A case of human herpesvirus 6 encephalitis following pediatric hematopoietic stem cell transplantation: early diagnosis and treatment matters.

Human herpesvirus 6 (HHV-6) is one of the life-threatening infectious complications with significant morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Clinically, the diagnosis of HHV-6 encephalitis can be challenging due to a lack of specific symptoms and definitive diagnostic tests. We report a pediatric HSCT recipient who developed late-onset HHV-6 encephalitis without typical radiographic findings. The routine viral infection monitoring protocol contributed to the prompt diagnosis of HHV-6 encephalitis and early therapeutic intervention. The patient was treated successfully without any neurological complications attributable to HHV-6 encephalitis. HHV-6 encephalitis should remain in the differential diagnosis as an important but treatable disease, even for several months after HSCT and even without radiographic findings. Whenever HHV-6 encephalitis is suspected, antivirals should be initiated promptly to prevent its complications.

Herpesviruses in the oral cavity of patients subjected to allogeneic hematopoietic stem cell transplantation and its relationship with oral mucositis.

OBJECTIVES: This study was performed to characterise oral shedding of herpesviruses in patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) and to investigate its relationship with oral mucositis (OM). MATERIALS AND METHODS: PCR and enzymatic digestion were conducted to identify oral shedding of herpesviruses and its correlation with OM development in 31 patients. The samples were collected at three sites in the oral cavity and at 5 times during follow-up; two additional collections were made from patients who developed ulcerative OM. RESULTS: HSV-1, EBV, CMV, HHV-6A, HHV-6B, and HHV-7 were detected in 4.97%, 16.02%, 4.41%, 2.20%, 3.31%, and 68% of the oral mucosal samples, respectively; 4.41%, 16.57%, 5.52%, 2.20%, 5.52%, and 63.53% of supragingival samples, respectively, and 4.41%, 18.23%, 2.76%, 1.65%, 2.75%, and 35.91% of subgingival samples, respectively. OM was diagnosed in 13 patients. The presence of HHV-7 in C1 (oral mucosa: p = 0.032) and C2 (supragingival: p = 0.009; subgingival: p = 0.002) was significantly increased in patients who developed OM, and patients exhibiting HHV-7 shedding in the oral cavity were 3.32-fold more likely to develop OM. CONCLUSIONS: Patients who developed OM showed higher HHV-7 shedding in the oral cavity at nadir (immediately prior to OM development), suggesting modifications to the inflammatory microenvironment. CLINICAL RELEVANCE: HHV-7 may be involved in oral dysbiosis in HSCT-related OM; enhanced understanding of its role in the pathogenesis of OM may lead to the development of strategies for managing and preventing this common side effect of alloHSCT.

Oral brincidofovir decreases the incidence of HHV-6B viremia after allogeneic HCT.

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.

Posterior reversible encephalopathy syndrome concurrent with human herpesvirus-6B encephalitis after allogeneic hematopoietic stem cell transplantation.

Posterior reversible encephalopathy syndrome (PRES) and human herpesvirus (HHV)-6 encephalitis are both serious neurological complications post hematopoietic stem cell transplantation. Although infection is one of the important causes of PRES, only few cases have reported the relation between PRES and viral infection. Herein, we report the first adult case of PRES concurrent with HHV-6 encephalitis after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. This case suggests that HHV-6 reactivation is associated with the pathogenesis of PRES. Also, PRES and HHV-6 encephalitis cause similar symptoms, and switching the immunosuppressant from calcineurin inhibitor to prednisolone for treating PRES may worsen HHV-6 encephalitis. Therefore, we should pay attention to the complication of HHV-6 encephalitis even after PRES is diagnosed.

Clinical characteristics of human herpesvirus-6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention.

After allogeneic hematopoietic stem cell transplantation (HSCT), human herpesvirus-6 (HHV-6) can cause serious central nervous system (CNS) disorder and typically presents as encephalitis. Another manifestation of HHV-6 is myelitis, which has not been fully evaluated. In this study, we retrospectively analyzed 19 patients who developed HHV-6 myelitis after allogeneic HSCT. Median onset was 20 days after transplantation (range, 13-31), with a cumulative incidence of 4.1% at day 40 after transplantation. Median age at transplant was 50 years (range, 17-61). Median copy number of HHV-6 DNA was 3000 copies/ml in cerebrospinal fluid (CSF; range, 200-100,000). The most common symptoms were pruritus, pain of the extremities/back, and numbness. Three patients subsequently developed encephalitis in the clinical course of myelitis; their HHV-6 copy numbers in CSF had been higher than 10,000 copies/ml at the onset of myelitis. Antiviral agents were initiated shortly after onset in all patients, resulting in recovery. These results suggest that myelitis would be an important subtype of HHV-6-associated CNS disorders after allogeneic HSCT, whose prognosis could be favorable by an early intervention. Transplant physicians should recognize early posttransplant neurological symptoms such as pruritus, pain, or numbness as possible signs of HHV-6 myelitis, which could also progress to encephalitis.

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

BACKGROUND: Human herpesvirus-6B (HHV-6B) infection after allogenic hematopoietic stem cell transplantation (allo-HSCT) is known to be associated with post-transplant limbic encephalitis in adults. Meanwhile, the association between HHV-6B infection and central nervous system complications remains unclear in pediatric allo-HSCT patients. METHODS: In this study, HHV-6B infection was monitored for more than 50 days after HSCT using virus isolation and real-time PCR. Clinical information such as patient background and encephalitis status was collected retrospectively from medical records. Risk factors for HHV-6B infection were determined by the Cox proportional hazards model, and the clinical features of HHV-6B encephalitis in pediatric allo-HSCT patients were elucidated. RESULTS: Human herpesvirus-6B infection was observed in 74 (33.8%) of 219 patients at 3-47 days (median 18, interquartile range 13-20). Risk factors identified in multivariable analysis were hematological malignancy (hazards ratio [HR], 5.0; 95% confidence interval [CI], 2.3/12.5; P < .0001), solid tumor (HR, 4.8; CI, 1.5/16.3; P = .0104), unrelated donor (HR, 2.1; CI, 1.0/4.6; P = .0378), and sex-mismatched donor (HR 1.8; CI, 1.1/3.0; P = .0257). HHV-6B encephalitis occurred in only one of the 219 patients (0.46%); this patient demonstrated the typical clinical course of posterior reversible encephalopathy syndrome. CONCLUSION: Hematological malignancy, solid tumor, unrelated donor, and sex-mismatched donor were significant risk factors for HHV-6B infection after pediatric allo-HSCT. In pediatric allo-HSCT patients, the incidence of HHV-6B encephalitis was low and the clinical features differed from those in adult patients.

Human herpesvirus 6 in transplant recipients: an update on diagnostic and treatment strategies.

PURPOSE OF REVIEW: The current review article focuses on recent advances in the approach to the diagnosis and treatment of human herpesvirus 6B (HHV-6B) in hematopoietic cell and solid organ transplant recipients. RECENT FINDINGS: Over the past few years, key studies have broadened our understanding of best practices for the prevention and treatment of HHV-6B encephalitis after transplantation. Moreover, important data have been reported that support a potential role of HHV-6B reactivation in the development of acute graft-versus-host disease and lower respiratory tract disease in transplant recipients. Finally, increasing recognition of inherited chromosomally integrated HHV-6 (iciHHV-6) and an expanding array of diagnostic tools have increased our understanding of the potential for complications related to viral reactivation originating from iciHHV-6 in donors or recipients. SUMMARY: Recent advances in diagnostic tools, disease associations, and potential treatments for HHV-6B present abundant opportunities for improving our understanding and management of this complex virus in transplant recipients.

Guidelines from the 2017 European Conference on Infections in Leukaemia for management of HHV-6 infection in patients with hematologic malignancies and after hematopoietic stem cell transplantation.

Of the two human herpesvirus 6 (HHV-6) species, human herpesvirus 6B (HHV-6B) encephalitis is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Guidelines for the management of HHV-6 infections in patients with hematologic malignancies or post-transplant were prepared a decade ago but there have been no other guidelines since then despite significant advances in the understanding of HHV-6 encephalitis, its therapy, and other aspects of HHV-6 disease in this patient population. Revised guidelines prepared at the 2017 European Conference on Infections in Leukaemia covering diagnosis, preventative strategies and management of HHV-6 disease are now presented.

Comparison of HHV-6 DNA detection in plasma and whole blood in allogeneic hematopoietic stem cell transplant recipients: frequent false-positive results for active HHV-6 infection using whole blood samples.

In this prospective observational study, we compared the human herpesvirus-6 (HHV-6) DNA load in serially collected paired plasma and whole blood (WB) samples from allogeneic hematopoietic stem cell transplantation (HSCT) recipients. A total of 721 paired samples were collected from 68 recipients. The positive rate for HHV-6 DNA was 9.7 and 35.0% in plasma and WB samples, respectively (P < 0.001). The correlation of HHV-6 DNA load between plasma and WB was poor (R2 = 0.250). After reaching peak levels, HHV-6 DNA showed a delayed decrease in WB in comparison with plasma (median, 28 versus 7 days, P < 0.001). We additionally tested HHV-6 mRNA status in 95 samples from eight patients. To identify positive HHV-6 mRNA, plasma HHV-6 DNA showed 55.0% sensitivity and 100% specificity, whereas WB HHV-6 DNA showed 90.0% sensitivity and 68.0% specificity. The false-positive rate for identifying positive HHV-6 mRNA was 0% for plasma HHV-6 DNA and 32.0% for WB HHV-6 DNA. Although WB was more sensitive than plasma for detecting HHV-6 reactivation, the rates of false positivity for active HHV-6 infection were higher for WB than for plasma.

Clinical course of human herpesvirus 6 infection in pediatric living donor liver transplantation.

Differentiation between active and latent viral infection is critical for analysis of HHV-6-associated disease. HHV-6 infection has been associated with several clinical manifestations; however, the precise role of HHV-6 in pediatric LDLT remains unclear. This retrospective cohort study included 33 pediatric patients who received LDLT. All of the recipients were monitored for HHV-6 infection using viral isolation and real-time PCR. HHV-6 infection was observed in 14 of 33 (42.4%) recipients, and HHV-6B infection occurred within 2 weeks after LDLT in 10 of 14 (71.4%) recipients. HHV-6 was isolated from 10 of 33 (30.3%) recipients. Multivariate analysis showed that independent predictors of HHV-6B infection were age (OR 0.975; 95% CI 0.943-0.999; P = .041), PELD (OR 1.091; P = .038), and biliary atresia (OR 16.48; P = .035). The occurrence of unexplained fever was significantly higher in recipients with HHV-6B infection (11/14) compared with uninfected recipients (6/19) (P = .013). Additionally, ALT levels at 8 and 9 weeks after transplantation were significantly higher in the recipients with HHV-6B infection. Younger age, high MELD/PELD score, and biliary atresia as an underlying disease were identified as risk factors for viral infection.

Long-term prognosis of human herpesvirus 6 reactivation following allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently have HHV-6 reactivation typically during the early phase following HSCT. The long-term clinical complications and prognosis, however, remain unclear. METHODS: Between September 2010 and October 2012, whole blood samples from 105 patients collected weekly from prior to 6 weeks after HSCT underwent multiplex polymerase chain reaction (PCR) to screen for viral DNA, followed by real-time PCR for quantitative estimation. In 48 patients, only HHV-6 was detected in at least one sample. In 30 patients, no viral DNA was detected. Long-term clinical records were reviewed in March 2016. All 48 HHV-6-positive patients, and 24 patients in whom no viral DNA detected, were followed up. RESULTS: Median maximum HHV-6 DNA load in the blood of the HHV-6 reactivation group (n = 48) was 11 800 copies/µg peripheral blood leukocyte DNA (range, 52-310 000 000). Hemophagocytic syndrome (HPS) was diagnosed in two subjects with HHV-6 reactivation. Acute graft-versus-host disease (GVHD) developed more frequently in patients with HHV-6 reactivation than in patients without viral reactivation (P = 0.002), but there was no difference in incidence of chronic GVHD. There was no difference in engraftment of neutrophils and platelets between groups. There was also no difference in overall survival between groups. Onset of HPS, however, was associated with lower overall survival (P = 0.009). CONCLUSIONS: Human herpesvirus 6 reactivation was associated with acute GVHD, but not with chronic GVHD, engraftment or overall survival. Onset of HPS, however, predicts lower overall survival.

Exogenous human herpesvirus 6 reinfection after tumor-infiltrating T-lymphocyte therapy.

Exogenous human herpes virus 6 (HHV-6) reinfection has never been reported in patients receiving tumor-infiltrating T lymphocytes therapy. We report an unusual case of HHV-6 infection following infusion of HHV-6 infected autologous T lymphocytes. HHV-6 infection could interfere with the tumor antigen immune recognition and the efficacy of immunotherapy.

High human herpesvirus 6 viral load in pediatric allogeneic hematopoietic stem cell transplant patients is associated with detection in end organs and high mortality.

Human Herpes Virus 6 (HHV-6) reactivation occurs in approximately half of patients following allogeneic hematopoietic stem cell transplant (HSCT). While encephalitis and delayed engraftment are well-documented complications of HHV-6 following HSCT, the extent to which HHV-6 viremia causes disease in children is controversial. We performed a retrospective review of HHV-6 reactivation and possible manifestations in pediatric allogeneic HSCT patients at a single institution. Of 89 children and young adults who underwent allogeneic HSCT over a three-and-a-half-year period, 34 patients reactivated HHV-6 early post-transplant. Unrelated donor stem cell source and lack of antiviral prophylaxis were risk factors for the development of HHV-6 viremia. Viremia correlated with the presence of acute graft-versus-host disease, but not chronic graft-versus-host disease. We identified two subgroups within the viremic patients-a high-risk viremic and tissue-positive group that reactivated HHV-6 and had suspected end-organ disease and a low-risk viremic but asymptomatic group that reactivated HHV-6 but did not exhibit symptoms or signs of end-organ disease. Peak viral load was found to be strongly associated with mortality. Prospective studies in larger numbers of patients are needed to further investigate the role of HHV-6 in causing symptomatic end-organ disease as well as the association of viral load with mortality.

Human Herpesvirus 6 Infection Following Haploidentical Transplantation: Immune Recovery and Outcome.

Human herpesvirus 6 (HHV-6) is increasingly recognized as a potentially life-threatening pathogen in allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively evaluated 54 adult patients who developed positivity to HHV-6 after alloSCT. The median time from alloSCT to HHV-6 reactivation was 34 days. HHV-6 was present in plasma samples from 31 patients, in bone marrow (BM) of 9 patients, in bronchoalveolar lavage fluid and liver or gut biopsy specimens from 33 patients, and in cerebrospinal fluid of 7 patients. Twenty-nine patients developed acute graft-versus-host disease (GVHD), mainly grade III-IV, and 15 had concomitant cytomegalovirus reactivation. The median absolute CD3+ lymphocyte count was 207 cells/µL. We reported the following clinical manifestations: fever in 43 patients, skin rash in 22, hepatitis in 19, diarrhea in 24, encephalitis in 10, BM suppression in 18, and delayed engraftment in 11. Antiviral pharmacologic treatment was administered to 37 patients; nonetheless, the mortality rate was relatively high in this population (overall survival [OS] at 1 year, 38% ± 7%). A better OS was significantly associated with a CD3+ cell count ≥200/µL at the time of HHV-6 reactivation (P = .0002). OS was also positively affected by the absence of acute GVHD grade III-IV (P = .03) and by complete disease remission (P = .03), but was not significantly influenced by steroid administration, time after alloSCT, type of antiviral prophylaxis, plasma viral load, or organ involvement. Although HHV-6 detection typically occurred early after alloSCT, better T cell immune reconstitution seems to have the potential to improve clinical outcomes. Our findings provide new insight into the interplay between HHV-6 and the transplanted immune system.

Encephalitis caused by an unusual human herpes virus type 6 and Toxoplasma gondii co-infection in a cord blood transplant recipient.

BACKGROUND: The case of a central nervous system human herpes virus type 6 (HHV-6) and Toxoplasma gondii co-infection after an umbilical cord blood transplantation in a chronic myelomonocytic leukaemia patient is reported. CASE REPORT: A 65-year-old Caucasian man underwent an umbilical cord blood transplantation within the context of chronic myelomonocytic leukaemia. On day 37 post-graft, he presented with a severe headache; PCRs of cerebrospinal fluid and blood were positive for T. gondii and HHV-6. The patient was treated with pyrimethamine and sulfadiazine associated with ganciclovir. CONCLUSION: HHV-6 reactivation can trigger a reactivation of T. gondii. This case suggests that patients who are seropositive for T. gondii and who present with HHV-6 reactivation should be monitored closely for toxoplasmosis.

[Human herpesvirus-6-associated diseases in hematopoietic stem cell transplantation: an update].

Human herpesvirus (HHV)-6 belongs to the Betaherpesvirinae subfamily of human herpesviruses. Primary HHV-6 infection commonly causes exanthem subitum. Like other herpesviruses, HHV-6 is capable of persisting in the host after the primary infection. Under conditions of immunosuppression, latent HHV-6 can be reactivated. Between 30% and 70% of patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) experience HHV-6 reactivation at 2-4 weeks after transplantation. Accumulating evidence indicates that HHV-6 is an actual cause of encephalitis after allo-HCT. Risk factors for HHV-6 encephalitis include cord blood transplantation and an inflammatory milieu, which occurs in the early period after allo-HCT. Although HHV-6 encephalitis is associated with a poor prognosis, no validated treatments or preventative measures have as yet been established. HHV-6 reactivation may also cause myelitis, bone marrow suppression, lung disease, hepatitis, delirium, and graft-versus-host disease. However, such associations have not been consistently demonstrated and causality remains uncertain. This review updates the latest information regarding the clinical syndrome accompanying HHV-6 reactivation, with a particular focus on HHV-6 encephalitis, in the form of a series of questions and answers.

Early human herpes virus type 6 reactivation in umbilical cord blood allogeneic stem cell transplantation.

Human herpes virus type 6 can reactivate in patients after allogeneic stem cell transplantation and has been associated with serious sequelae such as delayed engraftment and an increased risk of developing acute graft-versus-host disease (GVHD). This study investigated human herpes virus type 6 (HHV-6) reactivation within 60 days of transplantation in stem cell transplants utilizing single umbilical cord blood, double umbilical cord blood, or umbilical cord blood plus haploidentical stem cells. Of 92 patients, 60 (65%) had HHV-6 reactivation. Reactivation was not significantly influenced by any patient characteristics, disease characteristics, or by stem cell source (umbilical cord blood only versus haploidentical plus umbilical cord blood). We did not observe any impact of HHV-6 reactivation on neutrophil or platelet count recovery or on relapse-free survival. HHV-6 reactivation was associated with subsequent development of prerelapse acute GVHD (HR = 3.00; 95% CI, 1.4 to 6.4; p = 0.004).

Absence of human herpesvirus 6B detection in association with illness in children undergoing cancer chemotherapy.

The lymphotropic herpesviruses, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6B (HHV-6B) can reactivate and cause disease in organ transplant recipients; the contributions of HHV-6A and HHV-7 to disease are less certain. Less is known about their pathogenic roles in children undergoing treatment for malignancies. Children with newly diagnosed cancer were followed for 24 months. Clinical information and blood samples were collected during routine visits and during acute visits for fever or possible viral infections. Lymphotropic herpesvirus DNA in blood was measured by polymerase chain reaction (PCR). Although HHV-6B DNA was detected at least once in about half of the patients; the other viruses were seldom detected. There was no association between HHV-6B detection and individual acute clinical events, however, HHV-6B detection was more common in children who experienced more frequent acute clinical events. In children being treated for various malignancies, HHV-6B detection was common, but was not associated with individual events of acute illness. Thus, if HHV-6B is not assessed longitudinally, clinical events may be misattributed to the virus. The elevated frequency of detection of HHV-6B in sicker children is consistent with prior reports of its detection during apparently unrelated acute clinical events. J. Med. Virol. 88:1427-1437, 2016. © 2016 Wiley Periodicals, Inc.

Human herpesvirus-6 viremia is not associated with poor clinical outcomes in children following allogeneic hematopoietic cell transplantation.

HHV-6 is an evolving pathogen in the field of AlloHCT. However, the impact of HHV-6 on AlloHCT outcomes remains to be elucidated. We studied the incidence and clinical impact of HHV-6 viremia in children following AlloHCT. One hundred consecutive children were monitored weekly by plasma PCR for the first 180 days following AlloHCT for HHV-6, CMV, EBV, and ADV. HHV-6 viremia was defined as plasma PCR >1000 viral copies/mL. The median age was nine yr. Following AlloHCT, 19% (95% CI 11.3-26.7%) of patients had HHV-6 viremia, with the highest incidence of reactivation (14/19, 73%) occurring during day +15-day +98. The proportion of platelet engraftment by day +180 was lower in patients with HHV-6 viremia (58%) than in those without HHV-6 viremia (82%), p = 0.028. Delay in neutrophil and platelet engraftment was not associated with HHV-6 viremia in multivariate analysis. Similarly, HHV-6 viremia was not associated with TRM in multivariate analysis (p = 0.15). In summary, HHV-6 viremia is prevalent in pediatric AlloHCT recipients. Based on our study results, we recommend that HHV-6 PCR should only be performed on clinical suspicion.