Human Herpesvirus 6

Etiology

HHV-6A, HHV-6B, and HHV-7 share partial homology with human cytomegalovirus, the only other human β-herpesvirus. Both HHV-6A and HHV-6B replicate in T cells but differ in their mechanisms of cellular entry. HHV-6A uses CD46, whereas HHV-6B primarily binds to CD134, a receptor expressed only on activated T cells.[2] Like Epstein–Barr virus and HHV-8, also known as Kaposi sarcoma-associated herpesvirus, HHV-6 exhibits oncogenic potential and causes damage to immune cells. Once bound to its receptor, HHV-6 establishes latency in lymphocytes and exerts strong immunomodulatory effects that may lead to immunosuppression or chronic inflammation.[3]

By adulthood, more than 95% of individuals test seropositive for HHV-6A, HHV-6B, or both. Current serologic techniques do not reliably differentiate between the 2 organisms.[4] HHV-6 is now recognized as the primary cause of roseola infantum in children, with HHV-6B predominantly infecting infants and accounting for most cases of viral reactivation in both immunocompetent and immunocompromised hosts.

Most adults with chronic HHV-6 infection remain asymptomatic. Ongoing research continues to explore the role of HHV-6 in the central nervous system (CNS). In one study, over 70% of children with primary HHV-6 infection had detectable viral DNA in the cerebrospinal fluid (CSF) and presented with neurologic manifestations, such as frequent febrile seizures. In contrast, other studies report a 0% to 4% detection rate of HHV-6 DNA in the CSF of children with febrile seizures and adults with AIDS-related neurologic symptoms.[5] HHV-6 has been implicated in several illnesses among immunocompromised patients and may contribute to the development of Hodgkin lymphoma and other malignancies. Documented cases of opportunistic HHV-6A and HHV-6B infections include encephalitis, hepatitis, colitis, and pneumonitis.[6]

Epidemiology

Researchers have identified HHV-6B as the primary pathogen responsible for most symptomatic HHV infections. Although most individuals acquire HHV during early childhood, primary infection typically occurs within the first 2 years of life. During this period, the virus often presents as an undifferentiated febrile illness, though some children exhibit the characteristic features of roseola infantum. Seropositivity appears to decline with age, indicating a gradual decline in antibody levels over time. Although primary HHV infection is rare in adults, viral reactivation can occur throughout life. HHV affects individuals regardless of sex or race and is distributed globally.

In a large prospective study of North American children, HHV acquisition peaked between 6 and 9 months of age. Similar trends have been observed in the United Kingdom and Japan, where 97% to 100% of primary infections are attributed to HHV-6B. Although less is known about HHV-6A, studies suggest it is acquired later in life and often remains asymptomatic. However, symptomatic HHV-6A infections have been reported in children from Africa and the United States. In an endemic region of sub-Saharan Africa, HHV-6A emerged as the predominant variant among HIV-positive infants.[7] Seroprevalence varies widely by population, with reports ranging from 20% in pregnant Moroccan women to 100% in asymptomatic Chinese adults. Among ethnically diverse adult populations in Tanzania, Malaysia, Thailand, and Brazil, reported seroprevalence ranged from 39% to 80%.

Pathophysiology

Primary HHV-6 infection ranks among the most common causes of acute febrile illness in young children and accounts for a significant number of emergency visits, hospitalizations, and febrile seizures. HHV-6 is a member of the Betaherpesvirinae subfamily and the Roseolovirus genus. The virion has the typical herpesvirus structure, consisting of a central DNA core, an icosahedral capsid, a protein-rich tegument, and an outer lipid envelope.

The virus primarily targets mature CD4+ T cells and demonstrates broad immunomodulatory effects, including interference with natural killer cell activity. In vivo, HHV-6 infects CD4+ lymphocytes through the CD46 receptor and enters cells through receptor-mediated endocytosis. After entry, the virus replicates within the host cell, and its DNA persists in peripheral blood mononuclear cells following primary infection.

Although the exact mechanisms of HHV-6 transmission remain under investigation, saliva has been identified as the predominant route, particularly in maternal-infant transmission. An infectious virus has been detected in the saliva of nearly all individuals tested. One study found HHV-6 DNA in 90% of salivary samples, whereas another reported a lower detection rate through polymerase chain reaction (PCR) despite 63% of salivary gland biopsies testing positive. HHV-6 DNA has also been found in the CSF of children during both primary and latent infections and in the brain tissue of healthy adults on autopsy, supporting the CNS and salivary glands as potential reservoirs for latency and persistent infection.

History and Physical

Although the full spectrum of clinical features and disease associations linked to HHV-6 is still under investigation, substantial evidence supports its role in CNS disorders and disease in immunocompromised individuals, including transplant recipients.[8] In most cases, HHV-6 infection is benign and self-limiting. Symptomatic disease typically occurs in infants or immunocompromised adults experiencing viral reactivation.

HHV-6B is the established cause of exanthema subitum (roseola infantum), a common childhood illness marked by high fever and a transient rash. This variant accounts for 10% to 17% of acute febrile visits to the emergency department in children younger than 36 months.[9] Among children aged 12 to 15 months, primary HHV-6 infection causes over 36% of acute febrile episodes, with nearly all cases attributed to HHV-6B rather than HHV-6A.[10]

The diagnosis of roseola infantum is clinical. The condition typically begins with the abrupt onset of high fever, often reaching 40 °C (104 °F), lasting for 3 to 5 days. During this febrile phase, some children may exhibit periorbital edema, conjunctivitis, or tympanic membrane inflammation, although many remain active and appear well. Other pediatric findings can include lymphadenopathy, gastrointestinal symptoms, liver dysfunction, hepatitis, and bulging fontanelles.[11] Hepatitis and encephalitis-like symptoms are more common in adults. In transplant recipients, clinical manifestations may include fever, graft-versus-host disease, signs of graft rejection, interstitial pneumonitis, myelitis, and rash.[12]

Physical examination generally mirrors the clinical symptoms. In children, resolution of fever is often followed by a blanching, rose-pink maculopapular rash, measuring approximately 2 to 5 mm, typically surrounded by a pale halo. The rash spreads centrifugally and resolves within 1 to 2 days. However, some cases present with fever without rash.[13] Additional findings in children may include inflamed tympanic membranes and upper or lower respiratory tract signs, whereas adults may present with fever, hepatosplenomegaly, and lymphadenopathy.

Evaluation

HHV-6 can be diagnosed through PCR, serologic testing, or viral culture, with PCR being the most commonly used diagnostic method. However, in immunocompetent individuals, laboratory testing is rarely pursued due to the disease's typically self-limiting course. Saliva serves as the primary reservoir for viral transmission, with HHV-6 frequently isolated from salivary glands. No reports confirm transmission through blood transfusion or breastfeeding, but HHV-6 has been documented following organ transplantation. Most evidence indicates that HHV-6B is typically acquired in early childhood, while HHV-6A is more often acquired later in life. Both variants of the virus have been detected simultaneously in adults, suggesting that chronic infection affects a large portion of the population.

Laboratory findings in HHV-6 may include leukocytosis, leukopenia, or anemia. In patients with renal transplants or liver dysfunction, renal and hepatic function tests are recommended to assess for electrolyte abnormalities or hepatitis.

Radiologic imaging is guided by clinical presentation and is more often warranted in immunocompromised individuals. Chest radiographs may help evaluate for pneumonia or pneumonitis in adults, whereas imaging is less commonly necessary in children. Computed tomography of the head, with or without contrast, can help exclude other treatable conditions when CNS involvement is suspected. Lumbar puncture is appropriate in cases of suspected neurologic involvement. CSF typically reveals mild pleocytosis and elevated protein in HHV-6 infection. HHV-6 PCR testing of CSF may confirm the diagnosis (see Image. Human Herpesvirus 6 Cellular Infection).[14]

Treatment / Management

Currently, no approved compound exists exclusively for the treatment of HHV-6, and no vaccine is available. Antiviral prophylaxis for HHV-6 infection is generally not recommended. Early antiviral treatment is advised, particularly in cases of HHV-6 encephalitis. First-line therapy with intravenous ganciclovir and foscarnet is recommended for 3 to 4 weeks. In stem-cell transplant recipients, ganciclovir has demonstrated benefits and is the antiviral of choice.[15](B3)

HHV-6 infections in immunocompetent children are self-limiting and do not require treatment. Treatment for infants with roseola infantum is generally supportive, with antipyretics such as acetaminophen or ibuprofen recommended for high-grade fever and febrile seizure risk. Antiepileptics are unnecessary if a febrile seizure occurs. Patients with CNS involvement, including febrile seizures, should be admitted to the hospital.

Differential Diagnosis

The differential diagnosis of HHV-6 infection includes the following conditions:

• Infectious mononucleosis
• Cytomegalovirus infection
• Viral hepatitis
• Herpes simplex virus infection
• Meningitis
• Rubella
• Viral pneumonia
• Drug rash with eosinophilia and systemic symptoms (DRESS syndrome)

Several diseases may present with fever and rash, but HHV-6 is the primary etiologic agent in children with classic roseola infantum. Accurate diagnosis requires distinguishing HHV-6 from more severe conditions that demand prompt intervention.

In immunocompetent adults, HHV-6 infection can mimic mononucleosis, necessitating the exclusion of EBV and cytomegalovirus. In immunocompromised individuals, especially transplant recipients and those with AIDS, symptomatic HHV-6 infection is common and often occurs alongside cytomegalovirus, warranting immediate antiviral treatment. HHV-6 has also been associated with hepatitis, herpes simplex virus, meningitis, rubella, viral pneumonia, and DRESS syndrome.[16] Additional reports have documented HHV-6 in cases of multiple sclerosis encephalitis and interstitial pneumonitis.[17] Notably, only HHV-6A has been linked to Hashimoto thyroiditis.

Prognosis

Generally, primary HHV-6 infection is self-limiting, and immunocompetent individuals recover without sequelae. In contrast, immunosuppressed individuals may experience more severe illness. Reports have documented pneumonitis, hepatitis, and organ rejection in transplant recipients, with fatalities in patients who developed encephalitis or meningoencephalitis.[18] A survey from 2003 to 2004 in Japan found an unusually poor prognosis among patients with exanthema subitum–associated encephalitis, including 2 fatalities in children with HHV-6 encephalopathy and underlying mitochondrial disorders.[19][20] More recently, HHV-6 has also been linked to CNS infections in children in Sudan.[21]

Complications

HHV-6 primary infection is typically benign, with spontaneous resolution within 5 to 7 days. The most common complication of roseola infantum is febrile seizures. Additional complications often result from the virus's neurotrophic properties, particularly when the CNS is involved, as in meningoencephalitis or encephalopathy. In such cases, the virus can invade the brain during primary infection and remain dormant in brain tissue.[22] Instances of acute or subacute encephalitis occasionally accompanied by diffuse or multifocal demyelination have been documented. HHV-6 infrequently causes opportunistic infections in immunocompromised individuals. Reactivation of HHV-6A and HHV-6B has been detected following renal, liver, and bone marrow transplants.

A potential association between HHV-6 and tumor necrosis factor-α promoter polymorphisms has been recently investigated in relation to severe depressive disorders.[23] Although HHV-6 has also been suspected in the pathogenesis of Hashimoto thyroiditis, this association has not been supported by research evidence.[24]