Human Herpesvirus-6 Encephalitis Research Articles

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.

Association between human herpesvirus-6 encephalitis and antiviral prophylaxis after allogeneic hematopoietic stem cell transplantation in the letermovir era.

The impact of letermovir (LTV)-an anti-cytomegalovirus (CMV) drug-on human herpesvirus-6 (HHV-6) encephalitis is unclear. We hypothesized that LTV prophylaxis may increase the incidence of HHV-6 encephalitis by reducing anti-CMV therapies after allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the association between HHV-6 encephalitis and antiviral prophylaxis, 7985 adult patients from a nationwide registry who underwent their first HSCT between January 2019 and December 2021 were analyzed. The incidence of HHV-6 encephalitis on day 100 after HSCT was 3.6%; 11.5% for the broad-spectrum antiviral group (foscarnet, ganciclovir, or valganciclovir); 2.8% for the LTV group, and 3.8% for the other antiviral group (p < 0.001). These differences persisted when cord blood transplantation (CBT) was analyzed separately (14.1%, 5.9%, and 7.4%, p < 0.001). In the multivariate analysis, CBT (hazard ratio [HR]: 2.90), broad-spectrum antiviral prophylaxis (HR: 1.91), and grade II-IV acute graft-versus-host disease requiring systemic corticosteroids (HR: 2.42) were independent risk factors for encephalitis (all p < 0.001). The findings of this large modern database study indicate that broad-spectrum antiviral prophylaxis, rather than LTV prophylaxis, is paradoxically associated with HHV-6 encephalitis in the LTV era. This paradoxical finding needs to be further explored in future studies.

HHV-6 in Cerebrospinal Fluid in Immunocompetent Children

Background: Human herpes virus-6 (HHV-6) is a ubiquitous virus known as an etiological agent of exanthem subitum. HHV-6-encephalitis in immunocompetent children is a rare complication of the primary infection. There are a lack of data on the prevalence of HHV-6-encephalitis in Russia. The aim of our study was to analyze the prevalence of HHV-6 DNA in the cerebrospinal fluid (CSF) of immunocompetent children with suspected acute meningoencephalitis. Materials and Methods: A total of 712 CSF samples were tested using qualitative PCR over 12 years at N.F. Filatov Children’s City Clinical Hospital No.5, Saint-Petersburg, Russia. Results: HHV-6 DNA was detected in 20 (2.8%) of the samples. Retrospectively, we analyzed the medical records of 15 cases. There were seven boys and eight girls from 1 month to 7 years old; the mean age was 22.3 ± 5.6 months. Most HHV-6 DNA-positive cases were due to the primary form of HHV-6 infection. There were, in total, four cases of HHV-6-meningoencephalitis. All the children had a complete recovery, without neurological deficits or death. Conclusions: HHV-6 encephalitis is a very rare disease in immunocompetent children (four cases among 712 samples over 12 years). Additional studies are needed to develop accurate diagnostic criteria and therapeutic approaches.

Human herpesvirus-6 reactivation and disease after allogeneic haematopoietic cell transplantation in the era of letermovir for cytomegalovirus prophylaxis

ObjectivesLetermovir 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. MethodsWe 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. ResultsWe 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.

Viral Encephalitis after Hematopoietic Cell Transplantation: A Systematic Review

Viral encephalitis is a rare but serious complication after hematopoietic cell transplantation (HCT). The nonspecific early signs and symptoms and rapid progression can make it difficult to diagnose and treat in a timely fashion. To better inform clinical decision making in post-HCT viral encephalitis, a systematic review of prior studies of viral encephalitis was performed, with the goal of characterizing the frequency of various infectious etiologies and their clinical course, including treatments and outcomes. A systematic review of studies of viral encephalitis was performed. Studies were included if they described a cohort of HCT recipients who were tested for at least 1 pathogen. Of 1613 unique articles initially identified, 68 met the inclusion criteria, with a total of 72,423 patients studied. A total of 778 cases of encephalitis were reported (1.1%). Human herpesvirus 6 (HHV-6) (n=596), Epstein-Barr virus (n=76), and cytomegalovirus (n=33) were the most commonly reported causes of encephalitis, and HHV-6 encephalitis tended to occur the earliest, accounting for most cases prior to day +100 post-transplantation. Of 29,671 patients with available transplantation data, encephalitis was diagnosed in 282 of 4707 (6.0%) cord blood transplantation (CBT) recipients, in 372 of 24,664 (1.5%) non-CBT allogeneic HCT recipients, and in 5 of 300 (1.7%) autologous HCT recipients. Of the 282 CBT encephalitis cases, 270 (95.7%) were caused by HHV-6. Overall, 288 (37.0%) of the 778 patients with encephalitis died, and 75 deaths were attributable to encephalitis, with the time between diagnosis and death ranging from 3 to 192 days. Viral encephalitis occurs in approximately 1% of HCT recipients, and HHV-6 is the most common cause. Mortality following encephalitis in HCT recipients is high, indicating an urgent need for advancement in preventive and therapeutic strategies.

Once-Daily Foscarnet Is Effective for Human Herpesvirus 6 Reactivation after Hematopoietic Stem Cell Transplantation

Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and increased transplantation-related complications. We hypothesized that preemptive treatment with a short course of foscarnet at a lower cutpoint of plasma HHV-6 viral load would be effective in treating early HHV-6 reactivation, preventing complications and precluding hospitalization of these patients. We reviewed outcomes of adult patients (age ≥18 years) who received preemptive treatment with once-daily foscarnet 60 to 90 mg/kg for 7 days for HHV-6 reactivation after allo-HSCT at our institution between May 2020 and November 2022. Plasma HHV-6 viral load was monitored by quantitative PCR twice monthly in the first 100 days post-transplantation and twice weekly after reactivation until resolution. Eleven patients with a median age of 46 years (range, 23 to 73 years) were included in the analysis. HSCT was performed with a haploidentical donor in 10 patients and with an HLA-matched related donor in 1 patient. The most common diagnosis was acute leukemia (9 patients). Myeloablative and reduced-intensity conditioning regimens were used in 4 and 7 patients, respectively. Ten of the 11 patients received post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. The median follow-up was 440 days (range, 174 to 831 days), and the median time to HHV-6 reactivation was 22 days post-transplantation (range, 15 to 89 days). The median viral load at first reactivation was 3100 copies/mL (range, 210 to 118,000 copies/mL), and the median peak viral load was 11,300 copies/mL (range, 600 to 983,000 copies/mL). All patients received a short course of foscarnet at either 90 mg/kg/day (n = 7) or 60 mg/kg/day (n = 4). In all patients, plasma HHV-6 DNA was undetectable at completion of 1 week of treatment. No HHV-6 encephalitis or pneumonitis occurred. All patients achieved neutrophil and platelet engraftment after a median of 16 days (range, 8 to 22 days) and 26 days (range, 14 to 168 days), respectively, with no secondary graft failure. No complications related to foscarnet administration were noted. One patient with very high HHV-6 viremia had recurrent reactivation and received a second course of foscarnet as an outpatient. A short course of once-daily foscarnet is effective in treating early HHV-6 reactivation post-transplantation and may reduce the incidence of HHV-6-related and treatment-related complications and preclude hospitalization in these patients.

“Unspecified organic personality and behavioral disorder due to brain damage from HHV-6 encephalitis in child. case report and literature review”

IntroductionWe present a case of a 15 year-old boy diagnosed with Unspecified Personality and Beheavioral Disorder Due to Brain Damage from a Human Herpes Virus-6 Encephalitis.ObjectivesTo describe a case of an Unspecified Organic Personality and Behavioral Disorder secondary to brain damage from Human Herpes Virus-6 (HHV-6) Encephalitis in an 11 year-old childand to review recent literature, in order to improve clinical practice.MethodsClinical case report and brief review of literature. A bibliographic research was made in the database PubMed, using the terms “Viral Encephalitis” AND “Neuropsychiatric symptoms”; “Viral Encephalitis” AND “Behavioral Disorder”; “Long-Term Neurological Morbidity” AND “Viral Encephalitis”.Results15 year-old boy diagnosed with Unspecified Personality and Beheavioral Disorder Due to Brain Damage from a Human Herpes Virus-6 Encephalitis, secondary to immunosupression in the context of haematopoietic progenitor transplantation (HPT) at 11 years old. MRI showed supratentorial ventriculomegaly, atrophic changes in encephalon and right hippocampus with subcortical retraction secondary to previous encephalitis. Clinically, main changes appeared in behavior, presenting a serious frontal syndrome with high disinhibition, what implied severe social and academic difficulties. During the outpatient follow-up, the behavioural disorder is being pharmacologically treated with Risperidone 1,5mg per day with a partially favorable evolution. The patient presented intolerance to olanzapine, with an episode of low level of conciuosness after taking it.Bibliographic research results indicate that the gold standard treatment for behavioral disturbances are antipsychotics. Risperdidone is proven save for treatment in children. Results point out also the importance of an early multidisciplinar intervention, involving family training, rehabilitation resources and curricular adaptations.Image:Image 2:ConclusionsViral encephalitis may have serious neuropsychiatric consequences, especially during childhood while the brain development is not finished. When the neurological damage affects the frontal lobes of the brain, behavioural and personality disturbances are expected and an early multidisciplinar intervention should be considered. Antypsichotics are the gold standard pharmacological treatment for behavioural disturbances. During the scholar period, special curricular adaptations should be done in order to reduce study-related stress.Disclosure of InterestNone Declared

Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis.

Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient’s cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient’s leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-022-01369-4.

Human herpes virus 6 encephalitis presenting as fatal refractory status epilepticus: A case report and systematic review

Encephalitis secondary to human herpesvirus 6 (HHV-6) infection is frequently detected in immunocompromised patients; in contrast, HHV-6 encephalitis in immunocompetent patients is rare. We report a case of a previously healthy 46-year-old female with HHV-6 encephalitis who presented with status epilepticus unresponsive to multiple antiepileptic medications.

Human herpesvirus 6 and central nervous system disease in oncology patients: A retrospective case series and literature review.

Human herpesvirus 6 (HHV-6) can reactivate with immunosuppression and cause central nervous system (CNS) dysfunction. Much of the literature describes cases after hematopoietic stem cell transplantation (HSCT), ranging from encephalitis to a post-transplant acute limbic encephalitis syndrome (PALE). Outside of HSCT, studies of HHV-6 encephalitis are limited to case reports. This study was designed to review HHV-6 CNS infection, and evaluate all patients admitted to MD Anderson Cancer Center between March 2016 and December 2018 with detectable HHV-6 DNA in the cerebrospinal fluid (CSF). Patients with HHV-6 DNA detected in the CSF using the Viracor or Biofire® Meningitis Encephalitis Panel platforms and no other identified etiology were identified and demographic features, known risk factors, imaging findings, CSF analysis, treatments and patient outcomes were extracted from medical records. 725 patients underwent HHV-6 testing during the study timeframe, with 19 cases (2.6 %) of HHV-6 mediated CNS disease identified. Most patients, 13/19 (68 %), had undergone HSCT with median time to presentation of 31 days after transplant. Survival at 240 days after transplant was 62 %. CSF had lymphocyte predominance and nearly all patients had peripheral lymphopenia. Other at risk populations identified included patients who received chimeric antigen receptor (CAR) T-cell therapy and biologic immunotherapy. Notable discordance among testing platforms was found in 5/9 (55 %) instances. In addition to HSCT patients, HHV-6 reactivation leading to CNS disease also occurs in settings such as following adoptive T cell therapy or biologic immunotherapy. Significant diagnostic discordance exists between testing platforms.

Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts.

ObjectiveThe aim of this study was to analyze the clinical, radiologic, and biological features associated with human herpesvirus 6 (HHV-6) encephalitis in immunocompetent and immunocompromised hosts to establish which clinical settings should prompt HHV-6 testing.MethodsWe performed a retrospective research in the virology database of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) for all patients who tested positive for HHV-6 DNA in the CSF and/or in blood from January 2008 to September 2018 and separately assessed the number of patients meeting the criteria for HHV-6 encephalitis in the group of immunocompetent and immunocompromised hosts.ResultsOf the 926 patients tested for HHV-6 during the period of interest, 45 met the study criteria. Among immunocompetent hosts (n = 17), HHV-6 encephalitis was diagnosed to 4 infants or children presenting with seizures or mild encephalopathy during primary HHV-6 infection (CSF/blood replication ratio <<1 in all cases). Among immunocompromised hosts (n = 28), HHV-6 encephalitis was diagnosed to 7 adolescents/adults with hematologic conditions presenting with altered mental status (7/7), seizures (3/7), vigilance impairment (3/7), behavioral changes (2/7), hyponatremia (2/7), and anterograde amnesia (1/7). Initial brain MRI was altered only in 2 patients, but 6 of the 7 had a CSF/blood replication ratio >1.ConclusionsThe detection of a CSF/blood replication ratio >1 represented a specific feature of immunocompromised patients with HHV-6 encephalitis and could be of special help to establish a diagnosis of HHV-6 encephalitis in hematopoietic stem cell transplant recipients lacking radiologic evidence of limbic involvement.

臍帯血移植後HHV-6 脳炎に罹患し多彩な精神症状を呈した白血病の一例

臍帯血移植後HHV-6 脳炎に罹患し多彩な精神症状を呈した白血病の一例

Kinetics and clinical significance of human herpesvirus 6 DNA shedding in saliva after allogeneic hematopoietic stem cell transplantation.

Little is known about the kinetics and clinical significance of saliva human herpesvirus-6 (HHV-6) DNA after hematopoietic stem cell transplantation (HSCT). In this observational study, we quantified HHV-6 DNA in serially collected plasma and saliva from allogeneic HSCT recipients. Associations between the status of salivary HHV-6 DNA and the development of HHV-6 encephalitis, depression, and oral mucosal graft-versus-host disease (GVHD) were retrospectively analyzed. A total of 787 plasma and 434 saliva samples were collected from 56 patients. The cumulative incidence of HHV-6 DNA in plasma and saliva at 60days after transplantation was 51.8% and 83.9%, respectively. The peak level of salivary HHV-6 DNA was significantly higher in patients who displayed plasma HHV-6 DNA than in those who did not (median, 51,584copies/mL vs 587copies/mL; P<.0001). Salivary HHV-6 DNA levels increased after positive plasma HHV-6 DNA was detected and remained high during observation period. Despite the frequent occurrence of positive salivary HHV-6 DNA, no patient developed depression. Positivity of salivary HHV-6 DNA was not significantly associated with the development of HHV-6 encephalitis (P=1.00, Fisher's exact test) or oral mucosal GVHD (P=.71, Grey's test). No significant relationship between salivary HHV-6 DNA and these diseases was found even when comparing higher HHV-6 DNA loads in saliva. Salivary HHV-6 DNA levels increased after HHV-6 DNA was detected in the blood. However, no epidemiological evidence was shown to support a role of salivary HHV-6 in the development of HHV-6 encephalitis, depression, and oral mucosal GVHD.

Clinical, radiological, and electroencephalographic features of HHV-6 encephalitis following hematopoietic stem cell transplantation

BackgroundTo study the clinical, radiological, electroencephalographic, and cerebrospinal fluid (CSF) features of Human Herpes Virus 6 (HHV-6) encephalitis in leukemia patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). MethodsWe retrospectively reviewed all leukemia patients who underwent allogeneic HSCT between January 2010 and December 2018. The clinical, radiological, electroencephalographic, and CSF features of those with HHV6 encephalitis were recorded. ResultsA total of five cases of HHV6 encephalitis were identified. Three patients had Chronic Myelogenous Leukemia, one had Chronic Lymphocytic Leukemia and one had Acute Lymphoblastic Leukemia. All of them presented a few months after transplantation with altered mental status. Comorbidities included pancytopenia, sepsis, graft versus host disease, and multi-organ failure. EEG showed focal seizures originating from temporal lobes in two patients, generalized or focal periodic discharges in three patients, focal slowing in two patients, and diffuse slowing in three patients. MRI brain showed T2/FLAIR hyper-intensities in four patients; two of them in bilateral temporal lobes, one in the thalamus/hypothalamus/brainstem/cerebellum/basal ganglia, and one in the periventricular areas. CSF showed pleocytosis, high protein, and positive HHV-6 PCR. Foscarnet was used as an anti-viral agent. Anti-epileptics used were phenytoin, levetiracetam, and valproic acid. Four patients died in a few months, whereas one recovered completely. ConclusionsHHV-6 encephalitis can add significant morbidity and mortality to leukemic patients following allogeneic HSCT. Patients present with typical clinical features of encephalitis. Salient EEG characteristics include periodic discharges or overt temporal lobe seizures. MRI findings are T2/FLAIR signal hyperintensities, mainly in the temporal lobes.

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.

A Systematic Review of Sodium Disorders in HHV-6 Encephalitis.

Human herpesvirus 6 (HHV-6) encephalitis has a high mortality rate. Among those who survive, ~80% develop some type of permanent neurologic disorder. Early diagnosis and treatment may help prevent long-term sequelae. There have been several case reports as well as retrospective and prospective studies associating HHV-6 encephalitis with some form of sodium imbalance, either hyponatremia or hypernatremia; however, the exact frequency post-HCT is unknown, with reports ranging from 30% to 100%. We performed a systematic review of the literature and found 34 cases of HHV-6 encephalitis reported in conjunction with sodium imbalance that documented the timing of that imbalance relative to the onset of encephalitis. Sodium imbalance occurred before or at the onset of HHV-6 encephalitis in all but 2 cases (94%). This finding supports previous suggestions that sodium imbalance can be considered an early indicator of the potential development or presence of HHV-6 encephalitis in at-risk patient populations.

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.

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

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. We retrospectively analyzed 73 patients who underwent allo-HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2-3g/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 23days (range, 17-98days). 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. 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.

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell–Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients

The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.

Clinical Significance of Human Herpesvirus 6 Positivity on the FilmArray Meningitis/Encephalitis Panel.

A review of 15 patients who tested positive for human herpesvirus 6 (HHV-6) on the FilmArray Meningitis/Encephalitis panel revealed that the majority were unlikely to have HHV-6 encephalitis. Criteria to assist interpretation of HHV-6 positive results are presented.