HHV6-Associated Hydrocephalus in a Pediatric Hematopoietic Stem Cell Transplant Recipient: An Unusual Presentation.

Human herpesvirus 6 (HHV-6) is a widely spread DNA virus that is ubiquitous and persistent with primary infection occurring in early childhood, with reactivation of the infection a common phenomenon in severely immunocompromised hosts, including hematopoietic stem cell transplant (HSCT) patients, influencing morbidity and mortality. A wide spectrum of clinical presentations is reported in the literature with HHV-6 reactivation including post-transplant limbic encephalitis (PALE). We report the unusual case of a 6-year-old female 107 days postallogenic HSCT due to transfusion dependent beta thalassemia major who developed acute cerebellitis with secondary supratentorial hydrocephalus that required invasive surgical intervention. In addition to accompanying imaging findings, the patient tested positive for HHV-6 by PCR from both serum and CSF samples and demonstrated dramatic improvement with the institution of steroid therapy in addition to ganciclovir treatment. The availability of rapid diagnostic measures in addition to a multidisciplinary approach is crucial to manage HHV-6 encephalitis and associated complications in HSCT patients.

Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling.

Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus worldwide. However, whether and how HHV-6 infection influences the metabolic machinery of the host cell to provide the energy and biosynthetic resources for virus propagation remains unknown. In this study, we identified that HHV-6A infection promotes glucose metabolism in infected T cells, resulting in elevated glycolytic activity with an increase of glucose uptake, glucose consumption and lactate secretion. Furthermore, we explored the mechanisms involved in HHV-6A-mediated glycolytic activation in the infected T cells. We found increased expressions of the key glucose transporters and glycolytic enzymes in HHV-6A-infected T cells. In addition, HHV-6A infection dramatically activated AKT-mTORC1 signaling in the infected T cells and pharmacological inhibition of mTORC1 blocked HHV-6A-mediated glycolytic activation. We also found that direct inhibition of glycolysis by 2-Deoxy-D-glucose (2-DG) or inhibition of mTORC1 activity in HHV-6A-infected T cells effectively reduced HHV-6 DNA replication, protein synthesis and virion production. These results not only reveal the mechanism of how HHV-6 infection affects host cell metabolism, but also suggest that targeting the metabolic pathway could be a new avenue for HHV-6 therapy.

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.

Detection of human herpesvirus 6 DNA and chromosomal integration after allogeneic hematopoietic stem cell transplantation: A retrospective single center analysis.

INTRODUCTION: Human herpesvirus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant morbidity and mortality. METHODS: The epidemiology of HHV-6 infections and their impact on outcome after allo-HSCT were retrospectively analyzed in 689 adult allo-HSCT recipients (January 2015-December 2018). Chromosomal integration of HHV-6 (ciHHV-6) in the donor was retrospectively investigated to critically evaluate antiviral treatment strategies. RESULTS: HHV-6 DNA in any specimen was found in 89 patients. HHV-6 infections (encephalitis (one), gastroenteritis (44), dermatitis (two), hepatitis (one), or pneumonitis (five)) were diagnosed in 53/689 patients (7.7%). Elevated levels of HHV-6 DNA were found in 38 patients (5.5%). ciHHV-6, analyzed in patients with HHV-6 viral loads ≥104  copies/ml, was identified in four patients (10/38 patients; 10.5%). Two of those displayed copy numbers of HHV-6 ranging from ≥2 × 105 to 2.5 × 106  copies/ml (HHV-6A). Here, ciHHV-6 was integrated into donor and not into the patients' cells. In this series of allo-HSCT recipients, 10.5% of patients with blood viral loads of HHV-6 showed ciHHV-6. CONCLUSION: Screening of the donor for ciHHV-6 before initiation of antiviral therapy is recommended.

Synthesis and biological evaluation of novel rhodanine-based structures with antiviral activity towards HHV-6 virus.

An increased awareness of diseases associated with Human herpesvirus 6 (HHV-6) infection or reactivation has resulted in a growing interest in the evaluation of the best treatment options available for the clinical management of HHV-6 disease. However, no compound has yet been approved exclusively for HHV-6 infection treatment. For this reason, the identification of anti-HHV6 compounds provides a valuable opportunity for developing efficient antiviral therapies. A possible target for antiviral drugs is the virus-cell fusion step. In this study, we synthetized potential fusion intermediates inhibitors based on the rhodanine structure. The obtained derivatives were tested for cytotoxicity and for antiviral activity in human cells infected with HHV6. Level of infection was monitored by viral DNA quantification at different time points up to 7 days post infection. Among the synthetized derivatives, 9e showed a significative inhibitory effect on viral replication that lasted over 7 days, probably attributable to the particular combination of hydrophilic and hydrophobic substituents to the rhodanine moiety. Our results support the use of these amphipathic fusion inhibitors for the treatment of HHV-6 infections.

Retrospective case analysis of antiviral therapies for HHV-6 encephalitis after hematopoietic stem cell transplantation.

Human herpesvirus 6 (HHV-6) is one of the most common causes of encephalitis in allogeneic hematopoietic stem cell transplant (HCT) recipients and is associated with significant morbidity and mortality. There are no FDA-approved treatments specifically for HHV-6 encephalitis; HHV-6 disease is typically treated with CMV antivirals. A review of antiviral medications used to treat HHV-6 encephalitis was conducted by aggregating data from case reports found on PubMed. Articles were included if they examined at least one HCT patient diagnosed with HHV-6 encephalitis and described their treatment course and outcome. Key data were abstracted from 123 cases described in 52 studies. The proportion of patients with encephalitis who died or developed sequelae was 63.6% among ganciclovir monotherapy recipients (n = 44), 55.3% among foscarnet monotherapy recipients (n = 47), and 37.5% among recipients of combination therapy with foscarnet and ganciclovir (n = 32). Logistic regression revealed that recipients of foscarnet (OR 4.286, 95% CI 1.235-14.877, P = .022) and ganciclovir (OR 5.625, 95% CI 1.584-19.975, P = .008) monotherapies were more likely to develop sequelae compared to recipients of combination therapy, respectively. In multivariate analyses, non-cord blood transplant was identified as an independent risk factor for developing sequelae after receiving ganciclovir monotherapy (OR 5.999, 95% CI 1.274-28.254, P = .023). There was no difference in mortality between patients who received combination therapy and those who received monotherapy. In conclusion, combination therapy with foscarnet and ganciclovir may reduce sequelae, but not mortality, secondary to HHV-6 encephalitis.

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.

Human herpesvirus 6 encephalitis in a patient treated with everolimus for renal cell carcinoma.

INTRODUCTION: Everolimus is a mammalian target of rapamycin inhibitor and is approved as second-line treatment or beyond for renal cell carcinoma. We report a case of a 75-year-old male treated with everolimus for metastatic renal cell carcinoma, after sunitinib treatment, who was diagnosed with human herpesvirus 6 encephalitis. CASE REPORT: After 39 months of everolimus, 10 mg per day, our patient was admitted with fever, consciousness disorders and a partial epileptic crisis. Laboratory tests revealed lymphopenia (170 lymphocytes/mm3), and polymerase chain reaction in cerebrospinal fluid was positive for human herpesvirus 6. Brain magnetic resonance imaging study demonstrated hippocampal abnormality and a pontine lesion. MANAGEMENT AND OUTCOME: The patient stopped everolimus treatment indefinitely. He received ganciclovir initially intravenously, with a rapid clinical improvement, as well as polyvalent immunoglobulins were given to correct hypogammaglobulinemia. Two months later, antiviral therapy was switched to oral ganciclovir, which was never stopped. A new lumbar puncture was performed one month after the initiation of antiviral treatment, which did not reveal human herpesvirus 6 DNA anymore. DISCUSSION: Human herpesvirus 6 encephalitis is more common in hematopoietic stem cell transplant recipients and HIV patients. This is the first case probably associated to everolimus treatment. In contrast to most patients diagnosed with this infection, who either die or develop neurologic sequelae, our patient almost fully recovered two months later.

Primary infection with human herpes virus type 6, post-pediatric liver transplantation-A pathogen to remember.

BACKGROUND: In recent years, liver transplantation (LT) has become a well-accepted therapeutic modality for children with end-stage liver disease, with transplantation surgery being performed at a younger age. Human herpes virus 6 (HHV-6) infection occurs in most children within the first 2 years of life, therefore, data on primary HHV-6 infection in pediatric liver transplant recipients is scarce. OBJECTIVE: To describe the course of primary HHV-6 infection after pediatric LT. METHODS: Medical files, between the years 2015-2016, of post-LT pediatric patients with suspected primary HHV-6 infection were reviewed. Clinical and laboratory data for enrolled cases were evaluated. Primary infection was defined as DNAemia in children who were seronegative prior to transplantation or seroconversion from negative to positive IgG posttransplantation. RESULTS: Four cases of primary HHV-6 (type B) infection were identified among the 26 children who had undergone LT at our center during the study period. All patients were <1 year old and presented with fever, hepatitis, and elevated inflammatory markers, most (75%) within a short-period posttransplantation. All were initially treated with empiric antibiotics for a suspected bacterial infection and three underwent liver biopsy, one showing signs of rejection. Three were treated with antiviral therapy with a gradual resolution of symptoms. DISCUSSION: Primary HHV-6 should be taken into account in young children shortly after LT, especially when presenting with fever and elevated liver enzymes. Treatment with antiviral therapy should be considered. CONCLUSIONS: In young infants post-LT, a high index of suspicion may promote early detection of HHV-6 primary infection and prevent serious complications.

Human herpesvirus 6 encephalitis in patients administered mycophenolate mofetil as prophylaxis for graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Human herpesvirus 6 (HHV-6) encephalitis is a known life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, few studies have focused on the occurrence of HHV-6 encephalitis in patients receiving mycophenolate mofetil (MMF) combined with a calcineurin inhibitor as prophylaxis for graft-versus-host disease (GVHD). This study aimed to investigate the impact of MMF administered for GVHD prophylaxis in the occurrence of HHV-6 encephalitis after allo-HSCT and the characteristics of this condition. METHODS AND RESULTS: We retrospectively analyzed 73 patients who underwent allo-HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2-3 g/d) was administered along with a calcineurin inhibitor. Seven patients (8.0%) developed encephalitis due to HHV-6. The median period from allo-HSCT to the onset of HHV-6 encephalitis was 23 days (range, 17-98 days). The cumulative incidence of HHV-6 encephalitis on day 100 after treatment was 12% and 6% in patients who underwent cord blood transplantation (CBT) and non-CBT (ie, bone marrow transplantation and peripheral blood stem cell transplantation), respectively (P = 0.344). Neurological symptoms of encephalitis were more severe in non-CBT cases than those in CBT cases. All patients diagnosed with HHV-6 encephalitis were treated with ganciclovir or foscarnet. None of the enrolled patients died from HHV-6 encephalitis. CONCLUSIONS: Mycophenolate mofetil may have the potential to increase the frequency of severe HHV-6 encephalitis in patients undergoing CBT and non-CBT. Thus, MMF should be administered with caution, and patients should be monitored closely for HHV-6 encephalitis even those who did not undergo CBT.

Molecular detection of human herpesvirus 7 DNA in cerebrospinal fluid from adult patients with neurological disorders.

Neurological manifestations associated with HHV-7 have been described in primary infection in children, and very occasionally in immunocompromised adult patients. However, the role of HHV-7 reactivation as a cause of central nervous system (CNS) diseases in immunocompetent adults has not yet been defined. We retrospectively analyzed clinical and microbiological features of adults with neurological symptoms who underwent lumbar puncture and a multiplex polymerase chain reaction (PCR) for herpesviruses (HHV-1-8) and enteroviruses performed in cerebrospinal fluid (CSF), during a 4-year period. A total of 251 subjects were included. Mean age was 55 years, ranging 15-89. Globally, HHV-7 DNA was detected in CSF in 14 patients (5.6%). It was detected in 1 of 36 patients with microbiologically confirmed CNS infections, and in 7 of 172 patients with diagnoses of non-infectious neurological disorders (Specificity 0.96, 95% confidence interval 0.93-0.99). Additionally, HHV-7 DNA was detected in 6 of 21 patients (28.6%) with probable CNS infections (compatible clinical syndrome and CSF changes) in the absence of other causative agent: four meningitis, one myelitis, and one encephalitis. Treatment with foscarnet was effective in achieving improvement of symptoms and clearance of HHV-7 DNA in CSF in the cases of encephalitis and myelitis, while ganciclovir was ineffective in the case of encephalitis. Our results show that HHV-7 reactivation may cause CNS disease in immunocompetent adults and that detection of HHV-7 DNA in CSF as a false-positive result or as asymptomatic reactivation in adult patients with neurological diseases is uncommon. Foscarnet seems the first-line treatment for HHV-7 CNS disease.

HHV-6 in liver transplantation: A literature review.

Human herpesvirus 6 (HHV-6A and HHV-6B) can cause primary infection or reactivate from latency in liver transplant recipients, which can result in a variety of clinical syndromes, including fever, hepatitis, encephalitis and higher rates of graft dysfunction as well as indirect effects including increased risks of mortality, CMV disease, hepatitis C progression and greater fibrosis scores. Although HHV-6 infection is currently diagnosed by quantifying viral DNA in plasma or blood, biopsy to demonstrate histopathological effects of HHV-6 remains the gold standard for diagnosis of end-organ disease. HHV-6 reactivation may be restricted to the infected organ with no evidence of active infection in the blood. HHV-6 infections in liver transplant patients are mostly asymptomatic, but clinically significant tissue-invasive infections have been treated successfully with ganciclovir, foscarnet or cidofovir. Inherited chromosomally integrated HHV-6 (ciHHV-6), in either the recipient or the donor organ, may create confusion about systemic HHV-6 infection. Recipients with inherited ciHHV-6 may have an increased risk of opportunistic infection and graft rejection. This article reviews the current scientific data on the clinical effects, risk factors, pathogenesis, diagnosis and treatment of HHV-6 infections in liver transplant recipients.

Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals.

The roseoloviruses, human herpesvirus (HHV)-6A, HHV-6B, and HHV-7, can cause severe encephalitis or encephalopathy. In immunocompetent children, primary HHV-6B infection is occasionally accompanied by diverse clinical forms of encephalitis. Roseolovirus coinfections with heterologous viruses and delayed primary HHV-7 infection in immunocompetent adults result in very severe neurological and generalized symptoms. Recovery from neurological sequelae is slow and sometimes incomplete. In immunocompromised patients with underlying hematological malignancies and transplantation, frequent single or simultaneous reactivation of roseoloviruses elicit severe, lethal organ dysfunctions, including damages in the limbic system, brain stem, and hippocampus. Most cases have been due to HHV-6B with HHV-6A accounting for 2-3%. The most severe manifestation of HHV-6B reactivation is post-transplantation limbic encephalitis. Seizures, cognitive problems, and abnormal EEG are common. Major risk factors for HHV-6B-associated encephalitis include unrelated cord blood cell transplantation and repeated hematopoietic stem cell transplantation. Rare genetic disorders, male gender, certain HLA constellation, and immune tolerance to replicating HHV-6 in persons carrying chromosomally integrated HHV-6 might also predispose an individual to roseolovirus-associated brain damage. At this time, little is known about the risk factors for HHV-7-associated encephalitis. Intrathecal glial cell destruction due to virus replication, overexpression of proinflammatory cytokines, and viral mimicry of chemokines all contribute to brain dysfunction. High virus load in the cerebrospinal fluid, hippocampal astrogliosis, and viral protein expression in HHV-6B-associated cases and multiple microscopic neuronal degeneration in HHV-7-associated cases are typical laboratory findings. Early empirical therapy with ganciclovir or foscarnet might save the life of a patient with roseolovirus-associated encephalitis.

Successful treatment and FDG-PET/CT monitoring of HHV-6 encephalitis in a non-neutropenic patient: case report and literature review.

Human herpesvirus (HHV)-6 reactivation is associated with severe forms of encephalitis among patients undergoing hematopoietic stem cell transplantation. Cases in non-neutropenic patients are uncommon. The efficacy of ganciclovir and other compounds that are used for the treatment of HHV-6 encephalitis remains suboptimal and linked to toxicity. Valganciclovir, the oral prodrug of ganciclovir, could be practical to treat outpatients, but it is not commonly used for severe cases. We report a case of HHV-6 encephalitis in a non-neutropenic patient successfully treated with valganciclovir and undergoing therapeutic drug monitoring in plasma and in the cerebrospinal fluid. Resolution of infectious foci was documented by cerebral MRI and F18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). A review of the literature on HHV-6 encephalitis is also reported.

Human herpes virus-6 encephalitis causing severe anterograde amnesia associated with rituximab, azathioprine and prednisolone combination therapy for dermatomyositis.

Human herpes virus-6 (HHV-6) reactivation is a well-recognised complication following haematological stem cell transplantation, but it is novel in the context of combination immunomodulatory therapy for autoimmune disease. We report a case of severe anterograde amnesia caused by HHV-6 encephalitis in a young female patient on rituximab, azathioprine and prednisolone for dermatomyositis (DM). The use of targeted biologic treatments for systemic autoimmune connective tissue diseases (CTDs) is increasing, particularly when refractory to conventional management. The anti-CD20 B cell depleting monoclonal antibody, rituximab is now increasingly used, often in combination with conventional immunomodulatory treatments, in certain autoimmune neurological conditions and systemic CTDs including DM. Physicians should be aware of the possibility of HHV-6 in those who develop encephalitis while CD20 B cell deplete, especially in the presence of additional immunomodulatory therapies. Prompt diagnosis and treatment of HHV-6 encephalitis with evidence-based anti-viral therapy may help reduce the extent of irreversible morbidity such as amnesia.

Pediatric 8p11 eosinophilic myeloproliferative syndrome (EMS): A case report and review of the literature.

The 8p11 eosinophilic myeloproliferative syndrome (EMS) is an aggressive neoplasm driven by translocation of the fibroblast growth factor receptor 1 and often transforms to leukemias and lymphomas that are refractory to treatment. The first case was identified in 1983, and to date over 70 cases have been reported in the literature. Despite those reports, no consensus exists on management of this condition, and inconsistency in treatment regimens is even more pronounced in the pediatric literature. We report a case of a male infant with the 8p11 EMS, review the published pediatric experience with EMS, and discuss treatment strategies for this enigmatic hematological disorder.

Acute human herpes virus 7 (HHV-7) encephalitis in an immunocompetent adult patient: a case report and review of literature.

We report a case of an acute HHV-7 encephalitis involving the nucleus of the VI cranial nerve in an immunocompetent host. The patient was an adult male admitted to our Clinic with headache, diplopia, fever, nausea, vertigo, asthenia and general malaise. PCR for viral and bacterial genomes was run on both serum and cerebral spinal fluid (CSF) after performing lumbar puncture, resulting positive only for HHV-7 DNA on CSF. MRI showed hyperintensity in FLAIR signal in the dorsal pons, in the area of the VI cranial nerve nucleus. Empirical therapy with Acyclovir and Dexamethasone was started at the time of admission and was continued after the microbiology results. After three days of therapy diplopia, fever and other previous clinical manifestations improved and the patient recovered normal sight. Our case report contributes to a better understanding of the presentation, diagnosis and treatment of HHV-7 encephalitis in immunocompetent patients due to reactivation in adult age.