Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals

Abstract

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.

Prevalence of human herpesviruses infections in nonmalignant tonsils: The SPLIT study

“…CMV has been linked to several diseases in immunosuppressed patients such as retinitis, hepatitis, or pneumonia . HHV6B has been associated with several diseases such as roseola infantum in infants (as for HHV7), and also to encephalitis in transplant recipients . Finally, KSHV has also been classified as carcinogenic to humans (Group 1) due to the role it plays in Kaposi's sarcoma and primary effusion lymphoma…”

“…4 HHV6B has been associated with several diseases such as roseola infantum in infants 5,6 (as for HHV7 7 ), and also to encephalitis in transplant recipients. 8,9 Finally, KSHV has also been classified as carcinogenic to humans (Group 1) due to the role it plays in Kaposi's sarcoma and primary effusion lymphoma. 3 HHVs are generally acquired in the childhood or in adolescence, 2,10-15 and most primary infections remain asymptomatic or induce mild and unspecific symptoms.…”

Humanization of Murine Neutralizing Antibodies against Human Herpesvirus 6B

“…Approximately 21% of febrile seizure cases in children under the age of 2 years may be related to HHV-6B infection, and children with more-severe forms of seizure, such as status epilepticus, have been reported as HHV-6B positive (5). Meningitis and acute encephalitis can develop in some cases, and half of these patients experience severe neurological sequelae (6). Like other members of the herpesvirus family, HHV-6B establishes a lifelong latent infection (1).…”

“…Reactivation of HHV-6B is associated with drug-induced hypersensitivity syndrome (DIHS) or drug rash with eosinophilia and systemic symptoms (DRESS), which is a life-threatening syndrome (7,8). Reactivation also occurs in patients with immunocompromised status and has been reported in 40% to 70% of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (6,9). Severe complications, such as delayed engraftment, graft-versus-host disease, and encephalitis, occasionally develop after reactivation, with a poor prognosis (9)(10)(11)(12).…”

Endogenization and excision of human herpesvirus 6 in human genomes

“…In contrast to other herpesviruses, this may require integration of the viral genome into the host chromosome {Arbuckle, 2010}. HHV-6 viremia occurs in about 40% of immunosuppressed transplant recipients, in whom it can cause severe complications, including limbic encephalitis {Ongradi, 2017}. HHV-6 have also been associated with other neurological diseases including multiple sclerosis (reviewed in {Leibovitch, 2014}) and Alzheimer’s disease {Readhead, 2018}.…”