title: Human herpesvirus 6 reactivation on the 30th day after allogeneic hematopoietic stem cell transplantation can predict grade 2-4 acute graft-versus-host disease.
abstract: BACKGROUND
  Viral infections and their occult reactivation occasionally cause not only organ damage, but also exacerbation of acute graft-versus-host disease (aGVHD), which may increase transplantation-related mortality synergistically. To determine correlations between viral reactivation and transplantation-related complications, we performed various viral screening tests on the 30th day after allogeneic hematopoietic stem cell transplantation (HSCT), and assessed the clinical implications.
  
  
  METHODS
  Between August 2007 and January 2013, 49 patients (37 men, 12 women) underwent HSCT in our hospital. The stem cell sources were bone marrow (n = 21), peripheral blood (n = 13), and cord blood (n = 15). The presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpesvirus (HHV) 6, and HHV7 in plasma samples prospectively collected from HSCT recipients on day 30 after HSCT was assayed by quantitative polymerase chain reaction, and the correlations with transplantation-related complications were evaluated.
  
  
  RESULTS
  The positivities of CMV, EBV, HHV6, and HHV7 were 44.9%, 22.4%, 53.1%, and 18.3%, respectively. We analyzed transplantation-related complications, and a significant correlation was found only between HHV6 and grade 2-4 aGVHD from day 30 to day 100 (P < 0.001). Using a receiver operating characteristic curve, the area under the curve was calculated as 0.86 (95% confidence interval [CI], 0.74-0.98) between the viral load (VL) of HHV6 and grade 2-4 aGVHD. The sensitivity and specificity were 79% and 93%, respectively, when a cutoff value of 87 copies/mL was used. In multivariate analysis using the Fine and Gray proportional hazards model, the clinically determined high-risk patients (P = 0.004; hazard ratio [HR], 3.69; 95% CI, 1.52-9.00) and the positivity of HHV6 (P < 0.001; HR, 9.957; 95% CI, 2.68-37.06) were extracted as independent risk factors for the cumulative incidence of grade 2-4 aGVHD on or after post-HSCT day 30. The only risk factor extracted for the elevation of HHV6 VL >87 copies/mL was cord blood transplantation (P = 0.0032; odds ratio, 7.10; 95% CI, 1.98-30.00).
  
  
  CONCLUSIONS
  All of the risk factors previously reported to predict severe aGVHD were obtained only during, but not after, HSCT. Our study suggests that the reactivation of HHV6 (≥ 87 copies/mL) at 30 days after HSCT is a possible predictive marker for grade 2-4 aGVHD on or after post-HSCT day 30.
authors.affiliation: First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Gotoh
authors.forename: S
authors.initials: S
authors.lastname: Yoshizawa
authors.forename: S
authors.initials: S
authors.lastname: Katagiri
authors.forename: T
authors.initials: T
authors.lastname: Suguro
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: T
authors.initials: T
authors.lastname: Kitahara
authors.forename: D
authors.initials: D
authors.lastname: Akahane
authors.forename: S
authors.initials: S
authors.lastname: Okabe
authors.forename: T
authors.initials: T
authors.lastname: Tauchi
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: K
authors.initials: K
authors.lastname: Ohyashiki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006086:Graft vs Host Disease / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D015654:Herpesvirus 6, Human / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012307:Risk Factors; D019349:Roseolovirus Infections / Q000821:virology*; D014184:Transplantation, Homologous; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency; D055815:Young Adult
keywords: acute graft-versus-host disease; allogeneic hematopoietic stem cell transplantation; human herpesvirus 6