Antiviral therapy of two patients with chromosomally-integrated human herpesvirus-6A presenting with cognitive dysfunction
Section snippets
Background
Human herpesvirus 6 (HHV-6) is a neurotropic, lymphotropic, DNA virus with two variants – A and B.1 Like other herpesviruses, HHV-6 persists in latent reservoirs after primary infection. Primary HHV-6 infection is typically mild or asymptomatic in immunocompetent persons, but reactivated HHV-6 has been linked to a wide-range of conditions, including encephalitis,2 seizures,3 myocarditis,4, 5, 6 chronic fatigue syndrome (CFS)7, 8, 9 and multiple sclerosis.10, 11, 12, 13 Unique among
Objectives
In a previous study, we discovered CIHHV-6 in two patients of the current study, one of their parents, and a third sibling, the latter two of whom were asymptomatic.18 We now evaluated two siblings for possible infectious etiologies of their chronic neurological abnormalities.
Study design
Two patients with neurological abnormalities have been evaluated for HHV-6 viral load, late mRNA expression, and clinical symptoms before, during and after antiviral drug treatment.
Clinical symptoms and antiviral drug treatment of Patient A
Patient A had a history of asthma, atopic dermatitis, and persistent sinopulmonary and tonsil infections from age 5. At 12 years of age, she experienced three weeks of emotional lability and a sudden onset of severe stuttering which resolved after one week with minor residual speech difficulties. This episode was diagnosed as a seizure. Her EEG during the acute phase was abnormal with diffuse slowing and focal spikes, but an MRI was normal. At age 14, she had an evaluation by an immunologist
Discussion
In this report, we described two CIHHV-6 patients with debilitating CNS dysfunction that responded to therapy against replicating HHV-6A. In both patients, during symptomatic periods, whole blood analyses yielded high levels of HHV-6A DNA persistently greater than 5.5 log10 copies/mL. CSF analysis revealed low copy number (200–600 copies/mL) with no pleocytosis. HHV-6 late mRNA was detected in the serum at approximately 1000 copies/mL (Viracor), suggesting reactivation of the virus. Simultaneous
Funding
This study was supported by a grant from the HHV-6 Foundation.
Competing interests
All authors have no competing interest.
Ethical approval
The study was approved by the Institutional Review Board.
Acknowledgements
We would like to thank Nathan Zemke and Dharam Ablashi (HHV-6 Foundation) for their assistance with the preparation of the manuscript.
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Cited by (27)
Inherited chromosomally integrated HHV6 in an adult who presented with a generalized tonic clonic seizure
2023, Journal of the Neurological SciencesCurrent understanding of human herpesvirus 6 (HHV-6) chromosomal integration
2020, Antiviral ResearchCitation Excerpt :HHV-6A is less prevalent than HHV-6B, and its causal role in disease and route of transmission remains poorly understood. HHV-6A/B have been associated with a number serious diseases in immunocompromised individuals (Agut et al., 2015; Pantry and Medveczky, 2017) including ataxia, hypersomnia, mild dementia, encephalitis and seizures (Cameron et al., 2010; DE Bolle et al., 2005; Yao et al., 2010; Strenger et al., 2014; Ablashi et al., 1998, 2000; Ben-Fredj et al., 2013; Komaroff, 2006; Montoya et al., 2012). In addition, they have been linked to acute graft-versus-host disease (Phan et al., 2018a), drug induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (Miyagawa et al., 2016; Suzuki et al., 1998), Hashimoto's thyroiditis (Caselli et al., 2012), gastrointestinal diseases (Phan et al., 2018b), female infertility (Caselli et al., 2017; Marci et al., 2016), myocarditis (Stefanski et al., 2016; Leveque et al., 2011), and multiple sclerosis (Leibovitch and Jacobson, 2014; Soldan et al., 1997).
HHV-6-Associated Neurological Disease in Children: Epidemiologic, Clinical, Diagnostic, and Treatment Considerations
2020, Pediatric NeurologyCitation Excerpt :In centers where ciHHV-6 testing is not performed routinely, patients can be identified by the persistence of HHV-6 DNA in CSF or plasma over long periods of time.9,144 ciHHV-6 is able to reactivate from its integrated state in response to certain drugs (e.g., histone deacetylase inhibitors or steroids),145 immunosuppression,146 and even during the immunosuppression associated with pregnancy,147 leading to infectious virus and clinical manifestations that can include neurological symptoms.148 Like community strains of HHV-6, active ciHHV-6 has the potential to be a contributing factor in encephalitis.134
Clinical and laboratory features of human herpesvirus 6 chromosomal integration
2016, Clinical Microbiology and InfectionCitation Excerpt :There are examples where HHV-6 DNA loads were presumed to represent high levels of active infection although prolonged antiviral therapy did not reduce the viral DNA burden [41] and subsequent investigations identified iciHHV-6 as the source of the high HHV-6 loads. However, there are other cases where antiviral therapy has resulted in clinical resolution of neurological disease in patients with iciHHV-6 where not only were HHV-6 DNA loads used to monitor patients, but also the detection of HHV-6 transcripts, which were taken as a direct marker for viral replication [42,43]. More recently, antiviral therapy was reported to reduce HHV-6 viral RNA transcripts and decrease cardiac symptoms in patients with iciHHV-6 and unexplained symptoms of heart failure [40].
HHV-6A and HHV-6B in Recipients of Hematopoietic Cell Transplantation
2014, Human Herpesviruses HHV-6A, HHV-6B, and HHV-7, Third EditionCognitive Dysfunction from HHV-6A and HHV-B
2014, Human Herpesviruses HHV-6A, HHV-6B, and HHV-7, Third Edition
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These authors contributed equally to the work.