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Abstract: Human herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT., (© 2024. The Author(s).)

Objectives: Letermovir for cytomegalovirus (CMV) prophylaxis in allogeneic haematopoietic cell transplant (HCT) recipients has decreased anti-CMV therapy use. Contrary to letermovir, anti-CMV antivirals are also active against human herpesvirus-6 (HHV-6). We assessed changes in HHV-6 epidemiology in the post-letermovir era., Methods: We conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients comparing time periods before and after routine use of prophylactic letermovir. HHV-6 testing was at the discretion of clinicians. We computed the cumulative incidence of broad-spectrum antiviral initiation (foscarnet, (val)ganciclovir, and/or cidofovir), HHV-6 testing, and HHV-6 detection in blood and cerebrospinal fluid within 100 days after HCT. We used Cox proportional-hazards models with stabilized inverse probability of treatment weights to compare outcomes between cohorts balanced for baseline factors., Results: We analysed 738 patients, 376 in the pre-letermovir and 362 in the post-letermovir cohort. Broad-spectrum antiviral initiation incidence decreased from 65% (95% CI, 60-70%) pre-letermovir to 21% (95% CI, 17-25%) post-letermovir. The cumulative incidence of HHV-6 testing (17% [95% CI, 13-21%] pre-letermovir versus 13% [95% CI, 10-16%] post-letermovir), detection (3% [95% CI, 1-5%] in both cohorts), and HHV-6 encephalitis (0.5% [95% CI, 0.1-1.8%] pre-letermovir and 0.6% [95% CI, 0.1-1.9%] post-letermovir) were similar between cohorts. First HHV-6 detection occurred at a median of 37 days (interquartile range, 18-58) in the pre-letermovir cohort and 27 (interquartile range, 25-34) in the post-letermovir cohort. In a weighted model, there was no association between the pre-versus post-letermovir cohort and HHV-6 detection (adjusted hazard ratio, 1.08; 95% CI, 0.44-2.62)., Discussion: Despite a large decrease in broad-spectrum antivirals after the introduction of letermovir prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased clinically detected HHV-6 reactivation and disease., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Reactivation of human herpesvirus 6 (HHV-6) after allogeneic hematopoietic cell transplantation (HCT) is associated with neurologic complications, but the impact of donor and/or recipient inherited chromosomally integrated HHV-6 (iciHHV-6) on post-HCT central nervous system (CNS) symptoms and diagnostic and therapeutic interventions is not well understood. The aims of the present study were (1) to compare the cumulative incidence of CNS symptoms in the first 100 days following allogeneic HCT among patients with donor and/or recipient iciHHV-6 (iciHHV-6 pos )with that of patients with neither donor nor recipient iciHHV-6 (iciHHV-6 neg ) and (2) to assess the role of HHV-6 detection in driving potentially unnecessary interventions in iciHHV-6 pos patients. We performed a retrospective matched cohort study of 87 iciHHV-6 pos and 174 iciHHV-6 neg allogeneic HCT recipients. HHV-6 testing was performed at the discretion of healthcare providers, who were unaware of iciHHV-6 status. The cumulative incidence of CNS symptoms was similar in iciHHV-6 pos (n = 37; 43%) and iciHHV-6 neg HCT recipients (n = 81; 47%; P = .63). HHV-6 plasma testing was performed in similar proportions of iciHHV-6 pos (n = 6; 7%) and iciHHV-6 neg (9%) patients and was detected in all tested iciHHV-6 pos HCTs and 2 (13%) iciHHV-6 neg HCTs. This resulted in more frequent HHV-6-targeted antiviral therapy after iciHHV-6 pos HCT (odds ratio, 12.8; 95% confidence interval, 1.5 to 108.2) with associated side effects. HHV-6 plasma detection in 2 iciHHV-6 pos patients without active CNS symptoms prompted unnecessary lumbar punctures. The cumulative incidence of CNS symptoms was similar after allogeneic HCT involving recipients or donors with and without iciHHV-6. Misattribution of HHV-6 detection as infection after iciHHV-6 pos HCT may lead to unnecessary interventions. Testing for iciHHV-6 may improve patient management., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We sought to determine whether donor-derived human herpesvirus (HHV) 6B-specific CD4+ T-cell abundance is correlated with HHV-6B detection after allogeneic hematopoietic cell transplantation. We identified 33 patients who received HLA-matched, non-T-cell-depleted, myeloablative allogeneic hematopoietic cell transplantation and underwent weekly plasma polymerase chain reaction testing for HHV-6B for 100 days thereafter. We tested donor peripheral blood mononuclear cells for HHV-6B-specific CD4+ T cells. Patients with HHV-6B detection above the median peak viral load (200 copies/mL) received approximately 10-fold fewer donor-derived total or HHV-6B-specific CD4+ T cells than those with peak HHV-6B detection at ≤200 copies/mL or with no HHV-6B detection. These data suggest the importance of donor-derived immunity for controlling HHV-6B reactivation., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Human herpesvirus 6B (HHV-6B) frequently reactivates after allogeneic hematopoietic cell transplantation (HCT). There are no randomized studies of antiviral treatments to prevent HHV-6B reactivation. Brincidofovir has high in vitro activity against HHV-6B and other DNA viruses, but its in vivo activity for HHV-6B has not been demonstrated. We performed a post hoc analysis of a randomized controlled trial of twice-weekly oral brincidofovir for cytomegalovirus prophylaxis after allogeneic HCT to study the effect of brincidofovir on HHV-6B reactivation. We included patients randomized within 2 weeks of HCT and who received at least 6 consecutive doses of study drug after randomization. We tested plasma for HHV-6B through week 6 post-HCT. The cohort consisted of 92 patients receiving brincidofovir and 61 receiving placebo. The cumulative incidence of HHV-6B plasma detection through day 42 post-HCT was significantly lower among patients receiving brincidofovir (14.2%) compared with placebo (32.4%; log-rank, 0.019). In an adjusted Cox model, brincidofovir exposure remained associated with a lower hazard for HHV-6B plasma detection (hazard ratio, 0.40; 95% confidence interval, 0.20-0.80). In conclusion, brincidofovir prophylaxis reduced HHV-6B reactivation after allogeneic HCT in a post hoc analysis of a randomized controlled trial. These data support the study of intravenous brincidofovir for HHV-6B prophylaxis., (© 2020 by The American Society of Hematology.)

Acute graft-versus-host-disease (aGVHD) is a major complication following hematopoietic cell transplantations (HCTs). We have shown that HCT recipients in whom either the donor or patient had inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) have a higher incidence of developing more severe aGVHD. Previous studies established that increased proinflammatory cytokines are associated with increased risk for aGVHD and nonrelapse mortality post-HCT. We hypothesized that HCT recipients with donor or recipient iciHHV-6 (iciHHV-6 pos HCT cases) will have higher cytokine levels compared with HCT recipients without iciHHV-6 (iciHHV-6 neg HCT controls). We identified 64 iciHHV-6 pos HCT cases with plasma from days 7, 14, and/or 21 post-HCT and before aGVHD onset in patients who developed aGVHD. We identified 64 iciHHV-6 neg HCT controls matched for aGVHD risk factors. We also identified 28 donors with iciHHV-6 and 56 matched donors without iciHHV-6. We measured plasma cytokine concentrations for IL-6, suppression of tumorigenicity 2, T cell immunoglobulin and mucin-domain containing 3, TNFα, soluble TNF receptor 1 (TNFRp55), and C-reactive protein (CRP). We used Mann-Whitney tests and repeated-measures models to compare cytokine levels. iciHHV-6 pos HCT cases had higher CRP levels on day 7 and day 21 and higher TNFRp55 levels on day 14 and day 21 compared with iciHHV-6 neg HCT controls. These findings were recapitulated in a repeated-measures model. The differences were most evident among patients who subsequently developed aGVHD grades 2 to 4. Additionally, iciHHV-6 pos HCT cases had earlier-onset aGVHD (median, 20 versus 27 days post-HCT; P = .02). There were no differences in cytokine levels among healthy donors with or without iciHHV-6. This study demonstrates that HCT recipients with iciHHV-6 have higher proinflammatory cytokines that may be associated with increased risk for aGVHD., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Human herpesvirus 6B (HHV-6B) DNA is frequently detected in bronchoalveolar lavage fluid (BALF) from immunocompromised subjects with lower respiratory tract disease (LRTD). Whether HHV-6B is a pulmonary pathogen is unclear., Methods: We tested BALF for HHV-6B DNA using polymerase chain reaction in allogeneic hematopoietic cell transplantation (HCT) recipients who underwent a BAL for evaluation of LRTD from 1992 to 2015. We used multivariable proportional hazards models to evaluate the association of HHV-6B + BALF with overall mortality, death from respiratory failure, and the effect of anti-HHV-6B antivirals on these outcomes. We used branched-chain RNA in situ hybridization to detect HHV-6 messenger RNA ( U41 and U57 transcripts) in lung tissue., Results: We detected HHV-6B + BALF from 147 of 553 (27%) individuals. Subjects with HHV-6B + BALF, with or without copathogens, had significantly increased risk of overall mortality (adjusted hazard ratio [aHR], 2.18; 95% CI, 1.41-3.39) and death from respiratory failure (aHR, 2.50; 95% CI, 1.56-4.01) compared with subjects with HHV-6B - BALF. Subjects with HHV-6B + BALF who received antivirals within 3 days pre-BAL had an approximately 1 log 10 lower median HHV-6B BALF viral load, as well as a lower risk of overall mortality (aHR, 0.42; 95% CI, 0.16-1.10), compared with subjects with HHV-6B + BALF not receiving antivirals. We detected intraparenchymal HHV-6 gene expression by RNA in situ hybridization in lung tissue in all three tested subjects with HHV-6B + BALF and sufficient tissue RNA preservation., Conclusion: These data provide evidence that HHV-6B detection in BALF is associated with higher mortality in allogeneic hematopoietic cell transplantation recipients with LRTD. Definitive evidence of causation will require a randomized prevention or treatment trial.

Human herpesvirus 6B (HHV-6B) DNA is frequently detected in human samples. Diagnostic assays distinguishing HHV-6B reactivation from latency are limited. This has impaired strategies to diagnose and treat HHV-6B-associated diseases. We used RNA sequencing to characterize and compare the HHV-6B transcriptome in multiple sample types, including (i) whole blood from hematopoietic cell transplant (HCT) recipients with and without HHV-6B plasma viremia, (ii) tumor tissue samples from subjects with large B cell lymphoma infected with HHV-6B, (iii) lymphoblastoid cell lines (LCLs) from subjects with inherited chromosomally integrated HHV-6B or latent infection with HHV-6B, and (iv) HHV-6B Z29 infected SupT1 CD4 + T cells. We demonstrated substantial overlap in the HHV-6B transcriptome observed in in vivo and in vitro samples, although there was variability in the breadth and quantity of gene expression across samples. The HHV-6B viral polymerase gene U38 was the only HHV-6B transcript detected in all next-generation RNA sequencing (RNA-seq) data sets and was one of the most highly expressed genes. We developed a novel reverse transcription-PCR assay targeting HHV-6B U38, which identified U38 mRNA in all tested whole-blood samples from patients with concurrent HHV-6B viremia. No HHV-6B U38 transcripts were detected by RNA-seq or reverse transcription-real-time quantitative PCR (RT-qPCR) in whole-blood samples from subjects without HHV-6B plasma detection or from latently infected LCLs. A RT-qPCR assay for HHV-6B U38 may be useful to identify lytic HHV-6B infection in nonplasma samples and samples from individuals with inherited chromosomally integrated HHV-6B. This study also demonstrates the feasibility of transcriptomic analyses for HCT recipients. IMPORTANCE Human herpesvirus 6B (HHV-6B) is a DNA virus that infects most children within the first few years of life. After primary infection, HHV-6B persists as a chronic, latent infection in many cell types. Additionally, HHV-6B can integrate into germ line chromosomes, resulting in individuals with viral DNA in every nucleated cell. Given that PCR to detect viral DNA is the mainstay for diagnosing HHV-6B infection, the characteristics of HHV-6B infection complicate efforts to distinguish between latent and active viral infection, particularly in immunocompromised patients who have frequent HHV-6B reactivation. In this study, we used RNA sequencing to characterize the HHV-6B gene expression profile in multiple sample types, and our findings identified evidence-based targets for diagnostic tests that distinguish between latent and active viral infection., (Copyright © 2019 American Society for Microbiology.)

Human herpesvirus 6B (HHV-6B) is a ubiquitous pathogen that infects most individuals before the age of three years. HHV-6B reactivates in approximately 40% of transplant recipients where it has been associated with a number of important outcomes, especially in allogeneic transplant recipients. This article will review the epidemiology, clinical manifestations, diagnosis, and treatment of HHV-6B infection.

Successful and sustained CD4 + T-cell reconstitution is associated with increased survival after hematopoietic cell transplantation (HCT), but opportunistic infections may adversely affect the time and extent of immune reconstitution. Human herpesvirus 6B (HHV-6B) efficiently infects CD4 + T cells and utilizes as a receptor CD134 (OX40), a member of the TNF superfamily that antagonizes regulatory T-cell (T reg ) activity. Reactivation of HHV-6B has been associated with aberrant immune reconstitution and acute graft-versus-host disease (aGVHD) after HCT. Given that T reg counts are negatively correlated with aGVHD severity, we postulate that one mechanism for the poor CD4 + T-cell reconstitution observed shortly after transplant may be HHV-6B infection and depletion of peripheral (extra-thymic) CD4 + T cells, including a subpopulation of T reg cells. In turn, this may trigger a series of adverse events resulting in poor clinical outcomes such as severe aGVHD. In addition, recent evidence has linked HHV-6B reactivation with aberrant CD4 + T-cell reconstitution late after transplantation, which may be mediated by a different mechanism, possibly related to central (thymic) suppression of T-cell reconstitution. These observations suggest that aggressive management of HHV-6B reactivation in transplant patients may facilitate CD4 + T-cell reconstitution and improve the quality of life and survival of HCT patients.

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., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach > 90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus., Results: Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated., Conclusion: Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.

Human herpesvirus 6 (HHV-6) species have a unique ability to integrate into chromosomal telomeres. Mendelian inheritance via gametocyte integration results in HHV-6 in every nucleated cell. The epidemiology and clinical effect of inherited chromosomally integrated HHV-6 (iciHHV-6) in hematopoietic cell transplant (HCT) recipients is unclear. We identified 4319 HCT donor-recipient pairs (8638 subjects) who received an allogeneic HCT and had archived pre-HCT peripheral blood mononuclear cell samples. We screened these samples for iciHHV-6 and compared characteristics of HCT recipients and donors with iciHHV-6 with those of recipients and donors without iciHHV-6, respectively. We calculated Kaplan-Meier probability estimates and Cox proportional hazards models for post-HCT outcomes based on recipient and donor iciHHV-6 status. We identified 60 HCT recipients (1.4%) and 40 donors (0.9%) with iciHHV-6; both recipient and donor harbored iciHHV-6 in 13 HCTs. Thus, there were 87 HCTs (2%) in which the recipient, donor, or both harbored iciHHV-6. Acute graft-versus-host disease (GVHD) grades 2-4 was more frequent when recipients or donors had iciHHV-6 (adjusted hazard ratios, 1.7-1.9; P = .004-.001). Cytomegalovirus viremia (any and high-level) was more frequent among recipients with iciHHV-6 (adjusted HRs, 1.7-3.1; P = .001-.040). Inherited ciHHV-6 status did not significantly affect risk for chronic GVHD, hematopoietic cell engraftment, overall mortality, or nonrelapse mortality. Screening for iciHHV-6 could guide donor selection and post-HCT risk stratification and treatment. Further study is needed to replicate these findings and identify potential mechanisms., (© 2017 by The American Society of Hematology.)

The presence of inherited chromosomally integrated human herpesvirus 6 (ciHHV-6) in hematopoietic cell transplant (HCT) donors or recipients confounds molecular testing for HHV-6 reactivation, which occurs in 30 to 50% of transplants. Here we describe a multiplex droplet digital PCR clinical diagnostic assay that concurrently distinguishes between HHV-6 species (A or B) and identifies inherited ciHHV-6. By applying this assay to recipient post-HCT plasma and serum samples, we demonstrated reactivation of HHV-6B in 25% (4/16 recipients) of HCT recipients with donor- or recipient-derived inherited ciHHV-6A, underscoring the need for diagnostic testing for HHV-6 infection even in the presence of ciHHV-6., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Human herpesvirus 6 (HHV-6) has a unique ability to integrate into chromosomal telomeres. Vertical transmission via germ cell integration results in offspring with inherited chromosomally integrated (ci)HHV-6 in all nucleated cells, affecting ∼1% of the population., Objectives: Inherited ciHHV-6 may be a direct or indirect mediator of human disease, but efficient identification of affected individuals is a fundamental roadblock to larger studies exploring the clinical importance of this condition., Study Design: A group testing strategy was designed to efficiently identify individuals with inherited ciHHV-6. DNA was extracted from 2496 cellular samples from hematopoietic cell transplant (HCT) donor-recipient pairs. Pools of 12 samples were screened for HHV-6 DNA with quantitative (q)PCR. Individual samples from high positive pools were tested with qPCR, and high positive individual samples were tested for inherited ciHHV-6 using droplet digital (dd)PCR to determine HHV-6 DNA copies/cellular genome., Results: Thirty-one pools had high positive HHV-6 DNA detection with >10(3) HHV-6 DNA copies/μg. Each pool had one sample with >10(4) copies/μg HHV-6 DNA. Inherited ciHHV-6 was confirmed by ddPCR in every high positive sample (>10(3) HHV-6 DNA copies/μg), yielding a prevalence of 1.5% in HCT recipients and 0.96% in donors. We performed 580 qPCR tests to screen 2496 samples for inherited ciHHV-6, a 77% reduction in testing., Conclusions: Inherited ciHHV-6 can be efficiently identified by specimen pooling coupled with modern molecular techniques. This algorithm can be used to facilitate cost-effective identification of patients with inherited ciHHV-6, thereby removing a major hurdle for large-scale study of its clinical impact., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We identified 37 hematopoietic cell transplantation recipients with human herpesvirus 6 (HHV-6) central nervous system dysfunction and tested donor-recipient pairs for chromosomally integrated HHV-6 (ciHHV-6). One patient had ciHHV-6A with possible HHV-6A reactivation and encephalitis. There was no ciHHV-6 enrichment in this group, but larger studies are needed to determine if patients with ciHHV-6 are at increased risk for HHV-6-associated diseases or other complications., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Human herpesvirus 6 (HHV-6) is an opportunistic pathogen after hematopoietic cell transplantation (HCT) that is associated with central nervous system (CNS) dysfunction., Objectives: The aim of this study was to determine the frequency and significance of HHV-6 DNA detection in cerebrospinal fluid (CSF) after HCT., Study Design: We identified patients with HHV-6 DNA in CSF using quantitative PCR. Patients with neurologic symptoms and HHV-6 DNA in CSF without identification of an alternative etiology were categorized as having HHV-6 CNS dysfunction., Results: Among 3902 allogeneic HCT recipients from 1998 to 2012, 51 of 124 tested patients had HHV-6 DNA in CSF; 37 met criteria for HHV-6 CNS dysfunction and 14 (27%) did not. Patients with an alternative diagnosis had longer time to HHV-6 detection and lower viral load in CSF. Six patients without HHV-6 CNS dysfunction were not treated and had no morbidity attributable to HHV-6. Kaplan-Meier analysis demonstrated poor overall survival among all patients. Variables associated with higher all-cause mortality in a multivariable Cox model included alternative diagnosis (adjusted hazard ratio [aHR], 8.4; 95% CI, 1.7-40.9; P = 0.009) and higher peak plasma viral load (log(10) scale) (aHR, 1.4; 95% CI, 1.1-1.9; P = 0.01)., Conclusion: We identified a number of allogeneic HCT recipients with HHV-6 DNA in CSF who did not meet criteria for HHV-6 CNS dysfunction. All patients had poor survival. Whether CSF HHV-6 DNA detection in patients without associated CNS dysfunction independently contributes to mortality and warrants treatment is unclear; management of these patients warrants further investigation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Human herpesvirus 6 (HHV-6) latently infects a majority of adults. In about 1% of the population HHV-6 exists in a chromosomally integrated form (ciHHV-6) that resides in every somatic and germ cell and can be transmitted through the germ line. Patients with ciHHV-6 have been misdiagnosed and unnecessarily treated for active HHV-6 infection, sometimes with important side effects, based on results from quantitative molecular HHV-6 tests., Methods: A droplet digital PCR (ddPCR) assay was developed to identify ciHHV-6 in cellular patient samples by precisely determining the ratio of HHV-6 to cellular DNA. We validated the assay on confirmed ciHHV-6 patient samples and a cell line derived from a ciHHV-6 patient, and we analyzed hematopoietic stem cell transplant patients suspected of having ciHHV-6. We additionally evaluated whether the assay could be applied to stored plasma samples from a study of clinical correlates of HHV-6., Results: The ddPCR assay accurately identified ciHHV-6 in cellular samples (buffy coat, peripheral blood mononuclear cells), giving a ratio very close to 1 HHV-6/cell [mean (SD), 1.02 (0.03)] in fluorescence in situ hybridization-confirmed sample). In stored plasma samples, the assay performance was set by design to have 100% sensitivity, which resulted in 82% specificity for ciHHV-6., Conclusions: The possibility of ciHHV-6 is often overlooked in patients with detectable HHV-6 viral loads by quantitative PCR. Our ddPCR test provides rapid and accurate laboratory identification of ciHHV-6 from easily obtained cellular samples. In addition, the assay provides excellent sensitivity and specificity using stored plasma samples, facilitating retrospective analysis of the clinical significance of ciHHV-6.

Human herpesvirus 6 (HHV-6) reactivation has been associated with acute graft-versus-host-disease (aGVHD), cytomegalovirus reactivation, and mortality after allogeneic hematopoietic cell transplantation (HCT), but previous studies have yielded inconsistent results. We performed a large prospective study of allogeneic HCT recipients in order to more definitively define the relationships between HHV-6 and these important outcomes. Plasma specimens were collected prospectively from 315 allogeneic HCT recipients and tested for HHV-6 DNA at baseline and twice weekly for 12 weeks. Cox proportional hazards models were used to evaluate the time-dependent associations between HHV-6 reactivation and the targeted outcomes. HHV-6 was detected in 111 of 315 patients (35%) at a median of 20 days after HCT. HHV-6 reactivation was associated with subsequent cytomegalovirus reactivation (adjusted hazard ratio [aHR], 1.9; 95% confidence interval [CI], 1.3-2.8; P = .002). High-level HHV-6 (>1,000 HHV-6 DNA copies/mL) was associated with subsequent grades II to IV aGVHD (aHR, 2.4; 95% CI, 1.60-3.6; P < .001). High-level HHV-6 reactivation was also associated with nonrelapse mortality (aHR, 2.7; 95% CI, 1.2-6.3; P = .02). HHV-6 reactivation was independently and quantitatively associated with increased risk of subsequent cytomegalovirus reactivation, aGVHD, and mortality after HCT. A randomized antiviral trial is warranted to establish causality between HHV-6 and these endpoints and to determine if reducing HHV-6 reactivation will improve outcome after HCT., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Human herpesvirus 6 (HHV-6) frequently reactivates after solid-organ and hematopoietic cell transplantation (HCT), and it has been associated with important outcomes in these settings. In 1-2% of recipients or donors, HHV-6 was inherited through chromosomal integration. Although HHV-6 chromosomal integration has not been associated with disease, the resulting very high levels of HHV-6 DNA in human tissue and blood samples can be challenging to interpret in the transplant setting. This review addresses the recent findings regarding the clinical outcomes associated with HHV-6 as well as diagnostic and therapeutic concerns., Recent Findings: The evidence supports a causal association between HHV-6 and central nervous system disease. New studies have further characterized the impact of HHV-6 on the central nervous system. In addition, new studies have explored the associations between HHV-6 and other important outcomes. The implications of integrated HHV-6 in transplant recipients remain undefined, though the possibility of an association with organ rejection has been suggested. New exploratory data exist regarding the safety of antiviral prophylactic and preemptive strategies., Summary: Our understanding of the full clinical impact of HHV-6 in the transplant population remains incomplete. A large antiviral trial would not only help to further define causality between HHV-6 associated clinical outcomes but also start to define preventive strategies.

Objective: Transmission of human herpesvirus (HHV-6) type B is hypothesized to occur via saliva. We sought to determine whether behaviors promoting saliva sharing were associated with HHV-6B infection., Methods: Parents of young children participating in a natural history study of HHV-6B were asked to complete a questionnaire focused on family behaviors that result in saliva sharing., Results: Of 111 surveys, 109 (98%) were completed. Of the 109 participants, 37 (34%) were infected with HHV-6 before 1 year of age. Having older siblings (adjusted OR 4.1, 95% CI 1.5, 11.8) and receipt of parental saliva when kissed (adjusted OR 5.1, 95% CI 1.8, 14.5) were independently associated with younger age of HHV-6 infection. Dose-response relationships were demonstrated between HHV-6 infection before 1 year and both number of siblings and the frequency that the child received parental saliva when being kissed (p=0.006 and p=0.002, respectively)., Conclusions: Having older siblings and parents who shared saliva increased risk of HHV-6B acquisition in children. These data support the hypothesis that HHV-6 is transmitted primarily via saliva within families.

Human herpesvirus 6 infects virtually all children within the first few years of life and like other herpesviruses, establishes latency after primary infection. In immunocompromised hosts, especially hematopoietic cell transplant (HCT) recipients, HHV-6 has been demonstrated to reactivate frequently. This reactivation has been associated with a number of different clinical endpoints in HCT recipients, including central nervous system (CNS) disease. There have been many detailed descriptions of individual patients with HHV-6-associated encephalitis. In addition, longitudinal observational studies have established a correlation between systemic HHV-6 reactivation and CNS dysfunction. Further research is needed to define optimal diagnostic, prevention, and treatment strategies.

Objective: To evaluate the potential utility of identifying primary human herpesvirus (HHV)-6 infection in an emergency department setting by determining the frequency of HHV-6 viremia, diagnostic testing, and empiric treatment of serious bacterial infection (SBI) in HHV-6 viremic children, and concurrent SBI and HHV-6 viremia., Study Design: Children under age 2 years and who had a blood specimen taken for evaluation of fever were tested for HHV-6 by polymerase chain reaction (PCR). HHV-6 viremia was defined as detection of HHV-6 DNA in acute plasma., Results: A total of 32 of the 181 subjects (18%) had HHV-6 viremia. Children with HHV-6 viremia frequently underwent procedures for diagnosis and empiric treatment of SBI: 60% had bladder catheterizations, 6% had lumbar punctures, 47% had radiographs, 32% received empiric antibiotics, and 34% were hospitalized. Four of the 32 children with HHV-6 viremia (12.5%) were diagnosed with SBI, although none had a positive culture of blood or cerebrospinal fluid., Conclusions: Rapid diagnosis of HHV-6 viremia may not serve to adequately differentiate infants with and without SBI in acute care settings. Although no children with HHV-6 viremia had bacteremia or meningitis, it appears that additional criteria are needed to increase the specificity of HHV-6 PCR testing before withholding evaluation for SBI.

Human herpesvirus 6 (HHV-6) is a member of the Roseolovirus genus of the b-herpesvirus subfamily of human herpesviruses. HHV-6 infects virtually all children during the early years of life and, like other herpesviruses, establishes latency after primary infection. In immunocompromised hosts, especially transplant recipients, HHV-6 is able to reactivate and cause disease. There are two subtypes of HHV-6: type A and type B. The two subtypes share certain biological properties and a high level of sequence homology, but differ dramatically in their epidemiology. We have learned much about the epidemiology and clinical impact of HHV-6 in the decades since it was first identified, but many questions still remain. This update focuses on new findings regarding the epidemiology and clinical syndromes of HHV-6, especially as they pertain to primary infection, neurological disease, and the transplant setting. In addition, diagnostics and antiviral treatment are reviewed.

Background: Although human herpesvirus 6 (HHV-6) is known to reactivate during hematopoietic stem cell transplantation (HSCT), the clinical significance of this finding is controversial., Methods: We used a quantitative PCR test for HHV-6 to assay plasma samples prospectively collected from a cohort of 110 allogeneic HSCT recipients to evaluate the clinical effects of HHV-6 infection. A retrospective review of medical records was performed to determine clinical end points., Results: HHV-6 reactivation occurred in 52 (47%) of the 110 subjects. Factors that increased the risk of subsequent HHV-6 reactivation were hematologic malignancy that occurred at a time other than the first remission (adjusted P = .002), a mismatch in the sexes of donor and recipient (adjusted P=.05), younger age (adjusted P = .01), and the receipt of glucocorticoids (adjusted P = .06). HHV-6 reactivation was associated with subsequent all-cause mortality (adjusted hazard ration [HR], 2.9; 95% confidence interval [CI], 1.1-7.5), grade 3-4 graft-versus-host disease (GVHD) (adjusted HR, 4.9; 95% CI, 1.5-16), a lower probability of monocyte engraftment (adjusted HR, 0.42; 95% CI; 0.22-0.80), a lower probability of platelet engraftment (adjusted HR, 0.47; 95% CI, 0.21-1.1; P = .05) and a higher platelet transfusion requirement (adjusted P = .02). A higher level of HHV-6 DNA was associated with subsequent central nervous system (CNS) dysfunction (HR, 21; 95% CI, 1.8-249)., Conclusions: HHV-6 reactivation is common after allogeneic HSCT and is associated with subsequent delayed monocyte and platelet engraftment, increased platelet transfusion requirements, all-cause mortality, grade 3-4 GVHD, and CNS dysfunction.

Background: Serologic studies indicate that human herpesvirus 6 (HHV-6) infects 90 percent of children by two years of age. Little is known about the acquisition, virologic course, and clinical manifestations of HHV-6 infection., Methods: We prospectively studied a cohort of 277 children from birth through the first two years of life to define the pattern of acquisition of HHV-6. The children's saliva was tested weekly for HHV-6 DNA with the use of the polymerase chain reaction. Parents maintained a daily log of signs and symptoms of illness in their children., Results: Primary HHV-6 infection occurred in 130 children, with cumulative percentages of 40 percent by the age of 12 months and 77 percent by the age of 24 months. The peak age of acquisition was between 9 and 21 months. The acquisition of HHV-6 was associated with female sex (adjusted hazard ratio, 1.7; 95 percent confidence interval, 1.2 to 2.4) and having older siblings (adjusted hazard ratio, 2.1; 95 percent confidence interval, 1.4 to 2.9). Among 81 children with a well-defined time of acquisition of HHV-6, 93 percent had symptoms, and 38 percent were seen by a physician. None had seizures. As compared with children who had other illnesses, those with primary HHV-6 infection were more likely to have fever (P=0.003), fussiness (P=0.02), diarrhea (P=0.03), rash (P=0.003), and roseola (P=0.002) and were more likely to visit a physician (P=0.003)., Conclusions: The acquisition of HHV-6 in infancy is usually symptomatic and often results in medical evaluation. Roseola occurs in a minority of patients, and febrile seizures are infrequently associated with primary HHV-6 infection. Older siblings appear to serve as a source of HHV-6 transmission., (Copyright 2005 Massachusetts Medical Society.)

Background: The importance of human herpesvirus 6 (HHV-6) as a pathogen in febrile infants

We describe a 3-week-old male infant with an afebrile seizure in whom serologic and polymerase chain reaction (PCR) findings support concomitant primary human herpesvirus 6 (HHV-6) infection. Although HHV-6 infection has been associated with first-time febrile seizures and encephalitis in both immunocompetent and immunocompromised hosts, it has not been associated previously with afebrile seizures in healthy infants. This report provides additional evidence of the neuropathogenic potential of HHV-6., (Copyright 2002 Wiley-Liss, Inc.)

Human herpesvirus 6 (HHV-6) appears to cause central nervous system (CNS) syndromes, especially in hematopoietic stem cell transplant (HSCT) recipients. We reviewed our experience with HHV-6-associated CNS disease to evaluate both the clinical and virological presentation and response to antiviral therapy. A search of our virology database from January 1998 through June 2000 identified 11 HSCT recipients who had HHV-6 DNA detected by polymerase chain reaction in cerebrospinal fluid (CSF); 8 of whom had CNS dysfunction without another clear etiology identified. HHV-6 levels in serum and CSF were evaluated before and after ganciclovir and/or foscarnet therapy. Median log HHV-6 CSF levels appeared to decrease over time concurrent with antiviral therapy (serum level, 2.0 vs. 0 copies/mL [P=.38]; CSF level, 4.4 vs. 2.0 copies/mL [P=.13], sign test). Our data suggests that HHV-6 may cause moderate to severe CNS disease after HSC transplantation. Prospective studies are needed to define the spectrum of HHV-6-associated disease and to determine whether antiviral therapy offers clinical benefit.