Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

Ogata, Masao; Fukuda, Takahiro; Teshima, Takanori

doi:10.1038/bmt.2015.76

Cited by 107 publications

(97 citation statements)

References 92 publications

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“…Since 2008, preemptive therapy was started when HHV-6 DNA exceeded 125 copies/mL to prevent encephalitis. However, previous trials suggested HHV-6 DNA-guided preemptive therapy was inadequate in preventing HHV-6 encephalitis [24,32,33]. Further studies are needed to prove efficacy of preemptive therapy of HHV-6 encephalitis.…”

Section: Discussionmentioning

confidence: 95%

Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

Aoki

Numata

Yamamoto

et al. 2015

Biology of Blood and Marrow Transplantation

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Human herpesvirus-6 (HHV-6) is known to reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with development of acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the clinical significance of HHV-6 reactivation after allo-HSCT remains unclear. Therefore, we conducted a retrospective analysis to elucidate the impact of HHV-6 reactivation on transplantation outcomes. Of 236 patients who underwent allo-HSCT, 138 (58.5%) developed HHV-6 reactivation and 98 (41.5%) did not. Univariate analysis indicated that at 3 years, patients with HHV-6 reactivation had significantly higher NRM (27.7% versus 13.7%, P = .003) and worse overall survival (42.1% versus 59.0%, P = .008) than those without reactivation. In multivariate analysis, HHV-6 reactivation was associated with higher incidence of acute GVHD (hazard ratio [HR], 1.87; P = .01), cytomegalovirus reactivation (HR, 2.24; P < .001), and NRM (HR, 2.73; P = .007). Subgroup analysis stratified according to conditioning intensity indicated that a significant impact of HHV-6 reactivation on acute GVHD was observed only in patients who received myeloablative conditioning (MAC). These results indicate that HHV-6 reactivation was associated with development of acute GVHD, cytomegalovirus reactivation, and NRM. Furthermore, adverse impact of HHV-6 reactivation on transplantation outcomes was prominent in the setting of MAC.

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Section: Discussionmentioning

confidence: 95%

Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

Aoki

Numata

Yamamoto

et al. 2015

Biology of Blood and Marrow Transplantation

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“…13 HHV-6 encephalitis is therefore increasingly recognized as an important complication of allo-HSCT; however, many questions remain unanswered. Reported incidence of HHV-6 encephalitis among allo-HSCT recipients ranges from 0.96 to 11.6%, 5 mainly owing to small cohorts of cases. Although umbilical cord blood transplantation (CBT) represents a risk factor for HHV-6 encephalitis, 5,12,14 other risk factors remain unconfirmed.…”

Section: Introductionmentioning

confidence: 99%

“…Reported incidence of HHV-6 encephalitis among allo-HSCT recipients ranges from 0.96 to 11.6%, 5 mainly owing to small cohorts of cases. Although umbilical cord blood transplantation (CBT) represents a risk factor for HHV-6 encephalitis, 5,12,14 other risk factors remain unconfirmed. Treatment recommendations have been made based on in vitro data, [15][16][17] but few data are available on the clinical effectiveness.…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation

Ogata

Oshima

Ikebe

et al. 2017

Bone Marrow Transplant

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In this retrospective analysis using the Transplant Registry Unified Management Program, we identified 145 patients with human herpesvirus (HHV)-6 encephalitis among 6593 recipients. The cumulative incidences of HHV-6 encephalitis at 100 days after transplantation in all patients, recipients of bone marrow or PBSCs and recipients of cord blood were 2.3%, 1.6% and 5.0%, respectively. Risk factors identified in multivariate analysis were male sex, type of transplanted cells (relative risk in cord blood transplantation, 11.09, P o0.001; relative risk in transplantation from HLA-mismatched unrelated donor, 9.48, P o0.001; vs transplantation from HLA-matched related donor) and GvHD prophylaxis by calcineurin inhibitor alone. At 100 days after transplantation, the overall survival rate was 58.3% and 80.5% among patients with and without HHV-6 encephalitis, respectively (P o 0.001). Neuropsychological sequelae remained in 57% of 121 evaluated patients. With both foscarnet and ganciclovir, full-dose therapy (foscarnet ⩾ 180 mg/kg, ganciclovir ⩾ 10 mg/kg) was associated with better response rate (foscarnet, 93% vs 74%, P = 0.044; ganciclovir, 84% vs 58%, P = 0.047). HHV-6 encephalitis is not rare not only in cord blood transplant recipients but also in recipients of HLA-mismatched unrelated donors. In this study, development of HHV-6 encephalitis was associated with a poor survival rate, and neurological sequelae remained in many patients.

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“…HHV-6 reactivation facilitates transactivation of other herpesviruses, such as HHV-7 or human cytomegalovirus (HCMV) , and the spread of fungal infections (6)(7)(8)(9)(10). Interestingly, for several chronic neurological disorders such as multiple sclerosis (MS), Alzheimer's disease (AD), or chronic fatigue syndrome (CFS), markedly elevated HHV-6 titers were determined (11)(12)(13). Yet, whether HHV-6 has a causative role in these diseases or whether reactivation is a consequence of a deregulated and malfunctioning immune system requires elucidation.…”

mentioning

confidence: 99%

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Schmiedel

Tai

Levi‐Schaffer

et al. 2016

J Virol

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The Herpesviridae family consists of eight viruses, most of which infect a majority of the human population. One of the lessstudied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination. IMPORTANCEHuman herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination. Human herpesvirus 6 (HHV-6) (Roseolovirus) was long neglected in research and medical diagnostics; however, in the past few years, it gained increasing attention. A variety of clinical complications were found to be associated with HHV-6 infection, especially concerning immunocompromised patients, in whom it has the ability to cause severe morbidity and mortality (1, 2). HHV-6 is subclassified into two distinct variants, HHV-6A and HHV-6B, which are considered independent viruses but share major genome sequence homologies and epidemiologies (3,4). Similarly to other members of the herpesvirus family, HHV-6 causes a relatively short and mild primary disease called roseola infantum, usually in children up to the age of 2 years, with a sudden rise of fever and rash as major symptoms (5). Following this initial infection, HHV-6 establishes lifelong latency in about 90% of all individuals examined (2). Reactivation frequentl...

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Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

Cited by 107 publications

References 92 publications

Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

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