和死亡率。及时的免疫重建（IR）被认为可以预防 VR。

目的

我们研究了 IR（作为时间上的连续预测因子）和 VR（作为时变预测因子）之间的关系，以及 VR 与其他临床结局之间的关系。

方法

在这项回顾性分析中，纳入了 2004 年 1 月至 2014 年 9 月期间接受首次 HCT 的所有患者。IR（CD3/CD4/CD8 T、自然杀伤和 B 细胞）在 12 周内每两周测量一次，之后每月测量一次。主要观察终点是每周筛查腺病毒、EBV、人类疱疹病毒 6（HHV6）、巨细胞病毒（CMV）和 BK 病毒的 VR。临床结局包括总生存率（OS）、无事件生存率、非复发死亡率（NRM）和移植物抗宿主病。使用 Cox 比例风险和 Fine 和 Gray 竞争风险模型。

结果

共纳入 273 例患者（年龄 0.1-22.7 岁；中位随访时间 58 个月）。CD4 重建延迟预测腺病毒（风险比 [HR]，0.995；P=0.022）、EBV（HR，0.994；P=0.029）和 HHV6（HR，0.991；P=0.012）的再激活，但不预测 CMV（P=0.31）和 BK 病毒（P=0.27）的再激活。及时的 CD4 重建预测了腺病毒再激活的较短持续时间，其定义为 100 天内达到 50×10^6/L 或更高水平。腺病毒再激活预测了较低的 OS（HR，2.17；P=0.0039）和较高的 NRM（HR，2.96；P=0.0008）。同时的 CD4 重建消除了腺病毒再激活的这种负面影响（OS，P=0.67；NRM，P=0.64）。EBV 和 HHV6 的再激活是发生移植物抗宿主病的预测因素，而 CMV 和 BK 病毒的再激活并不能预测临床结局。