Detection of Active Human Herpesvirus–6 Infection in the Brain: Correlation with Polymerase Chain Reaction Detection in Cerebrospinal Fluid

Fotheringham, Julie; Akhyani, Nahid; Vortmeyer, Alexander O.; Donati, D.; Williams, Elizabeth L.; Oh, Unsong; Bishop, Michael; Barrett, John; Gea-Banacloche, Juan; Jacobson, Steven

doi:10.1086/510757

Cited by 103 publications

(88 citation statements)

References 16 publications

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“…Although HHV-6 DNA has been shown to persist longer in CSF compared with plasma or serum, 35 it has also been shown that, when both CSF and plasma have reverted to undetectable levels of HHV-6, active infection may still be ongoing in brain tissue. 43 More complete virologic assessment of patients with HHV-6 and delirium would improve understanding of the viral dynamics of HHV-6-related CNS disease.…”

Section: Discussionmentioning

confidence: 99%

HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients

Zerr

Fann

Breiger

et al. 2011

Blood

125

101

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Human herpesvirus 6 (HHV-6) is detected in the plasma of approximately 40% of patients undergoing hematopoietic cell transplantation (HCT) and sporadically causes encephalitis in this population. The effect of HHV-6 reactivation on central nervous system function has not been fully characterized. This prospective study aimed to evaluate associations between HHV-6 reactivation and central nervous system dysfunction after allogeneic HCT. Patients were enrolled before HCT. Plasma samples were tested for HHV-6 at baseline and twice weekly after transplantation until day 84. Delirium was assessed at baseline, 3 times weekly until day 56, and weekly on days 56 to 84 using a validated instrument. Neurocognitive testing was performed at baseline and at approximately day 84. HHV-6 was detected in 111 (35%) of the 315 included patients. Patients with HHV-6 were more likely to develop delirium (adjusted odds ratio ‫؍‬ 2.5; 95% confidence interval, 1.2-5.3) and demonstrate neurocognitive decline (adjusted odds ratio ‫؍‬ 2.6; 95% confidence interval, 1.1-6.2) in the first 84 days after HCT. Cord blood and unrelated transplantation increased risk of HHV-6 reactivation. These data provide the basis to conduct a randomized clinical trial to determine whether prevention of HHV-6 reactivation will reduce neurocognitive morbidity in HCT recipients. (Blood. 2011;117(19):5243-5249)

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Section: Discussionmentioning

confidence: 99%

HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients

Zerr

Fann

Breiger

et al. 2011

Blood

125

101

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“…To avoid PCR contamination, sample extraction, PCR mastermix preparation, and sample loading were performed at three separate locations in the laboratory. HHV-6 viral load was measured using HHV-6A or 6B-specific U90 primers in TaqMan quantitative PCR with 9700HT Fast Real Time PCR System (Applied Biosystems), as previously described (25,33,34). Briefly, for cell-free specimens, 5 μL of extracted DNA was amplified with a final concentration of 0.5 μM HHV-6A or 6B-specific primers and probes in a 20-μL reaction using TaqMan Universal Mastermix (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Human herpesvirus-6 entry into the central nervous system through the olfactory pathway

Harberts

Yao

Wohler

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

142

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Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson’s, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been associated with a wide variety of neurologic disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examined. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS.

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“…Autopsy studies of patients who died with HHV-6 encephalitis have shown the hippocampus has strong reactivity against HHV-6, 9,70 and HHV-6 has displayed tropism for astrocytes in the hippocampus. 70 HHV-6B will directly cause neuronal damage based on the finding that HHV-6B localizes to pathologically damaged regions.…”

Section: Pathogenesis: We Do Not Know How Hhv-6 Contributes To Cns DImentioning

confidence: 99%

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

Ogata

Fukuda²,

Teshima

2015

Bone Marrow Transplant

107

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Human herpesvirus-6 (HHV-6) encephalitis following allogeneic hematopoietic cell transplantation is a serious and often fatal complication accompanying reactivation of HHV-6B. Incidence varies among studies, but is reportedly 0-11.6% after bone marrow or PBSC transplantation and 4.9-21.4% after umbilical cord blood transplantation, typically around 2-6 weeks post transplant. Symptoms are characterized by memory loss, loss of consciousness and seizures. Magnetic resonance imaging (MRI) typically shows bilateral signal abnormalities in the limbic system. This complication is considered to represent acute encephalitis caused by direct virally induced damage to the central nervous system, but our understanding of the etiologies and pathogenesis is still limited. The mortality rate attributable to this pathology remains high, and survivors are often left with serious sequelae such as impaired memory and epilepsy. Despite the poor prognosis, no validated treatments or preventative measures have been established. Establishment of preventative strategies represents an important challenge. This article reviews the current knowledge of the clinical features, incidence, pathogenesis and treatment of HHV-6 encephalitis, and discusses issues needing clarification in the future to overcome this serious complication.

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Detection of Active Human Herpesvirus–6 Infection in the Brain: Correlation with Polymerase Chain Reaction Detection in Cerebrospinal Fluid

Cited by 103 publications

References 16 publications

HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients

HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients

Human herpesvirus-6 entry into the central nervous system through the olfactory pathway

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

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