Human Herpesvirus Type 6

Julia A. McMillan

Charles F. Grose

Human herpesvirus type 6 (HHV-6) was first isolated in 1986 from the white blood cells of adult patients with lymphoproliferative disorders and human immunodeficiency virus (HIV) infection. Its morphologic similarity to other known members of the family of human herpesviruses (herpes simplex viruses types 1 and 2, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus), include its lipid envelope, icosahedral symmetry, and large nucleocapsid (162 capsomeres). The double-stranded DNA of HHV-6 is most similar to that of human herpesvirus-7 but it shares significant homology and genome organization with cytomegalovirus (CMV) as well. Two variants of HHV-6 have been designated (variant A and variant B). HHV-6 primarily infects T lymphocytes (CD4⁺/CD8^–). The A and B variants of HHV-6 can be distinguished by monoclonal antibody and by growth characteristics in vitro.

EPIDEMIOLOGY

HHV-6 is transmitted through saliva and is acquired early in life, most frequently from close household contacts. Maternal antibody protects most infants from infection during their first few months of life, but 95% of children throughout the world become infected by 18 months. Virtually all infection in infants is due to the B variant. Latent virus persists throughout life in lymphocytes and monocytes and at low levels in various tissues. The virus is reactivated and intermittently shed in saliva, unaccompanied by symptoms, in healthy children and adults.

The A variant has been identified during reactivation in older individuals (including children) whose cellular immunity is compromised following bone marrow and organ transplantation.

PATHOGENESIS

Primary infection with HHV-6 is associated with antibody production and the presence of virus in peripheral blood mononuclear cells. The virus primarily infects CD4⁺ T lymphocytes, resulting in apoptosis and cytokine release. Protection from infection during the first few months of life is presumably due to passively transmitted maternal antibody. Susceptibility to dissemination during suppression of cellular immunity (as occurs following bone marrow and organ transplantation) suggests that control of reactivation is largely a function of cell-mediated immune function.

In vitro studies of HHV-6 infection of T-lymphocytes indicate that the virus has an immunosuppressive effect, reducing cytokine production and lymphoproliferation.

CLINICAL MANIFESTATIONS AND COMPLICATIONS

Primary HHV-6 infection usually is unrecognized or results in mild symptoms. Isolation of HHV-6 from peripheral blood mononuclear cells concomitant with a rise in antibody against HHV-6 was reported in 10% to 15% of children younger than 2 years presenting with fever to a pediatric emergency center. Rash was observed in only a minority of these children, but many of them had otitis media. HHV-6 infection has been documented also during illness associated with rash but no fever. Other findings described in infants with primary HHV-6 infection include pharyngitis, otitis media, diarrhea, pneumonia, hepatomegaly, hepatocellular dysfunction, intussusception, and febrile seizures. Complete recovery from infection in these patients has been the rule.

Roseola

Japanese investigators discovered the link between HHV-6 and roseola in 1988. The percentage of children whose primary HHV-6 infection manifests as roseola is not known, but studies in the United States and elsewhere indicate that the clinical syndrome recognized as roseola affects only a minority. It is now recognized that both HHV-6 and HHV-7 can cause the clinical constellation that results in a clinical diagnosis of roseola.

As early as 1870, the mild illness now called roseola infantum or exanthema subitum was recognized and described as being distinct from other exanthematous diseases of childhood. Typically, roseola affects infants and young children between the ages of 6 months and 3 years, with 80% of the cases occurring before age 18 months. Initial fever may reach 40.0°C to 40.5°C (104°F to 105°F), has an abrupt onset, and typically persists, either continuously or intermittently, for 3 to 4 days. During this febrile period, affected infants or children usually maintain near-normal appetite and behavior, although they may exhibit periods of irritability during times of increased fever.

Physical examination during this preeruptive phase yields few findings to distinguish roseola from other, more worrisome illnesses. Sometimes, palpebral edema is described, and careful examination usually reveals suboccipital lymphadenopathy. Mild erythema of the pharynx may be seen in approximately one-third of affected patients. Sometimes, a bulging or tense fontanelle is noted in young infants with roseola. The beginning of febrile illness may trigger a brief, slight elevation in the white blood cell count, with a predominance of neutrophils. During the bulk of the febrile period, however, the white blood cell count typically falls to 3,000 to 5,000 cells per millimeter, with a relative lymphocytosis.

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