Human Herpesvirus-6B Reactivation Is a Risk Factor for Grades II to IV Acute Graft-versus-Host Disease after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Abstract

Graft-versus-host disease (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Many studies have suggested that human herpesvirus-6B (HHV-6B) plays a role in acute GVHD (aGVHD) after HCT. Our objective was to systematically summarize and analyze evidence regarding HHV-6B reactivation and development of aGVHD. PubMed and EMBASE databases were searched using terms for HHV-6, HCT, and aGVHD, yielding 865 unique results. Case reports, reviews, articles focusing on inherited chromosomally integrated HHV-6, poster presentations, and articles not published in English were excluded. The remaining 467 articles were reviewed for the following requirements: a statistical analysis of HHV-6B reactivation and aGVHD was described, HHV-6B reactivation was defined by PCR, and blood (plasma, serum, or peripheral blood mononuclear cells) was used for HHV-6B PCR. Data were abstracted from publications that met these criteria (n = 33). Publications were assigned to 1 of 3 groups: (1) HHV-6B reactivation was analyzed as a time-dependent risk factor for subsequent aGVHD (n = 14), (2) aGVHD was analyzed as a time-dependent risk factor for subsequent HHV-6B reactivation (n = 1), and (3) analysis without temporal specification (n = 18). A statistically significant association (P < .05) between HHV-6B reactivation and aGVHD was observed in 10 of 14 studies (71%) in group 1, 0 of 1 study (0%) in Group 2, and 8 of 18 studies (44.4%) in Group 3. Of the 14 studies that analyzed HHV-6B as a risk factor for subsequent aGVHD, 11 performed a multivariate analysis and reported a hazard ratio, which reached statistical significance in 9 of these studies. Meta-analysis of these 11 studies demonstrated a statistically significant association between HHV-6B and subsequent grades II to IV aGVHD (hazard ratio, 2.65; 95% confidence interval, 1.89 to 3.72; P < .001). HHV-6B reactivation is associated with aGVHD, and when studies have a temporal component to their design, HHV-6B reactivation is associated with subsequent aGVHD. Further research is needed to investigate whether antiviral prophylaxis reduces incidence or severity of aGVHD.

Human herpesvirus‐6B infection in pediatric allogenic hematopoietic stem cell transplant patients: Risk factors and encephalitis

“…Most studies of these two conditions in HSCT patients have been carried out in adults and mixed populations (adults and children). [5][6][7]9,11,14,16,17,19,20,22,24,32,33 In pediatric HSCT patients, several studies have been conducted to elucidate Bold values are statistically significant. were risk factors for HHV-6B infection after transplant.…”

“…[5][6][7][8] Although the frequency and timing of HHV-6B infection after HSCT is clear, the nature of the association between HHV-6B infection and clinical manifestations in HSCT patients is still a matter of debate. It has been suggested that viral infection is associated with fever, 2,8 acute graft-versus-host disease (GVHD), 6,[8][9][10][11][12] engraftment delay, 6,13 and post-transplant acute limbic encephalitis (PALE). [14][15][16][17][18][19][20] Of these clinical manifestations, the strongest causal relationship has been demonstrated between viral infection and PALE.…”

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

“…HHV-6B is a highly prevalent beta-herpes virus, infecting about 90% of the individuals in many Western populations [1]. The occurrence of episodes of viral reactivation observed in immunosuppressed individuals such as transplant patients and human immunodeficiency virus (HIV)-1-infected individuals [5][6][7][8][9]. Both CD4 and CD8 T cells responding to HHV-6B have been observed [10][11][12][13], although a full understanding of the role of the different subsets in controlling the infection is still lacking.…”

Comparative Analysis of Roseoloviruses in Humans, Pigs, Mice, and Other Species

“…So far, the underlying mechanisms of viral integration remains poorly understood. Although previous studies have observed HHV-6A/B reactivation inducing diseases in patients [67][68][69][70], reactivation of the virus genome in vitro is challenging. In most cell lines, induction of reactivation using various reagents only results in the expression of some viral genes without the production of viral particles [55,71,72].…”