human herpesvirus 6

**Virology** - Family Herpesviridae, subfamily Betaherpesvirinae, genus Roseolovirus (HHV-6 and HHV-7). Enveloped, linear dsDNA, icosahedral capsid; replicates in the nucleus. - Two species: HHV-6A (less well understood; neurotropic, linked to some adult/immunocompromised disease) and HHV-6B (the cause of nearly all pediatric roseola). - Infects CD4+ T cells (primary target); receptor for HHV-6A is CD46, and for HHV-6B is CD134 (OX40). It also infects monocytes/macrophages and glial cells, and it establishes latency in monocytes/macrophages and bone marrow progenitors. - Transmission is via saliva (respiratory secretions), often from asymptomatic parents or caregivers. Nearly all children are seropositive by age 2-3. Maternal antibody wanes at about 6 months, so peak infection is at 6-24 months. - Chromosomally integrated HHV-6 (ciHHV-6) occurs in about 1% of people. The virus is inherited in the germline and integrated at telomeres, which gives persistently very high viral loads on PCR. Do not mistake it for active infection.

**Clinical: Roseola infantum (exanthem subitum, "sixth disease")** - Abrupt high fever (often greater than 39-40°C) for 3-5 days in a child who looks relatively well. - The fever breaks, and then a diffuse, blanching, pink maculopapular rash appears. It starts on the trunk and spreads to the neck and extremities, sparing the face. It is nonpruritic and lasts hours to 2 days. - Classic mnemonic: "rash appears as the fever disappears." - Other findings: Nagayama spots (erythematous papules on the soft palate and uvula), cervical or postauricular lymphadenopathy, and mild diarrhea or irritability. - **Febrile seizures** are the most common complication. HHV-6 is a leading cause of first febrile seizure. - Management is supportive (antipyretics). The disease is self-limited.

**Other associations** - **Immunocompromised hosts, especially HSCT and solid-organ recipients:** reactivation, typically 2-4 weeks after transplant. It causes encephalitis (**posterior limbic encephalitis**, with temporal lobe involvement and SIADH-related hyponatremia), delayed engraftment, bone marrow suppression, pneumonitis, and hepatitis. Treat with foscarnet or ganciclovir (cidofovir is an alternative). - Mononucleosis-like illness or hepatitis in adults with primary infection. - **DRESS syndrome:** HHV-6 reactivation is commonly seen with drug reaction with eosinophilia and systemic symptoms. - Possible associations (not definitive): multiple sclerosis, mesial temporal lobe epilepsy, and Alzheimer disease. - Tied to AIDS progression as a cofactor, since the virus infects CD4+ cells.

**Diagnosis** - Clinical in typical roseola. - PCR for viral DNA in blood or CSF. In immunocompromised patients, a quantitative PCR is preferred. Serology is less useful because most of the population is seropositive.

**Board pearls** - Sixth disease = roseola = HHV-6 (HHV-7 causes a similar milder, often later, "second" roseola). - High fever, then rash as the fever resolves, in a 1-2-year-old, with or without a febrile seizure. - Contrast with other childhood exanthems: - Measles: cough, coryza, and conjunctivitis, Koplik spots, and a rash that spreads cephalocaudally. - Rubella: postauricular lymphadenopathy and a mild rash. - Erythema infectiosum (parvovirus B19, fifth disease): "slapped cheek" rash. - Scarlet fever: sandpaper rash and strawberry tongue. - Other herpesviruses: - HHV-4 (EBV): mono, Burkitt lymphoma, and nasopharyngeal carcinoma. - HHV-5 (CMV): the other betaherpesvirus. It causes congenital infection and retinitis in AIDS. - HHV-8 (KSHV): Kaposi sarcoma.