Human herpesvirus 6

HHV-6 is a member of the Betaherpesvirinae group of the genus Roseolovirus, of which cytomegalovirus (CMV) was the only previously recognized human pathogen. HHV-6 consists of two related variants, HHV-6A and HHV-6B, that have 90% DNA homology and cannot be distinguished by serologic tests, but have distinctive molecular, cell culture, and clinical features. Infection is ubiquitous; 70% to 100% of adults worldwide have serologic evidence of HHV-6 infection. Infection follows a 2-week incubation period and most often occurs between the ages of 6 and 15 months.

Shedding and tissue tropism

HHV-6B is shed in saliva, which is an important vehicle of transmission (perhaps most often from mother to child). The virus is not found in breast milk. After primary infection, viral replication occurs in salivary glands and recurs during periodic episodes of reactivation and shedding, which decrease in frequency over time. Both variants are lymphotropic; primarily infect CD4-positive T cells; the A variant also infects CD8 cells. HHV-6 infects other lymphocytes, monocytes, macrophages, and epithelial and endothelial cells utilizing the CD46 molecule as its receptor. The virus is highly neurotropic with a central nervous system (CNS) site of latency. HHV-6 is unique among human herpesviruses in that its DNA can integrate into specific locations on chromosomes 1, 17, and 22. HHV-6 DNA integration into germ cells can result in inheritance of HHV-6 genetic elements and when it occurs, is associated with persistent high-level viremia. High-level viremia suggestive of chromosomal integration is uncommon but not rare; it was reported in 3% of blood donors in a recent British study but the prevalence may vary significantly by population group. One percent of newborns have congenital HHV-6 infection, the majority of instances of which occur in the setting of maternal chromosomal integration. Unlike CMV, transplacental transmission of HHV-6 only rarely results in clinical sequelae.

Infection in immunocompetent hosts

When detected, primary infection with HHV-6 is associated with fever ≥40°C, lasts 3 to 7 days, and then suddenly resolves. Infection with HHV-6B is characterized by fever followed by a maculopapular rash (exanthema subitum [ES] or roseola infantum or sixth disease) on the trunk, face, and neck; HHV-6 is a leading cause of skin rash and fever in children under 2 years of age. Malaise, otitis media, and gastrointestinal and respiratory symptoms are also common. It is estimated that HHV-6 may account for 20% to 25% of all emergency room visits for children 6 to 12 months of age and one-third of all febrile seizures in children <2 years of age in the United States. Encephalomeningitis is a rare complication; both HHV-6 variants can be recovered from cerebrospinal fluid (CSF), though the “A” variant is thought to be more neurotropic.

As in many other viral illnesses, the severe complications are more common in adults with primary infection; these include a mononucleosis-like syndrome, hepatitis, hemophagocytosis, thrombocytopenia, encephalitis, and/or fatal dissemination. HHV-6 may influence the occurrence of demyelinating diseases such as multiple sclerosis and Guillain–Barré syndrome, but a causal role has not been proven and research findings are often contradictory.

Infection in immunocompromised hosts

Active HHV-6B replication is frequently detected in immunocompromised hosts, such as bone marrow and solid organ transplant recipients. Most infections are identified 2 to 4 weeks post-transplantation. Serious infections can occur with a pattern that mimics CMV, including pneumonitis, colitis, hemorrhagic cystitis, encephalitis (most often involving the temporal lobe), hepatitis, bone marrow suppression, and graft-versus-host disease. HHV-6 contributes to the frequent occurrence of skin rash after bone marrow grafting and lesion histology can demonstrate lymphocytic basophilic inclusions and viral DNA. HHV-6 is associated with bronchiolitis obliterans among lung transplant recipients, and linked with eventual graft failure. HHV-6 activity may occur concurrently with CMV or HHV-7, making distinction of the clinical manifestations due to each virus difficult. Viremia may be particularly common after cord blood grafts. The intensity of HHV-6 viremia is related to the occurrence of clinical manifestations and graft-versus-host disease in allogeneic bone marrow transplant recipients. Similarly, extent of viremia is linked to graft failure after solid organ transplantation.

HHV-6 can function as an opportunistic pathogen in acquired immunodeficiency syndrome (AIDS) patients with reported cases of encephalitis, pneumonitis, and retinitis. HHV-6 or-7 reactivation has been associated with DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) which may respond to antiherpes treatment, though definitive studies have not been performed. As is the case for CMV, combination antiretroviral therapy (cART) appears to have reduced the incidence of serious HHV-6 infections in AIDS.

Detection of infection

The very high prevalence of infection, intermittent reactivation, and the occurrence of chromosomal integration must be considered in the interpretation of diagnostic tests for HHV-6; detection of virus does not necessarily indicate disease. Viral culture from peripheral blood mononuclear cells may be the gold standard for viral detection but it is not routinely available. Detection of HHV-6 DNA in either cellular or acellular specimens using polymerase chain reaction (PCR) is suggestive of active HHV-6 replication and occurs in

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