Viral Reactivations and Associated Outcomes in Context of Immune Reconstitution after Pediatric Hematopoietic Cell Transplantation

Publication date: Available online 7 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Rick Admiraal, Coco de Koning, Caroline A. Lindemans, Marc B. Bierings, Annemarie M.J. Wensing, A. Birgitta Versluys, Tom F.W. Wolfs, Stefan Nierkens, Jaap Jan Boelens
BackgroundViral reactivations (VR) following hematopoietic cell transplantation (HCT) contribute to significant morbidity and mortality. Timely immune reconstitution (IR) is suggested to prevent VR.ObjectivesWe studied the relation between IR (as a continuous over-time-predictor) and VR (as time-varying-predictor), and the relation between VR and other clinical outcomes.MethodsIn this retrospective analysis, all patients receiving a first HCT between January-2004 and September-2014 were included. IR (CD3/CD4/CD8 T-cells, NK- and B-cells) was measured bi-weekly until 12 weeks, and monthly thereafter. Main outcomes of interest were VR of adenovirus (AdV), Epstein-Barr-virus (EBV), human-herpesvirus 6 (HHV6), cytomegalovirus (CMV), and BK-virus, screened weekly. Clinical outcomes included overall-survival (OS), event-free-survival, non-relapse-mortality (NRM), and graft-versus-host-disease (GvHD). Cox-proportional-hazard- and Fine-Gray-competing-risk-models were used.Results273 patients (0.1-22.7 years; median follow-up 58 months) were included. Delayed CD4-reconstitution predicted reactivation of AdV (HR 0.995; p=0.022), EBV (HR 0.994, p=0.029), and HHV6 (HR 0.991, p=0.012), but not CMV (p=0.31) and BK (p=0.27). Duration of AdV-reactivation was shorter with timely CD4-reconstitution, defined as ≥50*10⁶ cells/L within 100-days. AdV-reactivation predicted lower OS (HR 2.17, p=0.0039) and higher NRM (HR 2.96, p=0.0008). Concomitant CD4-reconstitution abolished this negative effect of AdV-reactivation: OS (p=0.67) and NRM (p=0.64). EBV- and HHV6-reactivations were predictors for occurrence of GvHD, while CMV- and BK-reactivations did not predict clinical outcomes.ConclusionThese results stress the importance of timely CD4-reconstitution. Strategies to improve CD4-reconstitution may improve HCT-outcomes, including survival, and reduce the need for toxic anti-viral therapies.



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