title: Viral reactivations and associated outcomes in the context of immune reconstitution after pediatric hematopoietic cell transplantation.
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.
  
  
  OBJECTIVE
  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 × 106cells/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands; Pediatric Blood and Marrow Transplantation Program, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Admiraal
authors.affiliation: Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Coco C H
authors.initials: CCH
authors.lastname: de Koning
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lindemans
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Annemarie M J
authors.initials: AMJ
authors.lastname: Wensing
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: A Birgitta
authors.initials: AB
authors.lastname: Versluys
authors.affiliation: Department of Pediatric Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Tom F W
authors.initials: TFW
authors.lastname: Wolfs
authors.affiliation: Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
authors.affiliation: Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands; Pediatric Blood and Marrow Transplantation Program, University Medical Centre Utrecht, Utrecht, The Netherlands. Electronic address: j.j.boelens@umcutrecht.nl.
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Boelens
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000401:mortality / Q000821:virology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000074243:Immune Reconstitution; D007223:Infant; D011183:Postoperative Complications / Q000401:mortality / Q000821:virology*; D012189:Retrospective Studies; D016019:Survival Analysis; D014775:Virus Activation; D055815:Young Adult
keywords: Viral reactivations; clinical outcomes; hematopoietic cell transplantation; immune reconstitution