HHV-6 infection after allogeneic hematopoietic stem cell transplantation: From chromosomal integration to viral co-infections and T-cell reconstitution patterns

doi:10.1016/j.jinf.2015.09.039

Journal of Infection

Volume 72, Issue 2, February 2016, Pages 214-222

https://doi.org/10.1016/j.jinf.2015.09.039 Get rights and content

Highlights

•
4% of the HHV-6-infected patients after allogeneic hematopoietic stem cell transplantation were chromosomally integrated.
•
HHV-6 likely co-reactivates with CMV and BK virus after allogeneic hematopoietic stem cell transplantation.
•
HHV-6 infection is likely associated with delayed CD8+ T-cell recovery independently of graft-versus-host disease.
•
HHV-6 infection reduces the overall probability of survival after allogeneic hematopoietic stem cell transplantation.

Summary

Objectives

Human herpes virus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant clinical manifestations.

Methods

Case control study of HHV-6 infections after allo-HSCT. Chromosomal integration (ciHHV-6) for viral loads ≥ 5.5-log10 copies/mL was investigated. Viral co-infections, T-cell recovery, risk factors and outcome were compared in HHV-6- and non-HHV-6-infected patients. Antiviral treatment strategies were reviewed.

Results

Among 366 adult allo-HSCT recipients, 75 HHV-6 infections occurred. Three (4%) recipients were ciHHV-6. HHV-6 infections were associated with CMV (p = 0.05; sdHR 1.73, CI 0.99–3.02) and/or BKV infections (p < 0.0001; sdHR 4.63, CI 2.04–10.53) but not EBV reactivation (p = 0.34). A slower CD8+ T-cells recovery was observed until 6 months after allo-HSCT in the HHV-6-infected group (p < 0.001), independently of acute and/or chronic graft-versus-host disease. The overall probability of survival after allo-HSCT was diminished for active HHV-6-infected patients (p = 0.0326). Cord blood unit recipients had a higher risk of developing HHV-6 infection compared to bone marrow recipients (p = 0.0007; sdHR 3.82, CI 1.76–8.27). Anti-HHV-6 treatment achieved complete response in only 2/3 of the cases.

Conclusions

In this series of allo-HSCT recipients, 4% were ciHHV-6, active HHV-6 infection was likely associated with CMV and BKV co-reactivations, delayed CD8+ T-cell recovery and poorer outcome.

Introduction

Human herpes viruses 6 (HHV-6) include two separate species HHV-6A and HHV-6B that infect nearly all individuals during early infancy. HHV-6B is the causative agent of exanthema subitum, a childhood disease characterized by high fever and a mild skin rash, occasionally complicated by seizures or encephalitis; HHV-6A has not been etiologically linked to any disease.¹ HHV-6 establish life-long latency with a strong tropism for hematopoietic cells, including CD34+ progenitor stem cells.2, 3, 4 In vitro studies have shown that replication can occur in these latter cells through hematopoietic differentiation.⁵ HHV-6 reactivation is recognized as a pathogenic infection in immunocompromised hosts, particularly after allogeneic hematopoietic stem cell transplantation (allo-HSCT) throughout the aplasia-related immunodeficiency phase and the immunosuppressive therapy implemented for prevention of graft-versus-host disease (GvHD).⁶ HHV-6 genome has the ability to integrate into human chromosomes of cells, which can be transmitted as germinal cells to offspring and through allo-HSCT (Mendelian inheritance). This condition is present in ∼1% of the population and its implication in HHV-6 central nervous system (CNS) disease is discussed.7, 8, 9, 10, 11

HHV-6 infection after allo-HSCT is estimated to occur from 20 to 72% of the cases and HHV-6B reactivation is the rule rather than HHV-6A.8, 11, 12, 13, 14, 15, 16, 17, 18 In that setting, HHV-6-related clinical manifestations range from febrile rash to the severe post-transplantation acute limbic encephalitis (PALE).13, 18, 19 Biologically, HHV-6 infection is frequently associated with liver dysfunction,²⁰ hematopoietic recovery impairment.17, 21, 22, 23 Reported risk factors associated with HHV-6 infection include HLA mismatch, steroid treatment, the use of either unrelated donor or cord blood unit (CBU) grafts.12, 14, 15, 18 In addition, HHV-6 infection may increase the risk of acute GvHD and facilitate superinfections with cytomegalovirus (CMV).13, 24 PALE is the most serious complication linked to HHV-6 infection, commonly referred as the key criterion accounting for greater morbidity and lethality.16, 25, 26

As several aspects of HHV-6 infection still need to be addressed, this study focuses on 75 cases after allo-HSCT. We have investigated the possibility of chromosomally integrated human HHV-6 in recipients with whole blood HHV-6 levels that exceed 5.5-log10 copies/mL before or after allo-HSCT. We have tested the hypothesis that HHV-6 infections may correlate with other opportunistic and challenging virus infection(s) such as CMV, BK virus (BKV) and EBV as well as a slow CD4+ and CD8+ T cell recovery. We have determined HHV-6 infection incidence, risk factors, and impact of HHV-6 infection on transplantation outcome. Finally, therapeutic strategies applied to HHV-6-infected patients have been examined.

Section snippets

Patients, donors and disease characteristics

Patient's baseline characteristics are summarized in Table 1. According to the centre practice, whole blood quantitative HHV-6 DNA was measured once every 2 weeks from allo-HSCT to day 90, and monthly thereafter until month 12 post-allo-HSCT. The threshold delimiting HHV-6 infection was a whole blood HHV-6 DNAaemia ≥3-log10 copies/mL. Active HHV-6 infection and/or presence of ciHHV-6 in donor or recipient cells required to collect ≥2 consecutive HHV-6 DNAaemia above 3-log10 copies/mL.

Incidence of HHV-6 infection and co-infections with CMV, BKV and EBV after allo-HSCT

Between January 2008 and June 2013, 366 consecutive patients underwent allo-HSCT with bone marrow (BM) (n = 155, 42.3%), peripheral blood stem cells (PBSC) (n = 155, 42.3%) or cord blood units (CBU) (n = 56, 15.4%). Seventy-five (20.5%) patients developed HHV-6 infection, among whom, 51 (68%) had active HHV-6 infection. Transplant characteristics according to HHV-6 infection are given in Table 2. We observed significant differences in the HHV-6-infected group: a younger age, a higher number of

Discussion

The present study indicates that 4% of HHV-6-infected recipients were ciHHV-6, a higher proportion than usually reported in general population-based studies (∼1%).7, 11 Yet, it is unclear whether ciHHV-6 can be activated and directly involved in subsequent pathogenic effects.32, 33 Patient 2 experienced an authentic progressive CNS disease preceding fatal outcome in the setting of ciHHV-6A, hematological relapse and graft loss. This is consistent with another recent study that reported the

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

The authors thank Dr Agnès Gautheret-Dejean and Pr Henri Agut for their assistance.

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Human herpesvirus 6 infection after autologous stem cell transplantation: A multicenter prospective study in adult patients
2019, Journal of Infection
Citation Excerpt :
CD34+hematopoietic progenitors can indeed carry latent HHV-6 and hematopoietic differentiation can lead to HHV-6 reactivation giving an explanation for myelosuppression.39 In allo-SCT recipients, presence of HHV-6 DNA was significantly associated with delayed platelet and neutrophil engraftment.8,22 In our cohort of ASCT patients, we observed a delay in platelets and ANC reconstitution with consequences on durations of hospitalisations and need of late transfusions in patients with HHV-6 infections, potentially increasing the costs.
to prospectively evaluate the incidence and the clinical relevance on hematopoietic reconstitution of HHV-6 infection in autologous hematopoietic stem cell transplantation (ASCT) recipients.
HHV-6 DNA load was measured in whole blood specimens once during the 7 days before stem cell re-infusion and once a week after transplantation until hematopoietic recovery. Active HHV-6 infection was defined by 2 consecutive positive DNA loads.
from July 2012 to February 2015, 196 adult patients undergoing ASCT were enrolled. Twenty-two (11.2%) patients developed active HHV-6 infection with a cumulative incidence of 19% at 40 days after transplantation. The onset of active HHV-6 infection occurred with a median of 13 days after stem cell re-infusion. HHV-6 infection was associated with an increased frequency of non-infectious complications (OR = 5.05; 95%CI 1.78–14.32; P < 0.001). Moreover, the severity of these non-infectious complications was higher in recipients exhibiting HHV-6 infection (OR = 4.62; 95%CI 1.32–16.2; p < 0.01). Delayed neutrophils 10 (IQR: 8–14) vs 8 (IQR: 6–11) days and platelets recoveries 15 (IQR: 11.8–18.5) vs 8 (IQR: 4–14) days were observed in patients with active HHV-6 infection compared to non-infected ones.
in this study, 11.2% ASCT recipients presented active HHV-6 infection associated with significantly delayed hematologic reconstitution.
Lymphocyte Area Under the Curve as a Predictive Factor for Viral Infection after Allogenic Hematopoietic Stem Cell Transplantation
2019, Biology of Blood and Marrow Transplantation
Viral infection is a serious complication that can greatly affect patient mortality and morbidity after allogenic hematopoietic stem cell transplantation (allo-HSCT). For the early identification of patients at high risk for viral infection, we evaluated the impact of lymphocyte area under the curve (AUC) value as a new predictive factor for early immune reconstitution after allo-HSCT against viral infection. This study included 286 patients who underwent their first allo-HSCT at Kyoto University Hospital between 2005 and 2017. Lymphocyte AUC from day 0 to day +15 was calculated in the analysis of human herpesvirus 6 (HHV-6), and lymphocyte AUC from day 0 to day +30 was calculated in the analysis of other viruses (cytomegalovirus [CMV], adenovirus, BK virus, JC virus, and varicella zoster virus). The risk factors for each viral reactivation/infection were assessed by multivariate analysis. The median age at transplantation was 51years (range, 17 to 68 years). The median lymphocyte AUC was 63/μL (range, 0 to 5620/μL) at day +15 and 3880 (range, 0 to 118,260/μL) at day +30. An increase in lymphocyte AUC was significantly associated with a high frequency of HHV-6 reactivation (P = .033) and a low frequency of CMV antigenemia (P = .014). No apparent association was found between lymphocyte AUC and reactivation/infection of other viruses. Aplastic anemia as a primary disease (hazard ratio [HR], 5.34; P < .001) and cord blood as a donor source (HR, 3.05; P = .006) were other risk factors for HHV-6 reactivation. Other risk factors for CMV antigenemia included the occurrence of acute graft-versus-host disease (HR 2.21; P < .001) and recipient age (HR 1.55; P = .017). Higher lymphocyte AUC at day +30 was significantly associated with low treatment-related mortality (HR, .47; P = .045). Lymphocyte AUC may be a good predictive factor for immune reconstitution against CMV reactivation. It also provides valuable information for predicting HHV-6 reactivation and treatment-related mortality.
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
2018, Biology of Blood and Marrow Transplantation
Citation Excerpt :
Further clinical studies are needed to fully understand the implications in humans. Additionally, some researchers have suggested that the delay or absence of immune reconstitution, especially of CD4+ T cells, facilitates viral reactivation [33,66-68], which may subsequently contribute to a number of outcomes including aGVHD, graft failure, and increased mortality [69]. After allogeneic HCT, T cell reconstitution is a long process that proceeds along 2 pathways with distinct kinetics: (1) a thymus-independent phase that begins immediately during the early post-transplant period and is mediated by adoptively transferred graft-derived T cells or recipient T cells that survived conditioning and (2) a late thymus-dependent phase that is a prolonged, multistep process that can take up to 18 months after HCT, in which lymphomyeloid progenitor cells repopulate the thymus with thymocyte precursors that can reconstitute thymopoiesis [68,70].
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.
High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naïve lymphocytes and prevents TTV reactivation
2018, Leukemia Research
Citation Excerpt :
It is of interest that the zinc group did not develop any increase in TTV load at day +100, as opposed to what happened in the control group and what reported in literature [20]. The parallel decrease in CD8+ count in the control group could suggest a relationship between TTV replication and immune impairment; in fact, many studies demonstrated TTV replication during the reactivation of other viruses [21,22] and during the dose-increasing of the immunosuppressive therapy after organ transplant [23]. Finally, we did not observe any severe AEs, in spite of a high dose of zinc.
Zinc plays an important role in thymic function and immune homeostasis. We performed a prospective clinical trial using a high-dose zinc oral supplementation to improve the immune reconstitution after hematopoietic stem cell transplant (HSCT).
We enrolled 18 patients undergoing autologous HSCT for multiple myeloma. Nine patients were randomized to receive only a standard antimicrobial prophylaxis; whereas, nine patients received in addition 150 mg/day of zinc from day +5 to day +100 after transplant.
CD4+ naïve lymphocytes and TRECs showed a significant increase from day +30 until day +100 only in the zinc-treated group. Moreover, the load of Torquetenovirus, a harmless virus that replicates in course of immunedepression, increased at day +100 only in the control group. No severe adverse events were reported during the zinc consumption.
First data from the ZENITH trial suggest that high-dose zinc supplementation is safe and may enhance the thymic reconstitution after HSCT. Registered: http://Clinicaltrials.gov (NCT03159845); and EUDRACT: 2014-28 004499-47.
An infant case of severe hypereosinophilia and systemic symptoms with multiple drug hypersensitivity and reactivation of cytomegalovirus and BK virus
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The human cytomegalovirus decathlon: Ten critical replication events provide opportunities for restriction
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HHV-6 infection after allogeneic hematopoietic stem cell transplantation: From chromosomal integration to viral co-infections and T-cell reconstitution patterns

Highlights

Summary

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Patients, donors and disease characteristics

Incidence of HHV-6 infection and co-infections with CMV, BKV and EBV after allo-HSCT

Discussion

Conflict of interest

Acknowledgments

Biol Blood Marrow Transplant

Biol Blood Marrow Transplant

Biol Blood Marrow Transplant

J Clin Virol

Biol Blood Marrow Transplant

Blood

J Virol Methods

Biol Blood Marrow Transplant

J Clin Virol

Update on human herpesvirus 6 biology, clinical features, and therapy

Clin Microbiol Rev

Human herpesvirus 6 latently infects early bone marrow progenitors in vivo

J Virol

Immunomodulation and immunosuppression by human herpesvirus 6A and 6B

Future Virol

Interaction of human herpesvirus 6 with human CD34 positive cells

J Med Virol

Reactivation of human herpesvirus 6 during ex vivo expansion of circulating CD34+ haematopoietic stem cells

J Gen Virol

Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT

Bone Marrow Transplant

Chromosomally integrated human herpesvirus6: questions and answers

Rev Med Virol

Human herpesvirus 6 DNA in plasma after allogeneic stem cell transplantation: incidence and clinical significance

J Infect Dis

Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpesvirus 6 and clinical response to treatment with foscarnet plus ganciclovir

Clin Infect Dis

Human herpes virus-6 DNA in cerebrospinal fluid of children undergoing therapy for acute leukaemia

Br J Haematol